Arnold H. Slyper

Childhood Obesity, Adipose Tissue Distribution, and the Pediatric Practitioner

The prevalence of pediatric obesity is increasing in the United States. Sequelae from pediatric obesity are increasingly being seen, and long-term complications can be anticipated. Obesity is the most common cause of abnormal growth acceleration in childhood. Obesity in females is associated with an early onset of puberty and early menarche. Puberty is now occurring earlier in females than in the past, and this is probably related either directly or indirectly to the population increase in body weight. The effect of obesity on male pubertal maturation is more variable, and obesity can lead to both early and delayed puberty. Pubertal gynecomastia is a common problem in the obese male. Many of the complications of obesity seen in adults appear to be related to increased accumulation of visceral fat. It has been proposed that subcutaneous fat may be protective against the adverse effects of visceral fat. Males typically accumulate fat in the upper segment of the body, both subcutaneously and intraabdominally. In females, adiposity is usually subcutaneous and is found particularly over the thighs, although visceral fat deposition also occurs. Gender-related patterns of fat deposition become established during puberty and show significant familial associations. There are no reliable means for assessing childhood and adolescent visceral fat other than radiologically. Noninsulin-dependent diabetes is being seen more commonly in the pediatric population. Diabetes and impaired glucose tolerance are noted particularly in obese children with a family history of diabetes. In this situation, a glucose tolerance test may be indicated, even in the presence of fasting normoglycemia. Hypertriglyceridemia and low high-density lipoprotein–cholesterol levels are the primary lipid abnormalities of obesity and are related primarily to the amount of visceral fat. Low-density lipoprotein–cholesterol levels are not typically elevated in simple obesity. The offspring of parents with early coronary disease tend to be obese. Very low-density lipoprotein and intermediate-density lipoprotein particles, which are small in size, may be important in atherogenesis but they cannot be identified in a fasting lipid panel. The propensity to atherogenesis cannot be interpreted readily from a fasting lipid panel, which therefore should be interpreted in conjunction with a family history for coronary risk factors. Hypertriglyceridemia may be indicative of increased visceral fat, familial combined hyperlipidemia, familial dyslipidemic hypertension, impaired glucose tolerance, or diabetes. Almost half of adult females with polycystic ovary syndrome are obese and many have a central distribution of body fat. This condition frequently has its origins in adolescence. It is associated with increased androgen secretion, hirsutism, menstrual abnormalities, and infertility, although these may not be present in every case. Adults with polycystic ovary syndrome adults are hyperlipidemic, have a high incidence of impaired glucose tolerance and noninsulin-dependent diabetes, and are at increased risk for coronary artery disease. Weight reduction and lipid lowering therefore are an important part of therapy. Obstructive sleep apnea with daytime somnolence is a common problem in obese adults. Pediatric studies suggest that obstructive sleep apnea occurs in ∼17% of obese children and adolescents. Sleep disorders in the obese may be a major cause of learning disability and school failure, although this remains to be confirmed. Symptoms suggestive of a sleep disorder include snoring, restlessness at night with difficulty breathing, arousals and sweating, nocturnal enuresis, and daytime somnolence. Questions to exclude obstructive sleep apnea should be part of the history of all obese children, particularly for the morbidly obese. For many children and adolescents with mild obesity, and particularly for females, one can speculate that obesity may not be a great health risk. However, there are many individuals for whom obesity will contribute to morbidity and mortality, and in this instance, the family history often provides valuable clues. These patients in particular should be targeted for weight reduction. Only with a considerably increased research effort will we be able to provide answers as to how to prevent and treat the present-day explosion of obesity.

Allogenic Bone Marrow Transplantation in Severe Gaucher Disease

ABSTRACT: Gaucher disease is the most prevalent lyso-somal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid β-glucosidase and the resultant accumulation of glucosylcer-amide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocvte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neu-ronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytoge-netic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete re-constitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8–12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12–24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and hugs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time coarse aid rationale for studies directed to gene therapy via BMT for this disease after introduction of acid β-glncosidase gene constructs into autologous plu-ripotent stem cells of selected Gaucher disease patients.

The influence of carbohydrate quality on cardiovascular disease, the metabolic syndrome, type 2 diabetes, and obesity – an overview

Abstract There is compelling evidence that carbohydrate quality has important influences on cardiovascular disease, the metabolic syndrome, type 2 diabetes, and obesity. Cohort and interventional studies indicate that dietary fiber is an important determinant of satiation, satiety, and weight gain, and also protects against cardiovascular disease. Cohort studies have shown that vegetables and fruits protect against coronary heart disease, whereas whole grains provide protection against cardiovascular disease, type 2 diabetes, and weight gain. Dietary glycemia within the range eaten by most of the population seems not to have a significant influence on body weight, although it may influence waist circumference. There is strong evidence from interventional trials that dietary glycemia does influence insulin resistance and diabetes control. Moreover, replacing saturated fat with high-glycemic carbohydrate may increase cardiovascular risk. Soft drink consumption is a proven cause of weight gain, which may relate to the lack of satiation provided by these drinks. In large amounts, dietary fructose leads to greater adverse metabolic changes than equivalent amounts of glucose, although the extent to which fructose per se is contributing to many of the metabolic changes found in the obese, as distinct from the calories it provides, is still a matter of debate.

Low-density lipoprotein particle size is not a discriminating marker for atherogenic risk in male offspring of parents with early coronary artery disease☆

The aim of this study was to assess the importance of low-density lipoprotein (LDL) particle size as a marker of atherogenic risk in male offspring of a parent with early coronary artery disease (CAD) before the age of 60 years. CAD-positive (CAD+) offspring were recruited into two groups based on age, 15 to 30 years (n = 20) and 31 to 45 years (n = 41), and matched to CAD-negative (CAD-) offspring by age and body mass index (BMI) (n = 20 and 21 per group). LDL peak particle diameter was assessed by polyacrylamide gradient gel electrophoresis. There was no significant difference in LDL peak particle diameter between CAD+ and CAD- offspring (26.2 +/- 0.1 v 26.2 +/- 0.1 nm, mean +/- SE). There was also no difference between CAD+ offspring and CAD- offspring when comparisons were made within their own age group (26.5 +/- 0.1 nm in younger CAD+ offspring v 26.2 +/- 0.1 nm in younger CAD- offspring, and 26.0 +/- 0.1 nm in older CAD+ offspring v 26.1 +/- 0.2 nm in older CAD- offspring). Peak particle diameter was significantly greater in younger CAD+ offspring than in older CAD+ offspring (26.5 +/- 0.1 v 26.0 +/- 0.1 nm, P < .05). We conclude that small LDL particle size is not a discriminating marker for early atherogenic risk, and that measurement of LDL particle size has limited value in the assessment of coronary risk, at least in the age ranges we studied.

A Study of Chromosomal Aberrations and Chromosomal Fragility after Recombinant Growth Hormone Treatment

Increased chromosomal rearrangements and chromosomal fragility have been previously observed in lymphocytes of children treated with human GH, implying that treatment could predispose to malignancy. Twenty-four children with classic GH deficiency, neurosecretory GH dysfunction, and Turner syndrome were treated with recombinant human GH (0.3 mg·kg−1·wk−1). Metaphase cells were assessed for spontaneous chromosomal and chromatid aberrations at baseline and 6 mo into treatment. There were no significant differences in aberrations between baseline and the 6-mo samples. However, the mean frequency of chromatid-type aberrations on a per cell basis was significantly higher than at baseline, 0.0088 versus 0.0064 aberrations per cell (p < 0.024). Two patients contributed inordinately to this increase. A third sample from these two patients was almost identical to their baseline samples. Cells were also irradiated in vitro (3 Gy) to assess chromosomal fragility. After irradiation, no patient showed a significant difference for any aberration type, although there was a significantly lower frequency of ring chromosomes on a per cell basis in the 6-mo samples (p < 0.001). We find no evidence that GH therapy influences spontaneous chromosomal aberrations or chromosomal fragility.

Lack of Effect of Salt on the Glucose and Insulin Response to Mashed Potatoes, White Rice, and Lima Beans

The effect of 4.25 g of table salt on the insulin and glucose response to three forms of carbohydrate with varying glycemic indices was studied. There was no statistical difference in the peak response or area under the glucose or insulin curves for any of these foods in the presence of salt. It is concluded that salt has no effect on the absorption of starches.

Decreased glucose tolerance, not decreased insulin sensitivity, is a maturational abnormality in the male offspring of a parent with early coronary artery disease

We investigated whether the male offspring of a parent with early coronary artery disease (before the age of 60; n = 61) exhibit decreased insulin sensitivity compared with controls matched for age and body mass index (BMI) (n = 39). The insulin sensitivity index (S[I]) was determined by the minimal modeling method of Bergman from a frequently sampled intravenous glucose tolerance test with intravenous tolbutamide. Offspring and controls had a similar S[I], insulin-independent glucose utilization (S[G]), first-phase insulin response (AIR[G]), and area under the glucose curve. When subjects were separated into two age groups, younger subjects aged 15 to 30 years and older subjects aged 31 to 45 years, important differences were seen. S[G] was significantly increased in younger offspring compared with controls (22.8 +/- 2.3 v 16.8 +/- 2.3 x 10(-3) x min(-1), P < .05). Older offspring had a significantly increased area under the glucose curve compared with controls (18,250 +/- 322 v 17,225 +/- 347 mg/dL x min(-1), P < .05). Older offspring also had decreased S[I] compared with younger offspring (5.0 +/- 0.4 v 6.6 +/- 0.9 x 10(-4) x min(-1) x micro U/mL, P < .05), but this difference was eliminated after adjusting for BMI and waist to hip ratio (5.5 +/- 0.4 v5.8 +/- 0.9 x 10(-3) x min(-1), nonsignificant). This study does not support the concept that insulin resistance is an early atherogenic risk factor in offspring at risk for coronary disease because of their family history. However, it does point to the importance of maturational changes in glucose homeostasis in these offspring.

Human Growth Hormone (hGH) May Influence Chromosome Aberrations and Fragility 487

The influence of hGH treatment on spontaneous chromosome aberrations and chromosome fragility was tested in 23 naive patients aged 4 to 16 years. The breaking action of ionizing radiation was used as an indicator of chromosome fragility. 17 patients had growth hormone deficiency, 1 Turner syndrome, and 5 neurosecretory growth hormone dysfunction. Blood samples were taken at baseline and following 6 months of hGH treatment (0.3 mg/Kg/week). Lymphocyte cultures and cytogenetic preparations were established using standard cytogenetic techniques. Half of the cultures were irradiated with 3 Gy of gamma rays. All mitotic preparations were coded to ensure “blind” enumeration of aberrations. A one-way ANOVA was performed on log transformed data for analysis of aberrations per cell. There were no significant differences between pre-treatment (9,500 cells) and post-treatment (8,000 cells) cells for spontaneous chromosome-type aberrations (mean ± SEM) 4.2 × 10-3 ± 1.2 × 10-3 vs 7.9 × 10-3 ± 2.9 × 10-3 (p=0.08); for chromatid-type aberrations 9.2 × 10-3 ± 2.8 × 10-3 vs 1.1× 10-2 ± 4.0 × 10-3 (p=0.42); and for total aberrations (chromosome + chromatid) 1.3 × 10-2 ± 3.0× 10-3 vs 1.9 × 10-2 ± 7.0 × 10-3 (p=0.10). There were also no significant differences for radiation-induced aberrations (4,550 pretreatment cells and 4,850 post-treatment cells) for chromosome aberrations 1.12 ± 3.0 × 10-2 vs 1.05 ± 5.0 × 10-2 (p=0.18); for chromatid aberrations 2.6 × 10-2 ± 5.0 × 10-3 vs 2.0× 10-2 ± 3.0 × 10-3 (p=0.60); and for total aberrations 1.15 ± 3.0 × 10-2 vs 1.07 ± 5.0 × 10-2 (p=0.17). However, when the data were analyzed on a per chromosome basis (i.e. number of aberrant chromosomes ÷ total number of chromosomes scored) with binomial probability being applied to the raw data, small but significant differences were seen. Total spontaneous aberrations per cell (mean with 95% confidence limits) were: pre-treatment 2.65 × 10-4 (2.18 × 10-4 to 3.13 × 10-4) vs post-treatment 3.42 × 10-4 (2.83 × 10-4 to 4.02× 10-4) p<0.05), and for total radiation-induced aberrations 2.51 × 10-2 (2.44 × 10-2 to 2.57 × 10-2) vs 2.40 × 10-2 (2.34 × 10-2 to 2.47× 10-2) (p<0.05). This analysis suggests that 6 months of hGH treatment may lead to a significant increase in spontaneous chromosome aberrations and significant decrease in chromosome fragility. The disparity between the chromosome aberration and fragility data is unexplained and requires further investigation.

The influence of age on coronary risk factors: importance of body fat and VLDL metabolism 628

The clinical manifestations of coronary artery disease exhibit strong age dependence. To investigate this phenomenon, we examined for age-related changes in two groups of offspring of parents with early coronary disease (on or before age 60) - 10 subjects aged 15-25 years and 21 subjects aged 35-45 years. Familial hypercholesterolemia was excluded by history. For each subject, body mass index (BMI) was < 85th percentile for age. Fasting lipoproteins were measured after sequential ultracentrifugation. Triglyceride(TG) was measured hourly following a meal of fat. Vitamin A was added to the test meal as a chylomicron marker. Results: The following were significantly decreased in younger compared to older offspring: BMI, waist hip ratio, diastolic BP, fasting glucose, fasting TG (log transformed), VLDL apoprotein B, area under postprandial TG curve (log transformed) (all p<0.001), area under postprandial plasma and chylomicron retinyl palmitate curves (both p<0.01), and area under postprandial chylomicron remnant retinyl palmitate curve, VLDL TG (log transformed), and VLDL cholesterol (all three p<0.05). There were no significant differences in LDL cholesterol, HDL cholesterol, and fasting insulin between the two groups. After correcting for BMI and waist hip ratio, there were no significant differences between the two groups except for area under TG curve 1,097 ± 480 vs 2,208 ± 1,054 mg/dl•12 hr (mean ± 1 SD) and VLDL apo B 11.4 ± 3.2 vs 21.0 ± 7.6 mg/dl (both p<0.05). Conclusions: An increase in BMI and central fat deposition explains the increase with age in the above coronary risk factors, except for area under the TG curve and VLDL apo B. Independent changes in body fat and VLDL metabolism may be important in the age dependence of coronary artery disease.