tbuckley/cabot-search huggingface dataset:
Ion Channels: Too Complex for Rational Drug Design?
Authors: Steve A.N Goldstein, Thomas J Colatsky
Journal: Neuron (1996)

Beneath soaring eagles and snow-capped peaks, a Keystone Symposium was held from February 4–10, 1996, in Tamarron, Colorado. Under the banner, "Ion Channels as Therapeutic Targets," the organizers (Michael Cahalan, University of California, Irvine; K. George Chandy, University of California, Irvine; Doug Hanson, Pfizer; Alan North, Glaxo Institute) brought together scientists from academia and industry and dared us to admit to our successes and failures. At the heart of this challenge was a question: can drugs acting on ion channels be rationally designed? The driving motivation behind molecular-based drug design is clear: all drugs now marketed that act on ion channels were discovered empirically (either by clinical use for other indications or by broad functional screening) rather than by molecular insight, and most have been shown to have serious safety and efficacy problems. Granted, our new scientific methods are implicating ion channel dysfunction in some disease states and identifying new drug targets as well as new modes of drug action, but are we moving toward development of more successful ion channel modulating drugs? Here, we review the symposium presentations partitioned into three catagories: known targets and drugs in use, new targets and drug candidates, and new biology. The efforts of the organizers were rewarded with at least two tangible results: first, a foundation was laid for détente between accrued knowledge using older methods and newly emerging opportunities; second, the slopes remained barren and lecture hall full.
Molecular Divergence in the period Gene Between Two Putative Sympatric Species of the Lutzomyia longipalpis Complex
Authors: L. G. S. R. Bauzer, J. S. M. Gesto, N. A. Souza, R. D. Ward, J. G. C. Hamilton, C. P. Kyriacou, Alexandre A. Peixoto
Journal: Molecular Biology and Evolution (2002)
Is early induction or expectant management more beneficial in women with late preterm pre-eclampsia?
Authors: L. C. Chappell, F. Milne, A. Shennan
Journal: BMJ (2015)

This is one of a series of occasional articles that highlight areas of practice where management lacks convincing supporting evidence. The series adviser is David Tovey, editor in chief, the Cochrane Library. This paper is based on a research priority identified and commissioned by the National Institute for Health Research’s Health Technology Assessment programme on an important clinical uncertainty. To suggest a topic for this series, please email us at uncertainties@bmj.com.
Adrenal corticosteroid therapy
Authors: G. Goldstein
Journal: JAMA (1981)

To the Editor.—  We are concerned that the conclusions of Klinefelter et al, in their article entitled Single Daily Dose Prednisone Therapy (1979;241:2721-2723), tend to minimize the degree of adrenal suppression in their patients and could lead to a false sense of security about the adrenal status of patients receiving this form of therapy. The possible need for supplemental steroids during stress is mentioned only in the abstract and not in the body of the article, where the authors state that the majority of their patients had normal adrenal function, a conclusion not substantiated by their data.  The authors use the adrenocorticotropic (ACTH)-stimulation test to evaluate the function of the hypothalamic-pituitary-adrenal (HPA) axis. The test result was considered normal if there was at least a 7-μg/dL rise in plasma cortisol levels. This criterion is not adequate for a conclusion that adrenal function is normal. Barnes et al 1 required an
The Role of Numeracy in Understanding the Benefit of Screening Mammography
Authors: Lisa M. Schwartz
Journal: Annals of Internal Medicine (1997)

Background: Quantitative information about risks and benefits may be meaningful only to patients who have some facility with basic probability and numerical concepts, a construct called numeracy. Objective: To assess the relation between numeracy and the ability to make use of typical risk reduction expressions about the benefit of screening mammography. Design: Randomized, cross-sectional survey Setting: A simple random sample of 500 female veterans drawn from a New England registry. Intervention: One of four questionnaires, which differed only in how the same information on average risk reduction with mammography was presented. Measurements: Numeracy was scored as the total number of correct responses to three simple tasks. Participants estimated their risk for death from breast cancer with and without mammography. Accuracy was judged as each woman's ability to adjust her perceived risk in accordance with the risk reduction data presented. Results: 61% of eligible women completed the questionnaire. The median age of these women was 68 years (range, 27 to 88 years), and 96% were high school graduates. Both accuracy in applying risk reduction information and numeracy were poor (one third of respondents thought that 1000 flips of a fair coin would result in <300 heads). Accuracy was strongly related to numeracy: The accuracy rate was 5.8% (95% CI, 0.8% to 10.7%) for a numeracy score of 0, 8.9% (CI, 2.5% to 15.3%) for a score of 1, 23.7% (CI, 13.9% to 33.5%) for a score of 2, and 40% (CI, 25.1% to 54.9%) for a score of 3. Conclusions: Regardless of how information was presented, numeracy was strongly related to accurately gauging the benefit of mammography. More effective formats are needed to communicate quantitative information about risks and benefits.
Effects of Aspirin Responsiveness and Platelet Reactivity on Early Vein Graft Thrombosis After Coronary Artery Bypass Graft Surgery
Authors: Tyler J. Gluckman, Rhondalyn C. McLean, Steven P. Schulman, Thomas S. Kickler, Edward P. Shapiro, John V. Conte, Kathleen W. McNicholas, Jodi B. Segal, Jeffrey J. Rade
Journal: Journal of the American College of Cardiology (2011)
And just how do you define narrow therapeutic ratio?
Authors: J. R. Hoffman
Journal: BMJ (2011)

It is discouraging that the BMJ published a “lesson of the week” warning us of “chronic toxicity” from paracetamol ( N -acetyl- p -aminophenol; APAP) without a counter argument.1 Although paracetamol can be life threatening after intentional overdose, when taken in anything less than extremely large doses it is one of the safest drugs ever created. Fear mongering about paracetamol will surely lead to the substitution of far more dangerous alternatives.

Before N -acetylcysteine became available, acute liver failure …
Malnutrition in infants receiving cult diets.
Authors: E F Wheeler
Journal: BMJ (1979)

goods vehicles was more successful.It was followed by a marked decrease in deaths and injuries among occupants of goods vehicles-3700 fewer were killed in 1977 than in 1970.2In 1977 in magistrates courts in England and Wales 1-2 million persons were found guilty of motoring offences; of these 97°were fined.3Penalties for serious transgressions were too mild.In 82 480 driving licence offences, including driving while disqualified, a fine of £20 or less was imposed in 830oi, and £50 or less in 970°.In 7899 cases of dangerous driving the penalty was £50 or less in 51°', and £100 or less in 96o0.Fines must be increased if they are to remain a credible deterrent.Disqualification and penalties are ineffective in a small minority of habitual offenders, who often also have a past history of other criminal offences.These cases present a social as well as a legal problem.Adequate enforcement with suitable penalties can improve road behaviour, but the real answer is to persuade the public that traffic regulations are an essential ingredient of road safety.
Histoincompatibility and maternal immunological status as determinants of fetoplacental weight and litter size in rodents.
Authors: A E Beer, J R Scott, R E Billingham
Journal: The Journal of Experimental Medicine (1975)

Studies conducted upon inbred strains of mice, hamsters and rats have shown that following the interstrain matings the now familiar covert reactivity of pregnant females to the alloantigens of their conceptuses may benefit the latter in two ways; firstly, it exerts a significant influence upon placental weight, and indirectly upon the birth weight of the fetus-allogeneic placentas tending to be heavier than syngeneic placentas, and mothers specifically presensitized against alien paternal tissue antigens gestate fetuses with heavier placentas than normal females. Specifically tolerant mothers, on the other hand, produce smaller, F1 hybrid, fetoplacental (fp) units. The classic notion that the disparity between the birth weights of F1 hybrid and homozygous offspring is due to hybrid vigor has been challenged by the finding that DA and (DA times F1)F1 hybrid blastocysts transferred to the uteri of genetically tolerant (DA times F1)F1 hybrid rats produce fp units of similar weight Maternal immunological reactivity against the fetus qua allograft may make a significant contribution here. Additional support for the premise that maternal reactivity against fetal alloantigens in some way promotes the growth of the fp unit was afforded by the finding that excision of the para-aortic lymph nodes (which drain the uterine horns) from females before interstrain matings resulted in smaller fp units than in females subjected to sham operations. The finding with one rat strain combination that passive immunization of females with serum against their F1 hybrid conceptuses promoted the growth of the latter suggests that a humoral rather than a cellular immunity may be involved. Secondly, in the three species studied, it was observed that genetic disparity between a conceptus and its mother significantly improved its chances of implantation and development to term.
Empirical Validation for a Family-Centered Model of Care
Authors: Cindy L Hanson, Michelle J De Guire, Angle M Schinkel, Orville G Kolterman
Journal: Diabetes Care (1995)

OBJECTIVE To examine whether family relations and family-life stress predict adherence behaviors and metabolic control in youths by testing a theoretically- and empirically-based model. RESEARCH DESIGN AND METHODS HbA1c levels of 157 youths 12–20 years of age with insulin-dependent diabetes mellitus (IDDM) were evaluated, along with treatment adherence and psychosocial family data based on interviews and self-reports. A family-centered model for IDDM care was analyzed with the EQS structural modeling statistical program. An additional exploratory model including HbA1c levels 6 months earlier was also tested. RESULTS Positive family relations (high family cohesion and low family conflict), especially during the first years of illness, indirectly related to good metabolic control through positive adherence behaviors. High levels of family-life stress related to worse metabolic control directly, and also indirectly via poor family relations, which in turn related to poor adherence to treatment. Longer illness duration related indirectly to metabolic control via adherence to treatment. Longer illness duration also related to maternal perceptions of higher family-life stress. Older youths perceived more family-life stress as well. The older age of the youths related indirectly to poor metabolic control through its association with poor adherence behaviors and less cohesive and more conflictual family relations. Results were consistent when earlier levels of metabolic control were included in the model, except that the direct relationship between family-life stress and metabolic control became nonsignificant. CONCLUSIONS The findings suggest that a family-centered approach to diabetes care that facilitates positive family functioning and leads to lower levels of family-life stress may be useful in promoting optimal health outcomes.
When walking fails
Authors: D. S. Gordan
Journal: JAMA (1997)

To the Editor.  —If Dr Iezzoni 1 had lost her vision and told us about going to lighting stores and talking to opticians, would we not be amazed that she had not consulted an ophthalmologist? Why then should we not be amazed that she did not consult a physiatrist when she lost her ability to walk? Perhaps because medical schools, notably her own, have until very recently so marginalized rehabilitation that, even today, I am sure that only a minority of Dr Iezzoni's colleagues are aware that their own medical school now has a rehabilitation program and even fewer have ever referred a patient to it. Almost 50 years after the establishment of its certifying board, physiatry and the help it can provide to people like Dr Iezzoni remain, unfortunately, little known.
Cohort study of multiple brain lesions in sport divers: role of a patent foramen ovale
Authors: M. Knauth, S. Ries, S. Pohimann, T. Kerby, M. Forsting, M. Daffertshofer, M. Hennerici, K. Sartor
Journal: BMJ (1997)

<h3>Abstract</h3> <b>Objective:</b> To investigate the role of a patent foramen ovale in the pathogenesis of multiple brain lesions acquired by sport divers in the absence of reported decompression symptoms. <b>Design:</b> Prospective double blind cohort study. <b>Setting:</b> Diving clubs around Heidelberg and departments of neuroradiology and neurology. <b>Subjects:</b> 87 sport divers with a minimum of 160 scuba dives (dives with self contained underwater breathing apparatus). <b>Main outcome measures:</b> Presence of multiple brain lesions visualised by cranial magnetic resonance imaging and presence and size of patent foramen ovale as documented by echocontrast transcranial Doppler ultrasonography. <b>Results:</b> 25 subjects were found to have a right-to-left shunt, 13 with a patent foramen ovale of high haemodynamic relevance. A total of 41 brain lesions were detected in 11 divers. There were seven brain lesions in seven divers without a right-to-left shunt and 34 lesions in four divers with a right-to-left shunt. Multiple brain lesions occurred exclusively in three divers with a large patent foramen ovale (P=0.004). <b>Conclusions:</b> Multiple brain lesions in sport divers were associated with presence of a large patent foramen ovale. This association suggests paradoxical gas embolism as the pathological mechanism. A patent foramen ovale of high haemodynamic relevance seems to be an important risk factor for developing multiple brain lesions in sport divers. <h3>Key messages</h3> An increased prevalence of multiple brain lesions has been reported in scuba divers compared with non-diving controls It has been suggested that the brain lesions were due to arterial gas embolism and that the gas emboli could have entered the arterial circulation via a patent foramen ovale We investigated this hypothesis in volunteer sport divers who had made at least 160 scuba dives Brain lesions occurred in divers even in the absence of reported decompression sickness Multiple brain lesions occurred exclusively in divers with a large patent foramen ovale The association of multiple brain lesions with a large patent foramen ovale suggests paradoxical gas embolism as the pathological mechanism
Why we don't need built-in misbeliefs
Authors: Carol S. Dweck
Journal: Behavioral and Brain Sciences (2009)

Abstract In this commentary, I question the idea that positive illusions are evolved misbeliefs on the grounds that positive illusions are often maladaptive, are not universal, and may be by-products of existing mechanisms. Further, because different beliefs are adaptive in different situations and cultures, it makes sense to build in a readiness to form beliefs rather than the beliefs themselves.
CD8‐positive juvenile onset mycosis fungoides: an immunohistochemical and genotypic analysis of six cases
Authors: L.R. Whittam, E. Calonje, G. Orchard, E.A. Fraser‐Andrews, A. Woolford, R. Russell‐Jones
Journal: British Journal of Dermatology (2000)

Childhood cases of cytotoxic T-cell lymphoma have not been well described.We have undertaken an immunohistochemical and genotypic analysis of patients presenting with juvenile onset mycosis fungoides (MF).Of 10 patients presenting over a 3-year period, six exhibited a CD8-positive phenotype. These six patients were also CD2, CD3 and TIA1 positive, but CD56 negative. Apart from the cytotoxic phenotype, these patients had clinicopathological features that were indistinguishable from ordinary cases of MF, with slowly evolving patches and plaques. Three patients were staged as 1A and three as 1B, with no evidence of nodal or systemic disease.Patients responded well to conventional therapy, with no evidence of disease progression after 3 years follow-up. Epidermotropism was a prominent feature in four of the six cytotoxic cases. In two patients with an equivocal histology the diagnosis was confirmed by the finding of a clonal population, using polymerase chain reaction/single strand conformational polymorphism analysis of the T-cell receptor gamma gene in lesional skin. The same technique revealed that all blood samples analysed were polyclonal.These data show that cytotoxic T-cell lymphoma can pursue an indolent course and that cases of CD8-positive MF may be over-represented in childhood.
T‐cell subpopulations in patients with monoclonal gammopathies: Essential monoclonal gammopathy, multiple myeloma, and Waldenstrom macroglobulinemia
Authors: J. F. San Miguel, M. D. Caballero, M. Gonzalez
Journal: American Journal of Hematology (1985)

Abstract T‐cell subsets defined by monoclonal antibodies (OKT3, OKT4, and OKT8) were analyzed in 117 patients with monoclonal gammopathies—69 multiple myeloma (MM) (30 untreated and 39 treated), 14 Waldenström's macroglobulinaemia (WM), and 34 essential monoclonal gammopathy (EMG) patients. The percentage and absolute numbers of total T‐lymphocytes (E + , OKT3 + cells) were within the normal range in all groups except for the treated MM patients, in which a decrease in the absolute number could be observed. The percentages of OKT4 + cells were significantly lower in MM (35 ± 1.7) than in EMG patients (43 ± 2) and controls (50 ± 2). In contrast, OKT8 cells correspondingly increased in MM (38 ± 1.6) compared with EMG patients (29 ± 1) and controls (27 ± 1). The OKT4/0KT8 ratio was lower in MM than that in EMG patients and controls (p &lt; 0.01) and was shown to be one of the four most significant variables in a linear discriminant analysis used to distinguish between MM and EMG groups. The MM patients in clinical stage III as well as Bence‐Jones myeloma patients showed a more pronounced OKT4/0KT8 imbalance. The treatment did not influence the percent distribution of T‐cell Subpopulations. The patients with WM exhibit an alteration in the distribution of the T‐cell subsets similar to the MM patients with a T4/T8 ratio of 1.1±0.1. This imbalance was more pronounced in WM patients with monoclonal B‐lymphocytes in peripheral blood (leukaemic phase of WM). The functional significance of the altered T‐cell subsets in MM and WM patients remains to be established, though it is probable that such an imbalance plays an important role in regulating these B‐cell proliferations.
ONE-YEAR OUTCOMES AFTER TIROFIBAN VERSUS ABCIXIMAB INFUSION IN 745 PATIENTS WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION UNDERGOING PRIMARY INTERVENTION: INSIGHTS FROM THE MLTISTRATEGY TRIAL
Authors: Marco Valgimigli, Gianluca Campo, Matteo Tebaldi, Leonardo Bolognese, Maurizio Anselmi, Salvatore Colangelo, Nicoletta De Cesare, Alfredo E. Rodriguez, Maurizio Ferrario, Raul Moreno
Journal: Journal of the American College of Cardiology (2010)
Genetic influence of specific anticollagen antibody production in a mouse model of rheumatoid arthritis
Authors: Bruno Raposo, Doreen Dobritzsch, Hüseyin Uysal, Diana Ekman, Rikard Holmdahl
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Rheumatoid arthritis (RA) is an autoimmune disease affecting about 1% of the population. Though of unknown aetiology, it is considered to have a strong genetic influence, resulting in the activation of different immune cells and consequent bone and cartilage destruction of the joints. The production of anticollagen type II (CII) antibodies is a common feature between RA patients and the collagen-induced arthritis (CIA) mouse model. Understanding how distinct anti-CII epitopes are genetically selected could benefit the development of new RA therapies. Here, the authors assess the genetic influence of specific anti-CII antibody production in a mouse model of RA. <h3>Material and methods</h3> In this particular study, the authors have used as genetic variance tool a heterogeneous stock (HS) mice cohort of eight inbred mouse strains. Three of the major anti-CII B cell epitopes (C1, U1 and J1) were analysed by ELISA. Sequencing of the genes coding for the M2139 monoclonal antibody (J1-specific mAb) was additionally done for all the HS strains. <h3>Results</h3> A genome wide study of antibody response during CIA development suggested that specific anti-CII antibodies are regulated by the immunoglobulin heavy chain locus (IgH). The haplotype reconstruction analysis showed a preference for the anti-J1 antibody production by certain mouse strains, in detriment of anti-C1 antibodies. The authors thus hypothesised that the selection of particular IgHv genes is responsible for this J1 versus C1 epitope selection. Preliminary sequencing data of the genes coding for the M2139 monoclonal antibody in all the HS strains, supports the initial hypothesis. The difference relies on an amino acid change from a hydrophobic tryptophan to a polar amino acid (eg, threonine) in the CDR1 region. Three-dimensional structure of M2139 Fab with triple helical J1 peptide shows that the tryptophan in the CDR1 region of the heavy chain is contacting with a hydrophobic leucine amino acid in the J1 epitope. This interaction may be essential for recognition of the J1 epitope. Replacement of Trp by Thr in this position could abrogate the binding to J1 epitope. <h3>Conclusions</h3> CIA development in HS mice allowed for a genome wide study on anti-CII specific responses. The data revealed a genetic association with the production of anti-J1 antibodies. Sequencing of the genes coding for the anti-J1 mAb reveal an amino acid substitution influencing the polarity within the CDR1 region. Cloning and expression of these mutations and consequent anti-J1 binding properties will further on confirm or reject our hypothesis.
Abstract A35: Tyrosine kinase inhibitors block PDGFR-β signaling and suppress growth in malignant endothelial cells
Authors: Kevin Marley, Stuart C. Helfand
Journal: Cancer Research (2009)

Abstract Tyrosine kinase inhibitors (TKIs), including imatinib and dasatinib, have shown remarkable efficacy in controlling chronic myelogenous leukemia and gastrointestinal stromal tumors. Their role in treating other solid tumors is less clear. We are investigating the potential to control malignant endothelial cell (EC) growth with TKIs using a spontaneous canine hemangiosarcoma (HSA) model. Canine HSA is a highly malignant EC cancer with cellular features reminiscent of primitive endothelium. Controlling HSA cell growth has implications for improved outcomes of human and canine patients affected with EC cancer as well as for design of antiangiogenic strategies. We evaluated the effects of imatinib and dasatinib on constitutive tyrosine phosphorylation of platelet derived growth factor receptor-beta (PDGFR-β) that we previously determined to be abnormal in HSA cell cultures. Further, we correlated effects of these TKIs on HSA proliferation in vitro to determine if abnormal activation of PDGFR-β contributes to the HSA malignant phenotype. Dasatinib was approximately ten-fold more potent than imatinib in suppressing HSA cell growth. Dasatinib (100 nM) rapidly abrogated signal from full length and a possible truncated form (120 kDa) of phospho-PDGFR-β. Cells with constitutive activation of PDGFR-β also showed tyrosine phosphorylation of extracellular related kinase-1 (ERK-1), ERK-2, and Src suggesting these could be downstream partners of PDGFR-β in aberrant HSA signaling. Dasatinib markedly suppressed phosphorylation of Src in HSA cells. Taken together; these data suggest that tyrosine kinase inhibitors may affect endothelial cell growth in malignancy by blocking PDGFR-β or its downstream signaling partners. Citation Information: Cancer Res 2009;69(23 Suppl):A35.