tbuckley/cabot-search huggingface dataset:
MORPHOLOGIC ALTERATIONS PRODUCED BY COPPER IN NEURAL TISSUES WITH CONSIDERATION OF THE ROLE OF THE METAL IN THE PATHOGENESIS OF WILSON'S DISEASE
Authors: F. Stephen Vogel, John W. Evans
Journal: The Journal of Experimental Medicine (1961)

The injection into the cerebrospinal fluid of cats of 52 to 208 gamma of copper in the form of an albumin complex or as cupric sulfate, was followed by small elevations in the content of metal in the neural tissues, but regularly and promptly produced persistent quadriplegia and conspicuous histologic changes. Smaller amounts of copper caused less, or no, neurologic manifestations or histologic alterations. The earliest lesions were essentially unaccompanied by inflammation and were initially characterized by hydropic swelling of the myelin sheaths. They progressed rapidly to focal necrosis of all parenchymal components with marked degeneration of myelin and axis cylinders in the peripheral margins of the spinal cord, brain stem, mid-brain, and cerebrum. These histologic changes did not occur in neural tissues incubated in vitro in solutions of the copper-albumin complex. They did not appear in animals injected intraventricularly with ferric sulfate or saccharated iron. Considered together, the findings make it clear that copper in concentrations comparable to those present in the neural tissues of patients with Wilson's disease has the property of profoundly altering neural function and causing conspicuous morphologic alterations.
Determinants of survival in pulmonary Langerhans' cell granulomatosis (histiocytosis X). Groupe d'Etude en Pathologie Interstitielle de la Societe de Pathologie Thoracique du Nord
Authors: A Delobbe, J Durieu, A Duhamel, B Wallaert
Journal: European Respiratory Journal (1996)

The course of pulmonary Langerhans' cell granulomatosis (pulmonary LCG) is variable, difficult to predict and ranges from spontaneous remission to progressive respiratory insufficiency and death. To identify the determinants of survival, we performed a survival analysis on 45 patients with pulmonary LCG. The patients were aged 28 +/- 10 yrs (mean +/- SD) (range 12-62 yrs), 32 males and 13 females, almost exclusively current smokers (96%), and 78% presented symptoms at the time of diagnosis. Diagnosis was made by lung biopsy in 25 patients (56%) and by bronchoalveolar lavage (BAL) analysis in 20 patients (44%). The patients were followed for a median period of 6 yrs (range 1-29 yrs) after the diagnosis. During the period of observation, 33 (73%) patients survived (median follow-up period = 5.8 yrs; range, 1-29 yrs) and 12 (27%) died or underwent lung transplantation (median follow-up period = 8.4 yrs; range 1.4 - 16.1 yrs). The median survival was approximately 13 years. A univariate analysis demonstrated that diminished survival was significantly associated with: an older age at diagnosis (p = 0.0001); a lower forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio at diagnosis (p = 0.005); a higher residual volume/total lung volume (RV/TLC) ratio at diagnosis (p = 0.02); and steroid therapy during follow-up (p = 0.03). Additional predictive information on mortality was: age > 26 yrs (sensitivity 83%, specificity 64%); FEV1/FVC ratio < 0.66 (sensitivity 75%, specificity 86%); and a RV/TLC ratio > 0.33 (sensitivity 75%, specificity 63%). In multivariate Cox analysis, the combination of factors which gave the best prognostic value was FEV1/FVC ratio and age (p < 0.01). The present findings suggest that adverse prognosis factors at diagnosis in pulmonary Langerhans' cell granulomatosis include older age, lower FEV1/FVC ratio and higher RV/TLC ratio, with additional predictive information on mortality if aged > 26 yrs, FEV1/FVC ratio < 0.66, and RV/TLC ratio > 0.33.
Revalidation for doctors in the United Kingdom: the end or the beginning?
Authors: C. du Boulay
Journal: BMJ (2000)

Proposals for the revalidation of doctors in the United Kingdom were released last week in a consultation document from the General Medical Council (GMC).1 Elsewhere, notably in Canada and the United States, it is routine for doctors to undergo recertification at regular intervals to show that they are maintaining their skills and are competent. The purpose of revalidation is to reassure the public that their doctors are competent and abide by high ethical standards. Revalidation will be the culmination of an ongoing review of professional performance that should aid doctors in developing their skills while at the same time identifying at an early stage those who are performing poorly.

All doctors in the United Kingdom will undergo revalidation whether they work within or outside the NHS, are in training, or are in temporary employment. The stakeholders in revalidation include the individual doctor, the NHS, other healthcare providers and purchasers, the medical royal colleges, and, most importantly, the public. The challenge for doctors over the next year or so will be …
Radiofrequency Catheter Ablation in Infants ≤18 Months Old
Authors: Andrew D. Blaufox, Gary L. Felix, J. Philip Saul
Journal: Circulation (2001)

Background The objective of this study was to determine the indications, the safety, and the efficacy of pediatric radiofrequency catheter ablation (RFCA) in infants. Methods and Results Data from the pediatric RFCA registry were reviewed. Between August 1989 and January 1999, 137 infants, defined by age 0 to 1.5 years (median 0.7 years; weight 1.9 to 14.8 kg, median 10 kg), underwent 152 procedures in 27 of 49 registry centers (55%), compared with 5960 noninfants undergoing 6610 procedures during a comparable period. Structural heart disease was present in 36% of infants, compared with 11.2% of noninfants ( P &lt;0.0001). RFCA in infants was performed more commonly for drug resistance or life-threatening arrhythmias than in noninfants. No differences were found between infants and noninfants in success for all tachycardia substrates (87.6% versus 90.6%, P =0.11), for single accessory pathways (94.5% versus 91.5%, P =0.4), or for total (7.8% versus 7.4%, P =1) and major (4.6% versus 2.9%, P =0.17) complications. Neither success for infants with a single accessory pathway nor complications for the entire infant group were related to weight, age, center size, or the presence of structural heart disease. Centers that performed infant procedures, however, enrolled more patients overall in the registry than those that did not perform infant procedures, and successful procedures in infants were performed by more experienced physicians than failed procedures. Conclusions Compared with noninfants, RFCA in infants is usually performed for drug resistance or life-threatening arrhythmias, often in the presence of structural heart disease. The data support the use of RFCA by experienced physicians in selected infants.
Incidence of injury in amateur rugby league sevens
Authors: T J Gabbett
Journal: British Journal of Sports Medicine (2002)

To investigate the incidence, site, and nature of injuries sustained in amateur rugby league sevens tournaments.A total of 168 players competing in three amateur rugby league sevens tournaments were studied. All injuries sustained during matches were recorded. Information recorded included the name of the injured player and the time, cause, anatomical site, and nature of the injury.The incidence of injury was 283.5 per 1000 playing hours. Some 40% (113.4 per 1000 playing hours) of all injuries sustained were to the lower limb (chi(2) = 5.3, df = 1, p<0.05). Contusions were the most common type of injury (113.4 per 1000 hours, 40%, chi(2) = 9.5, df = 4, p<0.05), with most (198.4 per 1000 hours, 70%, chi(2) = 31.5, df =4, p<0.001) occurring in physical collisions and tackles. An increasing injury incidence was observed over the first (99.2 per 1000 hours), second (198.4 per 1000 hours), third (347.2 per 1000 hours), and fourth (694.4 per 1000 hours) matches played during the tournaments (chi(2) = 9.2, df = 3, p<0.05).The results of this study suggest that amateur rugby league sevens tournaments, which require players to compete repeatedly on the same day, may hasten the onset of fatigue and predispose to injury.
Chronic Fine Particulate Matter Exposure Induces Systemic Vascular Dysfunction via NADPH Oxidase and TLR4 Pathways
Authors: Thomas Kampfrath, Andrei Maiseyeu, Zhekang Ying, Zubair Shah, Jeffrey A. Deiuliis, Xiaohua Xu, Nisharahmed Kherada, Robert D. Brook, Kongara M. Reddy, Nitin P. Padture, Sampath Parthasarathy, Lung Chi Chen, Susan Moffatt-Bruce, Qinghua Sun, Henning Morawietz, Sanjay Rajagopalan
Journal: Circulation Research (2011)

Chronic exposure to ambient air-borne particulate matter of < 2.5 μm (PM₂.₅) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive.To investigate the molecular mechanisms by which PM₂.₅ mediates inflammatory responses in a mouse model of chronic exposure.Here, we show that chronic exposure to ambient PM₂.₅ promotes Ly6C(high) inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor (TLR)4 and Nox2 (gp91(phox)) deficiency prevented monocyte NADPH oxidase activation in response to PM₂.₅ and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47(phox) phosphorylation in TLR4 deficient animals. PM₂.₅ exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow-derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM₂.₅ exposure, whereas TLR4 deficiency attenuated this response.Taken together, our findings suggest that PM₂.₅ triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase-dependent mechanisms.
Novel Candidate Cancer Genes Identified by a Large-Scale Cross-Species Comparative Oncogenomics Approach
Authors: Jenny Mattison, Jaap Kool, Anthony G. Uren, Jeroen de Ridder, Lodewyk Wessels, Jos Jonkers, Graham R. Bignell, Adam Butler, Alistair G. Rust, Markus Brosch, Catherine H. Wilson, Louise van der Weyden, David A. Largaespada, Michael R. Stratton, P. Andy Futreal, Maarten van Lohuizen, Anton Berns, Lara S. Collier, Tim Hubbard, David J. Adams
Journal: Cancer Research (2010)

Comparative genomic hybridization (CGH) can reveal important disease genes but the large regions identified could sometimes contain hundreds of genes. Here we combine high-resolution CGH analysis of 598 human cancer cell lines with insertion sites isolated from 1,005 mouse tumors induced with the murine leukemia virus (MuLV). This cross-species oncogenomic analysis revealed candidate tumor suppressor genes and oncogenes mutated in both human and mouse tumors, making them strong candidates for novel cancer genes. A significant number of these genes contained binding sites for the stem cell transcription factors Oct4 and Nanog. Notably, mice carrying tumors with insertions in or near stem cell module genes, which are thought to participate in cell self-renewal, died significantly faster than mice without these insertions. A comparison of the profile we identified to that induced with the Sleeping Beauty (SB) transposon system revealed significant differences in the profile of recurrently mutated genes. Collectively, this work provides a rich catalogue of new candidate cancer genes for functional analysis.
Gene copy-number variations (CNVs) of complement<i>C4</i>and<i>C4A</i>deficiency in genetic risk and pathogenesis of juvenile dermatomyositis
Authors: Katherine E Lintner, Anjali Patwardhan, Lisa G Rider, Rabheh Abdul-Aziz, Yee Ling Wu, Emeli Lundström, Leonid Padyukov, Bi Zhou, Alaaedin Alhomosh, David Newsom, Peter White, Karla B Jones, Terrance P O'Hanlon, Frederick W Miller, Charles H Spencer, Chack Yung Yu
Journal: Annals of the Rheumatic Diseases (2015)

Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM.The study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR.Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2×10(-6)). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients.Complement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background.
Oral Poly(ADP-Ribose) Polymerase-1 Inhibitor BSI-401 Has Antitumor Activity and Synergizes with Oxaliplatin against Pancreatic Cancer, Preventing Acute Neurotoxicity
Authors: Davide Melisi, Valeria Ossovskaya, Cihui Zhu, Roberta Rosa, Jianhua Ling, Patrick M. Dougherty, Barry M. Sherman, James L. Abbruzzese, Paul J. Chiao
Journal: Clinical Cancer Research (2009)

Development of novel agents and drug combinations are urgently needed for treatment of pancreatic cancer. Oxaliplatin belongs to an important class of DNA-damaging organoplatinum agents, useful in pancreatic cancer therapy. However, increased ability of cancer cells to recognize and repair DNA damage enables resistance to these agents. Poly (ADP ribose) polymerase-1 is a sensor of DNA damage with key roles in DNA repair. Here, we report the therapeutic activity of the poly (ADP ribose) polymerase-1 inhibitor BSI-401, as a single agent and in combination with oxaliplatin in orthotopic nude mouse models of pancreatic cancer, and its effect on oxaliplatin-induced acute neurotoxicity.
Asthma phenotyping: Correlation between inflammatory phenotype, clinical parameters and associated comorbidities
Authors: Annelies Van Den Bergh, Sven Seys, Pieter Goeminne, Lieven Dupont, Dominique Bullens
Journal: European Respiratory Journal (2012)

Introduction:   Cluster analysis revealed 5 clinically different clusters of asthma: mild atopic (1), mild to moderate atopic(2), late-onset non-atopic (3), severe atopic (4) and severe with fixed airflow obstruction (5) (Moore et al, 2009).   Aim:   To link differential cell count and associated comorbidities (BMI, smoking, atopy, reflux, sinusitis and bronchiectasis) to 5 clusters of asthma based on clinical features (baseline FEV1, maximal FEV1 and age of onset).   Methods:    We retrospectively evaluated clinical records from 140 asthma patients (44% male; 43y ± 14) with induced sputa, recruited from outpatient clinic of the University Hospital Leuven between January 1st 2008 and November 1st 2011 and were free of exacerbation for three months prior to sputum induction.   Results:   Cluster 1 accounted for 37%, cluster 2 for 26%, cluster 3 for 14% and cluster 4 for 12%. Cluster 5 was too small for further analysis. Cluster 4 as defined by Moore and coworkers is significantly associated with more neutrophils (median: 72%, interquartile: 60-82%); p   Conclusion:   Severe atopic asthmatics have a predominant neutrophilic airway inflammation. Patients with late-onset non-atopic asthma have the highest rate of reflux. Previously unrecognized bronchiectasis were detected in 9% of patients.
Some athletes are immature…skeletally
Authors: Michael K Drew
Journal: British Journal of Sports Medicine (2015)

Older athlete age is a non-modifiable risk factor for groin pain in athletes; however, these studies are usually in adult populations. Underage athletes have been shown to pose approximately double the risk of adults in an Australian Rules football population.1 Developmental anatomy may be related to this increased risk, but this is still somewhat unknown. Maturation is related to age, gender, race and the environment,2 with injury rates increasing throughout the adolescent period.3 This indicates that the imposed environment's interplay with the developmental changes in puberty should be carefully monitored to reduce the risk of injury. Those who get …
Lung cancer in relation to exposure to silica dust, silicosis and uranium production in South African gold miners
Authors: E. Hnizdo, J. Murray, S. Klempman
Journal: Thorax (1997)

A nested case-control study for lung cancer was performed on a cohort of 2260 South African gold miners in whom an association between exposure to silica dust and risk of lung cancer was previously reported. The objective was to investigate an expanded set of risk factors and also cancer cell type.The 78 cases of lung cancer found during the follow up period from 1970 to 1986 were matched with 386 controls. Risk of lung cancer was related to smoking, exposure to silica dust, incidence of silicosis, and uranium production and the uranium content of the mine ore.The risk of lung cancer was associated with tobacco smoking, cumulative dust exposure, duration of underground mining, and with silicosis. The best predictive model included pack years of cigarette consumption (adjusted relative risk (RR) = 1.0 for < 6.5 pack years, 3.5 (95% confidence interval (CI) 0.7 to 16.8) for 6.5-20 pack years, 5.7 (95% CI 1.3 to 25.8) for 21-30 pack years, and 13.2 (95% CI 3.1 to 56.2) for more than 30 pack years) and silicosis (RR = 2.45 (95% CI 1.2 to 5.2)). No association was found with uranium production. The lung tumour cell type distribution was 40.3% small cell carcinoma, 38.8% squamous cell, 16.4% adenocarcinoma, and 4.5% large cell carcinoma. Small and large cell cancer combined were associated with exposure to dust.The results cannot be interpreted definitively in terms of causal association. Possible interpretations are: (1) subjects with high dust exposure who develop silicosis are at increased risk of lung cancer; (2) high levels of exposure to silica dust on its own is important in the pathogenesis of lung cancer and silicosis is coincidental; and (3) high levels of silica dust exposure may be a surrogate for the exposure to radon daughters.
Psychiatric Disorder and the Broad Autism Phenotype: Evidence From a Family Study of Multiple-Incidence Autism Families
Authors: J Piven, P Palmer
Journal: American Journal of Psychiatry (1999)

Several studies have shown familial aggregation of some axis I psychiatric disorders in families ascertained through a single autistic proband. In this study the authors examined the rate of axis I psychiatric disorders in nonautistic relatives from multiple-incidence autism families and the possible relationship of these disorders to the broad autism phenotype.The rates of axis I psychiatric disorders, assessed by using semistructured and family history interviews, were compared in parents, grandparents, and aunts and uncles ascertained through 25 families of multiple-incidence autism probands and 30 families of probands with Down's syndrome. The possible association between selected psychiatric disorders and the broad autism phenotype, assessed directly through semistructured interviews and observational rating measures, was also examined in the two groups of parents.The parents of the autistic probands had significantly higher rates of major depressive disorder and social phobia than the parents of the Down's syndrome probands. The high rate of depression in the parents of the autistic probands was consistent with the high rates of depression and anxiety detected in the grandparents and aunts and uncles in the autism families by family history. There was no evidence of an association, within individuals, between either depression or social phobia and the broad autism phenotype.Relatives of autistic individuals have high rates of major depression and social phobia that are not associated with the broad autism phenotype and cannot be explained by the increased stress associated with raising an autistic child. Alternative mechanisms and the scientific and clinical implications of these findings are discussed.
Transactivation and transrepression in the repression of inflammatory gene expression by dexamethasone
Authors: Elizabeth King, Joanna Chivers, Mark Giembycz, Robert Newton
Journal: European Respiratory Journal (2012)

BACKGROUND: The anti-inflammatory activities of glucocorticoids are attributed to the repression of inflammatory gene expression. Dogma states that this occurs via direct repression (transrepression) by the glucocorticoid receptor (GR) of transcription factors, such as NF-κB. However, evidence also suggests that gene induction (transactivation) by GR is important for repression.  AIMS: To assess the roles of transrepression and transactivation in the repression of inflammatory gene expression by dexamethasone (Dex).  METHODS AND RESULTS: The effect of Dex on 39 IL-1β-induced genes was examined in human pulmonary A549 cells by real-time PCR. Dex showed a range of activity in terms of the extent (E max ) and potency (EC 50 ) of repression on these genes. These parameters correlated, such that the most highly repressed genes were also the most potently repressed. While all 39 genes were NF-κB-dependent, this did not correlate with repression by Dex. Finally, inhibition of protein translation by cycloheximide (CHX) reduced IL-1β-induced expression of 19 genes (secondary response genes). Of the remaining 21 genes, CHX significantly prevented the Dex-dependent repression of 11 (∼50%), suggesting a role for transactivation. These 11 genes were significantly more sensitive (E max  and EC 50 ) to repression by dexamethasone when compared to genes showing repression that was insensitive to CHX (and which may represent a classical transrepression mechanism).  CONCLUSIONS: Repression of inflammatory gene expression by dexamethasone involves multiple mechanisms. Transactivation appears to play a significant role showing both high potency and high level of repression on target genes.