Publications by authors named "Mashiko Setshedi"

20 Publications

  • Page 1 of 1

Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.

Cell Rep 2021 May;35(6):109101

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.

Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.
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May 2021

Defining the advantages and exposing the limitations of endoscopic variceal ligation in controlling acute bleeding and achieving complete variceal eradication.

World J Gastrointest Endosc 2020 Oct;12(10):365-377

Departments of Surgery and Medicine, University of Cape Town Health Sciences Faculty, Cape Town 7925, South Africa.

Background: Bleeding esophageal varices (BEV) is a potentially life-threatening complication in patients with portal hypertension with mortality rates as high as 25% within six weeks of the index variceal bleed. After control of the initial bleeding episode patients should enter a long-term surveillance program with endoscopic intervention combined with non-selective β-blockers to prevent further bleeding and eradicate EV.

Aim: To assess the efficacy of endoscopic variceal ligation (EVL) in controlling acute variceal bleeding, preventing variceal recurrence and rebleeding and achieving complete eradication of esophageal varices (EV) in patients who present with BEV.

Methods: A prospectively documented single-center database was used to retrospectively identify all patients with BEV who were treated with EVL between 2000 and 2018. Control of acute bleeding, variceal recurrence, rebleeding, eradication and survival were analyzed using Baveno assessment criteria.

Results: One hundred and forty patients (100 men, 40 women; mean age 50 years; range, 21-84 years; Child-Pugh grade A = 32; B = 48; C = 60) underwent 160 emergency and 298 elective EVL interventions during a total of 928 endoscopy sessions. One hundred and fourteen (81%) of the 140 patients had variceal bleeding that was effectively controlled during the index banding procedure and never bled again from EV, while 26 (19%) patients had complicated and refractory variceal bleeding. EVL controlled the acute sentinel variceal bleed during the first endoscopic intervention in 134 of 140 patients (95.7%). Six patients required balloon tamponade for control and 4 other patients rebled in hospital. Overall 5-d endoscopic failure to control variceal bleeding was 7.1% ( = 10) and four patients required a salvage transjugular intrahepatic portosystemic shunt. Index admission mortality was 14.2% ( = 20). EV were completely eradicated in 50 of 111 patients (45%) who survived > 3 mo of whom 31 recurred and 3 rebled. Sixteen (13.3%) of 120 surviving patients subsequently had 21 EV rebleeding episodes and 10 patients bled from other sources after discharge from hospital. Overall rebleeding from all sources after 2 years was 21.7% ( = 26). Sixty-nine (49.3%) of the 140 patients died, mainly due to liver failure ( = 46) during follow-up. Cumulative survival for the 140 patients was 71.4% at 1 year, 65% at 3 years, 60% at 5 years and 52.1% at 10 years.

Conclusion: EVL was highly effective in controlling the sentinel variceal bleed with an overall 5-day failure to control bleeding of 7.1%. Although repeated EVL achieved complete variceal eradication in less than half of patients with BEV, of whom 62% recurred, there was a significant reduction in subsequent rebleeding.
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October 2020

A Randomized Controlled Trial of Intravenous N-acetylcysteine in the Management of Anti-tuberculosis Drug-Induced Liver Injury.

Clin Infect Dis 2020 Aug 26. Epub 2020 Aug 26.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Liver injury is a common complication of first-line anti-tuberculosis therapy. N-acetylcysteine (NAC) is widely used in patients with paracetamol toxicity with limited evidence of benefit in liver injury due to other causes.

Methods: We conducted a randomized, double-blind, placebo-controlled trial to assess whether intravenous NAC hastens liver recovery in hospitalized adult patients with anti-tuberculosis drug induced liver injury (AT-DILI). The primary endpoint was the time for serum alanine aminotransferase (ALT) to fall below 100 U/L. Secondary endpoints included length of hospital stay, in-hospital mortality and adverse events.

Results: Fifty-three participants were randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV-positive. Median serum ALT and total bilirubin at presentation were 462 U/L (IQR 266-790) and 56 μmol/L (IQR 25-100) respectively. Median time to ALT&100 U/L was 7.5 days (IQR 6 -11) in the NAC arm and 8 days (IQR 5 -13) in the placebo arm. Median time to hospital discharge was shorter in the NAC arm (9 days; IQR 6-15) than in the placebo arm (18 days; IQR 10-25), hazard ratio 1.73 (95% CI 1.13-2.65). Mortality was 14% overall and did not differ by study arm. The study infusion was stopped early due to an adverse reaction in 5 participants receiving NAC [nausea and vomiting (3), anaphylaxis (1), pain at drip site (1)].

Conclusion: NAC did not shorten time to ALT&100 U/L in participants with AT-DILI, but significantly reduced length of hospital stay. NAC should be considered in management of AT-DILI.
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August 2020

Systematic review of the global epidemiology of viral-induced acute liver failure.

BMJ Open 2020 07 20;10(7):e037473. Epub 2020 Jul 20.

Vaccines for Africa Initiative, School of Public Health and Family Medicine, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa.

Objectives: The aetiology and burden of viral-induced acute liver failure remains unclear globally. It is important to understand the epidemiology of viral-induced ALF to plan for clinical case management and case prevention.

Participants: This systematic review was conducted to synthesize data on the relative contribution of different viruses to the aetiology of viral-induced acute liver failure in an attempt to compile evidence that is currently missing in the field. EBSCOhost, PubMed, ScienceDirect, Scopus and Web of Science were searched for relevant literature published from 2009 to 2019. The initial search was run on 9 April 2019 and updated via PubMed on 30 September 2019 with no new eligible studies to include. Twenty-five eligible studies were included in the results of this review.

Results: This systematic review estimated the burden of acute liver failure after infection with hepatitis B virus, hepatitis A virus, hepatitis C virus, hepatitis E virus, herpes simplex virus/human herpesvirus, cytomegalovirus, Epstein-Barr virus and parvovirus B19. Data were largely missing for acute liver failure after infection with varicella-zostervirus, human parainfluenza viruses, yellow fever virus, coxsackievirus and/or adenovirus. The prevalence of hepatitis A-induced acute liver failur was markedly lower in countries with routine hepatitis A immunisation versus no routine hepatitis A immunisation. Hepatitis E virus was the most common aetiological cause of viral-induced acute liver failure reported in this review. In addition, viral-induced acute liver failure had poor outcomes as indicated by high fatality rates, which appear to increase with poor economic status of the studied countries.

Conclusions: Immunisation against hepatitis A and hepatitis B should be prioritised in low-income and middle-income countries to prevent high viral-induced acute liver failure mortality rates, especially in settings where resources for managing acute liver failure are lacking. The expanded use of hepatitis E immunisation should be explored as hepatitis E virus was the most common cause of acute liver failure.

Registration: PROSPERO registration number: CRD42017079730.
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July 2020

Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study.

Gastroenterology 2021 01 12;160(1):99-114.e3. Epub 2020 Apr 12.

Dhaka Medical College & Hospital, Dhaka, Bangladesh.

Background & Aims: Although functional gastrointestinal disorders (FGIDs), now called disorders of gut-brain interaction, have major economic effects on health care systems and adversely affect quality of life, little is known about their global prevalence and distribution. We investigated the prevalence of and factors associated with 22 FGIDs, in 33 countries on 6 continents.

Methods: Data were collected via the Internet in 24 countries, personal interviews in 7 countries, and both in 2 countries, using the Rome IV diagnostic questionnaire, Rome III irritable bowel syndrome questions, and 80 items to identify variables associated with FGIDs. Data collection methods differed for Internet and household groups, so data analyses were conducted and reported separately.

Results: Among the 73,076 adult respondents (49.5% women), diagnostic criteria were met for at least 1 FGID by 40.3% persons who completed the Internet surveys (95% confidence interval [CI], 39.9-40.7) and 20.7% of persons who completed the household surveys (95% CI, 20.2-21.3). FGIDs were more prevalent among women than men, based on responses to the Internet survey (odds ratio, 1.7; 95% CI, 1.6-1.7) and household survey (odds ratio, 1.3; 95% CI, 1.3-1.4). FGIDs were associated with lower quality of life and more frequent doctor visits. Proportions of subjects with irritable bowel syndrome were lower when the Rome IV criteria were used, compared with the Rome III criteria, in the Internet survey (4.1% vs 10.1%) and household survey (1.5% vs 3.5%).

Conclusions: In a large-scale multinational study, we found that more than 40% of persons worldwide have FGIDs, which affect quality of life and health care use. Although the absolute prevalence was higher among Internet respondents, similar trends and relative distributions were found in people who completed Internet vs personal interviews.
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January 2021

The global epidemiology of viral-induced acute liver failure: a systematic review protocol.

BMJ Open 2019 08 30;9(8):e029819. Epub 2019 Aug 30.

Vaccines for Africa Initiative, University of Cape Town, Cape Town, South Africa.

Introduction: The burden of viral-induced acute liver failure (ALF) around the world still remains unclear, with little to no data collected regarding the disease incidence in general and synthesised data on the relative contribution of different viruses to the aetiology of ALF is missing in the field. The aim of this review is to estimate the burden (prevalence, incidence, mortality, hospitalisation) of ALF following infection . Establishing the common aetiologies of viral-induced ALF, which vary geographically, is important so that: (1) treatment can be initiated quickly, (2) contraindications to liver transplant can be identified, (3) prognoses can be deterined more accurately, and most importantly, (4) vaccination against viral ALF aetiologies can be prioritised especially in under-resourced regions with public health risks associated with the relevant attributable diseases.

Methods And Analysis: EBSCOhost, PubMed, ScienceDirect, Scopus and Web of Science databases will be searched for relevant literature published and grey literature from 2009 up to 2019. Published cross-sectional and cohort studies will be eligible for inclusion in this review. Qualifying studies will be formally assessed for quality and risk of bias using a standardised scoring tool. Following standardised data extraction, meta-analyses will be carried out using STATA. Depending on characteristics of included studies, subgroup analyses and meta-regression analyses will be performed. This review will be reported according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines.

Ethics And Dissemination: No ethics approval is required as the systematic review will use only published data already in the public domain. Findings will be disseminated through publication in a peer-reviewed journal.

Prospero Registration Number: CRD42018110309.
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August 2019

Resection of complex pancreatic injuries: Benchmarking postoperative complications using the Accordion classification.

World J Gastrointest Surg 2017 Mar;9(3):82-91

Jake E Krige, Eduard Jonas, Urda K Kotze, Surgical Gastroenterology Unit, Department of Surgery, University of Cape Town Health Sciences Faculty, Observatory, Cape Town 7925, South Africa.

Aim: To benchmark severity of complications using the Accordion Severity Grading System (ASGS) in patients undergoing operation for severe pancreatic injuries.

Methods: A prospective institutional database of 461 patients with pancreatic injuries treated from 1990 to 2015 was reviewed. One hundred and thirty patients with AAST grade 3, 4 or 5 pancreatic injuries underwent resection (pancreatoduodenectomy, = 20, distal pancreatectomy, = 110), including 30 who had an initial damage control laparotomy (DCL) and later definitive surgery. AAST injury grades, type of pancreatic resection, need for DCL and incidence and ASGS severity of complications were assessed. Uni- and multivariate logistic regression analysis was applied.

Results: Overall 238 complications occurred in 95 (73%) patients of which 73% were ASGS grades 3-6. Nineteen patients (14.6%) died. Patients more likely to have complications after pancreatic resection were older, had a revised trauma score (RTS) < 7.8, were shocked on admission, had grade 5 injuries of the head and neck of the pancreas with associated vascular and duodenal injuries, required a DCL, received a larger blood transfusion, had a pancreatoduodenectomy (PD) and repeat laparotomies. Applying univariate logistic regression analysis, mechanism of injury, RTS < 7.8, shock on admission, DCL, increasing AAST grade and type of pancreatic resection were significant variables for complications. Multivariate logistic regression analysis however showed that only age and type of pancreatic resection (PD) were significant.

Conclusion: This ASGS-based study benchmarked postoperative morbidity after pancreatic resection for trauma. The detailed outcome analysis provided may serve as a reference for future institutional comparisons.
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March 2017

Hepatoepigenetic Alterations in Viral and Nonviral-Induced Hepatocellular Carcinoma.

Biomed Res Int 2016 26;2016:3956485. Epub 2016 Dec 26.

Division of Hepatology and Liver Research, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Groote Schuur Hospital, Observatory 7925, Western Cape, South Africa.

Hepatocellular carcinoma (HCC) is a major public health concern and one of the leading causes of tumour-related deaths worldwide. Extensive evidence endorses that HCC is a multifactorial disease characterised by hepatic cirrhosis mostly associated with chronic inflammation and hepatitis B/C viral infections. Interaction of viral products with the host cell machinery may lead to increased frequency of genetic and epigenetic aberrations that cause harmful alterations in gene transcription. This may provide a progressive selective advantage for neoplastic transformation of hepatocytes associated with phenotypic heterogeneity of intratumour HCC cells, thus posing even more challenges in HCC treatment development. Epigenetic aberrations involving DNA methylation, histone modifications, and noncoding miRNA dysregulation have been shown to be intimately linked with and play a critical role in tumour initiation, progression, and metastases. The current review focuses on the aberrant hepatoepigenetics events that play important roles in hepatocarcinogenesis and their utilities in the development of HCC therapy.
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January 2017

Surgical Management and Outcomes of Combined Pancreaticoduodenal Injuries: Analysis of 75 Consecutive Cases.

J Am Coll Surg 2016 05;222(5):737-49

Department of Surgery, University of Cape Town Health Sciences Faculty, Cape Town, South Africa; Trauma Centre, Groote Schuur Hospital, Observatory, Cape Town, South Africa.

Background: Combined pancreaticoduodenal injuries (CPDI) are complex and result in significant morbidity and mortality. Survival in CPDI after initial damage-control laparotomy (DCL) and pancreaticoduodenectomy was evaluated in a large cohort treated in a Level I trauma center. We hypothesized that bivariate analyses would accurately identify factors influencing morbidity and mortality.

Study Design: The records from a prospective database of 453 consecutive patients treated for pancreatic injuries between January 1990 and April 2015 were reviewed to identify those with CPDI. Primary and secondary end points assessed were death and morbidity.

Results: Seventy-five patients (69 men, median age 27 years, range 14 to 56 years) with CPDI, underwent 161 operations (range 1 to 9 operations). Twenty-nine patients with complex CPDI underwent a DCL and 46 had definitive treatment during the initial operation. Nineteen had a pancreaticoduodenectomy, either during the initial operation (n = 13) or after the DCL (n = 6). Postoperative complications occurred in 63 (84%) patients. Twenty-one (28%) patients died, including 15 (43%) of 35 patients with associated vascular injuries. Sixteen (84%) of the 19 patients who had a pancreaticoduodenectomy survived. Significantly more complications related to bleeding, disseminated intravascular coagulation, and hypovolemic shock occurred in those patients who eventually died and significantly more abdominal sepsis and fistulas occurred in patients who survived. Mortality was related to associated vascular injuries overall (p < 0.01), major visceral venous injuries (p < 0.011), and the combination of vascular plus the total number of associated organs injured (p < 0.046).

Conclusions: Despite using DCL in CPDIs, morbidity (84%) and mortality (28%) remain substantial. Careful selection of patients undergoing pancreaticoduodenectomy resulted in 84% survival. Associated vascular injuries, major visceral venous injuries, and combined vascular and associated organs injured influenced outcomes and mortality.
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May 2016

Identification of a novel and severe pattern of efavirenz drug-induced liver injury in South Africa.

AIDS 2016 06;30(9):1483-5

aDivision of Hepatology, Department of Medicine bDepartment of Anatomical Pathology and NHLS cInstitute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town Faculty of Health Sciences and Groote Schuur Hospital, Observatory, Cape Town, South Africa.

Efavirenz now forms part of many antiretroviral regimens in low and middle-income countries. Efavirenz-related drug-induced liver injury is not well characterized but is thought to occur less frequently than with nevirapine. We describe our observation of three defined clinicopathological patterns of injury, one of which, submassive necrosis, is associated with significant morbidity and mortality. A high baseline CD4, younger age and possibly female gender, predicts for the injury.
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June 2016

Accuracy and impact of Xpert MTB/RIF for the diagnosis of smear-negative or sputum-scarce tuberculosis using bronchoalveolar lavage fluid.

Thorax 2013 Nov 29;68(11):1043-51. Epub 2013 Jun 29.

Department of Medicine, Lung Infection and Immunity Unit, Division of Pulmonology & UCT Lung Institute, University of Cape Town, , Cape Town, Western Cape, South Africa.

Rationale: The accuracy and impact of new tuberculosis (TB) tests, such as Xpert MTB/RIF, when performed on bronchoalveolar lavage fluid (BALF) obtained from patients with sputum-scarce or smear-negative TB is unclear.

Methods: South African patients with suspected pulmonary TB (n=160) who were sputum-scarce or smear-negative underwent bronchoscopy. MTB/RIF was performed on uncentrifuged BALF (1 ml) and/or a resuspended pellet of centrifuged BALF (∼10 ml). Time to TB detection and anti-TB treatment initiation were compared between phase one, when MTB/RIF was performed as a research tool, and phase two, when it was used for patient management.

Results: 27 of 154 patients with complete data had culture-confirmed TB. Of these, a significantly lower proportion were detected by smear microscopy compared with MTB/RIF (58%, 95% CI 39% to 75% versus 93%, 77% to 98%; p<0.001). Of the 127 patients who were culture negative, 96% (91% to 98%) were MTB/RIF negative. When phase two was compared with phase one, MTB/RIF reduced the median days to TB detection (29 (18-41) to 0 (0-0); p<0.001). However, more patients initiated empirical therapy (absence of a positive test in those commencing treatment) in phase one versus phase two (79% (11/14) versus 28% (10/25); p=0.026). Consequently, there was no detectable difference in the overall proportion of patients initiating treatment (26% (17/67; 17% to 37%) versus 36% (26/73; 26% to 47%); p=0.196) or the days to treatment initiation (10 (1-49) versus 7 (0-21); p=0.330). BALF centrifugation, HIV coinfection and a second MTB/RIF did not result in detectable changes in accuracy.

Conclusions: MTB/RIF detected TB cases more accurately and more rapidly than smear microscopy and significantly reduced the rate of empirical treatment.
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November 2013

Resolution of chronic hepatitis delta infection after five years of peginterferon-adefovir: lessons from a case report.

Clin Res Hepatol Gastroenterol 2013 Jun 20;37(3):e81-4. Epub 2013 Feb 20.

Department of Bacteriology-Virology-Hygiene, associated with the French National Reference Center for HDV, Avicenne Hospital, Paris 13 University, 125, rue de Stalingrad, 93009 Bobigny cedex, France.

There is still some controversy about the treatment of hepatitis delta virus (HDV) infection and the treatment endpoints. A 48-year-old patient was treated with a combination of peginterferon-α and adefovir, and HDV RNA clearance occurred after 3 years of treatment. However, treatment was continued until HBs antigen (Ag) seroconversion, which occurred after 5 years of therapy. One year after the end of the treatment, the patient was still HBs Ag and HDV RNA negative. This case report suggests that combined peginterferon-α and adefovir may be effective in treating HDV infection and, if given over a longer period, may result in hepatitis B surface antigen (HBsAg) seroconversion. It highlights the interest of using HBsAg quantification associated with a sensitive RT-PCR approach for monitoring the treatment of chronic hepatitis delta. HBsAg seroconversion, or at least significant decrease, could be a more relevant endpoint than HDV RNA undetectability for discontinuing HDV treatment and preventing the occurrence of virological relapses.
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June 2013

Insulin resistance, ceramide accumulation, and endoplasmic reticulum stress in human chronic alcohol-related liver disease.

Oxid Med Cell Longev 2012 22;2012:479348. Epub 2012 Apr 22.

Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.

Background: Chronic alcohol-related liver disease (ALD) is mediated by insulin resistance, mitochondrial dysfunction, inflammation, oxidative stress, and DNA damage. Recent studies suggest that dysregulated lipid metabolism with accumulation of ceramides, together with ER stress potentiate hepatic insulin resistance and may cause steatohepatitis to progress.

Objective: We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation.

Methods: We assessed the integrity of insulin signaling through the Akt pathway and measured proceramide and ER stress gene expression, ER stress signaling proteins, and ceramide profiles in liver tissue.

Results: Chronic ALD was associated with increased expression of insulin, IGF-1, and IGF-2 receptors, impaired signaling through IGF-1R and IRS1, increased expression of multiple proceramide and ER stress genes and proteins, and higher levels of the C14, C16, C18, and C20 ceramide species relative to control.

Conclusions: In human chronic ALD, persistent hepatic insulin resistance is associated with dysregulated lipid metabolism, ceramide accumulation, and striking upregulation of multiple ER stress signaling molecules. Given the role of ceramides as mediators of ER stress and insulin resistance, treatment with ceramide enzyme inhibitors may help reverse or halt progression of chronic ALD.
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September 2012

Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study.

J Gastroenterol Hepatol 2012 Feb;27(2):385-9

Division of Gastroenterology, Department of Medicine, University of Cape Town, South Africa.

Background And Aim: The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure.

Methods: We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007.

Results: We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non-Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3-67.4).

Conclusions: Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.
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February 2012

Limited therapeutic effect of N-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis.

Alcohol Clin Exp Res 2011 Dec 25;35(12):2139-51. Epub 2011 Jul 25.

Department of Medicine, Brown University, Providence, Rhode Island, USA.

Background: Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. As inflammation and oxidative stress can promote insulin resistance, effective treatment with antioxidants, for example, N-acetylcysteine (NAC), may restore ethanol-impaired insulin signaling in the liver.

Methods: Adult male Sprague-Dawley rats were fed for 130 days with liquid diets containing 0 or 37% ethanol by caloric content, and simultaneously treated with vehicle or NAC. Chow-fed controls were studied in parallel. Liver tissues were used for histopathology, cytokine activation, and insulin/IGF-1 signaling assays.

Results: We observed significant positive trends of increasing severity of steatohepatitis (p = 0.016) with accumulation of neutral lipid (p = 0.0002) and triglycerides (p = 0.0004) from chow to control, to the ethanol diet, irrespective of NAC treatment. In ethanol-fed rats, NAC reduced inflammation, converted the steatosis from a predominantly microvesicular to a mainly macrovesicular histological pattern, reduced pro-inflammatory cytokine gene expression, ceramide load, and acid sphingomyelinase activity, and increased expression of IGF-1 receptor and IGF-2 in liver. However, NAC did not abrogate ethanol-mediated impairments in signaling through insulin/IGF-1 receptors, IRS-1, Akt, GSK-3β, or p70S6K, nor did it significantly reduce pro-ceramide or GM3 ganglioside gene expression in liver.

Conclusions: Antioxidant treatments reduce the severity of chronic alcohol-related steatohepatitis, possibly because of the decreased expression of inflammatory mediators and ceramide accumulation, but they do not restore insulin/IGF-1 signaling in liver, most likely due to persistent elevation of GM3 synthase expression. Effective treatment of alcohol-related steatohepatitis most likely requires dual targeting of oxidative stress and insulin/IGF resistance.
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December 2011

Changing trends and the impact of alcohol on the HIV/AIDS epidemic in South Africa: review.

SAHARA J 2011 ;8(2):89-96

Warren Alpert Medical School of Brown University, Providence, RI, USA.

The association between increased HIV infection and alcohol use has been extensively studied and is established. South Africa is among one of the sub-Saharan African countries with the highest prevalence and number of people living with HIV/AIDS in the world. Although recent evidence suggests that the epidemic has stabilised, infection rates remain unacceptably high. Alcohol use is on the increase, particularly in the groups most susceptible to HIV infection, namely women and young adults, and informs poor choices with respect to safer sexual practices. This paper reviews the association between alcohol and HIV. More specifically, however, it aims to explore the potential socio-politico-biological and cultural explanations as to the factors that intersect to drive these two epidemic diseases: alcoholism and HIV/AIDS in South Africa. Understanding some of the underlying factors will provide a framework to implement public health measures to curb HIV.
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May 2013

Rat strain differences in susceptibility to alcohol-induced chronic liver injury and hepatic insulin resistance.

Gastroenterol Res Pract 2010 16;2010. Epub 2010 Aug 16.

Departments of Medicine and Pathology, Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Pierre Galletti Research Building, 55 Claverick Street, Room 421, Providence, RI 02903, USA.

The finding of more severe steatohepatitis in alcohol fed Long Evans (LE) compared with Sprague Dawley (SD) and Fisher 344 (FS) rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories) ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1-3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation.
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July 2011

Acetaldehyde adducts in alcoholic liver disease.

Oxid Med Cell Longev 2010 May-Jun;3(3):178-85

Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA.

Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD), with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC). Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2-15%) versus cirrhosis (15-20%) is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular system and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC.
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December 2010

Ceramide-mediated insulin resistance and impairment of cognitive-motor functions.

J Alzheimers Dis 2010 ;21(3):967-84

Department of Pathology (Neuropathology), Rhode Island Hospital, Providence, RI 02903, USA.

Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) are associated with cognitive impairment, brain insulin resistance, and neurodegeneration. Recent studies linked these effects to increased pro-ceramide gene expression in liver and increased ceramide levels in serum. Since ceramides are neurotoxic and cause insulin resistance, we directly examined the role of ceramides as mediators of impaired signaling and central nervous system function using an in vivo model. Long Evans rat pups were administered C2Cer:N-acetylsphinganine or its inactive dihydroceramide analog (C2DCer) by i.p. injection. Rats were subjected to rotarod and Morris water maze tests of motor and cognitive function, and livers and brains were examined for histopathology and integrity of insulin/IGF signaling. C2Cer treatment caused hyperglycemia, hyperlipidemia, and mild steatohepatitis, reduced brain lipid content, and increased ceramide levels in liver, brain, and serum. Quantitative RT-PCR analysis revealed significant alterations in expression of several genes needed for insulin and IGF-I signaling, and multiplex ELISAs demonstrated inhibition of signaling through the insulin or IGF-1 receptors, IRS-1, and Akt in both liver and brain. Ultimately, the toxic ceramides generated in peripheral sources such as liver or adipose tissue caused sustained impairments in neuro-cognitive function and insulin/IGF signaling needed for neuronal survival, plasticity, and myelin maintenance in the brain. These findings support our hypothesis that a liver/peripheral tissue-brain axis of neurodegeneration, effectuated by increased toxic lipid/ceramide production and transport across the blood-brain barrier, could mediate cognitive impairment in T2DM and NASH.
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January 2011