Multicenter Cohort Study to Evaluate the Relationship between Radiological Findings and Disability in Moderate and Severe Head Injury Patients.

This was a multicenter cohort study to evaluate the relationship between radiological findings and disability in moderate and severe head injury patients. The study places were the Neurosurgery department of Sylhet M A G Osmani Medical College Hospital, Sylhet Women's Medical College Hospital (SWMCH) and King Faisal Hospital (KFH), Taif, KSA. Sample size was 104 and the study period was 36 months (July 2021 to December 2022). On the basis of radiological findings the participants were divided into three arms. The different arms were diffused traumatic brain injury (arm-1), focal traumatic brain injury (arm-2) and both (diffused and traumatic) types traumatic brain injury (arm-3). Outcome was assessed by modified Rankin Score (mRS). Mean age was significantly higher in female. Overall mean age was 40.28 year. Highest number was in the below 20-year age group followed by the 41-50-year age group. Lowest number of participants was in the above 60-year group. Improved group was significantly higher than 'not improved' and the 'died' group (p<0.00001). Improved participants were significantly higher in the arm-1 and arm-2. Mortality was significantly higher (p<0.00001) in the arm-3 group.

Identifying links between athletic identity and risk factors related to youth sport participation.

Introduction: The development of identity formation occurs during adolescence through experiences, ideals and principle. With greater accessibility to sports, recent trends have shown increased rates of sports specialization over the past decade in youth athletes. Athletic identity measures the strength an individual is tied to the athlete role and can be formed in conjunction to adolescent identity formation. More specialized youth athletes may have stronger ties to their athletic identity during their adolescent identity formation period. Methods: Youth basketball athletes were surveyed on specialization levels and athletic identity via the Athletic Identity Measurement Scale (AIMS), including three submeasures: social identity, exclusivity, and negative affectivity. Results: Participants showed stronger identification to social identity items and the weakest identification with exclusivity items. Athletes reporting more time spent playing their primary sport presented higher scores across all measures of athletic identity, and total athletic identity was stronger in athletes reporting specialization at an earlier age. Exclusivity and negative affectivity tended to increase with specialization level which may primarily be driven by specialized athletes choosing to quit non-primary sports. Discussion: Athletic identity may be worth noting as a psychological indicator of potential risk of injury. The long-term goal of this work is to provide the research and clinical community a greater understanding of a potential psychosocial risk factor as youth athletes continue specializing and spending more time training in a singular sport.

Two rare flavonoid glycosides from Litsea glutinosa (Lour.) C. B. Rob.: experimental and computational approaches endorse antidiabetic potentiality.

BACKGROUND: Litsea glutinosa (Lour.) C. B. Rob. belongs to the Litsea genus and is categorized under the family of Lauraceae. The study aimed to investigate the phytoconstituents and pharmacological properties of methanol extract of leaves of Litsea glutinosa, focusing on antidiabetic activity via in vivo and in silico techniques. METHODS: Extensive chromatographic and spectroscopic techniques were applied to isolate and characterize the constituents from the L. glutinosa plant species. The antidiabetic activity was studied in streptozotocin-induced diabetes mice, and the computational study of the isolated compounds was carried out by utilizing AutoDock Vina programs. In addition, the pharmacokinetic properties in terms of absorption, distribution, metabolism and excretion (ADME) and toxicological profiles of the isolated compounds were examined via in silico techniques. RESULTS: In the present study, two flavonoid glycosides 4΄-O-methyl (2 ̋,4 ̋-di-E-p-coumaroyl) afzelin (1) and quercetin 3-O-(2 ̋,4 ̋-di-E-p-coumaroyl)-α-L-rhamnopyranoside (2) were isolated from the leaves of L. glutinosa and characterized by 1H and 13C NMR, COSY, HSQC, HMBC, and mass spectral data. Although compounds 1 and 2 have been reported twice from Machilis litseifolia and Lindera akoensis, and Machilis litseifolia and Mammea longifolia, respectively, this is the first report of this isolation from a Litsea species. Administering the methanolic extract of L. glutinosa at doses of 300 and 500 mg/kg/day to mice with diabetes induced by streptozotocin led to a significant decrease in fasting blood glucose levels (p < 0.05) starting from the 7th day of treatment. Besides, the computational study and PASS analysis endorsed the current in vivo findings that the both isolated compounds exerted higher binding affinities to human pancreatic α-amylase and aldose reductase than the conventional drugs. The in silico ADMET analysis revealed that the both isolated compounds have a favorable pharmacokinetic and safety profile suitable for human consumption. CONCLUSION: According to the current outcomes obtained from in vivo and in silico techniques, the leaf extract of L. glutinosa could be a natural remedy for treating diabetes, and the isolated phytoconstituents could be applied against various illnesses, mainly hyperglycemia. However, more investigations are required for extensive phytochemical isolation and pharmacological activities of these phytoconstituents against broader targets with exact mechanisms of action.

Estimation of 10-Year Fracture Risk with and without Bone Mineral Density in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is the most common inflammatory arthritis affecting 0.5-1.0% of the general population worldwide and although RA is properly considered a disease of the joints, it can cause a variety of extra-articular manifestations. This study was performed to find out any discrepancy in fracture risk estimates with and without bone mineral density (BMD) in rheumatoid arthritis (RA) patients. This observational cross-sectional study was carried out in the Department of Rheumatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh from July 2013 to July 2015. Total 65 consecutive patients with RA fulfilling ACR/EULAR criteria aged 40-90 year were recruited. Ten year fracture risk of these patients was evaluated by the FRAX score with and without BMD and differences were observed. FRAX score without BMD revealed that major fracture risk was low in 58(89.2%) patients, moderate in 7(10.8%) patients but re-estimation with BMD revealed that 55(84.6%) patients remained in low risk group, 8(12.3%) patients in moderate risk group and 2(3.1%) patients went to the high risk group. In case of hip fracture risk without BMD, risk was low in 58(89.2%) patients, high in 7(10.8%) patients; but with BMD, 50(76.9%) patients remained in low risk group but risk of 15(23.1%) patients became high. Almost all the high risk patients (93.3%) were ≥55 years of age. Increasing age, female sex, disease duration and use of steroid were positively correlated with increased FRAX score where as high BMI and high BMD were associated with low FRAX score. But in multivariate analysis it was found that only relation with age was at statistically significant level. Significant numbers of patients with rheumatoid arthritis have high risk of fracture especially hip fracture. The mean of FRAX score increased in both major & hip osteoporotic fracture risk after adding BMD. More than half of the patients above fifty five years or more had high risk of fracture. So, BMD should be done in patients aged more than fifty five.

Development of a novel one-step triplex PCR assay for the simultaneous detection of porcine circovirus type 2, porcine parvovirus and classical swine fever virus in a single tube.

Co-infection of multiple pathogens complicates diagnosis, treatment and preventive measures based on clinical signs. Therefore, reliable diagnostic tool for timely reporting of suspected diseases is very much essential. A novel one-step triplex PCR assay was developed and evaluated for simultaneous detection of three important viruses namely porcine circovirus type 2 (PCV2), porcine parvovirus (PPV) and classical swine fever virus (CSFV) involved in reproductive problems in pigs. Each of the three pairs of oligonucleotide primers exclusively amplified the targeted fragment of the specific viruses. The multiplex PCR assay was found to be sensitive in detecting at least 300 pg of viral genomic DNA or RNA from a mixture of three viruses in a reaction. No amplification was obtained from other common viruses or pathogens, such as porcine reproductive and respiratory syndrome virus (PRRSV), Japanese encephalitis virus (JEV), porcine group A rotavirus (PoRVA), Escherichia coli and Staphylococcus aureus thereby indicating that the developed multiplex PCR has high specificity. Because of the sensitivity and specificity, the developed multiplex PCR assay will be a useful tool for clinical diagnosis of mixed infections of DNA and RNA viruses in pigs.

Efficacy of Carbetocin versus Oxytocin for the Prevention of Primary Post Partum Haemorrhage after Caesarean Section in Mymensingh Medical College Hospital, Bangladesh.

Prevention of postpartum haemorrhage has been a major issue for its life threatening impact on maternal morbidity and mortality worldwide. Conventional continuous infusion of oxytocin has been employed for this condition. Apparently, in place of conventional oxytocics, application of carbetocin with longer half-life shows the same clinical benefits. This requires doing this present study. To compare the effectiveness of I/V bolus cabetocin and oxytocin infusion used for prevention of primary PPH after caesarean section. This descriptive cross-sectional comparative study was carried out in Department of Obstetrics and Gynaecology, Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh from November 2015 to April 2016. A total of 100 pregnant women undergoing elective or emergency caesarean section were enrolled and divided into two groups on the basis of exclusion and inclusion criteria. Group I (n=50) received bolus of 100µgm IV carbetocin after delivery of the baby & Group II (n=50) received 20 IU of oxytocin in 1000ml of Hartman solution I/V in 8 hours continuous infusion after delivery of the baby. Baseline demographic and obstetric profile, indications for C/S, estimated blood loss, hemoglobin level, additional uterotonic agents, blood pressure and the diuresis were compared immediate postoperatively and 24 hours after operation. The patients were followed up for 24 hours after operation regarding outcomes variables. Baseline profiles were similar between two groups. Regarding haemodynamic effects, both drugs have a hypotensive effect but a greater reduction in blood pressure is found in oxytocin group. There was no significant difference in respect of estimated blood loss, blood transfusion, additional oxytocics and diuresis between two groups. It can be concluded that a single injection of carbetocin is as effective as continuous oxytocin infusion to prevent postpartum haemorrhage, with similar haemodynamic profile. So, carbetocin as a uterotonic agent is an acceptable alternative for prevention of postpartum haemorhage after caesarean section.

Four new isoflavones from Derris scandens and their in vitro antiproliferative effects.

Four new compounds (derriscandenon D (1), E (2), F (3), G (4)) and six known isoflavones (warangalone (5), millewanin E (6), rhynedlin A (7), 6,8-diprenylgenistein (8), isolupalbigenin (9), isoscandinone (10)) were isolated from the acetone extract of the branches of Derris scandens. These compounds were assayed for cell viability using the human lung carcinoma cell line A549, colorectal carcinoma cell line Colo205, epidermoid carcinoma cell line KB, the human acute lymphoblastic leukaemia cell line NALM-6, and human dermal fibroblasts. Compounds 2 and 3 significantly decreased the viability of KB cells, with IC50 values of 2.7 and 12.9 µM, respectively. In addition, compounds 2 and 3 reduced the mitochondrial membrane potential in KB cells. Compounds 2 and 3 strongly down-regulated the cell viability of cell lines KB and NALM-6, achieving IC50 values of 2.7 and 0.9 µM, respectively, compared with the positive control staurosporine at 1.25 and 0.01 µM, respectively.

Development of a rapid loop-mediated isothermal amplification (LAMP) assay for visual detection of porcine parvovirus (PPV) and its application.

Porcine parvovirus (PPV) infection is one of the most important causes of reproductive failure in pigs impacting the piggery industry globally with huge economic losses. A cost-effective, simple, rapid, specific, and sensitive method is critical for monitoring PPV infection on pig farms. The main aim of the present study was to develop and evaluate a loop-mediated isothermal amplification (LAMP) assay for rapid visual detection of porcine parvovirus (PPV) in pigs. A set of six LAMP primers including two outer primers, two inner primers, and two loop primers were designed utilizing the conserved region of capsid protein VP2 gene sequences of PPV and was applied for detection of PPV from porcine samples. Time and temperature conditions for amplification of PPV genes were optimized to be 30 min at 63 °C. The developed assay was ten-fold more sensitive than conventional PCR with analytical sensitivity of 20 pg and 200 pg, respectively. This is the first report of detection of PPV by LAMP assay from India. The assay did not cross-react with porcine circovirus type 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSV), or classical swine fever virus (CSFV). The LAMP assay was assembled into a LAMP assay kit of 20 reactions and was validated in different laboratories in India. The newly developed LAMP assay was proved to be a specific, sensitive, rapid, and simple method for visual detection of PPV which does not require even costly equipments for performing the test. It complements and extends previous methods for PPV detection and provides an alternative approach for detection of PPV.

Antimicrobial Sensitivity Pattern in Neonatal Sepsis in Neonatal Intensive Care Unit of Mymensingh Medical College Hospital.

This cross-sectional descriptive study was conducted at the neonatal intensive care unit (NICU) in the department of Neonatology, Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh from July 2017 to December 2017 to determine antimicrobial sensitivity pattern in neonatal sepsis. Ninety four neonates (0-28 days) who were admitted in NICU with suspected sepsis were included in this study by purposive sampling technique. After admission written informed consent from parents or guardians obtained and then septic screening along with blood culture and antimicrobial sensitivity was done. All data were compiled, tabulated and then analyzed by SPSS version 21.0. Among 94 cases, 68(72.3%) were preterm and 26(23.4%) were term. There was male predominance and male female ratio was 1.9:1. Most of the patient admitted within 72 hours of birth. Most (84%) had low birth weight (<2500gm). Pre-mature onset of labour, pre-mature rupture of membrane >18 hours, vaginal route of delivery, instrumental resuscitation, pre-lacteal feeding, bottle feeding were the major perinatal risk factors in this study. Early onset sepsis (76.6%) was most prevalent in this study. Blood culture yielded positive growth in 20(21.3%) cases. Among them, Klebsiella was found in 7(35%). E. coli in 6(30%), Acinetobacter was in 3(15%), Staphylococcus aureus in 2(10%) cases. Pseudomonas and Enterobacter were found in rest 2(10%) of the cases. Gram negative bacteria were found in 18(90%) cases. Klebsiella was sensitive to Imipenem (85.7%), Colistin (85.7%) and Ciprofloxacin (77.5%). Sensitivity of E. coli was Imipenem (100%), Colistin (100%), Amikacin (66.7%), Ciprofloxacin (66.7%), Netilmicin (66.7%) and Gentamicin (50%). Acinatobecter had sensitivity to Netilmicin, Colistin, Imipenem (100%). Staphylococcus was 100% sensitive to Imipenem, Netilmicin and Vancomycin. Pseudomonas was found sensitive to Imipenem (100%), Amikacin (100%), Netilmicin (100%) and Colistin (100%). Enterobacter was found highly sensitive to Ciprofloxacin, Colistin and Imipenem. Almost all organisms were resistant to Ampicillin, Gentamicin, Cefotaxime and Ceftazidime. Based on result it is concluded that Klebsiella pneumoniae and Escherichia coli are the leading cause of neonatal sepsis in this study and most of them resistant to multiple antibiotics. Organisms found more sensitive to Imipenem, Colistin, Ciprofloxacin and Netilmicin.

A Study of Association between H. Pylori Genotype and Chronic Gastritis.

The prevalence of Helicobacter pylori (HP) infection is very high in Bangladesh. Chronic gastritis due to H. pylori is commonly associated with important gastric diseases such as peptic ulcer diseases or gastric carcinoma and MALT-oma. The natural course of chronic gastritis is HP-associated antral gastritis or pangastritis or rarely atrophies. This study was done to see the association of H. pylori genotypes with chronic gastritis. This observational cross sectional study was carried out at Bangabandhu Sheikh Mujib Medical University from July 2012 to April 2013 to find out the association of H. pylori genotypes with chronic gastritis in dyspeptic patients of Bangladesh. A total of 50 dyspeptic subjects were involved in the study whose upper GI endoscopies were carried out in presence of an experienced endoscopist. During the procedure four biopsies were taken, two from the antrum and two from body of the stomach. Endoscopic diagnosis was categorized into normal and erosive gastritis. Two (one from antrum and one from body) biopsy samples were collected in phosphate buffer saline and PCR analysis carried out by Multiplex PCR assay. Another two were collected in 10% formalin and histopathological examination was done according to updated Sydney system of classification. Among 50 patents only 34 were PCR positive. So, only 34 subjects were included in the study. Among them 21 patients (61.8%) were male and 13 patients (38.2%) were female, with the mean age of 29.91 years. Endoscopy revealed erosive gastritis in 5(14.7%) patients and normal findings in 29(86.3%) patients. Amongst the strains, cagA gene was detected in 58.8% and was not significantly associated with severity of any parameter of chronic gastritis such as H. pylori density, inflammation (mononuclear infiltration), activity (neutrophilic infiltration), atrophy and intestinal metaplasia. All the strains were positive for vacA allele. s1m1 (55.9%) genotype was most predominant. No vacA allele (s1m1, s1m2, s2m1 and s2m2) were significantly associated with severity of chronic gastritis. In this study, H. pylori genotype -cagA, vacA-s1, s2, m1, m2 allele and histological grading of chronic gastritis according to updated Sydney system of classification is identified. This study will identify the genotypes associated with severe gastritis in our country and thereby help us to take appropriate preventive measure. Further study with larger sample size may be carried out to establish proper association between different genotypes and parameters of chronic gastritis.

Mathematical modelling of fungi-initiated siderophore-iron interactions.

Nearly all life forms require iron to survive and function. Microorganisms utilize a number of mechanisms to acquire iron including the production of siderophores, which are organic compounds that combine with ferric iron into forms that are easily absorbed by the microorganism. There has been significant experimental investigation into the role, distribution and function of siderophores in fungi but until now no predictive tools have been developed to qualify or quantify fungi-initiated siderophore-iron interactions. In this investigation, we construct the first mathematical models of siderophore function related to fungi. Initially, a set of partial differential equations are calibrated and integrated numerically to generate quantitative predictions on the spatio-temporal distributions of siderophores and related populations. This model is then reduced to a simpler set of equations that are solved algebraically giving rise to solutions that predict the distributions of siderophores and resultant compounds. These algebraic results require the calculation of zeros of cross products of Bessel functions and thus new algebraic expansions are derived for a variety of different cases that are in agreement with numerically computed values. The results of the modelling are consistent with experimental data while the analysis provides new quantitative predictions on the time scales involved between siderophore production and iron uptake along with how the total amount of iron acquired by the fungus depends on its environment. The implications to bio-technological applications are briefly discussed.

Three isoflavones from Derris scandens (Roxb.) Benth and their cancer chemopreventive activity and in vitro antiproliferative effects.

Three undescribed isoflavones, derriscandenon A, B, and C, together with seven known isoflavones were isolated and structurally characterized during a study of the chemical constituents in the leaves of Derris scandens (Roxb.) Benth (Leguminosae, Fabaceae) collected in Bangladesh. The inhibitory activity of the compounds against activation of Epstein-Barr virus antigen (EBV-EA) by 12-O-tetradecanoylphorbo-13-acetate (TPA) was measured to identify possible chemopreventive agents. Mild inhibitory effects (IC50 278-290 mol ratio/32 pmol TPA) against EBV-EA induction compared with curcumin (IC50 341 mol ratio/32 pmol TPA) were observed for four known compounds (lupalbigenin, isopalbigenin, glyurallin, and isangustone A). Next, we focused on antitumor effects and investigated cell viability, cell proliferation, and mitochondria membrane potential by using an MTT assay, a live cell monitoring system, and fluorescence staining. Of the seven isoflavones tested for cell viability, a dose-dependent decrease in cell viability was observed for four isoflavones (derriscandenon B and C, derrubone, and glyurallin) in KB cells and two compounds (derriscandenon B and isochandaisone) in NALM6-MSH+ cells. In addition, the proliferation of KB cells was significantly inhibited by these four compounds at a concentration of 5 µM. The mitochondria membrane potentials of KB cells treated with derriscandenon C, derrubone, and glyurallin at the IC50 concentration were decreased by about 55%, whereas undescribed compound derriscandenon B had no effect. Our results show that some of the compounds isolated from D. scandens may be suitable as seed compounds for cancer prevention and therapy.

Detecting relapse in youth with psychotic disorders utilizing patient-generated and patient-contributed digital data from Facebook.

Although most patients who experience a first-episode of psychosis achieve remission of positive psychotic symptoms, relapse is common. Existing relapse evaluation strategies are limited by their reliance on direct and timely contact with professionals, and accurate reporting of symptoms. A method by which to objectively identify early relapse warning signs could facilitate swift intervention. We collected 52,815 Facebook posts across 51 participants with recent onset psychosis (mean age = 23.96 years; 70.58% male) and applied anomaly detection to explore linguistic and behavioral changes associated with psychotic relapse. We built a one-class classification model that makes patient-specific personalized predictions on risk to relapse. Significant differences were identified in the words posted to Facebook in the month preceding a relapse hospitalization compared to periods of relative health, including increased usage of words belonging to the swear (p < 0.0001, Wilcoxon signed rank test), anger (p < 0.001), and death (p < 0.0001) categories, decreased usage of words belonging to work (p = 0.00579), friends (p < 0.0001), and health (p < 0.0001) categories, as well as a significantly increased use of first (p < 0.0001) and second-person (p < 0.001) pronouns. We additionally observed a significant increase in co-tagging (p < 0.001) and friending (p < 0.0001) behaviors in the month before a relapse hospitalization. Our classifier achieved a specificity of 0.71 in predicting relapse. Results indicate that social media activity captures objective linguistic and behavioral markers of psychotic relapse in young individuals with recent onset psychosis. Machine-learning models were capable of making personalized predictions of imminent relapse hospitalizations at the patient-specific level.

Discoidin domain receptor 2: An emerging pharmacological drug target for prospective therapy against osteoarthritis.

Discoidin domain receptor2 (DDR2), a cell membrane tyrosine kinase on chondrocytes surface plays main role in cell-ECM interaction during the progressive degeneration of articular cartilage in osteoarthritis. The degraded component of ECM, type II collagen upon DDR2 binding provokes synthesis of matrix metalloproteinases (MMPs), responsible for severe destruction of joint tissues. DDR2 knockout has been investigated to decline the expression of MMP-1 and 13. Previously, various molecules were effective in preclinical level against different targets in OA, but found to be collapsed in clinical trial due to insufficient target specificity and clinical toxicity. Review emphasizes the role of DDR2 in the degeneration of cartilage in osteoarthritis (OA) and its blocking by DDR2 antagonist attenuates the disease severity. DDR2 in chondrocytes contributes paramount role in degradation of cartilage at early stage of osteoarthritis via collagen 2 binding through the felicitation of TGF-ß signaling molecule and other triggering factors. DDR2 involvement in regulation of matrix metalloproteinase (MMP), cross talking interaction in maintenance of ECM-chondrocytes, bone developments, interference RNA and designing the DDR2 antagonists have been critically investigated. The exploration may conclude that the DDR2 could be the novel pharmacological target to prevent the progression of osteoarthritis at early stage because of over expression of DDR2 and MMP which further promotes severe cartilage degeneration. Owing to pharmacological specificity of DDR2 in OA as drug target, it is to be hypothesized that development of safe molecules as DDR2 antagonist could be the good option in the treatment of OA with promising landmark.

Association between HbA1c and the development of cystic fibrosis-related diabetes.

AIMS: To examine HbA1c as a predictor of risk for future development of cystic fibrosis-related diabetes and to assess the association with the development of retinopathy in people with cystic fibrosis-related diabetes. METHODS: A 7-year retrospective longitudinal study was conducted in 50 adults with cystic fibrosis, comparing oral glucose tolerance test results with HbA1c values in predicting the development of cystic fibrosis-related diabetes. Retinal screening data were also compared with HbA1c measurements to assess microvascular outcome. RESULTS: An HbA1c value ≥37 mmol/mol (5.5%; hazard ratio 3.49, CI 1.5-8.1) was significantly associated with the development of dysglycaemia, as defined by the oral glucose tolerance test over a 7-year period. Severity of diabetic retinopathy was associated with a higher HbA1c and longer duration of cystic fibrosis-related diabetes. CONCLUSION: There is a link between HbA1c level and the future development of dysglycaemia in cystic fibrosis based on oral glucose tolerance test, as well as microvascular outcomes. Although current guidance does not advocate the use of HbA1c as a diagnostic tool in cystic fibrosis-related diabetes, it may be of clinical use in determining individuals at risk of future development of cystic fibrosis-related diabetes.

TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome.

KEY POINTS: The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or 'sick sinus syndrome', can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker. 'Biopacemaking' utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success. We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na+ /Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development. TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue. Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers. ABSTRACT: The sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na+ /Ca2+ exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5 ± 13.6 bpm, SAP 144.1 ± 8.6 bpm, SAP-TBX18 214.4 ± 14.4 bpm; P < 0.001), improved heart rate stability (standard deviation of RR intervals fell from 39.3 ± 7.2 ms to 6.9 ± 0.8 ms, P < 0.01; root mean square of successive differences of RR intervals fell from 41.7 ± 8.2 ms to 6.1 ± 1.2 ms, P < 0.01; standard deviation of points perpendicular to the line of identity of Poincaré plots (SD1) fell from 29.5 ± 5.8 ms to 7.9 ± 2.0 ms, P < 0.05) and restoration of isoprenaline response (increases in rates of SAN 65.5 ± 1.3%, SAP 28.4 ± 3.4% and SAP-TBX18 103.3 ± 10.2%; P < 0.001). These changes were driven by a TBX18-induced switch in the dominant HCN isoform in SAP tissue, with a significant upregulation of HCN2 (from 1.01 × 10-5  ± 2.2 × 10-6 to 2.8 × 10-5  ± 4.3 × 10-6 arbitrary units, P < 0.001). Biophysically detailed computer modelling incorporating isoform-specific HCN channel electrophysiology confirmed that the measured changes in HCN abundance could account for the observed changes in beating rates. TBX3 and NCX1 were not effective in accelerating the rate of SAP tissue.

Ichnocarpus frutescens (L.) R. Br. root derived phyto-steroids defends inflammation and algesia by pulling down the pro-inflammatory and nociceptive pain mediators: An in-vitro and in-vivo appraisal.

Ichnocarpus frutescens, a climber plant, is distributed all over India. As its different parts are used as anti-inflammatory agent, so we re-investigated the roots to isolate compounds and evaluate its biological efficacy. Also, in-silico molecular docking was carried out to elucidate the structure activity relationship (SAR) of isolated compounds toward identifies the drug target enzyme with validation, which was further supported by anti-inflammatory in-vitro and in-vivo experimental models. The compounds have been undertaken mainly to investigate the anti-inflammatory and analgesic efficacy along with molecular docking investigation followed by anti-proteinase, anti-denaturation and cyclooxygenase (COX) inhibition studies. Inflammatory cytokines like TNF-α and IL-6 were assayed from lipopolysaccharides (LPS) and Concavallin (CON A) stimulated human PBMC derived macrophages by Enyme linked immune sorbent assay (ELISA) method. The purity index of the lead compound was determined by HPLC. The compounds were illustrated as 2-hydroxy tricosanoic acid (1), stigmasterol glucoside (2), stigmasterol (3), ß-sitosterol (4) and ß-sitosterol glucoside (5). The test molecules showed significant anti-denaturation, anti-proteinase and analgesic effect validated with docking study. Compounds exhibited anti-inflammatory and pain killing action due to dexamethasone like phytosterol property. Promising anti-denaturation and anti-proteinase activity offered by the compound 5, may hold its promise to fight against arthritis by rejuvenating the osteoblast cells and destroying the bone-resorpting complex of hydrated protein, bone minerals by secreting the acid and an enzyme collagenase along with pain management. The lead bioactive compound i.e. ß-sitosterol glucoside (compound 5) demonstrated considerable anti-inflammatory activity showing more than 90% protection against the inflammatory cytokines at 50 µM dose. The anti-denaturation and COX-2 inhibition shown by the compound 5 was also noteworthy with the significant IC50 (ranging from 0.25 to 2.56 µM) that also supporting its future promise for developing as anti-inflammatory agent. Since the most bio-active compound (5) elicit promising acute anti-inflammatory action and peripheral anti-nociceptive pain killing action with a significant ED50 dose of 3.95 & 2.84 mg/kg i.p. respectively in the in-vivo animal model. It could suggest its potentiality as a good in-vivo bio available agent to be an emerging anti-inflammatory drug regimen scaffold in the future. It also establishes significant in-vitro and in-vivo result co-relation. Therefore, the compound 5 could be believed as a potent lead for designing anti-inflammatory, anti-arthritic drug or pain killer without showing any untoward effect.

A mathematical model of nutrient influence on fungal competition.

Fungi have a well-established role in nutrient cycling and are widely used as agents in biological control and in the remediation of polluted landscapes. Competition for resources between different fungal communities is common in these contexts and its outcome impacts on the success of such biotechnological applications. In this investigation a mathematical model is constructed to represent competition between two fungal colonies that have access to different resources. It is shown that the model equations display a multitude of travelling wave solutions and that the outcome of competition between two fungal biomasses can be controlled through the simple manipulation of the nutrient resources available to each. The model equations are also numerically integrated to illustrate the range of outcomes arising from fungal competition and these results are placed in context of established experimental observations.