ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents.

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral oedema; only a minority of deaths in DKA are attributed to other causes. Cerebral oedema occurs in about 0.3-1% of all episodes of DKA, and its aetiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral oedema, and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.

Effect of feeding supplemental fibrolytic enzymes or soluble sugars with malic acid on milk production.

Two trials were conducted to evaluate effects of feeding supplemental fibrolytic enzymes or soluble sugars and malic acid on milk production. In trial 1, 257 cows at four sites were fed a basal diet consisting of no more than 60% of forage DM as corn silage and less than 40% as alfalfa hay. Cows were assigned randomly within site, parity, and two stages of lactation to: 1) control; 2) enzyme A; 3) enzyme B; and 4) soluble sugars and malic acid. There was a 14-d pretreatment and an 84-d treatment period. Enzyme solutions were sprayed on either the forage component or the TMR each day while mixing feed. Trial 2 was similar, except 122 cows at one site in the United Kingdom were fed diets containing forage that was 75% corn silage and 25% grass silage, and all cows began the study between 25 to 31 DIM. Mean milk productions for 233 cows that completed trial 1 were 32.9, 32.5, 32.4, and 32.9 kg/d for control, enzyme A, enzyme B, and soluble sugars and malic acid, respectively. Mean milk productions for 116 cows that completed trial 2 were 28.2, 27.9, 28.8, and 28.4 kg/d, respectively. In vitro analyses of the activities of enzyme solutions indicated that all major cellulose and hemicellulose degrading activities were present; however, the pH optima (approximate pH = 4 to 5) were more acidic, and the temperature optimum (approximately 50 degrees C) was greater than normal pH and temperature in the rumen. If fibrolytic activity in the rumen is a major mechanism of action of supplemental fibrolytic enzymes, it appears that considerable activity of these preparations was lost due to conditions in the rumen. In conclusion, feeding supplemental fibrolytic enzymes or malic acid with soluble sugars had no effect on milk production under the conditions used in this study.

Recommendations for the diagnosis and management of Turner syndrome.

Comprehensive recommendations on the diagnosis of Turner syndrome (TS) and the care of affected individuals were published in 1994. In the light of recent advances in diagnosis and treatment of TS, an international multidisciplinary workshop was convened in March 2000, in Naples, Italy, in conjunction with the Fifth International Symposium on Turner Syndrome to update these recommendations. The present paper details the outcome from this workshop. The genetics and diagnosis of the syndrome are described, and practical treatment guidelines are presented.

Effects of sustained release bovine somatotropin (sometribove) on animal health in commercial dairy herds.

The health of dairy cows given bovine somatotropin (bST) for one lactation was evaluated in 28 commercial herds located in four regions of the United States. At least six herds were in a region and at least one herd/region contained fewer than 60 cows. Cows (n = 1213) were assigned randomly to control or bST groups and were treated beginning in wk 9 to 10 of lactation and every 14 d until dry-off or d 400 of lactation. Management was according to site practices. Cows were observed for health-related signs by farm personnel daily and by the herd veterinarian biweekly. Average 305-d test-day milk yields were 932 kg greater for bST-treated cows. Pregnancy rates, days open, twinning, cystic ovaries, or abortions were unaffected by treatments. Supplementation of cows with bST had no effect on total mastitis cases, total days of mastitis, duration of mastitis, or the odds ratio of a cow to develop mastitis. Cows supplemented with bST used more medications for health events other than mastitis. This usage was associated primarily with treatments for disorders of the foot and hock. Supplemented cows had a slight increase in foot disorders. There was no effect of supplementation with bST on culling from the herd or removal from study. Overall, the results confirm that label directions for bST are adequate for safe use under field conditions. All clinical signs observed in this study occur normally in dairy herds and were managed in cows supplemented with bST.

Final height prediction in constitutional growth delay.

Methods to predict the final stature of children are commonly used in pediatric endocrinology since one of the questions that parents have about their short children is how tall he or she will be as an adult. There is a disparity between what the family wants and what the physician expects from a height prediction, and what is available. The family wants an accurate prediction of final height for their child. What the physician expects is a well-validated and accurate technique applicable to individual children and that can be trusted for use, not just with normally growing children, but also with children exhibiting abnormal growth. Unfortunately, what is available from the generally used height prediction methods are estimates, with fairly broad error limits, based on groups of normal children followed to adult height. The underlying problem in predicting final height is that there is considerable individual variation in the timing and tempo of puberty and the pubertal growth spurt in individual children which significantly impacts the validity of the techniques when applied to individual children. This article reviews the methods of height prediction that are available, and their limitations.

Diabetes mellitus and profound insulin resistance in Johanson-Blizzard syndrome.

Pancreatic exocrine insufficiency in Johanson-Blizzard syndrome (JBS) is well described but only two previous patient reports document pancreatic endocrine insufficiency manifested as diabetes mellitus, and each patient required only a modest dose of insulin to control hyperglycemia. We report a patient with JBS and new-onset diabetes mellitus with profound insulin resistance, with no clinical or laboratory evidence of pancreatic exocrine insufficiency.

Growth hormone use in pediatric growth hormone deficiency and other pediatric growth disorders.

The diagnosis and management of growth disorders in children, particularly disorders that respond to therapy with growth hormone (GH), raise challenging clinical and economic issues. Several such issues are presented in the following article in which Dr. Ron Rosenfeld examines the evaluation and diagnosis of the child with short stature; Dr. David B. Allen discusses the anabolic and metabolic indications for GH treatment in children; Dr. Margaret H. MacGillivray reviews GH dosing, height outcomes, and follow up; and Dr. Craig Alter presents the payer's perspective on the diagnosis and treatment of pediatric GH deficiency. In addressing the use of GH in other pediatric populations, Dr. Paul Saenger focuses on Turner syndrome, Dr. Henry Anhalt on chronic renal insufficiency of childhood, and Dr. Ray Hintz on idiopathic short stature. Dr. Harvey P. Katz presents one managed care organization's policy and implementation plan that is used to guide decisions regarding coverage for GH treatment.

Effects of red blood cell transfusion on resting energy expenditure in adolescents with sickle cell anemia.

BACKGROUND: Previous studies indicate that resting energy expenditure is elevated in children with sickle cell anemia, possibly caused in part by hemolysis and increased erythropoietic activity. The purpose of the present investigation was to determine whether erythrocyte transfusion normalizes resting energy expenditure in sickle cell anemia. METHODS: Five adolescents with sickle cell anemia (12-16 years old; 4 boys, 1 girl) were studied before and 1 week after erythrocyte transfusion before elective surgery or at the initial transfusion for growth failure. Resting energy expenditure was measured by indirect calorimetry, and laboratory measures were determined by routine, validated methods. Data comparisons were by nonparametric analysis. RESULTS: After erythrocyte transfusion, total hemoglobin levels increased (difference (D) = 15 g/l; p < 0.05), whereas hemoglobin S (D = -0.36; p < 0.05) and reticulocyte count (D = -0.12; p < 0.05) decreased. Mean pretransfusion resting energy expenditure was elevated to 124% above predicted levels (p < 0.05) and increased further to 134% above prediction (p < 0.05 vs. pretransfusion levels). Plasma triiodothyronine (T3) levels increased (D = 0.17 nmol/l; p < 0.05), reverse T3 (rT3) levels tended to decline (D = -0.04 nmol/l; p = 0.14), and rT3/T3 decreased (D = -0.03; p < 0.05). Plasma insulin-like growth factor-I (IGF-I) levels were low-normal before transfusion and did not change, despite the change in resting energy expenditure. CONCLUSIONS: The results confirm that resting energy expenditure is elevated in patients with sickle cell anemia. However, resting energy expenditure further increased after transfusion, despite decreased erythropoietic activity. A posttransfusion decrease in rT3/T3 may contribute to the increased resting energy expenditure. That there was no change in IGF-I implies that the growth hormone-IGF system is not involved in posttransfusion regulation of resting energy expenditure. Therefore, our data are not consistent with the hypothesis that increased resting energy expenditure in sickle cell anemia is directly related to erythropoietic activity. The mechanisms by which resting energy expenditure increases after transfusion in sickle cell anemia require additional investigation.

Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure.

BACKGROUND: Patients with acute renal failure (ARF) have high morbidity and mortality rates, particularly if they have serious comorbid conditions. Several studies indicate that in rats with ARF caused by ischemia or certain nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal function and suppresses protein catabolism. METHODS: Our objective was to determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance the recovery of renal function and is safe in patients with ARF. The study was designed as a randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals. Seventy-two patients with ARF were randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of patients). At baseline, the mean (+/- SD) APACHE II scores in the rhIGF-I and placebo-treated groups were 24 +/- 5 and 25 +/- 8, respectively. In the rhIGF-I and placebo groups, the mean (median) urine volume and urinary iothalamate clearances (glomerular filtration rate) were 1116 +/- 1037 (887) and 1402 +/- 1183 (1430) ml/24 hr and 6.4 +/- 5.9 (4.3) and 8.7 +/- 7.2 (4.4) ml/min and did not differ between the two groups. Patients were injected subcutaneously every 12 hours with rhIGF-I, 100 microgram/kg desirable body weight, or placebo for up to 14 days. Injections were started within six days of the onset of ARF. The primary end-point was a change in glomerular filtration rate from baseline. Other end points included changes from baseline in urine volume, creatinine clearance and serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or ultrafiltration, and mortality rate. RESULTS: During the treatment period, which averaged 10.7 +/- 4.1 and 10.6 +/- 4.5 days in the rhIGF-I and placebo groups, there were no differences in the changes from baseline values of the glomerular filtration rate, creatinine clearance, daily urine volume, or serum urea nitrogen, creatinine, albumin or transferrin. In patients who did not receive renal replacement therapy, there was also no significant difference in serum creatinine and urea between the two groups. Twenty patients in the rhIGF-I group and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve rhIGF-I-treated patients and 12 placebo-treated patients died during the 28 days after the onset of treatment. CONCLUSIONS: rhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity.

Final height of growth hormone-treated patients with growth hormone deficiency: the North American experience.

The results of treatment of growth hormone (GH)-deficient patients with recombinant GH are better than the results of treatment with pituitary GH. The reasons for this improvement include higher dosages, more consistent treatment, and daily administration. Under ideal circumstances, final height in patients with GH deficiency (GHD) can be within the normal range for adult height with GH treatment, and brought close to their target height. To achieve this result, it is important to diagnose and treat GHD early, use adequate doses of GH, and continue treatment until final height.

Mechanical maceration of alfalfa.

Maceration is an intensive forage-conditioning process that can increase field drying rates by as much as 300%. Because maceration shreds the forage and reduces its rigidity, improvements in bulk density, silage compaction, and ensiling characteristics have been observed. Macerating forage also increases the surface area available for microbial attachment in the rumen, thereby increasing forage digestibility and animal performance. Feeding trials with sheep have shown increases in DMI of 5 to 31% and increases in DM digestibility of from 14 to 16 percentage units. Lactation studies have demonstrated increases in milk production and BW gain for lactating Holstein cows; however, there is a consistent decrease in milk fat percentage when dairy cattle are fed macerated forage. In vitro studies have shown that maceration decreases lag time associated with NDF digestion and increases rate of NDF digestion. In situ digestibility studies have shown that maceration increases the size of the instantly soluble DM pool and decreases lag time associated with NDF digestion, but it may not consistently alter the rate or extent of DM and NDF digestion.

Effect of growth hormone treatment on adult height of children with idiopathic short stature. Genentech Collaborative Group.

BACKGROUND: Short-term administration of growth hormone to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height. However, the effect of long-term growth hormone therapy on adult height in these children is unknown. METHODS: We studied 121 children with idiopathic short stature, all of whom had an initial height below the third percentile, low growth rates, and maximal stimulated serum concentrations of growth hormone of at least 10 microg per liter. The children were treated with growth hormone (0.3 mg per kilogram of body weight per week) for 2 to 10 years. Eighty of these children have reached adult height, with a bone age of at least 16 years in the boys and at least 14 years in the girls, and pubertal stage 4 or 5. The difference between the predicted adult height before treatment and achieved adult height was compared with the corresponding difference in three untreated normal or short-statured control groups. RESULTS: In the 80 children who have reached adult height, growth hormone treatment increased the mean standard-deviation score for height (number of standard deviations from the mean height for chronologic age) from -2.7 to -1.4. The mean (+/-SD) difference between predicted adult height before treatment and achieved adult height was +5.0+/-5.1 cm for boys and +5.9+/-5.2 cm for girls. The difference between predicted and achieved adult height among treated boys was 9.2 cm greater than the corresponding difference among untreated boys with initial standard-deviation scores of less than -2, and the difference among treated girls was 5.7 cm greater than the difference among untreated girls. CONCLUSION: Long-term administration of growth hormone to children with idiopathic short stature can increase adult height to a level above the predicted adult height and above the adult height of untreated historical control children.

Should we treat children with idiopathic short stature?

The use of growth hormone (GH) to treat short children who are clearly GH-deficient is now well accepted. However, GH treatment of short children who have no currently recognizable abnormalities in their GH-insulin-like growth factor I axis remains controversial. Whether such children with so-called idiopathic short stature (ISS) should be treated with GH was the subject of an international workshop held in St.-Paul-de-Vence, France, in April 1999. This article summarizes the issues discussed at the workshop, including the definition of ISS, ethical and health-economic aspects of treatment, results from clinical trials and surveillance studies, and the use of prediction models in aiding treatment decisions.

Hypoglycemia attributable to insulin-like growth factor-II prohormone-producing metastatic leiomyosarcoma.

OBJECTIVE: To review the causes of nonpancreatic tumor-associated hypoglycemia and report the first case of hypoglycemia attributable to a leiomyosarcoma, which did not cause hypoglycemia in its primary site but only after metastasizing. METHODS: A case report is presented of a 62-year-old man with a gastric leiomyosarcoma diagnosed and surgically treated 8 years previously, who was found to have 14 large, rounded masses in his liver and a blood glucose level of 19 mg/dL. Biopsy of the largest mass revealed a leiomyosarcoma. RESULTS: Evaluation of the cause of the hypoglycemia revealed that circulating insulin, connecting peptide, proinsulin, insulin-like growth factor-I (somatomedin C), and insulin-like growth factor-II levels were below normal, whereas the insulin-like growth factor-II prohormone concentration was increased twofold. Basal and corticotropin-stimulated serum cortisol values were normal. CONCLUSION: This is the first case report of hypoglycemia occurring only after metastasis of a leiomyosarcoma. A possible causal relationship between the hypoglycemia and the increased circulating insulin-like growth factor-II prohormone is suggested, and alternative explanations and treatment are discussed.

Metabolic consequences of 5-year growth hormone (GH) therapy in children treated with GH for idiopathic short stature. Genentech Collaborative Study Group.

In a multicenter study the metabolic effects of 5 yr of GH therapy in children with idiopathic short stature were evaluated. Patients received 0.3 mg/kg.week recombinant human GH. Of the 121 patients who entered the study, data for 62 were analyzed at the final 5 yr point. Routine laboratory determinations were available for all 62 subjects at the 5 yr point. Special laboratory determinations, such as postprandial glucose and insulin, were available for only a subset of patients. Mean insulin-like growth factor I levels rose to 283 +/- 101 micrograms/L, within the normal range using age-appropriate reference standards. T4, cholesterol, triglycerides, blood chemistries, and blood pressure showed no significant changes during the 5-yr period. Mean baseline and 2-h postprandial glucose levels remained unchanged. Both fasting and postprandial insulin levels rose substantively from low normal levels to the normal range (median, 4.9-43 mU/L). Mean hemoglobin A1c levels remained within the normal range throughout the study. In summary, careful monitoring has not revealed any currently discernible metabolic side-effects of clinical significance after GH therapy in this 5-yr study of children with idiopathic short stature.

Recovery of growth hormone release from suppression by exogenous insulin-like growth factor I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I.

To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18-29 yr) received, in randomized order, 4-h i.v. infusions of recombinant human IGF-I (rhIGF-I; 3 microg/kg-h) or saline (control) from 25.5-29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4-4.0) vs. 4.8 (2.8-7.9) microg/L; P < 0.05]. A rebound increase in GH concentrations occurred 5-7 h after the end of rhIGF-I infusion [7.6 (4.6 -11.7) vs. 4.3 (2.5-6.0) microg/L; P < 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 +/- 43 vs. 263 +/- 44 microg/L; P < 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 +/- 36 vs. 202 +/- 23 microg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 +/- 0.4 vs. 0.88 +/- 0.3 microg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.

Disturbances of growth hormone-insulin-like growth factor axis and response to growth hormone in acidosis.

Severe chronic metabolic acidosis (CMA) in rats is associated with poor food intake and downregulation of growth hormone (GH), insulin-like growth factors (IGFs), and liver receptors; the administration of recombinant GH (rGH) fails to improve the growth failure. In mice with carbonic anhydrase II deficiency (CAD), a model of moderate CMA with food intake close to normal, we studied serum levels of GH, IGFs, and IGF-binding proteins, and the growth response to rGH. CAD was associated with low serum levels of GH in males. Randomized administration of rGH from approximately 5 to approximately 12 wk to CAD mice improved food efficiency and increased serum IGF-I levels, final length, and weight compared with placebo without affecting blood pH. Although administration of rGH also increased linear growth in healthy animals, the effect was less than that in CAD mice and was only observed when started before 6 wk of life. Thus growth failure in CAD mice is associated with a decrease in GH secretion in males but not in females. Long-term administration of rGH increases linear growth in CAD mice despite persistent CMA.