Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular mechanisms of interleukin-4-induced up-regulation of type I collagen gene expression in murine fibroblasts.

OBJECTIVE There is evidence that interleukin-4 (IL-4) plays a major role in the induction of extracellular matrix protein synthesis in fibrotic disease. We therefore examined the effect of IL-4 on collagen synthesis in primary fibroblasts isolated from normal and TSK/+ mice, which spontaneously develop a scleroderma-like syndrome characterized by diffuse cutaneous hyperplasia. METHODS Expression of the IL-4 receptor was determined by flow cytometry and Western blotting. The IL-4 signal transduction cascade was analyzed by Western blotting. We assessed the role of signal transducer and activator of transcription 6 (STAT-6) in IL-4 induction of alpha2(I) collagen promoter activity and message levels via luciferase reporter assay and real-time polymerase chain reaction. The activation status of the transcription factors activator protein 1 (AP-1) and Sp-1 upon stimulation with IL-4 in normal and TSK/+ fibroblasts was examined by electrophoretic mobility shift assay. RESULTS Flow cytometry and Western blotting showed that IL-4 receptor alpha expression was elevated in TSK/+ fibroblasts compared with normal fibroblasts. After IL-4 stimulation, janus-activated kinase 1 (JAK-1) and JAK-2 were phosphorylated to a greater degree in TSK/+ fibroblasts than in C57BL/6 fibroblasts. TSK/+ fibroblasts appeared to be hyperresponsive to IL-4, displaying increased synthesis of alpha1(I) collagen messenger RNA (mRNA), collagen protein, and activity of a luciferase reporter construct containing the -300 to +54 murine alpha2(I) collagen promoter. Overexpression of STAT-6 enhanced this effect, whereas expression of a dominant-negative STAT-6 abrogated the ability of IL-4 to induce alpha1(I) collagen mRNA in TSK/+ fibroblasts. Moreover, IL-4 induced increased DNA binding activity of transcription factors that are important for collagen synthesis. CONCLUSION Our observations indicate that IL-4 has a profound effect on several factors that have been identified as playing major roles in the regulation of collagen synthesis and suggest that IL-4 increases the expression of type I collagen through a mechanism involving the activation of transcription factors that bind to and activate collagen promoter.
Severe Human Illness Caused by Rift Valley Fever Virus in Mauritania, 2015

Background. Rift Valley Fever epizootics are characterized by numerous abortions and mortality among young animals. In humans, the illness is usually characterized by a mild self-limited febrile illness, which could progress to more serious complications.Objectives. The aim of the present prospective study was to describe severe clinical signs and symptoms of Rift Valley Fever in southern Mauritania. Patients and methods. Suspected cases were enrolled in Kiffa (Assaba) and Aleg (Brakna) Hospital Centers from September 1 to November 7, 2015, based on the presence of fever, hemorrhagic or meningoencephalitic syndromes, and probable contact with sick animals. Suspected cases were confirmed by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR). Results. There were thirty-one confirmed cases. The sex ratio M/F and the average age were 2.9 and 25 years old [range, 4-70 years old], respectively. Mosquito bites, direct contact with aborted or dead animals, and frequent ingestion of milk from these animals were risk factors observed in all patients. Hemorrhagic and neurological manifestations were observed in 81% and 13% of cases, respectively. The results of laboratory analysis showed high levels of transaminases, creatinine, and urea associated with thrombocytopenia, anemia, and leukopenia. All patients who died (42%) had a hemorrhagic syndrome and 3 of them had a neurological complication. Among the cured patients, none had neurologic sequelae. Conclusion. The hemorrhagic form was the most common clinical manifestation of RVF found in southern Mauritania and was responsible for a high mortality rate. Our results justify the implementation of a continuous epidemiological surveillance.
Defining menopause status: creation of a new definition to identify the early changes of the menopausal transition

Objective: Several menopausal staging definitions are currently being used in ongoing studies designed to identify changes occurring during menopause. The objective of this study was to determine which definition captures the earliest hormonal changes in the menopausal transition. Design: In this prospective cohort study, women aged 35 to 47 years were followed for 5 years. Women were classified as premenopausal, early transition, late transition, and postmenopausal by 2 different menopausal staging systems defined by bleeding patterns. Definitions from the Study of Women Health Across the Nation (SWAN) and Stages of Reproductive Aging Workshop (STRAW) were compared. A new menopausal staging system (PENN-5) was also developed with five groups rather than four to distinguish among women with more subtle changes in cycle length. For each staging system, a linear regression model was created comparing mean hormone values (inhibin B, FSH, LH, E2) and menopausal stages at each assessment. Race, body mass index, cycle day, smoking, and follow-up time were included in the model. Results: Statistically significant differences in mean inhibin B and FSH levels, but not estradiol levels, were detected between the earliest menopausal stages of each definition. Significant differences in LH values were detected among the earliest stages of the SWAN and STRAW definitions, but not the PENN-5 definition. Conclusions: Subtle changes in menstrual cycle length reflect significant changes in inhibin B and FSH levels during the menopausal transition. Therefore, it appears that subtle changes in bleeding pattern may be helpful in identifying the earliest hormonal changes during menopausal transition.
Angiogenesis, p53, bcl-2 and Ki-67 in the Progression of Prostate Cancer after Radical Prostatectomy

Within the past 5 years, research has increasingly addressed molecular alterations in prostate cancer (CaP). Mutations of tumor suppressor gene p53 have been found in a variety of cancers, including urologic neoplasms. Several studies have been conducted on CaP specimens, citing frequencies of p53 alterations in localized cancers ranging from 4 to 60% and with more advanced hormone refractory disease, as high as 94%. The majority of studies have revealed a low percentage of p53 abnormalities in early-stage (clinically organ-confined) CaP. The overwhelming bulk of evidence suggests that the frequency of p53 abnormalities does increase with disease progression and is highest in tissues from patients with hormone-refractory prostate cancer. More recently, our group and others have found that focal p53 expression in the primary tumor by immunohistochemistry is predictive of cancer recurrence after radical prostatectomy. bcl-2 is an oncogene critically involved in the apoptosis, or programmed cell death. Overexpression of bcl-2 protein by immunohistochemistry has been commonly detected in advanced hormone refractory CaP. Our group recently has also shown that bcl-2 protein expression in primary CaP is a predictor of cancer recurrence after radical prostatectomy. Furthermore, the combination of p53 and bcl-2 protein expression were both independent predictors of recurrence after surgery. Most recently, we have shown that even though p53 and bcl-2 are predictive biomarkers when sampling the radical prostatectomy specimen, they are not useful to predict postoperative recurrence when sampling the pretreatment needle biopsy. Ki-67 is an antigen of cellular proliferation. Immunohistochemical staining for Ki-67 in archival material can be performed using the MIB-1 antibody. Unlike our results with p53 and bcl-2, Ki-67 protein expression by immunohistochemistry using MIB-1 was not an independent prognostic marker for cancer recurrence after radical prostatectomy although it may have clinical utility in subsets of patients. Assessment of MIB-1 staining in CaP needle biopsy samples is underway. Tumor neovascularity, or angiogenesis, is necessary for cancers to grow and metastasize. Angiogenesis in CaP as a prognostic marker has received recent attention. Most studies have used factor VIII immunohistochemical staining and increased angiogenesis has been suggested as a staging and prognostic marker. Our group has recently conducted a large study of radical prostatectomy patients and used CD34 antigen immunohistochemistry to assess neovascularity. We did not find that this biomarker assessment was an independent prognostic marker of cancer recurrence after radical prostatectomy. Further work is being conducted in needle biopsy samples. More research is needed to assess new biomarkers and, most importantly, to standardize the methodology for sampling and assaying biomarkers in heterogeneous and multifocal prostate cancer.
Interaction of papillomaviruses with the cell surface

To initiate an investigation of the initial step in papillomavirus infection, we have examined the interaction of bovine papillomavirus type 1 (BPV) virions with C127 cells by two assays, binding of radioiodinated BPV virions to cell monolayers and BPV-induced focal transformation. Under physiological conditions, the labeled virions bound to the cell surface in a dose-dependent manner within 1 h. Antibody studies indicated that the interaction was specific and related to infectivity: polyclonal sera raised to BPV virions or to baculovirus-expressed BPV L1 virus-like particles (VLPs) inhibited BPV binding and focal transformation, while sera to denatured BPV virions, to denatured BPV L1, or to human papillomavirus type 16 (HPV-16) VLPs were not inhibitory. An exception was that antisera to BPV L2 were neutralizing but did not inhibit binding. Unlabeled BPV virions and BPV VLPs competed with binding to the cell surface in a concentration-dependent manner. Binding to the cell surface appeared to depend primarily on L1, since BPV VLPs composed of L1 alone or of L1/L2 were equally effective in inhibiting binding and focal transformation. VLPs of HPV-16 also inhibited BPV binding and BPV transformation of C127 cells, suggesting that they interact with the same cell surface molecule(s) as BPV virions. Radiolabeled BPV bound specifically to several mammalian cell lines of fibroblastic and epithelial origin, as well as to a human schwannoma and melanoma lines, although some lines bound up to 10 times as many counts as others. Radiolabeled HPV-16 VLPs bound to both human keratinocytes and mouse C127 cells. The results suggest that papillomaviruses bind a widely expressed and evolutionarily conserved cell surface receptor.
Establishment of a tear protein biomarker panel differentiating between Graves’ disease with or without orbitopathy

Background Graves’ orbitopathy (GO) is an autoimmune inflammatory ocular complication and one of the most frequent manifestations of Graves’ disease (GD). Clinical judgment of GO is subjective sometimes leading to clinical and therapeutic challenges. Better tools to diagnose this severe complication are warranted. Patients and methods The aim of the present study was to evaluate tear levels of LYZ, LACRT and AZGP1 in GD patients with or without GO, as possible biomarkers for GO. Tear samples were collected from GD patients with moderate-to-severe GO (n = 21) and no clinical signs of GO (n = 21). Additionally, 18 GD patients with mild GO and 9 patients without GO were included in a further part of the study. Results Tear levels of LYZ (p < 0.001), LACRT (p = 0.004) and AZGP1 (p = 0.001) were significantly elevated in GD patients with moderate-to-severe GO compared to GD patients without GO. The discriminatory power of the three biomarkers, combined in a panel was confirmed by ROC plot analysis, with an AUC value of 0.93 (sensitivity of 95%; specificity of 80%). Since LYZ showed the best performance in discriminating between GD patients with (moderate-to-severe) and without GO (in combination with limited sample volume available), LYZ levels were also measured in tears from GD patients with mild GO and without GO. Significantly higher levels of LYZ were measured in GD patients with mild GO compared to those without GO (p = 0.003). Conclusions We have established a novel three-protein biomarker panel that is able to discriminate between GD patients with and without GO, which might aid in diagnostic evaluation of GO as well as an indicator for disease activity.
T cell subset involvement in immune responses to Fasciola hepatica infection in cattle

The lymphocyte response to F. hepatica during a primary infection in cattle was analysed to define the role of T cell subsets in the immune response. Blood lymphocytes were isolated from eight cattle infected with F. hepatica via trickle infection over a ten‐day period and from two non‐infected controls. CD4+, CD8+ and γδ+ T cells were depleted from whole lymphocyte populations by magnetic bead depletion. Lymphocytes from infected animals demonstrated a transient, but marked elevation in responsiveness to F. hepatica antigen between weeks 3 and 8 post‐infection. Responses were attenuated by depletion of CD4+ and CD8+ T cells during this period. Depletion of γδ+ T cells attenuated antigen responses at one time point only, and at an earlier stage post‐infection than when αβ+ T cells were depleted. Responses to antigen correlated positively with both hepatic fluke burden and with the degree of hepatic damage. This suggests that the cellular immune response was not protective. Antigen responses in γδ+ T cell‐depleted populations were also associated with post‐mortem fluke burden and with hepatic damage. This suggests that γδ+ T cells are involved in down regulating αβ+ lymphocytes which may have a role in a non‐protective or immunopathological immune responses.
Public Awareness and Attitudes Toward Epilepsy in Finland

Summary: Public awareness and attitudes toward epilepsy were surveyed in Finland. Three thousand names were randomly selected from the population registry in the age range of 15 to 64 years. Of the 2,789 persons contacted, 2,272 (81%) answered a questionnaire about epilepsy. The social background of the respondents did not deviate significantly from that of the general population in this age range. The questionnaire consisted of 28 questions designed to determine the respondents' social background, acquaintance with epileptic persons, awareness of epilepsy, and opinions and attitudes about the disorder. Ninety‐five percent of the respondents had heard of epilepsy, 49% knew an epileptic person, 45% had seen a seizure, 15% were familiar with the causes of epilepsy, 12% knew how to help a person having a generalized convulsive seizure, and 1% would leave their jobs if they had to work with an epileptic person. The attitudes toward children with epilepsy were more charitable than toward epileptic adults. The factors of knowing an epileptic person, education, and age had the greatest influence on awareness and knowledge of epilepsy and to a lesser extent, attitudes toward it. The level of knowledge of epilepsy was rather low, especially in younger age groups. The results appeared useful for the Attitude Formation Program of the Finnish League for Epilepsy. Those processes that govern the forming and changing of attitudes toward epilepsy in school or work should be traced. An information campaign will be continued, and the survey of public attitudes toward epilepsy will be renewed in the future.
Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma.

PURPOSE To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study. PATIENTS AND METHODS Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients. CONCLUSION Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.
Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases

Semaphorins are a large family of transmembrane proteins. The gene for SEMA4A encodes a transmembrane protein comprising 760 amino acids. To investigate its association with human retinal degeneration, mutation screening of the SEMA4A gene was carried out on 190 unrelated patients suffering from a variety of eye diseases. We report the first observation of the involvement of SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD). We screened the DNA of 135 patients with RP, 25 patients with CRD, and 30 with LCA using SSCP and direct DNA sequencing for mutations in the SEMA4A gene. Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects. Both mutations identified occur in the conserved semaphorin domain. Multiple sequence alignments using Clustal analysis showed that R713Q is a conserved substitution and D345H is a semi-conserved substitution. We conclude that these mutations are a cause of various retinal degenerations.
Bloodstream infections in hospitalized adults with sickle cell disease: A retrospective analysis

Bloodstream infections (BSI) are a common cause of morbidity and mortality in people with sickle cell disease (SCD). In children with SCD, BSI are most often caused by encapsulated organisms. There is a surprising paucity of medical literature that is focused on evaluating SCD adults with BSI. We reviewed the charts of adults with SCD and BSI who were admitted to our hospital between April 1999 and August 2003. During this period a total of 1,692 hospital admissions for 193 adults with SCD were identified and 28% of these patients had at least 1 episode of positive blood cultures, with 69 episodes (17%) considered true BSI. Nosocomial BSI occurred in 34 episodes (49%). Among community BSI, in contrast to BSI in children with SCD, Streptococcus pneumoniae was rarely encountered. A high incidence of staphylococcal BSI in adults with SCD was noted. Twenty‐eight percent of all BSI were caused by Staphylococcus aureus, and 15 of 22 isolates (68%) of these were methicillin‐resistant. Gram‐negative organisms, anaerobes, and yeast were found in 21 (27%), 3 (4%), and 4 isolates (5%) of BSI, respectively. Since over 80% of BSI were considered catheter‐related, the higher incidence of gram‐positive bacterial infections was likely due to the presence of indwelling central venous catheters. Empiric therapy for adults with SCD suspected of having BSI, especially in the presence of indwelling central venous catheters, should include antimicrobial therapy targeted at gram‐positive bacteria (especially MRSA) and gram‐negative bacteria. Also, if patients are critically ill, consideration should be made to include antifungal agents. Additional research into the adult SCD population appears necessary to further define this problem. Am. J. Hematol. , 2006. © 2006 Wiley‐Liss, Inc.
Synthetic peptides mimicking the interleukin‐6/gp 130 interaction: a two‐helix bundle system. Design and conformational studies

The objective of our study was to mimic in a typical reductionist approach the molecular interactions observed at the interface between the gp 130 receptor and interleukin‐6 during formation of their complex. A peptide system obtained by reproducing some of the interleukin‐6/gp 130 molecular interactions into a two‐helix bundle structure was investigated. The solution conformational features of this system were determined by CD and NMR techniques. The CD titration experiments demonstrated that the interaction between the designed peptides is specific and based on a well‐defined stoichiometry. The NMR data confirmed some of the structural features of the binding mechanism as predicted by the rational design and indicated that under our conditions the recognition specificity and affinity can be explained by the formation of a two‐helix bundle. Thus, the data reported herein represent a promising indication on how to develop new peptides able to interfere with formation of the interleukin‐6/gp 130 complex. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.
Leaders and leadership in the school, college and university

Part 1 Introduction: leaders and leadership in the school, college and university - a prelude, Peter Ribbins. Part 2 Conversations: Mary Gray with Agnes McMahon Rosemary Whinn-Sladden with Viv Garrett Keith Bovair with Steve Rayner Roy Blatchford with Peter Earley Bernard Clarke with Lesley Anderson Helen Hyde with Peter Ribbins Mary Marsh with Janet Ouston Mick Brown with Len Cantor Kenneth Edwards with Hugh Busher. Part 3 Analysis: pathways to headship and principalship, Janet Ouston principals and headteachers as leading professionals, Viv Garrett principals and headteachers as chief executives, Hugh Busher.
Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ‐47965567

An increasing body of evidence suggests that the purinergic receptor P2X, ligand‐gated ion channel, 7 (P2X7) in the CNS may play a key role in neuropsychiatry, neurodegeneration and chronic pain. In this study, we characterized JNJ‐47965567, a centrally permeable, high‐affinity, selective P2X7 antagonist.