tbuckley/cabot-search huggingface dataset:
Is repeated flushing of Hickman catheters necessary?
Authors: H Gillies, H J Rogers, J Johnston, P G Harper, C J Rudge
Journal: BMJ (1985)

for nine days.The vocal cords were unaffected.Throughout this period resolution was monitored by serial endoscopies.The trachea and bronchi produced greatly increased amounts of mucus and were irrigated regularlv with saline.Persistent aspiration due to neuromuscular incoordination prevented oral feeding for eight weeks.He was discharged after three months and subsequently remained well.
Long-Term Results of Tumor Necrosis Factor α– and Melphalan-Based Isolated Limb Perfusion in Locally Advanced Extremity Soft Tissue Sarcomas
Authors: Jan P. Deroose, Alexander M.M. Eggermont, Albertus N. van Geel, Jacobus W.A. Burger, Michael A. den Bakker, Johannes H.W. de Wilt, Cornelis Verhoef
Journal: Journal of Clinical Oncology (2011)

Because there is no survival benefit of amputation for extremity soft tissue sarcomas (STSs), limb-sparing surgery has become the gold standard. Tumor size reduction by induction therapy to render nonresectable tumors resectable or facilitate function-preserving surgery can be achieved by tumor necrosis factor α (TNF) -based and melphalan-based isolated limb perfusion (TM-ILP). This study reports the long-term results of 231 TM-ILPs for locally advanced extremity STS.We analyzed 231 TM-ILPs in 208 consecutive patients (1991 to 2005), who were all candidates for functional or anatomic amputation for locally advanced extremity STS. All patients had a potential follow-up of up to 5 years. TM-ILP was performed under mild hyperthermic conditions with 1 to 4 mg of TNF and 10 to 13 mg/L of limb-volume melphalan. Almost all patients (85%) had intermediate- or high-grade tumors.The overall response rate (ORR) was 71% (complete response, 18%; partial response, 53%). Multifocal sarcomas had a significantly better ORR of 83% (P = .008). The local recurrence rate was 30% (n = 70); local recurrence rates were highest for multifocal tumors (54%; P = .001) and after previous radiotherapy (54%; P < .001). Five-year overall survival rate was 42%. Survival was poorest in patients with large tumors (P = .01) and with leiomyosarcomas (P < .001). Limb salvage rate was 81%.We demonstrated that TM-ILP results in a limb salvage rate of 81% in patients with locally advanced extremity STS who would otherwise have undergone amputation. Whenever an amputation is deemed necessary to obtain local control of an extremity STS, TM-ILP should be considered.
Guaiac based faecal occult blood testing for colorectal cancer screening: an obsolete strategy?
Authors: Graeme P Young, Callum G Fraser, Stephen P Halloran, Steven Cole
Journal: Gut (2012)

The recent paper by Scholefield and colleagues1 on the 20 year follow-up of the ‘Nottingham’ randomised controlled trial of guaiac based faecal occult blood test (gFOBT) colorectal cancer (CRC) screening, reports an intention to screen benefit of 13% reduced mortality from CRC and a participant benefit of 18% reduction, in spite of offering only biennial screening and with only 60% first round participation ( see page 1036 ). Their three ‘impact’ statements are an important basis for progressing screening worldwide using faecal tests.

The first impact statement is that such screening is worthwhile.

Given that several other controlled trials of gFOBT screening show mortality reduction from CRC,2–5 and that such screening is considered not only cost effective but cost saving,6 this cannot be disputed. Indeed, it is more than worthwhile—organised population based screening programmes must be implemented. However, a recent publication reviewing international programmes shows that fully organised screening is still in its infancy in many countries.7 Why then is CRC screening not universally accepted and/or fully implemented?

There are many reasons relating to the population, politics, public health, purse, providers of healthcare and profession. Space limitations preclude a full analysis but this recent paper by Scholefield et al 1 provides a platform on which to address some of these.

Their observed impact on CRC mortality of gFOBT screening was small, a reduction of just 13%, regardless …
A longitudinal study on the ammonia threshold in junior cyclists
Authors: Y Yuan, K-M Chan
Journal: British Journal of Sports Medicine (2004)

To identify the effect of a one year non-specific training programme on the ammonia threshold of a group of junior cyclists and to correlate ammonia threshold with other common physiological variables.The cyclists performed tests at three time points (T1, T2, T3) during the year. Follow up tests were conducted every six months after the original test. Ammonia threshold was obtained from a graded exercise with four minute steps.The relatively non-specific one year training programme was effective in inducing an increase in peak VO(2) (60.6 (5.9), 65.9 (7.4), and 64.6 (6.5) ml/min/kg at T1, T2, and T3 respectively) and endurance time (18.3 (4.5), 20.1 (5.2), and 27.0 (6.1) minutes at T1, T2, and T3 respectively), but was not effective for the sprint related variables. Ammonia threshold, together with lactate threshold and ventilatory threshold, was not significantly different at the three test times. Only endurance time correlated significantly with ammonia threshold (r = 0.915, p = 0.001).The findings suggest that a relatively non-specific one year training programme does not modify the ammonia threshold of junior cyclists. The significant correlation between ammonia threshold and endurance time further confirms that ammonia threshold is a measure of the ability to sustain exercise at submaximal intensities.
Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer
Authors: Christine L. Hann, Vincent C. Daniel, Elizabeth A. Sugar, Irina Dobromilskaya, Sara C. Murphy, Leslie Cope, Xue Lin, Jared S. Hierman, Daniel L. Wilburn, D. Neil Watkins, Charles M. Rudin
Journal: Cancer Research (2008)

Abstract Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line–based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line–based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models. [Cancer Res 2008;68(7):2321–8]
Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial
Authors: William MacNee, Richard J Allan, Ieuan Jones, Maria Cristina De Salvo, Lisa F Tan
Journal: Thorax (2013)

<h3>Rationale</h3> Chronic obstructive pulmonary disease (COPD) is a common lung disease leading to progressive decline in lung function. Inhibition of release of inflammatory mediators by p38 inhibitors may be a useful treatment for chronic inflammation of the airways thought to underlie the pathogenesis of the disease. <h3>Objectives</h3> To evaluate the efficacy and safety of PH-797804, a potent and selective p38 inhibitor, in adults with moderate to severe COPD (Global Initiative for Chronic Obstructive Lung Disease stage II/III). <h3>Methods</h3> This was a randomised, adaptive design, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were initially randomised to placebo, 0.5, 3, 6 or 10 mg PH-797804 once daily and treated for 6 weeks following a 2-week run-in. <h3>Measurements and main results</h3> The primary endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV<sub>1</sub>) compared with placebo after 6 weeks of treatment. Secondary endpoints included other spirometric parameters, transition dyspnoea index, rescue mediation use, high sensitivity C-reactive protein and symptoms. A total of 230 patients were assigned to treatment; placebo (n=45), 0.5 mg (n=20), 3 mg (n=47), 6 mg (n=70) and 10 mg (n=48). PH-797804 showed a statistically significant improvement in trough FEV<sub>1</sub> at week 6 compared with placebo of 0.086 litre (95% Bayesian CI 0.008 to 0.164) and 0.093 litre (95% CI 0.018 to 0·166) at 3 and 6 mg PH-797804, respectively. PH-797804 3 mg and 6 mg showed an improvement in the baseline dyspnoea index/transition dyspnoea index total focal score at week 6. PH-797804 was well tolerated at all doses studied. <h3>Conclusions</h3> PH-797804 demonstrated improvements over placebo in lung function parameters and dyspnoea in patients with moderate to severe COPD. <h3>TrialRegNo</h3> NCT00559910.
The nitroxyl anion (HNO) is a potent dilator of rat coronary vasculature
Authors: J FAVALORO, B KEMPHARPER
Journal: Cardiovascular Research (2006)

The nitroxyl anion (HNO) is the one-electron reduction product of NO(). This redox variant has been shown to be endogenously produced and to have effects that are pharmacologically distinct from NO(). This study investigates the vasodilator and chronotropic effects of HNO in the rat isolated coronary vasculature.Sprague-Dawley rat hearts were retrogradely perfused with Krebs' solution (8 ml/min) using the Langendorff technique. Perfusion pressure was raised using a combination of infusion of phenylephrine and bolus additions of the thromboxane mimetic U46619 to attain a baseline perfusion pressure of 100-120 mm Hg. The vasodilator effects of a nitroxyl anion donor, Angeli's salt, were examined in the absence and presence of HNO and NO* scavengers, K+ channel inhibition, and soluble guanylate cyclase (sGC) inhibition. In addition, the inotropic and chronotropic effects of Angeli's salt were examined in hearts at resting perfusion pressure (50-60 mm Hg) and compared to responses evoked by acetylcholine and isoprenaline.Angeli's salt causes a potent and reproducible vasodilatation in isolated perfused rat hearts. This response is unaffected by the NO* scavenger hydroxocobalamin (0.1 mM) but is significantly inhibited by the HNO scavenger N-acetyl-L-cysteine (4 mM), suggesting that HNO is the mediator of the observed responses. Vasodilatation responses to Angeli's salt were virtually abolished in the presence of the sGC inhibitor ODQ (10 microM). The magnitude of the vasodilatation response to Angeli's salt was significantly reduced in the presence of 30 mM K+, 10 microM glibenclamide and in the presence of the calcitonin gene-related peptide (CGRP) antagonist CGRP((8-37)) (0.1 microM). Angeli's salt had little effect on heart rate or force of contraction, whilst isoprenaline and acetylcholine elicited significant positive and negative cardiotropic effects, respectively.The HNO donor Angeli's salt elicits a potent and reproducible vasodilatation response. The results suggest that the response is elicited by HNO through sGC-mediated CGRP release and K(ATP) channel activation.
CELLULAR LOCALIZATION OF IMMUNOGLOBULINS WITH DIFFERENT ALLOTYPIC SPECIFICITIES IN RABBIT LYMPHOID TISSUES
Authors: Benvenuto Pernis, Gerolamo Chiappino, Andrew S. Kelus, Philip G. H. Gell
Journal: The Journal of Experimental Medicine (1965)

The cellular localization of allotypes in rabbit lymphoid tissues has been studied by immunofluorescence. In heterozygous animals the double staining for two allotypes controlled by allelic genes (A1 and A2; A4 and A5; A4 and A6) has shown the existence of two populations of plasma cells, one containing one allotype and the other the alternative one. The localization in different cells of immunoglobulins marked by allelic allotypic specificities has been confirmed by microspectrography of single cells. An exception to this rule was given by the presence in the germinal centers of lymphoid follicles of apparently uniform mixtures of products of the two allelic genes. Double staining for two allotypes controlled by genes at different loci showed, instead, the presence of many cells containing both allotypes; the number of these cells was highest in doubly homozygotes, in the other it was consistent with random association of non-allelic specificities. In addition double staining for one allotype and gamma G globulins in the lymphoid tissues of rabbits homozygous at the a or at the b locus, has shown the presence of cells containing immunoglobulins that lack one allotype.
Serotonin and Blood Pressure Regulation
Authors: Stephanie W. Watts, Shaun F. Morrison, Robert Patrick Davis, Susan M. Barman
Journal: Pharmacological Reviews (2012)

5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension.
Efficacy of St. John’s Wort Extract WS 5570 in Major Depression: A Double-Blind, Placebo-Controlled Trial
Authors: Y. Lecrubier, G. Clerc, R. Didi, M. Kieser
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: In a double-blind, randomized, placebo-controlled trial with 375 patients the authors investigated the antidepressant efficacy and safety of 300 mg t.i.d. of hydroalcoholic Hypericum perforatum extract WS 5570. METHOD: The study participants were male and female adult outpatients with mild to moderate major depression (single or recurrent episode, DSM-IV criteria). After a single-blind placebo run-in phase, the patients were randomly assigned, 186 to WS 5570 and 189 to placebo, after which they received double-blind treatment for 6 weeks. Follow-up visits were held after 1, 2, 4, and 6 weeks. The primary outcome measure was the change from baseline in the total score on the 17-item Hamilton Depression Rating Scale. In addition, analyses of responders (patients with at least a 50% reduction in Hamilton total score) and patients with remissions (patients with a total score of 6 or less on the Hamilton scale at treatment end) were carried out, and subscale/subgroup analyses were conducted. The design included an adaptive interim analysis performed after random assignment of 169 patients with options for group size adjustment or early termination. RESULTS: Compared to placebo, WS 5570 produced a significantly greater reduction in total score on the Hamilton depression scale and significantly more patients with treatment response or remission. It was more effective in patients with higher baseline Hamilton scores and led to global reduction of depression-related core symptoms, assessed with the melancholia subscale of the Hamilton scale. The placebo and WS 5570 groups had comparable adverse events. CONCLUSIONS: H. perforatum extract WS 5570 was found to be safe and more effective than placebo for the treatment of mild to moderate depression.
Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse.
Authors: L S Wicker, B J Miller, L Z Coker, S E McNally, S Scott, Y Mullen, M C Appel
Journal: The Journal of Experimental Medicine (1987)

Genetic analysis of the development of diabetes and insulitis has been performed in the nonobese diabetic (NOD) mouse strain, a model of insulin-dependent (type I) diabetes mellitus. (NOD X C57BL/10)F1, F2, and (F1 X NOD) first-, second-, and third-backcross generations were studied. The data obtained were consistent with the hypothesis that diabetes is controlled by at least three functionally recessive diabetogenic genes, or gene complexes, one of which is linked to the MHC of the NOD. In contrast, pancreatic inflammation leading to insulitis was found to be controlled by a single incompletely dominant gene. One of the two diabetogenic loci that is not linked to the MHC appears to be essential for the development of severe insulitis. This diabetogenic gene may be identical to the gene that controls the initiation of the autoimmune response that progresses to insulitis. Although this gene appears to be functionally recessive in its control of diabetes, it is incompletely dominant in its control of insulitis. The MHC-linked diabetogenic gene, although not required for the development of insulitis, apparently influences the progression of the autoimmune response since NOD MHC homozygotes in the backcross generations displayed the highest incidence and most severe cases of insulitis. Interestingly, we have found two MHC heterozygous backcross females that have become diabetic, suggesting that either the MHC-linked diabetogenic gene is not strictly recessive or that a recombination event has occurred between the diabetogenic gene and the K or I-A regions of the MHC. The third diabetogenic locus appears to influence the progression of severe insulitis to overt diabetes. In animals homozygous at this locus, diabetes may result from a decreased ability to develop a protective suppressor response to the autoimmune process.
Medication Use Leading to Emergency Department Visits for Adverse Drug Events in Older Adults
Authors: Daniel S. Budnitz, Nadine Shehab, Scott R. Kegler, Chesley L. Richards
Journal: Annals of Internal Medicine (2007)

The Beers criteria identify inappropriate use of medications in older adults. The number of and risk for adverse events from these medications are unknown.To estimate the number of and risk for emergency department visits for adverse events involving Beers criteria medications compared with other medications.Nationally representative, public health surveillance of adverse drug events and a cross-sectional survey of outpatient medical visits.National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance System, 2004-2005; National Ambulatory Medical Care Survey, 2004; and National Hospital Ambulatory Medical Care Survey, 2004.Persons 65 years of age or older seeking emergency department and outpatient care.Estimated number of and risks for emergency department visits for adverse drug events involving Beers criteria medications and other medications.Among U.S. patients 65 years of age or older, an estimated 177,504 emergency department visits (95% CI, 100,155 to 254,854 visits) for adverse drug events occurred both years. An estimated 3.6% (CI, 2.8% to 4.5%) of these visits were for adverse events medications considered to be always potentially inappropriate, according to the Beers criteria, and 33.3% (CI, 27.8% to 38.7%) of visits were for adverse events from 3 other medications (warfarin [17.3%], insulin [13.0%], and digoxin [3.2%]). Accounting for outpatient prescription frequency, the risk for emergency department visits for adverse events due to these 3 medications was 35 times (CI, 9.6 to 61) greater than that for medications considered to be always potentially inappropriate.Adverse events were identified only in emergency departments.Compared with other medications, Beers criteria medications caused low numbers of and few risks for emergency department visits for adverse events. Performance measures and interventions targeting warfarin, insulin, and digoxin use could prevent more emergency department visits for adverse events.
Gastric pH and microflora of normal and diarrhoeic infants.
Authors: H V Maffei, F J Nobrega
Journal: Gut (1975)

The microflora and pH of gastric contents were determined in breast-fed and in bottle-fed normal infants, in well nourished infants with acute diarrhoea and in infants with chronic diarrhoea and protein-calorie malnutrition. The last group of infants was reevaluated after recovery from diarrhoea and protein-calorie malnutrition. A bactericidal pH effect below 2-5 was observed. Bottle-fed controls had low pH values and low bacterial concentrations, whereas infants with chronic diarrhoea and protein-calorie malnutrition had high pH values and bacterial overgrowth, essentially of Gram-negative bacilli. After recovery, the only remaining alteration was the frequent isolation of yeast-like fungi in low concentrations. Infants with acute diarrhoea, except for the isolation more frequently of yeast-like fungi, presented no alterations; this seems to indicate that pH alterations and Gram-negative bacilli overgrowth occurred during the evolution of the disease to a chronic state. Breast-fed normal infants had hydrogen-ion concentrations similar to those of the chronic diarrhoea group, but without Gram-negative bacilli overgrowth, suggesting that other factors, besides pH, regulate bacterial growth in the gastric contents of these groups of infants.
Impact of transition from analog screening mammography to digital screening mammography on screening outcome in The Netherlands: a population-based study
Authors: J. Nederend, L.E.M. Duijm, M.W.J. Louwman, J.H. Groenewoud, A.B. Donkers-van Rossum, A.C. Voogd
Journal: Annals of Oncology (2012)
Statins in pregnancy
Authors: F. Haramburu, A. Daveluy, G. Miremont-Salame
Journal: BMJ (2015)

New safety data are reassuring, but suspension of treatment is still advisable

The linked study (doi:10.1136/bmj.h1035) by Bateman and colleagues1 is an important contribution to our knowledge about the teratogenic potential of statins in early pregnancy. It is a well designed epidemiological study of pregnancy and childbirth among a large cohort of US women enrolled in the US Medicaid programme between 2000 and 2007.

The authors analysed 886 996 pregnancies that ended with a liveborn infant, representing approximately 40% of all births in the United States during the study period. They used sophisticated analytical techniques, including high density propensity scoring, to compare otherwise similar women who did or did not use a statin during their first trimester. Propensity scoring helps minimise confounding by adjusting for the many important differences between exposed and unexposed women, such as prevalence of diabetes (which is higher among women taking statins) and use of other drugs. These techniques are rarely used in studies of medicines in pregnant women and are an important strength of the new work.

Bateman and colleagues’ study evaluates the teratogenic potential of statins taken in the first trimester of …