tbuckley/cabot-search huggingface dataset:
Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial
Authors: Joel M Kremer, Anthony S Russell, Paul Emery, Carlos Abud-Mendoza, Jacek Szechinski, Rene Westhovens, Tracy Li, Xianhuang Zhou, Jean-Claude Becker, Richard Aranda, Charles Peterfy, Harry K Genant
Journal: Annals of the Rheumatic Diseases (2011)

Objective To evaluate abatacept treatment over 3 years in patients with rheumatoid arthritis (RA) refractory to methotrexate (MTX). Methods Patients randomised to abatacept or placebo (+MTX) during the 1-year double-blind period of the A batacept in I nadequate responders to M ethotrexate (AIM) trial received open-label abatacept (+MTX) in the long-term extension (LTE). Safety was assessed for patients who received ≥1 dose of abatacept, regardless of randomisation group. Efficacy was assessed for patients randomised to abatacept who entered the LTE. Results 433 and 219 patients were randomised and treated with abatacept or placebo, respectively; 378 and 161 entered the LTE. At year 3, 440/539 patients were ongoing. No unexpected safety events were observed in the LTE. By year 3, incidence rates of adverse event and serious adverse events were 249.8/100 and 15.1/100 patient-years, respectively. Incidence rates were generally stable over time. At year 3, 84.8%, 63.4% and 37.5% of patients achieved American College of Rheumatology (ACR) criteria of 20, 50 and 70, respectively, compared with 82.3%, 54.3% and 32.4% of patients at year 1. Mean changes in Genant-modified Sharp scores were reduced progressively over 3 years, with significantly greater inhibition during year 3 compared with year 2 (p=0.022 for total score). Conclusion In MTX-inadequate responders with RA, abatacept provided consistent safety and sustained efficacy over 3 years. The data suggest an increasing inhibitory disease-modifying effect on radiographic progression.
The effect of intermittent positive pressure breathing and voluntary hyperventilation upon the distribution of ventilation and pulmonary blood flow to the lung in chronic obstructive lung disease.
Authors: G E Emmanuel, W M Smith, W A Briscoe
Journal: Journal of Clinical Investigation (1966)

Intermittent positive pressure breathing (IPPB) from an apparatus applying positive pressure to the mouth during inspiration is widely used in the treatment of obstructive lung disease.The literature has recently been well reviewed by Sheldon (1).There was early con- cern with its effects in decreasing cardiac output (2, 3), which are avoided by using equipment that gives a type III mask pressure curve and hence letting the positive pressure phase, i.e., inspira- tion, occur at a high flow rate and occupy only a small fraction of the respiratory cycle, expiration being prolonged and against zero mask pressure.This type of pressure curve is obtained with machines in current use.There have been many therapeutic successes following the use of IPPB in severe respiratory failure (1).Its value, however, is debated by some.For example, Sukumalchantra, Park, and Williams maintain that in patients in acute ventilatory failure it frequently fails to lower the arterial carbon dioxide tension (4).Most authors maintain that it is only useful, or is more useful, when given with bronchodilators (5-7).Some maintain that it is not only useless (5, 7) but actually harmful (5) to administer oxygen by this method, in that arterial CO2 rises during such treatment.Most workers, however, have found that arterial CO2 falls during IPPB both when air (8) or 02 (9) is given.
The effect of phenobarbital on cholesterol gallstones in hamsters
Authors: J. Lagarriga, I. A. D. Bouchier
Journal: Gut (1973)

This experimental study was undertaken to follow the influence of phenobarbital on bile chemistry and gallstone formation. Phenobarbital (400 mg/kg/day) was administered to golden hamsters receiving a diet known to induce cholesterol gallstones. After a 28-day period none of the control animals had gallstones whereas five of 12 animals with added phenobarbital developed stones. Ten of 19 animals on the lithogenic diet formed gallstones but when phenobarbital was added gallstones occurred in 16 of 19 hamsters. The administration of phenobarbital resulted in the production of bile which was relatively more saturated with cholesterol, the bile salt + phospholipid: cholesterol of 24.8 +/- 12.7 in control animals altering to 9.1 +/- 6.2 in animals receiving phenobarbital. Hepatic bilirubin uridine diphosphate-glucuronyl transferase activity was not increased in animals on phenobarbital. It was concluded that, in the hamster at least, there is no indication that large doses of phenobarbital will reduce the potential for gallstone formation.
Gender influences: the role of leg dominance in ACL injury among soccer players: Table 1
Authors: Robert Brophy, Holly Jacinda Silvers, Tyler Gonzales, Bert R Mandelbaum
Journal: British Journal of Sports Medicine (2010)

Objective This study intends to look at the role of leg dominance in anterior cruciate ligament (ACL) injury risk among soccer (football) athletes. The purpose of this study was to test the hypothesis that soccer players rupture the ACL of their preferred support leg more frequently than the ACL in their preferred kicking leg, particularly in non-contact injuries, despite differences in gender. Design Retrospective observational study. Setting Outpatient orthopaedic practice. Patients Subjects who had sustained an ACL injury due to direct participation in soccer. N=93 (41 male, 52 female). Interventions These noncontact injuries were sustained while playing soccer. Results For non-contact injuries, roughly half of the injuries occurred in the preferred kicking leg (30) and the contralateral leg (28). However, by gender, there was a significant difference in the distribution of non-contact injury, as 74.1% of males (20/27) were injured on the dominant kicking leg compared with 32% (10/31) of females (p&lt;0.002). Conclusions When limited to a non-contact injury mechanism, females are more likely to injure the ACL in their supporting leg, whereas males tend to injure their kicking leg. This research suggests that limb dominance does serve as an aetiological factor with regard to ACL injuries sustained while playing soccer. If follow-up studies confirm that females are more likely to injure their preferred supporting leg, future research should investigate the cause for this discrepancy, which could result from underlying gender-based anatomical differences as well as differences in neuromuscular patterns during cutting manoeuvres or kicking.
Effect of varying the pressurisation rate during noninvasive pressure support ventilation
Authors: G. Prinianakis, M. Delmastro, A. Carlucci, P. Ceriana, S. Nava
Journal: European Respiratory Journal (2004)

The aim of the study was to assess the effects of varying the pressurisation rate during noninvasive pressure support ventilation on patients' breathing pattern, inspiratory effort, arterial blood gases, tolerance to ventilation and amount of air leakage. A total of 15 chronic obstructive pulmonary disease patients recovering from an acute episode of hypercapnic acute respiratory failure were studied during four randomised trials with different levels of pressurisation rate. No significant changes were observed in breathing pattern and arterial blood gases between the different runs. The pressure time product of the diaphragm, an estimate of its metabolic consumption, was significantly lower with all pressurisation rates than with spontaneous breathing, but was significantly lowest with the fastest rate. However, air leak, assessed by the ratio between expired and inspired tidal volumes, increased and the patients' tolerance of ventilation, measured using a standardised scale, was significantly poorer with the fastest pressurisation rate. In chronic obstructive pulmonary disease patients recovering from an episode of acute hypercapnic respiratory failure and ventilated with noninvasive pressure support ventilation, different pressurisation rates resulted in different reductions in the pressure time product of the diaphragm; this reduction was greater with the fastest rate, but was accompanied by significant air leaks and poor tolerance.
TOB1 Is Regulated by EGF-Dependent HER2 and EGFR Signaling, Is Highly Phosphorylated, and Indicates Poor Prognosis in Node-Negative Breast Cancer
Authors: Mike W. Helms, Dirk Kemming, Christopher H. Contag, Heike Pospisil, Kai Bartkowiak, Alice Wang, Sheng-Yung Chang, Horst Buerger, Burkhard H. Brandt
Journal: Cancer Research (2009)

Abstract Clinical and animal studies have shown that coexpression of the receptor tyrosine kinases HER2 and epidermal growth factor (EGF) receptor (EGFR) indicates a highly metastatic phenotype of breast cancer. In a cellular model of this phenotype using differential gene expression analysis, we identified TOB1 to be up-regulated depending on EGF stimulation and transduction through phosphorylation of HER2 tyrosine 1248. mRNA expression analysis of breast cancers from a cohort of node-negative patients showed significantly shortened distant metastasis-free survival for patients with high TOB1 expression. In subsequent tissue microarray studies of 725 clinical samples, high HER2 and EGF protein levels were significantly correlated with TOB1 expression in breast cancer, whereas EGFR and EGF levels correlated with TOB1 phosphorylation. We did not observe a correlation between TOB1 expression and cyclin D1, which was previously suggested to mediate the antiproliferative effect of unphosphorylated TOB1. A positive correlation of TOB1 phosphorylation status with proliferation marker Ki67 suggests that elevated TOB1 phosphorylation might abrogate the antiproliferative effect of TOB1 in breast cancer. This suggests a new regulatory role for TOB1 in cancer progression with particular significance in HER2- and/or EGFR-positive breast cancers. [Cancer Res 2009;69(12):5049–56]
PP2A-B55β Antagonizes Cyclin E1 Proteolysis and Promotes Its Dysregulation in Cancer
Authors: YingMeei Tan, Dahui Sun, Weijian Jiang, Kathleen Klotz-Noack, Ajay A. Vashisht, James Wohlschlegel, Martin Widschwendter, Charles Spruck
Journal: Cancer Research (2014)

Abstract Cyclin E1 regulates the initiation of S-phase in cellular division. However, in many cancers, cyclin E1 is aberrantly overexpressed and this molecular phenotype correlates with increased tumor aggressiveness and poor patient survival. The molecular cause(s) of cyclin E1 abnormalities in cancers is poorly understood. Here, we show that cyclin E1 overexpression in cancer is promoted by dysregulation of the protein phosphatase PP2A-B55β. PP2A-B55β targets the N- and C-terminal phosphodegrons of cyclin E1 for dephosphorylation, thus protecting it from degradation mediated by the SCFFbxw7 ubiquitin ligase. Augmented B55β expression stabilizes cyclin E1 and promotes its overexpression in cancer-derived cell lines and breast tumors. Conversely, B55β ablation enforces the degradation of cyclin E1 and inhibits cancer cell proliferation in vitro and tumor formation in vivo. Therefore, PP2A-B55β promotes cyclin E1 overexpression by antagonizing its degradation and its inhibition could represent a therapeutic mechanism for abrogating cyclin E1 function in cancers. Cancer Res; 74(7); 2006–14. ©2014 AACR.
Abstract P008: Weight Gain and Cardiovascular Risk Reduction Associated With Tobacco Abstinence in Smokers With Serious Mental Illness
Authors: Anne N Thorndike, Susanne S Hoeppner, Corinne Cather, Gladys N Pachas, Eric D Achtyes, A. E Evins
Journal: Circulation (2015)

Background: In patients with serious mental illness, high prevalence of smoking and obesity-related risk factors contribute to high rates of cardiovascular disease (CVD) and premature mortality. The impact of smoking cessation on weight gain, obesity-related risk factors, and overall cardiovascular risk among this population is unknown. Methods: We conducted secondary analyses to assess weight gain and change in CVD risk of 87 smokers with serious mental illness (schizophrenia, schizoaffective disorder, and bipolar disorder) who participated in a randomized controlled trial to test the long-term effectiveness of varenicline on smoking cessation. Initially, 203 smokers with serious mental illness were enrolled into an open-label 12-week course of varenicline. Subjects who attained abstinence at the end of the open-label phase were eligible to participate in the randomized phase, and 87 subjects were randomized to continue either varenicline or placebo for the following 40 weeks. Smoking cessation at week 52 (end of treatment) was defined as 21-day point prevalence abstinence. We compared subjects who were abstinent at week 52 (N=33) to subjects who had relapsed to smoking (N=54) on changes in weight and Framingham 10-year CVD risk score over the 52-week trial; outcomes were modeled with repeated measures analyses of variance. Results: At baseline, subjects who achieved week 52 abstinence were older (52 vs. 46 years, p=0.01) and had higher fasting serum glucose (98 vs. 89 mg/dL, p=0.008) than subjects who relapsed, but they did not differ on sex, race, smoking characteristics, blood pressure, lipids, treatment for diabetes, or treatment with antipsychotic medications. Baseline mean body mass index did not differ between abstinent and relapsed subjects (31.4 vs. 32.4, p=0.52), but the baseline mean Framingham risk score was higher for abstinent than relapsed subjects (14.2% vs. 10.8%, p=0.02). Over the 52 week study period, abstinent subjects gained more weight than relapsed subjects (4.8 kg vs. 1.2 kg, p=0.002 for time*abstinence interaction), but the mean Framingham risk score decreased substantially for abstinent subjects and not for relapsed subjects (-7.6% vs. 0.0%, p=0.003 for abstinence effect adjusting for sex, site, varenicline or placebo, and antipsychotic medications). Conclusion: Despite the high prevalence of obesity at baseline and substantial weight gain associated with long-term abstinence, smoking cessation resulted in a large reduction in the Framingham estimated 10-year CVD risk among patients with serious mental illness.
Narrowband ultraviolet B therapy in psoriasis: randomized double-blind comparison of high-dose and low-dose irradiation regimens
Authors: M.M. Kleinpenning, T. Smits, J. Boezeman, P.C.M. van de Kerkhof, A.W.M. Evers, M.J.P. Gerritsen
Journal: British Journal of Dermatology (2009)

Background Ultraviolet (UV) B phototherapy is an established treatment option for psoriasis. The optimum dosage regimen still has to be determined. Within‐subject comparisons do not take into account the systemic effects of UVB phototherapy. The area of the body treated with low‐dose UVB may benefit from the systemic effects of the site treated with a higher UVB dose. Objectives To study the time to clearance in patients with psoriasis in a randomized controlled trial, in which patients were treated with narrowband UVB in either a high‐dose or a low‐dose regimen. Methods One hundred and nine patients were randomized to a high‐dose regimen (group 1) or to a low‐dose regimen (group 2). Patients of group 1 and 2 were irradiated with 40% and with 20% incremental doses, respectively, three times weekly. Psoriasis Area and Severity Index (PASI) was measured at baseline and at every 4‐week control visit. Treatment was stopped in cases of clearance (90% reduction of baseline PASI). Results No significant differences were found in the number of patients achieving clearance. The high‐dosage scheme resulted in four fewer treatments with no significant differences in cumulative UV dose, although more protocol adjustments were required in the beginning of the study because of erythema. After 3 months a significantly better clinical outcome was seen after high‐dose UVB therapy. Conclusions High‐dose UVB therapy results in fewer treatments with better long‐term efficacy, with cost‐effective benefits for hospital and patients. Therefore UVB phototherapy in a high‐dose regimen for psoriasis is recommended. However, a protocol adjustment in the second week with a high‐dose regimen is desirable to prevent erythema.
Detection of Na+ Transporter Proteins in Urine
Authors: J. ANDREW McKEE, SHAILESH KUMAR, CAROLYN A. ECELBARGER, PATRICIA FERNÁNDEZ-LLAMA, JAMES TERRIS, MARK A. KNEPPER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Previous studies have established that the vasopressin-regulated water channel of the collecting duct, aquaporin-2, is excreted in the urine, providing a means for assessment of regulation and dysregulation of aquaporin-2 in humans. This article addresses the hypothesis that membrane transporters from upstream nephron segments are normally detectable in urine. The experiments employed rabbit polyclonal antibodies against the major Na transporters of the proximal tubule (the type 3 Na-H exchanger [NHE3]), the thick ascending limb of Henle's loop (the bumetanide-sensitive Na-K-2Cl cotransporter [NKCC2]), and the distal convoluted tubule (the thiazide-sensitive Na-Cl cotransporter [NCC]) in immunoblotting experiments. All three of these transporters were readily detectable as high molecular weight complexes present in lowdensity membrane fractions from urine of normal rats. Cross linking studies of NHE3, NKCC2, and NCC revealed that high molecular weight complexes are normally present in renal tissue. The molecular weights of the complexes in urine matched those of the cross-linked complexes in native kidney tissue. The presence in urine of integral membrane proteins representative of each nephron segment raises the possibility that limited or comprehensive proteomic analysis of urine samples may be useful in clinical settings.
Quality and Outcomes Framework indicators should not be used without proper clinical evidence
Authors: P. Millares Martin
Journal: BMJ (2014)

<h3>Abstract</h3> Marine animals in the wild are often difficult to access, so that biologists have to extrapolate from the study of animals in captivity. However, the implicit assumption that physiological and cellular processes of animals in artificial environments are not significantly different from those in the wild has rarely been tested. Here we investigate the extent to which the biological state of an animal is impacted by captivity by comparing global gene expression in wild and captive crown-of-thorns starfish (COTS). We compare transcriptomes of three external tissues obtained from wild COTS with captive COTS maintained in aquaria for at least one week. On average, an astonishingly large 24% of the coding sequences in the genome are differentially expressed. Comparing transcriptomes from coelomocytes – cells in internal coelomic fluid – in wild and captive COTS, we find that 20% of the coding sequences in the genome rapidly change expression. These captive transcriptomes remained markedly different from the wild ones for more than 30 days in captivity, and showed no indication of reverting back to a wild state. Genes consistently upregulated in captivity include those involved in oxidative stress and energy metabolism, whereas genes downregulated are involved in intercellular signalling. These extensive changes in gene expression in captive COTS suggest that captivity has a profound and sustained impact on the physiology, behaviour and health of these echinoderms. The potential for such dramatic changes should be accounted for when designing studies seeking to understand wild animals.
What Mankind May Have Lost Through Evolutionary Development: A Moral Enthymeme
Authors: W. A. Hollis
Journal: BMJ (1915)

TIIE highly cultured product of twentieth century civilization-tlle moral plhilosopher-is accustomed to preen him.self upon hiis glorious descent from wlhat was a few miiillion years ago a mere lump of prinmaeval protoplasm.He as a rule overlooks the compensatory advantages tlle leisured and lowly strollers along the broad road of evolution still enjoy.In the following paper I shall briefly
Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest
Authors: Michael Holzer, Fritz Sterz, J. M. Darby, S. A. Padosch, K. B. Kern, B. W. Böttiger, K. H. Polderman, A. R.J. Girbes, M. Holzer, S. A. Bernard, M. D. Buist, P. Safar, P. M. Kochanek
Journal: New England Journal of Medicine (2002)

Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation.
Cancer Immunotherapy by Interleukin-21: Potential Treatment Strategies Evaluated in a Mathematical Model
Authors: Antonio Cappuccio, Moran Elishmereni, Zvia Agur
Journal: Cancer Research (2006)

Abstract The newly characterized interleukin (IL)-21 plays a central role in the transition from innate immunity to adaptive immunity and shows substantial tumor regression in mice. IL-21 is now developed as a cancer immunotherapeutic drug, but conditions for efficacious therapy, and the conflicting immunostimulatory and immunoinhibitory influence of the cytokine, are yet to be defined. We studied the effects of IL-21 on tumor eradication in a mathematical model focusing on natural killer (NK) cell–mediated and CD8+ T-cell-mediated lysis of tumor cells. Model parameters were estimated using results in tumor-bearing mice treated with IL-21 via cytokine gene therapy (CGT), hydrodynamics-based gene delivery (HGD), or standard interval dosing (SID). Our model accurately retrieved experimental growth dynamics in the nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8+ T-cell balance on tumor immunogenicity. Moreover, in melanoma, simulations of CGT-like dosing regimens, dynamically determined according to tumor mass changes, resulted in efficient disease elimination. In contrast, in fibrosarcoma, such a strategy was not superior to that of fixed dosing regimens, HGD or SID. Our model supports clinical use of IL-21 as a potent stimulator of cellular immunity against cancer, and suggests selecting the immunotherapy strategy according to tumor immunogenicity. Nonimmunogenic tumors, but not highly immunogenic tumors, should be controlled by IL-21 dosing, which depends on tumor mass at the time of administration. This method imitates, yet amplifies, the natural anticancer immune response rather than accelerates only one of the response arms in an unbalanced manner. (Cancer Res 2006; 66(14): 7293-300)