tbuckley/cabot-search huggingface dataset:
Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways
Authors: Fabio Candotti, Luigi Notarangelo, Roberta Visconti, John O’Shea
Journal: Journal of Clinical Investigation (2002)

JAK-STAT signaling in human diseaseNumerous examples indicate that mammalian development can be entirely normal in the absence of the immune system; indeed, prior to birth, individuals with even very severe immunodeficiencies are developmentally unaffected.Perhaps it is not surprising, therefore, that more than 95 different primary immunodeficiency syndromes have been identified, encompassing defects in lymphocytes, phagocytes, and complement proteins.Indeed, within the past several years, more than 70 separate genes have been identified whose mutations cause immunodeficiency.These discoveries have been made both by using candidate gene approaches and by positional cloning.In some cases, the generation of gene-targeted mice preceded the identification of human mutations, whereas in other cases, the reverse was true.Therapy for these disorders, ranging from replacement therapy to bone marrow transplantation and gene therapy, has also moved at a rapid pace.This field therefore provides outstanding examples of the power of molecular medicine, with tremendous opportunities for interplay between basic and clinical science.Many of the processes that govern development of lymphoid and hematopoietic cells are now understood in some detail.We know that the growth and development of hematopoietic precursors, which develop in the fetal liver and bone marrow, are dependent upon a panoply of cytokines.In addition, lymphocytes require appropriate signals from antigen receptors to mature properly (Figure 1).Additionally, other receptors and counter-receptors on lymphoid and antigen-presenting cells are critical for initiating immune responses (Figure 2).We will provide examples in which mutations affect each of these steps and consequently result in immunodeficiency (Table 1).Several excellent reviews provide comprehensive discussion of the genetic basis of primary immunodeficiencies (1, 2).Our goal is not to summarize this field in its entirety; rather, a major focus of this review will be the role of cytokines and their receptors in the pathogenesis of primary immunodeficiencies.Additionally, the identification of new genes associated with immunodeficiency disorders, insights from patient-derived mutations, the heterogeneity of clinical presentations, the significance of revertants, and advances in gene therapy will be highlighted.To an extent, the areas emphasized are also a reflection of our interests, but in general the lessons are applicable to most of the diseases encompassed by primary immunodeficiencies.
Elevated Expression of Valosin-Containing Protein (p97) Is Associated with Poor Prognosis of Prostate Cancer
Authors: Yuichi Tsujimoto, Yasuhiko Tomita, Yoshihiko Hoshida, Takuro Kono, Toshitsugu Oka, Shinji Yamamoto, Norio Nonomura, Akihiko Okuyama, Katsuyuki Aozasa
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Valosin-containing protein (VCP) has been shown to be associated with metastasis and prognosis in human cancers. In the present study, the correlation of VCP with recurrence and prognosis in patients with prostate cancer (PCA) receiving conservative therapy was examined. Experimental Design: VCP expression was analyzed immunohistochemically in 136 patients ranging from 46 to 92 years (median, 72 years), who received conservative therapy, including androgen deprivation, radiotherapy, or watchful waiting. Staining intensity of tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. The correlation of VCP expression between the mRNA and protein levels was examined in 10 patients. Results: Thirty-two cases (23.5%) showed level 1 and 100 (76.5%) level 2 VCP expression. Quantitative reverse transcription-PCR analysis revealed greater VCPmRNA expression in level 2 (n = 5) than level 1 cases (n = 5; P &amp;lt; 0.05). A significant difference was observed between VCP level 1 and 2 patients in the positive rate for the digital rectal examination (P &amp;lt; 0.01), serum prostate-specific antigen level (P &amp;lt; 0.0001), cancer volume (P &amp;lt; 0.0001), Gleason score (P &amp;lt; 0.0001), stage (P &amp;lt; 0.0001), and progression-free and overall survival (P &amp;lt; 0.0001 for both). Multivariate analysis revealed VCP expression level, serum prostate-specific antigen level, and Gleason score to be independent prognosticators for progression-free and overall survival. Progression of PCA was found in 9.4% of level 1 but in 64% of level 2 patients. Conclusions: PCA with level 1 VCP expression could be treated conservatively.
Atypical gastric bleeding in a 55-year-old man, beyond the scope of treatment?
Authors: Thomas G Bird, Ewen M Harrison, Hamish Ireland
Journal: Gut (2014)

A 55-year-old man was admitted with a 3-week history of haematemesis with abdominal and back pain. He had a background of severe alcohol related pancreatitis 5 years previously and possible gastric varices. At presentation he was shocked (pulse 127, blood pressure 94/68, lactate 7.1 mM). Haemoglobin 8.0 g/L, platelet count 447 000/µL, liver function tests and coagulation were normal. After resuscitation and antibiotics he underwent oesophagogastroduodenoscopy in the Intensive Care Unit. Fresh blood was seen in the stomach, with thrombus adherent to an ulcer on a raised area of mucosa at the incisura (figure 1A). During therapeutic adrenaline …
THE CHEMICAL NATURE OF RESIDUE ANTIGEN PREPARED FROM YEAST
Authors: J. Howard Mueller, Joseph Tomcsik
Journal: The Journal of Experimental Medicine (1924)

Residue antigen recognizable by the precipitin test can be prepared from yeast as from bacteria. The active material appears to be identical with a complex carbohydrate, the "yeast gum" of Salkowski. In the purest form of it obtained small amounts of both nitrogen and phosphorus are still present, either as impurities or as part of the molecule. The yeast gum is not antigenic in the sense of producing antibodies.
Assessment of epidemic projections using recent HIV survey data in South Africa: a validation analysis of ten mathematical models of HIV epidemiology in the antiretroviral therapy era
Authors: Jeffrey W Eaton, Nicolas Bacaër, Anna Bershteyn, Valentina Cambiano, Anne Cori, Rob E Dorrington, Christophe Fraser, Chaitra Gopalappa, Jan A C Hontelez, Leigh F Johnson, Daniel J Klein, Andrew N Phillips, Carel Pretorius, John Stover, Thomas M Rehle, Timothy B Hallett
Journal: The Lancet Global Health (2015)

Mathematical models are widely used to simulate the effects of interventions to control HIV and to project future epidemiological trends and resource needs. We aimed to validate past model projections against data from a large household survey done in South Africa in 2012.We compared ten model projections of HIV prevalence, HIV incidence, and antiretroviral therapy (ART) coverage for South Africa with estimates from national household survey data from 2012. Model projections for 2012 were made before the publication of the 2012 household survey. We compared adult (age 15-49 years) HIV prevalence in 2012, the change in prevalence between 2008 and 2012, and prevalence, incidence, and ART coverage by sex and by age groups between model projections and the 2012 household survey.All models projected lower prevalence estimates for 2012 than the survey estimate (18·8%), with eight models' central projections being below the survey 95% CI (17·5-20·3). Eight models projected that HIV prevalence would remain unchanged (n=5) or decline (n=3) between 2008 and 2012, whereas prevalence estimates from the household surveys increased from 16·9% in 2008 to 18·8% in 2012 (difference 1·9, 95% CI -0·1 to 3·9). Model projections accurately predicted the 1·6 percentage point prevalence decline (95% CI -0·3 to 3·5) in young adults aged 15-24 years, and the 2·2 percentage point (0·5 to 3·9) increase in those aged 50 years and older. Models accurately represented the number of adults on ART in 2012; six of ten models were within the survey 95% CI of 1·54-2·12 million. However, the differential ART coverage between women and men was not fully captured; all model projections of the sex ratio of women to men on ART were lower than the survey estimate of 2·22 (95% CI 1·73-2·71).Projections for overall declines in HIV epidemics during the ART era might have been optimistic. Future treatment and HIV prevention needs might be greater than previously forecasted. Additional data about service provision for HIV care could help inform more accurate projections.Bill & Melinda Gates Foundation.
Minimal Disseminated Disease in High-Risk Burkitt's Lymphoma Identifies Patients With Different Prognosis
Authors: Lara Mussolin, Marta Pillon, Emanuele S.G. d'Amore, Valentino Conter, Matilde Piglione, Luca Lo Nigro, Alberto Garaventa, Salvatore Buffardi, Maurizio Aricò, Angelo Rosolen
Journal: Journal of Clinical Oncology (2011)

Purpose To study minimal disseminated disease (MDD) in children with Burkitt's lymphoma (BL) and to determine its impact on prognosis. Patients and Methods We established a simplified long-distance polymerase chain reaction (LD-PCR) assay that can amplify up to 15 to 20 Kb of DNA sequence, making it possible to detect the t(8;14) at the genomic level with sensitivity of 10 −4 . We prospectively studied diagnostic biopsies and bone marrow aspirates from 134 patients affected by BL. Results A specific LD-PCR product was detected in 96 (72%) of 134 BL biopsies. Among 84 patients with t(8;14) positivity on tumor biopsy and bone marrow (BM), 26 (31%) had LD-PCR–positive BM, and 15 (18%) were positive at standard morphologic analysis. Twenty (85%) of 26 MDD-positive patients belonged to the R4 risk group, according to Berlin-Frankfurt-Munster definition. The 3-year progression-free survival was 68% (SE, 10%) in MDD-positive patients in R4 compared with 93% (SE, 5%) in MDD-negative patients in R4 (P = .03). By multivariate analysis (including MDD, sex, lactate dehydrogenase, CNS involvement), only MDD was predictive of higher risk of failure (hazard ratio, 4.7; P = .04). Conclusion MDD identifies a poor-prognosis subgroup among children with high-risk BL. To improve disease control in these patients, a more effective risk-adapted therapy, possibly including anti-CD20 monoclonal antibody, should be considered.
Association Between Enhanced Soluble CD40L and Prothrombotic State in Hypercholesterolemia
Authors: Francesco Cipollone, Andrea Mezzetti, Ettore Porreca, Concetta Di Febbo, Michele Nutini, Maria Fazia, Angela Falco, Franco Cuccurullo, Giovanni Davì
Journal: Circulation (2002)

Background — Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins. Methods and Results — We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B 2 , and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2. Conclusions — This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.
Derivation and Validation of Two Decision Instruments for Selective Chest CT in Blunt Trauma: A Multicenter Prospective Observational Study (NEXUS Chest CT)
Authors: Robert M. Rodriguez, Mark I. Langdorf, Daniel Nishijima, Brigitte M. Baumann, Gregory W. Hendey, Anthony J. Medak, Ali S. Raja, Isabel E. Allen, William R. Mower
Journal: PLoS Medicine (2015)

Unnecessary diagnostic imaging leads to higher costs, longer emergency department stays, and increased patient exposure to ionizing radiation. We sought to prospectively derive and validate two decision instruments (DIs) for selective chest computed tomography (CT) in adult blunt trauma patients.From September 2011 to May 2014, we prospectively enrolled blunt trauma patients over 14 y of age presenting to eight US, urban level 1 trauma centers in this observational study. During the derivation phase, physicians recorded the presence or absence of 14 clinical criteria before viewing chest imaging results. We determined injury outcomes by CT radiology readings and categorized injuries as major or minor according to an expert-panel-derived clinical classification scheme. We then employed recursive partitioning to derive two DIs: Chest CT-All maximized sensitivity for all injuries, and Chest CT-Major maximized sensitivity for only major thoracic injuries (while increasing specificity). In the validation phase, we employed similar methodology to prospectively test the performance of both DIs. We enrolled 11,477 patients-6,002 patients in the derivation phase and 5,475 patients in the validation phase. The derived Chest CT-All DI consisted of (1) abnormal chest X-ray, (2) rapid deceleration mechanism, (3) distracting injury, (4) chest wall tenderness, (5) sternal tenderness, (6) thoracic spine tenderness, and (7) scapular tenderness. The Chest CT-Major DI had the same criteria without rapid deceleration mechanism. In the validation phase, Chest CT-All had a sensitivity of 99.2% (95% CI 95.4%-100%), a specificity of 20.8% (95% CI 19.2%-22.4%), and a negative predictive value (NPV) of 99.8% (95% CI 98.9%-100%) for major injury, and a sensitivity of 95.4% (95% CI 93.6%-96.9%), a specificity of 25.5% (95% CI 23.5%-27.5%), and a NPV of 93.9% (95% CI 91.5%-95.8%) for either major or minor injury. Chest CT-Major had a sensitivity of 99.2% (95% CI 95.4%-100%), a specificity of 31.7% (95% CI 29.9%-33.5%), and a NPV of 99.9% (95% CI 99.3%-100%) for major injury and a sensitivity of 90.7% (95% CI 88.3%-92.8%), a specificity of 37.9% (95% CI 35.8%-40.1%), and a NPV of 91.8% (95% CI 89.7%-93.6%) for either major or minor injury. Regarding the limitations of our work, some clinicians may disagree with our injury classification and sensitivity thresholds for injury detection.We prospectively derived and validated two DIs (Chest CT-All and Chest CT-Major) that identify blunt trauma patients with clinically significant thoracic injuries with high sensitivity, allowing for a safe reduction of approximately 25%-37% of unnecessary chest CTs. Trauma evaluation protocols that incorporate these DIs may decrease unnecessary costs and radiation exposure in the disproportionately young trauma population.
The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies
Authors: Mario Delmar, William J. McKenna
Journal: Circulation Research (2010)

Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes transforms into the pumping function of the organ. Mechanical continuity is provided by desmosomes and adherens junctions, while gap junctions provide a pathway for passage of ions and small molecules between cells. These complexes preferentially reside at the site of end-end contact between myocytes, within the intercalated disc. Recognition that some forms of arrhythmogenic cardiomyopathy are caused by mutations in desmosomal protein genes has galvanized interest in the biology of the desmosome and its interactions with other junctional molecules. This review presents the cellular and molecular biology of the desmosome, current knowledge on the relation of desmosomal mutations and disease phenotypes, and an overview of the molecular pathophysiology of arrhythmogenic right ventricular cardiomyopathy. Clinical experience and results from cellular and animal models provide insights into the intercalated disc as a functional unit and into the basic substrates that underlie pathogenesis and arrhythmogenesis of arrhythmogenic right ventricular cardiomyopathy.
Medical cover for 'The Open' golf championship.
Authors: W A Hadden, S Kelly, N Pumford
Journal: British Journal of Sports Medicine (1992)

A review of 10 years' provision of medical cover at a major golf championship is presented. The average consultation rate was approximately 1 in 200 of those attending of whom 3% required transfer to hospital, the majority to orthopaedic or general medical departments. Familiarity with acute resuscitation and musculoskeletal complaints is required of the medical attendants. The provision of physiotherapy and chiropody services is essential, especially for the participants' complaints, two-thirds of which affected the axial skeleton. Good communications and close liaison with the Chief Marshal, Police and Ambulance Services are vital.
Augmented pain behavioural responses to intra-articular injection of nerve growth factor in two animal models of osteoarthritis
Authors: Sadaf Ashraf, Paul Ian Mapp, James Burston, Andrew John Bennett, Victoria Chapman, David Andrew Walsh
Journal: Annals of the Rheumatic Diseases (2013)

Nerve growth factor (NGF) is a promising analgesic target, particularly in osteoarthritis (OA) where existing therapies are inadequate. We hypothesised that pain responses to NGF are increased in OA joints. Here, NGF-evoked pain behaviour was compared in two rodent models of OA, and possible mechanisms underlying altered pain responses were examined.OA was induced in rat knees by meniscal transection (MNX) or intra-articular monosodium iodoacetate injection (MIA). Once OA pathology was fully established (day 20), we assessed pain behaviour (hindlimb weight-bearing asymmetry and hindpaw mechanical withdrawal thresholds) evoked by intra-articular injection of NGF (10 µg). Possible mechanisms underlying alterations in NGF-induced pain behaviour were explored using indomethacin pretreatment, histopathological evaluation of synovitis, and rtPCR for NGF receptor (tropomyosin receptor kinase (Trk)-A) expression in dorsal root ganglia (DRG).Both the MIA and MNX models of OA displayed reduced ipsilateral weight bearing and hindpaw mechanical withdrawal thresholds, mild synovitis and increased TrkA expression in DRG. NGF injection into OA knees produced a prolonged augmentation of weight-bearing asymmetry, compared to NGF injection in non-osteoarthritic knees. However, hindpaw mechanical withdrawal thresholds were not further decreased by NGF. Pretreatment with indomethacin attenuated NGF-facilitated weight-bearing asymmetry and reversed OA-induced ipsilateral TrkA mRNA up-regulation.OA knees were more sensitive to NGF-induced pain behaviour compared to non-osteoarthritic knees. Cyclo-oxygenase products may contribute to increased TrkA expression during OA development, and the subsequent increased NGF sensitivity. Treatments that reduce sensitivity to NGF have potential to improve OA pain.
Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma
Authors: D A Taylor, J L McGrath, L M Orr, P J Barnes, B J O'Connor
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Nitric oxide (NO) may be bronchoprotective in asthma, possibly due to a direct action on airway smooth muscle or through mast cell stabilisation. To investigate this the effects of two doses of nebulised N<sup>G</sup>-nitro-l-arginine methyl ester (l-NAME), a non-selective NO synthase (NOS) inhibitor, on exhaled NO levels and airway responsiveness to histamine, a direct smooth muscle spasmogen, and adenosine-5′-monophosphate (AMP), an indirect spasmogen which activates mast cells, were evaluated in patients with mild asthma. <h3>METHODS</h3> The study consisted of two phases each with a double blind, randomised, crossover design. In phase 1, 15 subjects inhaled either l-NAME 54 mg or 0.9% saline 30 minutes before histamine challenge. Nine of these subjects were studied in a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhaledl-NAME in a dose of 170 mg or 0.9% saline before being challenged with histamine and AMP. <h3>RESULTS</h3> The mean (95% CI) reduction in exhaled NO levels after l-NAME 54 mg was 78% (66 to 90) but this did not alter airway responsiveness; the geometric mean (SE) concentration provoking a fall of 20% or more in forced expiratory volume in one second (PC<sub>20</sub>) after l-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, respectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectively, for AMP. In contrast,l-NAME 170 mg reduced NO levels to a similar extent (81% (95% CI 76 to 87)) but increased airway responsiveness by approximately one doubling dose to both spasmogens; the geometric mean (SE) PC<sub>20</sub> for histamine after l-NAME 170 mg and saline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (p&lt;0.001), and for AMP was 11.8 (1.5) and 24.3 (1.4) mg/ml, respectively (p&lt;0.001). <h3>CONCLUSIONS</h3> These results suggest thatl-NAME increases airway responsiveness in asthma. This may occur through mechanisms separate from NO inhibition or through pathways independent of those responsible for production of NO measured in exhaled air.
Surgical vs Nonoperative Treatment for Lumbar Disk Herniation
Authors: James N. Weinstein, Tor D. Tosteson, Jon D. Lurie, Anna N. A. Tosteson, Brett Hanscom, Jonathan S. Skinner, William A. Abdu, Alan S. Hilibrand, Scott D. Boden, Richard A. Deyo
Journal: JAMA (2006)

ContextLumbar diskectomy is the most common surgical procedure performed for back and leg symptoms in US patients, but the efficacy of the procedure relative to nonoperative care remains controversial.ObjectiveTo assess the efficacy of surgery for lumbar intervertebral disk herniation.Design, Setting, and PatientsThe Spine Patient Outcomes Research Trial, a randomized clinical trial enrolling patients between March 2000 and November 2004 from 13 multidisciplinary spine clinics in 11 US states. Patients were 501 surgical candidates (mean age, 42 years; 42% women) with imaging-confirmed lumbar intervertebral disk herniation and persistent signs and symptoms of radiculopathy for at least 6 weeks.InterventionsStandard open diskectomy vs nonoperative treatment individualized to the patient.Main Outcome MeasuresPrimary outcomes were changes from baseline for the Medical Outcomes Study 36-item Short-Form Health Survey bodily pain and physical function scales and the modified Oswestry Disability Index (American Academy of Orthopaedic Surgeons MODEMS version) at 6 weeks, 3 months, 6 months, and 1 and 2 years from enrollment. Secondary outcomes included sciatica severity as measured by the Sciatica Bothersomeness Index, satisfaction with symptoms, self-reported improvement, and employment status.ResultsAdherence to assigned treatment was limited: 50% of patients assigned to surgery received surgery within 3 months of enrollment, while 30% of those assigned to nonoperative treatment received surgery in the same period. Intent-to-treat analyses demonstrated substantial improvements for all primary and secondary outcomes in both treatment groups. Between-group differences in improvements were consistently in favor of surgery for all periods but were small and not statistically significant for the primary outcomes.ConclusionsPatients in both the surgery and the nonoperative treatment groups improved substantially over a 2-year period. Because of the large numbers of patients who crossed over in both directions, conclusions about the superiority or equivalence of the treatments are not warranted based on the intent-to-treat analysis.Trial Registrationclinicaltrials.gov Identifier: NCT00000410