Vitamin D Oral Replacement in Children With Obesity Related Asthma: VDORA1 Randomized Clinical Trial.

Children with asthma and obesity are more likely to have lower vitamin D levels, but the optimal replacement dose is unknown in this population. The objective of this study is identifying a vitamin D dose in children with obesity-related asthma that safely achieves serum vitamin D levels of ≥ 40 ng/mL. This prospective multisite randomized controlled trial recruited children/adolescents with asthma and body mass index ≥ 85% for age/sex. Part 1 (dose finding), evaluated 4 oral vitamin D regimens for 16 weeks to identify a replacement dose that achieved serum vitamin D levels ≥ 40 ng/mL. Part 2 compared the replacement dose calculated from part 1 (50,000 IU loading dose with 8,000 IU daily) to standard of care (SOC) for 16 weeks to identify the proportion of children achieving target serum 25(OH)D level. Part 1 included 48 randomized participants. Part 2 included 64 participants. In Part 1, no SOC participants achieved target serum level, but 50-72.7% of participants in cohorts A-C achieved the target serum level. In part 2, 78.6% of replacement dose participants achieved target serum level compared with none in the SOC arm. No related serious adverse events were reported. This trial confirmed a 50,000 IU loading dose plus 8,000 IU daily oral vitamin D as safe and effective in increasing serum 25(OH)D levels in children/adolescents with overweight/obesity to levels ≥ 40 ng/mL. Given the critical role of vitamin D in many conditions complicating childhood obesity, these data close a critical gap in our understanding of vitamin D dosing in children.

Clitoromegaly Secondary to Exogenous Androgen Exposure From Paternal Skin to Skin Transfer.

Clitoromegaly is the abnormal enlargement of the clitoris. Its etiology is often divided into congenital and acquired causes, leading to a differential diagnosis that is quite broad. Workup often includes serum hormone testing, imaging studies, and sometimes an investigation into genetic and nonhormonal causes, which can be obtained from a detailed patient history. Exposure to exogenous or endogenous androgens can directly stimulate and enlarge the clitoris, resulting in early virilization. Transdermal testosterone gel can be transferred from the skin of an adult to the skin of a child. Topical testosterone gel is an approved therapy for the treatment of hypoandrogenism in males. While it offers a convenient means of treatment, there is a concern about unintentional exposure to females and children from skin contact with the application site. Here, we report a case of an infant who presented to a pediatric endocrinology clinic for clitoromegaly that was possibly due to exogenous exposure to testosterone.

Pediatric metabolic outcome comparisons based on a spectrum of obesity and asthmatic symptoms.

RATIONALE: Asthma and obesity are 2 of the most prevalent public health issues for children in the U.S. Trajectories of both have roughly paralleled one another over the past several decades causing many to explore their connection to one another and to other associated health issues such as diabetes and dyslipidemia. Earlier models have commonly designated obesity as the central hub of these associations; however, more recent models have argued connections between pediatric asthma and other obesity-related metabolic conditions regardless of children's obesity risk. OBJECTIVES: To examine the relationships between asthma, obesity, and abnormal metabolic indices. METHODS: We conducted a cross-sectional study of 179 children ages 7 to 12 years recruited from a rural, Appalachian region. Our model controlled for children's smoke exposure, body mass index percentile, and gender to examine the association between children's asthma (based on pulmonary function tests, medical history, medications, and parent report of severity), lipids (fasting lipid profile), and measures of altered glucose metabolism (glycosylated hemoglobin and homeostatic model assessment 2-insulin resistance). RESULTS: Our findings revealed a statistically significant model for low density lipids, high density lipids, log triglyceride, and homeostatic model assessment 2-insulin resistance; however, Asthma had a significant effect for the mean triglycerides. We also found an asthma-obesity interaction effect on children's glycosylated hemoglobin with asthmatic obese children revealing significantly higher glycosylated hemoglobin values than non-asthmatic obese children. CONCLUSIONS: Our findings support a connection between asthma and children's glycosylated hemoglobin values; however, this association remains entwined with obesity factors.

TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells.

Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action.

Reduced AMPK-ACC and mTOR signaling in muscle from older men, and effect of resistance exercise.

AMP-activated protein kinase (AMPK) is a key energy-sensitive enzyme that controls numerous metabolic and cellular processes. Mammalian target of rapamycin (mTOR) is another energy/nutrient-sensitive kinase that controls protein synthesis and cell growth. In this study we determined whether older versus younger men have alterations in the AMPK and mTOR pathways in skeletal muscle, and examined the effect of a long term resistance type exercise training program on these signaling intermediaries. Older men had decreased AMPKα2 activity and lower phosphorylation of AMPK and its downstream signaling substrate acetyl-CoA carboxylase (ACC). mTOR phosphylation also was reduced in muscle from older men. Exercise training increased AMPKα1 activity in older men, however, AMPKα2 activity, and the phosphorylation of AMPK, ACC and mTOR, were not affected. In conclusion, older men have alterations in the AMPK-ACC and mTOR pathways in muscle. In addition, prolonged resistance type exercise training induces an isoform-selective up regulation of AMPK activity.

An institutional experience with epidural analgesia in children and young adults undergoing cardiac surgery.

BACKGROUND: Allowing spontaneous respiration after cardiac surgery eliminates complications related to mechanical ventilation and optimizes cardiopulmonary interaction. Epidural analgesia has been proposed to promote early extubation after cardiac surgery. OBJECTIVE: To identify the characteristics of patients with epidural analgesia and safety profiles with respect to the timing of extubation following cardiac surgery. DESIGN AND METHOD: A retrospective chart review of patients who underwent cardiac surgery during a 5-year period. Demographic, procedural, and perioperative variables were analyzed to investigate factors that affect the timing of extubation. RESULTS: A total of 750 records were reviewed. The patients' median age was 12 months, and 52% were infants (<1 year). Seventy-five percent of the patients utilized cardiopulmonary bypass. The study population was classified into three groups according to the timing of extubation: 66% were extubated in the operating room or upon arrival at the PICU (Immediate), 15% were extubated within 24 h (mean, 10.8 h; 95% CI, 9.0-12.6) (Early), and 19% were extubated after 24 h (Delayed). For the Immediate and Early groups, multivariate logistic regression identified young age, increased cross-clamp time, and inotrope score as independent risk factors for the need for mechanical ventilation. Postextubation respiratory acidosis (mean P(a)CO(2), 50 mmHg; 95% CI, 49-51) was well tolerated by all patients. There were no neurologic complications related to the epidural technique. CONCLUSION: Epidural analgesia in children undergoing cardiac surgery provides stable analgesia without complications in our experience.