tbuckley/cabot-search huggingface dataset:
Thymus-independent positive and negative selection of T cells expressing a major histocompatibility complex class I restricted transgenic T cell receptor alpha/beta in the intestinal epithelium.
Authors: P Poussier, H S Teh, M Julius
Journal: The Journal of Experimental Medicine (1993)

We demonstrate that in the mouse intestinal epithelium the selection of T lymphocytes expressing a transgenic T cell receptor alpha/beta (TCR-alpha/beta) specific for male antigen (H-Y) in the context of H-2Db depends on the differential expression of H-Y and H-2Db in situ. In H-2Db transgenic males, there is no reduction in the number of intestinal intraepithelial lymphocytes (IEL), and the four main subsets of IEL expressing TCR-alpha/beta, defined by the differential expression of CD4, CD8 alpha, and CD8 beta, are present. Moreover, the level of expression of CD8 alpha and CD8 beta on CD8+ IEL subsets is unaltered. The frequency of CD8 alpha+ IEL expressing CD8 beta, in H-2Db male mice, however, is significantly decreased and these cells do not express the transgenic TCR. In contrast, virtually all CD8 alpha+beta- IEL in the same animals express the transgenic TCR. Still, these potentially autoreactive cells are refractile to H-Y/H-2Db stimulation in vitro. Both H-2Db and H-2Dd transgenic females contain high frequencies of cells expressing the transgenic TCR among CD8 alpha+beta- and CD8 alpha+beta+ IEL. However, two possibly related phenotypic features are peculiar to H-2Db female mice. The frequency of CD8 alpha+ IEL expressing CD8 beta is increased in these mice and, while in H-2Dd females the level of the transgenic TCR alpha chain expressed on CD8 alpha+beta+ IEL is uniformly low, some of the CD8 alpha+beta+ IEL in H-2Db females express a high level of both transgenic TCR chains. It is important to note, the ability of CD8 alpha+beta+ IEL to respond to H-Y/H-2Db stimulation in vitro is restricted to those coexpressing a high level of both transgenic TCR chains. The analysis of athymic radiation chimeras using adult thymectomized recipients of distinct H-Y/H-2 haplotypes, reconstituted with bone marrow from H-2Db transgenic females, demonstrates that all IEL subsets present in unmanipulated transgenic animals develop in the absence of a thymus. These IEL are phenotypically identical to those found in unmanipulated transgenic animals sharing the H-Y/H-2 haplotype of athymic recipients. Taken together, these results demonstrate that in the absence of male antigen, expression of H-2Db in the intestinal epithelium results in the positive selection of functional IEL specific for male antigen, in situ. When both H-Y and H-2Db are expressed in the intestinal epithelium, CD8 alpha+beta+ IEL expressing the transgenic TCR are negatively selected, while the frequency of nonfunctional CD8 alpha+beta- IEL expressing the transgenic CR is increased.(ABSTRACT TRUNCATED AT 400 WORDS)
Dose-intense therapy with etoposide, ifosfamide, cisplatin, and epirubicin (VIP-E) in 100 consecutive patients with limited- and extensive-disease small-cell lung cancer
Authors: S. Fetscher, W. Brugger, R. Engelhardt, L. Kanz, J. Hasse, H. Frommhold, M. Wenger, W. Lange, R. Mertelsmann
Journal: Annals of Oncology (1997)

We conducted a phase I/II trial to assess the feasibility and activity of VIP-E chemotherapy in small-cell lung cancer. End-points were treatment-related morbidity and mortality, response to treatment. duration of response, and survival.Two cycles of combination chemotherapy followed by granulocyte colony-stimulating factor (G-CSF) were given at a dose of etoposide (500 mg/m2), ifosfamide (4000 mg/m2), cisplatin (50 mg/m2), and epirubicin (50 mg/m2) to 100 consecutive patients with SCLC. Thirty patients (19 with LD, and 11 with ED SCLC) proceeded to VIC-E high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) at a cumulative dose of etoposide 1500 mg/m2, ifosfamide 12,000 mg/m2, carboplatin 750 mg/m2 and epirubicin 150 mg/m2 (VIC-E). Surgical resection of primary tumor was attempted at the earliest feasible point. Thoracic irradiation was given after completion of chemotherapy. RESULTS of conventional-dose VIP-E: 97 patients were evaluable for response. Objective response rate was 81% in LD-SCLC (33% CR, 48% PR; excluding patients in surgical CR) and 77% in ED-SCLC (18% CR, 58% PR). Treatment mortality was 2%. Median survival was 19 months in LD-SCLC and 6 months in ED-SCLC. Two-year survival was 36% in LD and 0% in ED SCLC. RESULTS OF HIGH-DOSE VIC-E: All 30 patients improved on or maintained prior responses. Four patients (13%) died of treatment-related complications. Median survival was 26 months in LD-SCLC and 8 months in ED-SCLC. Two-year survival was 53% in LD and 9% in ED SCLC.VIP-E chemotherapy is an effective induction therapy for SCLC. Compared with traditional protocols such as ACO or carboplatin/etoposide, response rates are slightly improved, while survival is not different. In the LD SCLC subgroup, high-dose chemotherapy improved response rates and survival, especially for patients in surgical CR prior to high-dose therapy. In ED SCLC, however, higher response-rates did not translate into improved survival. Selected LD-SCLC patients with good partial or complete remissions after prior therapy may benefit from HDC and PBSCT.
The prevention of occupational asthma
Authors: P. Cullinan, S. Tarlo, B. Nemery
Journal: European Respiratory Journal (2003)

There is sufficient understanding of the causation of occupational asthma for preventive action to be appropriate. To date, attempts appear to have been largely unsuccessful and this appears to be largely due to nonscientific/technical obstacles. These include the fragmented nature of the disease, its low public and industrial profile, and its comparative rarity in single workplaces. Nonetheless the disease has high individual and societal costs. Prevention strategies should be concentrated on workplace-exposure controls, accompanied by intense educational and managerial improvements. Methods of secondary prevention appear to be successful but require considerable refinement. Screening (out) of potential new employees is inefficient and likely to remain so; and in any case is beset by difficult ethical and legal issues. There are only a handful of published studies reporting evaluations of preventive programmes. None is entirely rigorous but each suggests that primary and secondary prevention are both feasible and highly effective. The evaluation of preventive strategies is difficult, not only because of the low incidence of the disease in individual workplaces but also because of the failure of many epidemiologists to engage in this work. Considerably more cooperation between scientists in the field, regulatory authorities and industry is required.
Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial
Authors: Anthony HV Schapira, Michael P McDermott, Paolo Barone, Cynthia L Comella, Stefan Albrecht, Helen H Hsu, Daniel H Massey, Yoshikuni Mizuno, Werner Poewe, Olivier Rascol, Kenneth Marek
Journal: The Lancet Neurology (2013)

BackgroundIn models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD).MethodsBetween May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30–79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854.FindingsOf 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (−0·4 points, 95% CI −2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was −15·1% (SE 2·1) for early and −14·6% (2·0) for delayed pramipexole (difference −0·5 percentage points, 95% CI −5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug.InterpretationBy clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6–9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects.FundingBoehringer Ingelheim GmbH.
Liver Biopsy Evaluation. Histological Diagnosis and Clinical Correlations
Authors: S HUBSCHER
Journal: Gut (2001)

Liver Biopsy Evaluation. Histological Diagnosis and Clinical Correlations . GC Kanel, J Korula (Pp 255; illustrated). Philadelphia: WB Saunders Company.

Interpretation of liver biopsy findings depends very much on clinicopathological correlation. In some cases, a liver biopsy may be taken in order to reach a primary diagnosis. In other cases, for example a patient with chronic hepatitis C infection, a diagnosis may already have been made and the biopsy is taken for other reasons, in this instance to assess the necroinflammatory grade and fibrosis stage.

This book, which is written by a pathologist (Gary C Kanel) and a physician (Jacob Korula), provides a practical approach to the assessment of liver biopsies and the correlation of histological …
MAPK-activated protein kinase-2 regulates physiological bone turnover
Authors: T. Braun, J. Lepper, P. Lezuo, G. Schett, J. Zwerina
Journal: Annals of the Rheumatic Diseases (2011)

Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is a main target of MAPK p38, a key intracellular signal transduction molecule mediating osteoclastogenesis and inflammation. MK2 deficient mice are healthy and fertile in contrast to p38 deficient mice. Aim of this study is to determine whether MK2 contributes to the regulation of physiological bone turnover and to identify a potential mechanism. To determine the bone phenotype the authors analysed a Tartrate resistant acid phosphatase (TRAP)-staining and a goldner staining of the tibia by histomorphometrie and did a μCT scan of the tibia. The mechanical stability of the bone was detected using the four point bending experiment. Serum bone turnover markers (Osteocalcin and RatLaps) and serum level of Receptor activator of nuclear factor κB ligand (RANKL) and Osteoprotegrin (OPG) were detected by ELISA. To analyse osteoclastogenesis the authors determined the number of osteoclast precursor cells in the bone marrow by Fluoreszenz activated cell sorter (FACS) and generated osteoclasts from bone marrow cells ex vivo. To analyse intracellular signalling pathways, the authors stimulated these osteoclasts with tumour necrosis factor α (TNFα) and detected the phosphorylation of kinases by western blot. Gene expression of osteoclasts was detected by real-time PCR. Histomorphometrie showed increased trabecular volume and trabecular number and decreased trabecular separation in MK2 deficient mice compared to wildtype. The μCT analysis confirmed these results and showed an increased bone density in MK2 deficient mice. Thus the four point bending experiment demonstrated a higher mechanical stability of bone of these mice. The number of osteoclasts was reduced while the number of osteoblasts was not altered in MK2 deficient mice. Serum Osteocalcin and RatLaps levels were decreased while OPG was increased and RANKL was not altered. Ex vivo osteoclastogenesis was clearly reduced in MK2 deficient mice compared to wildtype mice while the number of CD11b precursors in the bone marrow was equal. The phosphorylation of p38, serine/threonine protein kinase (AKT) and extracellular signal regulated kinase (ERK) was increased in TNFα stimulated MK2 deficient osteoclasts. Gene expression of TRAP, osteoclast associated receptor (OSCAR), matrix metalloproteinase 9 and receptor activator of nuclear factor κB (RANK) was decreased in MK2 deficient osteoclasts. MK2 deficient mice have an increased bone density and a reduced number of osteoclasts. This is due to impaired osteoclastogenesis in consequence of reduced expression of osteoclast specific genes. Thus MK2 plays an important role in physiological bone turnover by regulating osteoclastogenesis.
Influence of counterpulsation on collateral circulation after acute occlusion of the left anterior descending coronary artery in dogs
Authors: R. S. RENEMAN, A. H. M. JAGENEAU, W. K. A. SCHAPER, F. A. S. BROUWER, W. V. GERVEN
Journal: Cardiovascular Research (1972)

Journal Article Influence of counterpulsation on collateral circulation after acute occlusion of the left anterior descending coronary artery in dogs Get access R. S. RENEMAN, R. S. RENEMAN From the Experimental Laboratory of the Department of Cardiovascular Surgery, University Hospital, Utrecht, The Netherlands, and the Cardiovascular Department, Janssen Research Laboratory, Beerse, Belgium Search for other works by this author on: Oxford Academic PubMed Google Scholar A. H. M. JAGENEAU, A. H. M. JAGENEAU From the Experimental Laboratory of the Department of Cardiovascular Surgery, University Hospital, Utrecht, The Netherlands, and the Cardiovascular Department, Janssen Research Laboratory, Beerse, Belgium Search for other works by this author on: Oxford Academic PubMed Google Scholar W. K. A. SCHAPER, W. K. A. SCHAPER From the Experimental Laboratory of the Department of Cardiovascular Surgery, University Hospital, Utrecht, The Netherlands, and the Cardiovascular Department, Janssen Research Laboratory, Beerse, Belgium Search for other works by this author on: Oxford Academic PubMed Google Scholar F. A. S. BROUWER, F. A. S. BROUWER From the Experimental Laboratory of the Department of Cardiovascular Surgery, University Hospital, Utrecht, The Netherlands, and the Cardiovascular Department, Janssen Research Laboratory, Beerse, Belgium Search for other works by this author on: Oxford Academic PubMed Google Scholar W. VAN GERVEN W. VAN GERVEN From the Experimental Laboratory of the Department of Cardiovascular Surgery, University Hospital, Utrecht, The Netherlands, and the Cardiovascular Department, Janssen Research Laboratory, Beerse, Belgium Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 6, Issue 1, January 1972, Pages 45–53, https://doi.org/10.1093/cvr/6.1.45 Published: 01 January 1972
Genetics of Recurrent Early-Onset Major Depression (GenRED): Significant Linkage on Chromosome 15q25-q26 After Fine Mapping With Single Nucleotide Polymorphism Markers
Authors: Douglas F. Levinson, Oleg V. Evgrafov, James A. Knowles, James B. Potash, Myrna M. Weissman, William A. Scheftner, J. Raymond DePaulo, Raymond R. Crowe, Kathleen Murphy-Eberenz, Diana H. Marta, Melvin G. McInnis, Philip Adams, Madeline Gladis, Erin B. Miller, Jo Thomas, Peter Holmans
Journal: American Journal of Psychiatry (2007)

The authors studied a dense map of single nucleotide polymorphism (SNP) DNA markers on chromosome 15q25-q26 to maximize the informativeness of genetic linkage analyses in a region where they previously reported suggestive evidence for linkage of recurrent early-onset major depressive disorder.In 631 European-ancestry families with multiple cases of recurrent early-onset major depressive disorder, 88 SNPs were genotyped, and multipoint allele-sharing linkage analyses were carried out. Marker-marker linkage disequilibrium was minimized, and a simulation study with founder haplotypes from these families suggested that linkage scores were not inflated by linkage disequilibrium.The dense SNP map increased the information content of the analysis from around 0.7 to over 0.9. The maximum evidence for linkage was the Z likelihood ratio score statistic of Kong and Cox (Z(LR))=4.69 at 109.8 cM. The exact p value was below the genomewide significance threshold. By contrast, in the genome scan with microsatellite markers at 9 cM spacing, the maximum Z(LR) for European-ancestry families was 3.43 (106.53 cM). It was estimated that the linked locus or loci in this region might account for a 20% or less populationwide increase in risk to siblings of cases.This region has produced modestly positive evidence for linkage to depression and related traits in other studies. These results suggest that DNA sequence variations in one or more genes in the 15q25-q26 region can increase susceptibility to major depression and that efforts are warranted to identify these genes.
Atheroprotective Effect of Human Apolipoprotein A5 in a Mouse Model of Mixed Dyslipidemia
Authors: Roxane M. Mansouri, Eric Baugé, Philippe Gervois, Jamila Fruchart-Najib, Catherine Fiévet, Bart Staels, Jean-Charles Fruchart
Journal: Circulation Research (2008)

Hypertriglyceridemia is an independent risk factor for coronary artery disease. Because apolipoprotein (Apo)A5 regulates plasma triglyceride levels, we investigated the impact of human (h)ApoA5 on atherogenesis. The influence of hApoA5 transgenic expression was studied in the ApoE2 knock-in mouse model of mixed dyslipidemia. Our results demonstrate that hApoA5 lowers plasma triglyceride levels in Western diet-fed ApoE2 knock-in mice. Moreover, atherosclerotic lesion development was significantly decreased in the hApoA5 transgenic mice. Finally, pharmacologic activation of hApoA5 expression by the peroxisome proliferator-activated receptor-alpha agonist fenofibrate resulted in an enhanced atheroprotection. These results identify an atheroprotective role of hApoA5 in a mouse model of mixed dyslipidemia.
Interleukin 6 Influences Germinal Center Development and Antibody Production via a Contribution of C3 Complement Component
Authors: Manfred Kopf, Suzanne Herren, Michael V. Wiles, Mark B. Pepys, Marie H. Kosco-Vilbois
Journal: The Journal of Experimental Medicine (1998)

Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell–dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6–deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti–mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3–deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6–deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.
Executive functioning affects health behaviour in older people too
Authors: D. McMinn, J. Allan, M. Daly
Journal: BMJ (2013)

Marteau and Hall provide interesting insight into the important links between early life environments, poverty, deleterious health behaviours, and the cognitive abilities used to control such behaviours—the “executive functions.”1 They suggest that associations between early life exposure to poverty and subsequent reductions in executive functions contribute to health inequalities. They also acknowledge the possibility of bidirectionality in this association: “those starting life with …
Expression of Constitutively Active Raf-1 in the Mitochondria Restores Antiapoptotic and Leukemogenic Potential of a Transformation-deficient BCR/ABL Mutant
Authors: Paolo Salomoni, Mariusz A. Wasik, Richard F. Riedel, Krzysztof Reiss, John K. Choi, Tomasz Skorski, Bruno Calabretta
Journal: The Journal of Experimental Medicine (1998)

The oncogenic BCR/ABL protein protects hematopoietic cells from apoptosis induced by growth factor deprivation, but the mechanisms are only partially understood. A BCR/ABL mutant lacking amino acids 176–426 in the BCR domain (p185ΔBCR) failed to protect interleukin 3–deprived 32Dcl3 myeloid precursor cells from apoptosis, although it possessed tyrosine kinase activity and was capable of activating the Ras-Raf-MAP kinase pathway. Compared to p185 wild-type transfectants, p185ΔBCR-transfected cells showed markedly reduced levels of Bcl-2 and expressed the hypophosphorylated, proapoptotic form of BAD. Bcl-2 expression in the mitochondrial fraction of p185ΔBCR cells was also markedly diminished and mitochondrial RAF was undetectable. In p185ΔBCR cells transfected with a mitochondria-targeted, constitutively active RAF (M-Raf) BAD was expressed in the hyperphosphorylated form and released from the mitochondria into the cytosol. p185ΔBCR/M-Raf–transfected cells were completely resistant to apoptosis induced by growth factor deprivation in vitro. Moreover, constitutive expression of dominant-negative M-Raf (K375W) enhanced the susceptibility of 32Dcl3 cells expressing wild-type BCR/ABL to apoptosis. In severe combined immunodeficiency (SCID) mice, p185ΔBCR/M-Raf double transfectants were leukemogenic, whereas cells expressing only p185ΔBCR showed no leukemogenic potential. Together, these data support the existence of a BCR/ABL-dependent pathway that leads to expression of an active RAF in the mitochondria and promotes antiapoptotic and leukemia-inducing effects of BCR/ABL.