tbuckley/cabot-search huggingface dataset:
Isolation of a Regulatory Region of Activin Receptor-Like Kinase 1 Gene Sufficient for Arterial Endothelium-Specific Expression
Authors: Tsugio Seki, Kwon-Ho Hong, Jihye Yun, Seong-Jin Kim, S. Paul Oh
Journal: Circulation Research (2004)

Activin receptor-like kinase 1 (Acvrl1; Alk1) is a type I receptor for transforming growth factor-beta (TGF-beta). ALK1 plays a pivotal role in vascular development and is involved in the development of hereditary hemorrhagic telangiectasia 2 (HHT2), a dominantly inherited vascular disorder, and pulmonary hypertension. We have previously shown that Alk1 is expressed predominantly in arterial endothelial cells (ECs). Despite recent discoveries of a number of artery-specific genes, the regulatory elements of these genes have not been characterized. To investigate the cis-acting elements essential for the artery-specific Alk1 expression, we have generated a series of transgenic constructs with various lengths and regions of Alk1 genomic fragments connected to a LacZ reporter gene, and analyzed the reporter gene expression in transgenic mice. We found that a 9.2-kb genomic fragment, which includes 2.7-kb promoter region and the entire intron 2, is sufficient to drive arterial endothelium-specific expression. The defined regulatory region, as well as the transgenic mouse lines, would be invaluable resources in studying the mechanisms underlying angiogenesis, arteriogenesis, and vascular disorders, such as HHT and pulmonary hypertension. The full text of this article is available online at http://circres.ahajournals.org.
Transverse leukonychia of toenails due to repeated microtrauma
Authors: R. BARAN, C. PERRIN
Journal: British Journal of Dermatology (1995)

Twelve women were seen with multiple transverse bands on the nail plates of the great toes. The bands were separated by normal nail, and had the same contour as the distal edge of the lunula. This disorder, which is usually bilateral, results from pressure on the free edge of the nail plate when it is not trimmed short.
Proteinuria as a Predictor of Total Plasma Homocysteine Levels in Type 2 Diabetic Nephropathy
Authors: Allon N. Friedman, Lawrence G. Hunsicker, Jacob Selhub, Andrew G. Bostom
Journal: Diabetes Care (2002)

OBJECTIVE—Patients with diabetes who manifest proteinuria are at increased risk for cardiovascular events. Some studies suggest that proteinuria exerts its cardiovascular effects at least partly through a positive association with total plasma homocysteine (tHcy). Modestly sized but better designed contrary studies find no such link through a limited range of serum creatinine and proteinuria. We tested the hypothesis that proteinuria independently predicts tHcy levels in a larger cohort of type 2 diabetic patients with nephropathy throughout a much broader range of kidney disease and proteinuria. RESEARCH DESIGN AND METHODS—Baseline data for the cross-sectional study were obtained from 717 patients enrolled in the multicenter Irbesartan Diabetic Nephropathy Trial. All subjects had type 2 diabetes, hypertension, and proteinuria and were between 29 and 78 years of age. Data included age, sex, BMI, serum creatinine and albumin, LDL and HDL cholesterol, triglyceride, proteinuria and albuminuria, plasma folate, B12, and pyridoxal 5′-phosphate (PLP) (the active form of B6), HbA1c, and tHcy levels. Unadjusted and multivariable models were used in the analysis. RESULTS—Crude analyses revealed significant associations between tHcy and age (r = 0.074; P = 0.008), creatinine (r = 0.414; P &amp;lt; 0.001), PLP (r = −0.105; P = 0.021), B12 (r = −0.216; P &amp;lt; 0.001), folate (r = −0.241; P &amp;lt; 0.001), and HbA1c (r = −0.119; P = 0.003), with serum albumin approaching significance (r = 0.055; P = 0.072). Only serum creatinine, plasma folate, B12, serum albumin, sex, HbA1c, and age were independent predictors of tHcy after controlling for all other variables. CONCLUSIONS—By finding no independent correlation between proteinuria (or albuminuria) and tHcy levels, this study improves the external validity of previous negative findings. Therefore, it is unlikely that the observed positive association between proteinuria and cardiovascular disease is directly related to hyperhomocysteinemia.
Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group.
Authors: G Cocconi, D Cunningham, E Van Cutsem, E Francois, B Gustavsson, G van Hazel, D Kerr, K Possinger, S M Hietschold
Journal: Journal of Clinical Oncology (1998)

PURPOSE To compare raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC). PATIENTS AND METHODS A total of 495 patients were randomized to raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks. RESULTS The randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the raltitrexed group. Overall objective responses were comparable (19% raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 stomatitis (2% v 16%, P &lt; .001) and a reduced incidence of leukopenia (6% v 13%) and diarrhea (10% v 19%) occurred in the raltitrexed group (particularly at cycle 1 ). This resulted in fewer dose reductions at cycle 2 (4% raltitrexed v 28% 5-FU/LV) and early quality-of-life (QoL) benefits for raltitrexed patients. Reversible, clinically insignificant increases in transaminases were reported in 13% of raltitrexed patients. Palliative benefits of weight gain, improved performance status, and reduced disease-related symptoms were evident in both groups. CONCLUSION Raltitrexed is confirmed as an effective option in the first-line palliative management of ACC, with comparable efficacy to and tolerability advantages (in terms of reduced incidence of stomatitis, diarrhea, and leukopenia) over 5-FU/LV. Raltitrexed has the added convenience of an every 3 weeks dosing schedule.
<i>Haemophilus influenzae</i>Meningitis in an Adult
Authors: Carl W. Norden, Mary Lou Callerame, John Baum
Journal: New England Journal of Medicine (1970)

Serum obtained on the day of admission and four days later failed to kill 3 × 103 Haemophilus influenzae, Type B, isolated from the cerebrospinal fluid of a 33-year-old woman with meningitis. Serum obtained on days 16, 30 and 60 was bactericidal for 3 × 106 organisms. No factors that might have contributed to the patient's illness other than the lack of bactericidal antibody against H. influenzae, Type B, were detected. Bactericidal activity for the same organism was absent in eight of 29 "normal" adult serums. These results differ from studies performed in 1933, when all subjects over the age of 10 years who were tested showed bactericidal antibodies for this organism. The epidemiologic importance of the present findings in relation to current susceptibility of adults to infection with H. influenzae, Type B, remains to be determined.
Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study
Authors: Aatke van der Maas, Wietske Kievit, Bart J F van den Bemt, Frank H J van den Hoogen, Piet L van Riel, Alfons A den Broeder
Journal: Annals of the Rheumatic Diseases (2012)

Down-titration, or discontinuing infliximab, has proven to be feasible in RA patients. Therefore, our local treatment protocol includes tapering infliximab dose. This observational study describes the prevalence of successful down-titration in daily clinical practice and its effect on costs and quality of life (QoL).Infliximab was down-titrated with 25% of the original dose (3 mg/kg) every 8-12 weeks without interval change until discontinuation or flare in all RA patients with stable low 28-joint disease activity score (DAS28) and stable treatment for >6 months. During 1 year DAS28, RA medication, outpatient clinic visits, RA related absenteeism and EuroQoL5D (European QoL questionnaire, EQ5D) were documented. Prevalence of successful down-titration and changes in DAS28, QoL and costs were described.In 16% (95% CI 6 to 26) and 45% (95% CI 31 to 59), respectively, infliximab could be discontinued or down-titrated. Mean infliximab dose decreased significantly from 224 mg (95% CI 212 to 236 mg) at start, to 130 mg (95% CI 105 to 154 mg) after 1 year. Median DAS28 increased from 2.5 (p25-75=2.0-2.9) to 2.8 (2.2-3.6) (p=0.002). Extra corticosteroids were given in 8% of the visits. Disease modifying antirheumatic drugs were seldom changed. There was no statistical difference in QoL after down-titration. Mean reduction in the costs was €3474 (95% CI 2457 to 4492) per patient.In the majority of patients with stable low DAS28 and stable treatment, infliximab can be down-titrated or discontinued, which results in a considerable reduction in costs without influencing QoL.
Pancreatic and Gastric Somatostatin Release in Response to Intragastric and Intraduodenal Nutrients and HCl in the Dog
Authors: Volker Schusdziarra, Virginia Harris, J. Michael Conlon, Akira Arimura, Roger Unger
Journal: Journal of Clinical Investigation (1978)

The effects of the instillation of glucose, fat, casein hydrolysate, and HCl into the gastrointestinal tract upon plasma levels of somatostatin-like immunoreactivity (SLI) in the venous effluent of the pancreas, fundus and antrum of the stomach, and in the inferior vena cava (IVC) were determined in normal laparotomized dogs. Fasting SLI levels in the effluent plasma from these sites were significantly greater than IVC levels. The intragastric administration of glucose elicited a prompt and significant rise in SLI levels in pancreatic, fundic and antral venous plasma, and in IVC plasma; intraduodenal glucose elicited smaller increments. After intragastric fat, a smaller, more gradual increase in the pancreatic and fundic effluents was observed, whereas the rise in antral SLI was minute, and IVC SLI did not rise significantly. Intraduodenal fat elicited a prompt increase in the pancreatic and antral vein SLI levels, and a small but significant increase in fundic and IVC plasma which suggests faster release of enteric factors that influence SLI secretion in the pancreas and antrum. Intragastric casein hydrolysate elicited a prompt increase in SLI in both the pancreatic and fundic veins, the latter being marked, but the antral SLI response was small; IVC SLI rose significantly within 15 min. Intragastric HCl provoked a prompt and marked rise in pancreaticoduodenal and antral vein SLI but no increase in fundic vein SLI; IVC SLI levels rose significantly within 20 min. Intraduodenal HCl elicited an even more prompt and marked pancreatic SLI response, and SLI rose significantly in both the fundic and antral venous effluents; IVC SLI also rose more promptly. In dogs with a gastric fistula that prevented intraduodenal entry of HCl, intragastric HCl elicited only a very small and transient rise in pancreaticoduodenal vein SLI, markedly stimulated the antral SLI response, but completely suppressed fundic venous SLI levels. The results indicate that all three nutrients stimulate SLI release from the pancreas and stomach. The greater SLI response to intragastric, as opposed to intraduodenal, glucose suggests that unidentified local factors are of importance. The responses to the intraduodenal instillation of HCl and fat suggest a role of enteric hormones in the release of SLI from the pancreas and fundus and antrum of the stomach. Additionally, there is evidence of direct effects of HCl upon gastric SLI release.
Short-course Empiric Antibiotic Therapy for Patients with Pulmonary Infiltrates in the Intensive Care Unit
Authors: NINA SINGH, PAUL ROGERS, CHARLES W. ATWOOD, MARILYN M. WAGENER, VICTOR L. YU
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Inappropriate antibiotic use for pulmonary infiltrates is common in the intensive care unit (ICU). We sought to devise an approach that would minimize unnecessary antibiotic use, recognizing that a gold standard for the diagnosis of nosocomial pneumonia does not exist. In a randomized trial, clinical pulmonary infection score (CPIS) (Pugin, J., R. Auckenthaler, N. Mili, J. P. Janssens, R. D. Lew, and P. M. Suter. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am. Rev. Respir. Dis. 1991;143: 1121–1129) was used as operational criteria for decision-making regarding antibiotic therapy. Patients with CPIS ⩽ 6 (implying low likelihood of pneumonia) were randomized to receive either standard therapy (choice and duration of antibiotics at the discretion of physicians) or ciprofloxacin monotherapy with reevaluation at 3 d; ciprofloxacin was discontinued if CPIS remained ⩽ 6 at 3 d. Antibiotics were continued beyond 3 d in 90% (38 of 42) of the patients in the standard as therapy compared with 28% (11 of 39) in the experimental therapy group (p = 0.0001). In patients in whom CPIS remained ⩽ 6 at the 3 d evaluation point, antibiotics were still continued in 96% (24 of 25) in the standard therapy group but in 0% (0 of 25) of the patients in the experimental therapy group (p = 0.0001). Mortality and length of ICU stay did not differ despite a shorter duration (p = 0.0001) and lower cost (p = 0.003) of antimicrobial therapy in the experimental as compared with the standard therapy arm. Antimicrobial resistance, or superinfections, or both, developed in 15% (5 of 37) of the patients in the experimental versus 35% (14 of 37) of the patients in the standard therapy group (p = 0.017). Thus, overtreatment with antibiotics is widely prevalent, but unnecessary in most patients with pulmonary infiltrates in the ICU. The operational criteria used, regardless of the precise definition of pneumonia, accurately identified patients with pulmonary infiltrates for whom monotherapy with a short course of antibiotics was appropriate. Such an approach led to significantly lower antimicrobial therapy costs, antimicrobial resistance, and superinfections without adversely affecting the length of stay or mortality.
The Race for Ancestral Genetics in Clinical Trials
Authors: Mary Beckman
Journal: JNCI Journal of the National Cancer Institute (2006)

Fortunately, awareness of how ancestral genetics might contribute to risk of disease and drug response in people has risen over the last several years. Studies that look directly at the problem are on the rapid rise, and this increased interest has biotechnology companies lowering the cost of tests that determine genetic ancestry, thanks to a little competition. However, experts have yet to decide on how to genetically define ancestry, suggesting examining anywhere from a handful to hundreds of gene variants.
Isoproterenol amplifies 17β-estradiol-mediated vasorelaxation: role of endothelium/nitric oxide and cyclic AMP
Authors: H Chan
Journal: Cardiovascular Research (2002)

Objectives: Estrogen exerts cardiac protection via multiple cellular mechanisms. Estrogen modifies vasodilatation induced by certain relaxants such as β-adrenoceptor agonists. However, little is known whether low concentrations of β-adrenoceptor agonists would reciprocally influence the acute relaxant response to estrogen. The present study was designed to investigate the synergistic interaction between isoproterenol and 17β-estradiol, and the role of endothelium and cyclic AMP-dependent pathway in this interaction. Methods: Changes in vessel tone of the isolated rat mesenteric artery rings were measured using a force–displacement Grass transducer. Results: In 9,11-dideoxy-11α, 9α-epoxy-methanoprostaglandin F2α-preconstricted endothelium-intact rings, 17β-estradiol induced relaxations with pD2 of 5.06±0.06. Pretreatment of endothelium-intact rings with isoproterenol (1–3×10−9 M, 1 h incubation time) significantly enhanced 17β-estradiol-induced relaxation. This effect was inhibited by Rp-cGMPS triethylamine (3×10−6 M), and abolished in the presence of 3×10−5 M NG-nitro-l-arginine methyl ester or in endothelium-denuded rings. The effect of isoproterenol was antagonized by propranolol (3×10−6 M), ICI 118,551 (3×10−6 M), but not by atenolol (10−5 M). Rp-cAMPS triethylamine (3×10−6 M) abolished the effect of isoproterenol. Besides, exposure to 3×10−9 M forskolin for 1 h also potentiated the relaxant response to 17β-estradiol. Conclusion: In endothelium-intact rat mesenteric arteries pretreatment with low concentrations of isoproterenol enhanced the acute relaxant response to 17β-estradiol. This enhancement was dependent on the presence of endothelium and abolished by l-NAME via a β2-adrenoceptor-mediated cyclic AMP-dependent mechanism.
New Risk Factors for Atherosclerosis and Patient Risk Assessment
Authors: Jean-Charles Fruchart, Melchior C. Nierman, Erik S. G. Stroes, John J. P. Kastelein, Patrick Duriez
Journal: Circulation (2004)

Advances in our understanding of the ways in which the traditional cardiovascular risk factors, including standard lipid (eg, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) and nonlipid (eg, hypertension) risk factors, interact to initiate atherosclerosis and promote the development of cardiovascular disease have enhanced our ability to assess risk in the individual patient. In addition, the ongoing identification and understanding of so-called novel risk factors may further improve our ability to predict future risk when these are included along with the classic risk factors in assessing the global risk profile. This review briefly summarizes the evidence that some newer risk factors, including impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and high-sensitivity C-reactive protein, contribute to an increased risk of coronary and cardiovascular diseases.
Sensitization to Food and Spt Wheal Magnitud Among Children Attending to an Allergy Service in a Major Mexican City Near the United States
Authors: Adrian Yong Rodriguez, Sandra N. Gonzalez-Diaz, Alejandra Macias-Weinmann, Alfredo Arias-Cruz, Samuel Palma Gomez, Rafael Perez-Vanzzini, Julio J. Gutierrez-Mujica
Journal: Journal of Allergy and Clinical Immunology (2015)
Performance of Relaxed-Clock Methods in Estimating Evolutionary Divergence Times and Their Credibility Intervals
Authors: Fabia U. Battistuzzi, Alan Filipski, S. Blair Hedges, Sudhir Kumar
Journal: Molecular Biology and Evolution (2010)

The rapid expansion of sequence data and the development of statistical approaches that embrace varying evolutionary rates among lineages have encouraged many more investigators to use DNA and protein data to time species divergences. Here, we report results from a systematic evaluation, by means of computer simulation, of the performance of two frequently used relaxed-clock methods for estimating these times and their credibility intervals (CrIs). These relaxed-clock methods allow rates to vary in a phylogeny randomly over lineages (e.g., BEAST software) and in autocorrelated fashion (e.g., MultiDivTime software). We applied these methods for analyzing sequence data sets simulated using naturally derived parameters (evolutionary rates, sequence lengths, and base substitution patterns) and assuming that clock calibrations are known without error. We find that the estimated times are, on average, close to the true times as long as the assumed model of lineage rate changes matches the actual model. The 95% CrIs also contain the true time for ≥95% of the simulated data sets. However, the use of incorrect lineage rate model reduces this frequency to 83%, indicating that the relaxed-clock methods are not robust to the violation of underlying lineage rate model. Because these rate models are rarely known a priori and are difficult to detect empirically, we suggest building composite CrIs using CrIs produced from MultiDivTime and BEAST analysis. These composite CrIs are found to contain the true time for ≥97% data sets. Our analyses also verify the usefulness of the common practice of interpreting the congruence of times inferred from different methods as a reflection of the accuracy of time estimates. Overall, our results show that simple strategies can be used to enhance our ability to estimate times and their CrIs when using the relaxed-clock methods.
Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria
Authors: Alberto Pinzon-Charry, Tonia Woodberry, Vivian Kienzle, Virginia McPhun, Gabriela Minigo, Daniel A. Lampah, Enny Kenangalem, Christian Engwerda, J. Alejandro López, Nicholas M. Anstey, Michael F. Good
Journal: The Journal of Experimental Medicine (2013)

Malaria causes significant morbidity worldwide and a vaccine is urgently required. Plasmodium infection causes considerable immune dysregulation, and elicitation of vaccine immunity remains challenging. Given the central role of dendritic cells (DCs) in initiating immunity, understanding their biology during malaria will improve vaccination outcomes. Circulating DCs are particularly important, as they shape immune responses in vivo and reflect the functional status of other subpopulations. We performed cross-sectional and longitudinal assessments of the frequency, phenotype, and function of circulating DC in 67 Papuan adults during acute uncomplicated P. falciparum, P. vivax, and convalescent P. falciparum infections. We demonstrate that malaria patients display a significant reduction in circulating DC numbers and the concurrent accumulation of immature cells. Such alteration is associated with marked levels of spontaneous apoptosis and impairment in the ability of DC to mature, capture, and present antigens to T cells. Interestingly, sustained levels of plasma IL-10 were observed in patients with acute infection and were implicated in the induction of DC apoptosis. DC apoptosis was reversed upon IL-10 blockade, and DC function recovered when IL-10 levels returned to baseline by convalescence. Our data provide key information on the mechanisms behind DC suppression during malaria and will assist in developing strategies to better harness DC’s immunotherapeutic potential.