tbuckley/cabot-search huggingface dataset:
Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD
Authors: M. Doucet, A. Dube, D. R. Joanisse, R. Debigare, A. Michaud, M.-E. Pare, R. Vaillancourt, E. Frechette, F. Maltais
Journal: Thorax (2010)

Factors involved in the regulation of muscle mass in chronic obstructive pulmonary disease (COPD) are still poorly understood. Comparing the signalisation involved in muscle mass regulation between two muscles with different levels of activation within the same subjects is an interesting strategy to tease out the impact of local (muscle activity) versus systemic factors in the regulation of muscle mass. A study was undertaken to measure and compare the protein levels of p-AKT, AKT, Atrogin-1, p-p70S6K, p-4E-BP1, p-GSK3β as well as the mRNA expression of Atrogin-1, MuRF1 and FoxO-1 in the quadriceps and the diaphragm of 12 patients with COPD and 7 controls with normal lung function.Diaphragm biopsies were obtained during thoracic surgery and quadriceps samples were obtained from needle biopsies. Protein content and mRNA expression were measured by western blot and quantitative PCR, respectively.Increased mRNA expressions of Atrogin-1, MuRF1 and FoxO-1 were found in the quadriceps compared with the diaphragm only in patients with COPD. The quadriceps/diaphragm ratio for MuRF1 was higher in COPD. The protein level of p-p70S6K was decreased in the quadriceps compared with the diaphragm in patients with COPD. The quadriceps/diaphragm ratios of p-p70S6K and p-GSK3β were lower in patients with COPD than in controls.These results indicate a greater susceptibility to a catabolic/anabolic imbalance favouring muscle atrophy in the quadriceps compared with the diaphragm in patients with COPD. The balance between the atrophy and hypertrophy signalling is inhomogeneous between respiratory and lower limb muscles, suggesting that local factors are likely to be involved in the regulation of muscle mass in COPD.
Non-steroidal anti-inflammatory drugs and myocardial infarctions: comparative systematic review of evidence from observational studies and randomised controlled trials
Authors: P A Scott, G H Kingsley, C M Smith, E H Choy, D L Scott
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> The comparative risk of myocardial infarction (MI) with cyclo-oxygenase-2-specific drugs and traditional non-steroidal anti-inflammatory drugs (NSAIDs) was determined. <h3>Methods:</h3> The results of studies of a suitable size in colonic adenoma and arthritis—that had been published in English and from which crude data about MIs could be extracted—were evaluated. Medline, Embase and Cinahl (2000–2006) databases, as well as published bibliographies, were used as data sources. Systematic reviews examined MI risks in case-control and cohort studies, as well as in randomised controlled trials (RCTs). <h3>Results:</h3> 14 case-control studies (74 673 MI patients, 368 968 controls) showed no significant association of NSAIDs with MI in a random-effects model (OR 1.17; 95% CI 0.99 to 1.37) and a small risk of MI in a fixed-effects model (OR 1.32; 95% CI 1.29 to 1.35). Sensitivity analyses showed higher risks of MI in large European studies involving matched controls. Six cohort studies (387 983 patient years, 1 120 812 control years) showed no significant risk of MI with NSAIDs (RR 1.03; 95% CI 1.00 to 1.07); the risk was higher with rofecoxib (RR 1.25; 95% CI 1.17 to 1.34) but not with any other NSAIDs. Four RCTs of NSAIDs in colonic adenoma (6000 patients) showed an increased risk of MI (RR 2.68; 95% CI 1.43 to 5.01). Fourteen RCTs in arthritis (45 425 patients) showed more MIs with cyclo-oxygenase-2-specific drugs (Peto OR 1.6; 95% CI 1.1 to 2.4), but fewer serious upper gastrointestinal events (Peto OR 0.40; 95% CI 0.31 to 0.53). <h3>Conclusion:</h3> The overall risk of MI with NSAIDs and cyclo-oxygenase-2-specific drugs was small; rofecoxib showed the highest risk. There was an increased MI risk with cyclo-oxygenase-2-specific drugs compared with NSAIDs, but less serious upper gastrointestinal toxicity.
Serum Biomarkers of Bone Metabolism in Castration-Resistant Prostate Cancer Patients With Skeletal Metastases: Results From SWOG 0421
Authors: Primo N. Lara, Benjamin Ely, David I. Quinn, Philip C. Mack, Catherine Tangen, Erik Gertz, Przemyslaw W. Twardowski, Amir Goldkorn, Maha Hussain, Nicholas J. Vogelzang, Ian M. Thompson, Marta D. Van Loan
Journal: JNCI Journal of the National Cancer Institute (2014)

Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421).Markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test.Sera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005).Serum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.
Association of Oral Calcitriol with Improved Survival in Nondialyzed CKD
Authors: Abigail B. Shoben, Kyle D. Rudser, Ian H. de Boer, Bessie Young, Bryan Kestenbaum
Journal: Journal of the American Society of Nephrology (2008)

Parenteral vitamin D is associated with improved survival among long-term hemodialysis patients. Among nondialyzed patients with chronic kidney disease (CKD), oral activated vitamin D reduces parathyroid hormone levels, but the impact on clinical outcomes is unknown. We evaluated associations of oral calcitriol use with mortality and dialysis dependence in 1418 nondialysis patients with CKD and hyperparathyroidism in the Veterans' Affairs Consumer Health Information and Performance Sets database. Incident calcitriol users and nonusers were selected on the basis of stages 3 to 4 CKD, hyperparathyroidism, and the absence of hypercalcemia before calcitriol use and then were matched by age and estimated kidney function. During a median follow-up of 1.9 yr, 408 (29%) patients died and 217 (16%) initiated long-term dialysis. After adjustment for demographics; comorbidities; estimated kidney function; medications; and baseline levels of parathyroid hormone, calcium, and phosphorous, oral calcitriol use was associated with a 26% lower risk for death (95% confidence interval 5 to 42% lower; P = 0.016) and a 20% lower risk for death or dialysis (95% confidence interval 1 to 35% lower; P = 0.038). The association of calcitriol with improved survival was not statistically different across baseline parathyroid hormone levels. Calcitriol use was associated with a greater risk for hypercalcemia. In conclusion, oral calcitriol use is associated with lower mortality in nondialysis patients with CKD.
New challenge of hepatorenal syndrome: Prevention and treatment
Authors: Florence Wong, Laurence Blendis
Journal: Hepatology (2001)

Hepatorenal syndrome (HRS) remains one of the major therapeutic challenges in hepatology today. The pathogenesis is complex, but the final common pathway seems to be that sinusoidal portal hypertension, in the presence of severe hepatic decompensation, leads to splanchnic and systemic vasodilatation and decreased effective arterial blood volume. Renal vasoconstriction increases concomitantly, renal hemodynamics worsens, and renal failure occurs. Renal failure was shown 15 years ago to be potentially reversible after liver transplantation. This potential reversibility together with increased understanding of the pathogenesis has led to successful preliminary attempts to reverse HRS nonsurgically with combinations of splanchnic vasoconstrictors and colloid volume expansion, insertion of transjugular intrahepatic portovenous shunt radiologically, and improved forms of dialysis. Recent classification of HRS into the acute onset or severe type 1 with virtually 100% mortality and the more insidious less severe type II promises to shed more light on the pathogenesis of HRS, especially on the currently unrecognized precipitating factors. It is hoped that this classification will be included in the necessary and carefully performed clinical trials, which should lead to clearer indications for the available therapies. The challenge now is to use all this information to improve our management of cirrhotic patients to prevent occurrence of HRS in the future.
Rifampin. Levels in serum and saliva and effect on the meningococcal carrier state
Authors: L. F. Devine
Journal: JAMA (1970)

In a double blind study in naval recruits, rifampin reduced the percentage of meningococcal carriers by 80%, compared with controls. It was well tolerated in four daily 600-mg doses. Levels of rifampin in serum samples exceeded the minimal inhibitory concentration (MIC) of rifampin required to inhibit meningococci vitro. Rifampin levels in saliva exceeded the MIC for all meningococcal reference strains tested in vitro at 3.5 hours after a third 600-mg daily dose. At 6.5 hours after a fourth 600-mg dose, the range of rifampin levels in saliva samples extended above and below the range of MIC of rifampin for the reference strains. The efficacy of rifampin in the eradication of the meningococcal carrier state has been established. It should prove safe and effective in carriers of sulfadiazine-resistant meningococci under limited conditions.
Reversal of Chemotherapy-Induced Leukopenia Using Granulocyte Macrophage Colony-Stimulating Factor Promotes Bone Metastasis That Can Be Blocked with Osteoclast Inhibitors
Authors: Jinlu Dai, Yi Lu, Chunyan Yu, Jill M. Keller, Atsushi Mizokami, Jian Zhang, Evan T. Keller
Journal: Cancer Research (2010)

Hematopoietic growth factors are used to reverse chemotherapy-induced leukopenia. However, some factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) induce osteoclast-mediated bone resorption that can promote cancer growth in the bone. Accordingly, we evaluated the ability of GM-CSF to promote bone metastases of breast cancer or prostate cancer in a mouse model of chemotherapy-induced leukopenia. In this model, GM-CSF reversed cyclophosphamide-induced leukopenia but also promoted breast cancer and prostate cancer growth in the bone but not in soft tissue sites. Bone growth was associated with the induction of osteoclastogenesis, yet in the absence of tumor GM-CSF, it did not affect osteoclastogenesis. Two osteoclast inhibitors, the bisphosphonate zoledronic acid and the RANKL inhibitor osteoprotegerin, each blocked GM-CSF-induced tumor growth in the bone but did not reverse the ability of GM-CSF to reverse chemotherapy-induced leukopenia. Our findings indicate that it is possible to dissociate the bone-resorptive effects of GM-CSF, to reduce metastatic risk, from the benefits of this growth factor in reversing leukopenia caused by treatment with chemotherapy.
Itch characteristics in atopic dermatitis: results of a web-based questionnaire
Authors: A. Dawn, A.D.P. Papoiu, Y.H. Chan, S.R. Rapp, N. Rassette, G. Yosipovitch
Journal: British Journal of Dermatology (2008)

Itch significantly impairs the quality of life of patients with atopic dermatitis. However, only a few previous studies have examined the specific characteristics of itch in atopic dermatitis.To examine the frequency, intensity and perceived characteristics of pruritus among individuals with atopic dermatitis.Questionnaire reliability and validity were established in pilot testing. Survey participants completed the comprehensive, web-based 'Characteristics of itch' questionnaire. Participants provided anonymous demographic information and answered questions regarding itch intensity, frequency, timing, duration, location, associated symptoms and itch descriptors.A total of 304 individuals with atopic dermatitis completed the web-based questionnaire. Itch occurred at least once daily in 91% of the individuals surveyed. Of the 32 itch descriptors rated by survey participants, 31 demonstrated a statistically significant positive correlation with the participants' ratings of itch intensity (P < 0.001). More than half the survey participants reported pain (59%) and heat sensation (53%) associated with itch.The questionnaire was found to be a useful tool in characterization of itch. Pain appears to be an important component of atopic dermatitis. The strong correlation between itch descriptors and itch intensity suggests that such descriptors serve as strong indicators of the symptomatology in atopic dermatitis.
Length-dependent tension in the failing heart and the efficacy of cardiac resynchronization therapy
Authors: Steven A. Niederer, Gernot Plank, Phani Chinchapatnam, Matthew Ginks, Pablo Lamata, Kawal S. Rhode, Christopher A. Rinaldi, Reza Razavi, Nicolas P. Smith
Journal: Cardiovascular Research (2010)

Cardiac resynchronization therapy (CRT) has emerged as one of the few effective and safe treatments for heart failure. However, identifying patients that will benefit from CRT remains controversial. The dependence of CRT efficacy on organ and cellular scale mechanisms was investigated in a patient-specific computer model to identify novel patient selection criteria. A biophysically based patient-specific coupled electromechanics heart model has been developed which links the cellular and sub-cellular mechanisms which regulate cardiac function to the whole organ function observed clinically before and after CRT. A sensitivity analysis of the model identified lack of length dependence of tension regulation within the sarcomere as a significant contributor to the efficacy of CRT. Further simulation analysis demonstrated that in the whole heart, length-dependent tension development is key not only for the beat-to-beat regulation of stroke volume (Frank–Starling mechanism), but also the homogenization of tension development and strain. In individuals with effective Frank–Starling mechanism, the length dependence of tension facilitates the homogenization of stress and strain. This can result in synchronous contraction despite asynchronous electrical activation. In these individuals, synchronizing electrical activation through CRT may have minimal benefit.
The Use of Genetic Markers to Identify Lung Cancer in Fine Needle Aspiration Samples
Authors: Rajbir K. Gill, Madeline F. Vazquez, Arin Kramer, Megan Hames, Lijuan Zhang, Kerstin Heselmeyer-Haddad, Thomas Ried, Konstantin Shilo, Claudia Henschke, David Yankelevitz, Jin Jen
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We seek to establish a genetic test to identify lung cancer using cells obtained through computed tomography–guided fine needle aspiration (FNA). Experimental Design: We selected regions of frequent copy number gains in chromosomes 1q32, 3q26, 5p15, and 8q24 in non–small cell lung cancer and tested their ability to determine the neoplastic state of cells obtained by FNA using fluorescent in situ hybridization. Two sets of samples were included. The pilot set included six paraffin-embedded, noncancerous lung tissues and 33 formalin-fixed FNA specimens. These 39 samples were used to establish the optimal fixation and single scoring criteria for the samples. The test set included 40 FNA samples. The results of the genetic test were compared with the cytology, pathology, and clinical follow-up for each case to assess the sensitivity and specificity of the genetic test. Results: Nontumor lung tissues had ≤4 signals per nucleus for all tested markers, whereas tumor samples had ≥5 signals per nucleus in five or more cells for at least one marker. Among the 40 testing cases, 36 of 40 (90%) FNA samples were analyzable. Genetic analysis identified 15 cases as tumor and 21 cases as nontumor. Clinical and pathologic diagnoses confirmed the genetic test in 15 of 16 lung cancer cases regardless of tumor subtype, stage, or size and in 20 of 20 cases diagnosed as benign lung diseases. Conclusions: A set of only four genetic markers can distinguish the neoplastic state of lung lesion using small samples obtained through computed tomography–guided FNA.
Can care management enhance integration of primary and specialty care?
Authors: Michael Von Korff
Journal: BMJ (2004)

Dietrich et al report a randomised controlled trial in which community practices implemented enhanced care for depressive illness.1 The programme was a quality improvement initiative of the participating healthcare organisations, not a stand alone intervention provided by the researchers. Key elements included telephone follow up of patients by a care manager, support of the care manager and the primary care clinician by a psychiatrist, and increased attention to patient education and goal setting by the primary care clinician. The magnitude of benefits was comparable to those of some previous effectiveness trials in which interventions were delivered by researchers.2 On completion, the organisational changes …
Using lung cancer screening as an opportunity to diagnose COPD
Authors: Marianne L S Tinkler
Journal: Thorax (2012)

Early diagnosis of chronic obstructive pulmonary disease (COPD) allows increased opportunity for smoking cessation advice and treatment, which potentially improves prognosis. This single-centre, prospective cross-sectional study investigated whether screening CT scans could diagnose COPD without the need for pulmonary function testing (PFT).

One thousand one hundred and forty men, ex or current smokers (>16.5 pack year history), aged 50–75 years, …
Treatment of Scabies by T.E.T.M.S
Authors: T. M. Clayton
Journal: BMJ (1943)

Urban DistrictsGordon and Seaton (1942) drew attention to a new prepara- tion[(tetraetiylthiuram monosulphidqe-T.E.T.M.S.) which they was worthy of clinical trial, and their experiments on rats infested with itch-mites of the genus NotoeFdres gave reasonable grounds for assuming that this sarcopticide may give even better results in the treatment of human scabies than either dimethylthianthrene or benzyl benzoate preparations.Percival (1942) has demonstrated that a 5% solution was curative in 50 consecutive hos- pitalized or ambulatory cases, but that in 0.25% strength the results were much less satisfactory.The preparation used in the following series of cases was one kindly supplied by Messrs. Imperial Chemical Industries Ltd., and had the following formula: T.E.T.M.S., 25%; polyglycerol ricinoleate, 10% ; industrial methylated spirit, 65%.The solution was of a dark yellowish-brown colour and at temperatures below that of the body there was a tendency for crystals of a distinctive yellow colour to form, which, however, were easily redissolved with moderate increase in temperature.The makers recommend that one part of the preparation be added to four parts of water immediately before use and applied twice daily for three days.Force of circumstances, however, compelled deviation from this advice in my original series of cases, so that the 25% emulsion was used in con- centrated form, but the results of treatment lead me to assume that a useful purpose was served.About one ounce of the emulsion was sufficient to cover the body surface of an average- sized adult, and it was easy of application, not unpleasant to handle, and without objectionable odour.Since, at this time, no records were available as to the propensity of the preparation to produce a dermatitis it was several days' observation-nor was there anything detrimental except.that the solution stained the clothing.The stain, however, was easily removed.
Perifosine Inhibits Mammalian Target of Rapamycin Signaling through Facilitating Degradation of Major Components in the mTOR Axis and Induces Autophagy
Authors: Lei Fu, Young-Ae Kim, Xuerong Wang, Xiaoyun Wu, Ping Yue, Sagar Lonial, Fadlo R. Khuri, Shi-Yong Sun
Journal: Cancer Research (2009)

Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in both preclinical studies and clinical trials. This activity is partly associated with its ability to inhibit Akt activity. It has been shown that the mammalian target of rapamycin (mTOR) axis plays a critical role in regulation of cell proliferation and survival primarily through functioning both downstream and upstream of Akt. The current study reveals a novel mechanism by which perifosine inhibits Akt and the mTOR axis. In addition to inhibition of Akt, perifosine inhibited the assembly of both mTOR/raptor and mTOR/rictor complexes. Strikingly, perifosine reduced the levels of Akt and other major components including mTOR, raptor, rictor, 70-kDa ribosomal S6 kinase, and 4E-binding protein 1 in the mTOR axis by promoting their degradation through a GSK3/FBW7-dependent mechanism. These results thus suggest that perifosine inhibits the mTOR axis through a different mechanism from inhibition of mTOR signaling by classic mTOR inhibitors such as rapamycin. Moreover, perifosine substantially increased the levels of type II light chain 3, a hallmark of autophagy, in addition to increasing poly(ADP-ribose) polymerase cleavage, suggesting that perifosine induces both apoptosis and autophagy. The combination of perifosine with a lysosomal inhibitor enhanced apoptosis and inhibited the growth of xenografts in nude mice, suggesting that perifosine-induced autophagy protects cells from undergoing apoptosis. Collectively, we conclude that perifosine inhibits mTOR signaling and induces autophagy, highlighting a novel mechanism accounting for the anticancer activity of perifosine and a potential strategy to enhance the anticancer efficacy of perifosine by preventing autophagy.
Allelic variation in Helicobacter pylori: progress but no panacea
Authors: M J BLASER
Journal: Gut (1999)

See article on page 499  Helicobacter pylori colonisation in the stomach is associated with increased risk for the development of peptic ulcer disease and non-cardia gastric adenocarcinoma.1 However, the incidences of these diseases vary in different parts of the world, and these rates have been changing over the past century. It now is clear that the mere presence of H pylori is insufficient to account for this variation. Alternative hypotheses to explain differing outcomes include variation in bacterial strains, in host related factors, or in the particular interactions governing the long term equilibrium between H pylori strain populations and the colonised host.2 In this issue, Kidd et al (see page 499) explore whether H pylori strain differences are related to illness occurrence in South African patients undergoing endoscopy. Why was such a study undertaken?

Despite overall conservation of most genes, H pylori are a highly diverse bacterial species.3Their population structure indicates that they are freely recombining,4 which tends to eliminate clonal or allelic variation. Yet, in accordance with previous work, Kidd et al …