tbuckley/cabot-search huggingface dataset:
Systematic Review: Safety and Efficacy of Extended-Duration Antiviral Chemoprophylaxis Against Pandemic and Seasonal Influenza
Authors: Nayer Khazeni, Dena M. Bravata, Jon-Erik C. Holty, Timothy M. Uyeki, Christopher D. Stave, Michael K. Gould
Journal: Annals of Internal Medicine (2009)

Background: Neuraminidase inhibitors (NAIs) are stockpiled internationally for extended use in an influenza pandemic. Purpose: To evaluate the safety and efficacy of extended-duration (>4 weeks) NAI chemoprophylaxis against influenza. Data Sources: Studies published in any language through 11 June 2009 identified by searching 10 electronic databases and 3 trial registries. Study Selection: Randomized, placebo-controlled, double-blind human trials of extended-duration NAI chemoprophylaxis that reported outcomes of laboratory-confirmed influenza or adverse events. Data Extraction: 2 reviewers independently assessed study quality and abstracted information from eligible studies. Data Synthesis: Of 1876 potentially relevant citations, 7 trials involving 7021 unique participants met inclusion criteria. Data were pooled by using random-effects models. Chemoprophylaxis with NAIs decreased the frequency of symptomatic influenza (relative risk [RR], 0.26 [95% CI, 0.18 to 0.37]; risk difference [RD], −3.9 percentage points [CI, −5.8 to −1.9 percentage points]) but not asymptomatic influenza (RR, 1.03 [CI, 0.81 to 1.30]; RD, −0.4 percentage point [CI, −1.6 to 0.9 percentage point]). Adverse effects were not increased overall among NAI recipients (RR, 1.01 [CI, 0.94 to 1.08]; RD, 0.1 percentage point [CI, −0.2 to 0.4 percentage point]), but nausea and vomiting were more common among those who took oseltamivir (RR, 1.48 [CI, 1.86 to 2.33]; RD, 1.7 percentage points [CI, 0.6 to 2.9 percentage points]). Prevention of influenza did not statistically significantly differ between zanamivir and oseltamivir. Limitations: All trials were industry-sponsored. No study was powered to detect rare adverse events, and none included diverse racial groups, children, immunocompromised patients, or individuals who received live attenuated influenza virus vaccine. Conclusion: Extended-duration zanamivir and oseltamivir chemoprophylaxis seems to be highly efficacious for preventing symptomatic influenza among immunocompetent white and Japanese adults. Extended-duration oseltamivir is associated with increased nausea and vomiting. Safety and efficacy in several subpopulations that might receive extended-duration influenza chemoprophylaxis are unknown.
Prostaglandin D2 Selectively Induces Chemotaxis in T Helper Type 2 Cells, Eosinophils, and Basophils via Seven-Transmembrane Receptor Crth2
Authors: Hiroyuki Hirai, Kazuya Tanaka, Osamu Yoshie, Kazuyuki Ogawa, Kazumi Kenmotsu, Yasushi Takamori, Michiko Ichimasa, Kazuo Sugamura, Masataka Nakamura, Shoichi Takano, Kinya Nagata
Journal: The Journal of Experimental Medicine (2001)

Prostaglandin (PG)D2, which has long been implicated in allergic diseases, is currently considered to elicit its biological actions through the DP receptor (DP). Involvement of DP in the formation of allergic asthma was recently demonstrated with DP-deficient mice. However, proinflammatory functions of PGD2 cannot be explained by DP alone. We show here that a seven-transmembrane receptor, CRTH2, which is preferentially expressed in T helper type 2 (Th2) cells, eosinophils, and basophils in humans, serves as the novel receptor for PGD2. In response to PGD2, CRTH2 induces intracellular Ca2+mobilization and chemotaxis in Th2 cells in a Galphai-dependent manner. In addition, CRTH2, but not DP, mediates PGD2-dependent cell migration of blood eosinophils and basophils. Thus, PGD2 is likely involved in multiple aspects of allergic inflammation through its dual receptor systems, DP and CRTH2.
STUDIES ON HOST-VIRUS INTERACTIONS IN THE CHICK EMBRYO-INFLUENZA VIRUS SYSTEM
Authors: Werner Henle, Oscar C. Liu
Journal: The Journal of Experimental Medicine (1951)

Evidence has been presented that influenza viruses both of type A and B partially inactivated by ultraviolet irradiation may regain their capacity to propagate in the allantoic membrane of the chick embryo. In using such irradiated preparations as inocula for growth curve experiments it could be shown that the development of hemagglutinins as well as of infectivity preceded at rates resembling those noted with more than 10 times the amount of infective virus actually found in the irradiated seed. Partial inactivation of the inocula by heating to 56 degrees C. gave similar results. The phenomenon was observed only with seed irradiated for short periods of time so that the virus particles sustained only few hits of radiation. On prolonged exposure resulting in numerous hits per virus particle the capacity of reactivation was lost. Likewise, an irradiated preparation capable of reactivation in the allantoic membrane, could not be diluted more than about 30-fold and still clearly produce this phenomenon. This indicated that reactivation is obtained only when one host cell adsorbs more than one non-infective virus particle but not upon adsorption of a single particle. These data are in striking agreement with the phenomenon of "multiplicity reactivation" observed in the bacteriophage-E. coli system by Luria and Dulbecco.
Critical Roles for the Fas/Fas Ligand System in Postinfarction Ventricular Remodeling and Heart Failure
Authors: Yiwen Li, Genzou Takemura, Ken-ichiro Kosai, Tomoyuki Takahashi, Hideshi Okada, Shusaku Miyata, Kentaro Yuge, Satoshi Nagano, Masayasu Esaki, Ngin Cin Khai, Kazuko Goto, Atsushi Mikami, Rumi Maruyama, Shinya Minatoguchi, Takako Fujiwara, Hisayoshi Fujiwara
Journal: Circulation Research (2004)

In myocardial infarction (MI), granulation tissue cells disappear via apoptosis to complete a final scarring with scanty cells. Blockade of this apoptosis was reported to improve post-MI ventricular remodeling and heart failure. However, the molecular biological mechanisms for the apoptosis are unknown. Fas and Fas ligand were overexpressed in the granulation tissue at the subacute stage of MI (1 week after MI) in mice, where apoptosis frequently occurred. In mice lacking functioning Fas (lpr strain) and in those lacking Fas ligand (gld strain), apoptotic rate of granulation tissue cells was significantly fewer compared with that of genetically controlled mice, and post-MI ventricular remodeling and dysfunction were greatly attenuated. Mice were transfected with adenovirus encoding soluble Fas (sFas), a competitive inhibitor of Fas ligand, on the third day of MI. The treatment resulted in suppression of granulation tissue cell apoptosis and produced a thick, cell-rich infarct scar containing rich vessels and bundles of smooth muscle cells with a contractile phenotype at the chronic stage (4 weeks after MI). This accompanied not only alleviation of heart failure but also survival improvement. However, the sFas gene delivery during scar tissue phase was ineffective, suggesting that beneficial effects of the sFas gene therapy owes to inhibition of granulation tissue cell apoptosis. The Fas/Fas ligand interaction plays a critical role for granulation tissue cell apoptosis after MI. Blockade of this apoptosis by interfering with the Fas/Fas ligand interaction may become one of the therapeutic strategies against chronic heart failure after large MI.
Adherence to Statin Therapy and LDL Cholesterol Goal Attainment by Patients With Diabetes and Dyslipidemia
Authors: Elizabeth S. Parris, David B. Lawrence, Lisa A. Mohn, Laura B. Long
Journal: Diabetes Care (2005)

The purpose of this study was to assess the relationship between adherence to statin therapy and LDL cholesterol goal achievement in patients with diabetes and dyslipidemia.The records of patients being medically treated for dyslipidemia in a managed care diabetes program from January 2001 to December 2002 were used to assess LDL cholesterol goal attainment (<100 mg/dl) and to compute a 9-month medication possession ratio (percentage of days when medication was available [MPR], beginning with the first prescription in the database).A total of 653 patient records was analyzed. The average MPR was significantly higher for men than for women (0.75 vs. 0.66, P < 0.05). Overall, 44% (n = 290) of the patients achieved an LDL cholesterol level <100 mg/dl (52% of men and 37% of women, P < 0.05). A significant correlation emerged between MPR and plasma LDL cholesterol (P < 0.001), and MPR was significantly higher in patients who achieved the LDL cholesterol target than in those who did not (0.82 vs. 0.61, P < 0.05).Although statins are highly effective for decreasing LDL cholesterol levels in patients with dyslipidemia, including those with diabetes, failure to reach LDL cholesterol targets remains common. Adherence to statin therapy, as reflected by MPR, is closely related to LDL cholesterol goal attainment in patients with diabetes and dyslipidemia. The probability of goal achievement appears to increase substantially when the MPR is >0.80. Pharmacy records can be used to identify patients who are poorly compliant with statin therapy and at high risk for failure to attain LDL cholesterol goals. Because outcomes are directly related to patients' medication-taking behavior, when clinical goals (such as serum cholesterol levels) are not being reached, adherence should be the first item assessed by the clinician.
Giving imatinib a hand
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2008)

Researchers have discovered a new a way to make the anticancer drug imatinib more effective. By suppressing the oncogene AHI-1, Zhou and colleagues were able to hold chronic myeloid leukemia (CML) in check (page 2657).






Figure 1

A combination of imatinib and an AHI-1 blocker (red) killed more cells from imatinib-resistant CML patients than did imatinib alone (purple).




Imatinib is currently the most popular targeted therapy for CML. The leukemia is associated with the abnormal fusion of BCR with a kinase gene, ABL, which results in a perpetually active kinase known as BCR-ABL. Imatinib, a tyrosine kinase inhibitor, slows down the spread of cancer by blocking BCR-ABL activity. But the drug doesn't work in everyone and patients often relapse, most likely because the drug only targets mature cells, leaving CML stem cells behind. Scientists have therefore been hunting for complementary therapies that act on pathways left undeterred by kinase inhibitors.

Mutated versions of the recently identified protein AHI-1, whose function is unknown, have been shown to be highly expressed in leukemic stem cells—the same cells that express BCR-ABL in patients with CML. Here, Zhou et al. show that expressing AHI-1 in stem cells turns the cells cancerous in vitro, and these cells caused lethal leukemia when transferred into mice. When expressed in BCR-ABL–positive cells, AH1-1 exacerbated the growth-promoting effects of the fusion protein.

AHI-1's growth-promoting activity was attributed to the ability of AHI-1 to bind to BCR-ABL, along with an activated version of the downstream signaling protein JAK2. Cells expressing this complex were resistant to the kinase-blocking action of imatinib. Indeed, blocking AHI-1 in cells from imatinib-resistant CML patients restored the cells' sensitivity to the drug.

With this finding, the race is on to find a drug to block AH1-1. As other studies have recently suggested, the cure for CML and other leukemias may not lie in a miracle drug, but rather in a carefully concocted cocktail of targeted therapies.
Reproductive choices in 2000: the relative safety of current oral contraceptives
Authors: R G Edwards, J Cohen
Journal: Human Reproduction Update (1999)

This article provides an overview of the relative safety of current oral contraceptives (OCs) in the UK.  Since the inception of OCs the importance of safety has long been questioned.  It became an essential issue for manufacturing companies and is rigorously being examined by regulatory agencies in most countries.  Even with studies that had proven a low level of risks OCs still fell under strict scrutiny.  Differences of opinion have arisen between regulatory agencies in different countries and perhaps inevitably successive pill  scares  have emerged which were the result of the decision made by the UK Committee on Safety of medicines.  This decision provided a chain reaction among physicians and family planning clinics and led to apprehension among OC users especially among those that used third-generation OCs.
Injuries to polo riders: a prospective evaluation
Authors: M Costa-Paz, L Aponte-Tinao, D L Muscolo
Journal: British Journal of Sports Medicine (1999)

OBJECTIVE: To assess prospectively the incidence, nature, and severity of injuries to polo riders competing in the 1996 Argentine High Polo season. METHODS: Assessment, documentation, and provision of care for all injuries sustained during the 1996 season by one of the authors. Riders were also surveyed retrospectively for their previous polo injuries. RESULTS: 34 riders took part in the study. Nine injuries were sustained prospectively and 55 injuries were reviewed retrospectively (64 total). The injuries were categorised as minor (10), moderate (13), and major (41). Twenty five (39%) injuries occurred in the arms, 20 (31%) in the legs, 12 (19%) in the head, 3 (5%) in the back, and 4 (6%) in the face. A fracture occurred in 25 (39%) injuries as most resulted from a fall from the horse. Additionally, facial lacerations occurred prospectively in five riders but did not result in missed play. An overall injury rate of 7.8/1000 player-game hours was calculated. CONCLUSIONS: Although many sports have injury rates much greater than 8/1000 player-game hours, the severity of most injuries occurring in polo was classified as major, with fractures and facial lacerations common. The use of a helmet with a face protector is recommended to decrease injury to players. A doctor experienced in the management of serious trauma should be present at all polo matches.
The Roles of Therapy-Induced Autophagy and Necrosis in Cancer Treatment
Authors: Ravi K. Amaravadi, Craig B. Thompson
Journal: Clinical Cancer Research (2007)

Abstract Metabolic and therapeutic stresses activate several signal transduction pathways that regulate cell death and cell survival in cancer cells. Although decades of research unraveled the pathways that regulate apoptosis and allowed the development of novel diagnostic and therapeutic modalities in cancer treatment, only recently has the regulation and significance of tumor cell autophagy and necrosis become the focus of investigations. Necrosis is an irreversible inflammatory form of cell death. In contrast, autophagy is a reversible process that can contribute both to tumor cell death and survival. This review describes recent advances in understanding the regulation of autophagy and necrosis and their implications for cancer therapy. Currently available methods to measure autophagy and necrosis are highlighted. The effect of tumor cell autophagy and necrosis on host immunity is explored. Finally, therapeutic approaches that target autophagy and necrosis in cancer are described.
Phenotypic predictors of long-term response to inhaled corticosteroid and leukotriene modifier therapies in pediatric asthma
Authors: Jason E. Knuffman, Christine A. Sorkness, Robert F. Lemanske, David T. Mauger, Susan J. Boehmer, Fernando D. Martinez, Leonard B. Bacharier, Robert C. Strunk, Stanley J. Szefler, Robert S. Zeiger, Lynn M. Taussig
Journal: Journal of Allergy and Clinical Immunology (2009)
A Randomized Trial of a Telephone Care-Management Strategy
Authors: David E. Wennberg, Amy Marr, Lance Lang, Stephen O'Malley, George Bennett
Journal: New England Journal of Medicine (2010)

Studies have shown that telephone interventions designed to promote patients' self-management skills and improve patient-physician communication can increase patients' satisfaction and their use of preventive services. The effect of such a strategy on health care costs remains controversial.We conducted a stratified, randomized study of 174,120 subjects to assess the effect of a telephone-based care-management strategy on medical costs and resource utilization. Health coaches contacted subjects with selected medical conditions and predicted high health care costs to instruct them about shared decision making, self-care, and behavioral change. The subjects were randomly assigned to either a usual-support group or an enhanced-support group. Although the same telephone intervention was delivered to the two groups, a greater number of subjects in the enhanced-support group were made eligible for coaching through the lowering of cutoff points for predicted future costs and expansion of the number of qualifying health conditions. Primary outcome measures at 1 year were total medical costs and number of hospital admissions.At baseline, medical costs and resource utilization were similar in the two groups. After 12 months, 10.4% of the enhanced-support group and 3.7% of the usual-support group received the telephone intervention. The average monthly medical and pharmacy costs per person in the enhanced-support group were 3.6% ($7.96) lower than those in the usual-support group ($213.82 vs. $221.78, P=0.05); a 10.1% reduction in annual hospital admissions (P<0.001) accounted for the majority of savings. The cost of this intervention program was less than $2.00 per person per month.A targeted telephone care-management program was successful in reducing medical costs and hospitalizations in this population-based study. (Funded by Health Dialog Services; ClinicalTrials.gov number, NCT00793260.)
A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory, or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2
Authors: Beata Holkova, Jeffrey G. Supko, Matthew M. Ames, Joel M. Reid, Geoffrey I. Shapiro, Edward Brent Perkins, Viswanathan Ramakrishnan, Mary Beth Tombes, Connie Honeycutt, Renee M. McGovern, Maciej Kmieciak, Ellen Shrader, Martha D. Wellons, Heidi Sankala, Austin Doyle, John Wright, John D. Roberts, Steven Grant
Journal: Clinical Cancer Research (2013)

Abstract Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design. Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-minute loading infusion) followed by 20 mg/m2 (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. Clin Cancer Res; 19(7); 1873–83. ©2013 AACR.
GMC statement does not reflect actions
Authors: John Bridson
Journal: BMJ (2008)

Catto says that nothing could be further from the truth than the perception that the General Medical Council (GMC) is somehow determined unfairly to persecute paediatricians involved in child protection work (second letter). However, although the GMC made a similar response to the Guardian in April after our article in Pediatrics,1 2 a recent GMC panel in David Southall’s case produced a perverse and erroneous determination.3 We do not consider therefore that the GMC’s statement is yet reflected in its actions. The GMC’s actions have included:
The Body of Science
Authors: B. A. St. Andrews
Journal: JAMA (2003)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Trafficking Defects and Gating Abnormalities of a Novel <i>SCN5A</i> Mutation Question Gene-Specific Therapy in Long QT Syndrome Type 3
Authors: Yanfei Ruan, Marco Denegri, Nian Liu, Tiziana Bachetti, Morena Seregni, Stefano Morotti, Stefano Severi, Carlo Napolitano, Silvia G. Priori
Journal: Circulation Research (2010)

Sodium channel blockers are used as gene-specific treatments in long-QT syndrome type 3, which is caused by mutations in the sodium channel gene (SCN5A). Response to treatment is influenced by biophysical properties of mutations.We sought to investigate the unexpected deleterious effect of mexiletine in a mutation combining gain-of- function and trafficking abnormalities.A long-QT syndrome type 3 child experienced paradoxical QT prolongation and worsening of arrhythmias after mexiletine treatment. The SCN5A mutation F1473S expressed in HEK293 cells presented a right-ward shift of steady-state inactivation, enlarged window current, and huge sustained sodium current. Unexpectedly, it also reduced the peak sodium current by 80%. Immunostaining showed that mutant Nav1.5 is retained in the cytoplasm. Incubation with 10 micromol/L mexiletine rescued the trafficking defect of F1473S, causing a significant increase in peak current, whereas sustained current was unchanged. Using a Markovian model of the Na channel and a model of human ventricular action potential, we showed that simulated exposure of F1473S to mexiletine paradoxically increased action potential duration, mimicking QT prolongation seen in the index patient on mexiletine treatment.Sodium channel blockers are largely used to shorten QT intervals in carriers of SCN5A mutations. We provided evidence that these agents may facilitate trafficking of mutant proteins, thus exacerbating QT prolongation. These data suggest that caution should be used when recommending this class of drugs to carriers of mutations with undefined electrophysiological properties.