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					                              THE COLLEGES OF MEDICINE 0F SOUTH AFRICA

                                                              Sep 2003
                                                               Part I



                                                 PAPER 1

Question 1

a)       Discuss the specific management of severe malnutrition with acute
diarrhoea under the following headings

i)       Fluid therapy.
ii)      Electrolyte replacement.
iii)     Micronutrient supplementation.
iv)      Energy and protein provisions.
v)       Infection detection and control

DEFINITION/INTRODUCTION
DEFINITION AND CLASSIFICATION OF SEVERE MALNUTRITION
        Weight for height z score <3 std
        bipedal oedema
        visible muscle wasting
AND ACUTE DIARRHOEA
Change in frequency and consistency of stool

Specific management
Acute phase 0-6 days
Rehabilitation 2 to 6 weeks

Fluid management
Claasification: dehydration could be none, some or severe
(shock)
3 phases resuccitation- ivf for shock only crystalloid: ringer lactate or normal saline or colloid avoid human
products due transmission of infections. Care to avoid cardiac failure
rehydration: nasogastric tube fluids or ivf if decreased level of consciousness-1/2 DD
Calculate: degree of dehydration maintainence ongoing losses
Maintainance ORS latest lower sodium and increased potassium than standard ie special ORS: 45mmol
Na/ 40 mmol K/ Mg/ Zn/ Cu/Sucrose = isotonic solution why ? increased sodium causes greater risk of heart
failure
Rate: 5ml/kg every 30 minutes for first 2 hours and then 5 ml/kg for hours 4 to 10
Net decrease osm & increased potassium

Electrolyte disturbances
Major hypokalaemia & hypo and hyper natreamia
Defining these abnormalities and how they are corrected
Oedema marker of hypokalaemia
Correction of potassium 3-4 mmol/day routine but iv for serum levels below 2. appreciate deficit greater
intracellularly
Higher doses of 7.7 mmol/kg/d no difference in hospital stay but reduced deaths after 5 days
Decreased intracellular potassium results in increase Na and water retention. Decreased myocardial
function and transport of ions across cell membranes
Issue of low bicarbonate and acidosis
Here the issue of avoidance of correction by giving sodium bicarbonate but rather by improving circulating
volume

Trace elements
Magnesium –usually decreased results in lower potassium dose 0.4- 0.6 ummol kg/d
Zinc- decreased affects immune function, structure and function of mucosa suplementation decreases
mortality in measles and diarrhea
Selenium decreased affects cardiac function supplementation not assessed in trials
Copper deficit results in neutropenia, bone abnormality, microcytic hypochromic anaemia
Folate: decreased : results in anaemia
Iron: results in microcytic hypochromic anaemia – only supplement after acute phase post infection
supplementation improve cognition and growth
Treatment
Electrolyte mineral solution has KCl, MgCl, Zn Acetate and CuSo4
Multivitamin 2 x RDA
FOLATE 5 mg /d on day 1 then 1 mg per day
Zn acetate/ gluconate/ so4 = 2meq elemental zinc /kg/ day
Cu 0.3 mg elemental cu/kg/d
FeSO4 =3mg Fe/kg/day

Vitamins
A 50 000iu < 6 months/ 100000iu 6-12 months /200000 iu > 12 months
Or 100 000 IU day x 3 days
K low INR
E Supplementation

Energy and protein
Initial phase 1-7 days 330-420 kj/kg day energy and 1.0 to 1.5 g/kg/d protein
          Low osmalality and low lactose
          F=75a milk vs F75b(ceral based)
          Feed every 2 hours 1-2 days
Day and night
Volume 11 ml/kg/feed
130 ml /kg /day
reluctant to NGT
          3-5 days-16 ml/kg/feed =130 ml /kg/d
Rehabilitation: 630-920 KJ/kg/d energy & 4-5 g/kg d protein
          Child should want to feed
Goal 10g/kg /d
Gual increase not rapid because cardiac failure
F100 =420KJ/100 ml =2.9 g protein
Volume 22ml/kg/feed
Could use modifiec porridge/complementary feeds
Breast feeding continue but after diet
Gains > 10g/kg/d = well
<10g/kg/day look for cause
aids/hiv slower recovery



Infection detection and control
Clinical presentation:
 hypoglycaemia (blood sugar < 54 mg/dl) treatment 50ml of 10m% glucose/sucrose po/NGT or ivi if
unconscious dose 5ml /kg 10% glucose repeat blood sugar after 30 minutes feed 2 hourly
hypothermia treatment keep well clothed and heater if needed
lethargy, unable to feed
signs : absence of fever ,hypotension, warm shock
investigation: cxr, mantoux, urine & blood cultures, tb tests
stools examinations
mx: empitic antibiotics justifiable for 1st 7 days? Consider antitb
common infections UTI/ TB/PNEUMONIA
INFECTION CONTROL WATCH FOR NOSCOMIAL INFECTION
HYGIENE
b)          Explain the physiological impact of each intervention suggested


Acute malnutrition:
Affects all organs especially heart, hepar, kidneys & GIT
Fluids:
Intravascular volume: colloid oncotic pressure and hydrostatic pressure
Cardiac status watch for cardiac failure
Allows tissue perfusion and aerobic respiration
Electrolytes:
Hypokalaemia: impact on heart and kidneys
Hyper/hyponatraemia: cerebral oedema /seizure/ superior saggital sinus thrombus
Acidosis correction with soda bic results in cardiac and cns abnormalities

Trace elements
Zn immune function restoration, antioxidant, tissue (gut) integrity
Copper: benefit: uncertain but improves bone and white blood cell numbers and function
Selenium: stablizes heart
Folate & iron : improves anaemia. Growth &copgnition

Energy and protein
Enzyme function
Fighting infection
Growth and development
Cellular regeneration

Infection control
Allows recovery and growth and development
Decreases cytokines
Allow normal functioning of organ system


Question 2.

     a) Describe / Indicate schematically the type of visual defect found in each of the following lesions:
     i)     A lesion of one optic nerve
     ii)    A lesion of one optic tract
     iii)   Lesion in the optic chiasm
     iv)    Lesion in the geniculocalcarine tract (optic radiation)
     v)     Lesion destroying the primary visual cortex
     (area 17)

     b) Discuss retinopathy of prematurity (ROP)


     a) (i) A lesion of the left optic nerve will result in total blindness in the left eye.




     (ii) A lesion of the left optic tract will result in right homonymous hemianopsia.




     (iii) An optic chiasmal lesion causes bitemporal hemianopsia.
(iv) A lesion in the optic radiation will depend on which fibers are affected. In case of a left upper optic
radiation lesion, right homonymuos inferior quadrant anopsia will result. Where the lesion is in the left
lower optic radiation a right upper quadrant anopsia will be found.




(v) In case of the left visual cortex being destroyed the individual will present with right homonymous
hemianopsia. if both visual cortex areas are distroy there will be total blindness.




b) RETINOPATHY OF PREMATURITY (ROP)

Rop is a multifactorial vasoproliferative retinal disorder that increases in incidence with decreasing
gestational age. ROP is found in + 0,9% of all live births, with approximately 65% of infants with a birth
weight < 1250gm and 80% of those with a birth weight < 1000gm developing some degree of ROP.
Studies found that infants from multiple births are more likely to develop ROP than singleton babies of
similar weight and gestational age. In developed countries ROP is the second most common cause of
blindness in children < 6 yeas of age.

Pathogenesis:

i)      Normal development:
The retinal vessels start to migrate outward from the optic disc from 16 weeks of gestational age, this
migration is complete by 36 weeks on the nasal side and by 40 weeks on the temporal side. Before the
retinal vessels develop the avascular retina receives its oxygen by diffusion across the retina from the
choroid plexus.

ii)      Possible mechanisms of injury:
The onset of ROP consists of two stages.
         a)       The primary phase involves a initial insult, such as hyperoxia. hypoxia or hypotension, at a
critical stage in retinal vascularisation, resulting in vasoconstriction and decreased blood flow to
developing retina with a subsequent arrest in vascular development.
b)                During the second stage neovascularisation occurs. New vessels
grow through the retina into the vitreous, these vessels are permeable, and haemorrhage and oedema
can occur. Extensive and severe extraretinal fibrovascular proliferation can lead to retinal detachment and
abnormal retinal function. In the majority of cases however the disease process regresses and the
retinopathy gradually resolves.

iii)   Risk factors:
Many factors have been associated with ROP. The most consistent association has been with low
gestational age, low birth weight, duration of mechanical ventilation and the concentration and duration of
exposer to oxygen. Other factors implicated in the pathogenesis include vitamin E deficiency, bright light
exposure, hypocapnia and alkalosis, acidosis, intraventricular haemorrhage, bronchopulmonary dysplasia,
fluctuation in blood gas tension, sepsis, respiratory distress syndrome, dexamethasone exposure, and
patent ductus arteriosus.

Pathophysiology:
Excess oxygen concentration in the blood produces vasoconstriction of peripheral immature retinal
capillaries. In the early stages the vasoconstriction is reversible, but later become irreversible. The
severity of vascular involvement is directly proportional to the concentration and duration of oxygen
exposure. This is followed by neovascularisation of the avascular retina by new blood vessels growing out
of the retina, stimulated by vascular growth factors from the retina not vascularised. The new formed
vessels are strikingly abnormal, tortuous, growing in various directions and over the retinal surface, the
vessels also tend to leak blood and plasma into the vitreous body. Organisation of haemorrhages and
exudates leads to the formation of vitreous membranes and cause retinal detachment. Proliferation of
retrolental fibrous tissue produces leukocoria.

The disorder usually presents between 10 days to one month after birth. While the pathological changes
might be asymmetrical, bilateral involvement is nearly inevitable. The active phase generally subsides in a
few months and in the mild cases spontaneous regression is frequently seen.

In mild cases of ROP vasoproliferation occurs only in the retinal periphery, but in severe cases, the entire
retina will undergo neovascularisation. The outcome of ROP is affected by the extent of the abnormalities.
(hours of retinal involvement) as well as the location of abnormalities. The more posterior the
arteriovenous shunt or ridge, the worse the prognosis. Dilation and tortuosity of the posterior retinal
vessels are unfavourable signs.

Screening and diagnosis:
As no clinical signs or symptoms indicate the developments of ROP, early and regular retinal examination
in infants at risk is necessary and has to continue until retinal vessels have reached maturity. ROP is
diagnosed by examination with indirect opthalmoscopy. All infants weighing less than 1500g or less than
32 weeks gestational age should be examined, while infants born between 32 and 34 weeks gestational
age should be examined if they have been ill (severe RDS, hypotension requiring pressor support or
surgery in the first few weeks of life). Examination of infants born between 24 and 26 weeks should start
at the postnatal age of 6 weeks while those with more advanced gestational age should be examined from
4 weeks onward. Infants should be examined every 2 weeks until their retinal vessels can be considered
mature. If ROP is however diagnosed the infants should be examined more frequently depending on the
severity of their disease until the ROP has regressed or until it has reached a threshold for treatment.

Classification consist of four components:
1) Location refers to how far the retinal blood vessels have progressed. The retina is devided into three
concentric circles.
a) Zone 1 consists of an imaginary circle with the optic nerve at the centre and a radius of twice the
distance from the optic nerve to the macula.
b) Zone 2 extends from the edge of zone 1 to the equator on the nasal side of the eye and about half the
distance to the ora serrata on the temporal side.
c) Zone 3 consists of the outer crescent-shaped area extending from zone 2 out to the ora serrata
temporally.

2) Severity refers to the stage of the disease:
a) Stage 1. A demarcation line appears as a thin white line that separates the normal retina from the
undeveloped avascular retina.
b) Stage 2. A ridge scar tissue with height and width replace the line of stage 1. It extends inward from the
plane of the retina.
c) Stage 3. The ridge has extraretinal fibrovascular proliferation. Abnormal blood vessels and fibrous
tissue develop on the edge of the ridge and extend into the vitreous.
d) Stage 4. Partial retinal detachment may result when scar tissue pulls on the retina. Stage 4A is partial
detachment outside the macula, so that the chance for vision is good if the retina reattaches. Stage 4B is
partial detachment that involves the macula, thus limiting the likelihood of usable vision in that eye.
e) Stage 5. Complete retinal detachment occurs. The retina assumes a funnel-shaped appearance and is
described as open or narrow in the anterior and posterior regions.

3) Plus disease is an additional designation that refers to the presence of vascular dilatation and
tortuosity of the posterior retinal vessels. This indicate a more severe degree of ROP and may be
associated with iris vascular engorgement, puppillary rigidity, and vitreous haze. Plus disease associated
with zone 1 ROP tends to progress very rapidly and is termed rush disease.

4) Extent refers to the circumferential location of disease and is reported as clock hours in the appropriate
zone

Definition of threshold and prethreshold ROP
                                                                                     o
1) Threshold ROP is five or more continuous or eight cumulative clock hours (30 sectors) of stage 3 with
plus disease in either zone 1 or 2. This is the level of severity at which the risk of blindness is predicted to
approach 50% and thus treatment is recommended.



2) Prethreshold ROP is any of the following:
Zone 1 ROP of any stage less than threshold.
Zone 2 ROP with stage 2 and plus disease.
Zone 2 ROP with stage 3 without plus disease.
Zone 2 ROP at stage 3 with plus disease with fever than the threshold number of sectors of stage 3.
Children with prethreshold ROP have a 1 in 3 chance of needing surgery and a 1 in 6 chance of extreme
loss of vision if treatment is not done promptly when threshold is reached. With therapy they have a 1 in
12 chance of extreme visual loss.

Prognosis

1) Short-term prognosis: Factors that increase the risk of reaching threshold ROP include location of the
ROP posterior in zone1 or 2, increasing severity of stage, circumferential involvement, the presence of
plus disease. Most children with stage 1 or 2 ROP will have regression.

2) Long-term prognosis: Infants with ROP have an increased risk of myopia and other refractory errors,
strabismus, amblyopia, astigmatism, late retinal detachment, glaucoma, and vitreous haemorrhage.
Cicatricial disease refers to the residual scarring in the retina and may be associated with much later
retinal detachment.
The prognosis of stage 4 ROP depends on the macula involvement, the chances of vision is greater if the
macula is not involved. Careful follow-up by a paediatric ophthalmologist is essential.

Management:

1) Prevention: Prevent prematurity and exposure to excessive oxygen concentrations and oxygen for a
prolonged period. If diagnosed early and followed closely, interventions can take place before retinal
detachment occurs. Once the retina has detached, the prognosis is poor even with surgical reattachment.
2) Treatment:
i)      Cryotherapy for threshold ROP reduces unfavourable outcome from 51% to 31%. Cryotherapy is
done under general anaesthesia, freezing the entire avascular portion of the retina. Close follow-up is
needed to detect continued progression.
ii)     Laser therapy: Laser photocoagulation therapy has become the preferred treatment for ROP. This
therapy may be difficult in cases complicated with vitreous haemorrhage obscuring vision, when
cryotherapy should rather be done.
iii)    Retinal reattachment: Success seems to be very limited.
iv)     Supplemental oxygen: studies are underway to see whether administration of supplemental oxygen
will help prevent progression of prethreshold ROP.



Question 3

a)      Discuss the evaluation of efficacy and safety of
the different components of the combination vaccine DTPw/Hib/HBS.
b)      Discuss the challenges in the production and testing of an HIV-1 vaccine.

HIV vaccine production and testing
Introduction:
HIV 1:10 general public by 2006 17%of general population will have disease
By 2010 AIDS deaths will peak @2.5 more than non AIDS deaths
Challenges in productions and testing:
1.     mutation among virus
2.     production of adequate immune response
3.     without producing disease because no cure
4.     various strains, clades,subtypes and great diversity
5.     great drifts and shift
6.      suitable virus vector eg VEE or salmonella
7.      antigenic identification
8.      funding for research and financial consideration in admissions
9.      virulence factors
10.     cell mediated responses with CTL difficult to test adequacy of vaccine response also long term
protection
11.     no animal model
12.     regulatory issues/ expertise in administering and evaluating
13.     ethical review especially in countries where non-availability of HAART.
14.     Cross reactivity across clade; otherwise need specific vaccine for specific population need multi
strain cocktail
15.     target population-adolescence before sexual debut; infected and uninfected patients, high risk
groups
16.     establishment of clinical trial sites urban and rural disparities rich and poor diversity
17.     training of researchers
18.     protection of trial participants who have poor knowledge, poverty gender inequalities and social ills
19.     involve community
20.     vaccine access post trials procurement and distribution
21.     standard of care during trials
22.     phase 1/11/111 trials



Question 4

Write short notes on

a)     In utero lung fluid production, composition and function.

Answer:
Lungs are filled with liquid during fetal life and the lung itself, rather than the placenta or amniotic sac is
the source thereof. This liquid is essential for lung development and growth. It derives from sodium
coupled chloride secretion across the respiratory epithelium, a process that can be inhibited by diuretics
that block Na-K-Cl cotransport. The process is driven by epithelial cell Na-K-ATPase. The fetal lung
fluid/liquid is colorless and its chemical composition includes: high chloride concentration (~157 mmol/L),
high sodium concentration (~150 mmol/L), carbohydrates, proteins (low), phospholipids, inorganic
electrolytes (Ca and phosphate) and low levels of bicarbonate. The fluid/liquid volume is equal to the
normal functional residual capacity of a full-term newborn infant and exerts a „backward‟ pressure of ~
3cmH2O in the airway. This pressure stimulates lung growth and during the latter stages of gestation,
surfactant secretion. Constant production-reabsorption-expulsion takes place during gestation.
As birth approaches term gestation, the rate of liquid production and the volume of lung liquid decrease.
These changes follow increased expression of epithelium sodium channels and Na-K-ATPase. At the time
of labour and delivery of the baby, liquid production is switched to absorption. Thus, there is a switch from
chloride secretion to sodium absorption near birth. Although regulatory factors are not clearly understood,
they include: epinephrine (adrenalin), but not nor-adrenalin, and other Beta-adrenergic agonists,
hormones such as cortisol, triiodothyronine and aldosterone. Beta-adrenergic agonists are therefore
important because they have been shown to drive the epithelial uptake of sodium, which in turn, drives
liquid from the lung. Pharmacological agents used for inducing labor, such as Oxytocin infusion,
stimulates release of epinephrine, and thereby increases, lung fluid sodium and water absorption.

b)     Native (natural) lung surfactant composition.


Answer:
Lung surfactant composition is complex and a highly surface active material composed of lipids and
proteins which is found at the air-water interface of the lung alveolus. It is composed of:
1)     ~90% lipids
2)     ~10% proteins, including 4 surfactant-associated proteins, SP-A, B, C and D.
The majority of lipids are PHOSPHOLIPIDS (PL), of which, phosphatidylcholine (PC) is the most
abundant. The major PC is dipalmitoylphosphatidylcholine (DPPC), alternatively known as Lecithin. The
DPPC is essential for lowering surface tension.
Other PL‟s include: Phosphatidylglycerol, phosphatidylinositol and sphingomyelin.
SP-A and D are hydrophilic. Both are structurally related to collectins. SP-A is the most abundant SP and
is a glycoprotein, required for surfactant homeostasis, especially the formation of tubular myelin.
SP-D bind bacterial lipopolisaccharide. Plays a role in innate lung defence, but does not appear to play an
essential part in surface behaviour of lung surfactant.
SP-B and C are hydrophobic. Both are essential for optimal lung surfactant surface behaviour.


c)    La Place equation

Answer:
To understand how surface fluids impact on surface tension and therefore lung expansion, it is essential
to understand Laplace‟s Law and equation. Laplace‟s Law describes how the distending pressure (P) of a
liquid bubble (not an alveolus) is influenced by 1) surface tension (ST) of the bubble and the 2) size of the
bubble, radius (r). When applied to a sphere, like an alveolar-bubble, the equation is written as follows: P
= 2 ST/r
This arrangement says that the pressure required to keep a „bubble‟ open is directly proportional to the ST
of the liquid at the air-liquid interface and inversely related to the radius of the sphere. Or, as the ST
increases, the distending pressure required to hold the bubble open, increases, or a high pressure is
needed to keep a small alveolus open in the face of a high ST in the absence of surfactant.
                                                  Paper II



Question 1


Write short notes on

a)     Biochemical pathway of endogenous nitric oxide synthesis and breakdown.

Answer:
There are three nitric oxide synthase (NOS) isoforms neuronal NOS (nNOS), inducible NOS (iNOS) and
endothelial derived NOS (eNOS). The net biological effect of generated nitric oxide (NO) is complex, but
include diverse physiological functions including smooth muscle relaxation of the pulmonary and other
organ vasculature and a role in bronchodilation, angiogenesis, atherosclerosis, neurotransmission,
reproductive biology and the immune response.
NO, generated by eNOS, is involved in regulation of vascular tone and consequently tissue perfusion.
eNOS is the major isoform expressed by the cardiovascular system and expression occurs mainly in
vascular endothelium. Regulation of eNOS activity is through Calcium-dependent calmodulin, but other
mechanisms include induction of the enzyme by shear stress and hypoxia. Endogenous NO production is
a result of increased eNOS expression. Endothelial-derived NOS oxidizes terminal nitrogen atoms of L-
arginine, an amino acid. The resultant NO quickly diffuses into pulmonary vascular smooth muscle, where
it activates the soluble form of guanylate cyclase and increases the 2nd messenger, cGMP, resulting in
vasodilation.
NO is a very potent, short-acting, vasodilator. It has a high affinity for hemoglobin, combining with it 5-20
times faster than oxygen. NO binds mainly with heme-containing proteins and include interactions with
hemoglobin, cytochtome P450 and soluble guanylate cyclase. The combination with hemoglobin,
inactivates the NO. This inactivation results in the formation methemoglobin. Indirect actions of NO
include interactions with oxygen or superoxide anion with the formation of ONOO, NO2 and subsequent
nitration of molecules (when NO2 is added to a molecule).
In terms of clinical practice, monitoring of methemoglobin and NO2 is a prerequisite when inhaled NO is
administered.

b)     Caffeine versus aminophylline for the prevention of apnoea of prematurity.

Answer:
Both aminophylline and caffeine are methylxanthine-derivates. Aminophylline is the ethylenediamine salt
of theophylline and contains 70-85% anhydrous theophylline. Theophylline converts N7-methylates to
caffeine in the neonatal liver. Sixty percent of aminophylline is excreted unchaged by the kidney, the rest
as caffeine. It is inferred that the therapeutic respiratory effect of theophylline is provided by the
conversion to caffeine. Therefore the rationale to rather use caffeine, which, in addition, has a lower side-
effect profile
Acts on the respiratory center in brain stem by increasing the                       sensitivity to
catecholamines, strengthen diaphragmatic action, reduces REM sleep.
Aminophylline has a small therapeutic index & the treatment requires drug-level monitoring.
Side-effects are more common with aminophylline use and include: tachycardia, tachypnea, glucose
instability, restlessness, tremors, vomiting, feeding intolerance, decreased weight gain (increases
metabolic rate).
May induce diuresis and aggravate electrolyte disturbances.
Predispose to seizure activity, etc.
Caffeine is more cost-effective, is absorbed more rapidly when given enterally and its levels are more
stable.
.


c)     Parathyroid hormone related protein (PTHrP) with reference to the developing lung.

Answer:
PTHrP is a hormone and paracrine factor, initially identified as a product of human tumors, especially of
the lung. PTHrP is synthetized and secreted by the Type II alveolar cell and Clara cells. Regulation of
production and secretion is coupled to gestation and regulatory factors including mechanical stretch,
creates a „paracrine- loop‟ between mesenchymal cells (fibroblasts) and the alveolar type II cell. Type II
cells and fibroblasts are stretch-sensitive. Stretching, created by the pressure exerted by intraluminal fetal
lung liquid, results in mechanical transduction which stimulates Type II cell growth and differentiation and
the synthesis and secretion of PTHrP by the Type II cell, simultaneously with expression of its receptor on
the cell membrane of the fibroblast. The PTHrP- PTHrP-receptor interaction (afferent part of the loop)
stimulates uptake of lipids by the fibroblast as well as the production and secretion of IL-6 and IL-11. IL-6
and IL-11 completes the loop (efferent part) by stimulating the Type II cell to synthetise and secrete
surfactant phospholipids and proteins


Question 2


a) Tabulate the physiological action of the different adrenergic receptors in the body.
b) Discuss the indications, pharmacological action, the effect with regards to different dosages, as well as
the side effects of each of the following catecholamines:
                          i) Adrenaline
                          ii) Dopamine (Intropin)
                          iii) Dobutamine (Dobutrex)



a)
                                 Cholinergic Impuls           Receptor          Noradrenergic impulse
                                     responce                   type                  responce
Eye
  Radial muscle of iris                                       1             contraction (mydriasis)
  Sphincter muscle         contraction (miosis)               1
iris                       contraction for near vision        2             relaxation for far vision
  Ciliary muscle
Heart
  S-A Node                 chronotropy, vagal arrest          1,  2        heart rate
  Atia                      inotropy                          1,  2        inotropy
                            conduction velocity                              conduction velocity
A-V node                    conduction velocity               1,  2        conduction velocity
Bundle branches             conduction velocity               1,  2        conduction velocity
Ventricles                  inotropy                          1,  2        inotropy
Arterioles
    Coronary               constriction                       1, 2         constriction
                                                                            dilatation
      Skin & Mucosa        dilatation                         1,           constriction
      Skeletal muscle      dilatation                         1             constriction
                                                              2             dilatation

      Cerebral             dilatation                         1             contraction
      Pulmonary            dilatation                                        constriction
                                                              1
                                                                             dilatation
                                                              2
     Abdominal viscera                                                       constriction
     Renal                                                    1             dilatation
                                                              2
Systemic veins                                                1 2          constriction
                                                              2             dilatation
Lungs
    Bronchial muscle       contraction                        2             relaxation
    Bronchial glands       stimulation                        1             inhibition
                                                              2             stimulation
Stomach
    Motility & tone        increase                           1 2 2       decrease (usually)
    Sphincters             relaxation usually                 1             contraction (usually)
    Secretions             stimulation                        2             inhibition
Intestines
    Motility & tone          increase                           1 2 1        decrease (usually)
    Sphincters               relaxation usually                 2              contraction (usually)
    Secretions               stimulation                        1              inhibition
                                                                2
Gallbladder & ducts          Contraction                        2              relaxation
Urinary bladder
  Detrusor                   contraction                        2              relaxation (usually)
  Trigone &                  relaxation                         1              constriction
sphincter
Ureters
  Motility & tone            increase (?)                       1              Increase (usually)
Uterus                       variable                           1              contraction (pregnant)
                                                                2              relaxation (pregnant & not)
Male sex organ               erection                           1              ejaculation
Skin
   Pilomotor muscle                                             1              contraction
   Sweat glands              Generalised secretion              1              slight, localised secretion
Spleen capsule                                                  1              contraction
                                                                2              relaxation
Adrenal medulla              Secretion of adrenaline &
                             noradrenaline
Liver                                                           1 2           glycogenolysis
Pancreas
    Acini                     secretions                                       secretion
    Islets                    insulin & glucagon               2               insulin & glucagon
                             secretion                                          secretion
                                                                2               insulin & glucagon
                                                                                secretion
Salivary glands              profuse watery secretions          1              thick, viscous secretions
                                                                2              amylase sesretion
Lacrimal glands              secretion                                         secretion
Adipose tissue                                                  1 1 3        lipolysis
Juxtaglomerular cells                                           1               renin secretion
Pineal glands                                                                   melatonin synthesis and
                                                                                secretion


b)

                           Andrenalin                          Dopamine                           Dobutamine
                                                               (Intropin)                          (Dobutrex)
Indication        For inotropic support in           Used as an inotrope &               To treat a variety of low
s                 severe cardiovascular              vasopressor in neonatal and         cardiac output (CO) states
                  collapse and shock                 paediatric patients with            and normal or raised
                  associated with myocard            decreased cardiac output            systemic vascular resistance
                  dysfunction in those not           due to  contractile                (myocarditis, dilated
                  responding to other                functions, poor peripheral          cardiomyopathy, CO after
                  catecholamine drugs & in           perfusion without significant       surgery)
                  CPR.                               hypotension after volume
                  Anaphylaxis, upper airway          has been restored.
                  obstruction, severe asthma
Pharmaco          Dose dependant stimulation         Chemical precursor of               Synthetic catechol- amine a
-logical          of 1, 2 & 1 effects (formed     noradrenaline, has dose             racemic mixture of 2
mode of           from its precursor                 dependent 1, 1, 2, DA            different isomers, one 1 &
action            noradrenaline)                     (dopamenergic) &serotonin           2 receptor stimulating and
                                                     receptor stimulatory effects,       the other has 1 adrenargic
                                                     its effect is: DA equal to 1 >     effects
                                                     1 > serotonin (1- like) > 2
                                             effects. Dopamine differs
                                             from the other catechol-
                                             amines in that it induces the
                                             release of noradrenaline
                                             from presynaptic
                                             sympathetic nerves in the
                                             heart. Dopamine is the only
                                             inotrope that selectively
                                             raises blood flow in the renal
                                             and splanchnic bed
Effects     At 0.05 to 0.3 g/kg/ min        At a low dose, < 0.5 – 2         A dose of 5 - 20g/kg/min
regarding   virtually pure 1 & 2 effects   g/kg/min affects the            has little effect on heart rate
different   (enhances myocardial             dopaminergic (DA)                but due to 1 stimulation
doses       contractility, increase heart    receptors (vasodilatation of     cardiac contractility is
            rate, vasodilatation) as the     the splanchnic vascular          improved. This results from,
            dose increase, 1 effect         bed), with little adrenergic     decrease in systemic
            (vasocon- striction) increase    effect. At 2 – 6 g/kg/min DA    vascular resistance
            but 1 & 2 effects still        action persist, increasing       (afterload reduction). There
            persist, at a dose of > 1.0      cardiac contractility & heart    is also a direct vaso-dilatory
            g /kg/min 1- = 1 effect, at   rate due to 1 &                 effect on coronary vessels.
            higher doses 1- effect          noradrenaline release from       At doses of > 20g/ kg/min
            dominates (vasoconstriction)     nerve ends due to 2             1 adrenargic effects
                                             stimulation. At 6 - 15g/kg      dominate while the effect of
                                             /min 1 is maximally             afterload becomes less
                                             stimulated, at higher doses,     important.
                                             15-25g/kg/min, 1 effect
                                             persist but the 1- effect
                                             (vasoconstriction) dominate.
Side        Always to be adminstrated        Gets rapidly metabolised         With local infiltration the
effects     trough a central venous line     and has therefore to be          effect is not as severe as
            except short-term                given by continues infusion,     with dopamine, nor-, and
            administration, local            preferably through a central     adrenaline, it may increase
            infiltration may cause           line. Adverse effects are        intra-pulmonary shunting to
            necrosis. myocardial O2          usually seen at a high dose      a greater extent than the
            demand is increased, may         and include tachycardia,         other catecholamines.
            cause myocardial ischemia        arrhythmias, raised
            and arrhythmias especially       myocardial O2 consumption
                      +
            when K and/or PaO2               as well as excessive
            happen to be low. Even at a      vasoconstriction with
            low dose, renal and skin         peripheral gangrene, while
            vasoconstriction may be          local infiltration may cause
            significant. Adrenaline          tissue necrosis. It may
            increases pulmonary              depress the respiratory
            vascular resistance use         response to hypoxemia &
            with caution in pulmonary        and hypercapnia, especially
                                    +
            hypertension. Serum K may        in neonates and premature
            drop due to the stimulation      infants
                        +   +
            of the Na / K pump in
            skeletal muscle. Glycemia
            due to stimulation of
            glyconeogenesis &
            glycogenolysis and an
            inhibition of insulin
            production, a raised level of
            free fatty, aminoacids and
            glyserol, thus cholesterol
            and low-density lipoproteins
            and phospholipids levels
            rise.
Question 3

Write short notes on

a)       Anaemia of chronic disease.
b)       Innate immunity

a)       Anaemia of chronic disease
-        Anaemia in patients with infections, inflammatory disease, malignancies.
-        Usually normochrome normocytic (occ hypochrome especially if low iron stores)

Pathogenesis
1)       Decreased red cell survival (Red cells more rapidly phagocytosed)
2)       Problems with iron release from RE macrophages to erythroid precursors.
3)       Erythroid precursors have a poor response on erythropoietin (? negative effect of cytokines)
4)       Peptide hormone (Hepcidin) produced by liver and induced by inflammation – inappropriate
secretion (decreased intestinal iron absorption and secretion of iron by macrophages).

Diagnosis

Normochrome anaemia
Ferritin often increased (acute phase reactant)
Serum iron often low
Transferrin saturation decreased
Soluble transferrin receptor normal (high in iron deficiency anaemia)

b)       Innate immunity

Innate immunity is the immunity an individual has from birth (vs. acquired immunity which only develops
after contact with a noxious substance).

It includes the barrier of:
·         the skin (resistance to invasion of organisms)
·         stomach acid which destroys ingested material
·         phagocytosis by white cells and macrophages
·         substances in blood which also destroy foreign material i.e. lysozyme, the complement system,
natural killer lymphocytes


Question 4


a)       Discuss the oxygen haemoglobulin dissociation curve
b)       Detail the principles of pulse oximetry including technical and pathological factors that affect the
readings.
c)       Write short notes on methaemoglobinaemia

(a)Oxygen Haemoglobin Dissociation Curve
. This relates the partial pressure of oxygen to the percentage saturation of haemoglobin.
Features of this curve include:
     (1) At the normal P02 of arterial blood (100mm Hg) , the haemoglobin is 97.5 % saturated with 02.
     (2) At O2 tensions greater than 100 mmHg . haemoglobin cannot accept more O2.
     (3) When the PO2 is reduced from 100mm Hg down to 70 mm Hg , the haemoglobin saturation is 92%
          (ie “normal” despite a significant drop in PO2).
     (4) The sigmoid shape of the curve means that at a tissue oxygen tension of 60 down to
          10mm Hg , large amounts of O2 are rapidly made available for tissue utilization from
          haemoglobin
     (5) A variety of factors affect the curve itself- including a change in temperature ,pH,
        2,3DPG and type of haemoglobin.
(b)     PULSE OXIMETRY
      .
      Pulse oximetry estimates arterial oxygen saturation by measuring the absorption of light (of two
      wavelengths , approximately 660 nm and 940 nm) in human tissue beds. As light passes through
      human tissues, it is absorbed in various degrees by tissue and arterial blood , including various types of
      haemoglobin. The light absorption changes as the amount of blood in the tissue bed changes and as
      the relative amounts of oxygenated and deoxygenated haemoglobin change..
      A conventional pulse oximeter measures the ratio of the absorption of 2 wavelengths of light,
      discriminates the changes that it assumes are a result of pulsatile changes and oxygenation changes ,
      averages the readings over a short period of time, and then looks up the resulting absorption ratio in a
      table or calibration curve of corresponding arterial saturations.
      LIMITATIONS OF PULSE OXIMETRY
      1. ACCURACY
           During periods of desaturation below 70% the accuracy is poor.
      2. AMBIENT LIGHT
           , Ambient light can affect oximeter operation As skin pigmenatation darkens, oximeter performance
           deteriorates.
      3. DYSHAEMOGLOBINAEMIA
           Dyshaemoglobinaemia also compromises pulse oximetry readings, because pulse oximeters are
           unable to distinguish between oxygenated haemoglobin and the various dysfunctional
           haemoglobins such as methaemoglobin and carboxyhaemoglobin, which are unable to carry
           oxygen.
           .
      4. LOW PERIPHERAL PERFUSION
           Inaccurate data is provided when there is reduction in measured vascular pulsation.
      5. MOTION ARTEFACT
           Motion artefact limits the use of oximetry


(c )METHAEMOGLOBINAEMIA
        The iron of both oxygenated and deoxygenated haemoglobin is normally in the ferrous state
        (Fe2+), which is essential for its oxygen –transporting function. Oxidation of haemoglobin iron to
        the ferric state yields methaemoglobin, which is nonfunctional and colurs the blood brown; in
        sufficient concentration, it causes cyanosis.
        The blood of healthy persons contains methaemoglobin , but the intraerythrocytic
        Methaemoglobin reducing system maintains its concentration to less than 2% of the total
        haemoglobin.Methaemoglobin is normally produced in the erythrocyte by oxidation of haemoglobin.
         The enzyme nicotinamide adenine dinucleotide (NADH) –cytochrome b5 reductase catalyzes the
        reduction of methaemoglobin to haemoglobin.
        SICK NEONATES
        Sick neonates are at risk for methaemoglobinaemia because of their limited capacity for
        methaemoglobin reduction and their increased tendency for haemoglobin oxidation.
        Pathogenesis: A number of substances are capable of oxidizing haemoglobin directly and will do
        so in vitro. (nitrites, nitrates, chlorates, quinones)

          HEREDITARY METHAEMOGLOBINAEMIA
          (Deficiency of NADH Cytochrome b5 Reductase)

          Therapy : ascorbic acid
                 Methylene blue.
                                              PAPER III
QUESTION 1

Write short notes on

a)       Homeobox genes.
b)       Reducing substances in stool and urine.
c)       Regulation of renal phosphate excretion.
d)       Coagulase negative staphylococcus


a)       Homeobox genes

Family of genes that control development (cell differentiation, morphogenesis)
Homeobox genes encode proteins that tell the cells in the various segments of the developing embryo what
kind of structures to make.

e.g. Homeobox genes play a role in axial skeleton and limb development.

Mutations in hox genes can cause birth defects and also cancer.

Not unique in humans – also in plants, animals. Family of homeobox genes ± 170 different genes.

b)       Reducing substances in stool & urine

Stool: Disaccharide or monosaccharide intolerance (unabsorbed sugars in colon changed by bacteria to
short chain fatty acids + lactic acid).

 Stools acid with pH < 5,5 with reducing substances positive.

Not all sugars are reducing substances (sucrose is not)

Some drugs (i.e. lactulose) are also reducing substances.

Clinitest used.

Urine:   Most common use is as screening test for galactosaemia ( non-glucose reducing substance).

Non-glucose reducing substances further identified by chromatography.
Definitive test for galactosaemia – enzyme or mutation determination.
Any neonatal hepatic involvement (hepatitis) can give positive reducing substances


c)       Regulation of renal phosphate excretion.

Phosphate excretion by kidney depends on phosphate level in blood which again depends on phosphate in
glomerular filtrate (phosphate excreted by an overflow mechanism).

If low phosphate in glomerular filtrate -> nearly 100% of filtered phosphate is absorbed (proximal tubule). If
high phosphate in glomerular filtrate – excess phosphate is excreted in the urine (as when diet is high in
phosphate)

Parathyroid hormone can greatly increase phosphate excretion (is phosphaturic).

d)       Coagulase negative staphylococcus

Staphylococcus epi: unable to produce enzyme coagulase.

Ø        30 species

Coagulase negative staphylococ subdivided in 2 classes – Novobiocin susceptible or not.
Classic example in Novobiocin susceptible group is Staph epidermides.

Staph epi: Normal flora of skin and mucous membranes
Increase in prevalence of staph epid infections mostly secondary to indwelling catheters
( nosocomial, opportunistic infection often in immunocompromised patients)

In paediatrics: preterm; patients on chemotherapy

Occasionally staph epid endocarditis in immunocompetent patient.

Most coag negative staphylococci produce beta-lactamase and are meticillin resistant

Drug of choice for coagulase negative staphylococci is Vancomycin (or teicoplanin)



QUESTION 2

a)      Discuss the anion gap and classify the causes of metabolic acidosis
according to the anion gap.
b)      Describe the pathophysiology of ethylene glycol toxicity.
c)      Discuss the pathogenesis and management of tumour lysis syndrome



(a) ANION GAP AND METABOLIC ACIDOSIS

Acidosis refers to an abnormal increase in circulating acid with an accompanying decrease in buffering
capacity of the blood, manifested by a low serum bicarbonate concentration.
To maintain electric neutrality in the body, the total positively charged ions (cations) must equal the total
negatively charged ions (anions).
Normally, Na+ accounts for more than 90% of the extracellular cations, whereas Cl- and HCO3 constitute
approximately 85% of the anions. The ANION GAP , as used clinically, is the
calculated difference between the majority of measured cations (viz Na+) and the majority of measured
anions (viz, the sum of Cl- and HCO3-).           In general, the major causes of metabolic acidosis can be
divided into those conditions resulting from a loss of base (bicarbonate) from the body (NORMAL ANION
GAP), either from the kidneys or gastrointestinal tract, or from an abnormal accumulation of acid through
overproduction (diabetic ketoacidosis, lactic acidosis, or inborn metabolic errors)
OR
Undersecretion (type 1 –distal renal tubular acidosis; or chronic renal failure), or toxic ingestion
(INCREASED ANION GAP)
          Aetiology of Metabolic Acidosis

Normal Anion Gap
        Gastroenteritis or gastrointestinal drainage
         Renal tubular acidosis –type 2 (proximal)
         Mineralocorticoid deficiency (adrenal insufficiency)
        Increased Anion Gap (“MUDPILES” & others)
        Methanol injestion
        Uraemia
        Diabetic ketoacidosis
        Paradehyde overdose
        Iron or INH overdose
        Lactic acidosis, primary (inborn) or secondary (hypoxia)
        Ethanal or Ethylene glycol ingestion
        Salicylate ingestion
        Others : Renal tubular acidosis –type 1 (distal)
                  Inborn errors of carbohydrate, amino acid, or organic acid metabolism.
        (b)ETHYLENE GLYCOL POISONONG
        Ethylene glycol (EG) is a compound whose viscosity and thermal properties have led to its role as
        an anti-freeze agent in cars. After ingestion, ethylene glycol is rapidly absorbed from the GIT. The
        presence of EG produces the osmolar gap. The osmolar gap (Og ) is calculated by subtracting the
        calculated serum osmolality (Oc ) from measured osmolality (Om ), or Og = Om − Oc The enzyme
        alcohol dehydrogenase metabolizes ingested EG , which in itself is not a toxic compound. The
        products of its metabolism, glycolic and oxalic acids, however may lead to acidosis, renal failure,
        hypocalcaemia, , and death. Acidosis is attributable to the presence of glycolic , glyoxylic , and
        oxalic acids. An increased anion gap with a normal chloride concentration indicates retention of
        nonvolatile organic acids such as glycolic acid.Ethylene glycol is unique among alcohols in that a
        significant amount is eliminated unchanged in the urine. Ethylene glycol and its metabolites cause
        CNS depression..


(c )TUMOUR LYSIS SYNDROME
       Tumour lysis syndrome is a pattern of metabolic abnormalities resulting from spontaneous or
       treatment –related tumour necrosis or fulminant apoptosis. Acute lysis of tumour release of
       potassium, phosphates and nucleic acids into the circulation.
       FEATURES
       1)Hypocalcaemia
       2)Hyperuricaemia
       3)Renal failure
       4)Secondary acute precipitation of calcium and urates in kidney , obstructive uropathy, and
       dehydration may increase the primary metabolic abnormality.
       5)Multiple organ failure.

        Occurs most often with Burkitt‟s lymphoma and T Cell ALL. (large tumour loads and high sensitivity
        to chemotherapy). Also stage IV neuroblastoma

        RENAL FAILURE : due to : multifactorial.
          (Uric acid, phosphorus, and potassium all primarily excreted by the kidney).
        URIC ACID : release of intracellular purines from fragmented tumour nuclei increases levels of uric
        acid. Uric acid crystallizes in the collecting ducts and ureters.This leads to obstructive uropathy.
          .
        PHOSPHORUS
        Lymphoblasts are especially rich in phosphorus. Calcium phosphorus precipitation may lead to
        tissue damage or hypocalcaemia.
        HYPERKALAEMIA
        Hyperkalaemia is the most imminently dangerous consequence of tumour lysis syndrome.
        TREATMENT
        The ideal treatment is preventative.
        The basic preventative measures include :
            (1) HYDRATION - ivi fluids at a rate of 3 to 6 L/m2
            (2) ALKALINIZATION : bicarbonate
            (3) ALLOPURINOL : to decrease uric acid production
                 Allopurinol is a competitive inhibitor of xanthine oxidase
            (4) URATE OXIDASE converts uric acid to the water soluble allantoin, thereby
              Promoting uric acid excretion.
            IMPENDING RENAL FAILURE : Potassium intake must be stopped.
                                                IVI furosemide
                                                Kayexalate, calcium gluconate, Bicarbonate
            PHOSPHATE EXCRETION : aided by addition of aluminium hydroxide
            DIALYSIS (when conservative measures fail) –to remove uric acid , phosphate, improve
            metabolic problems
QUESTION 3

a)     Discuss the aetiology, pathophysiology and pathogenesis of hydrocephalus.
b)     Write short notes on:
       i)       false positive diagnostic tests and their implications
       ii)      meta-analysis



a) Hydrocephalus is not a specific disease but the result of a variety of causes of
impaired circulation or absorption of CSF (or, rarely, increased production of CSF). The
CSF is formed mainly by the choroid plexus in the ventricles, mostly in the lateral
ventricles. A normal child produces approximately 20 mL of CSF per hour.

CSF flows down a pressure gradient between the ventricular system and venous channels.
Normally, CSF flows from the lateral ventricles through the foramina of Monro into the
third ventricle, then through the narrow aqueduct of Sylvius into the fourth ventricle. CSF
leaves the fourth ventricle through the foramina of Luschka and Magendie into the
cisterns at the base of the brain. Hydrocephalus resulting from obstruction within the
ventricular system is called obstructive or noncommunicating hydrocephalus.


The CSF circulates from the basal cisterns posteriorly through the cistern system and
over the cerebral hemispheres. CSF is absorbed primarily by the arachnoid villi.
Hydrocephalus resulting from obliteration of the subarachnoid cisterns or malfuncion of
the arachnoid villi is called nonobstructive or communicating hydrocephalus.

Aetiology of obstructive or noncommunicating hydrocephalus
In children this is most commonly due to an abnormality of the aqueduct of Sylvius or a
lesion affecting the fourth ventricle. Aqueductal stenosis results from an abnormally
narrow aqueduct of Sylvius, often associated with branching or forking. Rarely,
aqueductal stenosis is associated with neurofibromatosis. Aqueductal gliosis as a result,
for instance, of neonatal meningitis or a subarachnoid hemorrhage in a premature infant
may also obstruct the aqueduct.

Compression by lesions outside the ventricular system can obstruct flow, such as
posterior fossa tumours or a malformation of the vein of Galen. Malformations of the
posterior fossa are prominent causes of obstructive hydrocephalus, including the Chiari
malformation and the Dandy-Walker syndrome.

Aetiology of nonobstructive or communicating hydrocephalus
This most commonly follows meningitis or a subarachnoid hemorrhage. In the premature
infant, blood in the subarachnoid spaces after intraventricular hemorrhage may cause
obliteration of the cisterns or arachnoid villi and obstruction of CSF flow.

Pneumococcal and tuberculous meningitis produce a thick exudate that obstructs the
basal cisterns. Intrauterine infections may also obstruct CSF pathways, as can leukemic
seeding of the subarachnoid space.
b)

A false positive test is a positive test result in a person without the target condition (as
defined by the reference standard). False positive tests reflect the specificity of a test i.e.
the higher the false positive rate the lower the specificity.

Potential harms of false positive tests include the harms of further unnecessary invasive
diagnostic tests or treatments.

Even if a subsequent more specific test excludes the condition, the false positive test can
result in unnecessary anxiety. “Labelling” of people as having conditions they do not
have can affect the person’s quality of life almost as much as having the condition itself
(e.g in HIV infection).

False positive tests are most likely to occur when testing for very unlikely conditions. For
example, a false positive rate of 10% (90% specificity) means that 10% of all normal
people will test falsely positive. Assuming that there is only a 1% chance of a condition,
and that the test picks up every true case, for every 100 people tested 10 will have false
positive tests and only one a true positive will be detected. In this situation there will thus
be only one true positive test for every 10 false positives. Caution should be exercised in
interpreting positive tests for unlikely conditions, or in doing the test at all.

In situations where it is necessary to test for unlikely conditions (e.g. in screening), a
positive test result from the initial (usually highly sensitive test) should be confirmed by a
second highly specific test.


ii.     Meta-analysis

Meta-analysis is a statistical technique that summarises the results of several studies in a
single estimate. In this estimate, more weight is given to the findings of studies of more
events and sometimes of higher quality. Single studies are often too small to detect
modest but important differences in the effects of therapy. By pooling data from a
number of smaller, but comparable, studies the necessary number of studies may be
reached to detect or exclude relatively small effects with confidence.

For a meta-analysis to be valid, the included studies need to represent all of those
published on the topic that meet clearly defined inclusion criteria (including quality
criteria). In other words, meta-analysis is appropriate only in the context of a systematic
review of all relevant studies. It is also important that individual studies are similar
(homogeneous) enough in conduct and results to be meaningfully combined.
QUESTION 4

Write short notes on:

a)       co-trimoxazole.
b)       the pathogenesis of clinical presentations of parvovirus B19 infection
c)       relative risk
d)       the p-value


a) Co-trimoxazole is a mixture of trimethoprim and sulfamethoxazole.(a sulphonamide).
Mechanism of action
Trimethoprim and sulfamethoxazole act synergistically to interfere with two steps of the
enzymatic pathway for the bacterial synthesis of tetrahydrofolic acid. Aulpphonamide
inhibits the incorporation of PABA into folic acid, ;and trimethopriom prevents the
reduction of dihydrofolate to tetrahydrofolate
Antibacterial spectrum
It has been used mainly for infections of the urinary tract, lungs, ears, and gastro-
intestinal tract. Initially active against a wide range of Gram positive and Gram negative
organisms, there is now widespread resistance to many organisms. It remains an
important agent for the prophylaxis and treatment of Pneumocyctis carinii pneumonia.
Absorption, distribution and excretion
The optimal ratio of trimethroprim to sulphamethoxazole concentrations is 1:20. With a
ratio of 1:5 for the administered drugs, the plasma concentration ratio is usually around
1:20, but can vary from 1:2 to 1:30. In the tissues it is often around 1:2 to 1:5 because the
more lipophilic trimethroprim penetrates many tissues better. About 50% of both
components are excreted in the urine in 24 hours.
Administration and dosage
Co-trimoxazole may be given orally or intravenously. The usual dosage for children is
18mg (3mg trimethoprim 3mg, sulphamethoxazole 15mg) per kg per day, taken twice
daily, with reduced dosage in renal impairment. Drink a full glass of water with each
dose. The therapeutic dose for Pneumocystis carinii is 120mg/kg per day for 14-21 days,
and for Pneumocystis prophylaxis 9mg/kg per dose, three times a week.
Adverse effects and precautions
·       The most commons side effects are gastrointestinal disturbances and skin
reactions. The most important severe and potentially fatal effects are blood dyscrasias
and severe skin reactions. Adverse effects may be more severe in HIV infected people,
and the elderly.
·       Should be given with care to patients with renal or hepatic impairment, and is
contra-indicated in severe renal or hepatic failure, with blood disorders or allergy to co-
trimoxazole. It should not be given to babies under six weeks of age because of a risk of
kernicterus
Interactions
May potentiate the effects of some drugs, such as oral anticoagulants, methotrexate and
phenytoin (possibly due to displacement of the drug from albumin), and sulphonylurea
compounds.

b.)    The pathogenesis of clinical presentations of parvovirus B19 infection

Anaemia
Parvovirus B19 infection affects primarily the erythroid cell line, specifically erythroid
precursors near the pronormoblast stage, causing anaemia. The erythrocyte P blood group
antigen acts as a receptor for the virus. Cell lysis results in depletion of erythroid cells
and a transient depression or arrest of erythropoiesis. Although thrombocytopenia and
neutropenia may occur this is apparently not due to viral invasion, and the pathogenesis is
unclear.

Individuals with chronic hemolytic anemia and increased red cell turnover are
particularly affected by B19 infection, where a transient arrest in red cell production can
lead to a precipitous fall in hemoglobin.

Humoral immunity is important in controlling the infection. People with impaired
humoral immunity are consequently at increased risk for serious or persistent infection,
such as chronic red cell aplasia, and sometimes failure of other marrow elements.

The virus can cross the placenta and infect the relatively immunocompromised fetus
during primary maternal infection. Most infections during pregnancy result in normal
deliveries at term, but some result in profound fetal anemia, high-output cardiac failure
and fetal hydrops. The cardiac failure may be exacerbated by a direct effect of the virus
on myocardial tissue (which also has P blood group antigen).

Fever, malaise, and rhinorrhea may occur early in the illness, as a result of a viremia with
nasopharyngeal viral shedding.

The exanthem and the arthritis that sometimes occurs appear to be postinfectious
phenomena related to the immune response, with edema in the epidermis and a
perivascular mononuclear infiltrate.

c.)    Relative risk

The relative risk is a measure of the strength of association between an exposure
(including a treatment) and a disease or other event. It is the ratio of the risk of an event
among an exposed population to the risk among the unexposed i.e. the number of times
more or less likely an event is to happen in one group compared with another. It is thus
the ratio of the absolute risk for each group.
If the absolute risk is the same in both groups, the RR is 1. If the event in the exposed
(e.g. treated) group is more likely than in the untreated group the RR is greater than 1.
For instance, a RR of 5 indicates that the exposed group have 5 times the absolute risk of
the event. If the event in the exposed (e.g. treated) group is less likely than in the
untreated group the RR is less than 1. For instance, a RR of 0.5 indicates that the exposed
group have one half the absolute risk of the event.


d.)    The p-value

       The p-value is the probability that an observed or greater difference of association
       between groups has occurred by chance, if it is assumed that there is in fact no
       real difference or association. The p-value is usually used as part of a process
       known as “hypothesis testing”. For example it may be hypothesised that there is
       no association or difference (a “nul hypothesis”), and the p-value used to assess
       how likely it is to have obtained the observed data if the null hypothesis were true
       (i.e. no difference or association). If this probability is less than 1/20 (a p-value of
       less than 0.05), the null hypothesis is conventionally rejected, and the alternative
       hypothesis (that there is a difference) is accepted. A finding with a p-value of less
       than 0.05 is conventionally described as being “statistically significant”, although
       the cut-off of 0.05 is entirely arbitrary. Because chance variation has a greater
       influence on the findings of smaller studies, the p-value is affected by the sample
       size.

				
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