MESLEKİ İNGİLİZCE
I-VI. YARI YILLAR DERS NOTLARI
Öğretim Üyeleri
Dr. Engin ULUKAYA (Ders yürütücüsü)
Dr. Ayberk KURT
Dr. Barbaros ORAL
Dr. Ülkü ÖZALP
Dr. Fadıl ÖZYENER
Dr. Özhan EYİGÖR
Dr. Hakan CANGÜL
Dr. Selçuk SÖZER
İÇİNDEKİLER (Ana Hatlarıyla!)
I-II. Yarıyıl Ders Notları..................................... 3 - 53
Dr. Engin ULUKAYA ................................................... 3-7
Dr. Fadıl ÖZYENER ..................................................... 8-13
Dr. Ülkü ÖZALP ........................................................... 14-19
Dr. Hakan CANGÜL ..................................................... 20-25
Dr. Barbaros ORAL ....................................................... 26-36
Dr. Ayberk KURT .......................................................... 37-41
Dr. Özhan EYİGÖR ....................................................... 42-48
Dr. Selçuk SÖZER ........................................................ 49-53
III-IV. Yarıyıl Ders Notları................................. 54 - 94
Dialogues (1-40)
V-VI. Yarıyıl Ders Notları.................................. 95 - 129
Dr. Engin ULUKAYA ................................................... 95-100
Dr. Fadıl ÖZYENER ...................................................... 101-105
Dr. Özhan EYİGÖR ...................................................... 106-110
Dr. Ayberk KURT ......................................................... 111-114
Dr. Selçuk SÖZER ......................................................... 115-119
Dr. Barbaros ORAL ....................................................... 120-124
Dr. Hakan CANGÜL ..................................................... 125-129
Examples of Letters, CV, Etc................................. 130 - 141
Letters .............................................................................. 130-137
CV ................................................................................... 138-141
Medical Glossary................................................... 142 - 156
2
I-II. YY Ders Notları
Dr. Engin ULUKAYA
Text 1: Scientists Clone First Human Blastocyst and Derive Stem Cell Line
NEW YORK (Reuters Health) Feb 12 - For the first time, researchers from Korea and the U.S. have
cloned a human blastocyst, according to a report released on Thursday in the online issue of
Science. From this blastocyst, they were able to derive a pluripotent embryonic stem cell line. The
researchers are hopeful that these cells could one day be used to treat a variety of disorders, such as
Parkinson's disease, diabetes and osteoarthritis.
"Because these cells carry the nuclear genome of the individual, after differentiation they could be
expected to be transplanted without immune rejection for treatment of degenerative disorders," lead
author Dr. Woo Suk Hwang, from Seoul National University, said in a statement. "Our approach
opens the door for the use of these specially developed cells in transplantation medicine."
Dr. Hwang and colleagues used somatic cell nuclear transfer (SCNT) technology to generate the
cloned embryos, a technique that, until now, has only been successfully applied to non-human
animals. Briefly, SCNT involves transferring the nucleus from a donor somatic cell into a nucleusfree oocyte isolated from the same donor.
The researchers attribute their success to a variety of factors, including the use of extremely fresh
donor eggs, strict timing protocols, and a technique that gently removes the nucleus from the
oocyte. The cells derived from the cloned blastocysts displayed morphologic and functional features
typically seen with embryonic stem cells. Testing in SCID mice, revealed their ability to form
teratomas with all three embryonic germ layers. Even after continuous proliferation for more than
70 passages, the cells retained a normal karyotype and appeared genetically identical to the somatic
donor cells.
"This study shows the feasibility of generating human embryonic stem cells from a somatic cell
isolated from a living person," the investigators conclude.
Science 2004, February 12th online issue.
Text 2: DSB
In vitro, the ratio of single- to double-strand DNA breaks (DSB) and their absolute values determine
the cell death pathway. The consequences of the generation of various numbers of DSB generated
in vivo in tumour cells have been analysed in two different experimental tumour models. According
to BLM (Bleomycin) dose, different cell death pathways are observed. At a low therapeutic dose, a
mitotic cell death pathway is detected. It is characterised by the appearance of 'atypical mitosis',
TUNEL and caspase-3 positive, 24 h after the treatment, and later by the presence of typical
apoptotic figures, mainly TUNEL positive but caspase-3 negative. Caspase-3 is thus an early
marker of apoptosis. Mitotic cell death is also followed by lymphocytic infiltration reaction. At high
doses of BLM, pseudoapoptosis is detected within a few minutes after the treatment. These cell
death pathways are discussed as a function of the number of DSB generated, by comparison with
previous results obtained in vitro using BLM or ionising radiation.
3
Text 3: Cancer Progression
Progression to Cancer
What probably happens is:
- A single cell — perhaps an adult stem cell — in a tissue suffers a mutation
(red line) in a gene involved in the cell cycle, e.g., an oncogene or tumor
suppressor gene.
- This results in giving that cell a slight growth advantage over other dividing
cells in the tissue.
- As that cell develops into a clone, some if its descendants suffer another
mutation (red line) in another cell-cycle gene.
- This further deregulates the cell cycle of that cell and its descendants.
- As the rate of mitosis in that clone increases, the chances of further DNA
damage increases.
- Eventually, so many (perhaps six or eight) mutations have occurred that the growth of that clone
becomes completely unregulated.
- The result: full-blown cancer.
Stem cells are cells that divide to form
one daughter that goes on to differentiate, and
one daughter that retains its stem-cell properties.
There is increasing evidence that most of the cells in a cancer are not able to proliferate out-ofcontrol (and to metastasize). Only those members of the clone that retain their stem-cell-like
properties can do so.
Colon Cancer: An Example
As an example:
Colon cancer:
Begins with the development of polyps in the epithelium of
the colon. Polyps are benign growths
As time passes, the polyps may get bigger.
At some point, nests of malignant cells may appear within
the polyps
If the polyp is not removed, some of these malignant
cells will escape from the primary tumor and
metastasize throughout the body.
Examination of the cells at the earliest, polyp, stage, reveals
that they contain one or two mutations associated with
cancer. Frequently these include
the deletion of a healthy copy of the APC (adenomatous
polyposis coli) gene on chromosome 5 leaving behind a
mutant copy of this tumor suppressor gene
One of the functions of the APC gene product is to help
attach the microtubules of the mitotic spindle to the the
kinetochores of the chromosomes. With only a defective
APC product available, chromosomes are lost from the
spindle producing aneuploid progeny. a mutant protooncogene (often RAS). The cells in the later stages of the disease show additional types of damage
such as deletions of p53 and another tumor-suppressor gene. Note that each of the mutations shown
4
probably occurs in one cell of the type affected. This cell then develops into the next stage of the
progression. The mutations do not necessarily occur in the order shown, although they often do.
Text 4: P53
The P53 gene was originally discovered because the protein product complexes with the SV40 large
T antigen. It was first thought that P53 was a dominant oncogene since cDNA clones isolated from
tumor lines were able to cooperate with the RAS oncogene in transformation assays. This proved to
be a misleading since the cDNA clones used in all these studies were mutated forms of wild-type
p53 and cDNAs from normal tissue were later shown to be incapable of RAS co-transformation.
The mutant p53 proteins were shown to be altered in stability and conformation as well as binding
to hsp70.
The protein encoded by P53 is a nuclear localized phosphoprotein. A domain near the N-terminus
of the p53 protein is highly acidic like similar domains found in various transcription factors. When
this domain is fused to the DNA-binding domain of the yeast GAL4 protein, the resulting chimera
is able to activate transcription from genes containing GAL4 response elements. This suggests that
p53 may be involved in transcriptional regulation.
A cellular protein, originally identified in a spontaneous transformed mouse cell line and termed
MDM2, has been shown to bind to p53. Complexing of p53 and MDM2 results in loss of p53
mediated trans-activation of gene expression. Significantly, amplification of the MDM2 gene is
observed in a significant fraction of most common human sarcomas.
Phosphorylation also regulates the activity of p53. The level of p53 is low after mitosis but
increases during G1. During S phase the protein becomes phosphorylated by the M-phase cyclinCDK complex of the cell cycle and also by casein kinase II (CKII.)
Sequences at the N-terminus of the p53 protein function as a transcription activator indicating the
role of p53 in the transcription of genes involved in suppression of cell growth. One major cellcycle regulating gene that is a target for p53 is the CDK inhibitory protein (CIP), p21 CIP. Activation
of p53 results in increased expression of p21CIP with a resultant arrest in the G1 and G2 phase of the
cell cycle.
Additionally, p53 protein has been shown to block the binding of DNA polymerase-a to SV40 large
T, blocking replication of SV40 DNA. It is suggested that p53 may also regulate the initiation of
DNA synthesis. Due to the involvemenof p53 in both transcription and DNA replication, the
various mutants of p53 may affect these properties in different ways. This may account for why
some mutants lose tumor suppressor activity while others behave as dominant oncogenes
Text 5: Mechanisms of Action of Retinoids
Retinoids function as ligands for the low molecular weight (16 000) intracellular receptors which
exist in both the cytoplasm and the nucleus. Retinoic acid, at physiologic pH, readily traverses
membranes and it is generally thought that retinoic acid enters cells by passive diffusion (Noy,
1992a and 1992b). However, cytoplasmic receptors for retinol (CRBP) and retinoic acid (CRABP)
appear to be important in controlling the flow of retinoids into the nucleus, thus regulating the
amount of retinoids that bind to the nuclear receptors. These cytoplasmic receptors are highly
conserved in animal species, which suggests an essential role in retinoid action, but their specific
functions are poorly understood. Possibilities include regulation of free retinoid within the cell,
thereby controlling the amount of retinoid reaching the nucleus; transport of retinoids to specific
nuclear receptors; functioning as a cofactor in retinoid metabolism; and preferential uptake from the
extracellular matrix (Fiorella, 1991; Sanquer, 1994).
In the nucleus there are two families of high molecular weight nuclear receptors, RAR and RXR,
each of which has three members (,,). These nuclear retinoid receptors belong to a large
superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid
hormone receptors, the peroxisome proliferator-activated receptor, some prostaglandin receptors
and a number of orphan receptors whose ligands are unknown (Pemrick et al, 1994; Pfahl et al,
1994). All-trans retinoic acid binds to RARs (Petkovich et al., 1987) while 9-cis retinoic acid is the
only naturally occurring ligand which is known to bind to the RXRs (Heyman et al, 1992). This is
5
also capable of activating RARs. 13-cis retinoic acid, 4-HPR (fenretinamide) and the arotenoids do
not appear to bind to either nuclear receptor family. It is therefore probable that 13-cis retinoic acid
has to be converted to all-trans retinoic acid for its biological action (Craven and Griffiths, 1996).
RARs and RXRs comprise various domains, including DNA binding and ligand binding regions.
The DNA binding domain, which contains cysteine-rich “zinc fingers”, recognises and binds DNA
sequences called retinoic acid and retinoid X response elements (RARE and RXRE, respectively)
within the promoter regions of target (retinoid inducible) genes (Lee et al, 1993).
Text 6: THE LOWRY PROTEIN ESTIMATION METHOD
The method measures the protein by measuring the number of tryosine residues on the protein, so if
your protein does not have tyrosine then it will not be much use.
Materials
2 % Na2CO3 (anhydrous) in 500 mls of 0.1 M NaOH. (Make up fresh each time).
1 % CuSO4 in 100 mls of distilled water. Keep at 4°C,
2% Sodium Tartarate in 100 mls of distilled water. Keep at 4°C.
Stock Folin-Cioceltau Reagent.
0.5M NaOH (make up to 200 mls).
Standard solution of BSA – 200 μg/ml in 0.5M NaOH.
Method
1. Dilute the standard BSA in 0.5M NaOH as shown in the table below:
Tube No.
1
2
3
4
5
6
7
8
mls of BSA
0
0.05
0.1
0.2
0.3
0.4
0.5
1.0
mls of 0.5 NaOH
1.0
0.95
0.9
0.8
0.7
0.6
0.5
0
Protein μgs/.ml
0
10
20
40
60
80
100
200
2. Dilute the unknown in 0.5 NaOH. Do a couple of dilutions just to make sure it is going to fit onto
the standard curve.
3. To a 100 mls flask add in the following order:
1 ml
1 % CuSO4
1 ml
2% Sodium tartarate
98 ml
2% Na2CO3
4. Add 5 mls of this mixture to each tube and leave on the bench for 10 minutes.
5. Add 0.5 mls of freshly prepared 50/50 dilution of Folin-Ciocalteau reagent in distilled water to
each tube.
6. Mix well and stand on the bench for 30 minutes.
7. After this time read each tube on a spectrophotometer at 750nm.
8. Plot the absorbances of the BSA solutions against their concentration and draw a graph.
9. Read off the unknow from the calibration curve.
This is quite a useful method and more accurate than just measuring the absorbance at 280nm.
The reference for this method is in J. Bio. Chem. 193 265.
6
Text 7: Table: Comparison of necrosis and apoptosis. TNFR1, Tumor necrosis factor receptor1; CTL, Cytotoxic Tlymphocytes.
FEATURE
NECROSIS
APOPTOSIS
Causes
Hyperthermia
Growth factor deprivation
Hypoxia
Senescence
Lytic viral infection
Unbalanced oncogene expression
High concentrations of toxic substances
Viral infection
Exposure to chemotherapeutic drugs
Irradiation
High levels of glucocorticoids
Activation of APO-1/Fas
Activation of TNFR1
Induction of CTL
Morphological
Loss of membrane integrity
Membrane blebbing, but no loss of integrity
features
Flocculation of chromatin
Aggregation of chromatin at the nuclear
Cell swelling
membrane (nuclear condensation)
Disintegration of organelles
Cell shrinkage
Dilatation of endoplasmic reticulum
No disintegration of organelles
Formation of large vacuoles
Fragmentation into apoptotic bodies which
Lysis
contain ribosomes, intact mitochondria
and nuclear material
Disruption of cytoskeleton and nucleoli
Biochemical features
Disrupted ion homeostasis
Tightly regulated process involving
No energy requirement
activation and enzymatic steps
o
(passive process, also occurs at 4 C
Energy (ATP)-dependent (active process,
Random digestion of DNA (smear of DNA
does not occur at 4 oC)
after agarose gel electrophoresis)
Non-random mono- and oligonucleosomal
Postlytic DNA fragmentation (=late event
length fragmentation of DNA at the
of death)
internucleosomal region (ladder pattern after
agarose gel electrophoresis=a marker of
apoptosis)
Prelytic DNA fragmentation (=early event of
cell death)
protein degradation (=late event in apoptosis)
Physiological
Death of cell groups
Death of single, individual cells
significance
Evoked by non-physiological disturbances
Induced by physiological stimuli
Release of lysosomal enzymes
Phagocytosis by adjacent cells or
Generation of oxygen radicals
macrophages
Phagocytosis by macrophages
No inflammatory response
Significant inflammatory response
7
Dr. Fadıl ÖZYENER
Text 8: DIFFUSE / INFUSE / PERFUSE
The verbs diffuse, infuse, and perfuse have a “pour” relationship that is really quite close—
etymological close, that is. Each of these terms has as its basis the Latin word fundere, “to pour,”
with only their individual prefixes giving a glimmer of the fine distinctions in their usage. The Latin
prefix dis-, “out, apart,” that is a part of diffuse specializes the sense of pouring to that of spreading
over a surface, through a space, or in a region: A fluid or gas diffuses throughout a given space at a
rate that is usually influenced by the surrounding temperature and pressure. When used as an
adjective, diffuse describes something that is spread out or dispersed and has a specific medical
usage describing something, such as a disease, that widely affects the body or an organ: The diffuse
nature of the cancer ruled out surgery as a means of therapy.
The verb infuse has the prefix in- as its first component. When a substance is infused, it is
introduced, usually by injection, into something else so as to fill or cause filling: A saline solution
was infused into the animal’s vein. Chemists also have a specific usage for this verb. It describes
the action of steeping or soaking a substance without boiling so as to extract its soluble properties.
This activity is not just restricted to chemistry laboratories but is also one that is commonly
conducted by many kitchen chemists who pop tea bags into cold water and set the concoction aside,
allowing the tea to infuse the water with its flavours and colours.
In the verb perfuse, meaning “to cause to flow through,” the prefix per- is linked to fundere, thus
giving a sense of “thorough, complete, or intense” to the pouring action. As with diffuse and infuse,
perfuse has a particular medical usage. It is used to describe the action of artificially supplying an
organ, a tissue, or the body with a fluid by circulating that fluid through blood vessels or other
natural channels: The organ was perfused with a solution containing a dye in order to determine the
rate at which the solution diffused into tissues surrounding the blood vessels.
Text 9: HEAT AND/OR TEMPERATURE
Heat and temperature represent two different but related properties of matter. Heat can be derived
from the entire energy of a quantity of matter, which is the sum of the kinetic and potential energies
of each molecular or atomic constituent. Kinetic energy is the energy associated with the motion of
each particle of matter, and potential energy is the energy stored in a particle as a result of its
position or condition, as opposed to its motion. Notice that there are no restrictions on the kinds of
energy that can be heat.
Temperature, on the other hand, is a measure of the average kinetic energy per molecular or atomic
constituent. Notice that two qualifiers are included in this statement: temperature is related to the
kinetic energy only; and temperature describes an average property per constituent particle.
Consider a large kettle of boiling water. If you measure the temperature of the water, you will find
that it is 100 °C. Suppose that you capture the steam that is rising off the surface of the kettle and
measure its temperature. You will find that the temperature of the steam is also 100 °C. Even
though the temperature of the steam and the water are identical, the energy content per molecule of
each is different. The molecules of water in the steam are at a higher potential energy than the
molecules of water in the liquid water since it requires additional energy to overcome the molecular
attraction that binds water molecules together in liquid form. This is the reason that being burned by
steam at 100 °C is more damaging than being burned by water at the same temperature. The kinetic
energy of the molecules is identical, but the potential energy of the steam is higher. Temperature is
related to the kinetic energy only.
Next, consider a large kettle of water and a small teapot of water. Suppose that the small teapot has
one-fourth the volume of the large kettle. Starting from the same temperature, it takes more energy
to boil the large kettle of water than it takes to boil the small teapot of water. For every molecule of
water in the small teapot that has an increase in kinetic energy, there are four molecules in the large
kettle that require the same average increase in kinetic energy. It requires four times as much
8
energy, and therefore four times as much heat, to excite the molecules in the large kettle to the same
temperature as that of the small teapot. Thus, heat is a measure of the total energy, while
temperature is an average property per molecule or atom.
Text 10: RENIN / RENNET / RENNIN
It was probably just another recipe swapped among Renaissance homemakers. To make cheese,
first slaughter a calf, then remove the inner lining of the fourth stomach, pour in milk, allow it to
curdle, remove the curds, squeeze them together to remove all the liquid, and set the ripened cheese
aside to age. The initial component for this concoction—the bag made of a calf’s stomach lining—
was called rennet, a word linked to an Old English and Old German verb meaning “to flow” or “to
run.” Exactly why the rennet caused milk to curdle remained unanswered for a couple of centuries.
Investigations in the late 1800s revealed the curdling was produced by a compound known as an
enzyme present in the juices of the stomach. This compound, it was shown, helped break apart a
protein called casein in the milk and, in the process, triggered the formation of another compound
that then bonded to the calcium in the milk, forming curds. The enzyme was dubbed rennin, a
combination of rennet and the suffix -in, “neutral chemical compound.” This suffix appears in the
names of other enzymes such as trypsin, the compound produced in the pancreas that breaks
proteins into smaller bits for use by the body.
While the stomach is the site of rennin production, the kidneys are the source for renin. Renin, in
fact, comes from Latin renes, “kidneys,” combined with -in. When a major upset such as
dehydration or haemorrhage causes the body’s blood pressure to become dangerously low,
specialized cells in the kidneys begin to produce renin. The renin circulates in the bloodstream
ready to perform its very specialized task: it clips two component parts, called amino acids, from
another blood-borne protein known as angiotensin. This newly abbreviated protein, now called
angiotensin I, is clipped further by another blood-carried compound to form angiotensin II. This
substance causes blood vessels to constrict, thus raising blood pressure back to normal levels and
ensuring the continued proper functioning of the body.
Text 11: THE COMPARTMENTS OF THE BODY
The body has three compartments. The first of these consist of active tissue, which is also known as
cell mass. This does most of the chemical work of the body. The second compartment consists of
supporting tissue. This is composed of bone minerals, extra cellular proteins, and the internal
environment, or the extra cellular fluid in the blood and lymph. The third compartment is the energy
reserve. This consists of fat, which lies round the principal internal organs and in adipose tissue.
These compartments cannot be separated by physical dissection, but it is possible to measure
them indirectly. This may be done using methods such as the dilution technique. The size of each
compartment varies according to the age, sex and health of the individual. In a healthy young man
the total body weight is divided approximately: 55 % cell mass, 30 % supporting tissue, and 15 %
energy reserve. A healthy young woman has normally twice as much fat.
Let us study the following statements carefully and decide whether they are true or not according to
the information in the reading passage above.
a) The first compartment of the body consists of cell mass.
b) The second compartment of the body is composed of bone minerals.
c) The internal environment is composed of the extra cellular fluid in the blood and lymph.
d) The energy reserve is composed of adipose tissue and fat which lay around the principal
internal organs.
e) The compartments of the body are measurable.
f) The dilution technique is the only method of measuring the compartments of the body.
g) The sum of the sizes of the compartments = the total body weight.
h) The energy reserve of a healthy young woman is approximately 30 % of her total body
weight.
9
Text 12: THE MEASUREMENTS OF THE COMPARTMENTS OF THE BODY
The weighing machine which can be found in any clinic is one of the doctor’s most useful tools for
assessing the general health of his patients. It must always be kept in mind, however, that the body
is not a uniform mass. It is composed of different compartments, each with a different function, and
these compartments are affected differently by different diseases. For example, oedema, which is
due to an increase in the extra cellular water, is a typical feature of many cardiac, renal and liver
diseases. In wasting diseases too, there is a reduction in the cell mass and in the energy reserve, but
there is an increase in the supporting tissue, which is caused by oedema. If the size of increase in
the supporting tissue equals the size of the reduction in the other two compartments, then the total
body weight remains constant. In cases like these, the weighing machine is too crude a tool to be an
accurate guide to health.
The different compartments of the body can be measured separately, but complicated laboratory and
clinical procedures are necessary. The approximate size of the cell mass may be calculated from the
size of the cell water, which is obtained from the difference between the total body water and the
extra cellular water. The size of the total body water may be measured by the dilution technique,
using substances such as deuterium oxide and ethyl alcohol. These may be administered orally or by
intravenous injection. The size of the extra cellular water may be measured by injecting into the
body substances such as sodium thiocyanate. The energy reserve can be determined by
measurements of body density. The weight of the bone minerals and the extra cellular proteins can
be calculated only by finding the difference between the total body weight and all other parts.
Measurement of the compartments of the body by these procedures has provided new insight into
how the body works in health and in disease. The procedures are too complicated, however, for use
in normal clinical practice.
Text 13: THE PROCESS OF DIGESTION
The process of digestion begins when food is taken into the mouth. Chewing breaks the food into
smaller pieces, thereby exposing more surfaces to the saliva. Saliva itself has a double function. It
moistens the food, so facilitating swallowing, and it contains ptyalin, which begins the conversion
of starch into simple sugars.
Although enzymatic action begins in the mouth, the major processes of digestion do not occur until
the food passes down through the oesophagus into the stomach. The stomach has both a chemical
and a physical function. The walls of the stomach, which are protected by a layer of mucus, secrete
gastric juices composed of several enzymes and hydrochloric acid. The most powerful enzyme is
pepsin, which begins the process of converting proteins into amino acids. In addition, during these
chemical reactions waves of contraction and relaxation, known as peristaltism, sweep the walls of
the stomach. They stir the food particles into a semi-solid mass known as chyme.
From the stomach, the chyme passes into the small intestine through the pyloric sphincter. Much
undigested material is still present. Proteins have not completely broken down, starches are still
being converted into simple sugars, and fats remain in large globules. In the small intestine the
process of digestion is completed by action of bile, which is secreted by the liver and released by
the gall bladder, and by the action of various enzymes, such as lipase and diastase, which are
secreted by the pancreas, and erepsin and invertase, secreted by the walls of the small intestine.
Foods which are still undigested pass on in a liquid state into the large intestine, and are now called
faeces.
Absorption of the products of the digestion takes place mainly through the wall of the small
intestine. Its inner surface is covered with minute hair-like projections called villi. Each villus
contains several blood capillaries and a specialized lymphatic vessel, known as a lacteal. Glucose,
fructose, galactose and amino acids are all absorbed directly into the blood by entering the blood
capillaries inside the villi. Glycerol and the fatty acids, on the other hand, pass into the lacteals. The
lymph then carries the fat up to the left internal jugular vein, where it enters the bloodstream.
10
Text 14: ENDURANCE- AND SPRINT-TYPE ATHLETES
The variability in pulmonary oxygen uptake ( Vo 2 ) response to exercise among subjects is reported
to be closely related to the level of “fitness” of the particular subject. Fitness may be dictated to a
large extent by different exercise training strategies as well as their predominant fibre types.
Skeletal muscle is “designed” to produce high-energy phosphate compounds (adenosine tri
phosphate [ATP]) that are used to initiate and sustain contraction. Although the underlying energygenerating processes are the same in all muscle fibres, one type of fibre seems “designed” for
prolonged repetitive contraction, known as type I, or slow twitch fibres. The other fibre type
contracts rapidly but has a limited capacity for prolonged repetitive contraction, known as type II,
or fast twitch. The relative proportion of these two fibre types varies from muscle group to muscle
group as well as from species to species. This variation in fibre type distribution in a given muscle
group, to a large extent, is dictated by heredity.
It is well known that endurance-type athletes have predominantly slow twitch muscle fibre types,
whereas sprint-type athletes have predominantly fast twitch ones: there is a type I predominance in
the leg muscles (as represented by vastus lateralis) of successful distance runners, and type II
predominance in the leg muscles of successful sprinters. It is quite clear, therefore that an athlete,
with a predominantly type I fibre composition, who wants to excel in marathon running, for
example, has advantages over an athlete with predominant type II fibre composition. On the other
hand, it can also be argued that athletes who had been successful at the endurance or sprint events in
the past are likely to have an “appropriate” fibre type distribution.
Endurance-type athletes are successful in performing sustained tasks, such as long distance running,
cycling or swimming. Those subjects with predominantly type I fibres may have increased number
and size of mitochondria, and risen concentrations of a number of “aerobic” enzymes in both the
cytosol and the mitochondria. These enzymatic changes facilitate the Krebs cycle and oxidative
phosphorylation so the capacity to metabolise oxidatively the end product of glycolysis –namely
pyruvate- as well as fatty acids and ketone bodies is increased.
Sprint-type athletes have the ability to perform powerful tasks aimed at completing high power
outputs in minimum time. In contrast to endurance-type athletes those are successful at events,
which involve a high frequency of muscular contraction and a low level of power, sprint-type
athletic events are characterised by a low rate of contraction and a high level of power.
Text 15: SYNAPTIC TRANSMISSION
The process by which the central and peripheral nervous systems can communicate is called
synaptic transmission and can be broken down into four steps. First, the neurotransmitter must be
synthesized and stored in vesicles so that when an action potential arrives at the nerve ending, the
cell is ready to pass it along to the next neuron. Next, when an action potential does arrive at the
terminal, the neurotransmitter must be quickly and efficiently released from the terminal and into
the synaptic cleft. The neurotransmitter must then be recognized by selective receptors on the
postsynaptic cell so that it can pass along the signal and initiate another action potential. Or, in
some cases, the receptors act to block the signals of other neurons also connecting to that
postsynaptic neuron. After its recognition by the receptor, the neurotransmitter must be inactivated
so that it does not continually occupy the receptor sites of the postsynaptic cell. Inactivation of the
neurotransmitter avoids constant stimulation of the postsynaptic cell, while at the same time freeing
up the receptor sites so that they can receive additional neurotransmitter molecules, should another
action potential arrive.
Most neurotransmitters are specific for the kind of information that they are used to convey. As a
result, a certain neurotransmitter may be more highly concentrated in one area of the brain than it is
in another. In addition, the same neurotransmitter may elicit a variety of different responses based
on the type of tissue being targeted and which other neurotransmitters, if any, are co-released. The
integral role of neurotransmitters on the normal functioning of the brain makes it clear to see how
an imbalance in any one of these chemicals could very possibly have serious clinical implications
11
for an individual. Whether due to genetics, drug use, the aging process, or other various causes,
biological dysfunction at any of the four steps of synaptic transmission often leads to such
imbalances and is the ultimately source of conditions such as schizophrenia, Parkinson's disease,
and Alzheimer's disease.
Text 16: EXERCISE AND THE FIBRINOLYTIC ACTIVITY
The risk of cardiovascular complications is reported to be several times higher in strenuous exercise
than in other daily activities. A delicate balance between coagulation and fibrinolysis is considered
important to avoid thrombus formation. There is evidence indicating that reduced blood fibrinolytic
activity (FA) is a risk factor for development of coronary artery disease, and possibly subsequent
myocardial infarction due to probable thrombus formation.
It is well established that physical exercise close to maximal capacity leads to various degrees of
increases in FA. The magnitude of the fibrinolytic response to exercise depends both on the
intensity and the duration of the exercise. The majority of the previous studies have focused on the
immediate changes occurring right after the cessation of exercise.
Increased FA following strenuous exercise appears to be a consequence of increased tPA (tissue
plasminogen activator) levels. It is proposed that the increasing level of epinephrine with the onset
of exercise stimulates the release of tPA from vascular endothelium. It has also been suggested that
hypoxia, acidosis or exercise-produced metabolites might stimulate tPA release. One of the
prominent regulators of FA is PAI-1 (plasminogen activator inhibitor type 1) which is not changed
or slightly increased after exercise. Thus, minimal exercise-affected PAI-1 forms less compounds
with already increased tPA which leads to more tPA activity. The possible contribution of u-PA
(urokinase-type plasminogen activator) to the augmentation of the FA should also be considered.
Alternatively, FA increase has been ascribed to a cellular component; possibly from neutrophilic
granulocytes which can release fibrinolytic enzymes.
It has been generally accepted that FA increases immediately after exercise by one or more of these
mechanisms. However, there is no agreement on the recovery period FA Dufaux et al have
reported that increased FA had returned to the pre-exercise level at the 30th and 60th min of
recovery period. Hansen et al showed that the increase in FA persisted at the 30th min after
exercise, but it was inhibited at the 2nd and 4th hours. Contrasting these studies, Röcker et al and
Arai et al indicated that the FA increase after exercise was still sustained many hours after the
exercise. The subjects in the last two study were highly trained sportsmen.
Although there are substantial numbers of studies investigating the FA changes in recovery period
after short-term maximal exercise in sportsmen, there are far few studies on sedentary subjects.
Sedentary people might have to perform sudden maximal exertions (like speeding up or down the
stairs, or running after bus) during daily life. The purpose of this research, therefore, is to focus on
the dynamics of FA in blood during recovery period of maximal exercise, especially in sedentary
(untrained) subjects.
Text 17: SOME CONSIDERATIONS ON PRURITIC DISEASES
The data concerning itching were derived mainly from the analysis of experimentally induced itch
sensation. Clinical pruritus, like clinical pain, is of course much more complex, and it is beyond the
scope of this review to give a comprehensive representation of the pathophysiology of pruritus. I
briefly outline the genesis of pruritus in select systemic and skin diseases to give a glimpse of the
diversity of pruritogenic mechanisms in disease.
The role of histamine is less important in pruritic diseases than in experimental paradigms. The
prototype of histamine-mediated itch would be urticaria, easily recognized by the wheal and flare
response when, for example, induced by contact with allergens in sensitized subjects. Rarely,
urticaria can also be induced by physical factors, as in heat or cold urticaria. In these patients, H1receptor antagonists rapidly ameliorate the specific coetaneous symptoms, including the itch. Most
pruritic diseases do not, however, exhibit any sign of urticaria, and treatment with histamine
receptor antagonists is of limited or no value.
12
Itch is a frequent and disturbing side effect in patients undergoing long-term haemodialysis. StåhleBäckdahl (1989) found that itching slowly increased and peaked at the second night without
dialysis; it was lowest on the day following dialysis, suggesting the accumulation of pruritogens
during dialysis-free intervals. Responses to histamine were enhanced, indicating an enhanced
sensitivity to pruritogens. Immuno -histochemistry revealed nerve fibre sprouting throughout all
epidermal layers in many ureic patients, which was never seen in control subjects. Ureic pruritus
may thus be characterized by the accumulation of pruritogens acting on abnormal coetaneous
innervations.
Itch is also a distressing sequel in various liver diseases. The pruritus of cholestasis can not be
mimicked by injection of bile acids. However, the accumulation of endogenous opioids has been
demonstrated in plasma of patients and in animal models. The microinjection of plasma from
patients with cholestatic pruritus into the medullary dorsal horn of monkeys elicited facial
scratching suggesting itch and was abolished by the opiate antagonist naloxone (Bergasa et al.
1993). In a controlled study, naloxone reduced but did not abolish pruritus and itch-related
scratching in cholestatic patients (Bergasa et al. 1995). Endogenous opioids may thus modulate the
pruritus of cholestasis, but other, unknown mediators may be involved.
These few examples may illustrate, admittedly in an arbitrary fashion, that the mechanisms of
clinical itch syndromes are complex, diverse, and far from being understood. Considering that the
neurophysiology of itch is poorly explained, this is even more applicable in pruritic disease. We
have only just begun to understand their pathophysiology.
13
Dr. Ülkü ÖZALP
Text 18:
The Public Health System in NYC
Purpose: Insure the health of the community
NYC Dept. of Health: One of the largest, and most respected Public Health systems in the US.
Public health responsibilities
• prevent epidemics and the spread of disease
• protect against environmental hazards
• prevent injuries
• promote and encourage healthy behavior
• respond to disasters and assist in recovery
• assure quality and accessibility of health services
How are these accomplished?
• Surveillance
• Investigation
• Community information
• Policy development and management
• Linking people to care
• Assuring a competent workforce
Surveillance
• Monitor vital statistics (rates for birth, death, specific diseases)
• Laboratory system reporting
• Provider reporting system
• Relationship w/ community --encourage communication in situations of doubt or concern
Investigation
• Response to any deviation from norm or cluster of unusual events
• Can include
• clinical investigation
• environmental investigation
• cross-jurisdictional sharing of information
Community information
Information is provided through:
• Provider networks
• Public media outlets
• Directly to the public
•
•
•
Policy Development and Management
Development and enforcement of public health laws, i.e.:
protection of water supply
proper disposal of waste and sewage
reporting of communicable diseases
•
Linking people to care
Community health workers
14
•
•
•
School health nurses
Community health centers
Immunization programs
Assuring a competent workforce
• Keeping abreast of new developments and changes (I.e. development of new drugs or therapies,
or changing antibiotic resistance patterns in the community)
• System of “lifelong learning” for public health workers
The Public Health System Process
• a continuous cycle of gathering information, deciding, acting, evaluating
• Public health is always evaluating the health of the community
Where are we now in NYC?
• NYC has a strong Department of Health with excellent working ties to
• CDC
• NYS DOH
• Academic resources
Columbia University Center for Public Health Preparedness
• Part of a national system of academic centers funded by the CDC
• With the NYC DOH, the Center prepares frontline public health workers to deal with threats
posed by bioterrorism
• Developing a core curriculum on preparedness for local health departments
•
•
•
•
•
•
•
•
•
Dissemination of Information
Information is going regularly to
• hospitals and practitioners
• laboratories
• community
New information resources are being developed
The Public Health Preparedness Partnership?
The community working with the public health infrastructure to assure a healthy community.
YOU are part of the public health system.
How can you participate?
Keep abreast of accurate information (know your source)
Stay connected to community health workers
Be alert for (and report) deviations from the norm
Practice healthy behaviors
Vaccinate appropriately
Bioterrorism
• Is not a new concept. Known about and recorded in ancient times.
• What is new: modern public health science can cope with bioterrorism. Methods available for
prevention, detection and treatment.
How concerned should I be about biological threats?
• Need to put biological threats in rightful context: unexpected outbreak of infectious diseases
• Concern warranted, but important not to overstate the threats to our safety
15
• Required technical know-how makes widespread dissemination of BT agents challenging
• Nation’s infectious disease surveillance system has been stepped up
• It’s flu season--’flu-like symptoms’ are probably flu
Anthrax
Three types:
• inhalation
• cutaneous (skin)
• gastrointestinal
As of November 7, 2001:
• Total cases: 22
• 10 cases of inhalation with 4 deaths
• 12 possible cases of cutaneous, all treated
Anthrax
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Caused by bacterial agent, Bacillus anthracis
Reservoir: soil
Naturally occurring disease of livestock
Infection is caused by exposure to spores
Does NOT spread from person to person
Epidemiology
Reservoir: Soil
Herbivores infected during grazing
Transmission to humans
• Contact with infected animals, hides, hair, wool, bone, bone products; biting flies
• Ingestion of contaminated meat
• Inhalation-industrial settings
Inhalation Anthrax
Not easy to catch; must inhale relatively large doses of very small-sized spores
Symptoms:
• severe respiratory distress
• meningitis: severe headache, stiff neck
• internal bleeding
Incubation period: 2-60 days
Treatment: antibiotics
Prognosis: Often fatal if antibiotics not started before symptoms develop
Cutaneous Anthrax
Most common form; exposure alone not sufficient to get infected
Symptoms:
• itching (up to a week after exposure)
• boil-like lesions (a few days later)
• characteristic ulcer with black center (another 2-6 days later)
Treatment: antibiotics
Prognosis: usually complete recovery with antibiotic treatment
Gastrointestinal Anthrax
• Can occur if large number of spores ingested (from undercooked meat of infected animals)
• Symptoms:
16
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
• nausea
• vomiting
• bloody diarrhea
Incubation period: 1-7 days
Treatment: antibiotics
Prognosis: 50% fatality without antibiotic treatment
Public Health Interventions
• Contacts identified and interviewed
• Samples taken:
• Environmental
• Potentially exposed individuals
• Treatment with antibiotics
• Community information and education
Smallpox
Once dreaded natural disease, but eradicated as natural infection 20 years ago
Caused by virus
Can spread from person to person
High case-fatality rates and transmissibility
Repositories in U.S. (CDC) and former Soviet Union (Moscow) established 1970
Weaponization: ? current status
Smallpox
Symptoms:
• flu-like beginning
• rash - usually starts on face and hands
• all lesions develop at the same time
Incubation period: 7-17 days
Treatment: rapid public health response; early recognition of cases & vaccination of exposed
Prognosis:
• individual - 30% fatality
• exposed people - vaccination 2-5 days after exposure
SMALLPOX - A Real Incident
In 1947, an outbreak of Smallpox hit New York City
• It started with one person who brought the disease via bus from Mexico on March 1
• That person entered a hospital on March 5 and died 5 days later
• The disease spread to 15 other people with 3 deaths
• Due to the deaths - 6,350,000 people were vaccinated within one month - exhausting the
entire U.S. supply of vaccine
“Medical Aspects of Chemical and Biological Warfare,” Office of the Surgeon General, U.S.
Army (1997)
Today - a maximum of 15 million doses of vaccine are available (new vaccine in development)
Some other organisms
Plague:
• bubonic
• pneumonic
Botulism
Tularemia
Concerns and questions?
Antibiotics?
17
•
•
•
•
Vaccination?
Buy a gas mask?
Safety of the water?
Mail?
•
•
•
•
•
Should I get a supply of antibiotics?
No…
Difficult to know when to take them
Overuse encourages resistance to antibiotics, undermining effectiveness when they are needed
Antibiotics lose their strength over time
Risks of side effects
Should I get vaccinated?
NO
• Anthrax or smallpox vaccine not warranted -- not available to the general public or medical
community
• No vaccines available for plague, botulism, or tularemia
YES
• You should get all recommended childhood and adult vaccinations including influenza and
pneumonia
• Tetanus vaccine recommended in the case of a wound
Should I buy a gas mask?
• No...
• Must have mask on at the right time -- and continue wearing it until the danger is past
• Most masks can only be worn a few hours before filters need to be changed
• Must be properly fitted to be effective
• Can make breathing difficult in people with impaired heart and lung function
Is the water supply safe?
• Yes...
• Most metropolitan systems sufficiently large--any contamination would be greatly diluted
• Steps taken during water treatment make it difficult to contaminate
• City, state, and federal agencies carefully monitoring water supplies
What is “suspicious” mail?
Suspicious features, according to the CDC:
• threatening messages
• no return address or excessive postage
• handwritten or poorly typed addresses
• oily stain, discolorations, or odor
• excessive weight, lopsided or uneven envelope
• excessive security material such as masking tape or string
Should I take precautions when opening my mail?
• If you get a suspicious letter or package:
• Do not handle or examine the package
• Leave the area and warn others not to enter
• Wash your hands with soap and water
• Report the incident to local law enforcement authorities -- call 911
18
•
•
•
Keeping informed
Accurate information is a MUST.
Inaccurate information does more harm than good and is in fact dangerous.
Rely on gold standard sources:
• CDC
• NYC-DOH
Resources Available on the Web
• CDC Bioterrorism Preparedness and Response:
http://www.bt.cdc.gov/
• NYC Department of Health
http://www.nyc.gov/html/doh/home.html
• Columbia University Center for Public Health Preparedness
http://cpmcnet.columbia.edu/dept/sph/CPHP/index.html
•
Center for Health Policy, Columbia University School of Nursing
http://cpmcnet.columbia.edu/dept/nursing/institute-centers/chphsr/index.html
•
Coping with Terrorism
http://www.helping.apa.org/daily/terrorism.html
•
19
Dr. Hakan CANGÜL
Text 19: Characteristic / Trait
You are going to the first hockey game of the season with someone you have never met. You have
agreed upon a time and a place to meet and you have described what you look like—tall with curly
hair, wire-rimmed glasses, and, in honor of the occasion, a Rangers jersey. What you have given
your hockey chum is a list of your characteristics. A characteristic is a feature or quality that helps
identify, tell apart, or describe recognizably a person or a group of people. The various features or
qualities that qualify as characteristics can roughly be divided into two groups: acquired and
inherited. Wire-rimmed glasses and a Rangers jersey represent acquired characteristics, while
height and type of hair are inherited characteristics. Such inherited characteristics are technically
referred to as traits, a term derived from Latin tractus, “drawing out, line.” In nontechnical usage,
characteristic is often the term of choice, but in technical applications, trait is the preferred term to
use when describing a genetically determined condition or feature.
Text 20: Congenital / Heritable
The process during which a fertilized human egg develops from embryo to fetus to newborn is an
exquisitely timed and delicately balanced one that is dependent upon the dictates of a multitude of
genes. These genes carry a wealth of information including the heritable traits that elicit those postbirth coos from relatives and friends. Characteristics or conditions that are heritable are intrinsic to
the genetic makeup of an individual and are capable of being passed from one generation to the
next. Conditions or characteristics that are congenital, on the other hand, are usually not part of the
organism’s normal genetic makeup. Congenital, derived from Latin com-, meaning “together,” and
genitus, meaning “born,” describes conditions or traits that are acquired either at birth or during the
nine months of development in the uterus. Most often, congenital indicates that some factor, such as
a drug, a chemical, an infection, or an injury, has upset the careful timing and balance of the
developmental process in a way that adversely affects the fetus. Thus, a baby can have a heritable
disease such as hemophilia, which can be passed on to future generations, or a congenital condition
such as spina bifida, which cannot be passed on.
Text 21: Exon / Intron / Axon
In 1844, when the American inventor Samuel Finley Breese Morse transmitted “What hath God
wrought” as a series of dots, dashes, and pauses along a telegraph wire stretched between
Washington, D.C., and Baltimore, Maryland, he inadvertently mimicked a cipher system nature has
used for millennia—DNA and RNA. Each of the genes contained in DNA and RNA is composed of
a particular arrangement of discrete “dots” or “dashes” of information, punctuated by “pauses” of
noninformation. When adeptly translated by specialized cellular components, this coded
information yields millions of protein “messages” that allow the body to function. The molecular
dots or dashes are called exons; the punctuations of silence are known as introns. The terms exon
and intron were first introduced into the scientific literature in the late 1970s when research began
to show that a gene was not simply read from one end to another when a protein was formed.
Instead, genes were found to be composed of information units that could be read, or expressed, in a
variety of combinations, thus making any one gene the template to any number of proteins. Exon,
then, is built from ex pressed and the suffix -on, “fundamental unit,” a suffix that also is used in
such words as photon and electron. Research also showed that exons did not exist in an unbroken
string within a gene but were separated by introns, units of nonexpression that, at least according to
current understanding, serve no function other than to provide silent patches between the
information-laden exons. Intron comes from the combination of intragenic, which means “within
the gene,” and the suffix -on.
20
The similar-sounding term axon is neurological rather than genetic and refers to the filamentous
process of a nerve cell. Its function is to conduct nerve impulses away from the body of the nerve
cell and toward other nerve cells or other cells or tissues. Axon comes from Greek axon, “axis,” and
first appeared as a neurological term in scientific literature in the early 1900s.
Text 22: Genotype / Karyotype / Phenotype
Can you roll your tongue? Not bend it so that the tip points toward the back of your mouth, but roll
it, bringing the outside edges together to form a tube of your tongue? If you can, you are one of 7 in
10 people whose genetic constitution, called their genotype, contains the gene for tongue-rolling. As
the numbers indicate, a lot of people are able to roll their tongues, or as a geneticist might say, the
phenotype of many people includes the ability to tongue-roll. Phenotype comes from Greek
phainein, “to show.” It describes a person’s physical and biochemical expression of his or her
genotype as well as a person’s physical manifestation of various environmental influences. For
example, a person’s natural color of hair and eyes, blood type, and fingerprints are phenotypic
expressions of genetically determined traits. An individual’s hair style, altered hair or eye color, and
style of eyeglasses or sunglasses are examples of phenotypic expressions of environmental
influences.
Analyzing a cell’s chromosomes, the cellular structures that convey genetic information, can give
clues to a person’s genotype and, ultimately, his or her phenotype. One method for doing such an
analysis involves making photographic enlargements of the chromosomes after they have been
arranged in an orderly manner, such as from largest to smallest. Such photographs are called
karyotypes. An example of such an analysis is a prenatal test, a procedure in which chromosomes
taken from a fetus are analyzed to determine whether any genetic diseases or disorders are present.
An analysis of the karyotype of these chromosomes can help determine whether the baby’s
genotype would result in a phenotype marked by Down syndrome, Klinefelter’s syndrome, or a
similar disorder that affects physical and mental development.
Text 23: Mitosis / Meiosis
Cells divide in two ways—by meiosis or mitosis. Meiosis, coming from the Greek word meaning
“less,” occurs in two distinct phases, each phase containing several stages. The activity of the first
phase produces two cells. During the second phase, these two cells split again, yielding a total of
four cells called gametes. Each gamete contains half the number of chromosomes—called the
haploid number—that other cells of the body have. In mammals, these gametes are called eggs
when they reside in the female and sperm when they are produced by the male. The other process of
cell division is called mitosis, from Greek mitos, “thread of a warp,” and the suffix -osis, “action” or
“process.” It occurs in four stages and produces cells that contain a full array—called the diploid
number—of chromosomes. These cells, known as somatic cells, are used for the maintenance,
functioning, and growth of the body and its parts.
Text 24: Transcription / Translation
It is a concept that is accepted by most everyone these days: The double helix of genetic material
known as DNA is the fundamental unit of heredity. These molecular maps use a unique copying
process to duplicate their information, thus allowing then to continually send out the information
needed to guide an organism’s growth and functioning. This copying process is called transcription,
built from the Latin prefix trans-, “across,” and scribere, “to write.” Far more than a simple letterfor-letter replication, transcription results in a strand of genetic material that is complementary to
one of the two strands of DNA; that is, it is built of molecular entities that are the perfect partners to
the components in that strand of DNA. This complementary molecule is known as mRNA or
messenger RNA. True to its name, mRNA serves as an information carrier, moving from the area of
the cell containing the DNA, known as the nucleus, to the area surrounding the nucleus, known as
the cytoplasm. Once in the cytoplasm, mRNA takes up residence in cellular workstations known as
ribosomes, locations that make it available to another form of RNA, known as tRNA or transfer
21
RNA. Each tRNA carries an organic compound known as an amino acid. By interpreting the
directions contained in mRNA, tRNAs position their amino acids in a particular sequence, a
sequence that ultimately forms a particular protein, one of the multitude of proteins vital to the
body’s functioning. This process of interpretation is called translation, from Latin trans- and latus,
“brought.” Thus, through the cellular processes of transcription and translation, the information of
DNA is neatly noted and cleverly transformed into a proteinic language that is readily understood—
and used—by the body.
Text 25: What the Genome Does Not Code For
It is useful–and sometimes reassuring–to consider what the human genome does not specify.
Ironically, one thing is fingerprints. Identical twins have identical DNA, but they do not have
identical fingerprints. Fingerprints develop; they are not genetically determined. The immune
system is more than the result of a genetic blueprint. It begins with proteins coded by genes, but
grows into something larger, not specified in the genes. In response to a history of chance exposure
to various antigens, the system becomes unique in every person. After bone marrow transplantation
it reconstitutes itself, and with a new history of antigen exposure it becomes a system different from
the prior immune systems of either donor or host.
DNA does not encode the functioning of the human brain. The proteins and the basic building plan
are coded in the DNA. However, the brain’s neurons have vastly more interconnections than can
possibly be specified even if all 3 billion bp in the genome were devoted to that one subject. The
interconnections and hence the function of the brain are built first as a self-organizing system and
second by experience. The self-organization of the early central nervous system is something
marvelous and beyond our current understanding. If a dozen or so primitive nerve cells are placed
in a culture dish, they will start to form interconnections. These tentative connections will re-form
several times, exchanging electrical nerve impulses. After some days, the nerve cells will have
formed a network; the connections are finalized. The entire brain appears to build itself by selfdirected organization in similar fashion.
After the brain is built it begins to learn, acquiring what we call knowledge by experience,
instruction, and conscious thinking. That knowledge does not flow back into the genes, as was
thought by some early biologist. We do not inherit acquired knowledge or behavior. Humans and
some animals can pass their knowledge to their offspring, but it is by teaching, not genes.
This may change! If we write into the genome of humans and animals, as we are about to do with
genetic engineering, then the genome does become the product of acquired knowledge. A
transgenic cloned human poses a terrible problem of what constitutes a person. We are much more
than our DNA, because our DNA alone is neither alive nor capable of specifying all that we are.
Text 26: Human Genome Project
The Human Genome Project, a plan to bring “big-science” resources to the challenge of sequencing
human DNA, began in 1990 and effectively ended in February 2001. The end, which is really just a
new beginning, was the publication of a draft of the human genome in the two major science
journals–Nature on February 15 and Science on February 16, 2001. The draft published in Nature
was the one produced by the government-sponsored Human Genome project itself. Science
published the human genome developed by Celera Genomics, a competing private company that
employed a different method for sequencing. In the end, the two cooperated to a good degree and
produced very similar results. The best way to access the human genome is through the Internet.
Let’s discuss some of the most important general findings that resulted from sequencing the human
genome. First, whose genome is it? Pooled DNA from a small number of people was used as the
source, so the human genome is really the average of a small number of individuals. Each of us will
deviate from the published human genome because of our uniqueness. To begin, each of us differs
at about 1 in every 1,000 bp. There are about 2.5 million single-nucleotide polymorphisms (SNPs)
in the genome. There are one base differences that characterize our individual variations in
noncoding DNA.
22
How many genes are there? About 30-35,000. The final number is not yet in, but it will likely be
close to this. A few years ago, estimates of the number of human genes would have been close to
100,000. The low number surprises us. However, genes are showing themselves to be more
versatile than their numbers suggest. Alternate splicing of exons allows a single gene to code for
more than one protein; three proteins per gene may be more typical.
What do we do with the information of the human genome? The next steps are understanding what
we have written down. The “hot-button” words now are proteomics and functional genomics.
Having the human genome database greatly speeds up all kinds of research. Every time we find a
growth factor, a signal molecule, or a transmitter; we can look into the genome and find where it
came from. Similarly, we can look in the genome for sequences that code for proteins with the
characteristics of a neuropeptide or a transmembrane receptor. We find sequences that look
promising because they resemble genes that we already know. These sequences then lead us to the
new gene and its protein product. The human genome is a library of information that is now open
for business. There is a treasure of information in the human genome leading to new drugs, new
diagnostics, and new medical knowledge. The next phase of discovery is learning to use the library
that we have so successfully copied from our own DNA.
Text 27: Medical Genetics
Although medical genetics has become a recognized specialty, it has also become abundantly clear
that human genetics provides important unifying concepts that illuminate and unify all medical
practice. To give patients and their families the full benefit of expanding genetic knowledge, all
physicians and their colleagues in the health professions need to understand the underlying
principles of human genetics. The existence of alternative forms of a gene (alleles) in the
population; the occurrence of similar phenotypes developing from mutation and variation at
different loci; the importance of gene-gene and gene-environmental interactions in disease; the role
of somatic mutation in cancer and ageing; the feasibility of prenatal diagnosis, presymptomatic
testing, and population screening; and the promise of powerful gene therapies are concepts that now
permeate all medical practice and will become only more important in the future. Thus, genetic
principles and approaches are not restricted to any one medical subspecialty.
One aspect of medical genetics practice relevant to all of medicine deserves special emphasis: it
focuses not only on the patient but also on the entire family. A comprehensive family history is an
important first step in the analysis of any disorder, whether or not the disorder is known to be
genetic. As pointed out by Childs, “to fail to take a good family history is bad medicine….” A
family history is important because it can be critical in diagnosis, may show that a disorder is
heredity, can provide information about the natural history of a disease and variation in its
expression, and clarify the pattern of inheritance. The diagnosis of a hereditary condition allows the
risk in other family members to be estimated, so that proper management, prevention, and
counseling can be offered to the patient and the family.
Text 28: Insulin Gene Transplantation
We give diabetic patients insulin. Yet, careful monitoring of diet and blood glucose coupled with
once or twice daily injections of insulin falls far short of the normal tight minute to minute
homeostasis of glucose. A goal for better therapy has been to transplant a new source of insulin.
Transplantation of beta cells of the pancreas has been problematic, with the usual need to overcome
the body’s rejection of foreign tissue. Transplantation of the insulin gene is an alternative. A
transplanted gene must be put into the right environment to produce insulin in response to the
correct signals. We must make a transplanted insulin gene respond properly; too much or too little
insulin is life threatening.
A recent experimental model successfully transplanted an engineered version of the human insulin
gene into a diabetic rat (Lee et al., 2000). This experiment demonstrates what must be achieved for
an insulin gene transplant to work in humans. A single peptide proinsulin is transcribed from the
INS gene. This proinsulin is converted into insulin by cleaving out the C piece joining the A and B
23
chains. Proinsulin, unaltered, has only 2% of insulin’s binding efficiency to the insulin receptor.
Lee’s group engineered a version of the INS gene that produced single chain insulin analogue (SIA)
not requiring enzymatic cleavage. They did this by replacing the code for the C peace with a shorter
code. The 35 amino acids (aa) in the C piece no longer need to be removed. Their SIA has 28%
efficiency in binding to the insulin receptor and produces 40% to 50% of insulin’s effect in
producing a hypoglycemic effect.
So now they have a gene that does not require enzymatic processing. The next step is to make it
respond to the signals that influence insulin. To achieve this they further engineered their gene to be
under the control of the hepatocyte specific L-type pyruvate kinase (LPK) promoter. This promoter
responds to glucose like the promoters for insulin.
The next step is to get this gene into the rat. These researchers used an established vector, the
adeno-associated virus. Virus containing the LPK-SIA gene was infused into rats. The gene transfer
cured rats that had been made diabetic with a chemical treatment, and the same curative was
achieved in mice with autoimmune diabetes. The near-normal glucose levels of these animals
persisted for 8 months (about 40% of a rodent life span). Simultaneous with the report of this
success, another group achieved success with a different engineered insulin gene with a different
promoter from the gut endocrine K cells (Cheung et al., 2000).
Ingenious, don’t you think? Refine the design of a gene, give it new control elements, put it into a
viral vector, and transplant it a diabetic animal. Our ability to manipulate gene is sophisticated. As
we understand even bits of the puzzle in complex polygenic diseases, we have the possibility of
intervening with this entirely new form of therapy.
Text 29: Multifactorial Inheritance
The most common cause of genetic disorders is multifactorial or polygenic inheritance. Traits that
are due to the combined effects of multiple genes are polygenic (many genes). When environmental
factors also play a role in the development of a trait, the term multifactorial is used to refer to the
additive effects of many genetic and environmental factors. Expression of these traits may follow a
normal, or "bell-shaped" curve. Examples of multifactorial traits include cleft lip and palate,
congenital hip dislocation, schizophrenia, diabetes, and neural tube defects such as spine bifida.
Multifactorial conditions tend to run in families, but the pattern of inheritance is not as predictable
as with single gene disorders. The chance of recurrence is also less than the risk for single gene
disorders. The degree of risk of a multifactorial disorder occurring in relatives is related to the
number of genes they share in common with the affected individual. The closer the degree of
relationship, the more genes in common. The degree of risk also increases with the degree of
severity of the disorder.
Although multifactorial conditions run in families, the risk is generally less than the 25% or 50%
seen in Mendelian conditions. Identical twins who are exactly alike genetically, do not always have
the same condition when inheritance is multifactorial. This indicates that there are nongenetic
factors that also play a role in the expression of multifactorial traits. For instance, the risk of
coronary heart disease increases with smoking or obesity. The risk of emphysema in individuals
with alpha-1-antitrypsin deficiency increases greatly with smoking. Maternal ingestion of valproic
acid, a medication for seizures, increases the risk of spine bifida. Maternal alcohol abuse or
uncontrolled diabetes increases the risk of having a child with a congenital heart defect.
Empiric risks are used to predict the recurrence of a multifactorial disorder. This is a risk that is
based on epidemiologic and population studies and on mathematical models. For many
multifactorial or polygenic disorders, parents who have had one affected child have a 3-5% risk in
future pregnancies of having another affected child. Affected individuals have a similar risk in
future progeny. More distant relatives, however, have a lower recurrence risk.
In conditions inherited in a multifactorial fashion, the risk may depend on the sex of the affected
individual. For example, pyloric stenosis is a multifactorial disorder that occurs five times more
frequently in males than in females. If a female child has pyloric stenosis, her risk and her parent's
risk of having another affected child would be higher than if a male child has pyloric stenosis.
24
Occurrence in a female suggests a greater genetic liability; presumably more abnormal genes are
segregating in the family.
25
Dr. Barbaros ORAL
Text 30:ON BEING A PHYSICIAN
Looking back over the past decade or the past century, it is easy to see that the scientific basis for
medical practice and the organization of hospitals and clinics have changed dramatically. The future
promises even more changes. Population growth, environmental pollution, emerging infectious
diseases, and global warming, for example, are worldwide problems that have immense medical
implications. But on the positive side, the human genome project and the imminent development of
new drugs and vaccines hold great promise.
Other aspects of medicine, however, have not changed so rapidly. In the community and in the
patient-doctor relationship, physicians are still seen as persons skilled in the art of healing and in
teaching others about health and disease. Physicians are still the ones who receive the extensive
training, the licensure by the state, and the approval of society to provide all levels of care: to give
advice for a healthy life, to examine and diagnose illness, to prescribe drugs to relieve suffering,
and to care for those who are seriously ill and dying. Although physicians now share the many
responsibilities involved in patient care and work closely with nurses, physician assistants,
pharmacists, technicians, therapists, and family members of patients, it is still the physician who
bears most of the responsibility for the care of the patient.
Being a patient's physician carries many responsibilities and requires at least three attributes. First,
knowledge of the applicable biomedical science and clinical medicine is necessary to understand a
patient's problem. There is no limit to the knowledge that may be needed, but it is important to be
able to answer correctly the patient's questions, such as “How did this happen to me?” and “Will I
be better soon?” The physician needs to understand disease processes well enough to identify and
categorize a patient's problem quickly. It is important, and sometimes critical, to know whether the
problem will resolve spontaneously or whether detailed investigations, consultations, or
hospitalization is needed. A thorough and up-to-date understanding of pathophysiology, diagnosis,
and treatment is essential for the day-to-day exchange of information that occurs between
physicians as they solve the problems of individual patients and work together to organize systems
to improve patient care.
In addition to having the specific skills necessary to diagnose and treat a patient, a good physician
must recognize the limits of his or her own personal skills. The ability to communicate—both to
speak and to listen—remains essential, especially for physicians providing primary care. Effective
and sensitive communication can be challenging in communities characterized by diverse cultures
and languages. At times, the physician must be, in part, an anthropologist to grasp the patient's
understanding of illness and of the roles of patient and doctor. Knowing how to communicate
empathically is also invaluable: it is important to welcome each patient at every visit, to reach out
and hold the hand of a troubled person, and to express understanding and concern.
The physical examination remains a fundamental skill; the ability to recognize the difference
between normal and abnormal findings, adjusting for age, sex, ethnicity, and other factors, is
crucial. Good record keeping is essential—with regard to both a written record and a mental
record—so that the circumstances of visits are remembered and changes in a patient's appearance or
other characteristics that may not have been recorded can be recognized. With practice and
attention, these skills—history taking, physical examination, and record keeping—can grow
throughout a professional lifetime. Other aspects of care, such as selecting and performing
diagnostic tests, procedures, and treatments, require evolving expertise. For all physicians, it is
necessary both to practice medicine and to study regularly to maintain all of these essential skills.
The third, but by no means least important, attribute is the physician's responsibility to the patient
and the medical community to conform to appropriate professional and ethical conduct. The first
principle of the doctor-patient relationship is that the patient's welfare is paramount. Putting the
patient first necessitates understanding the patient and the patient's values. It often means spending
precious personal time explaining illness, determining the best method of treatment, or dealing with
26
emergencies. It places the physician in service to the patient. Ethical conduct includes seeing clearly
and acknowledging situations in which the physician's interest may conflict with the interest of the
patient. Finally, personal exploitation of the intimacy and privacy of the doctor-patient relationship
is never allowed.
Thus, the physician's work—recognizing illness, providing advice and comfort, relieving pain and
suffering, and dealing with illness and death—has not changed much even since ancient times. On
another level, however, the work has changed greatly. Better medical record keeping, quantitative
observation, meticulous experimentation, and carefully conducted clinical trials have contributed to
the rapid evolution of medical practice in this century. Simultaneously, medical education at the
undergraduate, graduate, and postgraduate levels has been dedicated to the organization of a truly
scientific knowledge base and its translation into intellectually cohesive approaches to
understanding disease. Extraordinary advances in the biologic sciences, the development of medical
and surgical specialties, and the explosion of medical information have brought with them great
benefits. They have also added to the costs and the potential costs of almost every aspect of health
care.
Efficiency and cost containment are now watchwords of the payers for health service. Practice
guidelines, hospital care pathways, and other efforts to codify the practice of medicine are receiving
much attention. When based on good evidence, these efforts are beneficial; they save precious
resources—time and money—for both patients and physicians. The development of managed care
in the United States has created a new challenge for physicians: to serve as advocates for their
patients. In this role, physicians are responsible for overcoming organizational, geographic, and
financial barriers to the provision of services that are important for their patients. In organizations in
which guidelines for care have been established, it may be necessary for a physician to explain to
administrators the specific needs and problems of individual patients—sometimes over and over
again, because laypersons may be less apt to recognize that guidelines for clinical practice must
remain just guidelines. Because more and more physicians are salaried and thus bound to the needs
of populations of patients, physicians face the problem of balancing the needs of individual patients
with the expectations of the employer. This is a delicate and, in some places, even fragile balance.
To serve both patients and the employer well, a physician must develop good judgment in managing
patient care under conditions in which the allocation of resources is conservative.
The increasing organization of health care on a for-profit basis has raised new issues. The
physician's obligation to put the patient first, the thoroughness inculcated in physicians throughout
their training, and the increasing costs of diagnostic tests and therapies can collide head-on with
health care management's attempts to protect earnings for investors. Professional responsibility to
patients and the public good is clear and at times poses difficult challenges for the physician.
A profession is defined by a specialized body of knowledge requiring advanced training and by the
dedication of its practitioners to the public good over their own enrichment. In exchange,
professionals are granted considerable autonomy in setting standards and in the conduct of their
work. Circumstances within the medical profession have changed. The public in general and
patients in particular have much more knowledge of medicine than at any time in the past, and the
modern organization of medicine has severely restricted the autonomy of physicians. But delivery
of expert medical care and the welfare of the patient remain central to the physician's professional
responsibility. Maintaining professionalism as the ground moves under us is more important than
ever.
The weight of all these responsibilities may suggest that it is impossible, or nearly impossible, to be
a good physician. Quite the contrary, persons with vastly different personalities, interests, and
intellects have become and are becoming good physicians and are deeply satisfied in this role. The
information necessary for practicing medicine is now more accessible than ever before. The skills
the physician needs can be learned through experience, sharpened through practice, and focused
through specialization. The ethical requirements of physicians are not onerous. They are, in fact,
expectations of all good citizens, regardless of their careers. Being a physician is both exciting and
27
satisfying; it provides a unique opportunity to combine modern scientific knowledge with the
traditions of an ancient and honored profession in serving and helping one's fellow man.
Text 31: CELL
The Cell Membrane
The cell membrane functions as a semi-permeable barrier, allowing a very few molecules across it
while fencing the majority of organically produced chemicals inside the cell. Electron microscopic
examinations of cell membranes have led to the development of the lipid bilayer model (also
referred to as the fluid-mosaic model). The most common molecule in the model is the
phospholipid, which has a polar (hydrophilic) head and two nonpolar (hydrophobic) tails. These
phospholipids are aligned tail to tail so the nonpolar areas form a hydrophobic region between the
hydrophilic heads on the inner and outer surfaces of the membrane. This layering is termed a
bilayer since an electron microscopic technique known as freeze-fracturing is able to split the
bilayer.
Cholesterol is another important component of cell membranes embedded in the hydrophobic areas
of the inner (tail-tail) region. Most bacterial cell membranes do not contain cholesterol.
Proteins are suspended in the inner layer, although the more hydrophilic areas of these proteins
"stick out" into the cells interior and outside of the cell. These proteins function as gateways that
will, in exchange for a price, allow certain molecules to cross into and out of the cell. These integral
proteins are sometimes known as gateway proteins. The outer surface of the membrane will tend to
be rich in glycolipids, which have their hydrophobic tails embedded in the hydrophobic region of
the membrane and their heads exposed outside the cell. These, along with carbohydrates attached to
the integral proteins, are thought to function in the recognition of self.
The contents (both chemical and organelles)of the cell are termed protoplasm, and are further
subdivided into cytoplasm (all of the protoplasm except the contents of the nucleus) and
nucleoplasm (all of the material, plasma and DNA etc. within the nucleus).
The Cell Wall
Not all living things have cell walls, most notably animals and many of the more animal-like
Protistans. Bacteria have cell walls containing peptidoglycan. Plant cells have a variety of
chemicals incorporated in their cell walls. Cellulose is the most common chemical in the plant
primary cell wall. Some plant cells also have lignin and other chemicals embedded in their
secondary walls. The cell wall is located outside the plasma membrane. Plasmodesmata are
connections through which cells communicate chemically with each other through their thick walls.
Fungi and many protists have cell walls although they do not contain cellulose, rather a variety of
chemicals (chitin for fungi).
The nucleus
The nucleus occurs only in eukaryotic cells, and is the location of the majority of different types of
nucleic acids. Van Hammerling's experiment (click here for a diagram) showed the role of the
nucleus in controlling the shape and features of the cell. Deoxyribonucleic acid, DNA, is the
physical carrier of inheritance and with the exception of plastid DNA (cpDNA and mDNA, see
below) all DNA is restricted to the nucleus. Ribonucleic acid, RNA, is formed in the nucleus by
coding off of the DNA bases. RNA moves out into the cytoplasm. The nucleolus is an area of the
nucleus (usually 2 nucleoli per nucleus) where ribosomes are constructed.
The nuclear envelope is a double-membrane structure. Numerous pores occur in the envelope,
allowing RNA and other chemicals to pass, but the DNA not to pass.
Cytoplasm
The cytoplasm was defined earlier as the material between the plasma membrane (cell membrane)
and the nuclear envelope. Fibrous proteins that occur in the cytoplasm, referred to as the
cytoskeleton maintain the shape of the cell as well as anchoring organelles, moving the cell and
28
controlling internal movement of structures. Microtubules function in cell division and serve as a
"temporary scaffolding" for other organelles. Actin filaments are thin threads that function in cell
division and cell motility. Intermediate filaments are between the size of the microtubules and the
actin filaments.
Vacuoles and vesicles
Vacuoles are single-membrane organelles that are essentially part of the outside that is located
within the cell. The single membrane is known in plant cells as a tonoplast. Many organisms will
use vacuoles as storage areas. Vesicles; are much smaller than vacuoles and function in transport
within and to the outside of the cell.
Ribosomes
Ribosomes are the sites of protein synthesis. They are not membrane-bound and thus occur in both
prokaryotes and eukaryotes. Eukaryotic ribosomes are slightly larger than prokaryotic ones.
Structurally the ribosome consists of a small and larger subunit. Biochemically the ribosome
consists of ribosomal RNA (rRNA) and some 50 structural proteins. Often ribosomes cluster on the
endoplasmic reticulum, in which case they resemble a series of factories adjoining a railroad line.
Endoplasmic reticulum
Endoplasmic reticulum is a mesh of interconnected membranes that serve a function involving
protein synthesis and transport. Rough endoplasmic reticulum (Rough ER) is so-named because of
its rough appearance due to the numerous ribosomes that occur along the ER. Rough ER connects
to the nuclear envelope through which the messenger RNA (mRNA) that is the blueprint for
proteins travels to the ribosomes. Smooth ER; lacks the ribosomes characteristic of Rough ER and
is thought to be involved in transport and a variety of other functions.
Golgi Apparatus and Dictyosomes
Golgi Complexes are flattened stacks of membrane-bound sacs. They function as a packaging plant,
modifying vesicles from the Rough ER. New membrane material is assembled in various cisternae
of the golgi.
Lysosomes
Lysosomes are relatively large vesicles formed by the Golgi. They contain hydrolytic enzymes that
could destroy the cell. Lysosome contents function in the extracellular breakdown of materials.
Mitochondria
Mitochondria contain their own DNA (termed mDNA) and are thought to represent bacteria-like
organisms incorporated into eukaryotic cells over 700 million years ago (perhaps even as far back
as 1.5 billion years ago). They function as the sites of energy release (following glycolysis in the
cytoplasm) and ATP formation (by chemiosmosis). The mitochondrion has been termed the
powerhouse of the cell. Mitochondria are bounded by two membranes. The inner membrane folds
into a series of cristae, which are the surfaces on which ATP is generated.
Mitochondria and endosymbiosis
During the 1980s, Lynn Margulis proposed the theory of endosymbiosis to explain the origin of
mitochondria and chloroplasts from permanent resident prokaryotes. According to this idea, a larger
prokaryote (or perhaps early eukaryote) engulfed or surrounded a smaller prokaryote some 1.5
billion to 700 million years ago.
Instead of digesting the smaller organisms the large one and the smaller one entered into a type of
symbiosis known as mutualism, wherein both organisms benefit and neither is harmed. The larger
organism gained excess ATP provided by the "protomitochondrion" and excess sugar provided by
the "protochloroplast", while providing a stable environment and the raw materials the
29
endosymbionts required. This is so strong that now eukaryotic cells cannot survive without
mitochondria (likewise photosynthetic eukaryotes cannot survive without chloroplasts), and the
endosymbionts can not survive outside their hosts. Nearly all eukaryotes have mitochondria.
Mitochondrial division is remarkably similar to the prokaryotic methods that will be studied later in
this course.
Plastids
Plastids are also membrane-bound organelles that only occur in plants and photosynthetic
eukaryotes.
Chloroplasts are the sites of photosynthesis in eukaryotes. They contain chlorophyll, the green
pigment necessary for photosynthesis to occur, and associated accessory pigments (carotenes and
xanthophylls) in photosystems embedded in membranous sacs, thylakoids (collectively a stack of
thylakoids are a granum [plural = grana]) floating in a fluid termed the stroma. Chloroplasts contain
many different types of accessory pigments, depending on the taxonomic group of the organism
being observed.
Chloroplasts and endosymbiosis
Like mitochondria, chloroplasts have their own DNA, termed cpDNA. Chloroplasts of Green Algae
(Protista) and Plants (descendants of some Green Algae) are thought to have originated by
endosymbiosis of a prokaryotic alga similar to living Prochloron (Prochlorobacteria). Chloroplasts
of Red Algae (Protista) are very similar biochemically to cyanobacteria (also known as blue-green
bacteria). Endosymbiosis is also invoked for this similarity, perhaps indicating more than one
endosymbiotic event occurred.
Leukoplasts store starch, sometimes protein or oils. Chromoplasts store pigments associated with
the bright colors of flowers and/or fruits.
Cell Movement
Cell movement; is both internal, referred to as cytoplasmic streaming and external, referred to as
motility. Internal movements of organelles are governed by actin filaments. These filaments make
an area in which organelles such as chloroplasts can move. Internal movement is known as
cytoplasmic streaming. External movement of cells is determined by special organelles for
locomotion.
Cilia and flagella are similar except for length, cilia being much shorter. They both have the
characteristic 9 + 2 arrangement of microtubules.
Flagella work as whips pulling (as in Chlamydomonas or Halosphaera) or pushing (dinoflagellates,
a group of single-celled Protista) the organism through the water. Cilia work like oars on a viking
longship (Paramecium has 17,000 such oars covering its outer surface).
Pseudopodia are used by many cells, such as Amoeba, Chaos (Pelomyxa) and human leukocytes
(white blood cells). These are not structures as such but rather are associated with actin near the
moving edge.
Text 32: CELL DIVISION: BINARY FISSION AND MITOSIS
The Cell Cycle
Despite differences between prokaryotes and eukaryotes, there are several common features in their
cell division processes. Replication of the DNA must occur. Segregation of the "original" and its
"replica" follow. Cytokinesis ends the cell division process. Whether the cell was eukaryotic or
prokaryotic, these basic events must occur.
Cytokinesis is the process where one cell splits off from its sister cell. It usually occurs after cell
division. The Cell Cycle is the sequence of growth, DNA replication, growth and cell division that
all cells go through. Beginning after cytokinesis, the daughter cells are quite small and low on ATP.
They acquire ATP and increase in size during the G1 phase of Interphase. Most cells are observed
in Interphase, the longest part of the cell cycle. After acquiring sufficient size and ATP, the cells
30
then undergo DNA Synthesis (replication of the original DNA molecules, making identical copies,
one "new molecule" eventually destined for each new cell) which occurs during the S phase. Since
the formation of new DNA is an energy draining process, the cell undergoes a second growth and
energy acquisition stage, the G2 phase. The energy acquired during G2 is used in cell division (in
this case mitosis).
Regulation of the cell cycle is accomplished in several ways. Some cells divide rapidly (beans, for
example take 19 hours for the complete cycle; red blood cells must divide at a rate of 2.5 million
per second). Others, such as nerve cells, lose their capability to divide once they reach maturity.
Some cells, such as liver cells, retain but do not normally utilize their capacity for division. Liver
cells will divide if part of the liver is removed. The division continues until the liver reaches its
former size.
Cancer cells are those which undergo a series of rapid divisions such that the daughter cells divide
before they have reached "functional maturity". Environmental factors such as changes in
temperature and pH, and declining nutrient levels lead to declining cell division rates. When cells
stop dividing, they stop usually at a point late in the G1 phase, the R point (for restriction).
Prokaryotic Cell Division
Prokaryotes are much simpler in their organization than are eukaryotes. There are a great many
more organelles in eukaryotes, also more chromosomes. The usual method of prokaryote cell
division is termed binary fission. The prokaryotic chromosome is a single DNA molecule that first
replicates, then attaches each copy to a different part of the cell membrane. When the cell begins to
pull apart, the replicate and original chromosomes are separated. Following cell splitting
(cytokinesis), there are then two cells of identical genetic composition (except for the rare chance of
a spontaneous mutation).
The prokaryote chromosome is much easier to manipulate than the eukaryotic one. We thus know
much more about the location of genes and their control in prokaryotes.
One consequence of this asexual method of reproduction is that all organisms in a colony are
genetic equals. When treating a bacterial disease, a drug that kills one bacteria (of a specific type)
will also kill all other members of that clone (colony) it comes in contact with.
Eukaryotic Cell Division
Due to their increased numbers of chromosomes, organelles and complexity, eukaryote cell division
is more complicated, although the same processes of replication, segregation, and cytokinesis still
occur.
Mitosis
Mitosis is the process of forming (generally) identical daughter cells by replicating and dividing the
original chromosomes, in effect making a cellular xerox. Commonly the two processes of cell
division are confused. Mitosis deals only with the segregation of the chromosomes and organelles
into daughter cells.
Eukaryotic chromosomes occur in the cell in greater numbers than prokaryotic chromosomes. The
condensed replicated chromosomes have several points of interest. The kinetochore is the point
where microtubules of the spindle apparatus attach. Replicated chromosomes consist of two
molecules of DNA (along with their associated histone proteins) known as chromatids. The area
where both chromatids are in contact with each other is known as the centromere the kinetochores
are on the outer sides of the centromere. Remember that chromosomes are condensed chromatin
(DNA plus histone proteins).
During mitosis replicated chromosomes are positioned near the middle of the cytoplasm and then
segregated so that each daughter cell receives a copy of the original DNA (if you start with 46 in the
parent cell, you should end up with 46 chromosomes in each daughter cell). To do this cells utilize
microtubules (referred to as the spindle apparatus) to "pull" chromosomes into each "cell". The
microtubules have the 9+2 arrangement discussed earlier. Animal cells (except for a group of
31
worms known as nematodes) have a centriole. Plants and most other eukaryotic organisms lack
centrioles. Prokaryotes, of course, lack spindles and centrioles; the cell membrane assumes this
function when it pulls the by-then replicated chromosomes apart during binary fission. Cells that
contain centrioles also have a series of smaller microtubules, the aster, that extend from the
centrioles to the cell membrane. The aster is thought to serve as a brace for the functioning of the
spindle fibers.
-Prophase
Prophase is the first stage of mitosis proper. Chromatin condenses (remember that chromatin/DNA
replicate during Interphase), the nuclear envelope dissolves, centrioles (if present) divide and
migrate, kinetochores and kinetochore fibers form, and the spindle forms.
-Metaphase
Metaphase follows Prophase. The chromosomes (which at this point consist of chromatids held
together by a centromere) migrate to the equator of the spindle, where the spindles attach to the
kinetochore fibers.
-Anaphase
Anaphase begins with the separation of the centromeres, and the pulling of chromosomes (we call
them chromosomes after the centromeres are separated) to opposite poles of the spindle.
-Telophase
Telophase is when the chromosomes reach the poles of their respective spindles, the nuclear
envelope reforms, chromosomes uncoil into chromatin form, and the nucleolus (which had
disappeared during Prophase) reform. Where there was one cell there are now two smaller cells
each with exactly the same genetic information. These cells may then develop into different adult
forms via the processes of development.
Cytokinesis
Cytokinesis is the process of splitting the daughter cells apart. Whereas mitosis is the division of the
nucleus, cytokinesis is the splitting of the cytoplasm and allocation of the golgi, plastids and
cytoplasm into each new cell.
Text 33: CELL DIVISION: MEIOSIS AND SEXUAL REPRODUCTION
Meiosis
Sexual reproduction occurs only in eukaryotes. During the formation of gametes, the number of
chromosomes is reduced by half, and returned to the full amount when the two gametes fuse during
fertilization.
Ploidy
Haploid and diploid are terms referring to the number of sets of chromosomes in a cell. Gregor
Mendel determined his peas had two sets of alleles, one from each parent. Diploid organisms are
those with two (di) sets. Human beings (except for their gametes), most animals and many plants
are diploid. We abbreviate diploid as 2n. Ploidy is a term referring to the number of sets of
chromosomes. Haploid organisms/cells have only one set of chromosomes, abbreviated as n.
Organisms with more than two sets of chromosomes are termed polyploid. Chromosomes that carry
the same genes are termed homologous chromosomes. The alleles on homologous chromosomes
may differ, as in the case of heterozygous individuals. Organisms (normally) receive one set of
homologous chromosomes from each parent.
Meiosis is a special type of nuclear division which segregates one copy of each homologous
chromosome into each new "gamete". Mitosis maintains the cell's original ploidy level (for
example, one diploid 2n cell producing two diploid 2n cells; one haploid n cell producing two
haploid n cells; etc.). Meiosis, on the other hand, reduces the number of sets of chromosomes by
half, so that when gametic recombination (fertilization) occurs the ploidy of the parents will be
reestablished.
32
Most cells in the human body are produced by mitosis. These are the somatic (or vegetative) line
cells. Cells that become gametes are referred to as germ line cells. The vast majority of cell
divisions in the human body are mitotic, with meiosis being restricted to the gonads.
Life Cycles
Life cycles are a diagrammatic representation of the events in the organism's development and
reproduction. When interpreting life cycles, pay close attention to the ploidy level of particular parts
of the cycle and where in the life cycle meiosis occurs. For example, animal life cycles have a
dominant diploid phase, with the gametic (haploid) phase being a relative few cells. Most of the
cells in your body are diploid, germ line diploid cells will undergo meiosis to produce gametes,
with fertilization closely following meiosis.
Plant life cycles have two sequential phases that are termed alternation of generations. The
sporophyte phase is "diploid", and is that part of the life cycle in which meiosis occurs. However,
many plant species are thought to arise by polyploidy, and the use of "diploid" in the last sentence
was meant to indicate that the greater number of chromosome sets occur in this phase. The
gametophyte phase is "haploid", and is the part of the life cycle in which gametes are produced (by
mitosis of haploid cells). In flowering plants (angiosperms) the multicelled visible plant (leaf, stem,
etc.) is sporophyte, while pollen and ovaries contain the male and female gametophytes,
respectively. Plant life cycles differ from animal ones by adding a phase (the haploid gametophyte)
after meiosis and before the production of gametes.
Many protists and fungi have a haploid dominated life cycle. The dominant phase is haploid, while
the diploid phase is only a few cells (often only the single celled zygote, as in Chlamydomonas ).
Many protists reproduce by mitosis until their environment deteriorates, then they undergo sexual
reproduction to produce a resting zygotic cyst.
Phases of Meiosis
Two successive nuclear divisions occur, Meiosis I (Reduction) and Meiosis II (Division). Meiosis
produces 4 haploid cells. Mitosis produces 2 diploid cells. The old name for meiosis was reduction/
division. Meiosis I reduces the ploidy level from 2n to n (reduction) while Meiosis II divides the
remaining set of chromosomes in a mitosis-like process (division). Most of the differences between
the processes occur during Meiosis I.
-Prophase I
Prophase I has a unique event -- the pairing (by an as yet undiscovered mechanism) of homologous
chromosomes. Synapsis is the process of linking of the replicated homologous chromosomes. The
resulting chromosome is termed a tetrad, being composed of two chromatids from each
chromosome, forming a thick (4-strand) structure. Crossing-over may occur at this point. During
crossing-over chromatids break and may be reattached to a different homologous chromosome.
The alleles on this tetrad:
ABCDEFG
ABCDEFG
abcdefg
abcdefg
will produce the following chromosomes if there is a crossing-over event between the 2nd and 3rd
chromosomes from the top:
ABCDEFG
ABcdefg
abCDEFG
abcdefg
Thus, instead of producing only two types of chromosome (all capital or all lower case), four
different chromosomes are produced. This doubles the variability of gamete genotypes. The
occurrence of a crossing-over is indicated by a special structure, a chiasma (plural chiasmata) since
the recombined inner alleles will align more with others of the same type (e.g. a with a, B with B).
33
Near the end of Prophase I, the homologous chromosomes begin to separate slightly, although they
remain attached at chiasmata.
Events of Prophase I (save for synapsis and crossing over) are similar to those in Prophase of
mitosis: chromatin condenses into chromosomes, the nucleolus dissolves, nuclear membrane is
disassembled, and the spindle apparatus forms.
-Metaphase I
Metaphase I is when tetrads line-up along the equator of the spindle. Spindle fibers attach to the
centromere region of each homologous chromosome pair. Other metaphase events as in mitosis.
-Anaphase I
Anaphase I is when the tetrads separate, and are drawn to opposite poles by the spindle fibers. The
centromeres in Anaphase I remain intact.
-Telophase I
Telophase I is similar to Telophase of mitosis, except that only one set of (replicated) chromosomes
is in each "cell". Depending on species, new nuclear envelopes may or may not form. Some animal
cells may have division of the centrioles during this phase.
-Prophase II
During Prophase II, nuclear envelopes (if they formed during Telophase I) dissolve, and spindle
fibers reform. All else is as in Prophase of mitosis. Indeed Meiosis II is very similar to mitosis.
-Metaphase II
Metaphase II is similar to mitosis, with spindles moving chromosomes into equatorial area and
attaching to the opposite sides of the centromeres in the kinetochore region.
-Anaphase II
During Anaphase II, the centromeres split and the former chromatids (now chromosomes) are
segregated into opposite sides of the cell.
-Telophase II
Telophase II is identical to Telophase of mitosis. Cytokinesis separates the cells.
Comparison of Mitosis and Meiosis
Mitosis maintains ploidy level, while meiosis reduces it. Meiosis may be considered a reduction
phase followed by a slightly altered mitosis. Meiosis occurs in a relative few cells of a multicellular
organism, while mitosis is more common.
Gametogenesis
Gametogenesis is the process of forming gametes (by definition haploid, n) from diploid cells of the
germ line. Spermatogenesis is the process of forming sperm cells by meiosis (in animals, by mitosis
in plants) in specialized organs known as gonads (in males these are termed testes). After division
the cells undergo differentiation to become sperm cells. Oogenesis is the process of forming an
ovum (egg) by meiosis (in animals, by mitosis in the gametophyte in plants) in specialized gonads
known as ovaries. Whereas in spermatogenesis all 4 meiotic products develop into gametes,
oogenesis places most of the cytoplasm into the large egg. The other cells, the polar bodies, do not
develop. This all the cytoplasm and organelles go into the egg. Human males produce 200,000,000
sperm per day, while the female produces one egg (usually) each menstrual cycle.
Spermatogenesis
Sperm production begins at puberty at continues throughout life, with several hundred million
sperm being produced each day. Once sperm form they move into the epididymis, where they
mature and are stored.
Oogenesis
The ovary contains many follicles composed of a developing egg surrounded by an outer layer of
follicle cells. Each egg begins oogenesis as a primary oocyte. At birth each female carries a lifetime
34
supply of developing oocytes, each of which is in Prophase I. A developing egg (secondary oocyte)
is released each month from puberty until menopause, a total of 400-500 eggs.
Text 34: NATURAL KILLER CELLS
Natural killer (NK) cells constitute the third major population of lymphocytes, after T cells and B
cells. They were initially identified because they spontaneously (i.e., naturally) kill certain tumor
cells, a process that does not require prior exposure to the target. Like T cells and B cells, NK cells
are involved in host immune defense. They are more closely related to T cells than to B cells in that
they share effector functions, including the same killing mechanism and the capacity to produce
cytokines. Unlike other lymphocytes, NK cells are components of innate immunity—they respond
early against infections (and possibly tumors) and do not require gene rearrangement for maturation
and function. Much remains to be clarified regarding the nature of NK cell receptors and their
ligands. NK cells are negative for the T cell receptor (CD3) and B cell receptor (membrane
immunoglobulin). Most NK cells in human peripheral blood are CD56+; this feature can be used for
their identification, because expression of this adhesion-promoting molecule is restricted to NK
cells and a small population of T cells. NK cells also express the transmembrane form of the lowaffinity receptor for IgG (CD16 or FcγRIIIA) that is absent on mature T cells. When CD16 on the
NK cell binds the Fc portion of IgG that is coating a target, this receptor activates release of
cytoplasmic granules containing molecules that form pores in the target cell membrane and others
that mediate apoptosis, resulting in antibody-dependent cellular cytotoxicity. Natural killing is
mediated by the same mechanism, although CD16 is not required. Identification of the receptors
that initiate natural killing is a topic of active research.
Of note, NK cells are better able to kill cells that lack major histocompatibility complex (MHC) or
human leukocyte antigen (HLA) class I molecules, such as may result from tumorigenesis or viral
infection. Although decreased expression of MHC class I molecules may allow targets to evade
destruction by MHC class I-restricted cytotoxic T cells, it makes the targets more susceptible to
killing by NK cells. This finding led to the so-called missing-self hypothesis, which holds that NK
cells survey tissues for MHC class I molecules, which are normally expressed on most nucleated
cells in the body. If MHC class I expression is decreased or absent, the NK cells are released from
the negative influence of MHC class I and kill the target. This process may provide a fail-safe
mechanism to protect the body from disease processes that evade acquired, specific T cell
immunity.
Ongoing studies indicate that NK cells express a multitude of inhibitory receptors that guide their
capacity to kill tumor and virus-infected cells. These receptors, termed killer immuno globulin-like
receptors and CD94/NKG2 heterodimers, bind to HLA molecules on their targets. Subsequently,
specific tyrosine residues are phosphorylated within immunoreceptor tyrosine-based inhibitory
motifs (ITIMs) in the cytoplasmic domains. This results in the recruitment and activation of
cytoplasmic phosphatases that dephosphorylate molecules in the activation cascade, hence
inhibiting NK cell stimulation. NK cells also express related molecules lacking ITIMs. These
molecules are prime candidates for activation receptors that bind as yet uncharacterized molecules
on the surface of the target cell.
Early studies of NK cells focused on their role in tumor surveillance (i.e., the eradication of cancers
before they become clinically apparent). NK cells can be expanded in tissue culture by exposure to
high concentrations of the lymphokine IL-2, which results in production of lymphokine-activated
killer (LAK) cells. Adoptive transfer of LAK cells into patients with radiation- and chemotherapyresistant tumors can lead to remissions. However, high concentrations of IL-2 have to be
simultaneously administered, increasing the risk of potentially serious complications such as
pulmonary edema and capillary leak syndromes.
Subsequent studies have shown that NK cells also play a critical role in early innate immune
responses to viral infections. Persons who lack NK cells suffer recurrent, severe systemic viral
infections, particularly from herpesviruses. Depletion of NK cells has also been described in
patients with advanced HIV infection and AIDS. This depletion, which apparently results from
35
infection of the NK cell itself by herpesvirus 6 and HIV, may partially account for these patients'
susceptibility to opportunistic infections such as those from herpesvirus and cytomegalovirus.
NK cell lymphomas and leukemias are rarely found in Western populations, but are more common
in Asian populations. NK cell lymphomas often present as nasal tumors, are associated with
Epstein-Barr virus infections, and may occur in conjunction with autoimmune syndromes.
Natural killing by peripheral blood NK cells is altered in a variety of conditions. However, the
significance of such findings is unclear. On the other hand, as more reagents become available to
definitively detect NK cells in clinical specimens, the apparent role of NK cells in disease
pathogenesis will become clearer, as suggested by studies indicating marked expansion of NK cells
in synovial fluid of patients with early rheumatoid arthritis.
36
Dr. Ayberk KURT
Text 35: HUMAN ANATOMY
The term human anatomy comprises a consideration of the various structures which make up the
human organism. In a restricted sense it deals merely with the parts which form the fully developed
individual and which can be rendered evident to the naked eye by various methods of dissection.
Regarded from such a standpoint it may be studied by two methods: (1) the various structures may
be separately considered—systematic anatomy; or (2) the organs and tissues may be studied in
relation to one another—topographical or regional anatomy. It is, however, of much advantage to
add to the facts ascertained by naked-eye dissection those obtained by the use of the microscope.
This introduces two fields of investigation, viz., the study of the microscopic structure of the
various component parts of the body—histology—and the study of the human organism in its
immature condition, —embryology. Owing to the difficulty of obtaining material illustrating all the
stages of early development, gaps must be filled up by observations on the development of lower
forms—comparative embryology, or by a consideration of adult forms in the line of human ancestry
—comparative anatomy. The direct application of the facts of human anatomy to the various
pathological conditions constitutes the subject of applied anatomy. Finally, the appreciation of
structures on or immediately underlying the surface of the body makes the subject of special
study—surface anatomy.
Text 36: TERMINOLOGY
For descriptive purposes the body is supposed to be in the erect posture, with the arms hanging by
the sides and the palms of the hands directed forward.
The median plane is a vertical antero-posterior plane, passing through the center of the trunk. This
plane will pass approximately through the sagittal suture of the skull, and hence any plane parallel
to it is termed a sagittal plane. A vertical plane at right angles to the median plane passes, roughly
speaking, through the central part of the coronal suture or through a line parallel to it; such a plane
is known as a frontal plane or sometimes as a coronal plane. A plane at right angles to both the
median and frontal planes is termed a transverse plane.
The terms anterior or ventral, and posterior or dorsal, are employed to indicate the relation of parts
to the front or back of the body or limbs, and the terms superior or cephalic, and inferior or caudal,
to indicate the relative levels of different structures; structures nearer to or farther from the median
plane are referred to as medial or lateral respectively. The terms superficial and deep are strictly
confined to descriptions of the relative depth from the surface of the various structures; external and
internal are reserved almost entirely for describing the walls of cavities or of hollow viscera. In the
case of the limbs the words proximal and distal refer to the relative distance from the attached end
of the limb.
Text 37: BONE
Bone constitutes the fundamental element of all the joints. In the long bones, the extremities are the
parts which form the articulations; they are generally somewhat enlarged; and consist of spongy
tissue with a thin coating of compact substance. In the flat bones, the articulations usually take place
at the edges; and in the short bones at various parts of their surfaces. The layer of compact bone
which forms the joint surface, and to which the articular cartilage is attached, is called the articular
lamella. It differs from ordinary bone tissue in that it contains no Haversian canals, and its lacunæ
are larger and have no canaliculi. The vessels of the cancellous tissue, as they approach the articular
lamella, turn back in loops, and do not perforate it; this layer is consequently denser and firmer than
ordinary bone, and is evidently designed to form an unyielding support for the articular cartilage.
37
Text 38: SURFACES OF BONES
If the surface of a bone be examined, certain eminences and depressions are seen. These eminences
and depressions are of two kinds: articular and non-articular. Well-marked examples of articular
eminences are found in the heads of the humerus and femur; and of articular depressions in the
glenoid cavity of the scapula, and the acetabulum of the hip bone. Non-articular eminences are
designated according to their form. Thus, a broad, rough, uneven elevation is called a tuberosity,
protuberance, or process, a small, rough prominence, a tubercle; a sharp, slender pointed eminence,
a spine; a narrow, rough elevation, running some way along the surface, a ridge, crest, or line. Nonarticular depressions are also of variable form, and are described as fossæ, pits, depressions,
grooves, furrows, fissures, notches, etc. A short perforation is called a foramen, a longer passage a
canal. These non-articular eminences and depressions serve to increase the extent of surface for the
attachment of ligaments and muscles, and are usually well-marked in proportion to the muscularity
of the subject.
Text 39: JOINTS/ARTICULATIONS
The bones of the skeleton are joined to one another at different parts of their surfaces, and such
connections are termed Joints or Articulations. Where the joints are immovable, as in the
articulations between practically all the bones of the skull, the adjacent margins of the bones are
almost in contact, being separated merely by a thin layer of fibrous membrane, named the sutural
ligament. In certain regions at the base of the skull this fibrous membrane is replaced by a layer of
cartilage. Where slight movement combined with great strength is required, the osseous surfaces are
united by tough and elastic fibrocartilages, as in the joints between the vertebral bodies, and in the
interpubic articulation. In the freely movable joints the surfaces are completely separated; the bones
forming the articulation are expanded for greater convenience of mutual connection, covered by
cartilage and enveloped by capsules of fibrous tissue. The cells lining the interior of the fibrous
capsule form an imperfect membrane—the synovial membrane—which secretes a lubricating fluid.
The joints are strengthened by strong fibrous bands called ligaments, which extend between the
bones forming the joint.
Text 40: THE NERVOUS SYSTEM-I
The nervous system is the most complicated and highly organized of the various systems which
make up the human body. It is the mechanism concerned with the correlation and integration of
various bodily processes and the reactions and adjustments of the organism to its environment. In
addition the cerebral cortex is concerned with conscious life. It may be divided into two parts,
central and peripheral. The central nervous system consists of the encephalon or brain, contained
within the cranium, and the medulla spinalis or spinal cord, lodged in the vertebral canal; the two
portions are continuous with one another at the level of the upper border of the atlas vertebra. The
peripheral nervous system consists of a series of nerves by which the central nervous system is
connected with the various tissues of the body.
Text 41: THE NERVOUS SYSTEM-II
The nervous tissues are composed of nerve cells and their various processes, together with a
supporting tissue called neuroglia, which, however, is found only in the brain and medulla spinalis.
Certain long processes of the nerve cells are of special importance, and it is convenient to consider
them apart from the cells; they are known as nerve fibers. To the naked eye a difference is obvious
between certain portions of the brain and medulla spinalis, viz., the gray substance and the white
substance. The gray substance is largely composed of nerve cells, while the white substance
contains only their long processes, the nerve fibers. It is in the former that nervous impressions are
received, stored, and transformed into efferent impulses, and by the latter that they are conducted.
Hence the gray substance forms the essential constituent of all the ganglionic centers, both those in
the isolated ganglia and those aggregated in the brain and medulla spinalis; while the white
substance forms the bulk of the commissural portions of the nerve centers and the peripheral nerves.
38
Text 42: TENDONS
Tendons are white, glistening, fibrous cords, varying in length and thickness, sometimes round,
sometimes flattened, and devoid of elasticity. They consist almost entirely of white fibrous tissue,
the fibrils of which have an undulating course parallel with each other and are firmly united
together. When boiled in water tendon is almost completely converted into gelatin, the white fibers
being composed of the albuminoid collagen, which is often regarded as the anhydride of gelatin.
They are very sparingly supplied with bloodvessels, the smaller tendons presenting in their interior
no trace of them. Nerves supplying tendons have special modifications of their terminal fibers,
named organs of Golgi.
Text 43: APONEUROSES
Aponeuroses are flattened or ribbon-shaped tendons, of a pearly white color, iridescent, glistening,
and similar in structure to the tendons. They are only sparingly supplied with bloodvessels. 2 The
tendons and aponeuroses are connected, on the one hand, with the muscles, and, on the other hand,
with the movable structures, as the bones, cartilages ligaments, and fibrous membranes (for
instance, the sclera). Where the muscular fibers are in a direct line with those of the tendon or
aponeurosis, the two are directly continuous. But where the muscular fibers join the tendon or
aponeurosis at an oblique angle, they end, according to Kölliker, in rounded extremities which are
received into corresponding depressions on the surface of the latter, the connective tissue between
the muscular fibers being continuous with that of the tendon. The latter mode of attachment occurs
in all the penniform and bipenniform muscles, and in those muscles the tendons of which
commence in a membranous form, as the Gastrocnemius and Soleus.
Text 44: THE SYNOVIAL MEMBRANE
The synovial membrane invests the inner surface of the fibrous capsule, and is reflected over any
tendons passing through the joint cavity, as the tendon of the Popliteus in the knee, and the tendon
of the Biceps brachii in the shoulder. It is composed of a thin, delicate, connective tissue, with
branched connective-tissue corpuscles. Its secretion is thick, viscid, and glairy, like the white of an
egg, and is hence termed synovia. In the fetus this membrane is said, by Toynbee, to be continued
over the surfaces of the cartilages; but in the adult such a continuation is wanting, excepting at the
circumference of the cartilage, upon which it encroaches for a short distance and to which it is
firmly attached. In some of the joints the synovial membrane is thrown into folds which pass across
the cavity; they are especially distinct in the knee. In other joints there are flattened folds,
subdivided at their margins into fringe-like processes which contain convoluted vessels. These folds
generally project from the synovial membrane near the margin of the cartilage, and lie flat upon its
surface. They consist of connective tissue, covered with endothelium, and contain fat cells in
variable quantity.
Text 45: THE HEART
The heart is the central organ of the blood vascular system, and consists of a hollow muscle; by its
contraction the blood is pumped to all parts of the body through a complicated series of tubes,
termed arteries. The arteries undergo enormous ramification in their course throughout the body,
and end in minute vessels, called arterioles, which in their turn open into a close-meshed network of
microscopic vessels, termed capillaries. After the blood has passed through the capillaries it is
collected into a series of larger vessels, called veins, by which it is returned to the heart. The
passage of the blood through the heart and blood-vessels constitutes what is termed the circulation
of the blood, of which the following is an outline.
Text 46: WALLERIAN DEGENERATION
When nerve fibers are cut across, the central ends of the fibers degenerate as far as the first node of
Ranvier; but the peripheral ends degenerate simultaneously throughout their whole length. The
axons break up into fragments and become surrounded by drops of fatty substance which are
39
formed from the breaking down of the medullary sheath. The nuclei of the primitive sheath
proliferate, and finally absorption of the axons and fatty substance occurs. If the cut ends of the
nerve be sutured together regeneration of the nerve fibers takes place by the downgrowth of axons
from the central end of the nerve. At one time it was believed that the regeneration was peripheral
in origin, but this has been disproved, the proliferated nuclei in the peripheral portions taking part
merely in the formation of the so-called scaffolding along which the new axons pass.
Text 47: DISABLED / DISABILITY
Disabled is the clear preference in contemporary American English in referring to people having
either physical or mental impairments, with the impairments themselves preferably termed
disabilities. Handicapped —a somewhat euphemistic term— is still in wide use but is sometimes
taken to be offensive, while more recent coinages such as differently abled or handicapable are
generally perceived as condescending euphemisms and have gained little currency. The oftenrepeated recommendation to put the person before the disability would favor persons with
disabilities over disabled persons and person with paraplegia over paraplegic. Such expressions are
said to focus on the individual rather than on the particular functional limitation, and they are
preferred by many people who themselves have disabilities. Respect for the wishes of this group
calls for observing this rule, but the “person-first” construction has not found wide acceptance with
the general public, perhaps because it tends to sound unnatural or possibly because in English the
last word in a phrase usually has the greatest weight, thus undercutting the intended purpose.
Text 48: ABDUCTOR / ADDUCTOR
Standing upright. Riding a horse. Holding a glass, or a pen, or a paintbrush. Hitchhiking. Crossing
your fingers. Spreading your toes apart so you can wiggle them in the sand. These are all activities
that result from the actions of muscles known as abductors and adductors. Muscles that are
abductors move body parts away from each other or from the trunk of the body itself. For example,
an abductor muscle moves your thumb away from your index finger, allowing the popular “thumbs
up” salute or the widely recognized sign for “thumbing” a ride. Abductor comes from Latin
abducere, which is built of the prefix ab-, “away,” and the verb ducere, “to bring.” Adductor
muscles, in contrast, bring body parts together or bring them closer to the body. It is a group of
adductor muscles in the inner thigh, for example, that allows a rider to sit firmly astride a horse.
Once the rider has dismounted, the same group of adductors works in concert with other thigh
muscles to enable him or her to stand upright. Adductor comes from Latin adducere, which
combines ad-, “to,” and the verb ducere.
Text 49: FEMALE / MALE
Contrary to popular opinion, the word female is not derived from male, nor is it even related. In this
case, women preceded men. Female comes from the Latin word femella, “young woman, girl,”
which was a diminutive of femina, “woman.” Female came into English by way of Old French
around 1330 and was first spelled femele. Male came along in 1373, also from Latin via Old French.
But male derives from the Latin masculus, a diminutive of mas, “male.” As early as 1380 femelle
began to be influenced by male, and spellings with an a began to appear. Eventually, female became
the standard English spelling.
When used to refer to persons, male and female should be used in parallel and only when relevant:
Male and female guards were assigned to the rest rooms. Often people use female and male in a
way that draws attention to something perceived as unusual without realizing they are doing this.
When the sex of the person performing a job is irrelevant, phrases like a female police officer and a
male nurse are viewed by many as offensive, since the gender marking is gratuitous and carries the
implication that the norm in certain professions, such as police work, is to be a man and that the
norm in other professions, such as nursing, is to be a woman. As nouns, male and female are
generally used in technical, medical, or scientific writing, often to refer to groups of subjects in an
experiment, whether humans or other animals: The control group consisted of twelve females and
40
eleven males. Since male and female are used so much in zoology to designate animals, their
application to people can sometimes have comical overtones. Nevertheless, they represent a
convenient way to avoid repeating phrases like a boy or a man and girls and women: This disease
usually affects females.
Text 50: AUTHOR / WRITER
In February 1995, the discovery of the top quark spurred 2 4-page articles submitted to the journal
Physical Review Letters, each including over 400 authors. Although an article with this number of
authors submitted to a trade magazine might be an editor’s worst nightmare, at a professional
science journal 400 authors would be expected for a result 18 years in the making. Within scientific
journals, the term author takes on a broader meaning than the term writer. An author is someone
who has played a critical role in the outcome of an experiment or calculation. For example, an
author might be the individual who maintains crucial laboratory equipment or develops a useful
method of collecting data. In all cases, a writer is a person who has contributed to the actual writing
of the article and is one of the authors.
41
Dr. Özhan EYİGÖR
Text 51:
Read this example:
How is obstruction prevented?
Obstruction is prevented by clearing the mouth and throat of mucus, food and other
materials.
42
Answer these questions:
a) How is the airway kept open?
b) How are air leakages prevented?
c) How is expiration allowed to take place?
d) How does the operator extend the patient's head as far as possible?
e) How does the operator close the patient's nose?
You are supervising a demonstration of mouth-to-mouth resuscitation. Give instructions to
the operator(s), beginning as follows:
`First place the patient on his back on a firm surface. Then…………
Read this:
Text 52: The physical examination of the abdomen: palpation
The examiner should stand, sit or kneel comfortably beside the patient. His
hands should be warm. Palpation is undertaken in three phases: light palpation,
deep palpation and bimanual palpation.
Light palpation should commence in an area removed from the site of any pain
and the patient's face should be watched for any indication of tenderness or
pain.
1. To discover exactly where the pain located, the examiner
should………..
2. To enable him to carry out the examination properly, ……….
3. Why should the examiner`s hands be warm? (so that…..)
4. Why should palpation begin in an area where there is no pain? (so
that…)
43
Text 53: CELL
In general, all cells possess:
1. a cell membrane or plasmalemma;
2. one or more nuclei with nucleoli containing primarily deoxyribonucleic acid (DNA) and
ribonucleic acid (RNA), respectively;
3. cytoplasmic RNA;
4. a Golgi apparatus;
5. membranes in the form of vacuoles or saccules;
6. mitochondria; and
7. energy stored in the form of glycogen and lipid.
The plasmalemma, demonstrated by electron microscopy to be about 100 Angstroms (10 nm) in
thickness, cannot be resolved, per se, by light microscopy, because the use of visible light as the
illuminating source limits resolution to about 2750A (0.275 µm*). However, the plasmalemma
together with associated connective tissue and surface polysaccharide coat may be stained and
resolved as the cell boundary under certain conditions.
The nucleus is of special importance in understanding cell function. Because it is large enough for
detailed examination by the light microscope when stained even by routine methods (such as
hematoxylin and eosin, H. & E.), its varying functional states can be assessed. It has been
demonstrated that active DNA does not stain with nuclear stains; the nucleus may thus appear
empty except for a nucleolus, which will be stained. Inactive DNA is readily stained with
hematoxylin, toluidine blue, and other similar basic dyes. Most nuclei contain varying amounts of
functional (active) and nonfunctional (inactive) DNA. The stainable DNA may appear in clumps or
may be in a reticulated pattern. The functional DNA is termed euchromatin, whereas the
nonfunctional, or inactive, DNA is called heterochromatin. The nerve cell nucleus contains no
stainable DNA, which indicates its active involvement in the metabolism of the cell. By contrast,
the densely stained heterochromatin seen in the nucleus of the maturing red blood cell (or
erythrocyte), signals the termination of nuclear involvement in the cytoplasmic synthesis of
hemoglobin. Such nuclei are called pyknotic. In the case of the red blood cell, the useless
heterochromatin is eventually ejected from the cell and phagocytized by macrophages. During cell
division, the stainable, inactive DNA appears in the form of threads or rods called chromosomes.
The nucleus also contains one or more nucleoli, which stain routinely with one of the nuclear stains
cited previously. The nucleolus consists principally of RNA and is the source of cytoplasmic RNA.
Text 54: Estimation of Gestational Age
By convention, obstetricians date pregnancy in menstrual weeks, beginning from the first day of the
last normal menstrual period (LNMP). This is the menstrual age or gestational age. Embryonic or
fetal age begins at fertilization or conception, about two weeks after LNMP. Conceptional age is
used when the actual date of conception is known in patients who have undergone IV fertilization or
artificial insemination. Determination of the starting date of a pregnancy may be difficult in some
instances, partly because it depends on the mother's memory of an event that occurred several
weeks before she realized she was pregnant. In summary, two reference points are commonly used
for estimating age:
• onset of LNMP
• probable time of fertilization (conception)
Knowledge of embryonic age is important to obstetricians because it affects clinical management,
especially when invasive procedures such as chorionic villus sampling and amniocentesis are
necessary.
44
In some women, estimation of gestational age from the menstrual history alone may be unreliable.
The probability of error in establishing LNMP is highest in women who become pregnant after
cessation of oral contraception because the interval between discontinuance of hormones and the
onset of ovulation is highly variable. In addition, slight uterine bleeding ("spotting"), which
sometimes occurs after implantation of the blastocyst, may be incorrectly regarded by a woman as
light menstruation. Other contributing factors may include oligomenorrhea (scanty menstruation),
pregnancy in the postpartum period (i.e., several weeks after childbirth), and use of intrauterine
devices (IUDs). Despite possible sources of error, LNMP is commonly used by clinicians to
estimate the age of embryos and it is a reliable criterion in most cases.
Ultrasound assessment of the size of the chorionic (gestational) cavity and its embryonic contents
enables clinicians to obtain an accurate estimate of the date of conception. The zygote does not
form until about 2 weeks after LNMP; consequently, 14 ± 2 days must be deducted from the socalled menstrual (gestational) age to obtain the actual or fertilization age of an embryo.
The day fertilization occurs is the most accurate reference point for estimating age: this is
commonly calculated from the estimated time of ovulation because the ovum is usually fertilized
within 12 hours after ovulation. Because it may be important to know the actual age of an embryo
(for determining its sensitivity to teratogenic agents), all statements about age should indicate the
reference point used, that is, days after LNMP or after the estimated time of fertilization.
Text 55: Stub Wounds of the Heart
On 24 June a man aged 21 was admitted to the casualty department, having collapsed in the
street 20 minutes previously a few moments after a fight in a public house. He was severely
shocked, and had four stab wounds, each 1 cm. long: 2 in the left precordium and 2 in the left
flank. There were no signs of bleeding into the peritoneal cavity nor of pneumothorax, but the
head and neck became increasingly cyanosed and the jugular veins considerably distended.
At this point cardiac arrest occurred, but spontaneous rhythms returned following external
cardiac massage. Pericardiocentesis with a wide-bore needle yielded no blood. The patient was
therefore transferred to theatre for immediate thoracotomy. En route, cardiac arrest occurred for
the second time, and on arrival in theatre the patient was pulseless with fixed, widely dilated
pupils. The chest was opened immediately through the left fifth interspace and more than a litre
of partly clotted blood emptied from the left pleural cavity. On opening the pericardium half a
litre of clotted blood was evacuated and a bimanual cardiac massage commenced. Spontaneous
rhythms returned after 20 seconds. Brisk bleeding, uncontrolled by digital pressure, located a
transverse wound 2-5 cm. long high in the left ventricle just to the left of the anterior
interventricular artery. This was closed with interrupted silk sutures. There was no other
intrathoracic injury, but blood oozed from the abdomen through an incision in the left h emidiaphragm. Laparotomy revealed a laceration of the left lobe of the liver, causing the loss of
approximately 1 litre of blood into the peritoneal cavity. Post-operative progress was
uncomplicated apart from a moderate-sized pericardial effusion. When seen 1 month later the
patient remained well.
Text 56: The Nervous System
1
The basic unit of the nervous system is the neurone, or nerve cell. 2It consists of a cell body and its
processes. 3Each neurone has two types of process: a number of short, freely branching fibres called
dendrites, and a single process called the axon, which may or may not give off branches along its
course. 4The dendrites convey impulses to the cell body; the axon, which is the main conducting
fibre, conveys impulses away from the cell body. 5The axon varies in length in different kinds of
neurone. 6In a motor neurone it can be very long, running, for example, from a cell body in the
spinal cord to a muscle in the foot. 7Axons of the internuncial neurones, which provide links
between other neurones, are often short and difficult to distinguish from the dendrites.
(a) A neurone consists of a cell body, dendrites and an axon.
(b) The axon is a freely branching fibre.
45
(c) The main conducting fibre of a neurone is very long.
(d) Other neurones can be difficult to distinguish from the dendrites.
8
An unactivated nerve fibre maintains a state of chemical stability with concentrations of potassium
inside and outside the lining membrane in a ratio of 30:1. 9Thus the nerve fibre at rest is electrically
charged. 10A nerve impulse is a wave of depolarization created by a chemical imbalance. 11Sodium
passes through the membrane, releasing potassium. 12The depolarization of any part of the nerve
cell causes the depolarization of the next segment, and so on to the end of the fibre. 13The end of a
nerve fibre is not structurally joined to the next cell, but the small gap between them can be bridged
chemically. 14This functional junction is known as a synapse. 15Not all the chemicals which act as
transmitters are known but among the most important are acetyl choline and noradrenaline. 16Once
the synapse has been made, these chemicals are rapidly destroyed by enzymes. 17The nerve fibre
itself recharges within milliseconds.
(e) An unactivated nerve fibre contains thirty times more potassium than its surrounding tissue.
(f) A nerve impulse is a chemical imbalance.
(g) A synapse is a connection which is made over the small gap between the end of a nerve fibre
and the next cell.
(h) Acetyl choline is known to transmit impulses.
(i) Transmitters are destroyed by enzymes.
18
The brain and spine together form the central nervous system. 19Arising from the central
nervous system and supplying all parts of the body are the peripheral nerves, commonly referred
to simply as nerves. 20A nerve is a cord-like structure, usually containing bundles of conducting
fibres, which may be sensory or motor.
(j) The peripheral nerves arise from the brain and the spine.
(k) Nerves may contain axons from both sensory and motor neurones.
21
Twelve pairs of nerves arise from the brain and thirty-one pairs of nerves arise from the spine.
22
These are known as the cranial nerves and the spinal nerves respectively. 23Of the twelve cranial
nerves, five contain both sensory and motor fibres. 24The most important of these is the vagus, or
tenth nerve, which supplies the heart, most of the digestive organs, the pharynx and the larynx.
25
Of the remaining seven pairs of nerves, four contain motor fibres only, and three are entirely
sensory. 26The fourth and sixth nerves, for example, control the movement of the eyeball, and the
first nerve records smells.
27
In contrast, all the spinal nerves contain both sensory and motor fibres. 28There are eight pairs
of cervical nerves, twelve thoracic, five lumbar, five sacral, and one coccygeal. 29The spinal
nerves divide into two branches. 30The posterior branches serve the muscles and skin of the back
of their own region. 31The anterior branches of the thoracic nerves circle the thorax, supplying the
intercostal muscles and the skin. 32All other anterior branches form plexuses, or networks of nerve
fibres, from which nerves pass out to supply the cervical and pelvic regions and the upper and
lower limbs. 33Thus each limb nerve contains fibres from several spinal nerves. 34The sciatic
nerve, which emerges from the sacral plexus to serve the back of the thigh and the leg, contains
fibres from five spinal nerves: the fourth and fifth lumbar nerves, and the first, second and third
sacral nerves.
(1) Most of the cranial nerves contain both sensory and motor nerve fibres.
(m) The thirty-one pairs of nerves which arise from the spine are known as the cranial nerves and
the spinal nerves respectively.
(n) The cranial nerves supply the head and neck only.
Text 57: Connective Tissue
Connective tissue is primarily the supporting tissue of the body, acting as a packing material and
binding together the various bodily structures. There are several types of connective tissue, but
all are characterized by a large amount of intercellular matrix, which is mainly of a fibrous
nature. The cells which are scattered throughout the tissue are important only in that they
46
produce and maintain the matrix, and it is according to the structure and consistency of the
matrix that the tissues are classified.
The fibres found in connective tissue are chiefly of two kinds, collagenous and elastic.
Collagenous fibres are delicate wavy fibres which individually present an almost colourless
appearance but in mass make up a white tissue. The tissue is very tough, and particularly
resistant to tensile stress. The fibres are arranged in bundles, within which they run a wavy
course parallel to each other. Elastic fibres are yellow in colour, and unlike the white fibres
they run singly, branching frequently and anastomosing with each other.
Various types of cell are found in connective tissue, but the most important of these are the
fibroblasts, histiocytes and fat cells. Fibroblasts are flat, star-shaped cells with a large nucleus
and fairly clear cytoplasm. They are stationary cells, concerned with the production of
collagenous fibres. Histiocytes, on the other hand, have phagocytic properties, i.e. they are
able to ingest foreign material. They have also the power of amoeboid movement, and may
move about the tissue, removing cell debris from the tissue spaces. Histiocytes have a smaller
nucleus than that of the fibroblasts, and the cytoplasm is generally filled with granules and
vacuoles, which are a result of their phagocytic activity. Fat cells consi st mainly of a large
droplet of fat, surrounded by a thin envelope of cytoplasm. The cells are usually so swollen
with the fat that the nucleus is pushed to one side. Fat cells are normally arranged to form a
lobule, which is enclosed by a delicate collagenous sheath.
Fat cells are found in a tissue of few fibres, called adipose tissue. This is found in specific
areas of the body, e.g. the superficial fascia and the mesenteries of the peritoneum.
Other kinds of connective tissue are largely differentiated by the amount and proportion of the
collagenous and elastic fibres they contain. Collagenous fibres are found pure in tendons and
elastic fibres are found almost pure in certain ligaments, but most connective tissue is made
up of a mixture of collagenous and elastic fibres, with collagenous fibres predominating. The
total amount of fibres varies also. A loose network of white and yellow fibres lying on a
gelatinous base is known as areolar tissue. Areolar tissue lies between structures, holding
them in place. Sheaths, septa and capsules surrounding various muscles, glands, etc. are
formed by a very dense fibrous tissue.
Cartilage and bone are commonly considered to be very firm connective tissue. The fibres in
cartilage lie in a ground substance which is rubbery and resilient. The matrix of bone is
hardened by lime salts, mainly calcium phosphate.
Text 58: Techniques in the Studr of Cell Structure
Microscopic anatomy can be divided into two main parts: the study of tissues taken after
death and the study in vivo or in vitro of living tissues. In the study of tissues taken after death
the use of stains is of fundamental importance. Because particular types of cells and structures
within the cells attract particular dyes, the physical characteristics of many cel lular elements
are easily differentiated. Structures which are invisible because their refractility equals that of
their surrounding medium may often be defined by staining.
Histochemistry is the study of the chemical constituents of cells and tissues, the ir distribution
and function. It depends in large part on the use of selective stains. For example, acid
substances in the nucleus of a cell attract basic dyes. It is said that these acids have the
property of basophilia. A further distinction can be made between desoxyribonucleic acid and
ribonucleic acid. The former can be traced by the Feulgen Method, while the latter reacts to
an enzyme. Spectrographic methods can be used to determine the quantity of these chemicals
and changes in their distribution during cell activity. Rates of absorption, solubility and actual
chemical combination provide valuable data.
In addition to selective staining, it is possible to study certain tissues with the help of metallic
salts. Some elements attract deposits of these salts, but since many reagents act both by staining
and by impregnation with deposits, it is difficult to separate the two processes.
47
Tissues fixed and stained after death are usually studied in the form of film preparations or
sections. The specimen is frozen or sealed in paraffin or celloidin. A microtome is used to cut
the extremely thin sections required for microscopic examination. The preparation of a
microscopic section necessarily involves some distortion of the cell from its living counterpart.
Histological techniques involved in the investigation of the detailed anatomy of organs and
tissues and especially of embryonic development often depend on the use of serial sections and
enlarged models reconstructed from the sections. Serial sections can be prepared of embryos at
different stages of development. Each series of sections records one particular phase. When
placed in order the series shows the progressive elaboration of an embryo at different ages.
Large scale models can then be made of each section and these fitted together to give a threedimensional reconstruction of the embryo.
The study of tissues in vivo is the direct examination of living cells in situ by special optical
methods. The translucent organs of amphibians and larvae have been extensively studied of late,
as have the fluids and cellular structures visible through the membranes of anaesthetized
animals. It is also possible today to construct a viewing chamber using thin plates of mica or
plastic secured to test animals. Non-toxic dyes can be injected as an aid to examination and
such a chamber can be observed over considerable periods of time. Since cells and tissues are in
a state of continual activity and change, the value of such observations of living processes
cannot be overestimated.
Considerable advances in culture technique have increased the importance of the study of
tissues in vitro. Fresh tissue is placed in a suitable nutrient material and then aseptically sealed.
Successful cell culture depends on an acceptable nutrient, careful temperature control, frequent
cleansing away of metabolites, and growth stimulation by feeding embryonic extracts.
Examination in vitro is particularly valuable for muscle, nerve and epithelial tissue. It is also
possible to cultivate embryonic forms of whole organs such as the eye and the internal ear.
48
Dr. Selçuk SÖZER
Text 59:
MEDICINE
The Art of Science
Medicine is a branch of health science concerned with restoring and maintaining health and
wellness. Broadly, it is the practical science of preventing and curing diseases. However, medicine
often refers more specifically to matters dealt with physicians and surgeons.
Medicine is both an area of knowledge (a science), and the application of that knowledge (the
medical profession). The various specialized branches of the science of medicine correspond to
equally specialized medical professions dealing with particular organs or diseases. The science of
medicine is the body of knowledge about body systems and diseases, while the profession of
medicine refers to the social structure of the group of people formally trained to apply that
knowledge to treat disease.
There are traditional and schools of healing which are usually not considered to be part of (Western)
medicine in a strict sense. The most highly developed systems of medicine outside of the Western
or Hippocratic tradition are the Ayurvedic school (of India) and traditional Chinese medicine. The
remainder of this focuses on modern (Western) medicine.
The World Health Organization defines health as:
"A state of complete physical, mental and social well-being, and does not consist only of the
absence of disease or infirmity."
History of medicine
All human societies have medical beliefs - birth, death, disease and cures are explained in some
manner. Historically, throughout the world illness has often been attributed to witchcraft, demons or
the will of the gods, ideas that still retain some power, even in 'modern' societies, with faith-healing
and shrines still common. Modern medicine.
Medicine was revolutionized in the 18th century and beyond by advances in chemistry and
laboratory techniques and equipment, old ideas of infectious disease epidemiology were replaced
with bacteriology developed by Robert Koch and Louis Pasteur. For the first time actual cures were
developed for certain endemic infectious diseases. However the decline in the most lethal diseases
was more due to improvements in public health and nutrition than to medicine. It was not until the
20th century that there was a true breakthrough in medicine, with great advances in pharmacology
and surgery.
From 20th century we have witnessed a shift from a master-apprentice paradigm of teaching of
clinical medicine to a more "democratic" system of medical schools. With the advent of the
evidence-based medicine and great advances of information technology the process of change is
likely to evolve further. The evidence-based medicine has had a great impact on practice of
medicine throughout the world of modern medicine.
Modern western medicine, despite the hypochondria of western society, is uniquely effective and
widespread compared with all other medical forms. It is notably secular and material, indifferent to
ideas of the supernatural or the spirit and concentrating on the body to determine causes and cures.
The harsh scientific nature of modern medicine is the pinnacle of a very narrow concern, a
particular aspect of the human condition has been exulted at the cost of considerable social disquiet,
18th and 19th century concerns about body-snatching and attacks at doctors for 'playing god' in the
20th century. And the capabilities of modern medicine have done little to improve the lot of poorer
countries.
49
Text 60: BLOOD– A VERSATILE FLUID
What are the components of blood and what are their functions?
Blood is the source of life and of components that are essential to life. Thousands of years ago, long
before the development of medical science had begun, people already realised that blood is a vital
fluid. Since loss of blood could be fetal, it is not entirely illogical to suppose that administration of
blood may have the reverse effect.
In the epic of the Greek poet Homer, the hero Odysseus uses the blood of a ram to temporarily bring
the dead back to life. This demonstrates that the life-giving quilities of blood were recognised as
early as the ninth century BC.Traditionally regarded as’ breath of life’ for organs and tissues, blood
had a magical and symbolic association. This manifested itself most dominantly in blood sacrifices
to appease the gods. In traditional cultures, blood, is still used for special therapies, is drunk to cure
disease.
Fluid of Life
Blood is a versatile fluid. It has many different functions and it is therefore not surprising that it was
once called the ‘ fluid of life’. The key function of blood is to absorb oxygen in the lungs and
transport into all parts of the body. However, blood has many more functions, including the
transportation of nutrients, warmth, antibodies and hormons. Moreover, waste products from the
body are removed via the blood.
In 1637, William Harvey, accurately described the circulatory system and the central role of the
heart. The circulatory system comprises an extensively branch system of tubes. The heart pumps
blood through the body with great pressure in approximately 30 seconds. We distunguish between
the pulmonary and systemic circulation.
The pulmonary circulation transports blood from the hearth to the lungs, where the blood absorbs
oxygen and releases carbon dioxide (CO2). Thereafter the blood is returned to the heart.The
oxygenated blood then travels through the systemic circulation. The heart pumps the blood to all of
the organs via the major arteries,which branch into increasingly fine tubes, enabling the blood to
provide oxygen to all tissues. From the tissues, the oxygenated blood flows back to the heart via the
veins to again become part of the pulmonery circulation
The body of an adult human being contains five to six liters of blood, which is usually around 7.5
% of our total body weight. For example, a person weighing 75 kg has approximately 5.6 liters of
blood (one litre of blood weighs roughly one kilogram). Blood consists of cells and fluid (plasma).
There are three types of blood cells (erythrocytes), white blood cells (leukocytes and platelets
(trombocytes). Blood cells are produced in the red bone marrow, from where they are released into
the blood stream. In the fluid part of the blood, called plasma,blood cells are transported throughout
the body. Plasma contains a great variety of unique constituents.
Text 61: LEUKEMIA
Leukemia has been known for nearly 150 years and chronic myeloid leukemia (CML) was probably
the first form of leukemia to be recognized, as a distinct disease. It is now identified as a malignant
clonal multi-lineage myeloproliferative disease of hematopoietic stem cells characterized by a
differentiation block that leads to the accumulation of a large number of immature hematopoietic
cells in the bone marrow and the peripheral blood. The uncontrolled growth of malignant cells
impairs normal hematopoiesis leading to the clinical manifestations of the disease.
In the literature, the disease was first mentioned in 1845. There were two patients, described as
having massive splenomegaly associated with leukocytosis. At that time it seemed to be a novel
disease not explained by the other causes of splenomegaly and thought as a suppurative disease of
the blood. But the first important clue to its pathogenesis came very much later in 1960 by Nowell
and Hungerford who detected a consistent chromosomal abnormality and identified 22q. In 1973,
50
Rowley observed a constant chromosomal abnormality and termed as Philadelphia (Ph+, or just Ph)
chromosome, resulted from a reciprocal translocation that also involved chromosome 9; now, the
abnormality is designated as t(9;22)(q34;q11). And finally in the 1980s, the Ph chromosome was
shown to carry a unique fusion gene, termed BCR/ABL, the generation of which is now believed to
be the principal cause of the chronic phase of CML.
The story of CML expanded more when scientists were curious about the origin of the BCR/ABL
translocation and studies eventually combined with stem cell research. Many theories were
proposed but not many answers were available about how and when leukemia starts
It is generally believed that CML develops when a single, pluripotential, hematopoietic stem cell
acquires a translocation that creates a BCR/ABL fusion gene, which provides a proliferative
advantage to its progeny over normal hematopoietic cells. Thus allows the Ph-positive clones to
gradually displace residual normal hematopoiesis and manifest the disease. The consistent
molecular abnormality seen in any given patient is the evidence for this hypothesis, but the
mechanism by which the molecular and cytogenetic changes occur remains unknown.
The first experimental evidence to indicate the existence of hematopoietic stem cells (HSCs) was
the discovery in 1961 by Till and McCulloch. They found a population of clonogenic bone marrow
cells capable of generating myelo-erythroid colonies in the spleen of lethally irradiated recipients.
Furthermore, these colonies contained clonogenic cells that were capable of reconstituting the
immune system when they retransplanted into lethally irradiated secondary recipients and these
were proposed to be HSCs 6. The recent development of clonal assays, like methyl cellulose based
assays, for all major hematopoietic lineages, in addition to the availability of multiparameter
fluorescence-activated cell sorting (FACS), has facilitated the purification of HSCs from mice and
humans according to the cell-surface expression of specific molecules and their functional read-out
in vivo and in vitro 7 and opened a new era in stem cell research. After the identification and
prospective isolation of murine HSCs, considerable progress has been made towards the
characterization of the mechanisms that control their fates and homeostasis of the stem cell pool.
Moreover, now the availability of microarray technology provides more precise transcriptional
analysis of the early molecular events in stem cell field.
Stem cell regulation is a critical element in the control of normal hematopoiesis. Throughout life,
the process of hemopoiesis (from the Greek haima meaning blood and poiesis meaning production)
maintains the body’s requirements to produce the mature effector cells of the blood. In the steady
state, there is a tight regulatory control of this process and many of the factors involved like soluble
factors (colony stimulating factors (CSFs), and negative regulators), in addition to cell–cell and
cell–stromal interactions. All of these function to regulate HSC’s self renewal, proliferation and
differentiation. This finely tuned machinery maintains a steady-state level of functional HSCs in the
bone marrow and constantly provides progenitors for the various hematopoietic lineages.
Currently stem cells are defined as a single cell that is a clonal precursor of both more stem cells of
the same type as well as a defined set of differentiated progeny. The hierarchy starts when a stem
cell gives rise to self renewing oligolineage progenitors, which in turn give rise to progeny that are
more restricted in their differential potential, and finally to functionally mature cells. All stem cells
must self-renew and regulate the relative balance between self-renewal and differentiation. Selfrenewal without differentiation maintains the stem cell pool where as capability of differentiation
and pluripotency allows the efficient expansion of multiple cell phenotypes from a restricted stem
cell compartment that could satisfy the homeostasis. The process starts during or after cell division
when the two daughter cells of a stem cell each have to decide their fate. They have three options;
they can either choose to remain as HSCs, commit to differentiation, or die by apoptosis. Moreover,
they have to decide their future localization, to stay in the bone marrow or migrate to the periphery.
These processes of cell-fate decisions are critical for maintaining the numbers of normal
functioning HSCs in the bone marrow pool that will constantly provide progenitors for the various
hematopoietic lineages. The hierarchy of blood cell development from a hematopoietic stem cell
follows a pattern of increasing lineage commitment and decreasing self-renewal and differentiation
potential.
51
Text 62: Cancer and Aging
Cancer is an indiscriminate disease that can affect any human being. One in three people will get
cancer in their lifetime. However, the incidence of cancer greatly increases with age. It is estimated
that 60% of all cancers occur in people aged 65 or older. Although age is the most important factor,
it is not the sole determinant of cancer. There are many genetic and epigenetic factors that
contribute to the formation of cancer.
Cancer is an indiscriminate disease that can affect any human being. One in three people will get
cancer in their lifetime
In the next 25 years, the elderly population (>65 years of age) is expected to increase to 20% of the
total population of the U.S., up from 13% in 2000. As the elderly population increases, the
incidence of cancer in the elderly is also expected to increase. Aging is a complex and highly
individualized process, reflecting chronologic, as well as physiologic, age. Chronologic age, by
itself, does not accurately mirror the aging process. True aging reflects physiologic changes in the
body that affect function and form. Although aging is common to everyone, aging affects
individuals differently and at different paces.
Text 63: Physiological Foundation of Aging
Aging is a highly individualized, multidimensional process that is associated with changes in the
genetics, biochemistry, physiology, and anatomy of the body. As the body ages, deterioration
occurs in functional, emotional, socioeconomic, and cognitive areas . Functional status is a
benchmark of overall health and independence. Aging directly correlates with declining functional
status and increased functional dependency. Aging is also associated with the increased likelihood
of developing concurrent diseases, called comorbidities, and diseases which are typically linked to
aging, known as "geriatric syndromes" . Comorbidities complicate the overall health of the elderly
and significantly increase with advancing age. On average, people aged 65 and older report three
different, concurrent diseases . The most common comorbid diseases are depression, arthritis, and
cardiovascular disease. Both functional dependence and comorbidity are associated with a shorter
life expectancy .
Text 64: Cancer: Acute Aging
Many molecular mechanisms emphasize the association between aging and cancer. The
carcinogenic process involves genetic and epigenetic abnormalities to cells resulting in altered cell
functions. The age-related incidence of malignancy reflects the complexity of the carcinogenic steps
that are required in their development . Cancers are thought to arise through a stepwise
accumulation of mutations that favor uncontrolled cell growth, prevent apoptosis, recruit a blood
supply, avoid the immune system, and spread or metastasize .
Cancer is thought to be inherent to long-lived organisms, since they need to use continuous cell
growth for the development and maintenance of tissues and organs. Proliferating cells are more
prone to DNA damage and the acquisition of genetic instability than quiescent cells. This can result
in the occurrence of mutations that promote uncontrolled cell proliferation. In order to achieve
immortalization, such cells need to circumvent two failsafe mechanisms, replicative senescence
(cell aging) and cellular crisis, that are controlled by telomere shortening and the p53 and Rb tumorsuppressor pathways. Telomeres are nucleoprotein structures that cap chromosome ends and play an
important role in preventing chromosomal erosion. In most normal cells, telomeres shorten with
each cell division . Ultimately, this "mitotic clock" leads to cell senescence when telomere length
reaches a certain size . Activation of the p53 and Rb tumor-suppressor pathways plays an important
role in cell senescence and, subsequently, the elimination of cells with eroded, unstable
chromosomes. Unstable chromosomes are prone to chromosomal degradation, rearrangements,
aberrant fusion, and genetic instability, which are perpetuated by the loss of the p53 and Rb tumorsuppressor genes. Additionally, cancers can circumvent telomere shortening and senescence by
constitutively activating telomerase, a specialized reverse transcriptase enzyme that maintains and
52
extends the telomeric ends. Most human cells have low telomerase activities and, thus, limited
replication potentials.
Recent research in mice points to another connection between cancer and aging. Mice engineered to
upregulate activity of the p53 tumor-suppressor gene have a lower incidence of cancer
development. However, this comes at the price of premature aging and death. Thus, it appears that
the same mechanisms that protect us from cancer also contribute to aging. Tissue microenvironment
also plays an important role in the manifestation of cancer physiology. Autopsies of individuals
who died from trauma often reveal microscopic cancerous lesions. However, the incidence of
cancer among individuals of the same age is significantly lower, suggesting that the majority of
people carry microscopic lesions that do not manifest themselves as clinically recognizable cancer.
Folkman and Kalluri attribute this phenomenon to the body’s intrinsic capacity to prevent growth of
microscopic tumors through the control of angiogenesis and the activation of immune defenses . It
is possible that age-associated decline in overall health creates a microenvironment that fails to
suppress cancer growth.
Ageism is rooted in language, attitudes, beliefs, behaviors, and policies.
Healthy cellular and organism functions reflect a tension between cell proliferation and cell
senescence. Investigation of the paradox that cellular aging is also the trigger for the common
cancer is likely to contribute significantly to our understanding of tumor biology. Cell aging and
senescence may be the inherent defense mechanisms that prevent uncontrolled cell proliferation.
When senescence fails, cancer prevails.
Ageism
Ageism is defined as "prejudice toward, stereotyping of, and/or discrimination against any person or
persons directly and solely as a function of their having attained a chronological age which the
social group defines as old" .
Text 65: Collusion: The Unspoken Agreement
Collusion is a secret agreement or cooperation especially for a deceitful or illegal purpose.In this
case, collusion involves the spoken and unspoken interactions between caregiver and patient that
enable them to avoid sensitive subjects and promote a false sense of hope for the patient. The
caregiver and patient may both be equally tempted to unrealistically deny the issues and overtreat,
or fatalistically limit treatment.
The et al. describe a variety of collusive actions that occur at different stages throughout the course
of small cell lung cancer. Such actions include the concealment of prognosis, emphasis on treatment
to the exclusion of other important issues, use of ambiguous language, and adherence to the
"recovery plot." These allow the caregiver to impart hope, while the patient feels empowered that
they are actively combating their disease.
Collusion can take on many forms, but its ultimate goal is to avoid addressing painful issues and
inevitable outcomes. Caregivers and patients actively participate in collusion, which is mutually
beneficial because "the physician does and does not want to pronounce a death sentence, and the
patient does and does not want to hear it".
53
III-IV YY Ders Notları
54
V-VI. YY Ders Notları
Dr. Engin ULUKAYA
Text 66: Understanding Lung Cancer -- An Overview
Introduction
Lung cancer remains the most frequent causer of cancer death in the world. Approximately
150,000 patients are killed by lung cancer annually in the United States. Lung cancer death
accounts for about 30% of all cancer deaths. In the past few years, lung cancer has surpassed breast
cancer as the number one cause of cancer death in women, and its incidence rates continue to
increase in female patients.
These are distressing figures given the fact that lung cancer would be rare if not for cigarette
smoking. More than 80% of lung cancer cases are related to smoking. Other important causes of
lung cancer include exposure to asbestos and Radon.
Lung cancer represents a major health problem not only in the United States, but also worldwide.
Most lung cancers begin to grow silently, without any symptoms. Patients with lung cancer often do
not develop symptoms until the cancer is in an advanced stage. Surgery, chemotherapy, and
radiotherapy has all be utilized in the treatment of lung carcinoma. However, the overall survival of
all lung cancer patients are essentially unchanged in the past two decades.
This information booklet has been written to help you understand more about carcinoma of the
lung. We hope it answers some of the questions you may have about its diagnosis and treatment,
and addresses some of the feelings which are a large part of anyone's reaction to the diagnosis of
lung cancer.
Risk Factors of Lung Cancer
Researchers have discovered several causes of lung cancer--most are related to the use of tobacco.
Cigarettes. Smoking cigarettes causes lung cancer. Harmful substances (carcinogens) in tobacco
damage cells in the lungs. Over time, the damaged cells may become cancerous. The likelihood that
a smoker will develop lung cancer is affected by the age at which smoking began, how long the
person has smoked, the number of cigarettes smoked per day, and how deeply the smoker inhales.
Stopping smoking greatly reduces a person's risk for developing lung cancer.
Cigars and Pipes. Cigar and pipe smokers have a higher risk of lung cancer than nonsmokers. The
number of years a person smokes, the number of pipes or cigars smoked per day, and how deeply
the person inhales all affect the risk of developing lung cancer. Even cigar and pipe smokers who do
not inhale are at increased risk for lung, mouth, and other types of cancer.
Environmental Tobacco Smoke. The chance of developing lung cancer is increased by exposure
to environmental tobacco smoke (ETS)--the smoke in the air when someone else smokes. Exposure
to ETS, or secondhand smoke, is called involuntary or passive smoking.
Radon. Radon is an invisible, odorless, and tasteless radioactive gas that occurs naturally in soil
and rocks. It can cause damage to the lungs that may lead to lung cancer. People who work in mines
may be exposed to radon and, in some parts of the country, radon is found in houses. Smoking
increases the risk of lung cancer even more for those already at risk because of exposure to radon. A
kit available at most hardware stores allows homeowners to measure radon levels in their homes.
The home radon test is relatively easy to use and inexpensive. Once a radon problem is corrected,
the hazard is gone for good.
Asbestos. Asbestos is the name of a group of minerals that occur naturally as fibers and are used in
certain industries. Asbestos fibers tend to break easily into particles that can float in the air and stick
55
to clothes. When the particles are inhaled, they can lodge in the lungs, damaging cells and
increasing the risk for lung cancer. Studies have shown that workers who have been exposed to
large amounts of asbestos have a risk of developing lung cancer that is 3 to 4 times greater than that
for workers who have not been exposed to asbestos. This exposure has been observed in such
industries as shipbuilding, asbestos mining and manufacturing, insulation work, and brake repair.
The risk of lung cancer is even higher among asbestos workers who also smoke. Asbestos workers
should use the protective equipment provided by their employers and follow recommended work
practices and safety procedures.
Pollution. Researchers have found a link between lung cancer and exposure to certain air
pollutants, such as by-products of the combustion of diesel and other fossil fuels. However, this
relationship has not been clearly defined, and more research is being done.
Lung Diseases. Certain lung diseases, such as tuberculosis (TB), increase a person's chance of
developing lung cancer. Lung cancer tends to develop in areas of the lung that are scarred from TB.
Medical History. A person who has had lung cancer once is more likely to develop a second lung
cancer compared with a person who has never had lung cancer. Quitting smoking after lung cancer
is diagnosed may prevent the development of a second lung cancer.
Symptoms and Signs of Lung Cancer
Common signs and symptoms of lung cancer include:
Persistent cough that gets worse over time
Hemoptysis (Coughing up blood)
Constant chest pain
Shortness of breath, wheezing, or hoarseness
Repeated problems with pneumonia or bronchitis
Swelling of the neck and face
Loss of appetite or weight loss
Fatigue
Diagnosing Lung Cancer
To help find the cause of symptoms, the doctor evaluates a person's medical history, smoking
history, exposure to environmental and occupational substances, and family history of cancer. The
doctor may also perform a physical exam, a chest x-ray, and may order other tests. If lung cancer is
suspected, sputum cytology (the microscopic examination of cells obtained from a deep-cough
sample of mucus in the lungs) is a simple test that may be useful in detecting lung cancer. To
confirm the presence of lung cancer, the doctor must examine tissue from the lung. A biopsy--the
removal of a small sample of tissue for examination under a microscope by a pathologist--can show
whether a person has cancer. A number of procedures may be used to obtain this tissue:
Bronchoscopy. The doctor puts a bronchoscope (a thin, lighted tube) into the mouth or nose and
down through the windpipe to look into the breathing passages. Through this tube, the doctor can
collect cells or small samples of tissue.
Needle aspiration. A needle is inserted through the chest into the tumor to remove a sample of
tissue.
Thoracentesis. Using a needle, the doctor removes a sample of the fluid that surrounds the lungs to
check for cancer cells.
Thoracotomy. Surgery to open the chest is sometimes needed to diagnose lung cancer. This
procedure is a major operation performed in a hospital.
Treatment for Lung Cancer
Treatment of lung cancer depends on a number of factors, including the type of lung cancer (NonSmall Cell versus Small Cell Lung Cancer), the stage of the disease, and the general health of the
patient. Treatment methods include surgery, chemotherapy, radiotherapy, or the combination of
different treatment methods have been used in the treatment of lung cancer.
56
Surgery is an operation to remove the cancer. Surgery is the standard treatment for early stage
cancers.
Physicians may choose to resect tumors up to stage III A.
The type of surgery a doctor performs depends on the location of the cancer in the lung. An
operation to remove only a small part of the lung is called a segmental or wedge resection. When
the surgeon removes an entire lobe of the lung, the procedure is a lobectomy. Pneumonectomy is
the removal of an entire lung. Unfortunately, the majority of tumors cannot be removed by surgery
because of the size or location, and some patients cannot have surgery for other medical reasons.
Chemotherapy is the use of anticancer drugs to kill cancer cells throughout the body. Even after
cancer has been removed from the lung, cancer cells may still be present in nearby tissue or
elsewhere in the body. Chemotherapy may be used to control cancer growth or to relieve symptoms.
Most anticancer drugs are given by injection into a vein (IV); some are given in the form of a pill.
Another way to get IV chemotherapy is by means of a catheter, a thin tube that is placed into a large
vein and remains there as long as it is needed.
Radiation therapy, also called radiotherapy, involves the use of high-energy rays to kill cancer
cells. Radiation therapy is directed to a limited area and affects the cancer cells only in that area.
Radiation therapy may be used before surgery to shrink a tumor, or after surgery to destroy any
cancer cells that remain in the treated area. Doctors also use radiation therapy, often combined with
chemotherapy, as primary treatment instead of surgery. Radiation therapy may also be used to
relieve symptoms such as shortness of breath. Radiation for the treatment of lung cancer most often
comes from a machine (external radiation). The radiation can also come from an implant (a small
container of radioactive material) placed directly into or near the tumor (internal radiation).
Photodynamic therapy is the use of a special chemical that is injected into the bloodstream and
absorbed by cells. The chemical rapidly leaves normal cells but remains in cancer cells for a longer
period of time. A laser light is pointed at the cancer to activate the chemical and kill the cancer cells
that have absorbed it. Photodynamic therapy is used for lung cancers that are localized. It is also
being studied for use in controlling symptoms in advanced cases when tumors are pressing against
other organs, or when patients are too sick to receive other therapies.
Abstracts
Abstract 1: Interference by anti-cancer chemotherapeutic agents in the MTT-tumor
chemosensitivity
assay
Background: One of the major goals of oncology is to predict the response of patients with cancer
to chemotherapeutic agents by employing laboratory methods variously called 'tumor
chemosensitivity assays', 'drug response assays', or 'drug sensitivity assays', in vitro. The MTT
assay is one of the methods used to predict the drug response in malignancies. However, it may
suffer from interference by the anticancer drugs with the MTT assay. Methods: The MTT assay, a
colorimetric viability assay, was checked in a cell-free system in terms of its possible chemical
interactions with 22 different anticancer drugs. Results: It was found that epirubicine, paclitaxel,
doxetaxel, and cisplatin caused a relatively significant increase in absorbance values, resulting in
the MTT assay giving rise to false results (untrue increase in viability) although most of the drugs
tested did not seem to cause any significant change. Conclusion: It was concluded that before
employing the MTT assay, drugs (or any kind of substances) to be included in the assay should be
checked first in terms of possible chemical interactions with MTT, otherwise it may be impossible
to evaluate the MTT viability assay results correctly.
Abstract 2: Biological, histological, and clinical impact of preoperative IL-2 administration in
radically operable gastric cancer patients.
BACKGROUND AND OBJECTIVES: Surgery induces lymphocytopenia and this decrease of host
defenses, related to interleukin-2 (IL-2) endogenous imbalance during postoperative period could
promote the proliferation of possible micrometastases and the implantation of surgically
disseminated tumor cells. Moreover, tumor infiltrating lymphocytes (TILs), activated by
endogenous IL-2 release, are linked to prognosis in cancer patients. The aim of this randomized
57
study is to assess the biological (peripheral blood cells count, related to the grade of
immunosuppression), histological (TILs), and clinical (overall and disease-free survival) impact of
preoperative low doses administration of IL-2 in patients with radically operable gastric cancer.
METHODS: This prospective study enrolled 69 consecutive patients with histologically proven
gastric adenocarcinoma who underwent radical surgery from October 1999 to December 2002 (M/F
39/30; mean age 66; range 42-82) who underwent radical surgery from October 1999 to December
2000. Patients were randomized to be treated with surgery alone as controls (35 patients) or surgery
plus preoperative treatment with recombinant human IL-2 (34 patients). We considered the total
lymphocyte count and lymphocyte subset (CD4, CD4/CD8) during the preoperative period, before
IL-2 administration, and on the 14th and 50th day, peritumoral stromal (fibrosis) reaction,
neutrophils, lymphocytes, and eosinophils infiltration in tumor histology, and morbidity disease free
and overall survival were evaluated. RESULTS: Two groups were well matched for type of surgery
and extent of disease. All the patients underwent radical surgery plus D2 lymphadenectomy. At
baseline, there were no significant differences in total lymphocyte and lymphocyte subsets between
groups. The control group showed a significant decrease of total lymphocytes, CD4 cells, and
CD4/CD8 ratio at the 14th postoperative day relative to the baseline value. In the control group
65% of patients had a decrease of CD4 under 500 cells/mmc. Instead it has been observed in IL-2
group a significant increase over the control group values of total lymphocytes and CD4 cells (14th
total lymphocytes and CD4: IL-2 vs. control P < 0.05). Moreover in this group only 15% patients
had CD4 under 500 cells/mmc. This difference, in CD4 count, is significant even at the 50th
postoperative day (P = 0.006). IL-2 group showed lower postoperative complications (2/34 vs.
11/35; P < 0.05), and higher lymphocyte/eosinophil infiltration into the tumor (P < 0.0002). Median
follow-up was 26 months (range 10-48) and median overall and disease-free survivals were longer,
even if not significantly, in the IL-2 group than in the control arm (P = 0.07 and P = 0.06
respectively). CONCLUSIONS: This randomized study would suggest that a preoperative
immunotherapy with IL-2 is a well-tolerated treatment able to prevent surgery-induced
lymphocytopenia. IL-2 seems to neutralize the immunosuppression induced by operation and so to
stimulate the host reaction against tumor tissue (lymphocytes/eosinophils infiltration). Furthermore
IL-2 seems to have an impact on clinical course reducing morbidity of surgery and ameliorating
overall and disease-free survival.
Abstract 3: 4-(N-hydroxyphenyl)retinamide can selectively induce apoptosis in human
epidermoid carcinoma cells but not in normal dermal fibroblasts
The retinoid 4-(N-hydroxyphenyl)retinamide (4HPR, fenretinide) has both growth inhibitory and
apoptosis-inducing effects on a number of cancer cell lines in vitro and in vivo and has been entered
into a number of oncological trials. However, little is known about its mechanism(s) of action or its
effects on normal cells such as fibroblasts. In this study, the effects of fenretinide on both
epidermoid carcinoma cells of vulva (cell line A431) and normal human dermal fibroblasts, both as
monolayers and also grown in 3D cell culture systems, have been investigated. The 3D cell culture
system contained normal human fibroblasts embedded in a type I collagen gel with the carcinoma
cells seeded on top of the collagen gel, which mimics the epidermoid carcinoma. Fenretinide
significantly inhibited the rate of DNA synthesis of carcinoma cells, while there was little effect on
fibroblasts on monolayers, at 10(-6)-10(-5) M, which are clinically attainable doses. Fenretinide at 5
x 10(-6) M induced apoptosis characterised by cell shrinkage, membrane blebbing, nuclear
condensation and/or fragmentation, and cell detachment in carcinoma cells, but not fibroblasts from
monolayers. Fenretinide also reduced the viability of carcinoma cells in the 3D cell culture system
without affecting fibroblasts. These data show that fenretinide may preferentially induce apoptosis
in epidermoid carcinoma cells.
Abstract 4: Cell Death Pathways in Pancreatitis and Pancreatic Cancer.
The understanding of the regulation of apoptosis and necrosis, the two principal cell death
pathways, is becoming exceedingly important in investigations of the pathogenesis and treatment of
58
pancreatitis and pancreatic cancer. For example, in acute pancreatitis significant amounts of
pancreatic necrosis are associated with increased morbidity and mortality. Thus, determining the
key steps regulating necrosis should provide insights into potential therapeutic strategies for
improving outcome in these patients. On the other hand, in pancreatic cancer various survival
mechanisms act to prevent cell death, resulting in promotion of tumor growth and metastasis.
Resistance of pancreatic cancer to apoptosis is the key factor preventing responses to therapies.
Investigations of the regulation of cell death mechanisms specific to pancreatic cancer should lead
to improvements in our current therapies for this disease. The present review is designed to provide
information about cell death pathways in pancreatitis and pancreatic cancer with reference to areas
that need further investigation, as well as to provide measurement techniques adapted to pancreatic
tissue and cells.
Abstract 5: Cycloxygenase-2 suppresses hypoxia-induced apoptosis via a combination of
direct and indirect inhibition of p53 activity in a human prostate cancer cell line.
Although p53 inactivating mutations have been described in the majority of human cancers, its role
in prostate cancer is controversial as mutations are uncommon, particularly in early lesions. p53 is
activated by hypoxia and other stressors, and is primarily regulated by the Mdm2 protein.
Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to
prostaglandins (PGs) and other eicosanoids, is also induced by hypoxia. COX-2 and resultant PGs
increase tumor cell proliferation, resistance to apoptosis, and angiogenesis. Previous reports indicate
a complex, reciprocal relationship between p53 and COX-2. To elucidate the effects of COX-2 on
p53 in response to hypoxia, we transfected the COX-2 gene into the p53-positive, COX-2 negative
MDA-PCa-2b human prostate cancer cell line. The expression of functional p53 and Mdm2 was
compared in COX-2+ vs. COX-2- cells, under normoxic and hypoxic conditions. Our results
demonstrate that hypoxia increases both COX-2 protein levels and p53 transcriptional activity in
these cells. Forced expression of COX-2 increased tumor cell viability and decreased apoptosis in
response to hypoxia. COX-2+ cells had increased Mdm2 phosphorylation in either normoxic or
hypoxic conditions. Overexpression of COX-2 abrogated hypoxia-induced p53 phosporylation and
promoted the binding of p53 to Mdm2 protein in hypoxic cells. In addition, COX-2 expressing cells
exhibited decreased hypoxia-induced nuclear accumulation of p53 protein. Finally, forced
expression of COX-2 suppressed both basal and hypoxia-induced p53 transcriptional activity and
this effect was mimicked by the addition of PGE2 to wild-type cells. These results demonstrate a
role for COX-2 in the suppression of hypoxia-induced p53 activity via both direct effects and
indirect modulation of Mdm2 activity. These data imply that COX-2 positive prostate cancer cells
can have impaired p53 function even in the presence of wild-type p53 and that p53 activity can be
restored in these cells via inhibition of COX-2 activity.
Abstract 6: Assessment of IAP (inhibitor of apoptosis) proteins as predictors of response to
chemotherapy in advanced non-small-cell lung cancer patients
BACKGROUND: Expression of inhibitor of apoptosis family proteins (IAPs) has been shown in
vitro to decrease chemosensitivity through caspase inhibition. However, the role of IAPs as
predictors of response to chemotherapy in cancer patients remains to be determined. PATIENTS
AND METHODS: Using immunohistochemistry, we assessed the expression of the IAP proteins cIAP1, c-IAP2, and XIAP on tumors from 55 patients with advanced non-small-cell lung cancer
(NSCLC) treated with chemotherapy, and correlated that with the observed response to
chemotherapy, time to progression and overall survival.
RESULTS: Differences were observed in the pattern of staining among the IAP proteins. The
expression of c-IAP2 and XIAP was exclusively cytoplasmic. whereas c-IAP1 also displayed
nuclear staining. The median expression of tumor cells for c-IAP1, c-IAP2, and XIAP was 70%,
45%, and 25%, respectively, and a correlation was observed between c-IAP1 and c-IAP2 (P =
0.004), and c-IAP1 and XIAP expression (P = 0.013). However, no association was seen between
the expression of these proteins and sex, age, tumor size, stage, histology and grade of
59
differentiation. Interestingly, expression of c-IAP1, c-IAP2, and XIAP did not predict response to
chemotherapy. In addition, the expression of IAPs had no impact on the time to progression or
overall survival of this group of patients.
CONCLUSIONS: Our results indicate that: 1) there are differences in the level of expression and in
the subcellular distribution of c-IAP1, c-IAP2, and XIAP in tumors derived from NSCLC patients.
2) The expression of c-IAP1, c-IAP2 and XIAP does not predict the response to chemotherapy in
patients with advanced NSCLC. 3) The relation between expression of IAPs and chemosensitivity
in cancer patients may be more complex than anticipated by in vitro data.
60
Dr. Fadıl ÖZYENER
Text 67: Osteoporosis Overview
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural
deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures of
the hip, spine, and wrist. Men as well as women suffer from osteoporosis, a disease that can be
prevented and treated.
Prevention
To reach optimal peak bone mass and continue building new bone tissue as you get older, there are
several factors you should consider:
Calcium. An inadequate supply of calcium over the lifetime is thought to play a significant role in
contributing to the development of osteoporosis. Many published studies show that low calcium
intakes appear to be associated with low bone mass, rapid bone loss, and high fracture rates.
National nutrition surveys have shown that many people consume less than half the amount of
calcium recommended to build and maintain healthy bones. Good sources of calcium include low
fat dairy products, such as milk, yogurt, cheese and ice cream; dark green, leafy vegetables, such as
broccoli, collard greens, bok choy and spinach; sardines and salmon with bones; tofu; almonds; and
foods fortified with calcium, such as orange juice, cereals and breads. Depending upon how much
calcium you get each day from food, you may need to take a calcium supplement.
Calcium needs change during one's lifetime. The body's demand for calcium is greater during
childhood and adolescence, when the skeleton is growing rapidly, and during pregnancy and
breastfeeding. Postmenopausal women and older men also need to consume more calcium. This
may be caused by inadequate amounts of vitamin D, which is necessary for intestinal absorption of
calcium. Also, as you age, your body becomes less efficient at absorbing calcium and other
nutrients. Older adults also are more likely to have chronic medical problems and to use
medications that may impair calcium absorption.
Vitamin D. Vitamin D plays an important role in calcium absorption and in bone health. It is
synthesized in the skin through exposure to sunlight. While many people are able to obtain enough
vitamin D naturally, studies show that vitamin D production decreases in the elderly, in people who
are housebound, and during the winter. These individuals may require vitamin D supplementation
to ensure a daily intake of between 400 to 800 IU of vitamin D. Massive doses are not
recommended.
Exercise. Like muscle, bone is living tissue that responds to exercise by becoming stronger. The
best exercise for your bones is weight-bearing exercise, that forces you to work against gravity.
These exercises include walking, hiking, jogging, stair-climbing, weight training, tennis, and
dancing.
Smoking. Smoking is bad for your bones as well as for your heart and lungs. Women who smoke
have lower levels of estrogen compared to nonsmokers and frequently go through menopause
earlier. Postmenopausal women who smoke may require higher doses of hormone replacement
therapy and may have more side effects. Smokers also may absorb less calcium from their diets.
Alcohol. Regular consumption of 2 to 3 ounces a day of alcohol may be damaging to the skeleton,
even in young women and men. Those who drink heavily are more prone to bone loss and fractures,
both because of poor nutrition as well as increased risk of falling.
Medications that cause bone loss. The long-term use of glucocorticoids (medications prescribed for
a wide range of diseases, including arthritis, asthma, Crohn's disease, lupus, and other diseases of
the lungs, kidneys, and liver) can lead to a loss of bone density and fractures. Other forms of drug
therapy that can cause bone loss include long-term treatment with certain antiseizure drugs, such as
phenytoin (Dilantin®) and barbiturates; gonadotropin releasing hormone (GnRH) analogs used to
treat endometriosis; excessive use of aluminum-containing antacids; certain cancer treatments; and
61
excessive thyroid hormone. It is important to discuss the use of these drugs with your physician,
and not to stop or alter your medication dose on your own.
Prevention Medications. Various medications are available for the prevention, as well astreatment,
of osteoporosis. See section entitled "Therapeutic Medications."
Symptoms
Osteoporosis is often called the "silent disease" because bone loss occurs without symptoms. People
may not know that they have osteoporosis until their bones become so weak that a sudden strain,
bump, or fall causes a hip fracture or a vertebra to collapse. Collapsed vertebra may initially be felt
or seen in the form of severe back pain, loss of height, or spinal deformities such as kyphosis, or
severely stooped posture.
Treatment
A comprehensive osteoporosis treatment program includes a focus on proper nutrition, exercise, and
safety issues to prevent falls that may result in fractures. In addition, your physician may prescribe a
medication to slow or stop bone loss, increase bone density, and reduce fracture risk.
Nutrition. The foods we eat contain a variety of vitamins, minerals, and other important nutrients
that help keep our bodies healthy. All of these nutrients are needed in a balanced proportion. In
particular, calcium and vitamin D are needed for strong bones as well as for your heart, muscles,
and nerves to function properly.
Exercise. Exercise is an important component of an osteoporosis prevention and treatment program.
Exercise not only improves your bone health, but it increases muscle strength, coordination, and
balance and leads to better overall health. While exercise is good for someone with osteoporosis, it
should not put any sudden or excessive strain on your bones. Asextra insurance against fractures,
your doctor can recommend specific exercises to strengthen and support your back.
Therapeutic Medications. Currently, alendronate, raloxifene and risedronate are approved by the U.
S. Food and Drug Administration (FDA) for the prevention and treatment of postmenopausal
osteoporosis. Teriparatide is approved for the treatment of the disease in postmenopausal women
and men who are at high risk for fracture. Estrogen/hormone therapy (ET/HT) is approved for the
prevention of postmenopausal osteoporosis, and calcitonin is approved for treatment. In addition,
alendronate is approved for the treatment of osteoporosis in men, and both alendronate and
risedronate are approved for use by men and women with glucocorticoid-induced osteoporosis.
Abstracts:
Abstract 7: Oxygen Uptake Kinetics during Ramp-Incremental and Step-Decremental Cycle
Ergometry.
The Vo2 response to ramp-incremental cycle ergometry typically demonstrates the lagged-linear
first-order kinetics with a slope of ~10 ml/min/W, both above and below the lactate i.e. there is no
discernible Vo2 slow component (“excess” Vo2
L. We were interested in determining if a
reverse ramp profile would yield the same response dynamics. Ten healthy males (21-58 yr)
performed a maximum incremental ramp (IR) (15 W/min). On another day, the work rate was
increased abruptly to that maximum value, and then decremented at the same rate of 15 W/min
(DR). Five subjects also performed a submaximal DR test from 50 % of the peak power. Vo2 was
determined breath-by-breath. The IR Vo2 slope was 10.3 ± 0.7 ml/min/W, whereas the slope of the
descending limb of the DR was 14.2 ± 1.0 ml/min/W (p<0.005). The submaximal DR slope,
however, was only 9.8 ± 0.9 ml/min/W: not significantly different from that of the IR. This suggests
that the Vo2 response in the supra- L domain of the IR manifests not actual but pseudo-first- order
kinetics.
62
Abstract 8: The Effect of Chronic Smoking on Pulmonary Oxygen Uptake Kinetics during
Cycling Exercise.
It has been reported that acute smoking slows the pulmonary O2 uptake (VO2) kinetics and
decreases maximal VO2
no alteration on VO2max kinetics as an effect of chronic smoking in elite sportsmen (e.g. Morton &
Holmik, 1985), the data regarding sedentary subjects are more controversial.
This study is, therefore, designed to examine the effect of chronic smoking (on average at least 15
daily cigarettes past 12 months) on VO2 kinetics in sedentary subjects. Six healthy, male nonsmokers (NS, aged 20.8 ± 1.3 years); and 6 healthy chronic smokers (S, aged 20.6 ± 1.9 years)
participated in this study. After providing signed informed consent as approved by the Institutional
Ethics Committee, each subject initially performed ramp-incremental cycle ergometry to the limit
of tolerance for estimation of work loads and VO2max. On different days, subjects subsequently
completed square-wave exercise of three different intensities: 2 sub-maximal (50 and 80 % of
VO2max); and 1 supra-maximal (110 % VO2max); each for 15 min or to the limit of tolerance, (which
ever was reached first). Pulmonary O2 uptake was determined breath-by-breath throughout exercise
from the continuous monitoring of respired volumes (flowmeter; Sensor Medics, USA) and gas
concentration (metabolic analyser; Sensor Medics 2900C, USA). ANOVA and Mann-Whitney
tests were used to analyse the results.
Smokers and non-smokers did not differ significantly with respect to VO2max (31.7 ± 2,9 vs. 33.8 ±
2,8 ml.kg-1W-1, respectively). The time constant values for smokers (29  8.8 sec (± standard
deviation), 29.2 ± 8.5 sec and 24.2 ± 3.9 sec) were systematically longer, but not statistically
different, than the values for non-smokers (23.6 ± 6.0 sec, 23.8 ± 4.6 sec and 22.6 ± 5.8 sec) for 50,
80 and 110 %VO2max exercises, respectively. On the other hand, the gain (G1
2
50% VO2max was 10.2 ± 1.1 and 9.3 ± 0.7 ml.min-1W-1, for 80% VO2max was 8.7 ± 1.3 and 8.4 ±
1.1 ml.min-1W-1, and for 110% VO2max was 6.8 ± 1.2 and 7.3 ± 0.4 ml.min-1W-1 for S and NS,
respectively. Only the supramaximal value for S was significantly different from the others
(p<0.05).
In conclusion, our findings suggest that as the exercise increase in intensity, pulmonary O2 uptake
kinetics become more likely to be effected from chronic smoking -at least for this group.
Abstract 9: Negative accumulated oxygen deficit during heavy and very heavy intensity cycle
ergometry in humans.
The concept of the accumulated O2 deficit (AOD) assumes that the O2 deficit increases
monotonically with increasing work rate (WR), to plateau at the maximum AOD, and is based on
linear extrapolation of the relationship between measured steady-state oxygen uptake VO2 and WR
for moderate exercise. However, for high WRs, the measured VO2 increases above that expected
from such linear extrapolation, reflecting the superimposition of a "slow component" on the
fundamental VO2 mono-exponential kinetics. We were therefore interested in determining the effect
of the VO2 slow component on the computed AOD. Ten subjects (31 ± 12) years] performed
square-wave cycle ergometry of moderate (40%, 60%, 80% and 90% L), heavy (40%Delta), very
heavy (80%Delta) and severe (110% VO2peak) intensities for 10-15 min, where theta ( L) is the
estimated lactate threshold and Delta is the WR difference between L and VO2 peak. VO2 was
determined breath-by-breath. Projected "steady-state" VO2 values were determined from sub- tests.
The measured VO2 exceeded the projected value after approximately 3 min for both heavy and very
heavy intensity exercise. This led to the AOD actually becoming negative. Thus, for heavy exercise,
while the AOD was positive [0.63 (0.41) l] at 5 min, it was negative by 10 min [-0.61 (1.05) l], and
more so by 15 min [-1.70 (1.64) l]. For the very heavy WRs, the AOD was [0.42 (0.67) l] by 5 min
and reached -2.68 (2.09) l at exhaustion. For severe exercise, however, the AOD at exhaustion was
positive in each case: +1.69 (0.39) l. We therefore conclude that the assumptions underlying the
computation of the AOD are invalid for heavy and very heavy cycle ergometry (at least).
63
Physiological inferences, such as the "anaerobic work capacity", are therefore prone to
misinterpretation
Abstract 10: Chemoreflex drive and the dynamics of ventilation and gas exchange during
exercise at hypoxia.
We tested the hypothesis that the promotion of hypoxic ventilatory responsiveness (HVR) and/or
hypercapnic ventilatory responsiveness (HCVR) mostly acting on the carotid body with a changing
work rate can be attributed to faster hypoxic ventilatory dynamics at the onset of exercise. Eleven
subjects performed a cycling exercise with two repetitions of 6 minutes while breathing at FIO 12 =
12%. The tests began with unloaded pedalling, followed by three constant work rates of 40%, 60%,
and 80% of the subject's ventilatory threshold at hypoxia. Reference data were obtained at the 80%
ventilatory threshold work rate during normoxia. Using three inhaled 100% O2 breath tests, a
comparison of hypoxia and normoxia revealed an augmentation of HVR in hypoxia, which then
significantly increased proportionally with the increase in work rate. In contrast, HCVR using three
inhaled 10% CO2 breath tests was unaffected by the difference in work rate at hypoxia but did
exceed its level at normoxia. The decrease in the half-time of hypoxic ventilation became
significant with an increase in work rates and was significantly lower than at normoxia. Using a
multiregression equation, HVR was found to account for 63% of the variance of hypoxic ventilatory
dynamics at the onset of exercise and HCVR for 9%. O2 uptake on-kinetics and off-kinetics under
hypoxic conditions were significantly slower than under normoxic conditions, whereas they were
not altered by the changing work rates at hypoxia. These results suggest that the faster hypoxic
ventilatory dynamics at the onset of exercise can be mostly attributed to the augmentation of HVR
with an increase in work rates rather than to HCVR. Otherwise, O2 uptake dynamics are affected by
the lower O2, not by the changing work rates under hypoxic conditions.
Abstract 11: Capillaries within compartments: microvascular interpretation of dynamic
positron emission tomography data.
Measurement of exchange of substances between blood and tissue has been a long-lasting challenge
to physiologists, and considerable theoretical and experimental accomplishments were achieved
before the development of the positron emission tomography (PET). Today, when modelling data
from modern PET scanners, little use is made of earlier microvascular research in the
compartmental models, which have become the standard model by which the vast majority of
dynamic PET data are analysed. However, modern PET scanners provide data with a sufficient
temporal resolution and good counting statistics to allow estimation of parameters in models with
more physiological realism. We explore the standard compartmental model and find that
incorporation of blood flow leads to paradoxes, such as kinetic rate constants being time-dependent,
and tracers being cleared from a capillary faster than they can be supplied by blood flow. The
inability of the standard model to incorporate blood flow consequently raises a need for models that
include more physiology, and we develop microvascular models which remove the inconsistencies.
The microvascular models can be regarded as a revision of the input function. Whereas the standard
model uses the organ inlet concentration as the concentration throughout the vascular compartment,
we consider models that make use of spatial averaging of the concentrations in the capillary
volume, which is what the PET scanner actually registers. The microvascular models are developed
for both single- and multi-capillary systems and include effects of non-exchanging vessels. They are
suitable for analysing dynamic PET data from any capillary bed using either intravascular or
diffusible tracers, in terms of physiological parameters which include regional blood flow.
Abstract 12: Maximal but not submaximal performance is reduced by constant-speed 10-km
run.
AIM: Effects of endurance exercise on running economy, mechanics, force generating capacity and
their interactions were examined. During the exercise, metabolic, kinetic and kinematical variables
were recorded to find out adaptive mechanisms in the course of the fatiguing run. In addition,
64
before and after it maximal force and power production was tested. METHODS: Experimental
design: comparative. Setting: University. Participants and intervention: 7 men unaccustomed to
endurance training run 10 km at individually chosen constant speed (3.5+/-0.5 ms(-1)) on an indoor
track. Measures: 3-D ground reaction forces, electromyographic (EMG) activities from 7 leg
muscles, pulmonary ventilation, gas exchange, heart rate and movement kinematics were measured
during the run. Blood lactate and serum creatine kinase activity were determined. Maximal
voluntary contraction (MVC) with superimposed double twitch (DT), and passive DT tests in
plantarflexor muscles were performed before and after the 10 km run. Changes in 20 m sprint
performance were evaluated in before-after comparison. RESULTS: The 10 km run caused
significant reductions in maximal running speed (8.2 vs. 7.6 ms(-1), p<0.05), in MVC (1216 vs. 984
N, p<0.05), and in passive DT (271 vs. 211 N, p<0.05). During the submaximal run, however, the
subjects were able to maintain relatively constant oxygen consumption and running kinematics.
Greatest changes in EMG activity and kinetics were seen during the first 2 km. CONCLUSION:
After initial adjustment, the runners are able to maintain submaximal running speed with very little
changes in running economy, kinetics and kinematics. However, fatigue-induced impairment in the
force generating capacity of the contractile component can be revealed by tests measuring
maximum performance.
65
Dr. Özhan EYİGÖR
Text 68: Cirrhosis
What is Cirrhosis?
Cirrhosis is characterized anatomically by widespread nodules in the liver combined with fibrosis.
The fibrosis and nodule formation causes distortion of the normal liver architecture which interferes
with blood flow through the liver. Cirrhosis can also lead to an inability of the liver to perform its
biochemical functions. To understand the pathophysiology of cirrhosis, the normal anatomy and
physiology of the liver must first be briefly reviewed.
Liver Blood Flow
Oxygenated blood that has returned from the lungs to the left ventricle of the heart is pumped to all
of the tissues of the body. This is called the systemic circulation. After reaching the tissues, blood is
returned to the right side of the heart, from where it is pumped to the lungs and then returned to the
left side of the heart after taking up oxygen and giving off carbon dioxide. This is called the
pulmonary circulation. Blood from the gut and spleen flow to and through the liver before returning
to the right side of the heart. This is called the portal circulation and the large vein through which
blood is brought to the liver is called the portal vein. After passing through the liver, blood flows
into the hepatic vein, which leads into the inferior vena cava to the right side of the heart. The liver
also receives some blood directly from the heart via the hepatic artery. In the esophagus, stomach,
small intestine and rectum, the portal circulation and veins of the systemic circulation are
connected. Under normal conditions, there is little to no back flow from the portal circulation into
the systemic circulation.
Bilirubin Secretion
The liver is the site of bile formation. Bile contains bile salts, fatty acids, cholesterol, bilirubin and
other compounds. The components of bile are synthesized and modified in hepatocytes (the
predominant cell type in the liver) and secreted into small bile ducts within the liver itself. These
small bile ducts form a branching network of progressively larger ducts that ultimately become the
common bile duct that takes bile to the small intestine. Bilirubin is a yellow pigment that derives
primarily from old red blood cells. Bilirubin is taken up by hepatocytes from the blood, modified in
the hepatocytes to a water soluble form and secreted into the bile.
Biochemical Functions
The liver performs many biochemical functions. Blood clotting factors are synthesized in the liver.
Albumin, the major protein in the blood, is also synthesized in and secreted from the liver. The
modification and/or synthesis of bile components also takes place in the liver. Many of the body's
metabolic functions occur primarily in the liver including the metabolism of cholesterol and the
conversion of proteins and fats into glucose. The liver is also where most drugs and toxins,
including alcohol, are metabolized.
What Goes Wrong in Cirrhosis?
Cirrhosis results from damage to liver cells from toxins, inflammation, metabolic derangements and
other causes. Damaged and dead liver cells are replaced by fibrous tissue which leads to fibrosis
(scarring). Liver cells regenerate in an abnormal pattern primarily forming nodules that are
surrounded by fibrous tissue. Grossly abnormal liver architecture eventually ensues that can lead to
decreased blood flow to and through the liver.
Decreased blood flow to the liver and blood back up in the portal vein and portal circulation leads to
some of the serious complications of cirrhosis. Blood can back up in the spleen causing it to enlarge
and sequester blood cells. Most often, the platelet count falls because of splenic sequestration
66
leading to abnormal bleeding. If the pressure in the portal circulation increases because of cirrhosis
and blood back up (note: this can also sometimes occur in severe cases of acute hepatitis and liver
damage), blood can flow backwards from the portal circulation to the systemic circulation where
they are connected. This can lead to varicose veins in the stomach and esophagus (gastric and
esophageal varices) and rectum (hemorrhoids). Gastric and esophageal varices can rupture, bleed
massively and even cause death. Hypertension in the portal circulation, along with other hormonal,
metabolic and kidney abnormalities in cirrhosis, can also lead to fluid accumulation the abdomen
(ascites) and the peripheral tissue (peripheral edema).
Decreased bilirubin secretion from hepatocytes in cirrhosis leads to the back up of bilirubin in the
blood. This leads to jaundice, the yellow discoloration of the skin and eyes. As the water-soluble
form of bilirubin also backs up in the blood, bilirubin can also spill into the urine giving it a bright
yellow to dark brown color.
Abnormal biochemical function of the liver in cirrhosis can lead to several complications. The
serum albumin concentration falls which can lead to aggravation of ascites and edema. The
metabolism of drugs can change requiring dose adjustments. In men, breast enlargement
(gynecomastia) sometimes occurs because metabolism of estrogen in the liver is decreased.
Decreased production of blood clotting factors can lead to bleeding complications. Derangements in
the metabolism of triglycerides, cholesterol and sugar can occur. In earlier stages, cirrhosis
frequently can cause insulin resistance and diabetes mellitus. In later stages or in severe liver
failure, blood glucose may be low because it cannot be synthesized from fats or proteins.
Cirrhosis, especially in advanced cases, can cause profound abnormalities in the brain. In cirrhosis,
some blood leaving the gut bypasses the liver as blood flow through the liver is decreased.
Metabolism of components absorbed in the gut can also be decreased as liver cell function
deteriorates. Both of these derangements can lead to hepatic encephalopathy as toxic metabolites,
normally removed from the blood by the liver, can reach the brain. In its early stages, subtle mental
changes such as poor concentration or the inability to construct simple objects occurs. In severe
cases, hepatic encephalopathy can lead to stupor, coma, brain swelling and death.
Cirrhosis of the liver can also cause abnormalities in other organ systems. Cirrhosis can lead to
immune system dysfunction causing an increased risk of infection. Ascites fluid in the abdomen
often becomes infected with bacteria normally present in the gut (spontaneous bacterial peritonitis).
Cirrhosis can also lead to kidney dysfunction and failure. In end-stage cirrhosis, a type of kidney
dysfunction called hepatorenal syndrome can occur. Hepatorenal syndrome is almost always fatal
unless liver transplantation is performed.
Clinical Symptoms and Diagnosis of Cirrhosis
Cirrhosis is usually an easy diagnosis to make when any or all of the above abnormalities and
complications are present. This is especially true when the underlying liver disease can be
identified. The underlying liver disease (see below) is identified in most patients, however,
sometimes it will not be discovered. Such cases are called "cryptogenic" cirrhosis. Sometimes, other
conditions such as metastatic cancer, hepatic or portal vein thrombosis, severe acute hepatitis or
acute bile duct obstruction can cause some of the abnormalities seen in cirrhosis. A careful history
combined with special diagnostic tests will usually identify these conditions.
Some patients with cirrhosis, especially early in the course of the disease, will have no overt clinical
signs or symptoms. Some may have only subtle physical changes such as red palms, red spots that
blanch on their upper body (spider angiomata), hypertrophy of the parotid glands, gynecomastia or
fibrosis of tendons in the palms. Some patients may only have subtle abnormalities on blood tests,
and in some cases, all blood tests may be normal. Radiological and nuclear medicine tests may give
clues as to the presence of cirrhosis, but the diagnosis of cirrhosis must often be made by liver
biopsy.
67
Abstracts:
Abstract 13: Identification of neurones in the female rat hypothalamus that express oestrogen
receptor-alpha and vesicular glutamate transporter-2.
Oestrogen exerts its effects in the brain by binding to and activating two members of the nuclear
receptor family, oestrogen receptor (ER)-alpha and ER-beta. Evidence suggests that oestrogenreceptive neurones participate in the generation of reproductive behaviours and that they convey the
oestrogen message to gonadotropin-releasing hormone (GnRH) neurones. The aim of the present
study was to identify the neurochemical phenotype of a subset of oestrogen receptor-expressing
neurones. To this aim, we focused on the glutamate neuronal system, which is one of the most
important stimulators of GnRH synthesis and release. We used the presence of vesicular glutamate
transporter-2 (VGLUT2) mRNA as a specific marker to identify glutamate neurones and employed
dual in situ hybridization to localize ERalpha mRNA-(35S-labelling) and VGLUT2 mRNA(digoxigenin-labelling) expressing neurones within the hypothalamus. The results show that the
overall distribution of VGLUT2 mRNA and ERalpha mRNA are consistent with previous data in
the literature. Dual-labelled neurones were localized in the ventrolateral part of the ventromedial
nucleus where 81.3 +/- 3.4% of the ERalpha mRNA containing neurones expressed VGLUT2
mRNA, in the anteroventral periventricular nucleus (30% colocalization) and in the medial preoptic
nucleus (19% colocalization). Only 4.4% of the ERalpha expressing neurones in the arcuate nucleus
contained VGLUT2 mRNA. These findings reveal that certain subpopulations of oestrogenreceptive neurones are glutamatergic in select hypothalamic areas that are known to regulate
reproductive behaviour and GnRH neurones in the female rat. Thus, the oestrogen signal could be
propagated through glutamate neurones to distant sites and influence the activity of the postsynaptic
neurones.
Abstract 14: Kainate receptor subunit-positive gonadotropin-releasing hormone neurons
express c-Fos during the steroid-induced luteinizing hormone surge in the female rat.
During the preovulatory and estradiol-progesterone-induced GnRH-LH surge, a subpopulation of
GnRH neurons transiently expresses the transcription factor c-fos, which is a useful marker of cell
activation. To further characterize this subpopulation of GnRH neurons, multiple
immunohistochemical procedures were applied to visualize GnRH, c-Fos, KA2, GluR5, GluR6, and
GluR7 receptor subunits during different phases of the estrogen-progesterone-induced LH surge.
The results show that the LH surge begins at 1400 h and peaks at 1600 h before returning to
baseline late in the evening. At 1400 h, about 50% of the GnRH neurons contained c-Fos, and this
percentage remained high at 65% at 1600 and 2000 h. During the surge, 50% of the c-Fos-positive
GnRH neurons contained KA2 receptor subunit protein at 1400 h, 65% of the c-Fos-positive GnRH
neurons expressed the KA2 subunit at 1600 h, and 50% of the c-Fos-positive GnRH neurons
expressed the KA2 subunit at 2000 h. As KA2 subunits require other kainate-preferring subunits to
form functional receptor channels, we examined GnRH neurons for the presence of GluR5, GluR6,
and GluR7 messenger RNA (mRNA) and protein. The results show that the KA2-containing GnRH
neurons also contain GluR5 receptor subunit mRNA and protein, and that these GnRH neurons are
c-Fos positive during the steroid-induced LH surge. To determine whether administration of kainate
is sufficient to induce c-Fos in GnRH neurons, steroid-primed animals received iv injections of
subseizure-inducing amounts of kainic acid and were processed for immunohistochemistry and in
situ hybridization. The results show that kainic acid causes a significant increase in circulating LH;
however, it does not induce c-Fos in GnRH neurons, nor does it cause an increase in GnRH mRNA.
Together, the results suggest that a large subset of GnRH neurons expresses KA2 as well as GluR5
receptor subunits, which would allow the formation of functional glutamate receptor channels, and
that this subset of GnRH neurons is activated during the steroid-induced LH surge.
Abstract 15: Stem cells, aging, and cancer: inevitabilities and outcomes.
Given the unique abilities of a stem cell to self-renew, differentiate, and proliferate, it is no wonder
that they are critically important to an organism during development and to maintain homeostasis.
68
Likewise, when something goes awry within a stem cell, it is likely to have far-reaching effects,
since stem cells persist throughout the lifetime of the individual. Two significant biological
phenomena that involve stem cells are the inevitable process of aging and a major health issue
whose incidence increases with aging: cancer. In this review, we summarize evidence and theories
concerning these two stem cell processes. The inability of stem cells to be passaged indefinitely in
mice and the data supporting regular replication of the quiescent stem cell pool are discussed.
Further, the current evidence indicating a stem cell origin of acute myeloid leukemia, including
examples from both experimental mouse models and human clinical samples, is evaluated. Finally,
we propose a model in which aging of the stem cell population of the hematopoietic system in
particular can create conditions that are permissive to leukemia development; in fact, we suggest
that aging is a secondary event in leukemogenesis.
Abstract 16: Cancer stem cells in nervous system tumors.
Most current research on human brain tumors is focused on the molecular and cellular analysis of
the bulk tumor mass. However, evidence in leukemia and more recently in solid tumors such as
breast cancer suggests that the tumor cell population is heterogeneous with respect to proliferation
and differentiation. Recently, several groups have described the existence of a cancer stem cell
population in human brain tumors of different phenotypes from both children and adults. The
finding of brain tumor stem cells (BTSCs) has been made by applying the principles for cell culture
and analysis of normal neural stem cells (NSCs) to brain tumor cell populations and by
identification of cell surface markers that allow for isolation of distinct tumor cell populations that
can then be studied in vitro and in vivo. A population of brain tumor cells can be enriched for
BTSCs by cell sorting of dissociated suspensions of tumor cells for the NSC marker CD133. These
CD133+ cells, which also expressed the NSC marker nestin, but not differentiated neural lineage
markers, represent a minority fraction of the entire brain tumor cell population, and exclusively
generate clonal tumor spheres in suspension culture and exhibit increased self-renewal capacity.
BTSCs can be induced to differentiate in vitro into tumor cells that phenotypically resembled the
tumor from the patient. Here, we discuss the evidence for and implications of the discovery of a
cancer stem cell in human brain tumors. The identification of a BTSC provides a powerful tool to
investigate the tumorigenic process in the central nervous system and to develop therapies targeted
to the BTSC. Specific genetic and molecular analyses of the BTSC will further our understanding of
the mechanisms of brain tumor growth, reinforcing parallels between normal neurogenesis and
brain tumorigenesis.
Abstract 17: Glia as neural progenitor cells
Recent studies have substantially expanded our conception of the roles for glia in function and
maintenance of the adult nervous system. Of these reports, several have re-examined the lineage
relationships among neural stem cells, their early radial glial derivatives and their mitotically
competent neurogenic daughters. These studies have highlighted the role of radial cells in
development, and of their glial progeny postnatally, as both progenitors and regulators of neuronal
production and phenotype. In the adult mammalian brain, radial cell populations are scant, but their
glial derivatives participate in a gliovascular network that organizes not only the structural and
functional architecture of the brain but also its generative niches for resident progenitors – glial as
well as neuronal. As in other organs, these progenitors can reside as transit-amplifying pools, by
which lineage-biased progenitors expand to replenish discrete mature phenotypes. This review will
consider the types of transit-amplifying progenitor cells persistent in the adult mammalian CNS,
and the extent to which these derive from glial phenotypes. It will also discuss the interactions of
progenitor cells with their brethren that could specify their phenotype and fate, while defining the
permissive niches for cell genesis in the adult CNS.
69
Abstract 18: Restoration of fertility after treatment for cancer.
The late effects of chemotherapy and radiation treatment on fertility are an important issue for longterm survivors of cancer who may not have started or completed a family at the time of diagnosis.
Attempts at protecting reproductive function using hormonal manipulation have proved largely
unsuccessful and other strategies have to be considered. For men, semen cryopreservation allows
subsequent artificial insemination of a female partner or ivf but cryopreserved semen is a finite
resource, does not allow natural conception and is not an option for prepubertal boys. In an effort to
overcome this, research is in progress to investigate whether testicular cells harvested and
cryopreserved before the start of chemotherapy can be reintroduced to the testis after treatment and
resume normal spermatogenesis. This has been achieved in a mouse model and the results of
experimental protocols in men are awaited with interest. For women, harvested mature oocytes are
only poorly tolerant of the freezing process although immediate in vitro fertilization and
cryopreservation of embryos can be successful. An experimental technique of great interest is the
harvesting and cryopreservation of ovarian cortex before the start of sterilizing treatment. In ewes,
the reimplantation of autologous ovarian cortical tissue into surgically castrated animals has
resulted in resumption of oestrus, conceptions after normal matings and the birth of live offspring.
Recently, ovarian function has been re-established using a similar technique in a patient following
treatment for Hodgkin's lymphoma, but so far pregnancy has not been reported.
70
Dr. Ayberk KURT
Text 69: What is Alzheimer's disease?
Alzheimer's disease (AD) is a progressive disease of the brain that is characterized by impairment
of memory and a disturbance in at least one other thinking function (for example, language or
perception of reality). Many scientists believe that AD results from an increase in the production or
accumulation of a specific protein (beta-amyloid protein) that leads to nerve cell death. Loss of
nerve cells in strategic brain areas, in turn, causes deficits in the neurotransmitters, which are the
brain's chemical messengers.
Alzheimer's disease is not a normal part of aging and is not something that inevitably happens in
later life. Rather, it is one of the dementing disorders, which are a group of brain diseases that result
in the loss of mental and physical functions.
Who develops Alzheimer's disease?
The main risk factor for AD is increased age. As the population ages, the frequency of AD
continues to increase. 10 % of people over age 65 and 50 % of those over 85 have AD. The number
of individuals with AD is expected to be 14 million by the year 2050. In 1998, the annual cost for
the care of patients with AD in the United States was approximately $40,000 per patient.
There are also genetic risk factors for AD. The presence of several family members with AD has
suggested that, in some cases, heredity may influence the development of AD. A genetic basis has
been identified through the discovery of mutations in several genes that cause AD in a small
subgroup of families in which the disease has frequently occurred at relatively early ages (beginning
before age 50). Some evidence points to chromosome 19 as implicated in certain other families in
which the disease has frequently developed at later ages.
Studies of aging and dementia (general mental deterioration) in the general population have
identified three groups of subjects; persons who are not demented, those who are demented, and
individuals who cannot be classified because they have a cognitive (thinking, memory) impairment,
but do not meet the criteria for dementia.
What are the symptoms of Alzheimer's disease?
The onset of AD is usually very slow and gradual. Over time, however, it follows a progressively
more serious course. Among the symptoms that typically develop, none is unique to AD at its
various stages. It is important that suspicious changes be thoroughly evaluated before they become
inappropriately or negligently labeled AD.
Ten Warning Signs of Alzheimer's Disease
The Alzheimer's Association has developed the following list of warning signs that include
common symptoms of AD. Individuals who exhibit several of these symptoms should see a
physician for a complete evaluation.
Memory loss that affects job skills
Difficulty performing familiar tasks
Problems with language
Disorientation to time and place
Poor or decreased judgment
Problems with abstract thinking
Misplacing things
Changes in mood or behavior
Changes in personality
Loss of initiative
71
Problems of memory, particularly recent or short-term memory, are common early in the course of
AD. For example, the individual may, on repeated occasions, forget to turn off the iron or fail to
recall which of the morning's medicines were taken. Mild personality changes, such as less
spontaneity, or a sense of apathy and a tendency to withdraw from social interactions, may occur
early in the illness.
As the disease progresses, problems in abstract thinking or in intellectual functioning develop. The
person may begin to have trouble with figures when working on bills, with understanding what is
being read, or with organizing the day's work. Further disturbances in behavior and appearance may
also be seen at this point, such as agitation, irritability, quarrelsomeness, and a diminishing ability
to dress appropriately.
Later in the course of the disorder, affected individuals may become confused or disoriented about
what month or year it is, be unable to describe accurately where they live, or be capable of correctly
naming a place being visited. Eventually, patients may wander, be unable to engage in conversation,
seem inattentive and erratic in mood, appear uncooperative, and lose bladder and bowel control. In
extreme cases, persons may become totally incapable of caring for themselves, if the final stage is
reached. Death then follows, perhaps from pneumonia or some other problem that occurs in
severely deteriorated states of health. The average course of the disease from the time it is
recognized to death is about 6 to 8 years, but it may range from under 2 to over 20 years. Those
who develop the disorder later in life may die from other illnesses (such as heart disease), before
AD reaches its final and most serious stages.
Abstracts:
Abstract 19: Neurodegenerative changes associated with beta-amyloid deposition in the
brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1
transgenes.
Mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) lead to an increase in betaamyloid (Abeta) production. Despite the fact that a number of transgenic mice develop cerebral
Abeta plaques, few have been subjected to ultrastructural investigation and the sequence of events
leading to Abeta plaque formation is unclear. We therefore investigated the doubly transgenic
(mutant APP(K670N,M671L)-mutant PS1(M146L)) mouse, which develops Abeta deposits much
earlier than singly transgenic littermates. Widespread Abeta plaques with or without a distinct core
were found in gray matter. Abeta plaques were also present in white matter. Astrocytosis was
greater around gray matter plaques than around white matter plaques. In some plaques, Abeta cores
were associated with cell profiles containing prominent endoplasmic reticulum and a homogeneous
cytoplasm that appeared to be neuronal. The morphology and location of other profiles indicated
them to be microglia or oligodendrocytes. Some Abeta fibrils appeared to lie within these profiles,
but they may have been simply surrounded by the cell profile since the profile membrane was not
always visible. Dark atrophic neurons, whose morphology suggested that they were apoptotic, were
present around gray matter plaques. Cerebrovascular Abeta deposition was also observed in the
brains of APP/PS1 transgenic mice. Thus, the amyloid deposition and neuropathology observed in
APP/PS1 mouse brain are similar to those in Alzheimer's disease and they appear to develop earlier
and become more severe than in the other transgenic models currently available.
Abstract 20: Hyperphosphorylated tau and paired helical filament-like structures in the
brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1
transgenes.
Senile plaques composed mainly of beta-amyloid (Abeta) and neurofibrillary tangles principally
composed of hyperphosphorylated tau are the major pathological features of Alzheimer's disease
(AD). Despite the fact that increased expression of amyloid precursor protein (APP) and presenilin1 (PS1) transgenes in mice lead to increased Abeta deposition in plaquelike structures in the brain,
little is known about the nature and distribution of tau in these mice. Therefore the relationship
72
between Abeta and hyperphosphorylated tau was investigated in mice carrying mutant APP and
mutant PS1 transgenes using both light (LM) and electron microscopy (EM) with
immunocytochemistry. LM immunocytochemistry revealed cerebral Abeta deposits to be present
from 8 weeks of age, whereas hyperphosphorylated tau was not detected until 24 weeks of age,
when it appeared as punctate deposits in close association with the Abeta deposits in the cortex and
hippocampus. However, dystrophic neurites were not as heavily immunolabeled as they are in AD
brain. EM revealed that aggregations of straight filaments (10-12 nm wide) were present in some
cellular processes at the periphery of Abeta plaques in 8-month-old APP/PS1 mice. In one such
mouse, single filaments and paired filaments showing a helical configuration (50-55 nm half-period,
25 nm max. width) were present in a dark, atrophic hippocampal neuron. Immunogold labeling of
APP/PS1 mouse brain revealed hyperphosphorylated tau epitopes in some dystrophic neurites from
24 weeks of age that were similar to those present in AD. These results suggest that
hyperphosphorylated tau appears in APP/PS1 mouse brain after the onset of Abeta deposition and
although it is associated with Abeta deposits, its distribution is not identical to that in AD.
Abstract 21: Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus,
CA3 and CA1, in a mouse model of Down syndrome.
Ts65Dn mice are partially trisomic for the distal region of MMU16, which is homologous with the
obligate segment of HSA21 triplicated in Down syndrome (DS). Ts65Dn mice are impaired in
learning tasks that require an intact hippocampus. In order to investigate the neural basis of these
deficits in this mouse model of Down syndrome, quantitative light and electron microscopy were
used to compare the volume densities of neurons and synapses in the hippocampus of adult Ts65Dn
(n=4) and diploid mice (n=4). Neuron density was significantly lower in the CA1 of Ts65Dn
compared to diploid mice (p<0.01). Total synapse density was significantly lower in the dentate
gyrus (DG; p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. The
synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1
(p<0.001) of Ts65Dn compared to diploid mice. When the data were broken down by synapse type,
asymmetric synapse density was found to be significantly lower in the DG (p<0.001), CA3 (p<0.05)
and CA1 (p<0.001) of Ts65Dn compared to diploid mice, while such a difference in symmetric
synapse density was only present in the DG (p<0.01). The asymmetric synapse-to-neuron ratio was
significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to
diploid mice, but there were no such significant differences in symmetric synapse-to-neuron ratios.
These results suggest that impaired synaptic connectivity in the hippocampus of Ts65Dn mice
underlies, at least in part, their cognitive impairment.
Abstract 22: Cancer stem cells produce brain tumours
Mouse study demonstrates source of human cancer. Cancer stem cells from glioblastomas in human
brains triggered similar tumours in mice. The cells that lie at the root of human brain tumours have
been isolated, opening the door to treatments that stifle cancer at its source.
Researchers believe that tumours grow from a type of "cancer stem cell" that gives rise to other
cancerous cells. Cancer stem cells appear to have some of the properties of stem cells, such as the
potential to give rise to a larger population of cells, although they are not necessarily the same
thing. For example, they may be differentiated cells that undergo a backwards step to take on some
of these properties, although the pathway remains unclear.
Scientists have had little success tracking down these cells, because they are difficult to distinguish
from surrounding cells. To find the culprits underlying brain cancer, Sheila Singh and her coworkers at the Hospital for Sick Children, Toronto, Canada, turned to a protein called CD133,
which has been found on the surface of other stem cells in the body. The group took tissue samples
of brain tumours from children and adults and pulled out cells that were making the protein. When
the team injected 100 of these potential cancer stem cells into the brains of 19 mice, 16 of them
sprouted brain tumours. The results, which the team reports in Nature1, support the idea that such
cells are a subpopulation of brain cells that went awry, became cancer stem cells and gave rise to
73
the human tumours. Although the group have isolated cancer stem cells from human brains before2,
this study is the first to show that these cells can recreate the disease in animals. This confirms that
these cells are the ones that spawn tumours. Moreover, the cancer stem cells grew into tumours that
behaved similarly to those in the patients from which they came, resembling glioblastomas and
medulloblastomas, for example. This suggests that mice tumours will be a good way to study the
human disease.
Abstract 23: Mice regrow damaged spinal cord
Damaged spinal cords in mice have been encouraged to grow back by blocking a scar-causing
molecule. The result suggests a fresh approach to treatments for sufferers of spinal cord injury.
Spinal cord injuries have long been considered incurable because the affected nerve cells do not
grow back. Depending on the site and severity of damage, patients can be left paralysed and unable
to control important bodily functions. But in recent years, scientists seeking to reverse spinal cord
damage have been pursuing a number of different approaches. These include transplanting cells to
stimulate growth, removing factors that inhibit repair and using biocompatible materials to 'bridge'
gaps between damaged nerve ends. One major barrier to nerve regrowth is scar tissue. Now
researchers from the University of Melbourne seem to have found a way to prevent this scarring,
which they publish in this week's Journal of Neuroscience1.
Abstract 24: Scar Maker
The team found that mice bred without a molecule called EphA4 produce very little scar tissue
around damaged spinal nerves. The researchers believe this is because EphA4 plays an important
role in activating cells known as astrocytes, which are responsible for scar-tissue formation. To test
whether reducing scarring helps the animals to heal, the researchers cut the spinal cords of two
groups of mice: one group had normal levels of EphA4, the other group lacked the molecule. The
injury paralysed the left hind limb of the animals. The mice that lacked EphA4 regained all of their
stride length within three weeks, and after one month they had recovered ankle and toe movement.
In contrast, the control group recovered only 70% of their stride length, and no ankle or toe
movement. The researchers also found that a large percentage of the spinal cord nerves had regrown
across the damaged section in the mice that lacked EphA4, compared with hardly any in the control
group.
Abstract 25: Surprising the experts
Preliminary observations made by the researchers suggest that the same effect occurs in monkeys as
well as mice. If it holds true in humans too, then development of drugs that block EphA4 could
remove an important obstacle to spinal cord repair. "This is a very surprising finding," comments
Ole Kiehn, a neuroscientist at the Karolinska Institute in Stockholm, Sweden. He says the result is
promising from the point of view of developing treatments. "It needs to be seen, however, that this
works in humans," he cautions. The complexity of the body's nervous system means that many
factors come into play during spinal cord repair. An effective clinical treatment will almost
certainly need to combine a number of different approaches, including surgery.
"I find it very difficult to imagine that one molecule could make the difference between spinal
nerves being repaired or not," says Geoff Raisman, director of the new spinal repair unit at
University College London and pioneer of a method that involves transplanting 'pathway repairing'
cells from the nasal cavity to grow back spinal cord nerves. "I am surprised that they have got these
results."
He notes that the leap from mouse to man is also a large step in the world of spinal cord research.
Small animals sometimes get better on their own in a way that humans do not, he points out,
regardless of experimental treatment.
74
Dr. Selçuk SÖZER
Text 70: Blood Pressure
What is high blood pressure?
High blood pressure or hypertension means high pressure (tension) in the arteries. The arteries are
the vessels that carry blood from the pumping heart to all of the tissues and organs of the body.
Hypertension does not mean excessive emotional tension, although emotional tension and stress can
temporarily increase the blood pressure. High blood pressure is generally defined as a level
exceeding 140/90 mm Hg that has been confirmed on multiple occasions. The systolic blood
pressure, which is the top number, represents the pressure in the arteries as the heart contracts and
pumps blood into the circulation. The diastolic pressure, which is the bottom number, represents the
pressure in the arteries as the heart relaxes after the contraction. The diastolic pressure, therefore,
reflects the minimum pressure to which the arteries are exposed.
An elevation of the systolic and/or diastolic blood pressure increases the risk of developing heart
(cardiac) disease, kidney (renal) disease, hardening of the arteries (arteriosclerosis), eye damage,
and stroke (brain damage). These complications of hypertension are often referred to as end-organ
damage because damage to these organs is the end result of chronic (long duration) high blood
pressure. Accordingly, the diagnosis of high blood pressure in an individual is important so that
efforts can be made to normalize the blood pressure and, thereby, prevent the complications.
How is the blood pressure measured?
The blood pressure usually is measured with a small, portable instrument called a blood pressure
cuff (sphygmomanometer) (Sphygmo in Greek means pulse, and a manometer measures pressure.).
The blood pressure cuff basically consists of an air pump, a pressure gauge, and a rubber cuff. The
instrument registers the blood pressure in units called millimeters of mercury (mm Hg).
The cuff is placed around the upper arm and inflated to a pressure that blocks the flow of blood in
the main artery (brachial artery) that travels through the arm. Then, the pressure of the cuff on the
arm and artery is gradually released. As the pressure decreases, the health practitioner listens with a
stethoscope over the artery at the front of the elbow. The pressure at which the practitioner first
hears a pulsation over the artery is the systolic pressure. As the cuff pressure decreases further, the
pressure at which the pulsation finally stops is the diastolic pressure.
How clearly established is the normal level of blood pressure?
Even though most insurance companies, quite reasonably, consider high blood pressure to be
140/90 and higher for the general population, these levels may not be appropriate cut-offs for all
individuals. As a matter of fact, many experts in the field of hypertension view blood pressure
levels as a continuum, or range, from lower levels to higher levels. Such a continuum implies that
there are no clear or precise cut-off values to separate normal blood pressure from high blood
pressure.
For some people, blood pressure readings that are lower than 140/90 may be a more appropriate
normal cut-off level. For example, in certain situations, such as in patients with long duration
(chronic) kidney diseases that spill (lose) protein into the urine (proteinuria), the blood pressure is
ideally kept at 125/75, or even lower. The purpose of reducing the blood pressure to this level in
these patients is to slow the progression of kidney damage. Patients with diabetes (diabetes
mellitus) may likewise benefit from blood pressure that is maintained at a level lower than 140/90.
In addition, black persons, who have an increased risk for developing the complications of
hypertension, may decrease this risk by reducing their diastolic blood pressure to 80 mm Hg or less.
75
What causes hypertension?
Two forms of high blood pressure have been described -- essential (or primary) hypertension and
secondary hypertension. Essential hypertension is a far more common condition and accounts for
95% of the population with hypertension. The cause of essential hypertension is unknown. In
secondary hypertension, which accounts for 5% of all cases, the high blood pressure is secondary to
or caused by a specific abnormality in one of the organs or systems of the body. (Secondary
hypertension is discussed further in a separate section below.)
Essential hypertension affects approximately 75 million Americans, yet, as mentioned, its basic
cause or underlying defect is not known. Nevertheless, certain associations have been recognized in
people with essential hypertension. For example, the condition develops only in groups or societies
that have a fairly high intake of salt, exceeding 5.8 grams daily. In fact, salt intake may be a
particularly important factor in relation to essential hypertension in a number of varied situations.
Thus, excess salt may be involved in the hypertension that is associated with advancing age, black
racial background, obesity, hereditary (genetic) susceptibility, and kidney failure (renal
insufficiency).
Genetic factors are thought to play a prominent role in the development of essential hypertension.
However, the genes for hypertension have not yet been identified. (Genes are tiny portions of
chromosomes that produce the proteins that determine the characteristics of individuals.) The
current research in this area is focused on the genetic factors that affect the renin-angiotensinaldosterone system. This system helps to regulate blood pressure by controlling salt balance and the
tone (state of elasticity) of the arteries.
Approximately 30 % of cases of essential hypertension are attributable to genetic factors. For
example, in the United States, the incidence of high blood pressure is greater among blacks than
among whites or Asians. Also, in individuals who have one or two parents with hypertension, high
blood pressure is twice as common as in the general population. Rarely, certain unusual genetic
disorders affecting the hormones of the adrenal glands may lead to hypertension. (These identified
genetic disorders are actually considered secondary hypertension.)
As mentioned above, the underlying cause of essential hypertension is unknown. Nevertheless, it
has been found that the vast majority of patients with essential hypertension have in common a
particular abnormality of the arteries. That is, they have an increased resistance (stiffness or lack of
elasticity) in the tiny arteries that are most distant from the heart (peripheral arteries or arterioles).
The peripheral arteries supply blood containing oxygen and nutrients to all of the tissues of the
body. (The arterioles are connected by capillaries in the tissues to the venous system (or the veins),
which returns the blood to the heart and lungs.) Just what makes the peripheral arteries become stiff
is not known. Yet, this increased peripheral artery resistance is present, as well, in those people
whose essential hypertension is associated with genetic factors, obesity, lack of exercise, overuse of
salt, and aging.
What are the goals of anti-hypertensive treatment?
Keep in mind that high blood pressure is usually present for many years before its complications
develop. The idea, therefore, is to treat hypertension early, before it damages critical organs in the
body. Accordingly, increased public awareness and screening programs to detect early,
uncomplicated hypertension are the keys to successful treatment. The point is that by treating high
blood pressure successfully early enough, you can significantly decrease the risk of stroke, heart
attack, and kidney failure.
The goal for patients with combined systolic and diastolic hypertension is to attain a blood pressure
of 140/85 mm Hg. Bringing the blood pressure down even lower, as mentioned earlier, may be
desirable in black patients and patients with diabetes or chronic kidney failure.
What new class of anti-hypertensive drug is currently being tested?
A new class of anti-hypertensive drug, called a vasopeptidase blocker (inhibitor), has been
developed. Uniquely, it works on two different systems at the same time. It blocks that part of the
76
renin-angiotensin-aldosterone hormonal system that narrows (constricts) the peripheral arteries. It
also blocks that part of the body's salt regulating system that conserves salt. Accordingly, this class
of drug decreases the blood pressure by simultaneously dilating the peripheral arteries and
increasing the body's loss of salt (natriuresis).
One such drug that is currently being studied is called omapatrilat. In laboratory animals with high
blood pressure, this drug reduces the blood pressure and appears to protect the end-organs (heart,
kidney, and brain) from damage by the high blood pressure. Moreover, the drug dilates the
peripheral arteries, which increases blood flow to all tissues, and improves cardiac function in
hypertensive patients with heart failure. Not yet approved by the FDA, omapatrilat is undergoing
further testing to evaluate its effectiveness and safety.
Abstracts:
Abstract 26: STI571 as a targeted therapy for CML.
Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder that progresses
through distinct phases as the malignant clone progressively loses the capacity for terminal
differentiation. It is characterized by the (9;22) translocation and resultant production of the BcrAbl tyrosine kinase. Bcr-Abl functions as a constitutively activated tyrosine kinase, and this kinase
activity is absolutely required for the transforming function of the Bcr-Abl protein. In preclinical
studies, STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, specifically
inhibited the proliferation of Bcr-Abl-expressing cells in vitro and in vivo. STI571 has shown
remarkable results in all phases of CML. Although responses are seen in all phases of the disease,
durable responses are most common in earlier stage patients. Thus, STI571 has emerged as a
paradigm for gene product targeted therapy, offering expanded treatment options for patients with
CML.
Abstract 27: Chronic myelogenous leukemia as a paradigm of early cancer and possible
curative strategies.
The chronological history of the important discoveries leading to our present understanding of the
essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia
(CML) are first reviewed, focusing in particular on abnormalities that are responsible for the
massive myeloid expansion. CML is an excellent target for the development of selective treatment
because of its highly consistent genetic abnormality and qualitatively different fusion gene product,
p210(bcr-abl). It is likely that the multiple signaling pathways dysregulated by p210(bcr-abl) are
sufficient to explain all the initial manifestations of the chronic phase of the disease, although
understanding of the circuitry is still very incomplete. Evidence is presented that the signaling
pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate
with cytokines to increase the proportion of stem cells that are activated and thereby increase
recruitment into the committed progenitor cell pool, and that this increased activation is probably
the primary cause of the massive myeloid expansion in CML. The cooperative interactions between
Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between
multiple cytokines that are normally required for the activation of stem cells, while at the same time
causing numerous subtle biochemical and functional abnormalities in the later progenitors and
precursor cells. The committed CML progenitors have discordant maturation and reduced
proliferative capacity compared to normal committed progenitors, and like them, are destined to die
after a limited number of divisions. Thus, the primary goal of any curative strategy must be to
eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and
thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and
moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of
killing the majority of actively proliferating early CML progenitors with minimal effects on normal
progenitors. However, like their normal counterparts, most of the CML primitive stem cells are
quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well
77
as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important
reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors
and other drugs becomes increasingly important later. An outline of a possible curative strategy is
presented that attempts to take advantage of the subtle differences in the proliferative behavior of
normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl.
Abstract 28: From embryos to embryoid bodies: generating blood from embryonic stem cells.
Differentiation of embryonic stem (ES) cells in vitro yields abundant hematopoietic progenitors, but
achieving stable hematopoietic engraftment of irradiated mice has proven difficult, begging the
question of whether ES cells give rise to hematopoietic stem cells in vitro, and limiting the
application of ES cells as experimental and therapeutic models. We have employed a number of
hematopoietic regulatory genes to probe the nature and developmental potential of ES-derived
blood precursors. The chronic myeloid leukemia-associated BCR/ABL oncoprotein transforms a
novel class of ES-derived embryonic hematopoietic stem cell that represents a common progenitor
of primitive erythropoiesis and definitive lymphoid-myeloid blood development. Expression of the
homeobox gene HoxB4 generated normal, non-leukemic hematopoietic progenitors that enabled
long-term, multilineage hematopoietic engraftment in primary and secondary mouse recipients. We
have used these repopulating hematopoietic stem cells to model therapeutic transplantation from ES
cells. We treated an immunodeficient Rag2(-/-) mouse by therapeutic cloning, that is, isogenic ES
cell generation by somatic cell nuclear transfer, gene correction, and cell replacement therapy.
Comparable approaches with human ES cells are being developed to lay the foundation for cellular
therapies in patients with a variety of bone marrow diseases.
Abstract 29: Safety concerns related to hematopoietic stem cell gene transfer using retroviral
vectors.
Endogenous retroviruses have developed efficient methods during their life cycle for stable
integration into the host genome. Because of this ability, retroviral vectors were designed with the
goal of gene transfer into hematopoietic stem cells (HSCs). The ability to genetically modify HSCs
provides a vehicle for durable expression of potentially therapeutic transgenes in all lineages of
mature blood cells for the lifetime of the patient. Combined with bone marrow transplant, retroviral
gene transfer has many potential applications for a wide range of blood diseases. Advances in the
development of oncoretroviral vectors based on murine leukemia viruses (MLV) and more recent
development of human immunodeficiency virus (HIV)-based vectors have greatly increased the
gene transfer efficiency. Optimization of methods for gene transfer using MLV-based vectors has
substantially improved marking levels in mice, with lower levels in large animals and in human
clinical trials. With advances in gene transfer technology has also come renewed concern about
insertional mutagenesis and activation of oncogenes. Advanced techniques for integration site
analysis combined with sequence comparison using mouse and human genome databases has now
made it possible to begin to understand the spectrum of possible integration sites for both MLVand HIV-based vectors. Furthermore, other studies have shown positive and negative dosagedependent effects of transgene expression in mouse and human cells. Therefore, vector design and
safety testing are at the forefront of the field of gene therapy and this review discusses recent
developments.
Abstract 30: Immunotherapeutic approaches for hematologic malignancies.
The immune system has two complementary arms: one is older and seemingly more primitive,
called the innate immune system, found in both plants and animals. The second (already many
millions of years old!) is the adaptive or antigen-specific immune system, limited to vertebrate
animals. The human innate immune system has many cellular elements that include granulocytes,
monocytes, macrophages, natural killer (NK) cells, mast cells, eosinophils, and basophils.
Receptors for these cells are non-clonal, fixed in the genome, requiring no rearrangement, and
recognize conserved molecular patterns that are specific to pathogens. The adaptive immune system
78
(B cells and T cells) have receptors with great variation, able to recognize an almost an unlimited
number of highly specific pathogens through rearrangement of receptor gene segments, and can also
provide immunological memory so critical for vaccination. As the immune system has evolved to
recognize non-self, malignant transformation of self can likely escape immune surveillance with
relative ease. Contributors to this chapter are utilizing distinct components of either the innate or
adaptive immune system that recognize non-self, in combination with what we know about
differences between malignant and normal self, in an effort to develop novel and effective
immunologic approaches against hematologic malignancies. In Section I, Dr. Andrea Velardi
reviews the benefits of NK cell alloreactivity in mismatched hematopoietic transplantation, provides
updates on current clinical trials, and discusses further therapeutic perspectives emerging from
murine bone marrow transplant models. In Section II, Dr. David Scheinberg reviews novel
leukemic antigens being targeted by humanized monoclonal antibodies as well as mechanisms by
which antibody-mediated cytotoxicity occurs in vivo. In Section III, Dr. Ivan Borrello reviews
vaccine and adoptive T cell immunotherapy in the treatment of hematologic malignancies.
Specifically, he discusses the various vaccine approaches used as well as strategies aimed at
augmenting the tumor specificity of T cell therapies.
Abstract 31: Immunoprevention and immunotherapy of cancer in ageing.
Over the last few years there has been a growing interest in geriatric oncology, mainly because of
the evidence that advanced age is the greatest risk factor for the development of cancer and that,
since the elderly population is rapidly expanding, so too will the number of cancer patients. This
forecast necessitates the development of new and more specific strategies for the prevention and
cure of cancer in the elderly and as a result an ever-increasing need for oncologists, geriatricians
and researchers to work closely together. The increased incidence of cancer in elderly people has
been related to the age-associated changes occurring in the immune system, the so-called
immunosenescence. This phenomenon is best characterised by a remodelling of the immune system,
which appears early on and progresses throughout a person's life and mainly involves a decrease in
cellular functions. This review aims to provide a rationale for the development of specific
immunotherapeutic and immunopreventive regimens for the elderly. We also include a discussion
on the influence that immunosenescence has on the growth of tumours and the effectiveness of
immunogene therapy and cancer vaccination following a brief analysis of the age-related alterations
of the cell populations involved in antitumour immunity.
79
Dr. Barbaros ORAL
Text 71: Allergy
Introduction
In this review you will learn how allergy relates to the immune system. You will begin
understanding how and why certain people become allergic. The most common allergic diseases are
discussed briefly in this article.
What does an allergy mean?
An allergy refers to a misguided reaction by our immune system in response to bodily contact with
certain foreign substances. It is misguided because these foreign substances are usually harmless
and remain so to non- allergic people. Allergy-producing substances are called "allergens."
Examples of allergens include pollens, dust mite, molds, danders, and foods. To understand the
language of allergy it is important to remember that allergens are substances that are foreign to the
body and can cause an allergic reaction in certain people.
When an allergen comes in contact with the body, it causes the immune system to develop an
allergic reaction in persons who are allergic to it. When you inappropriately react to allergens that
are normally harmless to other people, you are having an allergic reaction and can be referred to as
allergic or atopic. Therefore, people who are prone to allergies are said to be allergic or "atopic."
Austrian pediatrician Clemens Pirquet (1874-1929) first used the term allergy. He referred to both
immunity that was beneficial and to the harmful hypersensitivity as "allergy." The word allergy is
derived from the Greek words "allos," meaning different or changed and "ergos," meaning work or
action. Allergy roughly refers to an "altered reaction." The word allergy was first used in 1905 to
describe the adverse reactions of children who were given repeated shots of horse serum to fight
infection. The following year, the term allergy was proposed to explain this unexpected "changed
reactivity."
How do allergies develop?
To help answer this question, let's look at a common household example. A few months after the
new cat arrives in the house, dad begins to have itchy eyes and episodes of sneezing. One of the
three children develops coughing and wheezing, especially when the cat comes into her bedroom.
The mom and the other two children experience no reaction whatsoever to the presence of the cat.
How can we explain this?
The immune system is the body's organized defense mechanism against foreign invaders,
particularly infections. Its job is to recognize and react to these foreign substances, which are called
antigens. Antigens are substances that are capable of causing the production of antibodies. Antigens
may or may not lead to an allergic reaction. Allergens are certain antigens that cause an allergic
reaction and the production of IgE.
The aim of the immune system is to mobilize its forces at the site of invasion and destroy the
enemy. One of the ways it does this is to create protective proteins called antibodies that are
specifically targeted against particular foreign substances. These antibodies, or immunoglobulins
(IgG, IgM, IgA, IgD), are protective and help destroy a foreign particle by attaching to its surface,
thereby making it easier for other immune cells to destroy it. The allergic person however, develops
a specific type of antibody called immunoglobulin E, or IgE, in response to certain normally
harmless foreign substances, such as cat dander. To summarize, immunoglobulins are a group of
protein molecules that act as antibodies. There are 5 different types; IgA, IgM, IgG, IgD, and IgE.
IgE is the allergy antibody.
(In 1967, the husband and wife team of Kimishige and Teriko Ishizaka detected a previously
unrecognized type of immunoglobulin in allergic people. They called it gamma E globulin or IgE.)
80
In the pet cat example, the dad and the youngest daughter developed IgE antibodies in large
amounts that were targeted against the cat allergen, the cat dander. The dad and daughter are now
sensitized or prone to develop allergic reactions on subsequent and repeated exposures to cat
allergen. Typically, there is a period of "sensitization" ranging from months to years prior to an
allergic reaction. Although it might occasionally appear that an allergic reaction has occurred on the
first exposure to the allergen, there must have been a prior contact in order for the immune system
to be poised to react in this way.
IgE is an antibody that all of us have in small amounts. Allergic persons, however, produce IgE in
large quantities. Normally, this antibody is important in protecting us from parasites, but not from
cat dander or other allergens. During the sensitization period, cat dander IgE is being overproduced
and coats certain potentially explosive cells that contain chemicals. These cells are capable of
causing an allergic reaction on subsequent exposures to the dander. This is because the reaction of
the cat dander with the dander IgE irritates the cells and leads to the release of various chemicals,
including histamine. These chemicals, in turn, cause inflammation and the typical allergic
symptoms. This is how the immune system becomes misguided and primed to cause an allergic
reaction when stimulated by an allergen.
On exposure to cat dander, the mom and the other two children produce other classes of antibodies,
none of which cause allergic reactions. In these non-allergic members of the family, the dander
particles are eliminated uneventfully by the immune system and the cat has no effect on them.
Who is at risk and why?
Allergies can develop at any age, possibly even in the womb. They commonly occur in children but
may give rise to symptoms for the first time in adulthood. Asthma may persist in adults while nasal
allergies tend to decline in old age.
Why, you may ask, are some people "sensitive" to certain allergens while most are not? Why do
allergic persons produce more IgE than those who are non-allergic? The major distinguishing factor
appears to be heredity. For some time, it has been known that allergic conditions tend to cluster in
families. Your own risk of developing allergies is related to your parents' allergy history. If neither
parent is allergic, the chance that you will have allergies is about 15%. If one parent is allergic, your
risk increases to 30% and if both are allergic, your risk is greater than 60%.
Although you may inherit the tendency to develop allergies, you may never actually have
symptoms. You also do not necessarily inherit the same allergies or the same diseases as your
parents. It is unclear what determines which substances will trigger a reaction in an allergic person.
Additionally, which diseases might develop or how severe the symptoms might be is unknown.
Another major piece of the allergy puzzle is the environment. It is clear that you must have a
genetic tendency and be exposed to an allergen in order to develop an allergy. Additionally, the
more intense and repetitive the exposure to an allergen and the earlier in life it occurs, the more
likely it is that an allergy will develop.
There are other important influences that may conspire to cause allergic conditions. Some of these
include smoking, pollution, infection, and hormones.
Where are allergens? Everywhere
We have seen that allergens are special types of antigens that cause allergic reactions. The
symptoms and diseases that result depend largely on the route of entry and level of exposure to the
allergens. The chemical structure of allergens affects the route of exposure. Airborne pollens, for
example, will have little effect on the skin. They are easily inhaled and will thus cause more nasal
and lung symptoms and limited skin symptoms. When allergens are swallowed or injected they may
travel to other parts of the body and provoke symptoms that are remote from their point of entry.
For example, allergens in foods may prompt the release of mediators in the skin and cause hives.
We will assume that allergens are defined as: the source of the allergy producing substance (e.g.
Cat), the substance itself (cat dander), or the specific proteins that provoke the immune response
81
(e.g. Feld1). Feld1, from the Felis domesticus (the domesticated cat), is the most important
chemical allergen in cat dander.
Allergens may be inhaled, ingested (eaten or swallowed), applied to the skin, or injected into the
body either as a medication or inadvertently by an insect sting.
Abstracts:
Abstract 32: Back to the future: antibody-based strategies for the treatment of infectious
diseases.
Before antibiotics, sera from immune animals and humans were used to treat a variety of infectious
diseases, often with successful results. After the discovery of antimicrobial agents, serum therapy
for bacterial infections was rapidly forsaken. In the last two decades, problems with treatment of
newly emerged, re-emerged, or persistent infectious diseases necessitated researchers to develop
new and/or improved antibody-based therapeutic approaches. This article reviews some information
on the use of antibodies for the treatment of infectious diseases, with special reference to the most
seminal discoveries and current advances as well as available treatment approaches in this field.
Abstract 33: Tularemia in Bursa, Turkey: 205 cases in ten years.
Tularemia is a zoonotic disease caused by the coccobacillus F. tularensis. Small epidemics and
sporadic cases were seen around Bursa since November 1988. In this study, a total of 205 cases of
tularemia were observed. All the cases were diagnosed on clinical, bacteriological and serological
grounds. The epidemics were thought to be waterborne. The majority of the patients were young
and female. In most of the cases the disease presented itself in oropharyngeal form (83%).
Analysing sera from the patients with microagglutination method demonstrated that titers were > or
= 1:160 in approximately 85% of the cases, including the ones in subclinical form. Five of ten
patients from who the bacteria was isolated were seronegative. Streptomycin was given to the most
of the patients by combining with tetracycline, doxycycline or chloramphenicol. The early
administration of these antibiotics (before the third week of disease) was found to be much more
effective to resolve the infection. As a result, the main mode of transmission of F. tularensis is
waterborne in our region. In our region, tularemia should be considered in differential diagnosis for
the cases with fever, tonsillopharyngitis and cervical lymphadenopathy to make an early diagnosis
and to design relevant treatment.
Abstract 34: Ex vivo adenovirus-mediated gene transfer and immunomodulatory protein
production in human cornea.
One attractive strategy to prevent or control allograft rejection is to genetically modify the donor
tissue before transplantation. In this study, we have examined the feasibility of gene transfer to
human corneal endothelium, using a number of recombinant adenovirus constructs. Ex vivo
infection of human corneas with adenoviral vectors containing lacZ, under transcriptional control of
either cytomegalovirus (CMV) or Rous sarcoma virus (RSV) promoters, provided high-level gene
expression, which was largely restricted to endothelium. Expression of the reporter gene persisted at
relatively high levels for up to 7 days, followed by a decline to indetectable levels by 28 days. RTPCR analysis of lacZ transcription showed a similar picture with a short period (3-7 days) of RNA
transcription after infection. In contrast, adenoviral DNA persisted for at least 56 days.
Subsequently, we examined the expression of a potential therapeutic gene, CTLA-4 Ig fusion
protein. Following infection of human corneas with adenoviral vectors encoding CTLA-4 Ig
protein, high levels of the fusion protein were detected in corneal culture supernatants for up to 28
days. This protein was functionally active, as determined by binding to B7.1 (CD80)-expressing
transfectants. This study suggests that genetic alteration of donor cornea before transplantation is a
feasible approach for preventing or controlling allograft rejection. Similar gene-based strategies
might also be feasible to prevent rejection of other transplanted tissues or organs.
82
Abstract 35: A method for determining the cytoprotective effect of catalase in transiently
transfected cell lines and in corneal tissue.
Both when developing gene constructs for therapeutic purposes and when testing the biological
function of proteins, it would be convenient to use cells or tissues that have been transiently
transfected with the gene of interest. However, determining the protective effects of transient gene
expression is complicated by a low transfection efficiency, resulting in only a minority of the cells
expressing the introduced gene and consequently a reduced sensitivity of assays measuring the
death of transfected cells. In this study we have developed a convenient technique for determining
cell death in transiently transfected vascular endothelial cell monolayers and in corneal tissue.
Vascular endothelial cells were cotransfected with human catalase cDNA and the lacZ gene
encoding beta-galactosidase, under conditions in which cells expressing beta-galactosidase also
expressed catalase. By assaying release of beta-galactosidase upon cell death, it was possible to
show that catalase transfection led to significant protection against the cytotoxic effect of increasing
concentrations of hydrogen peroxide. The assay was adapted to demonstrate the protective effects
of catalase transfection on hydrogen peroxide-mediated injury of intact corneal endothelium under
ex vivo culture conditions. This assay should also be useful for characterizing the cytoprotective
effects of other genes in transient transfection systems.
Abstract 36: Lipoadenofection-mediated gene delivery to the corneal endothelium: prospects
for modulating graft rejection.
BACKGROUND. Gene transfer to the corneal endothelium has potential for the prevention or
reversal of corneal allograft rejection. Previous work has examined adenoviral vectors for gene
transfer to endothelium. These have a number of theoretical and practical disadvantages, both for
experimental and clinical applications. We have therefore used lipoadenofection, in which plasmid
DNA is delivered using a combination of liposomes and adenovirus, to transfer marker genes to the
cornea. METHODS. Corneas were obtained from New Zealand White rabbits and cultured ex vivo
using standard conditions. The corneas were transfected using either lipofection or lipoadenofection
with plasmids encoding marker genes. The efficiency of gene transfer and the location and kinetics
of gene expression were determined. We also investigated the delivery of a gene construct
containing an inducible promoter that is activated by tumor necrosis factor (TNF), to determine
whether expression of the relevant genes could be controlled by exogenous factors such as
cytokines. RESULTS. This study shows that gene expression is limited to the endothelium and that
expression is transient. Furthermore, we have shown that expression of a gene controlled by an
inducible promoter only occurs when TNF is present. CONCLUSIONS. These data indicate that
lipofection is an efficient method to transfer therapeutic genes to the corneal epithelium, and that it
can be used to transfer constructs that utilize an inducible promoter controlled by TNF. As TNF is
present in the aqueous humor during allograft rejection, and this is in contact with the corneal
endothelium, this has the potential to restrict expression of a therapeutic gene to rejection episodes
in the cornea.
Abstract 37: Immunoglobulin subclasses and HLA alleles in immunoglobulin A deficiency.
OBJECTIVE: The term "IgA Deficiency (IgAD)" should be reserved for the individuals who do not
have detectable disorders known to be associated with low IgA levels. IgG subclass deficiency or a
lack of the IgG2 subclass that is specific against polysaccharide antigens, can be seen in many
cases. METHODS: Forty-five patients (27 males and 18 females; mean age 8.6 years, range 6.3 to
12.8 years) with IgA deficiency who had been admitted to the Department of Pediatric Immunology
in Uludag University School of Medicine, Turkey, were included in this study. Serum
immunoglobulin (Ig) class and IgG subclass levels, and HLA haplotypes were prospectively
determined in patients and healthy controls. RESULTS: Of the 45 patients with IgAD, 1 was found
to have a low level of IgG in the serum. Serum Ig levels were also examined in the families of 22
patients. Five patients had low-normal levels of IgM, whilst one had low levels of IgA and IgG. The
83
levels of IgG subclasses were assessed in 23 patients. One patient had a low level of IgG1; 2 had
low levels of both IgG2 and IgG3, and 11 had low levels of IgG3. IgG subclass concentrations were
found to be normal in control groups. HLA alleles were tested in 25 patients. An increased
prevelence of HLA-A1, -B8, -B14, -DR1, -DR3, and -DR7 were previously observed in patients
with IgA deficiency. In this study, HLA-A1 allel was found in 3 patients (12%), HLA-B14 in 3
patients (12%), HLA-DR1 in 10 patients (40%), HLA-DR7 in 4 patients (16%) and HLA-DR3 in 1
patient (4%). HLA-B8 allel was not found in any patient. Twenty-five children with normal IgA
levels have chosen as a control group. They had HLA-DR1 (36%), HLA-DR7 (16%), HLA-B8
(8%), HLA-DR3 (16%). HLA-A1 was not found in any member of our control group.
CONCLUSION: No statistically significant difference in HLA susceptibility alleles was found
between patients and healthy controls. Our data suggest that there may be heterogenous HLA
distribution patterns in IgA deficiency, or that HLA allel-associated tendency to IgA deficiency may
be polygenic.
84
Dr. Hakan CANGÜL
Text 72: Diabetes Mellitus
What is diabetes mellitus?
Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose)
levels, which result from defects in insulin secretion, or action, or both. Diabetes mellitus,
commonly referred to as diabetes, means "sweet urine." Elevated levels of blood glucose
(hyperglycemia) lead to spillage of glucose into the urine, hence the term sweet urine. Normally,
blood glucose levels are tightly controlled by insulin, a hormone produced by the pancreas. Insulin
lowers the blood glucose level. When the blood glucose elevates (for example, after eating food),
insulin is released from the pancreas to normalize the glucose level. In patients with diabetes
mellitus, the absence or insufficient production of insulin causes hyperglycemia. Diabetes mellitus
is a chronic medical condition, meaning it can last a lifetime.
What is the impact of diabetes?
Over time, diabetes mellitus can lead to blindness, kidney failure, and nerve damage. Diabetes
mellitus is also an important factor in accelerating the hardening and narrowing of the arteries
(atherosclerosis), leading to strokes, coronary heart diseases, and other blood vessel diseases.
Diabetes mellitus affects 15 million people (about 8% of the population) in the United States. In
addition, an estimated 12 million people in the United States have diabetes and don't even know it.
From an economic perspective, the total annual economic cost of diabetes in 1997 was estimated to
be 98 billion dollars in the United States. The per capita cost resulting from diabetes in 1997
amounted to $10,071, while to health care costs for people without diabetes incurred a per capita
cost of $2,699. During this same year, 13.9 million days of hospital stay were attributed to diabetes,
while 30.3 million physician office visits were diabetes related. Remember, these numbers reflect
only the population in the United States. Globally, the statistics are staggering.
Diabetes is the third leading cause of death in the United States after heart disease and cancer.
What causes diabetes mellitus?
Insufficient production of insulin (either absolutely or relative to the body's needs), production of
defective insulin (which is uncommon), or the inability of cells to use insulin leads to
hyperglycemia and diabetes mellitus. This latter condition affects mostly the cells of muscle and fat
tissues, and results in a condition known as "insulin resistance." This is the primary problem in type
2 diabetes. The absolute lack of insulin, usually secondary to a destructive process in the pancreas,
is the particular disorder in type 1 diabetes.
Glucose is a simple sugar found in food. Glucose is an essential nutrient that provides energy for the
proper functioning of the body cells. After meals, food is digested in the stomach and the intestines.
The glucose in digested food is absorbed by the intestinal cells into the bloodstream, and is carried
by blood to all the cells in the body. However, glucose cannot enter the cells alone and needs insulin
to aid in its transport into the cells. Without insulin, cells become starved of glucose energy despite
the presence of abundant glucose in the blood. In certain types of diabetes mellitus, the cells'
inability to utilize glucose gives rise to the ironic situation of "starvation in the midst of plenty".
The abundant, unutilized glucose is wastefully excreted in the urine.
Insulin is a hormone that is produced by specialized cells (beta cells) of the pancreas. (The pancreas
is a deep-seated organ in the abdomen located behind the stomach.) In addition to helping glucose
enter the cells, insulin is also important in tightly regulating the level of glucose in the blood. After
a meal, the blood glucose level rises. In response to the increased glucose level, the pancreas
normally releases insulin into the bloodstream to help glucose enter the cells and lower blood
glucose levels. When the blood glucose levels are lowered, the insulin release from the pancreas is
turned off. In normal individuals, such a regulatory system helps to keep blood glucose levels in a
85
tightly controlled range. In patients with diabetes mellitus, the insulin is either missing (as in type 1
diabetes mellitus), or insulin is relatively insufficient for the body's needs (as in type 2 diabetes
mellitus). Both cause elevated levels of blood glucose (hyperglycemia).
What are the symptoms of diabetes mellitus?
The early symptoms of untreated diabetes mellitus are related to elevated blood sugar levels, and
loss of glucose in the urine. High amounts of glucose in the urine can cause increased urine output
and lead to dehydration. Dehydration causes increased thirst and water consumption. The inability
to utilize glucose energy eventually leads to weight loss despite an increase in appetite. Some
untreated diabetes patients also complain of fatigue, nausea, and vomiting. Patients with diabetes
are prone to developing infections of the bladder, skin, and vaginal areas. Fluctuations in blood
glucose levels can lead to blurred vision. Extremely elevated glucose levels can lead to lethargy and
coma (diabetic coma).
How is diabetes mellitus diagnosed?
The fasting blood glucose (sugar) test is the preferred way to diagnose diabetes. It is easy to
perform and convenient. After the person has fasted overnight (at least 8 hours), a single sample of
blood is drawn and sent to the laboratory for analysis.
Normal fasting plasma glucose levels are less than 110 milligrams per deciliter (mg/dl). Fasting
plasma glucose levels of more than 126 mg/dl on two or more tests on different days indicate
diabetes. If the overnight fasting blood glucose is greater than 126 mg/dl on two different tests on
different days, the diagnosis of diabetes mellitus is made. A random blood glucose test can also be
used to diagnose diabetes. Random blood samples (if taken shortly after eating or drinking) may be
used to test for diabetes when symptoms are present. A blood glucose level of 200 mg/dl or higher
indicates diabetes, but it must be reconfirmed on another day with a fasting plasma glucose or an
oral glucose tolerance test.
When fasting a blood glucose stays above 110 mg/dl, but in the range of 110-126mg/dl, this is
known as impaired fasting glucose (IFG). While patients with IFG do not have the diagnosis of
diabetes, this condition carries with it its own risks and concerns, and is addressed elsewhere.
How is diabetes treated?
The major goal in treating diabetes mellitus is controlling elevated blood sugars (glucose) without
causing abnormally low levels of blood sugar. Type 1 diabetes mellitus is treated with insulin,
exercise, and a diabetic diet. Type 2 diabetes mellitus is first treated with weight reduction, a
diabetic diet, and exercise. When these measures fail to control the elevated blood sugars, oral
medications are used. If oral medications are still insufficient, insulin medications are considered.
Adherence to a diabetic diet is an important aspect of controlling elevated blood sugar in patients
with diabetes mellitus. The American Diabetes Association (ADA) has provided guidelines for a
diabetic diet. The ADA diet is a balanced, nutritious diet that is low in fat, cholesterol, and simple
sugars. The total daily calories are evenly divided into three meals. In the past two years, the ADA
has lifted the absolute ban on simple sugars. Small amounts of simple sugars are allowed when
consumed with a complex meal.
Weight reduction and exercise are important treatments of diabetes. Weight reduction and exercise
increase the body's sensitivity to insulin, thus helping to control blood sugar elevations.
Abstracts:
Abstract 38: Genetic counseling program in familial breast cancer: analysis of its
effectiveness, cost and cost-effectiveness ratio.
Women with a family history of breast cancer are at increased risk for developing this neoplasm.
Starting surveillance more frequently at a younger age than the general population and the
possibility of undergoing genetic testing are options for their medical management. We analyzed
the benefits and costs of our clinical program in familial breast cancer (FBC) and carried out a cost86
effectiveness analysis of such procedure. The benefits and costs of performing genetic counseling
and a screening program in FBC based on 143 high-risk families registered in our database between
June 1995 and December 2001 were analyzed. A decision tree was constructed to estimate the
survival benefit and cost-effectiveness of the clinical genetic counseling program compared with the
strategy of not performing any screening protocol. We estimated that the prevalence of a BRCA
mutation in an unaffected relative of our high-risk cohort was 10% and that 53% of the mutations
are found in the BRCA1 gene. We assigned a 58.5% lifetime risk of breast cancer for a 30-year-old
mutation carrier according to the SEER data. The effectiveness of the screening was obtained from
our experience and data for estimating survival were derived from other studies with longer followup. We used our local payment data to calculate the costs of the program. A mutation in the BRCA1
or BRCA2 genes was identified in 20% of the probands. Seventy primary breast cancer cases were
recorded since the onset of the program. Thirty percent of the tumors were diagnosed through the
screening program and 71% of them were lymph node-negative compared to 49% of the tumors
diagnosed outside the program (p=0.1). The cost-effectiveness ratio of our FBC genetic counseling
and screening program was 4,294 euros per life-year gained. The model was sensitive to the
prevalence of mutation carriers, the lifetime risk of breast cancer and the effectiveness of the
screening. In our setting and according to our model, this analysis suggests that a program of
genetic testing and screening for breast cancer in a high-risk population may be cost-effective.
These results need to be confirmed as more effective interventions for cancer prevention and
screening are being implemented.
Abstract 39: Outline of a medical genetics curriculum for internal medicine residency
training programs.
To keep pace with the rapid advances in medical genetics, internal medicine residency training
programs need to train internists to develop new attitudes, knowledge bases, and skill sets.
Currently, such programs have no medical genetics curriculum. Thus, to set a minimum standard
for genetics education in the context of training in internal medicine, the Internal Medicine
Residency Training Program Genetics Curriculum Committee was formed, with members
representing professional organizations of medical geneticists, internists, genetic counselors,
internal medicine and genetics residency program directors, and internal medicine residents. The
committee's task was to develop a concise outline of a medical genetics curriculum for residents in
internal medicine in accordance with requirements of the Residency Review Committee for Internal
Medicine of the Accreditation Council for Graduate Medical Education. The curriculum outline was
drafted and circulated for comment. Before publication, the final document was approved by those
member organizations that had a policy of approving curricula. Key learning objectives of the
curriculum include appreciation of the rapid advances in genetics, the need for lifelong learning, the
need for referral, and the role of genetic counselors and medical geneticists, as well as developing
the ability to construct and analyze a three-generation pedigree. A wide variety of teaching methods
can be useful in these regards, including didactic lectures, multimedia CD- ROMs, and clinical
experience. Teaching should be related to clinical experiences whenever possible. The curriculum
developed by the committee and presented in this article will assist in teaching residents the
attitudes, knowledge, and skills they will require.
Abstract 40: Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective
screen for missense mutations in the ATPase domain.
Germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1 are responsible
for the majority of hereditary non-polyposis colorectal cancer (HNPCC), an autosomal-dominant
early-onset cancer syndrome. Genetic testing of both MSH2 and MLH1 from individuals suspected
of HNPCC has revealed a considerable number of missense codons, which are difficult to classify
as either pathogenic mutations or silent polymorphisms. To identify novel MLH1 missense codons
that impair MMR activity, a prospective genetic screen in the yeast Saccharomyces cerevisiae was
developed. The screen utilized hybrid human-yeast MLH1 genes that encode proteins having
87
regions of the yeast ATPase domain replaced by homologous regions from the human protein.
These hybrid MLH1 proteins are functional in MMR in vivo in yeast. Mutagenized MLH1
fragments of the human coding region were synthesized by error-prone PCR and cloned directly in
yeast by in vivo gap repair. The resulting yeast colonies, which constitute a library of hybrid MLH1
gene variants, were initially screened by semi-quantitative in vivo MMR assays. The hybrid MLH1
genes were recovered from yeast clones that exhibited a MMR defect and sequenced to identify
alterations in the mutagenized region. This investigation identified 117 missense codons that
conferred a 2-fold or greater decreased efficiency of MMR in subsequent quantitative MMR assays.
Notably, 10 of the identified missense codons were equivalent to codon changes previously
observed in the human population and implicated in HNPCC. To investigate the effect of all
possible codon alterations at single residues, a comprehensive mutational analysis of human MLH1
codons 43 (lysine-43) and 44 (serine-44) was performed. Several amino acid replacements at each
residue were silent, but the majority of substitutions at lysine-43 (14/19) and serine-44 (18/19)
reduced the efficiency of MMR. The assembled data identifies amino acid substitutions that disrupt
MLH1 structure and/or function, and should assist the interpretation of MLH1 genetic tests.
Abstract 41: High concordance of bipolar I disorder in a nationwide sample of twins.
OBJECTIVE: The few studies of bipolar I disorder in twins have consistently emphasized the
genetic contribution to disease liability. The authors report what appears to be the first twin study of
bipolar I disorder involving a population-based twin sample, in which the diagnoses were made by
using structured, personal interviews. METHOD: All Finnish same-sex twins (N=19,124) born
from 1940 to 1957 were screened for a diagnosis of bipolar I disorder as recorded in the National
Hospital Discharge Register between 1969 and 1991 or self-reported in surveys of the Finnish Twin
Cohort in 1975, 1981, and 1990. Thirty-eight pairs were thereby identified and invited to participate
in the study; the participation rate was 68%. Lifetime diagnoses were made by using the Structured
Clinical Interview for DSM-IV. The authors calculated probandwise and pairwise concordances and
correlations in liability and applied biometrical model fitting. RESULTS: The probandwise
concordance rates were 0.43 (95% CI=0.10 to 0.82) for monozygotic twins and 0.06 (95% CI=0.00
to 0.27) for dizygotic twins. The correlations in liability were 0.85 and 0.41, respectively. The
model with no familial transmission was rejected. The best-fitting model was the one in which
genetic and specific environmental factors explained the variance in liability, with a heritability
estimate of 0.93 (95% CI=0.69 to 1.00). CONCLUSIONS: The high heritability of bipolar disorder
was demonstrated in a nationwide population-based twin sample assessed with structured personal
interviews.
Abstract 42: Relationship between dopaminergic neurotransmission, alcoholism, and reward
deficiency syndrome.
In this review, we described the neural substrates underlying Reward Deficiency syndrome which,
in turn, is posited to underlie alcohol dependency. Alcoholism is a complex, multifactorial disorder
that results from the interplay between genetic and environmental factors. The D(2) dopamine
receptor (DRD(2)) has been associated with pleasure, and the DRD(2) A1 allele has been referred to
as a reward gene. Evidence suggests that there is a tripartite interaction involving dopamine
receptor deficiency, a propensity to abuse alcohol, and reduced sensitivity to rewards. This
interaction relies heavily on genetic characteristics of the individual, with certain ethnic groups
having a greater tendency toward alcoholism than others. The DRD(2) has been one of the most
widely studied in neuropsychiatric disorders in general, and in alcoholism and other addictions in
particular. The dopamine D2 (DRD2) gene, and especially its allele TaqI A1 allele and its receptor,
also may be involved in comorbid antisocial personality disorder symptoms, high novelty seeking,
and related traits. The mesocorticolimbic dopaminergic pathway system plays an especially
important role in mediating reinforcement by abused drugs, and it may be a common denominator
for addictions such as alcoholism. When the mesocorticolimbic dopamine reward system
dysfunctions (perhaps caused by certain genetic variants), the end result is Reward Deficiency
88
syndrome and subsequent drug-seeking behaviors. Reward Deficiency syndrome refers to the
breakdown of the reward cascade, and resultant aberrant conduct, due to genetic and environmental
influences. Alcohol and other drugs of abuse, as well as most positive reinforcers, cause activation
and neuronal release of brain dopamine, which can decrease negative feelings and satisfy abnormal
cravings. A deficiency or absence of DRD(2) receptors then predisposes individuals to a high risk
for multiple addictive, impulsive, and compulsive behaviors. Although other neurotransmitters (e.g.,
glutamate, gamma-aminobutyric acid (GABA), and serotonin) may be important in determining the
rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and
for reinstating drug use during protracted abstinence. This article contains supplementary material,
which may be viewed at the American Journal of Medical Genetics website at
http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.
89
EXAMPLES OF LETTERS, CV, ETC..
90
MEDICAL GLOSSARY
91