Diagnostic accuracy, reproducibility and robustness of fibrosis blood tests in chronic hepatitis C: a meta-analysis with individual data

ObjectivesTo evaluate the diagnostic accuracy of liver fibrosis tests and its influencing factors in a meta-analysis with individual data.Design and methodsFour independent centers provided four blood tests and Metavir staging from 825 patients with chronic hepatitis C.ResultsFibroMeter AUROC (0.840) for significant fibrosis was superior to those of Fibrotest (0.803, p = 0.049), APRI (0.789, p = 0.001) and Hepascore (0.781, p < 0.001). The misclassification rate was lower for FibroMeter (23%) than for Fibrotest and Hepascore (both 28%, p < 0.001). The variation in the diagnostic cut-offs of tests among centers, reflecting the overall reproducibility, was: FibroMeter: 4.2%, APRI: 24.0%, Fibrotest: 24.2%, Hepascore: 35.0%. Accordingly, the proportion of patients diagnosed with significant fibrosis changed: FibroMeter: 0.8%, Hepascore: 2.4% (p = 0.02 vs FibroMeter), Fibrotest: 5.8% (p < 10^? 3), APRI: 18.2% (p < 10^? 3).ConclusionsThis study on clinical applicability shows significant differences in diagnostic accuracy, inter-center reproducibility, and robustness of biomarkers to changes in population characteristics between blood tests.     

Electrolytic lesions of the habenula attenuate brain stimulation reward

The present experiment used electrolytic lesions in combination with curve-shift scaling to study the functional relation between the habenula and four different brain sites that support operant responding for brain stimulation reward. Rats were implanted with a monopolar stimulation electrode aimed at the lateral hypothalamus, ventral tegmental area, dorsal raphe or median raphe nuclei, and a lesioning electrode in the ipsilateral habenula. Operant nose poking resulted in self-administration of trains of electrical pulses to one of the above stimulation sites. Reward thresholds were derived from response-number curves and defined as the pulse number necessary for half-maximal responding. Rats were tested daily at each of three current intensities that were chosen from individual number-current trade-off functions and that yielded baseline reward thresholds of approximately 10, 20 and 40 pulses/train. Testing resumed 24h after lesioning the habenula (100 muA anodal current, 20-25s) and continued for 3-4 weeks. A total of 19 rats completed the experiment. In five of these, habenular lesions clearly reduced the rewarding effectiveness of the stimulation; reward thresholds increased by approximately 30-245% (0.12-0.54 log10 units). Generally, lesion effects were observed at low and medium current intensities, developed gradually and did not recover. Histological analysis revealed that in two rats the stimulation electrode was located in the posterior lateral hypothalamus, two in the anterior ventral tegmental area and one in the area of the dorsal raphe. These results strongly suggest that the habenula constitutes an important component of the neural circuitry important for brain stimulation reward.     

Relation of the "hypertriglyceridemic waist" phenotype to earlier manifestations of coronary artery disease in patients with glucose intolerance and type 2 diabetes mellitus

This study tested the hypothesis that the "hypertriglyceridemic waist" phenotype (waist girth >90 cm [35.4 inches] in men and >85 cm [33.5 inches] in women, along with a plasma triglyceride concentration of >or=2.0 mmol/L [177 mg/dl]) as a covariate of metabolic syndrome features (hyperinsulinemia, hyperapolipoprotein B, and small low-density lipoprotein particles), is predictive of premature coronary artery disease (CAD) among patients with glucose intolerance or type 2 diabetes. Glucose intolerance and type 2 diabetes were assessed after an oral glucose tolerance test among 1,190 men and women using the American Diabetes Association criteria. Glycemic control was evaluated using hemoglobin A1c levels. CAD was considered present on the basis of a clinical history of retrosternal pains on exertion, electrophysiologically and clinically documented myocardial infarction, or angiographic evidence of coronary lesions. More than 53% of men (n = 103) with a waist circumference >or=90 cm (35.4 inches) and nearly 80% of women (n = 122) with a waist circumference >or=85 cm (33.5 in.) with triglyceride levels >or=2 mmol/L (177 mg/dl) were diagnosed with glucose intolerance or type 2 diabetes. Survival models revealed that those with glucose intolerance or type 2 diabetes with the "hypertriglyceridemic waist" phenotype experienced their first CAD symptoms 5 years earlier than those without this phenotype. This elevated and earlier risk of CAD was statistically significant (hazard ratio 2.0, 95% confidence interval 1.2 to 3.7, p = 0.02). In conclusion, the "hypertriglyceridemic waist" phenotype, an inexpensive and simple tool identifying subjects with metabolic syndrome features, is a significant marker of CAD manifestations occurring at an earlier age in those with glucose intolerance or type 2 diabetes.     

Structural neural correlates of impairments in social cognition in first episode psychosis

Several studies have demonstrated that patients with schizophrenia show impairments in social cognition and current evidence indicate that this deficit is associated with abnormal activity in specific brain regions. In addition to functional imaging studies, we believe that the identification of structural correlates of social cognitive processes may help to better understand the neural underpinnings of these specific skills. The main objective of this study was to investigate the relationship between gray matter density and social cognitive deficits in first episode of schizophrenia spectrum psychosis, using a comprehensive assessment that we previously demonstrated to be a highly sensitive measure of social cognitive deficits in this population. Thirty-eight patients with a first episode of psychosis participated in this study, and the Four Factor Test of Social Intelligence was used as a measure of social cognition. Social cognitive impairments in first episode psychosis were significantly correlated with reduced gray-matter density in the left middle frontal gyrus other regions within the mirror neuron system network (MSN), namely the right supplementary motor cortex, the left superior temporal gyrus and the left inferior parietal lobule. We concluded that structural abnormalities within the MSN may account for the social cognitive deficits present in some psychiatric disorders, such as schizophrenia.     

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.     

Relationship between prolactin secretion, and plasma risperidone and 9-hydroxyrisperidone concentrations in adolescents with schizophreniform disorder

BACKGROUND: Treatment with the atypical antipsychotic risperidone can result in elevated prolactin levels. To date, the relationships between plasma concentrations of prolactin, risperidone and its active 9-hydroxy-metabolite have been little investigated in adolescents with psychosis. METHODS: Prolactin levels were determined at baseline in 16 hospitalized drug-na?ve adolescents meeting DSM-IV criteria for schizophreniform disorder. Prolactin, risperidone, 9-hydroxyrisperidone levels were subsequently determined after 3 weeks of oral risperidone treatment. RESULTS: Compared with pretreatment values, prolactin levels at endpoint were significantly increased (p<0.00001) and correlated with risperidone doses (r=0.58, N=16, p<0.02), and plasma levels of risperidone (r=0.60, N=16, p<0.02) and 9-hydroxyrisperidone (r=0.54, N=16, p=0.03). CONCLUSIONS: These data suggest that risperidone's effect on prolactin release is dose-dependent in adolescents and is linked to both plasma risperidone and 9-hydroxyrisperidone concentrations.     

5-hydroxyoxindole, an indole metabolite, is present at high concentrations in brain

5-Hydroxyoxindole has been identified as a urinary metabolite of indole, which is produced from tryptophane via the tryptophanase activity of gut bacteria. We have demonstrated recently that 5-hydroxyoxindole is an endogenous compound in blood and tissues of mammals, including humans. To date, 5-hydroxyoxindole's role is unknown. The aim of this study was to compare 5-hydroxyoxindole levels in plasma and cerebrospinal fluid (CSF) during day-night and seasonal changes, as a common approach to pilot physiological characterization of any compound. Simultaneous blood and CSF sampling was performed in the ewe, because its size allows collection in quantities suitable for 5-hydroxyoxindole assay (HPLC-ED) in awake animals, without obvious physiological or behavioral disturbance. 5-Hydroxyoxindole concentration was quite stable in plasma (2-6 nM range), whereas, in CSF, it displayed marked day-night and photoperiodic variations (4-116 nM range). 5-Hydroxyoxindole levels in CSF were twofold higher at night than during the day and at least one order of magnitude higher during the long compared with the short photoperiod. These day/night and photoperiodic variations persisted after pinealectomy, indicating that 5-hydroxyoxindole rhythms in CSF are independent of melatonin formation. In conclusion, high levels of 5-hydroxyoxindole in the CSF during long photoperiod and its daily modulation suggest physiological involvement of 5-hydroxyoxindole in rhythmic adjustments in the brain, independently of the pineal gland.