Facile synthesis of elastin nanogels encapsulated decursin for castrated resistance prostate cancer therapy.

Nanogels offer hope for precise drug delivery, while addressing drug delivery hurdles is vital for effective prostate cancer (PCa) management. We developed an injectable elastin nanogels (ENG) for efficient drug delivery system to overcome castration-resistant prostate cancer (CRPC) by delivering Decursin, a small molecule inhibitor that blocks Wnt/ßcatenin pathways for PCa. The ENG exhibited favourable characteristics such as biocompatibility, flexibility, and low toxicity. In this study, size, shape, surface charge, chemical composition, thermal stability, and other properties of ENG were used to confirm the successful synthesis and incorporation of Decursin (DEC) into elastin nanogels (ENG) for prostate cancer therapy. In vitro studies demonstrated sustained release of DEC from the ENG over 120 h, with a pH-dependent release pattern. DU145 cell line induces moderate cytotoxicity of DEC-ENG indicates that nanomedicine has an impact on cell viability and helps strike a balance between therapeutics efficacy and safety while the EPR effect enables targeted drug delivery to prostate tumor sites compared to free DEC. Morphological analysis further supported the effectiveness of DEC-ENG in inducing cell death. Overall, these findings highlight the promising role of ENG-encapsulated decursin as a targeted drug delivery system for CRPC.

Celiac artery thrombosis presenting as acute abdomen.

Mesenteric vascular thrombosis, typically of the superior mesenteric artery, is a frequent occurrence in patients with hypercoagulable conditions. Isolated involvement of the celiac artery is rare. Patients with celiac artery thrombosis can present with an acute abdomen or occasionally with acid peptic symptoms. A delay in diagnosis is associated with high rates of morbidity and mortality. We present a rare case of splenic infarction with celiac trunk thrombosis in a 54-year-old patient with underlying antiphospholipid (APLA) syndrome who presented with epigastric pain that was mistaken for symptoms of acid reflux.

Dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose reduces endotoxemia-induced inflammation and oxidative stress: Implications in PAMP-associated acute and chronic pathology.

Pathogen-associated molecular patterns (PAMPs) like bacterial cell wall components and viral nucleic acids are known ligands of innate inflammatory receptors that trigger multiple inflammatory pathways that may result in acute inflammation and oxidative stress-driven tissue and organ toxicity. When dysregulated, this inflammation may lead to acute toxicity and multiorgan failure. Inflammatory events are often driven by high energy demands and macromolecular biosynthesis. Therefore, we proposed that targeting the metabolism of lipopolysaccharide (LPS)-driven inflammatory events, using an energy restriction approach, can be an effective strategy to prevent the acute or chronic detrimental effects of accidental or seasonal bacterial and other pathogenic exposures. In the present study, we investigated the potential of energy restriction mimetic agent (ERMA) 2-deoxy-D-glucose (2-DG) in targeting the metabolism of inflammatory events during LPS-elicited acute inflammatory response. Mice fed with 2-DG as a dietary component in drinking water showed reduced LPS-driven inflammatory processes. Dietary 2-DG reduced LPS-induced lung endothelial damage and oxidative stress by strengthening the antioxidant defense system and limiting the activation and expression of inflammatory proteins, viz., P-Stat-3, NfκΒ, and MAP kinases. This was accompanied by decreased TNF, IL-1ß, and IL-6 levels in peripheral blood and bronchoalveolar lavage fluid (BALF). 2-DG also reduced the infiltration of PMNCs (polymorphonuclear cells) in inflamed tissues. Altered glycolysis and improved mitochondrial activity in 2-DG-treated RAW 264.7 macrophage cells suggested possible impairment of macrophage metabolism and, therefore, activation in macrophages. Taken together, the present study suggests that inclusion of glycolytic inhibitor 2-DG as a part of the diet can be helpful in preventing the severity and poor prognosis associated with inflammatory events during bacterial and other pathogenic exposures.

One-pot synthesis of α-sulfoximinophosphonate via Kabachnik-Fields reaction.

Herein, we disclose a novel approach for the synthesis of hitherto unknown α-sulfoximinophosphonate via the Kabachnik-Fields reaction of aldehyde, dialkylphosphite and sulfoximine in the presence of InCl3 in THF at 70 °C. α-Sulfoximinophosphonate is synthesized in good yields and its synthetic utilities are proved by functionalizing bromine through the Pd-catalyzed Suzuki-Miyaura cross-coupling reaction and reduction of a nitro group through the Béchamp reduction.

A metal-free Petasis reaction towards the synthesis of N-(α-substituted)alkyl sulfoximines/sulfonimidamides.

Herein, we disclose a metal-free novel approach for the synthesis of N-(α-substituted)alkyl sulfoximines/sulfonimidamides via one-pot multicomponent Petasis reactions of aryl boronic acids, ortho-hydroxyarylaldehydes and sulfoximines/sulfonimidamides in moderate to very good yields. The presence of two chiral centres provides a mixture of diastereomers almost in a 1 : 1 ratio, which are separated successfully in most of the cases. The -OH functionality of Petasis products is further utilized to derive heterocycles via O-allylation, followed by intramolecular Heck cyclization, proving the synthetic utility of the products.

Machine learning-based radiomic evaluation of treatment response prediction in glioblastoma.

AIM: To investigate machine learning based models combining clinical, radiomic, and molecular information to distinguish between early true progression (tPD) and pseudoprogression (psPD) in patients with glioblastoma. MATERIALS AND METHODS: A retrospective analysis was undertaken of 76 patients (46 tPD, 30 psPD) with early enhancing disease following chemoradiotherapy for glioblastoma. Outcome was determined on follow-up until 6 months post-chemoradiotherapy. Models comprised clinical characteristics, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and 307 quantitative imaging features extracted from enhancing disease and perilesional oedema masks on early post-chemoradiotherapy contrast-enhanced T1-weighted imaging, T2-weighted imaging (T2WI), and apparent diffusion coefficient (ADC) maps. Feature selection was performed within bootstrapped cross-validated recursive feature elimination with a random forest algorithm. Naive Bayes five-fold cross-validation was used to validate the final model. RESULTS: Top selected features included age, MGMT promoter methylation status, two shape-based features from the enhancing disease mask, three radiomic features from the enhancing disease mask on ADC, and one radiomic feature from the perilesional oedema mask on T2WI. The final model had an area under the receiver operating characteristics curve (AUC) of 0.80, sensitivity 78.2%, specificity 66.7%, and accuracy of 73.7%. CONCLUSION: Incorporating a machine learning-based approach using quantitative radiomic features from standard-of-care magnetic resonance imaging (MRI), in combination with clinical characteristics and MGMT promoter methylation status has a complementary effect and improves model performance for early prediction of glioblastoma treatment response.

One-year clinical outcome of patients with nonvalvular atrial fibrillation: Insights from KERALA-AF registry.

BACKGROUND: We report patient characteristics, treatment pattern and one-year clinical outcome of nonvalvular atrial fibrillation (NVAF) from Kerala, India. This cohort forms part of Kerala Atrial Fibrillation (KERALA-AF) registry which is an ongoing large prospective study. METHODS: KERALA-AF registry collected data of adults with previously or newly diagnosed atrial fibrillation (AF) during April 2016 to April 2017. A total of 3421 patients were recruited from 53 hospitals across Kerala state. We analysed one-year follow-up outcome of 2507 patients with NVAF. RESULTS: Mean age at recruitment was 67.2 years (range 18-98) and 54.8% were males. Main co-morbidities were hypertension (61.2%), hyperlipidaemia (46.2%) and diabetes mellitus (37.2%). Major co-existing diseases were chronic kidney disease (42.1%), coronary artery disease (41.6%), and chronic heart failure (26.4%). Mean CHA2DS2-VASc score was 3.18 (SD ± 1.7) and HAS-BLED score, 1.84 (SD ± 1.3). At baseline, use of oral anticoagulants (OAC) was 38.6% and antiplatelets 32.7%. On one-month follow-up use of OAC increased to 65.8% and antiplatelets to 48.3%. One-year all-cause mortality was 16.48 and hospitalization 20.65 per 100 person years. The main causes of death were cardiovascular (75.0%), stroke (13.1%) and others (11.9%). The major causes of hospitalizations were acute coronary syndrome (35.0%), followed by arrhythmia (29.5%) and heart failure (8.4%). CONCLUSIONS: Despite high risk profile of patients in this registry, use of OAC was suboptimal, whereas antiplatelets were used in nearly half of patients. A relatively high rate of annual mortality and hospitalization was observed in patients with NVAF in Kerala AF Registry.

Ureteral Avulsion during Semirigid Ureteroscopy: A Single-Centre Experience.

AIMS: The aim of the study is to present our experience with the management of ureteral avulsions following semirigid ureteroscopy for ureteral stones. This is one of the largest series reported so far. METHODS AND MATERIALS: It is a retrospective and observational study done at Sri Ramachandra Institute of Higher Education and Research over the last 18 years. RESULTS: There were seven cases of ureteral avulsion following semirigid ureteroscopy. All patients were males with a mean age of 35.7 years. All had impacted stones, with proximal ureteric location in 6 patients and distal ureteric location in 1 patient. Five cases had two-point avulsions with loss of entire ureter. Two cases had one-point avulsion: one distal ureteric and the other mid-ureteric. Of the five cases with whole length ureteral avulsion, four were managed by classical ileal replacement of ureter and the the fifth case was managed by ileal replacement of ureter by the Yang-Monti technique. Of the two cases with one-point avulsion, one was managed by uretero-neocystostomy and the other by uretero-ureterostomy. All the patients had successful outcome. CONCLUSIONS: Even though rare, ureteral avulsion can potentially happen especially when dealing with impacted ureteric stones. Being conscious of the possible occurrence of this serious complication during any difficult ureteroscopy and exercising utmost care during the procedure are important preventive measures. However, this catastrophe can be successfully managed by either immediate definitive repair or in a staged manner.

Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort.

The PRKAG2 syndrome is a rare autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progressive conduction system disease and left ventricular hypertrophy. This study describes the phenotype, genotype and clinical outcomes of a South-Asian PRKAG2 cardiomyopathy cohort over a 7-year period. Clinical, electrocardiographic, echocardiographic, and cardiac MRI data from 22 individuals with PRKAG2 variants (68% men; mean age 39.5 ± 18.1 years), identified at our HCM centre were studied prospectively. At initial evaluation, all of the patients were in NYHA functional class I or II. The maximum left ventricular wall thickness was 22.9 ± 8.7 mm and left ventricular ejection fraction was 53.4 ± 6.6%. Left ventricular hypertrophy was present in 19 individuals (86%) at baseline. 17 patients had an WPW pattern (77%). After a mean follow-up period of 7 years, 2 patients had undergone accessory pathway ablation, 8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks-5; sinus node disease-2), 3 patients developed atrial fibrillation, 11 patients (50%) developed progressive worsening in NYHA functional class, and 6 patients (27%) experienced sudden cardiac death or equivalent. PRKAG2 cardiomyopathy must be considered in patients with HCM and progressive conduction system disease.

Fragmented QRS on electrocardiography as a predictor of myocardial scar in patients with hypertrophic cardiomyopathy.

Background: Fragmented QRS (fQRS) and Q waves are ECG findings in patients with myocardial scar. fQRS is more sensitive than pathological Q waves in detecting myocardial fibrosis in patients with coronary artery disease (CAD). Cardiac magnetic resonance (CMR) imaging is used for the diagnosis and for quantifying scar tissue in patients with HCM. Our aim was to correlate ECG parameters like fQRS and Q waves with the presence of late gadolinium enhancement (LGE) assessed by contrast CMR imaging to elucidate ECG markers which might predict scar tissue in HCM.Methods: This study is a retrospective analysis which included 39 patients who were diagnosed/suspected to have HCM on echocardiography and referred for contrast CMR imaging at our centre between 2010 and 2016. Presence of fQRS was correlated with scar demonstrated by LGE on CMR.Results: Twenty four (66.67%) patients had asymmetrical septal hypertrophy, 7 (19.44%) patients had apical involvement while 5 (13.89%) had concentric pattern. Only 4 (11.11%) patients had pathological Q waves in contiguous leads on surface ECG while fQRS in two contiguous leads was present in 23 (63.89%) patients. Presence of fQRS was more in patients with LGE on CMR than those without (84.61 versus 10%, p<.001). When presence of LGE in specific segments (anterior, lateral and inferior) was correlated with corresponding ECG leads, all the three segments showed significant correlation. The overall sensitivity, specificity, PPV and NPV of fQRS for predicting scar tissue were 84.6, 90.0, 95.6 and 69.2%, respectively.Conclusion: fQRS on surface ECG can be used as an indirect marker to predict the presence of fibrosis in HCM.

Implication of the Whitefly, Bemisia tabaci, Collagen Protein in Begomoviruses Acquisition and Transmission.

Begomoviruses are the largest group of plant viruses transmitted exclusively by the whitefly, Bemisia tabaci (Gennadius), in a persistent, circulative, and nonpropagative manner. Begomoviruses in association with B. tabaci cause enormous loss to world agricultural crops. Transmission, retention, and circulation of begomovirus in B. tabaci are facilitated by its interaction with several proteins of the insect and its endosymbionts. However, very few such proteins have been identified from B. tabaci that are involved in this specific interaction. Here, we have performed yeast two-hybrid assay between B. tabaci complementary DNA expression library and the coat protein (CP) of tomato leaf curl New Delhi virus (ToLCNDV) and cotton leaf curl Rajasthan virus (CLCuV). Collagen was the common protein found to be interacting with both of the viruses. The collagen protein was found to be localized in gut layers of B. tabaci. Additionally, pull-down and dot-blot assays confirmed the association of endogenous collagen with ToLCNDV CP. Immunolocalization analysis also showed colocalization of ToLCNDV particles and collagen within insect gut. Finally, B. tabaci fed on anticollagen antibody and exhibited ∼46% reduction in ToLCNDV transmission, suggesting a supportive role for collagen in virus transmission.

Paediatric auditory brainstem implantation: The South Asian experience.

INTRODUCTION: Paediatric Auditory Brainstem Implantation (ABI) is indicated for children with congenital cochlear aplasia, absent/hypoplastic vestibulocochlear nerve, for whom cochlear implantation is not possible. Knowledge of the anatomical landmarks and variants in anatomy of the brainstem is vital for ABI surgery. METHOD: Study was done at Auditory implant centre in Madras ENT research foundation, which includes 24 children who had undergone ABI surgery and are being followed up for 1 year, post operatively. Aims were to study the anatomical variants and the outcomes of ABI implantation. To determine if different anatomical variants effect placement of ABI electrode. To assess the patient outcomes by Categories of auditory Performance (CAP) scores and Speech Intelligibility Ratings (SIR) scores. RESULTS: All the candidates showed gradual improvement in audiological and verbal outcomes after the ABI. The mean CAP and SIR scores after 6 months of AVHT were 2.07 and 1.37 respectively. After 1 year of auditory verbal rehabilitation therapy CAP was 3.42 and SIR was 2.33. Flocculus of the cerebellum can be of different grades. Though, there was difficulty in insertion of the electrode in subjects with anatomical variants, the outcomes were comparable with other subjects. CONCLUSION: ABI surgery involves frequent anatomical variations surrounding the lateral recess which makes the positioning of the auditory prosthesis difficult. Variants during the surgery can make the placement of ABI electrodes difficult, but promising results were seen all the implantees.

Evaluation of spin within abstracts in obesity randomized clinical trials: A cross-sectional review.

This is a cross-sectional analysis of spin in randomized controlled trial (RCT) abstracts published in top-ranked obesity and general medicine journals. The top seven obesity and four general medicine journals were searched from 1 January 2016 to 31 December 2017. To be included in this study, a trial must be an RCT with non-significant primary endpoint (P > 0.05), exclusively randomize subjects with overweight or obesity or have a primary endpoint of weight loss. These studies were analysed by two reviewers for spin in the abstract. The primary endpoint of our investigation was the frequency and type of spin. The secondary endpoint was to assess whether funding source was associated with the presence of spin. Our PubMed search yielded 1143 articles. Primary screening excluded 992 articles, and full-text evaluation excluded an additional 106. Overall, 45 articles were included. Spin was identified in 21 of the 45 (46.7%) abstracts analysed. Evidence of spin was found in 17 (37.8%) abstract result sections and 11 (24.4%) abstract conclusion sections. Of the 39 RCTs reporting a clinical trial registry, 6 (15.4%) had evidence of selective reporting bias. Our study found that obesity medicine RCTs from top-ranked journals with non-significant primary endpoints published in 2016 and 2017 frequently have spin in their abstracts. Abstracts with evidence of spin may influence a reader's perception of new drugs or procedures. These results warrant a careful review of future RCTs, but may not be generalizable to RCTs published in lower-ranked journals.

Tuberculous otitis media: a resurgence?

OBJECTIVE: Tuberculosis is a global health problem that is especially prevalent in developing countries such as India. Recently, atypical presentation has become more common and a high index of suspicion is essential. This study analysed the various presenting symptoms and signs of tuberculous otitis media and the role of diagnostic tests, with the aim of formulating criteria for the diagnosis. METHODS: A total of 502 patients underwent tympanomastoidectomy over a two-year period. Microbiological and histopathological examinations and polymerase chain reaction analysis of tissue taken during tympanomastoidectomy were performed. RESULTS: A total of 25 patients (5 per cent) were diagnosed with tuberculous otitis media. Severe mixed hearing loss, facial palsy, labyrinthine fistula, post-aural fistula, perichondritis and extradural abscess were noted. CONCLUSION: There seems to be a resurgence in tuberculous otitis media in India. Microbiological, histopathological and polymerase chain reaction tests for tuberculosis are helpful for its diagnosis.

An unusual type of accessory pathway in tricuspid atresia.

The occurrence of pre-excitation in tricuspid atresia (TA) is slightly more common than that in normal children. The accessory pathway (AP), when it occurs in the setting of congenital atrioventricular valvar disease, is usually ipsilateral to the side of the abnormal valve. This report describes a patient with TA who had pre-excitation due to a left-sided AP that masked and modified the typical electrocardiographic features. The electrophysiological study confirmed an epicardial left posterior AP that was successfully ablated with radiofrequency energy, through the coronary sinus. Left-sided APs including epicardial ones may rarely be seen in TA and can potentially cause difficulties due to lack of vascular access to the heart after the Fontan surgery if arrhythmias occur. They are amenable to successful radiofrequency ablation and need to be dressed prior to Fontan surgery. .

Heart-type fatty acid-binding protein (H-FABP) as an early diagnostic biomarker in patients with acute chest pain.

BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is an emerging biomarker, which was found to be sensitive for the early diagnosis of acute myocardial infarction (AMI). We prospectively investigated the usefulness of H-FABP determination for the evaluation of acute chest pain in patients arriving at the emergency department. METHODS: Fifty-four patients presenting with acute ischemic chest pain were evaluated. H-FABP was estimated at admission using latex-enhanced immunoturbidimetric assay. Serial cardiac troponin I (cTnI), creatinine kinase-MB (CK-MB) determination, ischemia workup with stress testing, and/or coronary angiogram (CAG) were performed according to standard protocols. RESULTS: The sensitivity and specificity of H-FABP was 89.7% and 68%, for cTnI it was 62.1% and 100%, and for CK-MB it was 44.8% and 92%, respectively for diagnosis of AMI. The sensitivity of H-FABP was found to be far superior to initial cTnI and CK-MB, for those seen within 6h (100% vs. 46.1%, 33% respectively). On further evaluation of patients with positive H-FABP and negative cTnI, 71.4% of the patients had significant lesion on CAG, indicating ischemic cause of H-FABP elevation. Six patients with normal cTnI and CK-MB with high H-FABP had ST elevation on subsequent ECGs and were taken for primary angioplasty. CONCLUSION: H-FABP is a highly sensitive biomarker for the early diagnosis of AMI. H-FABP as early marker and cTnI as late marker would be the ideal combination to cover the complete diagnostic window for AMI. Detection of myocardial injury by H-FABP may also be applied in patients with unstable angina. H-FABP can also be used as a marker for early detection of STEMI before the ECG changes become apparent.

Pattern Recognition Receptors in Cancer Progression and Metastasis.

The innate immune system is an integral component of the inflammatory response to pathophysiological stimuli. Toll-like receptors (TLRs) and inflammasomes are the major sensors and pattern recognition receptors (PRRs) of the innate immune system that activate stimulus (signal)-specific pro-inflammatory responses. Chronic activation of PRRs has been found to be associated with the aggressiveness of various cancers and poor prognosis. Involvement of PRRs was earlier considered to be limited to infection- and injury-driven carcinogenesis, where they are activated by pathogenic ligands. With the recognition of damage-associated molecular patterns (DAMPs) as ligands of PRRs, the role of PRRs in carcinogenesis has also been implicated in other non-pathogen-driven neoplasms. Dying (apoptotic or necrotic) cells shed a plethora of DAMPs causing persistent activation of PRRs, leading to chronic inflammation and carcinogenesis. Such chronic activation of TLRs promotes tumor cell proliferation and enhances tumor cell invasion and metastasis by regulating pro-inflammatory cytokines, metalloproteinases, and integrins. Due to the decisive role of PRRs in carcinogenesis, targeting PRRs appears to be an effective cancer-preventive strategy. This review provides a brief account on the association of PRRs with various cancers and their role in carcinogenesis.

Identification of human papillomavirus-16 E6 variation in cervical cancer and their impact on T and B cell epitopes.

The infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for development of cervical cancer. The intra-type variations of HPV have different biological and pathological consequences with respect to disease progression. In the present study, six major Indian variants were experimentally identified in E6 gene of HPV-16 and showed their impact on immunogenicity by in silico methods. Four different phylogenetic lineages were observed in sequences including European (E) prototype, European variant, Asian and American Asian variant classes and complete absence of African phylogenetic lineages. On the prediction of B- and T-cell epitopes, 18 and 23 potent epitopes for MHC-II alleles, 10 potent MHC-I and 15 B-cell epitopes in each reference and variant sequence were identified. Interestingly, the presence of variation H78Y and L83V result in creation of four new epitopes for the HLA-DQA1*0101/DQB1*0501. Out of 15 B-cell predicted epitopes, three most potent epitopes were identified in both reference and variant sequence. Notably the amino acid stretch from amino acid 16-60 and 76-94 are very important for the immunological properties of E6 protein because these regions contain majority of the predicted epitopes. In future, this could control the cervical cancer by targeting these amino acid stretches for the development of HPV-16 vaccine.