tbuckley/cabot-search huggingface dataset:
Preregistration house officers in general practice: review of evidence
Authors: J. Illing
Journal: BMJ (2003)

To examine the strengths and weaknesses of the national and local schemes for preregistration house officers to spend four months in general practice, to identify any added value from such placements, and to examine the impact on career choices.Review of all studies that reported on placements of preregistration house officers in general practice.19 accounts of preregistration house officers' experience in general practice, ranging from single case reports to a national evaluation study, in a variety of locations in Scotland and England.Views of 180 preregistration house officers, 45 general practitioner trainers, and 105 consultant trainers.Main findings or themes weighted according to number of studies reporting them and weighted for sample size.The studies were unanimous about the educational benefits of the placements. The additional learning included communication skills, social and psychological factors in illness, patient centred consultations, broadening of knowledge base, and dealing with uncertainty about diagnosis and referral.Despite the reported benefits and recommendations of the scheme, it is not expanding. General practitioner trainers reported additional supervision that was unremunerated. The reforms of the senior house officer grade may resolve this problem by offering the placements to senior house officers, who require less supervision.
Maximal work capacity in relation to nutritional status in children with cystic fibrosis
Authors: VA Gulmans, K de Meer, HJ Brackel, PJ Helders
Journal: European Respiratory Journal (1997)

In children with cystic fibrosis, objective parameters of exercise tolerance are needed which are easy to measure in nonspecialized centres. We investigated maximal workload (W'max) in children with cystic fibrosis in relation to body weight and fat-free mass, and compared this with results for maximal oxygen consumption (V'O2,max). Fourteen patients with cystic fibrosis performed an incremental maximal exercise test on a bicycle ergometer. W'max, V'O2,max, body weight and fat-free mass were measured. W'max and V'O2,max were significantly correlated (r = 0.91; p &lt; 0.001). Using standard deviation scores in relation to reference values, W'max and V'O2,max per kilogram body weight were significantly higher than uncorrected W'max and V'O2,max (mean difference (95% CI) 0.63 (0.24-1.01) and 0.91 (0.32-1.49) SD units, respectively). There was no such difference after correction for fat-free mass. Standardized V'O2,max was significantly higher than standardized W'max (mean difference (95% CI): 1.59 (1.14-2.04)), also after correction for body weight and fat-free mass. In children with mild-to-moderate cystic fibrosis, maximal workload per kilogram fat-free mass, but not per kilogram body weight, is a useful parameter to correct for diminished nutritional status. In these patients, maximal workload is consistently lower than maximal oxygen consumption. Taking into account this difference, maximal workload and maximal workload per kilogram fat-free mass can be used for follow-up of paediatric patients with cystic fibrosis in nonspecialized settings.
Complexity of Lung Cancer Modifiers: Mapping of Thirty Genes and Twenty-five Interactions in Half of the Mouse Genome
Authors: N. Tripodis, A. A. M. Hart, R. J. A. Fijneman, P. Demant
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Numerous low-penetrance genes control susceptibility to cancer in experimental animals, but the overall genetic information on this group of genes (i.e., number of loci and their mutual interactions) is missing. We performed a systematic search, scanning roughly half of the mouse genome for lung cancer susceptibility (Sluc) genes affecting tumor size or number by using mouse recombinant congenic (RC) strains. In each RC strain (OcB), approximately 12.5% of the genome is derived from the lung cancer-resistant strain B10.O20, whereas the rest is derived from the lung cancer-susceptible strain O20. Methods: A total of 730 F2 hybrids from five (OcB × O20) crosses were tested. Pregnant mice were treated on day 18 of gestation with a single dose of N-ethyl-N-nitrosourea. When offspring were 16 weeks old, whole lungs were removed and sectioned semiserially, and the size of all lung tumors (n = 2658) was determined. Analysis of variance was used for detection of linkage, and models (including main effect and two-way interactions) were tested with a statistical program. Results: We detected a total of 30 Sluc loci (16 new plus 14 previously reported) and 25 two-way interactions. Some of these interactions are counteracting (e.g., Sluc17 and Sluc20), resulting in the partial or total masking of the individual independent effect (main effect) of each involved locus. Seven loci (Sluc1, Sluc5, Sluc12, Sluc16, Sluc18, Sluc20, and Sluc26) and two interactions (Sluc5 × Sluc12 and Sluc5 × Sluc26) were detected in more than one RC strain. Conclusions: The extrapolation of our results to the whole genome suggests approximately 60 Sluc loci (90% confidence intervals = 42 to 78). Despite the genetic complexity of lung cancer, use of appropriate mapping strategies can identify a large number of responsible loci and can reveal their interactions. This study provides an insight into the genetic control of lung tumorigenesis and may serve as a paradigm for investigating the genetics of other cancer types.
Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer
Authors: Aaron M. LeBeau, Sai Duriseti, Stephanie T. Murphy, Francois Pepin, Byron Hann, Joe W. Gray, Henry F. VanBrocklin, Charles S. Craik
Journal: Cancer Research (2013)

Abstract Components of the plasminogen activation system, which are overexpressed in aggressive breast cancer subtypes, offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared imaging and 111In single-photon emission computed tomography. Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard 18F-fluorodeoxyglucose at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. In addition, a radioimmunotherapy study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 177Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology. Cancer Res; 73(7); 2070–81. ©2013 AACR.
Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse
Authors: M C Arrieta, K Madsen, J Doyle, J Meddings
Journal: Gut (2008)

The addition of spermine or of spermidine to rat liver assay systems produced marked changes in a number of microsomal drug oxidations. The hydroxylation of aniline and the N-demethylation of ethylmorphine were both enhanced with concentrations of 1-10 mM spermine or of spermidine. The results with putrescine on ethylmorphine metabolism were less dramatic, and no effect could be observed with putrescine in studies with other drug substrates. In contrast to the enhancing effects, inhibition was observed when spermine or spermidine was added to p-nitroanisole O-demethylation assay mixtures, and no effect was observed in assays for acetanilide hydroxylation. The inhibiting and enhancing effects of the polyamines can be observed in assays containing liver preparations from both male and female rats, and those from rats pretreated with phenobarbital or 3-methylcholanthrene. In all studies, the alterations were kinetically noncompetitive. The effects were shown to be independent of the NADPH-generating system and the cation requirements, and were not mediated through an interaction with NADPH-cytochrome c reductase. The possibility is considered that the enhancing and inhibiting effects may be related to the ability of these polycations to bind to microsomal membranes and cause alterations at different sites of substrate interaction.
Megalin and Cubilin are Endocytic Receptors Involved in Renal Clearance of Hemoglobin
Authors: Jakub Gburek, Pierre J. Verroust, Thomas E. Willnow, John C. Fyfe, Wojciech Nowacki, Christian Jacobsen, Søren K. Moestrup, Erik I. Christensen
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The kidney is the main site of hemoglobin clearance and degradation in conditions of severe hemolysis. Herein it is reported that megalin and cubilin, two epithelial endocytic receptors, mediate the uptake of hemoglobin in renal proximal tubules. Both receptors were purified by use of hemoglobin-Sepharose affinity chromatography of solubilized renal brush-border membranes. Apparent dissociation constants of 1.7 μM for megalin and 4.1 μM for cubilin were determined by surface plasmon resonance analysis. The binding was calcium dependent in both cases. Uptake of fluorescence-labeled hemoglobin by BN-16 cells was inhibited by anti-megalin and anti-cubilin antibodies as well as by receptor-associated protein, a chaperone for LDL-receptor family proteins. Partial inhibition by myoglobin was observed, whereas bovine serum albumin, intrinsic factor-cobalamin complexes, and β2-microglobulin did not affect the uptake. By use of immunohistochemistry, it was demonstrated that uptake of hemoglobin in proximal tubules of rat, mouse, and dog kidneys occurs under physiologic conditions. Studies on normal and megalin knockout mouse kidney sections showed that megalin is responsible for physiologic clearance of hemoglobin. Labeling intensities in kidneys from normal and cubilin-malexpressing dogs were similar, which suggests that, in the normal state, the role of cubilin in uptake of hemoglobin is rather limited. However, cubilin is likely to assist hemoglobin endocytosis in settings of hemoglobinuria. In conclusion, the study provides a molecular explanation for long-standing observations of hemoglobin uptake in renal proximal tubules that involve the endocytic receptors megalin and cubilin. The findings may prove to be essential for further research on the pathophysiology of hemoglobinuric acute renal failure and proteinuria-associated tubulointerstitial nephritis.
Alcohol: Its Metabolism and Interaction With Nutrients
Authors: Charles S. Lieber
Journal: Annual Review of Nutrition (2000)

In the past, alcoholic liver disease was attributed exclusively to dietary deficiencies, but experimental and judicious clinical studies have now established alcohol's hepatotoxicity. Despite an adequate diet, it can contribute to the entire spectrum of liver diseases, mainly by generating oxidative stress through its microsomal metabolism via cytochrome P4502E1 (CYP2E1). It also interferes with nutrient activation, resulting in changes in nutritional requirements. This is exemplified by methionine, one of the essential amino acids for humans, which needs to be activated to S-adenosylmethionine (SAMe), a process impaired by liver disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. In baboons, SAMe attenuated mitochondrial lesions and replenished glutathione; it also significantly reduced mortality in patients with Child A or B cirrhosis. Similarly, decreased phosphatidylethanolamine methyltransferase activity is associated with alcoholic liver disease, resulting in phosphatidylcholine depletion and serious consequences for the integrity of membranes. This can be offset by polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines comprising dilinoleoylphosphatidylcholine (DLPC), which has high bioavailability. PPC (and DLPC) opposes major toxic effects of alcohol, with down-regulation of CYP2E1 and reduction of oxidative stress, deactivation of hepatic stellate cells, and increased collagenase activity, which in baboons, results in prevention of ethanol-induced septal fibrosis and cirrhosis. Corresponding clinical trials are ongoing.
Why localist connectionist models are inadequate for categorization
Authors: Robert M. French, Elizabeth Thomas
Journal: Behavioral and Brain Sciences (2000)

Two categorization arguments pose particular problems for localist connectionist models. The internal representations of localist networks do not reflect the variability within categories in the environment, whereas networks with distributed internal representations do reflect this essential feature of categories. We provide a real biological example of perceptual categorization in the monkey that seems to require population coding (i.e., distributed internal representations).
Glioma Tumor Stem-Like Cells Promote Tumor Angiogenesis and Vasculogenesis via Vascular Endothelial Growth Factor and Stromal-Derived Factor 1
Authors: Chris Folkins, Yuval Shaked, Shan Man, Terence Tang, Christina R. Lee, Zhenping Zhu, Robert M. Hoffman, Robert S. Kerbel
Journal: Cancer Research (2009)

Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.
A PHYSIOLOGICAL STUDY OF EXPERIMENTAL NEPHRITIS DUE TO BACTERIAL POISONS AND CYTOTOXIC SERA
Authors: Richard M. Pearce, A. B. Eisenbrey
Journal: The Journal of Experimental Medicine (1911)

The physiological study of experimental nephritis caused by poisons of bacterial origin demonstrates that the poisons may produce types of nephritis in which either vascular or tubular changes predominate. Diphtheria toxin produces a nephritis which in its late stage is of the vascular type, but in its early stage is distinctly tubular. Tuberculin and mallein uniformly cause lesions of the tubular type, which do not pass into the vascular type. Nephrotoxic and hemolytic immune sera cause changes in the kidneys which by physiological methods of observation present no evidence of vascular injury, but which are anatomically characterized by exudative glomerular lesions of moderate severity. This discrepancy between the results of anatomical and physiological study indicates that a lesion of the membrane controlling the passage of fluids may occur without alteration in the power of the vessels to contract and dilate. This fact is shown clearly by the lesion caused by hemolytic immune serum, which is in sharp contrast to the lesion caused by diphtheria toxin, since the latter substance not only alters the permeability of the membranes but also influences markedly the power of the vessels to contract and dilate. It is necessary therefore if the term "vascular" is used in its broadest sense, to recognize three types of vascular nephritis: (1) one in which little or no anatomical evidence of vascular injury is found, but in which physiological methods show profound vascular changes, as in arsenical nephritis; (2) one in which anatomical evidence of vascular (exudative) injury is prominent, but in which the physiological tests are negative, as in nephritis caused by a hemolytic immune serum; and (3) one in which both anatomical and physiological changes are prominent, as in diphtheria toxin nephritis.
Nuclear magnetic resonance (NMR) tomographic imaging for popliteal cysts in rheumatoid arthritis.
Authors: R G Hull, J A Rennie, C J Eastmond, J M Hutchison, F W Smith
Journal: Annals of the Rheumatic Diseases (1984)

The ability of nuclear magnetic resonance (NMR) tomographic imaging to show a change in proton spin-lattice relaxation time (T1 value) in the joints of patients with rheumatoid arthritis before and after treatment with intra-articular steroid has been assessed. Six patients with seropositive rheumatoid arthritis and clinical evidence of a popliteal cyst were examined by both NMR tomography and arthrography. In all cases the presence of active rheumatoid arthritis was shown by an increase in the T1 values of the synovium of the joints. After arthrography a consistent but small rise in T1 value was noted which fell to below the initial reading after treatment by intra-articular injection of an anti-inflammatory agent. In all cases the presence of the popliteal cyst was clearly shown by both NMR tomography and arthrography. The findings indicate that NMR tomography provides a sensitive method for the demonstration of inflammatory joint disease, popliteal cysts, and possibly for monitoring response to therapy.
N-Terminal Pro–Brain Natriuretic Peptide or Troponin Testing Followed by Echocardiography for Risk Stratification of Acute Pulmonary Embolism
Authors: Lutz Binder, Burkert Pieske, Manfred Olschewski, Annette Geibel, Beate Klostermann, Christian Reiner, Stavros Konstantinides
Journal: Circulation (2005)

Background— Brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP have recently emerged as promising parameters for risk assessment in acute pulmonary embolism (PE). However, their positive predictive value is low, and the prognostic implications of NT-proBNP or troponin elevation alone are questionable. Methods and Results— To determine whether the combination of NT-proBNP testing with echocardiography may identify both low-risk and high-risk patients with PE, we examined 124 consecutive patients with proved PE. All underwent echocardiography on admission to detect right ventricular dysfunction. NT-proBNP and troponin concentrations were measured in one core laboratory. The primary end point was death or major in-hospital complications. The cutoff level of 1000 pg/mL had a high negative predictive value (95% for a complicated course, 100% for death), but NT-proBNP ≥1000 pg/mL did not independently predict an adverse outcome. Combination of NT-proBNP testing with echocardiography identified 3 major risk groups. A positive echocardiogram was associated with a 12-fold elevation in complication risk compared with patients with low NT-proBNP ( P =0.002), whereas NT-proBNP elevation without right ventricular dysfunction on echocardiography only slightly increased the risk of an adverse outcome ( P =0.17). The combination of cardiac troponin testing with echocardiography yielded similar complication rates in the lowest-risk group and a similar magnitude of risk elevation for the highest-risk patients, but it also increased the number of intermediate-risk groups. Conclusions— Our results support a simple risk stratification algorithm for patients with PE, with the use of NT-proBNP or troponin testing as an initial step that should be followed by echocardiography if elevated levels of the biomarker are found.
Population-specific reference equations?
Authors: S. Stanojevic, A. Wade, T. J. Cole, J. Stocks
Journal: European Respiratory Journal (2006)

The recent paper by CHINN et al. [1], published in the European Respiratory Journal, describing sources of variation of forced expiratory volume in one second (FEV1) and forced vital capacity in the large multicentre European Community Respiratory Health Survey trial, raises important issues in the ongoing debate over the misuse of reference equations in respiratory medicine.The authors demonstrate potentially important population differences, which call into question the application of ethnicity-specific reference equations.
CCR5 Δ32 deletion and atopic asthma in India
Authors: J Batra, M Sharma, R Chatterjee, S Sharma, U Mabalirajan, B Ghosh
Journal: Thorax (2005)

Chemokine receptor 5 ( CCR5 ) contributes to the generation of a Th1 immune response by interacting with agonists such as RANTES, MIP-1α, and MIP-1β.1 A 32 base pair deletion (Δ32) in CCR5 has been proposed to protect individuals against HIV infection and to bias the immune system towards a Th2-driven response, thus affecting the susceptibility to develop allergic diseases such as asthma. In a study in Scottish children, Hall et al reported an association of CCR5 Δ32 with a reduced risk of asthma2 but found …
Analytical Identification of Ideal Pulmonary-Systemic Flow Balance in Patients With Bidirectional Cavopulmonary Shunt and Univentricular Circulation
Authors: Gerhard-Paul Diller, Anselm Uebing, Keith Willson, L. Ceri Davies, Konstantinos Dimopoulos, Sara A. Thorne, Michael A. Gatzoulis, Darrel P. Francis
Journal: Circulation (2006)

Background— In the present study, we extended previous mathematical modeling work on patients with bidirectional cavopulmonary (“bidirectional Glenn”) anastomosis to assess the potential utility of several descriptors of oxygen status. We set out to determine which of these descriptors best represents the overall tissue oxygenation. We also introduce a new descriptor, S o 2 min, defined as the lower of the superior and inferior vena cava oxygen saturations. Methods and Results— The application of differential calculus to a model of oxygen physiology of patients with bidirectional Glenn allowed simultaneous assessment of all possible distributions of blood flow and metabolic rate between upper and lower body, across all cardiac outputs, total metabolic rates, and oxygen-carrying capacities. When total cardiac output is fixed, although it may intuitively seem best to distribute flow to maximize oxygen delivery (total, upper body, or lower body), we found that for each variable, there are situations in which its maximization seriously deprives flow to the upper or lower circulation. In contrast, maximizing S o 2 min always gives physiologically sensible results. If the majority of metabolism is in the upper body (typical of infancy), then oxygenation is optimized when flow distribution matches metabolic distribution. In contrast, if the majority of metabolism is in the lower body (typical of older children and during exercise), oxygenation is optimal when flows are equal. Conclusions— In patients with bidirectional cavopulmonary anastomosis, because there is a tradeoff between flow distribution and saturation, it is unwise to concentrate on maximizing oxygen delivery. Maximizing systemic venous saturations (especially S o 2 min) is conceptually different and physiologically preferable for tissue oxygenation.