The functions of dendritic cells (DCs) are tightly regulated such that protective immune responses are elicited and unwanted immune responses are prevented. 1α25-dihydroxyvitamin D3 (1α25(OH)2D3) has been identified as a major factor that inhibits the differentiation and maturation of DCs, an effect dependent upon its binding to the nuclear vitamin D receptor (VDR). Physiological control of 1α25(OH)2D3 levels is critically dependent upon 25-hydroxyvitamin D3-1α-hydroxylase (1αOHase), a mitochondrial cytochrome P450 enzyme that catalyzes the conversion of inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to the active metabolite 1α25(OH)2D3. Using a human monocyte-derived DC (moDC) model, we have examined the relationship between DC VDR expression and the impact of exposure to its ligand, 1α25(OH)2D3. We show for the first time that moDCs are able to synthesize 1α25(OH)2D3 in vitro as a consequence of increased 1αOHase expression. Following terminal differentiation induced by a diverse set of maturation stimuli, there is marked transcriptional up-regulation of 1αOHase leading to increased 1αOHase enzyme activity. Consistent with this finding is the observation that the development and function of moDCs is inhibited at physiological concentrations of the inactive metabolite 25(OH)D3. In contrast to 1αOHase, VDR expression is down-regulated as monocytes differentiate into immature DCs. Addition of 1α25(OH)2D3 to moDC cultures at different time points indicates that its inhibitory effects are greater in monocyte precursors than in immature DCs. In conclusion, differential regulation of endogenous 1α25(OH)2D3 ligand and its nuclear receptor appear to be important regulators of DC biology and represent potential targets for the manipulation of DC function.

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A bstractThis work presents the fabrication, characterisation and the performance of a wearable, robust, flexible and disposable chemical barcode device based on a micro-fluidic platform that incorporates ionic liquid polymer gels (ionogels). The device has been applied to the monitoring of the pH of sweat in real time during an exercise period. The device is an ideal wearable sensor for measuring the pH of sweat since it does not contents any electronic part for fluidic handle or pH detection and because it can be directly incorporated into clothing, head-or wristbands, which are in continuous contact with the skin. In addition, due to the micro-fluidic structure, fresh sweat is continuously passing through the sensing area providing the capability to perform continuous real time analysis. The approach presented here ensures immediate feedback regarding sweat composition. Sweat analysis is attractive for monitoring purposes as it can provide physiological information directly relevant to the health and performance of the wearer without the need for an invasive sampling approach.

Cerebral palsy is commonly attributed to perinatal asphyxia. However, Schnekenberg et al. describe here four individuals with ataxic cerebral palsy likely due to de novo dominant mutations associated with increased paternal age. Therefore, patients with cerebral palsy should be investigated for genetic causes before the disorder is ascribed to asphyxia.

OBJECTIVE-The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes are largely unknown. Altered endogenous glucocorticoid metabolism, including 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1), which generates active cortisol from cortisone, and 5␣-reductase (5␣R), which inactivates cortisol, has been implicated. RESEARCH DESIGN AND METHODS-A total of 101 obese patients (mean age 48 Ϯ 7 years, BMI 34.4 Ϯ 4.3 kg/m 2 , 66 women, 35 men) underwent 75-g oral glucose tolerance testing (OGTT), body composition analysis (dual-energy X-ray absorptiometry), assessment of glucocorticoid metabolism (24-h urine steroid metabolite analysis by gas chromatography/mass spectrometry), and subcutaneous abdominal adipose tissue biopsies.RESULTS-A total of 22.7% of women had IGT compared with 34.2% of men. Two women and five men were diagnosed with type 2 diabetes. In women, adipose 11␤-HSD1 expression was increased in patients with IGT and correlated with glucose levels across the OGTT (R ϭ 0.44, P Ͻ 0.001) but was independent of fat mass. Total glucocorticoid secretion was higher in men with and without IGT (normal 13,743 Ϯ 863 vs. 7,453 Ϯ 469 g/24 h, P Ͻ 0.001; IGT 16,871 Ϯ 2,113 vs. 10,133 Ϯ 1,488 g/24 h, P Ͻ 0.05), and in women, it was higher in those with IGT (7,453 Ϯ 469 vs. 10,133 Ϯ 1,488 g/24 h, P Ͻ 0.001). In both sexes, 5␣R activity correlated with fasting insulin (men R ϭ 0.53, P ϭ 0.003; women R ϭ 0.33, P ϭ 0.02), insulin secretion across an OGTT (men R ϭ 0.46, P ϭ 0.01; women R ϭ 0.40, P ϭ 0.004), and homeostasis model assessment of insulin resistance (men R ϭ 0.52, P ϭ 0.004; women R ϭ 0.33, P ϭ 0.02).

Background-Aldosterone has emerged as a deleterious hormone in the heart, with mineralocorticoid receptor (MR) blockade reducing mortality in patients with severe heart failure. There is also experimental evidence that aldosterone contributes to the development of nephrosclerosis and renal fibrosis in rodent models, but little is known of its role in clinical renal disease. Methods and Results-We quantified MR, serum-and glucocorticoid-regulated kinase 1 (sgk1), and mRNA expression of inflammatory mediators such as macrophage chemoattractant protein-1 (MCP-1), transforming growth factor-␤1, and interleukin-6 in 95 human kidney biopsies in patients with renal failure and mild to marked proteinuria of diverse etiologic origins. We measured renal function, serum aldosterone, urinary MCP-1 protein excretion, and the amount of chronic renal damage. Macrophage invasion was quantified by CD68 and vascularization by CD34 immunostaining. Serum aldosterone correlated negatively with creatinine clearance (PϽ0.01) and positively with renal scarring (PϽ0.05) but did not correlate with MR mRNA expression or proteinuria. Patients with heavy albuminuria (Ͼ2 g/24 h; nϭ15) had the most renal scarring and the lowest endothelial CD34 staining. This group showed a significant 5-fold increase in MR, a 2.5-fold increase in sgk1 expression and a significant increase in inflammatory mediators (7-fold increase in MCP-1, 3-fold increase in transforming growth factor-␤1, and 2-fold increase in interleukin-6 mRNA). Urinary MCP-1 protein excretion and renal macrophage invasion were significantly increased in patients with heavy albuminuria. Conclusions-These studies support animal data linking aldosterone/MR activation to renal inflammation and proteinuria.Further studies are urgently required to assess the potential beneficial effects of MR antagonism in patients with renal disease.

β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

CBX is able to inhibit rapidly the generation of active GC in human adipose tissue. Importantly, limiting GC availability in vivo has functional consequences including decreased glycerol release.