Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al

Replicating Viral Vector-Based Vaccines for COVID-19: Potential Avenue in Vaccination Arena

The “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)” is the third member of human coronavirus (CoV) that is held accountable for the current “coronavirus disease 2019 (COVID-19)” pandemic. In the past two decades, the world has witnessed the emergence of two other similar CoVs, namely SARS-CoV in 2002 and MERS-CoV in 2013. The extent of spread of these earlier versions was relatively low in comparison to SARS-CoV-2. Despite having numerous reports inclined towards the zoonotic origin of the virus, one cannot simply sideline the fact that no animal originated CoV is thus far identified that is considered similar to the initial edition of SARS-CoV-2; however, under-sampling of the diverse variety of coronaviruses remains a concern. Vaccines are proved to be an effective tool for bringing the end to such a devastating pandemic. Many vaccine platforms are explored for the same but in this review paper, we will discuss the potential of replicating viral vectors as vaccine carriers for SARS-CoV-2

Doctor when can I drive? A systematic review and meta-analysis of return to driving after total hip arthroplasty

Background/Objective: Advice given to patients on driving resumption after total hip arthroplasty (THA) is inconsistent. Due to a lack of clear guidelines, surgeons’ recommendations range between 4–8 weeks after surgery to resume driving. Delays in driving return can have detrimental social and economic impact. However, it is important to ensure patients only resume driving once safe. This study presents a systematic review and meta-analysis of driving simulation studies after THA to establish when patients can safely return to driving postoperatively. Methods: A systematic review and meta-analysis using PRISMA guidelines was undertaken. Titles and abstracts were screened for inclusion, data was extracted, and studies assessed for bias risk. Review Manager, was used for statistical analysis. Values for brake reaction time (BRT) were included for meta-analysis. Results: 14 articles met the inclusion criteria. Of these, 7 measured BRT and were included in the meta-analysis. Pooled means of both right and left THA showed BRT around or above preoperative baseline at 1 week, 2 weeks and 3 weeks, and below baseline at 6 weeks, 12 weeks, 32 weeks and 52 weeks. Of these, the pooled means at 6, 32, and 52 weeks were significant (p < 0.05). Studies not meeting meta-analysis inclusion criteria were included in a qualitative analysis, examining self-reported postoperative driving return times which ranged from 6 days to over a year or in rare cases, never. Majority of patients (n = 960) self-reported driving return within approximately 6 weeks (pooling of mean values 32.9 days). Conclusions: The mean return to driving time recommended in the literature was 4.5 weeks. Based upon BRT meta-analysis, a return to baseline braking performance was noted at 6 weeks postoperatively. However, driving is a complex skill, and patient recommendation should be individualised based on factors such as vehicle transmission type, THA technique, surgical side, medication and comorbidities

Characterization and predictive value of near infrared 2-deoxyglucose optical imaging in severe acute pancreatitis

Background: Studying the uptake of 2-deoxy glucose (2-DG) analogs such as 2-Deoxy-2-[18F] fluoroglucose (FDG) is a common approach to identify and monitor malignancies and more recently chronic inflammation. While pancreatitis is a common cause for false positive results in human studies on pancreatic cancer using FDG, the relevance of these findings to acute pancreatitis (AP) is unknown. FDG has a short half-life. Thus, with an aim to accurately characterize the metabolic demand of the pancreas during AP in real-time, we studied the uptake of the non-radioactive, near infrared fluorescence labelled 2-deoxyglucose analog, IRDye1® 800CW 2-DG probe (NIR 2-DG; Li-Cor) during mild and severe biliary AP. Methods: Wistar rats (300 g; 8-12/group) were administered NIR 2-DG (10 nM; I.V.). Mild and severe biliary AP were respectively induced by biliopancreatic duct ligation (DL) alone or along with infusing glyceryl trilinoleate (GTL; 50 μL/100 g) within 10 minutes of giving NIR 2-DG. Controls (CON) only received NIR 2-DG. Imaging was done every 5-10 minutes over 3 hrs. Average Radiant Efficiency [p/s/cm2/sr]/[μW/cm2] was measured over the pancreas using the IVIS 200 in-vivo imaging system (PerkinElmer) using the Living Image® software and verified in ex vivo pancreata. Blood amylase, lipase and pancreatic edema, necrosis were measured over the course of AP. Results: NIR 2-DG uptake over the first hour was not influenced by AP induction. However, while the signal declined in controls and rats with mild AP, there was significantly higher retention of NIR 2-DG in the pancreas after 1 hour in those with GTL pancreatitis. The increase was > 3 fold over controls in the GTL group and was verified to be in the pancreas ex vivo. In vitro, pancreatic acini exposed to GTL had a similar increase in NIR 2-DG uptake which was followed by progressively worse acinar necrosis. Greater retention of NIR 2-DG in vivo was associated with worse pancreatic necrosis, reduced ATP concentrations and mortality, which were not predicted by the blood parameters. Conclusion: In-vivo fluorescent imaging of a non-radioactive near infrared 2-DG optical probe can predict the AP severity early during the disease

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons

Usual care and a self-management support programme versus usual care and a relaxation programme for people living with chronic headache disorders: a randomised controlled trial protocol (CHESS).

INTRODUCTION: Chronic headaches are poorly diagnosed and managed and can be exacerbated by medication overuse. There is insufficient evidence on the non-pharmacological approaches to helping people living with chronic headaches. METHODS AND ANALYSIS: Chronic Headache Education and Self-management Study is a pragmatic randomised controlled trial to test the effectiveness and cost-effectiveness of a self-management education support programme on top of usual care for patients with chronic headaches against a control of usual care and relaxation. The intervention is a 2-day group course based on education, personal reflection and a cognitive behavioural approach, plus a nurse-led one-to-one consultation and follow-up over 8 weeks. We aim to recruit 689 participants (356 to the intervention arm and 333 to the control) from primary care and self-referral in London and the Midlands. The trial is powered to show a difference of 2.0 points on the Headache Impact Test, a patient-reported outcome measure at 12 months post randomisation. Secondary outcomes include health related quality of life, self-efficacy, social activation and engagement, anxiety and depression and healthcare utilisation. Outcomes are being measured at 4, 8 and 12 months. Cost-effectiveness will be expressed in terms of incremental cost per quality-adjusted life year gained. ETHICS AND DISSEMINATION: This trial will provide data on effectiveness and cost-effectiveness of a self-management support programme for chronic headaches. The results will inform commissioning of services and clinical practice. North West - Greater Manchester East Research Ethics Committee have approved the trial. The current protocol version is 3.6 date 7 March 2019. TRIAL REGISTRATION NUMBER: ISRCTN79708100

Effects of chronic ascariasis and trichuriasis on cytokine production and gene expression in human blood: a cross-sectional study.

Background Chronic soil-transmitted helminth (STH) infections are associated with effects on systemic immune responses that could be caused by alterations in immune homeostasis. To investigate this, we measured the impact in children of STH infections on cytokine responses and gene expression in unstimulated blood. Methodology/Principal Findings Sixty children were classified as having chronic, light, or no STH infections. Peripheral blood mononuclear cells were cultured in medium for 5 days to measure cytokine accumulation. RNA was isolated from peripheral blood and gene expression analysed using microarrays. Different infection groups were compared for the purpose of analysis: STH infection (combined chronic and light vs. uninfected groups) and chronic STH infection (chronic vs. combined light and uninfected groups). The chronic STH infection effect was associated with elevated production of GM-CSF (P = 0.007), IL-2 (P = 0.03), IL-5 (P = 0.01), and IL-10 (P = 0.01). Data reduction suggested that chronic infections were primarily associated with an immune phenotype characterized by elevated IL-5 and IL-10, typical of a modified Th2-like response. Chronic STH infections were associated with the up-regulation of genes associated with immune homeostasis (IDO, P = 0.03; CCL23, P = 0.008, HRK, P = 0.005), down-regulation of microRNA hsa-let-7d (P = 0.01) and differential regulation of several genes associated with granulocyte-mediated inflammation (IL-8, down-regulated, P = 0.0002; RNASE2, up-regulated, P = 0.009; RNASE3, up-regulated, p = 0.03). Conclusions/Significance Chronic STH infections were associated with a cytokine response indicative of a modified Th2 response. There was evidence that STH infections were associated with a pattern of gene expression suggestive of the induction of homeostatic mechanisms, the differential expression of several inflammatory genes and the down-regulation of microRNA has-let-7d. Effects on immune homeostasis and the development of a modified Th2 immune response during chronic STH infections could explain the systemic immunologic effects that have been associated with these infections such as impaired immune responses to vaccines and the suppression of inflammatory diseases

A new heat propagation velocity prevails over Brownian particle velocities in determining the thermal conductivities of nanofluids

An alternative insight is presented concerning heat propagation velocity scales in predicting the effective thermal conductivities of nanofluids. The widely applied Brownian particle velocities in published literature are often found too slow to describe the relatively higher nanofluid conductivities. In contrast, the present model proposes a faster heat transfer velocity at the same order as the speed of sound, rooted in a modified kinetic principle. In addition, this model accounts for both nanoparticle heat dissipation as well as coagulation effects. This novel model of effective thermal conductivities of nanofluids agrees well with an extended range of experimental data