tbuckley/cabot-search huggingface dataset:
Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels
Authors: Stefan Wagner, Nataliya Dybkova, Eva C.L. Rasenack, Claudius Jacobshagen, Larissa Fabritz, Paulus Kirchhof, Sebastian K.G. Maier, Tong Zhang, Gerd Hasenfuss, Joan Heller Brown, Donald M. Bers, Lars S. Maier
Journal: Journal of Clinical Investigation (2006)

In heart failure (HF), Ca(2+)/calmodulin kinase II (CaMKII) expression is increased. Altered Na(+) channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na(+) channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIdelta(C) on Na(+) current (I(Na)) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIdelta(C) overexpression shifted voltage dependence of Na(+) channel availability by -6 mV (P < 0.05), and the shift was Ca(2+) dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKIIdelta(C) markedly increased persistent (late) inward I(Na) and intracellular Na(+) concentration (as measured by the Na(+) indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIdelta(C) overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na(+) channels. In vivo, transgenic CaMKIIdelta(C) overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na(+) channels. This alters I(Na) gating to reduce availability at high heart rate, while enhancing late I(Na) (which could prolong action potential duration). In mice, enhanced CaMKIIdelta(C) activity predisposed to VT. Thus, CaMKII-dependent regulation of Na(+) channel function may contribute to arrhythmogenesis in HF.
Archibald Stewart McCallum Lamont
Authors: Rosanne Lamont
Journal: BMJ (2005)

Former director of anaesthesia Royal Hobart Hospital, Tasmania (b Glasgow 1926; q Glasgow 1949; FFA RCS), d 27 August 2005.

Steward Lamont became interested in anaesthesia soon after graduating, and did his national service in the Royal Air Force in Iraq as an anaesthetist. He was a consultant in Leeds before being appointed director of anaesthesia at the Royal Hobart Hospital, Tasmania, in 1977. This was a time when there was a certain amount of upheaval in the Australian medical world. Medibank was being introduced, and several anaesthetists had resigned from the hospital. Stewart's first tasks were to stabilise the department and to encourage trainees to join. Eventually, a programme for junior staff was organised and sufficient registrars obtained their fellowship. He leaves a wife, Hanna, and a daughter.
Hypochondriacal Patients’ Appraisal of Health and Physical Risks
Authors: Arthur J. Barsky, David K. Ahern, E. Duff Bailey, Ralph Saintfort, Elizabeth B. Liu, Heli M. Peekna
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors' goal was to assess the degree to which hypochondriasis is accompanied by a heightened sense of risk of disease and other physical hazards. METHOD: Fifty-six patients meeting DSM-III-R criteria for hypochondriasis were compared with 127 nonhypochondriacal patients from the same primary care setting. Both groups completed a self-report questionnaire assessing the degree to which they felt at risk of developing various medical diseases or being subject to injury from accidents or criminal assault. RESULTS: Both groups of patients exhibited an optimistic bias in that they considered themselves to be less at risk than others of their age and sex. However, the hypochondriacal group had a significantly higher total risk score than did the nonhypochondriacal group. In large part, this intergroup difference was the result of the hypochondriacal patients' perception that they were likely to develop various diseases. The hypochondriacal group did not score significantly higher than the comparison group in estimating their risk of succumbing to accidents and criminal victimization. Perceived risk was significantly associated with the self-reported tendency to amplify benign bodily sensations. CONCLUSIONS: An exaggerated appraisal of risk, jeopardy, and vulnerability to disease may be part of the cognitive distortion seen in hypochondriasis. If this is confirmed, cognitive and behavioral therapies for hypochondriasis may need to include a focus on these patients' understanding and appraisal of risk.
US newspapers favor weaker studies, researchers say
Authors: M. McCarthy
Journal: BMJ (2014)

Major US newspapers tend to cover weaker medical research studies, favoring observational studies over randomized controlled trials (RCTs), a new study has found.

The study appeared in the online journal PLoS ONE .1 Senthil Selvaraj of the Department of Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, was the paper’s lead author.

In the study the researchers compared 75 …
How to interpret reduced forced expiratory volume in 1 s (FEV1)/vital capacity ratio with normal FEV1
Authors: G. Barisione, E. Crimi, S. Bartolini, R. Saporiti, F. Copello, R. Pellegrino, V. Brusasco
Journal: European Respiratory Journal (2009)

The aim of the present study was to determine whether the combination of low forced expiratory volume in 1 s (FEV 1 )/vital capacity (VC) ratio with normal FEV 1 represents a physiological variant or a sign of early airflow obstruction. We studied 40 subjects presenting with low FEV 1 /VC, but FEV 1 within the range of normality predicted by European Respiratory Society reference equations, and 10 healthy controls. All subjects completed two questionnaires and underwent comprehensive pulmonary function testing, which included methacholine challenge and single-breath nitrogen wash-out. According to the questionnaires, the subjects were assigned to three groups, i.e. rhinitis (n = 8), bronchial asthma (n = 13) and chronic obstructive pulmonary disease (COPD; n = 12). Subjects with negative responses to questionnaires were assigned to an asymptomatic group (n = 7). Airway hyperresponsiveness was found in four subjects of the rhinitis group, all of the asthma group, and 10 of the COPD group; in the last two groups, it was associated with signs of increased airway closure and gas trapping. Bronchodilator response to salbutamol was positive in only a few individuals across groups. In the asymptomatic group, no significant functional changes were observed, possibly suggesting dysanaptic lung growth. In subjects with low FEV 1 /VC and normal FEV 1 , questionnaires on respiratory symptoms together with additional pulmonary function tests may help to clarify the nature of this pattern of lung function.
A CASE OF SARCOIDOSIS WITH ERYTHRODERMIC LESIONS. TREATMENT WITH CALCIFEROL.
Authors: J. E. M. WIGLEY, L. A. MUSSO
Journal: British Journal of Dermatology (1951)

Journal Article A CASE OF SARCOIDOSIS WITH ERYTHRODERMIC LESIONS. TREATMENT WITH CALCIFEROL. Get access J. E. M. WIGLEY, F.R.C.P., J. E. M. WIGLEY, F.R.C.P. St. John's Hospital for Diseases of the Skin, London Search for other works by this author on: Oxford Academic Google Scholar L. A. MUSSO, M.R.C.P. L. A. MUSSO, M.R.C.P. St. John's Hospital for Diseases of the Skin, London Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 63, Issue 11, 1 November 1951, Pages 398–407, https://doi.org/10.1111/j.1365-2133.1951.tb13677.x Published: 01 November 1951
Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer
Authors: C. Lim, M.S. Tsao, L.W. Le, F.A. Shepherd, R. Feld, R.L. Burkes, G. Liu, S. Kamel-Reid, D. Hwang, J. Tanguay, G. da Cunha Santos, N.B. Leighl
Journal: Annals of Oncology (2015)
Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy
Authors: Hubing Shi, Willy Hugo, Xiangju Kong, Aayoung Hong, Richard C. Koya, Gatien Moriceau, Thinle Chodon, Rongqing Guo, Douglas B. Johnson, Kimberly B. Dahlman, Mark C. Kelley, Richard F. Kefford, Bartosz Chmielowski, John A. Glaspy, Jeffrey A. Sosman, Nicolas van Baren, Georgina V. Long, Antoni Ribas, Roger S. Lo
Journal: Cancer Discovery (2013)

Abstract BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAFV600-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K–PTEN–AKT–upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses. Significance: This study provides critical insights into how human BRAF-mutant melanoma, a malignancy with marked mutational burden, escapes from BRAF inhibitors. Understanding the core resistance pathways as well as tumor heterogeneity, fitness, and mutational patterns, which emerge under drug selection, lays a foundation to rationalize clinical studies and investigate mechanisms of disease progression. Cancer Discov; 4(1); 80–93. ©2013 AACR. See related commentary by Solit and Rosen, p. 27 This article is highlighted in the In This Issue feature, p. 1
Role of Sodium-Glucose Cotransporter 2 (SGLT 2) Inhibitors in the Treatment of Type 2 Diabetes
Authors: Muhammad A. Abdul-Ghani, Luke Norton, Ralph A. DeFronzo
Journal: Endocrine Reviews (2011)

Hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus, i.e., glucotoxicity, and it also is the major risk factor for microvascular complications. Thus, effective glycemic control will not only reduce the incidence of microvascular complications but also correct some of the metabolic abnormalities that contribute to the progression of the disease. Achieving durable tight glycemic control is challenging because of progressive β-cell failure and is hampered by increased frequency of side effects, e.g., hypoglycemia and weight gain. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to produce glucosuria and reduce the plasma glucose concentration. These oral antidiabetic agents have the potential to improve glycemic control while avoiding hypoglycemia, to correct the glucotoxicity, and to promote weight loss. In this review, we will summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic therapeutic approach.
ACUTE INVERSION OF THE UTERUS FOLLOWING LABOUR ON TWO OCCASIONS
Authors: N. S. Carruthers
Journal: BMJ (1915)

Gram-negative diplococei iin eacli loopful examinie(l.Sub- cultures were made from these brotlh tubes.The blood broth appeared to be sterile.Lumbar punceture was repeated and furtther inoculatioiis made.Microscopically the cerebro-spiinal fluidl showed no micro-organisms.On March 24th the subinoculations from the two ascitic glucose litmus broth tubes of Marel 20th, wlhichl onl Marchl 22nd contained Gram-niegative diplococci, had not grovn ; pre- sumably the broth growthl had died or metamorphiosed before the subinoculations were made.The nalsgar plates inioculated from freslh cerebro-spinal fluid on March 20tll showed a typical growth, afterwards verified, of the nieningococcus of Weich- selbaum, and microscopically films from the blood brotlh of March 21st showed a Gram-nerative diplococcus.Subculttures lrom this blood broth were ma(de.Onl Marlch 26th the subcultures from the bloodI brotlh of M,arch 21st onily slhowed eleveln verv mintlute coloniies on the two slopes, and were returned to tlhe inctubator, and(l freslh sub- cultures made from the blood broth of March 21st.On March 27tlh the eleveni minute colonies of tlhe previous ,day had scarcely inereased in size at all, but the slopes freshly inoculated from the blood sowni ini ascitic broth, wlliclh hla(l then lhad five days' inicubatioIn, showed a thini, apparently homogeneous, greyish translucent film of growtlh, whichl, examiinedl vith a pocket lenis, appeared puncietate, an(l, with a -low power of the microscope, as myriads of small colonies, some round, some oval, and all of fairly regular outlinie, moist anid coalescing when touched by platinium wire, adld emfilsifv- ijg very readily.Slide films preparedl from thjese, stained by Gram and counter-stainied with Bismarck brown, were very
Evidence b(i)ased medicine--selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications
Authors: H. Melander
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objectives</b> To investigate the relative impact on publication bias caused by multiple publication, selective publication, and selective reporting in studies sponsored by pharmaceutical companies. <b>Design</b> 42 placebo controlled studies of five selective serotonin reuptake inhibitors submitted to the Swedish drug regulatory authority as a basis for marketing approval for treating major depression were compared with the studies actually published (between 1983 and 1999). <b>Results</b> Multiple publication: 21 studies contributed to at least two publications each, and three studies contributed to five publications. Selective publication: studies showing significant effects of drug were published as stand alone publications more often than studies with non-significant results. Selective reporting: many publications ignored the results of intention to treat analyses and reported the more favourable per protocol analyses only. <b>Conclusions</b> The degree of multiple publication, selective publication, and selective reporting differed between products. Thus, any attempt to recommend a specific selective serotonin reuptake inhibitor from the publicly available data only is likely to be based on biased evidence.
Protein intake, chronic liver diseases, and hepatocellular carcinoma
Authors: Manlio Vinciguerra
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the article by Li et al.1 in which the authors demonstrate, using two different dietary indices, the Healthy Eating Index‐2010 (HEI‐2010) and the alternate Mediterranean Diet Score (aMED), that healthy eating is associated with lower risk of chronic liver disease (CLD) mortality and lower risk of hepatocellular carcinoma (HCC) incidence, in a prospective cohort of about half a million Americans. The role of diet in the insurgence of CLD and HCC is quite controversial. For instance, oleic acid, a major component of olive oil and a key ingredient of the Mediterranean diet, although it ameliorates fatty liver disease,2 paradoxically increases HCC metastasis in experimental models.3 The analysis of Li et al. to assess the role of individual dietary components positively or negatively associated with CLD and/or HCC uncovered that whole grains, dairy, vegetables, and nuts are inversely associated with deaths from CLD and with HCC using either HEI‐2010 or aMED scores1; moreover, a surprising positive association between fruit consumption, CLD, and HCC was found.1 Although these findings are very impactful, because they show that adhering to dietary recommendations may reduce the risk of developing HCC and dying of CLD, there is an important aspect to be stressed. A recent high‐profile study by Levine et al.4 showed that low protein intake, in particular the one of animal proteins (including dairy), is associated with a major reduction in all causes, cancer, diabetes, and overall mortality in the <65 years old population of 6,381 adults from NHANES III, a U.S. representative, cross‐sectional study. Despite the smaller sample size, these association data were robustly significant and received large media attention. Li et al. report conversely that total protein consumption, and even red and processed meat in the aMED score, are associated with lower HCC incidence and CLD mortality.1 It would be crucial for public health guidelines to understand and to discuss the cause of this epidemiological studies discrepancy on the role of (animal) protein intake in protecting from liver diseases on the one hand, and favoring all causes and cancer mortality on the other.
Blockade of Wnt/β-Catenin Signaling by Paricalcitol Ameliorates Proteinuria and Kidney Injury
Authors: Weichun He, Young Sun Kang, Chunsun Dai, Youhua Liu
Journal: Journal of the American Society of Nephrology (2010)

Recent studies implicate Wnt/β-catenin signaling in podocyte dysfunction. Because vitamin D analogs can inhibit β-catenin in other tissues, we tested whether the vitamin D analog paricalcitol could ameliorate podocyte injury, proteinuria, and renal fibrosis in adriamycin (ADR) nephropathy. Compared with vehicle-treated controls, paricalcitol preserved expression of nephrin, podocin, and WT1; prevented proteinuria; and reduced glomerulosclerotic lesions induced by ADR. Paricalcitol also inhibited expression of proinflammatory cytokines, reduced renal infiltration of monocytes/macrophages, hampered activation of renal myofibroblasts, and suppressed expression of the fibrogenic TGF-β1, CTGF, fibronectin, and types I and III collagen. Selective suppression of renal Wnt4, Wnt7a, Wnt7b, and Wnt10a expression after ADR accompanied these renoprotective effects of paricalcitol. Significant upregulation of β-catenin, predominantly in podocytes and tubular epithelial cells, accompanied renal injury; paricalcitol largely abolished this induction of renal β-catenin and inhibited renal expression of Snail, a downstream effector of Wnt/β-catenin signaling. Administration of paricalcitol also ameliorated established proteinuria. In vitro, paricalcitol induced a physical interaction between the vitamin D receptor and β-catenin in podocytes, which led to suppression of β-catenin–mediated gene transcription. In summary, these findings suggest that paricalcitol prevents podocyte dysfunction, proteinuria, and kidney injury in adriamycin nephropathy by inhibiting Wnt/β-catenin signaling.
Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells
Authors: Zizhen Kang, Chenhui Wang, Jarod Zepp, Ling Wu, Kevin Sun, Junjie Zhao, Unni Chandrasekharan, Paul E DiCorleto, Bruce D Trapp, Richard M Ransohoff, Xiaoxia Li
Journal: Nature Neuroscience (2013)
Differential responses of monolayer and differentiated airway epithelial cell cultures to NTHi infection
Authors: Kirsty Wilson, Lynne Bingle, Colin Bingle, Mark Everard
Journal: European Respiratory Journal (2012)

The innate defence functions of the lung require a patent airway epithelium and infections are often associated with epithelial defects and phenotypic alterations. Non-typeable Haemophilus influenzae (NTHi) one of the first bacterial species to infect children, reduces innate defences, allowing further colonisation with other pathogens, including RSV. We have established NTHi infections of lung derived cell lines and primary airway cells in differentiated cultures prior to the establishment of secondary infections with RSV as a model for paediatric RSV infection. A549, H292 and primary airway epithelial cells were grown in monolayer cultures in transwell inserts. Differentiated cultures of tracheobronchial epithelial (TBE) cells were grown at the ALI using established methods. The apical compartments of established cultures were infected with increasing doses of GFP tagged NTHi and followed for up to 7 days. Infection and cell viability was determined using confocal microscopy and bacterial counts at each time point. A549 and H292 cells, and undifferentiated primary cells became heavily infected and by day 7 almost complete loss of cells was associated with a loss of viable bacteria. Cytokine array studies showed that these cultures mounted limited cytokine responses. The ALI TBE cell cultures had an enhanced ability to overcome the same bacterial infections and this was associated with a marked cytokine response. This data suggests that differentiated epithelial cell cultures have an enhanced ability to overcome bacterial infection compared to monolayer cultures of epithelial cells. This is likely due to the innate defensive shield secreted from these complex cultures.
ATR Inhibition Broadly Sensitizes Ovarian Cancer Cells to Chemotherapy Independent of BRCA Status
Authors: Catherine J. Huntoon, Karen S. Flatten, Andrea E. Wahner Hendrickson, Amelia M. Huehls, Shari L. Sutor, Scott H. Kaufmann, Larry M. Karnitz
Journal: Cancer Research (2013)

Replication stress and DNA damage activate the ATR-Chk1 checkpoint signaling pathway that licenses repair and cell survival processes. In this study, we examined the respective roles of the ATR and Chk1 kinases in ovarian cancer cells using genetic and pharmacologic inhibitors in combination with cisplatin, topotecan, gemcitabine, and the PARP inhibitor veliparib (ABT-888), four agents with clinical activity in ovarian cancer. RNA interference (RNAi)-mediated depletion or inhibition of ATR sensitized ovarian cancer cells to all four agents. In contrast, while cisplatin, topotecan, and gemcitabine each activated Chk1, RNAi-mediated depletion or inhibition of this kinase in cells sensitized them only to gemcitabine. Unexpectedly, we found that neither the ATR kinase inhibitor VE-821 nor the Chk1 inhibitor MK-8776 blocked ATR-mediated Chk1 phosphorylation or autophosphorylation, two commonly used readouts for inhibition of the ATR-Chk1 pathway. Instead, their ability to sensitize cells correlated with enhanced CDC25A levels. In addition, we also found that VE-821 could further sensitize BRCA1-depleted cells to cisplatin, topotecan, and veliparib beyond the potent sensitization already caused by their deficiency in homologous recombination. Taken together, our results established that ATR and Chk1 inhibitors differentially sensitize ovarian cancer cells to commonly used chemotherapy agents and that Chk1 phosphorylation status may not offer a reliable marker for inhibition of the ATR-Chk1 pathway. A key implication of our work is the clinical rationale it provides to evaluate ATR inhibitors in combination with PARP inhibitors in BRCA1/2-deficient cells.
Pulmonary immune cells in health and disease: mast cells and basophils
Authors: JA Warner, C Kroegel
Journal: European Respiratory Journal (1994)

Mast cells and basophils are multifunctional immune cells and have been implicated in the pathogenesis of asthma and other pulmonary diseases. Although they are derived from distinct lineages, they share a number of important features which justifies discussing them collectively. This review covers the cellular characteristics and biological properties of both cell types, including origin, maturation and differentiation, morphological and phenotypical properties, as well as their capacity to secrete preformed and newly generated mediators of inflammation. In addition, the mechanisms of cell activation and priming of mast cells and basophils will be outlined, as well as the putative mechanisms through which both cell types communicate with other inflammatory cells. The final section of the review focuses on the possible pathogenetic role of mast cells and basophils in several pulmonary diseases, such as parasitic infections, allergic diseases, pulmonary fibrosis and malignant disorders.