tbuckley/cabot-search huggingface dataset:
Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients With Aortic Stenosis
Authors: Marc Richard Dweck, Charlotte Jones, Nikhil V. Joshi, Alison M. Fletcher, Hamish Richardson, Audrey White, Mark Marsden, Renzo Pessotto, John C. Clark, William A. Wallace, Donald M. Salter, Graham McKillop, Edwin J.R. van Beek, Nicholas A. Boon, James H.F. Rudd, David E. Newby
Journal: Circulation (2011)

Background— The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown. Methods and Results— Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P &lt;0.001). 18F-NaF uptake displayed a progressive rise with valve severity ( r 2 =0.540, P &lt;0.001), with a more modest increase observed for 18F-FDG ( r 2 =0.218, P &lt;0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (&gt;1.97), and 35% had increased 18F-FDG uptake (&gt;1.63). A weak correlation between the activities of these tracers was observed ( r 2 =0.174, P &lt;0.001). Conclusions— Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT01358513.
Chemotherapy Usage Patterns in a US-Wide Cohort of Patients With Metastatic Colorectal Cancer
Authors: T. A. Abrams, G. Meyer, D. Schrag, J. A. Meyerhardt, J. Moloney, C. S. Fuchs
Journal: JNCI Journal of the National Cancer Institute (2014)

Since the introduction of biologic therapies for the treatment of metastatic colorectal cancer (mCRC), few studies have examined patterns of care or predictors of specific treatment approaches. We assessed 4877 mCRC patients who received chemotherapy between January 2004 and March 2011 at academic, private, and community-based oncology practices subscribing to a US-wide chemotherapy order entry (system capturing disease, patient, provider, and treatment data. Multivariable analyses of these prospectively recorded characteristics were used to identify independent predictors of specific therapeutic choices. All statistical tests were two-sided. Throughout the study period, fluoropyrimidine/oxaliplatin combination was the most commonly used first-line chemotherapy regimen, representing 71% of first-line therapy by 2007. First-line bevacizumab use averaged 51%, peaking at 55% in 2006. Of those who received first-line bevacizumab, 34% continued to receive bevacizumab in the second-line. Only 26% of patients in our cohort ever received an anti-EGFR monoclonal antibody (cetuximab = 22%; panitumumab = 6%) at some point in their treatment course. Patients treated at academic centers, with longer duration of first-line therapy, and at sites in the western United States were statistically more likely to receive an anti-EGFR antibody. Anti-EGFR antibody use fell by 18% after the US Food and Drug Administration limited its use to patients with KRAS wild-type tumors in June 2009. Analysis of this US-wide mCRC cohort demonstrates that bevacizumab has been more consistently integrated into treatment regimens than anti-EGFR antibody therapies, particularly in first-line therapy. However, treatment choices vary substantially according to specific patient, practice, and provider characteristics.
Immunogenicity of Leukemia L1210 Cells After Neuraminidase Treatment<xref ref-type="fn" rid="FN1">2</xref>
Authors: J. George Bekesi, G. Arneault, L. Walter, James F. Holland
Journal: JNCI Journal of the National Cancer Institute (1972)

The kinetics of sialic acid release by Vibrio cholerae (VC) neuraminidase from L1210 tumor cells and the subsequent change of immunogenicity of such cells in OBA/2Ha mice were studied. Various concentrations of neuraminidase resulted in 3 possible conditions of immunogenicity of L1210 cells. 1) At low enzyme concentrations, cleavage of neuraminidase-susceptible sialic acid was incomplete and all recipients died from tumor after inoculation with enzymatically treated cells. 2) Enzyme concentrations of 20–50 IU/2.5 × 107 cells/ml incubation medium represented the optimal condition for L1210 cell treatment: Oncogenicity was lost and mice could be immunized. All immunized mice were refractory to 105 untreated L1210 cells, which represents about 100,000 times the LD50 of this tumor in DBA/2Ha mice. 3) Incubation of L1210 tumor cells with neuraminidase >75 IU caused loss of oncogenic properties, but at the same time, immunogenicity of such treated cells was eliminated. This reduced immunogenicity was evidenced by a decreasing fraction of mice resistant to the challenge by 105 untreated L1210 cells. Treatment of L1210 cells with VC neuraminidase caused a significant release of protein-bound sialic acid, e.g., N-acetylneuraminic acid and N-glycolylneuraminic acid. In addition to low molecular-weight substances, radioactive glycoprotein appeared in the incubation medium, irrespective of the incubation condition. Thus the increased immunogenicity in VC neuraminidase- treated L1210 cells is most likely attributable to the enzymatic removal of sialic acid rather than to release of a protein from tumor cell surfaces. Other neuraminidases and enzymes did not eliminate the oncogenicity of leukemia L1210; this precluded a study of their effect on immunogenicity.
Cost-Effectiveness of Preventive Strategies for Women with a <i>BRCA1</i> or a <i>BRCA2</i> Mutation
Authors: Kristin Anderson, Judith S. Jacobson, Daniel F. Heitjan, Joshua Graff Zivin, Dawn Hershman, Alfred I. Neugut, Victor R. Grann
Journal: Annals of Internal Medicine (2006)

Background: For BRCA1 or BRCA2 mutation carriers, decision analysis indicates that prophylactic surgery or chemoprevention leads to better survival than surveillance alone. Objective: To evaluate the cost-effectiveness of the preventive strategies that are available to unaffected women carrying a single BRCA1 or BRCA2 mutation with high cancer penetrance. Design: Markov modeling with Monte Carlo simulations and probabilistic sensitivity analyses. Data Sources: Breast and ovarian cancer incidence and mortality rates, preference ratings, and costs derived from the literature; the Surveillance, Epidemiology, and End Results (SEER) Program; and the Health Care Financing Administration (now the Centers for Medicare & Medicaid Services). Target Population: Unaffected carriers of a single BRCA1 or BRCA2 mutation 35 to 50 years of age. Time Horizon: Lifetime. Perspective: Health policy, societal. Interventions: Tamoxifen, oral contraceptives, bilateral salpingo-oophorectomy, mastectomy, both surgeries, or surveillance. Outcome Measures: Cost-effectiveness. Results of Base-Case Analysis: For mutation carriers 35 years of age, both surgeries (prophylactic bilateral mastectomy and oophorectomy) had an incremental cost-effectiveness ratio over oophorectomy alone of $2352 per life-year for BRCA1 and $100 per life-year for BRCA2. With quality adjustment, oophorectomy dominated all other strategies for BRCA1 and had an incremental cost-effectiveness ratio of $2281 per life-year for BRCA2. Results of Sensitivity Analysis: Older age at intervention increased the cost-effectiveness of prophylactic mastectomy for BRCA1 mutation carriers to $73 755 per life-year. Varying the penetrance, mortality rates, costs, discount rates, and preferences had minimal effects on outcomes. Limitations: Results are dependent on the accuracy of model assumptions. Conclusion: On the basis of this model, the most cost-effective strategies for BRCA mutation carriers, with and without quality adjustment, were oophorectomy alone and oophorectomy and mastectomy, respectively.
Community and personal risk factors for hepatitis C virus infection: a survey of 23 820 residents in Taiwan in 1991-2
Authors: M.-H. Lee, H.-I. Yang, C.-L. Jen, S.-N. Lu, S.-H. Yeh, C.-J. Liu, S.-L. You, C.-A. Sun, L.-Y. Wang, W. J. Chen, C.-J. Chen
Journal: Gut (2010)

<h3>Aim</h3> The aim of this study was to explore the community-level risk factors, such as high hepatitis C viruse (HCV)-RNA positive rate and limited medical resources in a township, for HCV infection, one major cause of liver cirrhosis and hepatocellular carcinoma. <h3>Methods</h3> This study enrolled 23 820 residents living in 155 villages of seven townships in Taiwan in 1991–2 to explore both individual and community risk factors for HCV infection. Antibodies against HCV (anti-HCV), HCV-RNA and HCV genotype in serum samples were determined by enzyme immunoassay, PCR and melting curve analysis, respectively. <h3>Results</h3> The overall anti-HCV seroprevalence was 5.5%, HCV-RNA was detectable in 68.1% of the seropositives of anti-HCV, and genotype 1 was the most prevalent genotype (54.6%). Personal risk factors for the seropositivity of anti-HCV included older age, female gender, low educational level and history of blood transfusion. Based on the multilevel analysis, persons living in villages with high HCV-RNA-positive rates and limited healthcare resources had an increased seroprevalence of anti-HCV after adjustment for individual risk factors. The multivariate-adjusted prevalence OR (95% CI) was 3.49 (1.80 to 6.76) and 8.48 (5.07 to 14.20) for villages with medium and high HCV-RNA positive rate, respectively. The multivariate-adjusted OR (95% CI) was was 1.75 (0.76 to 4.01) and 3.91 (2.25 to 6.80), respectively, for villages with medium and poor healthcare resources. <h3>Conclusions</h3> This study suggests that community risk factors contribute significantly to the variation in anti-HCV seroprevalence. It implies both the adequacy of healthcare resources and the treatment of patients positive for HCV-RNA may prevent individual residents from the acquisition of HCV infection from the community.
Further Improvement in Postprandial Glucose Control With Addition of Exenatide or Sitagliptin to Combination Therapy With Insulin Glargine and Metformin
Authors: Sabine Arnolds, Sibylle Dellweg, Janina Clair, Marie-Paule Dain, Michael A. Nauck, Klaus Rave, Christoph Kapitza
Journal: Diabetes Care (2010)

OBJECTIVE To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5–10 μg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET). RESEARCH DESIGN AND METHODS This was a single-center, randomized, open-label, active comparator–controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose ≤100 mg/dl). RESULTS The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 ± 104 vs. 612 ± 133 vs. 728 ± 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P &amp;lt; 0.0001), with the greatest reduction of −1.9 ± 0.7 under GLAR + MET + EXE (GLAR + MET + SITA −1.5 ± 0.7; GLAR + MET −1.2 ± 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of &amp;lt;7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose &amp;lt;50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (−0.9 ± 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 ± 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377). CONCLUSIONS EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings.
Vascular Reactivity in Heart Failure
Authors: Syed M. Karim, Albert Y. Rhee, Allison M. Given, Michael D. Faulx, Brian D. Hoit, Frank V. Brozovich
Journal: Circulation Research (2004)

Congestive heart failure (CHF) is a clinical syndrome, which is the result of systolic or diastolic ventricular dysfunction. During CHF, vascular tone is regulated by the interplay of neurohormonal mechanisms and endothelial-dependent factors and is characterized by both central and peripheral vasoconstriction as well as a resistance to nitric oxide (NO)-mediated vasodilatation. At the molecular level, vascular tone depends on the level of regulatory myosin light chain phosphorylation, which is determined by the relative activities of myosin light chain kinase and myosin light chain phosphatase (MLCP). The MLCP is a trimeric enzyme with a catalytic, a 20-kDa and a myosin targeting (MYPT1) subunit. Alternative splicing of a 3' exon produces leucine zipper positive and negative (LZ+/-) MYPT1 isoforms. Expression of a LZ+ MYPT1 has been suggested to be required for NO-mediated smooth muscle relaxation. Thus, we hypothesized that the resistance to NO-mediated vasodilatation in CHF could be attributable to a change in the relative expression of LZ+/- MYPT1 isoforms. To test this hypothesis, left coronary artery ligation was used to induce CHF in rats, and both the dose response relationship of relaxation to 8-Br-cGMP in skinned smooth muscle and the relative expression of LZ+/- MYPT1 isoforms were determined. In control animals, the expression of the LZ+ MYPT1 isoform predominated in both the aorta and iliac artery. In CHF rats, LVEF was reduced to 30+/-5% and there was a significant decrease in both the sensitivity to 8-Br-cGMP and expression of the LZ+ MYPT1 isoform. These results indicate that CHF is associated with a decrease in the relative expression of the LZ+ MYPT1 isoform and the sensitivity to 8-Br-cGMP-mediated smooth muscle relaxation. The data suggest that the resistance to NO-mediated relaxation observed during CHF lies at least in part at the level of the smooth muscle and is a consequence of the decrease in the expression of the LZ+ MYPT1 isoform.
Efficacy and Safety of Angiotensin II Receptor Blockade in Elderly Patients With Diabetes
Authors: Wolfgang C. Winkelmayer, Zhongxin Zhang, Shahnaz Shahinfar, Mark E. Cooper, Jerry Avorn, Barry M. Brenner
Journal: Diabetes Care (2006)

OBJECTIVE—While national guidelines recommend ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy in patients with diabetes and nephropathy, guidelines concerning elderly patients with diabetes have not endorsed these drugs. We sought to assess the nephroprotective efficacy and safety of ARB therapy in elderly patients by conducting age-specific subgroup analyses using data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. RESEARCH DESIGN AND METHODS—We studied 1,513 patients with type 2 diabetes and nephropathy who randomly received either losartan or placebo. We tested for effect modification by age of the effect of losartan on the incidence of the predefined end points (doubling of serum creatinine, end-stage renal disease [ESRD], or death) and the risk of adverse events. RESULTS—Of 1,513 participants, 421 (27.8%) were aged &amp;gt;65 years (maximum age 74 years). Age did not modify the efficacy of losartan in reducing the risk of the primary outcome, a composite of doubling of serum creatinine, ESRD, or death (Pinteraction = 0.66) or its individual components (all Pinteraction &amp;gt; 0.44). In patients aged &amp;gt;65 years, losartan reduced the risk of ESRD by 50% (95% CI 30–81, P = 0.005). We found no evidence that older patients were more likely to experience adverse events from losartan such as a rise in serum creatinine or hyperkalemia than younger patients. CONCLUSIONS—Elderly patients had the same level of benefits and risks as younger patients from treatment with losartan. Underuse of ACEI and ARB therapy in elderly patients because of the perceived lack of efficacy or a greater risk of adverse events appears unjustified.
PREFRONTAL LEUCOTOMY FOR THE ATTEMPTED PREVENTION OF RECURRING MANIC-DEPRESSIVE ILLNESSES
Authors: G. H. STEVENSON, A. MCCAUSLAND
Journal: American Journal of Psychiatry (1953)

1. Evidence is presented to indicate that recurring manic-depressive illnesses are not inevitable. 2. "Prophylactic electroshock" prevents some recurrences, but the method requires the prolonged cooperation of the patient and is often distressing and distasteful to the patient. Moreover, electroshock is not without its own hazards. 3. "Prophylactic leucotomy" also prevents some recurrences. It does not require the continued cooperation of the patient. Follow-up studies in our series of cases indicate that no patient has had a recurrence of symptoms, the maximum length of postleucotomy observation being approximately 4 years. A longer period of study is, of course, necessary, and we propose to follow these patients through our aftercare department for many years.
Individualized treatment for patients with low HCV load (Genotype 1): A viral kinetic approach
Authors: Harel Dahari, Scott J. Cotler
Journal: Hepatology (2014)

Pearlman and Ehleben's elegant study1 showed no difference in sustained virological response (SVR) rates with or without boceprevir in patients with HCV genotype-1 and low baseline viral load, LVL (<600,000 IU/mL) who were treated with pegylated-interferon-α (P) and ribavirin (R) and had undetectable HCV-RNA (<10 IU/mL) at week 4 (termed RVR). Pearlman and Ehleben's study suggests that P/R therapy is sufficient in this special population if patients are treated for 24 weeks. However, since triple therapy is expected to be more effective than P/R, the similar SVR rates observed with the two regimens suggests that cure took place much earlier than 24 or 28 weeks of treatment. Thus, treatment duration could be shortened if it were possible to predict the time to cure during the lead-in phase. Viral kinetic analysis during P/R lead-in phase provides a potential means to individualize treatment. The approach is illustrated in Fig. 1 using the standard biphasic model.2 In general, LVL patients with high baseline hepatitis C virus (HCV)-RNA, bHCV (e.g., 500,000 IU/mL) need faster second-phase slope of viral decline than patients with extremely low bHCV (e.g., 1,000 IU/mL) in order to reach RVR (Fig. 1, solid and dashed lines, respectively). If both patients in Fig. 1 reach HCV negativity close to week 4, the patient with low bHCV needs a much longer duration of therapy (32 weeks) in order to achieve SVR and would benefit from addition of an HCV-protease inhibitor (PI) compared to the patient with high bHCV (12 weeks). Our conservative theoretical approach suggests that the longest treatment duration needed to achieve cure could be estimated for each RVR patient based on their bHCV. Since some patients might reach HCV negativity before week 4, two additional viral-load measurements at day 2 and week 2 would provide more confidence in estimating time to cure by allowing for calculation of the first phase of decline and the second phase slope. Pearlman and Ehleben's exciting results indicate that patients with LVL can skip the addition of PI if they achieve an RVR after a lead-in phase of 4 weeks with P/R. Our modeling data suggest that the duration of therapy and need for a PI can be further individualized by viral kinetic analysis during the P/R lead-in phase. Further studies will be needed to verify this prediction. Supported by NIH grants R56/R01-AI078881 and P20-GM103452 and the U.S. Department of Energy contract DE-AC52-06NA25396. Harel Dahari, Ph.D.1,2 Scott J. Cotler, M.D.1 1The Program for Experimental and Theoretical Modeling Division of Hepatology Department of Medicine Loyola University Medical Center Maywood, IL 2Theoretical Biology and Biophysics Group Los Alamos National Laboratory Los Alamos, NM
Reversibility of Poststenotic Dilatation in the Femoral Arteries of Dogs
Authors: MARGOT R. ROACH
Journal: Circulation Research (1970)

Poststenotic dilatation (PSD) was produced in the femoral arteries of 14 adult dogs. After 9 days to 5 months, the band was removed. If the murmur disappeared, as it did immediately in all but four arteries, the PSD disappeared within 24 hours (studied radiologically by painting the arteries with radio-opaque thorium dioxide). In these four, the dilatation disappeared after the murmur did. Six arteries were studied at half-hour intervals for 16 hours after removal of band. In all of these, the dilatation increased during the first half hour, and then disappeared completely in 6 to 8 hours. Long term follow-up for 6 months showed no changes in diameter after the initial 24-hour period. The altered elastic properties of the distal segment previously described for the dilated segment returned to normal soon after the band was removed. The mechanism of this change is unknown, but may be produced by alterations of elastin crosslinks by vibration. We conclude that poststenotic dilatation is reversible, at least in the femoral arteries of dogs, if correction of the stenosis is associated with disappearance of the turbulence. The change is very rapid, and so does not appear related to synthesis of new connective tissue.
Vacuolar H+-ATPase B1 Subunit Mutations that Cause Inherited Distal Renal Tubular Acidosis Affect Proton Pump Assembly and Trafficking in Inner Medullary Collecting Duct Cells
Authors: Qiongqiong Yang, Guangmu Li, Satish K. Singh, Edward A. Alexander, John H. Schwartz
Journal: Journal of the American Society of Nephrology (2006)

Point mutations in the B1 subunit of vacuolar H+ -ATPase are associated with impaired ability of the distal nephron to secrete acid (distal renal tubular acidosis). For testing of the hypothesis that these mutations interfere with assembly and trafficking of the H+ -ATPase, constructs that mimic seven known point mutations in inherited distal renal tubular acidosis (M) or wild-type (WT) B1 were transfected into a rat inner medullary collecting duct cell line to express green fluorescence protein (GFP)-B1WT or GFP-B1M fusion proteins. In co-immunoprecipitation studies, GFP-B1WT formed complexes with other H+ -ATPase subunits (c, H, and E), whereas GFP-B1M did not. Proteins that were immunoprecipitated with anti-GFP antibody from GFP-B1WT cells had ATPase activity, whereas proteins from GFP-B1M cells did not. Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells. GFP-B1WT and GFP-B1M are present in the apical membrane and increased with cellular acidification. In GFP-B1WT cells, the apical membrane fraction of GFP-B1, endogenous B1, and the 31-kD subunits of the H+ -ATPase increased with cell acidification. In GFP-B1M cells, the endogenous B1 and 31-kD subunits did not increase with acidification. B1 point mutations prevent normal assembly of the H+ -ATPase and also may act as an inhibitor of H+ -ATPase function by competing with endogenous intact H+ -ATPase for trafficking in inner medullary collecting duct cells.