Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat

Superoxide is the proximal reactive oxygen species (ROS) produced by the mitochondrial respiratory chain and plays a major role in pathological oxidative stress and redox signaling. While there are tools to detect or decrease mitochondrial superoxide, none can rapidly and specifically increase superoxide production within the mitochondrial matrix. This lack impedes progress, making it challenging to assess accurately the roles of mitochondrial superoxide in cells and in vivo. To address this unmet need, we synthesized and characterized a mitochondria-targeted redox cycler, MitoParaquat (MitoPQ) that comprises a triphenylphosphonium lipophilic cation conjugated to the redox cycler paraquat. MitoPQ accumulates selectively in the mitochondrial matrix driven by the membrane potential. Within the matrix, MitoPQ produces superoxide by redox cycling at the flavin site of complex I, selectively increasing superoxide production within mitochondria. MitoPQ increased mitochondrial superoxide in isolated mitochondria and cells in culture ~a thousand-fold more effectively than untargeted paraquat. MitoPQ was also more toxic than paraquat in the isolated perfused heart and in Drosophila in vivo. MitoPQ enables the selective generation of superoxide within mitochondria and is a useful tool to investigate the many roles of mitochondrial superoxide in pathology and redox signaling in cells and in vivo

Return-to-Play Rates and Clinical Outcomes of Baseball Players After Concomitant Ulnar Collateral Ligament Reconstruction and Selective Ulnar Nerve Transposition.

Background: Injury to the ulnar collateral ligament (UCL) leading to medial elbow instability and possible ulnar neuritis is common in overhead-throwing athletes. Treatment may require UCL reconstruction (UCLR) and concomitant ulnar nerve transposition (UNT) for those with preoperative ulnar neuritis. Purpose: To evaluate the return-to-play (RTP) rates, clinical outcomes, and rates of persistent ulnar neuritis after concomitant UCLR and UNT in a cohort of baseball players with confirmed preoperative ulnar neuritis. Study Design: Case series; Level of evidence, 4. Methods: Eligible patients were those who underwent concomitant UCLR and UNT at a single institution between January 2008 and June 2018 and who had a minimum of 2 years of follow-up. Additional inclusion criteria were athletes who identified as baseball players and who had a confirmed history of ulnar neuritis. Patients were contacted at a minimum of 2 years from surgery and assessed with the Kerlan-Jobe Orthopaedic Clinic (KJOC) Shoulder and Elbow Score, Andrew-Timmerman (A-T) Elbow Score, Mayo Elbow Performance Score (MEPS), Single Assessment Numeric Evaluation (SANE) score, and a custom RTP questionnaire. Results: Included were 22 male baseball players with a mean age of 18.9 ± 2.1 years (range, 16-25 years). The mean follow-up was 6.1 ± 2.4 years (range, 2.5-11.7 years). Preoperatively, all 22 patients reported ulnar nerve sensory symptoms, while 4 (18.2%) patients reported ulnar nerve motor symptoms. At the final follow-up, 7 (31.8%) patients reported persistent ulnar nerve sensory symptoms, while none of the patients reported persistent ulnar nerve motor symptoms. Overall, 16 (72.7%) players were able to return to competitive play at an average of 11.2 months. The mean postoperative patient-reported outcome scores for the KJOC Shoulder and Elbow Score, MEPS, A-T Elbow Score, and SANE score were 77.9 ± 20.9 (range, 14-100), 92.7 ± 12.7 (range, 45-100), 86.1 ± 17.1 (range, 30-100), and 85.5 ± 14.8 (range, 50-100), respectively. Conclusion: This study demonstrated that after concomitant UCLR and UNT for UCL insufficiency and associated ulnar neuritis, baseball players can expect reasonably high RTP rates and subjective outcomes; however, rates of persistent sensory ulnar neuritis can be as high as 30%

Return to Play Criteria Following Operative Management of Acromioclavicular Joint Separation: A Systematic Review

Introduction: Acromioclavicular (AC) joint separation is a leading cause of shoulder injury among athletes. High grade injuries may require operative fixation, and comprehensive return to play guidelines have not yet been established. The purpose of this investigation is to summarize return to play criteria following operative management of AC joint separation. Methods: A systematic review of the literature was performed to evaluate clinical evidence regarding return to play following operative management of isolated AC joint separation. Studies satisfying inclusion criteria were analyzed for return to play timeline and other factors used to guide return to play following surgery. Results: Sixty-three studies with at least 1 explicitly stated return to play criterion were identified out of an initial database search of 1,253 published articles. Eight separate categories of return to play criteria were identified, the most common of which was time from surgery (95.2%). Return to play timelines ranged from 2 – 12 months, the most common timeline being 6 months (37.8%). Only 4 (6.3%) studies utilized conditional criteria to guide return to play, among which included range of motion, strength, clinical stability, radiographic stability, functional assessment, safety assessment, and hardware removal. Discussion: Most published studies utilize only time-based return to play criteria, and only a small number of studies employ patient-centered conditional criteria. While this systematic review helps provide a foundation for developing a comprehensive return to play checklist, further investigation is needed to establish safe and effective guidelines that will enable athletes to safely return to sport and minimize the recurrence of injury

Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease

Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD\u27s rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions

SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility

Mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures is associated with common variation at rs7587026, located in the promoter region of SCN1A. We sought to explore possible underlying mechanisms. SCN1A expression was analysed in hippocampal biopsy specimens of individuals with mesial temporal lobe epilepsy with hippocampal sclerosis who underwent surgical treatment, and hippocampal neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy individuals, hippocampal volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased SCN1A expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous scn1a, and performed EEG analysis on larval optic tecta at 4 day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippocampal SCN1A expression differed by rs7587026 genotype (Kruskal-Wallis test P = 0.004). Individuals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn's test P = 0.003), and to heterozygotes (Dunn's test P = 0.035). No statistically significant differences in hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal volume compared to major allele homozygotes (Cohen's D = - 0.28, P = 0.02), and to heterozygotes (Cohen's D = - 0.36, P = 0.009). Compared to wild type, scn1lab-overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA F(4,54) = 6.95 (P < 0.001)]. The number of EEG discharges correlated with the level of scn1lab overexpression [one-way ANOVA F(4,15) = 10.75 (P < 0.001]. Finally, we showed that a 50 bp promoter motif containing rs7587026 exerts a strong regulatory role on SCN1A expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing SCN1A expression in current strategies aiming to treat seizures in conditions involving SCN1A haploinsufficiency, such as Dravet syndrome

Measuring Distributional Effects of Fiscal Reforms

The purpose of this paper is to provide an overview of how to analyse the distributional effects of fiscal reforms. Thereby, distributional effects shall be differentiated by four subconcepts, i.e. 1.) the traditional concept of inequality, 2.) the rather novel concept of polarisation, 3.) the concept of progression in taxation, and 4.) the concepts of income poverty and richness. The concept of inequality and the concept of income poverty are the by far most widely applied concepts in empirical analyses, probably since they appear to be the most transparent ones in their structure as well as the most controversial ones in political affairs. However, the concepts of richness, polarisation and progression in taxation shall additionally be subject of this analysis, since they appear to be useful devices on the course of analysing cause and effect of the other two concepts

The Effects of ethanol and glycerol on the body and other sensory characteristics of Riesling wines

The effect of ethanol and glycerol concentration on the body, sweetness, acidity, aroma and flavour intensity, and perceived viscosity and hotness of three Riesling wines was assessed. The ethanol and glycerol contents of the wines were adjusted by addition to give three realistic levels (5.2, 7.2, 10.2 g/L glycerol and 11.6, 12.6 and 13.6 v/v ethanol). The nine treatment combinations (3 glycerol × 3 ethanol) were rated on the above attributes by a panel of trained tasters. Increased alcohol levels resulted in increased perceived hotness in all wines, and in higher body and perceived viscosity in two of the three wines. The effect of increasing glycerol content was less consistent with only one of each of the three wines showing increased viscosity and body. However, the mean viscosity ratings given to wines with 10 g/L glycerol was higher than at 5 g/L at all alcohol levels and for all wines, suggesting that differences in glycerol concentration typically displayed between dry white table wines can affect their perceived viscosity. Neither alcohol nor glycerol consistently affected sweetness, acidity, aroma or flavour intensity. Higher ratings of the abstract term 'body' were most commonly associated with higher ratings of flavour and/or perceived viscosity, suggesting that for the majority of tasters, these two attributes contributed to their interpretation of the term 'body'. Perceived hotness was not an important component of body, while the role of acidity in body perception was taster dependent.8 page(s

Effect of pH and alcohol on perception of phenolic character in white wine

The in-mouth perception of textures of white wine arising from the interactions among white wine phenolics, pH, and alcohol level was evaluated. Phenolics were extracted from white wines and added back to white wines that were adjusted to different pH and ethanol concentrations within wine realistic ranges. Adding phenolics to a white wine at pH 3.3 significantly increased its astringency, but the same addition did not contribute to the higher astringency elicited by the same wine when adjusted to pH 3.0. Higher phenolics generally increased bitterness and viscosity, but the effect depended on the source of the phenolics. Wines with added phenolics were generally perceived to be hotter, and significantly so when the wine was low in alcohol. The combined effect of phenolic content and alcohol concentration on astringency and bitterness was additive, suggesting that alcohol directly contributes to these attributes in white wines. Overall, the tastes and textures produced by white wine phenolics were more pronounced in wines with lower alcohol levels.5 page(s