tbuckley/cabot-search huggingface dataset:
Phosphoinositide 3-OH Kinase Inhibition Prevents Ventilation-induced Lung Cell Activation
Authors: Ulrike Uhlig, Heinz Fehrenbach, Robert A. Lachmann, Torsten Goldmann, Burkhard Lachmann, Ekkehard Vollmer, Stefan Uhlig
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

In acute respiratory distress syndrome patients, protective ventilation strategies reduce mortality and proinflammatory mediator levels. It has been suggested that some of the side effects of mechanical ventilation are caused by the excessive release of mediators capable of causing pulmonary inflammation and tissue destruction (biotrauma). Selective inhibition of this process might be used to minimize the side effects of artificial mechanical ventilation. This study was designed to identify the cell types and specific signaling mechanisms that are activated by ventilation with increased pressure/volume (overventilation). In isolated perfused mouse lungs, overventilation caused nuclear translocation of nuclear factor-κB (NF-κB) and enhanced expression of interleukin-6 mRNA in alveolar macrophages and alveolar epithelial type II cells. The phosphoinositide 3-OH kinase inhibitor Ly294002 prevented nuclear translocation of NF-κB and the subsequent release of interleukin-6 and macrophage inflammatory protein–2α in overventilated but not in endotoxic lungs. Similar results were obtained in rats in vivo, where Ly294002 prevented NF-κB activation by overventilation but not by endotoxin. These findings show that alveolar macrophages and alveolar epithelial type II cells contribute to the ventilation-induced release of proinflammatory mediators and that selective inhibition of this process is possible without inhibiting the activation of NF-κB by endotoxin.
Observations on Hydatid Disease of the Liver
Authors: P. M. Duncan
Journal: BMJ (1850)

LIVER. open; free diaphoresis, with less of that characteristic odour.gth.-Has continued quite free from pain ever since the last visit, moves about the bed with ease and comfort, and considers the weakness to be heronly ailmeit.Pulse 80; heart sounds natural.Substitute for the Potassxe Nitras (which she has taken to the present time) carbonate of ammonia, in infusion of quassia, three times a day.CAsE II.Thomas Barton, aged 32 years, a gatekeeper on the South Western Railway, sent for me, September 16th, 1850, and states that he has been ill three days.Was frst taken with rigors, pain in the limbs, and symptoms of general cold.He now complains of pain in the left knee and right ankle, which has been very acute the last two days.These joints are swollen, red, hot, and tender, and not benefitted by repeated infrictions of " Dredge's Heal-all."Much thirst and heat o skin; no difficulty of breathing; pulse 100; tongue furred; bowels constipated; urine depositing lithates.R. Pulv.Cath., scr.j., statim.-R.Pulv.Pot.Nit., scr.j, quartis hors ex oz.iss.Mist.Camph.Wrap the joints in flamnel and take slops.17th.-Much the same; urine scanty and high coloured; sediment abundant; bowels freely open.Diaphoresis.l9th.-Is in less pain in the knee and ankle; feels a stiffness of the shoulders; has perspired profusely; urine more abundant and clear.21st.-Muchbetter.Continue medicine.23rd.-Walkedout.Omit the Nit.Pot. and take a tonic for a few days.
Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency
Authors: Gilles Faury, Mylène Pezet, Russell H. Knutsen, Walter A. Boyle, Scott P. Heximer, Sean E. McLean, Robert K. Minkes, Kendall J. Blumer, Attila Kovacs, Daniel P. Kelly, Dean Y. Li, Barry Starcher, Robert P. Mecham
Journal: Journal of Clinical Investigation (2003)

Supravalvular aortic stenosis is an autosomal-dominant disease of elastin (Eln) insufficiency caused by loss-of-function mutations or gene deletion. Recently, we have modeled this disease in mice (Eln+/–) and found that Eln haploinsufficiency results in unexpected changes in cardiovascular hemodynamics and arterial wall structure. Eln+/– animals were found to be stably hypertensive from birth, with a mean arterial pressure 25–30 mmHg higher than their wild-type counterparts. The animals have only moderate cardiac hypertrophy and live a normal life span with no overt signs of degenerative vascular disease. Examination of arterial mechanical properties showed that the inner diameters of Eln+/– arteries were generally smaller than wild-type arteries at any given intravascular pressure. Because the Eln+/– mouse is hypertensive, however, the effective arterial working diameter is comparable to that of the normotensive wild-type animal. Physiological studies indicate a role for the renin-angiotensin system in maintaining the hypertensive state. The association of hypertension with elastin haploinsufficiency in humans and mice strongly suggests that elastin and other proteins of the elastic fiber should be considered as causal genes for essential hypertension.
In Vivo Incorporation of Acetate-1-C <sup>14</sup> into Cholesterol and Fatty Acids Following Testosterone Propionate Administration
Authors: Robert L. Raiford, Harry Y. c. Wong
Journal: Circulation Research (1962)

The administration of testosterone propionate for three weeks resulted in an increased incorporation of sodium acetate-1-C 14 into cholesterol and fatty acids. This increased conversion was evident in both the plain-mash and the atherogenic-diet cockerels. Thus, the hypocholesterolemic effect of testosterone propionate is not the result of a decreased synthesis of cholesterol and/or fatty acids. In addition, a trend towards lowering of the plasma and tissue cholesterol levels of the atherogenic-diet animals is indicated.
THE ROLE OF THE MICROBIAL FLORA IN UREMIA
Authors: Albert Einheber, Darryl Carter
Journal: The Journal of Experimental Medicine (1966)

Germfree rats were used in 3 experiments to study the effects of the microbial flora on survival time after acute uremia produced by a one-stage bilateral nephrectomy. Germfree rats, limited-flora rats, and conventionalized rats (all maintained continuously in isolators) were subjected to nephrectomy or to sham nephrectomy, deprived of food and water until they died, respectively, of uremia or of starvation, and their survival times compared. To establish a limited defined flora in advance of nephrectomy, germfree rats were either monocontaminated (Staphylococcus albus), dicontaminated (S. albus and Proteus mirabilis) or tetracontaminated (S. albus, S. faecalis, P. mirabilis, and E. coli); to conventionalize germfree rats, they were exposed to the mixed microbial flora contained in the cecal contents of ordinary rats, which was the source of the aforementioned bacteria and which included other uncharacterized microorganisms as well. The intestine of all rats with a limited flora persisted in a morphologic state that was virtually no different from that of the germfree rat, including the presence of an enlarged, thin-walled cecum; by contrast, the intestine of the conventionalized rats permanently assumed the morphological characteristics of ordinary, open-laboratory rats with the cecum reduced to normal size. After nephrectomy and food and water deprivation (death from anuria): (a) All germfree rats but one outlived their conventionalized counterparts in each of the 3 experiments; the 21 germfree rats (127 hr) lived, on the average, 2 days longer than did the 24 conventionalized rats (75 hr). No sex difference was demonstrated. (b) The rats with a limited flora died correspondingly sooner as the complexity of their flora increased; survival time of the tetracontaminated rats was significantly shorter than that of the germfree rats, and statistically no different from that of the conventionalized rats. After sham nephrectomy and food and water deprivation (delayed death from starvation): (a) All rats, irrespective of microbial status or sex, outlived their fasting nephrectomized partners. The conventionalized rats endured starvation approximately 2.5 wk longer than they did anuria and the germfree rats 1 wk longer. (b) All conventionalized rats, both male and female, outlived their respective germfree counterparts by about 1 wk. (c) All males, irrespective of microbial status, survived longer than did the females; the average difference was 4 days. The differences in tolerance to anuria or starvation did not correlate with initial body weight or rate of weight loss.
Hand eczema and atopic dermatitis in adolescents: a prospective cohort study from the BAMSE project
Authors: C. Grönhagen, C. Lidén, C.-F. Wahlgren, N. Ballardini, A. Bergström, I. Kull, B. Meding
Journal: British Journal of Dermatology (2015)

There is a well-known association between atopic dermatitis (AD) and hand eczema but less is known about how age at onset, persistence and severity of AD influence the risk of developing hand eczema.To examine the role of AD in the occurrence of hand eczema in adolescence. In addition, associations between asthma and rhinoconjunctivitis, sensitization to common airborne and food allergens, and hand eczema were studied.From the population-based birth cohort BAMSE, 2927 adolescents who had been followed up repeatedly concerning allergy-related disease were included. Questionnaires identified adolescents with hand eczema at 16 years, and their blood was analysed for specific IgE.A total of 152 (5·2%) adolescents had hand eczema at the age of 16 years. Many of these adolescents had a history of AD (n = 111; 73·0%) and asthma and/or rhinitis (n = 83; 54·6%), respectively. Children with AD (aged 0-16 years) had more than threefold increased odds ratios (OR) for having hand eczema; those with persistent or severe AD had a crude OR of 6·1 [95% confidence interval (CI) 4·0-9·1] and 5·3 (95% CI 2·9-9·6), respectively.We confirm a strong association between AD during childhood and hand eczema in adolescence. Children with persistent or more severe AD are at greater risk of developing hand eczema. Asthma and/or rhinoconjunctivitis, positive specific IgE or age at onset of AD are not associated with hand eczema in adolescence.
Lung function 8-18 years after intermittent positive pressure ventilation for hyaline membrane disease.
Authors: M J de Kleine, C M Roos, W J Voorn, H M Jansen, J G Koppe
Journal: Thorax (1990)

Lung function and respiratory symptoms were studied in 40 children aged 8-18 years who had been ventilated for hyaline membrane disease after birth; 11 had had bronchopulmonary dysplasia. Also studied were 38 age matched children who had had hyaline membrane disease but had not required ventilation, 25 unmatched children who were born prematurely but did not develop hyaline membrane disease, and 39 randomly selected pupils of similar age. There was no difference in thoracic gas volume, total lung capacity, inspiratory vital capacity, residual volume, or transfer factor for carbon monoxide between the groups. Respiratory symptoms during the three years before the study and the frequency of clinically diagnosed asthma in patients and their family were similar in all the children with hyaline membrane disease irrespective of whether they had been ventilated or had had bronchopulmonary dysplasia. The children with bronchopulmonary dysplasia, however, had a lower forced expiratory volume in one second (FEV1) before bronchodilator (73% predicted) than the other groups (88-95% predicted). Children who had required ventilation had lower values for specific airways conductance (sGaw) and a greater increase in FEV1 (delta FEV1) after salbutamol (13%) than non-ventilated children (6%); delta FEV1 was associated with the peak pressure of intermittent positive pressure ventilation, a family history of asthma and a history of wheezing, recurrent respiratory illnesses, and a doctor's diagnosis of asthma during the three years before the study. These findings indicate that after eight years of age patients with bronchopulmonary dysplasia have more reversible airways obstruction, compatible with increased bronchial smooth muscle tone.
Radical reform follows normalised deviance
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2013)

Any phrase can quickly become a cliche. Within seconds of its conception it can be tweeted around the world, depending on the number and dispersion of your followers. A little later you hear it on radio or television or read it on a website. When you see it again in your daily newspaper the following morning it already looks tired and annoyingly familiar. You've heard it everywhere. From originality to tedium within 24 hours. Hello, 21st century.

When the Mid Staffordshire report was published earlier this year, normalised deviance enjoyed such brief fascination. The problem with cliches is that we see the words but cease to think about their meaning. Normalised deviance deserves a better fate. Paul Barach and Grant Phelps remind us of the damaging impact of normalised deviance at Stafford Hospital and what approaches might be taken to reduce it.1

Other articles in this issue challenge behaviour that might be described as normalised deviance in different areas of medical practice. Informed consent was once an important advance in delivering better care and protecting patients. Yet Angela Coulter and colleagues believe that informed consent isn't sufficient because of the way clinicians have implemented it, the current process of consent, even if informed, does not place the patient central in the decision-making process.2 Consenting, they explain, implies passive acquiescence to the doctor's decision, instead of an active informed choice by the patient. Their argument for a new gold standard of ‘informed request' is a powerful one.

In general practice, a capitation-based payment system that pays per patient rather than per episode, can create perverse incentives whilst being unresponsive to patient complexity and new service demands. Azeem Majeed provides a clear account of how the current funding system works in general practice and why it is time to consider modifying it in favour of methods that link workload more closely to funding.3 Radical reform is required since the funding model is ill-equipped to meet the needs of primary care in the UK in the 21st century.

Perhaps you might struggle to agree that all these examples typify normalised deviance? If you do see something in the concept, you might also appreciate that when we indentify normalised deviance the only response is radical reform. That's why normalised deviance, however often we read or hear about it, should never become a cliche.
Rise in cytosolic Ca2+ and collapse of mitochondrial potential in anoxic, but not hypoxic, rat proximal tubules.
Authors: S M Peters, M J Tijsen, R J Bindels, C H Van Os, J F Wetzels
Journal: Journal of the American Society of Nephrology (1996)

It has been suggested that ischemic renal proximal tubular cell injury is mediated by an increase in cytosolic calcium concentrations ((Ca2+)i). However, measurements of (Ca2+)i in rat or rabbit proximal tubules exposed to hypoxia or anoxia have yielded ambiguous results. This study explored the possibility that the severity of oxygen deprivation and the energy state of the mitochondria are important determinants of (Ca2+)i. To this end, (Ca2+)i (measured with fura-2) and the mitochondrial membrane potential (measured with rhodamine 123) were studied simultaneously in individual rat proximal tubules in hypoxic and anoxic conditions. (Ca2+)i did not change during hypoxia, but increased rapidly during anoxia. Increases in (Ca2+)i were only observed in parallel with a decrease of rhodamine 123 fluorescence, which indicates a collapse of the mitochondrial membrane potential. The increase in (Ca2+)i during anoxia was prevented by incubating the tubules in a low Ca2+ medium, which did not interfere with the collapse of the mitochondrial membrane potential. Both hypoxic and anoxic incubation led to cell death, as assessed by the fluorescent dye propidium iodide. These results clearly demonstrate that the level of oxygen deprivation is critical in determining changes in (Ca2+)i. Because cell damage occurred in both hypoxic and anoxic conditions. It was concluded that an increase in (Ca2+)i is not a necessary prerequisite for the development of ischemic cell injury.
Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development
Authors: Melissa A. Tran, Charles D. Smith, Mark Kester, Gavin P. Robertson
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Deregulation of phosphatidylinositol 3-kinase/Akt and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathways occurs in melanoma and breast cancer, deregulating normal cellular apoptosis and proliferation. Therapeutic cocktails simultaneously targeting these pathways could promote synergistically acting tumor inhibition. However, agents with manageable toxicity and mechanistic basis for synergy need identification. The purpose of this study is to evaluate the preclinical therapeutic efficacy and associated toxicity of combining sorafenib with nanoliposomal ceramide. Experimental Design: Effects of sorafenib and nanoliposomal ceramide as single and combinatorial agents were examined on cultured cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assays and CalcuSyn software used to assess synergistic or additive inhibition. Western blotting measured cooperative effects on signaling pathways. Rates of proliferation, apoptosis, and angiogenesis were measured in size- and time-matched tumors to identify mechanistic basis for inhibition. Toxicity was evaluated measuring animal weight, blood toxicity parameters, and changes in liver histology. Results: Sorafenib and nanoliposomal ceramide synergistically inhibited cultured cells by cooperatively targeting mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling. A 1- to 2-fold increase in cellular apoptosis and 3- to 4-fold decrease in cellular proliferation were observed following combination treatment compared with single agents, which caused synergistically acting inhibition. In vivo, an ∼30% increase in tumor inhibition compared with sorafenib treatment alone and an ∼58% reduction in tumor size compared with nanoliposomal ceramide monotherapy occurred by doubling apoptosis rates with negligible systemic toxicity. Conclusions: This study shows that nanoliposomal ceramide enhances effectiveness of sorafenib causing synergistic inhibition. Thus, a foundation is established for clinical trials evaluating the efficacy of combining sorafenib with nanoliposomal ceramide for treatment of cancers.
Complete heart block in an adult with corrected transposition of the great arteries treated with permanent pacemaker.
Authors: S Amikam, J Lemer, Y Kishon, E Riss, H N Neufeld
Journal: Thorax (1979)

A 53-year-old patient with corrected transposition of the great arteries developed complete heart block with fainting episodes. After temporary pacing through the endocardium of the venous (anatomically left) ventricle, a permanent epicardial pacemaker was implanted. This case shows the progressive nature of the atrioventricular conduction disturbances, which are very common in association with this congenital cardiac anomaly.
Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer
Authors: Georgiana K. Ellis, Henry G. Bone, Rowan Chlebowski, Devchand Paul, Silvana Spadafora, Judy Smith, Michelle Fan, Susie Jun
Journal: Journal of Clinical Oncology (2008)

Purpose Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor–positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand, to protect against aromatase inhibitor–induced bone loss. Patients and Methods Eligible women with hormone receptor–positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (≤ 6 v &gt; 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). Results At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P &lt; .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. Conclusion In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.
The effects of acute and chronic cocaine use on the heart.
Authors: R A Kloner, S Hale, K Alker, S Rezkalla
Journal: Circulation (1992)

It is clear that cocaine has cardiotoxic effects. Acute doses of cocaine suppress myocardial contractility, reduce coronary caliber and coronary blood flow, induce electrical abnormalities in the heart, and in conscious preparations increase heart rate and blood pressure. These effects will decrease myocardial oxygen supply and may increase demand (if heart rate and blood pressure rise). Thus, myocardial ischemia and/or infarction may occur, the latter leading to large areas of confluent necrosis. Increased platelet aggregability may contribute to ischemia and/or infarction. Young patients who present with acute myocardial infarction, especially without other risk factors, should be questioned regarding use of cocaine. As recently pointed out by Cregler, cocaine is a new and sometimes unrecognized risk factor for heart disease. Acute depression of LV function by cocaine may lead to the presence of a transient cardiomyopathic presentation. Chronic cocaine use can lead to the above problems as well as to acceleration of atherosclerosis. Direct toxic effects on the myocardium have been suggested, including scattered foci of myocyte necrosis (and in some but not all studies, contraction band necrosis), myocarditis, and foci of myocyte fibrosis. These abnormalities may lead to cases of cardiomyopathy. Left ventricular hypertrophy associated with chronic cocaine recently has been described. Arrhythmias and sudden death may be observed in acute or chronic use of cocaine. Miscellaneous cardiovascular abnormalities include ruptured aorta and endocarditis. Most of the cardiac toxicity with cocaine can be traced to two basic mechanisms: one is its ability to block sodium channels, leading to a local anesthetic or membrane-stabilizing effect; the second is its ability to block reuptake of catecholamines in the presynaptic neurons in the central and peripheral nervous system, resulting in increased sympathetic output and increased catecholamines. Other potential mechanisms of cocaine cardiotoxicity include a possible direct calcium effect leading to contraction of vessels and contraction bands in myocytes, hypersensitivity, and increased platelet aggregation (which may be related to increased catecholamine). The correct therapy for cocaine cardiotoxicity is not known. Calcium blockers, alpha-blockers, nitrates, and thrombolytic therapy show some promise for acute toxicity. Beta-Blockade is controversial and may worsen coronary blood flow. In patients who develop cardiomyopathy, the usual therapy for this entity is appropriate.