tbuckley/cabot-search huggingface dataset:
Genetics of parentally reported asthma, eczema and rhinitis in 5-yr-old twins
Authors: C. E. M. van Beijsterveldt, D. I. Boomsma
Journal: European Respiratory Journal (2007)

The aim of the present study was to examine the genetic and environmental contributions to the individual differences in susceptibility to asthma, eczema and rhinitis in childhood and their role in the association among these conditions. Information on asthma, eczema and rhinitis was obtained by parental report. Parents were asked whether a physician had ever diagnosed the condition. Complete data were available for 8,633 5-yr-old twin pairs born between 1986 and 1998. The frequency of parentally reported asthma, eczema and rhinitis was 8.7, 16.8 and 4.4%, respectively, and was higher in males than females. Genetic factors accounted for approximately 90% of the variance in the susceptibility to asthma, eczema and rhinitis. The magnitude of genetic factors did not differ between males and females. The remaining part of the variance was explained by environmental factors not shared by family members. The phenotypic correlations between parentally reported asthma, eczema and rhinitis were moderate and mainly mediated by the same genetic factors. The high heritability and the limited influence of shared environmental factors may point to gene x environment interactions. Future research should focus on this type of interaction processes.
Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer
Authors: Scott N. Gettinger, Leora Horn, Leena Gandhi, David R. Spigel, Scott J. Antonia, Naiyer A. Rizvi, John D. Powderly, Rebecca S. Heist, Richard D. Carvajal, David M. Jackman, Lecia V. Sequist, David C. Smith, Philip Leming, David P. Carbone, Mary C. Pinder-Schenck, Suzanne L. Topalian, F. Stephen Hodi, Jeffrey A. Sosman, Mario Sznol, David F. McDermott, Drew M. Pardoll, Vindira Sankar, Christoph M. Ahlers, Mark Salvati, Jon M. Wigginton, Matthew D. Hellmann, Georgia D. Kollia, Ashok K. Gupta, Julie R. Brahmer
Journal: Journal of Clinical Oncology (2015)

Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting &gt; 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.
Distribution of immunoglobulin producing cells is different in normal human appendix and colon mucosa.
Authors: K Bjerke, P Brandtzaeg, T O Rognum
Journal: Gut (1986)

The densities of IgG-, IgA-, IgM- and IgD-producing immunocytes were determined by paired immunofluorescence staining and morphometric analysis in the lamina propria of normal appendix specimens. Normal colon specimens were used as reference material, mostly paired from individual subjects. The density (median of cells/mm2 lamina propria area) of IgA immunocytes tended to be slightly higher in the appendix than in the colon (1259 vs 962) and the same held true for IgM cells (71 vs 55). Conversely, the overall density of IgG immunocytes was much higher in the appendix than in the colon (95 vs 38). A striking feature was the fact that almost 50% of all immunocytes were of the IgG isotype adjacent to lymphoid follicles. It seemed justified to conclude, therefore, that the abundance of such follicles explains the overall enrichment of IgG-producing cells in normal appendix mucosa. These immunocytes most likely represent follicle derived B cells that have reached terminal maturation locally, whereas precursors generated from less mature memory clones probably emigrate and home ubiquitously to distant sites of the gut lamina propria where they develop into IgA-producing immunocytes.
What does adolescent undiagnosed wheeze represent? Findings from the Isle of Wight Cohort
Authors: Abid Raza, Ramesh J. Kurukulaaratchy, Jane D. Grundy, C. Bernie Clayton, Frances A. Mitchell, Graham Roberts, Susan Ewart, Alireza Sadeghnejad, S. Hasan Arshad
Journal: European Respiratory Journal (2012)

We sought to characterise adolescent wheeze in the absence of asthma, which we termed “undiagnosed wheeze”. The Isle of Wight Birth Cohort (n=1,456) was reviewed at 1, 2, 4, 10 and 18 yrs. Using questionnaire responses, “asthma” was defined as “ever had asthma” plus either “wheezing in the last 12 months” or “taking asthma treatment in the last 12 months”; “undiagnosed wheeze” as “wheeze in the last 12 months” but “no” to “ever had asthma”; and remaining subjects termed “non-wheezers”. Undiagnosed wheeze (prevalence 4.9%) accounted for 22% of wheezing at 18 yrs. This was largely adolescent-onset with similar symptom frequency and severity to diagnosed asthma. However, undiagnosed wheezers had significantly higher forced expiratory volume in 1 s to forced vital capacity ratio, less bronchodilator reversibility and bronchial hyperresponsiveness, and were less frequently atopic than asthmatics. Undiagnosed wheezers had earlier smoking onset, higher smoking rates and monthly paracetamol use than non-wheezers. Logistic regression identified paracetamol use (OR 1.11, 95% CI 1.01–1.23; p=0.03), smoking at 18 yrs (OR 2.54, 95% CI 1.19–5.41; p=0.02), rhinitis at 18 yrs (OR 2.82, 95% CI 1.38–5.73; p=0.004) and asthmatic family history (OR 2.26, 95% CI 1.10–4.63; p=0.03) as significant independent risk factors for undiagnosed wheeze. Undiagnosed wheeze is relatively common during adolescence, differs from diagnosed asthma and has strong associations with smoking and paracetamol use. Better recognition of undiagnosed wheeze and assessment of potential relevance to adult health is warranted.
A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice
Authors: Ulf Neumann, Heinrich Rueeger, Rainer Machauer, Siem Jacob Veenstra, Rainer M. Lueoend, Marina Tintelnot-Blomley, Grit Laue, Karen Beltz, Barbara Vogg, Peter Schmid, Wilfried Frieauff, Derya R. Shimshek, Matthias Staufenbiel, Laura H. Jacobson
Journal: Molecular Neurodegeneration (2015)

Alzheimer's disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans. Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared. In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease.
Inhibition of S100A11 gene expression impairs keratinocyte response against vaccinia virus through downregulation of the IL-10 receptor 2 chain
Authors: Lianghua Bin, Michael D. Howell, Byung Eui Kim, Clifton F. Hall, Joanne E. Streib, Donald Y.M. Leung
Journal: Journal of Allergy and Clinical Immunology (2009)
CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis
Authors: A. Capelli, A. Di Stefano, I. Gnemmi, C. F. Donner
Journal: European Respiratory Journal (2005)

CC chemokines play an important role in the pathogenetic mechanisms of interstitial lung disease, while a downregulation of CC chemokine receptor (CCR)5 in the fibrotic stages of sarcoidosis has been observed. To evaluate the involvement of CC chemokines and the expression of CCR5 in idiopathic pulmonary fibrosis (IPF) and, more specifically, in usual interstitial pneumonia, 35 subjects were studied. CC chemokine ligand (CCL)2, CCL3 and CCL4 levels were measured in the bronchoalveolar lavage fluid (BALF) of 18 nonsmoker control subjects and 17 patients affected by IPF. CCR5 expression was evaluated in alveolar macrophages and lymphocytes. The BALF levels of all chemokines were significantly increased in IPF: median (range) CCL3 1.6 (1.0-11.1) versus 1.2 (0.0-3.8) pg x mL(-1); CCL4 6.2 (1.3-96.0) versus 3.4 (0.3-6.8) pg x mL(-1); and CCL2 60.1 (16.7-251.3) versus 4.6 (0.5-119.4) pg x mL(-1). CCL2 levels correlated negatively with the carbon monoxide diffusing capacity of the lung (D(L,CO)) and arterial oxygen tension. CCR5 expression was significantly reduced in lymphocytes from IPF compared with controls. The CC chemokines investigated are involved in the inflammatory mechanisms of idiopathic pulmonary fibrosis, and the results are in agreement with the hypothesis of a downregulation of the T-helper 1 immunological response in this disease.
Antidepressants and liver disease
Authors: M. H. Morgan, A. E. Read
Journal: Gut (1972)

Patients with cirrhosis were found to be extremely sensitive to tranylcypromine, and the use of this drug for the treatment of depression in such patients is contraindicated. Amitriptyline has a wider margin of safety in such patients, but caution is necessary when the higher therapeutic doses are prescribed.
Tackling Taboo Topics
Authors: Jennifer K. Walter, Abby R. Rosenberg, Chris Feudtner
Journal: JAMA Pediatrics (2013)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor
Authors: Junlan Zhou, Yan Zhu, Min Cheng, Deepika Dinesh, Tina Thorne, Kian Keong Poh, Dongxu Liu, Chantal Botros, Yao Liang Tang, Nichole Reisdorph, Raj Kishore, Douglas W. Losordo, Gangjian Qin
Journal: Circulation (2009)

Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)-1b promoter (-338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation.Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2(-/-)) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2(-/-) mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2(-/-) mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie, ECE-1a, -1c, and -1d), and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays).Our results identify a cell-cycle-independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure.
Effects of Nutritive Factors on Metabolic Processes Involving Bioactivation and Detoxication of Chemicals
Authors: F. Peter Guengerich
Journal: Annual Review of Nutrition (1984)

The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved ...Read More
Multiplicities in Cancer Research: Ubiquitous and Necessary Evils
Authors: D. Berry
Journal: JNCI Journal of the National Cancer Institute (2012)

Scientific inquiry involves observations and measurements, some of which are planned and some of which are not. The most interesting or unusual observations might be regarded as discoveries and therefore particularly worthy of publication. However, the observational process is fraught with inferential land mines, especially if the discoveries are serendipitous. Multiple observations increase the probability of false-positive conclusions and have led to many false and otherwise misleading publications. Statisticians recommend adjustments to final inferences with the goal of reducing the rate of false positives, a strategy that increases the rate of false negatives. Some scientists object to making such adjustments, arguing that it should not be more difficult to determine the validity of a discovery simply because other observations were made. Which tack is right? How does one decide that any particular scientific discovery is real? Unfortunately, there is no panacea, no one-size-fits-all approach. The goal of this commentary is to elucidate the issues and provide recommendations for conducting and reporting results of empirical studies, with emphasis on the problems of multiple comparisons and other types of multiplicities, including what I call "silent multiplicities." Because of the many observations, outcomes, subsets, treatments, etc, that are typically made or addressed in epidemiology and biomarker research, these recommendations may be particularly relevant for such studies. However, the lessons apply quite generally. I consider both frequentist and Bayesian statistical approaches.
Skin cancer trends in Northern Ireland and consequences for provision of dermatology services
Authors: S.E.H. Hoey, C.E.J. Devereux, L. Murray, D. Catney, A. Gavin, S. Kumar, D. Donnelly, O.M. Dolan
Journal: British Journal of Dermatology (2007)

The incidence of skin cancer, both melanoma and nonmelanoma skin cancer (NMSC), is rising throughout the world. The evaluation of trends in skin cancer will allow better planning of the future development of skin cancer services.Using data collected from the Northern Ireland Cancer Registry (NICR), the incidence of the three major cutaneous cancers, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM), was determined and the workload associated with their management assessed.The records of patients with a first diagnosis of BCC, SCC or MM occurring between 1993 and 2002 were retrieved from the NICR database. The annual age- and sex-adjusted incidence rates of all three skin cancers were computed per 100 000 person-years by direct standardization according to the European Standard Population. Trends in incidence were estimated by calculating the estimated annual percentage change using Microsoft Excel. For patients registered with the NICR as having BCC, SCC or MM, the number of pathological reports where malignant samples had been examined was counted and then summed to provide the number of specimens examined each year between 1993 and 2004.For all three cancers the age-specific rates for both males and females increased with age, except for MM in men aged 75 years and over, where the rates were seen to decrease. Over the 12-year period there was a 62% increase in the overall number of skin cancer samples processed by local pathology laboratories and a 20% increase in the number of patients. These data highlight the fact that many patients will have more than one skin cancer, which reinforces the benefit in collecting data for both patient and sample numbers in order to obtain a true reflection of the workload. The data have also shown that more affluent men and women have higher rates of BCC and MM than their less affluent counterparts.In view of the data presented it is clear that management of NMSC and MM will impose significant demands on services in the years ahead. This will impact on the entire multidisciplinary team. Future planning, in terms of manpower and resources, will prove essential if we are to remain in a position to manage our patients with these malignant tumours appropriately.
Expression of bronchodilator response using forced oscillation technique measurements: absolute versus relative
Authors: C. Thamrin, C. L. Gangell, M. M. H. Kusel, A. Schultz, G. L. Hall, S. M. Stick, P. D. Sly
Journal: European Respiratory Journal (2010)

Chemotherapeutic agents used in the treatment of cancer often lead to dose-limiting bone marrow suppression and may initiate secondary leukemia.<i>N</i>,<i>N</i>′,<i>N</i>"-triethylenethiophosphoramide (thiotepa), a polyfunctional alkylating agent, is used in the treatment of breast, ovarian, and bladder carcinomas and is also being tested for efficacy in the treatment of central nervous system tumors. Thiotepa produces ring-opened bases such as formamidopyrimidine and 7-methyl-formamidopyrimidine, which can be recognized and repaired by the formamidopyrimidine glycosylase/AP lyase (Fpg) enzyme of<i>Escherichia coli</i>. Using this background information, we have created constructs using the <i>E. coli fpg</i> gene along with the functional equivalent human ortholog α-hOgg1. Although protection with the Fpg protein has been previously observed in Chinese hamster ovary cells, we demonstrate significant (100-fold) protection against thiotepa using the <i>E. coli</i> Fpg or the human α-hOgg1 cDNA in NIH3T3 cells. We have also observed a 10-fold protection by both the Fpg and α-hOgg1 transgenes against 1,3-<i>N</i>,<i>N</i>′-bis(2-chloroethyl)-<i>N</i>-nitrosourea (BCNU) and, to a lesser extent, mafosfamide (2-fold), an active form of the clinical agent cyclophosphamide. These latter two findings are novel and are particularly significant since the added protection was in an <i>O</i><sup>6</sup>-methylguanine-DNA methyltransferase-positive background. These results support our general approach of using DNA base excision repair genes in gene therapy for cellular protection of normal cells during chemotherapy, particularly against the severe myelosuppressive effect of agents such as thiotepa, BCNU, and cyclophosphamide.
Reflections on the Global Burden of Disease 2010 Estimates
Authors: Peter Byass, Maximilian de Courten, Wendy J. Graham, Lucie Laflamme, Affette McCaw-Binns, Osman A. Sankoh, Stephen M. Tollman, Basia Zaba
Journal: PLoS Medicine (2013)

The Institute for Health Metrics and Evaluation (IHME) and its partners recently completed what is probably the largest ever exercise undertaken in epidemiological modelling, the Global Burden of Disease 2010 (GBD-2010) estimates [1].These estimates attempt to characterise loss of health from disease and injury, including the effects of some major risk factors, on a global basis.They will find widespread use in coming years and influence developments in global health.However, it is important to realise that ''estimates are estimates, and not measurements''; they may perform better in some respects than others [2].Here, as a group of independent experts, we comment on some of the major issues raised by this important work, while noting that it is impossible to cover all the wealth of detail involved in any critique.We take collective responsibility for these views, though many specific points come from individual specialists among the authors.The Essay section contains opinion pieces on topics of broad interest to a general medical audience.