tbuckley/cabot-search huggingface dataset:
Ventilation-perfusion mismatching in acute severe asthma: effects of salbutamol and 100% oxygen.
Authors: E Ballester, A Reyes, J Roca, R Guitart, P D Wagner, R Rodriguez-Roisin
Journal: Thorax (1989)

Ventilation-perfusion (VA/Q) relationships and gas exchange were studied by the multiple inert gas technique in 19 patients admitted to hospital with acute severe asthma (FEV1 41% predicted) before and during the administration of intravenous salbutamol, inhaled salbutamol, or 100% oxygen. Eight patients received a continuous intravenous infusion of salbutamol (4 micrograms/min, total dose 360 micrograms) and were studied before treatment, after 60 and 90 minutes of treatment, and one hour after treatment had been discontinued. Six patients had measurements before and 15 minutes after inhaling 300 micrograms salbutamol from a metered dose inhaler on two occasions (total dose 600 micrograms) and one hour after the last dose. Measurements were also made in five patients before and while they breathed 100% oxygen for 20 minutes. At baseline (fractional inspired oxygen (FiO2) 21%) all patients showed a broad unimodal (n = 10) or bimodal (n = 9) distribution of blood flow with respect to VA/Q. A mean of 10.5% of the blood flow was associated with low VA/Q units without any appreciable shunt. One of the best descriptors of VA/Q inequality, the second moment of the perfusion distribution on a log scale (log SD Q), was moderately high with a mean of 1.18 (SEM 0.08) (normal less than 0.6). Measures of VA/Q inequality correlated poorly with spirometric findings. After salbutamol the increase in airflow rates was similar regardless of the route of administration. Intravenous salbutamol, however, caused a significant increase in heart rate, cardiac output, and oxygen consumption (VO2); in addition, both perfusion to low VA/Q areas and log SD Q increased significantly. Inhaled salbutamol caused only minor changes in heart rate, cardiac output, VO2, and VA/Q inequality. Arterial oxygen tension (PaO2) remained unchanged during salbutamol administration, irrespective of the route of administration. During 100% oxygen breathing there was a significant increase in log SD Q (from 1.11 to 1.44). It is concluded that patients with acute severe asthma show considerable VA/Q inequality with a high level of pulmonary vascular reactivity. Despite similar bronchodilator effects from inhaled and intravenous salbutamol, VA/Q relationships worsened only during intravenous infusion. PaO2 remained unchanged, however, because the change in VA/Q relationships was associated with an increase in metabolic rate and cardiac output.
Inhaled nitric oxide in hypoxaemic newborns who are candidates for extracorporeal life support
Authors: P Biban, D Trevisanuto, A Pettenazzo, P Ferrarese, E Baraldi, F Zacchello
Journal: European Respiratory Journal (1998)

The aim of this study was to evaluate the effect of inhaled nitric oxide (NO) in newborns with acute hypoxaemic respiratory failure and the impact of this NO therapy on survival and the need for extracorporeal membrane oxygenation (ECMO). A cohort of newborns with a gestational age of &gt; or = 34 weeks and an oxygenation index (OI) &gt; 25 were prospectively evaluated. Patients were given NO at an initial dose of 10 parts per million (ppm). Oxygenation parameters were evaluated prior and during NO inhalation. From January 1994 to December 1996, 20 infants were enrolled in the study. Based upon their outcome, patients were divided into two groups: survivors with no need for ECMO, group A (n=8) and survivors requiring ECMO or nonsurvivors, group B (n=12). All infants approached or met ECMO criteria before NO inhalation. Eight patients (40%) were successfully managed with NO and conventional treatment (group A). Newborns in this group showed a rapid and sustained improvement of systemic oxygenation during NO inhalation. Mean arterial oxygen tension (Pa,O2) increased significantly from 4.5 kPa (34 mmHg) (95% confidence interval (95% CI) 1.9-7.1 kPa (14.4-53.7 mmHg)) to 10.1 kPa (75.7 mmHg) (95% CI 6.5-13.6 kPa (49.1-1023 mmHg)) after 1 h and was 9.0 kPa (67.7 mmHg) (95% CI 7.1-11.0 kPa (53.1-82.4 mmHg)) at 24 h. Conversely, none of the oxygenation parameters improved in the 12 patients who ultimately required ECMO or died (group B). The results indicate that inhaled nitric oxide can improve systemic oxygenation in newborns with acute respiratory failure and may reduce the need for extracorporeal membrane oxygenation support in candidates. Lack of a rapid response to nitric oxide may be an early predictor of unfavourable short-term outcome, prompting a move towards alternative treatments.
Prednisolone With vs Without Pentoxifylline and Survival of Patients With Severe Alcoholic Hepatitis
Authors: Philippe Mathurin, Alexandre Louvet, Alain Duhamel, Pierre Nahon, Nicolas Carbonell, Jérôme Boursier, Rodolphe Anty, Emmanuel Diaz, Dominique Thabut, Romain Moirand, Didier Lebrec, Christophe Moreno, Nathalie Talbodec, Thierry Paupard, Sylvie Naveau, Christine Silvain, Georges-Philippe Pageaux, Rodolphe Sobesky, Valérie Canva-Delcambre, Sébastien Dharancy, Julia Salleron, Thong Dao
Journal: JAMA (2013)

Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown.To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone.Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome.Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days.Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment.In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = .91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = .07).In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline.clinicaltrials.gov Identifier: NCT01214226.
PSYCHIATRIC FACTORS IN MEDICAL STUDENTS IN DIFFICULTY: A FOLLOW-UP STUDY
Authors: RAYMOND W. WAGGONER, THORNTON WOODWARD ZEIGLER
Journal: American Journal of Psychiatry (1961)

1. A student evaluation and assistance program of the sort referred to here functions most satisfactorily if the number of psychologists and psychiatrists are sharply limited, and if they work together as a unit with the Admissions Committee and the Promotion Board. 2. Prognostic evaluations based upon such studies appear to be relatively valid. 3. More attention should be paid to personality characteristics and to motivation in the selection of students for the study of medicine. 4. Research should be undertaken to determine those factors which correlate best with success in the field of medicine. An example of such research is that which has been done by Dr. Lowell Kelly and his associates. This type of investigation should be continued and amplified.
Stromal ING1 expression induces a secretory phenotype and correlates with breast cancer patient survival
Authors: Satbir Thakur, Arash Nabbi, Alexander Klimowicz, Karl Riabowol
Journal: Molecular Cancer (2015)

Previous studies have established that levels of the Inhibitor of Growth 1(ING1) tumor suppressor are reduced in a significant proportion of different cancer types. Here we analyzed levels of ING1 in breast cancer patients to determine its prognostic significance as a biomarker for breast cancer prognosis.We used automated quantitative analysis (AQUA) to determine the levels of ING1 in the tumor associated stromal cells of 462 breast cancer samples. To better understand how high ING1 levels affect nearby epithelium, we measured the levels of cytokines and secreted matrix metalloproteases (MMPs), using an ELISA based assay in mammary fibroblasts overexpressing ING1. These cells were also used in a 3-dimensional co-culture with MCF7 cells to determine the effect of released MMPs and other cytokines on growing colonies.We find that high levels of ING1 in stroma are associated with tumor grade (p = 0.001) and size (p = 0.02), and inversely associated with patient survival (p = 0.0001) in luminal, but not in non-luminal cancers, suggesting that high stromal ING1 promotes cancer development. In this group of patients ING1 could also predict patient survival and act as a biomarker (HR = 2.125). While ING1 increased or decreased the expression of different cytokines, ING1 also increased the levels of MMP1, MMP3 and MMP10 by 5-8 fold, and concomitantly decreased levels of the tissue inhibitors of metalloproteases TIMP2, TIMP3 and TIMP4 by 1.5-3.3 fold, resulting in significant increases in MMP activity as determined by zymography. Co-culturing of MCF7 cells with stromal cells expressing ING1 in 3-dimensional organoid cultures suggested that MCF7 colonies were less well defined, suggesting that secreted MMPs might promote migration.These data indicate that stromal ING1 expression can predict the survival of patients with luminal breast cancer. High levels of ING1 in stromal cells can promote the development of breast cancer through increased expression and release of MMPs and down regulation of TIMPs, which may be an underlying mechanism of reduced patient survival.
Phase I and Pharmacokinetic Study of Aplidine, a New Marine Cyclodepsipeptide in Patients With Advanced Malignancies
Authors: Sandrine Faivre, Stéphanie Chièze, Catherine Delbaldo, Nora Ady-vago, Cecilia Guzman, Luis Lopez-Lazaro, Stéphanie Lozahic, José Jimeno, Fernando Pico, Jean Pierre Armand, José Antonio Lopez Martin, Eric Raymond
Journal: Journal of Clinical Oncology (2005)

Purpose To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer. Patients and Methods Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks. Results Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m 2 . Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m 2 . No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m 2 and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m 2 . Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma. Conclusion Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m 2 without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.
Methotrexate is the leading DMARD in Finland
Authors: T Klaukka
Journal: Annals of the Rheumatic Diseases (2003)

We read with interest the report by Aletaha et al on international questionnaires of the early treatment of rheumatoid arthritis (RA).1 We would like to draw attention to the newest statistics in Finland.

In Finland the sickness insurance scheme provides reimbursement (today 75%) for prescription drugs in chronic inflammatory rheumatic diseases, principally rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, chronic reactive arthritis, juvenile idiopathic arthritis, and systemic rheumatic diseases. Eligibility entails a medical certificate written by a specialist in rheumatology and approved by the welfare authorities. All patients who are entitled to reimbursement are centrally registered by the social insurance institution. Glucocorticoids and disease modifying antirheumatic drugs (DMARDs) are medicines which can be reimbursed in this category. …
Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses
Authors: Veronica Sanna, Antonio Di Giacomo, Antonio La Cava, Robert I. Lechler, Silvia Fontana, Serafino Zappacosta, Giuseppe Matarese
Journal: Journal of Clinical Investigation (2003)

In the work presented here, we explored the influence of leptin on the kinetics of experimental autoimmune encephalomyelitis (EAE) onset, in the EAE-associated inflammatory anorexia, and in the development of pathogenic T cell responses. We found that the expression of serum leptin increased before the clinical onset of EAE in disease-susceptible C57BL/6J (H-2(b)) and SJL/J (H-2(s)) strains of mice, which are models of chronic-progressive and relapsing-remitting EAE, respectively. This increase in serum leptin correlated with disease susceptibility, reduction in food intake, and decrease in body weight. Indeed, acute starvation, which is able to prevent the increase in serum leptin, delayed disease onset and attenuated clinical symptoms by inducing a T helper 2 cytokine switch. Furthermore, immunohistochemical analysis revealed a parallel in situ production of leptin in inflammatory infiltrates and in neurons only during the acute/active phase of both chronic-progressive and relapsing-remitting EAE. We also found that leptin secretion by activated T cells sustained their proliferation in an autocrine loop, since antileptin receptor antibodies were able to inhibit the proliferative response of autoreactive T cells in vitro. Given that leptin appears to regulate EAE susceptibility, inflammatory anorexia, and pathogenic T-cell immune function, we postulate that it may offer a potential target in the treatment of multiple sclerosis.
Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin
Authors: Matthew C. Riddle, Ronnie Aronson, Philip Home, Michel Marre, Elisabeth Niemoeller, Patrick Miossec, Lin Ping, Jenny Ye, Julio Rosenstock
Journal: Diabetes Care (2013)

To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA1c).We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA1c reduction from baseline was the primary end point.Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA1c from baseline was -0.4% (95% CI -0.6 to -0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, -3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, -1.3 kg; P < 0.0001) and insulin dosage (-3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo.By improving HbA1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.
Evaluation of B-type natriuretic peptide for risk assessment in unstable Angina/Non–ST-elevation myocardial infarction
Authors: David A. Morrow, James A. de Lemos, Marc S. Sabatine, Sabina A. Murphy, Laura A. Demopoulos, Peter M. DiBattiste, Carolyn H. McCabe, C.Michael Gibson, Christopher P. Cannon, Eugene Braunwald
Journal: Journal of the American College of Cardiology (2003)
Role of membrane immunoglobulin (Ig) crosslinking in membrane Ig-mediated, major histocompatibility-restricted T cell-B cell cooperation.
Authors: H P Tony, N E Phillips, D C Parker
Journal: The Journal of Experimental Medicine (1985)

Resting murine B lymphocytes can present rabbit anti-Ig to T cell lines specific for normal rabbit globulin. The T cell-B cell interaction is major histocompatibility complex (MHC)-restricted, and leads to activation, proliferation, and differentiation of the resting B cell into an antibody-secreting cell. Efficient antigen presentation and B cell activation depends upon binding of rabbit globulin to (membrane) mIg. To investigate the role of mIg in this polyclonal model for a T cell-dependent primary antibody response, we determined whether crosslinking of mIg is required either for efficient antigen presentation, as measured by helper T cell activation, or for the B cell response to T cell help, since all the direct effects of anti-Ig on B cells require crosslinking of mIg. We found that monovalent Fab' fragments of anti-IgM or anti-IgD work as efficiently as their divalent counterparts. Therefore, a signal transduced through the antigen receptor seems not to be required when T cell help is provided by an MHC-restricted T helper cell recognizing antigen on the B cell surface. Moreover, rabbit globulin bound to class I MHC molecules in the form of anti-H-2K also results in efficient antigen presentation and T cell-dependent B cell activation. However, mIg still appears to be specialized for antigen presentation, since anti-Ig is presented about three- to fivefold more efficiently than anti-H-2K.
Collagen diseases as a cause of constrictive pericarditis.
Authors: D K Cooper, W P Cleland, H H Bentall
Journal: Thorax (1978)

Seven patients with constrictive pericarditis associated with collagen disease underwent pericardiectomy with good results in all but one. The collagen disease was confirmed as rheumatoid arthritis in five patients, but in two its nature remained obscure. In one case the illness was marked by a persistent eosinophilia and eosinophilic infiltration of the pericardium. The association of constrictive pericarditis with rheumatoid arthritis and other collagenoses is briefly discussed.
Ecological and Genetic Barriers Differentiate Natural Populations of<i>Saccharomyces cerevisiae</i>
Authors: Katie J Clowers, Justin Heilberger, Jeff S Piotrowski, Jessica L Will, Audrey P Gasch
Journal: Molecular Biology and Evolution (2015)

How populations that inhabit the same geographical area become genetically differentiated is not clear. To investigate this, we characterized phenotypic and genetic differences between two populations of Saccharomyces cerevisiae that in some cases inhabit the same environment but show relatively little gene flow. We profiled stress sensitivity in a group of vineyard isolates and a group of oak-soil strains and found several niche-related phenotypes that distinguish the populations. We performed bulk-segregant mapping on two of the distinguishing traits: The vineyard-specific ability to grow in grape juice and oak-specific tolerance to the cell wall damaging drug Congo red. To implicate causal genes, we also performed a chemical genomic screen in the lab-strain deletion collection and identified many important genes that fell under quantitative trait loci peaks. One gene important for growth in grape juice and identified by both the mapping and the screen was SSU1, a sulfite-nitrite pump implicated in wine fermentations. The beneficial allele is generated by a known translocation that we reasoned may also serve as a genetic barrier. We found that the translocation is prevalent in vineyard strains, but absent in oak strains, and presents a postzygotic barrier to spore viability. Furthermore, the translocation was associated with a fitness cost to the rapid growth rate seen in oak-soil strains. Our results reveal the translocation as a dual-function locus that enforces ecological differentiation while producing a genetic barrier to gene flow in these sympatric populations.