Psychological stress is associated with relapse in type 1 autoimmune hepatitis.

BACKGROUND/AIM: The pathophysiological basis of relapse and recrudescence in type 1 autoimmune hepatitis (AIH) is poorly understood. This study examined factors associated with biochemical relapse in type 1 AIH, and specifically addressed whether psychological stress was associated with a relapsing-remitting disease course. METHODS: A case-control study design was used to analyse 33 patients with AIH followed at the Yale Liver Clinic during a 4-year period. Twenty-two patients with 46 episodes of relapse or recrudescence (cases) and 11 controls in long-term remission were identified during this period. Clinical variables were collected to establish factors associated with relapse. All patients were administered the Social Readjustment Rating Scale (SRRS), a psychological stress questionnaire consisting of 43 weighted life events. Stress is judged to be low when the score is 0-150; mild, 151-200; moderate, 201-300 and major >300. RESULTS: AST, ALT, prednisone dose and SRRS score were all significantly different between cases and controls. The mean SRRS score for cases with relapse/recrudescence was 239 vs 152 for the control group, P=0.048 and remained significant on ancova analysis which accounted for covariables, P=0.05. Cases also identified additional stressors not represented in the SRRS at a significantly higher rate than controls. Conversely, the controls spontaneously identified coping strategies that may have allowed them to manage stress more effectively. CONCLUSION: Psychological stress is a significant factor that is associated with relapse in type 1 autoimmune hepatitis. Management of AIH may benefit from strategies to reduce stress and promote psychological well being.

Correlation of DTI metrics in the wall and cavity of brain abscess with histology and immunohistochemistry.

Diffusion tensor imaging (DTI) was performed in eight patients with brain abscess (BA). The aim of this study was to see the difference in the relationship between intercellular cell adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) expression and DTI metrics measured in vivo in the wall and cavity of BA and its possible explanation vis-à-vis histology and immunohistochemistry. Neuroinflammatory molecules (NMs) were quantified from BA cavity aspirate of the patients and quantitative immunohistochemical analysis was performed for ICAM-1 and LFA-1 in the BA wall, showing maximal positive staining and correlated with DTI metrics. The fractional anisotropy (FA) significantly increased while mean diffusivity and spherical anisotropy significantly decreased in the BA wall compared to the BA cavity. In the BA wall, FA and linear anisotropy (CL) showed a significant positive correlation with ICAM-1 and LFA-1 expression whereas FA and planar anisotropy positively correlated with NMs quantified from aspirated pus respectively. Higher FA values in the BA wall compared to BA cavity, even when ICAM-1 and LFA-1 were expressed only in the macrophages and not in the collagen fibers, suggests that a combination of both concentric layers of collagen fibers as well as neutrophils and macrophages provide structural orientation and are responsible for increased FA. In the BA wall, increased CL was found compared to the cavity, indicating the presence of concentrically laid collagen fibers responsible for the diffusion of water molecules in the direction parallel to the collagen fibers. We conclude that in the BA, different mechanisms are operative for the changes in the DTI metrics in the wall and cavity; these conclusions are validated by histology and immunohistochemistry.

Correlation of diffusion tensor imaging with histology in the developing human frontal cerebrum.

Transient early cerebral laminar organization resulting from normal developmental events has been revealed in human beings through histology and imaging studies. DTI studies have postulated that the fractional anisotropy (FA)-based differentiation of different laminar structures reflects both differing cellular density over the glial fibers and fiber alignment in respective regions. The aim of this study was to correlate FA values in these transient zones with histology. Brain DTI was performed on 50 freshly aborted human fetuses with gestational ages (GA) ranging from 12 to 42 weeks. Regions of interest were placed on the cortical plate, subplate, intermediate and germinal matrix (GMx) zones of the frontal lobe to quantify FA values. Glial fibrillary acidic protein (GFAP), neurofilament (NF) and neuron-specific enolase (NSE) immunohistochemical analyses were performed for the cortical plate, intermediate zone and GMx. In the cortical plate, a significant positive correlation was observed between FA values and percentage area of GFAP expression in fetuses

Region-specific maturation of cerebral cortex in human fetal brain: diffusion tensor imaging and histology.

INTRODUCTION: In this study, diffusion tensor imaging (DTI) and glial fibrillary acidic protein (GFAP) immunohistochemical analysis in different cortical regions in fetal brains at different gestational age (GA) were performed. METHODS: DTI was performed on 50 freshly aborted fetal brains with GA ranging from 12 to 42 weeks to compare age-related fractional anisotropy (FA) changes in different cerebral cortical regions that include frontal, parietal, occipital, and temporal lobes at the level of thalami. GFAP immunostaining was performed and the percentage of GFAP-positive areas was quantified. RESULTS: The cortical FA values in the frontal lobe peaked at around 26 weeks of GA, occipital and temporal lobes at around 20 weeks, and parietal lobe at around 23 weeks. A significant, but modest, positive correlation (r = 0.31, p = 0.02) was observed between cortical FA values and percentage area of GFAP expression in cortical region around the time period during which the migrational events are at its peak, i.e., GA < or = 28 weeks for frontal cortical region and GA < or = 22 weeks for rest of the lobes. CONCLUSIONS: The DTI-derived FA quantification with its GFAP immunohistologic correlation in cortical regions of the various lobes of the cerebral hemispheres supports region-specific migrational and maturational events in human fetal brain.

Diffusion tensor imaging in the developing human cerebellum with histologic correlation.

Diffusion tensor imaging was performed on 24 freshly aborted human fetuses with gestational age ranging from 20 to 37 weeks to observe age-related fractional anisotropy changes in cerebellar cortex and cerebellar white matter. Quantitative immunohistochemical analysis was performed for glial fibrillary acidic protein in each fetus molecular layer of cerebellar cortex and myelin basic protein expression was quantified in myelinated areas of the middle cerebellar peduncles. The cerebellar cortical fractional anisotropy reached its peak value at 28 weeks, and then decreased gradually until 37 weeks. The time course of glial fibrillary acidic protein expression paralleled that of fractional anisotropy in the cerebellar cortex from 20 weeks of gestation upto the gestational age at which the fractional anisotropy reached its peak value (28 weeks). In the middle cerebellar peduncles, the fractional anisotropy increased continuously upto 37 weeks of gestational age and showed a significant positive correlation with myelin basic protein immunostained fibers. The fractional anisotropy quantification can be used to assess the migrational and maturation changes during the development of the human fetal cerebellum supported by the immunohistochemical analysis.

Dynamic contrast-enhanced derived cerebral blood volume correlates better with leak correction than with no correction for vascular endothelial growth factor, microvascular density, and grading of astrocytoma.

OBJECTIVE: To look for the impact of leak correction on correlation of perfusion indices with microvessel density (MVD) and vascular endothelial growth factor (VEGF) in astrocytomas. METHODS: Dynamic contrast-enhanced magnetic resonance imaging was performed in 64 patients with varying grades of astrocytoma. Perfusion indices (ie, relative cerebral blood volume (rCBV) with and without leak correction, relative cerebral blood flow (rCBF), permeability (k(trans)), and leakage (v(e)) were quantified. MVD and VEGF-expressing cells were quantified from the excised tumor tissues and were correlated with perfusion metrics. RESULTS: Perfusion indices showed significant difference among the astrocytoma grades. The corrected rCBV correlated better with MVD and VEGF. The corrected rCBV correlated (r = 0.853, P = <0.001) strongly, whereas the uncorrected rCBV (r = 0.592, P = <0.001) and k(trans) (r = 0.498, P = 0.001) correlated moderately with tumor grade. The corrected rCBV discriminated 100% low-grade from high-grade astrocytoma, while uncorrected rCBV did this in 95.5% low-grade and 71.4% high-grade astrocytoma. CONCLUSIONS: Corrected rCBV better correlates with grade and is more accurate in discriminating low-grade from high-grade astrocytoma compared with uncorrected rCBV.

Morbid obesity, nonalcoholic fatty liver disease, and weight loss surgery.

OBJECTIVE: This study examines the impact of biliopancreatic diversion, a malabsorptive variant of gastric bypass, on liver histology. METHODS: Liver samples were collected from 689 severely obese (BMI 47 +/- 9 kg m(2)) patients undergoing biliopancreatic diversion. Exclusion criteria included: history of hepatitis, exposure to hepatotoxic medications, prior weight loss surgery, and alcohol consumption greater than 100 grams per week. One group of 14 patients had cirrhosis in their initial biopsy. Eleven of those 14 patients underwent multiple biopsies to monitor their liver disease. A second group of 104 patients had re-operations and a second liver biopsy. A hepatopathologist conducted blind evaluations of all biopsy specimens looking for steatosis and fibrosis. RESULTS: All patients lost weight and showed improvement in their metabolic syndrome. Of the 104 patients undergoing re-operation with a second liver biopsy, 28 showed a decrease in severe fibrosis, while 42 patients developed mild fibrosis. On average, this group lost 38 +/- 18 kg over 41 +/- 25 post-surgical months. A sub-group analysis revealed an association between increased fibrosis and post-operative low serum albumin, diarrhea, pre-operative alcohol consumption, and menopausal status. The eleven patients with cirrhosis in their initial biopsy showed a reduction in their fibrosis grade (mean fibrosis grade from 5 to 3) during nine years of follow-up care. CONCLUSION: These findings indicate that significant weight loss after biliopancreatic diversion can improve liver histology in patients with advanced fibrosis.

Sustained virological response rate to pegylated interferon plus ribavirin for chronic hepatitis C in African Americans: results in treatment-naïve patients in a university liver clinic.

OBJECTIVE: The sustained virological response (SVR) to non-pegylated interferon-based regimens for chronic hepatitis-C virus (HCV) has been lower among African Americans compared to Caucasians, a finding attributed to the high proportion of genotype-1 infections in African Americans. To determine whether such a difference in SVR is still present with pegylated interferon and ribavirin regimens, we analyzed SVR rates among treated racial groups according to genotype. METHODS: Consecutive treatment-naïve patients of multiethnic and racial backgrounds attending a university liver clinic received either Peg alfa-2a or -2b plus ribavirin 1-1.2 g based on body weight for 24-48 weeks, depending on genotype. HCV RNA titers were analyzed at 0, six or 12 months, and six months posttreatment. RESULTS: Among the first 193 patients eligible for treatment, 73 received therapy [24 African Americans (genotype 1 in 88%); 49 non-African Americans (genotype 1 in 59%)]. Of the 120 patients not treated (33% African-American and 67% non-African-American), most either had mild hepatitis on biopsy, normal ALT values, an untreated psychiatric condition or had a low expectation of treatment efficacy. SVR results for the 73 patients who completed treatment indicate that African Americans and non-African Americans with genotype 1 have similarly low rates of SVR (19% in African Americans compared with 24% in non-African Americans, p=NS). CONCLUSION: Sustained viral response rates in our open-access liver clinic are similar for genotype-1 African Americans compared to non-African Americans receiving pegylated interferon and ribavirin. The predominance of genotype 1 among African-American patients likely accounts for the lower response rates, but genotype 1 in other racial groups is associated with a proportionately lower SVR as well as a risk for delayed relapse after SVR.

Hepatoprotection by 3-bromo-6-(4-chlorophenyl)-4-methylthio-2H-pyran-2-one against experimentally induced liver injury in rats.

Hepatoprotective activity of 3-bromo-6-(4-chlorophenyl)-4-methylthio-2H-pyran-2-one, an isostere of dimethyl ricinine, was evaluated in adult male albino rats intoxicated with carbon tetrachloride, paracetamol or thioacetamide. The test compound showed significant hepatoprotection at 6.0 mg kg(-1) body mass daily dose, given to the rats for seven consecutive days. The carbon tetrachloride, paracetamol and thioacetamide were given, respectively, on days 3, 5, and 7, on day 6 and on day 6 post treatment with the test compound. The protective effect was evident in a battery of serum and liver biochemical parameters related to hepatotoxicity.