tbuckley/cabot-search huggingface dataset:
Impact of Time to Treatment on Mortality After Prehospital Fibrinolysis or Primary Angioplasty
Authors: Philippe Gabriel Steg, Eric Bonnefoy, Sylvie Chabaud, Frédéric Lapostolle, Pierre-Yves Dubien, Pascal Cristofini, Alain Leizorovicz, Paul Touboul
Journal: Circulation (2003)

Background— CAPTIM was a randomized trial comparing prehospital thrombolysis with transfer to an interventional facility (and, if needed, percutaneous intervention) with primary percutaneous coronary intervention (PCI) in patients with ST-segment-elevation myocardial infarction (STEMI). Because the benefit of thrombolysis is maximal during the first 2 hours after symptom onset, and because prehospital thrombolysis can be implemented earlier than PCI, this analysis studied the relationship between the effect of assigned treatment and the time elapsed from symptom onset. Methods and Results— Randomization within 2 hours (n=460) or ≥2 hours (n=374) after symptom onset had no impact on the effect of treatment on the 30-day combined primary end point of death, nonfatal reinfarction, and disabling stroke. However, patients randomized &lt;2 hours after symptom onset had a strong trend toward lower 30-day mortality with prehospital thrombolysis compared with those randomized to primary PCI (2.2% versus 5.7%, P =0.058), whereas mortality was similar in patients randomized ≥2 hours (5.9% versus 3.7%, P =0.47). There was a significant interaction between treatment effect and delay with respect to 30-day mortality (hazard ratio 4.19, 95% CI 1.033 to 17.004, P =0.045). Among patients randomized in the first 2 hours, cardiogenic shock was less frequent with lytic therapy than with primary PCI (1.3% versus 5.3%, P =0.032), whereas rates were similar in patients randomized later. Conclusions— Time from symptom onset should be considered when one selects reperfusion therapy in STEMI. Prehospital thrombolysis may be preferable to primary PCI for patients treated within the first 2 hours after symptom onset.
Relaxed Constraint and Evolutionary Rate Variation between Basic Helix-Loop-Helix Floral Anthocyanin Regulators in Ipomoea
Authors: Matthew A. Streisfeld, Mark D. Rausher
Journal: Molecular Biology and Evolution (2007)

Regulatory genes are believed to play a large role in morphological diversification and are often characterized by elevated rates of evolution. Whether this rapid evolution is primarily due to adaptive differentiation or relaxed selective constraint remains an open question. We attempted to distinguish between these alternative outcomes in 2 transcription factors known to regulate the expression of anthocyanin pigmentation genes in flowers. We cloned the full-length coding region from 2 basic helix-loop-helix transcription factors from several species of Ipomoea with diverse flower colors and determined the selective forces operating on them. In both genes, rapidly evolving sites and indel mutations are clustered in nonbinding domains, but the extent of rate acceleration in these domains is reduced relative to most previously characterized plant transcription factors. Moreover, codon models of substitution rates and models evaluating the magnitude of change to physical amino acid properties demonstrate little evidence for adaptive evolution and suggest that elevated nonsynonymous substitution rates in these domains represent relaxed selective constraint. Although both genes show qualitatively similar patterns, their rates of evolution differ significantly due to an increased rate of nonsynonymous substitutions in the nonbinding domains in one copy, suggesting substantial differences in functional constraint on each gene. In general, these results provide additional evidence demonstrating that decreased constraint as opposed to positive selection is largely responsible for the frequently observed pattern of rapid evolution in particular domains of plant transcription factors. More specifically, they suggest that most of the amino acid substitutions are neutral and do not implicate a role for natural selection on these regulatory genes in the diversification of flower color in Ipomoea.
Effects of artificial depletion of the bile acid pool in man.
Authors: R P Jazrawi, C Bridges, A E Joseph, T C Northfield
Journal: Gut (1986)

In order to elucidate the relationship between bile acid pool size and cholesterol saturation index of fasting state gall bladder bile, we artificially depleted the bile acid pool in 12 healthy volunteers. Bile acid pool size decreased from 7.6 +/- 0.9 to 5.8 +/- 0.7 mmol (mean +/- SEM, p less than 0.01), and saturation index of fasting state gall bladder bile increased from 0.93 +/- 0.07 to 1.18 +/- 0.07 (p less than 0.001). There was no alteration in saturation index of basal or stimulated hepatic bile. There was no change in gall bladder storage of basal hepatic bile, nor in the proportion of the bile acid pool stored in the gall bladder. The bile acid mass in the gall bladder fell from 4.9 +/- 0.5 to 3.4 +/- 0.4 mmol (p less than 0.05) and phospholipid mass from 1.6 +/- 0.3 to 1.2 +/- 0.2 mmol (p less than 0.05), but there was no change in cholesterol mass. The gall bladder volume fell from 30 +/- 4 to 18 +/- 2 ml (p less than 0.01). These results suggest that artificial depletion of the bile acid pool increased saturation index of fasting state gall bladder bile without altering saturation index of basal or stimulated hepatic bile; it probably increased the ratio of basal: stimulated hepatic bile within the gall bladder by decreasing gall bladder storage of stimulated hepatic bile.
Ultrasonographic measurement of the median nerve in patients with rheumatoid arthritis without symptoms or signs of carpal tunnel syndrome
Authors: H. Berner Hammer, E. A Haavardsholm, T. Kristian Kvien
Journal: Annals of the Rheumatic Diseases (2006)

Ultrasonography (US) has shown increased cross-sectional area of the median nerve in carpal tunnel syndrome (CTS). Knowledge of the normal distribution of the areas is a prerequisite to evaluate pathology. Presently, the distribution of cross-sectional areas of the median nerve was explored in patients with rheumatoid arthritis (RA).The median nerves of patients with RA having no symptoms or signs of CTS were examined with bilateral US at the entrance of the carpal tunnel.A total of 154 patients with RA were included. The median nerve was divided in 11.7% of the hands. The mean (SD) cross-sectional areas of the undivided median nerves were not significantly different on either sides (8.3 (1.5) mm(2) on the right side and 8.3 (1.4) mm(2) on the left side). The areas of the examined 308 median nerves ranged from 5.0 to 12.8 mm(2), with the 97.5 centile being 11.1 mm(2). Areas >10.0 mm(2) were found in 10% of the patients.The mean cross-sectional areas of the median nerve in patients with RA were similar to those reported in healthy controls. However, 10% of the patients had values that overlap with areas commonly reported in patients with mild idiopathic CTS.
An exercise programme for the management of lateral elbow tendinopathy
Authors: D Stasinopoulos, K Stasinopoulou, M I Johnson
Journal: British Journal of Sports Medicine (2005)

Home exercise programmes and exercise programmes carried out in a clinical setting are commonly advocated for the treatment of lateral elbow tendinopathy (LET), a very common lesion of the arm with a well-defined clinical presentation. The aim of this study is to describe the use and effects of strengthening and stretching exercise programmes in the treatment of LET.Slow progressive eccentric exercises for LET should be performed with the elbow in extension, forearm in pronation, and wrist in extended position (as high as possible). However, it is unclear how the injured tendon, which is loaded eccentrically, returns to the starting position without experiencing concentric loading and how the "slowness" of eccentric exercises should be defined. Nor has the treatment regimen of the eccentric exercises of a supervised exercise programme been defined.Static stretching is defined as passively stretching a given muscle-tendon unit by slowly placing and maintaining it in a maximal position of stretch. We recommend the position should be held for 30-45 s, three times before and three times after eccentric exercises during each treatment session with a 30 s rest interval between each procedure. The treatment region of static stretching exercises when a supervised exercise programme is performed is unknown.A well designed trial is needed to study the effectiveness of a supervised exercise programme for LET consisting of eccentric and static stretching exercises. The issues relating to the supervised exercise programme should be defined so that therapists can replicate the programme.
Societal views on orphan drugs: cross sectional survey of Norwegians aged 40 to 67
Authors: A. S. Desser, D. Gyrd-Hansen, J. A. Olsen, S. Grepperud, I. S. Kristiansen
Journal: BMJ (2010)

To determine whether a general societal preference for prioritising treatment of rare diseases over common ones exists and could provide a justification for accepting higher cost effectiveness thresholds for orphan drugs.Cross sectional survey using a web based questionnaire.Norway.Random sample of 1547 Norwegians aged 40-67.Choice between funding treatment for a rare disease versus a common disease and how funds should be allocated if it were not possible to treat all patients, for each of two scenarios: identical treatment costs per patient and higher costs for the rare disease. Respondents rated five statements concerning attitudes to equity on a five point Likert scale (5=completely agree).For the equal cost scenario, 11.2% (9.6% to 12.8%) of respondents favoured treating the rare disease, 24.9% (21.7% to 26.0%) the common disease, and 64.9% (62.6% to 67.3%) were indifferent. When the rare disease was four times more costly to treat, the results were, respectively, 7.4% (6.1% to 8.7%), 45.3% (42.8% to 47.8%), and 47.3% (44.8% to 49.8%). Rankings for attitude on a Likert scale indicated strong support for the statements "rare disease patients should have the right to treatment even if more expensive" (mean score 4.5, SD 0.86) and "resources should be used to provide the greatest possible health benefits" (3.9, 1.23).Despite strong general support for statements expressing a desire for equal treatment rights for patients with rare diseases, there was little evidence that a societal preference for rarity exists if treatment of patients with rare diseases is at the expense of treatment of those with common diseases.
PTH-020 Factors Influencing Abnormal Gland Morphogenesis in Colorectal Cancer (CRC) - Translational Studies
Authors: R Topley, A Fatehullah, R Deevi, I Jagan, J Eves, M Loughrey, K Arthur, M Stevenson, F C Campbell
Journal: Gut (2013)

<h3>Introduction</h3> Disruption of colorectal gland formation characterises high grade, aggressive CRCs but causal mechanisms remain unclear. Glandular morphogenesis can be modelled in three-dimensional (3D) culture systems that enable investigation of specific oncogenic signals. We have shown that the tumour suppressor PTEN regulates 3D glandular morphogenesis in a Caco-2 colorectal organotypic model system through effects on the Rho-GTPase cdc42. Cdc42 is activated by specific guanine nucleotide exchange factors (GEFs) and influences gland lumen formation by regulation of apical membrane (AM) assembly. PTENknockdown inhibits cdc42, disrupts AM integrity and induces a vacuolar, multilumen glandular phenotype evocative of high grade CRC. While PTENhas catalytically -active or -inactive functional domains relevant to phosphatidylinositol 3-kinase (PI3K) activity, Caco-2 gland development was unaffected by PI3K signalling. <h3>Methods</h3> We used wild type PTEN-expressing Caco-2 cells and isogenic stable PTENknockdown Caco-2 (KD) clones in two- (2D) and three-dimensional (3D) cultures as model systems. Cell membrane localization of specific cdc42 GEFs was investigated by cell fractionation and immunoblot. Effects of catalytically -active or -inactive PTENmutants on cdc42 activity and/or AM integrity during 3D morphogenesis were investigated by transfection and confocal microscopy. Apical membrane integrity was assessed in human CRCby semiquantitative score of the AM marker, NHERF-1. CRCgland morphology was assessed by a validated grading system. <h3>Results</h3> PTENexpression enhanced cell membrane recruitment of cdc42 GEFs with a specific role in 3D morphogenesis (Tuba, ITSN2). PTENmutants containing an intact catalytically-inactive C2 domain enhanced cdc42 activity, restored AM integrity and rescued defective morphogenesis of 3D PTEN-KD Caco-2 cultures. Conversely, a C2 domain construct mutated at its CBR3 lipid-binding motif was ineffective. Fundamental attributes of the model system <i>viz,</i> associations between AM integrity and gland morphology were conserved and had prognostic significance in human CRC. <h3>Conclusion</h3> PTENdeficiency impairs GEF membrane recruitment, cdc42 activation, apical membrane assembly and CRCglandular morphogenesis in a predictive colorectal cancer model system. PTEN-cdc42 regulatory pathways influence AM integrity and colorectal glandular morphogenesis. Dissection of these networks may identify molecular targets for novel therapy, aimed at high grade CRC. <h3>Disclosure of Interest</h3> None Declared.
Nucleolar hypertrophy correlates with hepatocellular carcinoma development in cirrhosis due to HBV infection
Authors: D Trerè
Journal: Hepatology (2003)

Patients with cirrhosis are at significant risk for hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the relationship between the percentage of hepatocytes showing nucleolar hypertrophy and the development of HCC in cirrhosis of different causes. A total of 111 cirrhotic patients were studied, with a mean follow-up period of 83.3 months. Histologic sections from liver biopsy specimens were silver stained for selective visualization of the nucleolus; the nucleolar area was measured by image cytometry. Nucleoli with a size of 7 μm2 or greater were considered to be hypertrophic. The nucleolar index was obtained by calculating the percentage of hepatocytes disclosing a nucleolar area of 7 μm2 or greater. During the observation time, HCC was diagnosed in 39 of 111 patients. The incidence rate of HCC was greater in patients with nucleolar indexes of 2.5 or greater than in patients with nucleolar indexes of less than 2.5 (16.49%/y vs. 3.41%/y, respectively; P < .0001). The capacity of the nucleolar index to predict HCC development was separately tested in groups of patients divided by etiology, and it was found to be particularly relevant in hepatitis B virus (HBV)-related cirrhosis (P = .0006). Among patients with hepatitis C virus (HCV) infection, high nucleolar-index values were associated with a greater risk for HCC development, but the difference in the incidence rate of HCC between groups with a nucleolar index of 2.5 or greater and less than 2.5 was not statistically significant (P = .0944). In conclusion, our results have shown that high percentages of hepatocytes showing nucleolar hypertrophy significantly predict HCC development in patients with HBV infection, whereas their predictive value in HCV-related cirrhosis seems to be lower.
A combination of indole-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy
Authors: Yoshitaka Nakamura, Shingo Yogosawa, Yasuyuki Izutani, Hirotsuna Watanabe, Eigo Otsuji, Tosiyuki Sakai
Journal: Molecular Cancer (2009)

Abstract Background The chemopreventive effects of dietary phytochemicals on malignant tumors have been studied extensively because of a relative lack of toxicity. To achieve desirable effects, however, treatment with a single agent mostly requires high doses. Therefore, studies on effective combinations of phytochemicals at relatively low concentrations might contribute to chemopreventive strategies. Results Here we found for the first time that co-treatment with I3C and genistein, derived from cruciferous vegetables and soy, respectively, synergistically suppressed the viability of human colon cancer HT-29 cells at concentrations at which each agent alone was ineffective. The suppression of cell viability was due to the induction of a caspase-dependent apoptosis. Moreover, the combination effectively inhibited phosphorylation of Akt followed by dephosphorylation of caspase-9 or down-regulation of XIAP and survivin, which contribute to the induction of apoptosis. In addition, the co-treatment also enhanced the induction of autophagy mediated by the dephosphorylation of mTOR, one of the downstream targets of Akt, whereas the maturation of autophagosomes was inhibited. These results give rise to the possibility that co-treatment with I3C and genistein induces apoptosis through the simultaneous inhibition of Akt activity and progression of the autophagic process. This possibility was examined using inhibitors of Akt combined with inhibitors of autophagy. The combination effectively induced apoptosis, whereas the Akt inhibitor alone did not. Conclusion Although in vivo study is further required to evaluate physiological efficacies and toxicity of the combination treatment, our findings might provide a new insight into the development of novel combination therapies/chemoprevention against malignant tumors using dietary phytochemicals.
Plasminogen activator inhibitor-1 in sputum and nasal lavage fluids increases in asthmatic patients during common colds
Authors: Seong H. Cho, Seung J. Hong, Haimei Chen, Ali Habib, David Cho, Sun H. Lee, Joseph Kang, Theresa Ward, Homer A. Boushey, Robert P. Schleimer, Pedro C. Avila
Journal: Journal of Allergy and Clinical Immunology (2013)
Connective tissue massage.
Authors: G C Goats, K A Keir
Journal: British Journal of Sports Medicine (1991)

Connective tissue massage (CTM) is a manipulative technique that facilitates the diagnosis and treatment of a wide range of pathologies. Observation and subsequent manipulation of the skin and subcutaneous tissues can have a beneficial effect upon tissues remote from the area of treatment. These effects appear to be mediated by neural reflexes that cause an increase in blood flow to the affected region together with suppression of pain. CTM is becoming accepted more widely as research confirms the claims of an expanding population of practitioners.
KINETIC STUDIES ON IMMUNE HEMOLYSIS
Authors: Walter M. Bowman, Manfred M. Mayer, Herbert J. Rapp
Journal: The Journal of Experimental Medicine (1951)

The reversibility of the red cell-antibody combination has been demonstrated by means of experiments showing the transfer of antibody, either from red cell stromata to intact red cells, or from red cell to red cell. The extent of reversibility is variable with respect to different antisera. The transfer of antibody from stromata to intact red cells is not dependent upon the action of complement. Transfer of antibody can also take place after interaction of the stromata-antibody complex with complement. As a result, antibody molecules can perform hemolytic work over and over again, provided complement is available, and this leads to kinetic behavior of a catalytic character.
Immunohistochemical expression of retinoblastoma protein in cutaneous melanomas
Authors: M.C. SAENZ-SANTAMARIA, N.S. MCNUTT, C.R. SHEA
Journal: British Journal of Dermatology (1995)

Retinoblastoma protein (pRB) is the product of a tumour-suppressor gene (rb) mapped to chromosome 1 3q14. pRB acts as a control checkpoint at the G1 phase of the cell cycle, preventing cells from entering into the S phase. Mutational inactivation of both normal alleles leads to loss of pRB expression and the development of malignant neoplasms. Absence of pRB occurs in retinoblastomas, sarcomas and several other types of tumours. The potential role of pRB in the pathogenesis of cutaneous melanoma is unknown, and was the subject of this investigation. Formalin-fixed, paraffin-embedded sections of four cutaneous melanoma metastases, 17 primary invasive melanomas and 10 predominantly intradermal melanocytic naevi were studied. Monoclonal antibodies directed against pRB and K1-67 antigen were used after microwave beating of sections to restore antigenicity. pRB was not detected in morphologically normal epidermal melanocytes. In five naevi, only scattered cells (1%) expressed pRB, whereas in the other five naevi, pRB expression was undetectable. In contrast, pRB was detected in all primary and metastatic melanomas (5–70% of cells). Expression was always localized to nuclei. Ki-67 expression was detected only in the melanomas, with both cellular staining and regional localization similar to that shown by pRB in 13 of the 20 melanomas studied with both antibodies. pRB appears to be expressed at higher levels in melanomas than in benign naevi. It therefore seems unlikely that loss of rb expression is in important factor in the pathogenesis of melanoma.
Effect of heparin-induced lipolysis on the distribution of apolipoprotein e among lipoprotein subclasses. Studies with patients deficient in hepatic triglyceride lipase and lipoprotein lipase.
Authors: A Rubinstein, J C Gibson, J R Paterniti, G Kakis, A Little, H N Ginsberg, W V Brown
Journal: Journal of Clinical Investigation (1985)

In normal subjects, apolipoprotein E (apo E) is present on very low density lipoproteins (VLDL) (fraction I) and on particles of a size intermediate between VLDL and low density lipoproteins (LDL) (fraction II). The major portion of apo E is, however, on particles smaller than LDL but larger than the average high density lipoproteins (HDL) (fraction III). To investigate the possible role of the vascular lipases in determining this distribution of apo E among the plasma lipoproteins, we studied subjects with primary deficiency of either hepatic lipase or of lipoprotein lipase and compared them with normal subjects. Subjects with familial hepatic triglyceride lipase deficiency (n = 2) differ markedly from normal in that fraction II is the dominant apo E-containing group of lipoproteins. When lipolysis of VLDL was enhanced in these subjects upon release of lipoprotein lipase by intravenous heparin, a shift of the apo E from VLDL into fractions II and III was observed. In contrast, apolipoproteins CII and CIII (apo CII and CIII, respectively) did not accumulate in intermediate-sized particles but were shifted markedly from triglyceride rich lipoproteins to HDL after treatment with heparin. In subjects with primary lipoprotein lipase deficiency (n = 4), apo E was confined to fractions I and III. Release of hepatic triglyceride lipase by heparin injection in these subjects produced a shift of apo E from fraction I to III with no significant increase in fraction II. This movement of apo E from large VLDL and chylomicron-sized particles occurred with little hydrolysis of triglyceride and no significant shift of apo CII or CIII into HDL from triglyceride rich lipoproteins. When both lipoprotein lipase and hepatic triglyceride lipase were released by intravenous heparin injection into normal subjects (n = 3), fraction I declined and the apo E content of fraction III increased by an equivalent amount. Either moderate or no change was noted in the intermediate sized particles (fraction II). These data strongly support the hypothesis that fraction II is the product of the action of lipoprotein lipase upon triglyceride rich lipoproteins and is highly dependent on hepatic triglyceride lipase for its further catabolism. In addition, the hydrolysis by hepatic triglyceride lipase of triglyceride rich lipoproteins in general results in a preferential loss of apo E and its transfer to a specific group of large HDL.
Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial
Authors: C Chintu, GJ Bhat, AS Walker, V Mulenga, F Sinyinza, K Lishimpi, L Farrelly, N Kaganson, A Zumla, SH Gillespie, AJ Nunn, DM Gibb
Journal: The Lancet (2004)