Individual differences in glucose homeostasis: Do our early life interactions with bacteria matter?

Exposure to endotoxin during the neonatal period in the rat has been shown to alter the development of the hypothalamic-pituitary-adrenal axis, inducing hyper-responsivity and increased glucocorticoid production in later-life. Glucocorticoids are known to have major metabolic effects, therefore, early life endotoxin exposure may have potentially serious consequences for metabolic homeostasis in the exposed animal. The aims of this study were therefore to assess the effect of neonatal bacterial endotoxin exposure on subsequent glucose homeostasis, insulin action and corticosterone production from puberty through to senescence. Male Fischer-344 rat pups were treated with bacterial endotoxin (0.05 mg/kg Salmonella enteritidis i.p.) or vehicle (sterile pyrogen free saline) on days 3 and 5 postnatally. Insulin and glucose levels were assessed before and during and intraperitoneal glucose tolerance test (IPGTT) together with body mass on postnatal days 40, 80, and 400. In addition, circulating levels of corticosterone were measured at 0, 30, and 90 min following a 30-min restraint challenge at these ages. Neonatal endotoxin challenge did not alter fasting plasma glucose or insulin, but impaired glucose tolerance at puberty (p<.05), improved glucose tolerance in adulthood (p<.05) and had no effect at senescence. During the IPGTT insulin was reduced at all ages (p<.05) following neonatal endotoxin challenge, but insulin sensitivity was unaltered, except for an increase in adulthood (p<.05), which is consistent with the observed improvement in glucose tolerance at this age. Neonatal endotoxin challenge reduced body mass during puberty and senescence (p<.05) but did not alter basal or stressed plasma corticosterone levels at any of the three developmental time points examined. These findings suggest that variations in an individual's early life bacterial environment may contribute to differences in glucose homeostasis, insulin action and disease susceptibility later in life.     

Preadolescent conduct problems in girls and boys

OBJECTIVE: To examine sex differences in correlates of disruptive behavior disorders (DBDs) in preadolescent children using indicators of a wide range of well-established risk factors for DBDs and outcomes 3 years after initial assessment. METHOD: Analyses were based on data for 5- to 10-year-olds (n = 5,913) from the British Child and Adolescent Mental Health Survey 1999, and a 3-year follow-up of selected subsamples (n = 1,440) at ages 8 through 13 years. DSM-IV diagnoses were assigned using the Developmental and Well-Being Assessment at both contacts. RESULTS: Boys and girls were equally exposed to most social and family risks for DBDs, with little evidence of differential sensitivity to these risks. Boys were exposed more to neurodevelopmental difficulties, attention-deficit/hyperactivity disorder, and peer problems and had lower rates of prosocial behaviors; together, these factors and physical punishment could account for 54% of the observed sex differences in DBDs. At follow-up, outcomes for girls and boys with DBDs were very similar. For children with subthreshold conduct problems at initial assessment, boys were more likely to go on to exhibit DBDs than were girls (25% versus 7%). CONCLUSIONS: Sex differences in the levels of a variety of child characteristics and interpersonal factors are likely to be important in understanding sex differences in risk for DBDs in preadolescent samples.     

Sleep and COMT polymorphism in ADHD children: preliminary actigraphic data

OBJECTIVE: To examine whether COMT (catechol-O-methyltransferase) polymorphism modulates aspects of sleep in children diagnosed with attention-deficit/hyperactivity disorder (ADHD). METHOD: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were obtained for 34 children, 7.4 to 12 years old, diagnosed with ADHD (DSM-IV). Diagnosis was generated by the Diagnostic Interview Schedule for Children and was confirmed by multidisciplinary consensus. RESULTS: Children who were Val allele carriers had poorer sleep continuity compared with children with the Met-Met genotype while receiving a placebo and while receiving methylphenidate. CONCLUSIONS: The findings of the present study support the hypothesis that sleep disturbances in children with ADHD are related to the underlying pathophysiology of the disorder.     

Inhibition of glucose-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 by epinephrine in pancreatic beta-cells

Glucose sensing is essential for the ability of pancreatic beta-cells to produce insulin in sufficient quantities to maintain blood glucose within the normal range. Stress causes the release of adrenergic hormones that increase circulating glucose by promoting glucose production and inhibiting insulin release. We have shown that extracellular signal-regulated kinases 1 and 2 (ERK1/2) are responsive to glucose in pancreatic beta-cells and that glucose activates ERK1/2 by mechanisms independent of insulin. Here we show that glucose-induced activation of ERK1/2 is inhibited by epinephrine through the alpha2-adrenergic receptor. Epinephrine and the selective alpha2-adrenergic agonist UK14304 reduced insulin secretion and glucose-stimulated ERK1/2 activation in a pertussis toxin-sensitive manner, implicating the alpha subunit of a Gi family member. Alpha2-adrenergic agonists also reduced stimulation of ERK1/2 by glucagon-like peptide 1 and KCl, but not by phorbol ester or nerve growth factor. Our findings suggest that alpha2-adrenergic agonists act via a Gi family member on early steps in ERK1/2 activation, supporting the idea that ERK1/2 are regulated in a manner that reflects insulin demand.     

Giant aortic aneurysm 18 years after repair of double-outlet right ventricle with pulmonary stenosis

Substantial long-term morbidity after a successful operation in complex congenital heart defects is a matter of concern. We present a patient with a giant ascending aortic aneurysm 18 years after repair of a double-outlet right ventricle with pulmonary stenosis. Our report emphasizes the need for ongoing follow-up into adulthood.     

The effect of the 80-hour work week on general surgery resident operative case volume

To meet the new duty hour restrictions on July 1, 2003, our general surgery residency program underwent many changes. The purpose of this study was to examine whether the implementation of these changes, made in part to comply with new duty hour restrictions, would adversely impact general surgery residents' operative volume. The operative cases of categorical surgical residents were recorded from July 1, 2000 to December 31, 2004. The main outcome measure was the median number of operative cases performed by each resident per quarter (a 3-month period). The number of in-house calls each resident took per quarter was also recorded. From 2000 to 2004, the median number of in-house calls per quarter significantly decreased (27, 25, 15, 10, and 14, respectively; P < 0.001). The median number of operative procedures performed did not vary from quarter to quarter (P = 0.49). There was a trend toward an increase in number of cases performed at the postgraduate year (PGY) 1 (P = 0.07) and 2 (P = 0.04) levels, a decrease at the PGY3 level (P = 0.058), and no change at the PGY4 and 5 years. The 80-hour work week did not adversely affect the operative experience of our categorical surgical residents despite significant reductions of in-house call.     

Cellular fibromas of the ovary: a study of 75 cases including 40 mitotically active tumors emphasizing their distinction from fibrosarcoma

Cellular fibroblastic tumors of the ovary are currently classified as either cellular fibroma (CF) or fibrosarcoma. The former are characterized by bland nuclei, 3 or fewer mitotic figures per 10 high-power fields (MFs/10 HPFs), and a low malignant potential, whereas fibrosarcomas usually have severe nuclear atypia, > or = 4 MFs/10 HPFs, and an aggressive clinical course. The prognosis of cellular fibromatous tumors with > or = 4 MFs/10 HPFs and low-grade cytology is not established and it is the purpose of this study to investigate that aspect. It has been our anecdotal experience that otherwise typical CFs with > or = 4 MFs/10 HPFs usually have a benign clinical course, suggesting that such tumors should be regarded as "mitotically active cellular fibroma" (MACF) rather than fibrosarcoma. Seventy-five cellular fibromatous neoplasms were analyzed to determine their clinicopathologic features and the appropriateness of "MACF" as a designation for otherwise typical CFs with > or = 4 MFs/10 HPFs. The mean age of patients with CF (n = 35, 0 to 3 MFs/10 HPFs) and MACF (n = 40, > or = 4 MFs/10 HPFs) was 51 and 41 years, respectively. Patients most commonly presented with symptoms related to a pelvic mass. All tumors were unilateral. The mean tumor size of CFs was 8.0 cm and 9.4 cm for MACFs. The majority of the tumors were solid; approximately one-third of them had a cystic component. Ovarian surface adhesions, involvement of the ovarian surface, or both, was present in 6% of CFs and 10% of MACFs. Eleven percent of CFs and 13% of MACFs were associated with extraovarian involvement. All tumors consisted of cellular, intersecting bundles of spindle cells with bland nuclear features. The mean highest mitotic count for MACFs was 6.7 MFs/10 HPFs (range 4 to 19 MFs/10 HPFs). Follow-up of 3 months to 12 years (mean 4.75 y) was available in 18 of the 40 patients with MACFs and was uneventful in all cases. We conclude that cellular fibromatous neoplasms with bland cytology and elevated mitotic counts are associated with favorable patient outcome and should be diagnosed as MACF rather than fibrosarcoma, which usually have moderate to severe atypia and elevated mitotic rates. As prior observations have shown that even typical CFs can occasionally recur locally, particularly if they are associated with rupture or adherence, long-term follow-up for patients with CFs and MACFs is appropriate.