Analyzing fuzzy boundary value problems: a study on the influence of mitochondria and ER fluxes on calcium ions in neuron cells.

Cytosolic-free calcium ions play an important role in various physical and physiological processes. A vital component of neural signaling is the free calcium ion concentration often known as the second messenger. There are many parameters that effect the cytosolic free calcium concentration like buffer, voltage-gated ion channels, Endoplasmic reticulum, Mitochondria, etc. Mitochondria are small organelles located within the nervous system that are involved in processes within cells such as calcium homeostasis management, energy generation, response to stress, and cell demise pathways. In this work, a mathematical model with fuzzy boundary values has been developed to study the effect of Mitochondria and ER fluxes on free Calcium ions. The intended findings are displayed utilizing the physiological understanding that amyloid beta plaques and tangles of neurofibrillary fibers have been identified as the two main causes of AD. The key conclusion of the work is the investigation of [Formula: see text] for healthy cells and cells affected by Alzheimer's disease, which may aid in the study of such processes for computational scientists and medical practitioners. Also, it has been shown that when a unique solution is found for a specific precise problem, it also successfully deals with any underlying ambiguity within the problem by utilizing a technique based on the principles of linear transformation. Furthermore, the comparison between the analytical approach and the generalized hukuhara derivative approach is shown here, which illustrates the benefits of the analytical approach. The simulation is carried out in MATLAB.

Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity.

BACKGROUND & OBJECTIVES: The N-acetyltransferase 2 (NAT2) gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH). METHODS: In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs. RESULTS: Frequency of slow-acetylator genotype was commonly encountered and was not significantly different between DIH (82.8%) and non-DIH (77.2%) patients. However, the genotypic distribution of variant NAT2FNx015/FNx017 amongst slow-acetylator genotypes was significantly higher in DIH (56%) group as compared to non-DIH (39%) group (odds ratio 2.02; P=0.006). INTERPRETATION & CONCLUSIONS: The present study demonstrated no association between NAT2 genotype and DIH in the north Indian patients with tuberculosis.

A Kernelized Classification Approach for Cancer Recognition Using Markovian Analysis of DNA Structure Patterns as Feature Mining.

Nucleotide-based molecules called DNA and RNA are essential for several biological processes that affect both normal and cancerous cells. They contain the critical genetic material needed for normal cell growth and functioning. The DNA structure patterns that make up the genetic code affect cells' growth, behavior, and control. Different DNA structure patterns indicate different physiological effects in the cell. Knowledge of these patterns is necessary to identify the molecular origins of cancer and other disorders. Analyzing these patterns can help in the early detection of diseases, which is essential for the effectiveness of cancer research and therapy. The novelty of this study is to examine the patterns of dinucleotide structure in many genomic regions, including the non-coding region sequence (N-CDS), coding region sequence (CDS), and whole raw DNA sequence (W.R. sequence). It provides an in-depth discussion of dinucleotide patterns related to these diverse genetic environments and contains malignant and non-malignant DNA sequences. The Markovian modeling that predicts dinucleotide probabilities also reduces feature complexity and minimizes computational costs compared to the approaches of Kernelized Logistic Regression (KLR) and Support Vector Machine (SVM). This technique is effectively evaluated in essential case studies, as indicated by accuracy metrics and 10-fold cross-validation. The classifier and feature reduction, which are generated by Markovian probability, operate well together and can help predict cancer. Our findings successfully distinguish DNA sequences related to cancer from those diagnostics of non-cancerous diseases by analyzing the W.R. DNA sequence as well as its CDS and N-CDS regions.

A Comprehensive Fuzzy Model for Understanding Neuronal Calcium Distribution in Presence of VGCC, Na+/Ca2+ Exchanger, Buffer, and ER Fluxes.

Free Calcium ions in the cytosol are essential for many physiological and physical functions. The free calcium ions are commonly regarded as a second messenger, are an essential part of brain communication. Numerous physiological activities, such as calcium buffering and calcium ion channel flow, etc. influence the cytosolic calcium concentration. In light of the above, the primary goal of this study is to develop a model of calcium distribution in neuron cells when a Voltage-Gated Calcium Channel and Sodium Calcium Exchanger are present. As we know, decreased buffer levels and increased calcium activity in the Voltage-Gated Calcium Channel and Sodium Calcium Exchanger lead to Alzheimer's disease. Due to these changes, the calcium diffusion in that location becomes disrupted and impacted by Alzheimer's disease. The model has been constructed by considering key factors like buffers and ER fluxes when Voltage-Gated Calcium Channels and Sodium Calcium Exchangers are present. Based on the physiological conditions of the parameters, appropriate boundary conditions have been constructed in the fuzzy environment. This model is considered a fuzzy boundary value problem with the source term and initial boundary conditions are modeled by triangular fuzzy functions. In this, paper we observed the approximate solution of the mathematical model which was investigated by the fuzzy undetermined coefficient method. The solution has been performed through MATLAB and numerical results have been computed using simulation. The observation made that the proper operation of the Voltage-Gated Calcium Channel and Sodium Calcium Exchanger is critical for maintaining the delicate equilibrium of calcium ions, which regulates vital cellular activities. Dysregulation of Voltage-Gated Calcium Channel and Sodium Calcium Exchanger activity has been linked to neurodegenerative illnesses like Alzheimer's disease.

2D dynamic analysis of the disturbances in the calcium neuronal model and its implications in neurodegenerative disease.

Ca2+ signaling is an essential function of neurons to control synaptic activity, memory formation, fertilization, proliferation, etc. Protein and voltage-dependent calcium channels (VDCCs) maintain an adequate level of calcium concentration ([Ca2+]). An alteration in [Ca2+] leads to the death of the neurons that start the primary symptoms of the disease. The present study deals with cell memory-based mathematical modeling of Ca2+ that is characterized by the presence of protein and VDCC. We developed a two-dimensional Ca2+ neuronal model to study the spatiotemporal behavior of the Ca2+ profile. All principal parameters like buffer concentration, diffusion coefficient, VDCC fluxes, etc. are incorporated in this model. Apposite initial and boundary conditions are applied to the physiology of the problem. We obtained an approximate Ca2+ profile by the fractional integral transform method. The application of obtained results is performed to provide its implications to estimate the [Ca2+] in neurodegenerative disease. It is observed that the protein and VDCC provide a significant impact in the presence of cell memory. The memory of cells shrinks the Ca2+ flow from elevation and provides better results to estimated Ca2+ flow in the disease state.

Modelling and analysis of fractional-order vaccination model for control of COVID-19 outbreak using real data.

In this paper, we construct the SV1V2EIR model to reveal the impact of two-dose vaccination on COVID-19 by using Caputo fractional derivative. The feasibility region of the proposed model and equilibrium points is derived. The basic reproduction number of the model is derived by using the next-generation matrix method. The local and global stability analysis is performed for both the disease-free and endemic equilibrium states. The present model is validated using real data reported for COVID-19 cumulative cases for the Republic of India from 1 January 2022 to 30 April 2022. Next, we conduct the sensitivity analysis to examine the effects of model parameters that affect the basic reproduction number. The Laplace Adomian decomposition method (LADM) is implemented to obtain an approximate solution. Finally, the graphical results are presented to examine the impact of the first dose of vaccine, the second dose of vaccine, disease transmission rate, and Caputo fractional derivatives to support our theoretical results.

To study the effect of ER flux with buffer on the neuronal calcium.

Calcium signaling is decisive for cellular functions. This calcium random walk stipulates neuronal functions. Calcium concentration could provoke gene transcription, apoptosis, neuronal plasticity, etc. A malformation in calcium could change the neuron's intracellular behavior. Calcium concentration balancing is a complex cellular mechanism. This occurrence can be handled with the Caputo fractional reaction-diffusion equation. In this mathematical modeling, we have included the STIM-Orai mechanism and Endoplasmic Reticulum (ER) flux, Inositol Triphosphate Receptor (IPR), SERCA, plasma membrane flux, voltage-gated calcium entry, and different buffer interactions. A hybrid integral transform and Green's function approach were taken to solve the initial boundary problem. A closed-form solution of a Mittag-Leffler family function plotted using MATLAB software. Different parameters impact changes in the spatiotemporal behavior of the calcium concentration. Specific roles of organelles involved in Alzheimer's disease-affected neurons are computed. Ethylene glycol tetraacetic acid (EGTA), 1,2-bis(o-aminophenoxy)ethane N,N,N,N-tetraacetic acid (BAPTA), and S100B protein effects are also observed. In all simulations, we can say S100B and the STIM-Orai effect cannot be neglected. This model lights up the different approaches for calcium signaling pathway simulation. As a consequence, we determine that a generalized reaction-diffusion approach is a better fit realistic model.

Prevalence of multidrug-resistant tuberculosis among newly diagnosed cases of sputum-positive pulmonary tuberculosis.

BACKGROUND & OBJECTIVES: The prevalence of multidrug-resistant tuberculosis (MDR-TB) is increasing throughout the world. Although previous treatment for TB is the most important risk factor for development of MDR-TB, treatment-naοve patients are also at risk due to either spontaneous mutations or transmission of drug-resistant strains. We sought to ascertain the prevalence of MDR-TB among new cases of sputum-positive pulmonary TB. METHODS: This was a prospective, observational study involving newly diagnosed cases of sputum-positive pulmonary tuberculosis diagnosed between 2008 and 2009 carried out in New Delhi, India. All sputum-positive TB cases were subjected to mycobacterial culture and first-line drug-susceptibility testing (DST). MDR-TB was defined as TB caused by bacilli showing resistance to at least isoniazid and rifampicin. RESULTS: A total of 218 cases of sputum-positive pulmonary tuberculosis were enrolled between 2008 and 2009. Of these, 41 cases had negative mycobacterial cultures and DST was carried out in 177 cases. The mean age of the patients was 27.8 ± 10.2 yr; 59 patients (27%) were female. All patients tested negative for HIV infection. Out of 177 cases, two cases of MDR-TB were detected. Thus, the prevalence of MDR-TB among newly diagnosed pulmonary tuberculosis patients was 1.1 per cent. INTERPRETATION & CONCLUSIONS: MDR-TB prevalence is low among new cases of sputum-positive pulmonary TB treated at primary care level in Delhi. Nation-wide and State-wide representative data on prevalence of MDR-TB are lacking. Efforts should be directed towards continued surveillance for MDR-TB among newly diagnosed TB cases.

Brivaracetam: How Well Does It Fare as an Anti-Epileptic? A Review.

OBJECTIVES: Epilepsy is a common neurological ailment contributing to significant disability. About one-third of all epilepsy patients would be refractory to two or more medications. Brivaracetam (BRV) is one of the newer anti-seizure medications on which extensive data is available, but its efficacy as an early add-on agent (first/second adjuvant) is unclear. The principal objective of this review is to assess the efficacy of BRV as an early add-on agent in refractory Focal Onset Seizures (FOS) and its pharmacology and usage in various clinical situations associated with seizures. METHODS: We searched two databases, Medline and Cochrane Central, for papers on BRV and FOS, and selected six studies with randomized parallel control design to extract the data for a meta-analysis. We also did a comprehensive review of the available literature on its pharmacology and usage in various clinical scenarios associated with seizures. RESULTS: For the meta-analysis, we extracted 145 articles; six studies fulfilled the selection criteria that gave us data on 1938 patients who received Brivaracetam as an early add-on agent in FOS. The Risk Ratio (RR) (95% CI) for 50% responders across the trials was 1.88 (1.55-2.29). Similarly, the overall RR (95% CI) was 5.82 (2.15-15.70) for seizure freedom. CONCLUSION: Our analysis provides moderate evidence for Brivaracetam as an effective agent as an early adjuvant in FOS. Its efficacy for several other indications needs further clinical trials and evaluation.

Mathematical Modeling of Calcium Oscillatory Patterns in a Neuron.

Calcium oscillations are an imperative mode of signaling phenomenon. These oscillations are due to the active interactions taking place between some of the parameters like voltage gated calcium channels (VGCC), sodium calcium exchanger (NCX), calcium binding buffers, endoplasmic reticulum (ER) and mitochondria. The present paper focuses on the problem of higher level of calcium concentration in neurons which may further result into Alzheimer's Disease (AD). For this, a three-dimensional mathematical model having a system of differential equations depicting the changes in cytosolic calcium (in presence of buffers, VGCC and NCX), ER calcium and mitochondrial calcium, is formulated. A three-dimensional neuronal structure is targeted as the domain which is further discussed and solved using finite element technique in Comsol Multiphysics 5.4. Apposite boundary conditions matching well with the in-situ conditions are assumed. The obtained results clearly show the significance of the lower amount of the buffer and higher calcium mediated activities of VGCC, NCX, ER and mitochondria on calcium profile. These changes may lead to AD. To transit from AD condition to normal, exogenous buffers are added to check their significance. The results thus show that the replenishment of buffer may balance the amount of cell calcium and hence can affect positively on Alzheimer's affected cells.

Evaluation of risk factors for antituberculosis treatment induced hepatotoxicity.

BACKGROUND & OBJECTIVES: Antituberculosis (anti-TB) drug induced hepatotoxicity (DIH) is the most common side effect leading to interruption of therapy. Wide variations have been found in the reported incidence of hepatotoxicity during short-course chemotherapy. Several risk factors for hepatotoxicity have been suggested in previous studies. We undertook a prospective case-control study to assess the role of these putative risk factors in the development of DIH in patients receiving anti-TB treatment. METHODS: One hundred and seventy five consecutive cases with a diagnosis of anti-TB DIH were compared with 428 consecutive controls who took anti-TB drugs for the full duration of chemotherapy without clinical or biochemical evidence of hepatitis. Cases positive for markers of acute viral hepatitis were carefully excluded. Cases and controls were compared with respect to age, sex, site of tuberculosis, radiological extent of disease on chest radiograph, body mass index (BMI), mid-arm circumference (MAC) and liver function at baseline which included serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), serum total protein and serum albumin. RESULTS: Univariate logistic regression revealed that the risk of developing DIH was greater in older patients. Significantly greater percentage of cases had extrapulmonary tuberculosis (TB) (P<0.01). Also, a significantly higher percentage of cases had moderate to far advanced disease severity on chest radiograph (P<0.01). On multivariate logistic regression, the adjusted odds were significant (P<0.01) for age>35 yr, MAC<20 cm and hypoalbuminaemia (albumin<3.5 g/dl). INTERPRETATION & CONCLUSIONS: Older age, poor nutritional status including baseline hypoalbuminaemia were independent predictors of occurrence of anti-TB DIH. Clinicians should be vigilant for occurrence of hepatotoxicity in this high risk group.

Study of Antibiotic Susceptibility among Bacterial Isolates in Neonatal Intensive Care Unit of a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

INTRODUCTION: Neonatal sepsis is a major cause of neonatal morbidity and mortality worldwide, especially in developing countries like Nepal. Antibiotic resistance among microorganisms poses new challenges in the treatment of neonatal sepsis. The present study is conducted with the objectives of determining clinico-bacteriological profile and antibiotic susceptibility among isolated bacteria in a neonatal intensive care unit. METHODS: A descriptive cross-sectional study was conducted from January 1, 2017, to December 31, 2019, in the neonatal intensive care unit of a tertiary care hospital after obtaining ethical clearance from Institutional Review Committee (Reference Number: 2020-064). The sample size was calculated and 77 neonates with culture-proven sepsis were included in the study. The antibiotic susceptibility tests of the isolates were done by Kirby-Bauer disc diffusion method. Data entry was done in Statistical Packages for the Social Sciences version 20. RESULTS: Of the 841 specimens (blood, cerebrospinal fluid, urine, tracheal aspirate and pus) processed for culture, bacteria were isolated in 84 (10.0%) specimens. Among the 84, gram-negative bacilli were the predominant isolates 76 (90.5%); of which Acinetobacter baumannii was the most common 27 (32.1%). Both the Gram-negative and the Gram-positive bacteria showed high resistance to Penicillin and Cephalosporins. Gram-negative bacteria showed maximum sensitivity to Colistin, Carbapenems, Tigecycline and Fluoroquinolones. Gram-positive bacteria showed maximum susceptibility to Amikacin, Vancomycin and Carbapenems. CONCLUSIONS: Judicious use of antibiotics based on the updated knowledge of prevalent organisms in the local hospital setting and their antibiotic sensitivity pattern is of utmost importance for the effective treatment of neonatal sepsis.

Portraying the Effect of Calcium-Binding Proteins on Cytosolic Calcium Concentration Distribution Fractionally in Nerve Cells.

Nerve cells like neurons and astrocytes in central nervous system (CNS) take part in the signaling process which means the transformation of the information from one cell to another via signals. The signaling process is affected by various external parameters like buffers calcium-binding proteins, voltage-gated calcium channel. In the present paper, the role of buffers in the cytoplasmic calcium concentration distribution is shown. The elicitation in calcium concentration is due to the presence of lower amount calcium-binding proteins which can be shown graphically. The mathematical model is designed by keeping in mind the physiological condition taking place in CNS of mammalian brain. The thing to be noted here is that the more elicitation in the calcium concentration distribution results in the cell death which finally give neurodegenerative disease to the mammalian brain. The present paper gives a glimpse of Parkinson's diseases in particular. Computational results are performed in Wolfram Mathematica 9.0 and simulated on core(TM) i5-3210M CPU @ 2.50 GHz processing speed and 4 GB memory. It is found that the different types of buffer like ethylene glycol-bis([Formula: see text]-aminoethyl ether)-N,N,N',N'-tetraacetic acid, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and calmodulin have noteworthy effect at different fractions of time.

Incidence of metallo-beta-lactamase producing clinical isolates of Escherichia coli and Klebsiella pneumoniae in central Nepal.

BACKGROUND: The increasing and rapid spread of metallo-beta-lactamase (MBL) producing Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae represents an emerging public health threat. However, limited data is available on MBL production in clinical isolates of E. coli and K. pneumoniae from Nepal. We have therefore undertaken this study to ascertain the incidence of MBL production in clinical isolates of E. coli and K. pneumoniae at a tertiary care teaching hospital in central Nepal. METHODS: A total of 401 consecutive, non-duplicate isolates of E. coli (n = 216) and K. pneumoniae (n = 185) were recovered from various clinical samples between July and December, 2012. These isolates were screened for the detection of carbapenemase production on the basis of their reduced susceptibility to meropenem or ertapenem by the disc diffusion method. The screened isolates were further phenotypically studied for carbapenemase production by modified Hodge test (MHT). MBL production was detected by performing combined disc test by using imipenem discs with and without ethylenediaminetetraacetic acid (EDTA), which chelates zinc required for MBL activity. RESULTS: Out of 216 E. coli isolates, a total of 41 isolates (18.98%) and out of 185 K. pneumoniae isolates, a total of 39 isolates (21.08%) were suspected to be carbapenemase- producers on the basis of their reduced susceptibility to meropenem or ertapenem. Interestingly, all the initially suspected isolates of E. coli and K. pneumoniae for carbapenemase production were found to be positive in both MHT and combined disc test. However, few weakly positive reactions were observed in MHT. All the MBL producing isolates were multidrug-resistant (MDR). In addition, 75.60% E. coli and 71.79% of K. pneumoniae isolates producing MBL were found to be "pandrug- resistant". CONCLUSIONS: Our findings showed MBL production in a considerable number of E. coli and K. pneumoniae isolates with MDR and pandrug-resistant phenotypes. Combined disc method can provide a sensible choice for phenotypic detection of MBL production in clinical microbiology laboratories as detection of MBL in bacterial isolates is indispensable for establishing the effective antibiotic policies and infection control strategies in the hospital setting.