tbuckley/cabot-search huggingface dataset:
Impaired phosphorus conservation and 1,25 dihydroxyvitamin D generation during phosphorus deprivation in familial hypophosphatemic rickets.
Authors: K L Insogna, A E Broadus, J M Gertner
Journal: Journal of Clinical Investigation (1983)

The pathogenesis of familial hypophosphatemic rickets (FHR) is incompletely understood. We therefore examined the effects of acute dietary phosphorus deprivation to see whether renal phosphate conservation and increased 1,25 dihydroxyvitamin D [1,25(OH)2D] plasma levels, which normally follow restriction of phosphorus intake, could be induced in patients with FHR. Six healthy male volunteers (age 26 +/- 3 yr) and seven male patients with FHR (age 24 +/- 3 yr) were placed on a low phosphorus diet supplemented with aluminum hydroxide and studied over a 4-d period. The patients with FHR excreted more than five times as much phosphorus per day at the conclusion of the study than did the controls (176 +/- 61 mg/24 h vs. 33 +/- 11 mg/h). In the normal subjects, maximum tubular reabsorptive capacity for phosphorus/glomerular filtration rate (TmP/GFR) rose progressively during phosphorus deprivation, and the rise from base line was more than two times greater than that seen in patients with FHR. Immunoreactive parathyroid hormone levels and nephrogenous cyclic AMP were initially normal in both groups and no change was seen in either group with phosphorus deprivation. In the normal subjects, 1,25(OH)2D levels rose progressively over the 96 h of the study (49 +/- 3 to 63 +/- 6 pg/ml, P less than 0.05), while mean circulating 1,25(OH)2D in the patients with FHR did not change (34 +/- 3 to 29 +/- 3 pg/ml). The changes in individual plasma 1,25(OH)2D levels correlated strongly with the change in individual nephrogenous cyclic AMP measurements in the patients with FHR (r = +0.93), while no such correlation was observed in the normal subjects. These data demonstrate a defective renal response to phosphorus deprivation in patients with FHR including a qualitatively abnormal response in 1,25(OH)2D generation.
A developmental theory of implicit and explicit knowledge?
Authors: Diane Poulin-Dubois, David H. Rakison
Journal: Behavioral and Brain Sciences (1999)

Early childhood is characterized by many cognitive developmentalists as a period of considerable change with respect to representational format. Dienes &amp; Perner present a potentially viable theory for the stages involved in the increasingly explicit representation of knowledge. However, in our view they fail to map their multi-level system of explicitness onto cognitive developmental changes that occur in the first years of life. Specifically, we question the theory's heuristic value when applied to the development of early mind reading and categorization. We conclude that the authors fail to present evidence that dispels the view that knowledge change in these areas is dichotomous.
Mechanisms of adrenoceptor desensitisation in the failing human heart
Authors: S. E Harding, L. A Brown, D. G Wynne, C. H Davies, P. A Poole-Wilson
Journal: Cardiovascular Research (1994)

Journal Article Mechanisms of β adrenoceptor desensitisation in the failing human heart Get access Sian E Harding, Sian E Harding Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom: S E Harding, L A Brown, D G Wynne, C H Davies, P A Poole-Wilson. Correspondence to Dr Harding. Search for other works by this author on: Oxford Academic PubMed Google Scholar Lesley A Brown, Lesley A Brown Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom: S E Harding, L A Brown, D G Wynne, C H Davies, P A Poole-Wilson. Correspondence to Dr Harding. Search for other works by this author on: Oxford Academic PubMed Google Scholar Dylan G Wynne, Dylan G Wynne Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom: S E Harding, L A Brown, D G Wynne, C H Davies, P A Poole-Wilson. Correspondence to Dr Harding. Search for other works by this author on: Oxford Academic PubMed Google Scholar Crispin H Davies, Crispin H Davies Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom: S E Harding, L A Brown, D G Wynne, C H Davies, P A Poole-Wilson. Correspondence to Dr Harding. Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip A Poole-Wilson Philip A Poole-Wilson Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom: S E Harding, L A Brown, D G Wynne, C H Davies, P A Poole-Wilson. Correspondence to Dr Harding. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 28, Issue 10, October 1994, Pages 1451–1460, https://doi.org/10.1093/cvr/28.10.1451 Published: 01 October 1994 Article history Received: 03 February 1994 Accepted: 21 April 1994 Published: 01 October 1994
Efficacy and Safety of Methacholine Bronchial Challenge Performed by Auscultation in Young Asthmatic Children
Authors: CHAIM SPRINGER, SIMON GODFREY, ELIE PICARD, KAMAL UWYYED, MOSHE ROTSCHILD, SHAI HANANYA, NATAN NOVISKI, AVRAHAM AVITAL
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The measurement of bronchial reactivity is an important aid in the diagnosis of asthma, but the technique using spirometry is not feasible in young children. The aim of the present study was to determine the efficacy and safety of a modification of the chest auscultation method in the assessment of bronchial reactivity to inhaled methacholine in young asthmatic children. One hundred forty-six young children with asthma (mean age, 4.3 yr) underwent bronchial challenges with nebulized methacholine using the auscultation method (PCW). The end point was defined as the appearance of wheezing, oxygen desaturation, or tachypnea. For comparison, 30 children and young adults with asthma underwent bronchial provocation with methacholine using spirometry (PC(20)). A positive response using the auscultation method was observed in 95.9% of the younger children, and wheezes alone or in combination with other signs appeared in 80.8% of them. The mean desaturation at the end point was 4.6% (PCW) and 5.0% (PC(20)), with a similar pattern in the two groups. Cough was not helpful in determining the end point. We conclude that the modified auscultation method is effective and safe, with wheeze appearing at the end point in the large majority of the children.
MPs broadly welcome proposals for health research in UK
Authors: Zosia Kmietowicz
Journal: BMJ (2007)

A review by MPs of proposals on how £1bn (€1.5bn; $1.9bn) worth of publicly funded health research should be allocated in the United Kingdom has raised concerns about introducing targets to set research priorities.

The cross party Science and Technology Committee has broadly welcomed the conclusions reached by Sir David Cooksey in his review published in December ( BMJ 2006;333:1239, 16 Dec, doi: 10.1136/bmj.39059.559213.DB) on how healthcare research can be improved to bring more tangible benefits to patients.

The committee says it has reservations about some aspects of the proposals, however, and will be taking “a close interest in reviewing progress and how the new institutional arrangements will work in practice.”

In …
Familial systemic lupus erythematosus: the role of genetic and environmental factors
Authors: G E Eroglu
Journal: Annals of the Rheumatic Diseases (2002)

To examine the contribution of genetic and environmental factors to disease occurrence in 26 families with two or more members affected with systemic lupus erythematosus (SLE).Genetic and environmental factors were examined by HLA-A, B, C/DR typing and by determining the presence of lymphocytotoxic antibodies (LCA) in patients and their consanguineous and non-consanguineous relatives.No association between SLE and HLA-A, B, C antigens was found. There was, however, a significant association with HLA-DR2 in white subjects with SLE. The most striking finding was that HLA sharing was increased among the affected members, suggesting genetic similarities. Seven of 14 sib pairs (50%) who had concordant SLE were HLA identical as opposed to an expected 25%. Another interesting finding was that 15/18 (83%) patients with SLE and 11/22 (50%) consanguineous relatives had LCA, while 1/9 (11%) spouses, and 2/42 (5%) healthy controls had these antibodies.Genetic factors have a role in the development and expression of SLE. Environmental factors may trigger the disease in genetically susceptible hosts.
Defective Nrf2-dependent redox signalling contributes to microvascular dysfunction in type 2 diabetes
Authors: Gopal V. Velmurugan, Nagalingam R. Sundaresan, Mahesh P. Gupta, Carl White
Journal: Cardiovascular Research (2013)

In type 2 diabetes, antioxidant depletion contributes to increased oxidative stress in the microvasculature. The current study was designed to assess how oxidative stress contributes to functional changes in the microvasculature, and determine the importance, and the effects of pharmacologically targeting, the transcription factor Nrf2. Pressure myography was used to measure myogenic constriction in mesenteric arterioles from diabetic (db/db) and non-diabetic (db/m) mice. Compared with db/m, myogenic constriction was larger in db/db, independent of the endothelial cell layer, and directly correlated with elevated basal and pressure-induced reactive oxygen species (ROS) production. Nrf2 was depleted in db/db vessels and associated with down-regulation of Nrf2-regulated genes. Notably, expression of GCLC and GCLM, enzymes important for glutathione (GSH) synthesis, was dramatically reduced, as was total cellular GSH. Normal myogenic function was restored to db/db arterioles by incubation with cell-permeant GSH. Similarly, the db/db myogenic phenotype was recapitulated in the db/m vessels by pharmacological GSH depletion. Treatment with the Nrf2-activator sulforaphane increased Nrf2 and promoted its nuclear localization and increased GCLC and GCLM expression in both db/m and db/db. Sulforaphane dramatically lowered ROS signalling in db/db and reduced myogenic tone to levels similar to that seen in db/m vessels. Depleted Nrf2 and expression of its dependent genes compromises antioxidant capacity resulting in dysfunctional myogenic tone in diabetes that is reversed by the Nrf2-activator sulforaphane.
Tumor Angiogenesis as a Prognostic Assay for Invasive Ductal Breast Carcinoma
Authors: K. Axelsson, B.-M. E. Ljung, D. H. Moore, A. D. Thor, K. L. Chew, S. M. Edgerton, H. S. Smith, B. H. Mayall
Journal: JNCI Journal of the National Cancer Institute (1995)

Background: Tumor angiogenesis, as assayed by microvessel density, has been proposed as an independent prognostic marker for clinical outcome in breast cancer patients. Purpose: The present study evaluated the microvessel density assay and assessed its utility, alone and together with the evaluation of other tumor characteristics, in predicting outcome in patients with invasive ductal carcinomas. Methods: In a blinded design, cases of invasive ductal carcinoma were selected from a registry containing the records of and tumor specimens from 386 breast cancer patients treated at the Massachusetts General Hospital from 1977 through 1982. After the exclusion of ineligible patients and inadequate specimens, 220 patients were included in the study; their median time of follow-up was Hi years. Half of these patients ( n = 110) were positive for axillary lymph node metastases. Histologic sections of the tumors were stained immunocytochemically for factor VIII, a coagulation protein expressed by blood vessel endothelium, and for p53 protein. Independently, two analysts counted microvessels in three microscope fields selected from separate vascular regions of the tumor. Variability in microvessel scores between analysts and among different fields of the same tumor was summarized by the coefficient of variation. The kappa statistic tested for agreement between the analysts while correcting for chance agreement. The effects of tumor characteristics on metastasis-free survival and overall survival were tested univariately by the Harrington-Fleming rank test procedure. The effect of multiple factors on survival was tested under a Cox multivariate proportional hazards model. Results: Microvessel count showed considerable variability between the two analysts and among regions within each tumor, with an overall concordance for tumor classification of 73%. Univariate analysis revealed no association between microvessel count and any other tumor or patient characteristic. Multivariate analysis indicated, for these patients, that nodal status and p53 staining predicted metastasis-free survival and that nodal status, estrogen receptor (ER) status, and tumor grade predicted overall survival. Conclusions: Microvessel count showed much variation among different regions of each tumor. It did not predict metastasis-free survival or overall survival. Nodal status was the most powerful criterion to stratify these patients with invasive ductal carcinoma of the breast into different survival groups. Only ER status, tumor grade, and p53 staining had additional prognostic utility for these patients after they had been stratified by nodal status. [J Natl Cancer Inst 87:997–1008,1995]
HLA-DR polymorphism affects the interaction with CD4.
Authors: S Fleury, J Thibodeau, G Croteau, N Labrecque, H E Aronson, C Cantin, E O Long, R P Sékaly
Journal: The Journal of Experimental Medicine (1995)

Major histocompatibility complex (MHC) class II molecules are highly polymorphic and bind peptides for presentation to CD4+ T cells. Functional and adhesion assays have shown that CD4 interacts with MHC class II molecules, leading to enhanced responses of CD4+ T cells after the activation of the CD4-associated tyrosine kinase p56lck. We have addressed the possible contribution of allelic polymorphism in the interaction between CD4 and MHC class II molecules. Using mouse DAP-3-transfected cells expressing different isotypes and allelic forms of the HLA-DR molecule, we have shown in a functional assay that a hierarchy exists in the ability of class II molecules to interact with CD4. Also, the study of DR4 subtypes minimized the potential contribution of polymorphic residues of the peptide-binding groove in the interaction with CD4. Chimeras between the DR4 or DR1 molecules, which interact efficiently with CD4, and DRw53, which interacts poorly, allowed the mapping of polymorphic residues between positions beta 180 and 189 that can exert a dramatic influence on the interaction with CD4.
Development of additional autoimmune diseases in a multiethnic cohort of patients with systemic lupus erythematosus with reference to damage and mortality
Authors: S A Chambers, S C Charman, A Rahman, D A Isenberg
Journal: Annals of the Rheumatic Diseases (2007)

To determine the prevalence of other autoimmune diseases (AID) in black, Caucasian and South Asian patients with systemic lupus erythematosus (SLE) compared with the prevalence of these AID in the UK population, and to assess the impact of these additional AID on damage scores and mortality.The prevalence and chronology of development of additional AID in SLE patients was determined by case note review. Comparisons were made with prevalence data for AID in the general UK population. The impact of additional AID on mortality and damage scores at up to 10 years was determined in the index cases (patients who developed another AID either in the same year or within 5 years of onset of SLE) compared with controls matched for sex, age, ethnicity and year of onset of SLE.There was no significant difference in the total number of AID that developed in patients from each ethnic group but differences in the frequency of some AID were noted. Mortality and damage scores were worse at 5 years in the study cases than the controls, particularly in the peripheral vascular category.Patients with SLE might develop other AID that could complicate management of SLE by having an adverse impact on damage scores and mortality.
CORRECTIVE BRACE FOR THE UPPER EXTREMITY IN HEMIPLEGIA
Authors: Louis N. Rudin
Journal: JAMA (1953)

In the first few days after the occurrence of hemiplegia, the affected upper extremity is limp and appears flaccid, but actually, the muscles are spastic. After a variable short time a typical position is assumed. The upper extremity is adducted, the elbow flexed, the forearm pronated, and the wrist, fingers, and thumb flexed. If physical therapy and rehabilitation measures are not begun early, permanent contractures of muscles develop, and the upper extremity becomes fixed in the position described. There is a slow improvement in the brain tissue because of a partial resolution of the lesion. This results in improvement in the potential motor ability of the cortex. Unfortunately, this organic improvement of brain tissue cannot be translated into purposeful volitional movements, because the muscles and joints of the upper extremity have been fixed by contractures.  Many patients with hemiplegia of long duration have an increased potential ability to execute volitional
Should more patients with acute ischaemic stroke receive thrombolytic treatment?
Authors: J. M Wardlaw, P. A G Sandercock, V. Murray
Journal: BMJ (2009)

In developed countries, stroke is the third most common cause of death and the most common cause of dependency in adults. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) was licensed for use in highly selected patients within three hours of acute ischaemic stroke in the United States in 1996 on the basis of the National Institutes of Neurological Disorders and Stroke (NINDS) randomised controlled trial (n=624),1 which showed substantially lower combined rates of death or dependency with this treatment (140/1000 fewer) despite an excess of symptomatic intracranial haemorrhage (60/1000 more). The Cochrane review of all data from randomised trials of rt-PA and a meta-analysis of individual patient data agreed with these findings.2 3 In Europe, a conditional licence for use within three hours in highly selected patients was granted in 2002 on the basis of the NINDS trial plus data from two European randomised controlled trials (n=930).4 5

However, six years after European and 10 years after US licensing, fewer than 10% of eligible patients receive thrombolysis—1-7% in the US,6 7 3% in Canada,8 3% in Germany,9 and 3.3% in Sweden (www.riks-stroke.org)—and use of rt-PA varies greatly between European countries.10 Clinicians and managers are uncertain about how widely to use rt-PA in routine clinical practice.11 The fact that treatment licenses are based on data from fewer than 1000 randomised patients with narrow entry criteria, the substantial excess of symptomatic intracranial haemorrhage, plus the restricted licence conditions may worry many clinicians.

In 2009, a systematic review of all randomised trials comparing thrombolysis with control (mostly placebo) in patients with acute ischaemic stroke analysed 26 trials of various thrombolytic drugs, 11 of which tested rt-PA up to six hours after stroke (n=3977) (figure⇓).12 Compared with control, rt-PA given up to six …
RhoA: A therapeutic target for chronic myeloid leukemia
Authors: Poonam R Molli, Madhura B Pradhan, Suresh H Advani, Nishigandha R Naik
Journal: Molecular Cancer (2012)

Abstract Background Chronic Myeloid Leukemia (CML) is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL) the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. Methods To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. Results In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. Conclusions RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a therapeutic target in CML.