Circulating Tumour Necrosis Factor is highly correlated with brainstem serotonin transporter availability in humans

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [123I] -beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8 weeks was associated with a significant reduction in 5-HTT availability (Z= 2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression

Prosthesis use is associated with reduced physical self-disgust in limb amputees

Self-disgust is an emotion schema negatively affecting people’s body image and is triggered by bodily imperfections and deviations from the “normal” body envelope. In this study, we explore the idea that “normalising” the body in those with limb amputations via the prosthesis would be linked to reduced self-directed disgust. An international clinical community sample (N = 83) with mostly lower limb amputations completed measures about their demographics, prosthesis, adjustment, body image disturbance, psychological distress, and self-directed disgust in a survey design. Consistent with the “normalising” hypothesis, correlation and bootstrapped regression models revealed, first, that frequency of prosthesis use was significantly and negatively associated with physical self-disgust. Second, prosthesis use significantly mediated the exogenous effect of time since amputation on physical self-disgust. These results emphasise the psychological value of the prosthesis beyond its functional use, and stress its importance in normalising the body envelope in those with limb amputations, which may in turn promote psychological well-being

An evaluation of exact matching and propensity score methods as applied in a comparative effectiveness study of inhaled corticosteroids in asthma

Peer reviewedPublisher PD

Dysregulation of Connexin expression plays a pivotal role in psoriasis

Background: Psoriasis, a chronic inflammatory disease affecting 2–3% of the population, is characterised by epidermal hyperplasia, a sustained pro-inflammatory immune response and is primarily a T-cell driven disease. Previous work determined that Connexin26 is upregulated in psoriatic tissue. This study extends these findings. Methods: Biopsies spanning psoriatic plaque (PP) and non-involved tissue (PN) were compared to normal controls (NN). RNA was isolated and subject to real-time PCR to determine gene expression profiles, including GJB2/CX26, GJB6/CX30 and GJA1/CX43. Protein expression was assessed by immunohistochemistry. Keratinocytes and fibroblasts were isolated and used in 3D organotypic models. The pro-inflammatory status of fibroblasts and 3D cultures was assessed via ELISA and RnD cytokine arrays in the presence or absence of the connexin channel blocker Gap27. Results: Connexin26 expression is dramatically enhanced at both transcriptional and translational level in PP and PN tissue compared to NN (>100x). In contrast, CX43 gene expression is not affected, but the protein is post-translationally modified and accumulates in psoriatic tissue. Fibroblasts isolated from psoriatic patients had a higher inflammatory index than normal fibroblasts and drove normal keratinocytes to adopt a “psoriatic phenotype” in a 3D-organotypic model. Exposure of normal fibroblasts to the pro-inflammatory mediator peptidoglycan, isolated from Staphylococcus aureus enhanced cytokine release, an event protected by Gap27. Conclusion: dysregulation of the connexin26:43 expression profile in psoriatic tissue contributes to an imbalance of cellular events. Inhibition of connexin signalling reduces pro-inflammatory events and may hold therapeutic benefit

Modelling human embryoid body cell adhesion to a combinatorial library of polymer surfaces

Designing materials to control biology is an intense focus of biomaterials and regenerative medicine research. Discovering and designing materials with appropriate biological compatibility or active control of cells and tissues is being increasingly undertaken using high throughput synthesis and assessment methods. We report a relatively simple but powerful machine-learning method of generating modelsthat link microscopic or molecular properties of polymers or other materials to their biological effects. We illustrate the potential of these methods by developing the first robust, predictive, quantitative, and purely computational models of adhesion of human embryonic stem cell embryoid bodies (hEB) to the surfaces of 496-member polymers

Morphological and mechanical properties of the human patella tendon in adult males with achondroplasia

Achondroplasia is a genetic mutation of fibroblast growth factor receptor resulting in impaired growth plate development in long bones due to lower collagen turnover. Despite the characteristic shorter stature and lower strength in Achondroplasic groups, little is known of the tendon mechanical properties under loading. The aim of this study was therefore to conduct a between measure design of patella tendon (PT) mechanical properties (stress, strain, stiffness and Young's Modulus) in 10 men with Achondroplasia (22 ± 3 years) and 17 male controls (22 ± 2 years). PT mechanical properties were measured during isometric maximal voluntary contraction (iMVC) of the knee extensors using ultrasonography. The Achondroplasic group produced 54% less stress at iMVC than controls (29.4 ± 8.0 v 64.5 ± 14.0 MPa, P 0.05). Achondroplasic PT were 47% less stiff(748 ± 93 v 1418 ± 101 N·mm-1, P < 0.001, d = 6.89) and had a 51% lower Young's modulus (0.39 ± 0.09 v 0.77 ± 0.14 GPa, P < 0.001, d = 3.46) than controls at iMVC. Achondroplasic PT are indeed more compliant than controls which may contribute to lower relative force production. The causes of higher Achondroplasic PT compliance are unclear but are likely due to the collagen related genetic mutation which causes Achondroplasia

Generalized pustular psoriasis is a disease distinct from psoriasis vulgaris: evidence and expert opinion

Introduction: Generalized pustular psoriasis (GPP) is a rare, severe, clinically heterogeneous disease characterized by flares of widespread, noninfectious, macroscopically visible pustules that occur with or without systemic inflammation, and are associated with significant morbidity and mortality. Historically, GPP has been classified as a variant of psoriasis vulgaris (PV, or plaque psoriasis); however, accumulating evidence indicates that these are distinct conditions, requiring different treatment approaches. Areas covered: In this perspective article we review evidence that supports the classification of GPP as distinct from PV. Expert opinion: The histopathologic and clinical appearance of GPP is distinct from that of PV and fundamental differences exist between the two conditions in terms of genetic causes and expression-related mechanisms of disease development. GPP results from dysregulation of the innate immune system, with disruption of the interleukin (IL)-36 inflammatory pathway, induction of inflammatory keratinocyte responses, and recruitment of neutrophils. PV is driven by the adaptive immune system, with a key role played by IL-17. Considering GPP as a separate disease will enable greater focus on its specific pathogenesis and the needs of patients. Many treatments for PV have insufficient efficacy in GPP and a therapeutic approach developed specifically for GPP might lead to better patient outcomes. Plain Language Summary: Generalized pustular psoriasis (GPP) is a rare disease. During episodes of worsening disease, the immune system attacks the skin. This causes large areas of skin to become red and painful, pus-filled blisters suddenly form. Some people with GPP have a history of another, more common, skin condition called psoriasis vulgaris (PV). People with PV develop patches of scaly, itchy skin. In the past, GPP was classed as a type of PV and treated with the same medicines. However, these medicines do not work well in GPP. Researchers now understand more about what causes GPP and how it differs from PV. GPP can cause medical problems throughout the body, leading to life-threatening complications. This means that people with GPP often need urgent medical treatment in hospitals. People with PV are mostly treated outside of hospitals. Any other medical problems are not usually due to PV itself. Researchers have found several genes that are altered in people with GPP and PV, and they differ between the two diseases. For example, changes in a gene called IL36RN are common in GPP but are not seen in PV. The skin of people with these two diseases also looks different under a microscope. Knowing more about GPP and how it differs from PV will help people with GPP to be diagnosed more quickly. It will also help researchers to develop new medicines specifically for GPP, so people can receive better treatment in the future

pi-pi scattering in a QCD based model field theory

A model field theory, in which the interaction between quarks is mediated by dressed vector boson exchange, is used to analyse the pionic sector of QCD. It is shown that this model, which incorporates dynamical chiral symmetry breaking, asymptotic freedom and quark confinement, allows one to calculate $f_\pi$, $m_\pi$, $r_\pi$ and the partial wave amplitudes in $\pi$-$\pi$ scattering and obtain good agreement with the experimental data, with the latter being well described up to energies \mbox{$E\simeq 700$ MeV}.Comment: 23 Pages, 4 figures in PostScript format, PHY-7512-TH-93, REVTEX Available via anonymous ftp in /pub: login anonymou get pipi93.tex Fig1.ps Fig2.ps Fig3.ps Fig4.p

Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting

Acknowledgements The iHARP database was funded by unrestricted grants from Mundipharma International Ltd and Research in Real-Life Ltd; these analyses were funded by an unrestricted grant from Teva Pharmaceuticals. Mundipharma and Teva played no role in study conduct or analysis and did not modify or approve the manuscript. The authors wish to direct a special appreciation to all the participants of the iHARP group who contributed data to this study and to Mundipharma, sponsors of the iHARP group. In addition, we thank Julie von Ziegenweidt for assistance with data extraction and Anna Gilchrist and Valerie L. Ashton, PhD, for editorial assistance. Elizabeth V. Hillyer, DVM, provided editorial and writing support, funded by Research in Real-Life, Ltd.Peer reviewedPublisher PD