tbuckley/cabot-search huggingface dataset:
Severity prediction rules in community acquired pneumonia: a validation study
Authors: W S Lim
Journal: Thorax (2000)

The British Thoracic Society (BTS) developed a rule (BTSr) based on severity criteria to predict short term mortality in adults admitted to hospital with community acquired pneumonia (CAP). However, neither the BTSr nor a recent modification of it (mBTSr) have been validated in the UK. A case-control study was conducted in a typical UK population to determine the clinical factors predictive of mortality and to assess the performance of these rules.Cases were drawn from all patients with CAP who died in 1997 in five large hospitals in the Mid Trent area. Controls were randomly selected from survivors. Factors associated with mortality were identified following review of medical case notes and performance of the severity prediction rules assessed.Age >65 years, temperature <37 degrees C, respiratory rate >24 breaths/min, mental confusion, urea concentration of >7 mmol/l, sodium concentration of <135 mmol/l, and the presence of a pleural effusion, all determined on admission, were independently associated with in-hospital mortality on multivariate analysis. The BTSr was 52% sensitive and 79% specific in predicting death while the mBTSr displayed 66% sensitivity and 73% specificity.The value of three of the four factors (presence of mental confusion, raised respiratory rate, raised urea) used in the mBTSr as predictors of mortality is confirmed. However, the BTSr and mBTSr did not perform as well in this validation study which included a high proportion (48%) of elderly patients (> or =75 years) compared with the derivation studies.
Doctors don't need second signature before agreeing abortion, MPs hear
Authors: Adrian O'Dowd
Journal: BMJ (2007)

<h3>Abstract</h3> Factor V Leiden (<i>F5<sup>L</sup></i>) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized ENU mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for <i>F5<sup>L</sup></i> (<i>F5<sup>L/L</sup></i>) and haploinsufficient for tissue factor pathway inhibitor (<i>Tfpi</i><sup>+/−</sup>). <i>F8</i> deficiency enhanced survival of <i>F5<sup>L/L</sup> Tfpi</i><sup>+/−</sup> mice, demonstrating that <i>F5<sup>L/L</sup> Tfpi</i><sup>+/−</sup> lethality is genetically suppressible. ENU-mutagenized <i>F5<sup>L/L</sup></i> males and <i>F5<sup>L/+</sup> Tfpi</i><sup>+/−</sup> females were crossed to generate 6,729 progeny, with 98 <i>F5<sup>L/L</sup> Tfpi</i><sup>+/−</sup> offspring surviving until weaning. Sixteen lines exhibited transmission of a putative thrombosuppressor to subsequent generations, with these lines referred to as <i>MF5L</i> (<b>M</b>odifier of <b>F</b>actor <b>5 L</b>eiden) 1-16. Linkage analysis in <i>MF5L6</i> identified a chromosome 3 locus containing the tissue factor gene (<i>F3</i>). Though no ENU-induced <i>F3</i> mutation was identified, haploinsufficiency for <i>F3</i> (<i>F3</i><sup>+/−</sup>) suppressed <i>F5<sup>L/L</sup> Tfpi</i><sup>+/−</sup> lethality. Whole exome sequencing in <i>MF5L12</i> identified an <i>Actr2</i> gene point mutation (p.R258G) as the sole candidate. Inheritance of this variant is associated with suppression of <i>F5<sup>L/L</sup> Tfpi</i><sup>+/−</sup> lethality (p=1.7x10<sup>−6</sup>), suggesting that <i>Actr2</i><sup>p.R258G</sup> is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent <i>Actr2</i> knockin/knockout demonstrated that <i>Actr2</i> haploinsufficiency is lethal, supporting a hypomorphic or gain of function mechanism of action for <i>Actr2</i><sup>p.R258G</sup>. Our findings identify <i>F8</i> and the <i>Tfpi/F3</i> axis as key regulators in determining thrombosis balance in the setting of <i>F5<sup>L</sup></i> and also suggest a novel role for <i>Actr2</i> in this process. <h3>Significance Statement</h3> Venous thromboembolism (VTE) is a common disease characterized by the formation of inappropriate blood clots. Inheritance of specific genetic variants, such as the Factor V Leiden polymorphism, increases VTE susceptibility. However, only ~10% of people inheriting Factor V Leiden develop VTE, suggesting the involvement of other genes that are currently unknown. By inducing random genetic mutations into mice with a genetic predisposition to VTE, we identified two genomic regions that reduce VTE susceptibility. The first includes the gene for blood coagulation Factor 3 and its role was confirmed by analyzing mice with an independent mutation in this gene. The second contains a mutation in the Actr2 gene. These findings identify critical genes for the regulation of blood clotting risk.
Effects of vitamin D compounds on renal and intestinal Ca2+ transport proteins in 25-hydroxyvitamin D3-1α-hydroxylase knockout mice1
Authors: Joost G.J. Hoenderop, Annemiete W.C.M. Van der Kemp, Colleen M. Urben, Stephen A. Strugnell, René J.M. Bindels
Journal: Kidney International (2004)
Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers
Authors: Cheryl L. Day, Nilufer P. Seth, Michaela Lucas, Heiner Appel, Laurent Gauthier, Georg M. Lauer, Gregory K. Robbins, Zbigniew M. Szczepiorkowski, Deborah R. Casson, Raymond T. Chung, Shannon Bell, Gillian Harcourt, Bruce D. Walker, Paul Klenerman, Kai W. Wucherpfennig
Journal: Journal of Clinical Investigation (2003)

Containment of hepatitis C virus (HCV) and other chronic human viral infections is associated with persistence of virus-specific CD4 T cells, but ex vivo characterization of circulating CD4 T cells has not been achieved. To further define the phenotype and function of these cells, we developed a novel approach for the generation of tetrameric forms of MHC class II/peptide complexes that is based on the cellular peptide-exchange mechanism. HLA-DR molecules were expressed as precursors with a covalently linked CLIP peptide, which could be efficiently exchanged with viral peptides following linker cleavage. In subjects who spontaneously resolved HCV viremia, but not in those with chronic progressive infection, HCV tetramer–labeled cells could be isolated by magnetic bead capture despite very low frequencies (1:1,200 to 1:111,000) among circulating CD4 T cells. These T cells expressed a set of surface receptors (CCR7+CD45RA–CD27+) indicative of a surveillance function for secondary lymphoid structures and had undergone significant in vivo selection since they utilized a restricted Vβ repertoire. These studies demonstrate a relationship between clinical outcome and the presence of circulating CD4 T cells directed against this virus. Moreover, they show that rare populations of memory CD4 T cells can be studied ex vivo in human diseases.
ICER Evokes Dusp1-p38 Pathway Enhancing Chemotherapy Sensitivity in Myeloid Leukemia
Authors: Martina Pigazzi, Elena Manara, Alessandra Beghin, Emma Baron, Claudia Tregnago, Giuseppe Basso
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The inducible cyclic adenosine monophosphate (cAMP) early repressor (ICER) is found downregulated in acute myeloid leukemia (AML), failing to control cAMP response element binding protein (CREB) transcriptional activity, recently demonstrated to mediate AML progression. We aimed to characterize ICER's role in drug sensitivity by treating myeloid cell lines and primary AML with chemotherapics. Experimental design: The effects on CREB target genes induced by ICER restoration and drug treatment were studied by quantitative real-time PCR (qRT-PCR) and western blot. Cell cycle and apoptosis analysis were performed. Possible ICER-evoked pathways were investigated in vitro. The mechanism involved in enhanced drug sensitivity was described in primary AML cultures by silencing ICER main target genes. Results: AML cell lines reduced cell growth and enhanced apoptotic behavior after chemotherapy treatment if ICER was expressed. A significantly lowered expression of CREB target genes involved in cell cycle control (CyA1, B1, D1), and in the mitogen-activated protein kinase signaling pathway (ERK, AKT, DUSP1/4), was found after Etoposide treatment. The dual-specificity phosphatases DUSP1 and DUSP4, directly repressed by ICER, activated the p38 pathway, which triggered enhanced caspase-dependent apoptosis. The silencing of DUSP1/4 in HL60 confirmed the same enhanced drug sensitivity induced by ICER. Primary AML cultures, silenced for DUSP1 as well as restored of ICER expression, showed DUSP1 downregulation and p38 activation. Conclusion: ICER mediates chemotherapy anticancer activity through DUSP1-p38 pathway activation and drives the cell program from survival to apoptosis. ICER restoration or DUSP1 inhibition might be possible strategies to sensitize AML cancer cells to conventional chemotherapy and to inhibit tumor growth. Clin Cancer Res; 17(4); 742–52. ©2011 AACR.
αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease
Authors: Gauri Saini, Joanne Porte, Paul H. Weinreb, Shelia M. Violette, William A. Wallace, Tricia M. McKeever, Gisli Jenkins
Journal: European Respiratory Journal (2015)

Idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonitis are progressive interstitial lung diseases (ILDs) with limited treatment options and poor survival. However, the rate of disease progression is variable, implying there may be different endotypes of disease. We hypothesised that immunophenotyping biopsies from ILD patients might reveal distinct endotypes of progressive fibrotic disease, which may facilitate stratification when undertaking clinical trials of novel therapies for IPF.43 paraffin-embedded, formalin-fixed lung tissue sections were immunostained for five molecules implicated in the pathogenesis of the fibrosis: α-smooth muscle actin (αSMA), αvβ6 integrin, pro-surfactant protein C (SP-C), hepatocyte growth factor (HGF) and tenascin-C (TenC). Levels of immunostaining and numbers of fibroblastic foci were quantified using operator-dependent and -independent methods. The relationship of all these markers to overall survival was analysed.Staining revealed high levels of αSMA, αvβ6 integrin, pro-SP-C, HGF and TenC, and fibroblastic foci. Immunostaining varied across samples for all molecules but only the extent of αvβ6 integrin immunostaining was associated with increased mortality. There was no association with the other markers measured.Our data suggest high levels of αvβ6 integrin may identify a specific endotype of progressive fibrotic lung disease.
Hospitalized Psychoses after Renal Transplantation in the United States
Authors: Kevin C. Abbott, Lawrence Y. Agodoa, Patrick G. O’Malley
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Although it is recommended that renal transplant (RT) candidates routinely undergo screening for mental health–related conditions, national statistics for psychoses after RT have not been reported. This is a historical cohort study of 39,628 renal transplant recipients in the United States Renal Data System between July 1, 1994, and June 30, 1998, and followed until December 31, 1999. Adjusted hazard ratios (AHR) for time to hospitalization for both a primary and secondary discharge diagnosis of psychoses (ICD-9 codes 290.x-299.x) after RT and mortality/graft loss after psychosis were assessed by Cox Regression. In addition, rates of psychosis were compared with 178,986 patients with Medicare as their primary payer who started chronic dialysis from April 1, 1995, to June 29, 1999. The incidence of psychoses was 7.5/1000 person-years (PY) after RT compared with 7.2/1000 PY for all patients on chronic dialysis and 9.6/1000 PY for dialysis patients aged 65 yr or younger. Among RT recipients, graft loss (AHR, 2.97; 95% CI, 2.19 to 4.02), allograft rejection, and cadaveric donation were independently associated with psychosis, which was associated with an increased risk of both death (AHR, 2.09; 95% CI, 1.71 to 2.56; P < 0.001) and graft loss (AHR, 1.79; 95% CI, 1.15 to 2.78; P = 0.01). Graft loss due to noncompliance was significantly more common after psychosis (9.0% versus 3.7% in patients not hospitalized for psychosis; P < 0.001). The incidence of hospitalized psychosis was not substantially higher after RT compared with chronic dialysis patients. Psychoses were independently associated with increased risk of death and graft loss after renal transplantation, possibly mediated through medical non-adherence. E-mail: [email protected]
Access to Health Care in Contexts of Livelihood Insecurity: A Framework for Analysis and Action
Authors: Brigit Obrist, Nelly Iteba, Christian Lengeler, Ahmed Makemba, Christopher Mshana, Rose Nathan, Sandra Alba, Angel Dillip, Manuel W Hetzel, Iddy Mayumana, Alexander Schulze, Hassan Mshinda
Journal: PLoS Medicine (2007)

The Policy Forum allows health policy makers around the world to discuss challenges
Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection
Authors: Matthew J. Robinson, Fabiola Osorio, Marcela Rosas, Rui P. Freitas, Edina Schweighoffer, Olaf Groß, J. Sjef Verbeek, Jürgen Ruland, Victor Tybulewicz, Gordon D. Brown, Luis Ferreira Moita, Philip R. Taylor, Caetano Reis e Sousa
Journal: The Journal of Experimental Medicine (2009)

Innate immune cells detect pathogens via pattern recognition receptors (PRRs), which signal for initiation of immune responses to infection. Studies with Dectin-1, a PRR for fungi, have defined a novel innate signaling pathway involving Syk kinase and the adaptor CARD9, which is critical for inducing Th17 responses to fungal infection. We show that another C-type lectin, Dectin-2, also signals via Syk and CARD9, and contributes to dendritic cell (DC) activation by fungal particles. Unlike Dectin-1, Dectin-2 couples to Syk indirectly, through association with the FcRgamma chain. In a model of Candida albicans infection, blockade of Dectin-2 did not affect innate immune resistance but abrogated Candida-specific T cell production of IL-17 and, in combination with the absence of Dectin-1, decreased Th1 responses to the organism. Thus, Dectin-2 constitutes a major fungal PRR that can couple to the Syk-CARD9 innate signaling pathway to activate DCs and regulate adaptive immune responses to fungal infection.
Sequential or Concurrent Tamoxifen and Radiotherapy: To See or Not to See—<i>That</i> Is the Question!
Authors: Søren M. Bentzen, John R. Yarnold
Journal: Journal of Clinical Oncology (2005)

make much difference in the incidence of fibrosis-related late effects.A few studies have shown that TGF-␤ may enhance cellular radiosensitivity in vitro, 8-10 whereas other studies suggest the opposite. 11 The clinical relevance of these data remains to be demonstrated.
Elevated active secretory sphingomyelinase in antineutrophil cytoplasmic antibody-associated primary systemic vasculitis
Authors: Allan P Kiprianos, Matthew D Morgan, Mark A Little, Lorraine Harper, Paul A Bacon, Stephen P Young
Journal: Annals of the Rheumatic Diseases (2012)

Endothelial cell (EC) dysfunction (ECD) occurs in antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV)1 2 but improves with anti-tumour necrosis factor α (anti-TNFα) treatment,1 suggesting a key role for this cytokine. TNFα and interleukin 1 can induce secretion of acid sphingomyelinase (ASM) from ECs,3 4 which are the major source of this enzyme. ASM potently depresses calcium signals in lymphocytes5 and in EC (Church et al , unpublished observations). We hypothesised that endothelial inflammation in AASV would raise circulating levels of secretory sphingomyelinase (S-SMase), perpetuating vascular dysfunction.

Plasma from 18 patients with active AASV undergoing plasmapheresis (15 men, 3 women) were compared with 7 inflammatory renal disease controls and 9 healthy individuals. Sera were also collected from 20 AASV patients (9 women and 11 men) during active disease, after 14 weeks of immunosuppressive therapy and from patients in established remission on low-dose immunosuppression (6 months; n=7). Activity was assessed with the Birmingham vasculitis activity score (BVAS).6 S-SMase activity was assayed by hydrolysis of 6-((N-(7-nitrobenz- 2-oxa-1,3-diazol-4-yl)amino) hexanoyl)sphingosylphosphocholine (NBD C6-sphingomyelin)7 and the protein detected using immunoblotting following immunoprecipitation with an anti-ASM antibody (Santa-Cruz Biotechnology, Santa Cruz, CA, United States).

Plasma S-SMase activity was raised in patients with …
Antibodies that are specific for a single amino acid interchange in a protein epitope use structurally distinct variable regions.
Authors: S E Stark, A J Caton
Journal: The Journal of Experimental Medicine (1991)

We have analyzed how the immune system generates antibodies that are specific for analogues of an epitope on the influenza virus hemagglutinin (HA) that differ solely by the presence of Asp or Gly at amino acid 225. Most antibodies induced in response to HA(Asp225) use one of a few closely related variable (V) region structures that are encoded by characteristic VH/Vk gene segment combinations. Remarkably, none of these VH/Vk combinations was induced in response to HA(Gly225). Instead of modifying the HA(Asp225)-specific V regions by junctional variation or somatic mutation to recognize the altered epitope, new VH/Vk combinations were used. The expression of unique VH/Vk combinations appears to confer exquisite specificity to the selection of HA-specific B cells from the pre-immune repertoire.
Systolic Blood Pressure Relates to the Rate of Decline of Glomerular Filtration Rate in Type II Diabetes
Authors: Søren Nielsen, Anita Schmitz, Michael Rehung, Carl Erik Mogensen
Journal: Diabetes Care (1993)

OBJECTIVE To relate deterioration in kidney function to some potential cardiovascular risk factors in type II diabetic patients. RESEARCH DESIGN AND METHODS Twenty-four normoalbuminuric and 13 microalbuminuric patients completed a 3.4-yr prospective observational study. Glomerular nitration rate, urinary albumin excretion rate, blood pressure, glycemic control, and lipids were measured on entry and at the end of the study. Of the patients, 19 normoalbuminuric and 8 microalbuminuric (73%) patients had no history of antihypertensive treatment. RESULTS The glomerular filtration rate was significantly reduced during the follow-up period (−1.34 ± 0.54 ml · min−1 · 1.73 m−2 [mean ± SE], P &amp;lt; 0.02). The rate of decline varied considerably in normoalbuminuric and microalbuminuric patients (from −13.5 to 4.3 and from −7.0 to 4.2 ml · min−1 · 1.73 m−2 per year, respectively) but was on average not accelerated in normoalbuminuric or microalbuminuric patients (−1.3 ± 0.7 and −1.5 ± 0.8 ml · min−1 · 1.73 m−2 per year, respectively). Significant correlations were observed between the glomerular filtration rate fall rate and initial systolic blood pressure (r = −0.47, P &amp;lt; 0.01; patients without antihypertensive treatment: r = −0.42, P = 0.03) but not diastolic blood pressure. In a stepwise multiple linear regression analysis, baseline systolic blood pressure significantly determined the fall rate of the glomerular filtration rate (regression coefficient = −0.050, SE = 0.018, P = 0.011; patients without antihypertensive treatment: regression coefficient = −0.047, SE = 0.021, P = 0.030). CONCLUSIONS In these type II diabetic patients neither normoalbuminuria nor microalbuminuria are at an average associated with an accelerated decline in kidney function. Still, systolic blood pressure is a determining factor for the rate of decline in the glomerular filtration rate. A longer follow-up time with consecutive glomerular filtration rate measurements are needed to determine the long-term implications of normoalbuminuria and microalbuminuria on kidney function in type II diabetic patients.
THE SPREAD OF RHEUMATIC FEVER THROUGH FAMILIES
Authors: John R. Paul, Robert Salinger
Journal: Journal of Clinical Investigation (1931)

A number of epidemiological studies on rheumatic fever have been made, but in this disease, this field of endeavor is in its infancy as compared with other lines of approach.It has seemed to us, however, that here is another valuable weapon which may be brought to bear, not only because we would like to know more about the epidemiology of rheumatic fever, but it may tell us more about the nature of this obscure disease.Knowledge concerning the actual distribution and spread of human disease, that is, its epidemiology is obtained in two ways: by direct observation, and by statistical methods, the latter being wholly dependent upon the former.There has been no dearth of direct observations of one sort or another in rheumatic fever, but in spite of them, actual facts which lend themselves to statistical analyses along epidemiological lines are few.The difficulties seem to lie primarily in the nonspecific character of many of the clinical aspects of this disease.Some of its forms seem to be recognized with reasonable accuracy, but unfortunately no specific test has yet been devised to tell us when an individual actually has rheumatic fever, and we are thus unable to determine its true incidence or distribution.With these limitations in mind we have made an attempt to study the spread of rheumatic fever through families, as an epidemiological problem.We have chosen the family as a unit for study, (a) because it represents a small group in which an intimate investigation may be carried out; and (b), because one of the striking things about rheu- matic fever is its high familial incidence, of which there is ample evidence (1) (2) (3).Cohn (4) has assembled figures obtained by different observers on this point and calls attention to the fact that in so-called rheumatic families, 8-10 per cent of exposed persons are