Exploring the utility of EUS in Budd-Chiari syndrome: a multicenter multiobserver prospective cohort study.

BACKGROUND AND AIMS: The diagnosis of Budd-Chiari syndrome (BCS) is essentially radiologic and is needed to plan appropriate therapy. We therefore conducted this proof of concept study to assess the utility of EUS in assessing the anatomy of BCS. METHODS: This prospective, multicenter, observational study enrolled 50 consecutive patients with a diagnosis of BCS. All patients underwent a detailed EUS examination by 3 independent endosonographers, blinded to the anatomic details of BCS and others' findings. The EUS examination was compared between the endosonographers and with conventional angiography (where available) or magnetic resonance venography (MRV). Outcomes assessed were interobserver agreement, sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy in diagnosing pathologic lesions of BCS. RESULTS: Fifty BCS patients (mean age, 34 years [range, 13-65]) underwent EUS. Results showed good agreement among endosonographers for diagnosing right hepatic vein (κ = .716) and left hepatic vein lesions (κ = .722), moderate agreement for middle hepatic vein lesions (κ = .660), and very good agreement for inferior vena cava (IVC) lesions (κ = .823). EUS demonstrated high sensitivity and positive predictive value, low interobserver variability, and overall diagnostic accuracy for BCS lesions. CONCLUSIONS: EUS is a safe and accurate diagnostic tool for BCS. It can provide accurate mapping of hepatic veins, intrahepatic collaterals, and the IVC.

Pattern selection mechanism from the equilibrium point and limit cycle.

The outbreak of infectious diseases often exhibits periodicity, and this periodic behavior can be mathematically represented as a limit cycle. However, the periodic behavior has rarely been considered in demonstrating the cluster phenomenon of infection induced by diffusion (the instability modes) in the SIR model. We investigate the emergence of Turing instability from a stable equilibrium and a limit cycle to illustrate the dynamical and biological mechanisms of pattern formation. We identify the Hopf bifurcation to demonstrate the existence of a stable limit cycle using First Lyapunov coefficient in our spatiotemporal diffusion-driven SIR model. The competition between different instability modes induces different types of patterns and eventually spot patterns emerge as stable patterns. We investigate the impact of susceptible, infected, and recovered individuals on the type of patterns. Interestingly, these instability modes play a vital role in selecting the pattern formations, which is directly related to the number of observed spot patterns. Subsequently, we explain the dynamical and biological mechanisms of spot patterns to develop an effective epidemic prevention strategy.

Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model.

Mitochondria are vital organelles inside the cell and contribute to intracellular calcium (Ca2+) dynamics directly and indirectly via calcium exchange, ATP generation, and production of reactive oxygen species (ROS). Arrhythmogenic Ca2+ alternans in cardiac myocytes has been observed in experiments under abnormal mitochondrial depolarization. However, complex signaling pathways and Ca2+ cycling between mitochondria and cytosol make it difficult in experiments to reveal the underlying mechanisms of Ca2+ alternans under abnormal mitochondrial depolarization. In this study, we use a newly developed spatiotemporal ventricular myocyte computer model that integrates mitochondrial Ca2+ cycling and complex signaling pathways to investigate the mechanisms of Ca2+ alternans during mitochondrial depolarization. We find that elevation of ROS in response to mitochondrial depolarization plays a critical role in promoting Ca2+ alternans. Further examination reveals that the redox effect of ROS on ryanodine receptors and sarco/endoplasmic reticulum Ca2+-ATPase synergistically promote alternans. Upregulation of mitochondrial Ca2+ uniporter promotes Ca2+ alternans via Ca2+-dependent mitochondrial permeability transition pore opening. Due to their relatively slow kinetics, oxidized Ca2+/calmodulin-dependent protein kinase II activation and ATP do not play significant roles acutely in the genesis of Ca2+ alternans after mitochondrial depolarization, but their roles can be significant in the long term, mainly through their effects on sarco/endoplasmic reticulum Ca2+-ATPase activity. In conclusion, mitochondrial depolarization promotes Ca2+ alternans acutely via the redox effect of ROS and chronically by ATP reduction. It suppresses Ca2+ alternans chronically through oxidized Ca2+/calmodulin-dependent protein kinase II activation.

Bioconjugate-loaded solid lipid nanoparticles for enhanced anticancer drug delivery to brain cancer cells: An in vitro evaluation.

Background & objectives: The treatment of brain cancer is still challenging for an oncologist due to the presence of the blood-brain barrier (BBB) which inhibits the entry of more than 98 per cent of drugs used during the treatment of brain disease. The cytotoxic drugs used in chemotherapy for brain cancer treatment also affect the normal cells due to lack of targeting. Therefore, the objective of the study was to develop tween 80-coated solid lipid nanoparticles (SLNs) loaded with folic acid-doxorubicin (FAD) conjugate for site-specific drug delivery to brain cancer cells. Methods: The FAD conjugate was synthesized by the conjugation of folic acid with doxorubicin and characterized by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. SLNs loaded with FAD were prepared by the solvent injection method. The SLNs were characterized by the particle size, zeta potential, surface morphology, entrapment efficiency, etc. Results: The average particle size of FAD conjugate-loaded SLNs (SLN-C) was found to be 220.4±2.2 nm, with 36.2±0.6 per cent entrapment efficiency. The cytotoxicity and cellular uptake were determined on U87 MG cell lines. Half maximal inhibitory concentration value of the SLN-C was found to be 2.5 µg/ml, which confirmed the high antitumour activity against brain cancer cells. Interpretation & conclusions: The cell line studies confirmed the cytotoxicity and internalization of SLN-C in U87 MG brain cancer cells. The results confirmed that tween 80-coated SLNs have the potential to deliver the doxorubicin selectively in the brain cancer cells.

Nisin and nisin-loaded nanoparticles: a cytotoxicity investigation.

OBJECTIVE: Nisin is an antibacterial peptide with anticancer properties, but the main drawback is its rapid enzymatic degradation and limited permeation across the cell membrane. This research aims to overcome these drawbacks by developing nisin-loaded nanoparticles (NPN) with improved cytotoxic effects. SIGNIFICANCE: PLGA nanoparticles are one of the most effective biodegradable and biocompatible drug delivery carriers. In the present study, nisin-loaded nanoparticles showed enhanced anticancer effects. METHODS: NPN was prepared by a double emulsion solvent evaporation method and characterized for different parameters. The cytotoxic investigation of NPN was carried out on various cell lines, including A549, SW-620, HT-29, PC-3, MDA-MB-231, MCF-7, MiaPaca-2, and fR2 by sulforhodamine B (SRB) assay. Mechanistic investigation of cellular cytotoxicity was performed by using bright-field microscopy, DAPI staining, intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (ΔΨm), Western blotting and cellular uptake study. A comparative cytotoxicity study of nisin and NPN was performed on normal breast epithelial cells (fR2). RESULTS: NPN showed spherical shape, 289.09 ± 3.63 nm particle size, and 63.37 ± 3.12% entrapment efficiency. NPN was more cytotoxic to the MDA-MB-231 cell line, showing higher nuclear fragmentation, ROS generation, depletion of ΔΨm, and enhanced intracellular uptake with apoptosis signs compared with nisin and with no cytotoxicity on normal cells. CONCLUSIONS: The findings suggest that nisin delivery via PLGA nanoparticles can be used to treat cancer without significant effects on healthy cells.

Pattern mechanism in stochastic SIR networks with ER connectivity.

The diffusion of the susceptible and infected is a vital factor in spreading infectious diseases. However, the previous SIR networks cannot explain the dynamical mechanism of periodic behavior and endemic diseases. Here, we incorporate the diffusion and network effect into the SIR model and describes the mechanism of periodic behavior and endemic diseases through wavenumber and saddle-node bifurcation. We also introduce the standard network structured entropy (NSE) and demonstrate diffusion effect could induce the saddle-node bifurcation and Turing instability. Then we reveal the mechanism of the periodic outbreak and endemic diseases by the mean-field method. We provide the Turing instability condition through wavenumber in this network-organized SIR model. In the end, the data from COVID-19 authenticated the theoretical results.

Study of Serum Cystatin C and Serum Creatinine in Different Stages of Chronic Kidney Disease Patients.

There is lack of consistent surrogate markers of kidney function to identify established disease, especially in early stages of CKD. Creatinine remains within normal levels until a significant reduction in renal function has occured. Cystatin C appears to be unaffected by muscle mass, diet, or gender. Its clearance is only by glomerular filtration. The plasma concentration is not influenced by inflammation or liver disease. It is not affected by optical interferences. Considering these benefits, it is more useful when trying to detect mild to moderate impairment of kidney function. MATERIAL: An observational, analytical study was conducted over a duration of 18 months. The study participants were divided into 2 groups based on eGFR. OBSERVATION: 67.5% patients had raised Cystatin C as compared to only 12.5% who had raised Creatinine. In our study, we found that Serum Creatinine (r=-0.85, p< 0.001) was better than Cystatin C (r=-0.55, p< 0.001) in all stages of CKD. However, in patients with eGFR ≥ 60 ml/min/m2. Cystatin C (r = -0.68, p<0.001) was a more sensitive marker to detect renal dysfunction at an early stage as compared to Serum Creatinine (r = -0.48, p<0.001). Overall, the AUC (Area Under the Curve) for Serum Creatinine is more than Cystatin C. However, in patients with eGFR≥ 60ml/ min/1.73m2, AUC for cystatin C is more. Thus, Cystatin C is more sensitive than Serum Creatinine to detect early renal dysfunction. CONCLUSION: We found out that both serum creatinine and serum cystatin C were significantly increased across CKD groups but cystatin C is a better predictor of CKD than creatinine in stages with eGFR≥60 ml/min/1.73 m2 as serum cystatin C was found to be raised contrary to serum creatinine which was within normal limits, although in stages with eGFR<60 ml/min/1.73 m2 there was no significant difference between the two. We found out that normal serum creatinine levels during the stage of kidney disease with eGFR≥60 ml/min/1.73 m2 does not necessarily mean normal renal function. Cystatin C should be encouraged as a screening tool for early renal impairment in the patient as the risk of developing CKD, especially in long-standing hypertensive and diabetic patients as an adjunct to creatinine estimation. It should also be included in the management protocol for these patients.

Lactate-free AARC ACLF Score (LaFAS) - A Simple Userfriendly Score is the Best Prognostic Marker for Patients with Alcohol Induced ACLF in Western Indian Population in a Nontransplant Resource-limited Setting.

INTRODUCTION: Acute-on-Chronic liver failure (ACLF) is a disease with a distinct spectrum of liver injury, with a rapid downhill course Here we describe three new scores - Albumin Bilirubin Index (ALBI), platelet albumin bilirubin index (PALBI) and Lactate-free AARC ACLF score(LaFAS), in predicting short-term mortality in patients with alcohol induced ACLF when compared to standard validated scores. METHODS: Consecutive patients diagnosed as alcohol induced ACLF as per the APASL 2014 definition were included in the study. Standard scores - MELD, MELD-Na, Maddreys' discriminant function, CLIF-OF and CLIF-C ACLF scores, APACHE II, ALBI, PALBI and LaFAS were calculated. The endpoints of the study were to predict short term mortality in alcohol induced ACLF patients using ALBI, PALBI and LaFAS and finding the cut-offs of these new scores and comparing it with standard validated scores. RESULTS: 67 patients were studied with 97% being male. Mean age was 45.78 + 8.15 years.44 patients died. The cut-offs, area under the ROC curve; sensitivity and specificity, positive and negative predictive values of the new prognostication scores were, respectively: ALBI (-0.57; 0.948; 90.9% and 82.6%; 77.69% and 93.15%),LaFAS(7; 0.968; 95.5% and 96.7%; 95.075 and 96.99%), PALBI(-0.28; 0.59; 61.4% and 52.2%; 46.13% and 66.98%). LaFAS and ALBI outnumbered the valid prognostic scores in predicting short-term mortality. PALBI underperformed when compared to all other scores. CONCLUSION: Thus incorporating albumin and bilirubin in a mathematical equation (for ALBI) or combining it with creatinine and grade of hepatic encephalopathy (for LaFAS) would help in prognosticate the patients with ACLF on admission in a resource limited setting thus enabling them to be transferred to a transplant center.

Predictors of 1-month and 3-months Hospital Readmissions in Decompensated Cirrhosis: A Prospective Study in a Large Asian Cohort.

INTRODUCTION AND AIM: Considered as a healthcare quality indicator, hospital readmissions in decompensated cirrhosis predispose the patients and the society to physical, social and economic distresses. Few studies involving North American cohorts have identified different predictors. The aim of this study was to determine and validate the predictors of 1-month and 3-months readmission in an Asian cohort. MATERIAL AND METHODS: We prospectively studied 281 hospitalised patients with decompensated cirrhosis at a large tertiary care public hospital in India between August 2014 and August 2016 and followed them for 3 months. Data regarding demographic, laboratory and disease related risk factors were compiled. We used multivariate logistic regression to determine predictors of readmission at 1-month and 3-months and receiver operating curves (ROC) for significant predictors to obtain the best cut-offs. RESULTS: 1-month and 3-months readmission rates in our study were 27.8% and 42.3%, respectively. Model for End stage Liver Disease (MELD) score at discharge (OR:1.24, p < 0.001) and serum sodium (OR:0.94, p-0.039) independently predicted 1-month and MELD score (OR:1.11, p-0.003), serum sodium (OR:0.94, p-0.027) and male gender (OR:2.19, p-0.008) independently predicted 3-months readmissions. Neither aetiology nor complications of cirrhosis emerged as risk factors. MELD score >14 at discharge and serum sodium < 133 mEq/L best predicted readmissions; MELD score being a better predictor than serum sodium (p - 0.0001). CONCLUSIONS: High rates of early and late readmissions were found in our study. Further, this study validated readmission predictors in Asian patients. Structured interventions targeting this risk factors may diminish readmissions in decompensated cirrhosis.

Topography of Vertebral Artery Origin Plaques: Characteristics and Determinants.

BACKGROUND: Atherosclerotic plaques located at the vertebral artery ostium (VAo) are a mechanism for posterior circulation stroke, but little is known about VAo plaque topography and formation. In this study, we describe the topography of atherosclerotic plaques involving the origin of the vertebral artery (VA). METHODS: Cross-sectional analyses of extracranial duplex studies were performed, and VAo plaques were classified based on their topography in 3 groups: (1) exclusively at the VA ostium; (2) predominantly subclavian, with extension into the vertebral ostium; and (3) predominantly ostial, with extension into the subclavian artery). Chi-square and analysis of variance tests were performed to investigate the association between VAo plaque topography and continuous and categorical variables, respectively. RESULTS: A total of 99 of 481 (21%) ultrasound duplex studies showed VAo plaques. The majority of the plaques (60%) were found to extend from the subclavian to the ostium. Plaques occurred more frequently at the medial wall of the VAo. No vascular risk factors were associated with plaque formation; however, women were more likely to have plaques involving predominantly or exclusively the VAo (P = .004). CONCLUSIONS: We describe 3 different patterns of VAo involvement in patients with ostial atherosclerotic VA disease. VAo plaques occurred almost exclusively at the medial wall of the vessel. Women had more plaques involving predominantly the origin. Prospective studies are needed to investigate the clinical significance of these findings.

Correlation of Computed Tomography of Colonic Wall Thickening with Colonoscopy.

INTRODUCTION: Computed Tomography of abdomen frequently shows bowel wall thickening with different grades and characteristic of thickening. The correlation of bowel wall thickening (BWT) with endoscopic findings is not well described in Indian population. Therefore we did this study to determine the correlation of BWT with endoscopic findings. METHODS: Its Prospective single center study with 85 Consecutive patients with age group more than 12 years with CT scan abdomen showing bowel wall thickening were included in the study. Colonoscopy was done subsequently within a span of 15 days with appropriate bowel preparation. Colonoscopic correlation was done in relation to site, degree and characteristic of thickening. Biopsies were taken at the site of visible abnormalities on endoscopy and from normal appearing mucosa in case of strong suspicious of disease. RESULTS: Total of 85 (37 men) consecutive symptomatic patients with colonic wall thickening on computed tomography underwent colonoscopy. The mean age group was 34.2 (SD±17.35) years. Endoscopy was normal in 20 patients (24%) and abnormal in 65 patients (76.5%). Patients with mild thickening were more likely to have normal endoscopy than those with moderate/severe thickening (19 versus 1 patient; p<0.001). The abnormality rate was similar across different bowel segments (left vs right side; 85.7% versus 76.5%, p< 0.57). Out of 65 patients with endoscopic abnormality, 41 (62.12%) had tuberculosis, 10 (15.16%) had malignancy. Most common cause of IC thickening was secondary to tuberculosis (n=40, 95.2%). CONCLUSION: A proportion of patients with thickening on CT scan, especially mild, may have normal colonoscopy. Patients should be counseled about the same prior to colonoscopy. However, colonoscopy should be done to rule out abnormality even when CT shows mild thickening.

Granulated colloidal silicon dioxide-based self-microemulsifying tablets, as a versatile approach in enhancement of solubility and therapeutic potential of anti-diabetic agent: formulation design and in vitro/in vivo evaluation.

The current research work was executed with an aim to explore and promote the potential of self-microemusifying drug delivery systems (SMEDDS) in the form of tablets, in order to enhance solubility and oral bioavailability of poorly aqueous soluble drug Repaglinide (RPG). RPG-loaded liquid SMEDDS were developed consisting Labrafil M 1944CS, Kolliphor EL and Propylene glycol, which were then characterized on various parameters. After characterization and optimization, liquid SMEDDS were converted into solid form by adsorbing on Aeroperl® 300 pharma and polyplasdoneTM XL. Further, selection of suitable excipients was done and mixed with prepared solidified SMEDDS powder followed by the preparation of self-microemulsifying tablets (SMET's) wet granulation-compression method. SMET's were subjected to differential scanning calorimetry (DSC) and particle X-ray diffraction (RXRD) studies, results of which indicated transformation of crystalline structure of RPG because of dispersion of RPG at molecular level in liquid SMEDDS. This was further assured by micrographs obtained from scanning electron microscope. SMET's shown more than 85% (30 min) of in vitro drug release in contrast to conventional marketed tablets (13.2%) and pure RPG drug (3.2%). Results of in vivo studies furnished that SMET's had shown marked decrease in the blood glucose level and prolonged duration of action (up to 8 h) in comparison with conventional marketed tablets and pure RPG drug. In conclusion, SMET's serves as a promising tool for successful oral delivery of poorly aqueous soluble drug(s) such as RPG.

Targeted SLNs for management of HIV-1 associated dementia.

CONTEXT: HIV-1 associated dementia (HAD) is an evolving disease in the category of neurological disorders. OBJECTIVE: Nifedipine-loaded solid lipid nanoparticles (SLNs) were developed and coated with Tween 80 to facilitate enhanced brain drug delivery for the treatment of HAD. MATERIALS AND METHODS: SLNs were prepared using solvent injection method. Lipids consisted of tristearin, hydrogenated soya phosphatidylcholine (HSPC) (1.5:1 w/w). Nifedipine was model drug in this study. Tween 80 (0.5% v/v) was taken as key modulator. SLNs were characterized for particle shape, size, zeta potential, entrapment efficiency, in vitro drug release, DNA fragmentation, cytotoxicity potential and in vivo studies. RESULTS: The SLNs (plain and coated) were found to be in nanometric in size (∼120 nm) with more than 70% entrapment efficiency. In vitro drug release profile reflected sustained release up to 48 h. Tween 80-coated SLNs showed higher percentage of DNA fragmentation in vitro and enhanced cell viability in sulforhodamine assay (rat cortical cells) as compared to plain drug and uncoated SLNs due to facilitated uptake of SLNs and reversal of P-gp efflux by virtue of Tween 80. Biodistribution study performed on vital organs, i.e. brain, heart, liver, spleen, lungs and kidney showed increased accumulation of Tween 80-coated SLNs in the brain. DISCUSSION AND CONCLUSION: Tween 80 enhanced localization of SLNs in the brain as compared to uncoated SLNs. This approach can be employed effectively to transport chemotherapeutics across the BBB for management of HIV-1 associated dementia and other ailments.

Assessment of metal-associated health risk in different trophic levels in tropical estuary on the southeast coast of India.

Metal contamination in coastal and marine ecosystems has become a significant global concern due to its hazardous characteristics, environmental persistence, and ability to bioaccumulate in aquatic ecosystems. This poses a serious threat to the environment and the health of humans worldwide. To address these concerns, this study estimated the concentrations of metals in various trophic levels, including phytoplankton, zooplankton, bivalve, and fish. Monthly sampling was carried out in Pondicherry Fishing Harbor (PFH) and Pondicherry Open Sea (POS) between January 2017 and December 2018. The value of Cd, Pb, Cr, Co, Ni, Cu, Zn, and Mn in sediment at the PFH was considerably higher compared to the POS, indicating the impact of human activity there. The contamination factor (CF) for other metals was <0.5, suggesting minor contamination in the Pondicherry coastal sediment, the CF value for Cd was higher at PFH. Comparably, the risk index (RI) at the PFH was likewise greater because of Cd, leading to an overall risk grade of "considerable" at the PFH whereas it was "low" at the POS. The marine pollution index (MPI) showed minimal values in fish regardless of the collection sites, which was calculated based on the values of all metals. The estimated daily intake, target hazard quotient, and hazard index assessed for potential human health risk suggest that the values were within acceptable thresholds for adults and children for fish consumption from POS. However, the direct consumption of bivalve for the long term poses significant non-carcinogenic health risks in both age groups, particularly in children, who are 1.31 times more susceptible than adults. These findings highlight the need to evaluate the presence of metals in the food chain to determine their transfer to the different trophic levels, which can help mitigate the associated risks for sustainable coastal ecosystem management.

A Novel Technique for Fluorescence Lifetime Tomography.

Fluorescence lifetime has emerged as a unique imaging modality for quantitatively assessing in vivo the molecular environment of diseased tissues. Although fluorescence lifetime microscopy (in 2D) is a mature field, 3D imaging in deep tissues remains elusive and challenging owing to scattering. Herein, we report on a deep neural network (coined AUTO-FLI) that performs both 3D intensity and quantitative lifetime reconstructions in deep tissues. The proposed Deep Learning (DL)-based approach involves an in silico scheme to generate fluorescence lifetime data accurately. The developed DL model is validated both in silico and on experimental phantoms. Overall, AUTO-FLI provides accurate 3D quantitative estimates of both intensity and lifetime distributions in highly scattering media, demonstrating its unique potential for fluorescence lifetime-based molecular imaging at the mesoscopic and macroscopic scale.

Inulin: Unveiling its potential as a multifaceted biopolymer in prebiotics, drug delivery, and therapeutics.

In recent years, inulin has gained much attention as a promising multifunctional natural biopolymer with numerous applications in drug delivery, prebiotics, and therapeutics. It reveals a multifaceted biopolymer with transformative implications by elucidating the intricate interplay between inulin and the host, microbiome, and therapeutic agents. Their flexible structure, exceptional targetability, biocompatibility, inherent ability to control release behavior, tunable degradation kinetics, and protective ability make them outstanding carriers in healthcare and biomedicine. USFDA has approved Inulin as a nutritional dietary supplement for infants. The possible applications of inulin in biomedicine research inspired by nature are presented. The therapeutic potential of inulin goes beyond its role in prebiotics and drug delivery. Recently, significant research efforts have been made towards inulin's anti-inflammatory, antioxidant, and immunomodulatory properties for their potential applications in treating various chronic diseases. Moreover, its ability to reduce inflammation and modulate immune responses opens new avenues for treating conditions such as autoimmune disorders and gastrointestinal ailments. This review will attempt to illustrate the inulin's numerous and interconnected roles, shedding light on its critical contributions to the advancement of healthcare and biomedicine and its recent advancement in therapeutics, and conclude by taking valuable insights into the prospects and opportunities of inulin.