tbuckley/cabot-search huggingface dataset:
Shortening of the action potential and reduction of pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac purkinje fibers. An effect on Na or K currents?
Authors: E Carmeliet, T Saikawa
Journal: Circulation Research (1982)

The ionic mechanism underlying the shortening of the action potential and the reduction in pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac Purkinje fibers was investigated using the two-microelectrode voltage clamp technique.In the presence of lidocaine (1.85 to 3.7 x 10" 5 M), steady state currents were shifted outward over a broad range of potentials.In contrast, instantaneous currents (holding potential -40 mV) and steady state currents in 20 mM Cs-Tyrode were not affected at potentials negative to -60 mV, the outward shift being restricted to potentials positive to this level.This outward shift of the current at the plateau level by lidocaine was not observed in the presence of a maximal dose of tetrodotoxin (TTX); in Na-free medium, the effect of lidocaine was totally suppressed.On the pacemaker current, the major effect of lidocaine was to reduce the magnitude of the activation curve with no change in time constants or in the shape of the fully activated current-voltage relation.Quinidine and procainamide exerted similar effects on instantaneous currents.Quinidine affected the pacemaker in the same way as lidocaine, whereas procainamide had no effect on this current.The results indicate that local anesthetics do not increase the K inward rectifier current and have no effect on inward background current at potentials negative to -60 mV; the shift in steady state currents at these levels is due to a change in pacemaker current.Because the lidocaine-sensitive pacemaker current does not reverse at the presumed equilibrium potential for K ions, aiid the effect of lidocaine in the presence of 1 mM Ba is similar to that in normal Tyrode, it is concluded that the drug inhibits a pacemaker current which is activated on hyperpolarization and mainly carried by Na ions.The results with TTX and in Na-free medium demonstrate that lidocaine inhibits a Na current, sensitive to TTX.The shortening of the action potential in sheep cardiac Purkinje fibers by local anesthetics is not due to an increase in outward current but can be explained by a block of an inward current, through the TTX-sensitive channel.
Illness behaviour in the chronic fatigue syndrome and multiple sclerosis
Authors: P. D Campion, C. F Dowrick, R. H T Edwards
Journal: BMJ (1995)

EDITOR,--Peter Trigwell and colleagues compared patients with the chronic fatigue syndrome with patients with multiple sclerosis and report similar responses on Pilowsky's illness behaviour questionnaire.1 There is accumulating evidence that the chronic fatigue syndrome is a functional disorder, with psychological, social, and physical …
Trauma and Reiter's syndrome: development of 'reactive arthropathy' in two patients following musculoskeletal injury.
Authors: J J Wisnieski
Journal: Annals of the Rheumatic Diseases (1984)

Two patients are reported who developed arthropathies with some features of Reiter9s syndrome shortly after physical injury. Both were HLA-B27 positive. No other precipitating factors were identified, and the possibility that trauma may have precipitated a reactive arthropathy is discussed.
Can PKA activators rescue Na channel function in epicardial border zone cells that survive in the infarcted canine heart?
Authors: S BABA, W DUN, P BOYDEN
Journal: Cardiovascular Research (2004)

Objective and methods: In this study, we investigated the effects of a PKA stimulating cocktail on sodium currents from normal epicardial cells (NZs) and on those from cells dispersed from the epicardial zone of the 5-day infarcted canine heart (IZs). To do so, we used whole-cell voltage-clamp techniques.
Thumb base involvement in symptomatic hand osteoarthritis is associated with more pain and functional disability: Table 1
Authors: Jessica Bijsterbosch, Willemien Visser, Herman M Kroon, Tanja Stamm, Ingrid Meulenbelt, Tom W J Huizinga, Margreet Kloppenburg
Journal: Annals of the Rheumatic Diseases (2010)

Objective To assess the impact of different subsets of symptomatic hand osteoarthritis (OA) on pain and disability. Methods From 308 patients with hand OA a group with carpometacarpal joint (CMCJ) symptoms only (group I, n=20) was identified as well as groups with symptoms at the interphalangeal joints (IPJs) only (group II, n=138), and symptoms at both sites (group III, n=150). Hand pain and function, assessed with the AUSCAN, were compared between groups using linear mixed models. Radiological OA was assessed using the Kellgren–Lawrence grading scale. Results Mean (SD) AUSCAN scores for groups I, II and III were 23.1 (11.7), 18.3 (11.9) and 26.4 (12.5), respectively. After adjustment for age, gender, body mass index, family effects and number of symptomatic hand joints, significant differences in AUSCAN scores of 7.4 (95% CI 1.8 to 13.0) between groups I and II, and 5.7 (95% CI 2.7 to 8.6) between groups II and III were found. AUSCAN scores were 5.8 (95% CI 3.1 to 8.6) higher for patients with versus patients without CMCJ symptoms. Kellgren–Lawrence scores did not differ between groups. Conclusion In symptomatic hand OA, CMCJ OA contributes more to pain and disability than IPJ OA. Hence, treatment of CMCJ OA should be emphasised, even if it coincides with IPJ OA.
A Functional Single-Nucleotide Polymorphism in the <i>TRPC6</i> Gene Promoter Associated With Idiopathic Pulmonary Arterial Hypertension
Authors: Ying Yu, Steve H. Keller, Carmelle V. Remillard, Olga Safrina, Ann Nicholson, Shenyuan L. Zhang, Weihua Jiang, Nivruthi Vangala, Judd W. Landsberg, Jian-Ying Wang, Patricia A. Thistlethwaite, Richard N. Channick, Ivan M. Robbins, James E. Loyd, Hossein A. Ghofrani, Friedrich Grimminger, Ralph T. Schermuly, Michael D. Cahalan, Lewis J. Rubin, Jason X.-J. Yuan
Journal: Circulation (2009)

Background— Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role in the development of idiopathic pulmonary arterial hypertension (IPAH), whereas a rise in cytosolic Ca 2+ concentration triggers PASMC contraction and stimulates PASMC proliferation. Recently, we demonstrated that upregulation of the TRPC6 channel contributes to proliferation of PASMCs isolated from IPAH patients. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC6 gene promoter that are associated with IPAH and have functional significance in regulating TRPC6 activity in PASMCs. Methods and Results— Genomic DNA was isolated from blood samples of 237 normal subjects and 268 IPAH patients. Three biallelic SNPs, −361 (A/T), −254(C/G), and −218 (C/T), were identified in the 2000-bp sequence upstream of the transcriptional start site of TRPC6. Although the allele frequencies of the −361 and −218 SNPs were not different between the groups, the allele frequency of the −254(C→G) SNP in IPAH patients (12%) was significantly higher than in normal subjects (6%; P &lt;0.01). Genotype data showed that the percentage of −254G/G homozygotes in IPAH patients was 2.85 times that of normal subjects. Moreover, the −254(C→G) SNP creates a binding sequence for nuclear factor-κB. Functional analyses revealed that the −254(C→G) SNP enhanced nuclear factor-κB-mediated promoter activity and stimulated TRPC6 expression in PASMCs. Inhibition of nuclear factor-κB activity attenuated TRPC6 expression and decreased agonist-activated Ca 2+ influx in PASMCs of IPAH patients harboring the −254G allele. Conclusions— These results suggest that the −254(C→G) SNP may predispose individuals to an increased risk of IPAH by linking abnormal TRPC6 transcription to nuclear factor-κB, an inflammatory transcription factor.
MALPOSITIONS OF THE UTERUS
Authors: L. F. Nash
Journal: BMJ (1913)

persons--tllat the haphazard iuetlhod of enitrusting this most solemn of all acts of tlle State towards the inidividual to tlle discretion of an ignoranit artisan is unwortlly of a civilizedl commlllunity.I never suggested, as you imply, th,at tle cdoctor should be the hangmian.I do suggest that, if we still emiiploy the barbarous mnachinery of the gallows,
Nitric oxide, nitrates and ischaemic preconditioning
Authors: R Rakhit
Journal: Cardiovascular Research (1999)

Time for primary review 24 days. 

In 1986 Furchgott first suggested that endothelial-derived relaxing factor might be nitric oxide (NO) [1]. Since then the remarkable role of nitric oxide (NO) as a modulator of biological phenomena has led to the question of its involvement within the spectrum of cardiovascular disease. The resulting research has implicated NO in atherosclerosis, hypertension, cardiomyopathy, pre-eclampsia, endotoxaemia [2] and cardiac allograft rejection [3] providing important additional insights into the pathogenesis of vascular and heart muscle disease. Although initially characterised in the vasculature NO is present in heart muscle [4] whilst the relative expression of the three isoforms (ncNOS, iNOS, ecNOS) responsible for its synthesis may have important implications in disease pathology. Apart from a cytotoxic role, NO has a role in cytostasis both regulating normal homeostasis and protecting against cell injury [5]. This, has led to the hypothesis that NO is cardioprotective in ischaemic heart disease. In testing this hypothesis very recent research has implicated NO in the phenomenon of ischaemic preconditioning. The current evidence suggesting its involvement in this exciting field is the focus of this review.

Ischaemic preconditioning (PC) describes the profound myocardial protection that follows a short period of sublethal ischaemia and was recently considered by a NHBLI workshop to be the most powerful intervention to reduce myocardial infarct size other than reperfusion [6]. Initially described by Murray et al. in 1986 [7], in trying to understand the metabolic consequences of ischaemia, they found that brief periods of repetitive ischaemia in a canine model produced significant protection against myocardial cell death. There appears to be a bimodal distribution of protection with an initial more powerful but short-lived phase existing between 1 and 3 h (‘Early Preconditioning’) and a delayed less powerful phase occurring between 12 and 72 hours … 

* Corresponding author. Tel.: +44-171-922-8191; fax: +44-171-960-5659 m.marber{at}umds.ac.uk
Vasopressin Improves Vital Organ Blood Flow During Closed-Chest Cardiopulmonary Resuscitation in Pigs
Authors: Karl H. Lindner, Andreas W. Prengel, Ernst G. Pfenninger, Ingrid M. Lindner, Hans-Ulrich Strohmenger, Michael Georgieff, Keith G. Lurie
Journal: Circulation (1995)

Background This study was designed to compare the effects of epinephrine with those of vasopressin on vital organ blood flow during closed-chest cardiopulmonary resuscitation (CPR) in a pig model of ventricular fibrillation. Methods and Results Vasopressin was compared with epinephrine by randomly allocating 28 pigs to receive either 0.2 mg/kg epinephrine (n=7), 0.2 U/kg vasopressin (low dose) (n=7), 0.4 U/kg vasopressin (medium dose) (n=7), or 0.8 U/kg vasopressin (high dose) (n=7) after 4 minutes of ventricular fibrillation and 3 minutes of closed-chest CPR. Left ventricular myocardial blood flow, determined by use of radiolabeled microspheres during CPR, before and then 90 seconds and 5 minutes after drug administration was 17±2, 43±5, and 22±3 mL · min −1 · l00 g −1 (mean±SEM) in the epinephrine group; 18±2, 50±6, and 29±3 mL · min −1 · 100 g −1 in the low-dose vasopressin group; 17±3, 52±8, and 52±6 mL · min −1 · 100 g −1 in the medium-dose vasopressin group; and 18±2, 95±9, and 57±6 mL · min −1 · 100 g −1 in the high-dose vasopressin group ( P &lt;.001 at 90 seconds and 5 minutes between epinephrine and high-dose vasopressin, and P &lt;.01 at 5 minutes between epinephrine and medium-dose vasopressin). At the same times, calculated coronary systolic perfusion pressures were 12±2, 36±5, and 18±2 mm Hg in the epinephrine group; 10±1, 39±6, and 26±5 mm Hg in the low-dose vasopressin group; 11±2, 49±6, and 38±5 mm Hg in the medium-dose vasopressin group; and 10±2, 70±5, and 47±6 mm Hg in the high-dose vasopressin group ( P &lt;.01 at 90 seconds and 5 minutes between epinephrine and high-dose vasopressin); and calculated coronary diastolic perfusion pressures were 15±2, 24±2, and 19±2 mm Hg in the epinephrine group; 13±1, 25±2, and 20±1 mm Hg in the low-dose vasopressin group; 13±2, 25±2, and 21±2 mm Hg in the medium-dose vasopressin group; and 13±2, 35±3, and 24±2 mm Hg in the high-dose vasopressin group ( P &lt;.05 at 90 seconds between epinephrine and high-dose vasopressin). Total cerebral blood flow was significantly higher after high-dose vasopressin than after epinephrine ( P &lt;.05 at 90 seconds and P &lt;.01 at 5 minutes between groups). Five animals in the epinephrine, 5 in the low-dose vasopressin, 7 in the medium-dose vasopressin, and 6 in the high-dose vasopressin groups were successfully resuscitated and survived the 1-hour observation period. Conclusions We conclude that administration of vasopressin leads to a significantly higher coronary perfusion pressure and myocardial blood flow than epinephrine during closed-chest CPR in a pig model of ventricular fibrillation.
Some Aspects of Professor Koch's Treatment of Tuberculosis
Authors: I. B. Yeo
Journal: BMJ (1890)

ipg genius.I saw things which, while they excited my admira- tion, made me also feel ashamed that we in this country, from one circumstance or another, are so greatly behind our German brethren.The researches to which I desire specially to refer are still in progress, and fresh facts are accumulating day by day.As they have not yet been published, I am not at liberty to mention details, but there can be no harm in my saying thus much, that I saw, in the case of two of the most virulent infective diseases to which man is liable, the course of the otherwise deadly disease cut short in the animals on which the experiments were per- formed, by the injection of a small quantity of a material perfectly constant in character, an inorganic chemical substance as easily obtained as any article in the materia medica.And
Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial
Authors: David J Serisier, Diana Bilton, Anthony De Soyza, Philip J Thompson, John Kolbe, Hugh W Greville, David Cipolla, Paul Bruinenberg, Igor Gonda
Journal: Thorax (2013)

<h3>Background</h3> The delivery of antipseudomonal antibiotics by inhalation to <i>Pseudomonas aeruginosa</i>-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery. <h3>Methods</h3> Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive <i>P aeruginosa</i> at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum <i>P aeruginosa</i> bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation—after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study. <h3>Results</h3> DRCFI resulted in a mean (SD) 4.2 (3.7) log<sub>10</sub> CFU/g reduction in <i>P aeruginosa</i> bacterial density at day 28 (vs −0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events. <h3>Conclusions</h3> Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive <i>P aeruginosa</i>. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.
Expression of Erythropoietin and Its Receptor in the Human Retina
Authors: Marta García-Ramírez, Cristina Hernández, Rafael Simó
Journal: Diabetes Care (2008)

The purpose of this study was to evaluate erythropoietin (Epo) and Epo receptor (EpoR) expression in the retina and in vitreous fluid from diabetic and nondiabetic donors. To gain insight into the mechanisms responsible for the regulation of Epo production in the retina, we also assessed retinal expression of hypoxia-inducible factors (HIF-1alpha and HIF-2alpha).Eighteen postmortem eyes from 9 diabetic patients without clinically detectable retinopathy were compared with 18 eyes from 9 nondiabetic donors. mRNA of Epo, HIF-1alpha, and HIF-2alpha (quantitative RT-PCR) were measured separately in neuroretina and retinal pigment epithelium (RPE). Epo and EpoR were assessed in the retina (immunofluorescence by confocal laser microscopy) and in the vitreous fluid (radioimmunoassay and enzyme-linked immunosorbent assay, respectively).Epo and EpoR mRNAs were significantly higher in the RPE than in the neuroretina. Higher expression of Epo was detected in the retinas (both in the RPE and in the neuroretina) from diabetic donors. By contrast, EpoR expression was similar in both groups. We did not find any difference in HIF-1alpha and HIF-2alpha mRNA expression between diabetic and nondiabetic donors (both in RPE and neuroretina). Intravitreal Epo concentration was higher in diabetic donors than in nondiabetic control subjects. However, EpoR concentrations were similar in both groups.Epo overexpression is an early event in the retina of diabetic patients, and this is not associated with any change in EpoR. At this early stage, other factors apart from hypoxia seem to be more important in accounting for the Epo upregulation that exists in the diabetic retina.
A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma
Authors: Jianping Yuan, Satoshi Kashiwagi, Patrick Reeves, Jean Nezivar, Yuan Yang, Nadiah Hashim Arrifin, Mai Nguyen, Gilberte Jean-Mary, Xiaoyun Tong, Paramjit Uppal, Svetlana Korochkina, Ben Forbes, Tao Chen, Elda Righi, Roderick Bronson, Huabiao Chen, Sandra Orsulic, Timothy Brauns, Pierre Leblanc, Nathalie Scholler, Glenn Dranoff, Jeffrey Gelfand, Mark C Poznansky
Journal: Journal of Hematology & Oncology (2014)

Although dendritic cell (DC) vaccines are considered to be promising treatments for advanced cancer, their production and administration is costly and labor-intensive. We developed a novel immunotherapeutic agent that links a single-chain antibody variable fragment (scFv) targeting mesothelin (MSLN), which is overexpressed on ovarian cancer and mesothelioma cells, to Mycobacterium tuberculosis (MTB) heat shock protein 70 (Hsp70), which is a potent immune activator that stimulates monocytes and DCs, enhances DC aggregation and maturation and improves cross-priming of T cells mediated by DCs. Binding of this fusion protein with MSLN on the surface of tumor cells was measured by flow cytometry and fluorescence microscopy. The therapeutic efficacy of this fusion protein was evaluated in syngeneic and orthotopic mouse models of papillary ovarian cancer and malignant mesothelioma. Mice received 4 intraperitoneal (i.p.) treatments with experimental or control proteins post i.p. injection of tumor cells. Ascites-free and overall survival time was measured. For the investigation of anti-tumor T-cell responses, a time-matched study was performed. Splenocytes were stimulated with peptides, and IFNγ- or Granzyme B- generating CD3+CD8+ T cells were detected by flow cytometry. To examine the role of CD8+ T cells in the antitumor effect, we performed in vivo CD8+ cell depletion. We further determined if the fusion protein increases DC maturation and improves antigen presentation as well as cross-presentation by DCs. We demonstrated in vitro that the scFvMTBHsp70 fusion protein bound to the tumor cells used in this study through the interaction of scFv with MSLN on the surface of these cells, and induced maturation of bone marrow-derived DCs. Use of this bifunctional fusion protein in both mouse models significantly enhanced survival and slowed tumor growth while augmenting tumor-specific CD8+ T-cell dependent immune responses. We also demonstrated in vitro and in vivo that the fusion protein enhanced antigen presentation and cross-presentation by targeting tumor antigens towards DCs. This new cancer immunotherapy has the potential to be cost-effective and broadly applicable to tumors that overexpress mesothelin.
Reperfusion kinase phosphorylation is essential but not sufficient in the mediation of pharmacological preconditioning: Characterisation in the bi-phasic profile of early and late protection
Authors: R BELL, J CLARK, D HEARSE, M SHATTOCK
Journal: Cardiovascular Research (2006)

Objective: Pharmacological preconditioning (PPC) triggers early (ePPC) and delayed protection (dPPC), occurring within 1 h or after 24 h following the preconditioning stimulus, respectively, through recruitment of protein kinase signalling. Angiotensin II (ATII) is a recognised trigger of PPC, recruiting kinases and transcription factors known to be involved in both phases of protection. Our objectives were to determine whether ATII is capable of triggering dPPC and whether recruitment of pro-survival kinases, Akt and extracellular signal-regulated kinase (ERK), following the injurious ischaemic insult is essential for the mediation of PPC.
Electron microscopy of the plexiform lesion.
Authors: P Smith, D Heath
Journal: Thorax (1979)

Pulmonary arteries from a case of plexogenic pulmonary arteriopathy were studied with the electron microscope. Many muscular pulmonary arteries showed intimal fibrosis of concentric or "onion-skin" type. The cells embedded within this fibrosis resembled smooth muscle but since they also possessed some features of fibroblasts we refer to them as myofibroblasts. Myofibroblasts also occurred in plexiform lesions together with fibroblasts and "fibrillary cells". These fibrillary cells contained numerous, prominent filaments with a random orientation. They lined the vascular channels of the plexiform lesions as well as being present within the stroma. They appeared to phagocytose fibrin and then to organise the plexiform lesion into a fibrous scar. Fibrillary cells closely resemble vasoformative reserve cells and the cells of the cardiac myxoma and so-called "papillary tumour" of heart valves. They may, therefore, be primitive multipotential cells found throughout the entire cardiovascular system.