Increased fibrosis progression rates in hepatitis C patients carrying the prothrombin G20210A mutation

AIM: To examine whether hepatitis C virus (HCV)-infected patients who carry hypercoagulable mutationssuffer from increased rates of liver fi brosis. METHODS: We analyzed DNA samples of 168 HCV patients for three common hypercoagulable gene mutations: prothrombin 20210 (PT20210), factor V Leiden (FV Leiden) and methylene tetrahydrofolate reductase (MTHFR). The patients were consecutively recruited as part of the prospective Fibroscore Study in France. The effect of the various mutations on the rate of fi-bro...     

High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studies

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100–140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a “window of opportunity” in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD.     

Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response

Brain-derived neurotrophic factor (BDNF) and its intracellular kinase-activating receptor TrkB, have been implicated in the neurobiological mechanisms underlying the clinical manifestations of PTSD, especially those related to synaptic efficacy and neural plasticity. BDNF interacts with components of the stress response such as corticosterone, and plays an important role in growth, maintenance and functioning of several neuronal systems. This study employed an animal model of PTSD to investigate the relationship between prevalence rates of distinct patterns of behavioural responses to predator stress, circulating levels of corticosterone and local levels of mRNA for BDNF, TrkB and two other neurotrophic factors in selected brain areas. Animals whose behaviour was extremely disrupted by exposure selectively displayed significant down-regulation of mRNA for BDNF and up-regulation of TrkB mRNA in the CA1 subregion of the hippocampus, compared to animals whose behaviour was minimally or partially affected and to unexposed controls. The response was consistent throughout the entire study only in CA1. The consistent long-term the BDNF down-regulation and TrkB up-regulation associated with extreme behavioural compromise may be associated with chronic stress-induced psychopathological processes, especially in the hippocampus. The corresponding changes in neural plasticity and synaptic functioning may mediate clinical manifestations of PTSD.     

N-terminal and C-terminal fragments of IGFBP-4 as novel biomarkers for short-term risk assessment of major adverse cardiac events in patients presenting with ischemia

ObjectivesPregnancy Associated Plasma Protein A (PAPP-A)-derived N- and C-terminal fragments of IGF-binding protein-4 (NT- and CT-IGFBP-4) released from vulnerable atherosclerotic plaques are proposed to be used for cardiovascular risk assessment.Design and methodsNT- and CT-IGFBP-4 were measured by novel immunoassays in EDTA-plasma of 180 patients admitted to the emergency department with symptoms of myocardial ischemia but without ST-segment elevation. Six-month incidence of major adverse cardiac events (MACE), including myocardial infarction, cardiac death, percutaneous coronary interventions, and coronary artery bypass grafting was recorded.ResultsSixteen patients met the endpoint. NT- and CT-IGFBP-4 were strong predictors of MACE: area under ROC curve (AUC) 0.856 and 0.809, respectively. NT-IGFBP-4 concentrations ≥ 214 μg/L and CT-IGFBP-4 concentrations ≥ 124 μg/L were associated with increased risk of future MACE: adjusted hazard ratio 13.79 and 7.93, respectively.ConclusionsIGFBP-4 fragments can be utilized as biomarkers for MACE prediction in patients with suspected myocardial ischemia.     

Correlated expression of high-sensitivity C-reactive protein in relation to disease activity in inflammatory bowel disease: lack of differences between Crohn's disease and ulcerative colitis

BACKGROUND/AIMS: As opposed to regular C-reactive protein (CRP) assays, the introduction of high-sensitivity ones has enabled us to detect low grade inflammation in patients with inflammatory bowel disease (IBD). We addressed the subject of the degree of correlation between the concentration of high-sensitivity CRP (hs-CRP) and the inflammatory IBD activity score. METHODS: Included were 90 patients with Crohn's disease (CD), 70 with ulcerative colitis (UC) and 160 controls. Disease activity was determined using CD activity index (CDAI) for CD and Mayo score for UC. The Dade Boering BNII Nephelometer was used to determine the hs-CRP concentrations. RESULTS: The coefficient of correlation between hs-CRP and the disease activity score was similar for both UC (0.26) and CD (0.36). CONCLUSIONS: These findings are relevant for therapeutic intervention in which a greater absolute reduction in the hs-CRP concentration in CD patients (who generally present higher CRP concentrations than those found in UC) might be interpreted as a better response compared to the same absolute reduction in UC patients. This information is needed for clinicians using the hs-CRP assay to estimate IBD disease activity in daily practice.     

Psoriatic patients have a distinct structural and functional fecal microbiota compared with controls

Alterations in the gut microbiome have been implicated in the pathogenesis of several immune‐mediated inflammatory diseases such as psoriatic arthritis. This work aimed to characterize the gut microbial signature of patients with active psoriasis as compared with age‐, body mass index‐ and comorbidity‐matched non‐psoriatic controls and to correlate them with differential expression of metabolic pathways. Fecal samples were processed and 16S rRNA was sequenced. PICRUSt was used to perform an analysis of metabolic pathways. Of the 46 participants, 52% (n = 24) suffered from psoriasis. There was a significant difference in β‐diversity between the two groups. Psoriatic patients had a significant increase in the Firmicutes and Actinobacteria phyla as compared with matched controls. At the genus level, psoriatic patients had a unique bacterial composition. At the species level, the psoriatic patients showed significant increases in the relative proportions of (false discovery rate, <0.05) in Ruminoccocus gnavus, Dorea formicigenerans and Collinsella aerofaciens, while Prevotella copri and Parabacteroides distasonis were significantly decreased as compared with controls. PICRUSt analysis revealed increases in metabolic pathways related to lipopolysaccharide function in the psoriatic cohort. These data demonstrate unique fecal microbial and metabolic signatures in psoriatic patients.     

Opposing Effects of Diabetes and Tetracycline on the Degradation of Collagen Membranes in Rats

Background: Increased collagenolytic activity, characteristic of uncontrolled diabetes, may compromise collagen membrane (CM) survival. Tetracycline (TCN) possesses anticollagenolytic properties and delays CM degradation in healthy animals. This study evaluates the degradation of TCN‐‐immersed and ‐non‐immersed CMs in rats with diabetes compared to those with normoglycemia. Methods: Diabetes was induced in 15 12‐week‐old male Wistar rats by injection of 65 mg/kg streptozotocin. The control group consisted of 15 rats with normoglycemia. Sixty bilayered CM disks were labeled before implantation with aminohexanoyl‐biotin‐N‐hydroxy‐succinimide ester, of which 30 were immersed in 50 mg/mL TCN solution (experimental) or phosphate‐buffered saline (PBS) (control). In each animal, two disks (control and experimental) were implanted in two midsagittal calvarial defects in the parietal bone. Similar non‐implanted disks served as baseline. After 3 weeks, animals were euthanized, and the calvaria and overlying soft tissues were processed for demineralized histologic analysis. Horseradish peroxidase‐conjugated streptavidin was used to detect the biotinylated collagen. The area of residual collagen within the membrane disks was measured and analyzed with a digital image analysis system. Several slides from each specimen were also stained with hematoxylin and eosin. Statistical analysis consisted of paired and unpaired t tests. Results: The amount of residual collagen in PBS‐immersed disks was lower in rats with diabetes compared to rats with normoglycemia (69% of baseline versus 93%, respectively, P <0.001). TCN immersion increased the amount of residual collagen contents in both diabetic (83% of baseline) and healthy (97.5% of baseline) animals (P <0.0001). Conclusion: Diabetes increases CM degradation, whereas immersion in 50 mg/mL TCN solution before implantation presents an opposite effect.