Effect of Clemizole on Alpha-Synuclein-Preformed Fibrils-Induced Parkinson's Disease Pathology: A Pharmacological Investigation.

Parkinson's disease (PD) is a neurodegenerative disorder associated with mitochondrial dysfunctions and oxidative stress. However, to date, therapeutics targeting these pathological events have not managed to translate from bench to bedside for clinical use. One of the major reasons for the lack of translational success has been the use of classical model systems that do not replicate the disease pathology and progression with the same degree of robustness. Therefore, we employed a more physiologically relevant model involving alpha-synuclein-preformed fibrils (PFF) exposure to SH-SY5Y cells and Sprague Dawley rats. We further explored the possible involvement of transient receptor potential canonical 5 (TRPC5) channels in PD-like pathology induced by these alpha-synuclein-preformed fibrils with emphasis on amelioration of oxidative stress and mitochondrial health. We observed that alpha-synuclein PFF exposure produced neurobehavioural deficits that were positively ameliorated after treatment with the TRPC5 inhibitor clemizole. Furthermore, Clemizole also reduced p-alpha-synuclein and diminished oxidative stress levels which resulted in overall improvements in mitochondrial biogenesis and functions. Finally, the results of the pharmacological modulation were further validated using siRNA-mediated knockdown of TRPC5 channels, which also decreased p-alpha-synuclein expression. Together, the results of this study could be superimposed in the future for exploring the beneficial effects of TRPC5 channel modulation for other neurodegenerative disorders and synucleopathies.

Novel treatment with double scope technique for disconnected pancreatic duct syndrome with external pancreatic fistula.

Background and study aims External pancreatic fistula in association with disconnected pancreatic duct syndrome is a common sequelae of the percutaneous step-up approach for infected pancreatic necrosis and is associated with significant morbidity. The present study aimed to report the initial outcome of a novel technique of two-scope guided tractogastrostomy for management of this condition. Patients and methods The present study was a retrospective analysis of data from patients with external pancreatic fistula and disconnected pancreatic duct syndrome, who underwent two-scope-guided tractogastrostomy. All the patients had a 24F or larger drain placed in the left retroperitoneum. Transgastric echo endoscopy and sinus tract endoscopy were performed simultaneously to place a stent between the gastric lumen and the sinus tract. Technical success was defined as placement of the stent between the tract and the stomach. Clinical success was defined as successful removal of the percutaneous drain without the occurrence of pancreatic fluid collection, ascites, external fistula, or another intervention 12 weeks after the procedure. Results Three patients underwent two scope-guided tractogastrostomy. Technical and clinical success were achieved in all the patients. No procedure-related side effects or recurrence occurred in any of the patients. Conclusions Two-scope-guided tractogastrostomy for treatment of external pancreatic fistula due to disconnected pancreatic duct syndrome is a feasible technique and can be further evaluated.

Ophthalmologic profile of patients with systemic sclerosis.

PURPOSE: To study the ophthalmologic manifestations of systemic sclerosis (SSc) and its correlation with autoantibody profile. METHODS: A cross-sectional study on 200 eyes of 100 consecutive adult patients diagnosed with SSc was performed at a tertiary care center in Northern India. The examination of ocular adnexa, anterior segment, and posterior segment with slit-lamp biomicroscopy, tear film break-up time (TBUT), Schirmer's II test, and choroidal thickness measurement by swept-source ocular coherence tomography was done. Autoantibody profile was available for 85 patients, and its statistical association with the ocular examination findings was analyzed. RESULTS: In total, 100 patients (93 females and 7 males) were included. The mean age was 45.11 ± 11.68 years, and the mean disease duration was 6.93 ± 3.68 years. Meibomian gland disease was more commonly found in patients with the diffuse subtype of SSc (P = 0.037). Choroidal thickness was increased in 34% and decreased in 7% (reference range = 307 ± 79 mm) patients. Reduced TBUT, meibomian gland dysfunction, and eyelid stiffness had a statistically significant association with the presence of anti-Scl-70 antibody (P = 0.003, <0.0001, and 0.004, respectively). These patients had ocular fatigue, foreign body sensation, and burning sensation. No significant association was noted with the presence of SS-A/Ro and SS-B/La antibodies. CONCLUSION: This study highlights the need for an active comprehensive ophthalmic evaluation. Approximately 75% of the patients in our cohort had ocular involvement to varying extent. An isolated presence of anti-Scl70 antibody was also found to have a positive association with dry eye disease.

Multifunctional 58S Bioactive Glass/Silver/Cerium Oxide-Based Biocomposites with Effective Antibacterial, Cytocompatibility, and Mechanical Properties.

58S bioactive glass (BG) has effective biocompatibility and bioresorbable properties for bone tissue engineering; however, it has limitations regarding antibacterial, antioxidant, and mechanical properties. Therefore, we have developed BGAC biocomposites by reinforcing 58S BG with silver and ceria nanoparticles, which showed effective bactericidal properties by forming inhibited zones of 2.13 mm (against Escherichia coli) and 1.96 mm (against Staphylococcus aureus; evidenced by disc diffusion assay) and an increment in the antioxidant properties by 39.9%. Moreover, the elastic modulus, hardness, and fracture toughness were observed to be increased by ∼84.7% (∼51.9 GPa), ∼54.5% (∼3.4 GPa), and ∼160% (∼1.3 MPam1/2), whereas the specific wear rate was decreased by ∼55.2% (∼1.9 × 10-11 m3/Nm). X-ray diffraction, high-resolution transmission electron microscopy, and field emission scanning electron microscopy confirmed the fabrication of biocomposites and the uniform distribution of the nanomaterials in the BG matrix. The addition of silver nanoparticles in the 58S BG matrix (in BGA) increased mechanical properties by composite strengthening and bactericidal properties by damaging the cytoplasmic membrane of bacterial cells. The addition of nanoceria in 58S BG (BGC) increased the antioxidant properties by 44.5% (as evidenced by the 2,2-diphenyl-1-picrylhydrazyl assay). The resazurin reduction assay and MTT assay confirmed the effective cytocompatibility for BGAC biocomposites against mouse embryonic fibroblast cells (NIH3T3) and mouse bone marrow stromal cells. Overall, BGAC resulted in mechanical properties comparable to those of cancellous bone, and its effective antibacterial and cytocompatibility properties make it a good candidate for bone healing.

Isolated cavernous venous malformation of the eyelid.

Cavernous hemangioma, currently known as "cavernous venous malformation," is a common, benign, non-infiltrative, slowly progressive vascular malformation of the orbit presenting in adults. We report the case of a 9-year-old girl who presented with a painless palpable mass over the right upper eyelid of 7 years' duration. A computed tomography scan of the orbits revealed a heterogeneously enhancing, well-circumscribed mass in the right upper eyelid with no orbital extension. A transcutaneous excisional biopsy with histopathology disclosed cavernous venous malformation. The majority of cavernous venous malformations are intraconal and present in the fourth to fifth decade of life.

Contrast Enhanced CT Versus MRI for Accurate Diagnosis of Wall-thickening Type Gallbladder Cancer.

Introduction: Diagnosis of wall-thickening type gallbladder cancer (GBC) is challenging. Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly utilized to evaluate gallbladder wall thickening. However, there is a lack of data comparing the performance of CT and MRI for the detection of wall-thickening type GBC. Aim: We aim to compare the diagnostic accuracy of CT and MRI in diagnosis of wall-thickening type GBC. Materials and methods: This prospective study comprised consecutive patients suspected of wall-thickening type GBC who underwent preoperative contrast-enhanced CT and MRI. The final diagnosis was based on the histopathology of the resected gallbladder lesion. Two radiologists independently reviewed the characteristics of gallbladder wall thickening at CT and MRI. The association of CT and MRI findings with histological diagnosis and the interobserver agreement of CT and MRI findings were assessed. Results: Thirty-three patients (malignancy, 13 and benign, 20) were included. None of the CT findings were significantly associated with GBC. However, at MRI, heterogeneous enhancement, indistinct interface with the liver, and diffusion restriction were significantly associated with malignancy (P = 0.006, <0.001, and 0.005, respectively), and intramural cysts were significantly associated with benign lesions (P = 0.012). For all MRI findings, the interobserver agreement was substantial to perfect (kappa = 0.697-1.000). At CT, the interobserver agreement was substantial to perfect (k = 0.631-1.000). Conclusion: These findings suggest that MRI may be preferred over CT in patients with suspected wall thickening type GBC. However, larger multicenter studies must confirm our findings.

Venous Thrombosis in Acute Pancreatitis: What to and Not to Do?

Acute pancreatitis is an acute inflammatory condition of the pancreas that has not only local but systemic effects as well. Venous thrombosis is one such complication which can give rise to thrombosis of the peripheral vasculature in the form of deep vein thrombosis, pulmonary embolism, and splanchnic vein thrombosis. The prevalence of these complications increases with the severity of the disease and adds to the adverse outcomes profile. With better imaging and awareness, more cases are being detected, although many at times it can be an incidental finding. However, it remains understudied and strangely, most of the guidelines on the management of acute pancreatitis are silent on this aspect. This review offers an overview of the incidence, pathophysiology, symptomatology, diagnostic work-up, and management of venous thrombosis that develops in AP.

Agreement of Gallbladder Reporting and Data System for Gallbladder Wall Thickening at Ultrasonography: A Multireader Validation Study.

Objective: This article aims to evaluate the intrareader and interreader agreement of ultrasound (US) gallbladder reporting and data system (GB-RADS) and validate the risk of malignancy in each GB-RADS category. Materials and methods: This retrospective study comprised consecutive patients with nonacute gallbladder wall thickening who underwent US evaluation between January 2019 and December 2022. Three radiologists independently read the static US images and cine-loops for GB-RADS findings and assigned GB-RADS categories. The intraobserver (static images) and interobserver (static images and cine-loops) agreement was calculated using kappa statistics and Krippendorff's alpha. Another radiologist assigned a consensus GB-RADS category. The percentage of malignancy in each GB-RADS category was calculated. Results: Static US images of 414 patients (median age, 56 years; 288 women, benign = 45.6% and malignant = 54.4%) and cine-loops of 50 patients were read. There was weak to moderate intrareader agreement for most GB-RADS findings and moderate intrareader agreement for the GB-RADS category for all readers. On static images, the interreader agreement was acceptable for GB-RADS categories. On cine-loops, the interreader agreement for GB-RADS findings and categories was better than static images. The percentage of malignancy was 1.2%, 37%, 71.1%, and 89.1% in GB-RADS 2, 3, 4, and 5 categories. Conclusion: GB-RADS has moderate intrareader for GB-RADS categories. As originally proposed, the risk of malignancy is negligible in GB-RADS 2 category and highest in GB-RADS 5 category. However, the discriminatory performance of GB-RADS 3 and 4 categories is low. Larger multicenter studies with more readers must assess the reader agreement and validate the GB-RADS systems for wider clinical utilization.

Applications of artificial intelligence in biliary tract cancers.

Biliary tract cancers are malignant neoplasms arising from bile duct epithelial cells. They include cholangiocarcinomas and gallbladder cancer. Gallbladder cancer has a marked geographical preference and is one of the most common cancers in women in northern India. Biliary tract cancers are usually diagnosed at an advanced, unresectable stage. Hence, the prognosis is extremely dismal. The five-year survival rate in advanced gallbladder cancer is < 5%. Hence, early detection and radical surgery are critical to improving biliary tract cancer prognoses. Radiological imaging plays an essential role in diagnosing and managing biliary tract cancers. However, the diagnosis is challenging because the biliary tract is affected by many diseases that may have radiological appearances similar to cancer. Artificial intelligence (AI) can improve radiologists' performance in various tasks. Deep learning (DL)-based approaches are increasingly incorporated into medical imaging to improve diagnostic performance. This paper reviews the AI-based strategies in biliary tract cancers to improve the diagnosis and prognosis.

Abbreviated magnetic resonance imaging in hepatocellular carcinoma surveillance: A review.

Hepatocellular carcinoma (HCC) is one of the most common primary malignancies of the liver and a leading cause for cancer-related deaths worldwide. HCC surveillance aims at early detection. The recommended strategy for screening HCC is biannual ultrasound with or without alpha-fetoprotein. However, this strategy is associated with sub-optimal sensitivity. Abbreviated magnetic resonance imaging (AMRI) is a promising alternative to ultrasound (US) for surveillance of HCC. The data regarding the role of AMRI in HCC screening is evolving. There are different AMRI protocols, each having its merits and disadvantages. In this review, we discuss the need for AMRI, protocols of AMRI and hindrances to widespread adoption of AMRI.

Scrub Typhus: An Acute Precipitant for Acute on Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome with high mortality. Many acute precipitating factors have been implicated in triggering the acute event of ACLF, with bacterial infections being a common precipitant. However, many other precipitants can cause ACLF; therefore, identification of these factors early in the golden window and their treatment can result in improved prognosis. Scrub typhus usually presents as uncomplicated acute febrile illness but rarely as complicated. Few case reports of scrub-typhus-induced acute liver failure have been reported but none with scrub-typhus-precipitating ACLF so far. Therefore, we are reporting a case of scrub-typhus-precipitating ACLF, where timely intervention with antibiotics results in improved outcome.

Field-scale assessment of soil, water, plant, and soil microbiome in and around Rania-Khan Chandpur Chromium contaminated site, India.

Rania-Khan Chandpur site, (Kanpur Dehat, Uttar Pradesh, India), one of the highly Chromium (Cr) contaminated sites in India due to Chromite Ore Processing Residue (COPR), has been investigated at the field-scale. We found that the area around the COPR dumps was hazardously contaminated with the Cr where its concentrations in the surface water and groundwater were > 40 mgL-1, its maximum contents in the COPRs and in the soils of the adjoining lands were 9.6 wt% and 3.83 wt%, respectively. By exploring the vegetation and microbial distribution across the site, we advocate the appropriateness of Cynodon dactylon, Chrysopogon zizanioides, Cyperus sp., and Typha angustifolia as the most suitable phytoremediation agent because their association with Cr remediating bacterial species (Pseudomonas sp., Clostridium sp. and Bacillus sp.) was strong. Using this remarkable information for the bioremediation projects, this site can be re-vegetated and bioaugmented to remediate Cr in soils, waterlogged ditches, surface water, and in groundwater systems.

Outcomes of Self-expandable Metal Stents in Patients With Unresectable Gallbladder Cancer Undergoing Percutaneous Biliary Drainage.

Background: Biliary obstruction in gallbladder cancer (GBC) is associated with worse prognosis and needs drainage. In patients with biliary confluence involvement, percutaneous biliary drainage (PBD) is preferred over endoscopic drainage. However, PBD catheters are associated with higher complications compared to endoscopic drainage. PBD with self-expandable metal stents (SEMS) is desirable for palliation. However, the data in patients with unresectable GBC is lacking. Materials and methods: This retrospective study comprised consecutive patients with proven GBC who underwent PBD-SEMS insertion between January 2021 and December 2022. Technical success, post-procedural complications, clinical success, duration of stent patency, and biliary reinterventions were recorded. Clinical follow-up data was analysed at 30 days and 180 days of SEMS insertion and mortality was recorded. Results: Of the 416 patients with unresectable GBC, who underwent PBD, 28 (median age, 50 years; 16 females) with PBD-SEMS insertion were included. All SEMS placement procedures were technically successful. There were no immediate/early post-procedural complications/deaths. The procedures were clinically successful in 63.6% of the patients with hyperbilirubinemia (n = 11). Biliary re-interventions were done in 6 (21.4%). The survival rate was 89.3 % (25/28) at 30 days and 50% at 180 days. The median follow-up duration was 80 days (range, 8-438 days). Conclusion: PBD-SEMS has moderate clinical success and 6-months patency in almost half of the patients with metastatic GBC and must be considered for palliation.

Near-IR Capturing N-Methylbenzene Sulfonamide-Phenothiazine Incorporating Strong Electron Acceptor Push-Pull Systems: Photochemical Ultrafast Carrier Dynamics.

Unraveling the intriguing aspects of the intramolecular charge transfer (ICT) phenomenon of multi-modular donor-acceptor-based push-pull systems are of paramount importance considering their promising applications, particularly in solar energy harvesting and light-emitting devices. Herein, a series of symmetrical and unsymmetrical donor-acceptor chromophores 1-6, are designed and synthesized by the Corey-Fuchs reaction via Evano's condition followed by [2+2] cycloaddition retroelectrocyclic ring-opening reaction with strong electron acceptors TCNE and TCNQ in good yields (~60-85 %). The photophysical, electrochemical, and computational studies are investigated to explore the effect of incorporation of strong electron acceptors 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) and dicyanoquinodimethane (DCNQ) with phenothiazine (PTZ) donor. An additional low-lying broad absorption band extended towards the near-infrared (NIR) region suggests charge polarization after the introduction of the electron acceptors in both symmetrical and asymmetrical systems, leading to such strong ICT bands. The electrochemical properties reveal that reduction potentials of 3 and 6 are lower than those of 2 and 5, suggesting DCNQ imparts more on the electronic properties and hence largely contributes to the stabilization of LUMO energy levels than TCBD, in line with theoretical observations. Relative positions of the frontier orbitals on geometry-optimized structures further support accessing donor-acceptor sites responsible for the ICT transitions. Eventually, ultrafast carrier dynamics of the photoinduced species are investigated by femtosecond transient absorption studies to identify their spectral characteristics and target analysis further provides information about different excited states photophysical events including ICT and their associated time profiles. The key findings obtained here related to excited state dynamical processes of these newly synthesized systems are believed to be significant in advancing their prospect of utilization in solar energy conversion and related photonic applications.

A high throughput immuno-affinity mass spectrometry method for detection and quantitation of SARS-CoV-2 nucleoprotein in human saliva and its comparison with RT-PCR, RT-LAMP, and lateral flow rapid antigen test.

OBJECTIVES: Many reverse transcription polymerase chain reaction (RT-PCR) methods exist that can detect SARS-CoV-2 RNA in different matrices. RT-PCR is highly sensitive, although viral RNA may be detected long after active infection has taken place. SARS-CoV-2 proteins have shorter detection windows hence their detection might be more meaningful. Given salivary droplets represent a main source of transmission, we explored the detection of viral RNA and protein using four different detection platforms including SISCAPA peptide immunoaffinity liquid chromatography-mass spectrometry (SISCAPA-LC-MS) using polyclonal capture antibodies. METHODS: The SISCAPA-LC MS method was compared to RT-PCR, RT-loop-mediated isothermal amplification (RT-LAMP), and a lateral flow rapid antigen test (RAT) for the detection of virus material in the drool saliva of 102 patients hospitalised after infection with SARS-CoV-2. Cycle thresholds (Ct) of RT-PCR (E gene) were compared to RT-LAMP time-to-positive (TTP) (NE and Orf1a genes), RAT optical densitometry measurements (test line/control line ratio) and to SISCAPA-LC-MS for measurements of viral protein. RESULTS: SISCAPA-LC-MS showed low sensitivity (37.7 %) but high specificity (89.8 %). RAT showed lower sensitivity (24.5 %) and high specificity (100 %). RT-LAMP had high sensitivity (83.0 %) and specificity (100.0 %). At high initial viral RNA loads (<20 Ct), results obtained using SISCAPA-LC-MS correlated with RT-PCR (R2 0.57, p-value 0.002). CONCLUSIONS: Detection of SARS-CoV-2 nucleoprotein in saliva was less frequent than the detection of viral RNA. The SISCAPA-LC-MS method allowed processing of multiple samples in <150 min and was scalable, enabling high throughput.