Prevalence and clinicopathological Spectrum of Auto-Immune Liver Diseases & Overlap syndrome.

Aims: Autoimmune liver diseases (AILD) represent a spectrum of related yet distinct immune-mediated disorders. The literature on the prevalence of these AILDs in Indian population is scarce. This study aims to assess the prevalence and clinicopathological spectrum of various AILDs especially the overlap syndrome. Materials and Methods: A 10-year (2011-2020) cross-sectional, retrospective observational study of histological proven cases of AILD was conducted. Clinical, demographic, and laboratory parameters were retrieved. Two pathologists independently reviewed the liver biopsies and reassessed 18 histopathological parameters. Results: During the study period, 17664 liver biopsies were received, out of which 1060 (6%) biopsies of AILD were identified. After exclusion, we had 721 cases which revealed a distribution of autoimmune hepatitis (AIH)-64.7%, primary biliary cholangitis (PBC)-14.8%, primary sclerosing cholangitis (PSC)-7.6%, overlap AIH-PBC 11%, and overlap AIH-PSC 1.7%. AIH patients had significantly higher prevalence for severe lobular inflammation (27%, P ≤ 0.001), several lobular plasma cells (37%, P ≤ 0.001), central perivenulitis (30%, P ≤ 0.001), hepatic rosettes (51%, P ≤ 0.001), and necrosis (35.5%, P ≤ 0.001), while PBC patients had significantly higher frequency of florid duct lesions (11.2%, P ≤ 0.001), duct loss (83.17%, P ≤ 0.001), bile duct damage (76.6%, P ≤ 0.001), and periportal copper deposits (19.6%, P ≤ 0.001). Overlap AIH-PBC group had the highest proportion of severe portal inflammation (27.5%, P ≤ 0.001), prominent portal plasma cells (75%, P ≤ 0.001), moderate interface activity (53.7%, P ≤ 0.001), Mallory-Denk bodies (27.5%, P ≤ 0.001), and periportal cholate stasis (25%, P ≤ 0.001). Conclusion: Prevalence of biopsy-proven AILDs in our study cohort is 6%. AIH (64.7%) is the most common AILD followed by PBC (14.8%). Overlap syndrome (AIH-PBC) showed prevalence of 11%.

Liver volumetry in cirrhotic patients with or without hepatocellular carcinoma: Its correlation with Child-Pugh, model for end-stage liver diseases and indocyanine green dye test.

BACKGROUND AND OBJECTIVES: To evaluate the correlation between non-tumoral liver volume (NTLV) by computed tomography (CT) volumetry and indocyanine green retention at 15 minutes (ICG-r15%), Child-Pugh score (CTP) and model for end-stage liver diseases (MELD) score in cirrhotic patients having hepatocellular carcinoma (HCC) (group A) and in cirrhotics without HCC (group B). METHODS: As many as 111 consecutive patients with liver cirrhosis, who underwent triple-phase CT abdomen, were retrospectively included in our study. They were classified into group A (cirrhosis with HCC, n = 69) and group B (cirrhosis only, n = 42). Segmental liver volume, tumor and NTLV were calculated using Myrian XP-Liver segmentation software. In group B, NTLV was the same as the total liver volume (TLV). The correlation of NTLV with ICG-r15%, CTP and MELD scores was analyzed using appropriate correlation tests for each group. RESULTS: NTLV had a good and significant negative correlation with ICG-r15% (ρ = - 512; p < 0.001) in group A, but not in group B. It also had a significant negative correlation with CTP (ρ = - 251; p = 0.038) and MELD (ρ = - 323; p = 0.007) scores only in group A. Furthermore, ICG-r15% had a good and significant positive correlation with CTP and MELD scores in both groups (p < 0.05). CONCLUSION: NTLV showed a significant negative correlation with ICG-r15% in cirrhotic patients with HCC, but not in cirrhotic patients without HCC. Therefore, CT volumetry can be a valuable tool to predict the functional hepatic volume in patients of cirrhosis with HCC subjected for hepatectomy, where a facility of ICG-r15% is not available. However, further studies are needed to validate our findings in cirrhotic only patients.

Autoantibody Positivity Has No Impact on Histological Parameters in Nonalcoholic Fatty Liver Diseases.

Objectives: Previous reports on association of autoantibodies with histological severity in nonalcoholic fatty liver disease (NAFLD) have revealed inconsistent results. Therefore, this study was undertaken to find the impact of autoantibodies on histological severity of NAFLD. Methods: All cases with histological diagnosis of NAFLD during January 2016 to January 2021 were included in the study. Laboratory parameters were recorded, and histological assessment was done. The positivity of autoimmune markers was defined as presence of either antinuclear antibody (ANA; titer >1:80), anti-smooth muscle antibodies (ASMA), or anti-liver-kidney-microsomal antibodies (LKM-1; titer >1:40). Serum levels of CK18 - M30 and PIIINP were evaluated to assess the subtle changes in necroinflammatory activity and fibrosis in the liver. Results: Autoantibodies were present in 281/683 (41.1%, 95% CI 37.4-44.9) patients. ANA, ASMA, ANA + ASMA was seen in 20.9% (95% CI 17.9-24.2); 14.5% (95% CI 11.9-17.4); and 5.7% (95% CI 4.1-7.7) cases, respectively. No significant difference was noted between the two groups in terms of age and metabolic tests. No significant difference was noted in the histological parameters between groups with autoantibodies positivity and no-positivity. Mean value of CK18-M30 between cases with negative autoantibody; ANA positivity; ASMA positivity; and combined positivity of autoantibody were 178.2 ± 81.8, 161.6 ± 63.7, 153.2 ± 70.3 and 169.8 ± 42.9, respectively (P = 0.57). However, CK18-M30 and PIIINP showed a rising trend with NAFL, NASH, NASH + AIH (P < 0.001). Conclusions: Autoantibodies noted in 41% NAFLD cases. No significant necroinflammatory activity or fibrosis associated with presence of antibodies in NAFLD cases. However, CK-18-M30 showed a rising trend from NAFL to NASH to NASH + AIH.

Non-resolution of acute kidney injury in the first week portends the development of chronic kidney disease in critically ill patients with cirrhosis.

BACKGROUND: Renal tubular epithelial cells (RTECs) cause maladaptive repair and perpetuate renal fibrosis. AIM: To evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) and RTEC as risk factors for non-resolution of acute kidney injury (AKI-NR) at day seven and chronic kidney disease (CKD) in critically ill patients with cirrhosis. METHODS: We performed urinary NGAL and microscopy at enrolment and day 7 in all patients. We assessed 17 renal injury, endothelial injury and repair markers, genes for mitochondrial biogenesis by qRT-PCR in RTEC, and post-mortem renal biopsies for understanding mechanisms of AKI non-resolution (n = 30). RESULTS: We enrolled 310 patients, aged 48.1 ± 11.6 years, 87% male, 90% alcoholic. Of these, 36% had RTEC at enrolment, and 53% had AKI-NR on day 7. On mean follow-up of 136 days (range 43-365), 150 (48.3%) developed CKD. The presence of RTEC or granular casts, NGAL and AKI-NR were independent predictors of CKD development on competing risk analysis. Higher MCP-1, renal endothelial injury, decrease in tubular repair markers and failure of mitochondrial biogenesis in RTEC were seen in patients with AKI-NR compared with AKI-R (p < 0.05). Renal biopsies showed infiltration with monocyte-macrophage, increased α-SMA, and tubulointerstitial fibrosis. CONCLUSION: Almost two-thirds of critically ill patients with cirrhosis have AKI, which resolves in only one-half at day seven and predicts the development of CKD. Higher NGAL, RTEC, or granular casts were independent predictors of AKI-NR and CKD development. Enhanced tubular and endothelial injury, decreased repair, monocyte-macrophage infiltration and mitochondrial dysfunction in RTEC are associated with AKI non-resolution and risk of renal fibrosis.

In Vitro-In Vivo Correlation of Buprenorphine Transdermal Systems Under Normal and Elevated Skin Temperature.

PURPOSE: Application of external heat using a heating pad over buprenorphine transdermal system, Butrans® has been shown to increase systemic levels of buprenorphine in human volunteers. The purpose of this study was to perform in vitro permeation studies at normal as well as elevated temperature conditions to evaluate the correlation of in vitro data with the existing in vivo data. METHODS: In vitro permeation tests (IVPT) were performed on human skin from four donors. The IVPT study design was harmonized to a previously published clinical study design and skin temperature was maintained at either 32 ± 1 °C or 42 ± 1 °C to mimic normal and elevated skin temperature conditions, respectively. RESULTS: IVPT studies on human skin were able to demonstrate heat induced enhancement in flux and cumulative amount of drug permeated from Butrans® which was reasonably consistent with the corresponding enhancement observed in vivo. Level A in vitro-in vivo correlation (IVIVC) was established using unit impulse response (UIR) based deconvolution method for both baseline and heat arms of the study. The percent prediction error (%PE) calculated for AUC and Cmax values was less than 20%. CONCLUSIONS: The studies indicated that IVPT studies performed under the same conditions as those of interest in vivo may be useful for comparative evaluation of the effect of external heat on transdermal delivery system (TDS). Further research may be warranted to evaluate factors, beyond cutaneous bioavailability (BA) assessed using an IVPT study, that can influence plasma exposure in vivo for a given drug product.

A randomised-controlled trial (TARGET-C) of high vs. low target mean arterial pressure in patients with cirrhosis and septic shock.

BACKGROUND & AIMS: A high mean arterial pressure (MAP) target has been associated with improved renal outcomes in patients with cirrhosis, though it has not been studied in critically ill patients with cirrhosis and septic shock (CICs). We compared the efficacy of a high (80-85 mmHg; H-MAP) vs. low (60-65; L-MAP) target MAP strategy in improving 28-day mortality in CICs. METHODS: We performed open-label 1:1 randomisation of 150 CICs (H-MAP 75; L-MAP 75). The primary endpoint was 28-day mortality and secondary endpoints included reversal of shock, acute kidney injury (AKI) at day 5, the incidence of intradialytic hypotension (IDH), and adverse events. Endothelial markers were analysed in a subset of patients. RESULTS: The baseline characteristics were comparable. On intention-to-treat analysis, 28-day mortality (65% vs. 56%; p = 0.54), reversal of shock (47% vs. 53%; p = 0.41) and AKI development (45% vs. 31%;p = 0.06) were not different between the H-MAP and L-MAP groups, respectively. A lower incidence of IDH (12% vs. 48%; p <0.001) and higher adverse events necessitating protocol discontinuation (24% vs. 11%; p = 0.031) were noted in the H-MAP group. On per-protocol analysis (L-MAP 67; H-MAP 57), a significantly higher reversal of AKI (53% vs. 31%; p = 0.02) and a lower incidence of IDH (4% vs. 53%; p <0.001) were observed in the H-MAP group. Endothelial repair markers such as ADAMTS (2.11 ± 1.13 vs. 1.15 ± 0.48; p = 0.002) and angiopoietin-2 (74.08 ± 53.00 vs. 41.80 ± 15.95; p = 0.016) were higher in the H-MAP group. CONCLUSIONS: A higher MAP strategy does not confer a survival benefit in CICs, but improves tolerance to dialysis, lactate clearance and renal recovery. Higher adverse events indicate the need for better tools to evaluate target microcirculation pressures in CICs. IMPACT AND IMPLICATIONS: Maintaining an appropriate organ perfusion pressure during sepsis is the ultimate goal of haemodynamic management. A higher mean arterial pressure (MAP) improves renal outcomes in patients with hepatorenal syndrome. Patients with cirrhosis and septic shock have severe circulatory disturbances, low MAP, and poor tissue perfusion. In these patients, targeting higher MAP vs. lower MAP does not confer any survival benefit but is associated with more adverse events. A higher target strategy was associated with better tolerance and lesser episodes of hypotension on dialysis. Patients who could achieve the higher target MAP, without the development of adverse events, had improved renal outcomes and better lactate clearance. Higher MAP was also associated with improvements in markers of endothelial function. A higher target MAP strategy, with close monitoring of adverse events, may be recommended for patients with cirrhosis and septic shock. CLINICAL TRIAL NUMBER: NCT03145168.

Markers of Social and Emotional Health in College Students During the COVID-19 Pandemic.

Objective: Research on effects of the coronavirus disease 2019 (COVID-19) pandemic on the mental health of youth have mostly focused on the occurrence of negative states such as anxiety and depression. The objective of this study was to assess the social and emotional health of university students in India, as influenced by COVID-19 test results and the experience of isolation or quarantine.Methods: A cross-sectional online survey was conducted in India during July and early August 2021 among university students aged 20-25 years. The Social Emotional Health Survey-Higher Education (SEHS-HE) was used to assess 4 domains: belief in self, belief in others, emotional competence, and engaged living.Results: There were 187 respondents from 78 institutions in 14 of 29 states of India. The sample was 51% male. The mean SEHS-HE scores were approximately 75% of the maximum score in each domain. In multivariable regression analysis, sex, residence with family, and a negative COVID-19 report had little effect on SEHS-HE domains. COVID-19 positivity was associated with significantly lower scores on all domains (P < .01). Isolation/quarantine was associated with significantly or near-significantly higher scores on all domains (P < .01). In all cases, ß coefficients and the proportion of the variance explained by the regression were small.Conclusions: Major pandemic-related internal and environmental determinants of SEHS-HE remain to be identified. Strategies to improve the well-being of college students should be directed toward those who have tested positive for the disease. The experience of isolation/quarantine is not pathoplastic.

Efficacy of convalescent plasma therapy in the patient with COVID-19: a randomised control trial (COPLA-II trial).

IMPORTANCE: No proven treatment is available for severely ill COVID-19. Therapeutic use of COVID-19 convalescent plasma (COPLA) is under investigation. OBJECTIVE: To compare the efficacy of COPLA with standard medical therapy (SMT) alone in severe COVID-19 patients. DESIGN, SETTING AND PARTICIPANTS: A multicentric, open-labelled, phase-III randomised controlled trial conducted at two treatment centres with COPLA collected at the third dedicated centre in North-India, the coordinating centre during trial from June 2020 to December 2020. The study population comprised 400 participants in the ratio of 1:1 in each treatment group. INTERVENTION: One group received COPLA with SMT (n=200), and another group received SMT only (n=200). MAIN OUTCOME MEASURES: Primary outcome was time to clinical improvement measured by a two-point reduction in the ordinal scale. Secondary outcomes included duration of O2 therapy, the proportion of patients on mechanical ventilation at day-7, mortality, SARS-CoV-2 antibody levels, cytokine levels and incidence of adverse events. RESULTS: The median time to a two-point reduction in the ordinal scale in both groups was 9 days (IQR=7-13) (p=0.328). The median duration of O2 therapy was 8 days (IQR=6-12) in COPLA and 10 days (IQR=6-12) in SMT group (p=0.64). The PaO2/FiO2 ratio showed significant improvement at 7 days in COPLA group(p=0.036). There was no difference in mortality till 28 days in both groups (p=0.62). However, if COPLA was given within 3 days of hospital admission, a significant reduction in ordinal scale was observed (p=0.04). Neutralising antibody titres in COPLA group (80 (IQR 80-80)) were higher than SMT group (0 (IQR 0-80)) at 48 hours (p=0.001). COPLA therapy led to a significant reduction in TNF-α levels at 48 hours (p=0.048) and D-dimer at 7 days (p=0.02). Mild allergic reactions were observed in 3 (1.5%) patients in COPLA group. CONCLUSION AND RELEVANCE: Convalescent plasma with adequate antibody titres should be transfused in COVID-19 patients along with SMT in the initial 3 days of hospitalisation for better clinical outcomes. TRIAL REGISTRATION NUMBER: NCT04425915.

Number needed to screen to prevent progression of liver fibrosis to cirrhosis at primary health centers: An experience from Delhi.

BACKGROUND: Early diagnosis has been a bottleneck in the care of chronic liver disease patients and can be addressed by Community-based screening for liver fibrosis using non-invasive diagnostic techniques. OBJECTIVES: The study aimed to determine the prevalence of liver fibrosis and the number needed to screen (NNS) to prevent the progression of fibrosis, among adults visiting urban Primary Health Centres (PHC). METHODS: A facility-based cross-sectional study was conducted from May 2018 to April 2019 in 72 randomly chosen PHCs using a mobile screening van. A pre-tested questionnaire was used to collect relevant history from adult patients and patient attenders. A venous blood sample was collected for biochemical markers and Transient Elastography was also done to measure Liver stiffness (LSM). LSM ≥6.0 kPa was taken as the cut-off for detecting liver fibrosis. Lifestyle modifications and alcohol cessations were considered as interventions for non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) respectively, to calculate NNS. RESULTS: 7624 participants were recruited in the study with a mean age of 46 ± 12 years. Around 35.5% of participants had liver fibrosis and 3% had cirrhosis. Nearly 4% had ALD and 30% had NAFLD. NNS for preventing progression of fibrosis for ALD and NAFLD was 12 and 29 respectively. NNS was least among obese, diabetes and hypertensive participants. CONCLUSION: One-third of adults visiting urban PHCs had significant liver fibrosis. Low NNS to prevent the progression of fibrosis to cirrhosis among alcohol users and other high-risk groups, substantiates the need for screening among these groups.

The Play of Citrate Infusion with Calcium in Plateletpheresis Donors.

Citrate is the anticoagulant of choice for plateletpheresis. Citrate toxicity is common during plateletpheresis as citrate chelates calcium and causes hypocalcemia in donors. We have conducted this study to analyze the effects of routine citrate infusion during plateletpheresis on laboratory and clinical parameters. We also compared the dose of citrate delivered to donors during plateletpheresis using two different cell separators as Haemonetics MCS + and Trima Accel. The study was conducted on 50 plateletpheresis donors who were eligible for donation. Donor demographics and baseline parameters were recorded. Pre, mid and post-procedure blood samples were collected for hematological and biochemical analysis. We found a significant decrease in baseline iCa (1.23 ± 0.07 mmol/L) from start to mid-procedure (1.19 ± 0.006 mmol/L) which recovered at 30 min post procedure (1.2 ± 0.01 mmol/L). The incidence of citrate toxicity was 10%. In donors with citrate toxicity, the post-procedure recovery of iCa was not seen and there was a further decrease in iCa levels. We also found a significant fall in Hb and platelet count post plateletpheresis. We observed that lower PLT counts (< 200 × 103/µL) necessitated higher blood volume processing and therefore a higher anticoagulant (citrate) dose. The Trima Accel cell separator reached platelet target yield faster but with a higher citrate dose as compared to Hemonetics MCS + . Ionized calcium decreases significantly during plateletpheresis but recovers soon after the completion of the procedure. Serious adverse events were not observed during plateletpheresis. The mild citrate toxicity which occurred was easily managed by slowing the procedure and administering oral calcium to donors. Trima Accel and Hemonetics MCS + both collected platelets efficiently, with minimal donor discomfort.

Plasma neutrophil gelatinase-associated lipocalin and Interleukin-18 as predictors of acute kidney injury in renal transplant recipients: A pilot study.

Urine neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL- 18) have shown promise for predicting renal graft recovery. However, urinary flow rate variations may cause variable biomarker dilution. Plasma NGAL and IL-18 may form a biomarker panel that may help predict delayed graft function and slow graft function (SGF) in renal transplant recipients within the first two postoperative days earlier than serum creatinine. There are only a few studies in the literature using plasma NGAL for predicting renal graft recovery. Hence, we planned this study. This observational single-center, prospective cohort study was conducted in renal transplant recipients above 18 years of age. In 22 consecutive renal transplant recipients, we collected ethylenediaminetetraacetic acid-plasma samples 1 h before surgery and subsequently at 6 h, 24 h, and 48 h after surgery for NGAL and IL-18 by sandwich enzyme-linked immuno-sorbent assay technique. Serum creatinine was measured as a part of routine transplant protocol. In renal transplant recipients, neither serum levels of NGAL and IL-18 nor their trends could reliably predict SGF. The only significant correlation existed between serum creatinine at day 2 and IL-18 at day 2 with P = 0.023. Serum NGAL did not correlate with serum creatinine in this setting of renal transplantation. Patients with immediate graft function had a greater percentage decrease of creatinine at day 1 and day 2 (P = 0.002 and 0.001) The percentage change in IL-18 at 24 h and 48 h after transplant from baseline could predict the occurrence of early graft loss (EGL) (P = 0.05, 0.04). The cutoffs were -4.12% at day 1 and +3.39% at day 2 with area under receiver operator characteristics of 0.82 and 0.83, respectively. The percentage change in IL-18 may be a useful marker of EGL in renal transplant recipients. Serum NGAL and creatinine were not able to predict EGL.

Effect of Controlled Heat Application on Topical Diclofenac Formulations Evaluated by In Vitro Permeation Tests (IVPT) Using Porcine and Human Skin.

PURPOSE: Heat therapy is widely used for pain relief and may unintentionally be used in conjunction with pain relieving topical formulations. The purpose of this study was to evaluate the influence of heat on the permeation of diclofenac through porcine and human skin, comparing four marketed products. METHODS: In vitro permeation tests (IVPT) were performed on porcine skin from a single miniature pig and human skin from three donors. Skin temperature was maintained at either 32 ± 1°C or 42 ± 1°C to mimic normal and elevated skin temperature conditions, respectively. RESULTS: IVPT studies on porcine and human skin were able to demonstrate heat-induced enhancement in flux and cumulative amount of drug permeated from the four diclofenac products. The pivotal data showed the most significant heat-induced enhancement for the solution, followed by the patch and two gels in decreasing order of significance based on p values. Diclofenac solution showed the highest flux and cumulative amount permeated at both baseline and elevated skin temperature compared to the patch and gels. CONCLUSIONS: The studies demonstrated that exposure to heat can alter drug permeation from topical formulations, but the increased levels are not expected to lead to systemic concentrations that are of concern. Formulation design and excipients can influence drug permeation at elevated skin temperature.

Carvedilol Combined With Ivabradine Improves Left Ventricular Diastolic Dysfunction, Clinical Progression, and Survival in Cirrhosis.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) refers to impaired cardiac diastolic relaxation and may be improved by targeted heart rate reduction (THR). The authors evaluated whether a combination of carvedilol and ivabradine, an If channel blocker that reduces heart rate without affecting blood pressure, could improve LVDD and outcomes in cirrhosis. PATIENTS AND METHODS: THR was defined as heart rate reduction to 55 to 65 beats per minute. Of 260 patients with cirrhosis, 189 (72%) with LVDD were randomized to THR [group (Gr.)A; n=94; carvedilol±ivabradine)] or standard care (Gr.B; n=95; no ß-blockers) and followed for 12 months. RESULTS: In Gr.A, THR was achieved at 4 weeks in 88 (93%) patients (responders, R): 48 (61.5%) with carvedilol alone and 40 (86.9%) of 46 patients with additional ivabradine. In Gr.A, LVDD reversed in 16 (20.5%) and improved from grade 2 to 1 in 34 (35.4%)], whereas in Gr.B, it progressed from grade 1 to 2 in 10 (10.5%) patients. At 12 months, 21 (11.1%) patients died, 6 (14%) in Gr.A and 15 (18%) in Gr.B (P=0.240), but no mortality was seen in those who had persistent THR at 1 year (n=78; P=0.000). In multivariate analysis, model for end-stage liver disease [hazard ratio (HR), 1.52; 95% confidence interval (CI), 1.22-2.75; P=0.034] and E-wave transmitral/early diastolic mitral annular velocity (HR, 1.28; 95% CI, 1.23-2.42; P=0.048) predicted 1-year mortality. Nonresponders had an increased mortality risk (HR, 1.3; 95% CI, 1.2-1.8; P=0.046) independent of age, gender, and baseline model for end-stage liver disease. Levels of norepinephrine, N terminal brain natriuretic peptide, plasma renin activity, and aldosterone were reduced (P<0.01) in responders. More patients in Gr.B developed acute kidney injury (odds ratio, 4.2; 95% CI, 2.8-10.5; P=0.027) and encephalopathy (odds ratio, 6.6; 95% CI, 1.9-9.7; P=0.040). CONCLUSIONS: Ivabradine combined with carvedilol improves LVDD, achieves THR more often and reduces risk of encephalopathy, acute kidney injury with improved survival in patients with cirrhosis.

Paracentesis-Induced Circulatory Dysfunction With Modest-Volume Paracentesis Is Partly Ameliorated by Albumin Infusion in Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Paracentesis-induced circulatory dysfunction (PICD) is a serious complication of large-volume (>5 L) paracentesis in cirrhosis and is reduced with albumin infusion. There is a lack of data on PICD in acute-on-chronic liver failure (ACLF). Because ACLF patients have greater hemodynamic derangements than patients with decompensated cirrhosis, we investigated whether PICD could develop with modest-volume paracentesis (MVP) and the role of albumin infusion. APPROACH AND RESULTS: A total of 80 ACLF patients undergoing <5 L paracentesis were randomized to receive albumin (8 g/dL of ascitic fluid; n = 40) or no albumin (n = 40) and serially followed to detect PICD. Baseline characteristics were comparable between groups, including volume of ascitic tap (4.16 ± 0.23 versus 4.14 ± 0.27 L; P = 0.72) and plasma renin activity (PRA; 20.5 ± 7.03 versus 23.2 ± 8.24 ng/mL/hour; P = 0.12). PICD was more frequent in the no-albumin group than the albumin group (70% versus 30%; P = 0.001), with higher incidence of hepatic encephalopathy (50% versus 27.5%; P = 0.04), hyponatremia (67.5% versus 22.5%; P < 0.001), acute kidney injury (62.5% versus 30%; P = 0.001), and in-house mortality (62.5% versus 27.5%; P = 0.003). PRA of 25.15 ng/mL at day 3 had sensitivity and specificity of 71% and 68%, respectively, for development of PICD at day 6. Albumin infusion decreased the incidence of PICD at day 6 (odds ratio, 0.068; 95% confidence interval, 0.011-0.43; P = 0.005). CONCLUSIONS: PICD is common and develops even with MVP in ACLF patients. Albumin infusion decreases the incidence of PICD and mortality in patients with ACLF. Clinical trial identifier: NCT02467348.

Correlation of baseline Portal pressure (hepatic venous pressure gradient) and Indocyanine Green Clearance Test With Post-transarterial Chemoembolization Acute Hepatic Failure.

BACKGROUND: Liver failure (LF) is a serious complication of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). This could be influenced by the hemodynamic and functional status of the underlying cirrhotic liver. We evaluated baseline hepatic venous pressure gradient (HVPG) and indocyanine green (ICG) clearance as predictive factors for the development of LF in patients with liver cirrhosis undergoing TACE for HCC. METHODS: Forty-two patients with cirrhosis and HCC, referred for TACE, were clinically evaluated including the assessment of Child Turcotte Pugh score (CTP), Model for End-Stage Liver Disease (MELD), HVPG measurement, and ICG retention test. Predictors of development of hepatic failure after TACE were determined. RESULTS: In our study population, the mean age of the patients was 58 years, with mean CTP of 6.60 ± 1.149 and mean MELD score of 9.57 ± 2.923. The mean HVPG and ICG retention at 15 min was 13.57 ± 4.64 mmHg and 21.571 ± 12.434, respectively. Post-TACE Liver Failure (PTLF within 1 month after TACE) developed in 23.80% patients, whereas 76.19% patients did not have PTLF. The statistically significant preprocedure variables that might predict hepatic failure after TACE using univariate analysis were found to be high CTP, MELD score, ICG retention, HVPG, serum bilirubin, serum creatinine, alfa-fetoprotein levels, large tumor size, and low baseline serum albumin. On multivariate analysis, ICG was an independent factor predictive of hepatic failure after TACE. CONCLUSION: Pretreatment evaluation of routine liver function is of fundamental importance before TACE. Baseline ICG retention test (ICG-R15) is a marker indicating the state of liver function in patients undergoing TACE and is an independent predictor for PTLF. Our study concludes that with a cutoff of 25, ICG-R15 has 92.9% accuracy, 90% sensitivity, and 87.5% specificity to predict hepatic failure after TACE.

Left Ventricular Diastolic Dysfunction is Associated with Renal Dysfunction, Poor Survival and Low Health Related Quality of Life in Cirrhosis.

BACKGROUND: The presence of left ventricular diastolic dysfunction (LVDD) in patients with cirrhosis leads to a restriction of activities and a poor health related quality of life (HRQoL), which should be taken into consideration when treating them for liver and cardiac complications. AIMS: The prevalence, complications, predictors of HRQoL and survival in cirrhotic patients with LVDD were studied. METHODS: We report a prospective cohort study of 145 consecutive cirrhotic patients with LVDD who were evaluated for cardiac functional status at enrollment and followed up for hepatic complications, cardiac events, outcome and HRQoL using the Minnesota Living With Heart Failure Questionnaire (MLHFQ) over a period of 2 years. RESULTS: In total, 145 (mean age 61 years, 59% male) patients were included. Seventeen patients died with 10.5%, 22.5% and 40% mortality rates in patients with Grades 1, 2 and 3 LVDD respectively over 24 months. The parameters that were significant for predicting mortality on bivariate analysis were MELD, MELDNa, hepatic venous pressure gradient, MLHFQ, and left ventricular (LV) diastolic function (e' and E/e' ratio), but only MELD, MELDNa and E/e' remained significant on multivariate analysis. The E/e' ratio (8.7 ± 3.3 in survivors vs. 9.1 ± 2.3 in non-survivors) predicted outcome. On univariate analysis, the predictors of poor HRQoL were the Child-Pugh score ≥9.8 (OR 2.6; 95% confidence intervals (CI) 2.3-9.1, P = 0.041), MELD score ≥ 15.7 (OR 2.48; 95% CI 1.4-3.9, P = 0.029), refractory ascites (OR 1.9; 95% CI 1.1-6.1, P = 0.050), and E/e' ratio ≥7.6 (OR 1.9; 95% CI 1.8-7.1, P = 0.036) The presence of Class II/III (P = 0.046) symptoms of heart failure and MLHFQ≥ 45 (P = 0.042) were predictors of mortality at 24 months. CONCLUSION: The grade of LVDD correlates with liver function, clinical events, risk of renal dysfunction and HRQoL. Evaluation of novel therapies which target symptomatic improvement in LVDD, should be done with suitable outcome measures, including HRQoL assessment.

In vitro-in vivo correlations for nicotine transdermal delivery systems evaluated by both in vitro skin permeation (IVPT) and in vivo serum pharmacokinetics under the influence of transient heat application.

The in vitro permeation test (IVPT) has been widely used to characterize the bioavailability (BA) of compounds applied on the skin. In this study, we performed IVPT studies using excised human skin (in vitro) and harmonized in vivo human serum pharmacokinetic (PK) studies to evaluate the potential in vitro-in vivo correlation (IVIVC) of nicotine BA from two, matrix-type, nicotine transdermal delivery systems (TDS). The study designs used for both in vitro and in vivo studies included 1h of transient heat (42±2°C) application during early or late time periods post-dosing. The goal was to evaluate whether any IVIVC observed would be evident even under conditions of heat exposure, in order to investigate further whether IVPT may have the potential to serve as a possible surrogate method to evaluate the in vivo effects of heat on the bioavailability of a drug delivered from a TDS. The study results have demonstrated that the BA of nicotine characterized by the IVPT studies correlated with and was predictive of the in vivo BA of nicotine from the respective TDS, evaluated under the matched study designs and conditions. The comparisons of single parameters such as steady-state concentration, heat-induced increase in partial AUCs and post-treatment residual content of nicotine in TDS from the in vitro and in vivo data sets showed no significant differences (p≥0.05). In addition, a good point-to-point IVIVC (Level A correlation) for the entire study duration was achieved by predicting in vivo concentrations of nicotine using two approaches: Approach I requiring only an in vitro data set and Approach II involving deconvolution and convolution steps. The results of our work suggest that a well designed IVPT study with adequate controls can be a useful tool to evaluate the relative effects of heat on the BA of nicotine from TDS with different formulations.

Radiofrequency Glow Discharge as a Mode of Disinfection for Elastomeric Impression Materials.

INTRODUCTION: Prosthodontic practice involves procedures in which impressions of the maxillary and mandibular arches are mandatory. Cross infection is one of the major problems that can occur in regular dental practice. Every dentist should take utmost care to prevent cross infection as oral cavity is the source of variety of microorganisms which can often cause diseases that can be fatal. Although precautions, such as wearing of gloves and mask, sterilization of instruments are given importance, the need for disinfection of impressions is often neglected. Hence, the aim of the study was to assess the disinfection potential of radiofrequency glow discharge (RGD) by microbiological studies. MATERIALS AND METHODS: Disinfection potential of RGD on addition silicone (Reprosil, Dentsply, Milford DE, USA) was assessed. Total sample size was 20. Samples were divided into two groups of 10 each. Group I - control group and group II -RGD-treated group. Main groups were subdivided into subgroups A and B. Data collected were analyzed. RESULTS: The RGD-treated samples were found to be culture sterile which meant that there were no signs of growth of any organisms, thus proving the disinfection potential of RGD. CONCLUSION: From this study, we can conclude that RGD is a very rapid and handy device, which can disinfect saliva contaminated elastomeric impression material surfaces. CLINICAL SIGNIFICANCE: When compared with the difficulties and lack of efficiency encountered in disinfecting impressions by immersion and spray atomization, RGD can be very handy in dental clinics, as it is a very rapid and convenient method for infection control.

Src family protein tyrosine kinase regulates the basolateral K channel in the distal convoluted tubule (DCT) by phosphorylation of KCNJ10 protein.

The loss of function of the basolateral K channels in the distal nephron causes electrolyte imbalance. The aim of this study is to examine the role of Src family protein tyrosine kinase (SFK) in regulating K channels in the basolateral membrane of the mouse initial distal convoluted tubule (DCT1). Single-channel recordings confirmed that the 40-picosiemen (pS) K channel was the only type of K channel in the basolateral membrane of DCT1. The suppression of SFK reversibly inhibited the basolateral 40-pS K channel activity in cell-attached patches and decreased the Ba(2+)-sensitive whole-cell K currents in DCT1. Inhibition of SFK also shifted the K reversal potential from -65 to -43 mV, suggesting a role of SFK in determining the membrane potential in DCT1. Western blot analysis showed that KCNJ10 (Kir4.1), a key component of the basolateral 40-pS K channel in DCT1, was a tyrosine-phosphorylated protein. LC/MS analysis further confirmed that SFK phosphorylated KCNJ10 at Tyr(8) and Tyr(9). The single-channel recording detected the activity of a 19-pS K channel in KCNJ10-transfected HEK293T cells and a 40-pS K channel in the cells transfected with KCNJ10+KCNJ16 (Kir.5.1) that form a heterotetramer in the basolateral membrane of the DCT. Mutation of Tyr(9) did not alter the channel conductance of the homotetramer and heterotetramer. However, it decreased the whole-cell K currents, the probability of finding K channels, and surface expression of KCNJ10 in comparison to WT KCNJ10. We conclude that SFK stimulates the basolateral K channel activity in DCT1, at least partially, by phosphorylating Tyr(9) on KCNJ10. We speculate that the modulation of tyrosine phosphorylation of KCNJ10 should play a role in regulating membrane transport function in DCT1.

Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature.

Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, and of liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain. The utility of curcumin is limited by its color, lack of water solubility, and relatively low in vivo bioavailability. Because of the multiple therapeutic activities attributed to curcumin, however, there is an intense search for a "super curcumin" without these problems. Multiple approaches are being sought to overcome these limitations. These include discovery of natural curcumin analogues from turmeric; discovery of natural curcumin analogues made by Mother Nature; synthesis of "man-made" curcumin analogues; reformulation of curcumin with various oils and with inhibitors of metabolism (e.g., piperine); development of liposomal and nanoparticle formulations of curcumin; conjugation of curcumin prodrugs; and linking curcumin with polyethylene glycol. Curcumin is a homodimer of feruloylmethane containing a methoxy group and a hydroxyl group, a heptadiene with two Michael acceptors, and an alpha,beta-diketone. Structural homologues involving modification of all these groups are being considered. This review focuses on the status of all these approaches in generating a "super curcumin.".