Genetic susceptibility to psoriasis: an emerging picture

Psoriasis is recognized as a complex disease for which multiple genetic and non-genetic factors influence susceptibility. The major susceptibility locus resides in the MHC class I region and, until relatively recently, evidence for non-MHC loci was inconsistent. Like many common diseases, knowledge of the genetic basis of this condition has been advanced dramatically in recent times with the advent of genome-wide association studies using single nucleotide polymorphisms. Here, we give an overview of current knowledge of genetic risk factors for psoriasis and consider emerging studies that may further add to our understanding of the genetic basis of the disease

Sonic hedgehog signalling mediates astrocyte crosstalk with neurons to confer neuroprotection

Sonic hedgehog (SHH) is a glycoprotein associated with development that is also expressed in the adult CNS and released after brain injury. Since the SHH receptors patched homolog-1 and Smoothened are highly expressed on astrocytes, we hypothesized that SHH regulates astrocyte function. Primary mouse cortical astrocytes derived from embryonic Swiss mouse cortices, were treated with two chemically distinct agonists of the SHH pathway, which caused astrocytes to elongate and proliferate. These changes are accompanied by decreases in the major astrocyte glutamate transporter-1 and the astrocyte intermediate filament protein glial fibrillary acidic protein. Multisite electrophysiological recordings revealed that the SHH agonist, smoothened agonist suppressed neuronal firing in astrocyte-neuron co-cultures and this was abolished by the astrocyte metabolic inhibitor ethylfluoroacetate, revealing that SHH stimulation of metabolically active astrocytes influences neuronal firing. Using three-dimensional co-culture, MAP2 western blotting and immunohistochemistry, we show that SHH-stimulated astrocytes protect neurons from kainate-induced cell death. Altogether the results show that SHH regulation of astrocyte function represents an endogenous neuroprotective mechanism

Attitudes and Beliefs Regarding Pain in Interprofessional Education: A Multifaceted Dilemma

Purpose: To evaluate entry-level physical and occupational therapy student attitudes and beliefs toward treating a person with pain, at various levels of their didactic learning. Description: Across health professions, pain education varies considerably with its curricula of pain definitions, management principles, and interprofessional collaboration. The result of this discord has led to a broad range of behaviors and attitudes among health professions and their students, which can ultimately affect a person’s participation in society. Literature supports the importance of a curriculum that addresses students’ attitudes and beliefs toward treating people in pain in an attempt to preclude the formation of negative attitudes during clinical practice. Summary of Use: A modified open-ended sentence stem format was used to gather the qualitative data of 241 graduate students enrolled in occupational and physical therapy entry-level programs to assess their knowledge and attitudes toward pain. Students completed a questionnaire including two open-ended sentence stems. Verbatim transcripts of the students’ responses were thematically analyzed by five-blinded faculty, who constructed nine themes that reflected students’ responses. Interrater reliability was strong with an average of 89.4% agreement rating (range 68.1-97.6%). Analysis of the responses to the first stem, “People in pain are…” yielded four themes: 1) negative mood sate (suffering/unhappy); 2) negative trait or characteristic (wimpy/uncooperative); 3) needy; and 4) having real problems. The percentages of the students’ attitudes reflected in each theme were 28.8%, 5.1%, 42.7%, 23.4% respectively. Responses were dominated by themes related to a negative mood state and being needy. Negative attitudes toward treatment of persons in pain have been shown to contribute to disparities in pain care. Analysis of responses to the second stem question, “Working with patients in pain will be …” yielded five themes: 1) intellectually stimulating; 2) worthwhile/rewarding; 3) unpleasant/difficult; 4) challenging/complex; and 5) routine in practice. The frequency of responses were 8.3%, 33%, 19.8%, 38.9%, and 12.6% respectively and were dominated by themes suggesting that working with people in pain will be challenging yet rewarding. Importance to Member: Despite the frequency of pain problems in society, pain and the treatment of people in pain have not been major components of healthcare education. The International Association for the Study of Pain (IASP) provides a guideline for knowledge of pain management for entry-level physical and occupational therapists. Knowing what preconceived attitudes and beliefs students have in treating persons with pain can help drive the development of a pain curriculum that is both academically inclusive and behaviorally influential. As educators, we have the opportunity to address this multifaceted dilemma to meet the IASP guidelines and bridge the gap between interprofessional pain education and the optimal treatment of those in pain

POSaM: a fast, flexible, open-source, inkjet oligonucleotide synthesizer and microarrayer

DNA arrays are valuable tools in molecular biology laboratories. Their rapid acceptance was aided by the release of plans for a pin-spotting microarrayer by researchers at Stanford. Inkjet microarraying is a flexible, complementary technique that allows the synthesis of arrays of any oligonucleotide sequences de novo. We describe here an open-source inkjet arrayer capable of rapidly producing sets of unique 9,800-feature arrays

Recycling Argon through Metamorphic Reactions: the Record in Symplectites

The 40Ar/39Ar ages of metamorphic micas that crystallized at high temperatures are commonly interpreted as cooling ages, with grains considered to have lost 40Ar via thermally-driven diffusion into the grain boundary network. Recently reported laser-ablation data suggest that the spatial distribution of Ar in metamorphic micas does not always conform to the patterns predicted by diffusion theory and that despite high metamorphic temperatures, argon was not removed efficiently from the local system during metamorphic evolution. In the Western Gneiss Region (WGR), Norway, felsic gneisses preserve microtextural evidence for the breakdown of phengite to biotite and plagioclase symplectites during near isothermal decompression from c. 20–25 to c. 8–12 kbar at ~700°C. These samples provide an ideal natural laboratory to assess whether the complete replacement of one K-bearing mineral by another at high temperatures completely ‘resets’ the Ar clock, or whether there is some inheritance of 40Ar in the neo-crystallized phase. The timing of the high-temperature portion of the WGR metamorphic cycle has been well constrained in previous studies. However, the timing of cooling following the overprint is still much debated. In-situ laser ablation spot dating in phengite, biotite-plagioclase symplectites and coarser, texturally later biotite yielded 40Ar/39Ar ages that span much of the metamorphic cycle. Together these data show that despite residence at temperatures of ~700°C, Ar is not completely removed by diffusive loss or during metamorphic recrystallization. Instead, Ar released during phengite breakdown appears to be partially reincorporated into the newly crystallizing biotite and plagioclase (or is trapped in fluid inclusions in those phases) within a close system. Our data show that the microtextural and petrographic evolution of the sample being dated provides a critical framework in which local 40Ar recycling can be tracked, thus potentially allowing 40Ar/39Ar dates to be linked more accurately to metamorphic history

The interleukin 1 receptor antagonist anakinra to reduce disease severity of palmoplantar pustulosis in adults: APRICOT RCT and PLUM mechanistic study

Background: Palmoplantar pustulosis is a rare, debilitating, chronic skin disease involving the hands and feet, and there are limited treatment options. Mechanistic findings suggest that interleukin 1 may be a pathogenic driver. // Objective: To determine whether or not anakinra [Sobi (Swedish Orphan Biovitrum AB), Stockholm, Sweden], an interleukin 1 receptor antagonist, delivers therapeutic benefit in palmoplantar pustulosis. // Design: A Phase IV, randomised, double-blind, placebo-controlled study with two stages and an adaptive element (24 participants in stage 1, 64 participants in total) with an open-label extension. // Setting: Sixteen hospitals across England, Scotland and Wales. // Participants: Adults (aged ≥ 18 years) with a diagnosis of palmoplantar pustulosis and a disease duration of > 6 months and of sufficient impact and severity to require systemic therapy. // Interventions Participants were randomised (1 : 1) to daily self-administered subcutaneous injection of either anakinra or a placebo for 8 weeks. Main outcome measures The primary outcome was the Palmoplantar Pustulosis Area and Severity Index score measured at 0, 1, 4, 8 and 12 weeks, with the primary end point at 8 weeks adjusted for baseline. Secondary outcomes included other investigator-assessed efficacy measures of disease severity, safety measures and participant-reported measures of efficacy and impact. Results A total of 64 participants (mean baseline Palmoplantar Pustulosis Area and Severity Index score of 17.8, standard deviation 10.5) received anakinra (n = 31) or the placebo (n = 33). In the primary intention-to-treat analysis, which estimated the effect of the treatment policy, the mean treatment group difference at 8 weeks after adjustment for baseline Palmoplantar Pustulosis Area and Severity Index score was –1.65 (95% confidence interval –4.77 to 1.47; p = 0.300), in favour of anakinra relative to placebo, but was not statistically significant. Similarly, secondary investigator-assessed outcomes did not show statistical superiority of anakinra: the baseline-adjusted mean difference in fresh pustule count (palms and soles) between the anakinra group and the placebo group was 2.94 (95% confidence interval –26.44 to 32.33), in favour of placebo, and the mean difference in total pustule count was –30.08 (95% confidence interval –83.20 to 23.05), in favour of anakinra. Participant-assessed outcomes were consistent with these objective findings: the baseline-adjusted mean difference in Dermatology Life Quality Index between the anakinra group and the placebo group was 0.52 (95% confidence interval –2.04 to 3.07), in favour of placebo, and the mean difference in Palmoplantar Quality-of-Life Index was 1.27 (95% confidence interval –3.04 to 5.57), in favour of placebo. However, the proportion of participants who strongly agreed that treatment was worthwhile was greater in the anakinra group (12/29, 41%) than in the placebo group (4/28, 14%), a difference in proportion of 27% (95% confidence interval 5% to 49%). In the complier-average causal effect analysis, the baseline-adjusted mean treatment group difference in the week 8 Palmoplantar Pustulosis Area and Severity Index score in individuals who received ≥ 50% of injections was –2.30 (95% confidence interval –6.54 to 1.93; p = 0.287) and in those who received ≥ 90% of injections was –3.80 (95% confidence interval –10.76 to 3.16; p = 0.285), in favour of anakinra. No serious infections, significant neutropenia or other serious adverse events occurred. Injection site reactions were more frequent for those receiving anakinra (19/31, 61%) than for those receiving placebo (1/33, 3%). // Conclusions: There was no evidence that anakinra was superior to placebo. For the treatment of palmoplantar pustulosis, interleukin 1 blockade is not a useful intervention. // Limitations: The sample size was calculated to detect a large effect size. Treatment adherence was lower than expected. It cannot be ruled out that there was some selection bias towards less severe or unstable participants entering the trial given that the trial was placebo controlled with a required washout period. // Future work: Palmoplantar pustulosis remains an area of high unmet need and further research is recommended to (1) identify new drug targets, (2) determine the contributory role of drug exposure (including pharmacokinetics and adherence) and (3) validate outcome measures in palmoplantar pustulosis. // Trial registration: This trial is registered as ISCRTN13127147 and EudraCT 2015-003600-23. // Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 2. See the NIHR Journals Library for further project information

Comparison of Winter Cow Feeding Strategies on Offspring Carcass Characteristics and Meat Quality

Objective The objective of this research was to investigate effects of maternal prepartum dietary energy source (forage vs. concentrate) during mid and late gestation on carcass composition, and meat quality of offspring.Study Description Angus-based cows from 2 sources [n = 129 from SDSU (Experiment 1) and n = 70 from North Dakota State University (Experiment 2)] were stratified by body weight and age and placed into two treatment groups at a drylot facility during mid- and late-gestation: Concentrate (dams fed a concentrate-based diet) or Forage (dams fed a forage-based diet). Calves were finished and carcass data was collected. Striploins were collected for meat quality evaluation

Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Drug survival reflects a drug’s effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09–1.37), being a current smoker (HR 1.19; 95% CI: 1.03–1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00–1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71–0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45–1.84) or infliximab (HR 1.56; 95% CI: 1.16–2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37–0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients