Showing papers by "Hospital for Sick Children published in 1996"

Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM.

Abstract: We investigated the response of the glucose transport system to insulin, in the presence of ambient glucose concentrations, in isolated skeletal muscle from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) (age, 55±3 years, BMI 27.4±1.8 kg/m2) and seven healthy control subjects (age, 54±3 years, BMI 26.5±1.1 kg/m2). Insulin-mediated whole body glucose utilization was similar between the groups when studied in the presence of ambient glucose concentrations (approximately 10 mmol/l for the NIDDM patients and 5 mmol/l for the control subjects). Samples were obtained from the vastus lateralis muscle, by means of an open muscle biopsy procedure, before and after a 40-min insulin infusion. An increase in serum insulin levels from 54±12 to 588±42 pmol/l, induced a 1.6±0.2-fold increase in glucose transporter protein (GLUT4) in skeletal muscle plasma membranes obtained from the control subjects (p<0.05), whereas no significant increase was noted in plasma membrane fractions prepared from NIDDM muscles, despite a similar increase in serum insulin levels. At concentrations of 5 mmol/l 3-O-methylglucose in vitro, insulin (600 pmol/l) induced a 2.2-fold (p<0.05) increase in glucose transport in NIDDM muscles and a 3.4-fold (p<0.001) increase in the control muscles. Insulin-stimulated 3-O-methylglucose transport was positively correlated with whole body insulin-mediated glucose uptake in all participants (r=0.78,p<0.001) and negatively correlated with fasting plasma glucose levels in the NIDDM subjects (r=0.93,p<0.001). Muscle fibre type distribution and capillarization were similar between the groups. Our results suggest that insulin-stimulated glucose transport in skeletal muscle from patients with NIDDM is down-regulated in the presence of hyperglycaemia. The increased flux of glucose as a consequence of hyperglycaemia may result in resistance to any further insulin-induced gain of GLUT4 at the level of the plasma membrane.

The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations.

Abstract: Human dysplastic kidneys are developmental aberrations which are responsible for many of the very young children with chronic renal failure. They contain poorly differentiated metanephric cells in addition to metaplastic elements. We recently demonstrated that apoptosis was prominent in undifferentiated cells around dysplastic tubules (Winyard, P.J.D., J. Nauta, D.S. Lirenman, P. Hardman, V.R. Sams, R.A. Risdon, and A.S. Woolf. 1996. Kidney Int. 49:135-146), perhaps explaining the tendency of some of these organs to regress. In contrast, apoptosis was rare in dysplastic epithelia which are thought to be ureteric bud malformations. On occasion, these tubules form cysts which distend the abdominal cavity (the multicystic dysplastic kidney) and dysplastic kidneys may rarely become malignant. We now demonstrate that dysplastic tubules maintain a high rate of proliferation postnatally and that PAX2, a potentially oncogenic transcription factor, is expressed in these epithelia. In contrast, both cell proliferation and PAX2 are downregulated during normal maturation of human collecting ducts. We demonstrate that BCL2, a protein which prevents apoptosis in renal mesenchymal to epithelia] conversion, is expressed ectopically in dysplastic kidney epithelia. We propose that dysplastic cyst formation may be understood in terms of aberrant temporal and spatial expression of master genes which are tightly regulated in the normal program of human nephrogenesis.

Long-term therapy with deferiprone.

Abstract: Data from several trials have provided direct and supportive evidence for the efficacy of deferiprone in the treatment of iron overload in thalassemia major. Deferiprone has been shown to induce sustained decreases in body iron to concentrations associated with survival free from the complications of iron overload in deferoxamine (DFO)-treated patients. Despite this evidence of efficacy, the risk of agranulocytosis mandates a careful evaluation in patients willing and able to use DFO. The incidence of agranulocytosis associated with deferiprone is under study in a prospective multicenter trial in Canada, Italy and the United States, under corporate sponsorship (Apotex Research, Canada). The results of this study should determine the risk associated with the use of this agent, and may provide the data required for an FDA decision regarding licensing of this agent for the treatment of iron overload, a goal supported by investigators worldwide.

Thyroid Hormone and Attention in School‐Age Children with Congenital Hypothyroidism

Abstract: The relationship between attention and thyroid hormone was examined using a retrospective database of 85 7-year-old children with congenital hypothyroidism who received psychological evaluations and thyroid function tests on the same day. Four unique subgroups with different levels of thyroxine and thyrotropin were compared on psychological tasks and measures of attention. Children with high levels of both hormones were found to be significantly more distractable on an index of cognitive attention but were reportedly less hyperactive. Level of thyroxine accounted for over 10% of the variance in attention.

Blunt cardiac injuries in children: a postmortem study.

Abstract: We reviewed the records of the Chief Coroner for all pediatric (<16 years of age) trauma fatalities in Ontario (pediatric population of 2 million) for the period January 1, 1988 through December 31, 1990. Forty-one (14.5%) of 282 patients for which complete autopsy data were available had sustained cardiac injuries. Nineteen patients (46%) died at the scene of the accident, 15 patients (37%) died in an emergency department, and seven patients (17%) died during hospitalization. Rupture of a cardiac chamber occurred in 16 cases ; it was the main cause of death in eight cases and a contributing factor in the remainder. Cardiac contusion without chamber rupture was present in 25 cases, but in none of the cases was it the cause of death. Brain injury was the cause of death in 16 (64%) of the cases of cardiac contusion. Cardiac injuries are more common among children who die from blunt trauma than previous reports have suggested. However, because these injuries are often rapidly fatal, many patients die before they reach a hospital. With improvements in emergency medical services and the resulting reduction in transit time, more patients may reach trauma centers alive. A high index of suspicion and rapid diagnosis and treatment of these injuries can save the lives of some of these patients.

Pediatric renal transplantation into the abnormal urinary tract.

Abstract: Many children with end-stage renal disease have significant urinary tract problems other than irreversible loss of native kidney function. These significant other urinary tract problems if not corrected prior to transplantation, may significantly increase recipient mortality, graft loss, and patient morbidity. These other urinary tract problems may cause hydroureteronephrosis in the transplanted kidney, lead to an increased incidence of graft rejection, be the source of sepsis after subsequent immunosuppression, and cause hypertension. In addition, pre-existing urinary diversion, large interabdominal masses, or previous cancer require specific pre-transplant management plans. Potential pediatric transplant recipients with other significant urinary tract problems can be classified according to three parameters: anatomical extent, pathology, and pathophysiology of the significant other problems. Particular attention must be paid to pre-existing lower tract problems. Strategy must be worked out pre transplant as to how the lower urinary tract is going to store, hold, and empty urine. The means for assessing the potential recipients and strategies and techniques for correcting pre-existing problems have been summarized in this article.

Modern electronic and chemical thermometers used in the axilla are inaccurate

Abstract: Rectal and axillary temperatures were measured simultaneously in 83 children using three different thermometer devices providing 166 pairs of results. In the first series consisting of 22 febrile children (44 measurements) and 20 afebrile children (40 measurements), the rectal mercury measurement was compared to an axillary mercury and axillary Tempa-DOT thermometer. The axillary mercury had sensitivity of 14/22 (64%) and specificity of 20/20 (100%) while the Tempa-DOT had sensitivity of 15/22 (68%) and specificity of 19/20 (95%). In the second series comprising 21 febrile children (42 measurements) and 20 afebrile children (40 measurements) the axillary mercury had sensitivity of 11/21 (52%) and specificity of 20/20 (100%) while the electronic thermometer had sensitivity of 10/21 (48%) and specificity of 20/20 (100%). Regardless of the thermometer used, the axilla is a poor alternative to rectal measurements in the diagnosis of fever. Mercury-free thermometers, when used in the axilla are as poor alternatives to reetal measurements as mercury-in-glass thermometers.

A Piglet Model for Neonatal Amino Acid Metabolism During Total Parenteral Nutrition

Abstract: Premature birth is a leading cause of infant morbidity and mortality. An important factor in the care of these neonates is the establishment of appropriate nutritional strategies. Low birth weight (LBW) infants often have an inability to tolerate oral feedings, due to a variety of factors, including short bowel syndrome, gastrointestinal surgery, chronic severe diarrhea, immature bowel function1 and respiratory diseases.2 In these instances, the provision of nutrition by parenteral means is necessary. Total parenteral nutrition (TPN) involves the infusion of amino acids, glucose, lipid, vitamins and minerals directly into the venous circulation. As with all neonatal nutrition regimens, the aim in providing TPN to LBW infants is to promote the growth of the infant, without imposing undue stresses on metabolic pathways or creating adverse long term outcomes.

Nutrition and reproductive outcome in maternal phenylketonuria

Abstract: Maternal weight gain and intake of selected nutrients were correlated with plasma phenylalanine (Phe) concentrations and reproductive outcomes (in 150 and 142 subjects respectively) in the Maternal PKU Collaborative Study. Daily protein intake was negatively correlated with plasma Phe concentration. Birth length, weight and head circumference of offspring were negatively influenced by the length of time required for the maternal plasma Phe to decline below 600 mumol/l (10 mg/dl) and positively influenced by weight gain of mother as a percentage of recommended weight gain. Birth weight and length were positively correlated with maternal protein and energy intakes. During the first trimester, intakes of fat, calcium, phosphorus, vitamin A and folate were significantly greater in women who had a good reproductive outcome than by women who had a poor outcome. In addition to plasma Phe control in maternal phenylketonuria (PKU), maternal weight gain and dietary intake of protein, energy and fat were correlated with outcome. Therefore, nutrient intake and maternal weight gain should be considered along with plasma Phe concentration when managing the therapy of a pregnant woman with PKU.

Clinical and Economic Factors in the Treatment of Onychomycosis

Abstract: Onychomycosis is a fungal infection of fingernails and toenails. most cases of which are caused by dermatophytes. The disease accounts for l5% of all nail disease. and affects approximately 2 to 3% of people of all ages and both sexes. Topical treatment with tioconazole. amorolfine or ciclopirox has limited effectiveness. Oral griseofulvin 500 to 1000mg daily has been the mainstay of treatment. but prolonged therapy is required and success rates are low. Therapy with itraconazole 200mg daily for 3 to 6 months is more effective (70 to 85% success), although so—called ‘pulse’ therapy has shown similar success with potentially fewer adverse effects. Terbinafine 250mg daily produces clinical and mycological cure in approximately 80% of patients treated for 6 and 12 weeks for fingernail and toenail infections, respectively. The overall costs of treating onychomycosis are substantial, and it has been estimated that direct costs for Medicare patients with the disease were $US43 million in 1 year. In addition, the disease has a negative impact on quality of life, in the domains of mental functioning, health concern, social functioning and physical appearance. Few pharmacoeconomic analyses have been published, but all have indicated an advantage of oral terbinafine over griseofulvin and other oral agents. To date, no economic studies have been performed on topical agents. pulse therapy or combination treatments.

The International Collaborative Study on maternal phenylketonuria: organization, study design and description of the sample.

Abstract: The International Maternal Phenylketonuria (PKU) Collaborative Study commenced in 1984 to evaluate the efficacy of the low-phenylalanine diet in reducing the morbidity associated with maternal PKU syndrome. Four hundred and sixty eight (468) pregnancies resulted in 331 live births, 3 stillbirths, 61 spontaneous abortions, 2 ectopic pregnancies and 71 elective terminations. Since its inception, the study has steadily progressed toward its goal of diet initiation preconception or early in pregnancy. By 1994, 51% of the sample began the diet preconceptionally, with an additional 41% doing so by 8 weeks gestation. The number of adolescent pregnancies has decreased from 31% to 9%, college attendance has increased from 5% to 16%, number of women in the lowest socioeconomic classes has decreased from 95% to 59% and average IQ has increased from 78 to 88. The organization of the network of 130 referral centers and clinics within the U.S.A., Canada and Germany and the objectives of the scientific research investigation have served to provide a derived benefit of outreach, education, reproductive counseling and early diet intervention in a large cohort of PKU women.

Initial experience with one-stage endorectal pull-through procedures for Hirschsprung's disease

Abstract: To evaluate our experience with one-stage endorectal pull-through (ERPT) procedures (without colostomy) for Hirschsprung's disease (HD), we compared 7 such patients to a cohrt of 20 consecutive patients undergoing EROT folowing colostomy. Reasons for exclusion from hte cohort group included: (1) bowel obstruction requiring operation before 1 month of age; (2) presentation with enterocolitis (EC), intestinal perforation, or massive fecal distension; (3) long-segment disease; or (4) severe associated anomalies. The 7 male patients in the single-stage ERPT group first presented at a median age of 16 days (4 days–2.5 years) and were managed by regular digital dilation or colonic irrigation for between 1 and 6 months (median 2 months) prior to surgery. Single-stage procedures were performed at a median age and weight of 4 months (2 months–2.5 years) and 6.4 kg (4.5–13.8 kg), respectively Median hospitalization for these patients was 9 dyas. Postoperative complications occurred in 2 patients (29%), and included anastomotic stricture requiring outpatient dilation, and 1 case or recurrent EC that responded to a course of anal dilations. The cohort group (14 M, 6 F) presented at a median of 15 months. All underwent colostomy as a primary procedure. ERPT was deferred until a median age of 21 months, and the hospitalization after pull-through averaged 10 dyas (20 days including stay after colostomy). Four patient (20%) developed complications requiring reoperation following the initial colostomy. Complications after ERPT occurred in 5 patients (25%) and included 1 death from fulminant Hirschsprung's EC. Other complications included 1 anastomotic stricture and 2 mucosal prolapses requiring anoplasty. Long-term functional results were similar in both groups. Despit our limited experience, we conclude that one-stage ERPT can be safely performed in infants, including those under 3 months of age, with rectosigmoid HD. Total duration of hospitalization is reduced and colostomy complications are avoided. Functional outcome appears to be comparable between patients treated in one or two stages.

Outcome implications of the International Maternal Phenylketonuria Collaborative Study (MPKUCS): 1994.

Abstract: It is well established that women with phenylketonuria who remain untreated during pregnancy face serious problems in offspring outcome. Surveys have documented that maternal phenylalanine (Phe) blood concentrations above 1200 mumol/l are associated with microcephaly, congenital heart disease and intrauterine growth retardation among their offspring. To investigate the efficacy of the Phe restricted diet, the National Institute of Child Health and Human Development in Bethesda Maryland developed an international study to evaluate fetal outcome in pregnancies treated with the Phe restricted diet. The study involves over 100 metabolic clinics in the United States, Canada and Germany, and is now in its 10th year. The results included in this report are still preliminary in nature and the actual risk for such pregnancies remains to be determined.

Renal Replacement Therapy in Children

Abstract: Successful management of acute renal failure (ARF) in children, particularly infants, requires knowledge of the functional characteristics of the kidney during development and understanding of the metabolic balance of the growing child. The newborn kidney is immature containing only 17% of its adult cellular complement; at 6 months postnatally cell division is complete and further growth is due to an increase in cell size. Nephron formation is complete before birth but superficial cortical nephrons are not functionally mature; at birth the more mature juxtamedullary nephrons contribute a greater proportion of total glomerular filtration than in the adult. There is a proportional increase in juxtamedullary blood flow but total renal blood flow is low because of the high renal vascular resistance. Glomerular filtration rate (GFR) at birth averages about 20 ml/min/1.73 m2 body surface area but the rapid postnatal increase in renal blood flow is associated with a rapid rise in GFR to 48 ml/min/1.73 m2 at one month and to 80 ml/min/1.73 m2 by 6 months of age (1).

Congenital intrathoracic stomach.

Abstract: This paper reviews the presentation and management for congenital intrathoracic stomach (CIS). The features that distinguish CIS from congenital short oesophagus and acquired oesophageal shortening are emphasised. The study is based on a retrospective review of six patients treated between 1988 and 1994. The four youngest presented with vomiting and the older two with respiratory symptoms. Chest radiographs were abnormal in every case, although the precise diagnosis was confirmed by barium meal. All cases were repaired through an abdominal approach; in each case the oesophagus was of sufficient length to allow the stomach to lie below the diaphragm. CIS is an uncommon condition. The most frequent cause is a large hiatus hernia, and the transabdominal route is the most satisfactory approach for operative repair.

The pharmacokinetics and pharmacodynamics of the oral iron chelator deferiprone (L1) in relation to hemoglobin levels.

Abstract: Recently, we demonstrated that administration of the orally active iron chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron excretion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of whom had received a packed red cell transfusion of 15 cc/kg. 72 hours prior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical practice however, thalassemia patients, suppression of endogenous erythropoiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to transfusion. We hypothesized that hemoglobin levels will affect the ability of deferiprone to chelate iron. Ten regularly transfused patients with homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, were treated with deferiprone 75 mg/kg/day, administered every 6 hours (or every 12 hours) for 72 hours immediately prior to a blood transfusion in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion. The deferiprone-induced 24-hour urinary iron excretion was similar during both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given every 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 hours (p = 0.79). However, the calculated 24-hour area under the plasma concentration-time curve (AUC0-24) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 +/- 1,601.6 mg*min/l), than that observed when deferiprone was administered every 12 hours (8,250.1 +/- 1,235.7 mg*min/l) (p = 0.04). The pharmacokinetics of deferiprone when administered immediately prior to transfusions are different from those following transfusions. More studies assessing total body iron excretion are needed to determine the contribution of the fecal route in iron excretion.

Evidence of Nonverbal Learning Disability among Learning Disabled Boys with Sensory Integrative Dysfunction

Abstract: The presumed sensorimotor basis of the nonverbal learning disability syndrome was investigated among 90 learning disabled boys (M age = 6 yr., 8 mo., SD = 12.2 mo.) with sensory integrative dysfunction. The majority of the boys were Caucasian, lower to middle socioeconomic status, and from urban, English-speaking families. 14% (n = 13) of the boys satisfied core discrepancy criteria for nonverbal learning disability, including both a significantly higher Wechsler Verbal than Performance IQ and a higher standard score in Reading than Arithmetic on the Wide Range Achievement Test. Compared with a control group of 19 boys from the same sample who had no significant discrepancies, boys with nonverbal learning disability had significantly greater weaknesses in space visualization and visuomotor coordination. As predicted, rote verbal memory and syntactical strengths were also exhibited by boys with nonverbal learning disability, but the two groups did not differ significantly.

Interaction of heparin with synthetic peptides corresponding to the C-terminal domain of intestinal mucins

Abstract: Unlike most other mucins described to date, two intestinal mucins, rat MLP (rat Muc 2) and human MUC2 have a C-terminal tail that is enriched in cationic amino acids. The distribution of charge in each case resembles that of several well known heparin binding proteins. Peptides designated E20-14 and F13-15, corresponding to the C-terminal 14 amino acids of the two mucins, were synthesized and shown to bind 3 H-labelled heparin by a process that was saturable and mediated by strong electrostatic interactions, giving Kd values of 10 (-7) to 10 (-8) M. Using turbidometric analyses and native gel electrophoresis, we observed that peptide-heparin mixtures formed polydisperse aggregates that dissociated with a progressive increase in the concentration of heparin. Under certain conditions heparin protected the peptide from proteolysis by trypsin. Both heparin and dextran sulfate, the latter a highly sulfated synthetic polysaccharide, were potent inhibitors of 3 H-heparin binding to peptide E20-14, while less sulfated glycosaminoglycans were poorly- or non-inhibitory. Mucin in tissue dispersions and homogenates, or purified from rat intestine, did not bind to heparin, and failed to interact with an antibody specific for the peptide E20-14. Both mucin samples however, reacted with antibodies that recognize regions upstream of the C-terminal 14 amino acids. Immunofluorescent localization of E20-14 was confined to the basal perinuclear regions of goblet cells, whereas localization of an antibody to a flanking sequence on the N-terminal side of the C-tail, localized to mature mucin storage granules. These findings suggest that the heparin -binding C-tail of the mucin may be removed at an early stage of biosynthesis. Heparin-mucin complexes, if they form in vivo, are thus likely to be confined to the ER and/or Golgi compartments.

A novel family of repeat sequences in the mouse genome responsive to retinoic acid

Abstract: Repetitive DNA sequences form a substantial portion of eukaryotic genomes and exist as members of families that differ in copy number, length, and sequence. Various functions, including chromosomal integrity, gene regulation, and gene rearrangement have been ascribed to repetitive DNA. Although there is evidence that some repetitive sequences may participate in gene regulation, little is known about how their own expression may be regulated. During the course of gene trapping experiments with embryonic stem (ES) cells, we identified a novel class of expressed repetitive sequences in the mouse, using 5′ rapid amplification of cDNA ends-polymerase chain reaction (5′ RACE-PCR) to clone fusion transcripts from these lines. The expression of these repeats was induced by retinoic acid (RA) in cultured ES cells examined by Northern blot analyses. In vivo, their expression was spatially restricted in embryos and in the adult brain as determined by RNA in situ hybridization. We designated this family of sequences as Dr (developmentally regulated) repeats. The members of the Dr family, identified by cDNA cloning and through database search, are highly similar in sequence and show peculiar structural features. Our results suggest the expression of Dr-containing transcripts may be part of an ES cell differentiation program triggered by RA. The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession numbers U51725 (Dr-1), U51726 (Dr-2), and U51727 (Dr-3).

Familial neonatal atrial tachycardia.

Abstract: A father and his two sons each presented with atrial tachycardia in the newborn period. The father went on to develop dilated cardiomyopathy. The first son (who also had transposition of the great arteries) died from the arrhythmia after surgery. The second son is currently successfully managed pharmacologically.

Developmental monitoring in primary care.

Abstract: Monitoring child development is an essential part of primary health care. Successful surveillance depends on physicians' thorough knowledge of normal progress along the four developmental streams: motor, language, cognitive, and social and emotional. Being alert to "red flags" that suggest problems is important. Effective interventions can minimize developmental problems.