"Unravelling the impacts of climatic heat events on cardiovascular health in animal models".

Climate change has led to an increase in high ambient temperatures, causing extreme heat events worldwide. According to the World Meteorological Organization (WMO), July 2023 marked a historic milestone as the Earth reached its hottest recorded temperature, precisely hitting the critical threshold of 1.5 °C set by the Paris Agreement. This distressing development led to a stark warning from the United Nations, signaling the dawn of what they call "an era of global boiling". The increasing global temperatures can result in high heat stress which leads to various physiological and biochemical alterations in the human body. Given that cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality globally, heat events exacerbate this public health issue. While clinical and in-vitro studies have suggested a range of pathophysiological and biochemical mechanisms underlying the body's response to heat stress, the complex nature of organ-system level interactions makes precise investigation challenging. To address this knowledge gap effectively, the use of animal models exposed to acute or chronic heat stress can be invaluable. These models can closely replicate the multifaceted effects observed in humans during heat stress conditions. Despite extensive independent reviews, limited focus has been shed on the high heat-induced cardiovascular complications and their mechanisms, particularly utilizing animal models. Therefore, in this comprehensive review, we highlight the crucial biomarkers altered during heat stress, contributing significantly to various CVDs. We explore potential mechanisms underlying heat-induced cardiovascular dysfunction and damage, delving into various animal models. While traditional rodent models are commonly employed, we also examine less conventional models, including ruminants, broilers, canines, and primates. Furthermore, we delve into various potential therapeutic approaches and preventive measures. These insights hold significant promise for the development of more effective clinical interventions against the effects of heat stress on the human cardiovascular system.

A Comprehensive Pilot Study to Elucidate the Distinct Gut Microbial Composition and Its Functional Significance in Cardio-Metabolic Disease.

Cardio-metabolic disease is a significant global health challenge with increasing prevalence. Recent research underscores the disruption of gut microbial balance as a key factor in disease susceptibility. We aimed to characterize the gut microbiota composition and function in cardio-metabolic disease and healthy controls. For this purpose, we collected stool samples of 18 subjects (12 diseased, 6 healthy) and we performed metagenomics analysis and functional prediction using QIIME2 and PICRUSt. Furthermore, we carried out assessments of microbe-gene interactions, gene ontology, and microbe-disease associations. Our findings revealed distinct microbial patterns in the diseased group, particularly evident in lower taxonomic levels with significant variations in 14 microbial features. The diseased cohort exhibited an enrichment of Lachnospiraceae family, correlating with obesity, insulin resistance, and metabolic disturbances. Conversely, reduced levels of Clostridium, Gemmiger, and Ruminococcus genera indicated a potential inflammatory state, linked to compromised butyrate production and gut permeability. Functional analyses highlighted dysregulated pathways in amino acid metabolism and energy equilibrium, with perturbations correlating with elevated branch-chain amino acid levels-a known contributor to insulin resistance and type 2 diabetes. These findings were consistent across biomarker assessments, microbe-gene associations, and gene ontology analyses, emphasizing the intricate interplay between gut microbial dysbiosis and cardio-metabolic disease progression. In conclusion, our study unveils significant shifts in gut microbial composition and function in cardio-metabolic disease, emphasizing the broader implications of microbial dysregulation. Addressing gut microbial balance emerges as a crucial therapeutic target in managing cardio-metabolic disease burden.

Trial Sequential Analysis and Meta-Analysis of Olanzapine in Pediatric Patients for Chemotherapy-Induced Nausea and Vomiting (CINV).

Background and Objective: Olanzapine (OLZ) containing regimens are approved in adults for chemotherapy-induced nausea and vomiting (CINV) receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC), and the same has not been approved in the pediatric population. In order to generate data regarding the efficacy and safety of OLZ as an adjunct to the standard of care (SoC) for CINV in pediatric patients receiving HEC/MEC, the review authors performed this systematic review and meta-analysis. Methods: A systematic literature search was performed through the databases Cochrane Library, Pub Med, and clinicaltrials.gov, from inception to September 2023, using keywords: "chemotherapy" and "olanzapine," "nausea" and "vomiting." Randomized clinical trials published in English that analyzed the efficacy and safety of olanzapine as an adjunct to SoC were included. The essential outcomes included in this study were the proportion of patients with no emesis in the acute and delayed phase, patients with no nausea in the acute and delayed phase, the proportion of patients requiring rescue medication, and the proportion of patients with reduced CNS arousal. Results: In the OLZ group, a greater number of patients had no emesis both in the acute and delayed phase (RR = 1.22; 95% CI = 1.09-1.37; P = .0004); and (RR = 1.23; 95% CI = 0.92-1.63; P = .16) respectively. Similarly, a higher number of patients showed no nausea both in the acute and delayed phase (RR = 1.08; 95% CI = 0.78-1.48; P = .66) and (RR = 1.12; 95% CI = 0.79-1.61; P = .52) respectively. The use of rescue medication was significantly less in the OLZ group (RR = 0.62; 95% CI = 0.42-0.91; P = .01). More patients experienced reduced CNS arousal in the OLZ group (RR = 2.97; 95% CI = 2.02-4.38; P < .0001). Conclusions: Olanzapine as an adjunct to the SoC may be effective in acute emesis, which may also reduce the use of rescue medication. Reduced CNS alertness was the significant adverse effect observed. For other endpoints, more studies are required to substantiate its role in CINV.

Assessment of Potential Drug-drug Interactions (pDDIs) and Their Risk Factors Among Hospitalized Cardiac Patients in a Tertiary-care Center of Central India: A Retrospective Record-based Study.

Background: Patients with cardiovascular disorders (CVD) possess multiple comorbidities and are prone to be prescribed multiple drugs, thus predisposing them to various drug-drug interactions (DDIs). Objective: This study was carried out to assess the potential-DDIs (pDDIs) among the drugs prescribed to hospitalized patients with CVD and associated factors. Method: It was a retrospective study conducted with the help of the medical records department. Medical records of all the patients admitted to the cardiology department of our tertiary care center from January 1st, 2019, to December 31st, 2019, were included for analysis using Lexicomp, an up-to-date drug interaction screening tool. The pDDIs were divided into classes A, B, C, D, and X, and those belonging to classes D or X were considered clinically significant. Multiple logistic regression was used to analyze the association between the factors associated with and the occurrence of clinically significant pDDIs, with a P-value < .05 considered statistically significant. Results: Almost all the records reflected (335/338) at least 1 pDDI. A total of 4966 pDDIs were detected, of which the majority belonged to category C (75.3%), and 5.1% of pDDIs were clinically significant. The patients who were prescribed more than 10 drugs per day (OR = 2.46; 95% CI: 1.27-4.82; P = .008), prescribed parenteral formulation (OR = 1.84; 95% CI: 1.57-2.21; P < .0001), or had a diagnosis of acute coronary syndrome (OR = 2.33; 95% CI:1.1-5.12; P = .03) were associated with clinically significant pDDIs. Other factors, that is, female sex, use of fixed-dose combinations, and the triad of diabetes mellitus, hypertension, and dyslipidemia, were positively associated with clinically significant pDDIs. Conclusion: Even though every patient had at least 1 pDDI, the prevalence of clinically significant pDDIs was relatively less. Use of >10 drugs/day, parenteral formulation, patients with acute coronary syndrome were significantly associated with clinically significant pDDIs.

BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer.

Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15 Gy dose of radiation or three intravesical instillations of BCG (1 × 108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle-invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle-invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation. © 2021 The Pathological Society of Great Britain and Ireland.

A Novel Rhodamine Probe Acting as Chemosensor for Selective Recognition of Cu2+ and Hg2+ Ions: An Experimental and First Principle Studies.

Copper and Mercury ions have vital role to play in biological world as their excess or deficiency can cause different type of diseases in human being as well as biological species including plants and animals. Therefore, their detection at trace level becomes very important in term of biological. The current studies embody the fabrication, structural characterization and recognition behavior of a novel rhodamine B hydrazone formed when hydrazide of rhodamine B was condensed with 5-Allyl-3-methoxy salicylaldehyde (RBMA). RBMA was found to be responsive towards the very trace level of Cu2+ and Hg2+ among other tested cations so far. The sensing procedure is based on the classical opening of the spiroatom ring of rhodamine. The limit of detection (LOD) and binding constant is 5.35 ppm, 2.06 × 104 M-1 and 5.16 ppm, 1.26 × 104 M-1 for Cu2+ and Hg2+ ions respectively. The probable mechanism correlates the specific binding of RBMA with Cu2+ and Hg2+ ions. The 1:1 stoichiometry of RBMA with Cu2+ and Hg2+ ions have been supported by HRMS, FT-IR data, Job's plot, and binding constant data. Reversibility is well exhibited by RBMA by the involvement of CO32- ions via demetallation process. The real time application is well demonstrated by the use of paper strip test. The DFT study also carried out which agrees well with the experimental findings. The results displayed the novelty of this current work towards the trace level analysis of the Cu2+ and Hg2+ of the cations which are play the crucial role in industry.

A Comprehensive Review on Pharmacologically Active Phyto-Constituents from Hedychium species.

In this review, we describe and discuss the phytoconstituents present in Hedychium species and emphasize their potential as drug candidates. Though they are widely validated in vitro and in vivo models, to date, no efforts have been made to compile in a single review all the pharmacologically active phytoconstituents from Hedychium species, and their pharmacological and toxicity profile. In this study, we present a reinvestigation of the chemical constituents present in Hedychium species obtained from the essential oil and solvent extraction of the flowers, leaves and rhizomes under consideration. Key databases such as PubMed, Science Direct, Scopus, and Google Scholar amongst others were probed for a systematic search using keywords to retrieve relevant publications on this plant. An exhaustive electronic survey of the related literature on Hedychium species resulted in around 200 articles. Articles published between the years 1975-2021 were included. The studies conducted on either crude extracts, solvent fractions or isolated pure compounds from Hedychium species reported with a varied range of biological effects such as anti-inflammatory, analgesic, antidiabetic, potentially anti-asthmatic, and cytotoxic, among other related activities of the chemical constituents present in its essential oil and solvent extract deployed in this review. Traditional and herbal medication around the world that uses different parts of Hedychium species were considered for anti-inflammatory, skincare, analgesic, anti-asthmatic, anti-diabetic, antidotal uses, among others. These uses support the idea that chemical constituents obtained from solvent extraction may also exert the same action individually or in a synergistic manner. The review concluded that there is scope for computation and biological study to find out possible new targets for strengthening the potency and selectivity of the relevant compounds, and to find a commercial method for extraction of active pharmaceutical ingredients.

Effects of socio-economic status and daily variation on municipal solid waste composition: a preliminary analysis for sustainable planning and development in Aligarh City.

In the context of developing countries such as India, with great differences in people's living standards and different communities, municipal solid waste (MSW) management is one of the most promising problems in front of municipal organizations. Unlike every city in India, Aligarh City also faces the same problem of municipal solid waste management. This problem not only affects the esthetic view but is also hazardous to people nearby health. Currently, solid waste collected is either dumped in landfill unscientifically or partially treated by A to Z waste management (limited) by composting. In the present study, an effort was made to know about the per capita waste generation and variations in the quantity of different components of the MSW in five different regions of the city with dissimilar living standards. Also, weekly variation was analyzed in the study. One-way ANOVA analysis using Statistical Package for the Social Sciences is performed to investigate the variations in the mean composition of different components. The per capita solid waste generation in Aligarh City was found to be 0.42 kg/person/day. From the analysis, we came to know that compostable component (35.4%) is the highest, then inert (24.6%), plastic (12.2%), paper (10%), textile (9.2%), and sand (8.6%). After analysis, the results can help sort out the problem of MSW management in the city by selecting appropriate units as per the composition of MSW.

Surface activity, mechanisms, kinetics, and thermodynamic study of adsorption of malachite green dye onto sulfuric acid-functionalized Moringa oleifera leaves from aqueous solution.

In the present study, activated carbon prepared from H2SO4-functionalized Moringa oleifera leaves (ACMOL) was used as a potential adsorbent for the effective removal of malachite green (MG) dye from aqueous media. FT-IR, SEM, EDS, Zeta potential, XRD, BET, proximate, and CHNS analysis techniques were used for surface characterization of the ACMOL. The adsorption efficiency of the ACMOL was investigated as a function of varying adsorbent dosage (0.02-0.2 g/100 mL), pH (3.0-9.0), ionic strength (0.1-0.5 M KCl), urea concentration (0.1-0.5 M), contact time (30-210 min), and temperature (303-323 K). The representative adsorption isotherms belong to the typical L-type. Maximum percentage removal was found to be 84% (124.40 mg/g) for MG dye concentration (30 mg/L) at pH 7.0 and 303 K with ACMOL dose 0.02 g/100 mL. The adsorption kinetics and equilibrium experimental data of MG dye adsorption on the ACMOL were well explained by the pseudo-second-order kinetics (R2 = 0.99) and Langmuir isotherm model (R2 = 0.99), respectively. The value of adsorption and desorption coefficient was found to be 0.036 min-1 and 0.025 mg min-1/L, respectively. Thermodynamic study showed the spontaneous (ΔG° = - 31.33, - 31.92, and - 32.49 kJ/mol at temperatures 303 K, 313 K, and 323 K, respectively) and exothermic (ΔH° = - 13.7 kJ/mol) nature of the adsorption with some structural changes occurring on the ACMOL surface (ΔS° = 58.198 J/K·mol).

CRISPR-Cas system: from diagnostic tool to potential antiviral treatment.

This mini review focuses on the diagnosis and treatment of virus diseases using Crisper-Cas technology. The present paper describes various strategies involved in diagnosing diseases using Crispr-Cas-based assays. Additionally, CRISPR-Cas systems offer great potential as new therapeutic tools for treating viral infections including HIV, Influenza, and SARS-CoV-2. There are several major challenges to be overcome before this technology can be applied routinely in clinical settings, such as finding a suitable delivery tool, toxicity, and immunogenicity, as well as off-target effects. This review also discusses ways to deal with the challenges associated with Crisper-Cas technology. KEY POINTS: • Crisper technology is being applied to diagnose infectious and non-infectious diseases. • A new generation of CRISPR-Cas-based assays has been developed which detect pathogens within minutes, providing rapid diagnosis of diseases. • Crispr-Cas tools can be used to combat viral infections, specifically HIV, influenza, and SARS-CoV-2.

Processability and Oral Bioavailability Improvement of Itraconazole by Particle Engineering Technique.

The current study aimed to improve the processability and oral bioavailability of itraconazole (ITZ) via spherical agglomeration. ITZ-spherical agglomerates (ITZ-SA) and ITZ-poloxamer 407-spherical agglomerates (ITZ-PLX-SA) were optimized using Box-Behnken design. Here, the drug release was affected by polymer concentration and stirring speed, whereas particle size was altered by stirring speed, polymer concentration, and amount of bridging liquid. Heckel and Kawakita studies showed a reduction in mean yield pressure and remarkably lowered 1/b value than ITZ, indicating better compactibility and flowability of ITZ-PLX-SA. Physicochemical interactions were not observed during the process, as indicated by ATR-FTIR, DSC, and XRPD. The significant improvement in % drug release of ITZ-PLX-SA was attributed to better wettability and the presence of polymer than ITZ-SA and ITZ. The pharmacokinetic study in rats indicated fivefold enhanced Cmax and twofold improved AUC for ITZ-PLX-SA than plain drug. Thus, spherical agglomeration could improve overall processability and pharmacokinetic profile of ITZ.

Augmented Antitumor Activity for Novel Dual PI3K/BDR4 Inhibitors, SF2523 and SF1126 in Ewing Sarcoma.

Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.

Bacillus Calmette-Guérin Overexpressing an Endogenous Stimulator of Interferon Genes Agonist Provides Enhanced Protection Against Pulmonary Tuberculosis.

BACKGROUND: Stimulator of interferon genes (STING) is a key cytosolic receptor for small nucleotides and plays a key role in anticancer and antiviral immunity. Cyclic dinucleotide STING agonists may comprise a novel class of vaccine adjuvants capable of inducing cellular immune responses and protective efficacy against intracellular pathogens. METHODS: We generated a recombinant Bacillus Calmette-Guérin ([BCG] BCG-disA-OE) that overexpresses the endogenous mycobacterial diadenylate cyclase gene and releases high levels of the STING agonist bis-(3'-5')-cyclic dimeric adenosine monophosphate (c-di-AMP). We used a 24-week guinea pig vaccination-Mycobacterium tuberculosis (M.tb.) challenge model to test the protective efficacy of BCG-disA-OE versus wild-type BCG and measured lung weights, pathology scores, and M.tb. organ colony-forming unit (CFU) counts. RESULTS: BCG-disA-OE elicited significantly stronger tumor necrosis factor-α, interleukin (IL)-6, IL-1ß, interferon (IFN) regulatory factor 3, and IFN-ß levels than BCG-wild type (WT) in vitro in murine macrophages. In vivo in guinea pigs, we found that BCG-disA-OE reduced lung weights, pathology scores, and M.tb. CFU counts in lungs by 28% (P < .05), 34%, and 2.0 log10 CFU units (P < .05) compared with BCG-WT, respectively. CONCLUSIONS: We report a strategy of delivering a STING agonist from within live BCG. Overproduction of the STING agonist c-di-AMP significantly enhanced the protective efficacy of BCG against pulmonary and extrapulmonary tuberculosis. Our findings support the development of BCG-vectored STING agonists as a tuberculosis vaccine strategy.

Relative and Quantitative Phosphoproteome Analysis of Macrophages in Response to Infection by Virulent and Avirulent Mycobacteria Reveals a Distinct Role of the Cytosolic RNA Sensor RIG-I in Mycobacterium tuberculosis Pathogenesis.

Comparative phosphoproteomics of Mycobacterium tuberculosis (Mtb)- and Mycobacterium bovis BCG (BCG)-infected macrophages could be instrumental in understanding the characteristic post-translational modifications of host proteins and their subsequent involvement in determining Mtb pathogenesis. To identify proteins acquiring a distinct phosphorylation status, herein, we compared the phosphorylation profile of macrophages upon exposure to Mtb and BCG. We observed a significant dephosphorylation of proteins following Mtb infection relative to those with uninfected or BCG-infected cells. A comprehensive tandem mass tag mass spectrometry (MS) approach detected ∼10% phosphosites on a variety of host proteins that are modulated in response to infection. Interestingly, the innate immune-enhancing interferon (IFN)-stimulated genes were identified as a class of proteins differentially phosphorylated during infection, including the cytosolic RNA sensor RIG-I, which has been implicated in the immune response to bacterial infection. We show that Mtb infection results in the activation of RIG-I in primary human macrophages. Studies using RIG-I knockout macrophages reveal that the Mtb-mediated activation of RIG-I promotes IFN-ß, IL-1α, and IL-1ß levels, dampens autophagy, and facilitates intracellular Mtb survival. To our knowledge, this is the first study providing exhaustive information on relative and quantitative changes in the global phosphoproteome profile of host macrophages that can be further explored in designing novel anti-TB drug targets. The peptide identification and MS/MS spectra have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD013171.

Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis.

MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.

Assessment of Glycemic status, Insulin Resistance and Hypogonadism in HIV Infected Male Patients.

OBJECTIVES: The aim of the present study was to assess the glycemic status measured as Fasting Plasma Glucose (FPG) and glycosylated haemoglobin (A1C); prevalence of Insulin Resistance (IR), hypogonadism and to study their correlation with CD4 (CD4 lymphocyte) counts in HIV infected patients receiving ART. Correlation between percentage android fat and IR was also studied. METHODS AND MATERIALS: 84 HIV male patients as diagnosed by ELISA test aged 18 to 70 years were included in this case control study. Software IBM SPSS 20.1 and Microsoft Excel 2013 was used for analysis of data. The numerical data was compared using two tailed student t-test. Log transformation was used for the conversion of qualitative data (% android fat) to quantitative data so that it can be correlated to HOMA-IR. The level of significance was considered 0.05. RESULTS: Out of total 84 patients, 19 had FPG ≥ 100. 11(13%) had Impaired Fasting Glucose (IFG) and 8 (9.5%) had Diabetes Mellitus (DM). 20 patients had A1C > 5.6. Nine (10.7%) patients had Impaired Glucose Tolerance (IGT) and 11 (13.1%) patients had DM on the basis of A1C. 11 (13.1%) patients had DM based on either FPG or A1C criteria. Patients with higher percentage android fat had significantly higher IR. 33 (39%) patients had hypogonadism, six patients (7.1%) had primary hypogonadism; 24 (28.6%) had secondary hypogonadism and 3 (3.6 %) had compensatory hypogonadism. CONCLUSION: Patients with lower CD4 counts had significantly higher dysglycemia and IR. Serum testosterone levels were progressively lower (insignificant) with decreasing CD4 counts.

Repurposing ethyl bromopyruvate as a broad-spectrum antibacterial.

BACKGROUND: The emergence of drug-resistant bacteria is a major hurdle for effective treatment of infections caused by Mycobacterium tuberculosis and ESKAPE pathogens. In comparison with conventional drug discovery, drug repurposing offers an effective yet rapid approach to identifying novel antibiotics. METHODS: Ethyl bromopyruvate was evaluated for its ability to inhibit M. tuberculosis and ESKAPE pathogens using growth inhibition assays. The selectivity index of ethyl bromopyruvate was determined, followed by time-kill kinetics against M. tuberculosis and Staphylococcus aureus. We first tested its ability to synergize with approved drugs and then tested its ability to decimate bacterial biofilm. Intracellular killing of M. tuberculosis was determined and in vivo potential was determined in a neutropenic murine model of S. aureus infection. RESULTS: We identified ethyl bromopyruvate as an equipotent broad-spectrum antibacterial agent targeting drug-susceptible and -resistant M. tuberculosis and ESKAPE pathogens. Ethyl bromopyruvate exhibited concentration-dependent bactericidal activity. In M. tuberculosis, ethyl bromopyruvate inhibited GAPDH with a concomitant reduction in ATP levels and transferrin-mediated iron uptake. Apart from GAPDH, this compound inhibited pyruvate kinase, isocitrate lyase and malate synthase to varying extents. Ethyl bromopyruvate did not negatively interact with any drug and significantly reduced biofilm at a 64-fold lower concentration than vancomycin. When tested in an S. aureus neutropenic thigh infection model, ethyl bromopyruvate exhibited efficacy equal to that of vancomycin in reducing bacterial counts in thigh, and at 1/25th of the dosage. CONCLUSIONS: Ethyl bromopyruvate exhibits all the characteristics required to be positioned as a potential broad-spectrum antibacterial agent.

Protective effect of omeprazole and lansoprazole on ß-receptor stimulated myocardial infarction in Wistar rats.

We investigated the effect of omeprazole (OPZ) and lansoprazole (LPZ) on the pathophysiology of myocardial necrosis in rats by inspecting a series of indicators like hemodynamic parameters, biochemical estimations and histopathological changes in the myocardial tissue. Rats received either OPZ, LPZ (50 mg/kg/day, p.o.) individually for 7 days with concurrent administration of isoproterenol (ISO) (150 mg/kg, s.c.) on 6th and 7th day of study period to induce myocardial infarction. On the 8th day after measuring hemodynamic parameters, rats were killed and parameters were evaluated. ECG waves were found to be normal in the treatment group. ISO control rats revealed escalation in the oxidative stress as evidenced by depletion in the content of SOD, GSH, catalase and increase in the level of MDA and NO as compared with the normal rats. Treatment with OPZ and LPZ significantly reduced the ROS, indicated by an increase in the endogenous antioxidants and a decrease in NO and MDA levels. ISO control rats showed a significant elevation in the levels of pro-inflammatory cytokine TNF-α as compared to the normal and treatment group of rats. Administration of OPZ and LPZ does not exhibit any significant toxicity. Our findings reveal that multiple doses of OPZ and LPZ may have distinctly minimized the ISO-induced myocardial necrosis by declining the hmodynamic parameters, oxidative stress and pro-inflammatory cytokine TNF-α in myocardial infarcted rats.

The sound of music: A rare case of auditory Charles Bonnet syndrome in an elderly male.

BACKGROUND: Auditory Charles Bonnet syndrome describes a rare condition that presents with sensorineural hearing loss, which can result in musical hallucinations. METHODS: A Hispanic man, age 78, with no previous psychiatric history was evaluated at our clinic with a complaint of hearing voices and music. The patient was noted to have received cochlear implantation in his right ear in 2013, due to bilateral sensorineural hearing loss. He had auditometric testing completed in 2013 following the onset of hallucinations. RESULTS: Routine laboratory workup was unremarkable. Computed tomography of the brain revealed mucosal thickening in the left maxillary sinus and mild generalized cerebral atrophy. Over the course of 4 months, treatment with donepezil led to improvement in symptomatology. The Brief Psychiatric Rating Scale score decreased substantially from 15 to 6 over an 8-week period. The Clinical Global Impression-Severity scale score decreased from 4 to 2 and the Clinical Global Impression-Improvement scale score increased from 0 to 1 over the same period. CONCLUSIONS: Auditory Charles Bonnet syndrome should be considered in patients endorsing auditory hallucinations with hearing loss in whom the etiology is not clearly due to a psychiatric condition. The role of acetylcholine requires further elucidation; however, donepezil demonstrated efficacy in the treatment of musical hallucinations in our patient.