Clearance of Genotype 1b Hepatitis C Virus in Chimpanzees in the Presence of Vaccine-Induced E1-Neutralizing Antibodies

Accumulating evidence indicates that neutralizing antibodies play an important role in protection from chronic hepatitis C virus (HCV) infection. Efforts to elicit such responses by immunization with intact heterodimeric E1E2 envelope proteins have met with limited success. To determine whether antigenic sites, which are not exposed by the combined E1E2 heterodimer structure, are capable of eliciting neutralizing antibody responses, we expressed and purified each as separate recombinant proteins E1 and E2, from which the immunodominant hypervariable region (HVR-1) was deleted. Immunization of chimpanzees with either E1 or E2 alone induced antigen-specific T-helper cytokines of similar magnitude. Unexpectedly, the capacity to neutralize HCV was observed in E1 but not in animals immunized with E2 devoid of HVR-1. Furthermore, in vivo only E1-vaccinated animals exposed to the heterologous HCV-1b inoculum cleared HCV infection

Primary Skull Base Chondrosarcomas: A Systematic Review

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-25, pub-electronic 2021-11-26Publication status: PublishedBackground: Primary skull base chondrosarcomas (SBCs) can severely affect patients’ quality of life. Surgical-resection and radiotherapy are feasible but may cause debilitating complications. We systematically reviewed the literature on primary SBCs. Methods: PubMed, EMBASE, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of patients with primary SBCs. Clinical characteristics, management strategies, and treatment outcomes were analyzed. Results: We included 33 studies comprising 1307 patients. Primary SBCs mostly involved the middle-fossa (72.7%), infiltrating the cavernous-sinus in 42.4% of patients. Cranial-neuropathies were reported in 810 patients (62%). Surgical-resection (93.3%) was preferred over biopsy (6.6%). The most frequent open surgical approaches were frontotemporal-orbitozygomatic (17.6%) and pterional (11.9%), and 111 patients (21.3%) underwent endoscopic-endonasal resection. Post-surgical cerebrospinal-fluid leaks occurred in 36 patients (6.5%). Radiotherapy was delivered in 1018 patients (77.9%): photon-based (41.4%), proton-based (64.2%), and carbon-based (13.1%). Severe post-radiotherapy complications, mostly hypopituitarism (15.4%) and hearing loss (7.1%) were experienced by 251 patients (30.7%). Post-treatment symptom-improvement (46.7%) and reduced/stable tumor volumes (85.4%) showed no differences based on radiotherapy-protocols (p = 0.165; p = 0.062). Median follow-up was 67-months (range, 0.1−376). SBCs recurrences were reported in 211 cases (16.1%). The 5-year and 10-year progression-free survival rates were 84.3% and 67.4%, and overall survival rates were 94% and 84%. Conclusion: Surgical-resection and radiotherapy are effective treatments in primary SBCs, with acceptable complication rates and favorable local tumor control

Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes

OBJECTIVES—To investigate a B-cell–depleting strategy to reverse diabetes in naïve NOD mice

Viral Kinetics Suggests a Reconciliation of the Disparate Observations of the Modulation of Claudin-1 Expression on Cells Exposed to Hepatitis C Virus

The tight junction protein claudin-1 (CLDN1) is necessary for hepatitis C virus (HCV) entry into target cells. Recent studies have made disparate observations of the modulation of the expression of CLDN1 on cells following infection by HCV. In one study, the mean CLDN1 expression on cells exposed to HCV declined, whereas in another study HCV infected cells showed increased CLDN1 expression compared to uninfected cells. Consequently, the role of HCV in modulating CLDN1 expression, and hence the frequency of cellular superinfection, remains unclear. Here, we present a possible reconciliation of these disparate observations. We hypothesized that viral kinetics and not necessarily HCV-induced receptor modulation underlies these disparate observations. To test this hypothesis, we constructed a mathematical model of viral kinetics in vitro that mimicked the above experiments. Model predictions provided good fits to the observed evolution of the distribution of CLDN1 expression on cells following exposure to HCV. Cells with higher CLDN1 expression were preferentially infected and outgrown by cells with lower CLDN1 expression, resulting in a decline of the mean CLDN1 expression with time. At the same time, because the susceptibility of cells to infection increased with CLDN1 expression, infected cells tended to have higher CLDN1 expression on average than uninfected cells. Our study thus presents an explanation of the disparate observations of CLDN1 expression following HCV infection and points to the importance of considering viral kinetics in future studies of receptor expression on cells exposed to HCV

The potential utility of B cell-directed biologic therapy in autoimmune diseases

Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs—rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20—was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren’s syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still’s disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders

Human cell types important for Hepatitis C Virus replication in vivo and in vitro. Old assertions and current evidence

Hepatitis C Virus (HCV) is a single stranded RNA virus which produces negative strand RNA as a replicative intermediate. We analyzed 75 RT-PCR studies that tested for negative strand HCV RNA in liver and other human tissues. 85% of the studies that investigated extrahepatic replication of HCV found one or more samples positive for replicative RNA. Studies using in situ hybridization, immunofluorescence, immunohistochemistry, and quasispecies analysis also demonstrated the presence of replicating HCV in various extrahepatic human tissues, and provide evidence that HCV replicates in macrophages, B cells, T cells, and other extrahepatic tissues. We also analyzed both short term and long term in vitro systems used to culture HCV. These systems vary in their purposes and methods, but long term culturing of HCV in B cells, T cells, and other cell types has been used to analyze replication. It is therefore now possible to study HIV-HCV co-infections and HCV replication in vitro

The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up.

A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. To examine the risks and benefits of long-term hydroxyurea usage, patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea. The purpose of this follow-up was to search for adverse outcomes and estimate mortality. For each outcome and for mortality, exact 95% confidence intervals were calculated, or tests were conducted at alpha = 0.05 level (P-value \u3c0.05 for statistical significance). Although the death rate in the overall study cohort was high (43.1%; 4.4 per 100 person-years), mortality was reduced in individuals with long-term exposure to hydroxyurea. Survival curves demonstrated a significant reduction in deaths with long-term exposure. Twenty-four percent of deaths were due to pulmonary complications; 87.1% occurred in patients who never took hydroxyurea or took it for \u3c5 years. Stroke, organ dysfunction, infection, and malignancy were similar in all groups. Our results, while no longer the product of a randomized study because of the ethical concerns of withholding an efficacious treatment, suggest that long-term use of hydroxyurea is safe and might decrease mortality

Badania właściwości odcieku ze składowiska IBB za pomocą analiz biologicznych oraz fizykochemicznych

Yemen is one of the developing countries suffering from water pollution. Landfill is one of the sources of water pollution. A study of composition of landfill leachate was conducted at Ibb landfill, located at Al-Sahool area, north of Ibb City, Yemen. The leachate was sampled at five different landfill locations during dry season, due to the excessive generation of leachate during this season. The physicochemical characteristic of leachate, such as pH, temperature, EC, TDS, DO were measured in-situ. Also, biological parameters such as COD and BOD5, major anions and nitrogenous compound such as Cl, SO4, NO2, NO3, NH3-N, major cations (Na, Mg, Ca, K, Fe) and heavy metals (Pb, Zn, Ni, Cr, Cd, Cu) were analysed in the laboratory. The results showed that, the leachate from Ibb landfill is in methanogenic phase. The first leachate site at Al-Sahool area was characterized by the highest values of most physico-chemical parameters. However, the quantitative results of most studied parameters were generally decreased towards downstream sites (1-5). The BOD5/COD value of 0.1 to 0.7 obtained for leachate suggested the partially stabilization. The concentrations of heavy metals were found in relatively high levels (except Cu). Therefore, a leachate collection pond should be built to collect and treat the leachate to prevent further contamination as well as build more sanitary landfill facilities in Al-Sahool area to prevent further ecological contamination and keep public health safer.Jemen jest jednym z krajów, które borykają się z zanieczyszczeniem wód. Składowiska odpadów są jednym ze źródeł zanieczyszczeń wód. Celem pracy jest badanie właściwości oraz charakterystyka odcieku ze składowiska zlokalizowanego w mieście Al-sahool, w północnej części województwa IBB w Republice Jemenu. Próbki przeznaczone do badań pobrano z pięciu różnych lokalizacji na ww. składowisku. Próbki odcieku zebrano podczas pory suchej, ze względu na nadmierną ilość wytwarzania odcieków w tym sezonie. Właściwości fizykochemiczne takie jak pH, temperatura, przewodnictwo elektryczne właściwe (PE), suma substancji rozpuszczonych (SSR), rozpuszczony tlen (RT) zbadano na miejscu. Parametry biologiczne takie jak chemiczne zapotrzebowanie tlenu (ChZT), biologiczne zapotrzebowanie na tlen (BZT), główne aniony takie jak chlorek (Cl), siarczan (SO4) oraz azotowe związki takie jak azotyny (NO2), azotany (NO3), amoniak (NH3-N), główne kationy (Na, Mg, Ca, K, Fe) oraz metale ciężkie (Pb, Zn, Ni, Cr, Cd, Cu) analizowano w wojewódzkim laboratorium Wody i Służby Sanitarnej, IBB. Wyniki przeprowadzonych badań wykazały, iż badane odcieki są w metagonicznej fazie. Odcieki z pierwszej lokalizacji charakteryzują się najwyższymi wartościami głównych parametrów fizykochemicznych. Natomiast wyniki ilościowe większości badanych parametrów na ogół miały tendencję spadkową w kierunku lokalizacji (1-5). Wartości (BZT)/ (ChZT) od 0,1 do 0,7 otrzymano dla odcieku częściowo stabilizowanego. Koncentracja metali ciężkich była na wysokim poziomie (oprócz Cu). Wyniki badań rekomendują, że budowa basenu do gromadzenia ścieków, budowa sanitarnego składowiska jest bardzo potrzebna aby ochronić przed zanieczyszczeniami ekologicznymi

A Grid Connected Transformerless Inverter and its Model Predictive Control Strategy with Leakage Current Elimination Capability

This paper proposes a new single phase transformerless Photovoltaic (PV) inverter for grid connected systems. It consists of six power switches, two diodes, one capacitor and filter at the output stage. The neutral of the grid is directly connected to the negative terminal of the source. This results in constant common mode voltage and zero leakage current. Model Predictive Controller (MPC) technique is used to modulate the converter to reduce the output current ripple and filter requirements. The main advantages of this inverter are compact size, low cost, flexible grounding configuration. Due to brevity, the operating principle and analysis of the proposed circuit are presented in brief. Simulation and experimental results of 200W prototype are shown at the end to validate the proposed topology and concept. The results obtained clearly verifies the performance of the proposed inverter and its practical application for grid connected PV systems