ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1ß cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1ß release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.

Antihypertensive Drugs Aliskiren, Nebivolol, and Olmesartan Reduce Hypertension by Reducing Endothelial Microparticles and Regulating Angiogenesis.

The accelerated generation of endothelial microparticles (EMPs) and impaired angiogenesis are the markers of vascular pathology during various cardiovascular and inflammatory conditions including hypertension. Because studies comparing the effects of antihypertensive agents on these 2 parameters are limited, this study was designed to compare the effects of 3 antihypertensive agents: aliskiren, nebivolol, and olmesartan, on the EMP generation and angiogenesis. Changes in the hemodynamic parameters and serum EMP count were determined after 3 weeks of the drug treatments [aliskiren (30 mg/kg), nebivolol (10 mg/kg), or olmesartan (5 mg/kg) per orally] in L-NAME-induced rat model of hypertension. The 3 drugs prevented the rise in blood pressure and EMP count to a similar extent. Furthermore, nebivolol was found to possess more potent and concentration-dependent antiangiogenic activity compared with aliskiren, whereas olmesartan was devoid of such an effect. The EMPs generated by virtue of the respective drug treatments were found to be involved in mediating the antiangiogenic effect of nebivolol and aliskiren. In addition, olmesartan treatment also resulted in the increased eNOS expression. The results of this study show that the antihypertensive drugs, viz. aliskiren, nebivolol, and olmesartan, regulate the vascular health by their differential effects on the EMP generation and angiogenesis.

Zinc Alpha 2 Glycoprotein as an Early Biomarker of Diabetic Nephropathy in Type 2 Diabetes Mellitus Patients.

Background and objectives Microalbuminuria is an early sign of diabetic nephropathy (DN). However, pathological abnormalities occur before the onset of microalbuminuria. Renal impairment progresses in about 50% of cases in type 2 diabetes mellitus (T2DM) without significant albuminuria. Diabetes mellitus (DM) is linked with obesity, metabolic syndrome, and lifestyle changes, where adipokines play an important role. Zinc alpha 2 glycoprotein (ZAGP) is an adipokine, and in this study, it was assessed as a potential biomarker for early DN as well as its progression. Materials and methods This study was a cross-sectional case-control study conducted at a tertiary hospital in northern India. T2DM patients aged 18-65 years old were included in the study and were divided into four groups based on their albuminuria level. This study included 160 participants, with 40 participants in each group. Group I included healthy volunteers, while Groups II, III, and IV were normoalbuminuric, microalbuminuric, and macroalbuminuric diabetic patients, respectively. The groups were evaluated for demographic variables, biochemical parameters, urine albumin-creatinine ratio (UACR), and serum ZAGP. Data between the groups were compared statistically. Results This study included 160 participants, with 40 participants in each group. There was a significant difference between the groups based on the serum ZAGP (p<0.001). Serum ZAGP was significantly negatively correlated with serum creatinine, glycosylated hemoglobin (HbA1c), serum cholesterol, serum triglyceride, low-density lipoprotein (LDL) cholesterol, and UACR. ZAGP was positively correlated with the estimated glomerular filtration rate (eGFR). Conclusion The present study showed that ZAGP was an early biomarker of diabetic nephropathy, and its value decreased as DN progressed. It also suggested that ZAGP, an adipokine, has an anti-inflammatory mechanism of action and its depletion worsens the disease.

Comparative Study of Dysphagia-optimized Intensity Modulated Radiotherapy (Do-IMRT) and Standard Intensity Modulated Radiotherapy (S-IMRT) and Its Clinical Correlation in Head and Neck Cancer Patients.

OBJECTIVE: Dosimetric sparing of critical swallowing structures like constrictor muscles and larynx can lead to improved functional outcomes in head and neck cancer patients treated by chemoradiation. METHODS: A total of 50 Patients with newly diagnosed, biopsy proven AJCC stage II-IV head and neck squamous cell cancers (HNSCC) were prospectively studied. 25 patients were randomized in each arm of Dysphagia-optimized Intensity Modulated Radiotherapy (Do-IMRT) arm and Standard Intensity Modulated Radiotherapy (SIMRT) arm. Additional dose constraints were applied to the dysphagia/aspiration at risk structures (DARS) in Do-IMRT arm. The impact of using Do-IMRT was assessed by the difference in mean scores of MD Anderson Dysphagia Inventory (MDADI), University of Washington-Quality of Life (UW-QOL), and 100 ml Water Swallow Test (WST). RESULTS: Patients in both arms showed significant (P <0.01 or P < 0.001) improvement in MDADI (global and composite), UW-QOL and Water Swallow Test scores. However, the improvements were found significantly higher in Do-IMRT as compared to S-IMRT. Significant improvements i.e. mean change from baseline to 12 months (P <0.05 or P <0.01 or P <0.001) were 19. 2, 8.6, 14.3, 7.4, 18.6 and 22.0%  higher respectively in Do-IMRT as compared to S-IMRT  in MDADI global and composite scores, UW-QOL swallowing scores, and 100 ml Water Swallow  (swallowing volume, swallowing capacity and swallowing speed)  test scores. CONCLUSION: The Do-IMRT improves swallowing functions compared to S-IMRT in HNSCC patients treated with radical chemoradiation.

CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis.

Altered mitochondrial function without a well-defined cause has been documented in patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homolog (CLUH) only in the active UC tissues compared with the unaffected areas from the same patient and healthy controls. Stimulation with bacterial Toll-like receptor (TLR) ligands similarly reduced CLUH expression in human primary macrophages. Further, CLUH negatively regulated secretion of proinflammatory cytokines IL-6 and TNF-α and rendered a proinflammatory niche in TLR ligand-stimulated macrophages. CLUH was further found to bind to mitochondrial fission protein dynamin related protein 1 (DRP1) and regulated DRP1 transcription in human macrophages. In the TLR ligand-stimulated macrophages, absence of CLUH led to enhanced DRP1 availability for mitochondrial fission, and a smaller dysfunctional mitochondrial pool was observed. Mechanistically, this fissioned mitochondrial pool in turn enhanced mitochondrial ROS production and reduced mitophagy and lysosomal function in CLUH-knockout macrophages. Remarkably, our studies in the mouse model of colitis with CLUH knockdown displayed exacerbated disease pathology. Taken together, this is the first report to our knowledge explaining the role of CLUH in UC pathogenesis, by means of regulating inflammation via maintaining mitochondrial-lysosomal functions in the human macrophages and intestinal mucosa.

Cathepsin S as an early biomarker for cardiovascular disease in chronic kidney disease patients.

INTRODUCTION: A high incidence of cardiovascular disease (CVD) events and premature mortality is observed in patients with chronic kidney disease (CKD). Thus, new biomarkers that may help predict the development of CVD in early stages of CKD are being investigated along with other traditional risk factors. OBJECTIVE: To investigate cathepsin S as an early biomarker for CVD in patients with CKD. METHODS: A total of 64 patients with CKD were included and classified into 2 groups: CKD patients with established CVD and CKD patients with non-established CVD. All patients were submitted to routine investigations including complete blood count, random blood sugar, glycated hemoglobin (HbA1c), serum electrolytes, urea, creatinine, total protein, total albumin, calcium total, phosphorous, uric acid, vitamin D, parathormone, lipid profile, liver function test, measurement of serum cathepsin S (Cat S), and 2D Echo of the heart. RESULTS: The level of serum Cat S was increased in CKD patients with CVD (p <0.05) as well as in later stages of CKD (p <0.05). CVD was also more common in patients in early stage CKD. In early stages CKD, Cat S and CVD were positively correlated. CONCLUSION: These findings suggest that serum Cat S might be useful as an early biomarker for CVD in CKD patients.

Serum kallistatin as a marker of severity of liver fibrosis in cirrhosis: A cross-sectional observational study.

Background: Liver cirrhosis is among the leading causes of morbidity and mortality worldwide. Although liver biopsy is the gold standard for the assessment of liver fibrosis in cirrhosis, it has its own limitations. Therefore, noninvasive methods to detect liver fibrosis are widely preferred. However, they also have their own limitations. Thus, there is always a need to extend the battery of serum-based assays. Kallistatin is a protein synthesized primarily in the liver. As it is a negative acute-phase protein, its blood level decreases with a decline in liver function. In our study, we explored the relationship between serum kallistatin and radiological evidence of liver fibrosis by transient elastography to determine if kallistatin levels can be used as a diagnostic marker of liver fibrosis. Materials and Methods: A cross-sectional study of 1-year duration was conducted at a leading tertiary care hospital in northern India. Patients between 15 and 75 years of age having evidence of chronic liver disease were enrolled. All enrolled patients were evaluated by detailed history, physical examination, and relevant investigations. Serum kallistatin levels were quantified using the ELISA method. Grading of liver fibrosis was done using transient elastography. A FibroScan scoring card was used to convert FibroScan results measured in kPa into the Metavir scale F1-F4. Results: A total of 128 subjects, including 64 patients with cirrhosis and 64 healthy controls, were enrolled. Our study suggested that FibroScan values were significantly higher in cases as compared to controls. The kallistatin level of cases was significantly lower than that of controls. An inverse correlation was found between FibroScan value and kallistatin level among cases. Conclusion: We conclude that serum kallistatin levels are low in patients with liver fibrosis and can be used as a potential marker of liver fibrosis.

Phase III, Randomized, Double-blind, Placebo controlled trial of Efficacy, Safety and Tolerability of Antiviral drug Umifenovir vs Standard care of therapy in non-severe COVID-19 patients.

OBJECTIVE: To test efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients. METHODS: We carried out randomized, double-blind, placebo-controlled, multicenter, phase III trials involving adult (18-75 years), non-severe COVID19 patients, randomized 1:1 on placebo or Umifenovir (800 mg BID, maximum 14 days) respectively along with standard-of-care. The primary endpoint for Asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. For Moderate patients, the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale was assessed. RESULTS: 132 patients were recruited between 3rd October to 28th April 2021, of which 9 discontinued due to various reasons. In Mild-asymptomatic patients (n=82), we found that 73% patients in the Umifenovir arm were RT-PCR negative, while 40% patients in the placebo arm were negative (P=0.004) on day 5. However, in the moderate group (n=41), the WHO scores for the Umifenovir arm was not statistically significant (P=0.125 on day 3), while it was statistically significant in the Mild-asymptomatic group (P=0.019 on day 5). CONCLUSION: Umifenovir meets the primary and secondary endpoint criteria and exhibits statistically significant efficacy for Mild-asymptomatic patients. It is efficacious, safe and well-tolerated at the tested dosage of 800mg BID, maximum 14 days.

A machine learning-based approach to determine infection status in recipients of BBV152 (Covaxin) whole-virion inactivated SARS-CoV-2 vaccine for serological surveys.

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the vaccine effectiveness. Asymptomatic breakthrough infections have been a major problem in assessing vaccine effectiveness in populations globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines since whole virion vaccines generate antibodies against all the viral proteins. Here, we show how a statistical and machine learning (ML) based approach can be used to discriminate between SARS-CoV-2 infection and immune response to an inactivated whole virion vaccine (BBV152, Covaxin). For this, we assessed serial data on antibodies against Spike and Nucleocapsid antigens, along with age, sex, number of doses taken, and days since last dose, for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, our ensemble ML model classified 724 to be infected. For method validation, we determined the relative ability of a random subset of samples to neutralize Delta versus wild-type strain using a surrogate neutralization assay. We worked on the premise that antibodies generated by a whole virion vaccine would neutralize wild type more efficiently than delta strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, neutralization against Delta strain was more effective, indicating infection. We found 71.8% subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period. Our approach will help in real-world vaccine effectiveness assessments where whole virion vaccines are commonly used.

A Study to Assess the Dosimetric Impact of the Anatomical Changes Occurring in the Parotid Glands and Tumour Volume during Intensity Modulated Radiotherapy using Simultaneous Integrated Boost (IMRT-SIB) in Head and Neck Squamous Cell Cancers.

BACKGROUND: Anatomical variations in head and neck cancer during IMRT leads to volume shrinkage, results in dosimetric variations in tumour and normal tissue including parotid glands, with a risk of radiation toxicities. METHODS: 30 patients with a stage II-IV head and neck squamous cell carcinoma (HNSCC) were treated with definitive IMRT-SIB and concomitant chemotherapy. Volumetric and dosimetric variations were evaluated during the period of IMRT by recalculating and obtaining dose-volume histograms of re-contoured target volumes and parotid glands on repeat CT scans taken multiple times during treatment (CT1, CT2, CT3 and CT4). RESULTS: Result showed significant (p < 0.001) mean decrease in both primary and nodal tumors volume with time whereas increase (p < 0.01 or p < 0.001) in respective V100 (%) and D2% (Gy). The mean parotid gland dose increased (p < 0.01 or p < 0.001) with time, whereas parotid gland volume and distance between plan isocenter and centre of mass of parotid glands decreased (p < 0.05 or p < 0.001) with time. Patient's mean weight and neck circumference both decrease (p < 0.001) with time whereas ECOG score increase (p < 0.001) with time. The mucosal toxicity increased significantly (p < 0.001) with time. The change in both weight and neck circumference showed significant (p < 0.001) and direct (positive correlation) association with change in parotid gland volume. CONCLUSION: If the PTV and normal anatomy are changing with time, adaptive IMRT would be beneficial radiation dose delivery where possible.

Association of Pulmonary Hypertension With Inflammatory Markers and Volume Status in Hemodialysis Patients of End-Stage Renal Disease.

Background and objectives Pulmonary hypertension (PH) is an independent risk factor for increased mortality, especially in patients undergoing hemodialysis (HD), but the mechanism of its development is unknown. This study aimed at evaluating volume overload and inflammation as potential variables to cause its development in patients undergoing maintenance hemodialysis. Materials and methods This was an observational cross-sectional study conducted on patients undergoing hemodialysis at a tertiary hospital in northern India. Patients of end-stage renal disease, aged 18 years or more, on maintenance hemodialysis for over two months were included in the study. The patients were divided into two groups based on the presence or absence of PH, determined by measuring systolic pulmonary arterial pressure (SPAP). The severity of PH was defined as: mild (SPAP 35-45 mmHg), moderate (SPAP 46-55 mmHg), and severe (SPAP> 55mmHg). The two groups were evaluated for demographic variables, type of vascular access, biochemical parameters, and markers of inflammation and fluid overload. Data between the two groups were compared statistically. Results This study included a total of 82 patients showing the prevalence of PH to be 25.6% with a men-to-women ratio of 2:1. Out of 21 cases of PH, mild PH was found in seven (33.3%) cases, moderate in 14 (66.7%), and cases with severe PH were none. The two groups differed significantly in ejection fraction and markers of inflammation and volume status. Laboratory data associated with PH were alpha-1-acid glycoprotein (p<0.05) and pro-b-type natriuretic peptide (p <0.05). Conclusion The present study showed higher levels of inflammatory markers alpha-1-acid glycoprotein and pro-b-type natriuretic peptide and lower levels of ejection fraction in patients undergoing HD, indicating a significant association with PH.

Leptin DNA Methylation and Its Association with Metabolic Risk Factors in a Northwest Indian Obese Population.

BACKGROUND: It is well established that obesity is a major health risk in diabetes and associated diseases. Epigenetic changes, specially DNA methylation, play an important role in regulation of adipokines. The objective of the present study was to evaluate the DNA methylation status at the promoter region of the leptin gene in obese individuals and its association with metabolic risk factors. METHODS: The study included obese (n=100) and non-obese (n=75) individuals aged 25-45 years, and measured their physical, biochemical parameters (glucose, insulin, and lipid profiles) and leptin, DNA methyltransferase 1 (DNMT1), and DNA methyltransferase 3 beta (DNMT3b) mRNA expressions with real-time reverse transcription-polymerase chain reaction (qRT-PCR). DNA methylation of the leptin gene at the promoter region was analyzed by methyl-specific qPCR . RESULTS: The study found that the DNA methylation level at the promoter area of the leptin gene was negatively associated with weight in obese subjects. Furthermore, study findings showed that the DNA methylation level was negatively associated with fasting insulin, glucose, homeostatic model assessment for insulin resistance, and total cholesterol. There was also a higher expression of DNMT1 and DNMT-3b in obese subjects as compared with non-obese subjects. CONCLUSION: The leptin epigenetic profile may be associated with obesity and its associated metabolic risk factors.

Association of hepcidin and anemia in early chronic kidney disease.

Hepcidin is being extensively studied for anemia and inflammation in chronic kidney disease (CKD) patients. Hepcidin is thought to regulate iron metabolism by iron blockade through various mechanisms. Patients with CKD have early cardiac mortality due to anemia and subclinical inflammation; hence, we studied hepcidin as a biomarker in patients with early stage of CKD in relation to anemia and inflammation. In our cross-sectional study, a total of 80 patients were enrolled of whom, there were 25, 26, and 29 patients in CKD stages 1, 2, and 3, respectively. Patients were divided into normal iron level (39), functional iron deficiency (FID) (18), and absolute iron deficiency (AID) (23) based on transferrin saturation and ferritin. We found significantly high level of hepcidin (P <0.05) and high-sensitivity C-reactive protein (hsCRP) (P <0.05) in FID as compared to AID as well as normal iron level. We also found other inflammatory markers such as albumin, transferrin, and ferritin to be significantly associated with FID. In univariate analysis, hemoglobin (Hb) varied significantly with serum total iron-binding capacity (r = 0.40, P <0.001), log hsCRP (r = -0.32, P <0.01), and log ferritin (r = -0.23, P <0.05); however, Hb was not affected significantly with log hepcidin (r = -0.07, P >0.05). The study indicates that among early CKD patients with FID, there was high level of hepcidin along with other inflammatory parameters, which may be associated with poor cardiovascular disease outcome due to increased inflammation.

A case control study of clinical and biochemical parameters of metabolic syndrome with special attention among young and middle aged population.

BACKGROUND: Metabolic syndrome (MS) increases the risk of heart disease, stroke, and other complications. AIM: The aim of this study was to assess the clinical and biochemical parameters of MS and its complications (cerebrovascular accidents, cardiovascular accidents, DN or chronic kidney disease (CKD) compared with healthy controls especially among the younger population in Northern India. MATERIAL AND METHODS: A total of 245 (healthy, MS and it's complicated) aged 18-70 years participated in the Open-Label, Single Centered; hospital-based random selection case-control comparative study. All anthropometric and biochemical assessment was done after proper consent. The metabolic syndrome was determined by IDF criteria. RESULTS: The key risk parameters in three groups i.e. Control, Metabolic syndrome, and Complicated was TG (96.5 ±â€¯46.9, 194.1 ±â€¯87.8, 148.0 ±â€¯102.2). LDL (91.2 ±â€¯27.2, 114.0 ±â€¯31.8, 69.1 ±â€¯42.5, BP (120.1 ±â€¯9.9, 139.3 ±â€¯13.3, 132.1 ±â€¯15.0) and high fasting glucose (81.1 ±â€¯13.7, 164.5 ±â€¯84.3, 138.0 ±â€¯74.5). The hs-CRP is also significantly increased in the complicated group. The subanalysis of data also indicates that younger middle age (36-55 years) group both male and female is obese, hypertensive, diabetic with lipid abnormality according to IDF criteria. CONCLUSION: The risk factors like high TG, low HDL, high BP, and high fasting glucose were found higher particularly in younger population which may lead to diagnosis & complications of diabetes, hypertension and lipid abnormality. Due to changing physiology in young and middle age population these individuals are moving towards metabolic syndrome easily and needs frequent monitoring, preventive checkups, and lifestyle changes to prevent complications.

Intracarotid Sodium Nitroprusside on Fifth Post Ischemic Stroke Day in Middle Cerebral Artery Occlusion Rat Model.

INTRODUCTION: Ischemic stroke at later stages (>4.5 hour) have very few treatment options left. In those cases Nitric Oxide (NO) may provide promising results. NO is active in signaling pathways. Sodium Nitroprusside (SNP), a NO donor was tested earlier in rat Middle Cerebral Artery Occlusion (MCAO) model in early stages (5-60 minutes) and found useful but in delayed stroke cases (60-120 minutes) found useless. This was due to local inducible Nitric Oxide Synthase Enzyme (iNOS) and superoxide (causes destructive effect) formation which was skipped. AIM: To evaluate the effect of Intracarotid Sodium Nitroprusside (ICSNP) in MCAO rat model of ischemic stroke (I/R model) fifth post ischemic stroke day. MATERIALS AND METHODS: A total of 24 Sprague Dawley rats, weighing 250 gm to 280 gm, at CDRI-Lucknow, India were used. Rats were divided in three groups. Group A (n=4) were taken as sham with standard procedure but without any injection on fifth day, Group B (n=8) as control with injection of saline on fifth day and Group C (n=12) received SNP at dose of 3 mcg/kg/minute given directly in internal carotid artery via External Carotid Artery (ECA) with a modified intraluminal stump technique as Ischemia/Reperfusion (I/R) in ipsilateral MCAO at intracarotid artery region as a single dose therapy on fifth day and then wound was closed. Waited for full recovery for two hours, then neurobehavioural assessment scores were noted. Thereafter, the brains were quickly removed and sliced at 2 mm intervals. Animals showing no sign of neurological deficit, were excluded from the study. Tested animals were compared with control animals for neurological deficit, percentage of infarction by 2,3,5-Triphenyl Tetrazolium Chloride (TTC) staining, nNOS expression and scores were summed up. The statistical analysis was done by Newman-Keuls test, Graph Pad prism (version.5.0) and p<0.05 was considered statistically significant. RESULTS: ICSNP group (Group C) showed a good reduction in the cerebral infarction of 53.42% as compared to control (Group B). Group A mean change in Newman-Keuls test and Graph Pad prism (version.5.0) was showing increase of 1.44 points/6.55%, compared to Group B decrease of 0.7 points. A 60% decrease in ischemic zone noted in Group A. CONCLUSION: The use of single dose ICSNP is beneficial (53.42%) in fifth post stroke day.

Vitamin D levels and other biochemical parameters of mineral bone disorders and their association with diastolic dysfunction and left ventricular mass in young nondiabetic adult patients with chronic kidney disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with end-stage renal disease. Chronic kidney disease (CKD)-associated cardiovascular mortality is more prevalent in those with diastolic heart failure and is an early predictor, while increased left ventricular mass (LVM) is a strong independent risk factor. Hypovitaminosis D is extensively being studied as a nontraditional risk factor for CVD. The aim of the present study is to look at the association of Vitamin D and other parameters of mineral bone disorder (MBD) with diastolic dysfunction and LVM in nondiabetic young adult patients with CKD. This was a hospital-based, cross-sectional observational study. Groups I and II comprised nondiabetic predialysis CKD patients (stage 4 and 5) and healthy controls, respectively. Groups IA and IB comprised cases with and without diastolic dysfunction, respectively. Vitamin D level was measured by enhanced chemiluminescence method and intact parathyroid hormone (iPTH) by electrochemiluminescence method. Parameters for diastolic function and LVM were assessed by Doppler echocardiography, tissue Doppler imaging, and M-mode echocardiography. Vitamin D level was significantly lower in Group I as compared to Group II. Diastolic dysfunction was present in 48.8% of the cases and was significantly associated with serum phosphorus and calcium-phosphorous product, but not with Vitamin D level. A statistically significant positive correlation between LVM and iPTH was found in our study. Hyperphosphatemia and high calcium-phosphorous product can be a better early predictor of diastolic dysfunction than Vitamin D while secondary hyperpara-thyroidism with increased LVM may be a bad prognostic marker.

Cathepsin S as an early biomarker for cardiovascular disease in chronic kidney disease patients / Catepsina S como um biomarcador precoce para doença cardiovascular em pacientes com doença renal crônica

Abstract Introduction: A high incidence of cardiovascular disease (CVD) events and premature mortality is observed in patients with chronic kidney disease (CKD). Thus, new biomarkers that may help predict the development of CVD in early stages of CKD are being investigated along with other traditional risk factors. Objective: To investigate cathepsin S as an early biomarker for CVD in patients with CKD. Methods: A total of 64 patients with CKD were included and classified into 2 groups: CKD patients with established CVD and CKD patients with non-established CVD. All patients were submitted to routine investigations including complete blood count, random blood sugar, glycated hemoglobin (HbA1c), serum electrolytes, urea, creatinine, total protein, total albumin, calcium total, phosphorous, uric acid, vitamin D, parathormone, lipid profile, liver function test, measurement of serum cathepsin S (Cat S), and 2D Echo of the heart. Results: The level of serum Cat S was increased in CKD patients with CVD (p <0.05) as well as in later stages of CKD (p <0.05). CVD was also more common in patients in early stage CKD. In early stages CKD, Cat S and CVD were positively correlated. Conclusion: These findings suggest that serum Cat S might be useful as an early biomarker for CVD in CKD patients.

Resumo Introdução: Uma alta incidência de eventos de doença cardiovascular (DCV) e mortalidade prematura é observada em pacientes com doença renal crônica (DRC). Assim, novos biomarcadores que podem ajudar a prever o desenvolvimento de DCV nos estágios iniciais da DRC estão sendo investigados juntamente com outros fatores de risco tradicionais. Objetivo: Investigar a catepsina S como um biomarcador precoce para DCV em pacientes com DRC. Métodos: Um total de 64 pacientes com DRC foram incluídos e classificados em 2 grupos: pacientes com DRC com DCV estabelecida e pacientes com DRC com DCV não estabelecida. Todos os pacientes foram submetidos a investigações de rotina incluindo hemograma completo, glicemia aleatória, hemoglobina glicada (HbA1C), eletrólitos séricos, ureia, creatinina, proteína total, albumina total, cálcio total, fósforo, ácido úrico, vitamina D, paratormônio, perfil lipídico, teste de função hepática, medição da catepsina S sérica (Cat S), e Eco 2D do coração. Resultados: O nível de Cat S sérica esteve aumentado em pacientes com DRC com DCV (p <0,05), bem como em estágios posteriores da DRC (p <0,05). A DCV também foi mais comum em pacientes com DRC em estágio inicial. Em estágios iniciais da DRC, a Cat S e a DCV foram positivamente correlacionadas. Conclusão: Estes achados sugerem que a Cat S sérica pode ser útil como um biomarcador precoce para DCV em pacientes com DRC.

Understanding molecular markers in recurrent oral squamous cell carcinoma treated with chemoradiation.

INTRODUCTION: Oral cancer accounts for approximately 2.1% of all cancers worldwide. In India, oral squamous cell carcinoma (OSCC) is the most common cancer with half a million new cases diagnosed every year. More than 50% of patients eventually develop local recurrence or metastasis usually within the first 2-years following completion of treatment. It is beneficial to analyze the prognostic significance of Cyclin D1, p53 and EGFR which are critical mediators in the pathogenesis of OSCC. The objective of this study was to assess the association of expression of these markers with recurrence and pattern of recurrence in OSCC patients undergoing chemoradiation. MATERIALS AND METHODS: A Total 290 OSCC cases of locally advanced stage (III, IV) oral cancer with World Health Organization (W.H.O.) performance status of grade 0/1 in the year 2009-2012 were enrolled in the study. Treatment response was assessed according to W.H.O. criteria. Cyclin D1, EGFR and p53 expression in tumor tissue was estimated by immunohistochemical (IHC) method and quantified as percentage positive nuclei. RESULTS: During the 2-years follow up, 56 (19.3%) patients recurred, out of which, 47 (83.9%) were locoregional and 9 (16.1%) distant sites. On correlating, χ2 test showed significant (P < 0.05 or P < 0.01 or P < 0.001) association of marker expressions (Cyclin D1, EGFR and p53) with recurrence. The strong positive expressions of all three markers showed significant association with early time of recurrence. The multivariate logistic regression analysis showed significant (P < 0.05 or P < 0.01 or P < 0.001) association of recurrence with primary site, differentiation, Cyclin D1 and p53 expressions indicating these as an independent predictors of recurrence in OSCC. The Cyclin D1, EGFR and p53 expressions also showed significant (P < 0.001) poor survivals (OS, DFS and RFS) in patients with positive/strong positive expressions than negative expression suggesting their prognosis in OSCC. CONCLUSION: Our results signifies that tumors over expressing Cyclin D1, EGFR and p53 are resistant to chemoradiation and are associated with increased risk of locoregional recurrence and metastasis in OSCC patients undergoing chemoradiation.

Beneficial effects of nebivolol in comparison with atenolol on safety and tolerability in essential hypertension.

INTRODUCTION: Hypertension, "The silent killer" is a multifactorial disorder which is asymptomatic and if left untreated leads to lethal complications. Nebivolol is a third generation beta blocker with additional vasodilating property due to nitric oxide release. AIM: The current study aims to assess efficacy and safety of Nebivolol and compare with Atenolol. METHODS: This was prospective, double blind, comparative controlled clinical study. Total 90 patients were enrolled into study as per selection criteria. Patients were randomized to receive Atenolol and Nebivolol with 45 patients in each group for 12 weeks. RESULTS AND CONCLUSION: The mean reduction diastolic blood pressure in Nebivolol and Atenolol group was 10.77±2.60 and 10.05±2.83 respectively. The number of patients with adverse effect events was higher in the Atenolol than in the Nebivolol group (36.84% of Atenolol Vs 12.82% of Nebivolol). Thus it can be concluded that, for the same antihypertensive effect, Nebivolol was better tolerated than Atenolol.