tbuckley/cabot-search huggingface dataset:
T cells that encounter virus in the complete absence of a particular H-2 antigen are nonresponsive when stimulated again in the context of that H-2 antigen.
Authors: J R Bennink, P C Doherty
Journal: The Journal of Experimental Medicine (1980)

Immunologically naive BALB/c (H-2d) and C57BL/6J (B6) (H-2b) T-cell populations can, after filtration to remove alloreactive precursor lymphocytes, be induced to respond to vaccinia virus presented in the context of H-2Kk when stimulated in an appropriate recipient. Exposure to vaccinia virus 6 wk previously completely abrogated the capacity of BALB/c T cells to interact with H-2Kk-vaccinia virus. This is also true for negatively selected B6 thoracic duct lymphocytes taken at 14 or 18 d, but not at 6 wk after immunization: the discrepancy is thought to reflect the progressive emergence of new T cells in the latter group. No evidence could be found for the operation of suppression, and the results are considered to indicate that T cells that interact with virus in the absence of the relevant H-2 antigen are tolerized. Whereas stimulation to effector function is H-2 restricted, induction of immune paralysis may be unrestricted. The capacity of T-cell populations to respond to virus presented in the context of allogeneic H-2 determinants thus depends upon previous antigenic experience.
Rosai-Dorfman disease complicated by autoimmune haemolytic anaemia: case report and review of a multisystem disease with cutaneous infiltrates.
Authors: S.A. Grabczynska, C.T. Toh, N. Francis, C. Costello, C.B. Bunker
Journal: British Journal of Dermatology (2001)

We report a patient with sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease) who presented with widespread nodal and extranodal involvement affecting the skin, orbits and nasal sinuses, complicated by the development of autoimmune haemolytic anaemia. The aetiology and pathogenesis of this multisystem disorder are unknown but are thought to represent a reactive histiocytic process to an infective agent rather than a neoplastic or other primary condition. Prognosis is generally good but clinical or laboratory evidence of immune dysfunction tends to predict a poorer outcome. We describe the clinical course of the patient and review the literature on this disease.
Prevention of Hypertrophy by Overexpression of Kv4.2 in Cultured Neonatal Cardiomyocytes
Authors: Carsten Zobel, Zameneh Kassiri, The-Tin T. Nguyen, Yang Meng, Peter H. Backx
Journal: Circulation (2002)

Prolonged action potentials (APs) and decreased transient outward K+ currents (I(to)) are consistent findings in hypertrophic myocardium. However, the connection of these changes with cardiac hypertrophy is unknown. The present study investigated the effects of changes in I(to) and the associated alterations in AP on myocyte hypertrophy induced by phenylephrine.Chronic incubation of cultured neonatal ventricular rat myocytes (NVRMs) with phenylephrine (PE) reduced I(to) density and prolonged AP duration, leading to a 2-fold increase in the net Ca2+ influx per beat and a 1.4-fold increase in Ca2+-transient amplitude. PE treatment of chronically paced (2-Hz) NVRM also induced increases in cell size, protein/DNA ratio, atrial natriuretic factor mRNA expression, as well as beta/alpha myosin mRNA ratio. These hypertrophic changes were associated with a 2.4-fold increase in activation of nuclear factor of activated T-cells (NFAT), indicating increased activity of the Ca2+-dependent phosphatase calcineurin. Overexpression of Kv4.2 channels using adenovirus prevented the AP duration prolongation as well as the increases in Ca2+ influx and Ca2+-transient amplitude induced by PE. Kv4.2 overexpression also prohibited the PE-induced increases in cell size, protein/DNA ratio, atrial natriuretic factor expression, beta/alpha myosin mRNA ratio, and NFAT activation.Our results demonstrate that PE-mediated hypertrophy in NRVMs seems to require I(to) reductions and AP prolongation associated with increased Ca2+ influx and Ca2+ transients as well as calcineurin activation. The clinical implications of these studies and the possible involvement of other signaling pathways are discussed.
Hepatocyte Growth Factor Alters Renal Epithelial Cell Susceptibility to Uropathogenic Escherichia coli
Authors: John H. Wu, Barry J. Billings, Daniel F. Balkovetz
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. The urinary tract is frequently the source of Escherichia coli bacteremia. Bacteria from the urinary tract must cross an epithelial layer to enter the bloodstream. Hepatocyte growth factor (HGF) alters the polarity of Madin-Darby canine kidney (MDCK) epithelial cells. The role of cell polarity in determining renal epithelial resistance to Escherichia coli invasion is not well known. A model of polarized and HGF-treated MDCK epithelial cells grown on filters was used to study the role of epithelial cell polarity during the interaction of nonvirulent (XL1-Blue) and uropathogenic (J96) strains of Escherichia coli with renal epithelium. Basolateral exposure of MDCK cells to J96, but not XL1-Blue, resulted in loss of transepithelial resistance (TER), which was due to epithelial cytotoxicity and not degradation of epithelial junctional proteins by bacterial proteases. Apical exposure to both J96 and XL1-Blue did not alter TER. Pretreatment of polarized MDCK cell monolayers with HGF renders the cells sensitive to loss of TER and cytotoxicity by apical exposure to J96. Analysis by confocal microscopy demonstrated that HGF treatment of MDCK cell monolayers also greatly enhances adherence of J96 to the apical surface of the cell monolayer. These data demonstrate that the basolateral surface of polarized epithelia is more susceptible to J96 cytotoxicity. The data also support the hypothesis that processes that alter epithelial cell polarity increase sensitivity of epithelia to bacterial injury and adherence from the apical compartment.
Physical activity and television watching in relation to semen quality in young men
Authors: Audrey Jane Gaskins, Jaime Mendiola, Myriam Afeiche, Niels Jørgensen, Shanna H Swan, Jorge E Chavarro
Journal: British Journal of Sports Medicine (2013)

Background Semen quality appears to have declined over the past decades but reasons for this decline are unresolved. The concurrent increase in sedentary behaviour may be a contributing factor. The objective of this study was to evaluate the relationship of physical activity and television (TV) watching with sperm parameters in a population of young, healthy men. Methods Men aged 18–22 years (n=189) from the Rochester Young Men's Study (2009–2010) participated in this analysis. Physical activity (h/week of moderate and vigorous exercise) and TV watching (h/week of TV, video or DVD watching) over the past 3 months were assessed via questionnaire. Semen quality was assessed by sperm concentration, motility, morphology and total sperm count. Results Sperm concentration and total sperm count were directly related to physical activity after multivariable adjustment (p-trend=0.01 and 0.04); men in the highest quartile of moderate-to-vigorous activity (≥15 h/week) had 73% (95% CI 15% to 160%) higher sperm concentration than men in the lowest quartile (&lt;5 h/week). TV watching was inversely associated with sperm concentration and total sperm count in multivariable analyses (p-trend=0.05 and 0.06); men in the highest quartile of TV watching (&gt;20 h/week) had 44% (95% CI 15 to 63%) lower sperm concentration than men in the lowest quartile (0 h/week). These measures of physical and leisure time activities were not significantly associated with sperm motility or morphology. Conclusions In this population of healthy men, higher moderate-to-vigorous activity and less TV watching were significantly associated with higher total sperm count and sperm concentration.
Skewed X Chromosome Inactivation and Breast and Ovarian Cancer Status: Evidence for X-Linked Modifiers of BRCA1
Authors: Felicity Lose, David L. Duffy, Graham F. Kay, Mary A. Kedda, Amanda B. Spurdle
Journal: JNCI Journal of the National Cancer Institute (2008)

Background X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects.
Physical Activity and Risks of Proximal and Distal Colon Cancers: A Systematic Review and Meta-analysis
Authors: Terry Boyle, Tessa Keegel, Fiona Bull, Jane Heyworth, Lin Fritschi
Journal: JNCI Journal of the National Cancer Institute (2012)

Although there is convincing epidemiological evidence that physical activity is associated with a reduced risk of colon cancer, it is unclear whether physical activity is differentially associated with the risks of proximal colon and distal colon cancers. We conducted a systematic review and meta-analysis to investigate this issue.MEDLINE and EMBASE were searched for English-language cohort and case-control studies that examined associations between physical activity and the risks of proximal colon and distal colon cancers. A random-effects meta-analysis was conducted to estimate the summary relative risks (RRs) for the associations between physical activity and the risks of the two cancers. All statistical tests were two-sided.A total of 21 studies met the inclusion criteria. The summary relative risk of the main results from these studies indicated that the risk of proximal colon cancer was 27% lower among the most physically active people compared with the least active people (RR = 0.73, 95% confidence interval [CI] = 0.66 to 0.81). An almost identical result was found for distal colon cancer (RR = 0.74, 95% CI = 0.68 to 0.80).The results of this systematic review and meta-analysis suggest that physical activity is associated with a reduced risk of both proximal colon and distal colon cancers, and that the magnitude of the association does not differ by subsite. Given this finding, future research on physical activity and colon cancer should focus on other aspects of the association that remain unclear, such as whether sedentary behavior and nonaerobic physical activity are associated with the risk of colon cancer.
Cruelty, age, and thanatourism
Authors: Pierre L. van den Berghe
Journal: Behavioral and Brain Sciences (2006)

Two areas of research for testing Nell's theory are suggested. One is cruelty's seemingly negative correlation with age, which would confirm its linkage with testosterone, sex, and dominance. The other is the special field of leisure activity called thanatourism , that is, the transformation of loci of human horror into tourist attractions.
A Clinical View of Simple and Complex Renal Cysts
Authors: Garabed Eknoyan
Journal: Journal of the American Society of Nephrology (2008)

The availability and use of abdominal diagnostic ultrasonography or computed tomography has led to the frequent detection of asymptomatic renal cysts. The vast majority of these are simple cysts that are usually unilateral and solitary with well-defined structural and imaging features and whose occurrence, number, and bilaterality increase with age. Simple cysts are asymptomatic, except when complications such as hemorrhage, infection, or rupture lead to the development of complex cysts with calcification, demarcation irregularities, and multilobularity. The diagnostic challenges that cysts present are in the differentiation of the less common complicated complex cysts from those associated with malignancy and when numerous the possible heralding of genetic or acquired multicystic diseases of the kidney.
B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen.
Authors: J Lang, M Jackson, L Teyton, A Brunmark, K Kane, D Nemazee
Journal: The Journal of Experimental Medicine (1996)

To assess the sensitivity of B cell tolerance with respect to receptor/autoantigen affinity, we identified low affinity ligands to the 3-83 (anti-major histocompatibility complex class I) antibody and tested the ability of these ligands to induce central and peripheral tolerance in 3-83 transgenic mice. Several class I protein alloforms, including Kbm3 and Dk, showed remarkably low, but detectable, affinity to 3-83. The 3-83 antibody bound Kb with K lambda approximately 2 x 10(5) M-1 and bound 10-fold more weakly to the Kbm3 (K lambda approximately 2 x 10(4) M-1) and Dk antigens. Breeding 3-83 immunoglobulin transgenic mice with mice expressing these ultralow affinity Kbm3 and Dk ligands resulted in virtually complete deletion of the autoreactive B cells from the peripheral lymphoid tissues. These low affinity antigens also induced receptor editing, as measured by elevated RAG mRNA levels in the bone marrow and excess levels of id- variant B cells bearing lambda light chains in the spleen. Reactive class I antigens were also able to mediate deletion of mature B cells when injected into the peritoneal cavity of 3-83 transgenic mice. Although the highest affinity ligand, Kk, was consistently able to induce elimination of the 3-83 peritoneal B cells, the lower affinity ligands were only partially effective. These results demonstrate the remarkable sensitivity of the deletion and receptor-editing mechanisms in immature B cells, and may suggest a higher affinity threshold for deletion of peripheral, mature B cells.
Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis
Authors: John D Isaacs, Stanley B Cohen, Paul Emery, Paul P Tak, Jianmei Wang, Guiyuan Lei, Sarah Williams, Preeti Lal, Simon J Read
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Studies examining the relationship between serological status (rheumatoid factor and/or anticitrullinated antibody) and rituximab treatment outcome in rheumatoid arthritis (RA) have been hampered by limited numbers of seronegative patients. <h3>Objective</h3> To carry out a meta-analysis of trials from the rituximab RA clinical programme to investigate this relationship further. <h3>Methods</h3> This was a meta-analysis of four placebo-controlled, phase II or III clinical trials. The efficacy end point in all analyses was change from baseline in Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 24 weeks. Assay of serotype and missing data imputation methods were consistent across all studies. <h3>Results</h3> The population analysed comprised 2177 patients (rituximab, n=1416; placebo, n=761). Demographics and baseline disease characteristics were well balanced. When a fixed-effects meta-analysis approach was used, the overall-effect model indicated evidence of additional treatment benefit with rituximab in seropositive patients: reduction in DAS28-ESR at week 24 was on average 0.35 units (95% CI 0.12 to 0.84; n=1394) greater than in seronegative patients; this effect was not seen in placebo patients. Heterogeneity indices indicated significant uncertainty in the overall-effect model (Q=8.8, I=0.77; p=0.03 (χ<sup>2</sup> test)). Baseline Health Assessment Questionnaire score, pain visual analogue scale, swollen joint counts of 28 joints and race were significant contributors to this heterogeneity, with additional analysis indicating that these effects may predominate in early RA (methotrexate-naïve) populations. A dominant effect was seen in patients for whom one or more tumour necrosis factor inhibitors had failed. <h3>Conclusion</h3> Although the difference was modest, the overall-effect model indicates that seropositive patients respond better to rituximab than seronegative patients.
Limited thoracoplasty in the management of complicated pulmonary aspergillomas.
Authors: M al-Zeerah, K Jeyasingham
Journal: Thorax (1989)

Complicated pulmonary aspergilloma is a life threatening condition. Indications for surgery are few and the procedures conservative. Three patients were successfully treated with limited thoracoplasty. Limited thoracoplasty in combination with other conservative measures may provide effective palliation in selected cases.
Acute‐on‐chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults
Authors: Yu Shi, Ying Yang, Yaoren Hu, Wei Wu, Qiao Yang, Min Zheng, Shun Zhang, Zhaojun Xu, Yihua Wu, Huadong Yan, Zhi Chen
Journal: Hepatology (2015)

Patients with acute-on-chronic liver failure (ACLF) represent a heterogeneous population. The aim of the study is to identify distinct groups according to the etiologies of precipitating events. A total of 405 ACLF patients were identified from 1,361 patients with cirrhosis with acute decompensation and categorized according to the types of acute insults. Clinical characteristics and prognosis between the hepatic group and extrahepatic group were compared, and the performance of prognostic models was tested in different groups. Two distinct groups (hepatic-ACLF and extrahepatic-ACLF) were identified among the ACLF population. Hepatic-ACLF was precipitated by hepatic insults and had relatively well-compensated cirrhosis with frequent liver and coagulation failure. In contrast, extrahepatic-ACLF was exclusively precipitated by extrahepatic insults, characterized by more severe underlying cirrhosis and high occurrence of extrahepatic organ failures (kidney, cerebral, circulation, and respiratory systems). Both groups had comparably high short-term mortality (28-day transplant-free mortality: 48.3% vs. 50.7%; P = 0.22); however, the extra-hepatic-ACLF group had significantly higher 90-day and 1-year mortality (90-day: 58.9% vs. 68.3%, P = 0.035; 1-year: 63.9% vs. 74.6%, P = 0.019). In hepatic-ACLF group, the integrated Model for End-Stage Liver Disease (iMELD) score had the highest area under the receiver operating characteristic curve (auROC = 0.787) among various prognostic models in predicting 28-day mortality, whereas CLIF-Consortium scores for ACLF patients (CLIF-C-ACLF) had the highest predictive value in the other group (auROC = 0.779).ACLF precipitated by hepatic insults is distinct from ACLF precipitated by extrahepatic insults in clinical presentation and prognosis. The iMELD score may be a better predictor for hepatic-ACLF short-term prognosis, whereas CLIF-C-ACLF may be better for extrahepatic-ACLF patients.
Splenic schooling dampens inflammation
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

When confronted with potentially lethal bacterial sepsis, the brain tells the spleen to shut down the production of inflammatory cytokines, according to Huston and colleagues on page 1623. This may help explain why splenectomy renders people more prone to the immunological overreaction of septic shock when infected with certain types of bacteria.






Figure 1

Vagus nerve delivers antiinflammatory signals to the spleen.




When the brain detects inflammation or injury, it sends signals along the vagus nerve—the meandering nerve that regulates vital functions such as heart rate and digestion. This signal triggers the release of the neurotransmitter acetylcholine (Ach) from peripheral nerve endings. Ach then binds to its receptor on immune cells and inhibits the production of inflammatory cytokines, in part by inhibiting the activation of the transcription factor NF-κB. This circuit is known as the cholinergic antiinflammatory pathway.

Electrical stimulation of the vagus nerve suppresses cytokine production in several rodent models of inflammation. During bacterial sepsis, according to Huston et al., the vagus nerve's stop signal must be delivered to the spleen, as removing the spleen or severing the branch of the vagus nerve that innervates the spleen abolished the antiinflammatory effect.

The spleen produced the bulk of the shock-inducing cytokine TNF in this model, possibly explaining why this organ had to receive the vagus nerve signal. But senior author Kevin Tracey suspects that Ach release always occurs in the spleen, even when the inflammation is happening elsewhere—a hunch they are now testing in an arthritis model.

Tracey thinks that vagus nerve signals might educate white blood cells in the spleen, through which circulating cells transit every 2 to 3 min. How immune cells might translate this splenic schooling to inflammation control at distant sites remains to be determined. In the meantime, implanted pacemaker-like devices that zap the vagus nerve—used to treat seizure disorders—might also be useful for treating inflammatory diseases.
Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation
Authors: Betty K. Hamilton, Lisa Rybicki, Robert Dean, Navneet S. Majhail, Housam Haddad, Donna Abounader, Rabi Hanna, Ronald Sobecks, Hien Duong, Brian T. Hill, Edward Copelan, Brian Bolwell, Matt Kalaycio
Journal: American Journal of Hematology (2014)

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced-intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA-identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA+MTX. Patients receiving MMF + CSA had rapid neutrophil (median 11 vs. 19 days with MTX+CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2-4 (MMF+CSA 37% vs. MTX+CSA 39%) or 3-4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non-relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P = NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3-4 acute GVHD (HR 2.92, 95% CI 1.2-7.15, P = 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed.