Effectiveness of Vitamin D and Alpha-Lipoic Acid in COVID-19 Infection: A Literature Review.

Over three years since the World Health Organization (WHO) declared COVID-19 a pandemic, it is still a global burden. Vaccines against COVID-19, caused by SARS-CoV-2, are available and effective for preventing disease. However, their protective effects are not 100%. Currently, the U.S. Food and Drug Administration (FDA) has only approved a limited number of inpatient treatments for COVID-19, such as remdesivir, baricitinib, and tocilizumab. These medications have indications and contraindications applicable to a select patient population. Finding additional effective therapies that are widely available with limited risk could be vital in optimizing treatment strategies for this viral illness. Some vitamins and supplements have been identified as potential options for managing COVID-19. Vitamin D (VD) deficiency has been associated with respiratory tract infections. Moreover, alpha-lipoic acid (ALA) is a powerful antioxidant and helps reduce inflammatory responses in many pathologic conditions. This review aims to analyze the current evidence regarding the effectiveness of VD and alpha-lipoic acid in COVID-19 infection in both outpatient and hospitalized patients. Relevant randomized controlled trials (RCTs) were identified via the PubMed database from January 1, 2021, to December 31, 2023. Inclusion criteria were as follows: the study design was a randomized controlled trial (RCT), the usage of a constant dose during the intervention period without any additional boluses, and a research ethics committee approved it. Exclusion criteria included a lack of an outcome or apparent intervention, additional boluses, or a single-dose regimen in all the interventional groups. There were 11 studies with a total sample size of 35,717 patients that met the criteria for this review. A total of 10 RCTs examined the efficacy of VD, and one RCT that reviewed the efficacy of ALA was identified. All of the articles investigated the use of VD or ALA during the treatment of COVID-19. The endpoints of each study varied, including length of stay in hospital, viral load, SARS-CoV-2 infection rate, mechanical ventilation, inflammatory markers, clinical symptoms, Sequential Organ Failure Assessment (SOFA) score, and mortality. In 8/10 VD supplementation trials, significant differences were identified between the interventional and placebo groups in the aforementioned parameters. In 2/10 VD supplementation trials, no significant differences were identified. The ALA supplementation RCT found no differences between the interventional and placebo groups in the SOFA score and 30-day all-cause mortality rate. The current literature suggests that VD can potentially reduce the SARS-CoV-2 infection rate, oxygen requirements, inflammatory markers, clinical symptoms, and mortality. Regarding ALA, although there was a suggestion of benefit, it was not statistically significant. Common limitations among the different studies included relatively small sample sizes, different geographical patient locations among studies, and differences in dosages. Trials investigating the effects of higher doses of VD supplementation on SARS-CoV-2 infection should be conducted. More research is needed to define best practices and optimal dosing protocols for the use of VD in COVID-19.

Retrospective evaluation of a right heart parameter score in the assessment of precapillary pulmonary hypertension in dogs (2017-2021): 135 cases.

OBJECTIVE: To determine if emergency and critical care residents can identify moderate to severe precapillary pulmonary hypertension on cardiologist-obtained cineloops using a pulmonary hypertension score (PHS) and report the interobserver variability of the PHS. DESIGN: Multicenter, retrospective, case-control study from 2017 to 2021. SETTING: Private referral center and veterinary teaching hospital. ANIMALS: One hundred and thirty-five client-owned dogs that underwent diagnostic echocardiography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records of dogs with stage B1 myxomatous mitral valve disease (MMVD) and dogs diagnosed with precapillary pulmonary hypertension (PCPH) via echocardiograms were reviewed. Dogs were categorized by a cardiologist into 5 groups (normal, B1 MMVD, mild, moderate, and severe PCPH) based on Doppler pulmonary pressure gradients and right heart morphology. Cineloops from each case were subjectively evaluated by emergency and critical care residents for the presence of right atrial and ventricular enlargement, right ventricular hypertrophy, interventricular septal flattening, and pulmonary artery and trunk enlargement to form a composite pulmonary hypertension score out of 8 (PHS8). When available, signs of peritoneal effusion and distention of the caudal vena cava were subjectively assessed to generate a pulmonary hypertension score out of 10 (PHS10). There was excellent discrimination of moderate to severe PCPH versus grouped absent to mild PCPH using PHS8 (area under the receiver operator curve [AUC] [95% confidence interval, CI] = 0.90 [0.84-0.95], P < 0.0001) and PHS10 (AUC [95% CI] = 0.89 [0.81-0.97], P < 0.0001). PHS8 ≥3 was 64% sensitive and 98% specific for moderate to severe PCPH (positive likelihood ratio [LR+] 32, negative likelihood ration [LR-] 0.37). PHS10 ≥ 3.3 was 64% sensitive and 92% specific for moderate to severe PCPH (LR+ 8, LR- 0.39). Interobserver agreement was good to excellent (intraclass correlation coefficient [ICC] = 0.74 [95% CI: 0.66-0.80], n = 135). CONCLUSIONS: Residents identified moderate to severe PCPH in dogs using PHS on cineloops previously obtained by a cardiologist. The interrater agreement was good to excellent with limited training. Prospective studies to determine if residents can obtain diagnostic images for PHS are warranted.

The relationship between cellular protein content and selenium accumulation in freshwater microalgae.

Variability in the bioconcentration of selenium (Se) by primary producers at the base of the food web results in uncertainty in predictions of bioaccumulation and ecological risk to higher trophic level organisms. Water chemistry, speciation of Se, and periphyton community composition have all been suggested as factors that contribute to variability in bioconcentration by primary producers; however, the role of physiological composition of periphyton species in influencing the bioconcentration of Se has not been previously evaluated. To determine if a relationship exists between algal protein content and Se accumulation, Parachlorella kessleri, Chlorella vulgaris, and Raphidocelis subcapitata were exposed to Se (as selenate) and analyzed for total protein and tissue Se content in the exponential and stationary growth phases. Protein content and Se accumulation in R. subcapitata in the stationary phase were also measured under two light intensities. No relationship between cellular protein content and Se accumulation was found for algae in the exponential phase; however, a strong relationship was found in the stationary phase among species and for R. subcapitata under differing light intensities. Absolute Se accumulations by P. kessleri, C. vulgaris, and R. subcapitata in the stationary phase were statistically different; however, the concentrations of Se in protein were similar across species. These results suggest that cellular protein content in microalgae influences Se bioconcentration and that algal protein content may improve Se bioaccumulation modeling in food webs. Integr Environ Assess Manag 2024;00:1-10. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes.

Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD. This study specifically examines the contribution of endothelial cell-specific human NOX5 expression in renal pathology in a transgenic mouse model of DKD. This study additionally compares NOX5 with the previously characterized NADPH oxidase, NOX4, in terms of their relative roles in DKD. Regardless of NOX4 pathway, this study found that endothelial cell-specific expression of NOX5 exacerbates renal injury, albuminuria and fibrosis. This is attributed to the activation of the endothelial mesenchymal transition (EMT) pathway via enhanced ROS formation and the modulation of redox-sensitive factors. These findings underscore the potential therapeutic significance of NOX5 inhibition in human DKD. The study proposes that inhibiting NOX5 could be a promising approach for mitigating the progression of DKD and strengthens the case for the development of NOX5-specific inhibitors as a potential therapeutic intervention.

Extending social accountability mandates to biomedical research in Canadian faculties of medicine.

Background: Social accountability (SA), as defined by Boelen and Heck, is the obligation of medical schools to address the needs of communities through education, research and service activities. While SA is embedded within health profession education frameworks in medicine, they are rarely taught within graduate-level (MSc/PhD) education. Methods: As these programs train future medical researchers, we invited first-year graduate students enrolled in a mandatory professionalism class at our institution (n = 111) to complete a survey on their perceptions of the importance of SA in their research, training, and future careers. Results: Over 80% (n = 87) of respondents agreed that SA is relevant and felt committed to integrating it into their future research activities, only a limited number of students felt confident and/or supported in their abilities to integrate SA into their research. Conclusions: Specific SA training in graduate education is necessary for students to effectively incorporate elements of SA into their research, and as such support the SA mandates of their training institutions. We posit that awareness of SA principles formalizes the professional standards for biomedical researchers and is thus foundational for developing a professionalism curriculum in graduate education programs in medicine. We propose an expansion of the World Health Organization (WHO) partnership pentagon to include partners within the research ecosystem (funding partners, certification bodies) that collaborate with biomedical researchers to make research socially accountable.

Contexte: La responsabilité sociale (RS), telle que définie par Boelen et Heck, est l'obligation pour les facultés de médecine de répondre aux besoins des communautés par l'entremise de l'éducation, de la recherche et des activités de service. Bien que la responsabilité sociale soit intégrée dans les cadres de formation des professionnels de santé en médecine, elle est rarement enseignée au niveau des études supérieures (MSc/PhD). Méthodes: Étant donné que ces programmes forment les futurs chercheurs médicaux, nous avons invité les étudiants de première année inscrits à un cours obligatoire sur le professionnalisme dans notre établissement (n = 111) à participer à une enquête sur leurs perceptions de l'importance de la RS dans leur recherche, leur formation et leur future carrière. Résultats: Plus de 80 % (n = 87) des répondants ont reconnu la pertinence de la RS et se sont engagés à l'intégrer dans leurs futures activités de recherche, mais seul un nombre limité d'étudiants se sont sentis confiants et/ou soutenus dans leurs capacités à intégrer la RS dans leur recherche. Conclusions: Une formation propre à la RS dans le cadre des études supérieures est nécessaire pour que les étudiants puissent intégrer efficacement des éléments de la RS dans leur recherche, et ainsi promouvoir les mandats de RS de leurs établissements de formation. Nous estimons que la sensibilisation aux principes de la RS formalise les normes professionnelles des chercheurs biomédicaux et qu'elle est donc fondamentale pour l'élaboration d'un programme de professionnalisme dans les programmes d'études supérieures en médecine. Nous proposons d'élargir le pentagone du partenariat de l'Organisation mondiale de la santé (OMS) pour y inclure les partenaires de l'écosystème de la recherche (partenaires financiers, organismes de certification) qui collaborent avec les chercheurs biomédicaux pour rendre la recherche socialement responsable.

Tracing two decades of carbon emissions using a network approach.

According to the guidelines of the Intergovernmental Panel on Climate Change, carbon emissions are attributed to the producers of goods and services. This approach has been challenged by recent literature, advocating an attribution criterion based on consumers, i.e. accounting for the carbon embedded into the goods imported by each country. Quantifying the effectiveness of such a consumption-based accounting requires understanding the complex structure of the graph induced by the flows of emissions between world countries. To this aim, we have considered a balanced panel of a hundred of countries and constructed the corresponding Carbon Trade Network for each of the past twenty years. Our analysis highlights the tendency of each country to behave either as a 'net producer'-or 'net exporter'-of emissions or as a 'net consumer'-or 'net importer'-of emissions; besides, it reveals the presence of an unexpected, positive feedback: despite individual exchanges having become less carbon-intensive, the increasing trade activity has ultimately risen the amount of emissions directed from 'net exporters' towards 'net importers'. Adopting a consumption-aware accounting would re-distribute responsibility between these two groups, possibly reducing disparities.

ACR benchmark testing of a novel high-speed ring-gantry linac kV-CBCT system.

A new generation cone-beam computed tomography (CBCT) system with new hardware design and advanced image reconstruction algorithms is available for radiation treatment simulation or adaptive radiotherapy (HyperSight CBCT imaging solution, Varian Medical Systems-a Siemens Healthineers company). This study assesses the CBCT image quality metrics using the criteria routinely used for diagnostic CT scanner accreditation as a first step towards the future use of HyperSight CBCT images for treatment planning and target/organ delineations. Image performance was evaluated using American College of Radiology (ACR) Program accreditation phantom tests for diagnostic computed tomography systems (CTs) and compared HyperSight images with a standard treatment planning diagnostic CT scanner (Siemens SOMATOM Edge) and with existing CBCT systems (Varian TrueBeam version 2.7 and Varian Halcyon version 2.0).  Image quality performance for all Varian HyperSight CBCT vendor-provided imaging protocols were assessed using ACR head and body ring CT phantoms, then compared to existing imaging modalities. Image quality analysis metrics included contrast-to-noise (CNR), spatial resolution, Hounsfield number (HU) accuracy, image scaling, and uniformity. All image quality assessments were made following the recommendations and passing criteria provided by the ACR. The Varian HyperSight CBCT imaging system demonstrated excellent image quality, with the majority of vendor-provided imaging protocols capable of passing all ACR CT accreditation standards. Nearly all (8/11) vendor-provided protocols passed ACR criteria using the ACR head phantom, with the Abdomen Large, Pelvis Large, and H&N vendor-provided protocols produced HU uniformity values slightly exceeding passing criteria but remained within the allowable minor deviation levels (5-7 HU maximum differences). Compared to other existing CT and CBCT imaging modalities, both HyperSight Head and Pelvis imaging protocols matched the performance of the SOMATOM CT scanner, and both the HyperSight and SOMATOM CT substantially surpassed the performance of the Halcyon 2.0 and TrueBeam version 2.7 systems. Varian HyperSight CBCT imaging system could pass almost all tests for all vendor-provided protocols using ACR accreditation criteria, with image quality similar to those produced by diagnostic CT scanners and significantly better than existing linac-based CBCT imaging systems.

Prevention of iatrogenic fluid overload with naloxone infusions: A patient safety initiative.

A higher number of patients admitted to hospital systems are requiring a naloxone infusion for treatment of opioid toxicity. Although naloxone is a safe antidote for the treatment of opioid toxicity, this is not without the risk of iatrogenic harm. During standard pharmacy medication safety review process, it was identified that our standard naloxone concentration protocol would deliver 4 times the standard maintenance fluid rate to our pediatric patient population. After this risk was identified, a multidisciplinary review process of our naloxone infusion protocol was performed to help mitigate the potential risk of fluid overload. Our updated naloxone infusion protocol will result in close to a 10-fold reduction in fluids required for our naloxone infusion protocol to better align with the American Society of Health-System Pharmacists' Standardize 4 Safety Initiative and reduce the potential for iatrogenic harm.

Measuring Implicit Bias in ICU Notes Using Word-Embedding Neural Network Models.

BACKGROUND: Language in nonmedical data sets is known to transmit human-like biases when used in natural language processing (NLP) algorithms that can reinforce disparities. It is unclear if NLP algorithms of medical notes could lead to similar transmissions of biases. RESEARCH QUESTION: Can we identify implicit bias in clinical notes, and are biases stable across time and geography? STUDY DESIGN AND METHODS: To determine whether different racial and ethnic descriptors are similar contextually to stigmatizing language in ICU notes and whether these relationships are stable across time and geography, we identified notes on critically ill adults admitted to the University of California, San Francisco (UCSF), from 2012 through 2022 and to Beth Israel Deaconess Hospital (BIDMC) from 2001 through 2012. Because word meaning is derived largely from context, we trained unsupervised word-embedding algorithms to measure the similarity (cosine similarity) quantitatively of the context between a racial or ethnic descriptor (eg, African-American) and a stigmatizing target word (eg, nonco-operative) or group of words (violence, passivity, noncompliance, nonadherence). RESULTS: In UCSF notes, Black descriptors were less likely to be similar contextually to violent words compared with White descriptors. Contrastingly, in BIDMC notes, Black descriptors were more likely to be similar contextually to violent words compared with White descriptors. The UCSF data set also showed that Black descriptors were more similar contextually to passivity and noncompliance words compared with Latinx descriptors. INTERPRETATION: Implicit bias is identifiable in ICU notes. Racial and ethnic group descriptors carry different contextual relationships to stigmatizing words, depending on when and where notes were written. Because NLP models seem able to transmit implicit bias from training data, use of NLP algorithms in clinical prediction could reinforce disparities. Active debiasing strategies may be necessary to achieve algorithmic fairness when using language models in clinical research.

Impact of Human Recombinant Irisin on Tissue-Engineered Skeletal Muscle Structure and Function.

Tissue engineering of exogenous skeletal muscle units (SMUs) through isolation of muscle satellite cells from muscle biopsies is a potential treatment method for acute volumetric muscle loss (VML). A current issue with this treatment process is the limited capacity for muscle stem cell (satellite cell) expansion in cell culture, resulting in a decreased ability to obtain enough cells to fabricate SMUs of appropriate size and structural quality and that produce native levels of contractile force. This study determined the impact of human recombinant irisin on the growth and development of three-dimensional (3D) engineered skeletal muscle. Muscle satellite cells were cultured without irisin (control) or with 50, 100, or 250 ng/mL of irisin supplementation. Light microscopy was used to analyze myotube formation with particular focus placed on the diameter and density of the monotubes during growth of the 3D SMU. Following the formation of 3D constructs, SMUs underwent measurement of maximum tetanic force to analyze contractile function, as well as immunohistochemical staining, to characterize muscle structure. The results indicate that irisin supplementation with 250 ng/mL significantly increased the average diameter of myotubes and increased the proliferation and differentiation of myoblasts in culture but did not have a consistent significant impact on force production. In conclusion, supplementation with 250 ng/mL of human recombinant irisin promotes the proliferation and differentiation of myotubes and has the potential for impacting contractile force production in scaffold-free tissue-engineered skeletal muscle.

Repairing Volumetric Muscle Loss with Commercially Available Hydrogels in an Ovine Model.

Volumetric muscle loss (VML) is the loss of skeletal muscle that exceeds the muscle's self-repair mechanism and leads to permanent functional deficits. In a previous study, we demonstrated the ability of our scaffold-free, multiphasic, tissue-engineered skeletal muscle units (SMUs) to restore muscle mass and force production. However, it was observed that the full recovery of muscle structure was inhibited due to increased fibrosis in the repair site. As such, novel biomaterials such as hydrogels (HGs) may have significant potential for decreasing the acute inflammation and subsequent fibrosis, as well as enhancing skeletal muscle regeneration following VML injury and repair. The goal of the current study was to assess the biocompatibility of commercially available poly(ethylene glycol), methacrylated gelatin, and hyaluronic acid (HA) HGs in combination with our SMUs to treat VML in a clinically relevant large animal model. An acute 30% VML injury created in the sheep peroneus tertius (PT) muscle was repaired with or without HGs and assessed for acute inflammation (incision swelling) and white blood cell counts in blood for 7 days. At the 7-day time point, HA was selected as the HG to use for the combined HG/SMU repair, as it exhibited a reduced inflammation response compared to the other HGs. Six weeks after implantation, all groups were assessed for gross and histological structural recovery. The results showed that the groups repaired with an SMU (SMU-Only and SMU+HA) restored muscle mass to greater degree than the groups with only HG and that the SMU groups had PT muscle masses that were statistically indistinguishable from its uninjured contralateral PT muscle. Furthermore, the HA HG, SMU-Only, and SMU+HA groups displayed notable efficacy in diminishing pro-inflammatory markers and showed an increased number of regenerating muscle fibers in the repair site. Taken together, the data demonstrates the efficacy of HA HG in decreasing acute inflammation and fibrotic response. The combination of HA and our SMUs also holds promise to decrease acute inflammation and fibrosis and increase muscle regeneration, advancing this combination therapy toward clinically relevant interventions for VML injuries in humans.

Ivermectin Toxicokinetics in Rainbow Trout (Oncorhynchus mykiss) following P-glycoprotein Induction.

Alterations in ivermectin (IVM, 22,23-dihydro avermectin B1a+22,23-dihydro avermectin B1b) toxicokinetics following P-glycoprotein (P-gp) induction by clotrimazole (CTZ) were examined in rainbow trout (Oncorhynchus mykiss) to assess the potential importance of P-gp activity levels in xenobiotic distribution and kinetics in fish. Control and fish pretreated with CTZ (30 µmol/kg) were administered 175 µg/kg 3H-IVM into the caudal vasculature. At various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) following injection, tissues (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad and fat) were removed analyzed for IVM-derived radioactivity. IVM concentration declined in blood, liver, kidney and gill, and concentrations in other tissues remained constant over the sampling period. The highest measured concentrations were found in kidney, followed by liver, with the lowest values found in brain, eye and gonad. The highest % of the administered dose was found in the liver and kidney in the immediate hours post-administration, and in the intestines and fat at 24 h post-administration. P-gp induction by CTZ did not alter IVM distribution or any calculated toxicokinetic parameter (AUC, mean residence time, T1/2, clearance rate, volume of distribution), suggesting that P-gp induction may be limited or that P-gp plays a lesser role in xenobiotic kinetics in fish compared to mammals.

Left atrial measurement in lateral versus sternal recumbency in cats undergoing focused cardiac ultrasound examination.

Objective: To compare left atrial measurements carried out by an emergency and critical care (ECC) clinician on cats in lateral and sternal recumbency. Animals and procedures: A prospective observational study was conducted between December 2019 and January 2021 at the university teaching hospital at University of Liège. One hundred and two hospitalized cats were enrolled. Focused cardiac ultrasound (FOCUS) was performed in right lateral and sternal recumbency by a single FOCUS-trained ECC resident. Standard right parasternal long- and short-axis views were recorded. After randomization of the cineloops, the same blinded resident measured maximal left atrial dimension (LAD) and the ratio of left atrial to aortic diameter (LA:Ao). Reproducibility was assessed using the Bland-Altman method. Results: The LA:Ao and LAD measurements in lateral (LA:Ao median: 1.37, range: 1.02 to 3.22; LAD median: 13.25, range: 7.90 to 32.90) and sternal (LA:Ao median: 1.38, range: 1.06 to 3.22; LAD median: 13.00, range: 8.00 to 32.90) recumbency were not significantly different (bias: -0.003, CI -0.014, 0.007; and bias: -0.101, CI -0.231, 0.029, respectively). Conclusions and clinical relevance: The FOCUS technique was successfully applied in sternal recumbency in almost all cats. The LAD and LA:Ao measured in sternal and lateral recumbency were not significantly different. Cardiac left atrial measurements obtained using FOCUS can be reliably assessed in sternal recumbency in hospitalized, stable cats.

Mesure de l'oreillette gauche en décubitus latéral versus sternal chez les chats soumis à une échographie cardiaque focalisée. Objectif: Comparer les mesures de l'oreillette gauche effectuées par un clinicien des urgences et soins intensifs (ECC) sur des chats en décubitus latéral et sternal. Animaux et procédures: Une étude observationnelle prospective a été menée entre décembre 2019 et janvier 2021 au CHU de l'Université de Liège. Cent deux chats hospitalisés ont été enrôlés. L'échographie cardiaque focalisée (FOCUS) a été réalisée en décubitus latéral droit et sternal par un seul résident ECC formé au FOCUS. Des vues parasternales droites grand et petit axe standards ont été enregistrées. Après randomisation des cineloops, le même résident en aveugle a mesuré la dimension auriculaire gauche maximale (LAD) et le rapport entre le diamètre de l'oreillette gauche et celui de l'aorte (LA:Ao). La reproductibilité a été évaluée à l'aide de la méthode de Bland-Altman. Résultats: Les mesures LA:Ao et LAD en décubitus latéral (LA:Ao médian : 1,37, intervalle : 1,02 à 3,22; LAD médian : 13,25, intervalle : 7,90 à 32,90) et sternal (LA:Ao médian : 1,38, intervalle : 1,06 à 3,22; médiane LAD : 13,00, intervalle : 8,00 à 32,90) n'étaient pas significativement différents (biais : −0,003, IC −0,014, 0,007; et biais : −0,101, IC −0,231, 0,029, respectivement). Conclusions et pertinence clinique: La technique FOCUS a été appliquée avec succès en décubitus sternal chez presque tous les chats. Le LAD et LA:Ao mesurés en décubitus sternal et latéral n'étaient pas significativement différents. Les mesures de l'oreillette cardiaque gauche obtenues à l'aide de FOCUS peuvent être évaluées de manière fiable en décubitus sternal chez les chats hospitalisés et stables.(Traduit par Dr Serge Messier).

The effects of P-glycoprotein induction on ivermectin-induced behavioural alterations in zebrafish (Danio rerio) under varying diets.

The neuroprotective effects of inducing the blood-brain barrier ATP-binding cassette protein transporter P-glycoprotein (P-gp) with clotrimazole (CTZ) in both fed and fasted zebrafish (Danio rerio) against the CNS-toxicant ivermectin (IVM, 22,23-dihydro avermectin B1a + 22,23-dihydro avermectin B1b) were examined. Zebrafish were administered 2 µmol/kg IVM intraperitoneally, and various behavioural assays (swimming performance, exploratory behaviour, olfactory responses, motor coordination, and escape responses) were used to measure neurological dysfunction. IVM administration alone caused a decrease in mean swim speed (91 % of controls), maximal speed (71 %), passage rate (81 %), 90° turns (81 %), and response to food stimulus (39 %). IVM exposure also increased the percent time that fish spent immobile (45 % increase over controls) and the percent of lethargic fish (40 % increase). Fish administered 30 µmol/kg of the P-gp inducer CTZ intraperitoneally 3 d prior to IVM exposure exhibited a change in only the % time spent immobile. These data indicate that P-gp induction may be limited in protecting the zebrafish CNS from IVM over baseline. Fasted fish did not differ from fed fish in the effects of IVM on behaviour, and no differences were seen following P-gp induction with CTZ. These results suggest that this chemical defence system is not downregulated when fish are challenged with limited energy availability.

The effects of SLICE®- and ivermectin-contaminated sediment on avoidance behaviour and oxygen consumption in marine benthic invertebrates.

Pest management strategies to reduce sea lice infestations in the salmon aquaculture industry include in-feed treatments with ivermectin (IVM) and SLICE® (active ingredient [AI] emamectin benzoate [EMB]), which can result in local contamination of the environment. These compounds partition to sediments, have moderate persistence, and may pose a risk to non-target benthic organisms. The sub-lethal effects of EMB, IVM and a combination of both (EMB/IVM) on the benthic amphipod Eohaustorius estuarius and polychaete Nereis virens at environmentally relevant sediment concentrations were examined in subchronic exposures (28-30-d). E. estuarius avoided sediment containing >50 µg/kg IVM alone and in combination with EMB. N. virens avoided sediment with >50 µg/kg IVM and >0.5 µg/kg EMB/IVM and exhibited impaired burrowing and locomotory behaviour with both treatments. Oxygen consumption was significantly decreased in E. estuarius (up to 50% compared to controls) and increased in N. virens (by âˆ¼ 200%) when exposed to EMB, IVM and EMB/IVM at concentrations <5 µg/kg. IVM, SLICE® and combination exposures at environmentally relevant concentrations caused adverse effects in E. estuarius and N. virens which could significantly alter organism fitness near salmon aquaculture operations.

Engineered Tissue Graft for Repair of Injured Infraspinatus Rotator Cuff Tendon.

Rotator cuff tears constitute a vast majority of shoulder-related injuries, occurring in a wide population range and increasing in incidence with age. Current treatments for full thickness tears use suture to secure the ruptured tendon back to its native attachment site and often retear due to improper enthesis regeneration. To reduce the occurrence of retear, our laboratory developed an engineered tendon graft for rotator cuff repair (ETG-RC) to serve as an underlayment to traditional suture repair. We hypothesize the ETG-RC will aid in the repair of the torn rotator cuff tendon by promoting the regeneration of a functional enthesis. This devitalized graft fabricated from ovine-derived bone marrow stromal cells was evaluated for biomechanical and histomorphology properties in an ovine infraspinatus rotator cuff repair model. Compared with a current standard practice Suture-Only model, the ETG-RC repair showed comparable high strain-to-failure forces, greater fibrocartilage deposition, regeneration of zonal gradients, and Shapey's fibers formation, indicative of enthesis regeneration. Enthesis regeneration after rotator cuff repair should repair mechanical properties and alleviate the need for subsequent surgeries required due to retear. The ETG-RC could potentially be used for repairing other tendon injuries throughout the body.

The Proteome of Circulating Large Extracellular Vesicles in Diabetes and Hypertension.

Hypertension and diabetes induce vascular injury through processes that are not fully understood. Changes in extracellular vesicle (EV) composition could provide novel insights. Here, we examined the protein composition of circulating EVs from hypertensive, diabetic and healthy mice. EVs were isolated from transgenic mice overexpressing human renin in the liver (TtRhRen, hypertensive), OVE26 type 1 diabetic mice and wild-type (WT) mice. Protein content was analyzed using liquid chromatography-mass spectrometry. We identified 544 independent proteins, of which 408 were found in all groups, 34 were exclusive to WT, 16 were exclusive to OVE26 and 5 were exclusive to TTRhRen mice. Amongst the differentially expressed proteins, haptoglobin (HPT) was upregulated and ankyrin-1 (ANK1) was downregulated in OVE26 and TtRhRen mice compared with WT controls. Conversely, TSP4 and Co3A1 were upregulated and SAA4 was downregulated exclusively in diabetic mice; and PPN was upregulated and SPTB1 and SPTA1 were downregulated in hypertensive mice, compared to WT mice. Ingenuity pathway analysis identified enrichment in proteins associated with SNARE signaling, the complement system and NAD homeostasis in EVs from diabetic mice. Conversely, in EVs from hypertensive mice, there was enrichment in semaphroin and Rho signaling. Further analysis of these changes may improve understanding of vascular injury in hypertension and diabetes.

High fat diet is protective against kidney injury in hypertensive-diabetic mice, but leads to liver injury.

Chronic kidney disease (CKD) is a worldwide health burden with increases risk of end-stage renal function if left untreated. CKD induced in the context of metabolic syndrome (MS) increases risks of hypertension, hyperglycemia, excess body fat and dyslipidemia. To test if combining a high-fat diet (HFD) regimen onto the hypertensive/ diabetic phenotype would mimic features of MS induced-CKD in mice, hyperglycemia was induced in genetically hypertensive mice (Lin), followed by HFD regimen. For that, 8-week-old male were subjected to streptozotocin (STZ) intraperitoneal (i.p.) injections (50 mg/kg, 5 days consecutive). LinSTZ were fed a 60% kCal HFD for 8 weeks. Lin mice treated with STZ developed polydipsia, became hypertensive and hyperglycemic. HFD induced weight gain, protected against glomerular hypertrophy, scarring, and albuminuria at endpoint compared to regular diet fed LinSTZ. On the other hand, HFD induced steatosis, liver fibrosis, inflammation, and increase in AST/ALT ratio, characteristics of non-alcoholic liver disease. Taken together, our results show that LinSTZ mice fed a HFD did not lead to a more robust model of MS-induced CKD, protected against kidney injury, but inducing liver damage. More studies are necessary to understand the kidney protective mechanisms of HFD when superimposed with hypertension and type 1 diabetes.