Unraveling the unexpected aggregation behavior of Pyrazole-Based compounds Targeting Mycobacterium tuberculosis UDP-Galactopyranose mutase.

A pyrazole-based compound, MS208, was previously identified as an inhibitor of UDP-Galactopyranose Mutase from Mycobacterium tuberculosis (MtUGM). Targeting this enzyme is a novel therapeutic strategy for the development of new antituberculosis agents because MtUGM is an essential enzyme for the bacterial cell wall synthesis and it is not present in human. It was proposed that MS208 targets an allosteric site in MtUGM as MS208 followed a mixed inhibition model. DA10, an MS208 analogue, showed competitive inhibition rather than mixed inhibition. In this paper, we have used an integrated biophysical approach, including thermal shift assays, dynamic light scattering and nuclear magnetic resonance experiments, to show that MS208 and many analogues displayed unexpected aggregation behavior against MtUGM.

The growth curve determination and economic trait correlation for Qinchuan bull population.

Carcass weight, as a measure of meat yield, and body measurements are directly correlated traits in livestock. However, longitudinally collected phenotype records of local breeds are not comprehensive. The research was performed on Qinchuan bull population to understand their growth and development, and data from Qinchuan bull that was weighed and measured at birth, 6, 12, 18, and 24 months of age was analyzed. Furthermore, Logistic, Brody, Gompertz, and Bertallanffy were used to fit the growth curves for weight and body size traits. The results showed that the four curve models have good fitting degrees for the weight and body size (R2 > 0.99), and the Bertallanffy model exhibited a good fit to the measured data of body weight, and the model estimated the inflection point of body weight as (5.43 months of age, 122.01 kg). Particularly, the limited mature body weight can reach 557.8 kg by the Brody model. Body weight was significantly positively correlated with body height, hip height, body length, chest circumference, abdominal girth, and calf girth (p < 0.0001), and the correlation between body weight and body length was the highest (r = 0.975). The regression equation predicting body weight was Y = -275.691 + 3.28 X3 + 1.311 X4 - 0.397 X5.

Roles of MEF2A and HOXA5 in the transcriptional regulation of the bovine FoxO1 gene.

The Forkhead box factor 1 (FoxO1) gene plays a vital role in the growth and development of skeletal muscle. In the present study, expression analysis of the bovine FoxO1 gene exhibited the highest expression in longissimus dorsi muscle followed by its expression in adipose tissue. Moreover, high mRNA expression of FoxO1 gene was found in differentiated bovine myoblasts and adipocytes at day 6 of induced differentiation (p < 0.05). The regulatory pattern of the bovine FoxO1 gene was investigated through screening and dual-luciferase activity of the 1.7 kb 5'UTR (untranslated region) within pGL3-basic vector and a core promoter region was explored at (-285/-27) upstream of the transcription start site. The transcription factors (TFs) MEF2A and HOXA5 within the core promoter region (-285/-27) were found as the regulatory cis-acting element. The siRNA interference of the TFs, chromatin immunoprecipitation (ChIP) assay, and site-directed mutation validated that MEF2A and HOXA5 binding occurs in the region -285/-27 bp and performs an essential role in the transcriptional regulation of bovine FoxO1 gene. These findings explored the regulatory network mechanism of the FoxO1 gene in skeletal muscle development and adipogenesis for the bovine breed improvement program.

Bioinformatics analysis and the association of polymorphisms within the caprine GDF9 gene promoter with economically useful traits in Damani goats.

The blood sample from 60 Damani does were collected and genomic DNA was extracted, and DNA integrity were investigated. A 447 bp promoter fragment of the GDF9 gene was amplified and Sanger sequenced for the identification of GDF9 gene polymorphism. Three novel SNPs were identified at positions g. 97(T > A), g. 142 (G > G) and g. 313(C > T) in the promoter region of the caprine GDF9 gene which significantly (P < 0.05) influenced litter size, body measurement, and milk production traits in Damani goats. The genotype CT of SNP1 significantly (P < 0.05) improved litter size, genotype GG of SNP2 significantly (P < 0.05) enhanced milk production, while the genotypes CC of SNP3 significant (P < 0.05) increased body measurement traits in Damani goats. Moreover, in SNP1 loss of 3 transcription factors (TF) binding sites occurred, SNP2 caused loss of two TFs binding sites, and SNP3 caused loss of a single TF binding site. Similarly, SNP1 and SNP2 caused the gain of three new potential TF binding sites, and SNP3 caused gain of two new TF binding sites. It is concluded that caprine GDF9 gene could be used as a candidate gene for litter size, milk production and body measurement traits in Damani goats through marker-assisted selection for future breeding program.

Hepatotoxic effect of tramadol and O-desmethyltramadol in HepG2 cells and potential role of PI3K/AKT/mTOR.

1. The aim of this study was to compare the in vitro cytotoxic effect of tramadol and M1 metabolite in HepG2 cell line, the underlying mechanism, and PI3K/AKT/mTOR as potential target.2. Concentrations representing therapeutic level for tramadol (2 µM) and M1 metabolite (0.5 µM) were used. In addition, other increasing concentrations representing higher toxic levels were used (6, 10 µM for tramadol and 1.5, 2.5 µM for M1 metabolites). Cytotoxicity was assessed at 24, 48 and 72 h.3. Both tramadol and M1 metabolites were able to produce cytotoxicity in a dose and time dependent manner. Insignificant difference was detected between cells exposed to tramadol and M1 metabolite at therapeutic concentrations. Tramadol-induced apoptotic and autophagic cell death while M1 metabolite-induced apoptosis only. For PI3K/AKT/mTOR pathway, the therapeutic concentration of tramadol was only able to increase phosphorylation of AKT while higher toxic concentrations were able to increase phosphorylation of whole pathway; Meanwhile, M1 metabolite was able to increase the phosphorylation of the whole pathway significantly in therapeutic and toxic concentrations.4. In conclusion, both tramadol and M1 are equally cytotoxic. Apoptosis and autophagy both mediate hepatic cell death. PI3K/AKT pathway is involved in apoptosis induction while autophagy is regulated through mTOR independent pathway.

Cellular and molecular alterations of buffalo oocytes cultured under two different levels of oxygen tension during in vitro maturation.

This study was conducted to monitor the cellular and molecular changes of buffalo cumulus-oocytes complexes (COCs) cultured under high or low oxygen levels. Morphologically good quality COCs (n = 1627) were screened using brilliant cresyl blue (BCB) staining and placed into three groups (BCB+, BCB- and control). All groups of COCs were cultured under low (5%) or high (20%) oxygen tensions. Intracellular and molecular changes including oocyte ultrastructure, lipid contents, mitochondrial activity and transcript abundance of genes regulating different pathways were analyzed in the matured oocyte groups. The results revealed that oxygen tension did not affect cumulus expansion rates, however the BCB+ group had a higher (P ≤ 0.05) expansion rate compared with the BCB- group. BCB- oocytes recorded the lowest meiotic progression rate (P ≤ 0.05) under high oxygen levels that was linked with an increased level of reactive oxygen species (ROS) compared with the BCB+ oocytes. Ultrastructure examination indicated that BCB+ oocytes had a higher rate of cortical granules migration compared with BCB- under low oxygen tension. In parallel, our results indicated the upregulation of NFE2L2 in groups of oocytes cultured under high oxygen tension that was coupled with reduced mitochondrial activity. In contrast, the expression levels of MAPK14 and CPT2 genes were increased (P ≤ 0.05) in groups of oocytes cultured under low compared with high oxygen tension that was subsequently associated with increased mitochondrial activity. In conclusion, data from the present investigation indicated that low oxygen tension is a favourable condition for maintaining the mitochondrial activity required for nuclear maturation of buffalo oocytes. However, low-quality oocytes (BCB-) responded negatively to high oxygen tension by reducing the expression of gene-regulating metabolic activity (CPT2). This action was an attempt by BCB- oocytes to reduce the increased levels of endogenously produced ROS that was coupled with decreased expression of the gene controlling meiotic progression (MAPK14) in addition to nuclear maturation rate.

Antifungal and immunomodulatory potentials of propolis nanoparticles against Fusarium solani in Swiss Albino mice.

The nanotechnology has an important role in improving the efficacy and safety in therapy. The present study explains the antifungal and the immunomodulatory potency of propolis nanoparticles (PNPs) against Fusarium solani in Albino Mice. Disc diffusion method was used for antifungal efficacy of PNPs. Moreover, PNPs exhibited a progressive decrease in the % of viable Vero cells and suppressed the virulence factors of Fusarium saloni including adhesion and biofilm formation. In animal experiments, lymphoid cell, peritoneal phagocytes, red blood cell RBCs and white blood cell WBCs counts and the activities of T and B-lymphocytes were determined. In addition, T-cell mitogenesis cells, serum level of interleukin 2 (IL-2) and haemoglobin Hb concentration were measured. PNPs exhibited high inhibition zone with most of Fusarium solani isolates. The results indicated that treatment of mice by PNPs showed a marked rise in the number of cells from thymus, spleen, mesenteric lymph nodes and bone marrow. Furthermore, PNPs caused statistically significant raised in Hb concentration and WBCs count. These results confirmed that many biological activities attributed to PNPs and is as an adjuvant for immune enhancement.

Prevalence of human immunodeficiency virus among pulmonary tuberculosis patients: A cross-sectional study.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is an endemic disease in Sudan, where it has rapidly become the major complication of human immunodeficiency virus (HIV) infection. Thus, this study aimed to determine the prevalence of HIV among TB patients and evaluate the co-infection rate. The association of HIV prevalence with gender, age, and duration of treatment as risk factors was also determined. A descriptive cross-sectional study was performed in Omdurman Abu Anga Hospital, Khartoum, Sudan, from October 2018 to March 2019. A total of 281 blood samples were obtained randomly from pulmonary TB patients. The plasma was examined for the presence of HIV antibodies using sandwich ELISA. A structured questionnaire was used during data collection. A noticeable marker for HIV immunoglobulin M/immunoglobulin G was found in 12 patients (4.3%), of which five patients (41.7%) were diagnosed as new TB cases. Moreover, the relationship between age, sex, and duration of TB treatment and the prevalence of HIV was not significantly different (P > 0.05). In conclusion, the prevalence of HIV antibodies among TB pulmonary patients is high. Therefore, all TB patients should be examined for HIV risk factors and advised to undergo HIV testing. Further studies are essential to provide more insights into the epidemiology of the co-infection to better report the double burden of HIV and TB among TB patients in Sudan.

Torsemide versus furosemide after acute decompensated heart failure: a retrospective observational study.

BACKGROUND: Loop diuretics are recommended by clinical practice guidelines to treat volume overload in acute decompensated heart failure (ADHF). The effectiveness of switching furosemide to torsemide versus optimizing the furosemide dose following ADHF has not yet been evaluated. METHODS: This retrospective observational study aimed to assess the impact of switching furosemide to torsemide versus optimizing the furosemide dose after ADHF on HF-related hospitalization within 1 month and 6 months of discharge. The study included patients previously on furosemide admitted with ADHF to the Heart Hospital in Qatar between January 1, 2016 and June 30, 2017. The study included 2 groups: (1) patients discharged on torsemide; and (2) patients discharged on an optimized furosemide dose. Cox proportional hazard regression analysis was used to determine the association between diuretic use and hospitalization. RESULTS: Of the 232 patients included, 45 received torsemide and 187 received an optimized furosemide dose upon discharge. The majority of patients included were males (54%) with a mean age of 67 ± 12 years, and presented with HF with reduced ejection fraction (57%) and had a history of coronary artery disease (68%). The 1-month and 6-month HF-related hospitalization did not differ between the torsemide and optimized furosemide groups (aHR = 0.72; 95% CI 0.23-2.3, p = 0.57; aHR = 0.94, 95% CI 0.45-1.8, p = 0.87), respectively. CONCLUSION: Switching furosemide to torsemide after ADHF was not associated with reduced HF-related hospitalization compared to receiving an optimized furosemide dose. Larger prospective clinical trials are needed to confirm the findings of this study.

Antifungal potency of Nigella sativa seeds extract against Rhizopus stolonifer and their effect of immunomodulatory against aflatoxin-fed mice.

The present study describes the antifungal potency of Nigella sativa seeds extract and the effect of immunomodulatory of N. sativa against aflatoxin- fed mice. Disc diffusion method was used for antifungal efficacy of aqueous extract of N. sativa. In animal experiments, lymphoid cell count, total and differential counts of PEC, the phagocytic activity of PEC and detection of the plaque-forming were determined. E-rosette-forming cells (RFC), T-cell mitogenesis assay cells, ALT and AST were detected. The aqueous extract of N. sativa (50%) exhibited high inhibition zone with most of isolates of R. stolonifera.The results indicated that treatment of mice by using N. sativa showed marked rise in the number of cells from thymus and PLN with dose 0.50 g and absolute number and comparative ratio of macrophages (P < 0.01) with the doses 0.40 and 0.50 g. There is gradually rise in the scavenger activity of PEC with the dose 0.50 g at 60 min. Serum level of ALT was markedly reduced with dose 0.50 g as compared with a control group. These results indicated that N. sativa is promising modifier of biological response.

Prevalence and predictors of frailty in a high-income developing country: A cross-sectional study.

Background: Frailty is a state of vulnerability and a decreased physiological response to stressors. As the population ages, the prevalence of frailty is expected to increase. Thus, identifying tools and resources that efficiently predict frailty among the Saudi population is important. We aimed to describe the prevalence and predictors of frailty among Saudi patients referred for cardiac stress testing with nuclear imaging. Methods: We included 876 patients (mean age 60.3 ± 11 years, women 48%) who underwent clinically indicated cardiac nuclear stress testing between January and October 2016. Fried Clinical Frailty Scale was used to assess frailty. Patients were considered frail if they had a score of four or higher. Multivariate adjusted logistic regression models were used to determine the independent predictors of elderly frail patients. Results: In this cohort, the median age of the included patients was 61 years, and the prevalence of frailty was 40%. The frail patients were older, more frequently women, and had a higher body mass index. Additionally, frailty was associated with a higher prevalence of cardiovascular risk factors: hypertension (85% vs. 70%) and diabetes (75% vs. 60%). In a fully adjusted logistic regression model, women, hypertension, and obesity (BMI ≥ 30 kg/m2) were independent predictors of elderly frail patients. Conclusions: With the aging of the Saudi population, frailty prevalence is expected to increase. Elderly, obesity, hypertension, and female gender are risk factors of frailty. Interventions to reduce frailty should be focused on this high-risk population.

The role of myocardial viability in contemporary cardiac practice.

Ischemic heart disease (IHD) remains the single most common cause of death worldwide. Ischemic cardiomyopathy is a major sequel of coronary artery disease. The economic health burden of IHD is substantial. In patients with old myocardial infarction (OMI), the extent of viable myocardium (VM) directly affects the short- and long-term outcome. There is a considerable collection of observational data showing substantial improvement in patients with significant left ventricular dysfunction when the need for revascularization is guided by preoperative assessment of viability and hibernation. However, a major challenge for present cardiovascular imaging is to identify better ways to assess viable but inadequately perfused myocardium and thus optimize selection of patients for coronary revascularization. Several non-invasive techniques have been developed to detect signs of viability. Hence, our aim is to provide the reader a state-of-the art review for the assessment of myocardial viability.

Pattern and predictors of interpersonal violence among adolescent female students in Egypt.

Violence among female adolescents is a major public health problem. The objective of this study is to detect the pattern and predicting factors of interpersonal violence among adolescent female students in a nursing high school in Cairo. A cross-sectional study was conducted during the academic year 2011-2012 and included a total of 220 students using a self-administered questionnaire. Physical violence exposure at home, school and community among studied adolescents were 65.5, 30.4 and 25.9% respectively. Verbal violence was found in 55, 69 and 60% at home, school and community respectively. Finally 5 and 41.3% of studied students were exposed to sexual violence at home and community respectively. The highest violence exposure score was at school from teachers while the highest score of being violent was mainly towards the community. Multivariate regression analysis for violence scores revealed that younger students, students from urban residence and higher crowding index were significant predictors for total violence exposure and being violent scores. Prevention programmes should be given for all students especially high risk ones (young age, urban residence and high crowdness index families) and their families to address and overcome this problem.

Silent stealth: painless aortic dissection masquerading as heart failure.

A male patient in his 50s presented to the emergency department with a three-day history of shortness of breath, New York Heart Association class IV, and oxygen desaturation. His physical examination revealed a large volume radial pulse with bibasal crepitation in the lungs and a soft diastolic murmur in the aortic area on auscultation of his heart. He was managed on the line of decompensated heart failure. Transthoracic echocardiography showed a dissection flap in the ascending aorta with acute severe aortic regurgitation. A subsequent urgent CT angiography of the whole aorta confirmed a complex type A aortic dissection with an aneurysmal ascending aorta. An emergency type A aortic dissection repair (modified Bentall's procedure) was done. The patient made a good recovery, was discharged successfully 2 weeks after the procedure and was doing well on postoperative follow-up.

Mutational analysis of consanguineous families and their targeted therapy against dwarfism.

Dwarfism is a medical term used to describe individuals with a height-vertex measurement that falls below two standard deviations (-2SD) or the third percentile for their gender and age. Normal development of growth is a complicated dynamic procedure that depends upon the coordination of different aspects involving diet, genetics, and biological aspects like hormones in equilibrium. Any severe or acute pathologic procedure may disturb the individual's normal rate of growth. In this research, we examined four (A-D) Pakistani consanguineous families that exhibited syndromic dwarfism, which was inherited in an autosomal recessive pattern. The genomic DNA of each family member was extracted by using phenol-chloroform and Kit methods. Whole Exome Sequencing (WES) of affected family members (IV-11, III-5, IV-4 and III-13) from each group was performed at the Department of Medical Genetics, University of Antwerp, Belgium. After filtering the exome data, the mutations in PPM1F, FGFR3, ERCC2, and PCNT genes were determined by Sanger sequencing of each gene by using specific primers. Afterward, FGFR3 was found to be a suitable drug target among all the mutations to treat achondroplasia also known as disproportionate dwarfism. BioSolveIT softwares were used to discover the lead active inhibitory molecule against FGFR3. This research will not only provide short knowledge to the concerned pediatricians, researchers, and family physicians for the preliminary assessment and management of the disorder but also provide a lead inhibitor for the treatment of disproportionate dwarfism.Communicated by Ramaswamy H. Sarma.

The potential Association of Bisphenol A exposure and type 1 diabetes mellitus among Dakahlia Governorate's children sample, Egypt.

Background: Bisphenol A (BPA) is an endocrine disrupter affecting glucose homeostasis. Objectives: This study aimed to investigate BPA's relationship with Type 1 Diabetes Mellitus (T1DM) in Dakahlia Governorate's children, in Egypt. Subjects materials and methods: The study had two parts: clinical and experimental. Clinical Study was conducted on 200 children, equally divided into control and T1DM groups. They underwent: demographic data, height, weight, body mass index, glycosylated HbA1C, random blood glucose, and urinary BPA measurements. Experimental Study was conducted on 60 adult albino rats. Rats were randomly divided into three equal groups: control group: received 0.5 mL of pure olive oil, group 1: received 20 mg/kg/day BPA, and group 2: received 100 mg/kg/day BPA orally for 6 weeks. Fasting and two hours postprandial glucose levels were measured at the beginning and end of the study. Histopathological examination and imaging study of the pancreas were done. Results: In clinical study: HbA1C and random blood glucose levels in diabetic children showed a significant increase compared to control. Children in control group showed controlled HbA1C, while the T1DM group showed 86% with poor diabetic control. There was a significant increase in BPA level in the T1DM group compared to the control. Rats that received BPA showed a marked increase in fasting and two hours postprandial glucose levels, histopathological changes in the pancreas with more changes determined in the high dose group, and a significant decrease in the islets of Langerhans diameters with group 2 more affected. Conclusion: So, BPA exposure could be considered a risk factor for T1DM in children.

Fabrication and evaluation of anticancer potential of diosgenin incorporated chitosan-silver nanoparticles; in vitro, in silico and in vivo studies.

The discovery of effective therapeutic approaches with minimum side effects and their tendency to completely eradicate the disease is the main challenge in the history of cancer treatment. Fenugreek (FGK) seeds are a rich source of phytochemicals, especially Diosgenin (DGN), which shows outstanding anticancer activities. In the present study, chitosan-silver nanoparticles (ChAgNPs) containing Diosgenin (DGN-ChAgNPs) were synthesized and evaluated for their anticancer activity against breast cancer cell line (MCF-7). For the physical characterization, the hydrodynamic diameter and zeta potential of DGN-ChAgNPs were determined to be 160.4 ± 12 nm and +37.19 ± 5.02 mV, respectively. Transmission electron microscopy (TEM) showed that nanoparticles shape was mostly round with smooth edges. Moreover, DGN was efficiently entrapped in nanoformulation with good entrapment efficacy (EE) of ~88 ± 4 %. The in vitro anti-proliferative activity of DGN-ChAgNPs was performed by sulforhodamine B (SRB) assay with promising inhibitory concentration of 6.902 ± 2.79 µg/mL. DAPI staining, comet assay and flow cytometry were performed to validate the anticancer potential of DGN-ChAgNPs both qualitatively and quantitatively. The percentage of survival rate and tumor reduction weight was evaluated in vivo in different groups of mice. Cisplatin was used as a standard anticancer drug. The DGN-ChAgNPs (12.5 mg/kg) treated group revealed higher percentage of survival rate and tumor reduction weight as compared to pure DGN treated group. These findings suggest that DGN-ChAgNPs could be developed as potential treatment therapy for breast cancer.

The A-dip of aortic regurgitation.

Careful analysis of the aortic regurgitation (AR) Doppler signal often provides important information regarding left heart hemodynamics. Here we illustrate a pattern on the AR signal, known as the A-dip that suggests the presence of elevated LVEDP.

Association between sleep and behavioural problems among children with enuresis.

AIM: This study was conducted to describe sleep problems in a sample of children with enuresis and to investigate the association between sleep and behavioural problems. METHODS: In this cross-sectional study, 100 children with enuresis were recruited from paediatric enuresis clinic. The children's sleep problems and behaviours were assessed by the Children's Sleep Habits Questionnaire and Child Behaviour checklist. RESULTS: The most frequently reported sleep problems were in daytime sleepiness, bedtime resistance and sleep anxiety subscales. Children with T-scores ≥ 60 in internalising, externalising and total behavioural problems had higher scores on daytime sleepiness subscale and total score than children with T-scores < 60. Multivariate logistic regression analysis revealed that daytime sleepiness subscale was significantly related to behavioural disturbances. CONCLUSIONS: Sleep problems are common among this sample of children with enuresis, and the presence of sleep disturbance such as daytime sleepiness could explain the association between enuresis and disturbed daytime behaviour.