tbuckley/cabot-search huggingface dataset:
Scenario analysis of the future of medicines
Authors: H Leufkens, F Haaijer-Ruskamp, A Bakker, G Dukes
Journal: BMJ (1994)

pectoris; it has been reproduced both by exercise testing and rapid atrial pacing and is associated with typical electrocardiographic changes.I believe that symptomatic angina occurs in about one quarter of heart transplant patients.Presumably the basis is re- innervation.JMP: We performed a study in 28 cardiac transplant patients having a second operation up to five years after transplantation, and we could not find any anatomical evidence of re-innervation.PNH: Perhaps there was some re-innervation in the present case which took longer than five years, although an alternative mechanism for pain might be ischaemia ofthe residual native atrial tissue left in situ.RH: My right atrium is certainly sensitive to manipulation at catheterisation, and about one in four ofmy 28 ventricular biopsies have been painful.KAD: Does the type of plasma concentration of paraprotein or the findings on serum amyloid P component scintigraphy have any prognostic value in systemic AL amyloidosis?PNH: A serum paraprotein is often completely absent in AL amyloidosis, and even free monoclonal immunoglobulin light chains cannot be found in the urine of 15% of patients.The biophysical properties of the monoclonal protein, which are unique in each case, presumably do have an influence on the disease.We have noted that long term survival is associated with, among other things, a small whole body load of amyloid, as shown by serum amyloid P component scanning.The factors that ultimately affect survival include not only the anatomical distribution and extent of the amyloid but also the effect it has on organ function, which varies remarkably from case to case and possibly at different times in the same patient.1 Kyle RA, Greipp PR.Anyloidosis (AL): clinical and laboratory features in 229 cases.
Clinical epidemiology--how important now?
Authors: V Binder
Journal: Gut (2005)

The putative risk of haematopoietic cancer in relation to modern strong immunosuppressive treatment in inflammatory bowel disease

Chronic diseases have become an increasing portion of modern medicine in the Western world and the goals for treatment are not only to relieve symptoms and their influence on daily life for patients but also to avoid long term complications of the disease and of the treatment given. 

The rules for obtaining evidence of the benefit of a new treatment have been widely accepted, with the randomised controlled study as the “gold standard”. Such studies give some guarantee of the effect of a given treatment modality. The possible long term side effects however cannot be secured against in studies carried out over a few months, the usual length of a controlled trial.

The natural history of a chronic disease—how will the disease proceed if no medical intervention is carried out—should ideally be the background for any therapeutic trial. For the immediate short term course, the placebo arm of a controlled study is sufficient. Knowledge of the long term natural course of the disease however does not exist as both the medical profession and patients themselves have continuously interfered and tried to relieve the consequences of the disease. Gradually therefore, the meaning of “natural course” has changed to “the course of the disease when treated in accordance with established and …
Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214)
Authors: R. Timothy D. Oliver, Graham M. Mead, Gordon J.S. Rustin, Johnathan K. Joffe, Nina Aass, Robert Coleman, Rhian Gabe, Philip Pollock, Sally P. Stenning
Journal: Journal of Clinical Oncology (2011)

Purpose Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. Patients and Methods Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). Results Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (&gt; 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). Conclusion These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.
Functional Variants in Cell Death Pathway Genes and Risk of Pancreatic Cancer
Authors: Ming Yang, Tong Sun, Li Wang, Dianke Yu, Xuemei Zhang, Xiaoping Miao, Junniao Liu, Dan Zhao, Hui Li, Wen Tan, Dongxin Lin
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Fas-Fas ligand (FasL)–mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. This study examined the association between functional variants of Fas (−1377G→A and −670A→G), FasL (−844T→C), and caspase-8 (CASP8) six-nucleotide deletion polymorphism (−652 6N ins→del) and risk of pancreatic cancer. Experimental Design: Genotypes were determined in 397 cases with pancreatic cancer and 907 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression, and all statistical tests were two sided. Results: We found a significant decrease in risk of pancreatic cancer associated with FasL and CASP8 but not Fas polymorphisms. Compared with noncarriers, the ORs of developing pancreatic cancer for FasL −844CT and TT carriers were 0.73 (95% CI, 0.57-0.94) and 0.35 (95% CI, 0.19-0.63), and for CASP8 −652 6N ins/del and del/del carriers were 0.65 (95% CI, 0.50-0.85) and 0.56 (95% CI, 0.33-0.98), respectively. Gene-gene interaction between the FasL and CASP8 variants further reduced the cancer risk in a multiplicative manner (OR for the presence of both FasL −844TT and CASP8 −652 6N del/del genotype, 0.10; 95% CI, 0.01-0.75). On the other hand, a multiplicative joint effect between the FasL −844CC or CASP8 −652 6N ins/ins genotype and smoking or diabetes mellitus in intensifying risk of pancreatic cancer was also evident. Conclusions: These results suggest that genetic variations in the death pathway genes FasL and CASP8 are involved in susceptibility to developing pancreatic cancer.
Cardiac Resynchronization Treatment of Heart Failure
Authors: Ayesha Hasan, William T. Abraham
Journal: Annual Review of Medicine (2006)

Cardiac resynchronization therapy (CRT) is well established as a treatment for patients with moderate to severe heart failure on optimal medical therapy. Early studies demonstrated improved functional capacity and evidence of reverse remodeling; more recently, CRT has been associated with a survival benefit in advanced heart failure both with and without a defibrillator. We review the eight landmark trials in CRT. To date, criteria have focused on electrical delay, but echocardiographic parameters emphasize the importance of mechanical delay or ventricular dyssynchrony. With the exponential rise in implants, new issues have emerged, such as optimal device programming, identifying appropriate candidates, and accounting for cases without clinical benefit from CRT.
Teaching medical students about tobacco
Authors: R. Richmond
Journal: Thorax (1999)

BACKGROUND: Respiratory symptoms such as cough and wheeze are associated with significant morbidity, including school absenteeism. METHODS: A respiratory questionnaire was sent to the parents of all 5727 children aged 7-9 years of age registered with 95 general practitioners in the Southampton area to determine (a) the prevalence of asthma, cough and wheeze, (b) the effects of respiratory symptoms on school absenteeism, and (c) the use of anti-asthma medication. RESULTS: A total of 4830 parents replied (response rate 86%). The 12 month prevalence of wheeze in the absence of cough was 5.5%, cough in the absence of wheeze was 10.0%, and 7.6% reported cough and wheeze; 15.2% of children had been diagnosed. Of the 4830 who replied, 12.7% were receiving bronchodilators, 0.6% xanthine derivatives, 1.7% sodium cromoglycate, and 4.1% inhaled corticosteroids. In all, 348 (7.2%) children had missed more than five days of schooling in the preceding year for respiratory symptoms, while 43 children (0.9%) had missed more than 20 days of schooling in the preceding year. Of the children who had missed more than five days of schooling, 43% reported cough and wheeze, 33% cough alone, and 16% wheeze alone in the preceding year. Compared with children who coughed, those who wheezed were significantly more likely to be diagnosed as asthmatic and to be receiving bronchodilators or inhaled corticosteroids. CONCLUSIONS: In this study, cough was the most frequently reported symptom amongst children missing more than five days of schooling per year.
BRAF Fusions Define a Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition
Authors: Katherine E. Hutchinson, Doron Lipson, Philip J. Stephens, Geoff Otto, Brian D. Lehmann, Pamela L. Lyle, Cindy L. Vnencak-Jones, Jeffrey S. Ross, Jennifer A. Pietenpol, Jeffrey A. Sosman, Igor Puzanov, Vincent A. Miller, William Pao
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Recurrent “driver” mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically relevant molecular subsets of melanoma, but more than 30% are “pan-negative” for these recurrent mutations. We sought to identify additional potential drivers in “pan-negative” melanoma. Experimental Design: Using a targeted next-generation sequencing (NGS) assay (FoundationOne™) and targeted RNA sequencing, we identified a novel PAPSS1-BRAF fusion in a “pan-negative” melanoma. We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne™, as well as melanoma RNA, whole-genome and whole-exome sequencing data in The Cancer Genome Atlas (TCGA), to determine the potential frequency of BRAF fusions in melanoma. We characterized the signaling properties of confirmed molecular alterations by ectopic expression of engineered cDNAs in 293H cells. Results: Activation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF was abrogated by mitogen-activated protein kinase kinase (MEK) inhibition but not by BRAF inhibition. NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a “pan-negative” sample; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive. Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 “pan-negative” cases. Conclusions: BRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of “pan-negative” cases. Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy. Clin Cancer Res; 19(24); 6696–702. ©2013 AACR.
Sarcoidosis-associated fatigue
Authors: Marjolein Drent, Elyse E. Lower, Jolanda De Vries
Journal: European Respiratory Journal (2012)

Sarcoidosis-associated fatigue is globally recognised as a disabling symptom. Fatigue has been reported in up to 50–70% of sarcoidosis patients, causing impaired quality of life. The aetiology of this troublesome problem remains elusive and is usually multifactorial. Fatigue can be a consequence of treatment itself, including as a complication of corticosteroid therapy. The diagnosis of sarcoidosis-associated fatigue requires an extensive evaluation to identify and treat potentially reversible causes. Granuloma formation and cytokine release may be involved in its aetiology. However, despite adequate sarcoidosis treatment, many patients continue to experience fatigue. Comorbidities associated with sarcoidosis, including depression, anxiety, hypothyroidism and altered sleep patterns, may all contribute to fatigue. Despite an exhaustive search for treatable clinical causes of fatigue, most patients’ complaints of fatigue are not correlated with clinical parameters of disease activity. Recent studies have demonstrated the effectiveness of various neurostimulants, including methylphenidate, for the treatment of sarcoidosis-associated fatigue. These and other agents may be useful adjuncts for the treatment of sarcoidosis-associated fatigue. Obviously, there is a need for studies evaluating the causes and new therapeutic options of sarcoidosis-associated fatigue. Psychological interventions should also be examined.
Communication and internal states: What is their relationship?
Authors: Michael Bamberg
Journal: Behavioral and Brain Sciences (1993)

Common folks “have” emotions and talk to others; and sometimes they make “their” emotions the topic of such talk. The emotions seem to be “theirs,” since they can be conceived of as private states (or events); and they can be topicalized, because we seem to be able to attribute or lend a conventionalized public form (such as a linguistic label or name) to some inner (and therefore nonpublic) state or event. This is the way much of our folk-talk and folk-thinking about emotions, the expression thereof, the role of language in these expressions, and communication in general are organized. However, as we have shown (Bamberg &amp; Lindenberger 1984), such talk serves the purpose of communicating effectively and reaching mutual understanding.
Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
Authors: Xi Chen, Hannah V. McCue, Shi Quan Wong, Sudhanva S. Kashyap, Brian C. Kraemer, Jeff W. Barclay, Robert D. Burgoyne, Alan Morgan
Journal: Molecular Neurodegeneration (2015)

Many neurodegenerative diseases are associated with protein misfolding/aggregation. Treatments mitigating the effects of such common pathological processes, rather than disease-specific symptoms, therefore have general therapeutic potential.Here we report that the anti-epileptic drug ethosuximide rescues the short lifespan and chemosensory defects exhibited by C. elegans null mutants of dnj-14, the worm orthologue of the DNAJC5 gene mutated in autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. It also ameliorates the locomotion impairment and short lifespan of worms expressing a human Tau mutant that causes frontotemporal dementia. Transcriptomic analysis revealed a highly significant up-regulation of DAF-16/FOXO target genes in response to ethosuximide; and indeed RNAi knockdown of daf-16 abolished the therapeutic effect of ethosuximide in the worm dnj-14 model. Importantly, ethosuximide also increased the expression of classical FOXO target genes and reduced protein aggregation in mammalian neuronal cells.We have revealed a conserved neuroprotective mechanism of action of ethosuximide from worms to mammalian neurons. Future experiments in mouse neurodegeneration models will be important to confirm the repurposing potential of this well-established anti-epileptic drug for treatment of human neurodegenerative diseases.
A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor
Authors: Tetsuro Orita, Hiroyuki Tsunoda, Naohiro Yabuta, Kiyotaka Nakano, Takeshi Yoshino, Yuichi Hirata, Toshihiko Ohtomo, Jun-ichi Nezu, Hirofumi Sakumoto, Kouichiro Ono, Mikiyoshi Saito, Eiji Kumagai, Masahiko Nanami, Akihisa Kaneko, Takashi Yoshikubo, Masayuki Tsuchiya
Journal: Blood (2004)
Cell fate regulated by nuclear factor‐κB‐ and activator protein‐1‐dependent signalling in human melanocytes exposed to ultraviolet A and ultraviolet B
Authors: P. Wäster, I. Rosdahl, K. Öllinger
Journal: British Journal of Dermatology (2014)

BackgroundUltraviolet (UV) radiation constitutes an important risk factor for malignant melanoma, but the wavelength responsible for the initiation of this disease is not fully elucidated. Solar UV induces multiple signalling pathways that are critical for initiation of apoptotic cell death as a cellular defence against malignant transformation.
The long term treatment with B-carotene in erythropoietic protoporphyria: a controlled trial
Authors: M. F. CORBETT, A. HERXHEIMER, I.A. MAGNUS, C. A. RAMSAY, A. KOBZA-BLACK
Journal: British Journal of Dermatology (1977)

Journal Article The long term treatment with B‐carotene in erythropoietic protoporphyria: a controlled trial Get access M. F. CORBETT, M. F. CORBETT Ealing, London Search for other works by this author on: Oxford Academic Google Scholar A. HERXHEIMER, A. HERXHEIMER Departments of Medicine and Pharmacology, Charing Cross Hospital Medical School, Fulham Palace Road, London W6 8RF Search for other works by this author on: Oxford Academic Google Scholar I.A. MAGNUS, I.A. MAGNUS Department of Photohiology, institute of Dematology, Homerton Grove, London EF 6BX Professor I.A.Magnus, Department of Photobiology, Institute of Dermatology, Homerton Grove, London E9 6BX. Search for other works by this author on: Oxford Academic Google Scholar C. A. RAMSAY, C. A. RAMSAY Photobiology and Therapy Unit, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada Search for other works by this author on: Oxford Academic Google Scholar A. KOBZA‐BLACK A. KOBZA‐BLACK Department of Pharmacology, Institute of Dermatology, Homerton Grove, London E9 6BX Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 97, Issue 6, 1 December 1977, Pages 655–662, https://doi.org/10.1111/j.1365-2133.1977.tb14273.x Published: 01 December 1977
Mortality and Morbidity During Delivery Hospitalization Among Pregnant Women With Epilepsy in the United States
Authors: Sarah C. MacDonald, Brian T. Bateman, Thomas F. McElrath, Sonia Hernández-Díaz
Journal: JAMA Neurology (2015)

<h3>Importance</h3> Between 0.3% and 0.5% of all pregnancies occur among women with epilepsy. Evidence suggests an increase in perinatal morbidity and mortality among women with epilepsy. However, these risks have not been quantified in large population-based samples. <h3>Objective</h3> To report on the risk for death and adverse outcomes at the time of delivery for women with epilepsy in the United States. <h3>Design, Setting, and Participants</h3> Retrospective cohort study of pregnant women identified through delivery hospitalization records from the 2007-2011 Nationwide Inpatient Sample. From this representative sample of 20% of all US hospitals, we obtained a weighted sample of delivery hospitalizations from 69 385 women with epilepsy and 20 449 532 women without epilepsy. <h3>Main Outcomes and Measures</h3> Obstetrical outcomes including maternal death, cesarean delivery, length of stay, preeclampsia, preterm labor, and stillbirth. <h3>Results</h3> Women with epilepsy had a risk of death during delivery hospitalization of 80 deaths per 100 000 pregnancies, significantly higher than the 6 deaths per 100 000 pregnancies found among women without epilepsy (adjusted odds ratio [OR], 11.46 [95% CI, 8.64-15.19]). Women with epilepsy were also at a heightened risk for other adverse outcomes, including preeclampsia (adjusted OR, 1.59 [95% CI, 1.54-1.63]), preterm labor (adjusted OR, 1.54 [95% CI, 1.50-1.57]), and stillbirth (adjusted OR, 1.27 [95% CI, 1.17-1.38]), and had increased health care utilization, including an increased risk of cesarean delivery (adjusted OR, 1.40 [95% CI, 1.38-1.42]) and prolonged length of hospital stay (&gt;6 days) among both women with cesarean deliveries (adjusted OR, 2.13 [95% CI, 2.03-2.23]) and women with vaginal deliveries (adjusted OR, 2.60 [95% CI, 2.41-2.80]). <h3>Conclusions and Relevance</h3> Findings suggest that women with epilepsy are at considerably heightened risk for many adverse outcomes during their delivery hospitalization, including a more than 10-fold increased risk of death, and that increased clinical attention is imperative for these pregnancies.
Does Pre-Enucleation Chemotherapy Lead to Increased Risk of Metastasis in Advanced Retinoblastoma?
Authors: Batriti S. Wallang, Suryasnata Rath
Journal: Journal of Clinical Oncology (2011)

critical to avoid disease progression that results from chemotherapy resistance, and a delay in implementing this phase might have been the most significant factor that led to relapse.Therefore, we concur with the conclusion of Zhao et al 1 that enucleation should not be delayed in patients with group D or E eyes in whom preoperative extent of disease evaluation fails to show evidence of extraocular extension.However, we believe that pre-enucleation chemotherapy is the treatment of choice for children with clinical or radiologic evidence of orbital disease and possibly for those with massive buphthalmia.If preoperative chemotherapy needs to be administered because families decline enucleation for their children, it should be restricted to one to two cycles, with the sole aim of providing time for the family and the treating group to negotiate and accept the concept of enucleation.This is a valid option for families who reject initial enucleation and whose children would die of disseminated disease if they received no treatment. 12,13In these situations, the value of pathology risk factors to predict theriskofextraocularrelapseaftersecondaryenucleationmaybemisleading, and adjuvant therapy de-escalation that is based on pathology results may not be safe.Additional study would be necessary to generate guidelines for adjuvant therapy in this population.