tbuckley/cabot-search huggingface dataset:
Sex Difference in Myelodysplastic Syndrome Survival and Balance in Randomized Clinical Trials
Authors: Tomas Radivoyevitch, Yogen Saunthararajah
Journal: Journal of Clinical Oncology (2013)

TO THE EDITOR: In a worthwhile effort to explore alternative regimens of the deoxycytidine analog decitabine to treat lowor intermediate-1–risk myelodysplastic syndromes (MDSs), GarciaManero et al compared two low-dose subcutaneous regimens in a randomized phase II trial. However, the efficacy and safety populations were not identical in a pertinent, but not discussed, regard: there was a significant imbalance in sex distribution between the treatment arms (arm A women, 18 of 43 [42%]; arm B women, 2 of 22 [9%]; Fisher’s exact test P .0096). Multiple reports from individual institutions have described substantial and significantly better overall survival of women with MDS, a highly significant difference (log-rank P .001) that is also evident in the SEER database (Fig 1A). Furthermore, the analyses that generated the International Prognostic Scoring System in MDSs demonstrated a significant role of sex in predicting clinical outcome, even in multivariable analyses that incorporated the standard components of the International Prognostic Scoring System (myeloblast percentage, cytogenetics, cytopenias; P .001). The largest impact on survival seemed to be in low-risk MDS categories, an impression that was also supported by the SEER data, in which the clear sex dichotomy in MDS survival contrasts with similar survival (log-rank P .051) in men and women with acute myeloid leukemia (Fig 1B). The reasons for sex differences in overall survival in MDSs (or in other cancers such as liver cancer) are incompletely understood. Male sex is associated with faster molecular aging as measured by telomere length or DNA methylation profiles. Therefore, one possibility is that faster cellular/molecular aging in men simultaneously increases probabilities for abnormal genetic or epigenetic programs and decreases the number of normal cells that can compete with or compensate for abnormal cells. Another contributing factor, in the context of patients with MDSs who are treated with cytidine analogs such as decitabine or 5-azacytidine, is a sex difference in the expression of the enzyme cytidine deaminase, which is the major determinant of the plasma half-lives of these drugs: cytidine deaminase expression is significantly higher in male compared to female liver, in both mice and humans, and consequently, produces shorter decitabine half-lives in men. Shorter decitabine half-lives, especially with low-dose regimens wherein drug exposure time may already be close to the minimal thresholds required for efficacy, may negatively affect treatment outcomes in men. In short, sex is a significant determinant of MDS clinical outcomes and should be balanced in randomized clinical trials to avoid confounded interpretation and conclusions.
Rapid Changes in Postprandial Blood Glucose Produce Concentration Differences at Finger, Forearm, and Thigh Sampling Sites
Authors: John M. Ellison, Janet M. Stegmann, Sandra L. Colner, Ragui H. Michael, Manoj K. Sharma, Kenneth R. Ervin, David L. Horwitz
Journal: Diabetes Care (2002)

OBJECTIVE—To compare pre- and postmeal capillary blood glucose concentrations measured at the finger, forearm, and thigh in adults with diabetes. RESEARCH DESIGN AND METHODS—For phase 1, capillary blood glucose concentrations were measured at six time points (premeal and at ∼60, 90, 120, 150, and 180 min postmeal) using a blood glucose monitoring system and technician-obtained samples collected from finger, forearm, and thigh sites of 42 adults with diabetes. The finger samples were also tested with a laboratory instrument. For phase 2, ∼14 weeks later, the testing procedures were repeated with 38 subjects from the original study population. RESULTS—Meter finger results were accurate at all time points. Alternate sites tended to produce lower glucose readings compared to finger readings at times when glucose was increasing rapidly (60 and 90 min postmeal). Forearm-to-finger differences correlated with rates of glucose change (r = 0.56, P &amp;lt; 0.001), as did the thigh-to-finger differences (r = 0.52, P &amp;lt; 0.001). Other factors, such as subject age, BMI, diabetes type, and insulin dependence did not have a significant impact on site differences. When the testing procedures were repeated with the same subjects, the pattern of site differences was consistent, although individual results were variable. CONCLUSIONS—Changes in blood glucose immediately after a meal may be identified at finger sites before detection at forearm or thigh sites. Alternate site testing appears to be a useful option for routine self-monitoring before meals; however, patients and clinicians should recognize that results may be different from fingertip results when glucose levels are changing rapidly.
Effects of dietary calcium and phosphate on the intestinal interactions between calcium, phosphate, fatty acids, and bile acids.
Authors: M J Govers, R Van der Meet
Journal: Gut (1993)

Luminal free fatty acids and bile acids may damage the colonic epithelium and stimulate proliferation, which may increase the risk of colon cancer. It has been suggested that only soluble calcium ions (Ca2+) precipitate fatty acids and bile acids, thus reducing their lytic activity. Consequently, precipitation of luminal Ca2+ by dietary phosphate should inhibit these effects. To evaluate the proposed antagonistic effects of dietary calcium and phosphate, we studied the intestinal interactions between calcium, phosphate, fatty acids, and bile acids in rats fed purified diets that differed only in the concentrations of calcium and phosphate. Increased dietary calcium drastically decreased the solubility of fatty acids in the ileum, colon, and faeces, as well as the solubility of bile acids in the colon and faeces. Although dietary calcium strongly increased the total faecal fatty acid concentration and hardly affected the total faecal bile acid concentration, the fatty acid and bile acid concentrations in faecal water were drastically decreased by dietary calcium. Consequently, the lytic activity of faecal water was decreased. Dietary phosphate did not interfere with these intestinal effects of calcium. These results indicate that dietary phosphate does not inhibit the protective effects of dietary calcium on luminal solubility and the lytic activity of fatty and bile acids.
Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension
Authors: V. Mainguy, F. Maltais, D. Saey, P. Gagnon, S. Martel, M. Simon, S. Provencher
Journal: Thorax (2009)

<h3>Background</h3> A majority of patients with idiopathic pulmonary arterial hypertension (IPAH) display persistent exercise intolerance despite new specific therapies. Whether patients with IPAH exhibit peripheral muscle dysfunction that may contribute to this limitation remains unknown. The hypothesis that the muscles of patients with IPAH are weaker and display morphological changes compared with those of control subjects and that those changes partly correlate with their exercise capacity was tested. <h3>Objective</h3> To characterise quadriceps function, morphology and the enzymatic profile of patients with IPAH. <h3>Methods</h3> Exercise capacity, limb muscle cross-sectional area by CT scan, quadriceps strength by maximal voluntary contraction and non-volitional magnetic stimulation of the femoral nerve (quadriceps twitch; TWq), and muscle morphology and enzymatic profile by quadriceps biopsy of 10 patients with IPAH were compared with those of 10 matched controls subjects. <h3>Results</h3> Patients with IPAH displayed a lower proportion of type I muscle fibres (p=0.05), a lower maximal voluntary contraction (p=0.05) and TWq (p=0.01), and an increased muscular phosphofructokinase/3-hydroxyacyl-CoA-dehydrogenase ratio (p=0.05). They also tended to have lower thigh muscle cross-sectional area (p=0.15). Maximal oxygen uptake correlated with quadriceps strength (R<sup>2</sup>=0.42, p=0.04), and oxygen uptake at anaerobic threshold correlated with muscle oxidative capacity assessed by oxidative enzyme level for citrate synthase (R<sup>2</sup>=0.45, p=0.05) and 3-hydroxyacyl-CoA-dehydrogenase (R<sup>2</sup>=0.86, p&lt;0.01), and type I fibre capillarity (R<sup>2</sup>=0.57, p=0.02). <h3>Conclusion</h3> Patients with IPAH present significant peripheral muscle changes that partly correlated with their exercise capacity.
Measuring the Performance of Markers for Guiding Treatment Decisions
Authors: Holly Janes, Margaret S. Pepe, Patrick M. Bossuyt, William E. Barlow
Journal: Annals of Internal Medicine (2011)

Treatment selection markers, sometimes called predictive markers, are factors that help clinicians select therapies that maximize good outcomes and minimize adverse outcomes for patients. Existing statistical methods for evaluating a treatment selection marker include assessing its prognostic value, evaluating treatment effects in patients with a restricted range of marker values, and testing for a statistical interaction between marker value and treatment. These methods are inadequate, because they give misleading measures of performance that do not answer key clinical questions about how the marker might help patients choose treatment, how treatment decisions should be made on the basis of a continuous marker measurement, what effect using the marker to select treatment would have on the population, or what proportion of patients would have treatment changes on the basis of marker measurement. Marker-by-treatment predictiveness curves are proposed as a more useful aid to answering these clinically relevant questions, because they illustrate treatment effects as a function of marker value, outcomes when using or not using the marker to select treatment, and the proportion of patients for whom treatment recommendations change after marker measurement. Randomized therapeutic clinical trials, in which entry criteria and treatment regimens are not restricted by the marker, are also proposed as the basis for constructing the curves and evaluating and comparing markers.
Ca <sup>2+</sup> Control of Transcription
Authors: Gerrit Isenberg
Journal: Circulation Research (2004)

he Ca 2ϩ hypothesis of transcription suggests that increments in the cytosolic Ca 2ϩ concentration [Ca 2ϩ ] c can activate transcription.4][5] The article by Pulver et al in this issue 6 demonstrates a close correlation between the increase in [Ca 2ϩ ] c , phosphorylation of nuclear CREB, and the expression of c-fos.Pulver et al introduce the idea that transcriptional activation may be regulated by store-operated Ca 2ϩ entry (SOCE) 7-9 as it is activated when thapsigargin blocks the Ca 2ϩ -ATPase SERCA, thereby depleting the SR Ca 2ϩ content.The authors demonstrate this thapsigargin effect not only in cultured VSMC but also in VSMC of intact arteries.They conclude that SOCE may activate transcription and may therefore control the differentiated (contractile) or proliferative (secretory) phenotype of VSMC. 10 Ca 2؉ -Mediated Phosphorylation of CREBThe Ca 2ϩ /cAMP response element binding protein CREB is a transcription factor. 11CREB transcriptional activation occurs through its binding to the CREB-binding protein, CBP, a co-activator protein that links to many factors of the general transcriptional machinery.Phosphorylation of CREB at Ser-133 increases its affinity for CBP, and it can be observed with phospho-specific antibodies.CREB can be phosphorylated not only at SER-133 but also at S-142.Phosphorylation is mediated by a variety of kinases, with the cAMP/PKA pathway often being the principal modulator. 12In the case of Ca 2ϩ -dependent activation, CREB phosphorylation is thought to result from the following signaling cascade: 13 Ca 2ϩ binds to calmodulin, Ca 2ϩ /CaM enters the nucleus and activates calmodulin-dependent kinase IV (CaMKIV), with Ca 2ϩ / CaMKIV phosphorylating CREB.In addition, Ca 2ϩ /CaM activates CaMKIV kinases that substantially enhance Ca 2ϩ / CaMKIV activity.Further, Ca 2ϩ /CaMKIV can regulate CREB binding protein by direct phosphorylation. 13
Diabetes Mellitus, Prediabetes, and Incidence of Subclinical Myocardial Damage
Authors: Elizabeth Selvin, Mariana Lazo, Yuan Chen, Lu Shen, Jonathan Rubin, John W. McEvoy, Ron C. Hoogeveen, A. Richey Sharrett, Christie M. Ballantyne, Josef Coresh
Journal: Circulation (2014)

Background— Persons with prediabetes and diabetes mellitus are at high risk for cardiovascular events. However, the relationships of prediabetes and diabetes mellitus to the development of subclinical myocardial damage are unclear. Methods and Results— We measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at 2 time points, 6 years apart, among 9051 participants of the community-based Atherosclerosis Risk in Communities Study with no diabetes mellitus, or prediabetes, and without cardiovascular disease including silent myocardial infarction by ECG. First, we examined the incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ≈14 years of follow-up among persons with and without incident elevations in hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes mellitus, prediabetes, and diabetes mellitus were 3.7%, 6.4%, and 10.8%, respectively. Compared with normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.40 (95% CI, 1.08–1.80) for prediabetes and 2.47 (95% CI, 1.78–3.43) for diabetes mellitus. Persons with diabetes mellitus and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (hazard ratio, 6.37 [95% CI, 4.27–9.51]), death (hazard ratio, 4.36 [95% CI, 3.14–6.07]), and coronary heart disease (hazard ratio, 3.84 [95% CI, 2.52–5.84]) compared with persons without diabetes mellitus and no incident elevation in hs-cTnT. Conclusions— Prediabetes and diabetes mellitus were independently associated with the development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular cause.
Medical outcome after immediate computed tomography or admission for observation in patients with mild head injury: randomised controlled trial
Authors: Jean-Luc af Geijerstam, Sven Oredsson, Mona Britton
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To compare immediate computed tomography during triage for admission with observation in hospital in patients with mild head injury. <b>Design</b> Multicentre, pragmatic, non-inferiority randomised trial. <b>Setting</b> 39 acute hospitals in Sweden. <b>Participants</b> 2602 patients (aged ≥ 6) with mild head injury. <b>Interventions</b> Immediate computed tomography or admission for observation. <b>Main outcome measure</b> Dichotomised extended Glasgow outcome scale (1-7 <i>v</i> 8). The non-inferiority margin was 5 percentage points. <b>Results</b> At three months, 275 patients (21.4%) in the computed tomography group had not recovered completely compared with 300 (24.2%) admitted for observation. The difference was - 2.8 percentage points, non-significantly in favour of computed tomography (95% confidence interval - 6.1% to 0.6%). The worst outcomes (mortality and more severe loss of function) were similar between the groups. In the patients admitted for observation, there was a considerable delay in time to treatment in those who required surgery. None of the patients with normal findings on immediate computed tomography had complications later. Patients9 satisfaction with the two strategies was similar. <b>Conclusions</b> The use of computed tomography in the management of patients with mild head injury is feasible and leads to similar clinical outcomes compared with observation in hospital. <b>Trial registration</b>ISRCTN81464462[controlled-trials.com].
Lymphangioleiomyomatosis: the pathophysiology of diminished exercise capacity.
Authors: R S Crausman, C A Jennings, R L Mortenson, L M Ackerson, C G Irvin, T E King
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Dyspnea with exertion is nearly always present in patients with pulmonary lymphangioleiomyomatosis, but the mechanisms underlying exercise impairment have not been well defined. Spirometry, lung volumes, lung mechanics, and exercise physiology were performed on a cohort of 16 patients. We determined the relative contribution of airflow limitation, gas exchange abnormalities, and pulmonary vascular abnormalities to the exercise performance achieved. The patients had normal TLC and Vtg, but RV was elevated in 88% of the subjects. A moderate to severe obstructive pattern was present in 69% of the subjects, and the DLCO was reduced, often markedly, in 81% of the subjects. Exercise performance was limited (work load, 68% +/- 6) with abnormalities of ventilatory function and gas exchange present. Strong correlations between overall exercise performance (percent predicted VO2max and maximal work load achieved) and indices of airflow and vascular involvement were present. Poor exercise performance was due primarily to ventilatory limitation. The etiology of this ventilatory limitation appears twofold. First, subjects had a reduced ventilatory ceiling because of airflow limitation. Second, subjects demonstrated an excessive ventilatory response as a result of increased dead-space ventilation thought to be due to disease-associated cystic changes and associated pulmonary vascular dysfunction or destruction.
Decreased Neurotrophin TrkB Receptor Expression Reduces Lesion Size in the Apolipoprotein E–Null Mutant Mouse
Authors: Rosemary Kraemer, Peter James Baker, K. Craig Kent, Yuanfen Ye, Jun Ji Han, Rafael Tejada, Michael Silane, Rita Upmacis, Ruba Deeb, Yaoxin Chen, Daniel M. Levine, Barbara Hempstead
Journal: Circulation (2005)

Accumulation of macrophages and smooth muscle cells in the vascular wall is critical for the development of atherosclerotic lesions. Although much is known about the factors that regulate macrophage recruitment to the vascular wall, the ability of growth factors to regulate smooth muscle cell recruitment in lesion development in vivo is unclear. Our previous studies demonstrated that neurotrophins and their receptors, the Trk receptor tyrosine kinases, are potent chemotactic factors for smooth muscle cells, and the expression of brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, is upregulated in human atherosclerotic lesions.TrkB(+/-) mice on a 129/B6 background were backcrossed to apolipoprotein E (ApoE)-null (ApoE(-/-)) mice on the C57Bl/6 background for 6 to 8 generations. Immunohistochemical analysis demonstrated BDNF immunoreactivity in areas of macrophage and smooth muscle cell infiltration, whereas TrkB immunoreactivity was predominant in areas of neointimal smooth muscle cells. Moreover, haplodeficient expression of TrkB in ApoE(-/-) mice was associated with a 30% to 40% reduction in lesion size compared with ApoE(-/-) mice with normal expression of TrkB and a 45% decrease in smooth muscle cell accumulation in the lesions. Finally, reconstitution with bone marrow from ApoE(-/-) mice with normal TrkB expression did not restore lesion development in TrKB(+/-)/ApoE(-/-) mice.These results suggest that TrkB expression on smooth muscle cells contributes to lesion development in the cholesterol-fed ApoE-null mutant mouse. These data demonstrate, for the first time, a role for the neurotrophin TrkB receptor in atherosclerotic lesion development.
A Behavioral Approach to the Treatment of Stuttering
Authors: JOHN PAUL BRADY
Journal: American Journal of Psychiatry (1968)

A behavioral analysis of the disorder of stuttering is presented. The author outlines a program of treatment for severe adult stutterers which is based partly on this behavioral analysis and partly on empirical observations about means of influencing the frequency and severity of stuttering. The treatment involves the use of a miniaturized electronic metronome which is worn behind the ear like the hearing aid it resembles.
Alcoholic drinks and skin cancer - boozing on the beach and beyond
Authors: J.C. van der Pols
Journal: British Journal of Dermatology (2014)

Journal Article Alcoholic drinks and skin cancer – boozing on the beach and beyond Get access J.C. van der Pols J.C. van der Pols School of Population Health The University of Queensland Herston Road Herston QLD 4006 Australia Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 171, Issue 6, 1 December 2014, Pages 1295–1296, https://doi.org/10.1111/bjd.13456 Published: 01 December 2014
Phase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1
Authors: Charles L. Loprinzi, Rui Qin, Ernie P. Baclueva, Kathleen A. Flynn, Kendrith M. Rowland, David L. Graham, Nancy K. Erwin, Shaker R. Dakhil, Donald J. Jurgens, Kelli N. Burger
Journal: Journal of Clinical Oncology (2009)

Hot flashes are a common problem for which effective and safe treatments are needed. The current trial was conducted on the basis of preliminary promising data that pregabalin decreased hot flashes.A double-blind, placebo-controlled, randomized trial design was used to compare pregabalin at target doses of 75 mg twice daily and 150 mg twice daily with a placebo. Hot flash frequencies and scores (frequency times mean severity) were recorded daily during a baseline week and for six treatment weeks. The primary end point for this study was the change-from-baseline hot flash score during treatment week 6 between the 150 mg twice daily target pregabalin treatment and placebo. Nonparametric Wilcoxon rank sum tests, two-sample t tests, and chi(2) tests were used to compare the primary and secondary hot flash efficacy end points between pregabalin treatments and placebo.Hot flash score changes available for 163 patients during the sixth treatment week compared with a baseline week decreased by 50%, 65%, and 71% in the placebo, and target 75 mg twice daily and 150 mg twice daily pregabalin arms, respectively (P = .009 and P = .007, comparing respective pregabalin arms to the placebo arm). While some toxicities were significantly more common in the pregabalin arms, being more evident with the higher dose, pregabalin was generally well tolerated by most patients.Pregabalin decreases hot flashes and is reasonably well tolerated. A target dose of 75 mg twice daily is recommended. Its effects appear to be roughly comparable to what has been reported with gabapentin and with some newer antidepressants.