Jan Arteriosclerosis

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					Jan. 9
    i)  mortality of all ages (especially infant)
         - „rectangular curve‟ (instead of more downward linear line; “ \ “ shape)
         - The progressive elimination of early death caused the curve to move toward the
              “ideal” curve that would occur if there were no premature deaths. Now little room for
              „improvement‟ towards the ideal left
    ii) Change in cause of mortality
         - developed world:
                  o < 1840: infectious disease prevalent, point-onset types and occur to any age (some
                      sensitive periods)
                  o 2000‟s: chronic disease, such as heart disease, cancer, diabetes. Gradual onset (late,
                      > 50 yr), „lifestyle‟ disease, we now live long enough to get such chronic disease, 
                      incidence rate is global (2001: 45% burden of disease by lifestyle disease; 2020:
                      will be 57%)
         - Examples:
                  o Cardiovascular disease: constellation of disorders,  ability of heart to circulate
                       Arteriosclerosis: arterial wall has  thickness,  elasticity, various types
                        (atherosclerosis is most common), 1st indication is fatty streaks (lipid laden cells at
                        endothelial lining) that later form fibrous plaque and become calcified after many
                        yrs. Causes  in elasticity, occlusion
                       Hypertension:  BP (systolic/diastolic)
                        1˚ (essential) hypertension is idiopathic, no symptoms
                        2˚ hypertension: caused by changes in renal function, vascular function, etc.

                      Comprises:  vascular resistance,  cardiac output, develops over time
                      Eventually: generalized arteriosclerosis, nephrosclerosis, left ventricular
                       hypertrophy, coronary, aortic, cerebral, peripheral and atherosclerosis

                o Cancer: uncontrolled division of non-differentiated monoclonal tissues,  risk with
                  age, develops over yrs,
                          3 stage model:
                              Initiation: somatic cells divide, normal  exposed to “initiator”
                             (environmental agent that is carcinogenic)  transformed via genetic
                             mutation  permanent change
                              Promotion: agent stimulates cell division, cell initiated have
                             uncontrolled divisions, delay (many yrs) after initiation, further
                             mutations (loss of DNA repair mechanisms, accelerate mutation rate)
                              Progression: decades after initiation/promotion, involves process of
                             growth /metastasis, loss of cell specify, can divide away from influences,
                             often 1st symptoms, cancer risk associated with lifestyle, occupation, etc.
                             Long delay between “causes” & symptoms

                o Diabetes:
                          most common endocrine disease, associated with peripheral
                            neuropathies, atherosclerosis, peripheral & coronary artery disease
                          Caused by hyperglycemia due to:
                              insulin production: loss of pancreatic β cells, „insulin dependent
                            diabetes mellitus‟ a.k.a. Type 1, 10-13% cases in Canada & U.S.,
                            usually age of onset < 30 yrs
                                insulin effectiveness:  secretion response to glucoses,  tissue
                              glucose uptake, „non-insulin-dependent diabetes mellitus‟ a.k.a. Type 2,
                              usually > 30yrs, most common form, incidence , by 2025 incidence
                              increased by 2-3 X
                                   Development of type 2 diabetes:
                                         o 1st, mild hyperglycemia,  response to insulin,  insulin
                                             production, adolescence / young adulthood, symptoms in
                                             mid-late adulthood, associated with obesity

ix) How can health problems develop over time?
    o WHO report (2002), 4 theoretical models;
    1. insult at specific time  lifelong effect on structure / function  disease at later time
           o Prenatal factors: undernutrition, teratogens (ethanol, etc)
    2. Critical period influence on later modifiers:  risk only if later exposure to factors, prenatal
       under nutrient, adolescence smoking onset,
    3. Accumulation of risks / correlated results: risk factors cluster, exposure to one  risk of being
       exposed to others, if prenatal under nutrient then  risk of post natal malnutrition /
    4. Accumulation of risks / independent results: separate, independent risk factors, combine to 
       risk of disease, ex. high saturated fat diet & smoking (they are independent of each other, but
       their combined effect is exponentially bad),

   Challenge: to determine which model applies,
   o Ex. intrauterine growth retardation (IUGR):  risk of “metabolic syndrome”, critical period?,
      but followed by  catch-up growth,  or  or ?,
   o Also: health problems can develop as result of natural developmental processes, natural effects
      of late aging, Problem is how to determine if processes are natural?,

Recurring themes in development
1. Reductionism vs. Systems approaches
    i) Ancient debate: substance vs. form
    ii) Scientific revolution: claimed that knowledge should be based on measurable quantities,
    o Descartes came up with Cartesian reductionism with mechanistic view of biology (thinking
         that reducing the subject to its basic components is the best way of understanding it)
    o Harvey who found circulation applied Cartesian principles to “life”. Other attempts (digestion,
         metabolism) had  success with this approach
    iii) 20th century organismic biology:  in systems thinking (physiology, econology), recognize
    relationships at different levels of organization,

2. Genetics environment & epigenetics: organism comes from a single cell, cells contain programs,
blueprint for development?, this material ensures;
    o Continuity of species-specific traits
    o Individual variation (required for evolution)
    But gene expression varies; function of role of environment, both intracellular & external
    environments, important adaptation mechanism.
    Ex. 1: gene repair mechanism‟s response to environment stimuli  varying rate of mutations,
    insure survival of species?
    Ex. 2: regulator genes response to environment: influence survival of individuals?
    Now, we have epigenetic view.
3. Essentialism vs. Population approaches
    i) Essentialism: Aristotle said each system in nature has one true value (Natural state), variation
    caused by interference (unnatural)
    ii) Laplace (1780s): used astronomy, 2 types of causes;
         1. Constant causes: unchanging: all individuals should have constant value
         2. Disturbing causes: variation from constant value
   - Pre-Darwinian concept: generational change
         - traits predetermined
                  - due to inherited factors
                  - differences due to interference in development
                  - view still present today?
                  - concept of errors in life sciences (error term in statistics)
         - typological thinking (“what is the essential nature of a thing, person, etc?”  assumes that
              everything has a certain nature that is born with) : no distinction between individual &
              population, if individual differs from population mean, due to random/systematic “error”
   iii) population approach
         - Darwin: variability among individuals within population necessary
                  - adaptation  evolution
                  - now: variability natural, necessary property
         - Galton (mid 1800‟s): systematic study of variability as natural phenomenon, variability
              normal in living systems, statistical tools allow for variability (standard deviation,
              correlation coefficient), mean values artificial, abstractions
                  - now: “what are characteristics of populations?”, these info does not tell us about
                      particular individual

                                   Reproduction I: Gametogenesis
    - why sexual reproduction?
       - theory: 2 benefits:  stability (genetic)     adaptation / ability to evolve
       - sexually reproduction is less genetically diverse, they tend to keep the same genes, thus more
            stable. They evolve by having different types of alleles.
   - how does sexual reproduction succeed?
       - alternate diploid  haploid states
       - most life cycle  multicellular, diploid
       - reproduction = transition: diploid  new diploid (requires haploid intermediate, through

- sperm & egg and are from diploid precursors (germ cells) through meiosis (reduction division).
- Meiosis is different from mitosis.
    - duplicate chromosomal materials  paired chromosomes
    - pairs separate, move along spindle  two new cells

Meiosis and development
1) Critical stages of meiosis
    i. replication of DNA: each strand replicated once / meiosis
         - if error, mutation occurs, especially critical if in gene coding region
   ii. recombination: breaking / recombination of DNA double strand
         - many errors occur,
        - associated with expression of DNA repair genes
  iii. chromosome segregation: if error, non-disjunction of homologous chromosomes
        - if it occurs, daughter cells with unequal number of chromosomes
        - function of recombination (if no recombination  no segregation) – recombination increases

2) Mutations vs. Non-disjunction
   - 3 sources of point mutations (substitutions)
       i) spontaneous: none during replication, unstable purine/pyrimidine bases, low frequency
       ii) errors of replication: function of frequency of mitosis
                - usually faithful (after repair): 1 mutation / 10 billion base pairs, there are 3 billion
                    base pairs, 100 – 200 million pairs as genes,
       iii) errors of recombination: recombination  double strand breaks, associated with 
              expression of DNA repair genes,  potential for DNA damage
   - meiotic prophase: recombination of non-sister chromatids of homologous chromosomes. If not,
       homologous chromosomes don‟t separate successfully. This leads to aneuploidy (trisomy or
       monosomy, but trisomy is most common)
   - Trisomy: occur in all chromosomes (not „seen‟ in #1, due to death of zygote). Most common is in
       #16 (fatal), then 21 (second smallest in size, possibly the reason why these children do survive),
       18 (fatal) and 13 (fatal). These people usually die at an early age
   - non-segregation in humans: 10-25% human conceptions have abnormal chromosomes (most are
       fatal, except sex chromosomes). 50% spontaneous abortions due to chromosomal abnormalities,
       but compromise < 1% of live births (abandoning „defective‟ babies is necessary as the process
       is very energy costly. This system has many errors, but does give a balance between stability
       and evolution)

   Sex differences in meiosis
   - spermatogenesis vs. oogenesis
   - similar meiosis stages, but different timing and spindle formation differs

   1. Human spermatogenesis
       i) germ cell: spermatogonia
                 o divide continuously at low rate (mitosis)
                 o diploid: 46 chromosomes
       ii) puberty: most remain in mitosis
                 o few  intermediate spermatogonia
                 1. differentiate to 1˚ spermatocyte (enter meiosis)
                 2. 1st meiotic division (become 2˚ spermatocyte)
                 3. 2nd meiotic division (cells become spermatids that are unflagellated but are haploid.
                    Cells are continuous – attached via cytoplasm to share gene products)
                 4. Spermiogenesis (still immature, must acquire flagella, acrosomal cap, maturation
                    occurs in seminiferous tubule – testes - & vas deferens)
                 5. Spermatozoa (now mature sperm)
          - process (spermatogonium  mature sperm) takes 74 days
          - meiosis lasts about 1 week
          - continuous process: < 120 million spermatozoa / testicle / day
          - lifetime: < 1013
   2. Human oogenesis
       i) germ cell: oognonia
          - divide continuously until 7th month gestation (mitosis). Produce total of 7 million
       ii) > 7 months, most die
          - no further mitosis. Rest differentiate  1˚ oocytes
          - 1st meiotic prophase
          - stops at diplotene phase. Here, genetic recombination and homologous chromosomes
       iii) birth: oocytes encased by epithelial cells
          - form primordial follicles
          - each follicle contained in > 1 layer of cells (nourishment)
                 - ½ million / ovary
       iv) puberty: upto 40,000 / ovary
          - primordial follicles  1˚ follicles
          - each month, some 1˚ follicles grow
          - become 2˚ follicles
               - 1 follicle  mature follicle (Graafian follicle)
               - LH surge < ovulation  resume meiosis 1
                          - spindles reorient: ensure most cytoplasm remains in 1st daughter cell, which
                               becomes 2˚ oocyte. Others become polar body
                          - mature follicle release 1 ova
                          - if fertilized, 2nd meiosis division begins
                          - repeat 400 times (avg)
                          - then ova degenerate (follicular atresia)
       v) menopause: no remaining ova

Question 1: are mutations equally likely to come from father & mother?
       i) different #‟s of replications
          - spermatogenesis
                - zygote  puberty: 36 divisions
                - after puberty: 23 / yr (by 20 yr, 200; 45 yr, 800)
          - oogenesis: zygote  puberty 24 divisions
                - by 40 yr, 24
          - since father has more divisions, more chance of father producing more mutations
       ii) mutation rate on Y chromosome
          - ~ 2X rate of other chromosomes
       iii) source of new mutations
          - most NEW mutations from father
          - some exceptions
                - deletions, recombinations occur less in males? (recombination rate  in females)
       iv) triplet repeat syndromes
          - Huntington‟s disease, fragile X syndrome
          - HD  in severity if passed by father
          - greater  # of repeats of amino acids

Question 2: are aneuploidy equally likely to come from father & mother?
       - 85-90% human aneuploidy from mother
       - gametes:
               - 20% oocytes aneuploidy
               - 4% sperm
              - selection of healthy mature sperm?
       - maternal age effect? (suspended meiosis of mother‟s eggs is the cause)

Question 3: what is the effect of maternal vs. paternal age?
       i) birth / death records – European royalty
           - slightly  lifespan if aged fathers
           - this is true for daughters only (longevity genes on X chromosome? only daughter gets X
                from father as sons get Y)
       ii) dominant genetic disease if normal parents
           - due more to paternal than maternal age
       iii) aneuploidies
           -  risk with increasing maternal age
           - slight  with paternal age

4. Summary
- Male / female differences in reproductive outcome
    o Males:  risk new / worse mutations
    o Females:  risk aneuploidy
    o Both:  risk with increasing age
           Age effect greater for females
    o But:
           Males  susceptible to cumulative effect of mutagens? (since females don‟t go through
             meiosis after birth, so less genetic damage)
            risk with age?
    o Implications for public health?

                             Reproduction II: fertilization & implantation
- Most sperm  remain outside cervix
   o Few enter uterus, oviduct (healthy sperms have much better chance at these obstacles)
             Live 24-48 h
- Stages:
   1. Ovulation: oocyte in metaphase II  released from follicle  surrounded by 2 barriers to
        sperm ( Protein coat called zona pellucida follicular cells that form cumulus and corona
   2. Preparation of sperm:
        o  capacitation (removal of glycoprotein coat from acrosomal membrane, takes several hrs,
            this prepares memberane for acrosomal reaction)
        o  acrosomal reaction (reaction to substances from corona, ova  acrosomal memberane
            fuses with zona  acrosomal contents released which facilitates prnetration of zona and
            this takes < 1hr)
        o  cell membranes fuse, sperm  egg cytoplasm (at this point, egg go through 2nd meiotic
            division of which produces 1 daughter cell & 2nd polar body. Haploid chromosomes
            become female pronucleus while sperm nucleus become male pronucleus in egg
        o  prevention of polyspermy:
                 Depolarization of cell membrane: prevent fusion with sperm
                 Release of granules below cell membrane: form barrier to sperm
Cell division
- 1st cleavage in 24hr of sperm penetration
- First 3-4 days, 16 cells stage is called morula
   o Encased in zona pellucida. Zona pellucida forces initiation of invagination
- 16 cells, it becomes blastocyst (after cavitation)

- 4-6 days post fertilization  enter uterus
- By the time of blastocyst  2 cell types appear
   o Outer layer: trophectoderm
   o Inner cell mass: embryoblast
- Zona pellucida removed at this point
- Trophectoderm  trophoblast cells
   o Contact endometrial cells (at embryogical pole)
   o Interact: both secrete enzymes
   o Blastocyte penetrate endometrium

                                    Early pregnancy termination

- Many conceptions are not live births
- 1950‟s: hysterectomy specimens
   - many signs of implantations without embryos
   - many abnormal embryos
- France (1970‟s)
   - 100 conceptions : 69 viable > 1 wk
                       42 > 2 wks
                       37 > 6 wks
                       31 at birth
- hCG studies: human chorionic gonadotropin
   - from trophoblast cells (from day 6)
        - mRNA expression starts at day 4 (you can know about conception from day 4)
   - allows early diagnosis of pregnancy
   - studies: about 30% of pregnancies “lost” after implantation
- most due to chromosomal / genetic abnormalities

Male fertility
- adequate production of normal spermatozoa
- transmission of sperm through seminal ducts
- deposition in vagina
1) endocrine levels
    - FSH, LH, testosterone
         - steroids, alcohol, drugs, caffeine
2) semen analysis
    - count
    - motility: quantitative (> 60% motile), qualitative (purposeful movement ex. just circle around)
    - presence of other cells (i.e. leukocytes for infection)
    - viscosity
   - chemical analysis of semen (fructose, etc)
   - 1992: BMJ
        -  “quality” of semen over 50 yrs
        - sperm count:
                - 1940‟s: 60 million / mL
                - 1990‟s: 20 million / mL
        - seminal volume: 3.4  2.75 mL
   - data supported in 2000 study
3) sperm morphology
   - < 40% abnormal
        - environmental exposures (heavy metals, hydrocarbons)
4) clinical exam
   - varicoceles (enlarged veins in testes) : increase temp to kill sperms
   - ductal obstructions (vas deferens)
        - gonorrhea, TB
   - cryptorchidism (testis don‟t descend: cause high temp)

Female fertility
   - regular menstrual cycle  ovulation
   - adequate environment for sperm
   - respondent corpus luteum  progesterone production
   - adequate hormones for pregnancy
1) endocrine levels
   - FSH, LH, estrogen, progesterone
        - smoking, drugs, malnutrition, exercise-induced amenorrhea,
2) ovulation
   - temp ( 0.5 ˚C)
   - ovarian ultrasound
        - environmental exposures
3) clinical examination
   - visual inspection of uterus and ovaries
   - looking for obstructions and scarring
        - PID, STD‟s (gonorrhea, chlamydia) MAY be causes, but no necessarily

   - failure to conceive > 1yr
   - developed world
        - 20% couples have failures
            - 8-10% couples > 2 yrs (this increases with age)
   - developing world
        - up to 30-40% have failures

Reproductive technologies

Duration & stages
1) Duration
   - approx. 270 days > fertility
        - OR 284 days > start last menstrual period
   - “normal” range = 240 – 300 days
   - estimate birth date:
        - first day of last period – 3 months + 7 days
   - Example: 1st day of last period = Dec. 7, 2007. Due date = (Dec 7 – 3 months) + 7 days
                                        = Sept. 7 + 7 days = Sept. 14, 2008
2) Stages
   - development in phases
        1) growth: cell division, some differentiation
        2) morphogenesis: form tissues, organs and systems
        3) differentiation / maturation: maturation of physiological / anatomical processes

1. Embryonic stage (approx. 1st trimester): 4-8 wks, establishment of organs & systems
      (organogenesis), formation of body form (head & tail folds)
2. Early fetal stage (approx. 2nd trimester):  growth, elaboration of structures (looks more human), 
      body length,  weight gain, relative size of head  (because body is getting bigger faster),
      relative length of upper limbs , lanugo hair (hair removed later in pregnancy), begin functional
      maturation (heart beat, response to light & sound – blinking, thumbsucking, low coordination
      between systems, low coordination especially in nervous and respiration systems and this is why
      premature birth survival rate is low), movement detected by mother
3. Late fetal stage (approx. 3rd trimester):  body mass,  fat deposition, lanugo hair disappears as
      fetus is able to maintain body temp better, maturation of system (especially lungs, nervous
      system), prepare for birth,

Development of the placenta
- placenta: site of maternal / fetal nutrient, gas exchange
- 2 components: maternal & fetal tissues combined

1. Development
   - implant: zona pellucida breaks down (2nd week)
   - blastocyst  cavity: blastocoel
        - surrounded by cell layer: trophoblast
        - endometrial pole, inner cells proliferate
                - embryoblast
   - trophoblast (embryonic pole)  layers
        - outer: syncytiotrophoblast
        - as they divide, poorly defined cells
        - contains vacuoles (lacunae)
        - maternal capillaries : endothelial lining erodes (holes created are called sinusoids and their
          development continues with lacunae). Lacunae serve as space for blood to flow into
        - maternal embryo blood supply (2 wks)
                -  4 wks: 2 tissues:  uterus: deciduas basalis  trophoblast: chorion frondosum
                - they fuse to become placenta
                -  8 wks: attach to embryo by umbilical cord
2. Functions
   i) exchange of gases
        - oxygen, carbon dioxide do diffusion. At the end of term (full infant), 20-30 cc / min O2
   ii) nourishment
        - amino acids
                - active transportaion (+ve balance)
                 - few high molecule weight polypeptides
                          - exceptions: transferring (transports Fe to fetus)
                 - free fatty acids
                          - some pass through diffusion (-ve balance)
                          - very few EFA‟s, cholesterol
                          - almost no triglyceral, phospholipids
                 - carbohydrates
                          - transported by facilitated diffusion (can transp 4X materal concentration)
                          - ex. glucose, vitamins (lipid soluble ones through diffusion and water soluble
                               through active transportation)
                          - minerals, electrolytes (facilitated diffusion, active transportation)
   iii) metabolism
        - synthesize glycogen, fatty acids, cholesterol
   iv) immunocompetence
        - obtain maternal antibodies (some)
        - diphtheria, smallpox, measles
        - IgG: transported via active transport. IgM, A, E, D do not cross (due to high MW)
   v) endocrine function
        - progesterone (maintains pregnancy)
        - estrogen 9especially late pregnancy)
                 - drops at end
        - gonadotropins (hCG)
        - human placental lactogen that acts peripherally as an insulin antagonist. Aids in fetal glucose
             uptake. Causes maternal diabetogenic (diabetic)
   vi) barrier function
        - prevent transformation of some substances
        - most maternal peptide hormones (high MW) kept out, but some steroids cross (ex. DES,
             testosterone), some infectious agents (rubella, pertussis cross), and few drugs
   vii) excretion
        - urea, uric acid, CO2 (diffusion)
        - bilirubin (made when red blood cells die, toxic)

Pregnancy and maternal health
Complications of pregnancy
i) Ectopic pregnancy
    - “implantation” outside uterus
    - usually planted in fallopian tube (most common)
    - may occur in other sites (rare); abdomen, ovaries, cervix
    - 1-2 % incidence (increasing)
    - Risk factors: late age, PID (pelvic inflammatory disease), previous abortions, pregnancies with
         IUD. These can be fatal.
    - Treatment: remove embryo, surgery or drugs
ii) Spontaneous abortion (miscarriage)
    - < 20 wks
    - occurs 30-50% conception, 15% known pregnancy
    - most grossly abnormal fetuses
iii) Gestational diabetes
    - 3-10% of pregancies
    - decreased carbohydrate tolerance (can‟t take up enough).  through pregnancy,  after birth
    - insulin resistance /  insulin release
    - marker for preclinical Type II diabetes? (pre-diabetic stage? Indication?)
    -  risk for mother
    - if untreated,  risk to fetus? (of developing obesity, diabetes?)
          -  risk of respiratory distress
          - 2003 study: effects on fetal malformations inconsistent
iv) Pre-eclampsia / eclampsia (toxemia of pregnancy)
    - increased BP, hypertension
    - pre-eclampsia: > 20 wks
    - 5% pregnancies
    - untreated, may become eclmpsia involving convulsion, coma, renal failure, fatal in 50% of fetuses,
          13% of mothers
    - Risk factors: pre-existing high BP
v) Abruptio placentae
    - 2% of pregnancies
    - separate placenta from uterine wall (3rd trimester). Could be partial or complete
    - range of symptoms:
          - severe: hemorrhage, premature delivery, death (fetus & mother)
vi) Placenta previa
    - implantation near cervix
    - < 1% of pregnancies
          - severe: placenta covers cervix
          - require Cesarean delivery
vii) Rh incompatibility
    - erythoroblastosis fetalis (hemolytic anemia)
    - Rh: blood group antigen
          - Rh- recess to Rh+
    - 85% Caucasians Rh+ (higher in other groups?)
    - Caucasian: 7-8% matings btw Rh- mother / Rh+ father
    - Rh- mother impregnanted by Rh+ father
          - Rh+ fetus
          - fetal RBC‟s reach mother, mainly at parturition (birth)
          - mother produces antibodies
          - 1st pregnancy unaffected. Few antibodies formed during pregnancy, mostly after birth.
          - subsequent pregnancies, destroy fetal RBC‟s (if they are Rh+).
          - RBC destruction produce bilirubin. Before birth, cleared by placenta (due to small quantity).
                 After birth, accumulates. May cause death, mental retardation.
    - < 1969: 20,000 cases / yr
    - today, treatable
          - RhoGam (Rh anti-serum): must be used for the 1st baby to stop antibody production
                   - administer after 28 wks & after birth
                   - destroys fetal RBC crossing placenta (mother‟s system would no longer recognize Rh)
          - today, < 4000 cases / yr

Complications of birth
i) episiotomy
    - incision of perineal tissue
    - prevent tearing
ii) breech presentation (head not coming out first)
    - 4 X mortality rate
iii) Caesarian section
    - surgical removal of baby
    - usually, if used for prior delivery
    - no longer recommended
         1985 = 9.1 vaginal birth / 100 previous CS
         1993 = 33.4 vaginal birth / 100 previous CS
    - factors influencing CS delivery:
         - MD practices, hospital policy, hospital resources, patient education, patient demands
    - Canada:
         - CS rates among highest in world
         - lower than US, but above UK Norway, Sweden

 Up to here for Midterm 1

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