Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass.

Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the β cell in adult mice reportedly has more modest effects. To inactivate Tcf7l2 highly selectively in β cells from the earliest expression of the Ins1 gene (∼E11.5) we have therefore used a Cre recombinase introduced at the Ins1 locus. Tcfl2(fl/fl)::Ins1Cre mice display impaired oral and intraperitoneal glucose tolerance by 8 and 16 weeks, respectively, and defective responses to the GLP-1 analogue liraglutide at 8 weeks. Tcfl2(fl/fl)::Ins1Cre islets displayed defective glucose- and GLP-1-stimulated insulin secretion and the expression of both the Ins2 (∼20%) and Glp1r (∼40%) genes were significantly reduced. Glucose- and GLP-1-induced intracellular free Ca(2+) increases, and connectivity between individual β cells, were both lowered by Tcf7l2 deletion in islets from mice maintained on a high (60%) fat diet. Finally, analysis by optical projection tomography revealed ∼30% decrease in β cell mass in pancreata from Tcfl2(fl/fl)::Ins1Cre mice. These data demonstrate that Tcf7l2 plays a cell autonomous role in the control of β cell function and mass, serving as an important regulator of gene expression and islet cell coordination. The possible relevance of these findings for the action of TCF7L2 polymorphisms associated with Type 2 diabetes in man is discussed

LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess ("glucotoxicity") is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0-12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E<0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P=1.3×10(-33)) and hypoxia-regulated (HIF1; P=2.5×10(-16)) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.-Kone, M., Pullen, T. J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S., Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J., Thorens, B., Reimann, F., Gribble, F., McGinty, J. A., Chen, L., French, P. M., Birzele, F., Hildebrandt, T., Uphues, I., Rutter, G. A. LKB1 and AMPK differentially regulate pancreatic β-cell identity

Changes in meltwater chemistry over a 20-year period following a thermal regime switch from polythermal to cold-based glaciation at Austre Broggerbreen, Svalbard

Our long-term study gives a rare insight into meltwater hydrochemistry following the transition of Austre Brøggerbreen from polythermal to cold-based glaciation and its continued retreat. We find that the processes responsible for ion acquisition did not change throughout the period of records but became more productive. Two regimes before and after July/August 2000 were identified from changes in solute concentrations and pH. They resulted from increased chemical weathering occurring in ice-marginal and proglacial environments that have become progressively exposed by glacier retreat. Carbonate carbonation nearly doubled between 2000 and 2010, whilst increases in the weathering of silicate minerals were also marked. In addition, the end of ablation season chemistry was characterized by reactions in long residence time flow paths like those in subglacial environments, in spite of their absence in the watershed. Furthermore, the retreat of the glacier caused the sudden re-routing of meltwaters through its immediate forefield during 2009, which more than doubled crustal ion yields in this particular year and influenced chemical weathering in 2010 regardless of a low water flux. Such a “flush” of crustally derived ions can be meaningful for downstream terrestrial and marine ecosystems. We therefore find that, during glacier retreat, the recently exposed forefield is the most chemically active part of the watershed, making high rates of weathering possible, even when ice losses have caused a switch to cold-based conditions with no delayed subglacial drainage flowpaths. In addition, the drainage system reorganization events result in significant pCO2 depletion in an otherwise high pCO2 system

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study

Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council

Application of work study techniques to quantify the work of community pharmacists

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN036606 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The excitation of the 2S and 2P states of atomic high resolution electron impact and photoionization studies of helium and xenon using synchrotron radiation

SIGLEAvailable from British Library Document Supply Centre- DSC:D85589 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Varidase: the science behind the medicament

Varidase used throughout the world for the topical treatment of purulent and suppurating wounds. The efficacy of the product is centred on two enzymes streptokinase and streptodornase; but these represent only a small proportion of the bulked solid. This article gives an overview of the preparation and mode of action of Varidase as well as showing some of the research and development that has gone into improving the assessment of its quality and composition

A Meta-Analytic Review of the Common-Sense Model of Illness Representations

A meta-analysis of empirical studies (N = 45) adopting Leventhal, Meyer and Nerenz's (1980) Common Sense Model (CSM) of illness representations is presented. The average corrected intercorrelation matrix for the sample of studies showed that the CSM illness cognition dimensions of consequences, control/cure, identity and timeline followed a logical pattern supporting their construct and discriminant validity across illness types. A content analysis classified coping strategies into seven distinctive categories and health outcomes into six categories. Examining the average corrected correlation coefficients across the studies revealed that perceptions of a strong illness identity were significantly and positively related to the use of coping strategies of avoidance and emotion expression. In addition, perceived controllability of the illness was significantly associated with cognitive reappraisal, expressing emotions and problem-focused coping strategies. Perceptions of the illness as highly symptomatic, having a chronic timeline and serious consequences was significantly correlated with avoidance and expressing emotions coping strategies. Further, perceptions that the illness was curable/controllable was significantly and positively related to the adaptive outcomes of psychological well-being, social functioning and vitality and negatively related to psychological distress and disease state. Conversely, illness consequences, timeline and identity exhibited significant, negative relationships with psychological well being, role and social functioning and vitality. The analyses provide evidence for theoretically predictable relations between illness cognitions, coping and outcomes across studies