We read with interest the article by C S Zipitis, G A Markides and I
L Swann regarding the cost of prevention and treatment of vitamin D
deficiency [1]. We agree with the proposal that local authorities should
provide funds to supplement vitamin D in ‘at risk’ ethnic minority groups.
Similar to Burnley, Oldham has a large Asian community of 20.8%.
Between December 2002 and March 2004, we i...
We read with interest the article by C S Zipitis, G A Markides and I
L Swann regarding the cost of prevention and treatment of vitamin D
deficiency [1]. We agree with the proposal that local authorities should
provide funds to supplement vitamin D in ‘at risk’ ethnic minority groups.
Similar to Burnley, Oldham has a large Asian community of 20.8%.
Between December 2002 and March 2004, we identified 9 cases of vitamin D
deficiency. Out of these 9 patients 8 were of Asian origin.Six presented
with hypocalcaemic symptoms (seizures, carpopedal spasms/cramps) and three
presented with signs of rickets.
All patients responded well to treatment with Vitamin D. Three
children also received oral calcium supplements.
A recent study on the prevalence of rickets in adults in the UK [2]
showed a high prevalence of vitamin D deficiency (24%) in inner city
Birmingham. One in 3 Asians were deficient. No data are available on the
prevalence in children in the UK. Our experience and that of others [3]
shows a growing number of vitamin D deficient patients. Looking at both
financial and health implications we support the introduction of
supplemental vitamin D to at risk populations as the most cost effective
measure.
References:
1. Zipitis CS, Markides GA, Swann IL. Vitamin D deficiency:
prevention or treatment? Archives of Disease in childhood 2006;91: 1011-
1014
2. Ford L, Graham V, Wall A, Berg J.Vitamin D concentrations in an UK
inner-city multicultural outpatient population. Ann Clin Biochem.
2006;43(pt6): 468-473
3. Mughal MZ. Resurgence of vitamin D deficieny rickets in the UK.
Osteoporosis
Review 2005;13(1): 10-13.
4. Odeka EB, Tan J; nutritional Rickets is increasingly diagnosed in
children of ethnic origin ; Arch Dis child 2005; 90; 1203-1204.
The letter from Eisenhut (1) questions the benefits of intravenous
rehydration of children with gastroenteritis with Normal Saline because of
the possibility of hyperchloraemic acidosis and suggests that Ringers
Lactate (RL) or an equivalent solution might offer advantages over Normal
Saline (NS).
Our study of 102 children with gastroenteritis judged to need
intravenous fluids, compared p...
The letter from Eisenhut (1) questions the benefits of intravenous
rehydration of children with gastroenteritis with Normal Saline because of
the possibility of hyperchloraemic acidosis and suggests that Ringers
Lactate (RL) or an equivalent solution might offer advantages over Normal
Saline (NS).
Our study of 102 children with gastroenteritis judged to need
intravenous fluids, compared plasma and urinary electrolyte changes after
randomisation to receive either 0.9% saline + 2.5% dextrose (NS n=51) or
0.45% saline + 2.5% dextrose (N/2 n=51).(2) The infusion rate was at the
discretion of the treating physician according to either a rapid
replacement protocol (RRP; 10mL/kg/hour for 4 hours) or standard
replacement protocol (SRP; replacement of estimated percent dehydration
over 24 hours).
Data on acidosis and plasma concentrations of chloride were not
presented in our original manuscript (2) but are available in all
children. At baseline, the children were normochloraemic (mean +SD
chloride 100.4 ±3.4 mmol/L) with a raised anion gap (AG). Mean bicarbonate
(a surrogate for acidosis) was low (17.8 ±3.0 mmol/L). Ninety of 102 had a
bicarbonate <22 mmol/L associated with a mean AG of 21 ±3.5 mmol/L.
After 4 hours (T4) the chloride concentration increased to 105 ±3.0
mmol/L in the NS group, versus 102 ±2.7 mmol/L in the N/2 group
(p<0.001). At the same time both groups experienced a similar
improvement in their acid base status, with a rise in bicarbonate (mean
±SD T4 bicarbonate NS vs N/2 19 ±3.2 mmol/L vs 19 ±2.6 mmol/L
respectively, p=0.12) and fall in AG (mean T4 AG NS vs N/2 16 ±3.8 mmol/L
vs 17 ±2.6 mmol/L respectively, p=0.2). Separate analysis of the
approximately three quarters of children that completed 4 hours of the RRP
demonstrated almost identical chloride, bicarbonate and anion gap changes
(data not shown). In the 16 children (NS n=8, N/2 n=8) who received IV
fluids for 24 hours the chloride changes persisted (median [range] T24
chloride NS vs N/2 107 mmol/L [105-115] vs 105 mmol/L [100-110]
respectively, p=0.04) but with continued improvement in bicarbonate and AG
in both groups (median T24 bicarbonate NS vs N/2 19 mmol/L [15-20] vs 20
mmol/L [12-24] respectively, p=0.4, median T24 AG NS vs N/2 16 mmol/L [10-
17] vs 16 mmol/L [13-20] respectively, p=0.4).
Infusion of normal saline was associated with hyperchloraemia but not
acidosis even after 24 hours of intravenous fluids compared with a lower
chloride solution. The near identical changes in bicarbonate and anion gap
in these two groups could have one of two explanations. Firstly, the
chloride load from normal saline in the volumes given does not cause
acidosis. Alternatively, the chloride load may have some impact on
acidosis that is offset by the superior ability of normal saline over a
hypotonic saline solution to refill the intravascular space and improve
tissue perfusion, important in dehydration.
Infusion of large volumes of normal saline including during
resuscitation or surgery can result in hyperchloraemic acidosis.(3-9) This
has also been reported in response to RL or its equivalents, albeit to a
lesser extent.(3,6,9) Studies comparing the two fluids have usually shown
no difference in clinical outcome,(3,5,6,9,10) except in those at high
risk such as the elderly.(7) There are no data in children apart from the
report of Durward et al,(11) who found that the development of
hyperchloraemic acidosis in children post cardiac surgery receiving normal
saline as their ‘maintenance’ fluid had no clinical sequelae. As far as we
are aware there are also no data comparing normal saline and RL in adults
who are salt depleted as is frequently the case with gastroenteritis.(12)
The improvement in plasma sodium in our study patients who received
NS versus N/2, together with the similar improvements in bicarbonate and
anion gap in the two groups casts doubt on the clinical significance of
the modest hyperchloraemia demonstrated. When infused in large volumes
normal saline has been shown to maintain a normal plasma sodium compared
to a drop with RL.(5,8) In the setting of pre-existing salt depletion and
non-osmotic ADH activity such as we have shown in gastroenteritis (13)
this may be important.
Eisenhut also questions the safety of rapid intravenous replacement
of dehydration in children with gastroenteritis. It was not a primary aim
of our study to identify clinical and biochemical differences between
those who received RRP compared with SRP; however in both this (2) and an
earlier observational study of children receiving only N/2,(13) we found
that the children receiving more prolonged fluids (either SRP alone or RRP
followed by SRP) rather than those receiving RRP alone who experienced
potentially clinically significant dilutional hyponatraemia. Further, it
has been well documented that rapid replacement of fluid deficit either
orally or intravenously in childhood gastroenteritis is safe and well
tolerated,(14-16) has significant health economics benefits and is widely
recommended.(17-19)
K Neville, C Verge, A Rosenberg, M O’Meara, J Walker
References:
1. Eisenhut M. Adverse effects of rapid isotonic saline infusion.
Archives of Disease in Childhood.91(9):797, 2006.
2. Neville KA, Verge CF, Rosenberg AR, O'Meara MW, Walker JL.
Isotonic is better than hypotonic saline for intravenous rehydration of
children with gastroenteritis: a prospective randomised study. Archives of
Disease in Childhood.91(3):226-32, 2006.
3. Brill SA, Stewart TR, Brundage SI, Schreiber MA. Base deficit
does not predict mortality when secondary to hyperchloremic acidosis.
Shock.17(6):459-62, 2002.
4. Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal
saline and physiological Hartmann's solution: a randomized double-blind
crossover study. Clinical Science.104(1):17-24, 2003.
5. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline
infusion produces hyperchloremic acidosis in patients undergoing
gynecologic surgery.. Anesthesiology.90(5):1265-70, 1999.
6. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J,
Nelson DR. Normal saline versus lactated Ringer's solution for
intraoperative fluid management in patients undergoing abdominal aortic
aneurysm repair: an outcome study. Anesthesia & Analgesia.93(4):817-
22, 2001.
7. Wilkes NJ, Woolf R, Mutch M, Mallett SV, Peachey T, Stephens R et
al. The effects of balanced versus saline-based hetastarch and crystalloid
solutions on acid-base and electrolyte status and gastric mucosal
perfusion in elderly surgical patients.. Anesthesia &
Analgesia.93(4):811-6, 2001.
8. Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of
intravenous lactated Ringer's solution versus 0.9% sodium chloride
solution on serum osmolality in human volunteers. Anesthesia &
Analgesia.88(5):999-1003, 1999.
9. Kellum JA. Fluid resuscitation and hyperchloremic acidosis in
experimental sepsis: improved short-term survival and acid-base balance
with Hextend compared with saline. Critical Care Medicine.30(2):300-5,
2002.
10. Lowery BD, Cloutier CT, Carey LC. Electrolyte solutions in
resuscitation in human hemorrhagic shock. Surgery, Gynecology &
Obstetrics.133(2):273-84, 1971.
11. Durward A, Tibby SM, Skellett S, Austin C, Anderson D, Murdoch
IA. The strong ion gap predicts mortality in children following
cardiopulmonary bypass surgery. Pediatric Critical Care Medicine.6(3):281-
5, 2005.
12. Hirschhorn N. The treatment of acute diarrhea in children. An
historical and physiological perspective. American Journal of Clinical
Nutrition.33(3):637-63, 1980.
13. Neville KA, Verge CF, O'Meara MW, Walker JL. High antidiuretic
hormone levels and hyponatremia in children with gastroenteritis.
Pediatrics.116(6):1401-7, 2005.
14. Nager AL, Wang VJ. Comparison of nasogastric and intravenous
methods of rehydration in pediatric patients with acute dehydration.
Pediatrics. 2002;109:566-72.
15. Phin SJ, McCaskill ME, Browne GJ, Lam LT. Clinical pathway using
rapid rehydration for children with gastroenteritis. Journal of
Paediatrics & Child Health.39(5):343-8, 2003.
16. Reid SR, Bonadio WA. Outpatient rapid intravenous rehydration to
correct dehydration and resolve vomiting in children with acute
gastroenteritis. Annals of Emergency Medicine.28(3):318-23, 1996.
17. Practice parameter: the management of acute gastroenteritis in
young children. American Academy of Pediatrics, Provisional Committee on
Quality Improvement, Subcommittee on Acute Gastroenteritis. Pediatrics.
1996;97:424-35.
18. Armon K, Stephenson T, MacFaul R, Eccleston P, Werneke U. An
evidence and consensus based guideline for acute diarrhoea management.
Archives of Disease in Childhood. 2001;85:132-42.
19. Sandhu BK. European Society of Pediatric Gastroenterology
Hanwood. Practical guidelines for the management of gastroenteritis in
children. Journal of Pediatric Gastroenterology & Nutrition.
2001;33:Suppl-9.
The need to promote and support breastfeeding is unquestionable.
There is strong evidence that exclusive and prolonged breastfeeding has
multiple health benefits for mothers and their infants. American Academy
of Pediatrics (AAP) and World Health Organization (WHO) recommend
exclusive breastfeeding for the first 6 months of life. Both the AAP and
American College of Obstetricians and Gynecologists (ACO...
The need to promote and support breastfeeding is unquestionable.
There is strong evidence that exclusive and prolonged breastfeeding has
multiple health benefits for mothers and their infants. American Academy
of Pediatrics (AAP) and World Health Organization (WHO) recommend
exclusive breastfeeding for the first 6 months of life. Both the AAP and
American College of Obstetricians and Gynecologists (ACOG) recommend that
doctors counsel mothers on breastfeeding. Studies suggest, however, that
both pediatricians and gynecologists/obstetricians lack confidence in
their skills to support breastfeeding. Most of doctors agree with the
statement: “Exclusive breastfeeding for the first 6 months of life is
unrealistic for many mothers” Furthermore, most of them rate their advice
to breastfeeding mothers on how many weeks to breastfeed as not very
important. Doctors report on barriers to support breastfeeding and their
confidence in their own skills in this area. Limited time during
appointments to give routine advice on feeding and to address
breastfeeding problems are rated most frequently as very important.
Pediatricians and gynecologists/obstetricians are the least confident in
resolving problems of not producing enough breast milk, breast pain or
tenderness. Many doctors do not feel confident in their skills to support
breastfeeding and may have a limited time to address the issue during
visits. The picture that emerges is the need for greater support of
clinicians in terms of providing them with the time to educate and counsel
on breastfeeding and its importance and of mothers in assisting them when
they confront difficulties. The strong evidence exists that clinical
interventions can improve breastfeeding rates. Doctors’ regarding formula
supplementation of healthy infants in their opinions about the importance
of their breastfeeding advice are associated with the likelihood that
mothers will continue exclusive breastfeeding. Polices to enhance doctors'
abilities to address breastfeeding problems within the constraints of busy
practices could improve their ability to support exclusive breastfeeding.
European countries do not fully comply with the policies and
recommendations of the Global Strategy on Infant and Young Child Feeding
that they endorsed during the 55th World Health Assembly in 2002.
Poland is an average European country as far as the number of baby
friendly hospitals is concerned. We have only 62 baby friendly hospitals
among above 450 obstetric-neonatal hospitals in Poland (<15%of births
occur in baby friendly hospitals). The implementation of the Baby-Friendly
Hospital Initiative is difficult and rather slow. There is Committee for
Breastfeeding Promotion, a non – governmental organization, whose members,
mainly International Board Certified Lactation Consultants, run trainings
which prepare hospitals for breastfeeding protection, promotion and
support. During these trainings midwifes and nurses show very deep
interest in the problem while doctors, both pediatricians and
gynecologists/obstetricians, rarely take part in full, 18–hour training.
The necessity to do their job, in their opinion, makes it impossible for
them to get involved in breastfeeding protection, promotion and suport.
Professional medical associations do not recommend the Initiative.
Infants born in baby friendly hospitals are more likely to be breastfed
for a longer time than born in non-baby friendly facilities. The duration
of breastfeeding is associated with the 10 steps. But in my opinion
breastfeeding rates could increase faster when pediatricians and
gynecologists/obstetricians would like to protect, promote and support
breastfeeding. They ignore recommendations of the Committee, which are
not, in their opinion, convincing as there are no recommendations of
Polish scientific associations concerning lactation and breastfeeding.
Pediatricians and other health care professionals ignore principles of
AAP, ACOG and many international organizations. They do not encourage
development of formal training in breastfeeding and lactation either in
medical schools or in residency, fellowship training programs and
practicing pediatrics.
So, who is ignored?
References:
1. Taveras EM, Li R, Grummer-Stawn L, Richardson M, Marshall R, Rego VH,
Miroshnik I, Lieu TA. Opinions and practices of clinicians with
continuation of exclusive breastfeeding.Pediatrics 2004: 113: 283-290.
2. Cattaneo A, Yngve A, Koletzko B, Guzman LR. Protection, promotion and
support of breast-feeding in Europe: current situation. Public Health
Nutrition 2005;8(1):39-46.
3. Merten S, Dratva J, Ackerman-Liebrich U. Do Baby-Friendly Hospitals
Influence Breastfeeding Duration on a National Level. Pediatrics
2005;116:702-708.
4. AAP Policy Statement. Breastfeeding and the Use of Human Milk.
Pediatrics 2005;115:496-506
In rats "impaired microcirculatory alteration in septic shock is more
severe than hemorrhagic shock" (1). Endotoxin [which is used to induce
septic shock in animal models and when translocating from the gut is
thought to contribute to the development of septic shock in the
critically ill] increases serum lactate by "inactivation of pyruvate
dehydrogenase (PDH), unrelated to changes in tissue PO2" (2)...
In rats "impaired microcirculatory alteration in septic shock is more
severe than hemorrhagic shock" (1). Endotoxin [which is used to induce
septic shock in animal models and when translocating from the gut is
thought to contribute to the development of septic shock in the
critically ill] increases serum lactate by "inactivation of pyruvate
dehydrogenase (PDH), unrelated to changes in tissue PO2" (2). The
inference is that the elevation of blood lactate in septic shock may have
nothing to do with the adequacy of tissue oxygenation. As PDH is also
inactivated by a decline in energy charge, which should be accompanied by
a fall in tissue pH if indeed its stochiometric surrogate, the
inactivation might alternatively be due to a fall in tissue pH. This would
explain why augmenting PDH activity with dichloroacetate (DCA) normalized
lactate levels without influencing oxygen delivery and uptake relations
and did not appear to be of any value in managing septic patients (3).
If PDH is inhibited by a fall in energy charge and/or tissue pH
lactate could be generated and oxidative phosporylation continue if some
of the pyruvate continued to be converted into acetyl-CoA and ATP yield
maintained or even increased by shifting substrate utilization from
glucose to fatty acids. If so a sudden fall in tissue pH could be the
stimulus for a reverse Randle effect; the increased availability of
circulating free fatty acids (FFA) inhibiting the rate of glycolysis in
heart and resting skeletal muscle. An alternative explanation might be
that an excess of oxygen promoted by the inhibition of PDH generates free
radicals which are the stimulus for the reverse Randle effect.
Untreated faecal peritonitis in pigs caused an increase in PCO(2)-gap
and a drop in intramucosal pH (pHi) (4). A blind loop of the small
intestine was constructed in this study for repeated tissue biopsies to
measure intestinal energy-related metabolites and lactate concentration.
The intestinal energy metabolism was not disturbed until the end of the
experimental period when the energy charge decreased and there was a
moderate rise in lactate concentration.
This important study is consistent with the claim (5) that ATP
degradation, measured from tissue metabolities, is a late event relative
to the fall in tissue pH. This suggests that the initial fall in tissue pH
might indeed be an active cytoprotective event induced by reversal of the
direction of ATP synthase activity, apoptosis putatively being a later
product of the same cytoprotective phenomenon (6). If so the fall in pH
accompanying the subsequent degradation of ATP degradation might be the
only product of unreversed ATP hydrolysis per se if that is indeed
responsible for the fall in pH in these circumstances.
Regardless of the mechanisms involved the importance of these
observations in pigs is that measuring the intramucosal pH should increase
the sensitivity and accuracy of any measure of the magnitude of the energy
charge made by microdialysis or even NMR spectroscopy. [The confounding
effect of fluids shifts from intracellular to extracellular compartments
upon the measurement of pH by NMR, which could make the measurements
uninterpretable in the critically ill, has been addressed elsewhere. The
tonometric method avoids the potential error by assuming that the
unterstitial [HCO3-] is the same as that in arterial blood.] In other
words a fall in tonometric measurement of tissue pH and potentially
reversible cellular dysfunction might occur in the absence of any evidence
of ATP degradation.
.
The administration of epinephrine "dramatically decreased microcirculatory
blood flow...visualized in the sublingual mucosa at baseline and 0.5, 1,
and 5 mins of ventricular fibrillation, at 1 and 5 mins of precordial
compression, and at 1 and 5 mins after return of spontaneous circulation"
in rats (7) . The authors interpreted a discrease in their study of
septic shock as evidence of "impaired microcirculatory alteration" . The
reverse might be truer if a fall in pH upregulates oxidative
phosphorylation by increasing the magnitude of the protonmotive force
and/or increasing nutrient energy density by shifting consumption from
glucose to fatty acids, Opie now believeing that in the failing heart both
glucose and fatty acids might be needed for ATP resynthesis (8). The
adverse effects of fatty acids on ischemic-reperfusion injury in the
myocardium might be mediated, at least in part, by oxygen-derived free
radicals(9) whose release appears to be enhanced by inhaling oxygen.
Free radicals can uncouple oxidative phosphorylation. Indeed in
isolated perfused rat hearts which had undergone 30 min of total global
ischaemia followed by 30 min of reperfusion palmitate increased the
formation of free radicals (ROS) and reperfusion contracture. Furthermore
TMZ, a potential inhibitor of palmitate-induced mitochondrial uncoupling,
decreased the formation of free radicals by palmitate and improved
postischemic mechanical dysfunction (10). This can explain why
withholding oxygen or even inhaling CO in low doses can be beneficial in
these circumstances (11).
As a fall in extracellular pH impairs myocardial function (12)
raising the extracellular pH might be expected to improve myocardial
function unless the rate of ATP hydrolysis induced by the increased
workload imposed on a failing heart exceeds its capacity for ATP
resynthesis and causes a decline in energy charge in accordance with the
refinement of Daniel Atkinson's hypothesis. Bicarboinate infusions might,
therefore, either improve myocardfial performance by elevating the
extracellular pH or make it worse by down-regulating oxidative
phosphorylation thus greatly increasing the need for nutrient delivery.
That would explain why sodium bicarbonate infusion during
resuscitation of infants at birth has an equivocal effect upon outcome
(13). Sodium bicarbonate infusions might still be of value in reversing a
chronic metabolic acidosis (14). by reversing the inhibitory effects of an
accompanying decline in energy charge upon ATP-dependent enzymatic
activity.
The tonometric measurement of pH is especially accurate in sepis
(15).
References:
1. Fang X, Tang W, Sun S, Huang L, Chang YT, Castillo C, Weil MH.
Comparison of buccal microcirculation between septic and hemorrhagic
shock.
Crit Care Med. 2006 Dec;34(12 Suppl):S447-S453.
2. Curtis SE, Cain SM. Regional and systemic oxygen delivery/uptake
relations and lactate flux in hyperdynamic, endotoxin-treated dogs.
Am Rev Respir Dis. 1992 Feb;145(2 Pt 1):348-54.
3. Preiser JC, Moulart D, Vincent JL. Dichloroacetate administration
in the treatment of endotoxin shock.
Circ Shock. 1990 Mar;30(3):221-8.
4. Ljungdahl M, Rasmussen I, Ronquist G, Haglund U. Intramucosal pH
and pCO(2) do not strictly correlate with intestinal energy metabolism in
experimental peritonitis. Eur Surg Res. 2000;32(3):182-90.
5. Nutrient and energy supply-dependency
Richard G Fiddian-Green (31 October 2003) eLetter re: D F Treacher and R
M Leach
ABC of oxygen: Oxygen transport1. Basic principles
BMJ 1998; 317: 1302-1306
6. Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V,
Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine
heart.
Ann Thorac Surg. 2004 Apr;77(4):1376-83.
7. Fries M, Weil MH, Chang YT, Castillo C, Tang W. Microcirculation
during cardiac arrest and resuscitation. Crit Care Med. 2006 Dec;34(12
Suppl):S454-S457.
8. Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE,
Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid
depletion acutely decreases cardiac work and efficiency in cardiomyopathic
heart failure.
Circulation. 2006 Nov 14;114(20):2130-7.
9. Gambert S, Vergely C, Filomenko R, Moreau D, Bettaieb A, Opie LH,
Rochette L. Adverse effects of free fatty acid associated with increased
oxidative stress in postischemic isolated rat hearts.
Mol Cell Biochem. 2006 Feb;283(1-2):147-52.
10. Durante W, Johnson FK, Johnson RA. Role of carbon monoxide in
cardiovascular function.
J Cell Mol Med. 2006 Jul-Sep;10(3):672-86.
11. Opie L. Effect of extracellular pH on function and metabolism of
isolated perfused rat heart.
Am J Physiol. 1965 Dec;209(6):1075-80.
12. Beveridge CJ, Wilkinson AR. Sodium bicarbonate infusion during
resuscitation of infants at birth.
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004864.
13. Hoste EA, Colpaert K, Vanholder RC, Lameire NH, De Waele JJ, Blot
SI, Colardyn FA. Sodium bicarbonate versus THAM in ICU patients with mild
metabolic acidosis.
J Nephrol. 2005 May-Jun;18(3):303-7.
14. Kutala VK, Khan M, Mandal R, Ganesan LP, Tridandapani S, Kalai T,
Hideg K, Kuppusamy P. Attenuation of myocardial ischemia-reperfusion
injury by trimetazidine derivatives functionalized with antioxidant
properties.
J Pharmacol Exp Ther. 2006 Jun;317(3):921-8.
15. Antonsson JB, Boyle CC 3rd, Kruithoff KL, Wang HL, Sacristan E,
Rothschild HR, Fink MP. Validation of tonometric measurement of gut
intramural pH during endotoxemia and mesenteric occlusion in pigs. Am J
Physiol. 1990 Oct;259(4 Pt 1):G519-23.
In rats "impaired microcirculatory alteration in septic shock is more
severe than hemorrhagic shock" (1). Endotoxin [which is used to induce
septic shock in animal models and when translocating from the gut is
thought to contribute to the development of septic shock in the
critically ill] increases serum lactate by "inactivation of pyruvate
dehydrogenase (PDH), unrelated to changes in tissue PO2" (2)...
In rats "impaired microcirculatory alteration in septic shock is more
severe than hemorrhagic shock" (1). Endotoxin [which is used to induce
septic shock in animal models and when translocating from the gut is
thought to contribute to the development of septic shock in the
critically ill] increases serum lactate by "inactivation of pyruvate
dehydrogenase (PDH), unrelated to changes in tissue PO2" (2). The
inference is that the elevation of blood lactate in septic shock may have
nothing to do with the adequacy of tissue oxygenation. As PDH is also
inactivated by a decline in energy charge, which should be accompanied by
a fall in tissue pH if indeed its stochiometric surrogate, the
inactivation might alternatively be due to a fall in tissue pH. This would
explain why augmenting PDH activity with dichloroacetate (DCA) normalized
lactate levels without influencing oxygen delivery and uptake relations
and did not appear to be of any value in managing septic patients (3).
If PDH is inhibited by a fall in energy charge and/or tissue pH
lactate could be generated and oxidative phosporylation continue if some
of the pyruvate continued to be converted into acetyl-CoA and ATP yield
even be increased by shifting substrate utilization to fatty acids. If so
a sudden fall in tissue pH might be the stimulus for sufficient a reverse
Randle effect, the increased availability of circulating free fatty acids
(FFA) inhibiting the rate of glycolysis in heart and resting skeletal
muscle. An alternative explanation might be that an excess of oxygen
promoted by the sudden inhibition of PDH generates free radicals which
induce a reverse Randle effect.
Untreated faecal peritonitis in pigs caused an increase in PCO(2)-gap
and a drop in gut intramucosal pH (pHi) (4). A blind loop of the small
intestine was constructed in this study for repeated tissue biopsies to
measure intestinal energy-related metabolites and lactate concentration.
The intestinal energy metabolism was not disturbed until the end of the
experimental period when the energy charge decreased and there was a
moderate rise in lactate concentration. This important study is
consistent with the claim (5) that ATP degradation, measured from tissue
metabolities, is a late event relative to the fall in tissue pH.
This suggests that the initial fall in tissue pH might indeed be an
active cytoprotective event induced by reversal of the direction of ATP
synthase activity, apoptosis putatively being a later product of the same
cytoprotective phenomenon (6) as previously mooted. If so the fall in pH
accompanying the subsequent degradation of ATP degradation might be the
only product of unreversed ATP hydrolysis per se if that is indeed
responsible for the fall in pH in these circumstances. Regardless of the
mechanisms involved the importance of these observations in pigs is that
measuring the intramucosal pH should increase the sensitivity and accuracy
of any measure of the magnitude of the energy charge made from ATP
degradation products be they measured by microdialysis or by NMR
spectroscopy. In other words reversible cellular dysfunction might occur
in the absence of ATP degradation.
.
The administration of epinephrine "dramatically decreased microcirculatory
blood flow...visualized in the sublingual mucosa at baseline and 0.5, 1,
and 5 mins of ventricular fibrillation, at 1 and 5 mins of precordial
compression, and at 1 and 5 mins after return of spontaneous circulation"
in rats (7) . The authors interpreted a discrease in their study of
septic shock as evidence of "impaired microcirculatory alteration" . The
reverse might be truer if a fall in pH upregulates oxidative
phosphorylation by increasing the magnitude of the protonmotive force
and/or increasing nutrient energy density by shifting consumption from
glucose to fatty acids, Opie now believeing that in the failing heart both
glucose and fatty acids might be needed for ATP resynthesis (8). The
adverse effects of fatty acids on ischemic-reperfusion injury in the
myocardium might be mediated, at least in part, by oxygen-derived free
radicals(9) whose release appears to be enhanced by inhaling oxygen.
In isolated perfused rat hearts which had undergone 30 min of total
global ischaemia followed by 30 min of reperfusion palmitate increased the
formation of free radicals (ROS) and reperfusion contracture. Furthermore
TMZ, a potential inhibitor of palmitate-induced mitochondrial uncoupling,
decreased the formation of free radicals by the palmitate and improved
postischemic mechanical dysfunction (10). This can explain why
withholding oxygen or even inhaling CO in low doses can be beneficial in
these circumstances (11).
As a fall in extracellular pH impairs myocardial function (12)
raising the extracellular pH might be expected to improve myocardial
function unless the rate of ATP hydrolysis induced by the increased
workload imposed on a failing heart exceeds its capacity for ATP
resynthesis and causes a further decline in energy charge in accordance
with the Daniel Atkinson's hypothesis. Bicarboinate infusions might,
therefore, either improve myocardial performance by elevating the
extracellular pH and/or decreasing the need for coronary artery perfusion
by shifting substrate utilization to fatty acids. It might,
althernatively, make it worse by down-regulating oxidative phosphorylation
and/or inducing uncoupling by the same means and/or greatly increasing the
need for nutrient delivery. That could explain why sodium bicarbonate
infusion during resuscitation of infants at birth has an equivocal effect
upon outcome (13). Sodium bicarbonate infusions might still be of value in
reversing a chronic metabolic acidosis (14).
Knowing what was happening to the tissue pH could be a great help in
patient anagement.
References:
1. 2. Fang X, Tang W, Sun S, Huang L, Chang YT, Castillo C, Weil MH.
Comparison of buccal microcirculation between septic and hemorrhagic
shock.
Crit Care Med. 2006 Dec;34(12 Suppl):S447-S453.
2. Curtis SE, Cain SM. Regional and systemic oxygen delivery/uptake
relations and lactate flux in hyperdynamic, endotoxin-treated dogs.
Am Rev Respir Dis. 1992 Feb;145(2 Pt 1):348-54.
3. Preiser JC, Moulart D, Vincent JL. Dichloroacetate administration
in the treatment of endotoxin shock.
Circ Shock. 1990 Mar;30(3):221-8.
4. Ljungdahl M, Rasmussen I, Ronquist G, Haglund U. Intramucosal pH
and pCO(2) do not strictly correlate with intestinal energy metabolism in
experimental peritonitis. Eur Surg Res. 2000;32(3):182-90.
5. Nutrient and energy supply-dependency
Richard G Fiddian-Green (31 October 2003) eLetter re: D F Treacher and R
M Leach
ABC of oxygen: Oxygen transport1. Basic principles
BMJ 1998; 317: 1302-1306
6. Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V,
Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine
heart.
Ann Thorac Surg. 2004 Apr;77(4):1376-83.
7. Fries M, Weil MH, Chang YT, Castillo C, Tang W. Microcirculation
during cardiac arrest and resuscitation. Crit Care Med. 2006 Dec;34(12
Suppl):S454-S457.
8. Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE,
Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid
depletion acutely decreases cardiac work and efficiency in cardiomyopathic
heart failure.
Circulation. 2006 Nov 14;114(20):2130-7.
9. Gambert S, Vergely C, Filomenko R, Moreau D, Bettaieb A, Opie LH,
Rochette L. Adverse effects of free fatty acid associated with increased
oxidative stress in postischemic isolated rat hearts.
Mol Cell Biochem. 2006 Feb;283(1-2):147-52.
10. Durante W, Johnson FK, Johnson RA. Role of carbon monoxide in
cardiovascular function.
J Cell Mol Med. 2006 Jul-Sep;10(3):672-86.
11. Opie L. Effect of extracellular pH on function and metabolism of
isolated perfused rat heart.
Am J Physiol. 1965 Dec;209(6):1075-80.
12. Beveridge CJ, Wilkinson AR. Sodium bicarbonate infusion during
resuscitation of infants at birth.
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004864.
13. Hoste EA, Colpaert K, Vanholder RC, Lameire NH, De Waele JJ, Blot
SI, Colardyn FA. Sodium bicarbonate versus THAM in ICU patients with mild
metabolic acidosis.
J Nephrol. 2005 May-Jun;18(3):303-7.
14. Kutala VK, Khan M, Mandal R, Ganesan LP, Tridandapani S, Kalai T,
Hideg K, Kuppusamy P. Attenuation of myocardial ischemia-reperfusion
injury by trimetazidine derivatives functionalized with antioxidant
properties.
J Pharmacol Exp Ther. 2006 Jun;317(3):921-8.
Gammelgaard et al have to be commended for their study which attempts
to throw light on some of the complex issues, ethical and otherwise,
surrounding parental attitudes towards research in children.(1) While
agreeing broadly with the authors' conclusions regarding the feasibility
of setting up a research project which conforms to parental perceptions,
we would like to stress the need for viewing this i...
Gammelgaard et al have to be commended for their study which attempts
to throw light on some of the complex issues, ethical and otherwise,
surrounding parental attitudes towards research in children.(1) While
agreeing broadly with the authors' conclusions regarding the feasibility
of setting up a research project which conforms to parental perceptions,
we would like to stress the need for viewing this in a wider perspective.
The COPSAC study involves follow up of infants who are healthy at the
outset, with a view to early identification of asthma and related allergic
disorders, which are relatively common and usually not life threatening in
the general paediatric population. All the mothers involved had suffered
from similar conditions, thus equipping them with a unique insight into
the disease, as well as a possible 'motive' to allow even invasive testing
for early diagnosis in their children. In contrast, many paediatric
research studies involve children newly diagnosed with severe and often
fatal conditions such as malignancies and immunodeficiencies. Another
major area of research in children is the evaluation of newer therapies by
randomised trials. It is questionable whether parents faced with such
situations can be compared with their counterparts in the COPSAC study.
It may be noted that the 'parent' in this study was almost always the
mother. This possibly is based on the premise that it is more difficult to
recruit fathers and that the mother's opinion on research is
representative. However, previous workers have demonstrated the fallacy
associated with both these assumptions.(2) An ideal study trying to
address parental perceptions on research should hence aim to recruit
comparable proportions of both mothers and fathers across a range of
sociocultural backgrounds.
The 'motivation' of mothers as recorded in this study is based on the
cumulative experiences over a couple of years since the start of the
study. Whether this is consistent with actual feelings and true
motivations at the point of inception of the study is not clear. This
assumes obvious importance when applied to parents approached with consent
for a research study soon after the disclosure of a serious and possibly
lethal diagnosis. The emotional trauma inherent in such situations makes
the dynamics of parental participation in the consenting process
significantly different from the simplistic model of COPSAC study.(3)
It is obvious that parental outlooks are affected by a diverse set of
variables and hence cannot be predicted from such a study with limited
sample size confined to mothers who also had suffered from the same
condition. Recent studies have highlighted issues like parental worries
about possible financial tie-ups between physicians and pharmaceutical
companies.(4) It is also worth pointing out that parents have been known
to give consent for studies involving significant potential risks with no
obvious benefit to their children, when placed in a vulnerable
position.(5)
The authors have rightly concluded that it is possible to implement
invasive research studies on children while achieving an accepable level
of parental satisfaction. However, caution must be applied when
extrapolating this conclusion to all types of paediatric research. The
importance of realising the individualistic nature of each research study
and the variety of factors influencing parental opinion cannot be over-
emphasised.
References:
(1) Gammelgaard A, Knudsen LE, Bisgaard H. Perceptions of parents on
the participation of their infants in clinical research. Arch Dis Child
2006; 91 : 977-980.
(2) Woollett A., White DG, Lyon ML. Studies involving fathers:
Subject refusal, attrition and sampling bias. Current Psychological
Reviews 1982; 2 : 193-212.
(3) Deatrick JA, Angst DB, Moore C. Parents' views of their
children's participation in phase I oncology clinical trials. J Pediatr
Oncol Nurs 2002; 19(4) : 114-121.
(4) Hampson LA, Agrawal M, Joffe S, Gross CP, Verter J, Emanuel EJ.
Patients' views on financial conflicts of interest in cancer research
trials. N Engl J Med 2006; 355(22) : 2330-2337.
(5) Singhal N, Oberle K, Burgess E, Huber-Okrainec J. Parents'
perceptions of research with newborns. J Perinatol 2002; 22 : 57-63.
We were interested to read Dixon-Woods et al’s (1) work on patching
and parental factors that affect compliance. A parent recently presented
our eye clinic with her own novel approach to ensuring her five-year-old
son with Langherhans cell histiocytosis X wore his patches (see figure 1).
The child was seen as an outpatient at the local hospital for two years
and had not achieved a visual acuity better...
We were interested to read Dixon-Woods et al’s (1) work on patching
and parental factors that affect compliance. A parent recently presented
our eye clinic with her own novel approach to ensuring her five-year-old
son with Langherhans cell histiocytosis X wore his patches (see figure 1).
The child was seen as an outpatient at the local hospital for two years
and had not achieved a visual acuity better than 6/18 in either eye. He
wore a small prescription of plano/-0.75 in both eyes and had minimal
posterior cortical cataract with a right esotropia of convergence excess
type. Eletrophysiology testing showed that pattern VEPs gave good
responses down to 12-and-a-half-minute check sizes so a regime of
intensive patching for four weeks was prescribed. The visual acuity at
this point was LogMAR 0.58 in the right eye and LogMAR 0.24 on the left.
The patient had never patched before and, as he was required to patch for
10 of the 12 hours he was awake, this method cleverly combined several of
the suggested methods into one. Mother decorated the patch to her son’s
wishes, thus customising it, involving some meticulous artwork in easily
recognisable designs. Once successfully worn, the child then earned the
right to enter it into that day’s patch chart space, thus establishing a
routine “like an advent calendar”. On the days when a patch was not worn,
a gap was left with an explanation given and the alternative used (eg a
plastic shield with the sticky area of the patch cut away from the skin).
Leaving gaps was clearly an incentive to resume the patching as the series
of lively designs filling each box made a handsome wall chart. Where
resistance was encountered mother explained the necessity of the patching
regime. Once established, a cloth patch worn over the glasses made a
successful substitute for the patch, mainly as the child knew this was
much more comfortable: “He knows he’s getting off lightly” said mother.
She again brought an original touch to the cloth eye patch, decorating it
to her son’s taste.
At the end of this four week period, the visual acuity had improved to
LogMAR 0.34 in the right eye and LogMAR 0.26 on the left, this success
providing a further incentive to patch.
Interestingly, ‘anti-normalisation’ was a more successful strategy in this
child, who enjoyed the attention of schoolfriends to his different patches
and now insists on wearing the patch during school hours allowing him to
relax at home. Mother said the patches took her “five minutes” to “whip
up”. I just wanted to make it fun” she says.
This method demonstrated a parent-centred and devised approach to a
difficult problem in which concordance (2) and compliance (3) have
traditionally been difficult. We commend this parent’s imagination and
strategy in not forcing her son to wear the patch on some days, a non-
coercive approach that has been shown to be productive in, for example,
type 1 diabetic children at mealtimes (4).
References:
1. Dixon-Woods M, Awan M, Gottlob I. Why is compliance with occlusion
therapy for amblyopia so hard? A qualitative study. Arch Dis Child
2006;91;491-494.
2. Newsham D. Parental non-concordance with occlusion therapy. Br J
Opthalmol 2000;84:957-962.
3. Searle A, Norman P, Harrad R, Vedhara K. Psychosocial and clinical
determininants of compliance with occlusion therapy for amblyopic
children. Eye 2002;16; 150-155.
4. Patton S, Dolan L, Powers S. Mealtime Interactions relate to dietary
adherence and glycemic control in young children with type 1 Diabetes.
Diabetes Care 29;5;1002-1006.
The paper from Cardiff by Ravi kumara et al and the comprehensive
summary by Beattie is timely and to a great extent serve to remind
professionals who deal with patients with Coeliac disease(CD) of the
current thinking on this subject.
In my experience in caring for patients with gastroenterological ailments
in a DGH, the spectrum of the cases I have been exposed to are clearly
highlighted in these pap...
The paper from Cardiff by Ravi kumara et al and the comprehensive
summary by Beattie is timely and to a great extent serve to remind
professionals who deal with patients with Coeliac disease(CD) of the
current thinking on this subject.
In my experience in caring for patients with gastroenterological ailments
in a DGH, the spectrum of the cases I have been exposed to are clearly
highlighted in these papers.
The patients I have managed, commonly fall into the following groups;-
•Those children who typically fail to thrive after weaning to wheat
containing solids
•The Caucasian or mostly non-Caucasian child who present with
profound anaemia – mostly nutritional (so called). A number of these cases
have been noted with CD.
•The child who presents with growth failure
•The child with conditions usually associated with CD e.g. Down’s,
William’s and Turner syndrome respectively, type 1 diabetes and auto
immune thyroid disease.
•The patient with symptoms and with negative serology but positive
biopsy.
Serology testing is generally available and I still use the Crosby capsule
to obtain Jejunal biopsy. I do however encounter occasional problem with
sedation in a few patients. Those patients referred for endoscopic
duodenal biopsy do have to ‘compete’ for theatre time which is
increasingly proving difficult to secure.
Nice has directed that patients with type 1 diabetes should be screened
every 3 years instead of a yearly program. I am not clear of the evidence
base as I have seen patients on my list who had negative result one year
and becoming positive the next year.
In such cases the 3 year rule would have resulted in some delay with
diagnosis.
There is a place for flexibility and vigilance here.
Is the incidence of CD truly increasing or just an increased awareness and
improved diagnostic methods?
The Archivist’s mention in your journal (2006;91:611) of the recent
success of Human Botulism Immune Globulin (BIG-IV) in the treatment of
infant botulism noted that this orphan drug was available only in the
United States, where it is licensed. BIG-IV demonstrated efficacy by
shortening mean hospital stay by almost one month, from 5.7 weeks to 2.2
weeks. However, your contributor could not have...
The Archivist’s mention in your journal (2006;91:611) of the recent
success of Human Botulism Immune Globulin (BIG-IV) in the treatment of
infant botulism noted that this orphan drug was available only in the
United States, where it is licensed. BIG-IV demonstrated efficacy by
shortening mean hospital stay by almost one month, from 5.7 weeks to 2.2
weeks. However, your contributor could not have known that some months
after publication of the BIG-IV clinical trials (NEJM 2006;354:462-71),
the decision was reached to make BIG-IV available internationally on a
trial basis (to assess the balance of supply and demand). Thus far, four
infant botulism patients in Canada have been treated with BIG-IV.
Physicians who wish to obtain BIG-IV to treat their patients with
suspected infant botulism will need to do so in compliance with their
country’s regulations for importation of locally unlicensed medicines.
Treatment should not be delayed for laboratory confirmation of diagnosis
because hospital stay is shortened significantly only when the medicine is
given within seven days of hospital admission. Obtaining BIG-IV is
arranged through clinical consultation with the on-call physician of the
California Infant Botulism Treatment and Prevention Program by telephoning
510-231-7600 at any time. Email may be sent to ibtpp@infantbotulism.org
but will be read only during normal working hours in California.
Additional information on the medicine and the steps needed to obtain it
may be found at the Program’s website www.infantbotulism.org, which should
be visited before making contact with the Program.
Stephen S. Arnon, M.D.
Infant Botulism Treatment and Prevention Program
California Department of Health Services
Richmond CA 94804
I read with interest the paper from Oxford by Craze et al(1) and
agree with the general gist of the subject.
As a paediatrician with interest in medical student education, I
facilitate the teaching of paediatrics to the students posted to my DGH
for the 6-8weeks scheduled for paediatrics and have examined on the
subject. The observations in the paper from Oxford clearly reflects my
experience.
Over the...
I read with interest the paper from Oxford by Craze et al(1) and
agree with the general gist of the subject.
As a paediatrician with interest in medical student education, I
facilitate the teaching of paediatrics to the students posted to my DGH
for the 6-8weeks scheduled for paediatrics and have examined on the
subject. The observations in the paper from Oxford clearly reflects my
experience.
Over the years I have exposed students to this subject by using the
following approach
~ Introductory notes and videos on how to examine children
~ Practical bedside teaching on systems examination
~ Practical sessions while attached to SHOs
~ Daily attendance at Consultant ward rounds (Hot week)
~ Teaching on consent issues and competence emphasized
~ evaluation usually carried out to encourage confidence.
At the beginning of the posting,most students find this task daunting
but later could accommodate this. Paediatric patients are spread over
clinical set ups be it community or hospital and so an 'encounter' is
almost inevitable.
This paper from Oxford will help to stress the importance of this subject
and process in medical student training.I will be refering my students to
this piece of information -very timely.
Reference:
1)J Craze T Hope; Teaching medical students to examine children;ADC 2006;
91; 966-968;doi;10.1136/adc.2005.092502.
Dear Editor,
We read with interest the article by C S Zipitis, G A Markides and I L Swann regarding the cost of prevention and treatment of vitamin D deficiency [1]. We agree with the proposal that local authorities should provide funds to supplement vitamin D in ‘at risk’ ethnic minority groups.
Similar to Burnley, Oldham has a large Asian community of 20.8%. Between December 2002 and March 2004, we i...
Dear Editor,
The letter from Eisenhut (1) questions the benefits of intravenous rehydration of children with gastroenteritis with Normal Saline because of the possibility of hyperchloraemic acidosis and suggests that Ringers Lactate (RL) or an equivalent solution might offer advantages over Normal Saline (NS).
Our study of 102 children with gastroenteritis judged to need intravenous fluids, compared p...
Dear Editor,
The need to promote and support breastfeeding is unquestionable. There is strong evidence that exclusive and prolonged breastfeeding has multiple health benefits for mothers and their infants. American Academy of Pediatrics (AAP) and World Health Organization (WHO) recommend exclusive breastfeeding for the first 6 months of life. Both the AAP and American College of Obstetricians and Gynecologists (ACO...
Dear Editor,
In rats "impaired microcirculatory alteration in septic shock is more severe than hemorrhagic shock" (1). Endotoxin [which is used to induce septic shock in animal models and when translocating from the gut is thought to contribute to the development of septic shock in the critically ill] increases serum lactate by "inactivation of pyruvate dehydrogenase (PDH), unrelated to changes in tissue PO2" (2)...
Dear Editor,
In rats "impaired microcirculatory alteration in septic shock is more severe than hemorrhagic shock" (1). Endotoxin [which is used to induce septic shock in animal models and when translocating from the gut is thought to contribute to the development of septic shock in the critically ill] increases serum lactate by "inactivation of pyruvate dehydrogenase (PDH), unrelated to changes in tissue PO2" (2)...
Dear Editor,
Gammelgaard et al have to be commended for their study which attempts to throw light on some of the complex issues, ethical and otherwise, surrounding parental attitudes towards research in children.(1) While agreeing broadly with the authors' conclusions regarding the feasibility of setting up a research project which conforms to parental perceptions, we would like to stress the need for viewing this i...
Dear Editor,
We were interested to read Dixon-Woods et al’s (1) work on patching and parental factors that affect compliance. A parent recently presented our eye clinic with her own novel approach to ensuring her five-year-old son with Langherhans cell histiocytosis X wore his patches (see figure 1). The child was seen as an outpatient at the local hospital for two years and had not achieved a visual acuity better...
Dear Editor,
The paper from Cardiff by Ravi kumara et al and the comprehensive summary by Beattie is timely and to a great extent serve to remind professionals who deal with patients with Coeliac disease(CD) of the current thinking on this subject. In my experience in caring for patients with gastroenterological ailments in a DGH, the spectrum of the cases I have been exposed to are clearly highlighted in these pap...
Dear Editor,
The Archivist’s mention in your journal (2006;91:611) of the recent success of Human Botulism Immune Globulin (BIG-IV) in the treatment of infant botulism noted that this orphan drug was available only in the United States, where it is licensed. BIG-IV demonstrated efficacy by shortening mean hospital stay by almost one month, from 5.7 weeks to 2.2 weeks. However, your contributor could not have...
Dear Editor,
I read with interest the paper from Oxford by Craze et al(1) and agree with the general gist of the subject. As a paediatrician with interest in medical student education, I facilitate the teaching of paediatrics to the students posted to my DGH for the 6-8weeks scheduled for paediatrics and have examined on the subject. The observations in the paper from Oxford clearly reflects my experience. Over the...
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