tbuckley/cabot-search huggingface dataset:
Left ventricular O2 requirements of pressure and volume loading in the normal canine heart and inaccuracy of pressure-derived indices of O2 demand
Authors: J VINTEN-JOHANSEN, R J. BARNARD, G. D BUCKBERG, H. BECKER, H. W DUNCAN, J. M ROBERTSON
Journal: Cardiovascular Research (1982)

The purpose of this study was to: a) re-evaluate the left ventricular O2 requirements (MVO2) of pressure and volume-loading; and b) assess the accuracy of pressure-derived indices of left ventricular (LV) O2 demand under pressure-loading and volume-loading conditions. Using a right heart bypass preparation (heart rate 150 beats·min−1), mean arterial pressure (7.3 to 22.9 kPa) and cardiac output (0.8 to 6.0 litre·min−1) were varied independently. Adequate left ventricular O2 supply was demonstrated by normal transmural distribution of blood flow, normal myocardial lactate metabolism, and intact reactive hyperaemic responses. For equivalent increases in cardiac external work (from 2 to 4 joules·min−1) pressure-loading and volume-loading resulted in similar increases in O2 uptake (59% and 49%, respectively, P = 0.21). MVO2 was consistently greater for volume-loading than for pressure-loading at any SPTI, pressure-rate product, and triple product. The prediction of O2 demands by these indices under these loading conditions collectively was unreliable (r = 0.30 to 0.42). O2 requirements of the left ventricle with both pressure-loading and volume-loading were highly correlated (r = 0.82 to 0.99) with meridional wall stress. We conclude that: 1) volume-loading conditions have a greater O2 requirement than appreciated previously; 2) pressure loads and volume loads require similar O2 uptake in the normal canine heart for similar external work; 3) currently used pressure-derived indices are unreliable predictors of LV O2 demand when loading conditions are varied; and 4) O2 requirements are more uniformly related to meridional wall stress.
Precipitation of the thyrotropin receptor and identification of thyroid autoantigens using Graves' disease immunoglobulins.
Authors: P Heyma, L C Harrison
Journal: Journal of Clinical Investigation (1984)

The thyrotropin (TSH) receptor is a putative target for autoantibodies in Graves' hyperthyroidism and therefore, should be capable of being identified, isolated, and structurally characterized by immunological means. To this end, four sera from patients with hyperthyroidism, three of which inhibited the binding of 125I-TSH to Triton-solubilized human thyroid membranes, were used to isolate TSH receptors by immunoprecipitation. To account for an effect of TSH binding or receptor occupancy on the ability of Graves' immunoglobulins to precipitate TSH receptors, two approaches were taken: (a) specific 125I-TSH binding activity was measured after solubilized thyroid membranes had been incubated with Graves' sera followed by precipitation with Staphylococcus protein A ("receptor depletion"); (b) TSH binding sites were labeled with 125I-TSH and the complexes were precipitated using Graves' sera and Staphylococcus protein A ("receptor precipitation"). The three sera which inhibited 125I-TSH binding depleted 125I-TSH binding activity between 30-80%. Preformed complexes between Staphylococcus protein A and immunoglobulins in these sera were also able to deplete 125I-TSH binding activity. However, after receptor depletion, the one serum that did not inhibit 125I-TSH binding was associated with a significant increase in 125I-TSH binding. All four sera specifically precipitated 80-100% of receptors identified by prelabeling with 125I-TSH. The dilutions of sera that precipitated 50% of 125I-TSH-receptor complexes ranged from 1:150-1:20. Complexes were partially precipitated by high concentrations of control sera (1:20), but the relative potency of control sera was at least fourfold less than Graves' sera. Immunoprecipitates of 125I-labeled thyroid membranes were analysed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography to reveal Graves'-specific bands of reduced molecular weights of 100-110,000, 80-90,000, and 70-75,000. These bands were similar to those obtained from 125I-labeled thyroid membranes purified by TSH affinity chromatography. Thus, Graves' immunoglobulins: (a) precipitate unoccupied and occupied TSH receptors, (b) in one case, neither inhibit binding nor immunodeplete the unoccupied receptor but immunoprecipitate 125I-TSH-receptor complexes, suggesting that binding of TSH may initiate an interaction between the binding site and a separate immunoreactive molecule, and (c) identify the molecular structure of Graves' autoantigens, putatively, the TSH receptor.
Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR‐2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro‐BNP for the evaluation of dyspnoea and THIS‐diet
Authors: John G.F. Cleland, Alison P. Coletta, Andrew L. Clark
Journal: European Journal of Heart Failure (2007)
Bone marrow transplantation in canine mucopolysaccharidosis I. Effects within the central nervous system.
Authors: R M Shull, N E Hastings, R R Selcer, J B Jones, J R Smith, W C Cullen, G Constantopoulos
Journal: Journal of Clinical Investigation (1987)

Five dogs with mucopolysaccharidosis I, a model of human Hurler/Scheie syndrome, were transplanted with marrow from phenotypically normal littermates at 5 mo of age. At 3 and 9 mo posttransplantation, biopsies of cerebral cortex, liver, and cerebrospinal fluid were obtained. The alpha-L-iduronidase levels in these tissues were 0.8-7.4, 26-45, and 6.3-14.9% of the paired donor tissues, respectively. Although iduronidase was present in relatively low levels in the recipients' brains and cerebrospinal fluid at both biopsy times, reduction in brain glycosaminoglycan (GAG) was comparable to that observed in liver. Ultrastructural studies of cells within the transplanted dogs' brains showed less lysosomal distension and storage product than in affected, nontransplanted, littermate controls. The most marked clearing of stored GAG was in cells surrounding blood vessels, but decreased lysosomal storage in neurons and glial cells was also observed. Urinary GAG excretion also decreased to near normal levels by 5 mo posttransplantation.
The dynamic biliary epithelia: Molecules, pathways, and disease
Authors: Steven P. O’Hara, James H. Tabibian, Patrick L. Splinter, Nicholas F. LaRusso
Journal: Journal of Hepatology (2012)

Cholangiocytes, the cells lining bile ducts, are a heterogenous, highly dynamic population of epithelial cells. While these cells comprise a small fraction of the total cellular component of the liver, they perform the essential role of bile modification and transport of biliary and blood constituents. From a pathophysiological standpoint, cholangiocytes are the target of a diverse group of biliary disorders, collectively referred to as the cholangiopathies. To date, the cause of most cholangiopathies remains obscure. It is known, however, that cholangiocytes exist in an environment rich in potential mediators of cellular injury, express receptors that recognize potential injurious insults, and participate in portal tract repair processes following hepatic injury. As such, cholangiocytes may not be only a passive target, but are likely directly and actively involved in the pathogenesis of cholangiopathies. Here, we briefly summarize the characteristics of the reactive cholangiocyte and cholangiocyte responses to potentially injurious endogenous and exogenous molecules, and in addition, present emerging concepts in our understanding of the etiopathogenesis of several cholangiopathies.
Ammonia inhibits cAMP-regulated intestinal Cl- transport. Asymmetric effects of apical and basolateral exposure and implications for epithelial barrier function.
Authors: M Prasad, J A Smith, A Resnick, C S Awtrey, B J Hrnjez, J B Matthews
Journal: Journal of Clinical Investigation (1995)

The colon, unlike most organs, is normally exposed to high concentrations of ammonia, a weak base which exerts profound and diverse biological effects on mammalian cells. The impact of ammonia on intestinal cell function is largely unknown despite its concentration of 4-70 mM in the colonic lumen. The human intestinal epithelial cell line T84 was used to model electrogenic Cl- secretion, the transport event which hydrates mucosal surfaces and accounts for secretory diarrhea. Transepithelial transport and isotopic flux analysis indicated that physiologically-relevant concentrations of ammonia (as NH4Cl) markedly inhibit cyclic nucleotide-regulated Cl- secretion but not the response to the Ca2+ agonist carbachol. Inhibition by ammonia was 25-fold more potent with basolateral compared to apical exposure. Ion substitution indicated that the effect of NH4Cl was not due to altered cation composition or membrane potential. The site of action of ammonia is distal to cAMP generation and is not due simply to cytoplasmic alkalization. The results support a novel role for ammonia as an inhibitory modulator of intestinal epithelial Cl- secretion. Secretory responsiveness may be dampened in pathological conditions associated with increased mucosal permeability due to enhanced access of lumenal ammonia to the basolateral epithelial compartment.
A Study of Ventricular Arrhythmias Associated with Acute Myocardial Infarction in the Canine Heart
Authors: ALBERT L. WALDO, GERARD A. KAISER
Journal: Circulation (1973)

A study was designed to correlate changes in bipolar epicardial electrograms recorded from normal and acutely infarcted myocardium with the onset of ventricular arrhythmias. Electrodes were sewn to selected sites on the left ventricle, and after control electrograms and ECG's were recorded, the left anterior descending coronary artery was doubly ligated close to its origin. Electrograms recorded from within the infarct initially manifested diminished amplitude and increased duration of the deflection which reflected depolarization. The appearance of ventricular arrhythmias during phase 1 of Harris was associated with the appearance in electrograms recorded from within the infarct of continuous electrical activity which extended beyond the T wave of the preceding beat and preceded the onset of the arrhythmia. During the continuous electrical activity, it was not possible to delineate which deflections of the electrogram reflected depolarization or repolarization and it was suggested that the continuous electrical activity was localized fibrillation. For three experiments in which no arrhythmias occurred during phase 1 of Harris and for all animals which survived into phase 2 of Harris, the absence of ventricular arrhythmias was correlated with the absence of continuous electrical activity or locallized fibrillation recorded from within the area of the infarct.
Calmodulin-Dependent Cyclic Nucleotide Phosphodiesterase (PDE1) Is a Pharmacological Target of Differentiation-Inducing Factor-1, an Antitumor Agent Isolated from <b> <i>Dictyostelium</i> </b>
Authors: Kasumi Shimizu, Taku Murata, Toshiro Tagawa, Katsunori Takahashi, Ryoki Ishikawa, Yumiko Abe, Kohei Hosaka, Yuzuru Kubohara
Journal: Cancer Research (2004)

Abstract The differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum is a potent antiproliferative agent that induces growth arrest and differentiation in mammalian cells in vitro. However, the specific target molecule(s) of DIF-1 has not been identified. In this study, we have tried to identify the target molecule(s) of DIF-1 in mammalian cells, examining the effects of DIF-1 and its analogs on the activity of some candidate enzymes. DIF-1 at 10–40 μm dose-dependently suppressed cell growth and increased the intracellular cyclic AMP concentration in K562 leukemia cells. It was then found that DIF-1 at 0.5–20 μm inhibited the calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase (PDE1) in vitro in a dose-dependent manner. Kinetic analysis revealed that DIF-1 acted as a competitive inhibitor of PDE1 versus the substrate cyclic AMP. Because DIF-1 did not significantly affect the activity of other PDEs or CaM-dependent enzymes and, in addition, an isomer of DIF-1 was a less potent inhibitor, we have concluded that PDE1 is a pharmacological and specific target of DIF-1.
Is it denial or wisdom to accept life threatening illness?
Authors: A. Rifkin
Journal: BMJ (2001)

EDITOR—Like Cuddihy,1 I have a life threatening illness. What I find interesting is how I can spend most of my time not thinking about my prognosis. Is this denial or wisdom? Calling it denial makes my relative comfort into a pathological mental mechanism. Perhaps I should not complain about it. Most of us prefer ignorance about how our …
BASIC PSYCHIATRY IN MEDICAL PRACTICE
Authors: John C. Whitehorn
Journal: JAMA (1952)

The practice of medicine is one of the fields of human endeavor most markedly modified from time to time by the progress in basic sciences. Revolutionary changes in medicine were brought about by the development of bacteriology and sanitary engineering. That revolution preceded the active careers of the present generation of physicians; but we of this generation have witnessed and participated in a great change produced by the development of chemotherapy and the antibiotic drugs. The net results of accumulated scientific gains have been a much greater effectiveness in the treatment and prevention of acute infectious disease, and a considerable lengthening of the average span of life, with a change in the types of distress and disability for which medical aid is sought. The physician's practice, whether general or specialized, has come to include a larger and larger proportion of more chronic illness. Bit by bit, radical advances are being
Impaired net hepatic glycogen synthesis in insulin-dependent diabetic subjects during mixed meal ingestion. A 13C nuclear magnetic resonance spectroscopy study.
Authors: J H Hwang, G Perseghin, D L Rothman, G W Cline, I Magnusson, K F Petersen, G I Shulman
Journal: Journal of Clinical Investigation (1995)

Hepatic glycogen concentration was measured in six subjects with insulin-dependent diabetes mellitus (IDDM) and nine weight-matched control subjects using 13C nuclear magnetic resonance spectroscopy during a day in which three isocaloric mixed meals were ingested. The relative fluxes of the direct and indirect (3 carbon units-->-->glycogen) pathways of hepatic glycogen synthesis were also assessed using [1-13C]glucose in combination with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. Mean fasting hepatic glycogen content was similar in the two groups. After each meal, hepatic glycogen content increased, peaking 4-5 h after the meal in both groups. By 11:00 p.m. the IDDM subjects had synthesized only 30% of the glycogen that was synthesized by the control group [IDDM subjects, net increment = 44 +/- 20 (mean +/- SE) mM; control subjects, net increment = 144 +/- 14 mM; P < 0.05]. After breakfast the flux through the gluconeogenic pathway relative to the direct pathway of hepatic glycogen synthesis was 1.7-fold greater in the IDDM subjects (59 +/- 4%) than in the control subjects (35 +/- 4%, P < 0.0003). In conclusion, under mixed meal conditions, subjects with poorly controlled IDDM have a major defect in net hepatic glycogen synthesis and augmented hepatic gluconeogenesis. The former abnormality may result in an impaired glycemic response to counterregulatory hormones, whereas both abnormalities may contribute to postprandial hyperglycemia.
Reduced Myocardial Sarcoplasmic Reticulum Ca <sup>2+</sup> -ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy
Authors: Fuji Somura, Hideo Izawa, Mitsunori Iwase, Yasushi Takeichi, Ryoji Ishiki, Takao Nishizawa, Akiko Noda, Kohzo Nagata, Yoshiji Yamada, Mitsuhiro Yokota
Journal: Circulation (2001)

The relationship between left ventricular (LV) contractile functional reserve and gene expression of Ca(2+)-handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified.We calculated the maximum first derivative of LV pressure (LV dP/dt(max)) and the LV pressure half-time (T(1/2)) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction >55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na(+)/Ca(2+) exchanger were quantified by use of a real-time quantitative reverse transcription-polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dt(max) with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate-LV dP/dt(max) relation was biphasic at physiological pacing rates. Both the mean maximal wall thickness and the LV hypertrophy score in group B were greater than in group A (20+/-5 versus 15+/-3 mm and 7+/-1 versus 5+/-2 points, respectively). SERCA2 mRNA levels were significantly lower in group B (SERCA2/GAPDH ratio 0.34+/-0.15) compared with group A (0.72+/-0.27) and control subjects (0.85+/-0.47), whereas the mRNA expression of ryanodine receptor-2, phospholamban, calsequestrin, and Na(+)/Ca(2+) exchanger were similar in all groups.These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca(2+) handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction.
Language and Communication in the Mentally Handicapped
Authors: B. H Kirman
Journal: BMJ (1976)

Malignancy is now the commonest disease causing death in children over the age of 1 year.At a time when encouraging results in the treatment of some childhood malignancies are being reported this book provides a timely, succinct, but accurate and well- informed survey of the current position.Its authors are distinguished American paediatricians and oncologists, to whom we owe much of the modern concept of a team approach by a paediatrician, oncologist, surgeon, and radiotherapist in the management
A breathless man with diffuse chest pain
Authors: M. Chetty, R. Alluri, G. P Currie
Journal: BMJ (2009)

A 63 year old white man was referred to hospital with a two month history of left sided diffuse chest pain, weight loss, and progressive breathlessness on exertion. He was a retired joiner and had a 20 pack year history of smoking. He had not recently travelled abroad. He was taking bendroflumethiazide for hypertension. On examination, his blood pressure and heart rate were normal, respiratory rate was 14 beats per minute, and oxygen saturation was 97% on air. He had no clubbing, pedal oedema, or lymphadenopathy. Respiratory examination showed dullness and reduced breath sounds in the left lower and middle zones. Cardiac and abdominal examinations were normal. Chest radiography showed a moderate left sided pleural effusion, and electrocardiography was normal. Renal function, biochemistry, and bone profile were normal. Straw coloured pleural fluid was aspirated under ultrasound guidance; subsequent analysis showed total protein of 44 g/l (total serum protein 68 g/l), glucose 5.3 mmol/l, and lactate dehydrogenase 423 U/l, with no malignant cells or microbial growth.
Hiccups and bilateral carotid artery dissection
Authors: R A Badawi, J Birns, D J Ramsey, L Kalra
Journal: Journal of the Royal Society of Medicine (2004)

Internal carotid artery dissection is a common cause of stroke in young patients without vascular risk factors.1 Whilst some dissections occur in patients with known genetic predisposing factors, many are either caused by direct neck trauma or precipitated by an event involving head or neck movement.
NATIONAL INSURANCE AND UNALLOCATED PERSONS
Authors: F. Porter
Journal: BMJ (1919)

<h3>Objective</h3> Public life restrictions associated with the COVID-19 pandemic caused reductions in physical activity (PA) and decreases in mental and somatic health. Considering the interplay between these factors, we investigated the effects of digital home exercise (DHE) during government-enforced lockdowns. <h3>Methods</h3> A multicentre randomised controlled trial was performed allocating healthy individuals from nine countries (N=763; 523 female) to a DHE or an inactive control group. During the 4-week main intervention, DHE members engaged in live-streamed multicomponent home exercise. Subsequently, both groups had access to prerecorded workouts for an additional 4 weeks. Outcomes, assessed weekly, included PA level (Nordic Physical Activity Questionnaire-Short), anxiety (Generalized Anxiety Disorder Scale-7), mental well-being (WHO-5 Questionnaire), sleep quality (Medical Outcome Study Sleep Scale), pain/disability (Chronic Pain Grade Scale) and exercise motivation (Self-Concordance Scale). Mixed models were used for analysis. <h3>Results</h3> Live-streamed DHE consistently increased moderate PA (eg, week 1: 1.65 times more minutes per week, 95% CI 1.40 to 1.94) and vigorous PA (eg, week 1: 1.31 times more minutes per week, 95% CI 1.08 to 1.61), although the effects decreased over time. In addition, exercise motivation, sleep quality and anxiety were slightly improved for DHE in the 4-week live streaming period. The same applied to mental well-being (mean difference at week 4: +0.99, 95% CI 0.13 to 1.86), but an inverted trend was observed after live streaming was substituted by prerecorded exercise. <h3>Conclusions</h3> Live-streamed DHE represents an efficacious method to enhance PA and selected markers of health during pandemic-related public life restrictions. However, research on implementation is warranted to reduce dropout rates. <h3>Trial Registration number</h3> DRKS00021273.
A Population-Based Twin Study of Alcoholism in Women
Authors: Kenneth S. Kendler
Journal: JAMA (1992)

<h3>Objective.</h3> —To clarify the role of genetic factors in the etiology of alcoholism in women. <h3>Design and Setting.</h3> —Personal structured psychiatric interviews conducted by researchers "blinded" to the status of the co-twin in an epidemiologic sample of 1030 female-female twin pairs of known zygosity from the population-based Virginia Twin Registry. <h3>Measures.</h3> —Three definitions of lifetime prevalence of alcoholism based on<i>Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised</i>criteria: (1) alcoholism with tolerance or dependence; (2) alcoholism with or without tolerance-dependence; and (3) alcoholism with or without tolerance-dependence or problem drinking. <h3>Results.</h3> —Using narrow, intermediate, or broad definitions, the probandwise concordance for alcoholism was consistently higher in monozygotic than in dizygotic twin pairs. Multifactorial threshold models suggested that the heritability of liability to alcoholism in women is in the range of 50% to 60%. <h3>Conclusions.</h3> —The results support the hypothesis that genetic factors play a major role in the etiology of alcoholism in women. Women should be well represented in the efforts currently under way to elucidate the molecular basis of the genetic susceptibility to alcoholism. (<i>JAMA</i>. 1992;268:1877-1882)