Impact of environmental factors in predicting daily severity scores of atopic dermatitis

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease that affects 20% of children worldwide. Environmental factors including weather and air pollutants have been shown to be associated with AD symptoms. However, the time‐dependent nature of such a relationship has not been adequately investigated. This paper aims to assess whether real‐time data on weather and air pollutants can make short‐term prediction of AD severity scores.MethodsUsing longitudinal data from a published panel study of 177 paediatric patients followed up daily for 17 months, we developed a statistical machine learning model to predict daily AD severity scores for individual study participants. Exposures consisted of daily meteorological variables and concentrations of air pollutants, and outcomes were daily recordings of scores for six AD signs. We developed a mixed‐effect autoregressive ordinal logistic regression model, validated it in a forward‐chaining setting and evaluated the effects of the environmental factors on the predictive performance.ResultsOur model successfully made daily prediction of the AD severity scores, and the predictive performance was not improved by the addition of measured environmental factors. Potential short‐term influence of environmental exposures on daily AD severity scores was outweighed by the underlying persistence of preceding scores.ConclusionsOur data does not offer enough evidence to support a claim that weather or air pollutants can make short‐term prediction of AD signs. Inferences about the magnitude of the effect of environmental factors on AD severity scores require consideration of their time‐dependent dynamic nature.     

Comparing downstream consequences of normal exercise stress echocardiograms and cardiac computed tomography angiography scans in patients suspected of having of obstructive coronary artery disease: a retrospective cohort study of Tricare beneficiaries

The International Journal of Cardiovascular Imaging - To compare overall number of downstream tests and total costs between negative exercise stress echocardiograms (ESE) or cardiac computed...     

Enamel and dentin mineralization in familial hypophosphatemic rickets: a micro-CT study

Objectives:

The aim of the present study was to analyse the mineralization pattern of enamel and dentin in patients affected by X-linked hypophosphatemic rickets (XLHR) using micro-CT (µCT), and to associate enamel and dentin mineralization in primary and permanent teeth with tooth position, gender and the presence/absence of this disease.

Methods:

19 teeth were collected from 5 individuals from the same family, 1 non-affected by XLHR and 4 affected by XLHR. Gender, age, tooth position (anterior/posterior) and tooth type (deciduous/permanent) were recorded for each patient. Following collection, teeth were placed in 0.1% thymol solution until µCT scan. Projection images were reconstructed and analysed. A plot profile describing the greyscale distance relationship in µCT images was achieved through a line bisecting each tooth in a region with the presence of enamel and dentin. The enamel and dentin mineralization densities were measured and compared. Univariate ANOVA and post hoc Tukey tests were used for all comparisons.

Results:

Teeth of all affected patients presented dentin with a different mineralization pattern compared with the teeth of healthy patients with dentin defects observed next to the pulp chambers. Highly significant differences were found for gray values between anterior and posterior teeth (p < 0.05), affected and non-affected (p < 0.05), as well as when position and disease status were considered (p < 0.05).

Conclusions:

In conclusion, the mineralization patterns of dentin differed when comparing teeth from patients with and without FHR, mainly next to pulp chambers where areas with porosity and consequently lower mineral density and dentin defects were found.     

Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD⁺) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD⁺ precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m²) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD⁺ levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD⁺ boosters can also directly affect skeletal muscle mitochondrial function in humans.     

Female Gender and Diabetes Mellitus Increase the Risk of Recurrence after Laparoscopic Incisional Hernia Repair

Background

Laparoscopic hernia repair is used widely for the repair of incisional hernias. Few case studies have focussed on purely ‘incisional’ hernias. This multicentre series represents a collaborative effort and employed statistical analyses to provide insight into the factors predisposing to recurrence of incisional hernia after laparoscopic repair. A specific hypothesis (ie, laterality of hernias as well as proximity to the xyphoid process and pubic symphysis predisposes to recurrence) was also tested.

Methods

This was a retrospective study of all laparoscopic incisional hernias undertaken in six centres from 1 January 2004 to 31 December 2010. It comprised a comprehensive review of case notes and a follow-up using a structured telephone questionnaire. Patient demographics, previous medical/surgical history, surgical procedure, postoperative recovery, and perceived effect on quality of life were recorded. Repairs undertaken for primary ventral hernias were excluded. A logistic regression analysis was then fitted with recurrence as the primary outcome.

Results

A total of 186 cases (91 females) were identified. Median follow-up was 42 months. Telephone interviews were answered by 115/186 (62%) of subjects. Logistic regression analyses suggested that only female sex (odds ratio (OR) 3.53; 95% confidence interval (CI) 1.39–8.97) and diabetes mellitus (3.54; 1–12.56) significantly increased the risk of recurrence. Position of the defect had no statistical effect.

Conclusions

These data suggest an increased risk of recurrence after laparoscopic incisional hernia repair in females and subjects with diabetes mellitus. These data will help inform surgeons and patients when considering laparoscopic management of incisional hernias. We recommend a centrally hosted, prospectively maintained national/international database to carry out additional research.     

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband–parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P=1.5 × 10⁻⁴). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P=0.018) and de novo mutations (P=0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N=614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.     

Isolation and characterisation of microsatellite loci for the ancient cephalopod,Nautilus pompilius

Conservation Genetics Resources - A microsatellite-enriched genomic library was created from a single Nautilus pompilius individual and clones/fragments sequenced using Sanger and Illumina MiSeq...     

A segment of cold shock protein directs the folding of a combinatorial protein

It has been suggested that protein domains evolved by the non-homologous recombination of building blocks of subdomain size. In earlier work we attempted to recapitulate domain evolution in vitro. We took a polypeptide segment comprising three beta-strands in the monomeric, five-stranded beta-barrel cold shock protein (CspA) of Escherichia coli as a building block. This segment corresponds to a complete exon in homologous eukaryotic proteins and includes residues that nucleate folding in CspA. We recombined this segment at random with fragments of natural proteins and succeeded in generating a range of folded chimaeric proteins. We now present the crystal structure of one such combinatorial protein, 1b11, a 103-residue polypeptide that includes segments from CspA and the S1 domain of the 30S ribosomal subunit of E. coli. The structure reveals a segment-swapped, six-stranded beta-barrel of unique architecture that assembles to a tetramer. Surprisingly, the CspA segment retains its structural identity in 1b11, recapitulating its original fold and deforming the structure of the S1 segment as necessary to complete a barrel. Our work provides structural evidence that (i) random shuffling of nonhomologous polypeptide segments can lead to folded proteins and unique architectures, (ii) many structural features of the segments are retained, and (iii) some segments can act as templates around which the rest of the protein folds.