Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110α that reactivates latent HIV-1

Combination antiretroviral therapy (cART) can effectively suppress HIV-1 replication, but the latent viral reservoir in resting memory CD4+ T cells is impervious to cART and represents a major barrier to curing HIV-1 infection. Reactivation of latent HIV-1 represents a possible strategy for elimination of this reservoir. In this study we describe the discovery of 1,2,9,10-tetramethoxy-7H-dibenzo[de,g]quinolin-7-one (57704) which reactivates latent HIV-1 in several cell-line models of latency (J89GFP, U1 and ACH-2). 57704 also increased HIV-1 expression in 3 of 4 CD8+-depleted blood mononuclear cell preparations isolated from HIV-1-infected individuals on suppressive cART. In contrast, vorinostat increased HIV-1 expression in only 1 of the 4 donors tested. Importantly, 57704 does not induce global T cell activation. Mechanistic studies revealed that 57704 reactivates latent HIV-1 via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. 57704 was found to be an agonist of PI3K with specificity to the p110a isoform, but not the p110β, δ or γ isoforms. Taken together, our work suggests that 57704 could serve as a scaffold for the development of more potent activators of latent HIV-1. Furthermore, it highlights the involvement of the PI3K/Akt pathway in the maintenance of HIV-1 latency. © 2014 Doyon et al

A novel mitochondrial DnaJ/Hsp40 family protein BIL2 promotes plant growth and resistance against environmental stress in brassinosteroid signaling

Funding Information: Acknowledgments We thank Dr. Tsuyoshi Nakagawa (Shimane University) for the gift of the gateway vectors, pGWB2, pGWB80, pGWB5, and pGWB3. This work was supported in part by funding from the Program for Promotion of Basic Research Activities for Innovation Bioscience (PROBRAIN) to T.N. and T.A., and CREST, Japan Science and Technology Agency to T.N. and T.A.Plant steroid hormones, brassinosteroids, are essential for growth, development and responses to environmental stresses in plants. Although BR signaling proteins are localized in many organelles, i.e., the plasma membrane, nuclei, endoplasmic reticulum and vacuole, the details regarding the BR signaling pathway from perception at the cellular membrane receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1) to nuclear events include several steps. Brz (Brz220) is a specific inhibitor of BR biosynthesis. In this study, we used Brz-mediated chemical genetics to identify Brz-insensitive-long hypocotyls 2-1D (bil2-1D). The BIL2 gene encodes a mitochondrial-localized DnaJ/Heat shock protein 40 (DnaJ/Hsp40) family, which is involved in protein folding. BIL2-overexpression plants (BIL2-OX) showed cell elongation under Brz treatment, increasing the growth of plant inflorescence and roots, the regulation of BR-responsive gene expression and suppression against the dwarfed BRI1-deficient mutant. BIL2-OX also showed resistance against the mitochondrial ATPase inhibitor oligomycin and higher levels of exogenous ATP compared with wild-type plants. BIL2 participates in resistance against salinity stress and strong light stress. Our results indicate that BIL2 induces cell elongation during BR signaling through the promotion of ATP synthesis in mitochondria.Peer reviewe

Antimigraine medication use and associated health care costs in employed patients

Migraine is under diagnosed and suboptimally treated in the majority of patients, and also associated with decreased productivity in employees. The objective of this retrospective study is to assess the antimigraine medication use and associated resource utilization in employed patients. Patients with primary diagnosis of migraine or receiving antimigraine prescription drugs were identified from an employer-sponsored health insurance plan in 2010. Medical utilization and health care costs were determined for the year of 2010. Generalized linear regression was applied to evaluate the association between health care costs and the use of antimigraine medications by controlling covariates. Of 465 patients meeting the study criteria, nearly 30% that had migraine diagnosis were prescribed antimigraine medications, and 20% that had migraine diagnosis were not prescribed antimigraine medications. The remaining 50% were prescribed antimigraine medications but did not have migraine diagnosis. Patients with antimigraine medication prescriptions showed lower frequency of emergency department visits than those without antimigraine medication prescriptions. Regression models indicated an increase in migraine-related health care costs by 86% but decreases in all-cause medical costs and total health care costs by 42 and 26%, respectively, in the antimigraine medication use group after adjusting for covariates. Employed patients experienced inadequate pharmacotherapy for migraine treatment. After controlling for covariates, antimigraine prescription drug use was associated with lower total medical utilization and health care costs. Further studies should investigate patient self-reported care and needs to manage headache and develop effective intervention to improve patient quality of life and productivity

Methods and timing of biliary drainage for acute cholangitis: Tokyo Guidelines

Biliary drainage is a radical method to relieve cholestasis, a cause of acute cholangitis, and takes a central part in the treatment of acute cholangitis. Emergent drainage is essential for severe cases, whereas patients with moderate and mild disease should also receive drainage as soon as possible if they do not respond to conservative treatment, and their condition has not improved. Biliary drainage can be achieved via three different routes/procedures: endoscopic, percutaneous transhepatic, and open methods. The clinical value of both endoscopic and percutaneous transhepatic drainage is well known. Endoscopic drainage is associated with a low morbidity rate and shorter duration of hospitalization; therefore, this approach is advocated whenever it is applicable. In endoscopic drainage, either endoscopic nasobiliary drainage (ENBD) or tube stent placement can be used. There is no significant difference in the success rate, effectiveness, and morbidity between the two procedures. The decision to perform endoscopic sphincterotomy (EST) is made based on the patient’s condition and the number and diameter of common bile duct stones. Open drainage, on the other hand, should be applied only in patients for whom endoscopic or percutaneous transhepatic drainage is contraindicated or has not been successfully performed. Cholecystectomy is recommended in patients with gallbladder stones, following the resolution of acute cholangitis with medical treatment, unless the patient has poor operative risk factors or declines surgery

Measurement of coronary calcium scores by electron beam computed tomography or exercise testing as initial diagnostic tool in low-risk patients with suspected coronary artery disease

We determined the efficiency of a screening protocol based on coronary calcium scores (CCS) compared with exercise testing in patients with suspected coronary artery disease (CAD), a normal ECG and troponin levels. Three-hundred-and-four patients were enrolled in a screening protocol including CCS by electron beam computed tomography (Agatston score), and exercise testing. Decision-making was based on CCS. When CCS≥400, coronary angiography (CAG) was recommended. When CCS<10, patients were discharged. Exercise tests were graded as positive, negative or nondiagnostic. The combined endpoint was defined as coronary event or obstructive CAD at CAG. During 12±4 months, CCS≥400, 10–399 and <10 were found in 42, 103 and 159 patients and the combined endpoint occurred in 24 (57%), 14 (14%) and 0 patients (0%), respectively. In 22 patients (7%), myocardial perfusion scintigraphy was performed instead of exercise testing due to the inability to perform an exercise test. A positive, nondiagnostic and negative exercise test result was found in 37, 76 and 191 patients, and the combined endpoint occurred in 11 (30%), 15 (20%) and 12 patients (6%), respectively. Receiver-operator characteristics analysis showed that the area under the curve of 0.89 (95% CI: 0.85–0.93) for CCS was superior to 0.69 (95% CI: 0.61–0.78) for exercise testing (P<0.0001). In conclusion, measurement of CCS is an appropriate initial screening test in a well-defined low-risk population with suspected CAD

Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer

Background: Contrast enhanced ultrasound (CEUS) is an imaging technique which appeared on the market around the year 2000 and proposed for the detection of liver metastases in gastrointestinal cancer patients, a setting in which accurate staging plays a significant role in the choice of treatment. Methods: A total of 109 patients with colorectal (n = 92)or gastric cancer prospectively underwent computed tomography (CT) scan and conventional US evaluation followed by real time CEUS. A diagnosis of metastases was made by CT or, for lesions not visibile at CT, the diagnosis was achieved by histopathology or by a malignant behavior during follow-up. Results: Of 109 patients, 65 were found to have metastases at presentation. CEUS improved sensitivity in metastatic livers from 76.9% of patients (US) to 95.4% (p < 0.01), while CT scan reached 90.8% (p = n.s. vs CEUS, p < 0.01 vs US). CEUS and CT were more sensitive than US also for detection of single lesions (87 with US, 122 with CEUS, 113 with CT). In 15 patients (13.8%), CEUS revealed more metastases than CT, while CT revealed more metastases than CEUS in 9 patients (8.2%) (p = n.s.). Conclusion: CEUS is more sensitive than conventional US in the detection of liver metastases and could be usefully employed in the staging of patients with gastrointestinal cancer. Findings at CEUS and CT appear to be complementary in achieving maximum sensitivity. © 2007 Piscaglia et al; licensee BioMed Central Ltd

Is there a gender difference in noninvasive coronary imaging? Multislice computed tomography for noninvasive detection of coronary stenoses

<p>Abstract</p> <p>Background</p> <p>Multislice computed tomography (MSCT) coronary angiography is the foremost alternative to invasive coronary angiography.</p> <p>Methods</p> <p>We sought to compare the diagnostic accuracy of MSCT in female and male patients with suspected coronary disease. Altogether 50 women and 95 men underwent MSCT with 0.5 mm detector collimation. Coronary artery stenoses of at least 50% on conventional coronary angiography were considered significant.</p> <p>Results</p> <p>The coronary vessel diameters of all four main coronary artery branches were significantly larger in men than in women. The diagnostic accuracy of MSCT in identifying patients with coronary artery disease was significantly lower for women (72%) compared with men (89%, <it>p </it>< 0.05). Also sensitivity (70% vs. 95%), positive predictive value (64% vs. 93%), and the rate of nondiagnostic examinations (14% vs. 4%, all: <it>p </it>< 0.05) were significantly worse for women. The effective radiation dose of MSCT coronary angiography was significantly higher in the examination of women (13.7 ± 1.2 mSv) than of men (11.7 ± 0.9 mSv, <it>p </it>< 0.001), mainly as a result of the fact that the radiosensitive female breast (contributing 24.5% of the dose in women) is in the x-ray path.</p> <p>Conclusion</p> <p>Noninvasive coronary angiography with MSCT might be less accurate and sensitive for women than men. Also, women are exposed to a significantly higher effective radiation dose than men.</p