SUGER Flashcards
What is mendelian genetics?
Fault in a single gene
Rare
What is complex trait genetics?
Changes in lots of genes
Common
E.g. diabetes, asthma
What is somatic genetics?
Any alteration at the cellular level in somatic tissues occurring after fertilization
E.g. cancer
What is ADPKD?
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited condition that causes small fluid-filled sacs called cysts to develop in the kidneys
What is autoregulation in the kidney and what are the 2 mechanisms?
Maintains constant GFR and excretion of water and waste products
Tubuloglomerular feedback
Myogenic mechanism
How does tubuloglomerular autoregulation work?
Increase in BP
Increase in blood flow to glomerulus and pressure
Increases GFR (more filtration and delivery NaCl to macula densa)
Afferent arteriole contraction to reduce blood supply to glomerulus
Decrease BP = afferent arteriole vasodilation to increase blood supply to glomerulus
How does the renin-angiotensin-aldosterone system work?
(tubuloglomerular)
Renin stimulates Angiotensinogen to angiotensin 1 to angiontensin 2:
- Increase sympathetic activity, excrete more NaCl and K
- Secrete aldosterone and ADH
Water and salt retention
Negative feedback to juxtaglomerular apparatus
How does the myogenic reflex work when BP increases? (only in pre-glomerular resistance vessels)
Increase bp stretches wall
Opens stretch-activated cation channels
Membrane depolarisation
Opens voltage-dependent calcium and intracellular calcium increases
Smooth muscle contracts
Increases vascular resistance
Minimises change in GFR
What makes up the filtration barrier?
Fenestrated capillary endothelium
Glomerular basement membrane (charged)
Podocytes (visceral epithelium)
Filtration slits and slit diaphragms
What is the juxtaglomerular apparatus?
Modified muscular layer of afferent arteriole
Juxtaglomerular cells and macula dense
Located in the hillum of every glomerulus
What is the arterial supply of the kidneys?
Abdominal Aorta
Renal artery
Interlobar artery
Arcuate artery
Interlobular artery
Afferent arteriole
Glomerular capillary
How does blood drain out of the kidneys after the glomerulus?
Efferent arteriole
Peritubular capillaries
Vasa recta
Interlobular veins
Arcuate veins
Interlobar veins
Renal vein
IVC
What makes up the nephron?
Blood vessels
Glomerulus
Bowman’s capsule
Proximal convoluted tubule
Loop of Henle
Distal convoluted tubule
Collecting duct
What is the function of the kidneys?
Removal of waste products
Removal of excess fluids
Balance salt, water and pH
Control of blood pressure
RBC production
Factors determining which molecules can get through the filtration barrier?
Pressure
Size of the molecule
Charge of the mulecule
Rate of blood flow
Protein binding
What makes up the kidney?
Capsule
Medulla
Cortex
Adipose tissue
How does pressure affect filtration?
Favours filtraion: glomerular capillary bp
Opposes filtration: fluid pressure in Bowman’s space, osmotic forces in the protein and plasma (pulling water back)
How does size affect filtration?
Small molecules and ions up to 10kDa can pass freely (glucose, uric acid, potassium, creatinine)
Larger molecules restricted (plasma proteins like albumin)
How does charge affect filtration?
Glomerular basement membrane has a fixed negative charge so repels negatively charged ions (albumin)
Neutral or positive molecules can get through easier
How does rate of blood flow affect filtration?
GFR higher with lower flow in afferent
GFR lower with really high flow (peaks in the middle) in efferent
How much urine is produced?
1ml per minute
How does protein binding affect filtration?
Bound to protein more likely to stay within system
Filter fluid usually protein free
Affects drugs, calcium, thryoxine
What causes nephrotic syndrome?
Damage to filtration barrier causing protein leaking (albumin, clotting cascade, infection defence)
Main cause is diabetes
What is glomerular filtration rate?
filtration volume per unit time (minutes)
What determines GFR?
Net filtration pressure
Permeability of filtration barrier
Surface area available for filtration
What regulates GFR?
Sympathetic NS - strong symp stimulation constricts AA, decreased renal blood flow and gfr (important in bleeding, shock)
Hormones/autocoids
Eqtn for GFR
GFR = KF(filtration coefficient) x (PGC - (PBS + πGC))
How do NSAIDs affect kidney?
Constrict AA
Decrease GFR
What are good markers to measure GFR?
Not secreted or absorbed by nephron
Freely filtered
Not metabolised
Creatinine usually used (is secreted by tubules)
What is a normal GFR?
125ml/min
What can affect creatinine?
Age, gender, ethnicity, height, weight, renal tubule handling
Dietary protein intake, creatinine supplements, medications
Examples of markers for measuring GFR
Creatinine (normally used)
Cystatin C
Inulin (gold standard)
Where does filtration occur in kidneys?
Glomerulus from capillaries into Bowman’s space across barrier of several layers
What maintains GFR?
Autoregulation and tubuloglomerular feedback
What is acidosis?
Disorder tending to make blood more acid than normal
What is alkalosis?
Disorder tending to make blood more alkaline than normal
What is acidemia?
Low blood pH
What is alkalemia?
High blood pH
What can affect blood pH?
Resp - CO2 conc
Metabolic - intrinsic acid (products of metabolism), extrinsic acid (diet, toxins), buffer capacity (bicarb)
Central relationship between bicarbonate and CO2
What is the Henderson-Hasselbalch eqtn?
pH = pKa + log([A-]/[HA])
What is the HH eqtn for carbonic acid?
(don’t need to memorise)
pH = pKaH2CO3 + log([HCO3-]/[H2CO3])
pH = 6.1 + log([HCO3-]/0.03 x pCO2)
What do you measure in an ABG?
pH
pO2
pCO2
HCO3- / Std HCO3-
Base excess
May include other measures (eg lactate, Na+, K+)
What is standard bicarbonate (std HCO3-)
The bicarbonate conc standardised to pCO2 5.3kPa and temp 37
(what the bicarb would be if everything else was sorted out)
What is base excess?
How much acid would be required to return pH to normal under standard conditions
Base excess in acidosis = negative
What is the absolute bicarbonate affected by?
respiratory and metabolic components
Clinical features of metabolic acidosis
Tachypnoea, sighing respirations
hyperventilation to increase CO2 excretion
Long term- growth issues in children, muscle wasting
What is the anion gap?
[Na+] + [K+] – [Cl-] – [HCO3-]
Normal 10-16
Created artificially by what is measured in the bloodstream
Theoretical to diagnose metabolic acidosis
What is happening in a high anion gap?
Cl- normal
Bicarb low
What can cause high anion gap acidoses?
Renal failure
Lactic acidosis
Ketoacidosis
Acid ingestion (eg salicylate poisoning)
What causes a normal anion gap?
GI HCO3- loss: Diarrhoea, small bowel fistula, urinary diversion
Renal tubular acidosis
What can cause metabolic alkalosis?
Alkali ingestion
GI acid loss: vomiting
Renal acid loss: hyperaldosteronism, hypokalaemia
Compensatory mechanism for alkalosis
Limited by hypoxic drive
Hypoventilation
renal bicarbonate excretion
What causes respiratory acidosis?
Any cause of resp failure
What is respiratory acidosis?
CO2 retention leading to increased carbonic acid dissociation
What is the compensatory mechanism for resp acidosis?
Increased renal H+ excretion and bicarbonate retention (but only if chronic)
If not present = come on suddenly
What is respiratory alkalosis?
CO2 depletion due to hyperventilation
Causes: type 1 resp failure, anxiety/panic
What is the compensatory mechanism for resp?
Increased renal bicarbonate loss (if chronic)
What do these suggest:
pO2: 10,1kpa
pCO2: 3.5kpa
pH: 7.11
std HCO3-: 9mmol/L
Base excess: -19.7
Glucose 53 mmol/L
Metabolic acidosis from diabetic ketoacidosis
What do these suggest:
pO2: 7.8kpa
pCO2: 3.9kpa
pH: 7.5
std HCO3-: 22
Base excess: 0
Respiratory alkalosis
What are the normal values for pO2 and pCO2?
pO2: 9.5-12kpa
pCO2: 4.6-6.0kpa
What are the normal values for standard HCO3-?
22-26mmol/L
What are the normal values for base excess?
0-2
What do these suggest?
pO2: 11kpa
pCO2: 5.4kpa
pH: 7.47
std HCO3-: 28mmol/L
base excess: 5mEq/L
Metabolic alkalosis
What do these suggest:
pO2: 7.9kpa
pCO2: 8.9kpa
pH: 7.29
std HCO3-: 27.9mmol/L
base excess: 3.8mEq/L
Respiratory acidosis
What do these suggest?
pO2: 8.7kpa
pCO2: 7.3kpa
pH: 7.13
std HCO3-: 18mmol/L
base excess: -10mEq/L
Mixed acidosis
What is the rate of renal blood flow?
1250ml/min
What is the rate of glomerular filtration?
120ml/min
What is the rate of renal plasma flow?
700ml/min
What are proximal tubules and what do they do?
Metabolically active cells – lots of mitochondria
Active reabsorption of multiple solutes
Sodium gradient generated by Na/K ATPases
Vulnerable to hypoxia and toxicity
What is renal glycosuria?
Defect: sodium glucose transporter 2 (SGLT2)
Mechanism: failure of glucose reabsorption
Benign
What are SGLT2 inhibitors used for?
Treatments for type 2 diabetes (as more glucose passed out in urine)
Used in heart failure and chronic kidney disease
What is aminoaciduria: cystinuria?
Defect: renal basic amino acid transporter (rBAT)
Mechanism: Failure of cystine reabsorption, increased urinary cystine concentration – stone formation
What is aminoaciduria?
an abnormal amount of amino acids in the urine
What is hypophosphataemic rickets?
Commonest form is X-linked hypophosphataemic rickets (XLH)
Defect: PHEX - zinc dependent metalloprotease
PHEX mutation results in increase FGF-23 levels, leading to decreased expression and activity of NaPi-II in proximal tubule
Can’t be fixed by adding vit D as an issue with phosphate
What is hypophosphataemia?
a plasma phosphate concentration of less than 0.8 mmol/L
How does bicarbonate reabsorption work?
Acid cycles between tubular cells and lumen
Na+ and HCO3- reabsorbed into blood
What is proximal renal tubular acidosis?
Defect: Na/H antiporter
Mechanism: Failure of bicarbonate reabsorption
Clinical features: Acidosis, impaired growth
Treatment: Bicarbonate supplementation
What is Fanconi syndrome?
Mechanism: generalised proximal tubular dysfunction, possibly due to failure to generate sodium gradient by Na/K ATPase
Causes: genetic, myeloma, lead poisoning
What does the loop of Henle do?
Generates medullary concentration gradient
Active Na reabsorption in thick ascending limb
What do the distal tubule and collecting duct do?
Distal tubule and cortical collecting duct allow “fine tuning” of sodium reabsorption, potassium and acid-base balance
Collecting duct mediates water reabsorption and urine concentration
What does aldosterone do?
Na and K in tubular lumen
3Na+ into blood stream, 2K+ out into lumen = gradient
Bicarbonate and potassium reabsorbed
Exchanges sodium for potassium or acid
acts on the principal cells of the collecting ducts in the nephron
increases the expression of apical epithelial Na+ channels (ENaC) to reabsorb urinary sodium
What are the juxtaglomerular apparatus cells like?
Thicker cells
Less actin/myosin but lots of granules containing renin
Increased number of smooth muscle cells
Cells act as barometer to changes in BP
(low BP, less distended walls, renin release)
What is the filtration barrier in the kidney?
Fluid goes from the blood to the Bowman’s space - (the filtrate)
The distal part of the nephron (tubule) responsible for secretion and reabsorption
What is the anatomical position of pancreas?
Retroperitoneal, posterior to greater curvature of stomach
12-15cm long, head is near C-portion of duodenum
What are the cell types in the pancreas?
small clusters of glandular epithelial cells
98-99% of cells are clusters called acini
exocrine functions = acinar
endocrine functions = islet
What do acinar cells do in pancreas?
Manufacture and secrete fluid and digestive enzymes, called pancreatic juice, which is released into the gut
What do islet cells do in pancreas?
Manufacture and release several peptide hormones into portal vein
What do the islet cells do?
Site of insulin (beta cells) and glucagon (alpha cells) secretion in the pancreas
What is the role of insulin?
Reduce glucose output from liver and increases glucose storage - decreases glycogenolysis and gluconeogenesis
Suppresses lipolysis and breakdown of muscle
Helps with protein synthesis
Important for storing energy
What is the role of glucagon?
Mobilises glucose by breakdown of fatty and amino acids
Stimulates peripheral release of gluconeogenic precursors (AA, glycerol), lipolysis
What do alpha and beta islet cells secrete?
Alpha - glucagon
Beta - insulin
What are the affects on glycogenolysis and gluconeogenesis from insulin and glucagon?
Insulin decreases (glucose levels go down)
Glucagon increases
How is insulin secreted by beta cell?
High glucose levels
Glucose enters cells (GLUT2) and is phosphorylated by glucokinase - glucose-6-phosphate
ADP to ATP
ATP closes potassium channel so K can’t leave
Cell membrane depolarised, Ca voltage channel opens and Ca moves in
Promotes exocytosis of proinsulin
What is the structure of proinsulin?
Proinsulin contains the A and B chains of insulin joined by C peptide
Disulfide bridges link A and B chains
Presence of C peptide implies endogenous insulin production
What makes up the biphasic insulin release?
B cells sense glucose rising and want to metabolise it
First phase: rapid release of stored product
Second phase: slower release of newly synthesised hormone
How is glucose sensed?
Primary glucose sensors in the pancreatic islets
Also in medulla, hypothalamus and carotid bodies
Sensory cells in gut wall also stimulate insulin release from pancreas - incretins
What happens when glucose too high?
Body makes glycogen in short term (glycogenesis)
Long term lipogenesis
What happens when glucose is too low?
Short term glycogenolysis
Long term gluconeogenesis from amino acids/lactate
What are incretins?
Gut hormones stimulating insulin release, released after eating
Slow rate of gastric emptying
What does dipeptidyl peptidase IV do?
Cleaves GLP-1 molecule making its inactive
Can’t stimulate beta-cells to make more insulin
Prevents hypoglycaemia
What happens when not eating for period of time?
In fasting state, glucose comes from liver
Muscles use free-fatty acids for fuel
Insulin levels are low
What happens after eating?
Glucose rises
Insulin secreted and alpha cells suppressed
40% of glucose goes to liver, 60% goes to periphery (muscles mostly)
Excess glucose converted into fats
How does CHO regulation work?
hypoglycaemia stimulates glucagon release
glycogen converted to glucose and glucose from AA/lactic acids
glucose released from liver - normal levels
if glucose continues to rise, hyperglycaemia inhibits glucagon
hyperglycaemia releases insulin
How does vasoconstriction of afferent arteriole affect GFR?
Decreases GFR
Decreased renal blood flow decreases Pgc
How does vasodilation of afferent arteriole affect GFR?
Increases GFR
Increased renal blood flow so increased Pgc
How does vasoconstriction of efferent arteriole affect GFR?
Increases GFR
Decreased renal blood flow after glomerulus so more blood in glomerular capillaries, increases Pgc
How does vasodilation of efferent arteriole affect GFR?
Decreases GFR
Less blood resistance post glomerulus so decreased Pgc
Eqtn for net ultrafiltration pressure in glomerulus
Pgc - (Pbs + πgc)
What does Pgc mean?
Hydrostatic pressure in glomerular capillary
What does Pbs mean?
Hydrostatic pressure in filtrate in Bowman’s space
What does πgc mean?
Oncotic pressure, the concentration of protein in capillary blood in the glomerulus
How does a decrease in the concentration of plasma proteins affect GFR?
Increases GFR as decreases oncotic pressure
How does an increase in conc of plasma proteins affect GFR?
Decreases GFR as higher oncotic pressure
What could cause an increase in Pbs and how does that affect GFR?
Pbs can be increased by blockage of urine (e.g. a stone)
Decreases GFR
What happens when Y chromosome present? (46XY)
Y chromosome contains SRY gene on distal part of short arm
SRY initiates steps to form testes from undifferentiated gonad
Testes produce mullerian inhibiting factor
Which prevents mullerian duct development
What happens when no Y chromosome is present? (46XX)
Ovaries and Mullerian ducts will form
Uterus and fallopian tubes form
Where are the spermatozoa produced?
Testis in spermatogenesis
What makes up ejaculation?
Spermatozoa and seminal plasma
Where in the testis is sperm produced and which cells promote sperm production?
seminiferous tubules
sertoli cells promote sperm cell development
What is the purpose of blood testis barrier?
tight junctions between
sertoli cells; separating sperm from immune system
What do seminiferous tubules in testis drain into?
rete testis
Why are the testis outside the body?
Testis need 35 degree heat
Further from body, arterial blood cools as it descends down to testes
What does mitosis produce and where does it occur?
produces 2 genetically identical daughter
cells
occurs in tissue repair & embryonic growth
What does meiosis produce?
Gamete haploid cells required for sexual reproduction
Where does mitosis occur in males?
Seminiferous tubules
What does spermatogonia produce and what do they do?
produce 2 kinds of daughter cells
– type A remain outside blood-testis barrier & produce more daughter cells until death
– type B differentiate into primary spermatocytes (pass through blood testis barrier)
What does spermiogenesis do?
Transforms spermatids into spermatozoa
Discards excess cytoplasm and grows tails
How long does spermatogenesis take?
64 days
How does hypothalamo-pituitary-testicular axis work?
- The hypothalamus secretes GnRH.
- GnRH to anterior pituitary gland receptors
- promotes LH and FSH release
- LH and FSH travel in the bloodstream to the testicles.
- LH stimulates Leydig cells in testicles to produce testosterone
- FSH stimulates Sertoli cells to produce androgen binding globulin (ABG) and inhibin:
- ABG binds to testosterone and prevents it from leaving the seminiferous tubules
- Inhibin helps support spermatogenesis and inhibits the production of FSH, LH and GnRH - Negative feedback = decreased LH and FSH
What is in the head of the sperm cell?
nucleus contains haploid set of chromosomes
acrosome contains enzymes that penetrate the egg
basal body
What is in the midpiece of the sperm cell tail?
Mitochondria
What are the different spermatic ducts?
Efferent ductules
– 12 small ciliated ducts collecting sperm
from the rete testes and transporting it
to the epididymis
Epididymis
– site of sperm maturation & storage
Ductus (vas) deferens
Ejaculatory duct
What else makes up semen apart from sperm?
fructose provide energy for sperm motility
fibrinogen
clotting enzymes convert fibrinogen to fibrin causing semen to clot
fibrinolysin liquefies semen within 30 mins
prostaglandins stimulate female peristaltic contractions
Components of semen
60% seminal vesicle fluid, 30% prostatic & 10% sperm and
trace of bulbourethral fluid
How much seminal fluid (semen) is expelled during orgasm?
2-5ml
How does the hypothalamo-pituitary-gonadal axis work? (females)
- Gonadotropin releasing hormone (GnRH) stimulates LH and FSH release from anterior pituitary
- FSH binds to granulosa cells to stimulate follicle growth, permit the conversion of androgens to oestrogens and stimulate inhibin secretion
- LH acts on theca cells to stimulate production and secretion of androgens
- moderate oestrogen and progesterone negative feedback
What are the phases of the ovarian cycle?
Follicular phase
Ovulation
Luteal phase
What are the phases of the uterine cycle?
Proliferative phase- alongside follicular, preparing for fertilisation
Secretory phase- alongside luteal phase,
Menses- start of new cycle in absence of fertilisation
What happens in the proliferative phase in the uterine cycle?
Preparing the reproductive tract for fertilisation and implantation
Oestrogen initiates
- fallopian tube formation
- thickening of the endometrium
- increased growth and motility of the myometrium and production of a thin alkaline cervical mucus (to facilitate sperm transport).
What happens in the secretory phase in the uterine cycle?
Progesterone stimulates:
- further thickening of the endometrium into a glandular secretory form
- thickening of the myometrium
- reduction of motility of the myometrium
- thick acidic cervical mucus production (a hostile environment to prevent polyspermy), - changes in mammary tissue
What is the menses?
marks the beginning of a new menstrual cycle
occurs in the absence of fertilisation once the corpus luteum has broken down and the internal lining of the uterus is shed.
What happens during the follicular phase?
- Beginning of new cycle
- During menses follicles start to develop independently of gonadotropins
- Increase in FSH and LH stimulate oestrogen and growth
- Oestrogen rises, FSH decreases so only one follicle can complete cycle
- High oestrogen, positive feedback, LH surge
What happens during the luteal phase in ovarian cycle?
- corpus luteum produces oestrogens, progesterone and inhibin to maintain conditions for fertilisation and implantation
- absence of fertilisation, the corpus luteum spontaneously regresses after 14 days (hormones fall and HPG goes back to start
- with fertilisation, the syncytiotrophoblast of the embryo produces human chorionic gonadotropin (HcG), exerting a luteinising effect, maintaining the corpus luteum
When does ovulation occur?
In response to LH surge in follicular phase
What happens in ovulation?
After LH surge, follicle ruptures
Oocyte moves to fallopian tube by fimbria
Viable for fertilisation for 24hours
What happens to follicle after ovulation?
follicle remains luteinised, secreting oestrogen and now also progesterone, reverting back to negative feedback on the HPG axis
What happens on the first day of fertilisation?
4-7 hours after gamete fusion the two sets of haploid chromosomes form the female and male pronucleus
Syngamy
What happens in syngamy?
Male and Female pronucleus migrate to centre (cytoskeletal system plays important role)
Haploid chromosomes synthesize DNA in preparation for the first mitotic division
The pronuclear membranes breakdown
The mitotic metaphase spindle forms
What happens on day 2 of fertilisation?
Max of 4 cells
Approx 24 hours after fertilisation, the ooplasm divides into two equal halves
Cleavage
Why is cleavage important in embryo?
Successive cleavages result in an increase in cell number – essential to provide sufficient cells for differentiation
What happens on day 3 of fertilisation?
5 cells
Early cleavage stage embryos are ‘totipotent
What happens on day 4 of fertilisation?
Compaction
Cells flatten and maximise intracellular contacts
Tight junctions form
Polarisation of outer cells
What happens on day 5 of fertilisation?
Trophectoderm forms
Fluid filled cavity expands
Blastocyst starts to appear
What happens during hatching past day 6?
Blastocyst expansion and enzymatic factors cause the embryo to hatch from the ZP.
Necessary for implantation
What is the energy requirement like for early embryo?
Early embryo (fertilisation to 4 cell stage) has lower energy consumption
From 5 cell stage, embryo needs energy for activity (high glucose and complex nutrient requirements)
Where do exogenous nutrients come from in vivo?
Cumulus cells
Fallopian tube secretions
Uterine secretions
Growth factors and cytokines
What are the stages of embryonic attachment/implantation?
apposition- unstable adhesion of blastocyst to uterine wall
attachment- stable adhesion
invasion - grows into uterine wall, penetrates endometrium
What happens during expansion on day 5-6 of fertilisation?
Cavity expands
Diameter increases
ZP thins
What is the decidual reaction?
Progesterone primed endometrial stromal cells adjacent to the blastocyst differentiate into metabolically active, secretory cells – Decidual Cells
What is HCG?
Human Chorionic Gonadotropin
Produced in placenta
Rise in HCG from day 7-8 signify onset of implantation
What is the role of HCG?
Essential to sustain early pregnancy
Supports the corpus luteum (progesterone production)
Interacts with the endometrium via specific receptors
How does Pre-implantation Genetic Diagnosis work?
involves testing cell(s) from embryos created outside the body by IVF for a genetic disorder
What does testosterone do?
Stimulates spermatogenesis in the testes
Maintenance of libido (sexual drive)
Development of secondary sexual characteristics (pubic, axillary and facial hair)
Growth of external genitalia
Deepening of voice
Muscle growth
Bone growth
Promotion of anabolic reactions
Function of LH in males
stimulates the Leydig cells in the testes to produce testosterone
Function of FSH in males
Drives sperm production in the Sertoli cells of the testes (spermatogenesis)
Synthesis of proteins important for the production and action of steroid hormones
Function of LH and FSH in females
Stimulate the ovary to produce mature gametes, as well as synthesise and secrete oestrogens and progestins
What does LH bind to in females?
theca cells (to produce progestins and androgens) on developing follicles as well as granulosa cells
corpus luteum after ovulation
What is corpus luteum?
tissue in the ovary that forms at the site of a ruptured follicle following ovulation.
It produces oestrogens, progesterone and inhibin to maintain conditions for fertilisation and implantation
What does FSH bind to granulosa cells to do?
- Increase production of enzymes that catalyse the production of steroid hormones, stimulating follicle growth
- Increase production of activins and inhibins
- Help convert androgens to oestrogen
What are some epigenetic factors?
Histone modification
DNA methylation
What is incontinence?
lack of voluntary control over urination or defecation
How is urine stored?**
Low pressure
What is the neural control of continence like in non-potty trained children?
coordinated voiding
no control of when- reflex bladder
What is the neural control of continence like in adults?
coordinated voiding
control of when
What is the neural control of continence like in elderly?
coordinated voiding
no control of when- reflex bladder
What happens during bladder filling?
b2-3 receptors in wall of bladder activated, bladder relaxtion
hypogastric nerve causes bladder neck contraction
pudendal nerve causes tonic contraction of sphincter
What happens during bladder emptying?
Sympathetic off, neck relaxation
sphincter muscle and pelvic floor muscles relax
The bladder simultaneously contracts and starts to empty itself of urine
What is the guarding reflex?
Symp outflow in hypogastric nerve to bladder outlet
Pudendal outflow to external urethral sphincter
a progressive, involuntary increase in the external urethral sphincter activity during bladder filling
What is the voiding reflex?
Intense bladder afferent firing in pelvic nerve
Spinobulbospinal reflex triggered
Parasympathetic outflow
Bladder contraction
Bladder neck relaxation and sphincter relaxation
What is the spinobulbospinal reflex?
Afferent signals to periaqueductal gray
Pontine micturition centre triggered
What is lower urinary tract dysfunction?
Failure to store/ void - bladder or outlet issue
What is stress incontinence?
Leakage on coughing, straining
Urethral hypermobility, weakness in pelvic floor
More common in older women
What is urgency incontinence?
Leakage with urgency
Sensory symptom, detrusor overactivity
What is mixed incontinence?
Loss of urine associated with urgency and exertion
What is overflow incontinence?
Underactivity of the bladder or bladder outlet obstruction
What is total incontinence?
Continuous urine leakage
Normally anatomical problems
What is the function of the urinary tract?
To collect the continuously produced urine
To store it under safe conditions
To void it when socially appropriate
Where is the sacral micturition centre?
s2-4
What does the proximal CT do?
active reabsorption: Na, Cl, glucose, amino acids, HCO3
confined to renal cortex
What does the loop of Henle do?
Na reabsorption
generation of medullary concentration gradient
Development of a hypertonic interstitum
urinary dilution
What does the distal CT do?
fine regulation of Na reabsorption, K+ and acid base balance
Impermeable to passive movement of water and Na
Absorbs calcium
What does the collecting duct do?
similar to distal tubule, + acid secretion, regulated H2O reabsorption concentrating urine
What is cystinuria?
tubular defect in uptake of cystine
autosomal rec
increase urinary cystine conc
What does SGLT2 do?
responsible for reabsorption of 80-90% of the glucose filtered by the kidney glomerulus
Functions of the skin
Waterproof barrier
Physical barrier
Vitamin D synthesis
Endocrine organ
UV barrier
Barrier to infection
Immune organ
Sensory organ
Thermoregulation
Energy store / Shock absorber
What are the 3 layers of the skin?
Epidermis (outermost)
Dermis
Subcutis
How is the skin waterproof?
Tight junctions between cells in stratum granulosum, epidermal lipids and keratin in stratum corneum form both an inside-out and outside-in barrier to water
Prevents transepidermal water loss
What are the functions of the epidermis?
Waterproofing
Physical barrier
Immune function
Vitamin D synthesis (Endocrine)
UV protection
Thermoregulation
What are the functions of the dermis?
Thermoregulation
Vitamin D synthesis (Endocrine)
Sensory organ
What are the functions of the subcutis?
Thermoregulation
Energy reserve
Vitamin D storage
Endocrine organ
Shock absorber
How does the skin work as a physical barrier?
Structure of skin helps resist trauma
Stratified epithelium helps resist abrasive forces
Fat in subcutis acts as shock absorber
How is vit D synthesised?
Sunlight cleaves 7-dehydrocholesterol into cholecalciferol (D3)
Converted in the liver to 25-hydroxyvitaminD3
Converted in the kidney to 1,25-dihydroxyvitaminD
What does vit D do?
Maintains calcium balance in the body
How is sex determined?
Migration of primordial germ cells from dorsal endoderm to urogenital ridge by weeks 6-8
Indifferent gonad develops
Presence of SRY gene (on Y chromosome) = male, absence = female
When in utero do the testes differentiate?
Week 9
When in utero do the ovaries develop?
Present by weeks 11-12
Process of male sex development
XY chromosomes- SRY gene present on Y
Stimulates primitive sex cords to form testis cords
Portion of testis cords breaks off to form rete testis
Remaining testis cords form germ cells and sertoli cells
Sertoli cells produce anti-mullerian hormone and mullerian ducts degenerate
Leydig cells between testis cords produce testosterone in week 8
Pathway of DHEA to DHT
DHEA
Androstenedione
Testosterone
Dihydrotestosterone
How does female internal genitalia develop?
No testosterone so mullerian ducts develop
This system goes on to form uterus, fallopian tubes and upper 1/3 of vagina
How does male internal genitalia develop?
Testosterone and AMH present
Mullerian ducts regress
Wolffian system develops into epididymis, vas deferens, seminal vesicles, ejaculatory ducts
How does female external genitalia develop?
Cloacal folds form genital tubercle
Genital tubercle elongates a little to form clitoris
Urethral folds form labia minora
Genital swellings form labia majoria
UG groove stays open to form vestibule
How does male external genitalia develop?
Cloacal folds form genital tubercle
Rapid elongation of genital tubercle becomes phallus
Urethral folds are pulled to form groove which closes to form penile urethra
Genital swellings become scrotal swellings
What hormone action takes place on the skin?
Androgens stimulate hair follicles and sebaceous glands
Thyroxine acts on keratinocytes, follicles, sebaceous glands, fibroblasts and eccrine glands
Melanocyte stimulating hormone increases skin pigmentation
What hormone synthesis takes place on the skin?
Androgen (5α-dihydrotestosterone) synthesis
Fibroblasts make binding protein for insulin-like growth factor 1 to increase effectiveness
Vit D3
How do UV-A and B damage the skin?
Burns
Suppress action of Langerhans cells
Photo-aging
DNA damage (skin cancers)
What does skin colour depend on?
Melanin
Carotenoids
Oxy/deoxyhaemoglobin
Where is melanin synthesised?
Melanosomes in melanocytes (which share with keratinocytes nearby)
Which enzyme helps create melanin
Tyrosinase makes melanin from tyrosine
What are the 2 types of melanin?
Pheomelanin (red/yellow)
Eumelanin (brown/black), darker skin = more eumelanin
Everyone has both present
Does melanocyte density vary across the body?
Yes
More on face, arms
Small amount on palms
What does histamine release in the skin cause?
Vasodilation, swelling, itching
UV light can cause histamine release
What happens in immediate pigment darkening?
photooxidation of existing melanin
redistribution of melanosomes
occurs within minutes and lasts hours-days
What happens in persistent pigment darkening?
oxidation of melanin
occurs within hours, lasts 3-5 days
What happens in delayed tanning?
UVB better than UVA at stimulating
increased melanin synthesis
Occurs 2-3 days after UV exposure, maximal at 10-28 days
What happens when the skin is damaged?
Keratinocytes secrete cytokines which recruit immune cells
How is the skin a sensory organ?
Merkel cells in basal epidermis: light touch
Encapsulated mechanoreceptors in dermis: pressure, touch, vibration
Sensory nerve endings: pain, itch, temp
How much do you sweat an hour?
1-3 L sweat per hour
What is the insulating layer in the skin?
Subcutaneous fat
How does the body lose heat via the skin?
Cutaneous blood flow
Eccrine sweating
How does piloerection (goosebumps) work?
Arrector pili muscles innervated by sympathetic α1-adrenergic fibres
Contraction raises cutaneous hairs
Likely little significant impact on heat conservation
What does the posterior pituitary gland secrete?
ADH and oxytocin
Where are ADH and oxytocin made?
supraoptic and paraventricular nuclei of the hypothalamus
stored in the posterior pituitary gland
What does ADH do?
acts on the kidney’s collecting ducts to increase water reabsorption
How does ADH secretion happen?
Osmolarity increases
Chemoreceptors contract and afferent signals sent to hypothalamus
ADH secretion increased
What is the action of ADH?
Acts through a G-protein coupled receptor to increase the transcription and insertion of Aquaporin–2 channels to the apical membrane of the distal convoluted tubes and collecting ducts
Permeability of DCT and CD to water increases
Water moves back into bloodstream
Total blood volume increases
What inhibits ADH release?
Atrial natriuretic peptide (ANP), which is released by stretched atria in response to increases in blood pressure
What is osmolality?
Concentration of particles per kilo of fluid
What is osmolarity?
Concentration of particles per litre of solution
What stimulates oxytocin?
Infant suckling on nipple
Baby’s head increasing pressure on cervix
What are the main functions of oxytocin?
regulation of lactation
control of uterine contractions in labour
What are the 3 hormone structures?
Steroids (cortisol)
Peptides (insulin)
Thyroid hormones (thyroxine)
What are catecholamines synthesised from?
Tyrosine
What are 3 catecholamines?
Dopamine
Adrenaline
Noradrenaline
How is thyroxine synthesised?
Iodide from plasma taken up and oxidised to iodine by thyroperoxidase (TPO)
Iodine binds to tyrosine residues of thryoglobulin forming diiodotyrosine
TPO converts DIT to T3 and T4
What receptors can hormones have an effect through?
Cell surface receptors (G protein coupled), e.g. for insulin
Intracellular receptors, e.g. steroid
What are thyroid hormones important for?
Basal metabolic rate
growth
What are parathyroid hormones important for?
Calcium regulation
What does cortisol do?
Glucose regulation
Inflammation
What does the anterior pituitary secrete?
Adrenocorticotrophic hormone
Thyroid stimulating hormone
Growth hormone
LH
FSH
Prolactin
What is the blood supply of the anterior pituitary?
has no arterial blood supply but receives blood through a portal venous circulation from the hypothalamus
What does the hypothalamus do?
Important for homeostasis & primitive functions – appetite, thirst, sleep, temperature regulation
Control of autonomic function via brainstem
autonomic centres
Control of endocrine function via pituitary gland
What are the releasing hormones of the hypothalamus?
Thyrotropin releasing hormone (TRH) for TSH
Corticotropin releasing hormone (CRH) for ACTH
Gonadotropin releasing hormone for FSH and LH
GH releasing hormone (GHRH) (Somatostatin – inhibitory) for GH
Dopamine (inhibitory) for Prolactin
What does ACTH regulate?
Cortisol
How does ACTH regulate glucocorticoid synthesis?
Acutely stimulates cortisol release
Stimulates corticosteroid synthesis (and capacity)
CRH stimulates ACTH release
Negative feedback of cortisol on CRH and ACTH production
What stimulates and suppresses growth hormone?
Released throughout life
Pulsatile
Stimulated by low glucose, exercise, sleep
Suppressed by hyperglycaemia
Effects mediated by GH and IGF1
What are the actions of growth hormone?
Linear growth in kids
Acquisition of bone mass
Stimulates: protein synthesis, lipolysis, glucose metabolism
Regulates body composition
Psychological well being
What happens to TSH and thyroxine in pituitary failure?
Both low
What do LH and FSH stimulate?
LH stimulates sex hormone secretion
FSH stimulates development of follicles
What does prolactin do?
Essential for lactation
Levels increase dramatically in pregnancy and during breast-feeding
Inhibits gonadal activity through central suppression of GnRH
What does the zona glomerulosa of the adrenal gland cortex synthesise?
Mineralocorticoids- aldosterone
What does the zona fasciculata of the adrenal gland cortex synthesise?
Glucocorticoids- cortisol
What does the zona reticularis in the adrenal gland cortex synthesise?
Androgens – DHEA, androstenedione
What does the medulla of the adrenal gland synthesise?
Catecholamines
What is the structure of corticosteroids?
Cholesterol precursor for all adrenal steroidogenesis
three cyclohexane rings
single cyclopentane ring
What do corticosteroids do?
Bind to specific intracellular receptors
Alter gene transcription directly or indirectly
Exact action depends on structure, ability to bind specific receptors
What do corticosteroids do?
Bind to specific intracellular receptors
Alter gene transcription directly or indirectly
Exact action depends on structure, ability to bind specific receptors
What do glucocorticoids do?
Important in homeostasis, e.g. response to stress
Essential to life
Increase glucose mobilisation
Maintenance of circulation
Immunomodulation
How are glucocorticoids transported?
In circulation heavily bound to proteins, e.g. 90% to Corticosteroid-Binding Globulin, 5% to albumin
What regulates glucocorticoid synthesis?
ACTH and CRH
Diurnal rhythm
Stress
Illness
Describe the HPA axis
hypothalamic-pituitary-adrenal (HPA) axis
Stress/blood loss/cytokines trigger CRH from hypothalamus
CRH triggers ACTH from anterior pituitary
ACTH binds to MC2r at adrenal glands and stimulates glucocorticoids release
Cortisol
Cortisol negative feedback to HT
What are the 2 main mineralocorticoids?
Deoxycorticosterone
Aldosterone
What is the main function of mineralocorticoids?
Critical to salt and water balance
What is the action of aldosterone?
acts on the principal cells of the collecting ducts in the nephron.
increases the expression of apical epithelial Na+ channels (ENaC) to reabsorb urinary sodium
What are the adrenal androgens?
Dehydroepiandrosterone (DHEA)
Androstenedione
Both very weak androgens
What is the adrenal medulla?
Specialised ganglia supplied by sympathetic preganglionic neurones
Part of the autonomic NS
Main site of adrenaline synthesis
What is the production of catecholamines in the adrenal medulla?
80% adrenaline
20% noradrenaline
Small amounts of dopamine
Can testosterone be converted to oestrogen?
Yes
Via aromatase to oestradiol
Can DHT be converted to oestrogen?
No
Which hormone drives development of male external genitalia?
Androgens- DHT
Which hormone drives development of female external genitalia?
Oestrogen
What can stimulate growth hormone?
Exercise
Stress
Hypoglycaemia
Fasting
High protein meals
Perinatal development
Puberty
What can suppress growth hormone?
Hypothyroidism
Hyperglycaemia
High carbohydrate meals
Glucocorticoid excess
Aging
What is puberty?
Describes the physiological, morphological, and behavioural changes as the gonads switch from infantile to adult forms
What are the definitive signs of puberty?
Females: first menstrual bleed
Males: first ejaculation
What can determine growth?
Parental phenotype and genotype
Quality and duration of pregnancy
Nutrition
Specific system and organ integrity
Psycho-social environment
Growth promoting hormones and factors
Where is growth hormone synthesised?
somatotroph cells in anterior pituitary
What happens to female secondary sex characteristics at puberty?
Ovarian oestrogens regulate the growth of breast and female genitalia
Ovarian and adrenal androgens control pubic and axillary hair
What happens to male secondary sex characteristics at puberty?
Testicular androgens:
–External genitalia and pubic hair growth
–enlargement of larynx and laryngeal muscles, voice deepening
Difference between T3 and T4
T3 has 3 iodines attached, T4 has 4
How is T3 produced?
mono-deiodination of T4
What is T3?
The biologically active hormone
What happens when thyroid hormone reaches target cell?
Moves into cell nucleus by transmembrane transporter
Changes action of mRNA that is produced
Which enzyme is responsible for the production of thyroid hormone?
Thyroid peroxidase
What would a thyroid function test look like in hypothyroidism?
Increased serum TSH
Decreased serum T3 and T4
What would a thyroid function test look like in hyperthyroidism?
Decreased serum TSH
High T3&4
What are the binding proteins of T4 and T3?
Albumin
Transthyretin
TBG
What does the parathyroid gland do?
Regulate calcium and phosphate levels
Secrete parathyroid hormone in response low calcium or high phosphate
What does parathyroid hormone do?
Increases calcium reabsorption in renal distal tubule
Increases intestinal calcium absorption (via activation of vitamin D)
Increases calcium release from bone (stimulates osteoclast activity)
Decrease phosphate reabsorption
What is the structure of pth and what does it bind to?
84 amino acid peptide but biological activity in first 34 amino acids
Cleaved into smaller peptides
Binds to G protein coupled receptors mainly in kidney and osteoblasts
What does the parathyroid hormone do to the kidney?
PTH increases distal tubular reabsorption of calcium (+ inhibition of PO4 reabsorption)
PTH also stimulates production of the active form of vitamin D
What is the negative feedback of PTH?
Transcription inhibited by 1,25D3
Translation inhibited by increased serous calcium
What produces calcitonin?
thyroid c-cells
What does calcitonin do?
released in hypercalcaemia,
inhibits bone resorption (by direct effect on
osteoclasts)
Not essential to life
What is food energy density?
kcal/g
How can you reduce the energy density of food?
Incorporating water
Air
Method of cooking
Reduction of fats/sugar
What is energy compensation?
Adjustment of energy intake following the ingestion of a particular food
What is the role of alcohol in overconsumption?
Consumed in liquid form
Least satiating macronutrient
Efficiently oxidised at expense of fat
Additive to total daily energy intake and stimulates intake
What type of imaging is used in the reproductive tract?
Ultrasound
What is renin released in response to?
Sympathetic stimulation
Reduced sodium-chloride delivery to the distal convoluted tubule
Decreased blood flow to the kidney
What is renin?
a peptide hormone released by the granular cells of the juxtaglomerular apparatus in the kidney
facilitates the conversion of angiotensinogen to angiotensin I
What affect does angiotensin 2 have?
Increases ADH
Increases thirst
Vasoconstriction
Stimulates adrenal cortex to release aldosterone
What does aldosterone do?
promotes salt and water retention by acting at the distal convoluted tubule to increase expression of epithelial sodium channels. Increases the activity of the basolateral sodium-potassium ATP-ase
What is the direct renal mechanism for rising BP?
Blood volume or pressure rises
More filtration, less reabsorption
More leaves in urine
Blood volume or pressure falls
What does cortisol do?
Increases plasma glucose
Stimulate lipolysis in adipose tissue
Immunosuppression
Anti-inflammation
Protein and fat metabolism
Bone metabolism – limit osteoblast activity
Regulate calcium absorption from the GI tract
Regulate behaviour, mood and cognition through activity on the CNS
How is vitamin D synthesised?
7-dehydrocholesterol in the skin combined with UV B to form vitamin D
25-OH vitamin D in liver
- Kidney to make 1,25 (OH)2 vitamin D to go to bone and intestine
- Kidney to make 1,24,25- (OH)3 vitamin D to become calcitroic acid
What is the nephron?
Functional unit of kidney
1 million parallel make urine
What is the renal corpuscle?
Glomerulus and Bowman’s capsule
What is ultrafiltration?
filtration that occurs under pressure
What do the PCT reabsorb into interstitium then capillary?
65% of water, sodium, K and Cl
100% of glucose, amino acids
85-90% of bicarbonate
What are symporters?
transporters that move two (or more) molecules in the same direction e.g. SGLTs
What are antiporters?
transporters that move two (or more) molecules in opposite directions e.g. Na+/H+ antiporter
What is cotransport?
movement of multiple solutes through the same channel
What happens to the concentration along the PCT?
solute concentration in the tubule decreases while the solute concentration in the interstitium increases
What does the thin descending limb of the loop of henle reabsorb?
Water passively through aquaporin-1 channels
Small amounts of urea and sodium
What does the thin ascending limb of loop of henle reabsorb?
Sodium through ENaC
Cl-
Impermeable to water as no aquaporins
What happens at the thick ascending limb of the loop of Henle?
Active sodium reabsorption through Na+/K+ ATPase
Results in hypotonic solution to DCT
What does the collecting duct do?
mediates water reabsorption and maintains acid base homeostasis
water reabsorbed through ADH and aquaporins
What is the role of the early DCT?
absorption of ions, including sodium, chloride and calcium. It is impermeable to water
macula densa here
What are the main 2 cell types in late DCT and collecting duct?
Principal
Intercalated
What do principal cells in the nephron do?
Na and water reabsorption and K excretion
What do intercalated cells in the nephron do?
secrete H or HCO3 for acid-base homeostasis
What happens to the hormones in menopause?
Ovaries have less functional follicles
Less oestrogen and progesterone
Less inhibition on hypothalamus and pituitary
More GnRH
More FSH and LH secreted erractically
When has a women entered menopause?
12 months since last period
Which cells in the parathyroid secrete PTH?
Chief cells
What does increased levels of aldosterone cause (for K+)?
reduced levels of potassium in the blood
