1
Q
what is the urinary bladder composed of? (parts) what happens at each part?
A
• The urinary bladder is a smooth muscle chamber composed of two main parts:
- The body – urine collects here.
- The neck - is a funnel-shaped extension of the body, passing inferiorly and anteriorly into the urogenital triangle and connecting with the urethra. The lower part of the bladder neck is also called the posterior urethra because of its relation to the urethra.
2
Q
what is the smooth muscle of the bladder?
A
detrusor muscle
3
Q
detrusor muscle
- direction of fibres
- pressure inside bladder - what happens
- how are the smooth muscle cells of the muscle arranged and why
A
Its muscle fibres extend in all directions.
When contracted, can the pressure inside the bladder is increased. This allows the emptying of the bladder (normal range = ≤ 15-20 cmH20)
Smooth muscle cells of the detrusor muscle fuse with one another so that low-resistance electrical pathways exist from one muscle cell to the other.
- Therefore, an action potential can spread throughout the detrusor muscle, from one muscle cell to the next, to cause contraction of the entire bladder at once.
4
Q
where is the posterior wall of the bladder? what is on the posterior wall?
A
On the posterior wall of the bladder, lying immediately above the bladder neck, is a small triangular area called the trigone.
5
Q
what is the mucosa of the trigone like compared to the remainder of the bladder mucosa?
A
smooth, in contrast to the remaining bladder mucosa, which is folded to form rugae.
6
Q
where do the two ureters enter the bladder? how do they pass into the bladder?
A
The two ureters enter the bladder at the uppermost angles of the trigone.
Each ureter, as it enters the bladder, courses obliquely through the detrusor muscle and then passes another 1-2cm beneath the bladder mucosa before emptying into the bladder.
7
Q
where does the bladder open into the posterior urethra? how long is it? what composed of? what is the muscle called? what form is it in?
A
At the lowermost apex of the trigone, the bladder neck opens into the posterior urethra.
This is 2-3cm long, and its wall is composed of detrusor muscle interlaced with a large amount of elastic tissue.
The muscle in this area is called the internal sphincter.
o Its natural tone normally keeps the bladder neck and posterior urethra empty of urine and, therefore, prevents emptying of the bladder until the pressure in the main part of the bladder rises above a critical threshold.
8
Q
what happens beyond the posterior urethra? what does thin contain in wall?
A
Beyond the posterior urethra, the urethra passes through the urogenital diaphragm, which contains a layer of muscle called the external sphincter of the bladder.
9
Q
why type of muscle is the external sphincter? what are the other muscles in the bladder? what does this mean the external sphincter can do? what control are they under?
A
This muscle is a voluntary skeletal muscle, in contrast to the muscle of the bladder body and bladder neck, which is entirely smooth muscle.
The external sphincter muscle is under voluntary control of the nervous system and can be used to consciously prevent urination even when involuntary controls are attempting to empty the bladder.
- Internal sphincter = smooth muscle = involuntary control (parasympathetic)
- External sphincter = skeletal muscle = voluntary control (somatic)
10
Q
what is normal urine flow?
A
20-50 ml/s.
11
Q
describe the innervation of the bladder
- what is the principal nerve supplying the bladder
A
• Parasympathetic Innervation (autonomic) - the principal nerve supply of the bladder is by way of the PELVIC SPLANCHNIC NERVES, which connect with the spinal cord through the sacral plexus (S2,3,4):
Sensory nerve fibres(afferent)
- These detect the degree of stretch in the bladder wall.
- Stretch signals from the posterior urethra are especially strong and are mainly responsible for initiating the reflexes that cause bladder emptying.
Motor nerve fibres (efferent)
- These terminate on ganglion cells located in the wall of the bladder.
- Short postganglionic nerves then innervate the detrusor muscle (M3 receptor).
- This aids micturition.
• Sympathetic Innervation (autonomic) - the bladder receives sympathetic innervation from the sympathetic chain through the HYPOGASTRIC NERVES (L2).
These cause relaxation of detrusor muscle (B3 receptor) and contraction of urethra (a1 receptor), thus allowing bladder to fill.
Some sensory nerve fibres also pass by way of the sympathetic nerves and may be important in the sensation of fullness and, in some instances, pain.
• Somatic Innervation (voluntary) - other innervation of the bladder is skeletal motor fibres transmitted through the PUDENDAL NERVE to the external sphincter.
These innervate and provide voluntary control over the skeletal muscle of the external sphincter (ACh). (nicotinic receptor)
Higher centres can override this contraction and cause the external sphincter to relax.
- Parasympathetic nervous system drives the voiding of the bladder - makes the detrusor muscle in the wall contract
- Adrenergic system relaxes the wall of the bladder and constricts the outflow of the bladder
- If your ANS is not working properly (spinal injury or neuropathy in diabetes) it can affect these nerves so affects bladder control
12
Q
what are the roots of parasympathetic nerve fibres? what does this innervation cause?
A
• Parasympathetic nerve fibres (S2,3,4) cause:
Contraction of detrusor muscle in the body of the bladder (M3 receptor).
Relaxation of the urethra.
This aids micturition.
13
Q
what are the roots of sympathetic nerve fibres? what does this innervation cause?
A
• Sympathetic nerve fibres (T11-L2) cause:
Relaxation of the detrusor muscle in the body of the bladder (B3 receptor).
Contraction of the urethra (a1 receptor).
This aids the filling of the bladder.
14
Q
what are the roots of the somatic nerve fibres? what does this innervation cause?
A
• Somatic nerve fibres (S2,3,4) cause:
Contraction of the external sphincter.
Higher centres can override this contraction and cause the external sphincter to relax.
15
Q
what is micturition? what are the two main steps?
A
• Micturition is the process by which the urinary bladder empties when it becomes filled.
• This involves two main steps:
1. The bladder fills until the tension in its walls rises above a threshold level.
2. This elicits a nervous reflex called the micturition reflex that empties the bladder or, if this fails, at least causes a conscious desire to urinate.
16
Q
is the micturition reflex an autonomic spinal cord reflex?
A
Although the micturition reflex is an autonomic spinal cord reflex, it can also be inhibited or facilitated by centres in the cerebral cortex or brain stem.
17
Q
what is the composition of urine expelled from the bladder like compared to that flowing out collecting ducts?
A
Urine that is expelled from the bladder has the same composition as fluid flowing out of the collecting ducts of the kidneys.
18
Q
urine flows from the collecting ducts into where? causing what? what does this do?
A
- Urine flows from the collecting ducts into the renal calyces, thus stretching them.
- This increases their pacemaker activity, which in turn initiates peristaltic contractions that spread to the renal pelvis and then downward along the length of the ureter, thereby forcing urine from the renal pelvis to the bladder.
19
Q
what do the walls of the ureters contain?
A
smooth muscle
20
Q
what is the smooth muscle of the ureters innervated by?
A
innervated by both sympathetic and parasympathetic nerves and by an intramural plexus (nerve plexus within the wall) that extends along the entire length of the ureters.
21
Q
what are peristaltic contractions in the ureter enhanced and inhibited by?
A
Peristaltic contractions in the ureter are enhanced by parasympathetic stimulation and inhibited by sympathetic stimulation.
22
Q
where do the ureters enter? what prevents back flow of urine? what can sometimes happen? what can this lead to?
A
• The ureters enter the bladder through the detrusor muscle in the trigone region.
The normal tone of the detrusor muscle in the bladder wall tends to compress the ureter, thereby preventing back flow of urine from the bladder when pressure builds up in the bladder during micturition or bladder compression.
- Sometimes, the contraction of the bladder during micturition does not always lead to complete occlusion of the ureter (valve).
- As a result, some of the urine in the bladder is propelled backward into the ureter - vesicoureteral reflux.
- Such reflux can lead to enlargement (dilatation) of the ureters.
- If severe it increases the pressure in the renal calyces and the renal medulla, causing renal dysfunction.
23
Q
are the ureters supplied with many pain nerve fibres? what happens when a ureter becomes blocked? what is this called? why important?
A
- The ureters are well supplied with pain nerve fibres.
- When a ureter becomes blocked (e.g. by a ureteral stone), intense reflex constriction occurs, associated with severe pain.
- Also, the pain impulses cause a sympathetic reflex back to the kidney to constrict the renal arterioles, thereby decreasing urine output from the kidney.
- This effect is called the ureterorenal reflex and is important for preventing excessive flow of fluid into the pelvis of a kidney with a blocked ureter.
24
Q
what are the micturition contractions a result of?
A
the micturition reflex
25
describe the micturition reflex
As the bladder is filling, sensory stretch receptors in the bladder wall, especially by the receptors in the posterior urethra, initiate a stretch reflex.
Sensory signals from these stretch receptors are conducted to the sacral plexus through the ‘sensory’ afferents of the pelvic splanchnic nerves and then reflexively back to the bladder through the ‘motor’ efferent fibres of the same pelvic splanchnic nerves.
When the bladder is only partially filled, these micturition contractions usually relax and the detrusor muscles stop contracting, and pressure falls back to the baseline.
As the bladder continues to fill, the micturition reflexes become more frequent and cause greater contractions (more powerful) of the detrusor muscle.
Once a micturition reflex begins, it is “self-regenerative”.
That is, initial contraction of the bladder activates the stretch receptors to cause a greater increase in sensory impulses to the bladder and posterior urethra, which causes a further increase in reflex contraction of the bladder; thus, the cycle is repeated again and again until the bladder has reached a strong degree of contraction.
After a little while, the self-regenerative reflex begins to fatigue and the regenerative cycle of the micturition reflex ceases, permitting the bladder to relax.
26
what happens to micturition reflexes as the bladder becomes more and more filled?
what happens once the micturition reflex becomes powerful enough?
what happens if this inhibition is more potent in the brain than the voluntary constrictor signals to the external sphincter? if not what happens?
* As the bladder becomes more and more filled, micturition reflexes occur more frequently and more powerfully.
* Once the micturition reflex becomes powerful enough, it causes another reflex, which passes through the pudendal nerves to the external sphincter to inhibit it.
* If this inhibition is more potent in the brain than the voluntary constrictor signals to the external sphincter, urination will occur.
* If not, urination will not occur until the bladder fills still further and the micturition reflex becomes more powerful.
27
The micturition reflex is a completely autonomic spinal cord reflex, but it can be inhibited or facilitated by centres in the brain. where are these centres located? facilitative or inhibitory?
1. Brainstem (pons) – these are strong facilitative and inhibitory centres.
2. Cerebral cortex – these are mainly inhibitory but can become excitatory.
28
although the micturition reflex causes micturition, what normally exerts final control of micturition? how?
higher centres
1. The higher centres keep the micturition reflex partially inhibited, except when micturition is desired.
2. The higher centres can prevent micturition, even if the micturition reflex occurs, by continual tonic contraction of the external sphincter until a convenient time presents itself.
3. When it is time to urinate, the cortical centres can facilitate the sacral micturition centres to help initiate a micturition reflex and at the same time inhibit the external urinary sphincter so that urination can occur.
29
how is voluntary urination usually initiated?
1. Voluntary contraction of abdominal muscles.
2. This increases the pressure in the bladder and allows extra urine to enter the bladder neck and posterior urethra under pressure, thus stretching their walls.
3. This stimulates the stretch receptors, which excites the micturition reflex and simultaneously inhibits the external urethral sphincter.
30
usually, all the urine will be emptied with rarely more than how much left in the bladder?
5-10 ml
31
micturition reflex contraction cannot occur if what happens? what happens in each case? what are common causes?
1. The sensory nerve fibres from the bladder to the spinal cord are destroyed, thereby preventing transmission of stretch signals from the bladder.
When this happens, a person loses bladder control, despite intact efferent fibres from the cord to the bladder and despite intact neurogenic connections within the brain.
Instead of emptying periodically, the bladder fills to capacity and overflows a few drops at a time through the urethra.
o This is called overflow incontinence.
A common cause of atonic bladder is crush injury to the sacral region of the spinal cord.
2. The spinal cord is damaged above the sacral region but the sacral cord segments are still intact.
As a result, typical micturition reflexes can still occur.
However, they are no longer controlled by the brain.
3. There is damage to the brain stem.
This interrupts most of the inhibitory signals.
The uninhibited neurogenic bladder results in frequent and relatively uncontrolled micturition.
Facilitative impulses passing continually down the cord keep the sacral centres so excitable that even a small quantity of urine elicits an uncontrollable micturition reflex, thereby promoting frequent urination.
32
what is the prostate gland?
a compound tubuloalveolar exocrine gland of the male reproductive system.
33
what is function of prostate? fluid is what volume of the semen? along with what?
The function of the prostate is to secrete a slightly alkaline fluid, milky/white in appearance, that in humans constitutes roughly 30% of the volume of the semen along with spermatozoa and seminal vesicle fluid.
* Antegrade ejaculation (prostate closes to allow for antegrade instead of retrograde ejaculation)
* Contributes to 25% ejaculate volume
* Milieu for sperm to thrive - nutrition, antimicrobial (Zn, selenium)
* Prostatic specific antigen (PSA) enzyme (controls ejaculate) - semen coagulation, semen liquefaction
34
what does the alkalinity of semen do? how is semen made alkaline?
* The alkalinity of semen helps neutralise the acidity of the vaginal tract, prolonging the lifespan of sperm.
* Semen is made alkaline overall with the secretions from the other contributing glands - seminal vesicle fluid.
35
describe difference between spermatozoa expelled together with mainly seminal vesicular fluid compared to those expelled in prostatic fluid?
Better motility
Longer survival
Better protection of the genetic material
36
what does the prostate also contain (other than glands)?
some smooth muscles that help expel semen during ejaculation.
37
structure of prostate gland
- size
- where
- within
- what does urethra merge with
- how can prostate be divided
- does it have a capsule
- where is it sheathed
* A healthy male prostate is the size of a walnut.
* It surrounds the urethra just below the urinary bladder and can be felt during a rectal exam.
* Within the prostate, the urethra coming from the bladder is called the prostatic urethra and merges with the 2 ejaculatory ducts (from the seminal vesicles – one form each side of the body).
* The prostate can be divided in 2 ways: by ZONE or by LOBE.
* The prostate does not have a capsule; rather an integral fibromuscular band surrounds it.
* It is sheathed in the muscles of the pelvic floor, which contract during the ejaculatory process.
38
what is the zone classification used for? what are the different zones?
in the pathology of the prostate
- transition zone
- peripheral zone
- central zone
- fibromuscular zone (anterior zone)
39
transitional zone
- what percentage of gland at puberty
- where
- what special about it
- what responsible for
• Transitional zone – up to 5% of gland at puberty
This zone surrounds the proximal urethra.
It is the region of the prostate gland that grows throughout life
Therefore, responsible for the disease of benign prostatic hyperplasia (BPH)
- about 30% of prostate cancer happens here
40
peripheral zone
- what percentage of gland
- where
- what does it surround
- how big
- what important about it
- what responsible for
• Peripheral zone – up to 70% of gland
The sub-capsular portion of the posterior aspect of the prostate gland that surrounds the distal urethra.
This region is the largest and closest to the rectum - can easily be felt during a digital rectal examination (DRE).
70–80% of prostatic cancers originate here
41
central zone
- what percentage of gland
- what does it surround
• Central zone – up to 25% of gland
| This zone surrounds the ejaculatory ducts.
42
fibromuscular zone
- what percentage of gland
- what is it
- what is it composed of and what not
• Fibromuscular zone – up to 5% of gland
This isn’t actually a zone but rather a sheath on the anterior aspect of the prostate.
This zone is usually devoid of glandular components, and composed of muscle and fibrous tissue
43
what is the male sexual response? what does sperm go through? what causes excretion?
During male ejaculation, sperm is transmitted from the ductus deferens into the male urethra via the ejaculatory ducts, which lie within the prostate gland.
During orgasm, smooth muscle tissue in the prostate contracts in order to push semen through the urethra.
It is possible for men to achieve orgasm solely through stimulation of the prostate gland.
44
what are the prostatic secretions like? what composed of?
The prostatic secretions are a milky white mixture of simple sugars (such as fructose and glucose), enzymes, and alkaline chemicals.
45
in the secretions, what percentage is the protein content? what does it include?
```
less than 1%
Proteolytic enzymes – to break down coagulants and other proteins, to make the semen more viscous
Citric acid
Prostatic acid phosphatase
Beta-microseminoprotein
Prostate-specific antigen (PSA)
Zinc – antimicrobial
```
46
what do the sugars secreted by the prostate function as?
as nutrition for sperm as they pass into the female body to fertilize ova.
47
what do enzymes in the secretions do?
they work to break down proteins (coagulants) in semen after ejaculation to free sperm cells from the viscous semen.
48
what do the alkaline chemicals in the prostatic secretion do?
neutralise acidic vaginal secretions to promote the survival of sperm in the female body.
49
regulation of growth and division
- where is testosterone produced
- what happens to it
- what is the ultimate mediator of prostatic growth
- how
- what can also stimulate growth
Testosterone is produced in the testicles.
It travels to the prostate and is converted to dihydrotestosterone (DHT) in the stromal cells by the action of the enzyme type 2 5α-reductase.
Dihydrotestosterone (DHT) is the ultimate mediator of prostatic growth as it causes CELL GROWTH and INHIBITS APOPTOSIS.
DHT binds to nuclear androgen receptors, which regulate the gene expression that support the growth and survival of prostatic epithelium and stromal cells.
Although testosterone can also bind to androgen receptors and stimulate growth, DHT is 10 times more potent.
Binding of DHT to androgen receptor (AR) activates the transcription of androgen-dependent genes.
50
is DHT a direct mitogen for prostate cells?
no, instead DHT-mediated transcription of genes results in the increased production of several growth factors and their receptors.
51
what is the most important among these growth factors transcribed through DHT binding to receptor? what are other ones produced in BPH? what do they do?
Most important among these are members of the fibroblast growth factor (FGF) family, and particularly FGF-7 (keratinocyte growth factor).
Other growth factors produced in BPH are FGF-1 and FGF-2 which promote fibroblast proliferation.
52
what is through to contribute to BPH?
Although the ultimate cause of BPH is unknown, it is believed that DHT-induced growth factors act by increasing the proliferation of stromal cells and decreasing the death of epithelial cells.
53
what may exacerbate clinical symptoms of lower urinary tract obstruction caused by prostatic enlargement?
by contraction of prostatic smooth muscle mediated by α1-adrenergic receptors.
54
how is the flow of urine through the prostatic urethra controlled?
The urethra runs from the bladder, through the prostate, and out through the penis.
The muscle fibres of the prostate are wrapped around the urethra and are under involuntary nervous system control (SNS – hypogastric nerve (a1)).
These fibres contract to slow and stop the flow of urine.
55
give a summary of the male genital system
- pathway
- roles of different parts
* The male genital system begins with the 2 testis where sperm is produced.
* The epididymis is system of convoluted small tubules leading from each testis and emptying into the vas deferens.
* After being joined by the duct of the seminal vesicles, the vas deferens becomes the ejaculatory duct which enters the prostate where it joins with the urethra to convey the sperm contained in semen to the penis.
* The walnut sized prostate gland is situated just beneath the bladder and encircles the upper part of the urethra.
* It secretes alkaline fluids rich in enzymes and prostaglandins.
* This secretion is important to the survival and performance of the sperm.
* The seminal vesicles also play an important role in contributing secretions which enhance the sperms chance of success.
* During ejaculation the connection between the bladder and the urethra is closed while the prostate, seminal vesicles, urethra and the penis all undergo rhythmical contraction moving forward the semen which is composed semen plus secretions from the prostate, seminal vesicles and minor glands.
56
what is the aging male prone to developing?
enlargement of the prostate known as BPH (benign prostate hyperplasia)
57
what does the prostate contain? what happens in BPH?
• The prostate contains small glands, muscle fibres and connective tissue.
In BPH all of these enlarge, resulting in the enlargement of the prostate gland.
58
what are the first changes in BPH?
first changes in BPH involve proliferation of glandular tissue in the transitional zone.
59
what is constantly happening in prostate? what is thought to be an important factor in causing BPH?
* New cells are constantly being formed by division as a result of the pathogenesis of BPH.
* Room has to be made for these new cells by a special process of apoptosis so that in normal health the number of cells being produced is balanced by the number of cells being removed.
* Impairment of apoptosis is thought to be an important factor in causing BPH.
60
what happens as the prostate enlarges? what does this cause?
it compresses the prostatic urethra, causing disruption to the normal flow of urine.
61
when epithelial cells multiply excessively in either BPH or in prostate cancer, they may release what? why normally released? why do levels increase? what is the difference in this release between BPH and prostate cancer?
• When epithelial cells multiply excessively in either BPH or in prostate cancer, they may release an excessive amount of a glycoprotein called prostate specific antigen (PSA) into the circulation (normal range = 0-4ng/ml):
Normally, the prostate epithelial cells secrete prostate 'specific' antigen (PSA). This is required to liquefy the semen.
The level of this will increase if the prostate enlarges because there are more epithelial cells secreting PSA.
In prostate cancer, there are more cells than in BPH. Therefore, in prostate cancer, the level of PSA in the blood is greater than that in BPH.
62
what are risk factors for BPH?
- Age and Male
- Androgens
- Functional androgen receptors
- Obesity
- Diabetes (& elevated fasting glucose)
- Dyslipidaemia
- Oestrogens
- Genetic
63
what reduces risk of BPH?
- Castration
- Moderate/severe physical exercise
- Weight loss
- Modification of cardiovascular risk
64
how common is BPH? in which age? what percentage of men aged 40 have histologic evidence? how many of those with microscopic evidence have clinically detectable enlargement of the prostate and develop clinical symptoms? what percentage of 71-80 year olds have BPH on autopsy?
• BPH is an extremely common disorder in men over 50-65.
• Incidence:
Histologic evidence can be seen in approximately 20% men aged 40.
Prevalence of BPH after Autopsy (left)
Prevalence of BPH after Clinical (right)
23% aged 41-50 yrs 14% aged 40-49 yrs
42% aged 51-60 yrs 24% aged 50-59 yrs
71% aged 61-70 yrs 43% aged 60-69 yrs
82% aged 71-80 yrs 40% aged 70-79 yrs
Only 50% of those who have microscopic evidence of BPH have clinically detectable enlargement of the prostate, and of these individuals, only 50% develop clinical symptoms.
30% of white Americans over 50 years having moderate-severe symptoms.
65
what are the symptoms of BPH?
• BPH may cause lower UT symptoms.
• Storage Symptoms:
Going frequently to pass urine
A feeling that the bladder is full (urgency)
Waking up at night to pass urine (nocturia)
Leakage of urine when one does not get to the toilet in time (urge incontinence)
• Voiding Symptoms:
Needing to wait for the stream to start (hesitancy)
Weak stream
The stream starts and stops intermittently
Having to push and strain to pass urine
Dribbling at the end of urination
Sensation of incomplete bladder emptying
• Sometimes, despite urination, the bladder may not empty completely causing a large post-void residual urinary problem, increasing the risk of infection/ bladder stone formation/ cancer development.
66
what are complications of BPH?
* Infection <1 – 12%
* Renal Failure < 2.5%
* Bladder calculi 0.3 – 3.4%
* Incontinence <1%
* Retention 1 – 2%/yr
* Haematuria
67
what are investigations for BPH?
* Abdominal examination – usually palpate to check for a distended bladder.
* Rectal examination – prostate feels enlarged but smooth. (nodules would indicate cancer)
68
what are two types of drug treatments for BPH?
- anti-androgen
| - alpha1-adrenergic receptor antagonists
69
anti-androgen
- what are examples
- mechanism of action
- effect on PSA
- Finasteride, Dutasteride
- Block the enzyme 5α-reductase type 2.
- This slows the conversion of testosterone into DHT, thus slowing down the growth of the stromal and epithelial prostate cells.
- This also promotes apoptosis.
- Reduces PSA (due to promotion of apoptosis)
- 5-alpha reductase inhibitors
- slowly shrink the prostate so that is stops pressing on the urethra, making it easier to urinate
- can shrink the prostate by around a quarter after 6 to 12 months of treatment
- usually offered these if your prostate is very large – because they work particularly well in men who have a larger prostate
- e.g. finasteride, dutasteride
- reduce the amount of PSA in your blood – means doctor will need to change way they look at any PSA tests you have
70
what are the benefits of anti-androgens?
```
Safe
Reduce prostate volume
Reverse pathology
Reduced risk of complications
Reduce risk of surgery
```
71
what are the drawbacks of anti-androgens?
```
Slow Acting
Erectile Dysfunction
Gynaecomastia
Reduced Libido
Reduce PSA too much
```
72
alpha1-adrenergic receptor antagonists (alpha-1 blockers)
- examples
- dose
- mechanism of action
- effect on PSA
- Tamsulosin, Alfuzosin, Doxazosin
- Competitive inhibition for the binding site of the α1-adrenergic receptors.
- Causes prostatic smooth muscle relaxation.
- This reduces urethral occlusion.
- These drugs may also encourage apoptosis.
- No effect on PSA
```
• Tamsulosin (Flomax) - 0.4 mg od
• Alfuzosin (Xatral) - 10 mg od
• *^ Doxazosin (Cardura) - 1 - 8 mg od
• requires titration
^ antihypertensive
```
- Alpha-blockers
- relax muscles in prostate and around opening of the bladder, making it easier to urinate
- they don’t cure an enlarged prostate but they can help to relieve symptoms
- usually first type of medicine you will be offered, unless your prostate is very large
e. g. Tamsulosin, alfuzosin, doxazosin, terazosin
73
what are the benefits of alpha1-adrenergic receptor antagonists?
Quick Acting
Safe
Selective
Long Lasting
```
Advantages:
• Rapid onset
• Safe (very)
• Doesn’t alter PSA
• Symptoms improvement maintained
```
74
what are the drawbacks of alpha1-adrenergic receptor antagonists?
Dizziness
Drowsiness
Headaches
Little or no sperm on edjaculation
Side effects:
• Postural hypotension - 2 - 5% (due to receptors in arterioles)
• Retrograde ejaculation (relaxed prostate at bladder neck) (means its working)
• Headaches
75
how are these drugs given, together or separately? what can also be given?
* Both these drugs are given in combination because the anti-androgen drugs are better, but they are short acting.
* Phytotherapy may also be used – ‘saw palmetto’ extracts.
* In acute retention or retention with overflow, the first priorities are to relieve pain and to establish urethral catheter drainage.
76
when does BPH require surgery?
Deterioration in renal function or the development of upper tract dilatation requires surgery.
77
what surgical procedures can be carried out? (BPH)
Bladder neck incision
Trans-urethral resection of prostate (TURP)
Holium laser enucleation of prostate (HOLEP)
Open prostectomy
Prostatic stent
78
transurethral resection of the prostate (TURP)
- when is it used, what line of therapy
- what happens
Transurethral resection of the prostate (TURP)/Transurethral Prostatectomy
• This has been the gold standard in terms of reducing symptoms, improving flow rates, and decreasing post-voiding residual urine.
• It is indicated as a first line of therapy in recurrent urinary retention.
• If urethral catheterisation is impossible, suprapubic catheter drainage should be done.
TURP (transurethral resection of the prostate)
- Remove parts of the prostate that have grown too large and are pressing on the urethra
- Most common type of surgery for an enlarged prostate
- During the operation, the surgeons passes a thin tube up your penis into your urethra
- They then pass an electrically-heated wire loop through the tube and use it to remove small pieces of prostate tissue
79
TURP
- what is it
- when necessary
- anaesthesia
- describe procedure
• A surgical procedure that removes part/all of the prostate.
• This would be necessary if:
The first treatments for prostate enlargement, such as medication, fail to control symptoms.
An enlarged prostate leads to complications such as bladder stones, infections or difficulty emptying it.
• This is performed under general/spinal anaesthesia:
General – unconscious throughout the procedure
Spinal/epidural – awake throughout but not feel anything
* A device called the resectoscope is used which is a thin metal tube consisting of a light, a camera and a loop wire.
* The resectoscope is inserted into the urethra and guided to the site of the prostate.
* An electric current is used to heat the loop of wire, and the heated wire is used to cut away the section of your prostate that is causing the symptoms.
* After the procedure, a catheter is used to pump saline water into the bladder and flush away pieces of prostate that have been removed.
* Before the surgery, NaCl is administered IV.
* This is to make the smooth muscles in the prostate and the bladder more apparent.
* Glycine may also be used for this purpose, but the prostatic venous sinuses absorb this – it is then metabolized in the portal bed and kidneys. Ammonia is a major by-product of glycine metabolism.
80
what are the advantages of TURP?
```
No strain to urinate
More control over holding in urine
No more nocturia
Stronger stream of urine
No more pads
```
81
what are the disadvantages of TURP?
Loss of ability to ejaculate (retrograde ejaculation – 70%) and ED (erectile dysfunction)
Stricture (narrowing)
82
HOLEP
- what is this
- what happens
- what are advantages
Holmium Laser Enucleation of the Prostate (HOLEP)
• An alternative to this method is the Holmium laser enucleation of the prostate (HOLEP):
In this a laser is used to separate excess tissue from the prostate into the bladder and the tissue is then removed.
HOLEP causes less blood loss, involves a shorter stay in hospital and is suitable for moderate to large prostates.
83
pathogenesis of BPH
* Mainly due to impaired cell death – lack of apoptosis.
* This results in the accumulation of senescent cells in the prostate.
* Androgens (mainly DHT), which mediate the development of BPH, can not only increase cellular proliferation, but also inhibit cell death.
* Stromal cells are responsible for androgen-dependent prostatic growth because the type 2 5α-reductase enzyme is only found in the stromal cells.
• As well as the enlargement of the glandular tissue, fibroblasts also proliferate and enlarge.
This is because of excessive FGF growth factors.
As a result of this fibrosis, the bladder wall can’t contract properly and so there is residual urine volume left over always, increasing the risk of infections etc.
84
what happens to growth and multiplication in prostate cancer? what happens in addition to this?
* In prostate cancer the growth and multiplication of cells escapes from normal control.
* In addition there is impairment of apoptosis (usually a gene mutation of p53).
85
where does prostate cancer usually occur?
in the peripheral zone
86
what happens in prostate cancer compared to BPH? (in terms of cell multiplication and subsequent effects)
* Unlike the situation in BPH where cell multiplication is much more controlled, in prostate carcinoma the malignant cells multiply out of control, begin to invade the stroma which is the connective tissue of the prostate and extend beyond it to the surrounding structures such as the seminal vesicles.
* Having breached the capsule, the tumour is now able to spread more widely.
87
where do malignant cells metastasise to?
* Malignant cells may invade the lymphatic system travelling to regional lymph nodes and then onto the liver and/or lungs.
* If tumour cells enter the blood stream they can metastasise to the bones as well.
88
epidemiology of prostate cancer
- how common
- age
- by the age of 80, what percentage of men have malignant foci within gland
* Prostatic carcinoma accounts for 7% of all cancers in men.
* It is the 6th most common cancer in the world.
* Malignant change within the prostate becomes increasingly common with advancing age.
* By the age of 80 years, 80% of men have malignant foci within the gland, but most of these appear to lie dormant.
89
histologically what is prostate cancer?
an adenocarcinoma
90
what are thought to play a role in the aetiology of prostate cancer
* Histologically, the tumour is an adenocarcinoma.
| * Hormonal factors (androgens) are thought to play a role in the aetiology
91
screening
- what can be used for detection of cancer
- who shouldn't have screening
- why should tests be interpreted with caution
* Serum prostate-specific antigen (PSA) can be used for the detection of this cancer.
* Many men over 70 have evidence of prostate cancer at post mortem with no symptoms of the disease and it has been suggested that over 75-year-olds should not have screening PSAs.
* The test must be interpreted with caution due to the natural increase in PSA with age, BPH and with prostatitis.
* It may be life saving for the individual diagnosed with a high grade tumour that is still amenable to curative treatment.
* There is a dilemma with the screening of prostate cancer.
* This is because such screening methods can lead to over-diagnosing of patients who don’t require treatment.
* As a result, a lot of the healthcare money is wasted on such treatment.
92
what does urinary tract obstruction increase susceptibility to? what does unrelieved obstruction almost always lead to?
Obstruction increases susceptibility to infection and to stone formation, and unrelieved obstruction almost always leads to permanent renal atrophy (hydronephrosis).
93
what are the different types of obstruction? where can it occur? where are common sites of UT obstruction caused by a kidney stone?
* Obstruction may be sudden or insidious, partial or complete, unilateral or bilateral; it may occur at any level of the urinary tract from the urethra to the renal pelvis.
* The most common sites of UT obstruction causes by a kidney stone are: (1) uretropelvic junction (between ureter and renal pelvis), (2) pelvic brim (where ureters cross the bifurcation of common iliac artery), (3) uretrovesicular junction (where the ureters enter the bladder).
94
what is hydronephrosis?
dilation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to obstruction to the outflow of urine.
95
does glomerular filtration persist with complete obstruction? what does this cause? what happens next? what are the initial functional alterations? what can happen? does GFR ever decrease? how does obstruction eventually lead to interstitial fibrosis?
* Even with complete obstruction, glomerular filtration persists.
* Because of this continued filtration, the affected calyces and pelvis become dilated.
* The high pressure in the pelvis is transmitted back through the collecting ducts into the renal cortex, causing renal atrophy, but it also compresses the renal vasculature of the medulla, causing a diminution in inner medullary blood flow, both the perfusion and clearance are deficient (this can be picked up on a dynamic isotope renogram)
* The medullary vascular defects are initially reversible, but lead to medullary functional disturbances.
* Accordingly, the initial functional alterations caused by obstruction are largely tubular, manifested primarily by impaired concentrating ability (can lead to metabolic acidosis).
* Only later does the GFR begin to fall.
* Obstruction also triggers an interstitial inflammatory reaction, leading eventually to interstitial fibrosis.
96
what are the clinical features of urinary tract obstruction?
Acute obstruction may provoke pain attributed to distention of the collecting system or renal capsule.
Most of the early symptoms are produced by the underlying cause of the hydronephrosis.
Unilateral complete or partial hydronephrosis may remain silent for long periods, since the unaffected kidney can maintain adequate renal function.
Ultrasonography is a useful non-invasive technique in the diagnosis of obstructive uropathy.
In bilateral partial obstruction the earliest manifestation is inability to concentrate the urine, reflected by polyuria and nocturia.
Complete bilateral obstruction results in oliguria (small amounts of urine production) or anuria and is incompatible with survival unless the obstruction is relieved.
Curiously, after relief of complete urinary tract obstruction, postobstructive diuresis occurs.
This can often be massive, with the kidney excreting large amounts of urine that is rich in sodium chloride.
97
what occurs with ageing and accounts for the progressive reduction in GFR seen with advancing years?
progressive sclerosis of glomeruli and development of atheromatous renal vascular disease
98
what GFR is normal for patients in their 80s?
50–60 mL/min (about half the normal value for a young adult) may be regarded as ‘normal’ in patients in their 80’s.
99
what may mask this deterioration in renal function
* The reduction in muscle mass often seen with ageing may mask this deterioration in renal function in that the serum creatinine concentration may be less than 120mmol/L in an elderly patient whose GFR is 50 mL/min or lower.
* The serum creatinine as a measure of renal function in elderly must take this into account.
100
how common is urinary incontinence in elderly? women and men?
common in the elderly with 25% of women and 15% of men over 65 having a problem.
101
what is acute renal failure?
an abrupt decline in the renal function with increased creatinine and increased blood urea nitrogen levels (uraemia).
102
what is acute renal failure due to? what else can it be accompanied by?
• This is failure of renal excretory function due to depression of the GFR.
• This is accompanied to a variable extent by:
Failure of erythropoietin production (this can lead to a low Hb count and cause anaemia)
Failure of vitamin D hydroxylation
Failure of regulation of acid–base balance (this can lead to metabolic acidosis)
Failure of regulation of salt and water balance and blood pressure.
103
how is renal failure classified?
Renal failure results in reduced excretion of nitrogenous waste products (e.g. urea).
A raised serum urea concentration (uraemia) is classified as:
- Prerenal – caused by impaired perfusion to the kidneys.
- Renal – caused by acute tubular necrosis/ iscahemia/ toxins.
- Postrenal – caused by obstruction in the urinary tract.
104
what are the laboratory tests for prostate cancer? and kidney function?
- cloudy urine
- urine sample
- filled and distended bladder
- urine Na+ and osmolarity
- serum electrolytes
105
cloudy urine
| - what would this show?
Due to mild presence of semen in the urine (after retro-ejaculation)/ UTI/ presence of proteins in the urine/ dehydration.
106
urine sample
- what test for
- what indicate
* This tests for sugar, protein, or blood in the urine.
* Can be carried out quickly as a urine dipstick test.
* Blood can signify diseases in the kidney, urinary system or bladder.
* Sugar is a sign of diabetes.
* Protein would indicate kidney disease.
* PSA can indicate cancer.
107
filled and distended bladder
- what could cause be
- what happens
* A cause of this is an enlarged prostate.
* The prostate can block off the urethra, which makes urinating difficult, if not impossible.
* A person with a distended bladder will not be able to urinate, even if they feel the urge to do so.
* They may also feel some pain in the lower abdomen as a result of the condition.
108
urine Na+ and osmolarity
- what test used to see
- what happens to it and why
* Sodium test is used to see whether a patient is properly hydrated.
* It also evaluates kidney function.
• Due to atrophy of the kidney parenchyma, perfusion and clearance in the kidney is highly affected:
This means that the kidney is not able to filter the blood well or clear it so all the sodium filtered is not reabsorbed back into the blood so there is a decrease.
Also, the backflow of urine increases the tubular fluid in the kidneys. This dilutes the Na+ ions present in the tubular fluid in the kidneys, thus decreasing the osmolarity of the urine.
109
serum electrolytes - potassium levels
| - what happens
Hyperkalaemia
• This is due to the fact that there is renal dysfunction and so the person cannot secrete K+ into the tubular fluid (urine).
• Therefore, K+ ions build up in the cells.
110
serum electrolytes - pH
| - what would renal dysfunction cause to happen
Decreased Blood pH
• This is due to renal dysfunction.
• The kidney is unable to secrete H+ ions into the urine.
• The kidney is unable to reabsorb HCO3- ions from urine.
• This causes metabolic acidosis, and a subsequent decrease in the pH.
111
serum electrolytes - pCO2
| - what happens and why
Decreased pCO2
• Due to the metabolic acidosis, the patient hyperventilates as respiratory compensation.
• This means the person hyperventilates and so the pCO2 decreases.
112
serum urea and creatinine
| - what happens and why
Serum Urea and Creatinine elevated
• Due to renal dysfunction, urea isn’t secreted into urine, and so it build up in the blood.
• Also, there is less perfusion to the kidneys and so urea and creatinine cannot be filtered into the nephron through the glomerulus, and so builds up in the blood.
113
serum electrolytes - haemoglobin concentration
= what happens
- why
- what's normal
Haemoglobin conc. 9.4g/dl
• Due to renal dysfunction, the kidneys secrete less erythropoietin into the blood.
• This means that there is reduced maturation of the RBCs, and a subsequent drop in the level of serum haemoglobin.
• Normal haemoglobin range = 13-18 g/dl
114
what are the different was of imaging the kidney?
```
Abdominal radiographs
Ultrasound
Fluoroscopy
Nuclear medicine
CT
MRI
```
115
abdominal radiograph
- what does this involve/what is seen
- what is primary indication
- what can also be done
- what do you look for in an abdominal x-ray
• This involves imagining of the kidney, ureter and bladder (KUB radiograph)
• Radiation is used (x-rays)
• Primary indication is urinary tract calculus
• Intravenous urography (IVU)
This is an x-ray procedure used to assess problems in the KUB.
A contrast dye is injected intravenously.
- give dye and then do an x-ray - allows you to see the ureters nicely (find if got ureteric stone) - stopped using as much because use CT much more
```
What to look for in an abdominal x-ray:
• Look for organs
• Look for gas
• Calcification - kidney stone, gallstones, bladder stones and bones
• Foreign bodies - cholecystectomy
```
116
ultrasound
- what does this involve/what is seen
- what used to do
- when commonly used
* Involves imaging of the kidneys and the urinary bladder only. (ureters not so much because they’re very small)
* The testes can also be imaged using ultrasound.
* There is no radiation involved. Only the use of sound waves.
* This is used commonly in paediatric radiology - no radiation
* Operator dependent - got to know what you’re doing - hard to know what is what - and patient dependent
117
fluoroscopy
- what does this involve/what is seen
- what is this used as part of
- what is used to do
- what can be used for
- what intervention
• Involved imaging of kidneys, ureters and bladder (KUB).
• This is used as part of a screening regime.
• There is continual use of x-rays (radiation).
• Cystograms are used in paediatric radiology. A cystogram is an examination that takes pictures of the bladder and urethra. (looking at bladder - look at reflux)
Contrast material is introduced into your bladder through the catheter, then x-rays are taken.
• It can be used for urethrograms too.
• intervention: nephrostomy (opening between the kidney and the skin) and antegrade (go in direction of normal flow - puncture through kidney into ureter) (retrograde through bladder into ureter to kidney) ureteric stent (due to blockage in ureter e.g. tumour or something pushing on ureter)
• Multiple x-rays are being taken and you see a video image
Fluoroscopy is a type of medical imaging that shows a continuous X-ray image on a monitor, much like an X-ray movie. During a fluoroscopy procedure, an X-ray beam is passed through the body.1
118
CT
- what happens
- what testing/used for
- what are indications
* Rotating x-ray tube and detector
* IV contrast – renal function (contrast can damage kidneys if there is a problem with the kidneys)
* Urinary tract calculi (main reason we use CT)
* Renal tumours (size, has it spread)
* Urinary tract tumours
* Cancer staging
* Renal cyst characterisation (if unsure on ultrasound)
* CT radiation - particularly worrying with children
* CT urogram - using contrast
119
MRI
- what happens/what involve
- what used for
- what for prostate cancer
- what are indications
* Magnet and coils : radiowaves and magnetic fields
* No radiation
* Soft tissue
* IV contrast
* Time - takes about 20 minutes, compared to 2 mins for CT
* Diffusion weighted imaging (gives bit more information about what seeing - whether it’s a tumour, cyst, abscess) – multi-parametric imaging for prostate cancer
* Renal lesion characterisation
* Renal and urinary tract tumours
* Prostate cancer - now much more involved in diagnosis - instead of doing biopsy first you do MRI first - will tell you if there is a tumour and whether it is a serious tumour - if you don’t think there’s a tumour there you just monitor PSA and try avoid doing biopsy
• CT is first line - then if need more information do MRI
Multi-parametric MRI - if there’s a tumour, it will be dark on one set of images and dark on the other
120
nuclear medicine
- what happens
- why used
- what involve
* Radioactive tracer and Gamma camera
* Radiation
* Assessment of function - see how well the kidneys are working, see if any scarring, if its obstructed
* Technetium-99m
* DMSA : dimercaptosuccinic acid
* MAG 3 : mercaptoacetyltriglycine
121
what are the following:
- benign prostate hyperplasia
- benign prostate hypertrophy
- benign prostate enlargement
- bladder outlet obstruction
- prostatism
* Benign prostate hyperplasia (BPH) (increasing number of cells)
* Benign prostate hypertrophy (BPH) (cells are getting bigger but same number of cells)
* Benign prostate enlargement (BPE) (both BPHs apply when you have enlargement)
* Bladder outlet obstruction (BOO)
* prostatism - this word is no longer used as it implies that the problem is due to the prostate which it might not be - might be the bladder or the urethra
* Lower urinary tract symptoms (LUTS) - most encompassing terminology
* Maybe prostate or bladder or both
122
what are storage/irritative issues?
* frequency
* Urgency
* Nocturia
* incontinence - urge (can’t get to loo on time due to an irritative/overactive bladder - not really a dangerous symptom)
* Enuresis (childhood)
123
what are voiding/obstructive issues?
* poor flow
* Hesitancy
* Intermittency
* Incomplete voiding
* Straining
* Dribbling
* Incontinence - overflow (incontinence due to obstruction - dangerous incontinence - retention can get worse and cause back pressure to the kidneys - can lead to renal failure)
124
what is the international prostate symptom score (IPSS)? what does it involve? what used for?
* Symptom score - recognised across the world (euro world)
* Symptom score shows you how well the treatment is working - monitor progress
* Use it to direct whether the patient needs treatment
* 7 aspects to this score
* Maximum score of 35
* Range of obstructive and irritative symptoms
125
IPSS & quality of life
| - what are the scores
* Scores: 1-7 = mild, 8-19 = moderation, and >_20 = severe
* If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?
* 0 = delighted -> 5 = unhappy
126
what are you looking for when examining the abdomen, genitals and prostate?
• Abdomen and Genitals - palpable bladder, phimosis (genitals) (when the foreskin is too tight to be pulled back over the glans penis)
Examining prostate:
• DRE (digital rectal examination) or
• PR (Per rectum)
• Smooth, rubbery, midline sulcus (prostate has two lobes) (should be preserved unless you have a tumour), size (difficult to gauge size of this - not really expected to say what it is) of prostate
• Normal prostate should feel like the tip of your nose or a tensed quadricep muscle)
127
how much does DRE raise PSA? what else elevates PSA? what is half-life of PSA?
* Raises it at most by about 0.5
* There are some things that will elevate PSA - infection or even ejaculation
* PSA half-life is about 3 days - so if a patient is border line repeat is at another time
128
what complications are there with the lower urinary tract?
* Infection - <1 - 12% (mid-stream urine)
* Urinary retention - 1 - 2%/yr (can cause renal failure if really severe) (examine patient)
* Renal impairment - < 2.5% (check renal function)
* Underlying prostate/bladder cancer (haematuria/mid-stream urine, PSA)
129
what are essential investigations of lower urinary tract?
* U&Es, creatinine, eGFR (estimated GFR)
* PSA (prostate specific antigen)
* Mid-stream urine for infection/haematuria
• Not necessary unless indicated: ultrasound urinary tract - kidneys and bladder residual volume (only do if abnormal renal function)
* MSU
* Urine does not usually have any bacteria in it
* An MSU is best as the first bit of urine that you pass may be contaminated with bacteria from the skin
Looking for abnormal findings:
• Examination: palpable bladder/phimosis/abnormal feeling prostate
• Bloods - renal impairment/raised PSA
• Urine - UTI/haematuria
• Assess severity of symptoms
130
what are the causes of enlarged prostate?
age and testosterone - both needed
131
what is the incidence of BPH and LUTS?
* By the time you are 50, 10% of men will have urinary symptoms and a 1/3 will have histological evidence of an enlarged prostate
* By the time you reach 100, 100% of men will have histological evidence of hyperplasia and hypertrophy and probably 100% will have symptoms
* Although 80% men at 80 have histological BPH, bit less will have symptoms and less than 20% will have surgery as most will have treatment
132
what is the pathogenesis of BPH? most popular theory?
* As you get older and you pee more and more, each void causes a little bit of trauma to the urethra, which produces an inflammatory response and this causes proliferative factors (epithelial growth factors) - causes a local enlargement of the cells around
* This is the middle bit (zone) of the prostate - transition zone - slightly spongy
* As this zone gets bigger, the bladder undergoes hypertrophy to try and overcome the narrowing of the urethra
* Various growth factors
* Proliferation of prostate glands, smooth muscle (in prostate), connective stroma
* Essential ingredients - age, testosterone
* Lack of apoptosis (natural cell death)
133
alpha-adrenergic receptors
- what happens when stimulated
- what happens if blocked
* When stimulated, in constricts (have a lot in arterioles)
| * If you can block this then you will relax some of the constriction around the bladder neck
134
glands in prostate
- how does testosterone get to prostate cells
- what converted to
- how potent is this
- what happens if you block this conversion
- how effective are these drugs
* Testosterone passes through wall of vein/vessel and reaches the prostate cell
* When it enters the prostate, it is converted to dihydrotestosterone - about a 1000 times more potent than testosterone
* If you can block this conversion within the prostate cell, then it will shrink
* Drugs can act on glandular side and shrink it by about 20-25% (drugs that we looked at before look at the muscular side of the prostate)
135
5-alpha reductase inhibitors
- what do these do
- example and dose
- advantages
- disadvantages
(blocks the testosterone in the bloodstream and blocks it in the prostate?)
* Finasteride (Proscar) 5 mg od
* Dutasteride (Avodart) 0.5 mg od
```
Advantages:
• Improves and maintains relief
• Shrinks prostate
• Reverses pathology
• Reduces urinary retention
• Promotes hair growth (side benefit) (due to receptors in hair - female/male balance)
```
Disadvantages:
• Slow onset (few months)
• Erectile dysfunction/reduced libido (5%)
• Reduces PSA (will half it over few months) (so have to remember this when monitoring this in terms of cancer? - would have to times it by 2)
• Gynaecomastia (man boobs)
136
which treatment maintains the improvement of symptoms?
* it’s the alpha reductase inhibitors that maintains the improvement of symptoms as there is only so much you can do to the muscle but you can maintain it through decreasing hormone conversion
* Combination treatment
137
what is other medication that can be used to treat BPH and its symptoms?
* Viagra - phosphodiesterase 5 inhibitors (PDE5i) and others - relaxing smooth muscle of the prostate (relaxing blood vessels and therefore blood flow into the erectile vessels of the penis)
* Anticholinergic - treat overactive bladder symptoms, e.g. urgency, frequency
* Phototherapy - saw palmetto (plant), zinc, selenium (a lot of these in the prostate) (more like homeopathy)
138
what do you have to do if medical therapy fails?
Tube drainage
- Catheters: permanent, self-catheterisation (several times a day to empty the bladder)
- Stents: prostate stent
Surgery (if doesn’t want catheter)
139
what are the surgical options?
* Transurethral resection of prostate (TURP) - create a channel through the prostate like coring an apple
* Holmium enucleation of prostate HoLEP - laser
140
what are the red flags?
* Urinary incontinence - sinister vs. benign (obstructive is the one that can be sinister)
* Renal impairment
* Haematuria
* Recurrent urinary infections
* Raised PSA
141
how can negative emotion affect pain?
* Anxiety and depression predict postoperative pain
| * Negative emotions can increase perception of pain
142
how are stress and healing linked?
stress is associated with impaired healing
143
what is psychological preparation for surgery?
* Techniques that affect outcomes by altering emotions, cognitions, behaviour
* What feel, what think, what do
144
what is the goal when giving sensory information before surgery?
reduce discrepancy between expected and actual sensation
145
what are cognitive interventions?
* Change how a person thinks - goal: reduce negative thinking and/or anxiety
* e.g.
* Reframing cognitions - training to find positive responses to worrying situations - e.g. reason for surgeon’s visit
* Distraction - encourage thinking about something else
146
what re the various relaxation techniques that can be taught for pre-surgery?
* Simple relaxation - systematically relax each muscle group
* Progressive muscle relaxation - slowly tense, then relax, each muscle group
* Guided imagery
• Can also practice hypnotic techniques
147
how can modelling be used? different types? who used in?
Observe a person in similar situation -> learn to cope with that event:
• ‘mastery model’: model calm, relaxed
• ‘coping model’: model finds situation challenging but successfully copes
Has been used with adults but more commonly used with children
148
what are the different interventions that can be used in preparation for surgery?
* Procedural information
* Sensory information
* Behavioural information
* Cognitive information
* Relaxation techniques
* Hypnosis
* Emotion-focused interventions
149
what is the loop of Henle important for?
for concentrating urine
150
describe the glomerlus. what happens in glomerular disease?
• Capillary loops
* Podocyte cells
* Basement membrane (prevents big molecules leaking out into urine - this is negatively charged and so repels albumin which is also negatively charged)
* Endothelial cells
* As well as the basement membrane, slit diaphragm between foot processes of the epithelial cells also act as a barrier for big molecules
* In glomerular disease, these barriers break down, leading to large molecules leaking into the urine
151
how many glomeruli in a human kidney? what about in patients with hypertension?
* Normotensives = 1 - 2 million per kidney (don’t know what causes such a big range)
* Essential hypertension = 0.5 - 1 million per kidney
* Patients with hypertension had significantly fewer glomeruli per kidney than matched normotensive controls
152
what do nephron tubules and collecting ducts do?
Modify the glomerular ultrafiltrate
153
what should you look for in glomerular diseases?
protein and red blood cells in the urine
154
what would kill you if you removed your kidneys? what else would happen?
If you removed your kidneys, the toxins that would kill you would be electrolyte disturbances, in particular potassium - dangerous if above 5 mmol in blood -> asystole
• If hydrogen ions build up you breathe very quickly (futile)
• Sodium and water - if they build up they go into the interstitium - spaces become water logged and you can get pulmonary oedema which can kill you - If it builds up in your legs they swell up and you get high blood pressure
155
what are different types of oedema? when is it especially severe?
(peripheral and internal, including pulmonary oedema and ascites)
Oedema is especially severe when severe proteinuria and hypoalbuminaemia are present = the nephrotic syndrome
156
what does hyperkalaemia produce on ECG?
peaked T waves
157
what are clear histological signs of kidney disease?
damaged glomerulus
158
what is the bladder? what pressure like? what does renal tract include?
* Is not just the kidney but includes the ureter and the urinary bladder
* The bladder is a low pressure reservoir which intermittently and completely expels urine per urethra (shouldn’t be more than a few mls of urine left)
* It contains smooth muscle bundles under autonomic nervous control
159
what are the key clinical symptoms and signs of disease of the lower renal tract?
* Dysuria
* Frequency of micturition
* Incontinence of urine
* Poor urinary stream
* Haematuria
* Pain (caused by acute bladder outflow obstruction, renal colic, urosepsis etc.)
160
what can primary disease of the lower tract cause?
secondary kidney failure mediated by impairment of urine flow
161
what are the two ways of classifying kidney and urinary tract diseases?
* Congenital malformations
* Acquired (non-tumours)
* Acquired (tumours)
* Genetic causes
* Environmental causes
162
what are they three main histological varieties of kidney malformations? which least and most severe?
* Hypoplasia (too few nephrons) (most mild abnormal kidney) (smaller kidney than normal)
* Dysplasia (undifferentiated kidney sometimes with cysts)
* Agenesis (absent kidney) (most severe)
163
can you survive as a foetus without kidneys? how common are malformed kidneys? what problems do they cause?
You can survive as a foetus without kidneys as the placenta acts as a filter
• however if you are not surrounded by enough amniotic fluid, your lungs don’t develop properly - it opens up the lungs and makes them grow before birth
* Half of all UK children with kidneys that don’t work were born with malformed kidneys
* Worldwide, 100,000 children are estimated to have kidney failure caused by malformed kidneys
* Many adults with failing kidneys were born with malformed kidneys
164
what is renal coloboma syndrome?
* Autosomal dominant disease
* Optic nerve malformation - blindness
* small, malformed kidneys - kidney failure
* PAK2 - needed for both to develop properly
165
what are the causes of acquired kidney failure?
‘Pre-renal’ causes:
• Shock (e.g. massive blood loss, septicaemia)
• Cardiac and liver failure
Intrinsic kidney disease:
• Glomerular disease (e.g. Alport syndrome (problem with basement membrane?), diabetes mellitus (sclerosis and fibrosis) and immune-mediated glomerulonephritis)
• Tubular disease (e.g. pyelonephritis, autosomal dominant polycystic disease (kidneys fairly normal when born but cysts develop through life and they start to squash out all the normal tissue), nephrotoxins)
‘Post-renal’ causes
• Urinary flow impairment (e.g. stones, tumours and dysfunctional bladders); need to block both kidneys
• Base of the bladder can get blocked by prostatic disease (benign or cancer) - bladder will work harder in short term but will fail in the long run and back up to the kidney = damage to kidney = post-renal renal failure
166
what happens to glomeruli in diabetes mellitus?
* Early on, GFR is actually increased (because of kidney growth (due to hyperglycaemia))
* Without treatment, there follows a progressive decline in renal function with sclerosis of glomeruli
167
what happens in acute kidney injury?
Tubule cell death and partial regeneration
• usually after necrosis the injury will regenerate
168
ADPKD
- what is it
- how common
- cause of what percentage of end-stage renal failure in adults
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)
• ADPKD affects 1/1000 people
• UK Renal Registry: polycystic kidney disease is the cause of 9% end-stage renal failure in adults (usually kidney failure when you’re 50-60 years old - usually had children at this point)
• Can also get aneurysms in their brain that can rupture
169
what therapies can be given to patients with polycystic kidney disease
Therapies targeting the cyst epithelial in PKD - vasopressin (antidiuretic hormone) receptor antagonists
• They slow the growth of cysts
• Probably gives 5 or 10 more years before they reach end-stage kidney disease
170
kidneys cancers
- how common compared to other cancers
- where originate
- where grow where metastasise
- what treatment
- type in children and adults
* 5th or 6th commonest in adults
* Almost always originates in the tubules
* Grows in the kidney and can metastasise to the lungs or brain
* Not many good treatments
* Children - Wilms tumour (most common type of kidney cancer in children)
* Adults - clear cell carcinoma
171
bladder and ureter cancers
- how common is bladder cancer
- what time of cancer - histology
- where does cancer start
- where does it go
• Bladder cancer very common in adults
* Transitional cell carcinoma
* Staging
* Histology
- Bladder polyp, it always starts in the epithelium and then that cancer can go into the detrusor muscle, can metastasis to the lymph nodes
172
prostate cancer
- what histology
- where metastasise
* Adenocarcinoma histology
* Sclerotic metastases (bone?)
An enlarged prostate gland can be palpated
173
does kidney failure cause jaundice?
no
174
what does kidney failure cause?
* Difficulty breathing
* High blood pressure
* Leg swelling
* Sudden death from hyperkalaemia
175
how can renal failure appear to cause jaundice?
Liver failure can cause pre-renal failure, however with primary kidney disease you don’t get jaundice
176
what is renal colic?
pain caused by a urinary tract stone (urolithiasis) - the pain can be anywhere in the urinary tract
177
what do refugees have that asylum seekers don't?
‘well-founded fear of persecution’
Asylum seekers in process of being assessed to gain legal status -> refugees have ‘status’ or ‘leave to remain’ - often temporary
178
what is Maslow's hierarchy of need?
```
• Physiological
• Safety
• love/belonging
• Esteem
• Self-actualisation
What is most important to discuss, what are they in most need of?
```
179
what are the risk factors for prostate cancer?
* Age - if man survives to age of 80, there’s 80% risk of finding prostatic cancer cells - not necessarily symptoms
* Race - higher risk in black men
* Family history - BRCA gene involved
* Nationality
* Genetics
* Diet
* Exercise and maintaining healthy weight may decrease risk
1/8 men get prostate cancer in their lifetime
180
what are prostate cancer symptoms?
Local (LUTS):
• Obstructive - urinary retention
• Irritative - frequency, nocturia
Metastatic:
• Pain etc. - because most common site of metastasis from prostate is to the bone
• However can go to local lymph nodes or other places which leads to different symptoms
Systemic:
• Fatigue, weight loss
• Common from whatever cancer
181
what is involved in investigating prostate cancer?
* History and examination
* DRE
* PSA
* Biopsy
* Multiparametric MRI
182
what are the confounding factors of PSA levels?
```
Increase:
• Benign prostatic hypertrophy
• Age
• Prostatitis
• Ejaculation
• DRE
```
Decrease:
• Drugs - Finasteride/Dutasteride
• Obesity
• Herbal preparations
183
what are the different biopsies for prostate cancer?
- how done
- how many samples
- where samples from
- what find out
Transrectal ultrasound guided (TRUS) biopsy
• Biopsy taken through the rectal wall under ultrasound guidance
• About 12 samples taken
• But only get to the peripheral zone - don’t get to the transitional zone
Template biopsy
• Transperineal
• Multiple samples taken
• In patients who have the right symptoms and everything but aren’t diagnosed from the transrectal, you do this
* Type of tumour - adenoma - most common - cancer of glandular tissue
* Grade of tumour
* Percentage of tumour
* Stage of cancer
184
what used for grading tumours?
TUMOUR GRADE - GLEASON SCORE
* Grading system used to define aggressiveness
* Score of 3-5 are considered cancerous
* Addition of 2 most common scores (histologist looking at different cells/tissues) - Gleason score
* GI (3+3) to GI (5+5)
185
what are the different grade group for Gleason scores? what is percentage of 5 years relapse free survival (RFS)?
```
1 = 3 + 3 = 6 - 96%
2 = 3 + 4 = 7 (more 3 than 4) - 88%
3 = 4 + 3 = 7 (more 4 than 3) - 63%
4 = 4 + 4 = 8 - 48%
5 = 4 + 5 = 9, 5 + 4 = 9, 5 + 5 = 10 - 26%
```
186
describe multiparametric MRI
| - what it involves
T1 & T2 images (these are structural imaging)
Functional imaging
• Dynamic contrast enhanced (DCE) DWI
• Diffusion weighted imaging (DWI)
Its about diffusion, water and fat
Functional imaging looks at how water diffuses across cells
If you have cancer (a lot of cells together), water doesn’t diffuse as well, if you have normal cells, cells are far apart and water diffuses better
When you merge the different types of sequences that a radiologist would do together, you can work out whether this blob is at high risk of cancer or not
- Multiparametric MRI of the prostate is essentially any functional form of imaging used to supplement standard anatomical T1 and T2-weighted imaging
- The functional sequences of choice are DCE MRI and DWI
187
what are the two basic types of MRI images? what are differences?
* Two basic types of MRI images are T1-weighted and T2-weighted images
* The timing of radiofrequency pulse sequences used to make T1 images results in image which highlight fat tissue within the body
* The timing of radiofrequency pulse sequences used to make T2 images results in images which highlight fat AND water within the body
* T1 images - 1 tissue type is bright = FAT
* T2 images - 2 tissue types are bright = FAT AND WATER
DCE measures T1 changes in tissue over time ?
188
what is functional imaging?
Molecular and cellular information about the prostate regarding the functional environment of water in prostate tissue
189
what does cancer staging mean? why important? what system?
WHAT DOES CANCER STAGING MEAN?
* A way of describing a cancer - size and extent
* Allows the doctor to determine prognosis
* TNM system
* Formulation of treatment plan
Don’t normally care about the stages, want to know if it’s stage 4 and then what risk patients are at?
190
what are the different stages of prostate cancer?
STAGE I PROSTATE CANCER (T1)
* Cancer confined to prostate T1a-2a
* PSA <10
* Grade group 1
STAGE II PROSTATE CANCER
Stage IIA
• T1a-2a
• PSA 10-20
• Grade group 2
Stage IIB
• T1-2
• PSA < 20
• Grade group 2
Stage IIC
• T1-2
• PSA < 20
• Grade group 3 - 4
ETC…
STAGE IV PROSTATE CANCER
* In any cancer, stage IV means metastatic disease
* Generally not curable
191
what are the prognostic groupings for localised/locally advanced prostate cancer?
PROGNOSTIC GROUPINGS FOR LOCALISED/LOCALLY ADVANCED PROSTATE CANCER
This is the more important bit for treatment
Low risk
• T1-T2a and Gleason score 6 and PSA < 10 ng/ml
Intermediate risk
• T2b-T2c or Gleason score 7 or PSA 10-20
High risk
• T3a or Gleason score 8-10 or PSA > 20
192
what is the treatment of localised prostate cancer?
* Active surveillance
* Surgery
* External beam radiotherapy
* Brachytherapy
LOW/INTERMEDIATE RISK PROSTATE CANCER
* Active surveillance
* Prostatectomy
* External beam - zap it from radiotherapy
* Brachytherapy - zap it from inside out - involves placing radioactive material inside your body
193
what does active surveillance involve?
* Regular monitoring
* PSA
* DRE
* mpMRI (multiparametric MRI)
* Biopsy
194
what surgery is it? what does in involve?
Removal of:
• Prostate
• Lymph nodes
• And seminal vesicles (cancer can invade into this)
Open or laparoscopic surgery
THE DA VINCI ROBOT
* Surgeon operates from a console with a 3D screen
* Grasp controls to manipulate surgical tools within the patient
* Robotic arms translate finger, hand and wrist movements
* Very high-precision
195
what is brachytherapy? how used in low and high doses?
‘radiotherapy where a sealed source is placed inside or next to the area that requires treatment’
Aka internal radiotherapy
Low dose rate
• Implanting radioactive source into the prostate
High dose rate (intermediate/high risk disease)
• Used as mono therapy
• or in combination with EBRT (external beam radiation therapy)
196
what is intermediate/high risk prostate cancer? what type of treatment?
* Localised disease with higher risk of disease progression
* Important to adequately stage disease
* Recommend active treatment if patient is fit
197
what can be added to EBRT?
ADDITION OF ADT TO EBRT
ADT = androgen deprivation therapy
We know that testosterone can make prostate cancer grow, so we switch that off
Ten year overall survival improves by just under 20% - not bad!
198
what are the different ADT treatment options?
GnRH agonists (e.g. Leuprolide and Goserelin)
• May initially result in an increase in testosterone so needs pre treatment with anti-androgen
• 3 monthly depot injections
GnRH antagonist (e.g. Degarelix)
• More expensive but without an increase in testosterone and licensed for urgent treatment
• Monthly injections so mostly initial treatment and then transfer to GnRH agonist
Orchiectomy - outpatient procedure
• Not nice
• Don’t do anymore
GnRH agonists (LHRH agonists) – lower the amount of testosterone made by the testes = chemical castration
When LHRH agonists are first given, testosterone levels go up briefly before falling to very low levels. This effect is called flare and results from the complex way in which these drugs work. Men whose cancer has spread to the bones may have bone pain. If the cancer has spread to the spine, even a short-term increase in tumor growth as a result of the flare could press on the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-androgens (discussed below) for a few weeks when starting treatment with LHRH agonists.
LHRH antagonists
- Works like the LHRH agonists, but it lowers testosterone levels more quickly and doesn’t cause tumour flare like the LHRH agonists do
- Can also be considered a form of medical castration
199
what is ADT treatment like? what are side effects?
not pleasant
Sexual
• Decreased libido
• Erectile dysfunction
Mental
• Lack of initiative
• Emotional lability
• Decreased memory and cognitive function
Metabolic
• Lipid changes
• Diabetes mellitus
```
Physical
• Hot flushes
• Fatigue
• Weight gain
• Hair changes
• Breast pain
• Decreased muscle mass
• Decreased bone mineral density
• Decreased penile size
```
200
is metastatic prostate cancer curable? what is aim of treatment? what are some treatments?
* Disease has spread outside the prostate
* Not curable
* Aim of treatment: disease control - can control is for years - unique to prostate cancer
Some treatments:
Docetaxel - chemotherapy (treatment option for men with cancer that has spread to remote body locations or cancers that don't respond to hormone therapy)
Abiraterone - hormone therapy (treatment for prostate cancer that has spread to other parts of your body)
- CYP17 inhibitor
- Blocks an enzyme called CYP17, which helps stops these cells (LHRH agonists and antagonists can stop the testicles from making androgens, but other cells in the body, including prostate cancer cells themselves, can still make small amounts, which can fuel cancer growth.) from making androgens
201
what is hormone sensitive vs. castrate-resistant prostate cancer?
Means some patients respond to ADT and some progress on ADT
Castrate-resistant prostate cancer = prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels – many early-stage prostate cancers need normal levels of testosterone to grow, but castrate-resistant prostate cancer do not
202
what are castrate-resistant prostate cancer treatment options?
ADT has stopped working
Abiraterone, Enzalutamide -> Docetaxel -> Cabazitaxel
203
how is cancer in bone treated?
RADIUM 223
* Any active bone cells want to take it on
* But if its radioactive it takes it in and radiates itself
* Treat cancer in bone
204
what are the survival benefits of early detection of prostate cancer?
Early detection can find localised cancer but survival benefits still uncertain
205
what are equivalent therapeutic tools for localised prostate cancer?
surgery and radiation
206
what is effective for metastatic prostate cancer?
hormonal therapy
207
what is the most common type of prostate cancer?
Acinar adenocarcinoma found in the peripheral zone
208
what is used for imaging the prostate?
MRI and ultrasonography provide good imaging of the prostate and increase the yield of positive biopsies by targeting abnormal areas (ultrasound guides you when doing the biopsy)
209
does ADT get rid of cancer?
ADT does not get rid of cancer it just keeps in under control - good treatment for older people who are less fit
So if a patient is young and fit enough and the cancer is local then you can get rid of the cancer using radiotherapy and surgery
210
what are the different imaging modalities that can be used to image the kidney and urinary tract?
* Abdominal radiographs
* Ultrasound
* Fluoroscopy
* Nuclear medicine
* Computed tomography
* Magnetic resonance imaging
211
summarise physiology of micturition - youtube
- Prostate is between the internal and external sphincter (men)
- External sphincter in urogenital diaphragm
- Females don’t have an internal sphincter but they do have an external sphincter
- M3 receptors found in the bladder
- Beta adrenergic receptor (B3) found in bladder
- Alpha1 adrenergic receptor on the internal sphincter
- Nicotinic receptor on external sphincter
- Pelvic nerve (parasympathetic) -> ACh -> M3 receptor -> contraction of muscle
- Pudendal nerve (somatic) -> ACh -> nicotinic receptor -> contraction of external sphincter (we are firing are pudendal nerve when we are trying to hold in our urine)
- Hypogastric nerve (sympathetic) -> noradrenaline -> B3 receptor -> relaxation of detrusor muscle and a1 receptor -> contraction of internal sphincter
- Sympathetic system is responsible for urine retention
- Parasympathetic system is responsible for voiding
- 4th nerve is a sensory pelvic nerve (afferent) coming from the detrusor muscle – stimulated when bladder is stretched
Empty bladder:
- When little stretching of bladder, the sensory pelvic nerve will only send slow impulses to the spinal cord sacral region
- This will stimulate sympathetic hypogastric nerve -> alpha1 receptor = contraction of internal sphincter and B3 receptor = relaxation of detrusor muscle
- Signal to pelvic parasympathetic nerve is being inhibited
- However, there are signals that can stimulate the pudendal nerve -> contraction – so can hold urine in voluntarily
Full bladder:
- Lots of stretching and pelvic nerve will send fast signals to sacral region of spinal cord
- Stimulates neurones in pontine micturition centre -> inhibition of hypogastric sympathetic nerve (no relaxation of detrusor muscle and no contraction of internal sphincter)
- These neurones stimulate pelvic efferent nerves -> M3 receptor -> contraction of detrusor muscle
- Also neurones from pons micturition centre inhibit pudendal nerve (this is under our control) -> no contraction = relaxation of external sphincter
Voiding reflex: once you start peeing, you continue to pee
212
what are the causes of prostate cancer?
Inherited gene mutations:
- RNASEL – normal function of this tumour suppressor gene is to help cells die when something goes wrong inside them
- BRCA1 and BRCA2 = tumour suppressor genes – help repair mistakes in a cell’s DNA (or cause the cell to die if the mistake can’t be fixed) – these genes (especially BRCA2) account for a small number of prostate cancers
- DNA mismatch repair genes (such as MSH2 and MLH1) – these genes normally help fix mistakes (mismatches) in DNA that are made when a cell is preparing to divide into 2 new cells
-men inherited with mutations in these genes have a condition known as Lynch syndrome (HNPCC) and are at increased risk of colorectal, prostate and some other cancers
- HOXB13 – this gene is important in the development of the prostate gland – mutations in this gene have been inked to early-onset prostate cancer – mutation is rare
Acquired gene mutations:
- Androgens, such as testosterone, promote prostate cell growth – having higher levels of androgens might contribute to prostate cancer risk in some men
- Some research found that men with high levels of insulin-like growth factor-1 are more likely to get prostate cancer
213
what can be used to treat urinary incontinence?
- Medications
- anticholinergics calm overactive bladders and may help patients with urge incontinence
- topical oestrogen may reinforce tissue in the urethra and vaginal areas and lessen some of the symptoms
- imipramine = tricyclic antidepressant
214
what are normal and abnormal PSA levels?
A normal PSA level is considered to be 4.0 nanograms per milliliter (ng/mL) of blood. For men in their 50s or younger, a PSA level should be below 2.5 in most cases. Older men often have slightly higher PSA levels than younger men.
The following are some general PSA level guidelines: 0 to 2.5 ng/mL is considered safe. 2.6 to 4 ng/mL is safe in most men but talk with your doctor about other risk factors. 4.0 to 10.0 ng/mL is suspicious and might suggest the possibility of prostate cancer.
215
tamsulosin
- mechanism of action
- side effects
- dose
a. mechanism of action
- alpha-1 receptor antagonist
- selective antagonist at alpha-1A and alpha-1B adrenoreceptors in the prostate, prostatic capsule, prostatic urethra and bladder neck
- blockage of these receptors causes relaxation of smooth muscles in the bladder neck and prostate
- used to improve urination in men with BPH
b. Side effects
- Low blood pressure
- Dizziness
- Nausea
- Headache
- Abnormal ejaculation
- Back pain
- Blurred vision
- Tooth problems
- Fever
- Sleep problems
- Decrease libido
c. Dosage
400micrograms/0.4mg once daily
- Used by men to treat symptoms of an enlarged prostate (BPH)
- Does not shrink the prostate but works by relaxing the muscles in the prostate and the bladder
- This helps to relive symptoms of BPH such as difficulty in beginning the flow of urine, weak stream and the need to urinate often or urgently
- Tamsulosin belongs to class of drugs = alpha-blockers
216
finasteride
- mechanism of action
- side effects
- dosage
a. Moa
- Orally active testosterone 5-alpha reductase inhibitor
- Surgical alternative for treatment of BPH
- 5alpha-reductase = intracellular enzyme that converts the androgen testosterone into DHT
b. Side effects
- Impotence
- Loss of libido
- Trouble having an organism
- Abnormal ejaculation
- Swelling in your hands or feet
- Swelling or tenderness in your breasts
- Dizziness
- Weakness
c. Dosage
5mg tablet daily
Medicine Sem 4
flashcards
Decks in class (23)
# Cards
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Case 1252
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Case 2225
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Case 3184
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Case 4304
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Case 5329
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Case 6152
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Case 7175
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Case 8216
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Case 9207
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Case 1 Anatomy77
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Case 2 Anatomy66
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Case 3 Anatomy100
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Case 4 Anatomy109
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Case 6 Anatomy86
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Case 7 Anatomy99
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Case 8 Anatomy72
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Case 9 Anatomy56
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Case 1 Histology32
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EBM26
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Drugs123
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Case 3 Histology34
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Case 6 Histology32
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Case 9 Histology14
