tbuckley/cabot-search huggingface dataset:
Chest wall compliance in infants and children with neuromuscular disease.
Authors: C Papastamelos, H B Panitch, J L Allen
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Respiratory muscle weakness is the primary cause of respiratory dysfunction in neuromuscular disease (NMD), but structural abnormalities of the chest wall also play a role. In adults with NMD, restrictive lung disease is in part caused by reduced chest wall compliance (C(W)), believed to reflect stiffening of connective tissue resulting from chronically reduced chest wall motion in the presence of respiratory muscle weakness. We hypothesized that chronic limitation of chest wall motion in young children with NMD leads to structural underdevelopment of the chest wall, and results in increased, rather than decreased, C(W). In 18 subjects with NMD, ranging from 3 mo to 3.8 yr of age, we compared C(W) with values obtained in children without NMD. A modification of the Mead-Whittenberger technique was used, with respiratory muscle relaxation provided by brief manual ventilation. Respiratory system compliance (Crs) and lung compliance (C(L)) were calculated from airway opening pressure, transpulmonary pressure, and tidal volume. C(W) was calculated as 1/C(W) = 1/Crs - 1/C(L) during manual ventilation. C(W)/kg was higher in subjects with NMD than in controls, at 5.2 +/- 2.8 (mean +/- SD) versus 2.4 +/- 0.8 ml/cm H2O (p < 0.001). In subjects who had normal lung compliance values during spontaneous breathing (C(Lspont)), C(W)/C(Lspont) was significantly greater in subjects with NMD (5.5 +/- 3.2) than in controls (1.9 +/- 1.0) (p < 0.001). By predisposing to rib cage deformation and reduced end-expiratory lung volume, abnormally high C(W) in infants and young children with NMD may contribute to respiratory dysfunction.
FoxO3 hastens autophagy and shrinks the heart but does not curtail pathological hypertrophy in adult mice
Authors: X. Wang, H. Su
Journal: Cardiovascular Research (2011)

This editorial refers to ‘FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model’ by T.G. Schips et al ., doi:10.1093/cvr/cvr144 

The FoxO subfamily of Forkhead box transcription factors regulate many target genes that are involved in diverse cellular processes. FoxO proteins show partial functional redundancy due to the conserved DNA-binding domain, but also exhibit isoform specificity with regard to cellular function.1 Three of the four FoxO isoforms—FoxO1, FoxO3, and FoxO4, but not FoxO6—are expressed in the heart. The biological functions of FoxO proteins in the heart have been mainly revealed by studies on FoxO1 and FoxO3 using either cultured cardiomyocytes or loss-of-function animal models. Combined loss of FoxO1 and FoxO3 in the heart does not affect cardiac development,1 suggesting functional redundancy of FoxO proteins in regulating cardiac development. Indeed, loss of all three FoxO isoforms is required for an oncogenic phenotype in mice.2 So far, a viable animal model of FoxO gain-of-function is lacking, hindering a better understanding on the pathophysiological significance of FoxO proteins in adult hearts.

Schips et al .3 report the first mouse model of cardiac-specific and temporally controllable …
COMMUNITY TREATMENT OF END-STAGE RENAL FAILURE BY DIALYSIS AND RENAL TRANSPLANTATION FROM CADAVER DONORS
Authors: A.G.R. Sheil, J.R. Johnson, B.G. Storey, J.A. Charlesworth, A. Sharp, J.R. Sands, J.H. Stewart, J. May, J.H. Rogers, R. Wright, J.M. Johnston, J. Loewenthal
Journal: The Lancet (1969)
DNase in cystic fibrosis: the challenge of assessing response and maximising benefit
Authors: J A. INNES
Journal: Thorax (1998)

Since nebulised recombinant human DNase was licensed for use in cystic fibrosis patients in March 1994, controversy has continued over how this relatively expensive drug should be used to maximum benefit. By cleaving DNA released from dead inflammatory cells it is dramatically effective in reducing sputum viscoelasticity in vitro.1 In vivo, phase 2 trials showed encouraging improvements in spirometric2 3 and other inflammatory indices,4 and the major phase 3 trial used to support licensing5 showed that once daily treatment gave a relatively modest (5.8%) improvement in forced expiratory volume in one second (FEV1) at 24 weeks, with a significant (after age adjustment of the groups) reduction in exacerbations requiring parenteral antibiotics. This large randomised trial (968 patients) was notable, not only for the significance of the mean results, but also for the wide variability of individual responses to treatment. For example, 30% of actively treated patients showed an increase in FEV1 of over 10%, but 6% had a fall of more than 10% (so, by inference, 64% had a change in FEV1 of less than …
Time course of changes in intracellular K+, Na+, and pH of subendocardial Purkinje cells during the first 24 hours after coronary occlusion.
Authors: R P Kline, M S Hanna, K P Dresdner, A L Wit
Journal: Circulation Research (1992)

We investigated the basis for the alterations in the intracellular potassium and sodium activity occurring in subendocardial Purkinje fibers surviving in 24-hour infarcts by examining ion activities in these Purkinje fibers removed from infarcting hearts at earlier times. Specifically, we examined intracellular potassium activity, sodium activity, and pH at 1 and 3 hours after ligation of the left anterior descending coronary artery, and we correlated the changes in ion activity with changes in maximum diastolic potential. We tested various mechanistic hypotheses relating to how the ion activity changes develop and how they affect membrane potential. We found that intracellular sodium activity in tissue removed 1 hour after ligation was on average already maximally elevated by a factor of 2 over control (19.2 +/- 2.0 mM [mean +/- SEM] versus 9.4 +/- 0.4 mM). Potassium activity diminished progressively over the first 24 hours (from normal of 112.0 +/- 2.7 to 61.6 +/- 2.8 mM), although half of the decrease occurred during the first hour (to 86.8 +/- 4.1 mM). Intracellular pH did not change at either 1 or 3 hours. Whereas maximum diastolic potential depolarization exceeded the calculated depolarization of the potassium equilibrium potential by a factor of 2 in 24-hour infarcts, the depolarization at 1 and 3 hours could be more nearly attributed to the loss of potassium. The change in the dependence of maximum diastolic potential on potassium equilibrium potential may be due to changes in membrane conductance caused by ionic or biochemical factors. The changes in ion activity continuously develop during the first day after ligation and may be due to multiple factors and mechanisms.
An Investigation of Inhaled Ozone Dose and the Magnitude of Airway Inflammation in Healthy Adults
Authors: Ian S. Mudway, Frank J. Kelly
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Exposure to ozone has been associated in epidemiologic and field studies with a range of health outcomes: increased daily mortality (1); impaired lung function (2–4); and inflammation and epithelial injury in recreational runners (5) and cyclists (6), as well as increased hospital admissions for preexisting respiratory disease (7, 8). A biological basis for these responses has been provided by findings from animal (9) and human laboratorybased studies (10), where transient decrements in lung function, increased hyperreactivity, and airway inflammation have all been demonstrated after exposure to environmentally relevant concentrations of ozone (11, 12). Although the database for ozoneinduced health effects is considerable, a number of issues remain unresolved. The relationship between inhaled ozone dose and the magnitude of the resultant pulmonary response has been limited to a consideration of transient lung function decrements (12–14), as these measurements are noninvasive and easy to perform. Similar analyses addressing the relationship between ozone dose and acute pulmonary inflammation and tissue injury have not been performed. Here, the available database is more limited, and issues related to variation in study design, airway sampling, and the endpoints studied have made a similar approach more problematic. Establishing these relationships is vital in determining threshold doses of ozone below which adverse responses are negligible in the healthy population. As the magnitude of lung function decrements is not simplistically related to epithelial injury or inflammation (15), one cannot rely on estimates derived from these modeling studies to determine threshold values for these other biologically important endpoints. Here, we describe the first attempt to model the ozone dose– inflammatory response based on a metaanalysis of data from published human chamber studies, where airway responses were assessed using bronchoscopy-based lavage. Analyses of inflammatory responses were based on the percentage of neutrophils recovered by bronchoscopy-based lavage in response to a set ozone dose, expressed as a function of concentration (mg/m), Ve (L/minute/m body surface area), and exposure time (minutes) CVT (mg/m body surface area). Analysis of altered permeability responses was more complex and relied on the fold increase in
Prevention of HIV-1 Infection with Early Antiretroviral Therapy
Authors: Myron S. Cohen, Ying Q. Chen, Marybeth McCauley, Theresa Gamble, Mina C. Hosseinipour, Nagalingeswaran Kumarasamy, James G. Hakim, Johnstone Kumwenda, Beatriz Grinsztejn, Jose H.S. Pilotto, Sheela V. Godbole, Sanjay Mehendale, Suwat Chariyalertsak, Breno R. Santos, Kenneth H. Mayer, Irving F. Hoffman, Susan H. Eshleman, Estelle Piwowar-Manning, Lei Wang, Joseph Makhema, Lisa A. Mills, Guy de Bruyn, Ian Sanne, Joseph Eron, Joel Gallant, Diane Havlir, Susan Swindells, Heather Ribaudo, Vanessa Elharrar, David Burns, Taha E. Taha, Karin Nielsen-Saines, David Celentano, Max Essex, Thomas R. Fleming
Journal: New England Journal of Medicine (2011)

Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples.In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death.As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01).The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).
Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase
Authors: Yiqun Wang, Yu Huang, Karen S.L. Lam, Yiming Li, Wing Tak Wong, Hongying Ye, Chi-Wai Lau, Paul M. Vanhoutte, Aimin Xu
Journal: Cardiovascular Research (2009)

Endothelial dysfunction is a key event that links obesity, diabetes, hypertension, and cardiovascular diseases. The aim of the present study was to examine the protective effect of the alkaloid drug berberine against hyperglycemia-induced cellular injury and endothelial dysfunction. In both cultured endothelial cells and blood vessels isolated from rat aorta, berberine concentration dependently enhanced phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and promoted the association of eNOS with heat shock protein 90 (HSP90), leading to an increased production of nitric oxide. Furthermore, berberine attenuated high glucose-induced generation of reactive oxygen species, cellular apoptosis, nuclear factor-κB activation, and expression of adhesion molecules, thus suppressing monocyte attachment to endothelial cells. In mouse aortic rings, berberine elicited endothelium-dependent vasodilatations and alleviated high glucose-mediated endothelial dysfunction. All these beneficial effects of berberine on the endothelium were abolished by either pharmacological inhibition of adenosine monophosphate-activated protein kinase (AMPK) or adenovirus-mediated overexpression of a dominant negative version of AMPK. Berberine protects against endothelial injury and enhances the endothelium-dependent vasodilatation, which is mediated in part through activation of the AMPK signalling cascade. Berberine or its derivatives may be useful for the treatment and/or prevention of endothelial dysfunction associated with diabetes and cardiovascular disease.
The relationship of dietary patterns with adult lung function and COPD
Authors: S. O. Shaheen, K. A. Jameson, H. E. Syddall, A. Aihie Sayer, E. M. Dennison, C. Cooper, S. M. Robinson
Journal: European Respiratory Journal (2010)

Previous studies of diet and lung function have focused on associations with individual nutrients and foods, and not dietary patterns. The relationships between dietary patterns and lung function and spirometrically defined chronic obstructive pulmonary disease (COPD) were investigated in 1,551 males and 1,391 females in Hertfordshire, UK. Dietary information was obtained by food frequency questionnaire and dietary patterns were identified using principal components analysis. Using regression analysis, after controlling for confounders, a “prudent” pattern (high consumption of fruit, vegetables, oily fish and wholemeal cereals) was positively associated with forced expiratory volume in 1 s (FEV<sub>1</sub>) (trend p-value &lt;0.001 in males, 0.008 in females) (difference in FEV<sub>1</sub> between top and bottom quintiles of pattern score, 0.18 L (95% CI 0.08–0.28 L) in males, 0.08 L (95% CI 0.00–0.16 L) in females). This pattern was also positively associated with forced vital capacity (FVC) in both sexes. Males with a higher “prudent” pattern score had a higher FEV<sub>1</sub>/FVC (trend p-value 0.002) and a lower prevalence of COPD (odds ratio comparing top <i>versus</i> bottom quintile 0.46, 95% CI 0.26–0.81; trend p-value 0.012). Associations in males were stronger in smokers than nonsmokers (interaction p-value for FEV<sub>1</sub>/FVC 0.002). A “prudent” dietary pattern may protect against impaired lung function and COPD, especially in male smokers.
Multidrug-Resistant Plasmodium vivax Associated with Severe and Fatal Malaria: A Prospective Study in Papua, Indonesia
Authors: Emiliana Tjitra, Nicholas M Anstey, Paulus Sugiarto, Noah Warikar, Enny Kenangalem, Muhammad Karyana, Daniel A Lampah, Ric N Price
Journal: PLoS Medicine (2008)

Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia.Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08-1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl) was the major complication associated with Pv, accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126).In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing.
Autoimmune disease in mice due to integration of an endogenous retrovirus in an apoptosis gene.
Authors: J Wu, T Zhou, J He, J D Mountz
Journal: The Journal of Experimental Medicine (1993)

The MRL-lpr/lpr mouse strain is a model of systemic autoimmune disease. In this model, intrinsic defects of intrathymic T cell development include defective deletion of self-reactive T cells and expression of endogenous retroviruses. Defective deletion of self-reactive T cells in the thymus has been proposed to be due to germline mutation in the Fas apoptosis gene. Using different fragments of a Fas cDNA probe, we determined that the lpr/lpr mutation is a 5.3-kb insertion of DNA within the second intron of the Fas gene. cDNA corresponding to this region was then derived from thymic RNA from MRL-lpr/lpr and MRL- +/+ mice using the polymerase chain reaction. All thymic RNA samples from MRL-lpr/lpr mice yielded a unique product that was 168 bp larger than that of MRL- +/+ mice. Complete sequence analysis indicated that this inserted sequence had 98% homology with a sequence from the 3' long terminal repeat of the early transposon (ETn). RNA analysis indicated higher expression of ETn RNA in the thymus of MRL-lpr/lpr than MRL- +/+ mice. The interdependence of ETn expression and abnormal Fas expression was then analyzed in a CD2-Fas transgenic mouse model in which a full-length murine Fas cDNA under the regulation of the CD2 promoter and enhancer was used to correct defective Fas expression in T cells of MRL-lpr/lpr mice. In these mice, reduced thymic ETn expression was observed, confirming that high ETn expression is related to abnormal Fas expression. These results establish a link between endogenous retrovirus expression, abnormal Fas expression, and autoimmune disease.
Body Contour for Radiotherapy
Authors: L. A. Firth
Journal: BMJ (1970)

months resulted in early and continued overall improvement.The stools became firmer and the frequency reduced to two or three a day.There was relief of the abdominal pain and discomfort.His weight has remained constant at 8-st.(55 kg.).He has been maintained for 11 months on one tablet t.d.s. with no evidence of tolerance developing, and now has returned to his normal work as a garage mechanic.My thanks to Dr. B.
RANDOMIZED TRIAL OF HIGH DOSE FUROSEMIDE-HYPERTONIC SALINE IN ACUTE DECOMPENSATED HEART FAILURE WITH ADVANCED RENAL DISEASE
Authors: Richard S. Engelmeier, Thao T. Le, Salem E. Kamalay, Kyle N. Utecht, Timothy P. Nikstad, Jeffrey W. Kaliebe, Karen Olson, German Larrain
Journal: Journal of the American College of Cardiology (2012)
β-Glucan Antigenemia Anticipates Diagnosis of Blood Culture–Negative Intraabdominal Candidiasis
Authors: Frederic Tissot, Frederic Lamoth, Philippe M. Hauser, Christina Orasch, Ursula Flückiger, Martin Siegemund, Stefan Zimmerli, Thierry Calandra, Jacques Bille, Philippe Eggimann, Oscar Marchetti
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Rationale: Life-threatening intraabdominal candidiasis (IAC) occurs in 30 to 40% of high-risk surgical intensive care unit (ICU) patients. Although early IAC diagnosis is crucial, blood cultures are negative, and the role of Candida score/colonization indexes is not established.Objectives: The aim of this prospective Fungal Infection Network of Switzerland (FUNGINOS) cohort study was to assess accuracy of 1,3-β-d-glucan (BG) antigenemia for diagnosis of IAC.Methods: Four hundred thirty-four consecutive adults with abdominal surgery or acute pancreatitis and ICU stay 72 hours or longer were screened: 89 (20.5%) at high risk for IAC were studied (68 recurrent gastrointestinal tract perforation, 21 acute necrotizing pancreatitis). Diagnostic accuracy of serum BG (Fungitell), Candida score, and colonization indexes was compared.Measurements and Main Results: Fifty-eight of 89 (65%) patients were colonized by Candida; 29 of 89 (33%) presented IAC (27 of 29 with negative blood cultures). Nine hundred twenty-one sera were analyzed (9/patient): median BG was 253 pg/ml (46–9,557) in IAC versus 99 pg/ml (8–440) in colonization (P < 0.01). Sensitivity and specificity of two consecutive BG measurements greater than or equal to 80 pg/ml were 65 and 78%, respectively. In recurrent gastrointestinal tract perforation it was 75 and 77% versus 90 and 38% (Candida score ≥ 3), 79 and 34% (colonization index ≥ 0.5), and 54 and 63% (corrected colonization index ≥ 0.4), respectively. BG positivity anticipated IAC diagnosis (5 d) and antifungal therapy (6 d). Severe sepsis/septic shock and death occurred in 10 of 11 (91%) and 4 of 11 (36%) patients with BG 400 pg/ml or more versus 5 of 18 (28%, P = 0.002) and 1 of 18 (6%, P = 0.05) with BG measurement less than 400 pg/ml. β-Glucan decreased in IAC responding to therapy and increased in nonresponse.Conclusions: BG antigenemia is superior to Candida score and colonization indexes and anticipates diagnosis of blood culture–negative IAC. This proof-of-concept observation in strictly selected high-risk surgical ICU patients deserves investigation of BG-driven preemptive therapy.
Introduction to the Theme “Precision Medicine and Prediction in Pharmacology”
Authors: Paul A. Insel, Susan G. Amara, Terrence F. Blaschke
Journal: The Annual Review of Pharmacology and Toxicology (2015)

Since the spread of tobacco from the Americas hundreds of years ago, tobacco cigarettes and, more recently, alternative tobacco products have become global products of nicotine addiction. Within the evolving alternative tobacco product space, electronic ...Read More