tbuckley/cabot-search huggingface dataset:
Phase II Study of Oral Fludarabine Phosphate in Relapsed Indolent B-Cell Non-Hodgkin's Lymphoma
Authors: Kensei Tobinai, Takashi Watanabe, Michinori Ogura, Yasuo Morishima, Yoshiaki Ogawa, Ken-ichi Ishizawa, Hironobu Minami, Atae Utsunomiya, Masafumi Taniwaki, Takashi Terauchi, Shigeru Nawano, Masaki Matsusako, Yoshihiro Matsuno, Shigeo Nakamura, Shigeo Mori, Yasuo Ohashi, Masaki Hayashi, Taku Seriu, Tomomitsu Hotta
Journal: Journal of Clinical Oncology (2005)

Purpose Although intravenous (IV) fludarabine phosphate is effective against indolent B-cell non-Hodgkin's lymphoma (B-NHL), IV administration for 3 to 5 consecutive days is inconvenient in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine phosphate in patients with indolent B-NHL, we conducted a multicenter phase II study. Patients and Methods Patients with relapsed indolent B-NHL received fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-NHL except for MCL (IL) cohort. The primary end point was the overall response rate (ORR). Results Fifty-two patients, including 46 in the IL cohort (41 with follicular lymphoma) and six in the MCL cohort, were registered, and all patients were eligible. Forty-one patients (79%) had received rituximab as prior therapy. In the IL cohort, the ORR and complete response rate were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively. One of six patients with MCL achieved a partial response. The median times to treatment failure for the 46 patients in the IL cohort and for the six patients in the MCL cohort were 8.6 and 6.1 months, respectively. Hematologic toxicities, including grade 4 neutropenia (37%), were the most frequent toxicities, and nonhematologic toxicities were mild. Conclusion Oral fludarabine phosphate is highly effective in patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation.
Evaluation of bronchodilator activity of A. precatorius leaves
Authors: Ravindra Patil, Dnyaneshwar Taur, Raju Patil
Journal: European Respiratory Journal (2013)

Introduction: Asthma affects about 300 million people worldwide. The current synthetic drugs used for the treatment of asthma have some adverse effects. Abrus precatorius Linn. (Fabacease) is a climbing shrub. The leaves and roots are sweet in taste and traditionally used to asthma and bronchititis.  Aim and Objectives: However, the objective of present study to evaluate ethanol extract of A. precatorius leaves for bronchodilator activity.  Method: In present study ethanol extract of A. precatorius (200 & 400 mg/kg) was evaluated on histamine induced bronchospam in guinea pig using salbutamol (2 mg/kg) as standard drug (Patel, K.G. et al. Iranian Biomedical J 2008; 12(3): 191-196). The time required for onset of preconvulsive dyspnoea was recorded.  Results: Result of study reveals that ethanol extract of A. precatorius at dose 200 & 400 mg/kg significantly protects guinea pig against histamine induced bronchoconstriction in a dose dependent manner as shown in Figure 1.  Conclusions: In conclusion A. precatorius may be used in the treatment of asthma and bronchititis.
Setting of noninvasive pressure support in young patients with cystic fibrosis
Authors: B. Fauroux, F. Nicot, S. Essouri, N. Hart, A. Clément, M.I. Polkey, F. Lofaso
Journal: European Respiratory Journal (2004)

The aim of the current study was to compare a clinical noninvasive method of setting up noninvasive pressure support ventilation (PS-NI) in young patients with cystic fibrosis (CF), based on parameters such as breathing frequency, arterial oxygen saturation and comfort rating, with a more invasive method (PS-I) targeted at optimising unloading of the inspiratory muscles and enhancing patient-ventilator synchronisation. PS-NI and PS-I were compared in random order in 10 children with CF. PS-NI differed from PS-I with regard to the level of inspiratory pressure (n=5), rate of inspiratory pressurisation (n=1), inspiratory trigger sensitivity (n=2) and expiratory trigger sensitivity (n=5). Although both methods modified breathing pattern, improved oxygen saturation and reduced diaphragmatic pressure time product (450±91 cmH 2 O·s −1 ·min −1 during spontaneous breathing, and 129±125 and 104±75 cmH 2 O·s −1 ·min −1 during PS-NI and PS-I, respectively), patient-ventilator synchrony and patient comfort were enhanced more during PS-I. In young patients with cystic fibrosis, setting up pressure support using a clinical noninvasive approach based on easily measurable parameters, such as respiratory rate and comfort rating, is as effective as a more invasive technique based on unloading of the inspiratory muscles and optimising patient-ventilator synchronisation. However, whilst the standard clinical method is satisfactory in the majority of patients, more invasive measurements should be considered in patients who have difficulty synchronising with the ventilator to enhance patient tolerance and compliance.
The Rumpel-Leede Sign Associated With a Noninvasive Ambulatory Blood Pressure Monitor
Authors: William B. White
Journal: JAMA (1985)

<h3>To the Editor.—</h3> The ambulatory blood pressure recorder is a recently developed device useful in the evaluation of the blood pressure and heart rate in those patients demonstrating lability in the physician's office or clinic.<sup>1</sup>The technique of ambulatory monitoring has also become popular in the evaluation of the efficacy of antihypertensive drugs.<sup>2</sup>In the past few years, a number of noninvasive blood pressure-monitoring units that utilize a standard sphygmomanometer attached to a programmable portable motor-driven pump have become available.<sup>3,4</sup>I would like to describe a previously unreported complication of ambulatory blood pressure monitoring. <h3>Report of a Case.—</h3> A 65-year-old diabetic woman with a history of marked fluctuation in blood pressure levels in her physician's office was referred for ambulatory blood pressure monitoring. Her usual medications were timolol maleate, hydrochlorothiazide, nifedipine, and NPH insulin. There had been no previous history of easy bruisability, skin lesions, bleeding episodes,
EXCITATORY AMINO ACID TRANSPORTERS: A Family in Flux
Authors: R. P. Seal, S. G. Amara
Journal: The Annual Review of Pharmacology and Toxicology (1999)

▪ Abstract As the most predominant excitatory neurotransmitter, glutamate has the potential to influence the function of most neuronal circuits in the central nervous system. To limit receptor activation during signaling and prevent the overstimulation of glutamate receptors that can trigger excitotoxic mechanisms and cell death, extracellular concentrations of excitatory amino acids are tightly controlled by transport systems on both neurons and glial cells. l-Glutamate is a potent neurotoxin, and the inadequate clearance of excitatory amino acids may contribute to the neurodegeneration seen in a variety of conditions, including epilepsy, ischemia, and amyotrophic lateral sclerosis. To establish the contributions of carrier systems to the etiology of neurological disorders, and to consider their potential utility as therapeutic targets, a detailed understanding of transporter function and pharmacology is required. This review summarizes current knowledge of the structural and functional diversity of excitatory amino acid transporters and explores how they might serve as targets for drug design.
To block, or not to block in advanced cirrhosis and ascites: that is the question
Authors: Aleksander Krag, Bjørn Stæhr Madsen
Journal: Gut (2014)

To block, or not to block in advanced cirrhosis and ascites: that is the question; Whether 'tis nobler in the mind to suffer the slings and arrows of outrageous non-selective β-blockers (NSBB), or to take arms against a sea of criticism. These words rephrase Prince Hamlet's contemplation of death and suicide in William Shakespeare's tragedy Hamlet . He bemoans the pains and unfairness of life but acknowledges that the alternative may still be worse.

NSBBs have been studied since the early 1960s and have been a cornerstone in clinical hepatology where they have benefitted more patients and saved more lives than any other drug in this field over the past three decades (table 1).1 ,2 In addition, NSBBs continue to be intensively studied and have become the Holy Grail in portal hypertension.

View this table:

Table 1 
Meta-analytical data on the efficacy of NSBBs for primary and secondary prophylaxis treatment of variceal bleeding



In 2010, the scientific community was shocked as data came out suggesting that NSBBs were associated with poor survival in patients with refractory ascites.3 That study led to subsequent debates and a number of additional observational studies with conflicting results (table 2). Nevertheless, a serious concern regarding the safety of NSBB in advanced cirrhosis has been raised3 ,4 which should be weighed against the potential benefit of NSBBs and alternative treatment options (table 1, figure 1). None of the randomised controlled trials (RCTs) on NSBB to date have specifically assessed safety and efficacy in advanced stage disease and consequently no strong recommendations can be made. Previous RCTs on NSBB excluded patients with advanced liver disease or only included a small number of these patients.5 ,6 Until we have specific RCTs evaluating NSBB in late stage cirrhosis, large observational studies are needed and may …
Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy
Authors: C. Visco, L. Arcaini, E. Brusamolino, S. Burcheri, A. Ambrosetti, M. Merli, E. Bonoldi, M. Chilosi, A. Viglio, M. Lazzarino, G. Pizzolo, F. Rodeghiero
Journal: Annals of Oncology (2006)
Limited effects of post-ischemic NHE blockade on [Na+]i and pHi in rat hearts explain its lack of cardioprotection
Authors: M Ten Hove
Journal: Cardiovascular Research (2003)

Objective: Na+/H+ exchanger (NHE) blockade fails as reperfusion therapy in patients with acute myocardial infarction. In experimental studies, the reports on the efficacy of NHE blockade only during reperfusion are inconsistent. Differences in the severity of ischemia and in drug delivery may explain these inconsistencies. Little is known about the primary goal of post-ischemic NHE blockade, i.e. reduction of Na+i overload. Methods: Isolated rat hearts were subjected either to 60 min of low flow (0.2 ml/min) ischemia or 25 min of zero flow ischemia. Hearts were reperfused with or without the selective NHE blocker cariporide added to the perfusate. [Na+]i and pHi were measured with simultaneous 23Na and 31P NMR spectroscopy. Results: After 60 min of low flow ischemia [Na+]i had risen to 424±14% of baseline and pHi was 6.36±0.03. After low flow ischemia [Na+]i and pHi recovered similarly in treated and untreated hearts. Recovery of the rate pressure product (RPP) was poorly in both groups. After 25 min of zero flow ischemia [Na+]i had risen to 279±7% of baseline and pHi was 6.12±0.02. NHE blockade after zero flow ischemia caused [Na+]i to decrease during the first 30 s of reperfusion, followed by a partial and transient rise during the second 30 s. Untreated hearts showed a very small rise in [Na+]i during the first minute. pHi recovered 30 s slower in cariporide treated hearts than in untreated hearts (p<0.05). No effect of cariporide on RPP could be detected since RPP recovered fully in untreated hearts. The end diastolic pressure, however, was increased during reperfusion to a similar extent in both groups. Conclusion: The lack of cardioprotection under these specific conditions of zero flow and low flow ischemia can be explained by the fact that NHE blockade only resulted in a small and transient effect on [Na+]i and pHi.
Comprehensive Analysis of DNA Repair Gene Variants and Risk of Meningioma
Authors: Lara Bethke, Anne Murray, Emily Webb, Minouk Schoemaker, Kenneth Muir, Patricia McKinney, Sarah Hepworth, Polyxeni Dimitropoulou, Artitaya Lophatananon, Maria Feychting, Stefan Lönn, Anders Ahlbom, Beatrice Malmer, Roger Henriksson, Anssi Auvinen, Anne Kiuru, Tiina Salminen, Christoffer Johansen, Helle Collatz Christensen, Michael Kosteljanetz, Anthony Swerdlow, Richard Houlston
Journal: JNCI Journal of the National Cancer Institute (2008)

Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility.We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case-control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided.The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1-interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; P(trend) = 8.95 x 10(-6); P = .009 after adjusting for multiple testing).We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.
The overlap syndrome of asthma and COPD: what are its features and how important is it?
Authors: P G Gibson, J L Simpson
Journal: Thorax (2009)

There is a need to re-evaluate the concept of asthma and chronic obstructive pulmonary disease (COPD) as separate conditions, and to consider situations when they may coexist, or when one condition may evolve into the other. Epidemiological studies show that in older people with obstructive airway disease, as many as half or more may have overlapping diagnoses of asthma and COPD (overlap syndrome). These people are typically excluded from current therapy trials, which limit the generalisability of these trials, and this presents a problem for evidence-based guidelines for obstructive airway diseases. Studying overlap syndrome may shed light on the mechanisms of COPD development. Overlap syndrome is recognised by the coexistence of increased variability of airflow in a patient with incompletely reversible airway obstruction. Patients typically have inflammatory features that resemble COPD, with increased airway neutrophilia, as well as features of airway wall remodelling. Overlap syndrome can develop when there is accelerated decline in lung function, or incomplete lung growth, or both. The risk factors for these events are shared, such that increasing age, bronchial hyper-responsiveness, tobacco smoke exposure, asthma and lower respiratory infections/exacerbations are significant risk factors for both incomplete lung growth and accelerated loss of lung function. Studying these events may offer new insights into the mechanisms and treatment of obstructive airway diseases.
Harvesting Evolutionary Signals in a Forest of Prokaryotic Gene Trees
Authors: K. Schliep, P. Lopez, F.-J. Lapointe, E. Bapteste
Journal: Molecular Biology and Evolution (2010)

Phylogenomic studies produce increasingly large phylogenetic forests of trees with patchy taxonomical sampling. Typically, prokaryotic data generate thousands of gene trees of all sizes that are difficult, if not impossible, to root. Their topologies do not match the genealogy of lineages, as they are influenced not only by duplication, losses, and vertical descent but also by lateral gene transfer (LGT) and recombination. Because this complexity in part reflects the diversity of evolutionary processes, the study of phylogenetic forests is thus a great opportunity to improve our understanding of prokaryotic evolution. Here, we show how the rich evolutionary content of such novel phylogenetic objects can be exploited through the development of new approaches designed specifically for extracting the multiple evolutionary signals present in the forest of life, that is, by slicing up trees into remarkable bits and pieces: clans, slices, and clips. We harvested a forest of 6,901 unrooted gene trees comprising up to 100 prokaryotic genomes (41 archaea and 59 bacteria) to search for evolutionary events that a species tree would not account for. We identified 1) trees and partitions of trees that reflected the lifestyle of organisms rather than their taxonomy, 2) candidate lifestyle-specific genetic modules, used by distinct unrelated organisms to adapt to the same environment, 3) gene families, nonrandomly distributed in the functional space, that were frequently exchanged between archaea and bacteria, sometimes without major changes in their sequences. Finally, 4) we reconstructed polarized networks of genetic partnerships between archaea and bacteria to describe some of the rules affecting LGT between these two Domains.
The Late Surgeon-Major Parke
Authors: F. E. Clarke
Journal: BMJ (1895)

A 2.5 yr old female beagle presented for acute abdominal pain and vomiting after consuming limited offerings of green potato skins. Progressive complications associated with suspected ingestion of a higher potency toxin followed within 5 hr. Subsequent investigations revealed a significant ingestion of an Australian shrub commonly called a “Yesterday, Today, and Tomorrow” tree (<i>Brunfelsia australis</i>). The toxic principle for this emerging toxicity is referred to as “strychnine-like” and is potentially lethal with gastrointestinal, central nervous system, and cardiac pathology. This plant is currently being aggressively promoted by United States nurserymen for its dramatic tri-colored blooms and drought resistance.
Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy
Authors: Daniela Cardinale, Maria Teresa Sandri, Alessandro Martinoni, Alessio Tricca LabTech, Maurizio Civelli, Giuseppina Lamantia, Saverio Cinieri, Giovanni Martinelli, Carlo M Cipolla, Cesare Fiorentini
Journal: Journal of the American College of Cardiology (2000)
A Phase I Study of DMS612, a Novel Bifunctional Alkylating Agent
Authors: Leonard J. Appleman, Sanjeeve Balasubramaniam, Robert A. Parise, Christine Bryla, Christophe E. Redon, Asako J. Nakamura, William M. Bonner, John J. Wright, Richard Piekarz, David R. Kohler, Yixing Jiang, Chandra P. Belani, Julie Eiseman, Edward Chu, Jan H. Beumer, Susan E. Bates
Journal: Clinical Cancer Research (2014)

DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-minute intravenous infusion on days 1, 8, and 15 of an every-28-day schedule.Patients with advanced solid malignancies were eligible. Enrollment followed a 3+3 design. PKs of DMS612 and metabolites were assessed by mass spectroscopy and PD by γ-H2AX immunofluorescence.A total of 31 patients, including those with colorectal (11), RCC (4), cervical (2), and urothelial (1) cancers, were enrolled. Six dose levels were studied, from 1.5 mg/m(2) to 12 mg/m(2). DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mg/m(2). The MTD was determined to be 9 mg/m(2) with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9 mg/m(2) dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. γ-H2AX immunofluorescence revealed dose-dependent DNA damage in both peripheral blood lymphocytes and scalp hairs.The MTD of DMS12 on days 1, 8, and 15 every 28 days was 9 mg/m(2). DMS612 appears to be an alkylating agent with unique tissue specificities. Dose-dependent PD signals and two partial responses at the MTD support further evaluation of DMS612 in phase II trials.
SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis
Authors: T. Luger, E.J.M. Van Leent, M. Graeber, S. Hedgecock, M. Thurston, A. Kandra, J. Berth-Jones, J. Bjerke, E. Christophers, J. Knop, A.C. Knulst, M. Morren, A. Morris, S. Reitamo, J. Roed-Petersen, E. Schoepf, K. Thestrup-Pedersen, P.G.M. Van Der Valk, J.D. Bos
Journal: British Journal of Dermatology (2001)

Background SDZ ASM 981 is a selective inhibitor of the production of pro‐inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. Objectives This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0·05%, 0·2%, 0·6% and 1·0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. Methods This was a double‐blind, randomized, parallel‐group, multicentre dose‐finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0·05%, 0·2%, 0·6%, or 1·0%, matching vehicle cream, or the internal control 0·1% betamethasone‐17‐valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. Results A clear dose–response relationship for SDZ ASM 981 was evident, with 0·2%, 0·6% and 1·0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0·041, 0·001 and 0·008, respectively) in terms of baseline to end‐point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1·0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0·6% and 1·0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42·9%, 48·9% and 34·9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1·0% cream was similar to that of the lower concentrations. Conclusions 1·0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.