Histone deacetylase inhibitor induces DNA damage,which normal but not transformed cells can repair

Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (γH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, γH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death.     

The blossoming of evidence-based clinical rheumatology: The Arthritis Research Campaign's Clinical Trials Collaboration in association with the MRC Clinical Trials Unit,BSR and BOA

Competing demands for scarce healthcare resources have accentuatedthe requirement for routine clinical practice to be evidence-based.One of the benchmarks for evidence-based medicine is the appropriatelyconducted randomized controlled trial (RCT). Although epidemiologicalstudies, whether case–control or cohort in design, havecontributed enormously to the generation of hypotheses and permitthe controlled evaluation of therapeutic interventions, theyare susceptible to biases through selection, information ascertainmentand confounding. While RCTs are also susceptible to such biases,the process of randomization and of blinded evaluation of outcomespermits the closest approximation in clinical research to theconduct of a hypothesis-testing laboratory experiment. Historically,there have been several obstacles to the execution of high-qualityRCTs to address important rheumatological questions. One     

Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods.

OBJECTIVE--The SAVE study showed that captopril improves mortality in patients with left ventricular dysfunction after myocardial infarction and that this benefit occurred even in patients with no clinically overt heart failure. On the basis of this, it seems important to identify correctly which patients have left ventricular dysfunction after a myocardial infarction. The objective was to compare various methods of identifying patients with left ventricular dysfunction (left ventricular ejection fraction, LVEF, < or = 40%) after acute myocardial infarction. The methods compared were echocardiography (quantitative and qualitative visual assessment), clinical evaluation (subjective assessment and three clinical score methods), and measurement of plasma concentrations of cardiac natriuretic peptide hormones (atrial and brain natriuretic peptides, ANP and BNP). DESIGN--Cross sectional study of left ventricular function in patients two to eight days after acute myocardial infarction. SETTING--Coronary care unit of a teaching hospital. PATIENTS--75 survivors of a recent myocardial infarction aged 40 to 88 with no history of cardiac failure and without cardiogenic shock at the time of entry to the study. MAIN OUTCOME MEASURES--Sensitivities and specificities of the various methods of detecting left ventricular dysfunction were calculated by comparing them with a cross sectional echocardiographic algorithm for LVEF. RESULTS--Clinical impression was poor at identifying LVEF < 40% (sensitivity 46%). Clinical scoring improved this figure somewhat (modified Peel index sensitivity 64%). Qualitative visual assessment echocardiography was a more sensitive method (sensitivity 82%) for detecting LVEF < 40%. Plasma BNP concentration was also a sensitive measure for detecting left ventricular dysfunction (sensitivity 84%) but plasma ANP concentration was much poorer (sensitivity 64%). CONCLUSION--Left ventricular dysfunction is easily and reliably detected by echocardiographic measurement of LVEF and also by a quick qualitative echocardiographic assessment but is likely to be missed by clinical assessment alone. High concentrations of plasma BNP maybe another useful indicator of left ventricular dysfunction, particularly in hospitals where not all patients can be screened by echocardiography or radionuclide ventriculography after myocardial infarction.     

Insights in Public Health: Initiating Bicycle Sharing in Hawai‘i: Lessons Learned from a Small Pilot Bike Share Program

In 2011, a small pilot bike share program was established in the town core of Kailua, Hawai‘i, with funding from the Hawai‘i State Department of Health. The Kailua system consisted of two stations with 12 bicycles, and the goal was to secure additional funding to expand the station network in the future. Community feedback consistently indicated support for the bike share program. However, system metrics showed low levels of usage, averaging 41.5 rides per month (2011–2014). From observational data, users were primarily tourists. With minimal local staff, the bike share program had limited resources for promotion and education, which may have hindered potential use by local residents. Management of station operations and bike maintenance were additional, ongoing barriers to success. Despite the challenges, the pilot bike share program was valuable in several ways. It introduced the bike share concept to Hawai‘i, thereby helping to build awareness and connect an initial network of stakeholders. Furthermore, the pilot bike share program informed the development of a larger bike share program for urban Honolulu. As limited information exists in the literature about the experiences of smaller bike share programs and their unique considerations, this article shares lessons learned for other communities interested in starting similar bike share programs.     

Ebola in West Africa—CDC’s Role in Epidemic Detection,Control, and Prevention

Since Ebola virus disease was identified in West Africa on March 23, 2014, the Centers for Disease Control and Prevention (CDC) has undertaken the most intensive response in the agency’s history; >3,000 staff have been involved, including >1,200 deployed to West Africa for >50,000 person workdays. Efforts have included supporting incident management systems in affected countries; mobilizing partners; and strengthening laboratory, epidemiology, contact investigation, health care infection control, communication, and border screening in West Africa, Nigeria, Mali, Senegal, and the United States. All efforts were undertaken as part of national and global response activities with many partner organizations. CDC was able to support community, national, and international health and public health staff to prevent an even worse event. The Ebola virus disease epidemic highlights the need to strengthen national and international systems to detect, respond to, and prevent the spread of future health threats.     

Correction: Water-floating nanohybrid films of layered titanate–graphene for sanitization of algae without secondary pollution

Correction for ‘Water-floating nanohybrid films of layered titanate–graphene for sanitization of algae without secondary pollution’ by In Young Kim et al., RSC Adv., 2016, 6, 98528–98535.

In the published paper, the affiliations of Eui-Ho Hwang and Woo-Bin Jin were wrongly designated, and the corrected version is shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

The conserved lymphokine element 0 is a powerful activator and target for corticosteroid inhibition in human interleukin-5 transcription

The role of eosinophilia in allergic disorders indicates hIL-5 as a potential target for therapy. The conservation of hIL-5 gene proximal elements suggests they are important in controlling expression. Corticosteroids are important in the treatment of allergy, and are powerful inhibitors of IL-5 expression. This study aimed at understanding the role of hIL-5 conserved proximal elements, and elucidating the target of corticosteroid activity, in hIL-5 gene expression. Methods used include transient transfection of PBMC and PER117 cells with hIL-5 deletion constructs, EMSA, Western Blotting, and RT-PCR.

The conserved proximal CLE0/TATA elements driving a reporter gene gave similar or higher expression than a 500 bp promoter in primary human T cells and a T-cell line. Two and three copies of IL-5 CLE0 upstream of the silent IL-4 minimal promoter gave 30–45 fold increases in expression in forward orientation, but little activity in reverse orientation. Consequently, CLE0 is a powerful activator but not a classical enhancer. Deletion analysis identified CLE0 as the key element in the inhibition of IL-5 reporter constructs by dexamethasone, and RT-PCR analysis indicated that GILZ expression correlated with dexamethasone-induced inhibition of IL-5. Ectopic expression of GILZ, confirmed by western blotting, gave a 90% inhibition of promoter constructs in absence of dexamethasone. CLE0 is a powerful activator sufficient for the inducible expression of IL-5, and functions when moved upstream in a heterologous promoter. CLE0 is also the main target for IL-5 inhibition by dexamethasone, and we present evidence consistent with a role of GILZ in this.     

Effectiveness of second-opinion radiology consultations to reassess the cervical spine CT scans: a study on trauma patients referred to a tertiary-care hospital

PURPOSE

A second opinion is a valuable resource in confirming proper medical diagnosis and treatment. This study evaluates the effectiveness of second-opinion radiology consultations to reassess the cervical spine computed tomography (CT) scans of the trauma patients referred to our hospital.

METHODS

Cervical spine CT scans of 301 consecutive adult trauma patients, who were referred to our hospital from outside institutions, were analyzed. The emergency radiologists at our institution completed the over-read reports on the CT images obtained at the outside facilities. A single radiologist compared the outside- and over-read reports and determined the discrepancy of the radiologic reports.

RESULTS

Based on the outside reports, 31% of the CT scans had cervical traumatic injury. In 92% of patients, the first-read and the over-read reports had consistent radiologic findings. About 90% of the positive, and 93% of the negative radiologic findings, were reported consistently in the over-read reports. Our analysis showed that the over-read reporting resulted in reassurance of negative findings in 63%; confirmation of positive findings in 29%; clearing a false diagnosis in 3%; and detection of a missed diagnosis in 5%. A rescan was done in 80% of patients with inconsistent and 20% of patients with consistent findings (P < 0.05). The most common missed radiologic findings in the first-reports were transverse and spinous process fractures and the most common misdiagnoses were dens fractures.

CONCLUSION

For a service offering second-opinion consultations on cervical spine trauma, review of outside CT studies improves diagnosis and benefits patient care.The quality of healthcare has become a target of increasing public scrutiny and governmental concern while radiologic evaluation has assumed an increasingly important role in the diagnosis and management of patients (1). Public attention and awareness have increased and amplified the focus on the quality of healthcare (2). Some medical errors are extremely costly particularly with respect to patient morbidity and mortality.Patients referred to the tertiary care centers often arrive with radiologic imaging having already been performed at the primary institution. As part of the care to be delivered by the radiologists at the referral center, a second-opinion interpretation of the imaging studies is often requested, and the formal reports are incorporated into the patient’s permanent medical record at the referral institution where the patient’s management and treatment are determined.The added value of the point-of-care second interpretations can be viewed from the medical perspective of guiding and expediting appropriate treatment as well as from the financial perspective of avoiding unnecessary studies, at times incurring additional patient radiation exposure, when initial examinations need to be repeated or when additional examinations are suggested by the radiologist at an outside institution (3).Multidetector CT is an essential part of the assessment of patients suspected of having cervical spine injury after trauma. Despite all the advantages of multidetector CT, suspected spinal injury continues to be a daily challenge in clinical practice (4). Spine injuries are frequently missed; therefore, a second opinion can potentially improve the diagnosis (5). The purpose of this study was to evaluate the effectiveness of second-opinion radiology consultations to reassess the cervical spine CT scans of the trauma patients referred to our hospital.