tbuckley/cabot-search huggingface dataset:
Survival kinases in ischemic preconditioning and postconditioning
Authors: D HAUSENLOY, D YELLON
Journal: Cardiovascular Research (2006)

Despite nearly twenty years of research into the field of ischemic preconditioning, the actual mechanism of protection remains unclear. However, much progress has been made in elucidating the signal transduction pathways that convey the extracellular signal initiated by the preconditioning stimulus to the intracellular targets of cardioprotection, with many of these pathways involving the activation of a diverse array of survival protein kinase cascades. The powerful protective benefits of ischemic preconditioning have not yet been realised in the clinical arena, not least because of the prerequisite for any preconditioning intervention to be applied prior to the onset of index ischemia, which in the case of an acute myocardial infarction is difficult to institute. In this regard, the newly described phenomenon of ischemic postconditioning, which comprises a cardioprotective intervention that can be applied at the time of myocardial reperfusion, offers a far more attractive and amenable approach to myocardial protection. Interestingly, certain survival protein kinase cascades recruited at the time of myocardial reperfusion appear to be shared by both ischemic preconditioning and postconditioning, thereby offering a potentially common target of cardioprotection. The often disputed roles these different protein kinases play in mediating the cardioprotective effects of ischemic preconditioning and postconditioning are reviewed in this article, and include protein kinases C, G, and A, members of the MAPK family (Erk1/2, p38, JNK and BMK1), the PI3K-Akt cascade, and the JAK-STAT pathway.
EPICARDIAL ADIPOSE THICKNESS IS STRONGLY RELATED WITH DECREASED CORONARY FLOW RESERVE IN PATIENTS WITH ANGIOGRAPHICALLY NORMAL CORONARY ARTERIES
Authors: Toshio Saito, Eiichi Hyodo, Hisateru Takeda, Akihisa Hanatani, Takashi Muro, Minoru Yoshiyama
Journal: Journal of the American College of Cardiology (2011)
Total Excitation of the Isolated Human Heart
Authors: DIRK DURRER, R. TH. VAN DAM, G. E. FREUD, M. J. JANSE, F. L. MEIJLER, R. C. ARZBAECHER
Journal: Circulation (1970)

To obtain information concerning the time course and instantaneous distribution of the excitatory process of the normal human heart, studies were made on isolated human hearts from seven individuals who died from various cerebral conditions, but who had no history of cardiac disease. Measurements were made from as many as 870 intramural terminals. In the isolated human hearts three endocardial areas were synchronously excited 0 to 5 msec after the start of the left ventricular activity potential. These areas increased rapidly in size during the next 5 to 10 msec and became confluent in 15 to 20 msec. The left ventricular areas first excited were (1) high on the anterior paraseptal wall just below the attachment of the mitral valve; (2) central on the left surface of the interventricular septum and (3) posterior paraseptal about one third of the distance from apex to base. The last part of the left ventricle to be activated usually was the posterobasal area. Endocardial activation of the right ventricle was found to start near the insertion of the anterior papillary muscle 5 to 10 msec after onset of the left ventricular cavity potential. Septal activation started in the middle third of the left side of the interventricular septum, somewhat anteriorly, and at the lower third at the junction of the septum and posterior wall. The epicardial excitation pattern reflected the movements of the intramural excitation wave. Conduction velocity was determined in one heart by an appropriate stimulation technic. Atrial excitation, explored in two hearts, spread more or less according to concentric isochronic lines. Control studies, carried out on five canine hearts, disclosed that the pattern of ventricular excitation did not change after isolation and perfusion. However, total excitation was completed earlier in the isolated heart, and conduction velocity increased. Careful mapping illustrations are presented.
Immigration status of overseas doctors
Authors: F Ahemd
Journal: BMJ (1994)

EDITOR, - The Home Office's regulations restricting the stay of overseas doctors in Britain to four years was implemented from 1 April 1985.1 The doctors could work without a work permit for this period for training purposes, and, though there was no provision in the immigration rules to extend the period, the Home Office has used its discretion to allow people to switch their immigration status on the recommendation of the Department of Employment. Work permits have been issued to some doctors in specific jobs …
Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema
Authors: N Minematsu, H Nakamura, M Iwata, H Tateno, T Nakajima, S Takahashi, S Fujishima, K Yamaguchi
Journal: Thorax (2003)

<b>Background:</b> Nicotine is responsible for smoking dependence and is mainly metabolised by CYP2A6. Several types of genetic polymorphism of <i>CYP2A6</i> have been reported, but their relation to smoking habit and chronic obstructive pulmonary disease (COPD) phenotypes has not been fully clarified. <b>Methods:</b> 203 current or ex-smokers (lifelong cigarette consumption (CC) ≥10 pack years) with subclinical and established COPD phenotypes were clinically evaluated and pulmonary function tests and a chest CT scan were performed (smoker group). The non-smoker group consisted of 123 healthy volunteers. <i>CYP2A6</i> genotypes were determined in both groups. <b>Results:</b> The percentage of subjects with a <i>CYP2A6del</i> allele (genotype D) was lower in heavy smokers (20.5%, n=88, CC ≥60 pack years) than in light smokers (37.4%, n=115, CC 10–59 pack years, χ<sup>2</sup>=6.8, p=0.01) or non-smokers (36.1%, n=122, χ<sup>2</sup>=6.0, p=0.01); lower in ex-smokers (20.7%, n=111) than in current smokers (41.3%, n=92, χ<sup>2</sup>=10.1, p&lt;0.01); and lower in smokers with a high LAA (low attenuation area) score on the chest CT scan (18.4%, n=76, LAA ≥8.0) than in those with a low LAA score (37.0%, n=127, LAA &lt;8.0, χ<sup>2</sup>=7.8, p&lt;0.01). <b>Conclusions:</b> Subjects with the <i>CYP2A6del</i> allele tend not to be heavy habitual smokers but can be light habitual smokers. The <i>CYP2A6del</i> polymorphism may inhibit smokers from giving up smoking, but appears to function as a protective factor against the development of pulmonary emphysema independent of smoking habit.
Opening family courts to media may deter medical expert witnesses
Authors: D. Payne
Journal: BMJ (2009)

Government plans to allow limited press reporting of family court proceedings in England and Wales will make it harder to recruit expert medical witnesses, a debate on the proposals has heard.

The justice secretary, Jack Straw, had said that the Children, Schools and Families Bill, announced in the Queen’s speech last month, will expose family courts to greater public scrutiny, making them more open and accountable.

Alistair MacDonald, a barrister from Birmingham, told a debate on the planned changes hosted by the Family Justice Council in London on 9 December, that clause 34 of the bill, …
Modulation of the hydro-osmotic effect of vasopressin on the rabbit cortical collecting tubule by adrenergic agents
Authors: Radha K. Krothapalli, W. Brian Duffy, Harry O. Senekjian, Wadi N. Suki
Journal: Journal of Clinical Investigation (1983)

The effects of catecholamines on antidiuretic hormone ([Arg8]-vasopressin [AVP])-induced water absorption were evaluated in cortical collecting tubules isolated from the rabbit kidney and perfused in vitro. In the presence of AVP (100 μU/ml), net fluid volume absorption (Jv, nanoliters per minute per millimeter) was 1.14±0.12 and osmotic water permeability coefficient (Pf, X 10-4 centimeters per second) was 217.3±39.9. The addition of the alpha-adrenergic agonist, phenylephrine (PE), in a concentration of 10-6 M resulted in a significant decrease in Jv and Pf to 0.83±0.13 (P < 0.001) and 148.8±41.8 (P < 0.02), respectively. Increasing the concentration of PE to 10-5 M resulted in a further decrease in Jv and Pf to 0.53±0.05 (P < 0.05 vs. PE 10-6 M) and 88.5±9.0 (P 0.05 vs. PE 10-6 M), respectively. In a separate group of tubules, in the presence of AVP (100 μU/ml) and PE (10-5 M), Jv and Pf were 0.35±0.07 and 66.0±17.3, respectively. The addition of the alpha-adrenergic antagonist, phentolamine (PH), in a concentration of 10-6 M resulted in a significant increase in Jv to 1.07±0.19 (P < 0.001) and Pf to 193.3±35.9 (P < 0.005). PH (10-5 M) alone did not significantly affect Jv and Pf in the presence of AVP (100 μU/ml) nor in the presence of 8-bromo adenosine 3',5' cyclic monophosphate (8-BrcAMP). Jv and Pf were 1.20±0.21 and 174.0±25.8, respectively, in the presence of 8-BrcAMP (10-4 M).
On the Mechanism of the Splay in the Glucose Titration Curve in Advanced Experimental Renal Disease in the Rat*
Authors: Stewart W. Shankel, Alan M. Robson, Neal S. Bricker
Journal: Journal of Clinical Investigation (1967)

Glucose titration studies were performed in rats with unilateral chronic pyelonephritis before and after removal of the contralateral control kidneys. Identical studies were performed in animals with unilateral partial renal infarction in which the experimental kidneys had a marked reduction in nephron population but no anatomic deformation in the surviving nephrons. In the initial studies, both groups of animals were free of clinical and chemical abnormalities of uremia. In the follow-up studies uremic abnormalities were present. Minimal splay was observed in the titration curves in the initial studies; marked splay was present in the group data from the same kidneys in the subsequent studies. Thus a marked reduction in the nephron population was associated with the evolution of splay in both groups of animals. In association with the increase in splay, the mean values for maximal glucose transport increased; thus a defect in glucose transport can be excluded as the basis of the splay. Glomerular filtration rate increased proportionately more than the maximal transport of glucose; hence the ratios of glomerular filtration rate to maximal glucose transport increased consistently. The possibility of asymmetric hypertrophy of glomerular and tubular functions among the nephron population imposed by scar tissue or other anatomic deformities was considered, but the results in the animals with partially infarcted kidneys militate against this explanation. The splay also could reflect an asymmetric alteration in the distribution of glomerulotubular balance among the residual units initiated by functional adaptations. Finally, the splay could relate to an alteration in the kinetics of glucose transport without any change in the level of functional homogeneity. The possible nature of these has been considered in the text.
Abstract A41: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma
Authors: Adam Kiezun, Jennifer Perry, Peter Tonzi, Eliezer Van Allen, Scott L. Carter, Sylvan Baca, Ami Bhatt, Michael Lawrence, Loren Walensky, Nikhil Wagle, Jaume Mora, Carmen deTorres, Cinzia Lavarino, Liliana Velasco-Hidalgo, Rocio Cardenas-Cardos, Simone dos Santos Aguiar, Jose A. Yunes, Gabriela Mercado, Jorge Melendez-Zajgla, Charles Roberts, Levi Garraway, Carlos Rodriguez-Galindo, Todd Golub, Stuart Orkin, Gad Getz, Katherine Janeway
Journal: Cancer Research (2014)

Abstract Osteosarcoma is the most common primary bone tumor and yet there have been no substantial advances in treatment or survival in over 2 decades. We examined 59 tumor/normal pairs by whole-genome, whole-exome and RNA-Sequencing. Only TP53 was mutated at significant frequency across the 59 samples. The mean non-silent somatic mutation rate was 1.2 mutation per megabase and there were a median of 231 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the inter-tumor heterogeneity, the extent of genomic instability and the difficulty in acquiring a large sample size in a rare tumor we used several methods to identify genomic events contributing to osteosarcoma proliferation and survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach and a genome-wide, pooled short hairpin RNA (shRNA) screen all point to the PI3K/mTOR pathway as a potential central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo. Citation Format: Adam Kiezun, Jennifer Perry, Peter Tonzi, Eliezer Van Allen, Scott L. Carter, Sylvan Baca, Ami Bhatt, Michael Lawrence, Loren Walensky, Nikhil Wagle, Jaume Mora, Carmen deTorres, Cinzia Lavarino, Liliana Velasco-Hidalgo, Rocio Cardenas-Cardos, Simone dos Santos Aguiar, Jose A. Yunes, Gabriela Mercado, Jorge Melendez-Zajgla, Charles Roberts, Levi Garraway, Carlos Rodriguez-Galindo, Todd Golub, Stuart Orkin, Gad Getz, Katherine Janeway. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A41.
A comparative study of the characteristics of intraepithelial and lamina propria lymphocytes of the human nasal mucosa
Authors: R. Pawankar, M. Okuda
Journal: Allergy (1993)

The phenotypes and receptors of the intraepithelial lymphocytes which are a major component of the mucosal immune system are of considerable interest. Intraepithelial lymphocytes, especially those of the intestines, are well documented. The nasal intraepithelial lymphocytes probably play a key role in the immune defense of the entire respiratory tract. However, documentation of these lymphocytes is limited to only a few nondescriptive studies by immunohistological methods. In our previous paper, we examined the subsets of the nasal intraepithelial lymphocytes by two‐color flow cytometry after culture with monoclonal antibody against CD3 and PMA. The mucosal immune system, which comprises the lymphoid tissue associated with the mucosal surface, consists of lymphocyte populations from both the epithelium and the lamina propria. In this paper (a sequel to our previous study), we have carried out a comparative study of the intraepithelial lymphocytes and lamina propria lymphocytes of the human nasal mucosa. In the 42 patients (with allergic rhinitis/infectious hypertrophic rhinitis) whom we examined, T lymphocytes were predominant in the epithelium as well as the lamina propria. B lymphocytes were detected only in the lamina propria. CD8 + T cells (suppressor/cytotoxic) and CD4‐8 ‐(double‐negative) (DN) comprised the major population of the intraepithelial lymphocytes. The CD4+/CD8+ ratio was 0.5 ± 0.1. In contrast, the lamina propria showed a predominance of CD4 + T cells (helper/inducer), with a CD4 +/CD8 + ratio of 1.3 ± 0.2. CD3 + 4–8‐(double‐negative T cells) were comparable in number in the epithelium and the lamina propria. CD8 + T cells of the epithelium were predominantly cytotoxic T cells, and CD4 + T cells were predominantly helper T cells. In the lamina propria, CD8 + T cells were predominantly of the suppressor type. In the analysis of the T‐cell receptors of the epithelium and the lamina propria, there was a predominance of the αβ receptor‐bearing T cells in both. However, in the double‐negative T‐cell population of the epithelium, γδ heterodimer predominated over αβ. In order to verify the influence of culture conditions on the percentages of the individual subsets of lymphocytes, we examined the peripheral blood lymphocytes by flow cytometry before and after culture under the same conditions. We found no significant change in the different subsets caused by culture except a slight reduction in the percentage of suppressor T cells as well as a significant increase in activated T cells. We therefore wish to emphasize that the nasal intraepithelial lymphocytes are heterogenous in phenotype, and are dominated by double‐negative cells and CD8 + T cells. Moreover, the nasal lamina propria lymphocytes are also heterogenous in phenotype, and differ in proportion from the intraepithelial lymphocytes. What is of utmost interest is the preferential location of the γδ receptor‐bearing T cells in the epithelium and their relative absence in the lamina propria.
Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats
Authors: G LIN, G CRAIG, L ZHANG, V YUEN, M ALLARD, J MCNEILL, K MACLEOD
Journal: Cardiovascular Research (2007)

The purpose of the present study was to determine whether increased activation of the RhoA/Rho-kinase (ROCK) pathway occurs in diabetic cardiomyopathy and whether acute inhibition of this pathway improves contractile function of the diabetic heart.Male Wistar rats were made diabetic with streptozotocin. Twelve to fourteen weeks later, the effects of acute administration of the ROCK inhibitors Y-27632 and H-1152 on cardiac contractile function were measured both in vitro, in isolated working hearts, and in vivo, using echocardiography. Changes in the expression and activity of RhoA, and the effect of ROCK inhibition on changes in the phosphorylation of the downstream target of ROCK, LIM kinase 2, and on actin polymerization in diabetic hearts were also determined.Perfusion of isolated working hearts from diabetic rats with Y-27632 or H-1152 acutely improved left ventricle developed pressure and the rates of contraction and relaxation. Acute administration of H-1152 also significantly improved the percent fraction shortening, an index of left ventricle contractility, in vivo in diabetic rats. The expression and activity of RhoA in cardiomyocytes from diabetic rats were significantly increased, as was the phosphorylation of LIM kinase 2. This was associated with an increase in actin polymerization (the F-actin to G-actin ratio). Both the increase in LIM kinase 2 phosphorylation and actin polymerization were attenuated by ROCK inhibition.These data suggest that activation of the RhoA/ROCK signaling pathway plays a critical role in the development of diabetic cardiomyopathy, and that ROCK is an excellent therapeutic target in the treatment of this condition.
Ethical Choices After a Nuclear Attack
Authors: John Dawson
Journal: JAMA (1989)

To the Editor. —  In wondering whether our report entitled Selection of Casualties for Treatment After Nuclear Attack was a spoof or a serious exercise in planning, Dr Cassel 1 neglects a third and correct possibility. The report's intention was to stimulate debate by presenting an accurate but provocative account of the ethical choices that would face survivors after a nuclear attack.  As the preface states, the public health authorities in the United Kingdom had failed to confront the realities of nuclear attack, but have drawn up civil defense plans that broadly regard it as an extension of conventional war. The British Medical Association's annual meeting therefore asked the association to open a public debate on the ethical issues that would face surviving health workers after a nuclear attack.  If Selection of Casualties offends against deeply held ethical sensibilities, perhaps that is because it describes the unthinkable truth about the
How (not) to be a good patient
Authors: Daniel K Sokol
Journal: BMJ (2004)

Last Saturday, as I leapt in the air, salmon-like, to head the winning goal for the local football team, a clumsy defender bashed his head against mine. The impact of his forehead created such a deep, unsightly dent over my right eye that the other players, visibly repulsed by the wound, called for an ambulance. When the ambulance finally arrived, several interminable minutes past the government's eight minute target, the two paramedics waltzed in, sprightly and cheerful, in their green and yellow overalls. I was bothered by their apparent indifference to my plight—the alarming possibility of death or of life as a vegetable—but I mustered the inner strength to answer their questions: “How did it happen?” “Where were you hit?” “Where does it hurt?” and so on. I was trolleyed into the ambulance and taken to the hospital. The ambulance did not howl on the way there, which angered me further. Was my potentially life threatening injury not serious enough to warrant …
US health reform provides free preventive services, but battles loom
Authors: J. H. Tanne
Journal: BMJ (2010)

When provisions of the US health reform legislation take effect on 23 September, new insurance plans will have to offer consumers 45 free screenings and other preventive services recommended by the US Preventive Services Task Force, among many other preventive services.

US consumers use preventive services at only about half the recommended rate, said the health and human services secretary, Kathleen Sebelius. 

New plans will have to cover all of the task force’s 21 “A” graded and 24 “B” recommendations free of charge.

The recommendations differ depending on the recipient’s age, sex, and risk factors. Among the “A” recommendations are aspirin to prevent cardiovascular disease; screening pregnant women for bacteriuria, chlamydia, syphilis, and hepatitis B and testing for Rh incompatibility; blood pressure testing; cervical cancer screening; cholesterol measurement; colorectal cancer screening; folic acid supplementation for premenopausal women; screening newborns for sickle cell disease, hypothyroidism, and phenylketonuria; prophylactic treatment of newborns for …
766. Immunotherapy for Her2-Positive Medulloblastoma: Regression of Experimental Tumors by Transfer of Her2-Redirected T Cells In Vivo
Authors: Nabil M. Ahmed, Maheshika K. Ratnayake, Barbara Savoldo, Laszlo Perlaky, Gianpietro Dotti, Winfried Wels, Meenakshi B. Bhattacharjee, H. David Shine, Cliona M. Rooney, Helen E. Heslop, Stephen Gottschalk
Journal: Molecular Therapy (2006)

Background: The long-term objective of this project is to develop an innovative HER2-targeted immunotherapeutic approach for medulloblastoma. HER2 is expressed in 40% of medulloblastomas and at present less than one third of patients with HER2-positive tumors are cured by conventional therapies. The aim of this study was to determine if T cells grafted with a HER2-specific chimeric antigen receptor (CAR) recognize and kill HER2-positive medulloblastomas.
Cowboys Ain't Milkboys
Authors: John A. Churchill
Journal: JAMA (1986)

To the Editor.—   fine article by Relda Niederhofer entitled The Milk Sickness 1 deserves additional comment. Recent taxonomic revision of genus Eupatorium has resulted in the name change of the agent of milk sickness from Eupatorium rugosum Houtt to Ageratina altissima R. M. King and H. Rob. 2   This plant thrives neither in forest nor on grassland, but it multiplies explosively on recently cut-over hardwoods. This environment was created on a massive scale by the settlers who then grazed livestock in the slash to continue the conversion of forest to grass.   Haplopappus heterophyllus Gray, now named Isocoma wrightii Rydb, of southwestern rangeland also contains the milk sickness poison, trematone. 1 No human casualties have yet been reported from this source, but then cowboys don't drink much milk! 3