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Year 1 Revision – Tricky Keeping People Healthy Topics Omar SalimILOs • Testis/Ovary • Gametogenesis, spermatogenesis, oogenesis • Placenta • Teratogens • Malnutrition & Obesity • Vaccines • Screening • ContraceptionT estis • Testis = male gonad that produces spermatozoa & androgens • Lies inside scrotum, supplied by testicular artery, venous drainage to pampiniform plexus of veins • Tunica vaginalis = outer covering, serous membrane derived from peritoneum • Tunica albuginea = deep connective tissue capsule, sends septa into gland dividing it into 200-300 lobules • Each lobule contains 1-4 seminiferous tubules, contains interstitial (Leydig), sertoli and spermatogonium cells • 2 ends join together to form straight tubules à form rete testis (anastomosing network) • 15-20 efferent ductules leave rete testis to drain into epididymis • Epididymis – highly convoluted, comprises head, body & tail, connects testicle & vas deferens, various functions including sperm storage, peristaltic contractions of smooth muscle conduct spermatozoa to vas. • Vas (ductus) deferens – at ejaculation, transfer sperm to urethra via peristalsis .Ovaries • Ovaries exists in a pair, only one active in each cycle • Covered by germinal epithelium (peritoneum), divided into cellular & medulla layer • Suspended to broad ligament of uterus by mesovarium (fold of peritoneum conveying blood vessels to ovaries) • Ovarian ligament attaches ovaries to uterus • Suspensory ligament attaches ovaries to pelvic wall • Beneath epithelium is tunica albuginea = connective tissue capsule • Ovarian cortex = makes gametes & endocrine secretions, houses stroma cells & • Corpus luteum from Graafian remnants, makes hormones that support uterustion • Ovarian medulla = central vascular stroma. Lymphatics, nerves & vesselsGametogenesis • Gametogenesis = process by which specialised generative cells called gametes are formed • Gametes develop from primordial germ cells that divide mitotically before birth à produce stem cells (oogonia, spermatogonia)Gametogenesis Differences: • Males produce more gametes per germ cell → 4 spermatids after 2 meiotic divisions vs 1 oocyte + 3 polar bodies • Gamete maturation starts before puberty in females (arrests in meiosis I in resting/dictyate state), after puberty in males • Meiosis II arrests in secondary oocytes during oogenesis and only completes after fertilization • Finite oogonia, spermatogonia regenerated continuously • Oogonia XX chromosomes, spermatogonia XY • Unequal cytoplasmic distribution in spermatid, equal distribution in oocyteSpermatogenesis • In seminiferous tubules: spermatogonium à spermatozoon • Spermatogonia divide mitotically to produce daughter cells – one replaces stem cell stock, other forms primary spermatocyte • Each diploid primary spermatocyte undergoes reductive division (meiosis I) to form 2 haploid secondary spermatocytes • Secondary spermatocytes undergo meiosis II to form 4 haploid spermatids • Nourished by Sertoli cells, spermatids undergo spermiogeneis to become spermatozoa, takes ~2 months: a. Nucleus condenses b. Acrosome forms (organelle with enzymes for fertilization of ovum) c. Most of cytoplasm shedSpermatogenesis Spermiogenesis: 1. Golgi phase – proacrosomal granules pinch off from Golgi; primitive flagellum formation 2. Cap phase – granules fuse & form acrosomal cap that associates with nuclear envelope, chromatin condensation starts, flagellum grows 3. Acrosomal phase – chromatin condensation, elongation, get nucleus with closely adhered acrosome, centriole forms fibres around flagellum. 4. Maturation phase (spermiation) – residual body forms (excess cytoplasm, sertoli cells phagocytose), sperm enter seminiferous tubule lumenSpermatogenesis • Non-motile spermatozoa then travel suspended in fluid towards straight tubule → rete testes → efferent duct then into ductus epididymis via peristaltic contraction • In epididymis sperm mature and become motile (sperm can remain in epididymis for 1-21 days)Oogenesis • In ovaries: oogonia à oocytes • Maturation begins during foetal period, not completed until puberty • In early foetal life, oogonia undergo mitotic division à diploid 1°oocytes, proceed with meiosis I but arrest in dictyate stage • Just before ovulation, 1°oocyte completes meiosis I à haploid 2°oocyte + polar body • Meiosis II begins in 2°oocyte but stops at metaphase II → fertilisation triggers meiosis II completion à ovum + 2 more polar bodies • Surrounded by cuboidal follicular cells (called granulosa cells in multilaminar cell) • Cumulus oophorus = cluster of granulosa cells surrounding & supporting oocyte • Zona pellucida = glycoprotein material surrounding primary oocyte • Antrum = fluid-filled chamber of ovarian follicle • Corona radiata = single layer of cells immediately surrounding oocyte • Granulosa cell proliferation (FSH stimulates) & fluid accumulation à Graafian folliclePlacenta - Development • At end of week 1 of gestation, inner cell mass of blastocyst burrows into endometrium à trophoblast differentiates into syncytiotrophoblast (outer) & cytotrophoblast (cellular layer). • In week 2 conceptus embedded in endometrium (‘decidua’) • Trophoblast & layer of extra-embryonic mesoderm form chorion (becomes fetal part of placenta) • Chorion develops villi, together with decidua basalis (adjoining deep part of endometrium) forms placenta • Maternal blood vessels eroded by invading syncytiotrophoblast discharge blood into intervillous spaces. Physiological exchange occurs between mother & fetal blood in vessels that develop from mesoderm in villi.Placenta - Functions • Fetal blood (low O2/nutrients) flows through umbilical arteries to villus capillaries, returns via umbilical vein • Maternal blood (rich in O2/nutrients) flows from uterine arteries into large blood sinuses surrounding villi, then back into uterine veins • Very short distance separates maternal & fetal circulations so O2 & substrates (glucose/fatty acids/ antibodies) diffuse into fetal blood • Maternal antibodies transferred to fetus giving passive immunity (e.g. against diphtheria, smallpox, measles) • Waste products from fetus (e.g. CO2, urea, bilirubin) pass through placenta into maternal circulation for disposal • Glucose transported by facilitated diffusion, amino acids by active transport • Metabolism – synthesises glycogen, cholesterol, fatty acids & other nutrients, produces energy for embryoPlacenta – Disorders • Barker Hypothesis – idea of fetal origins hypothesis e.g. if baby too small & does not get sufficient nutrients in utero, predisposed to developing adult diseases (e.g. hypertension) • If nutrient demand exceeds supply, can cause lower birth weight & altered fetal metabolism • Placental insufficiency (e.g. pre-eclampsia, intrauterine growth restriction) can à vascular problems, obesity, malnutrition, CVD in later life • Pre-eclampsia – BP ≥ 140/90mmHg + proteinurea (>300mg/24h) after 20 weeks gestation in previously normotensive women • Left untreated can progress to eclampsia (life-threatening, convulsions) • ~5-10% pregnancies in developed world, among leading UK causes of maternal mortality • Abnormal invasion of trophoblasts into maternal tissue – spiral arteries not fully remodelled to high flow, so fetus cannot get as many nutrients as normally would/needs • Placenta undergoes oxidative stress, maternal systemic inflammatory response to placentaPlacenta - Sampling • Placental sampling for prenatal diagnosis of fetal genetic disorders • Chorionic villus sampling – samples chorionic villi of placenta (essentially trophoblasts) - These should contain the same chromosome complement as the fetus. - 10-14 weeks gestation - Miscarriage rate – 1-2% • Amniocentesis – samples amniotic fluid (contains fetal cells) - These cells can be cultured & fetal chromosomes analysed - Actually fetal cells so more likely than CVS to represent chromosome complement of baby - Done later (less time to make a decision) -14-16 weeks - Lower risk of miscarriage (1%)T eratogens • Tdefectsgy = study of abnormal development of congenital • Teratogen = an agent that can disturb development of an embryo/foetus • Teratogenesis = process by which congenital malformations are produced in embryo/fetus • Timing and susceptibility to teratogens: • Pre-germ layer stage (weeks 1-2) • Embryonic period (weeks 3-8) • Foetal period (weeks 9-38) • A critical period exists for each teratogen. Critical periods – CNS develops from day 14 & develops all way through birth, maximal sensitivity period from weeks 2-14 • Embryonic period is most susceptible (organ development)Teratogens T eratogens • Drugs – tetracyclines (deposited in bones & teeth), streptomycin (inner ear defects), methotrexate (folic acid inhibitor), antineoplastic drugs • Alcohol – foetal alcohol syndrome, big problem in WoS. • Facial deformities, low birth weight, small head circumference, developmental delay, poor co-coordination/motor/socialisation skills. • Due to liver not being fully developed in utero so when crosses placenta cannot be metabolised so gives foetus high blood alcohol concentration • Illicit substances – heroin dependency in babies, cocaine can à premature labour, spontaneous abortion, cardiac malformations, genitourinary & behavioural disorders. • Industrial pollutants, ionising radiation (rapidly kills proliferating cells) • Hormones – androgens can cause masculinisation of female genitalia • Infectious agents (eg. HIV) • Rubella critical in first 3 months of pregstncy • CMV causes spontaneous abortion in 1 3 months • Herpes can cause mental retardation • Protozoan parasites can à microcephaly, hydrocephalus or mental retardationGrowth Charts • Growth chart = range of normal distribution for that gender at particular age of child • Made from series of cross sectional samples of measurements from children at different ages • Standard centile lines evenly spaced & include extreme outer centiles (0.4 & th 99.6 ) th • Eg. Child on 25 centile = out of 100 children of same age & gender arranged into height order, should be 25 children shorter and 75 taller. Child within normal range but below average height • Considerations – charts made 20 years ago (modern children heavier & taller than when standards created), based on bottle fed infants, children measured to create centile lines from UKGrowth Charts • Baby weight, length & BMI measured • Growth charts are marker of child’s well-being, abnormal/static growth often sign of disease/malnutrition • Height & weight tend to track within one centile – disparity suggests weight issues so need to calculate BMI • Measurements outside normal range or big change within normal range tends to reflect underlying pathology, but extreme individuals not always unhealthy & normal range not always healthyMalnutrition & Obesity • Malnutrition – refers to both undernutrition & over-nutrition • Can also be due to specific deficiencies, not just calories. (e.g. vitamins, minerals) • Causes: • Food shortages • Poverty • Poor diet • Mental health problems (e.g. anorexia, bulimia) • Digestive/GI problems (e.g. ulcerative colitis, Crohn’s, coeliac) • Alcoholism → gastritis/pancreatic damageMalnutrition & Obesity • Obesity – defined in adults as BMI > 30 • Associated problems: • Diabetes (type II) - (especially SE Asian origin) • Ischaemic heart disease • Stroke • Hypertension • Osteoarthritis • Some cancers (breast, colon, renal) • Mental health problems • Examples of socioeconomic factors implicated in conditions: • Older population growing à more elderly people living in poverty, spending on social services (e.g. home carers, meals on wheels not sufficient to meet demand) • Proliferation of obesogenic environments - Readily available, cheap & heavily marketed calorific foods - Increase in labour saving devices (e.g. motor vehicles, lifts, food delivery apps) - Decreased participation in active leisure pursuits & total energy expenditureV accines • Immunity = protection from infectious disease • Active immunity = protection produced by person’s own immune system by natural infection or artificial immunisation • Passive immunity = protection transferred from another person/animal as an antibody. Either natural (transplacental) or artificial (immunoglobulin) • Vaccination = induced immunity by vaccine administration • Immunisation = includes both vaccine-induced immunity & transfer of antibodies/immunoglobulin i.e. stimulation of immune system & what happens after receiving vaccination • Antigen = live or inactivated substance capable of producing immune response, or any substance that can be bound by an antibody • Antibody = protein molecule (immunoglobulin) produced by B lymphocytes to help eliminate a pathogenV accines • Selective vaccination – for vaccine that does not need to be given to all, only those at increased risk of disease (e.g. travel, occupational risk, high risk groups, outbreak control) • Mass vaccination for: • Eradication – disease & causal agent have been removed worldwide (e.g. smallpox) • Elimination – disease has disappeared from one WHO region, but remains elsewhere (e.g. polio) • Containment – disease no longer constitutes significant public health problem (e.g. Hib)V accines • Immune system review – 2 systems: innate & adaptive (acquired) • In•atPhysical barriers (skin, mucous membranes) • Additional defences (e.g. gut flora, sweat, tears, saliva) • Proteins (e.g. lysozyme, complement, interferons) • Phagocytic cells (macrophages & polymorphonuclear leucocytes) • Innate – non-specific, no memory, acts as immediate responseV accines • Adaptive immune system – if innate response not sufficient to eliminate pathogen à presented to more specialised cells = lymphocytes • Stimulates humoral response (B-cell response via antibodies), cellular response (T-cells) & creation of memory cells (ensures rapid immune response to pathogen when encountered in future) • Slow at first before response occurs (~4 days) • Specific – one antibody recognises only one antigen • Activation of T-cells by antigen presenting cells (APCs) à multiplication of effector T-cells à recruit macrophages, create memory T-cells, activate B cells & kill pathogens (cytoxic killer T-cells) • Activation of B cells by direct recognition of antigens produces specific antibodies à eliminate pathogen. Activation by T-cells leads to B-cells becoming plasma cells or memory B-cells • IgM & IgG are main antibodies in immune response. Work via neutralisation, opsoniation and complement activation.V accines • Live vaccines (e.g. MMR, BCG) = attenuated (weakened virulence) strains that replicate in host, closest to natural infection so elicit strong, long-lasting immune response • Cons – can revert to virulence, poor stability, contraindicated in e.g. pregnancy, immunosuppressed • Inactivated vaccines = suspensions of whole intact killed organisms (eg. influenza, rabies, Hep A), acellular & sub-unit vaccines (e.g. diphtheria, HPV, pertussis) or recombinant vaccines (e.g. Men B and Hep B). Stable, fewer contraindications • Cons – may not cause infection, may need several doses, shorter-lasting immunity, adjuvant needed (added to enhance body’s immune response to vaccine) • Conjugate vaccines = subunit vaccine that combines weak antigen (commonly polysaccharide antigens) with strong antigen as a carrier so immune system has stronger responseV accines • Herd Immunity – for each disease, there is a certain level of immunity in population that protects whole population since pathogen stops spreading. • Provides indirect protection of unvaccinated individuals (e.g. MMR given to infants protects pregnant women from rubella). • Basic reproductive number (R0) = used to measure transmission potential of disease, refers to average number of secondary infections produced by typical case of an infection in a population where everyone is susceptible • For epidemic to occur: R0 >1 (so number of cases increasing)case of measles à 15 new secondary casesV accines • Other therapies used to control vaccine-preventable diseases = antibody preparations: - Human Source – pooled blood preparations from donors - Monoclonal - Animal source (e.g. diphtheria anti-toxin) • Pros: - Rapid - Preventative - Can be given to those where vaccine contraindicated • Cons: - Expensive - Potential for adverse events - Limited evidence base for some - No lasting immunityScreening • Screening = process of identifying apparently healthy people who may have an increased risk of a disease or condition • Not given to everyone (not universal) • Detect disease at an early stage before patients are symptomatic • Not diagnostic – there is diagnostic stage to screening but screening initially separates people into groups of high & low risk • Benefits of screening – simple, affordable, acceptable, low complication risk • Limitations – does not provide definitive diagnosis, can be controversial, can cause harm at individual/population level (false positives/negatives, over diagnosis/over treatment, resource allocation and opportunity costs)Screening • WHO screening criteria: - Important health problem - Accepted treatment/useful intervention available - Natural history of disease adequately understood - Latent/early symptomatic stage - Suitable & acceptable screening test - Facilities for diagnosis & treatment available - Agreed policy on whom to treat - Treating early more beneficial than treating at later stage - Cost economically balanced in relation to potential medical care expenditure as a whole - Case finding continuing process, not once & for all projectScreening • Sensitivity (true positive rate) = how good test is at identifying those who have condition • Sensitivity = those with condition and a positive test/those with condition • Specificity (true negative rate) = how good test is at identifying those who do not have the condition • Specificity = those without condition and negative test/ those without condition • Positive predictive value ® How likely is a positive result to be true? • Negative predictive value ® How likely is a negative result to be true?Screening • Examples of screening programmes: - Cervical cancer ® women 25-64 every 5 years - Diabetic retinopathy screening ® yearly for diabetics aged >12 - Bowel cancer ® 50-74 (men and women) every 2 years - Breast cancer ® 50-70 every 3 years - Abdominal Aortic Aneurysm (triple A) ® USS in men when turn 65 - Antenatal screening – tests for parents (maternal HIV), genetic screening, Downs - Newborn inherited metabolic conditions (heel prick) & hearing testContraception • Emergency contraceptives: • Copper coil (most effective & works immediately, up to 5 days after) • Pills – levonelle (72hrs), ellaone (5 days) • User-dependent (e.g. condoms, diaphragms, pill) or non-user dependent (e.g. implant, coil) • Much higher failure rate for user-dependent • Combined pill or mini pill (progesterone only) - 8 in 100 get pregnant/1 year. Can make periods lighter and less painful, improve acne, reduce risk of ovarian/uterine/colon cancer plus fibroids/ovarian cysts & breast disease. • Contraceptive implant – releases progesterone, works for up to 3 years. 5 in 10,000 become pregnant/1y. Does not interfere with sex, normal fertility returns, can reduce heavy periods. • Mirena coil – 7 days to start working. 2 in 1000 become pregnant/1st year. Works for 3-5 years, does not interfere with sex, periods lighter/shorter/less painful & may stop. Normally fertility returns after removal.Contraception • Copper coil – inserted for emergency use then removed or kept in for longer-lasting option, works immediately, very effective, does not interfere with sex, fertility returns to normal when removed, 8 in 1000 pregnant/1y. Can make periods heavier/more painful • Condoms (female and male) – male (15 in 100 pregnancies) & female (21 in 100 pregnancies), only need to use during sex, protect from STIs, no hormonal side effects, female can be inserted before sex. Not very effective at preventing pregnancy, can interrupt sex, may slip off/split • Diaphragm/caps – fit inside vagina & covered with spermicide (cover cervix). 12 in 100 women get pregnant/1y, can insert before sex so does not interfere, may cause irritation st • Hormone injections – every 13 weeks, contains progesterone. 3 in 100 become pregnant/1 year. Does not interfere with sex, can reduce heavy periods, can give some protection against uterine cancer, must remember to get regular injections on time. • Combined hormonal patch – 8 in 100 people become pregnant. Have to remember to replace patch once/week. Easier than pill. Does not interfere with sex, can improve acne & make periods lighter • Combined hormonal ring – 8 in 100 people become pregnant. Replace every 3 weeks, sits inside vagina. Similar side effects/advantages to pill/patch • Male & female sterilisation – very effective but not 100%Quiz 1. Which structure transfers sperm to the urethra at ejaculation? • Seminiferous tubule • Straight tubule • Epididymis • Vas deferens • Efferent ductuleQuiz 1. Which structure transfers sperm to the urethra at ejaculation? • Seminiferous tubule • Straight tubule • Epididymis • Vas deferens • Efferent ductuleQuiz 2. What is the first phase of spermiogenesis? • Acrosomal • Maturation • Cap • Primary • GolgiQuiz 2. What is the first phase of spermiogenesis? • Acrosomal • Maturation • Cap • Primary • GolgiQuiz 3. Which ligament attaches the ovary to the pelvic wall? • Ovarian • Suspensory • Uterosacral • Broad • UterineQuiz 3. Which ligament attaches the ovary to the pelvic wall? • Ovarian • Suspensory • Uterosacral • Broad • UterineQuiz 4. What structure becomes the fetal part of the placenta? • Inner cell mass • Syncytiotrophoblast • Cytotrophoblast • Chorion • Decidua basalisQuiz 4. What structure becomes the fetal part of the placenta? • Inner cell mass • Syncytiotrophoblast • Cytotrophoblast • Chorion • Decidua basalisQuiz 5. What period of gestation is most susceptible to teratogens? • 1-2 weeks • 2-14 weeks • 3-8 weeks • 4-18 weeks • 9-38 weeksQuiz 5. What period of gestation is most susceptible to teratogens? • 1-2 weeks • 2-14 weeks • 3-8 weeks • 4-18 weeks • 9-38 weeksQuiz 6. In the adaptive immune system, which antibody is produced first in response to a pathogen? • IgD • IgE • IgG • IgMQuiz 6. In the adaptive immune system, which antibody is produced first in response to a pathogen? • IgD • IgE • IgG • IgMQuiz 7. Which of the following screening programmes involves screening 50-70 year olds every 3 years? • Bowel cancerr • Cervical cancer • Prostate cancer • Abdominal aortic aneurysmQuiz 7. Which of the following screening programmes involves screening 50-70 year olds every 3 years? • Bowel cancerr • Cervical cancer • Prostate cancer • Abdominal aortic aneurysmQuiz 8. Which of these methods of contraception can make periods heavier? • Copper coil • Mirena coil • Combined oral contraceptive pill • Contraceptive implantQuiz 8. Which of these methods of contraception can make periods heavier? • Copper coil • Mirena coil • Combined oral contraceptive pill • Contraceptive implant