Assessment of methadone clinic staff attitudes toward hepatitis C evaluation and treatment

We used a 25-item, self-administered questionnaire to assess staff's perceived barriers and willingness to engage in onsite treatment of hepatitis C virus (HCV) at the Beth Israel Medical Center methadone maintenance treatment program (MMTP) at its Harlem sites. Of 80 participants, 50% were counselors and 24% were directly involved in referral or HCV testing. Although 92% of the MMTP staff indicated that they discuss HCV evaluation and treatment with patients at least annually, 70% believed that less than 25% of patients accept referral for HCV treatment and attend their initial appointment. Most staff (66%) supported onsite HCV evaluation and treatment, although support was higher among those with a bachelor's degree or higher (p = 0.046). Lack of infrastructure was perceived as the greatest obstacle to onsite treatment. Educational interventions and skill building for staff to confidently engage and support MMTP patients in HCV treatment may be necessary prerequisites for onsite HCV management in MMTPs.     

Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C

Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-gamma (Mig/CXCL9), and interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR. The intrahepatic localization of chemokine producer cells and CXCR3(+) lymphocytes was determined in selected patients by immunohistochemistry. We found elevated intrahepatic mRNA expression of all three chemokines, most markedly CXCL10, in chronic HCV-infected patients with higher necroinflammation and fibrosis. By multivariable multivariate analysis, intrahepatic CXCL10 mRNA expression levels were significantly associated with lobular necroinflammatory grade and HCV genotype 1. In the lobular region, CXCL10-expressing and CXCL9-expressing hepatocytes predominated in areas with necroinflammation. Strong CXCL11 expression was observed in almost all portal tracts, whereas CXCL9 expression varied considerably among portal tracts in the same individual. Most intrahepatic lymphocytes express the CXCR3 receptor, and the number of CXCR3(+) lymphocytes was increased in patients with advanced necroinflammation. CONCLUSION: These findings suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the development of necroinflammation and fibrosis in the liver parenchyma in chronic HCV infection.     

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

Notch is an intercellular signaling pathway related mainly to sprouting neo-angiogenesis. The objective of our study was to evaluate the angiogenic mechanisms involved in the vascular augmentation (sprouting/intussusception) after Notch inhibition within perfused vascular beds using the chick area vasculosa and MxCreNotch1(lox/lox) mice. In vivo monitoring combined with morphological investigations demonstrated that inhibition of Notch signaling within perfused vascular beds remarkably induced intussusceptive angiogenesis (IA) with resultant dense immature capillary plexuses. The latter were characterized by 40 % increase in vascular density, pericyte detachment, enhanced vessel permeability, as well as recruitment and extravasation of mononuclear cells into the incipient transluminal pillars (quintessence of IA). Combination of Notch inhibition with injection of bone marrow-derived mononuclear cells dramatically enhanced IA with 80 % increase in vascular density and pillar number augmentation by 420 %. Additionally, there was down-regulation of ephrinB2 mRNA levels consequent to Notch inhibition. Inhibition of ephrinB2 or EphB4 signaling induced some pericyte detachment and resulted in up-regulation of VEGFRs but with neither an angiogenic response nor recruitment of mononuclear cells. Notably, Tie-2 receptor was down-regulated, and the chemotactic factors SDF-1/CXCR4 were up-regulated only due to the Notch inhibition. Disruption of Notch signaling at the fronts of developing vessels generally results in massive sprouting. On the contrary, in the already existing vascular beds, down-regulation of Notch signaling triggered rapid augmentation of the vasculature predominantly by IA. Notch inhibition disturbed vessel stability and led to pericyte detachment followed by extravasation of mononuclear cells. The mononuclear cells contributed to formation of transluminal pillars with sustained IA resulting in a dense vascular plexus without concomitant vascular remodeling and maturation.     

A model of plaid motion perception based on recursive Bayesian integration of the 1-D and 2-D motions of plaid features

We describe a theoretical and computational model of the perception of plaid pattern motion which fully accounts for the majority of cases in which misperception of the direction of motion of Type II plaids has been observed [Yo, C., & Wilson, H. (1992). Perceived direction of moving two-dimensional patterns depends on duration, contrast, and eccentricity. Vision Research 32, 135-147]. The model consists of two stages: in the first stage local motion detectors signal both the one-dimensional (1-D) and two-dimensional (2-D) motion of the high luminance features (blobs) in the plaid pattern; in the second stage these local motion signals are combined using a recursive Bayesian least squares estimation process. We demonstrate both theoretically and using simulations of the computational model that the estimated direction of the plaid motion for Type II plaids is initially dominated by the 1-D motion of the longer edges of the elongated blobs, which is in a direction close to the vector sum direction of the component gratings. The recursive estimation process which combines the local motion signals in the second stage of the model results in a dynamic shift in the estimated plaid direction towards the direction of the 2-D motion of the blobs, which corresponds to the veridical plaid direction.     

Efficacy of lamotrigine and vigabatrin in drug-resistant epilepsies of childhood

It was the purpose of this study to compare the efficacy and side effects of lamotrigine (LTG) and vigabatrin (VGB) as add-on therapy in epilepsies of childhood resistant to conventional drugs. Retrospective analysis of the medical charts and electroencephalograms of 134 children (LTG 57, VGB 77) was performed considering the various epileptic seizures and syndromes. In general, LTG and VGB had similar efficacy, with 30-40% of patients demonstrating significant improvement. Few differences according to seizure type and epileptic syndrome were observed. Primary generalized tonic-clonic seizures more frequently improved and less frequently worsened with LTG than with VGB. In tonic seizures the treatment results were significantly more favorable with VGB. Only insignificantly better results occurred with LTG in the generalized group and with VGB in the localization-related group. VGB was significantly more effective in symptomatic than in idiopathic and cryptogenic syndromes. The frequency of adverse reactions with both drugs was close to 60%. However, treatment had to be discontinued because of severe rashes in only a few patients taking LTG or because of behavior disturbances in patients taking VGB.     

Tissue microarray analysis of EGFR gene amplification and gain in Bulgarian patients with colorectal cancer

Colorectal cancer is one of the most common neoplastic diseases and a leading cause of cancer-related deaths. Overexpression of epidermal growth factor receptor (EGFR) is commonly associated with this cancer. The aim of our study was to determine the frequency of epidermal growth factor receptor gene amplification and gain in a large number of colorectal carcinomas, arranged in a tissue microarray, in order to assess their role in colorectal cancer development. A tissue microarray of 498 patients with colorectal tumors was constructed, and 239 samples for EGFR copy number changes were successfully analyzed by fluorescence in situ hybridization. No amplification of EGFR was detected in our cohort of patients with colorectal tumors, and the EGFR gene was upregulated in only 2 tumors (0.84%). Therefore, the development of colon cancer in patients cannot be explained by copy number changes of the EGFR gene.     

Case of Aicardi-Goutières syndrome with long-lasting increase of cerebrospinal interferon-alpha

Aicardi-Goutières syndrome is a rare progressive encephalopathy characterized by a typical clinical picture, bilateral basal ganglia calcifications, leukodystrophy and brain atrophy, lymphocytosis, and elevated interferon-alpha in the cerebrospinal fluid. Among the cases described to date, variability in the clinical expression or in the cerebrospinal fluid abnormalities has been reported. We present a case with a delayed diagnosis at the age of 8 years, when brain computed tomography was done because there was no first image from the age of 8 months, when the disease started. Symmetric basal ganglia calcifications were visualized and led to purposeful investigation of the cerebrospinal fluid. It revealed an interferon-alpha titer of 103 IU/mL, which, together with the progressive brain damage and disease course, was crucial for the diagnosis. This rare finding of long-term highly elevated interferon-alpha in the cerebrospinal fluid is discussed with respect to the clinical course.     

The use of human nasal in vitro cell systems during drug discovery and development.

The nasal route is widely used for the administration of drugs for both topical and systemic action. At an early stage in drug discovery and during the development process, it is essential to gain a thorough insight of the nasal absorption potential, metabolism and toxicity of the active compound and the components of the drug formulation. Human nasal epithelial cell cultures may provide a reliable screening tool for pharmaco-toxicological assessment of potential nasal drug formulations. The aim of this review is to give an overview of the information relevant for the development of a human nasal epithelial cell culture model useful during drug discovery and development. A primary goal in the development of in vitro cell culture systems is to maintain differentiated morphology and biochemical features, resembling the original tissue as closely as possible. The potential and limitations of the existing in vitro human nasal models are summarized. The following topics related to cell culture methodology are discussed: (i) primary cultures versus cell lines; (ii) cell-support substrate; (iii) medium and medium supplements; and (iv) the air-liquid interface model versus liquid-liquid. Several considerations with respect to the use of in vitro systems for pharmaceutical applications (transport, metabolism, assessment of ciliary toxicity) are also discussed.     

Oxidative stress and hypoxia: implications for plasminogen activator inhibitor-1 expression

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of urokinase-type and tissue-type plasminogen activators. It has gained special interest among clinicians because a number of pathological conditions, such as myocardial infarction, atherosclerosis, thrombosis, several types of cancer, and the metabolic syndrome, as well as type 2 diabetes mellitus, are associated with increased PAI-1 levels. Interestingly, a number of these diseases are also accompanied by oxidative stress and the enhanced production of reactive oxygen species or tissue hypoxia. This article tries to summarize some aspects leading to enhanced PAI-1 production under oxidative stress or hypoxia.