tbuckley/cabot-search huggingface dataset:
THE OPTIMAL RATIO OF FAT-TO-CARBOHYDRATE IN THE DIET
Authors: Scott M. Grundy
Journal: Annual Review of Nutrition (1999)

▪ Abstract A major issue in human nutrition is the optimal relation of carbohydrate-to-fat in the diet. According to some investigators, a high proportion of fat energy to total energy favors the development of several chronic diseases. Among these are obesity, coronary heart disease, diabetes, and cancer. The theory that a high proportion of fat relative to other nutrients promotes the development of obesity is founded on research with experimental animals and in human population surveys. This theory has been difficult to prove in prospective feeding studies in humans; therefore it remains a contentious issue. Regarding coronary heart disease, little evidence supports a claim that a high proportion of dietary fat predisposes to disease. On the other hand, strong evidence bolsters the claim that certain fatty acids raise the risk for coronary heart disease. These include saturated fatty acids and trans fatty acids, both of which raise serum cholesterol levels. In contrast, neither monounsaturated nor polyunsaturated fatty acids raise serum cholesterol levels and seemingly pose little risk for coronary disease. The relationship between dietary fat and type 2 diabetes is tied largely to the issue of obesity, because obesity is a major cause of diabetes. Although animal studies and epidemiological studies have implicated dietary fat as a factor in cancer, recent prospective epidemiological data in humans have cast doubt on the possibility of a strong relationship. In summary, clear evidence points to the need to reduce intakes of saturated and trans fatty acids in the diet. Beyond this change, a balanced ratio of unsaturated fatty acids to carbohydrate leading to fat intake of approximately 30% of total energy seems appropriate for the American public.
Bupropion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression
Authors: A. John Rush, Madhukar H. Trivedi, Stephen R. Wisniewski, Jonathan W. Stewart, Andrew A. Nierenberg, Michael E. Thase, Louise Ritz, Melanie M. Biggs, Diane Warden, James F. Luther, Kathy Shores-Wilson, George Niederehe, Maurizio Fava
Journal: New England Journal of Medicine (2006)

After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another.We randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg. The study was conducted in 18 primary and 23 psychiatric care settings. The primary outcome was symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study. Scores on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), obtained at treatment visits, determined secondary outcomes, including remission (a score of 5 or less at exit) and response (a reduction of 50 percent or more on baseline scores).Remission rates as assessed by the HRSD-17 and the QIDS-SR-16, respectively, were 21.3 percent and 25.5 percent for sustained-release bupropion, 17.6 percent and 26.6 percent for sertraline, and 24.8 percent and 25.0 percent for extended-release venlafaxine. QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion, 26.7 percent for sertraline, and 28.2 percent for extended-release venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events.After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (ClinicalTrials.gov number, NCT00021528.).
Investigating the potential of essential oils as penetration enhancer for transdermal losartan delivery: Effectiveness and mechanism of action
Authors: Indu Vashisth, Abdul Ahad, Mohd. Aqil, Suraj P. Agarwal
Journal: Asian Journal of Pharmaceutical Sciences (2014)

The effect of tea tree oil (TTO), cumin oil (CO), rose oil (RO) and aloe vera oil (AVO) on the skin permeation of losartan potassium (LP) was investigated. In vitro skin permeation studies were carried out using rat skin. The mechanism of skin permeation enhancement of LP by essential oils treatment was evaluated by FTIR, DSC, activation energy measurement and histopathological examination. Both concurrent ethanol/enhancer treatment and neat enhancer pretreatment of rat SC with all the oils produced significance increase in the LP flux over the control. The effectiveness of the oils as the penetration enhancers was found to be in the following descending order: AVO > RO > CO > TTO. However, only AVO was the only enhancer to provide target flux required to deliver the therapeutic transdermal dose of LP. FTIR and DSC spectra of the enhancer treated SC indicated that TTO, CO, RO and AVO increased the LP permeation by extraction of SC lipids. The results of thermodynamic studies and histopathological examination of AVO treated SC suggested additional mechanisms for AVO facilitated permeation i.e. transient reduction in barrier resistance of SC and intracellular transport by dekeratinization of corneocytes which may be attributed to the presence of triglycerides as constituents of AVO. It is feasible to deliver therapeutically effective dose of LP via transdermal route using AVO as penetration enhancer.
Attitudes Toward Research Participation and Investigator Conflicts of Interest Among Advanced Cancer Patients Participating in Early Phase Clinical Trials
Authors: Stacy W. Gray, Fay J. Hlubocky, Mark J. Ratain, Christopher K. Daugherty
Journal: Journal of Clinical Oncology (2007)

Although both financial and intrinsic conflicts of interest can exist throughout the drug development process, little is known about how advanced cancer patients enrolled onto early phase clinical trials perceive investigator conflicts of interests.We interviewed 102 advanced cancer patients enrolled onto phase I clinical trials using a standardized survey that addressed multiple issues related to conflicts of interest and research participation.Fifty-five percent of patients would not be concerned if physicians involved in running a clinical trial had financial conflicts of interest, whereas 65% of patients would be concerned if physicians involved in running a trial had intrinsic conflicts of interest. Most patients reported that potential conflicts of interest should be disclosed to patients on research trials (52% for financial conflicts of interest and 61% for more intrinsic conflicts of interest). Most patients would be willing to participate in trials after learning conflict of interest information (63%). Younger patients expressed more concern regarding financial conflict of interest than older patients (odds ratio, 6.22; 95% CI, 1.41 to 27.24).Patients with advanced cancer are equally, if not more, concerned about traditional intrinsic conflicts of interest as compared with financial conflicts of interest. Patients generally believed that conflict of interest information should be disclosed to research participants. The fact that younger patients expressed more concern about financial conflicts of interest may have the potential to influence clinical trial participation rates. The actual impact of conflict of interest disclosure to research subjects needs to be evaluated more carefully.
Normal cognition in transgenic BRI2-Aβ mice
Authors: Jungsu Kim, Paramita Chakrabarty, Amanda Hanna, Amelia March, Dennis W Dickson, David R Borchelt, Todd Golde, Christopher Janus
Journal: Molecular Neurodegeneration (2013)

Abstract Background Recent research in Alzheimer’s disease (AD) field has been focused on the potential role of the amyloid-β protein that is derived from the transmembrane amyloid precursor protein (APP) in directly mediating cognitive impairment in AD. Transgenic mouse models overexpressing APP develop robust AD-like amyloid pathology in the brain and show various levels of cognitive decline. In the present study, we examined the cognition of the BRI2-Aβ transgenic mouse model in which secreted extracellular Aβ1-40, Aβ1-42 or both Aβ1-40/Aβ1-42 peptides are generated from the BRI-Aβ fusion proteins encoded by the transgenes. BRI2-Aβ mice produce high levels of Aβ peptides and BRI2-Aβ1-42 mice develop amyloid pathology that is similar to the pathology observed in mutant human APP transgenic models. Results Using established behavioral tests that reveal deficits in APP transgenic models, BRI2-Aβ1-42 mice showed completely intact cognitive performance at ages both pre and post amyloid plaque formation. BRI2-Aβ mice producing Aβ1-40 or both peptides were also cognitively intact. Conclusions These data indicate that high levels of Aβ1-40 or Aβ1-42, or both produced in the absence of APP overexpression do not reproduce memory deficits observed in APP transgenic mouse models. This outcome is supportive of recent data suggesting that APP processing derivatives or the overexpression of full length APP may contribute to cognitive decline in APP transgenic mouse models. Alternatively, Aβ aggregates may impact cognition by a mechanism that is not fully recapitulated in these BRI2-Aβ mouse models.
Sodium oxybate therapy provides multidimensional improvement in fibromyalgia: results of an international phase 3 trial
Authors: Michael Spaeth, Robert M Bennett, Beverly A Benson, Y Grace Wang, Chinglin Lai, Ernest H Choy
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Fibromyalgia is characterised by chronic musculoskeletal pain and multiple symptoms including fatigue, multidimensional function impairment, sleep disturbance and tenderness. Along with pain and fatigue, non-restorative sleep is a core symptom of fibromyalgia. Sodium oxybate (SXB) is thought to reduce non-restorative sleep abnormalities. This study evaluated effects of SXB on fibromyalgia-related pain and other symptoms. <h3>Methods</h3> 573 patients with fibromyalgia according to 1990 American College of Rheumatology criteria were enrolled at 108 centres in eight countries. Subjects were randomly assigned to placebo, SXB 4.5 g/night or SXB 6 g/night. The primary efficacy endpoint was the proportion of subjects with ≥30% reduction in pain visual analogue scale from baseline to treatment end. Other efficacy assessments included function, sleep quality, effect of sleep on function, fatigue, tenderness, health-related quality of life and subject9s impression of change in overall wellbeing. <h3>Results</h3> Significant improvements in pain, sleep and other symptoms associated with fibromyalgia were seen in SXB treated subjects compared with placebo. The proportion of subjects with ≥30% pain reduction was 42.0% for SXB4.5 g/night (p=0.002) and 51.4% for SXB6 g/night (p&lt;0.001) versus 26.8% for placebo. Quality of sleep (Jenkins sleep scale) improved by 20% for SXB4.5 g/night (p≤0.001) and 25% for SXB6 g/night (p≤0.001) versus 0.5% for placebo. Adverse events with an incidence ≥5% and twice placebo were nausea, dizziness, vomiting, insomnia, anxiety, somnolence, fatigue, muscle spasms and peripheral oedema. <h3>Conclusion</h3> These results, combined with findings from previous phase 2 and 3 studies, provide supportive evidence that SXB therapy affordsimportant benefits across multiple symptoms in subjects with fibromyalgia.
Variability and lack of predictive ability of asthma end-points in clinical trials
Authors: J. Zhang, C. Yu, S.T. Holgate, T.F. Reiss
Journal: European Respiratory Journal (2002)

While a consensus definition of the clinical parameters important in asthma control exists, an adequate objective definition of a response to asthma treatment and parameters for prediction of that response remain undefined. Given that asthma is a complex biological disease and that different parameters may measure dissimilar aspects of the disease status, this study assessed the relationship among several end-points of asthma control, and attempted to select a combination of variables measured before (baseline characteristics) or early in asthma therapy which would be predictive of a long-term clinical response. Data from two previously reported clinical studies which included montelukast, inhaled beclomethasone, and placebo in mild-to-moderate asthmatics (n=1,576) were analysed. The forced expiratory volume in one second (FEV 1 ), daily symptoms score (DSS), β-agonist use, and morning peak expiratory flow (PEF AM ) were recorded during the baseline period and throughout the 12-week treatment period. For the long-term response, as measured during the last 9 weeks of treatment, there was a large within-patient variability and no more than a moderate correlation between the changes in FEV 1 and PEF AM ; DSS and FEV 1 ; and DSS and β-agonist use. The overall predictive values for FEV 1 and DSS were 70–80%. The results showed that multiple measurements over a length of time are needed to establish a more complete profile of response, and that demographic and early treatment responses had a small but inadequate ability to predict future response. This study demonstrates the complex relationship among asthma end-points and the difficulty of reliably estimating long-term response using common, surrogate clinical markers of asthma control.
Chronic obstructive pulmonary disease and polycythemia
Authors: R. D. Reynolds
Journal: JAMA (1979)

<h3>To the Editor.—</h3> The editorial by William R. Barclay, MD (240:1520, 1978), regarding the report of Graham and Houston (240:1491, 1978) on the ability of persons with mild to moderate chronic obstructive pulmonary disease to tolerate short periods at high altitudes is worthy of note. Other factors also may warrant consideration, including the RBC mass. We recently observed a patient with previously undiagnosed chronic obstructive pulmonary disease who had polycythemia, gastrointestinal bleeding, and prolonged partial thromboplastin time (PTT), and who subsequently died of thrombotic complications. The case also illustrates the importance of ensuring that the required dilutional factors are met when determining the PTT. 10 20 30 40 50 60 70 Activated Partial Thromboplastin Time, s Variability of partial thromboplastin time with changes in ratio of sodium citrate to plasma volumes. Shaded area represents normal range (25 to 35 s) and demonstrates range of permissible sodium citrate dilution. <h3>Report of</h3>
Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen for Patients With Previously Treated Chronic Lymphocytic Leukemia
Authors: Nicole Lamanna, Matt Kalaycio, Peter Maslak, Joseph G. Jurcic, Mark Heaney, Renier Brentjens, Andrew D. Zelenetz, Denise Horgan, Alison Gencarelli, Katherine S. Panageas, David A. Scheinberg, Mark A. Weiss
Journal: Journal of Clinical Oncology (2006)

Purpose Purine analogs and alkylators are important agents for treating chronic lymphocytic leukemia (CLL). Early studies combining fludarabine and chlorambucil were abandoned owing to increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin appears to be the least myelosuppressive. We previously reported that pentostatin and cyclophosphamide (PC) is active and well-tolerated in patients with relapsed or refractory CLL. Subsequently, we added rituximab, and now report on this three-drug combination. Patients and Methods We treated 46 patients with either previously treated CLL (32 patients) or other low-grade B-cell neoplasms (14 patients). Patients received pentostatin 4 mg/m 2 , cyclophosphamide 600 mg/m 2 , and rituximab 375 mg/m 2 (PCR). All drugs were administered on the same day (rituximab omitted from cycle 1), and patients received six cycles at 3-week intervals. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. Results The median age was 62 years (range, 30 to 80 years). The median number of prior regimens was two (range, one to seven). For CLL patients, there were 24 responses (75%), including eight complete responses (25%). In fludarabine-refractory patients, 75% responded. Toxicity was acceptable, with grade 3/4 infections (including fever of unknown origin) in 28%. The regimen was well tolerated, with 72% of patients receiving the planned treatment at full dose. Conclusion PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen, we find that rituximab did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Based on these results, we are currently studying PCR as initial therapy for patients with CLL.
ACC/AHA guidelines for the management of patients with acute myocardial infarction
Authors: Thomas J. Ryan, Jeffrey L. Anderson, Elliott M. Antman, Blaine A. Braniff, Neil H. Brooks, Robert M. Califf, L. David Hillis, Loren F. Hiratzka, Elliott Rapaport, Barbara J. Riegel, Richard O. Russell, Earl E. Smith, W. Douglas Weaver, James L. Ritchie, Melvin D. Cheitlin, Kim A. Eagle, Timothy J. Gardner, Arthur Garson, Raymond J. Gibbons, Richard P. Lewis, Robert A. O'Rourke
Journal: Journal of the American College of Cardiology (1996)
Systemic upregulation of neutrophil -defensins and serine proteases in neutrophilic asthma
Authors: K. J. Baines, J. L. Simpson, L. G. Wood, R. J. Scott, P. G. Gibson
Journal: Thorax (2011)

<h3>Background</h3> The well-characterised airway inflammatory phenotypes of asthma include eosinophilic, neutrophilic, mixed eosinophilic/neutrophilic and paucigranulocytic asthma, identified based on the proportion of sputum granulocytes. Systemic inflammation is now recognised as an important part of some airway diseases, but the involvement of systemic inflammation in the pathogenesis of airway inflammatory phenotypes of asthma remains unknown. <h3>Methods</h3> Induced sputum samples and peripheral blood were collected from participants with asthma (n=36). Airway inflammatory cell counts were performed from induced sputum and inflammatory phenotype assigned based on the airway eosinophil and neutrophil cut-offs of 3% and 61%, respectively. RNA was extracted from whole blood and gene expression profiles were generated (Illumina Humanref-8 V3) and analysed using GeneSpring GX11. <h3>Results</h3> There were six genes classified as differentially expressed between the four asthma phenotypes, including the α-defensins (<i>DEFA</i>) 1, 1B, 3 and 4 and neutrophil proteases cathepsin G (CTSG) and elastase (ELA2). Systemic expression of <i>DEFA1</i>,<i>1B</i>,<i>3</i>,<i>4</i>,<i>CTSG</i> and <i>ELA2</i> was significantly higher in the neutrophilic asthma (NA) phenotype. Microarray results of the α-defensins and neutrophil proteases were successfully validated using real-time PCR. Plasma elastase was significantly increased in people with neutrophilic airway inflammation. <h3>Conclusion</h3> There is systemic upregulation of α-defensin and neutrophil protease expression in NA, which may represent proinflammatory effects on the bone marrow and the release of immature neutrophils into the circulation. This demonstrates a systemic inflammatory component in NA that further differentiates this from other asthma phenotypes and indicates different mechanisms in NA.
Phase II Multicenter Trial of Maintenance Biotherapy After Induction Concurrent Biochemotherapy for Patients With Metastatic Melanoma
Authors: Steven J. O'Day, Michael B. Atkins, Peter Boasberg, He-Jing Wang, John A. Thompson, Clay M. Anderson, Rene Gonzalez, Jose Lutzky, Thomas Amatruda, Evan M. Hersh, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2009)

Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival.One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival.The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively.Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge.
Anti-CD19-Targeted Liposomal Doxorubicin Improves the Therapeutic Efficacy in Murine B-Cell Lymphoma and Ameliorates the Toxicity of Liposomes with Varying Drug Release Rates
Authors: Theresa M. Allen, Davis R. Mumbengegwi, Gregory J.R. Charrois
Journal: Clinical Cancer Research (2005)

Abstract Some formulations of liposomal doxorubicin with intermediate rates of drug release have shown increased levels of toxicity in mice. Because antibody-mediated targeting of liposomal drugs influences the pharmacokinetics, mechanism of uptake, and selectivity of the associated drugs, we hypothesized that anti-CD19-mediated targeting of liposomal doxorubicin might moderate the toxicity of the problem formulations. Phosphatidylcholine/cholesterol liposomal formulations of doxorubicin having faster, intermediate, and slower drug release rates were prepared by altering the fatty acyl chain length or degree of saturation of the phosphatidylcholine component. Pharmacokinetic and biodistribution studies and in vivo drug release rates were determined in mice using liposomes dual labeled with [3H]cholesteryl hexadecylether and [14C]doxorubicin. Therapeutic studies were done in xenograft models of human B lymphoma (Namalwa cells). The rate of clearance of the liposomal lipid was similar for all formulations (average t1/2, 18 hours), but the rate of clearance of doxorubicin was dependent on the release rate of the formulation (t1/2, 2-315 hours). Liposomes with the slowest drug release rates showed no toxicity and exhibited therapeutic activity that was superior to the other formulations when targeted with anti-CD19; liposomes with the most rapid drug release rates also showed no toxicity but showed little therapeutic effect even when targeted. Liposomes with intermediate drug release rates exhibited varying degrees of toxicity. The toxicities could be reduced and even overcome by targeting with anti-CD19 antibodies. For these formulations, therapeutic effects were intermediate between those found for liposomes with the fastest and slowest drug release rates.