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Introduction Electronic cigarettes (e-cigs) have increased in popularity as a potentially less harmful alternative to tobacco smoking; however, the literature suggests “vaping” can cause endothelial damage, which can adversely affect erectile function. While there is a known link between smoking cigarettes and erectile dysfunction (ED), the effect of e-cigs on erectile function has been understudied. Objectives To review the evidence for e-cig use causing endothelial dysfunction, to explore endothelial dysfunction as a potential mechanism for ED, and to determine if there is literature to support e-cigs as a cause of ED. Methods A literature review was performed to identify publications pertaining to e-cig consumption and ED. Publications regarding e-cig consumption and vascular or endothelial damage were also included. The search was conducted through PubMed, MEDLINE database, the Cochrane Library Central Search, Web of Science, and Google Scholar. We identified 40+ publications for review, including 6 clinical trials and 3 basic science studies. Results The literature suggests that e-cig use induces oxidative stress, including the direct formation of reactive oxygen species and hydroxyl radicals, leading to endothelial damage. Endothelial dysfunction is a potential mechanism for ED, but there is a paucity of studies evaluating the relationship between e-cig use and ED. Conclusion E-cig use may cause ED in men, but more studies, specifically clinical trials, are needed to establish a relationship between e-cigs and ED. E-cig-induced endothelial dysfunction is a potential mechanism for ED that is worth exploring further. J Pincus, V Sandoval, B Dick, et al. E-Cigarette-Associated Endothelial Damage: A Potential Mechanism for Erectile Dysfunction. Sex Med Rev 2021;XX:XXX–XXX.

Background Myocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphate–sensitive potassium (KATP) channel opener diazoxide (DZX) via an unknown mechanism. KATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with KATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. Methods Myocyte volume and contractility were compared following Tyrode's physiologic solution (20 minutes) and stress (hyperkalemic cardioplegia [CPG] ± DZX; n = 5-20 each; 20 minutes) with or without MitoSNO (n = 5-11 each) at the end of stress, followed by Tyrode's solution (20 minutes). Isolated mouse hearts received CPG ± DZX (n = 8-10 each) before global ischemia (90 minutes) with or without MitoSNO (n = 8 each) at the end of ischemia, followed by reperfusion (30 minutes). Left ventricular (LV) pressures were compared using a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. Results Stress (CPG) was associated with reduced myocyte contractility that was prevented by DZX and MitoSNO individually; however, their combination was associated with loss of cardioprotection. Similarly, DZX and MitoSNO improved LV function after prolonged ischemia compared with CPG alone, and cardioprotection was lost with their combination. Conclusions MitoSNO and DZX provide cardioprotection that is lost with their combination, suggesting mutually exclusive mechanisms of action. The lack of a synergistic beneficial effect informs the current knowledge of the cardioprotective mechanisms of DZX and will aid planning of future clinical trials.

Purpose of review African–American men in the USA have a higher incidence of and mortality from prostate cancer (PCa), with a longstanding debate about the cause for these worse outcomes. This review examines differences in tumour biology and socioeconomics for African–American and Non-Hispanic White (NHW) men to answer the question ‘why AA men face higher risks for lethal PCa’ and draw a management consensus to redress the imbalance. Recent findings Recent evidence from over the past 2 years suggests the reasons why African–American men face a higher risk of lethal PCa are multifactorial, with contributions from differences in tumour biology as well as socioeconomic and healthcare access factors. Regarding tumour biology, genomic and transcriptome profiling suggests African–American men have upregulated expression of genes related to inflammatory pathways with downregulation of DNA repair genes. In contrast, NHW men have higher DNA repair pathways and metabolic pathways involving glycolysis and cell cycle activity. In addition, epidemiological evidence suggests equal healthcare access ensures equal PCa specific outcomes, implying African–American men's disease is not inherently more lethal. However, differences in tumour biology remain, which may explain specific differences in PCa incidence and the clinical findings of African–American men's increased response to immunotherapy and radiotherapy in recent trials. Summary Regardless of racial differences in disease outcomes and the factors causing them, African–American and NHW men seem to have diseases unique to their ancestry. This supports the exploration of personalized PCa treatment approaches, leveraging translational basic science research to uncover these differences and devise specific individualized methods therapeutic regimes to address them.

Acetazolamide was developed nearly 70 years ago and continues to be used for niche indications. Mechanisms of action are relatively less well-studied than clinical applications. Several potential uses span the spectrum of neurological illnesses, but yet neurological side effects complicate short- and long-term applications for many patients. This review examines the basic science and clinical usages of acetazolamide germane to neurological and psychiatric spectrums. The existing publications were reviewed from the time of the drug’s inception to April 2021. This review utilized access as available in PubMed, EMBASE, CINAHL Plus, and the Cochrane Library. Acetazolamide is firmly established as first-line prevention for altitude sickness. Outside of declining use for glaucoma, most other medical indications are few, highly selective, and/or partially beneficial. In the past, carbonic anhydrase inhibition has been the proposed mainstay of acetazolamide’s mode of action, but more contemporary studies have focused on cellular membrane ion/water channel activity. Prolonged use of acetazolamide is nevertheless likely to be limited due to common adverse events unless more effective mitigating approaches are discovered. A better understanding of acetazolamide’s clinical impact and molecular mechanisms is sure to elaborate on both healthy physiological mechanisms and disease.

Aims Accurate determination of intra-atrial conduction velocity (CV) is essential to identify arrhythmogenic areas. The most optimal, commonly used, estimation methodology to measure conduction heterogeneity, including finite differences (FiD), polynomial surface fitting (PSF), and a novel technique using discrete velocity vectors (DVV), has not been determined. We aim (i) to identify the most suitable methodology to unravel local areas of conduction heterogeneities using high-density CV estimation techniques, (ii) to quantify intra-atrial differences in CV, and (iii) to localize areas of CV slowing associated with paroxysmal atrial fibrillation (PAF). Methods and results Intra-operative epicardial mapping (>5000 sites, interelectrode distances 2 mm) of the right and left atrium and Bachmann’s bundle (BB) was performed during sinus rhythm (SR) in 412 patients with or without PAF. The median atrial CV estimated using the DVV, PSF, and FiD techniques was 90.0 (62.4–116.8), 92.0 (70.6–123.2), and 89.4 (62.5–126.5) cm/s, respectively. The largest difference in CV estimates was found between PSF and DVV which was caused by smaller CV magnitudes detected only by the DVV technique. Using DVV, a lower CV at BB was found in PAF patients compared with those without atrial fibrillation (AF) [79.1 (72.2–91.2) vs. 88.3 (79.3–97.2) cm/s; P Conclusions Areas of local conduction heterogeneities were most accurately identified using the DVV technique, whereas PSF and FiD techniques smoothen wavefront propagation thereby masking local areas of conduction slowing. Comparing patients with and without AF, slower wavefront propagation during SR was found at BB in PAF patients, indicating structural remodelling.

Basic science has enriched our understanding of the pathophysiology of severe asthma. Clinical translation of these discoveries has resulted in biologic therapies that target key components of asth...

Degenerative cervical myelopathy (DCM) is a recently coined term encompassing a variety of age-related and genetically associated pathologies, including cervical spondylotic myelopathy, degenerative disc disease, and ligamentous aberrations such as ossification of the posterior longitudinal ligament. All of these pathologies produce chronic compression of the spinal cord causing a clinical syndrome characterized by decreased hand dexterity, gait imbalance, and potential genitourinary or sensorimotor disturbances. Substantial variability in the underlying etiology of DCM and its natural history has generated heterogeneity in practice patterns. Ongoing debates in DCM management most commonly center around clinical decision-making, timing of intervention, and the ideal surgical approach. Pivotal basic science studies during the past two decades have deepened our understanding of the pathophysiologic mechanisms surrounding DCM. Growing knowledge of the key pathophysiologic processes will help us tailor personalized approaches in an increasingly heterogeneous patient population. This article focuses on summarizing the most exciting approaches in personalizing DCM patient treatments including biomarkers, factors affecting clinical decision-making, and choice of the optimal surgical approach. Throughout we provide a concise review on the conditions encompassing DCM and discuss the underlying pathophysiology of chronic spinal cord compression. We also provide an overview on clinical-radiologic diagnostic modalities as well as operative and nonoperative treatment strategies, thereby addressing knowledge gaps and controversies in the field of DCM.

Objective Antibody-dependent enhancement (ADE) affects host-virus dynamics in fundamentally different ways: i) enhancement of initial virus acquisition, and/or ii) increased disease progression/severity. Here we address the question whether anti-HIV-1 antibodies can enhance initial infection. While cell-culture experiments hinted at this possibility, in-vivo proof remained elusive. Design We used passive immunization in nonhuman primates challenged with simian-human immunodeficiency virus (SHIV), a chimera expressing HIV-1 envelope. We purified IgG from rhesus monkeys with early-stage SHIV infection - before cross-neutralizing anti-HIV-1 antibodies had developed - and screened for maximal complement-mediated antibody-dependent enhancement (C'-ADE) of viral replication with a SHIV strain phylogenetically distinct from that harbored by IgG donor macaques. IgG fractions with maximal C'-ADE but lacking neutralization were combined to yield enhancing anti-SHIV IgG (enSHIVIG). Results We serially enrolled naive macaques (Group 1) to determine the minimal and 50% animal infectious doses required to establish persistent infection after intrarectal SHIV challenge. The first animal was inoculated with a 1:10 virus-stock dilution; after this animal's viral RNA load was >104copies/ml, the next macaque was challenged with 10x less virus, a process repeated until viremia no longer ensued. Group 2 was pretreated intravenously with enSHIVIG 24 hours before SHIV challenge. Overall, Group 2 macaques required 3.4-fold less virus compared to controls (p = 0.002). This finding is consistent with enhanced susceptibility of the passively immunized animals to mucosal SHIV challenge. Conclusion These passive immunization data give proof of IgG-mediated enhanced virus acquisition after mucosal exposure - a potential concern for antibody-based AIDS vaccine development.

Osteolysis is one of the most prominent reasons of revision surgeries in total joint arthroplasty. This biological phenomenon is induced by wear particles and corrosion products that stimulate inflammatory biological response of surrounding tissues. The eventual responses of osteolysis are the activation of macrophages leading to bone resorption and prosthesis failure. Various factors are involved in the initiation of osteolysis from biological issues, design, material specifications, and model of the prosthesis to the health condition of the patient. Nevertheless, the factors leading to osteolysis are sometimes preventable. Changes in implant design and polyethylene manufacturing are striving to improve overall wear. Osteolysis is clinically asymptomatic and can be diagnosed and analyzed during follow-up sessions through various imaging modalities and methods, such as serial radiographic, CT scan, MRI, and image processing-based methods, especially with the use of artificial neural network algorithms. Deep learning algorithms with a variety of neural network structures such as CNN, U-Net, and Seg-UNet have proved to be efficient algorithms for medical image processing specifically in the field of orthopedics for the detection and segmentation of tumors. These deep learning algorithms can effectively detect and analyze osteolytic lesions well in advance during follow-up sessions in order to administer proper treatments before reaching a critical point. Osteolysis can be treated surgically or nonsurgically with medications. However, revision surgeries are the only solution for the progressive osteolysis. In this literature review, the underlying causes, mechanisms, and treatments of osteolysis are discussed with the main focus on the possible computer-based methods and algorithms that can be effectively employed for the detection of osteolysis.

Aim Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Since current therapies often fail to prevent arrhythmic events in certain LQTS subtypes, new therapeutic strategies are needed. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing IKs current. Methods and results We investigated the effects of DHA in wild type (WT) and transgenic long QT Type 1 (LQT1; loss of IKs), LQT2 (loss of IKr), LQT5 (reduction of IKs), and LQT2–5 (loss of IKr and reduction of IKs) rabbits. In vivo ECGs were recorded at baseline and after 10 µM/kg DHA to assess changes in heart-rate corrected QT (QTc) and short-term variability of QT (STVQT). Ex vivo monophasic action potentials were recorded in Langendorff-perfused rabbit hearts, and action potential duration (APD75) and triangulation were assessed. Docosahexaenoic acid significantly shortened QTc in vivo only in WT and LQT2 rabbits, in which both α- and β-subunits of IKs-conducting channels are functionally intact. In LQT2, this led to a normalization of QTc and of its short-term variability. Docosahexaenoic acid had no effect on QTc in LQT1, LQT5, and LQT2–5. Similarly, ex vivo, DHA shortened APD75 in WT and normalized it in LQT2, and additionally decreased AP triangulation in LQT2. Conclusions Docosahexaenoic acid exerts a genotype-specific beneficial shortening/normalizing effect on QTc and APD75 and reduces pro-arrhythmia markers STVQT and AP triangulation through activation of IKs in LQT2 rabbits but has no effects if either α- or β-subunits to IKs are functionally impaired. Docosahexaenoic acid could represent a new genotype-specific therapy in LQT2.

Purpose To compare the histological healing and radiographic effects of tendons transferred to ossified or unossified bone using different tendon fixation techniques Methods Nine new-born piglets underwent bilateral tendon transfers to either the ossified boney calcaneal body or unossified apophysis. The tendons were fixed using metallic suture anchors, sutures alone or a bone tunnel. At six weeks of age, calcanei were harvested, radiologically imaged and then prepared for histology. A semi-quantitative aggregated scoring system with values ranging from 0 (poor) to 15 (excellent), was used to grade healing at the surgical enthesis and the apophyseal ossification was graded by five independent reviewers in triplicate using a modified (1 to 4) validated scoring system. Results Histologically, the cartilaginous transfers utilizing the tunnel and suture techniques also demonstrated the best average aggregated scores of entheses healing rivalling that measured in transfers using the classic bone tunnel technique (clinical benchmark), whereas suture anchor fixation demonstrated the worst healing in both the ossified and unossified samples. All three transfer techniques caused at least minor alterations in apophyseal ossification, with the most significant changes observed in the metallic suture anchor cohort. The tunnel and suture techniques demonstrated similar and more mild abnormalities in ossification. Conclusion Tendon transfers to unossified bone heal histologically as well as transfers classically performed through tunnels in bone. Suture fixation or tunnel techniques appear radiographically and histologically superior to suture anchors in our newborn porcine model. Level of evidence

The objective of this systematic review is to examine metabolic dysfunction, specifically metabolic syndrome and its components, as well as type 2 diabetes mellitus (T2DM) as it relates to individuals with a diagnosis of Autism Spectrum Disorder (ASD). We searched PubMed, Embase, Cochrane, PsychInfo, and Scopus from January 1, 1998 to October 12, 2018 for English, peer-reviewed, original articles containing adult and pediatric populations with any form of ASD and metabolic dysfunction, including T2DM, hyperglycemia, hypertension, dyslipidemia, or central obesity. Exclusion criteria included studies without ASD-specific results, basic science research, review papers, case studies, and medication clinical trials. Eight studies were included in this review, with a total of 70,503 participants with ASD and 2,281,891 in comparison groups. Within ASD populations, higher prevalence for metabolic syndrome components hyperglycemia, hypertension, and dyslipidemia were observed, as well as increased incidence and prevalence of T2DM. However, heterogeneity of study definitions and measurements should be noted. While there is evidence of increased prevalence of T2DM, hyperglycemia, hypertension, and dyslipidemia for those with ASD, the relationship is poorly understood. There is also lack of research investigating central obesity and risk of metabolic syndrome as a diagnosis. More research addressing these gaps is warranted to evaluate the risk of metabolic dysfunction in populations with ASD.

Objective: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STIs) that are known to increase HIV susceptibility in women. Design: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. Methods: The first study (n = 11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis and Trichomonas vaginalis. Six animals were CAB-LA treated and five were controls. The second study (n = 9) included a triple STI model with repeated exposures to C. trachomatis, T. vaginalis and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared with untreated controls over time. Results: All six CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges, while the untreated animals became SHIV-infected after a median of two challenges (log-rank P

There is an extensive debate on the neurological consequences of 2019 novel coronavirus disease (COVID-19) and its impact on Parkinson’s disease (PD) patients, which seems to puzzle neurologists. Links between viral infections and PD have long been suspected and studied, but the exact relationship remains elusive. Since severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) enters the brain through multiple routes and has a direct impact on the brain, cumulative damage occurs due to the activation of proinflammatory cytokines and chemokines. SARS-CoV-2 seems to aggravate PD due to its effects on α-synuclein, mitochondrial dysfunction, and dopamine depletion. A few studies have even highlighted the higher vulnerability of PD patients to COVID-19. The sudden dramatic change in lifestyle caused by the pandemic and the widespread lockdowns that were implemented have added to the hidden sorrows of PD patients, as they already have a compromised mechanism for coping with stress. This review summarizes insights from basic science and the clinical effect of SARS-CoV-2 infection on the human brain, with a specific focus on PD.

IgA nephropathy (IgAN) is a major cause of chronic kidney disease (CKD) and end-stage renal disease worldwide. Currently, clinical interventions for IgAN are limited, and many patients seek out alternative therapies such as traditional Chinese medicine (TCM). In the last several years, TCM has accumulated ample application experiences and achieved favorable clinical effects. This article summarizes high-quality research from basic science to clinical applications aimed to provide more evidence-based medicine proof for the clinical treatment of IgAN. In summary, qi and yin deficiency accounted for the largest proportion in IgAN patients, and the treatment of IgAN should be based on supplementing qi and nourishing yin. Further, for patients with severe IgAN, the treatment combination of Chinese and Western medicines is better than pure Chinese medicine or hormone therapy. In addition, the pharmacological mechanism of Chinese herbal medicines is mostly based on restoring the immune function, relieving the inflammation damage, and inhibiting proliferation of the glomerular mesangial cells.

Nongenetic heterogeneity, or gene expression stochasticity, is an important source of variability in biological systems. With the advent and improvement of single molecule resolution technologies, it has been shown that transcription dynamics and resultant transcript number fluctuations generate significant cell-to-cell variability that has important biological effects and may contribute substantially to both tissue homeostasis and disease. In this respect, the pathophysiology of stem cell-derived malignancies such as acute myeloid leukemia and myelodysplastic syndromes, which has historically been studied at the ensemble level, may require reevaluation. To that end, it is our aim in this review to highlight the results of recent single-molecule, biophysical, and systems studies of gene expression dynamics, with the explicit purpose of demonstrating how the insights from these basic science studies may help inform and progress the field of leukemia biology and, ultimately, research into novel therapies.

Purpose of review To answer several important clinical questions, the Consortium for the study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) research consortium has established several ongoing clinical cohort studies focused on pancreatitis in adults and children, pancreatic cancer, and diabetes associated with pancreatic disease. These will provide a unique resource for clinical and basic science research into these hard-to-treat diseases. Recent findings The cause, natural history, and prognosis of acute relapsing and chronic pancreatitis in adults and children are being delineated. The mechanisms of diabetes associated with chronic pancreatitis, acute pancreatitis, and pancreatic cancer are being defined. The ability to predict the presence of early-stage pancreatic cancer, thought the presence of new-onset diabetes, is being explored as a strategy to improve survival. The CPDPC is now also turning to developing clinically useful biomarkers, and initiating clinical trials in these difficult to treat pancreatic diseases. Summary These large prospective patient cohorts, established and followed up by the CPDPC, provide a unique resource to improve the care of patients of all ages with pancreatitis, and to allow earlier diagnosis of pancreatic cancer.

Mental health symptoms secondary to trauma exposure and substance use disorders (SUDs) co-occur frequently in both clinical and community samples. The possibility of a shared aetiology remains an important question in translational neuroscience. Advancements in genetics, basic science, and neuroimaging have led to an improved understanding of the neural basis of these disorders, their frequent comorbidity and high rates of relapse remain a clinical challenge. This project aimed to conduct a review of the field’s current understanding regarding the neural circuitry underlying posttraumatic stress disorder and SUD. A comprehensive review was conducted of available published literature regarding the shared neurobiology of these disorders, and is summarized in detail, including evidence from both animal and clinical studies. Upon summarizing the relevant literature, this review puts forth a hypothesis related to their shared neurobiology within the context of fear processing and reward cues. It provides an overview of brain reward circuitry and its relation to the neurobiology, symptomology, and phenomenology of trauma and substance use. This review provides clinical insights and implications of the proposed theory, including the potential development of novel pharmacological and therapeutic treatments to address this shared neurobiology. Limitations and extensions of this theory are discussed to provide future directions and insights for this shared phenomena.

Purpose of the review While there has been a longstanding interest in metabolic disease in pulmonary hypertension, publications in the last several years have translated basic science findings to human disease and even led to recently published studies of metabolic therapy in pulmonary arterial hypertension that are discussed here. Recent findings Progress has been made in four key areas including mechanisms of insulin resistance in pulmonary arterial hypertension, the role of obesity in pulmonary vascular disease, novel clinical trials targeting metabolism in pulmonary hypertension, and the role of metabolism in chronic thromboembolic pulmonary hypertension. Summary : Insulin resistance in pulmonary arterial hypertension is primarily in the lipid axis. There are systemic manifestations of insulin resistance including right ventricular lipotoxicity. Obesity is associated with elevation of right ventricular systolic pressure even in a healthy population and therapies in pulmonary arterial hypertension that target metabolism hold promise for improving exercise, right ventricular function, and visceral adiposity. Finally, there are emerging data that chronic thromboembolic pulmonary hypertension is similarly characterized by metabolic alterations, though the specific metabolites may be different from pulmonary arterial hypertension.

Surgery is required for cure of most solid tumors, and general anesthesia is required for most cancer surgery. The vast majority of cancer surgery is facilitated by general anesthesia using volatile inhalational agents such as isoflurane and sevoflurane. Only recently have the immunologic and oncologic effect of inhalational agents, and their alternative, propofol-based total intravenous anesthesia (TIVA), come under investigation. Between January 2019 and June 2020, English language articles on PubMed were searched for the keywords “Propofol” “TIVA” or “IV anesthesia” and either “cancer surgery” or “surgical oncology.” Duplicates were removes, manuscripts classified as either in vitro, animal, translational, or clinical studies, and their results summarized within these categories. In-vitro and translational data suggest that inhalational anesthetics are potent immunosuppressive and tumorigenic agents that promote metastasis, while propofol is anti-inflammatory, anti-tumorigenic, and prevents metastasis development. Clinically there is a recurring association, based largely on retrospective, single institution series, that TIVA is associated with significant improvements in disease-free interval and overall survival in a number of, but not all, solid tumors. The longer the surgery is, the more intense the surgical trauma is, the more aggressive the malignancy is, and the higher likelihood of an association is. Prospective randomized trials, coupled with basic science and translational studies, are needed to further define this association.

© Translational Andrology and Urology. All rights reserved. This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/., Erectile dysfunction (ED) impacts a significant portion of the aging male population. Standard treatments such as oral medications, intracavernosal injections, intraurethral suppositories, vacuum erection aids, and penile prosthesis placement have stood the test of time. Recently, there has been a growing interest in the concept of regenerative medicine with the goal of restoring or renewing functional tissue. Low intensity shock wave therapy (LiSWT) is one example of a regenerative therapy. A strong body of basic science data suggests that shockwaves, when applied to local tissue, will encourage blood vessel and nerve regeneration. Clinical evidence supports the use of LiSWT to treat conditions ranging from ischemic heart disease, musculoskeletal injuries, and even chronic non-healing wounds. LiSWT is also being used to treat male sexual dysfunction conditions such as Peyronie's Disease and ED. The first studied application of LiSWT for ED was published in 2010. Since then multiple randomized, sham-controlled trials have sought to evaluate outcomes for this novel therapy in men with vasculogenic ED. Additionally, several meta-analyses are available with pooled data suggesting that LiSWT results in a significantly greater improvement in erectile function relative to sham-control. Despite these promising findings, the current body of literature is marred by significant heterogeneity relating to treatment protocols, patient populations, and follow-up duration. Further work is necessary to determine optimal device technologies, patient characteristics, and treatment duration prior to considering LiSWT as standard of care for men with ED.

Objectives RA is a chronic autoimmune disease characterized by joint inflammation and tissue destruction. Immune responses mediated by T cells and autoantibodies are known to play critical roles in RA. Collagen type II (CII)-induced arthritis (CIA) is a commonly used animal model of human RA. We have previously reported the identification of a new T cell inhibitory molecule CD300c. Here we investigate the ability of recombinant CD300c-IgG2a Fc (CD300c-Ig) fusion protein to prevent and treat CIA. Methods Mice were induced to develop CIA by CII and injected with CD300c-Ig or control Ig protein before or after CIA symptoms occur. The mice were examined for CIA clinical and pathological scores, and analysed for the expression of proinflammatory cytokines, the percentage and activation of CD4 T cells and regulatory T cells, CII-specific T cell proliferation and cytokine production, and CII-specific autoantibody production. Results In a prevention model, CD300c-Ig significantly decreases CIA incidence, and reduces clinical and pathological arthritis scores. In the treatment model, CD300c-Ig ameliorates established CIA. The beneficial effects of CD300c-Ig are related to decreased expansion and activation of T cells in the spleen and reduced expression of proinflammatory cytokines in the joints. CD300c-Ig also inhibits CII-specific T cell proliferation and Th1 and Th17 cytokine production. In addition, CD300c-Ig treatment reduced the production of CII autoantibodies in the serum. Furthermore, CD300c-Ig inhibits the proliferation and activation of T cells from RA patients in vitro. Conclusion CD300c-Ig protein has the potential to be used in the treatment of patients with RA.

Graefe's archive for clinical and experimental ophthalmology 259(8), 2251-2257 (2021). doi:10.1007/s00417-021-05235-8, Published by Springer, Heidelberg

Menopause-associated and hormone-associated cognitive research has a rich history built from varied disciplines and species. This review discusses landmark rodent and human work addressing cognitive outcomes associated with varied experiences of menopause and hormone therapy. Critical variables in menopause and cognitive aging research are considered, including menopause etiology, background hormone milieu and parameters of exposure to estrogens and progestogens. Recent preclinical research has identified that menopause and ovarian hormone fluctuations across many neurobiological systems affect cognitive aging, mapping novel avenues for future research. Preclinical models provide insight into complex interdisciplinary relationships in a systematic and highly controlled fashion. We highlight that acknowledging the strengths and weaknesses for both preclinical and clinical research approaches is vital to accurate interpretation, optimal translation and the direction of future research. There is great value in collaboration and communication across preclinical and clinical realms, especially regarding reciprocal feedback of findings to advance preclinical models, improve experimental designs and enrich basic science translation to the clinic. In searching for biological mechanisms underlying the cognitive consequences of menopause and hormone therapies, it is noteworthy that clinical and preclinical scientists are grounded in the same fundamental goal of optimizing health outcomes for women across the lifespan.

Neointimal cells are an elusive population with ambiguous origins, functions, and states of differentiation. Expansion of the venous intima in arteriovenous fistula (AVF) is one of the most prominent remodeling processes in the wall after access creation. However, most of the current knowledge about neointimal cells in AVFs comes from extrapolations from the arterial neointima in non-AVF systems. Understanding the origin of neointimal cells in fistulas may have important implications for the design and effective delivery of therapies aimed to decrease intimal hyperplasia (IH). In addition, a broader knowledge of cellular dynamics during postoperative remodeling of the AVF may help clarify other transformation processes in the wall that combined with IH determine the successful remodeling or failure of the access. In this review, we discuss the possible anatomical sources of neointimal cells in AVFs and their relative contribution to intimal expansion.

Objective HIV-1 infection triggers immune activation, as reflected by the upregulation of various cytokines. This immune activation remains elevated despite antiretroviral therapy (ART) and leads to early age-related diseases. Here, we addressed the mechanisms of sustained immune activation in HIV-1-infected human lymphoid tissues ex vivo. Design/method We investigated several potential causes of immunoactivation, including: a proinflammatory effect of ART drugs themselves; an early HIV-1-triggered cytokine storm, which could in turn trigger a sustained cytokine dysregulation; herpesvirus reactivation; HIV-1 protein release; and production of defective virions and extracellular vesicles. Tissue immune activation was evaluated from measurements of cytokines in culture medium using multiplexed immunoassays. Results Neither ART itself nor simulated cytokine storms nor exogenously added HIV-1 proteins triggered a sustained cytokine upregulation. In contrast, defective (replicative-incompetent) virions and extracellular vesicles induced sustained cytokine upregulation, as did infectious virus. Tissue immune activation was accompanied by reactivation of cytomegalovirus. Conclusion The system of ex-vivo human lymphoid tissue allowed investigation, under laboratory-controlled conditions, of possible mechanisms involved in persistent immune activation in HIV-1 patients under ART. Mechanisms of this immunoactivation identified in ex-vivo tissues may indicate potential therapeutic targets for restoration of immune system homeostasis in HIV-1-infected patients.

Although acute coronary syndromes (ACS) remain one of the leading causes of death, the clinical presentation has changed over the past three decades with a decline in the incidence of ST-segment elevation myocardial infarction (STEMI) and an increase in non-STEMI. This epidemiological shift is at least partially explained by changes in plaque biology as a result of the widespread use of statins. Historically, atherosclerotic plaque rupture of the fibrous cap was thought to be the main culprit in ACS. However, plaque erosion with an intact fibrous cap is now responsible for about one third of ACS and up to two thirds of non-STEMI. Two major research approaches have enabled a better understanding of plaque erosion. First, advanced intravascular imaging has provided opportunities for an 'optical biopsy' and extensive phenotyping of coronary plaques in living patients. Second, basic science experiments have shed light on the unique molecular characteristics of plaque erosion. At present, patients with ACS are still uniformly treated with coronary stents irrespective of the underlying pathobiology. However, pilot studies indicate that patients with plaque erosion might be treated conservatively without coronary stenting. In this Review, we discuss the patient phenotype and the molecular characteristics in atherosclerotic plaque erosion and provide our vision for a potential major shift in the management of patients with plaque erosion.

Aims Coronavirus disease of 2019 (COVID-19) has rapidly become a worldwide pandemic. Many clinical trials have been initiated to fight the disease. Among those, hydroxychloroquine and azithromycin had initially been suggested to improve clinical outcomes. Despite any demonstrated beneficial effects, they are still in use in some countries but have been reported to prolong the QT interval and induce life-threatening arrhythmia. Since a significant proportion of the world population may be treated with such COVID-19 therapies, evaluation of the arrhythmogenic risk of any candidate drug is needed. Methods and results Using the O'Hara-Rudy computer model of human ventricular wedge, we evaluate the arrhythmogenic potential of clinical factors that can further alter repolarization in COVID-19 patients in addition to hydroxychloroquine (HCQ) and azithromycin (AZM) such as tachycardia, hypokalaemia, and subclinical to mild long QT syndrome. Hydroxychloroquine and AZM drugs have little impact on QT duration and do not induce any substrate prone to arrhythmia in COVID-19 patients with normal cardiac repolarization reserve. Nevertheless, in every tested condition in which this reserve is reduced, the model predicts larger electrocardiogram impairments, as with dofetilide. In subclinical conditions, the model suggests that mexiletine limits the deleterious effects of AZM and HCQ. Conclusion By studying the HCQ and AZM co-administration case, we show that the easy-to-use O'Hara-Rudy model can be applied to assess the QT-prolongation potential of off-label drugs, beyond HCQ and AZM, in different conditions representative of COVID-19 patients and to evaluate the potential impact of additional drug used to limit the arrhythmogenic risk.

Aims/hypothesis The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. Methods A total of 361 patients with type 1 diabetes (192 patients with onset HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. Results The susceptible DR3 (β = −0.09, p = 0.0009) and DR4-DQ8 (β = −0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (β = 0.21, p = 0.0314) and DR12 (β = 0.27, p DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (β = −0.21, p = 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset Conclusions/interpretation In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies. Graphical abstract

We describe a proteomics analysis to determine the molecular differences between normothermically perfused (normothermic machine perfusion, NMP) human kidneys with urine recirculation (URC) and urine replacement (UR). Proteins were extracted from 16 kidney biopsies with URC (n = 8 donors after brain death [DBD], n = 8 donors after circulatory death [DCD]) and three with UR (n = 2 DBD, n = 1 DCD), followed by quantitative analysis by mass spectrometry. Damage‐associated molecular patterns (DAMPs) were decreased in kidney tissue after 6 hours NMP with URC, suggesting reduced inflammation. Vasoconstriction was also attenuated in kidneys with URC as angiotensinogen levels were reduced. Strikingly, kidneys became metabolically active during NMP, which could be enhanced and prolonged by URC. For instance, mitochondrial succinate dehydrogenase enzyme levels as well as carbonic anhydrase were enhanced with URC, contributing to pH stabilization. Levels of cytosolic and the mitochondrial phosphoenolpyruvate carboxykinase were elevated after 24 hours of NMP, more prevalent in DCD than DBD tissue. Key enzymes involved in glucose metabolism were also increased after 12 and 24 hours of NMP with URC, including mitochondrial malate dehydrogenase and glutamic‐oxaloacetic transaminase, predominantly in DCD tissue. We conclude that NMP with URC permits prolonged preservation and revitalizes metabolism to possibly better cope with ischemia reperfusion injury in discarded kidneys., The authors perform a proteomics analysis to identify molecular differences between normothermically machine perfused and discarded human kidneys with urine recirculation and urine replacement using lactated Ringers.

Macrophages have emerged at the forefront of research in immunology and transplantation because of recent advances in basic science. New findings have illuminated macrophage populations not identified previously, expanded upon traditional macrophage phenotypes, and overhauled macrophage ontogeny. These advances have major implications for the field of transplant immunology. Macrophages are known to prime adaptive immune responses, perpetuate T-cell-mediated rejection and antibody-mediated rejection, and promote allograft fibrosis. In this review, macrophage phenotypes and their role in allograft injury of solid organ transplants will be discussed with an emphasis on kidney transplantation. Additionally, consideration will be given to the prospect of manipulating macrophage phenotypes as cell-based therapy. Innate immunity and macrophages represent important players in allograft injury and a promising target to improve transplant outcomes.

Objectives Frey's syndrome (FS) describes the phenomenon of gustatory sweating and is a cause of significant social embarrassment for sufferers. It has been attributed to aberrant growth of parasympathetic salivatory fibers in the auriculotemporal nerve toward overlying sweat glands. However, the exact mechanism behind this growth is unknown. This review aims to expand and elucidate the theory of aberrant regeneration in FS. Methods A review of the recent literature on nerve regeneration was conducted in order develop further insights into the etiology of both adult onset and pediatric FS. Results Neurturin, a neurotrophic factor released by both salivary and sweat glands, was identified as a possible key player in the etiology of FS. Conclusion Further research into the role of neurturin could help to elucidate the pathogenic mechanisms underlying the condition and might reveal neurturin to be a potential target for pharmacological intervention. Level of Evidence NA (Basic Science Review).

BackgroundAneurysm wall degeneration is linked to growth and rupture. To address the effect of aspirin (ASA) on aneurysm formation under various wall conditions, this issue was analyzed in a novel rabbit bifurcation model.MethodsBifurcation aneurysms created in 45 New Zealand White rabbits were randomized to vital (n=15), decellularized (n=13), or elastase-degraded (n=17) wall groups; each group was assigned to a study arm with or without ASA. At follow-up 28 days later, aneurysms were evaluated for patency, growth, and wall inflammation at macroscopic and histological levels.Results36 rabbits survived to follow-up at the end of the trial. None of the aneurysms had ruptured. Patency was visualized in all aneurysms by intraoperative fluorescence angiography and confirmed in 33 (92%) of 36 aneurysms by MRI/MRA. Aneurysm size was significantly increased in the vital (without ASA) and elastase-degraded (with and without ASA) groups. Aneurysm thrombosis was considered complete in three (50%) of six decellularized aneurysms without ASA by MRI/MRA. Locoregional inflammation of the aneurysm complex was significantly reduced in histological analysis among all groups treated with ASA.ConclusionASA intake prevented inflammation of both the periadventitial tissue and aneurysm wall, irrespective of initial wall condition. Although ASA prevented significant growth in aneurysms with vital walls, this preventive effect did not have an important role in elastase-degraded pouches. In possible translation to the clinical situation, ASA might exert a potential preventive effect during early phases of aneurysm formation in patients with healthy vessels but not in those with highly degenerative aneurysm walls.

This review explores the role of diet in the pathogenesis and treatment of inflammatory bowel disease and highlights various contemporary dietary options in the treatment of adult and pediatric inflammatory bowel disease. The role of diet in inflammatory bowel disease has become clearer through epidemiologic, basic science, and interventional studies. Multiple dietary treatment strategies are used as primary or adjunctive therapy in inflammatory bowel disease to varying degrees of success. While the field of nutrition and nutritional therapy in inflammatory bowel disease has evolved with supporting evidence from basic science and clinical research, further studies are necessary to fully understand the impact and potential of diet and dietary therapy in the management of IBD.

Background TNF-α and IL-6 are both pleiotropic cytokines playing major roles in cancer-associated cytokine networks. They have previously been investigated for their function in skin malignancies, mostly melanomas, and studies on non-melanoma skin cancer (NMSC) patients are relatively rara. In this study, we aimed to investigate the associations of serum levels of IL-6 and TNF-α with NMSCs and its clinicopathological features. Methods This cases-control study was carried out to assess the serum levels of TNF-α and IL-6 in 70 NMSC patients, in comparison with 30 healthy individuals, by means of flow cytometric bead-based immuneoassay. Results Serum levels of both TNF-α and IL-6 were significantly higher in NMSC patients (6.470 vs. 4.355 pg/ml; p = 0.0468, respectively), compared to healthy individuals (3.205 vs. 0.000 pg/ml; p = 0.0126, respectively). In the subgroup analysis, squamous cell carcinomas patients had higher serum levels of IL-6 compared to healthy individuals (3.445 vs. 0.000 pg/ml; p = 0.0432). No other significant differences were observed in the serum levels of these two cytokines among different clinicopathological subgroups of the patients. Conclusion The increased levels of TNF-α and IL-6 in NMSC patients can be introduced as an epiphenomenon of a complex cancer-induced cytokine cascade.

Rationale This literature review describes the pathophysiological mechanisms of the current classes of proteins, cells, genes, and signaling pathways relevant to moyamoya angiopathy (MA), along with future research directions and implementation of current knowledge in clinical practice. Objective This article is intended for physicians diagnosing, treating, and researching MA. Methods and results References were identified using a PubMed/Medline systematic computerized search of the medical literature from January 1, 1957, through August 4, 2020, conducted by the authors, using the key words and various combinations of the key words "moyamoya disease," "moyamoya syndrome," "biomarker," "proteome," "genetics," "stroke," "angiogenesis," "cerebral arteriopathy," "pathophysiology," and "etiology." Relevant articles and supplemental basic science articles published in English were included. Intimal hyperplasia, medial thinning, irregular elastic lamina, and creation of moyamoya vessels are the end pathologies of many distinct molecular and genetic processes. Currently, 8 primary classes of proteins are implicated in the pathophysiology of MA: gene-mutation products, enzymes, growth factors, transcription factors, adhesion molecules, inflammatory/coagulation peptides, immune-related factors, and novel biomarker candidate proteins. We anticipate that this article will need to be updated in 5 years. Conclusion It is increasingly apparent that MA encompasses a variety of distinct pathophysiologic conditions. Continued research into biomarkers, genetics, and signaling pathways associated with MA will improve and refine our understanding of moyamoya's complex pathophysiology. Future efforts will benefit from multicenter studies, family-based analyses, comparative trials, and close collaboration between the clinical setting and laboratory research.

PURPOSE OF REVIEW: Cancer Cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers, and potential therapies. RECENT FINDINGS: Both in mice and human, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in pre-cachexia. Inflammatory pathways, mitochondrial dysfunction, and gut microbiota have recently been studied to play an important role in muscle fatigue in pre-clinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue. SUMMARY: Heightened inflammation within muscle, altered muscle function, and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

Parkinson’s disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential risk factor, and there is supporting although not entirely consistent epidemiologic and basic science evidence to support its role. Encephalitis caused by influenza has included parkinsonian features. Epidemiological evidence is most compelling for an association between PD and hepatitis C virus. Infection with Helicobacter pylori may be associated not only with PD risk but also response to levodopa. Rapidly evolving knowledge regarding the role of the microbiome also suggests a role of resident bacteria in PD risk. Biological plausibility for the role for infectious agents is supported by the known neurotropic effects of specific viruses, particular vulnerability of the substantia nigra and even the promotion of aggregation of alpha-synuclein. A common feature of implicated viruses appears to be production of high levels of cytokines and chemokines that can cross the blood-brain barrier leading to microglial activation and inflammation and ultimately neuronal cell death. Based on multiple avenues of evidence it appears likely that specific bacterial and particularly viral infections may increase vulnerability to PD. The implications of this for PD prevention requires attention and may be most relevant once preventive treatments for at-risk populations are developed.

The impressive advances in the several disciplines including neurophysiology, molecular biology, neuroimmunology, neurogenetics, neuroimaging, and neuropharmacology of epilepsies have been stimulating a mutual interaction among basic scientists, clinicians, and professionals from other disciplines, leading to the identification of clinical questions and then the design of basic science paradigms to test enigmatic clinical issues. Based on a clinical observation that the coexistence of genetic (idiopathic) generalized typical absence and mesial temporal lobe epilepsy in the same patient is extremely rare and debatable, we addressed the rare coexistence in the same individual, designed an experimental approach to test the validity of this clinical concept and to study the underlying mechanisms involved. Here we presented evidence of a mutual cross-interaction in the circuits involved in typical absence and temporal lobe epilepsy. This article delineates a phenomenological picture and comprehends a theoretical understanding of a mutual cross-interaction in typical absence as a representative of genetic generalized epilepsies and limbic epilepsy in which seizures often start from the mesial temporal lobe.

Objective: Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir. Design: We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial. Methods: We compared changes in mean serum folate and occurrence of low serum folate (

Scientists from multiple basic disciplines and an international group of physician-scientists from the field of obstetrics and gynecology presented recent studies and discussed new and evolving theories of uterine fibroid etiology, growth and development at The Basic Science of the Uterine Fibroids meeting, sponsored by the Campion Fund and the National Institute of Environmental Health Sciences. The purpose was to share up-to date knowledge and to stimulate new concepts regarding the basic molecular biology and pathophysiology of uterine fibroids, and to promote future collaborations. The meeting was held at the National Institutes of Environmental Health Sciences in North Carolina on February 28, 2020. Speakers reviewed recent advances in cellular and molecular processes that contribute to fibroid growth and new opportunities for treatment. At the conclusion of the conference, attendees identified important new directions for future research.

Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin‐like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion‐induced liver damage in a dose‐dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage., The lectin‐like domain of thrombomodulin suppresses liver ischemia and reperfusion injury in mice via inhibition of the high‐mobility group box 1 / Toll‐like receptor 4 pathway, even after the insult has started.

Aims Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF. Methods and results Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed. Conclusions Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs.

OBJECTIVES: Almonds are a rich source of phenolic and polyphenolic compounds, which have antioxidant activity. In vitro and in vivo studies have demonstrated that topical application of almond oil and almond skin extract reduces UVB-induced photoaging. Ultraviolet-B (UVB) protection by oral almond consumption has not been previously studied in humans. It was the objective to investigate whether oral almond consumption can increase resistance to UVB radiation and reduce skin aging in healthy Asian women. METHODS: Thirty-nine female participants (18–45 years) with Fitzpatrick skin type II-IV were randomly assigned to consume either 1.5 oz of almonds or 1.8 oz of pretzels daily for 12 weeks. Minimal erythema dose (MED) was determined using a standardized protocol, which determined the minimal radiation inducing erythema on the inner arm 24 hours following UVB exposure. Facial skin texture was evaluated by two dermatologists using the Clinician's Erythema Assessment scale and Allergan Roughness scale. Facial melanin index, hydration, sebum, and erythema were determined using a cutometer. RESULTS: Women who consumed almonds, experienced a significant increase in MED from 415 ± 64 to 487 ± 59 (18.7 ± 19.2%, P = 0.006) from baseline to week 12 compared to women in the pretzel group from 415 ± 67 to 421 ± 67 (1.8 ± 11.1%). The exposure time to reach minimal erythema was also increased significantly in the almond group from 160 ± 23 to 187 ± 25 (17.5 ± 22.2%) compared to the pretzel group from 165 ± 27 to 166 ± 25 (1.7 ± 14%) (p=0.026). There were no differences noted between the groups consuming almonds versus pretzels in Allergan roughness, melanin, hydration, or sebum on facial skin. CONCLUSIONS: Our findings suggest that daily oral almond consumption may lead to enhanced protection from UVB photodamage by increasing the MED. Protection from other UV radiation was not tested and therefore almond consumption will not replace other methods of sun protection such as application of sunscreen or wearing protective closing. FUNDING SOURCES: Almond Board of California.

Introduction. The rapid development of basic science enabled us to significantly expand our understanding of various intercellular interactions. Epithelial-mesenchymal transition (EMT) is known to play a key role in certain tissue formation in the embryonic period. However, recent data show that EMT can also be observed in some pathological conditions, in particular, in various neoplasm development. This suggests that there are a number of alternative and fundamentally new mechanisms for the tumor formation and progression. Thus, EMT, which occurs in carcinomas, increases the invasiveness, immunoresistance, immunity to therapy, and the metastatic potential. Knowledge of EMT features and their timely recognition in morphological tumor diagnosis is of great predictive importance for patients. The aim of the research was to study the morphologi-cal features of epithelial-mesenchymal transition in the main types of gastric cancer. Materials and methods. We studied specimens of gastric carcinomas (N=64) including 31 cases of diffuse type, 19 cases of intestinal type, and 14 cases of mixed type. Results. All cases of the diffuse carcinoma group showed spread EMT features, which appeared already in the mucosa and completed with positive vimentin expression in 93.5% of cases. The malignant cell prolifera-tive activity was low; however, in 29% of cases we detected areas of moderate or even high activity. In the intestinal type gastric cancer, EMT developed as a result of tumor progression, it arose more often in the deeper layers and was incomplete and focal. As a rule, the proliferative activity of tumor cells was high and moderate. Vascular invasion occurred more often in diffuse type (90.3%), less often in mixed type (71.4%), and even less often in the intestine type (55.8%) gastric carcinoma. Conclusion. The variety of morphological features of EMT, its frequency, prevalence, completeness, and sequence in the development of various types of gastric cancer determines the features of their clinical manifestation and influences their further management. Keywords: gastric cancer, diagnosis, histological main types, EMT, morphopathology

Aims Unipolar voltage (UV) mapping is increasingly used for guiding ablative therapy of atrial fibrillation (AF) as unipolar electrograms (U-EGMs) are independent of electrode orientation and atrial wavefront direction. This study was aimed at constructing individual, high-resolution sinus rhythm (SR) UV fingerprints to identify low-voltage areas and study the effect of AF episodes in patients with mitral valve disease (MVD). Methods and results Intra-operative epicardial mapping (interelectrode distance 2 mm) of the right and left atrium, Bachmann’s bundle (BB), and pulmonary vein area was performed in 67 patients (27 male, 67 ± 11 years) with or without a history of paroxysmal AF (PAF). In all patients, there were considerable regional variations in voltages. UVs at BB were lower in patients with PAF compared with those without [no AF: 4.94 (3.56–5.98) mV, PAF: 3.30 (2.25–4.57) mV, P = 0.006]. A larger number of low-voltage potentials were recorded at BB in the PAF group [no AF: 2.13 (0.52–7.68) %, PAF: 12.86 (3.18–23.59) %, P = 0.001]. In addition, areas with low-voltage potentials were present in all patients, yet we did not find any predilection sites for low-voltage potentials to occur. Conclusion Even in SR, advanced atrial remodelling in MVD patients shows marked inter-individual and regional variation. Low UVs are even present during SR in patients without a history of AF indicating that low UVs should carefully be used as target sites for ablative therapy.

Purpose Posterior ocular trauma and the subsequent fibrotic retinal complication termed proliferative vitreoretinopathy (PVR) are leading causes of blindness in children and young adults. A previous study suggested that changes occurring within the first month post-trauma can lead to development of PVR later. The aim of this study was to examine the effect of dasatinib, a tyrosine kinase inhibitor clinically used to treat chronic myeloid leukemia, on fibrotic changes occurring within the first month following ocular trauma. Methods A previously established swine ocular trauma model that mimics both contusion and penetrating injuries was used. Dasatinib was administered on days 4 and 18 post-trauma via intravitreal injection of either bolus solution or suspension of a sustained release system incorporated in biodegradable poly (lactic-co-glycolic acid) (PLGA) nanoparticles. Animals were followed up to day 32, and the development of traction full-thickness fold in the posterior retina was assessed. Results A full-thickness retinal fold extending from the wound site developed in 3 out of 4 control eyes injected with PLGA nanoparticles alone at 1 month. Administration of dasatinib solution had little preventative effect with 6 out of 7 eyes developing a fold. In contrast, dasatinib-incorporated PLGA nanoparticle injection significantly reduced the incidence of fold to 1 out of 10 eyes. Conclusions Injection of dasatinib-incorporated PLGA significantly reduced early fibrotic retinal changes which eventually lead to PVR following posterior ocular trauma. Thus, our sustained dasatinib release system can potentially be used to both prevent and/or broaden the surgical treatment window for PVR.

Traumatic peripheral nerve injuries present a particular challenge to hand surgeons as mechanisms of nerve-healing pose serious limitations to achieving complete functional recovery. The loss of distal axonal segments through Wallerian degeneration results in the loss of neuromuscular junctions and irreversible muscle atrophy. Current methods of repair depend on the outgrowth of proximal nerve fibers following direct end-to-end repair or gap repair techniques. Investigational techniques in nerve repair using polyethylene glycol (PEG) nerve fusion have been shown to bypass Wallerian degeneration by immediately restoring nerve axonal continuity, thus resulting in a rapid and more complete functional recovery. The purpose of this article is to review the current literature surrounding this novel technique for traumatic nerve repair, paying particular attention to the underlying physiology of nerve healing and the current applications of PEG fusion in the laboratory and clinical setting. This article also serves to identify areas of future investigation to further establish validity and feasibility and encourage the translation of PEG fusion into clinical use.

Complex composition is one of the most important features of the immune system, involving many types of organs, tissues, cells, and molecules that perform immune functions. The normal function of each component of the immune system is the guarantee for maintaining the relatively stable immune function of the body. When the self-immune tolerance mechanism of the body is unregulated or destroyed, the immune system reacts to autoantigens, resulting in damage to self-tissues and organs or an immunopathological state with abnormal functions. Autoimmune diseases are diverse, and their pathogenesis is complicated. Various immune cells and their interactions play significant roles in the occurrence and development of diseases. The solution to heterogeneity of immune cells is the basic science and translational understanding of how genes and the environment interact to induce disease so that we can develop personalized medicine, a goal that has to this point eluded scientists. Single-cell RNA sequencing (scRNA-Seq) refers to a new technique allowing high-throughput sequencing analysis of the whole transcriptome to reveal the gene expression status of individual cells. It has emerged as an indispensable tool in the field of life science research, and can help identify the complex mechanism of cell heterogeneity, discover new cell subsets, and help uncover the molecular mechanisms of pathogenesis, the evolution of disorders, and drug resistance. This information can provide us with new strategies for diagnosis and prognostic evaluation, as well as monitoring treatment responses. In this review, we summarize the crucial experimental procedures used for single-cell RNA sequencing, and the current applications of this technique to study autoimmune diseases are described in detail. This technique will be widely used in more in-depth studies of autoimmune diseases and will contribute to the diagnosis and therapies of these disorders.