Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α–based therapies to IFN-α–free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia.METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed.RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed.CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01441180","term_id":"NCT01441180"}}NCT01441180.FUNDING. Intramural Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, and National Cancer Institute; German Research Foundation.     

Synthesis,characterization, and computational studies on phthalic anhydride-based benzylidene-hydrazide derivatives as novel,potential anti-inflammatory agents

A series of phthalic anhydride-based substituted benzylidene-hydrazide derivatives (3a–i) was synthesized. The synthesized derivatives were authenticated by TLC, UV–visible, FTIR, NMR, and mass spectroscopic techniques and further screened for in vivo anti-inflammatory and analgesic activities by carrageenan-induced rat paw oedema and tail immersion methods, respectively, using diclofenac sodium as standard drug. The derivatives 3d, 3e, and 3h were found to be most active anti-inflammatory and analgesic agents among all the synthesized derivatives. The physico-chemical similarity of the derivatives with standard drugs was assessed by calculating various physicochemical properties using software programs. The percent similarity of synthesized derivatives was found to be good except 3i. The derivatives were subjected to QSAR by multilinear regression using Analyze it version 3.0 software and two statistically sound models were developed with R ² (0.933–0.960), $ R_{{adj}}^{2} $ (0.595–0.762) and Q ² (0.999) with good F (2.76–4.84) values. Molecular docking studies were performed by MVD software (version 2012.5.0.0). The derivative 3h has emerged out as most potent anti-inflammatory agent with highest dock score, i.e., ?93.64.     

Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening

BACKGROUND: Long-term benefits of newborn screening (NBS) for cystic fibrosis (CF) have been established with respect to nutritional status, but effects on pulmonary health remain unclear. HYPOTHESIS: With early diagnosis and commencement of standardised treatment, lung function at ～3 months of age is normal in NBS infants with CF. METHODS: Lung clearance index (LCI) and functional residual capacity (FRC) using multiple breath washout (MBW), plethysmographic (pleth) FRC and forced expirations from raised lung volumes were measured in 71 infants with CF (participants in the London CF Collaboration) and 54 contemporaneous healthy controls age ～3 months. RESULTS: Compared with controls, and after adjustment for body size and age, LCI, FRC(MBW) and FRC(pleth) were significantly higher in infants with CF (mean difference (95% CI): 0.5 (0.1 to 0.9), p=0.02; 0.4 (0.1 to 0.7), p=0.02 and 0.9 (0.4 to 1.3), p<0.001, z-scores, respectively), while forced expiratory volume (FEV(0.5)) and flows (FEF(25-75)) were significantly lower (-0.9 (-1.3 to -0.6), p<0.001 and -0.7 (-1.1 to -0.2), p=0.004, z-scores, respectively). 21% (15/70) of infants with CF had an elevated LCI (>1.96 z-scores) and 25% (17/68) an abnormally low FEV(0.5) (below -1.96 z-scores). While only eight infants with CF had abnormalities of LCI and FEV(0.5), using both techniques identified abnormalities in 35% (24/68). Hyperinflation (FRC(pleth) >1.96 z-scores) was identified in 18% (10/56) of infants with CF and was significantly correlated with diminished FEF(25-75) (r=-0.43, p<0.001) but not with LCI or FEV(0.5). CONCLUSION: Despite early diagnosis of CF by NBS and protocol-driven treatment in specialist centres, abnormal lung function, with increased ventilation inhomogeneity and hyperinflation and diminished airway function, is evident in many infants with CF diagnosed through NBS by 3 months of age.     

Using Multiple Sampling Approaches to Measure Sexual Risk‐taking Among Young People in Haiti: Programmatic Implications

No previous published research has examined the applicability of varying methods for identifying young people who are at high risk of experiencing unintended pregnancy and acquiring HIV infection. This study compares three surveys of young people aged 15–24 in Port‐au‐Prince, Haiti, in terms of their sociodemographic characteristics and sexual behaviors and the surveys' usefulness for identifying young people at high risk and for program planning. The surveys consist of responses from: a representative sample of young people in the 2005–06 Haiti Demographic and Health Survey (HDHS), a 2004 facility‐based study, and a 2006–07 venue‐based study that used the Priorities for Local AIDS Control Efforts (PLACE) method. The facility‐based and PLACE studies included larger proportions of single, sexually experienced young people and people who knew someone with HIV/AIDS than did the HDHS. More respondents in the PLACE sample had multiple sex partners in the past year and received money or gifts in return for sex, compared with respondents in the facility study. At first and last sex, more PLACE respondents used contraceptives, including condoms. Experience of pregnancy was most commonly reported in the data from the facility‐based sample; however, more ever‐pregnant PLACE respondents than others reported ever having terminated a pregnancy. Program managers seeking to implement prevention activities should consider using facility‐ or venue‐based methods to identify and understand the behaviors of young people at high risk.     

Abnormalities in central auditory maturation in children with language-based learning problems.

OBJECTIVE: To examine maturation of the central auditory pathways in children with language-based learning problems (LP). METHODS: Cortical auditory evoked potentials (CAEPs) recorded from 26 children with LP were compared to CAEPs recorded from 38 typical children. CAEP responses were recorded in response to a speech sound, /uh/, which was presented in a stimulus train with decreasing inter-stimulus intervals (ISIs) of 2000, 1000, 560, and 360 ms. RESULTS: We identified three atypical morphological categories of CAEP responses in the LP group. Category 1 responses revealed delayed P1 latencies and absent N1/P2 components. Category 2 responses revealed typical P1 responses, but delayed N1 and P2 responses. Category 3 responses revealed generally low-amplitude CAEP responses. A fourth sub-group of LP children had normal CAEP responses. CONCLUSIONS: Overall, the majority of children with LP had abnormal CAEP responses. These children fell into distinct categories based on the abnormalities in maturational patterns of their CAEP responses. SIGNIFICANCE: We describe a rate sensitive stimulation paradigm which may be used to identify and categorize LP children who exhibit abnormal patterns of central auditory maturation.     

Role of videofluorography in assessing functional abnormalities in patients of head and neck cancer treated with chemoradiotherapy

Aim:   The major toxicity following treatment for head neck cancer is swallowing dysfunction which can be easily assessed by videofluorography (VFG), allowing documentation of the site and extent of abnormality thereby facilitating directed management.
Methods:   Between October 2003 and January 2007, 56 patients with locally advanced head and neck cancer were treated by an accelerated radiotherapy schedule with concurrent weekly cisplatin chemotherapy. Three months following treatment, these patients were locally disease free clinically, but complained of varying degrees of dysphagia and were subjected to a VFG evaluation.
Results:   This group comprised 52 men and four women with a median age of 56 years. The primary site distribution was: oral cavity (9), oropharynx (22), larynx (19), hypopharynx (5) and unknown primary (1). Swallowing function abnormalities in the form of structural displacement and temporal delays were documented and recorded as weakness of the tongue musculature ( n  = 6), palatal kink ( n  = 8), premature leak into the oropharynx ( n  = 20), impaired hyoid elevation ( n  = 23), impaired epiglottic tilt ( n  = 26), unilateral pharyngeal wall impairment ( n  = 16), residuum in vallecula or pyriform fossa ( n  = 30), aspiration in trachea ( n  = 29) and loss of nasopharyngeal seal ( n  = 7). Multiple abnormalities of different sub-sites were seen in each patient.
Conclusion:   VFG can document dysmotility disorders of upper aero-digestive tract like dysfunction of the base of tongue, larynx and pharyngeal musculature leading to stasis of the bolus and vallecular residuum, epiglottis dysmotility resulting in silent aspirations, and inadequate nasopharyngeal seal leading to nasal regurgitation. A clinical correlation alongwith quantification of VFG findings is required.     

Collagen XVIII modulation is altered during progression of oral dysplasia and carcinoma

Background:  Collagen XVIII is a ubiquitous basement membrane (BM) component and a precursor of endostatin.
Methods:  Using immunohistochemistry and in situ hybridization, we studied the expression and localization of collagen XVIII in different stages of normal oral wound healing, epithelial dysplasia and squamous cell carcinoma (SCC).
Results:  In mild epithelial dysplasias collagen XVIII appeared as a continuous signal in the BM, whereas in severe epithelial dysplasias and in the invasive areas of oral SCCs collagen XVIII was absent. In situ hybridization showed that collagen XVIII mRNA expression did not decrease in severe dysplasia or oral carcinoma samples when compared with the mild dysplasias.
Conclusions:  The results indicate that the absence of collagen XVIII protein in severe oral dysplasias is related to the processing of the protein rather than to changes in mRNA expression.