Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne

Organizing Engineering Work - A Comparative-Analysis

This article analyzes the organization of engineering work in six industrial capitalist countries. It identifies four major models for the organization of engineering work; the engineering profession did not succeed in achieving professional “closure” in any of the six countries under review. A review of the historical evolution of the organization of engineering work in each of the six countries reveals that engineering has been shaped by a complex interaction among the profession itself, employers, the state, labor, and preindustrial forces. However, none of the national variations on the four models for organizing engineering labor is stable or without internal contradiction because of the ambiguous “intermediate” position of engineers

Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

BACKGROUND: The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF

Estrogen-like activity of seafood related to environmental chemical contaminants

BACKGROUND: A wide variety of environmental pollutants occur in surface waters, including estuarine and marine waters. Many of these contaminants are recognised as endocrine disrupting chemicals (EDCs) which can adversely affect the male and female reproductive system by binding the estrogen receptor and exhibiting hormone-like activities. In this study the estrogenic activity of extracts of edible marine organisms for human consumption from the Mediterranean Sea was assayed. METHODS: Marine organisms were collected in two different areas of the Mediterranean Sea. The estrogenic activity of tissues was assessed using an in vitro yeast reporter gene assay (S. cerevisiae RMY 326 ER-ERE). Concentrations of polychlorinated biphenyls (PCBs) (congeners 28, 52, 101, 118, 138, 153, 180) in fish tissue was also evaluated. RESULTS: Thirty-eight percent of extracts showed a hormone-like activity higher than 10% of the activity elicited by 10 nM 17b-estradiol (E2) used as control. Total PCB concentrations ranged from 0.002 up to 1.785 ng/g wet weight. Chemical analyses detected different levels of contamination among the species collected in the two areas, with the ones collected in the Adriatic Sea showing concentrations significantly higher than those collected in the Tyrrhenian Sea (p < 0.01). CONCLUSION: The more frequent combination of chemicals in the samples that showed higher estrogenic activity was PCB 28, PCB 101, PCB 153, PCB 180. The content of PCBs and estrogenic activity did not reveal any significant correlation

The effects of vaccination and immunity on bacterial infection dynamics in vivo.

Salmonella enterica infections are a significant global health issue, and development of vaccines against these bacteria requires an improved understanding of how vaccination affects the growth and spread of the bacteria within the host. We have combined in vivo tracking of molecularly tagged bacterial subpopulations with mathematical modelling to gain a novel insight into how different classes of vaccines and branches of the immune response protect against secondary Salmonella enterica infections of the mouse. We have found that a live Salmonella vaccine significantly reduced bacteraemia during a secondary challenge and restrained inter-organ spread of the bacteria in the systemic organs. Further, fitting mechanistic models to the data indicated that live vaccine immunisation enhanced both the bacterial killing in the very early stages of the infection and bacteriostatic control over the first day post-challenge. T-cell immunity induced by this vaccine is not necessary for the enhanced bacteriostasis but is required for subsequent bactericidal clearance of Salmonella in the blood and tissues. Conversely, a non-living vaccine while able to enhance initial blood clearance and killing of virulent secondary challenge bacteria, was unable to alter the subsequent bacterial growth rate in the systemic organs, did not prevent the resurgence of extensive bacteraemia and failed to control the spread of the bacteria in the body.This work was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/I002189/1].This is the published manuscript. It was originally published by PLOS One here: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1004359

Differential expression of MUC genes in endometrial and cervical tissues and tumors

BACKGROUND: Mucin glycoprotein's are major components of mucus and are considered an important class of tumor associated antigens. The objective of this study was to investigate the expression of human MUC genes (MUC1, MUC2, MUC5B, MUC5AC and MUC8) in human endometrium and cervix, and to compare and quantitate the expression of MUC genes in normal and cancerous tissues. METHODS: Slot blot techniques were used to study the MUC gene expression and quantitation. RESULTS: Of the five-mucin genes studied, MUC1, MUC5B and MUC8 showed high expression levels in the normal and cancerous endometrial and cervical tissues, MUC2 and MUC5AC showed considerably lower expression. Statistically, higher levels of MUC1, MUC5B and MUC8 were observed in endometrial adenocarcinomas compared to normal tissues. In contrast, only MUC1 levels increased with no significant changes in expression of MUC5B and MUC8 in cervical tumors over normal cervical tissues. CONCLUSION: Endometrial tumors showed increased expression of MUC1, MUC5B and MUC8 over normal tissues. Only MUC1 appears to be increase, in cervical tumors. All the studied tissues showed high and consistent expression of MUC8 mRNA. Low to neglible levels of MUC2 and MUC5AC were observed in all studied endometrial and cervical tissues

Wnt Signalling Pathway Parameters for Mammalian Cells

Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a computational model of Wnt signalling supported by experimental data from analysis of time-dependent concentration of Wnt signalling proteins in Xenopus egg extracts. Subsequent studies have used the Xenopus quantitative data to infer Wnt pathway dynamics in other systems. As a basis for understanding Wnt signalling in mammalian cells, a confocal live cell imaging measurement technique is developed to measure the cell and nuclear volumes of MDCK, HEK293T cells and 3 human colorectal cancer cell lines and the concentrations of Wnt signalling proteins β-catenin, Axin, APC, GSK3β and E-cadherin. These parameters provide the basis for formulating Wnt signalling models for kidney/intestinal epithelial mammalian cells. There are significant differences in concentrations of key proteins between Xenopus extracts and mammalian whole cell lysates. Higher concentrations of Axin and lower concentrations of APC are present in mammalian cells. Axin concentrations are greater than APC in kidney epithelial cells, whereas in intestinal epithelial cells the APC concentration is higher than Axin. Computational simulations based on Lee's model, with this new data, suggest a need for a recalibration of the model

Pancreatic enzyme replacement therapy in patients with pancreatic cancer: A national prospective study

Objective: UK national guidelines recommend pancreatic enzyme replacement therapy (PERT) in pancreatic cancer. Over 80% of pancreatic cancers are unresectable and managed in non-surgical units. The aim was to assess variation in PERT prescribing, determine factors associated with its use and identify potential actions to improve prescription rates. Design: RICOCHET was a national prospective audit of malignant pancreatic, peri-ampullary lesions or malignant biliary obstruction between April and August 2018. This analysis focuses on pancreatic cancer patients and is reported to STROBE guidelines. Multivariable regression analysis was undertaken to assess factors associated with PERT prescribing. Results: Rates of PERT prescribing varied among the 1350 patients included. 74.4% of patients with potentially resectable disease were prescribed PERT compared to 45.3% with unresectable disease. PERT prescription varied across surgical hospitals but high prescribing rates did not disseminate out to the respective referring network. PERT prescription appeared to be related to the treatment aim for the patient and the amount of clinician contact a patient has. PERT prescription in potentially resectable patients was positively associated with dietitian referral (p = 0.001) and management at hepaticopancreaticobiliary (p = 0.049) or pancreatic unit (p = 0.009). Prescription in unresectable patients also had a negative association with Charlson comorbidity score 5–7 (p = 0.045) or >7 (p = 0.010) and a positive association with clinical nurse specialist review (p = 0.028). Conclusion: Despite national guidance, wide variation and under-treatment with PERT exists. Given that most patients with pancreatic cancer have unresectable disease and are treated in non-surgical hospitals, where prescribing is lowest, strategies to disseminate best practice and overcome barriers to prescribing are urgently required

Behavioural and Developmental Interventions for Autism Spectrum Disorder: A Clinical Systematic Review

Background: Much controversy exists regarding the clinical efficacy of behavioural and developmental interventions for improving the core symptoms of autism spectrum disorders (ASD). We conducted a systematic review to summarize the evidence on the effectiveness of behavioural and developmental interventions for ASD. Methods and Findings: Comprehensive searches were conducted in 22 electronic databases through May 2007. Further information was obtained through hand searching journals, searching reference lists, databases of theses and dissertations, and contacting experts in the field. Experimental and observational analytic studies were included if they were written in English and reported the efficacy of any behavioural or developmental intervention for individuals with ASD. Two independent reviewers made the final study selection, extracted data, and reached consensus on study quality. Results were summarized descriptively and, where possible, meta-analyses of the study results were conducted. One-hundred-and-one studies at predominantly high risk of bias that reported inconsistent results across various interventions were included in the review. Meta-analyses of three controlled clinical trials showed that Lovaas treatment was superior to special education on measures of adaptive behaviour, communication and interaction, comprehensive language, daily living skills, expressive language, overall intellectual functioning and socialization. High-intensity Lovaas was superior to low-intensity Lovaas on measures of intellectual functioning in two retrospective cohort studies. Pooling the results of two randomized controlle

Treatment of Acne Keloidalis Nuchae: A Systematic Review of the Literature

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition that leads to fibrotic plaques, papules and alopecia on the occiput and/or nape of the neck. Traditional medical management focuses on prevention, utilization of oral and topical antibiotics, and intralesional steroids in order to decrease inflammation and secondary infections. Unfortunately, therapy may require months of treatment to achieve incomplete results and recurrences are common. Surgical approach to treatment of lesions is invasive, may require general anesthesia and requires more time to recover. Light and laser therapies offer an alternative treatment for AKN. The present study systematically reviews the currently available literature on the treatment of AKN. While all modalities are discussed, light and laser therapy is emphasized due to its relatively unknown role in clinical management of AKN. The most studied modalities in the literature were the 1064-nm neodymium-doped yttrium aluminum garnet laser, 810-nm diode laser, and CO(2) laser, which allow for 82–95% improvement in 1–5 sessions. Moreover, side effects were minimal with transient erythema and mild burning being the most common. Overall, further larger-scale randomized head to head control trials are needed to determine optimal treatments