The contribution of Kv7 channels to pregnant mouse and human myometrial contractility.

Premature birth accounts for approximately 75% of neonatal mortality and morbidity in the developed world. Despite this, methods for identifying and treating women at risk of preterm labour are limited and many women still present in preterm labour requiring tocolytic therapy to suppress uterine contractility. The aim of this study was to assess the utility of Kv7 channel activators as potential uterine smooth muscle (myometrium) relaxants in tissues from pregnant mice and women. Myometrium was obtained from early and late pregnant mice and from lipopolysaccharide (LPS)-injected mice (day 15 of gestation; model of infection in pregnancy). Human myometrium was obtained at the time of Caesarean section from women at term (38-41 weeks). RT-PCR/qRT-PCR detected KCNQ and KCNE expression in mouse and human myometrium. In mice, there was a global suppression of all KCNQ isoforms, except KCNQ3, in early pregnancy (n= 6, P < 0.001 versus late pregnant); expression subsequently increased in late pregnancy (n= 6). KCNE isoforms were also gestationally regulated (P < 0.05). KCNQ and KCNE isoform expression was slightly down-regulated in myometrium from LPS-treated-mice versus controls (P < 0.05, n= 3-4). XE991 (10 μM, Kv7 inhibitor) significantly increased spontaneous myometrial contractions in vitro in both human and mouse myometrial tissues (P < 0.05) and retigabine/flupirtine (20 μM, Kv7 channel activators) caused profound myometrial relaxation (P < 0.05). In summary, Kv7 activators suppressed myometrial contraction and KCNQ gene expression was sustained throughout gestation, particularly at term. Consequently, activation of the encoded channels represents a novel mechanism for treatment of preterm labour

Multi-pulse addressing of a Raman quantum memory: configurable beam splitting and efficient readout

Quantum memories are vital to the scalability of photonic quantum information processing (PQIP), since the storage of photons enables repeat-until-success strategies. On the other hand the key element of all PQIP architectures is the beam splitter, which allows to coherently couple optical modes. Here we show how to combine these crucial functionalities by addressing a Raman quantum memory with multiple control pulses. The result is a coherent optical storage device with an extremely large time-bandwidth product, that functions as an array of dynamically configurable beam splitters, and that can be read out with arbitrarily high efficiency. Networks of such devices would allow fully scalable PQIP, with applications in quantum computation, long-distance quantum communications and quantum metrology.Comment: 4 pages, 3 figure

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Hannu Laaksovirta konsortion jäsenenä.The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.Peer reviewe

'Care and Prevent': rationale for investigating skin and soft tissue infections and AA amyloidosis among people who inject drugs in London.

BACKGROUND: Skin and soft tissue infections (SSTIs) are a leading cause of morbidity and mortality among people who inject drugs (PWID). International data indicate up to one third of PWID have experienced an SSTI within the past month. Complications include sepsis, endocarditis and amyloid A (AA) amyloidosis. AA amyloidosis is a serious sequela of chronic SSTI among PWID. Though there is a paucity of literature reporting on AA amyloidosis among PWID, what has been published suggests there is likely a causal relationship between AA amyloidosis and injecting-related SSTI. If left untreated, AA amyloidosis can lead to renal failure; premature mortality among diagnosed PWID is high. Early intervention may reverse disease. Despite the high societal and individual burden of SSTI among PWID, empirical evidence on the barriers and facilitators to injecting-related SSTI prevention and care or the feasibility and acceptability of AA amyloidosis screening and treatment referral are limited. This study aims to fill these gaps and assess the prevalence of AA amyloidosis among PWID. METHODS: Care and Prevent is a UK National Institute for Health Research-funded mixed-methods study. In five phases (P1-P5), we aim to assess the evidence for AA amyloidosis among PWID (P1); assess the feasibility of AA amyloidosis screening, diagnostic and treatment referral among PWID in London (P2); investigate the barriers and facilitators to AA amyloidosis care (P3); explore SSTI protection and risk (P4); and co-create harm reduction resources with the affected community (P5). This paper describes the conceptual framework, methodological design and proposed analysis for the mixed-methods multi-phase study. RESULTS: We are implementing the Care and Prevent protocol in London. The systematic review component of the study has been completed and published. Care and Prevent will generate an estimate of AA amyloidosis prevalence among community recruited PWID in London, with implications for the development of screening recommendations and intervention implementation. We aim to recruit 400 PWID from drug treatment services in London, UK. CONCLUSIONS: Care and Prevent is the first study to assess screening feasibility and the prevalence of positive proteinuria, as a marker for AA amyloidosis, among PWID accessing drug treatment services. AA amyloidosis is a serious, yet under-recognised condition for which early intervention is available but not employed

International Consortium for Health Outcome Measurement Set of Outcomes That Matter to People Living With Inflammatory Arthritis: Consensus From an International Working Group

© 2018, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: The implementation of value-based health care in inflammatory arthritis requires a standardized set of modifiable outcomes and risk-adjustment variables that is feasible to implement worldwide. Methods: The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary working group that consisted of 24 experts from 6 continents, including 6 patient representatives, to develop a standard set of outcomes for inflammatory arthritis. The process followed a structured approach, using a modified Delphi process to reach consensus on the following decision areas: conditions covered by the set, outcome domains, outcome measures, and risk-adjustment variables. Consensus in areas 2 to 4 were supported by systematic literature reviews and consultation of experts. Results: The ICHOM Inflammatory Arthritis Standard Set covers patients with rheumatoid arthritis (RA), axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis (JIA). We recommend that outcomes regarding pain, fatigue, activity limitations, overall physical and mental health impact, work/school/housework ability and productivity, disease activity, and serious adverse events be collected at least annually. Validated measures for patient-reported outcomes were endorsed and linked to common reporting metrics. Age, sex at birth, education level, smoking status, comorbidities, time since diagnosis, and rheumatoid factor and anti-citrullinated protein antibody lab testing for RA and JIA should be collected as risk-adjustment variables. Conclusion: We present the ICHOM inflammatory arthritis Standard Set of outcomes, which enables health care providers to implement the value-based health care framework and compare outcomes that are important to patients with inflammatory arthritis

Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination

The contribution of oligodendrocytes to remyelination in functional recovery after spinal cord injury is not fully understood. Here, the authors show that oligodendrocyte progenitor cell differentiation is not required for functional recovery after spinal cord injury in mice

Nasal Acai Polysaccharides Potentiate Innate Immunity to Protect against Pulmonary Francisella tularensis and Burkholderia pseudomallei Infections

Pulmonary Francisella tularensis and Burkholderia pseudomallei infections are highly lethal in untreated patients, and current antibiotic regimens are not always effective. Activating the innate immune system provides an alternative means of treating infection and can also complement antibiotic therapies. Several natural agonists were screened for their ability to enhance host resistance to infection, and polysaccharides derived from the Acai berry (Acai PS) were found to have potent abilities as an immunotherapeutic to treat F. tularensis and B. pseudomallei infections. In vitro, Acai PS impaired replication of Francisella in primary human macrophages co-cultured with autologous NK cells via augmentation of NK cell IFN-γ. Furthermore, Acai PS administered nasally before or after infection protected mice against type A F. tularensis aerosol challenge with survival rates up to 80%, and protection was still observed, albeit reduced, when mice were treated two days post-infection. Nasal Acai PS administration augmented intracellular expression of IFN-γ by NK cells in the lungs of F. tularensis-infected mice, and neutralization of IFN-γ ablated the protective effect of Acai PS. Likewise, nasal Acai PS treatment conferred protection against pulmonary infection with B. pseudomallei strain 1026b. Acai PS dramatically reduced the replication of B. pseudomallei in the lung and blocked bacterial dissemination to the spleen and liver. Nasal administration of Acai PS enhanced IFN-γ responses by NK and γδ T cells in the lungs, while neutralization of IFN-γ totally abrogated the protective effect of Acai PS against pulmonary B. pseudomallei infection. Collectively, these results demonstrate Acai PS is a potent innate immune agonist that can resolve F. tularensis and B. pseudomallei infections, suggesting this innate immune agonist has broad-spectrum activity against virulent intracellular pathogens

Alpha helices are more robust to mutations than beta strands

The rapidly increasing amount of data on human genetic variation has resulted in a growing demand to identify pathogenic mutations computationally, as their experimental validation is currently beyond reach. Here we show that alpha helices and beta strands differ significantly in their ability to tolerate mutations: helices can accumulate more mutations than strands without change, due to the higher numbers of inter-residue contacts in helices. This results in two patterns: a) the same number of mutations causes less structural change in helices than in strands; b) helices diverge more rapidly in sequence than strands within the same domains. Additionally, both helices and strands are significantly more robust than coils. Based on this observation we show that human missense mutations that change secondary structure are more likely to be pathogenic than those that do not. Moreover, inclusion of predicted secondary structure changes shows significant utility for improving upon state-of-the-art pathogenicity predictions

SUDOSCAN: A Simple, Rapid, and Objective Method with Potential for Screening for Diabetic Peripheral Neuropathy.

Clinical methods of detecting diabetic peripheral neuropathy (DPN) are not objective and reproducible. We therefore evaluated if SUDOSCAN, a new method developed to provide a quick, non-invasive and quantitative assessment of sudomotor function can reliably screen for DPN. 70 subjects (45 with type 1 diabetes and 25 healthy volunteers [HV]) underwent detailed assessments including clinical, neurophysiological and 5 standard cardiovascular reflex tests (CARTs). Using the American Academy of Neurology criteria subjects were classified into DPN and No-DPN groups. Based on CARTs subjects were also divided into CAN, subclinical-CAN and no-CAN. Sudomotor function was assessed with measurement of hand and foot Electrochemical Skin Conductance (ESC) and calculation of the CAN risk score. Foot ESC (μS) was significantly lower in subjects with DPN [n = 24; 53.5(25.1)] compared to the No-DPN [77.0(7.9)] and HV [77.1(14.3)] groups (ANCOVA p<0.001). Sensitivity and specificity of foot ESC for classifying DPN were 87.5% and 76.2%, respectively. The area under the ROC curve (AUC) was 0.85. Subjects with CAN had significantly lower foot [55.0(28.2)] and hand [53.5(19.6)] ESC compared to No-CAN [foot ESC, 72.1(12.2); hand ESC 64.9(14.4)] and HV groups (ANCOVA p<0.001 and 0.001, respectively). ROC analysis of CAN risk score to correctly classify CAN revealed a sensitivity of 65.0% and specificity of 80.0%. AUC was 0.75. Both foot and hand ESC demonstrated strong correlation with individual parameters and composite scores of nerve conduction and CAN. SUDOSCAN, a non-invasive and quick test, could be used as an objective screening test for DPN in busy diabetic clinics, insuring adherence to current recommendation of annual assessments for all diabetic patients that remains unfulfilled

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference