Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9

Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). The functional responses of keratinocytes to different PAMPs have not yet been fully established. Here we show that keratinocytes constitutively express TLR1, 2, 3, 4, 5, 6, 9, and 10 mRNA, but not TLR7 and 8. Stimulation of keratinocytes with TLR3, 4, 5, and 9 ligands resulted in differential immune-associated responses. Tumor necrosis factor-alpha, CXC chemokine ligand 8 (CXCL8), CCL2, and C chemokine ligand 20 (CCL20) release was enhanced in response to all PAMPs tested, in a time- and dose-dependent manner. Only TLR9 ligand CpG-oligodeoxynucleotides (ODNs) and TLR3 ligand poly-I:C could additionally induce type I IFNs. CCL27 production was selectively induced by poly-I:C and flagellin, whereas CXCL9 and CXCL10 were exclusively induced by CpG-ODNs and/or poly-I:C. Upregulation of ICAM-1, HLA-DR, HLA-ABC, FasR, and CD40 was mainly observed in response to poly-I:C, flagellin, and lipopolysaccharide. Furthermore, PAMP triggering resulted in the phosphorylation of phosphorylated-IkappaB alpha and in the nucleus translocation of NF-kappaB p65. Altogether, these findings stress an unexpectedly multifaceted role of keratinocytes in innate immunity as evident by their differential, TLR-mediated responses to PAMPs associated with different classes of pathogens.     

Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study

Background  

Antipsychotic are the cornerstone in the treatment of schizophrenia. They also have a number of side-effects. Constipation is thought to be common, and a potential serious side-effect, which has received little attention in recent literature.     

The expression of excessive exercise co-segregates with the risk of developing an eating disorder in women

Excessive exercise (EE) is an important symptom of eating disorders (ED) and is a likely risk factor for developing ED, however, no population-based studies have been performed on the relationship between EE and obtaining ED diagnosis. The aim of this study was to examine the co-occurrence of EE and ED diagnosis in a general population of women. Data for 778 females (age min=30, max=55) from the Saint Thomas Twin Registry, London were used. Phenotypes analyzed included self-reported time spent on physical activity per week, ED diagnosis, Eating Disorder Inventory results (EDI-III), age, BMI and kinship (twin pair). Generalized Estimating Equation analysis showed that only EE (>5 h of exercise per week) and Bulimia Subscale of EDI-III were significantly associated with obtaining ED diagnosis throughout the life. These data revealed that the odds of ever being diagnosed with an ED are more than 2.5 times higher for excessive exercisers compared to individuals with lower activity levels. These data support the notion that EE may be an important risk factor for developing an ED in women.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Strong signatures of selection in the domestic pig genome

Domestication of wild boar (Sus scrofa) and subsequent selection have resulted in dramatic phenotypic changes in domestic pigs for a number of traits, including behavior, body composition, reproduction, and coat color. Here we have used whole-genome resequencing to reveal some of the loci that underlie phenotypic evolution in European domestic pigs. Selective sweep analyses revealed strong signatures of selection at three loci harboring quantitative trait loci that explain a considerable part of one of the most characteristic morphological changes in the domestic pig—the elongation of the back and an increased number of vertebrae. The three loci were associated with the NR6A1, PLAG1, and LCORL genes. The latter two have repeatedly been associated with loci controlling stature in other domestic animals and in humans. Most European domestic pigs are homozygous for the same haplotype at these three loci. We found an excess of derived nonsynonymous substitutions in domestic pigs, most likely reflecting both positive selection and relaxed purifying selection after domestication. Our analysis of structural variation revealed four duplications at the KIT locus that were exclusively present in white or white-spotted pigs, carrying the Dominant white, Patch, or Belt alleles. This discovery illustrates how structural changes have contributed to rapid phenotypic evolution in domestic animals and how alleles in domestic animals may evolve by the accumulation of multiple causative mutations as a response to strong directional selection.Several subspecies of wild boars have contributed to the development of the domestic pig, and there is a considerable divergence time between them (on the order of 1 million y) (1–4). The domestication process has, to a large extent, been going on in parallel in Asia and Europe. For instance, black coat color in Asian and European domestic pigs is caused by independent missense mutations in the melanocortin 1 receptor (MC1R) that occurred on haplotypes originating from the Asian and European wild boar, respectively (5). Since animal breeding became more organized in the 18th century, the selection goals in pigs have evolved in response to demand. The early focus on selection for fatness was driven by demand for energy-rich food and tallow for candles. In contrast, there has been very strong selection for lean growth (high protein and low fat content) during the last 60 y, driven by the demand for reduced caloric intake in modern society. Several mutations with major effects on lean growth have already been identified, including a missense mutation in Ryanodine receptor 1 (RYR1) (6), a missense mutation in PRKAG3 encoding the gamma 3 subunit of AMP-activated protein kinase (7), and a single base change at a repressor binding site in intron 3 of insulin-like growth factor 2 (IGF2) (8).Here we used the pig draft genome sequence (Sscrofa10.2) (4) and whole-genome resequencing to reveal loci that have been under selection during and since pig domestication. We searched for selective sweeps and genetic variants showing marked allele frequency differences between pig and wild boar populations. The results are based on the combined analyses of two datasets: (i) mate pair reads from eight different pools of pigs and wild boars sequenced to ∼5× coverage/pool, and (ii) paired-end fragment reads (100 + 100 bp) from 37 individual pigs and 11 wild boars, each sequenced to ∼10× coverage (

Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice

Polyunsaturated fatty acids (PUFAs) are one of the main cellular building blocks, and dietary changes in PUFA composition are proposed as a potential route to influence brain development. For example, initial studies indicated that there is a relation between blood omega-6(n-6)/omega-3(n-3) PUFA ratios and neurodevelopmental disease diagnosis. To study the consequences of dietary n-6/n-3 PUFA ratio changes, we investigated the impact of a n-3 supplemented and n-3 deficient diet in developing BTBR T?+?Itpr3tf/J (BTBR) – a mouse inbred strain displaying Autism Spectrum Disorder (ASD)-like symptomatology - and control C57BL/6J mice. This study showed that pre- and postnatal changed dietary n-6/n-3 ratio intake has a major impact on blood and brain PUFA composition, and led to delayed physical development and puberty onset in both strains. The PUFA induced developmental delay did not impact adult cognitive performance, but resulted in reduced social interest, a main ASD behavioral feature. Thus, both chronic dietary n-3 PUFA supplementation and depletion may not be beneficial.     

Psychopharmacological prescribing practices in pregnancy for women with severe mental illness: A multicentre study

There is little known about real world psychopharmacological prescribing practices in managing pregnant women with severe mental illness (SMI). This study utilised a sample of 535 women with a SMI across two hospitals in Australia. This included women with psychotic disorders, bipolar disorder and a range of non-psychotic disorders. The majority of women with a SMI in pregnancy were prescribed psychotropic medication as part of their management. Furthermore, more than one class of agent was prescribed for 31% of women with psychotic disorders and 30% of women with bipolar disorder. Differences between sites were identified in prescribing practices across the mental disorders. This included the variation in rates of use of multiple agents and pattern of use across pregnancy. This study also identified that women with a SMI had elevated rates of gestational hypertension, gestational diabetes mellitus, smoking and obesity in pregnancy and neonates admitted following delivery compared with the Australian average. These findings suggest that studies that examine associated risks for severe mental disorders or their treatments on pregnancy and infant outcomes should take into account the prescribing practices including the likelihood of exposure to polypharmacy and a range of potential confounding co-morbidities and exposures. The discrepancies in reported findings for pregnancy and infant outcomes following use of antipsychotic and mood stabiliser agents such as lithium may be at least partially accounted for by the complexity of multiple exposures that includes use of multiple psychopharmacological agents, co-exposures such as smoking and co-morbid conditions such as obesity.     

SPET brain imaging with 201 diethyldithiocarbamate in acute ischaemic stroke

Thirty-five patients with acute ischaemic stroke were studied within 24 h after hospital admission with thallium 201 diethyldithiocarbamate single photon emission tomography (²⁰¹TI-DDC SPET) and X-ray computed tomography (CT).²⁰¹TI-DDC is a non-redistributing agent that allows postponed imaging after early administration and early therapeutic intervention. In 16 patients both investigations were performed within 24 h after stroke onset. The sensitivity of SPET was 94% and of CT 81 % in the first 24 h, when hypodensity and obliteration of sulci were used as CT reading criteria. When only hypodensity was used as a criterion, the sensitivity of CT was 50% in this group. Sensitivity of CT compared with SPET became increasingly better in patients with older infarcts (1–18 days). In two-thirds of patients, the lesion demonstrated on SPET was larger than that on CT, and this was especially so with older infarcts. Crossed cerebellar diaschisis occurred in 69% of patients. The high sensitivity of²⁰¹TI-DDC SPET in the first 24 h after ischaemic stroke and the favourable properties of this radiopharmaceutical make it a method of interest in the assessment of initial perfusion defects in early experimental stroke therapies.     

Attachment transition, addiction and therapeutic bonding-An integrative approach

In the light of the attachment theory and research outlines the authors develop the concept that addiction is a delayed maladaptive attachment transition in young adults. They look into the relevance of this theoretical framework for therapy in adulthood, especially addiction therapy, connect it with an approach, that understands addiction as fear of intimacy and discuss the clinical implications of therepeutic bonding as a specialized approach for this condition.