tbuckley/cabot-search huggingface dataset:
Oesophageal motility, luminal pH, and electrocardiographic-ST segment analysis during spontaneous episodes of angina like chest pain.
Authors: D G Hick, J F Morrison, J F Casey, W al-Ashhab, G J Williams, G A Davies
Journal: Gut (1992)

The relation between oesophageal motility, luminal pH, and spontaneous pain events in 47 patients with recurrent angina like pain and normal coronary arteries was investigated. Preliminary investigation by conventional station pull through manometry (SPTM), was followed by a 24 hour period of ambulatory oesophageal motility and luminal pH monitoring. Computerised analysis of motility and pH data recorded during chest pain was then compared with pre-elected control samples taken before and after symptoms. Concurrent real time electrocardiographic (ECG)-ST segment analysis was performed to catalogue any ECG-STT wave changes indicative of myocardial ischaemia. SPTM showed a high group percentage incidence of simultaneous contractions (mean (SD) 11.1 (2.3)%) and a raised lower oesophageal sphincter tone (57.4 (15.2) mm Hg). During ambulatory monitoring, 35 patients experienced one or more episode of angina, providing a total of 59 pain events, although no significant change in group motility and reflux parameters peculiar to episodes of chest pain were found. Ischaemic ECG changes were detected in 10 (21%) patients, but were accompanied by pain in only two. Independent analysis of the ECG traces corresponding to these purported ischaemic ECG events determined them unequivocal in three patients and probable in a further two. No apparent correlation was noted, however, between these ECG events and corresponding patterns of motility or reflux.
Conceptualizing Overdiagnosis in Cancer Screening
Authors: P. M. Marcus, P. C. Prorok, A. B. Miller, E. J. DeVoto, B. S. Kramer
Journal: JNCI Journal of the National Cancer Institute (2015)

The aim of cancer screening is to detect asymptomatic cancers whose treatment will result in extension of life, relative to length of life absent screening. Unfortunately, cancer screening also results in overdiagnosis, the detection of cancers that, in the absence of screening, would not present symptomatically during one's lifetime. Thus, their detection and subsequent treatment is unnecessary and detrimental. This definition of overdiagnosis, while succinct, does not capture the ways it can occur, and our interactions with patients, advocates, researchers, clinicians, and journalists have led us to believe that the concept of overdiagnosis is difficult to explain and, for some, difficult to accept. We propose a dichotomy, the "tumor-patient" classification, to aid in understanding overdiagnosis. The tumor category includes asymptomatic malignant disease that would regress spontaneously if left alone, as well as asymptomatic malignant disease that stagnates or progresses too slowly to be life threatening in even the longest of lifetimes. The patient category includes asymptomatic malignant disease that would progress quickly enough to be life threatening during a lifetime of typical length, but lacks clinical relevance because death due to another cause intercedes prior to what would have been the date of symptomatic diagnosis had screening not occurred. Cancer screening of most organs is likely to result in overdiagnosis of both types. However, the ratio of tumor- to patient-driven overdiagnosis almost certainly varies, and may vary drastically, by organ, screening modality, patient characteristics, and other factors.
Histamine challenges discriminate between symptomatic and asymptomatic children
Authors: B. Niggemann, S. Illi, C. Madloch, K. Völkel, S. Lau, R. Bergmann, E. von Mutius, U. Wahn
Journal: European Respiratory Journal (2001)

The aims of this study were to investigate a threshold value for bronchial responsiveness in children aged 7 yrs, which discriminates between symptomatic and asymptomatic children, and to identify determinants of this responsiveness. Titrated bronchial histamine challenges using the reservoir method were performed in 645 children aged 7 yrs, from the birth cohort Multicentre Allergy Study (MAS). When defining a reference population of healthy children within the MAS cohort, the 95th percentile of the provocative concentration causing a 20% fall in forced expired volume in one second PC 20 among these asymptomatic study subjects amounted to 0.60 mg·mL −1 . This resulted in a specificity of 93.0% and a sensitivity of 45.9%, for discriminating between “current wheezers” and “non-current wheezers”. Determinants of airway responsiveness at this age were pulmonary function, sensitization to indoor allergens, total immunoglobulin E and current wheeze. The results indicate that a very low cut-off provocative concentration causing a 20% fall in forced expired volume in one second (&lt;1.0 mg·mL −1 ) defines airway hyperresponsiveness in children aged 7 yrs using the reservoir method. Provocation protocols for histamine challenges in this age group should therefore start with concentrations markedly below 1.0 mg·mL −1 .
Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: possible mediation of hypoxia-inducible factor-1α
Authors: Y Huang, K-M Du, Z-H Xue, H Yan, D Li, W Liu, Z Chen, Q Zhao, J-H Tong, Y-S Zhu, G-Q Chen
Journal: Leukemia (2003)
Acoustic Detection of Coronary Artery Disease
Authors: John Semmlow, Ketaki Rahalkar
Journal: Annual Review of Biomedical Engineering (2007)

Coronary artery disease (CAD) occurs when the arteries to the heart (the coronary arteries) become blocked by deposition of plaque, depriving the heart of oxygen-bearing blood. This disease is arguably the most important fatal disease in industrialized countries, causing one-third to one-half of all deaths in persons between the ages of 35 and 64 in the United States. Despite the fact that early detection of CAD allows for successful and cost-effective treatment of the disease, only 20% of CAD cases are diagnosed prior to a heart attack. The development of a definitive, noninvasive test for detection of coronary blockages is one of the holy grails of diagnostic cardiology. One promising approach to detecting coronary blockages noninvasively is based on identifying acoustic signatures generated by turbulent blood flow through partially occluded coronary arteries. In fact, no other approach to the detection of CAD promises to be as inexpensive, simple to perform, and risk free as the acoustic-based approach. Although sounds associated with partially blocked arteries are easy to identify in more superficial vessels such as the carotids, sounds from coronary arteries are very faint and surrounded by noise such as the very loud valve sounds. To detect these very weak signals requires sophisticated signal processing techniques. This review describes the work that has been done in this area since the 1980s and discusses future directions that may fulfill the promise of the acoustic approach to detecting coronary artery disease.
Ca2+ homeostasis in Brody's disease. A study in skeletal muscle and cultured muscle cells and the effects of dantrolene an verapamil.
Authors: A A Benders, J H Veerkamp, A Oosterhof, P J Jongen, R J Bindels, L M Smit, H F Busch, R A Wevers
Journal: Journal of Clinical Investigation (1994)

Brody's disease, i.e., sarcoplasmic reticulum (SR) Ca(2+)-dependent Mg(2+)-ATPase (Ca(2+)-ATPase) deficiency, is a rare inherited disorder of skeletal muscle function. Pseudo-myotonia is the most important clinical feature. SR Ca(2+)-ATPase and Ca2+ homeostasis are examined in m. quadriceps and/or cultured muscle cells of controls and 10 patients suffering from Brody's disease. In both m. quadriceps and cultured muscle cells of patients, the SR Ca(2+)-ATPase activity is decreased by approximately 50%. However, the concentration of SR Ca(2+)-ATPase and SERCA1 are normal. SERCA1 accounts for 83 and 100% of total SR Ca(2+)-ATPase in m. quadriceps and cultured muscle cells, respectively. This implies a reduction of the molecular activity of SERCA1 in Brody's disease. The cytosolic Ca2+ concentration ([Ca2+]i) at rest and the increase of [Ca2+]i after addition of acetylcholine are the same in cultured muscle cells of controls and patients. The half-life of the maximal response, however, is raised three times in the pathological muscle cells. Addition of dantrolene or verapamil after the maximal response accelerates the restoration of the [Ca2+]i in these muscle cells. The differences in Ca2+ handling disappear by administration of dantrolene or verapamil concomitantly with acetylcholine. The reduced Ca2+ re-uptake from the cytosol presumably due to structural modification(s) of SERCA1 may explain the pseudo-myotonia in Brody's disease. Single cell measurements suggest a beneficial effect of dantrolene or verapamil in treating patients suffering from Brody's disease.
Dilution of a mepivacaine-adrenaline solution in isotonic sodium bicarbonate for reducing subcutaneous infiltration pain in ambulatory phlebectomy procedures: A randomized, double-blind, controlled trial
Authors: Leo Moro, Francesco-Maria Serino, Stefano Ricci, Gloria Abbruzzese, Raffaele Antonelli-Incalzi
Journal: Journal of the American Academy of Dermatology (2014)
Evidence for Positive Selection on Drosophila melanogaster Seminal Fluid Protease Homologs
Authors: A. Wong, M. C. Turchin, M. F. Wolfner, C. F. Aquadro
Journal: Molecular Biology and Evolution (2007)

Proteins present in the seminal fluid of Drosophila melanogaster (accessory gland proteins Acps) contribute to female postmating behavioral changes, sperm storage, sperm competition, and immunity. Consequently, male-female coevolution and host-pathogen interactions are thought to underlie the rapid, adaptive evolution that characterizes several Acp-encoding genes. We propose that seminal fluid proteases are likely targets of selection due to their demonstrated or potential roles in between-sex interactions and immune processes. We use within- and between-species sequence data for 5 predicted protease-encoding Acp loci to test this hypothesis. Our polymorphism-based analyses find evidence for positive selection at 2 genes, both of which encode predicted serine protease homologs. One of these genes, CG6069, also shows evidence for consistent selection on a subset of codons over a deeper evolutionary time scale. The second gene, CG9997, was previously shown to be essential for normal sperm usage, suggesting that sexual selection may underlie its history of adaptation.
Patterns of airway disease and the clinical diagnosis of asthma in the Busselton population
Authors: A.W. Musk, M. Knuiman, M. Hunter, J. Hui, L.J. Palmer, J. Beilby, M. Divitini, S. Mulrennan, A. James
Journal: European Respiratory Journal (2011)

The aim of this study was to examine how objective measures related to lung function cluster in the general population and how the patterns relate to asthma and bronchitis as diagnosed by a doctor (DDA and DDB, respectively). A cross-sectional survey of an age-stratified random general population sample of 1,969 adults from the electoral register of Busselton (Australia) was performed in 2005–2007. Respiratory symptoms, DDA ever, DDB ever, recent wheezing and smoking history, together with anthropometric measurements, forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC), methacholine challenge or bronchodilator response, exhaled nitric oxide (eNO), skin-prick tests to common allergens, and blood eosinophil and neutrophil counts were studied. Cluster analysis (variables sex, age, atopy, FEV 1 % predicted, FEV 1 /FVC, airway hyperresponsiveness, eNO, log eosinphil count, log neutrophil count and body mass index) was used to identify phenotypic patterns. Seven clusters (subjects with DDA and DDB, respectively) were identified: normal males (n=467; 7 and 13%), normal females (n=477; 12 and 18%), obese females (n=250; 16 and 28%), atopic younger adults (n=330; 21 and 17%), atopic adults with high eNO (n=130; 30 and 25%), atopic males with reduced FEV 1 (n=103; 33 and 32%) and atopic adults with bronchial hyperreactivity (n=212; 40 and 26%). The clinical diagnosis of asthma (ever) and bronchitis (ever) is not specific for any of the clustering patterns of airway abnormality.
Protein Kinases, Protein Phosphorylation, and the Regulation of Insulin Secretion from Pancreatic β-Cells.
Authors: Peter M. Jones, Shanta J. Persaud
Journal: Endocrine Reviews (1998)

I. Introduction II.Protein Kinases in ␤-Cells: Expression and Characteristics A. Ca 2ϩ /calmodulin-dependent protein kinases B. Cyclic nucleotide-dependent protein kinases C. Ca 2ϩ /phospholipid-dependent protein kinases D. Mitogen-activated protein kinases E. Protein tyrosine kinases III.Phosphorylation of Endogenous Proteins in ␤-Cells A. Methods for studying protein phosphorylation in ␤-cells B. Endogenous kinase substrates in ␤-cells IV.Protein Kinases and the Regulation of Insulin Secretion A. Ca 2ϩ /calmodulin-dependent protein kinases B. Cyclic nucleotide-dependent protein kinases C. Ca 2ϩ /phospholipid-dependent
Multifaceted Intervention to Improve Medication Adherence and Secondary Prevention Measures After Acute Coronary Syndrome Hospital Discharge
Authors: P. Michael Ho, Anne Lambert-Kerzner, Evan P. Carey, Ibrahim E. Fahdi, Chris L. Bryson, S. Dee Melnyk, Hayden B. Bosworth, Tiffany Radcliff, Ryan Davis, Howard Mun, Jennifer Weaver, Casey Barnett, Anna Barón, Eric J. Del Giacco
Journal: JAMA Internal Medicine (2013)

Adherence to cardioprotective medication regimens in the year after hospitalization for acute coronary syndrome (ACS) is poor.To test a multifaceted intervention to improve adherence to cardiac medications.In this randomized clinical trial, 253 patients from 4 Department of Veterans Affairs medical centers located in Denver (Colorado), Seattle (Washington); Durham (North Carolina), and Little Rock (Arkansas) admitted with ACS were randomized to the multifaceted intervention (INT) or usual care (UC) prior to discharge.The INT lasted for 1 year following discharge and comprised (1) pharmacist-led medication reconciliation and tailoring; (2) patient education; (3) collaborative care between pharmacist and a patient's primary care clinician and/or cardiologist; and (4) 2 types of voice messaging (educational and medication refill reminder calls).The primary outcome of interest was proportion of patients adherent to medication regimens based on a mean proportion of days covered (PDC) greater than 0.80 in the year after hospital discharge using pharmacy refill data for 4 cardioprotective medications (clopidogrel, β-blockers, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [statins], and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers [ACEI/ARB]). Secondary outcomes included achievement of blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) level targets. RESULTS Of 253 patients, 241 (95.3%) completed the study (122 in INT and 119 in UC). In the INT group, 89.3% of patients were adherent compared with 73.9% in the UC group (P = .003). Mean PDC was higher in the INT group (0.94 vs 0.87; P< .001). A greater proportion of intervention patients were adherent to clopidogrel (86.8% vs 70.7%; P = .03), statins (93.2% vs 71.3%; P < .001), and ACEI/ARB (93.1% vs 81.7%; P = .03) but not β-blockers (88.1% vs 84.8%; P = .59). There were no statistically significant differences in the proportion of patients who achieved BP and LDL-C level goals.A multifaceted intervention comprising pharmacist-led medication reconciliation and tailoring, patient education, collaborative care between pharmacist and patients' primary care clinician and/or cardiologist, and voice messaging increased adherence to medication regimens in the year after ACS hospital discharge without improving BP and LDL-C levels. Understanding the impact of such improvement in adherence on clinical outcomes is needed prior to broader dissemination of the program.clinicaltrials.gov Identifier: NCT00903032.
Variation in Caesarean Section Rates in the US: Outliers, Damned Outliers, and Statistics
Authors: Gordon C. S. Smith
Journal: PLoS Medicine (2014)

Gordon C. Smith discusses the study by Katy Kozhimannil and colleagues that examines variations in cesarean section rates in the US and argues for the need for high-quality routine data collection to better understand the reasons for these variations. Please see later in the article for the Editors' Summary.
Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus
Authors: Iulia Diaconu, Vincenzo Cerullo, Mari L.M. Hirvinen, Sophie Escutenaire, Matteo Ugolini, Saila K. Pesonen, Simona Bramante, Suvi Parviainen, Anna Kanerva, Angelica S.I. Loskog, Aristides G. Eliopoulos, Sari Pesonen, Akseli Hemminki
Journal: Cancer Research (2012)

Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (T(H)1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)-mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the T(H)1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8(+) T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of T(H)1 cytokines.
Five-Year Clinical Course Associated With DSM-IV Alcohol Abuse or Dependence in a Large Group of Men and Women
Authors: Marc A. Schuckit, Tom L. Smith, George P. Danko, Kathleen K. Bucholz, Theodore Reich, Laura Bierut
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The prognostic validity of the DSM-IV diagnoses of alcohol abuse and alcohol dependence was evaluated by examining the 5-year clinical course associated with those diagnoses in a large group of predominantly blue-collar men and women. METHOD: Personal semistructured interviews were carried out 5 years after an initial evaluation with 1,346 (75%) of the approximately 1,800 men and women participating in the Collaborative Study on the Genetics of Alcoholism who were eligible for follow-up. RESULTS: About two-thirds of the 298 subjects with DSM-IV alcohol dependence at baseline maintained that diagnosis during the 5-year study period. Fifty-five percent of the 288 subjects with DSM-IV alcohol abuse at baseline continued to meet one or more of the 11 DSM-IV abuse/dependence criteria, and 3.5% went on to meet the criteria for dependence at follow-up. Among the 760 subjects with no alcohol diagnosis at baseline, 2.5% met the criteria for alcohol dependence and 12.8% for alcohol abuse at follow-up. Baseline characteristics that predicted the occurrence of any of the 11 DSM-IV abuse/dependence criteria during the 5-year interval included male gender, lack of marital stability, presence of several of the criteria for dependence, and history of illicit drug use. CONCLUSIONS: The data suggest that over 5 years the DSM-IV diagnosis of alcohol dependence predicts a chronic disorder with a relatively severe course, while DSM-IV alcohol abuse predicts a less persistent, milder disorder that does not usually progress to dependence.
BAK multimerization for apoptosis, but not bid binding, is inhibited by negatively charged residue in the BAK hydrophobic groove
Authors: Abul Azad, Alan Storey
Journal: Molecular Cancer (2013)

BCL-2 family proteins BAK and BAX orchestrate outer mitochondrial membrane permeabilization (MOMP) during apoptosis by forming pores in the membrane to release apoptogenic factors that commits a cell to death. BAK and BAX therefore function as a 'point of no return' in the apoptotic cascade. BAK activation is a multi-step process involving conformational changes, mediated by BH3-only proteins or p53, which lead eventually to oligomerization and pore formation. Further, recent reports show that BAK activation is also linked to and dependent upon dephosphorylation of both tyrosine and serine residues.We hypothesized that phosphorylation of BAK at tyrosine residue 110 (Y110) was functionally important during the BAK activation process. BAK/BAX double knockout HCT116 cells expressing a phosphor-mimetic BAK mutant (BAK Y110E), showed impaired dimerization and multimerization capacity when treated with either UV irradiation or etoposide when compared to cells reconstituted to express wild-type BAK. The Y110E mutant also showed decreased release of cytochrome c from isolated mitochondria challenged with tBid protein, resulting in a failure to activate caspase 3. Interestingly, co-immunoprecipitation experiments suggest that a negative charge at this residue may be important for the recruitment of Bid to BAK, but conversely that this also impairs BAK:BAK interactions.These findings implicate dephosphorylation of Y110 as having an important mechanistic role in BAK activation, and underscores how post-translational modifications are intimately linked and coupled to the protein-protein interactions required for BAK activation during apoptosis.
Slipped capital femoral epiphyses associated with the withdrawal of a gonadotrophin releasing hormone
Authors: Eugène van Puijenbroek, Emil Verhoef, Linda de Graaf
Journal: BMJ (2004)

Leuprorelin, buserelin, and triptorelin belong to the group of gonadotrophin releasing hormone (GnRH) analogues. Kempers and Noordam previously reported an association between slipped capital femoral epiphysis during treatment with buserelin and triptorelin, or shortly after discontinuation of these drugs.1

The Netherlands Pharmacovigilance Centre Lareb received a report concerning an 11 year old girl who had been using leuprorelin 3.75 mg once monthly over four years, for precocious puberty. Seven months after the last injection she experienced pain in her right leg. …