Mammary duct luminal epithelium controls adipocyte thermogenic programme.

Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots2-7. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors 'mammokines'. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve-ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.

Systems Genetics Approaches in Mouse Models of Group A Streptococcal Necrotizing Soft-Tissue Infections.

Mouse models are invaluable resources for studying the pathogenesis and preclinical evaluation of therapeutics and vaccines against many human pathogens. Infections caused by group A streptococcus (GAS, Streptococcus pyogenes) are heterogeneous ranging from mild pharyngitis to severe invasive necrotizing fasciitis, a subgroup of necrotizing soft-tissue infections (NSTIs). While several strains of mice including BALB/c, C3H/HeN, CBA/J, and C57BL/10 offered significant insights, the human specificity and the interindividual variations on susceptibility or resistance to GAS infections limit their ability to mirror responses as seen in humans. In this chapter, we discuss the advanced recombinant inbred (ARI) BXD mouse model that mimics the genetic diversity as seen in humans and underpins the feasibility to map multiple genes (genetic loci) modulating GAS NSTI. GAS produces a myriad of virulence factors, including superantigens (SAg). Superantigens are potent immune toxins that activate T cells by cross-linking T cell receptors with human leukocyte antigen class-II (HLA-II) molecules expressed on antigen-presenting cells. This leads to a pro-inflammatory cytokine storm and the subsequent multiple organ damage and shock. Inbred mice are innately refractive to SAg-mediated responses. In this chapter, we discuss the versatility of the HLA-II transgenic mouse model that allowed the biological validation of known genetic associations to GAS NSTI. The combined utility of ARI-BXD and HLA-II mice as complementary approaches that offer clinically translatable insights into pathomechanisms driven by complex traits and host genetic context and novel means to evaluate the in vivo efficiency of therapies to improve outcomes of GAS NSTI are also discussed.

The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice.

We report the genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human apolipoprotein E*3-Leiden and cholesteryl ester transfer protein and fed a "Western" diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors are involved. Moreover, genome-wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. Conclusion: The pathways showed substantial overlap between our mouse model and the human disease.

Sex differences in metabolism and cardiometabolic disorders.

PURPOSE OF REVIEW: Sex differences are pervasive in metabolic and cardiovascular traits, yet they have often been ignored in human and animal model research. Sex differences can arise from reversible hormonal effects, from irreversible organizational (developmental) processes, and from gene expression differences from the X and Y chromosomes. We briefly review our current understanding of the impact of these factors in metabolic traits and disorders, with an emphasis on the recent literature. RECENT FINDINGS: Novel sex differences continue to be identified for metabolic and cardiovascular traits. For example, it is now clear that gut microbiota tend to differ between men and women, with potentially large implications for disease susceptibility. Also, tissue-specific gene regulation differs between men and women, contributing to differential metabolism. These new insights will open up personalized therapeutic avenues for cardiometabolic diseases. SUMMARY: Sex differences in body fat distribution, glucose homeostasis, insulin signaling, ectopic fat accumulation, and lipid metabolism during normal growth and in response to hormonal or nutritional imbalance are mediated partly through sex hormones and the sex chromosome complement. Most of these differences are mediated in a tissue-specific manner. Important future goals are to better understand the interactions between genetic variation and sex differences, and to bring an understanding of sex differences into clinical practice.

Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR.

Elevated hepatic ceramide levels have been implicated in both insulin resistance (IR) and hepatic steatosis. To understand the factors contributing to hepatic ceramide levels in mice of both sexes, we have quantitated ceramides in a reference population of mice, the Hybrid Mouse Diversity Panel that has been previously characterized for a variety of metabolic syndrome traits. We observed significant positive correlations between Cer(d18:1/16:0) and IR/hepatic steatosis, consistent with previous findings, although the relationship broke down between sexes, as females were less insulin resistant, but had higher Cer(d18:1/16:0) levels than males. The sex difference was due in part to testosterone-mediated repression of ceramide synthase 6. One ceramide species, Cer(d18:1/20:0), was present at higher levels in males and was associated with IR only in males. Clear evidence of gene-by-sex and gene-by-diet interactions was observed, including sex-specific genome-wide association study results. Thus, our studies show clear differences in how hepatic ceramides are regulated between the sexes, which again suggests that the physiological roles of certain hepatic ceramides differ between the sexes.

Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse.

Host genetic variations play an important role in several pathogenic diseases, and we have previously provided strong evidences that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive Group A Streptococcus (GAS) infections, including sepsis and necrotizing soft tissue infections (NSTIs). Our initial studies with conventional mouse strains revealed that host genetic variations and sex differences play an important role in orchestrating the severity, susceptibility and outcomes of NSTIs. To understand the complex genetic architecture of NSTIs, we utilized an unbiased, forward systems genetics approach in an advanced recombinant inbred (ARI) panel of mouse strains (BXD). Through this approach, we uncovered interactions between host genetics, and other non-genetic cofactors including sex, age and body weight in determining susceptibility to NSTIs. We mapped three NSTIs-associated phenotypic traits (i.e., survival, percent weight change, and lesion size) to underlying host genetic variations by using the WebQTL tool, and identified four NSTIs-associated quantitative genetic loci (QTL) for survival on mouse chromosome (Chr) 2, for weight change on Chr 7, and for lesion size on Chr 6 and 18 respectively. These QTL harbor several polymorphic genes. Identification of multiple QTL highlighted the complexity of the host-pathogen interactions involved in NSTI pathogenesis. We then analyzed and rank-ordered host candidate genes in these QTL by using the QTLminer tool and then developed a list of 375 candidate genes on the basis of annotation data and biological relevance to NSTIs. Further differential expression analyses revealed 125 genes to be significantly differentially regulated in susceptible strains compared to their uninfected controls. Several of these genes are involved in innate immunity, inflammatory response, cell growth, development and proliferation, and apoptosis. Additional network analyses using ingenuity pathway analysis (IPA) of these 125 genes revealed interleukin-1 beta network as key network involved in modulating the differential susceptibility to GAS NSTIs.

A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response.

Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene Trp53inp2 as a cardiomyocyte glucose utilization-specific factor. Trp53inp2 gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that Trp53inp2 serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHY Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify Trp53inp2 as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.

Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections.

Host genetic variations play an important role in several pathogenic diseases, and we previously provided strong evidence that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive group A Streptococcus (GAS) patients, including sepsis and necrotizing soft tissue infections (NSTIs). The goal of the present study was to investigate how genetic variations and sex differences among four commonly used mouse strains contribute to variation in severity, manifestations, and outcomes of NSTIs. DBA/2J mice were more susceptible to NSTIs than C57BL/6J, BALB/c, and CD-1 mice, as exhibited by significantly greater bacteremia, excessive dissemination to the spleen, and significantly higher mortality. Differences in the sex of the mice also contributed to differences in disease severity and outcomes: DBA/2J female mice were relatively resistant compared to their male counterparts. However, DBA/2J mice exhibited minimal weight loss and developed smaller lesions than did the aforementioned strains. Moreover, at 48 h after infection, compared with C57BL/6J mice, DBA/2J mice had increased bacteremia, excessive dissemination to the spleen, and excessive concentrations of inflammatory cytokines and chemokines. These results indicate that variations in the host genetic context as well as sex play a dominant role in determining the severity of and susceptibility to GAS NSTIs.

Metal-mediated modulation of streptococcal cysteine protease activity and its biological implications.

Streptococcal cysteine protease (SpeB), the major secreted protease produced by group A streptococcus (GAS), cleaves both host and bacterial proteins and contributes importantly to the pathogenesis of invasive GAS infections. Modulation of SpeB expression and/or its activity during invasive GAS infections has been shown to affect bacterial virulence and infection severity. Expression of SpeB is regulated by the GAS CovR-CovS two-component regulatory system, and we demonstrated that bacteria with mutations in the CovR-CovS two-component regulatory system are selected for during localized GAS infections and that these bacteria lack SpeB expression and exhibit a hypervirulent phenotype. Additionally, in a separate study, we showed that expression of SpeB can also be modulated by human transferrin- and/or lactoferrin-mediated iron chelation. Accordingly, the goal of this study was to investigate the possible roles of iron and other metals in modulating SpeB expression and/or activity in a manner that would potentiate bacterial virulence. Here, we report that the divalent metals zinc and copper inhibit SpeB activity at the posttranslational level. Utilizing online metal-binding site prediction servers, we identified two putative metal-binding sites in SpeB, one of which involves the catalytic-dyad residues (47)Cys and (195)His. Based on our findings, we propose that zinc and/or copper availability in the bacterial microenvironment can modulate the proteolytic activity of SpeB in a manner that preserves the integrity of several other virulence factors essential for bacterial survival and dissemination within the host and thereby may exacerbate the severity of invasive GAS infections.

Hepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and de novo lipogenesis.

Recent studies demonstrate that liver secretory proteins, also known as hepatokines, regulate normal development, obesity, and simple steatosis to non-alcoholic steatohepatitis (NASH) progression. Using a panel of ∼100 diverse inbred strains of mice and a cohort of bariatric surgery patients, we found that one such hepatokine, inter-trypsin inhibitor heavy chain 3 (ITIH3), was progressively lower in severe non-alcoholic fatty liver disease (NAFLD) disease states highlighting an inverse relationship between Itih3/ITIH3 expression and NAFLD severity. Follow-up animal and cell culture models demonstrated that hepatic ITIH3 overexpression lowered liver triglyceride and lipid droplet accumulation, respectively. Conversely, ITIH3 knockdown in mice increased the liver triglyceride in two independent NAFLD models. Mechanistically, ITIH3 reduced mitochondrial respiration and this, in turn, reduced liver triglycerides, via downregulated de novo lipogenesis. This was accompanied by increased STAT1 signaling and Stat3 expression, both of which are known to protect against NAFLD/NASH. Our findings indicate hepatokine ITIH3 as a potential biomarker and/or treatment for NAFLD.

When diet meets genetics.

Gene expression profiling of a diverse mouse population helps to decipher how a fat-rich diet contributes to inflammatory bowel disease.

Treatment of Parkinson's Disease: Current Treatments and Recent Therapeutic Developments.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative syndrome defined by a variety of motor, cognitive, and psychomotor dysfunctions. The current pharmaceutical treatment focuses on treating the condition's symptoms. They are primarily concerned with reducing illness symptoms or avoiding dopamine metabolism. As our understanding of disease pathogenesis improves, new therapeutic approaches emerge. OBJECTIVE: This article aims to describe the standard Parkinson's medications based on symptoms and requirements. It emphasizes recent advancements in symptomatic therapy for motor indications and achievements in the research and clinical testing of medicines that promise to enable disease modification in patients with already-manifest PD. METHODS: Information for this paper was found by looking through Google Scholar and reading several research and review articles from Bentham Science, Science Direct, Elsevier, Frontiers, Taylor & Francis, and other publishers. RESULT: Parkinson's disease therapeutic interventions are now limited to symptomatic therapy, mostly in dopaminergic medications and deep brain stimulation (DBS). They have the potential to deliver great therapeutic progress, yet they can also have serious drawbacks that decrease a patient's quality of life. The progress of pluripotent stem cell therapies and genome engineering procedures has sparked renewed hope for the treatment of a wide range of human illnesses, particularly genetic abnormalities. CONCLUSION: The current Parkinson's therapy trends are successful and continually evolving, with several drugs currently undergoing clinical trials. As these new therapies constantly coming out and can be used together, they will likely change how Parkinson's disease is treated in the coming years.

Research Progress of Indole Alkaloids: Targeting MAP Kinase Signaling Pathways in Cancer Treatment.

Cancer is the leading cause of morbidity and mortality in people throughout the world. There are many signaling pathways associated with cancerous diseases, from which the Mitogen-activated protein kinase (MAPK) pathway performs a significant role in this regard. Apoptosis and proliferation are correlated with MAPK signaling pathways. Plenty of experimental investigations were carried out to assess the role of indole alkaloids in MAPK-mediated cancerous diseases. Previous reports established that indole alkaloids, such as vincristine and evodiamine are useful small molecules in cancer treatment via the MAPK signaling system. Indole alkaloids have the anticancer potential through different pathways. Vincristine and evodiamine are naturally occurring indole alkaloids that have strong anticancer properties. Additionally, much research is ongoing or completed with molecules belonging to this group. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment. Additionally, we focused on the advancement in the role of indole alkaloids, with the intention of modifying the MAPK signaling pathways to investigate potential new anticancer small molecules. Furthermore, clinical trials with indole alkaloids in cancer treatment are also highlighted.

Indole alkaloids from marine resources: Understandings from therapeutic point of view to treat cancers.

Cancer is the leading cause of mortality all over the world. Scientific investigation has demonstrated that disruptions in the process of autophagy are frequently interrelated with the emergence of cancer. Hence, scientists are seeking permanent solutions to counter the deadly disease. Indole alkaloids have been extensively studied and are acknowledged to exhibit several bioactivities. The current state of disease necessitates novel pharmacophores development. In recent decades, indole alkaloids have become increasingly significant in cancer treatment and are also used as adjuvants. A substantial amount of pharmacologically active molecules come from indole alkaloids, which are widely distributed in nature. Indole alkaloids derived from marine organisms show immense potential for therapeutic applications and seem highly effective in cancer treatment. A couple of experiments have been conducted preclinically to investigate the possibility of indole alkaloids in cancer treatment. Marine-derived indole alkaloids possess the ability to exhibit anticancer properties through diverse antiproliferative mechanisms. Certain indole alkaloids, including vincristine and vinblastine, were verified in clinical trials or are presently undergoing clinical assessments for preventing and treating cancer. Indole alkaloids from marine resources hold a significant functionality in identifying new antitumor agents. The current literature highlights recent advancements in indole alkaloids that appear to be anticancer agents and the underlying mechanisms.

Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy.

Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

Children And Adolescents With Irritable Bowel Syndrome: Treatment And Management.

BACKGROUND: Irritable bowel syndrome (IBS) is a disorder that causes stomach pain in children and adolescents. It may also impact one's quality of life. IBS is linked to gastrointestinal issues such as diarrhoea and constipation. Despite the identification of several potential pathophysiological pathways, the aetiology of IBS remained unknown. OBJECTIVE: The aim of this paper is to discuss the diagnosis, pathogenesis, case studies and treatment of Irritable bowel syndrome in children and adolescents. METHOD: This systematic review covered relevant papers from the previous ten years that were accessible in Science Direct, Elsevier, NCBI, and Web of Science related to the pathophysiology and function of pharmacological drugs such as antidepressants, antispasmodics, prokinetics, and antibiotics in children with irritable bowel syndrome. RESULT: Only a few prospective therapy techniques have been investigated in children, and even fewer of those have been demonstrated to be effective. This article presents case studies including 50-59 children, which demonstrate a favourable acceptable impact that is more effective than a placebo in terms of reducing symptoms and improving the overall quality of life in children who have irritable bowel syndrome. Furthermore, the majority of the pathophysiological explanations and treatment options discussed are based on adult studies. These major issues arose when treating paediatric IBS, and they must be addressed in order to properly treat children with IBS. Trials that focus on many combinations of pharmacological and non-pharmacological therapies seem to be more helpful. DISCUSSION: In recent years, a number of systematic reviews have been conducted to evaluate the efficacy of medication treatments in children for IBS; however, the dependability of these systematic reviews needs to be further investigated owing to the various experimental designs and levels of evidence used. This article highlights paediatric therapy options, including pharmaceutical medications such as antidepressants, antispasmodics, prokinetics, and antibiotics. The goal is to alleviate IBS symptoms while also enhancing the quality of life for children with this illness.

Comparative Study on the effectiveness of Glycopyrrolate/Formoterol versus Tiotropium/Formoterol in patients with Chronic Obstructive Pulmonary Disease.

Background: Chronic Obstructive Pulmonary Disease (COPD) has several implications on health, lifestyle, and economic burden. Combinational therapy using muscarinic antagonists and beta-2 agonists has long been warranted for use as maintenance therapy. A lack of studies directly comparing Glycopyrrolate/Formoterol (GFF) versus Tiotropium/Formoterol (TFF) was observed which led us to analyze the effectiveness of these combinations. Methods: In this pilot, prospective, randomized, open-label, parallel-arm, 12-week period study, 60 patients with COPD (moderate-severe) were randomized in a 1:1 ratio to receive either GFF or TFF (n = 30 each). The primary outcome was to demonstrate non-inferiority between the two groups concerning FEV1 for 12 weeks. The secondary outcome was the assessment of the ratio of FEV1/FVC and state of health evaluation by St. George's Respiratory Questionnaire (SGRQ). Results: Out of 60 participants, 58 subjects completed the study. At week 12, the mean and standard deviation value of FEV1 between groups were 1.49 ± 0.38 and 1.38 ± 0.30 (p > 0.05) and FEV1/FVC ratio were 0.67 ± 0.09 and 0.74 ± 0.08 (p < 0.01) respectively. A significant difference was observed in the FEV1 and FEV1/FVC values in comparison with baseline versus last follow up in both the groups (p < 0.01). However, no remarkable variation was identified in the FEV1 values over the two groups. The health status assessment by SGRQ showed significant improvement in both groups after the treatment. Conclusion: Non-inferiority of GFF when compared to TFF was established along with good tolerability and comparable adverse effect profile.

Sex differences in heart mitochondria regulate diastolic dysfunction.

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a "two-hit" mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.

Role of fluoxetine in pharmacological enhancement of motor functions in stroke patients: A randomized, placebo-controlled, single-blind trial.

BACKGROUND: Stroke is the primary cause of disability worldwide, the second most common cause of dementia and the third leading cause of death. Only few studies were conducted to study the role of fluoxetine in motor recovery in either ischemic or hemorrhagic stroke patients with probably less severe paresis. However, the current study evaluates both the effectiveness and safety of fluoxetine in the stroke population with a more severe motor deficit. METHODS: Patients who had acute or subacute stroke with hemiparesis and aged between 18 and 80 years with medical research council (MRC) scale score <4 were included in this randomized, Single-blind, placebo-controlled trial in 1:1 ratio to placebo or fluoxetine 20 mg/day orally for 90 days. The primary outcome measures were changes in barthel index, time taken to complete nine hole peg test and number of hand tapping movements in 30 s by the affected limb between baseline, 45th day and 90th day. The secondary outcome measure was evaluation of the drug tolerability. RESULTS: A total of 168 patients were assigned to fluoxetine (n = 84) or placebo (n = 84) group. Mean BI score significantly improved at 90th day in fluoxetine group (70.42 ± 10.56) than in placebo group (44.23 ± 8.52). Mean dexterity value decreased significantly at 90th day (2.61 ± 0.81) compared to baseline (3.98 ± 0.53) in fluoxetine group. However higher rate of decrease of mean dexterity value was seen in fluoxetine group when compared to placebo group. Mean number of hands tapping movements in 30 s increased significantly at 90th day (16.33 ± 3.58) compared to baseline (9.83 ± 2.92) in fluoxetine group. Few ADR reported during this study were dizziness, drowsiness and insomnia. CONCLUSION: The present study indicates that early prescription of fluoxetine is safe and may enhance motor function in patients presenting with severe motor impairments after stroke. However, the findings of the study should be confirmed in future controlled studies with large sample size.