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

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.

A clinically euthyroid child with a large goiter due to a thyroglobulin gene defect: clinical features and genetic studies.

A 10-year old child born to consanguineous parents presented with an extremely large goiter, a low free T4 level and free T4 index, and normal TSH concentration. The findings of undetectable thyroglobulin (TG) and low free T4, and an elevated free T3/free T4 ratio suggested the possibility of a defect in TG synthesis. Noteworthy aspects of this case were the extremely elevated thyroidal radioiodide uptake despite a normal TSH concentration and the fact that the reduction in the size of her goiter only occurred when her TSH was suppressed below the normal range. Gene sequencing revealed that the patient was homozygous for a donor splice site mutation in intron 30 (IVS30+1G>C). Isolation of RNA obtained from the thyroid gland by fine needle aspiration and sequencing of the TG cDNA confirmed the prediction that exon 30 was skipped, resulting in an in-frame loss of 46 amino acids.

A paradigm shift for the prevention and treatment of individual and global obesity.

The prevalence of obesity and overweight has plateaued in developed countries, although at high levels, but in most parts of the world, it continues to increase. Current recommendations for preventing and treating obesity are based mainly on the notion that overeating results from hedonic eating as a result of unlimited access to palatable foods, particularly those high in sugar and fat, and that hedonic centers are able to "override" the body's homeostatic mechanisms. This article proposes that the homeostatic mechanisms affecting appetite and satiety are more important in chronic overeating, and that sufficient evidence exists for adopting a new paradigm for controlling individual and global obesity based on controlling energy homeostasis via the enteroendocrine and gut microbiota systems. Many obese children and adolescents have chronic hunger, supporting the notion that they have a homeostatic rather than hedonic abnormality. The effectiveness of weight loss drugs and bariatric surgery suggests that the brain centers controlling energy homeostasis are able to override centers controlling hedonic drives. Energy homeostasis can also be influenced by nutrition, in particular, by avoiding sweetened drinks and consuming whole grains, vegetables, fruits and other foods that are high in dietary fiber, and thereby influence appetite and satiety. New recommendations are outlined for preventing and treating individual and global obesity based on a paradigm that targets appetite and satiety.

Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.

Patients with pseudohypoparathyroidism type Ib (PHP-Ib) have hypocalcemia and hyperphosphatemia due to renal parathyroid hormone (PTH) resistance, but lack physical features of Albright hereditary osteodystrophy. PHP-Ib is thus distinct from PHP-Ia, which is caused by mutations in the GNAS exons encoding the G protein alpha subunit. However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS. Furthermore, loss of methylation at a differentially methylated region (DMR) of this locus, exon A/B, has been observed thus far in all investigated sporadic PHP-Ib cases and the affected members of multiple AD-PHP-Ib kindreds. We now report that affected members and obligate gene carriers of 12 unrelated AD-PHP-Ib kindreds and four apparently sporadic PHP-Ib patients, but not healthy controls, have a heterozygous approximately 3-kb microdeletion located approximately 220 kb centromeric of GNAS exon A/B. The deleted region, which is flanked by two direct repeats, includes three exons of STX16, the gene encoding syntaxin-16, for which no evidence of imprinting could be found. Affected individuals carrying the microdeletion show loss of exon A/B methylation but no epigenetic abnormalities at other GNAS DMRs. We therefore postulate that this microdeletion disrupts a putative cis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib.

Effective methimazole dose for childhood Graves' disease and use of free triiodothyronine combined with concurrent thyroid-stimulating hormone level to identify mild hyperthyroidism and delayed pituitary recovery.

Appropriate methimazole dosing for initial treatment of childhood Graves' disease is uncertain. A retrospective chart review was performed on 5 to 17 year-old children treated for Graves' disease. Patients were divided into two groups depending on initial methimazole dosing: low-dose and high-dose regimens using <0.5 mg/kg/day and >0.5 mg/kg/day, respectively. The low-dose regimen was effective in 5/12 (42%) of patients and the high-dose regimen was effective in 27/33 (82%) of patients (p = 0.016). There was also a statistically significant dose/time interaction for levels of free thyroxine (T4) (p = 0.025). During treatment, 63.3% of diagnosable samples showed unambiguous hyperthyroidism or triiodothyronine (T3) toxicosis, 16.7% elevated free T3 with normal free T4 and T3 levels, indicating borderline hyperthyroidism, and 20% showed thyroid-stimulating hormone (TSH) suppression with normal or low levels of free T4 and free T3, indicating delayed recovery of pituitary TSH secretion. Free T3 levels combined with concurrent TSH levels permit differentiation of mild hyperthyroidism from delayed pituitary recovery.

Atypical presentation of shock from acute adrenal insufficiency in an adolescent male.

OBJECTIVE: To report an atypical presentation of shock and acute adrenal insufficiency in an adolescent male. CASE SUMMARY: A 14-year-old boy with a history of nocturnal enuresis presented with a clinical picture suggestive of septic shock refractory to aggressive fluid and vasopressor management. History and physical examination were suggestive of shock secondary to an infectious etiology, associated with skin findings of hyperpigmentation. The laboratory studies were remarkable for normal sodium, potassium, glucose, as well as normal renin levels. Hydrocortisone therapy led to improvement of his blood pressure and allowed weaning of vasopressor medications. Further laboratory studies, including adrenocorticotropic hormone stimulation test and adrenal antibodies, confirmed the diagnosis of primary adrenal insufficiency. CONCLUSION: Acute adrenal insufficiency is an uncommon cause of shock in the adolescent population. We report a clinical presentation suggestive of shock secondary to acute adrenal insufficiency remarkable for an atypical clinical and laboratory presentation. We further provide information on the management of acute adrenal crisis.

The pediatric obesity epidemic: causes and controversies.

Obesity in children and adolescents has reached alarming proportions in the United States. Nutritional surveys do not indicate a significant increase in caloric intake in children and adolescents over the last 3 decades, although caloric intake has increased recently in adolescent females. Dietary fat has also been falling. There is no conclusive evidence linking physical inactivity to the obesity epidemic, and longitudinal studies indicate that physical inactivity may be the result of obesity rather than its cause. Hence, attention should be focused on dietary carbohydrate. Carbohydrate intake has increased as a result of the decrease in dietary fat. Indirect evidence also indicates that the quality of carbohydrate has been changing, so that American children are eating more carbohydrates with a higher glycemic index. It is proposed that high-glycemic-index diets lead to excessive weight gain as a consequence of postprandial hyperinsulinemia. Low-glycemic-index diets lower postprandial insulin levels and insulin resistance. It seems likely that diets restricted in sweetened sodas and noncitrus juices and containing ample whole grains, vegetables, and fruit could have a major impact on the prevalence of pediatric obesity.

Clinical review 168: What vascular ultrasound testing has revealed about pediatric atherogenesis, and a potential clinical role for ultrasound in pediatric risk assessment.

Coronary vascular disease is one facet of a generalized disturbance of vascular function present throughout the vascular tree. Dysfunction of the endothelium leads to thickening of the intima and media of the vessel wall of large and medium-sized muscular arteries and large elastic arteries, such as the aorta, carotid, and iliac arteries. Flow-mediated dilatation of the brachial artery is one of several tests used to assess dysfunction of the endothelium using high resolution ultrasound. Endothelial dysfunction has been demonstrated in children with heterozygous familial hypercholesterolemia, type 1 diabetes, morbid obesity, and homozygous homocystinuria and in the offspring of a parent with early coronary disease. High resolution ultrasound has also confirmed postmortem findings that atherogenesis has its beginnings in childhood and adolescence, with the demonstration of increased carotid artery intima-medial thickening in children with familial hypercholesterolemia, familial combined hyperlipidemia, and type 1 diabetes and in the offspring of a parent with early coronary disease. In combination with family history and traditional risk factors, ultrasound evaluation of brachial artery flow-mediated vasodilation and carotid artery intima-medial thickening could be used in a clinical setting to assess coronary risk in high risk pediatric patients.

Acanthosis nigricans, vitamin D, and insulin resistance in obese children and adolescents.

OBJECTIVES: The aim of this study is to identify factors accounting for the variation in 25-hydroxyvitamin D levels in a pediatric obese population. PATIENTS AND METHODS: One hundred and forty-nine obese children and adolescents (BMI ≥95th percentile) were evaluated in a pediatric endocrine office. Acanthosis nigricans (AN) skin lesions were rated on a 4-point scale. RESULTS: The 25-hydroxyvitamin D levels were significantly different between those without AN and those with any severity of AN (p=<0.001). Insulin levels were only significantly different between those with no and severe AN (p=0.007). A general linear model showed that month of visit predicted 19.0% of the variation and AN an additional 2.2%. When AN was dropped from the full model, log-transformed HOMA-IR remained insignificant (p=0.164). CONCLUSIONS: Season of evaluation was the main determinant of 25-hydroxyvitamin D levels. Severity of AN was a stronger predictor of 25-hydroxyvitamin D level variation than the measure of insulin resistance HOMA-IR.

Increased hunger and speed of eating in obese children and adolescents.

OBJECTIVES: This quality improvement program examined self-reported hunger, over-eating, and eating speed in obese and normal-weight children and adolescents prior to an interventional component. PATIENTS AND METHODS: Food frequency questionnaires were presented to 127 obese and 42 normal-weight patients, and perceived hunger, food intake and eating speed were rated. RESULTS: Obese patients reported significantly greater hunger than normal-weight patients (62.2% vs. 21.4%, p<0.001) and faster eating (55.7% vs. 23.3%, p<0.001). Patients reporting being "always" or "often hungry" were more than six times likely to be obese (OR=6.49, 2.86-14.73, p<0.001), while rapid speed of eating yielded a four-fold increase in likelihood of obesity (OR=4.15, 1.77-9.72, p<0.001). Hunger and speed of eating were also highly associated (p<0.001). CONCLUSIONS: Increased hunger and eating speed were highly prevalent in these obese pediatric patients and may reflect abnormalities of satiety and satiation.

The pubertal timing controversy in the USA, and a review of possible causative factors for the advance in timing of onset of puberty.

Previously used standards for the diagnosis of precocious puberty in girls no longer appear to be appropriate in the USA, in that a significant number of girls are being seen in paediatricians' offices with breast budding before 8 years of age. The timing of menarche, however, has changed little over the past few decades. Early maturing girls are more likely to become obese in adolescence and adulthood than normal or late maturing girls. Early maturing white girls are heavier at the onset of puberty, but this is not the case for African-American girls or boys of either race. Boys and girls with premature pubarche may be more hyperinsulinaemic than normal children, and girls with premature pubarche more likely to develop functional ovarian and adrenal hyperandrogenism. Early menarche is preceded by prepubertal hyperinsulinaemia. It is proposed that pubertal onset, although not necessarily the tempo of puberty, is influenced by hyperinsulinaemia and insulin resistance. If this hypothesis is correct, insulin resistance may be more prevalent in US children than previously recognized. An advance in timing of onset of puberty has not been noted in other countries, although it is likely that this phenomenon may become more prevalent as other countries adopt a more American lifestyle and diet.