tbuckley/cabot-search huggingface dataset:
The "Saatchi bill" is mistargeted and will put vulnerable patients at risk
Authors: N. Poole
Journal: BMJ (2014)

The Medical Innovation Bill is unnecessary, mistargeted, and will put vulnerable patients at risk.1 In its response to the public consultation, the BMA said it “strongly believes that the draft bill should not become law.”2 I agree.

The bill’s laudable aim is to promote responsible medical innovation, but the draft on which the government has consulted seeks to do so by providing that doctors who …
Effects of intravenous broxaterol on respiratory drive and neuromuscular coupling in COPD patients
Authors: F Gigliotti, G Gurrieri, R Duranti, M Gorini, G Scano
Journal: European Respiratory Journal (1993)

Broxaterol, a new selective beta 2-agonist, has been shown to exert inotropic effects on both fresh and fatigued canine diaphragm. We evaluated the effect of broxaterol on the activation and force output of the respiratory muscles in patients with chronic obstructive pulmonary disease (COPD). We studied 9 patients with moderate to severe COPD. Each patient was infused with saline and Broxaterol (200 micrograms) in saline alternately. We measured lung volumes, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), breathing pattern, P0.1, respiratory muscle EMG (diaphragm, EMGd, and parasternal, EMGp) and P0.1/EMGd ratio. Measurements were made under control conditions and at 15, 30, 60, and 120 min after each infusion. Broxaterol, but not saline, resulted in a slight but significant increase in vital capacity (VC), forced expiratory volume in one second (FEV1) and MIP, and a decrease in functional residual capacity (FRC). Breathing pattern did not change, while EMG significantly decreased, and P0.1/EMGd significantly increased in 5 of the 9 patients after broxaterol. These data seem to indicate that by partially unloading the respiratory muscles, broxaterol results in decreased muscle activation (EMG). Increase in chest wall neuromuscular coupling (P0.1/EMGd) may also be observed.
Synthesis of the active metabolite of vitamin D, 1,25(OH)2D3, by synovial fluid macrophages in arthritic diseases.
Authors: M E Hayes, J Denton, A J Freemont, E B Mawer
Journal: Annals of the Rheumatic Diseases (1989)

Synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been shown in cells from knee joint synovial fluid of 20 patients with inflammatory rheumatoid disease, reactive or psoriatic arthritis, or gout, all of which had high synovial fluid cell counts, and by cells from a patient with aseptic necrosis of a femoral condyle after short term (less than 24 hours) or long term (seven days) primary culture. Cells from 18 patients with inflammatory arthritis, five of which had low synovial fluid cell counts and cells from six patients with osteoarthritis were unable to synthesise this metabolite from 25-hydroxyvitamin D3 (25(OH)D3). Macrophages are believed to be the cells responsible for synthesising 1,25(OH)2D3 because these were significantly more numerous in samples that formed 1,25(OH)2D3; they were also the predominant cell type present in the aseptic necrosis sample and the only cell type present in preparations maintained for one week in monolayer culture.
Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital
Authors: Ching-Hon Pui, John T. Sandlund, Deqing Pei, Dario Campana, Gaston K. Rivera, Raul C. Ribeiro, Jeffrey E. Rubnitz, Bassem I. Razzouk, Scott C. Howard, Melissa M. Hudson, Cheng Cheng, Larry E. Kun, Susana C. Raimondi, Frederick G. Behm, James R. Downing, Mary V. Relling, William E. Evans
Journal: Blood (2004)
Visually-Guided Balloon Catheter Ablation of Atrial Fibrillation
Authors: Vivek Y. Reddy, Petr Neuzil, Sakis Themistoclakis, Stephan B. Danik, Aldo Bonso, Antonio Rossillo, Antonio Raviele, Robert Schweikert, Sabine Ernst, Karl-Heinz Kuck, Andrea Natale
Journal: Circulation (2009)

Electric isolation of the pulmonary veins (PVs) can successfully treat patients with paroxysmal atrial fibrillation. However, it remains technically challenging to identify the left atrial-PV junction and sequentially position the ablation catheter in a point-by-point contiguous fashion to isolate the PVs. In this study, a novel endoscopic ablation system was used to directly visualize and ablate tissue at the left atrial-PV junction with laser energy.This study consisted of 2 phases: a short-term (n=9) and long-term (n=11) canine experimental validation phase and a multicenter clinical feasibility phase (n=30 paroxysmal atrial fibrillation patients). After transseptal puncture, the balloon-based endoscopic ablation system was advanced to each PV ostium, and arcs of laser energy (90 degrees to 360 degrees ) were projected onto the target left atrial-PV junction. Electric PV isolation was defined with a circular multielectrode catheter. In the short-term preclinical experimental phase, 15 of 17 targeted PVs (88%) were successfully isolated. Pathological examination revealed well-demarcated circumferential lesions with minimal endothelial disruption. In the long-term experiments, 9 of 10 targeted veins (90%) remained persistently isolated (at 4 to 8 weeks). In the clinical phase, 105 of 116 PVs (91%) were successfully isolated. After a single procedure, the 12-month drug-free rate of freedom from atrial fibrillation was 60% (18 of 30 patients). There were no significant PV stenoses, but adverse events included 1 episode of cardiac tamponade, 1 stroke without residual defect, and 1 asymptomatic phrenic nerve palsy.This study establishes the feasibility of a novel paradigm for AF ablation: direct visualization to guide catheter ablation of the left atrial-PV junction.
Evaluation of diffusion parameters as early biomarkers of disease progression in glioblastoma multiforme
Authors: I. S. Khayal, M.-Y. C. Polley, L. Jalbert, A. Elkhaled, S. M. Chang, S. Cha, N. A. Butowski, S. J. Nelson
Journal: Neuro-Oncology (2010)

The purpose of this study was to evaluate diffusion parameters at pre-, mid-, and post-radiation therapy (RT) in contrast-enhancing and nonenhancing lesions of postsurgical glioblastoma multiforme patients treated with the standard of care RT concurrently with temozolomide (TMZ) followed by adjuvant TMZ and an antiangiogenic drug. The diffusion parameters explored include baseline and short-term changes in apparent diffusion coefficient, fractional anisotropy, and eigenvalues. These diffusion parameters were examined as early markers for disease progression by relating them to clinical outcome of 6-month progression-free survival. The results indicated that changes from mid- to post-RT were significantly different between patients who progressed within 6 months vs those who were free of progression for 6 months after initiation of therapy. The study also showed that the changes in diffusion parameters from the mid- to post-RT scan may be more significant than those from pre- to mid-RT and pre- to post-RT. This is important because the mid-RT scan is currently not performed as part of the standard clinical care.
Multicenter trial of dynamic cardiomyoplasty for chronic heart failure
Authors: Anthony P. Furnary, Mariell Jessup, Luiz F.P. Moreira
Journal: Journal of the American College of Cardiology (1996)

The purpose of this study was to prospectively assess the effect of dynamic cardiomyoplasty in patients with symptomatic chronic heart failure. Since the first procedure was performed in 1985, dynamic cardiomyoplasty has been developed for use in patients with chronic heart failure. The aging population in developed countries has made heart failure a growing public health concern. Heart transplantation is appropriate or available for only a small proportion of these patients because of limited donor supply. Effective alternatives to transplantation are needed. Eight centers in North and South America performed 68 cardiomyoplasty procedures between May 1991 and September 1993. Data were prospectively collected every 6 months and compared with preoperative values using paired t tests, chi-square tests and actuarial survival analyses. Patients had a mean (±SD) age of 57 ± 1 years and were predominantly male (53 [78%] of 68). Heart failure etiology was classified as idiopathic in 47 (69%) of 68 patients and ischemic in 21 (31%). The in-hospital mortality rate was 12% (8 of 68), and the survival rate at 6 and 12 months was 75 ± 5% and 68 ± 6%, respectively. Objective improvements were seen at 6 months (n = 49) in left ventricular ejection fraction (23 ± 1% vs. 25 ± 1%, p = 0.05), stroke volume (50 ± 2 vs. 56 ± 3 ml/beat, p = 0.02) and left ventricular stroke work index (26 ± 1 vs. 30 ± 2 g/m2 per beat, p = 0.01). Improvements in mean New York Heart Association functional class (3 ± 0.04 vs. 1.8 ± 0.1, p = 0.0001) and activity of daily living score (59 ± 3 vs. 80 ± 2, p = 0.0001) were also observed. There were no significant changes at 6 months in peak oxygen consumption (15 ± 1 vs. 16 ± 1 ml/kg per min), cardiac index (2.26 ± 0.08 vs. 2.33 ± 0.08 liters/min per m2), pulmonary capillary wedge pressure (19 ± 2 vs. 18 ± 1 mm Hg) or heart rate (87 ± 2 vs. 82 ± 3 beats/min). These data suggest that dynamic cardiomyoplasty improves ventricular systolic function, reduces symptoms of heart failure and improves objective measures of quality of life in patients with congestive heart failure. This improvement occurred without changes in peak exercise capacity, ventricular filling pressure or actuarial survival.
Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries
Authors: S BANAI
Journal: Cardiovascular Research (2004)

Objective: Tyrphostin AGL-2043 is a potent tricyclic quinoxaline inhibitor of PDGF β-receptor tyrosine kinase (PTK), Kit, and Flt3. We have shown previously that selective inhibition of PDGF β-receptor PTK by tyrphostins markedly reduces SMC proliferation and migration in vitro, reduces neointima formation in balloon-injured porcine femoral arteries, and reduces neointimal stenosis in stented porcine coronary arteries when administered intramurally within biodegradable nanoparticles. The present study was designed to determine the effect of AGL-2043 delivered from a stent-based, biodegradable polymeric coating on neointima formation in the porcine coronary artery model. Methods and Results: Stents coated with biodegradable, polylactic/glycolic acid (PLGA) polymer, with (n=13) or without (n=11) 180 mcg AGL-2043 were implanted into the proximal LAD of 24 Sinclair mini-pigs (34±4 kg) to achieve a 1.1:1 stent/artery diameter ratio. The delivery of drug from stent to tissue was confirmed by high-performance liquid chromatography. After 28 days, histomorphometric analysis showed that in-stent stenosis in animals treated with AGL-2043 was reduced by 50% (51±21% versus 26±10%, p=0.001), the absolute neointimal area was reduced by 44% (2.38±1.04 versus 1.31±0.43 mm2, p=0.004), and the absolute luminal area was increased by 57% (2.19±1.09 versus 3.39±0.59 mm2, p=0.003). There were no significant differences between control and AGL-2043 in injury score (1.24±0.11 vs. 1.15±0.12, p=0.07) or inflammation score (1.19±0.35 vs. 1.07±0.33, p=0.41). Moreover, the difference in % in-stent stenosis between control and treated animals remained highly significant even after normalizing the % stenosis to the degree of injury (p=0.0008) or to the inflammation score (p=0.001). Mortality for this study was zero. Tissue concentration in segments 1 cm proximal and distal to the stents, were negligible or zero at 1 h, 24 h, and 4 weeks after stent implantation. Conclusion: Stent-based delivery of tyrphostin AGL-2043 from a biodegradable polymeric coating reduces in-stent neointimal hyperplasia in porcine coronary arteries by 50% after 28 days and preserves lumen area. Long-term studies should be the next step in testing applicability to the human interventional setting.
Wilms' Tumor 1 Gene Expression in Hepatocellular Carcinoma Promotes Cell Dedifferentiation and Resistance to Chemotherapy
Authors: Maria J. Perugorria, Josefa Castillo, M. Ujue Latasa, Saioa Goñi, Victor Segura, Bruno Sangro, Jesús Prieto, Matías A. Avila, Carmen Berasain
Journal: Cancer Research (2009)

The Wilms' tumor 1 gene (WT1) encodes a transcription factor involved in cell growth and development. As we previously reported, WT1 expression is hardly detectable in normal hepatic tissue but is induced in liver cirrhosis. Although WT1 has been found to be overexpressed in a number of malignancies, the role of WT1 in hepatocarcinogenesis has not been clarified. We found that WT1 is expressed in several human hepatocellular carcinoma (HCC) cell lines, including PLC/PRF/5 and HepG2, and in HCC tumor tissue in 42% of patients. WT1 small interfering RNAs did not affect proliferation rate of HCC cells but abrogated their resistance to anoikis. Transcriptome analysis of PLC/PRF/5 cells after WT1 knockdown showed up-regulation of 251 genes and down-regulation of 321. Ninety percent of the former corresponded to metabolic genes, mostly those characterizing the mature hepatocyte phenotype. On the contrary, genes that decreased upon WT1 inhibition were mainly related to defense against apoptosis, cell cycle, and tumor progression. In agreement with these findings, WT1 expression increased the resistance of liver tumor cells to doxorubicin, a compound used to treat HCC. Interestingly, doxorubicin strongly enhanced WT1 expression in both HCC cells and normal human hepatocytes. Among different chemotherapeutics, induction of WT1 transcription was restricted to topoisomerase 2 inhibitors. When WT1 expression was prohibited, doxorubicin caused a marked increase in caspase-3 activation. In conclusion, WT1 is expressed in a substantial proportion of HCC contributing to tumor progression and resistance to chemotherapy, suggesting that WT1 may be an important target for HCC treatment.
Telespirometry performed by general practitioners for early diagnosis of obstructive airway disease: Our experience
Authors: Alassandro Giuseppe Fois, Sandra Manca, Salvatore Ostera, Dante Zeminian, Fulvio Glisenti, Gian Mauro Meloni, Pietro Pirina
Journal: European Respiratory Journal (2014)

Introduction: Telespirometry is a novel validated instrument to detect airflow limitation in COPD and asthma patients; it consisting of a portable spirometer that transmits the lung ventilatory values on line from general practitioner's office to a Pneumologic center. The spirometry is the gold standard for the diagnosis of obstructive lung disease.

Aim: To evaluate if the Telespirometry , performed in the general practitioner's office, could improve the early diagnosis of obstructive airway disease.

Methods: After a short course on performance and interpretation of Telespirometry, 10 general practitioners enrolled current or ex-smokers patients with or without respiratory symptoms ad subjects with respiratory symptoms but not history of asthma or COPD. Telespirometry was sent on line to a central office where was interpreted by a pulmonary specialist of our center and the results returned to GP's in real time.

Results: 198 subjects were enrolled, (45.45% male and 54.54% female; mean age 53.14 (SD 13.63). 75.76% performed an acceptable Telespirometry. The data showed an obstructive ventilatory patten in 15.15% (43.33%mild; 26.66% moderate; 30% severe), a restrictive in 1.01% and a mixed ventilatory patten in 2.02%.

Conclusions: Telespirometry, performed by GP, may improve the early diagnosis of obstructive airway disease, and could be used in clinical practice to the monitoring and the management of COPD and Asthma.
Changes in fatty acid composition of plasma, liver microsomes, and erythrocytes in liver cirrhosis induced by oral intake of thioacetamide in rats
Authors: Eliane Moreira, Luis Fontana, José Luis Periago, Fermín Sánchez De Medina, Ángel Gil
Journal: Hepatology (1995)

The aim of this study was to evaluate the changes in fatty acid composition of lipids of plasma, erythrocytes, and liver microsomes in rats with liver cirrhosis induced by oral intake of thioacetamide and to determine to what extent the experimental model reproduces the fatty acid tissue alterations reported in human cirrhosis. Two groups of rats were studied. The control group received water ad libitum, and the experimental group received 0.03% w/v thioacetamide in drinking water for 2, 4, and 6 months. At these times, lipids of plasma, erythrocytes, and liver microsomes were extracted, and their fatty acid compositions were determined. Thioacetamide intake led to macronodular and micronodular cirrhosis at 2 months. These alterations progressed at 4 months and eventuated in liver tumors at 6 months. Thioacetamide-treated rats showed a drop in total plasma fatty acids, higher percentages of palmitic acid in all lipid fractions, and lower levels of stearic acid in erythrocyte lipids and liver microsomal phospholipids. Oleic acid increased in plasma cholesteryl esters and phospholipids, as well as in erythrocyte lipids and liver microsomal phospholipids. In plasma lipids and liver microsomal phospholipids, the percentages of arachidonic and docosahexaenoic acids decreased. The latter also decreased in erythrocyte lipids. In addition, liver microsomes showed a higher cholesterol/lipid phosphorus molar ratio. The experimental model of cirrhosis obtained by intake of thioacetamide in drinking water for 4 months reproduces many of the fatty acid tissue alterations that appear in human cirrhosis and may serve to ascertain the biochemical mechanisms involved in these changes.
p38 Mitogen-Activated Protein Kinase Pathway Is Involved in Protein Kinase Cα–Regulated Invasion in Human Hepatocellular Carcinoma Cells
Authors: Yi-Hsien Hsieh, Trang-Tiau Wu, Chih-Yang Huang, Yih-Shou Hsieh, Jin-Ming Hwang, Jer-Yuh Liu
Journal: Cancer Research (2007)

Abstract Protein kinase Cα (PKCα) has been suggested to play an important role in tumorigenesis, invasion, and metastasis. In this study, we investigated the signal pathways selectively activated by PKCα in human hepatocellular carcinoma (HCC) cells to determine the role of mitogen-activated protein kinases (MAPK) in PKCα-mediated HCC migration and invasion. A stable SK-Hep-1 cell clone (siPKCα-SK) expressing DNA-based small interfering RNA (siRNA) PKCα was established and was then characterized by cell growth, migration, and invasion. The expression of PKCα was decreased in siPKCα-SK, and cell growth, migration, and invasion were reduced. These changes were associated with the decrease in p38 MAPK phosphorylation level, but not in c-jun-NH2-kinase-1/2 (JNK-1/2) and extracellular signal-regulated kinase-1/2 (ERK-1/2). This phenomenon was confirmed in the SK-Hep-1 cells treated with antisense PKCα olignucleotide. The p38 MAPK inhibitor SB203580 or dominant negative p38 mutant plasmid (DN-p38) was used to evaluate the dependency of p38 MAPK in PKCα-regulated migration and invasion. Attenuation of cell migration and invasion was revealed in the SK-Hep-1 cells treated with the SB203580 or DN-p38, but not with ERK-1/2 inhibitor PD98059 or JNK-1/2 inhibitor SP600125. Overexpression of constitutively active MKK6 or PKCα may restore the inactivation of p38 and the attenuation of cell migration and invasion in siPKCα-SK. Similar findings were observed in the stable HA22T/VGH cell clone expressing siRNA PKCα. This study provides new insight into the role of p38 MAPK in PKCα-mediated malignant phenotypes, especially in PKCα-mediated cancer cell invasion, which may have valuable implications for developing new therapies for some PKCα-overexpressing cancers. [Cancer Res 2007;67(9):4320–7]
Nicardipine prevents calcium loading and "oxygen paradox" in anoxic single rat myocytes by a mechanism independent of calcium channel blockade.
Authors: O Hano, H S Silverman, P S Blank, E D Mellits, R Baumgardner, E G Lakatta, M D Stern
Journal: Circulation Research (1991)

The protective effect of nicardipine (1 and 4 microM) against reoxygenation injury was studied in an unstimulated rat single myocyte oxygen paradox model in comparison with control (no drug) or nifedipine (1 microM). Either concentration of nicardipine was strongly protective, approximately doubling the duration of ATP depletion (rigor) that cells could withstand without undergoing hypercontracture when reoxygenated. Nifedipine (1 microM), which matched the negative inotropic effect of nicardipine (4 microM) (as measured by extent of shortening when stimulated), had no protective effect against reoxygenation injury. Neither drug affected the time to rigor, which is a measure of the rate at which the resting cell consumes its endogenous glycogen stores during anaerobic metabolism. Intracellular calcium, measured with the fluorescent probe indo-1, which partitions into both cytosol and mitochondria, rose progressively throughout the rigor period. This rise in calcium was almost totally suppressed by nicardipine (1 microM) but was unaffected by nifedipine. We conclude that nicardipine possesses a direct protective effect on the myocardium not shared by all dihydropyridines. This effect is associated with the prevention of intracellular, and probably mitochondrial, calcium loading but is probably not due to blockade of the L-type calcium channel or reduction of metabolic rate.
Discussion: Assessment of psoriatic arthritis
Authors: P J Mease
Journal: Annals of the Rheumatic Diseases (2005)

of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) for Outcome Measures in Rheumatology (OMERACT) 8 (May 2006) and will have task forces addressing them in the form of research projects, questionnaires, and consensus exercises.Which joints should be included in psoriatic arthritis (PsA) assessment: carpometacarpal joints, distal interphalangeal (DIP) joints, feet DIPs?Should we perform 76, 68, 44, or 28 joint counts?Can feet DIPs be distinguished from proximal interphalangeal (PIP) joints clinically and/or radiologically?Can they be distinguished from osteoarthritis radiologically?Should we count or score?Mease: When we set about to assess joints in the original etanercept trial, our assumption was that we needed to capture a larger number of joints than in typical rheumatoid arthritis (RA) trials, including the DIP joints of both hands and feet, as well as the carpometacarpal (CMC) joints which can be commonly affected, thus using a 76/74 joint count.Some have countered that it is difficult in many patients to assess the DIP joints of the feet, especially the smaller ones, and that assessment of the CMC joint may not be valid.Further, radiologists have grumbled that it is often difficult to distinguish the DIP joints, especially in the feet.Thus the perennial question is: Is it sufficient to count the joints, or does it add more information to score relative degree of tenderness and swelling in each joint?The Erlangen analysis of raw data from the etanercept and infliximab phase II trials suggests that counts are as distinguishing as scores, and that 76, 68, 44, and 28 joint counts are all adequate to detect differences between treatment and placebo.The only caveat is that it is worthwhile to assess at least 68 joints at study entry in order to qualify a patient, especially oligoarticular patients.FitzGerald would omit the second through fifth proximal interphalangeal (PIP) joints of the toes as difficult to assess.Gladman: However, this may be important not only at study entry.If a patient happens to have a number of feet or distal joints involved and they are not included in the 44 or 28 joint count, how can they be followed during a trial?Therefore, it seems reasonable to perform a 68 joint count, even though it may take a couple more minutes per patient, to collect all appropriate information on these patients and to achieve proper analysis at the end of a trial.