The latent stem cell population is retained in the hippocampus of transgenic Huntington's disease mice but not wild-type mice

The demonstration of the brain's ability to initiate repair in response to disease or injury has sparked considerable interest in therapeutic strategies to stimulate adult neurogenesis. In this study we examined the effect of a progressive neurodegenerative condition on neural precursor activity in the subventricular zone (SVZ) and hippocampus of the R6/1 transgenic mouse model of Huntington's disease (HD). Our results revealed an age-related decline in SVZ precursor numbers in both wild-type (WT) and HD mice. Interestingly, hippocampal precursor numbers declined with age in WT mice, although we observed maintenance in hippocampal precursor number in the HD animals in response to advancement of the disease. This maintenance was consistent with activation of a recently identified latent hippocampal precursor population. We found that the small latent stem cell population was also maintained in the HD hippocampus at 33 weeks, whereas it was not present in the WT. Our findings demonstrate that, despite a loss of neurogenesis in the HD hippocampus in vivo, there is a unique maintenance of the precursor and stem cells, which may potentially be activated to ameliorate disease symptoms

The association between retinal vascular geometry changes and diabetic retinopathy and their role in prediction of progression: an exploratory study

Background: The study describes the relationship of retinal vascular geometry (RVG) to severity of diabetic retinopathy (DR), and its predictive role for subsequent development of proliferative diabetic retinopathy (PDR). Methods. The research project comprises of two stages. Firstly, a comparative study of diabetic patients with different grades of DR. (No DR: Minimal non-proliferative DR: Severe non-proliferative DR: PDR) (10:10: 12: 19). Analysed RVG features including vascular widths and branching angles were compared between patient cohorts. A preliminary statistical model for determination of the retinopathy grade of patients, using these features, is presented. Secondly, in a longitudinal predictive study, RVG features were analysed for diabetic patients with progressive DR over 7 years. RVG at baseline was examined to determine risk for subsequent PDR development. Results: In the comparative study, increased DR severity was associated with gradual vascular dilatation (p = 0.000), and widening of the bifurcating angle (p = 0.000) with increase in smaller-child-vessel branching angle (p = 0.027). Type 2 diabetes and increased diabetes duration were associated with increased vascular width (p = <0.05 In the predictive study, at baseline, reduced small-child vascular width (OR = 0.73 (95 CI 0.58-0.92)), was predictive of future progression to PDR. Conclusions: The study findings suggest that RVG alterations can act as novel markers indicative of progression of DR severity and establishment of PDR. RVG may also have a potential predictive role in determining the risk of future retinopathy progression. © 2014 Habib et al.; licensee BioMed Central Ltd

The Adolescent Cardio-Renal Intervention Trial (AdDIT): retinal vascular geometry and renal function in adolescents with type 1 diabetes

Aims/hypothesis We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes. Methods A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as ‘high-risk’ for future albuminuria and the lower two tertiles were deemed ‘low-risk’. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1–Q5) for associations with log10 ACR and ACR risk groups. Results Greater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2–Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1–Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control. Conclusions/interpretation Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.This work was supported by the National Health and Medical Research Council of Australia (NHMRC 632521), JDRF (08-2007-902), Diabetes UK (DUK PO NO 2177 BDA:RD06/003341) and the British Heart Foundation

Annual and Seasonal Patterns of Dietary Intake in Australian Adults: A Prospective Cohort Study

Poor diet is a major risk factor for non-communicable disease. The aims of this study were to describe temporal patterns and seasonal changes in diet across the year in Australian adults. A total of 375 adults from a prospective cohort study conducted between 1 December 2019 and 31 December 2021 in Adelaide, Australia, were asked to complete the Dietary Questionnaire for Epidemiological Studies at eight timepoints over a year. Average intakes over the previous month of total energy, macronutrients, healthy food groups, and discretionary foods and beverages were derived. Temporal patterns in diet were analysed descriptively. Multilevel linear regression modelling was used to assess seasonal differences in diet. Of the 375 participants recruited, 358 provided sufficient data for analysis. Intake of total energy, all macronutrients, and most discretionary foods and beverages peaked in December. Total energy intake was higher in summer than in autumn, winter, and spring. Fruit intake was higher in summer than in winter. Consumption of alcoholic beverages was higher in summer than in autumn, winter, and spring. Consumption of non-alcoholic beverages was higher in summer than in autumn and winter. This study identified temporal differences in dietary intake among Australian adults. Seasonal effects appear to be driven largely by increases in consumption of foods and beverages over the December (summer) holiday period. These findings can inform the design and timing of dietary interventions.</p

Real-world accuracy of wearable activity trackers for detecting medical conditions: systematic review and meta-analysis

Background: Wearable activity trackers, including fitness bands and smartwatches, offer the potential for disease detection by monitoring physiological parameters. However, their accuracy as specific disease diagnostic tools remains uncertain. Objective: This systematic review and meta-analysis aims to evaluate whether wearable activity trackers can be used to detect disease and medical events. Methods: Ten electronic databases were searched for studies published from inception to April 1, 2023. Studies were eligible if they used a wearable activity tracker to diagnose or detect a medical condition or event (eg, falls) in free-living conditions in adults. Meta-analyses were performed to assess the overall area under the curve (%), accuracy (%), sensitivity (%), specificity (%), and positive predictive value (%). Subgroup analyses were performed to assess device type (Fitbit, Oura ring, and mixed). The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Diagnostic Test Accuracy Studies. Results: A total of 28 studies were included, involving a total of 1,226,801 participants (age range 28.6-78.3). In total, 16 (57%) studies used wearables for diagnosis of COVID-19, 5 (18%) studies for atrial fibrillation, 3 (11%) studies for arrhythmia or abnormal pulse, 3 (11%) studies for falls, and 1 (4%) study for viral symptoms. The devices used were Fitbit (n=6), Apple watch (n=6), Oura ring (n=3), a combination of devices (n=7), Empatica E4 (n=1), Dynaport MoveMonitor (n=2), Samsung Galaxy Watch (n=1), and other or not specified (n=2). For COVID-19 detection, meta-analyses showed a pooled area under the curve of 80.2% (95% CI 71.0%-89.3%), an accuracy of 87.5% (95% CI 81.6%-93.5%), a sensitivity of 79.5% (95% CI 67.7%-91.3%), and specificity of 76.8% (95% CI 69.4%-84.1%). For atrial fibrillation detection, pooled positive predictive value was 87.4% (95% CI 75.7%-99.1%), sensitivity was 94.2% (95% CI 88.7%-99.7%), and specificity was 95.3% (95% CI 91.8%-98.8%). For fall detection, pooled sensitivity was 81.9% (95% CI 75.1%-88.1%) and specificity was 62.5% (95% CI 14.4%-100%). Conclusions: Wearable activity trackers show promise in disease detection, with notable accuracy in identifying atrial fibrillation and COVID-19. While these findings are encouraging, further research and improvements are required to enhance their diagnostic precision and applicability. </p

Hyperglycemia and Diabetes Downregulate the Functional Expression of TRPV4 Channels in Retinal Microvascular Endothelium

Retinal endothelial cell dysfunction is believed to play a key role in the etiology and pathogenesis of diabetic retinopathy. Numerous studies have shown that TRPV4 channels are critically involved in maintaining normal endothelial cell function. In the current paper, we demonstrate that TRPV4 is functionally expressed in the endothelium of the retinal microcirculation and that both channel expression and activity is downregulated by hyperglycaemia. Quantitative PCR and immunostaining demonstrated molecular expression of TRPV4 in cultured bovine retinal microvascular endothelial cells (RMECs). Functional TRPV4 activity was assessed in cultured RMECs from endothelial Ca2+-responses recorded using fura-2 microfluorimetry and electrophysiological recordings of membrane currents. The TRPV4 agonist 4α-phorbol 12,13-didecanoate (4-αPDD) increased [Ca2+]i in RMECs and this response was largely abolished using siRNA targeted against TRPV4. These Ca2+-signals were completely inhibited by removal of extracellular Ca2+, confirming their dependence on influx of extracellular Ca2+. The 4-αPDD Ca2+-response recorded in the presence of cyclopiazonic acid (CPA), which depletes the intracellular stores preventing any signal amplification through store release, was used as a measure of Ca2+-influx across the cell membrane. This response was blocked by HC067047, a TRPV4 antagonist. Under voltage clamp conditions, the TRPV4 agonist GSK1016790A stimulated a membrane current, which was again inhibited by HC067047. Following incubation with 25 mM D-glucose TRPV4 expression was reduced in comparison with RMECs cultured under control conditions, as were 4αPDD-induced Ca2+-responses in the presence of CPA and ion currents evoked by GSK1016790A. Molecular expression of TRPV4 in the retinal vascular endothelium of 3 months' streptozotocin-induced diabetic rats was also reduced in comparison with that in age-matched controls. We conclude that hyperglycaemia and diabetes reduce the molecular and functional expression of TRPV4 channels in retinal microvascular endothelial cells. These changes may contribute to diabetes induced endothelial dysfunction and retinopathy

Fast Retinal Vessel Detection and Measurement Using Wavelets and Edge Location Refinement

The relationship between changes in retinal vessel morphology and the onset and progression of diseases such as diabetes, hypertension and retinopathy of prematurity (ROP) has been the subject of several large scale clinical studies. However, the difficulty of quantifying changes in retinal vessels in a sufficiently fast, accurate and repeatable manner has restricted the application of the insights gleaned from these studies to clinical practice. This paper presents a novel algorithm for the efficient detection and measurement of retinal vessels, which is general enough that it can be applied to both low and high resolution fundus photographs and fluorescein angiograms upon the adjustment of only a few intuitive parameters. Firstly, we describe the simple vessel segmentation strategy, formulated in the language of wavelets, that is used for fast vessel detection. When validated using a publicly available database of retinal images, this segmentation achieves a true positive rate of 70.27%, false positive rate of 2.83%, and accuracy score of 0.9371. Vessel edges are then more precisely localised using image profiles computed perpendicularly across a spline fit of each detected vessel centreline, so that both local and global changes in vessel diameter can be readily quantified. Using a second image database, we show that the diameters output by our algorithm display good agreement with the manual measurements made by three independent observers. We conclude that the improved speed and generality offered by our algorithm are achieved without sacrificing accuracy. The algorithm is implemented in MATLAB along with a graphical user interface, and we have made the source code freely available

Blocking Connexin-43 mediated hemichannel activity protects against early tubular injury in experimental chronic kidney disease

Background: Tubulointerstitial fibrosis represents the key underlying pathology of Chronic Kidney Disease (CKD), yet treatment options remain limited. In this study, we investigated the role of connexin43 (Cx43) hemichannel-mediated adenosine triphosphate (ATP) release in purinergic-mediated disassembly of adherens and tight junction complexes in early tubular injury. Methods: Human primary proximal tubule epithelial cells (hPTECs) and clonal tubular epithelial cells (HK2) were treated with Transforming Growth Factor Beta1 (TGFβ1) ± apyrase, or ATPγS for 48h. For inhibitor studies, cells were co-incubated with Cx43 mimetic Peptide 5, or purinergic receptor antagonists Suramin, A438079 or A804598. Immunoblotting, single-cell force spectroscopy and trans-epithelial electrical resistance assessed protein expression, cell-cell adhesion and paracellular permeability. Carboxyfluorescein uptake and biosensing measured hemichannel activity and real-time ATP release, whilst a heterozygous Cx43+/- mouse model with unilateral ureteral obstruction (UUO) assessed the role of Cx43 in vivo. Results: Immunohistochemistry of biopsy material from patients with diabetic nephropathy confirmed increased expression of purinergic receptor P2X7. TGFβ1 increased Cx43 mediated hemichannel activity and ATP release in hPTECs and HK2 cells. The cytokine reduced maximum unbinding forces and reduced cell-cell adhesion, which translated to increased paracellular permeability. Changes were reversed when cells were co-incubated with either Peptide 5 or P2-purinoceptor inhibitors. Cx43+/- mice did not exhibit protein changes associated with early tubular injury in a UUO model of fibrosis. Conclusion: Data suggest that Cx43 mediated ATP release represents an initial trigger in early tubular injury via its actions on the adherens and tight junction complex. Since Cx43 is highly expressed in nephropathy, it represents a novel target for intervention of tubulointerstitial fibrosis in CKD

Off-target effects of bacillus Calmette–Guérin vaccination on immune responses to SARS-CoV-2: implications for protection against severe COVID-19

Background and objectives: Because of its beneficial off-target effects against non-mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID-19). Using samples from participants in a placebo-controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID-19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS-CoV-2. Methods: This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID-19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ-irradiated SARS-CoV-2-infected or mock-infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single-cell immunophenotyping was made by flow cytometry. Results: BCG vaccination, but not placebo vaccination, reduced SARS-CoV-2-induced secretion of cytokines known to be associated with severe COVID-19, including IL-6, TNF-α and IL-10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS-CoV-2. Conclusions: The immunomodulatory signature of BCG’s off-target effects on SARS-CoV-2 is consistent with a protective immune response against severe COVID-19