tbuckley/cabot-search huggingface dataset:
7th Inning Stretch
Authors: Mayer B. Davidson
Journal: Diabetes Care (2005)

First, I should explain what the “7th inning stretch” is to the many readers who may not be familiar with American baseball. In each inning in baseball, both teams come to bat and are allowed three outs (the definition of an “out” is not important here). Each baseball game consists of nine innings (unless there is a tie at the end of nine innings, but again this is not important for this editorial). At the beginning of the 7th inning, it is custom for the fans watching the game to stand up and stretch. In keeping with my custom of sharing the status of the journal with the readership from time to time (usually in the January issue), this is our 7th inning stretch. The Associate Editors and I initially agreed to serve for 3 years with an “option to renew” for 2 more years (if the American Diabetes Association [ADA] so wishes). We all renewed with the exception of Mark Peyrot, PhD, who had served 2 years with the previous editorial team as well as 3 years with us and certainly deserved a rest, and Richard Rubin, PhD, who has just started as the Vice President, Health Care and Education, of the ADA and will have many new responsibilities. I thank both of them for their outstanding contributions to keep the journal in the forefront of psychosocial research in diabetes. Thus, the current editorial team has completed 3 of 5 years (not quite six of nine innings, but close enough).

The best news to share with you is that the impact factor for Diabetes Care has greatly increased from 5.477 in 2002 to 7.501 in 2003. The impact factor is a measure of the frequency with which the “average” article in a journal …
Passive smoking and asthma exacerbation
Authors: J Britton
Journal: Thorax (2005)

Further evidence to advance the public, political, and legal process towards effective public protection from the effects of passive and active smoking

Cigarette smoke is a toxic mixture containing around 4000 different chemicals including a range of carcinogens, irritants, and toxins.1 It is therefore no surprise that inhaling cigarette smoke, either actively as a cigarette smoker or passively through exposure to exhaled and sidestream smoke from other smokers, is bad for health.1 In fact, active smoking kills more people in economically developed countries than any other preventable cause, and currently accounts for over 100 000 deaths (or about 20% of all deaths) each year in the UK.2 Worldwide the annual death total is currently close to 5 million.3 Passive smoking is also a major problem, causing at least 12 000 deaths each year in the UK,4 or about 2% of the current annual total, and probably a similar proportion in other developed countries. On these figures alone it should be clear that we have sufficient evidence to conclude that preventing exposure to cigarette smoke, either active or passive, should be a fundamental priority of all clinical and public health practice. We already know what the main health effects of smoking are, or in relation to passive smoking, are likely to be. So do we need more research defining …
Tumor Burden Modeling Versus Progression-Free Survival for Phase II Decision Making
Authors: Lee D. Kaiser
Journal: Clinical Cancer Research (2012)

Randomized Phase II oncology trial endpoints for decision making include both progression-free survival (PFS) and change in tumor burden as measured by the sum of longest diameters (SLD) of the target lesions. In addition to observed SLD changes, tumor shrinkage and growth parameters can be estimated from the patient-specific SLD profile over time. The ability of these SLD analyses to identify an active drug is contrasted with that of a PFS analysis through the simulation of Phase II trials via resampling from each of 6 large, Phase II and III trials, 5 of which were positive and one negative. From each simulated Phase II trial, a P value was obtained from 4 analyses-a log-rank test on PFS, a Wilcoxon rank-sum test on the minimum observed percentage change from baseline in SLD, and 2 nonlinear, mixed-effects model analyses of the SLD profiles. All 4 analyses led to approximately uniformly distributed P values in the negative trial. The PFS analysis was the best or nearly the best analysis in the other 5 trials. In only one of the positive studies did the modeling analysis outperform the analysis of the minimum SLD. In conclusion, for the decision to start a Phase III trial based on the results of a randomized Phase II trial of an oncology drug, PFS appears to be a better endpoint than does SLD, whether analyzed through simple SLD endpoints, such as the minimum percentage change from baseline, or through the modeling of the SLD time course to estimate tumor dynamics.
mtDNA Lineage Expansions in Sherpa Population Suggest Adaptive Evolution in Tibetan Highlands
Authors: Longli Kang, Hong-Xiang Zheng, Feng Chen, Shi Yan, Kai Liu, Zhendong Qin, Lijun Liu, Zhipeng Zhao, Lei Li, Xiaofeng Wang, Yungang He, Li Jin
Journal: Molecular Biology and Evolution (2013)

Sherpa population is an ethnic group living in south mountainside of Himalayas for hundreds of years. They are famous as extraordinary mountaineers and guides, considered as a good example for successful adaptation to low oxygen environment in Tibetan highlands. Mitochondrial DNA (mtDNA) variations might be important in the highland adaption given its role in coding core subunits of oxidative phosphorylation in mitochondria. In this study, we sequenced the complete mtDNA genomes of 76 unrelated Sherpa individuals. Generally, Sherpa mtDNA haplogroup constitution was close to Tibetan populations. However, we found three lineage expansions in Sherpas, two of which (C4a3b1 and A4e3a) were Sherpa-specific. Both lineage expansions might begin within the past hundreds of years. Especially, nine individuals carry identical Haplogroup C4a3b1. According to the history of Sherpas and Bayesian skyline plot, we constructed various demographic models and found out that it is unlikely for these lineage expansions to occur in neutral models especially for C4a3b1. Nonsynonymous mutations harbored in C4a3b1 (G3745A) and A4e3a (T4216C) are both ND1 mutants (A147T and Y304H, respectively). Secondary structure predictions showed that G3745A were structurally closing to other pathogenic mutants, whereas T4216C itself was reported as the primary mutation for Leber's hereditary optic neuropathy. Thus, we propose that these mutations had certain effect on Complex I function and might be important in the high altitude adaptation for Sherpa people.
Respiratory mechanics and dust exposure in byssinosis
Authors: A. Bouhuys, K. P. Van de Woestijne
Journal: Journal of Clinical Investigation (1970)

Acute exposures to hemp dust, in healthy subjects as well as hemp workers with byssinosis, resulted in two different responses. Men with symptoms (chest tightness, coughing, and wheezing) after exposure showed decreases of forced expiratory volumes (FEV1.0), flow rates on maximum expiratory flow-volume (MEFV) curves, and of vital capacity (VC), while airway conductance (Gaw: TGV ratio) did not decrease significantly (“flow rate response”). Men without symptoms after exposure showed no changes of VC, FEV1.0, and MEFV curves, but had a significantly decreased airway conductance (“conductance response”). The flow rate response is attributed to a pharmacological bronchoconstrictor effect of hemp dust on small airways, the conductance response to a mechanical or reflex effect of hemp dust on large airways. Both responses were abolished by a bronchodilator drug. The type of response reflects a difference between individuals and is not related to age, smoking habits, or prior exposure history. Men with normal control function data had either a flow rate or a conductance response. All men with abnormal control data had a flow rate response.
ATBF1-A Messenger RNA Expression Is Correlated with Better Prognosis in Breast Cancer
Authors: Zhenhuan Zhang, Hiroko Yamashita, Tatsuya Toyama, Hiroshi Sugiura, Yoshiaki Ando, Keiko Mita, Maho Hamaguchi, Makoto Kawaguchi, Yutaka Miura, Hirotaka Iwase
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The AT motif-binding factor 1 (ATBF1) gene was first identified as a suppressor of the α-fetoprotein (AFP) gene through its binding to an AT-rich enhancer element of this gene. The gene is located at chromosome 16q22.3-q23.1 where loss of heterozygosity has been observed in various malignant tumors, especially in breast cancer. It was also found that in highly malignant AFP-producing gastric cancer cells the expression of AFP is inhibited by ATBF1-A. This led us to hypothesize that there was a link between levels of ATBF1 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients. Experimental Design: In the present study, the level of ATBF1-A mRNA expression was analyzed using quantitative real-time reverse transcriptase-PCR, in 153 female patients with invasive carcinoma of the breast. ATBF1-A protein expression was also determined by immunohistochemistry from available 90 cases of paired tissues. An association was sought between ATBF1-A expression and various clinicopathologic factors. Results: ATBF1-A mRNA was expressed at significantly higher levels in breast cancer patients with no axillary lymph node involvement, with small tumors measuring &amp;lt;2 cm and in estrogen receptor-α–positive tumors. By contrast, no relationship was found between ATBF1-A mRNA expression and ATBF1-A protein expression, and also no relationship was found between ATBF1-A protein expression and any of the other clinicopathologic factors. Patients expressing high levels of ATBF1-A mRNA tended to have a better prognosis than those expressing low levels. Univariate and multivariate prognostic analyses showed that ATBF1-A mRNA expression is an independent prognostic factor for disease-free survival. Conclusions: In breast cancer, levels of ATBF1-A mRNA may serve as a predictive indicator of lymph node metastasis. The results of this study also imply that ATBF1-A gene expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator for breast cancer progression.
Does<i>Helicobacter pylori</i>eradication really reduce the risk of gastric cancer at the population level?
Authors: Zhu Wang, Yang Yu, Wenjuan Yang, Bin Chen, Xiao Li
Journal: Gut (2012)

The development of gastric cancer is related to multiple factors, including gene, diet, environment and Helicobacter pylori infection. The Maastricht IV consensus stated that the eradication of H pylori reduces the risk of gastric cancer development.1 Although the results from epidemiological and animal studies support this statement, no existing human clinical trial has resulted in the same outcome. However, H pylori eradication for gastric cancer prevention is still recommended in the consensus (recommendation level 1C). We believe it may be premature to put forward such a statement based on existing evidence.

To investigate whether enough evidence exists to support H pylori eradication at the population level, we examined the randomised controlled clinical trials (RCTs) referenced in the consensus. The RCT conducted by Wong et al 2 …
Differential requirement for OBF-1 during antibody-secreting cell differentiation
Authors: Lynn M. Corcoran, Jhagvaral Hasbold, Wendy Dietrich, Edwin Hawkins, Axel Kallies, Stephen L. Nutt, David M. Tarlinton, Patrick Matthias, Philip D. Hodgkin
Journal: The Journal of Experimental Medicine (2005)

Resting B cells can be cultured to induce antibody-secreting cell (ASC) differentiation in vitro. A quantitative analysis of cell behavior during such a culture allows the influences of different stimuli and gene products to be measured. The application of this analytical system revealed that the OBF-1 transcriptional coactivator, whose loss impairs antibody production in vivo, has two effects on ASC development. Although OBF-1 represses early T cell–dependent (TD) differentiation, it is also critical for the completion of the final stages of ASC development. Under these conditions, the loss of OBF-1 blocks the genetic program of ASC differentiation so that Blimp-1/prdm1 induction fails, and bcl-6, Pax5, and AID are not repressed as in control ASC. Retroviral complementation confirmed that OBF-1 was the critical entity. Surprisingly, when cells were cultured in lipopolysaccharide to mimic T cell–independent conditions, OBF-1–null B cells differentiated normally to ASC. In the OBF-1−/− ASC generated under either culture regimen, antibody production was normal or only modestly reduced, revealing that Ig genes are not directly dependent on OBF-1 for their expression. The differential requirement for OBF-1 in TD ASC generation was confirmed in vivo. These studies define a new regulatory role for OBF-1 in determining the cell-autonomous capacity of B cells to undergo terminal differentiation in response to different immunological signals.
Age at Onset and the Risk of Proliferative Retinopathy in Type 1 Diabetes
Authors: Kustaa Hletala, Valma Harjutsalo, Carol Forsblom, Paula summanen, Per-Henrik Groop
Journal: Diabetes Care (2010)

OBJECTIVE Age at onset of type 1 diabetes influences the risk of microvascular complications. However, the long-term risk of proliferative retinopathy within the wide spectrum of age at onset of type 1 diabetes is less well known. RESEARCH DESIGN AND METHODS A sample of 1,117 consecutively recruited patients was drawn from the FinnDiane Study population (4,800 patients). Type 1 diabetes was defi ned as age at onset ≤40 years, insulin treatment initiated within 1 year, and C-peptide ≤0.3 nmol/1. Retinopathy status was graded based on ophthalmic records and/or fundus photographs. The risk of proliferative retinopathy was studied in age-at-onset groups 0–4, 5–14, and 15–40 years. RESULTS The mean durations to proliferative retinopathy were 24.3 (22.7–25.9) years in the 0–4 years group, 20.1 (19.2–21.1) years in the 5–14 years group, and 21.6 (19.8–23.3) years in the 15–40 years group (P &amp;lt; 0.001). In a Cox regression model, with A1C, blood pressure, sex, and BMI as covariates, the highest risk of proliferative retinopathy was observed in the 5–14 years group (hazard ratio 1.90 [95% CI 1.45–2.48], P &amp;lt; 0.001). Diabetes onset 0–4 vs. 5–14 years made no difference in the long-term risk of proliferative retinopathy (P = 0.2). When split into two groups, age at onset &amp;lt; 15 years was associated with a higher long-term risk than age at onset &amp;gt;15 years (1.82 [1.40–2.36], P &amp;lt; 0.001). CONCLUSIONS Age at onset significantly modifies the long-term risk of proliferative retinopathy. The highest risk is in age-at-onset group 5–14 years, whereas the lowest risk is in age-at-onset group 15–40 years.
Risk factors for nosocomial Legionella pneumophila pneumonia.
Authors: J Carratala, F Gudiol, R Pallares, J Dorca, R Verdaguer, J Ariza, F Manresa
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Over a 5-yr period, from January 1985 to January 1990, we prospectively studied 300 episodes of nosocomial pneumonia in a 1,000-bed teaching hospital. All cases had an accurate bacteriologic diagnosis obtained by means of highly reliable techniques. Legionella pneumophila caused a total of 36 episodes; 22 were endemic and 14 occurred during an epidemic outbreak. No patient with Legionella pneumonia had been intubated before infection. To identify risk factors for nosocomial L. pneumophila pneumonia, we compared the 22 endemic cases of nosocomial pneumonia due to L. pneumophila with the 264 cases due to other bacteria. After adjusting for other variables by means of logistic regression analysis, cytotoxic chemotherapy (OR = 5.2; 95% CI, 1.5 to 17.9) and use of corticosteroids (OR = 4.6; 95% CI, 1.5 to 14.1) were positively associated with L. pneumophila pneumonia, whereas previous antibiotic therapy (OR = 0.2; 95% CI, 0.1 to 0.8) and lowered consciousness (OR = 0.2; 95% CI, 0.07 to 0.8) were negatively associated. The major risk factors for Legionella pneumonia delineated in this study should be considered in the clinical approach to and empiric therapy of patients with suspected nosocomial pneumonia.
An ill wind
Authors: L. Farrell
Journal: BMJ (1996)

Caring for dying patients is one of the most demanding aspects of general practice, and also one of the most rewarding. A senior colleague likened it to maternity care in his day. “When you delivered a baby in a house,” he said, “that family would trust you forever. Now home births are gone, and caring for the dying is the only way to forge that kind of bond.”

Dying patients can now be kept very comfortable at home, and the palliative care movement, in particular the Macmillan Fund and the sadly defunct Lisa Sainsbury Foundation, must take credit for its zeal in getting its message across. Of course, other less philanthropic …
Fluctuations in the affinity and concentration of insulin receptors on circulating monocytes of obese patients: effects of starvation, refeeding, and dieting.
Authors: R S Bar, P Gorden, J Roth, C R Kahn, P De Meyts
Journal: Journal of Clinical Investigation (1976)

The binding of 125I-insulin to insulin receptors on circulating monocytes of obese patients and normal volunteers has been determined under various dietary states. In the basal, fed state the monocytes of obese patients with clinical insulin resistance (n= 6) bound less insulin than normals (n =10) because of a decrease in insulin receptor concentration (obese = 6,000-13,000 sites per monocyte versus normals 15,000-28,000 sites per monocyte). The single obese patient without evidence of clinical insulin resistance demonstrated normal binding of insulin with 16,000 sites per monocyte. In all patients, the total receptor concentration was inversely related to the circulating levels of insulin measured at rest after an overnight fast. For the obese patients with basally depressed insulin binding, a 48-72-h fast lowered circulating insulin and increased binding to normal levels but only at low hormone concentrations; this limited normalization of 125I-insulin binding was associated with increased receptor affinity for insulin without change in receptor concentration. Refeeding after the acute fasting periods resulted in return to the elevated plasma insulin levels, the basal receptor affinity, and the depressed insulin binding observed in the basal, fed state. Chronic diet restored plasma insulin levels, insulin binding, and receptor concentration to normal without change in affinity. When the data from this study are coupled with previous in vivo and in vitro findings they suggest that the insulin receptor of human monocytes is more sensitive to regulation by ambient insulin than the receptors of obese mice and cultured human lymphocytes. The results further indicate than an insulin receptor undergoes in vivo modulation of its interaction with insulin by changing receptor concentration and by altering the affinity of existing receptors.
Transferable Anergy: Superantigen Treatment Induces CD4+ T Cell Tolerance That Is Reversible and Requires CD4−CD8− Cells and Interferon γ
Authors: Linda S. Cauley, Keith A. Cauley, Fillipa Shub, Gail Huston, Susan L. Swain
Journal: The Journal of Experimental Medicine (1997)

Bacterial superantigens induce peripheral unresponsiveness in CD4+ T cell populations that express appropriate Vbeta chains. We have used Vbeta3/Valpha11 T cell receptor transgenic (Tg) mice and the Vbeta3-specific superantigen staphylococcal enterotoxin A (SEA) to further investigate the mechanisms that contribute to such unresponsiveness. As in other models, in vivo exposure to SEA rendered the Tg CD4+ cells unresponsive to subsequent restimulation in vitro with antigen or mitogens. However, when the SEA-treated CD4+ cells were completely purified away from all other contaminating cells, they regained the ability to proliferate and secrete cytokines. Moreover, enriched CD4-CD8- cells from the SEA-treated mice suppressed the responses of fresh control CD4+ cells in mixed cultures indicating that the apparent "anergy" was both transferable and reversible. Further analysis demonstrated that interferon gamma, but not the Fas receptor, played a critical role in the suppression.
Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators
Authors: N Kageyama, M Miura, M Ichinose, M Tomaki, J Ishikawa, Y Ohuchi, N Endoh, K Shirato
Journal: European Respiratory Journal (1997)

This study examines the role of endogenous nitric oxide (NO) in airway microvascular leakage induced inflammatory mediators, which play an important role in asthmatic airways. Guinea-pigs were anesthetized and mechanically-ventilated with monitoring of arterial blood pressure, and airway microvascular leakage induced by intravenous injection of substance P (SP), leukotriene D4 (LTD4) and histamine was evaluated using Evans blue dye and Monastral blue dye in the presence and absence of the NO synthase inhibitors, L-NG-nitroarginine methyl ester (L-NAME) and L-NG-monomethyl arginine (L-NMMA). The effect of a soluble guanylate cyclase inhibitor, LY83583, on SP-induced dye leakage was also examined. Intravenous injection of SP (1 microgram.kg-1), LTD4 (1 microgram.kg-1) and histamine (100 micrograms.kg-1) significantly increased dye extravasation at all airway levels. Pretreatment with L-NAME (10 mg.kg-1 i.v.) and L-NMMA (100 mg.kg-1 i.v.) significantly inhibited SP-induced extravasation, and L-arginine (100 mg.kg-1 i.v.) reversed L-NAME-induced inhibition. L-NAME (10 mg.kg-1 i.v.) also significantly inhibited LTD4-induced dye extravasation only in central airways, and this inhibitory effect was abolished by a neurokinin-1 (NK1) antagonist, FK888 (10 mg.kg-1 i.v.) pretreatment. Histamine-induced dye extravasation was not affected by L-NAME. LY83583 (2.5 and 7.5 mg.kg-1 i.v.) partially but significantly reduced SP-induced dye leakage. These results suggest that endogenous nitric oxide plays a role in neurokinin-1 receptor-mediated airway microvascular leakage, and presumably involves the guanylate cyclase pathway.
Myocardial Amino Acid Transport in the Isolated Rabbit Right Ventricular Papillary Muscle
Authors: MICHAEL LESCH, RICHARD GORLIN, EDMUND H. SONNENBLICK
Journal: Circulation Research (1970)

The amino acid analog, alpha-aminoisobutyric acid (AIB) has been used to study myocardial amino acid transport in the isolated rabbit right ventricular papillary muscle. Intracellular AIB accumulation is linear for 2 hours and reaches a plateau at 3 hours at an intracellular/extracellular concentration gradient of 3.4. Anoxia does not inhibit this process whereas simultaneous inhibition of aerobic and anaerobic metabolism inhibits AIB accumulation. Intracellular AIB accumulation follows Michealis-Menten kinetics with a Km of 6.8 x 10 -3 M and a V max of 6.6 µmoles. ml intracellular fluid -1 . hour -1 . Sodium ion is obligatory for the transport process whereas no absolute potassium or calcium requirement exists. Ouabain, 10 -5 M, inhibits AIB uptake. Myograph techniques were utilized to determine the effect on AIB accumulation of subjecting unstimulated papillary muscles to various degrees of passive stretch. Muscles incubated at any tension above zero developed a greater intracellular/extracellular fluid AIB concentration ratio than muscles incubated at zero tension. These data suggest that increased myocardial wall tension may be a mechanical stimulus capable of inducing adaptive changes in myocardial metabolism.