Deletion of FUNDC2 and CMC4 on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men.

BACKGROUND: Hypergonadotropic hypogonadism (HH) is characterized by low sex steroid levels and secondarily elevated gonadotropin levels with either congenital or acquired etiology. Genetic factors leading to HH have yet to be fully elucidated. METHODS: Here, we report on genome and transcriptome data analyses from a male patient with HH and history of growth delay who has an inherited deletion of chromosome Xq28. Expression analyses were done for this patient and his unaffected family members and compared to normal controls to identify dysregulated genes due to this deletion. RESULTS: Our patient's Xq28 deletion is 44,806 bp and contains only two genes, FUNDC2 and CMC4. Expression of both FUNDC2 and CMC4 are completely abolished in the patient. Gene ontology analyses of differentially expressed genes (DEGs) in the patient in comparison to controls show that significantly up-regulated genes in the patient are enriched in Sertoli cell barrier (SCB) regulation, apoptosis, inflammatory response, and gonadotropin-releasing regulation. Indeed, our patient has an elevated follicle stimulating hormone (FSH) level, which regulates Sertoli cell proliferation and spermatogenesis. In his mother and sister, who are heterozygous for this deletion, X-chromosome inactivation (XCI) is skewed toward the deleted X, suggesting a mechanism to avoid FSH dysregulation. CONCLUSION: Compared to the previously reported men with variable sized Xq28 deletions, our study suggests that loss of function of FUNDC2 and CMC4 results in dysregulation of apoptosis, inflammation, and FSH, and is sufficient to cause Xq28-associated HH.

An Open-Label Prospective Study to Compare the Efficacy and Safety of Topical Fluticasone Versus Tacrolimus in the Proactive Treatment of Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD), a chronic, recurrent inflammatory skin condition primarily affects children. Topical treatment, systemic treatment, and phototherapy are mainstays of treatment. Topical corticosteroids (TCS) are first-line therapy for AD but are associated with various adverse effects. Topical calcineurin inhibitors (TCI) can be used as an alternative to TCS. OBJECTIVE: The aim of the study is to compare the efficacy of topical preparations of fluticasone and tacrolimus in reducing the severity of disease and, to assess the quality of life (QoL), and to estimate if any association exists between severity of disease and QoL. METHODS: Thirty-seven children with AD randomly received one of the 2 topical treatments, with daily application for the first 4 weeks in the acute phase and twice weekly for next 4 weeks in the maintenance phase. The severity of disease was assessed using SCORing Atopic Dermatitis (SCORAD), and QoL was assessed using the Children's Dermatology Life Quality Index (CDLQI). RESULTS: At the end of the acute phase, there was a reduction in SCORAD score of 69.29% in the fluticasone group and 64.2% in the tacrolimus group (P < 0.001). In the maintenance phase, the score had risen in the fluticasone group by a mean difference of 0.81, while in the tacrolimus group it decreased by 0.99. Both fluticasone and tacrolimus groups improved in children's QoL (P < 0.001). Positive correlation (r = 0.4668) exists between SCORAD and QoL. The most common adverse skin reaction noted was skin burning with tacrolimus. CONCLUSIONS: Fluticasone and tacrolimus are equally efficacious in the treatment of AD and have similar benefits with children's QoL. Tacrolimus is better than fluticasone at reducing the extent of lesions.

Glycation of HDL blunts its anti-inflammatory and cholesterol efflux capacities in vitro, but has no effect in poorly controlled type 1 diabetes subjects.

BACKGROUND: High-density lipoproteins (HDL) modified by glycation have been reported to be dysfunctional. Little is known regarding the anti-inflammatory effects on adipocytes of glycated HDL. AIMS: We tested whether modification of HDL in vitro by glycolaldehyde (GAD), malondialdehyde (MDA) or glucose affected HDL's anti-inflammatory properties and ability to promote cholesterol efflux. To determine whether similar changes occur in vivo, we examined modifications of apolipoprotein A1 (APOA1) and APOA2 and anti-inflammatory and cholesterol efflux properties of HDL isolated from subjects with type 1 diabetes in poor glycemic control. RESULTS: In vitro modification with both GAD and MDA blunted HDL's ability to inhibit palmitate-induced inflammation and cholesterol efflux in adipocytes. Modification of HDL by glucose had little impact on HDL function, like the response using HDL isolated from subjects with diabetes. Mass spectrophotometric analysis revealed that lysine residues in APOA1 and APOA2 of HDL modified by GAD and MDA in vitro differed from those modified by glucose, which resembled that seen with HDL from patients with type1 diabetes. CONCLUSIONS: Modification of lysine residues in HDL by GAD and MDA in vitro does not mirror the HDL glycation in vivo in patients with diabetes, but resembles HDL modified in vitro by glucose.