Neutralizing antibodies to interferon-α and circulating interferon in patients with chronic hepatitis C non-responding to pegylated interferon plus ribavirin re-treated by pegylated interferon-α-2a and ribavirin (ANRS HC16 GAMMATRI substudy)

A lack of antiviral response in patients with chronic hepatitis C treated with pegylated (PEG)‐interferon (IFN)‐α‐2a + ribavirin (RIBA) may be explained by neutralizing antibodies to IFN‐α‐2a. The aim of this study was to assess neutralizing antibodies to IFN‐α‐2a and IFN levels in non‐responder patients who were re‐treated by PEG IFN‐α‐2a and RIBA for 12 weeks. Non‐responders to a first‐line treatment of PEG IFN‐α‐2a + RIBA were included for treatment with PEG IFN‐α‐2a (180 µg/week) + RIBA (1,000 mg/day if <75 kg, 1,200 mg otherwise) for 48 weeks. HCV RNA was measured at week 12. IFN levels and neutralizing antibodies to IFN‐α‐2a were measured retrospectively on stored sera at baseline and weeks 4 and 12, using a quantitative sandwich ELISA for neutralizing antibodies to IFN‐α‐2a. Twenty‐three patients were non‐responders and 19 patients were responders at week 12 of the initial phase of the second‐line treatment. Non‐responders and responders did not differ statistically: baseline age (median age 47 vs. 50 years), HCV RNA (median 6.8 vs. 6.4 log₁₀ copies/ml), gender (70% vs. 73% males), genotype (genotype 1: 91% vs. 80%). The median IFN‐α‐2a levels (pg/ml) at weeks 0, 4, and 12 (interquartile range) did not differ between the 19 responders to initial phase of second‐line treatment and the 23 non‐responders: <3.3 (<3.3–371.4), 1457.3 (106.8–3284.8), and 1,652 (90.8–5,000); 84.5 (3.3–277.4), 1407.4 (120.2–2443.4), and 1620.1 (120.2–2287.1), respectively. Among non‐selected consecutive non‐responder patients, re‐treatment with PEG IFN‐α‐2a + RIBA is associated with virological response regardless of the presence of antibody‐mediated resistance to conventional IFN treatment. J. Med. Virol. 82:2027–2031, 2010. © 2010 Wiley‐Liss, Inc.     

Systemic injection of products of activated neutrophils and H2O2 in myeloperoxidase-immunized rats leads to necrotizing vasculitis in the lungs and gut.

The strong association of anti-neutrophil cytoplasmic antibodies with various forms of systemic vasculitis suggests a role for these autoantibodies in the pathophysiology of systemic vasculitis. In the present study, we tested the hypothesis that release of neutrophil lysosomal enzymes in the presence of an anti-myeloperoxidase (anti-MPO) immune response may underlie the development of systemic vasculitis. Brown Norway rats were immunized with MPO in complete Freund's adjuvant or complete Freund's adjuvant alone. Two weeks after immunization, rats bad developed antibodies to human and rat MPO as measured by enzyme-linked immunosorbent assay. Next, rats were intravenously infused with 400 micrograms of a human neutrophil lysosomal extract containing 200 micrograms of MPO followed by 0.5 ml of a 1 mmol/L solution of H2O2 through a cannula inserted into the right jugular vein. Rats were sacrificed at 4 hours, 24 hours, 7 days, or 14 days, and several organs (lungs, heart, liver, spleen, gut, and kidneys) were examined for vasculitic lesions and inflammatory cell infiltrates. Macroscopically, patchy hemorrhagic spots were observed in the lungs and gut of MPO-immunized rats at days 7 and 14 after systemic infection of the neutrophil lysosomal extract and H2O2. Such changes were not observed at earlier time points or in control immunized rats. Histologically, the lungs of MPO-immunized rats sacrificed at days 7 and 14 showed patchy inflammatory cell infiltrates associated with vasculitis, granuloma formation, giant cells, and foci of hemorrhage. At 14 days, early signs of fibrosis were found with deposition of collagen and proliferation of fibroblasts. Furthermore, a prominent leukocytoclastic vasculitis was found in the small intestine of these rats characterized by fibrinoid necrosis and an extensive neutrophilic infiltrate. No inflammatory changes were found in the other organs studied (heart, liver, spleen, and kidneys). Control immunized rats, sacrificed at days 7 and 14 showed only some small foci of inflammatory infiltrates in the lungs whereas no inflammatory changes were found in the gastrointestinal tract. These studies show that release of products from activated neutrophils in the presence of anti-MPO autoantibodies may be relevant to the pathogenesis of anti-MPO-associated vasculitides.     

Task-Specific Perturbation Training Improves the Recovery Stepping Responses by Women With Knee Osteoarthritis Following Laboratory-Induced Trips

Trip-specific training improves the kinematics of trip-specific compensatory stepping response (CSR) in the laboratory and reduces prospectively measured trip-related fall-rate of middle age and older women. We examined whether one session of trip-specific perturbation training could improve recovery step kinematics in women with knee osteoarthritis (OA), a condition known to increase fall risk. Seventeen women with self-reported symptomatic knee OA (age 61.1 ± 7.7 years, body mass index [BMI] 29.7 ± 5.9 kg/m²) and 22 control women (age 59.5 ± 6.8 years, BMI 28.4 ± 6.2 kg/m²) completed a brief training protocol consisting of 20 trials of treadmill-delivered trip-specific perturbations. We assessed pre- and post-training recovery step length and trunk kinematics at the instant of recovery step completion. Repeated-measures analysis of variance was used to determine the significance of between-group differences following the training protocol, and to evaluate the significance of within-group pre-to-post changes in the variables of interest. The group by training interaction effects for step length (p = 0.466), trunk flexion angle (p = 0.751), and trunk angular velocity (p = 0.413) were not significant and the pre-to-post changes in step length were not significant (p = 0.286). However, pre-to-post trunk flexion angle improved by 26% and 34% in the OA and control groups, respectively (p < 0.001) and trunk flexion angular velocity decreased by 193% in the OA group and by 32% in the control group, respectively (p < 0.001), often reflecting a transition to the direction of extension. The results suggest that trip-specific training can improve CSR kinematics in women with knee OA. It is important to determine, the effectiveness of trip-specific training in decreasing trip-specific fall-rate by women with knee OA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:663–669, 2020     

fMRI capture of auditory hallucinations: Validation of the two‐steps method

Our purpose was to validate a reliable method to capture brain activity concomitant with hallucinatory events, which constitute frequent and disabling experiences in schizophrenia. Capturing hallucinations using functional magnetic resonance imaging (fMRI) remains very challenging. We previously developed a method based on a two‐steps strategy including (1) multivariate data‐driven analysis of per‐hallucinatory fMRI recording and (2) selection of the components of interest based on a post‐fMRI interview. However, two tests still need to be conducted to rule out critical pitfalls of conventional fMRI capture methods before this two‐steps strategy can be adopted in hallucination research: replication of these findings on an independent sample and assessment of the reliability of the hallucination‐related patterns at the subject level. To do so, we recruited a sample of 45 schizophrenia patients suffering from frequent hallucinations, 20 schizophrenia patients without hallucinations and 20 matched healthy volunteers; all participants underwent four different experiments. The main findings are (1) high accuracy in reporting unexpected sensory stimuli in an MRI setting; (2) good detection concordance between hypothesis‐driven and data‐driven analysis methods (as used in the two‐steps strategy) when controlled unexpected sensory stimuli are presented; (3) good agreement of the two‐steps method with the online button‐press approach to capture hallucinatory events; (4) high spatial consistency of hallucinatory‐related networks detected using the two‐steps method on two independent samples. By validating the two‐steps method, we advance toward the possible transfer of such technology to new image‐based therapies for hallucinations. Hum Brain Mapp 38:4966–4979, 2017. © 2017 Wiley Periodicals, Inc.     

Intra-operative touch preparation cytology following lumpectomy for breast cancer: A series of 400 procedures

AimsAchieving negative margins is essential in conservative treatment for breast cancer. The conventional method for intra-operative assessment of resection margins is gross or histological examination of frozen sections. We describe and evaluate the contribution of an original intra-operative touch preparation cytology (IOTPC) technique (400 procedures) performed on 396 patients.Materials and methodsIOTPC consists of touching glass slides to the surfaces of interest after gently pressing the spatially localized specimen taken according to predetermined conditions. The result is conveyed to the surgeon immediately and compared with the conventional histological findings after embedding in paraffin.ResultsThe average response time is 10 min, which renders the technique compatible with standard operating room procedures and its cost is reasonable. The method has a sensitivity of 88.6%, specificity of 92.2%, positive predictive value of 73.6%, negative predictive value of 97%, and correlation with paraffin section histology of 91.5%. Only 5 true false negatives were found in this series and the technique prevented 11.75% of secondary re-excision procedures for positive margins.ConclusionIOTPC is a reliable extemporaneous method for assessing surgical margins in conservative treatment for breast cancer and a useful tool for surgeons.     

Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis. An erratum to this article can be found at