ApoA-I Induction as a Potential Cardioprotective Strategy: Rationale for the SUSTAIN and ASSURE Studies

Background  

Considerable interest has focused on the development of therapies that target the functionality of high-density lipoproteins (HDL). Upregulation of endogenous synthesis of the major protein on HDL particles, apolipoprotein A-I (apoA-I), represents a novel approach to generation of new HDL particles. The Study of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation (SUSTAIN, NCT01423188) study aims to evaluate the lipid efficacy, safety and tolerability of an apoA-I inducer (RVX-208). The ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE, NCT01067820) study aims to evaluate the effect of RVX-208 on plaque burden.     

CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.     

Autistic Adults May Be Erroneously Perceived as Deceptive and Lacking Credibility

Journal of Autism and Developmental Disorders - We hypothesized that autistic adults may be erroneously judged as deceptive or lacking credibility due to demonstrating unexpected and atypical...     

Comparison of rectilinear biphasic waveform with biphasic truncated exponential waveform in a pediatric defibrillation model

OBJECTIVE: To compare the rectilinear biphasic waveform with a biphasic truncated exponential waveform for pediatric defibrillation. DESIGN: Prospective, randomized study. SETTING: Experimental laboratory of a university-affiliated research institute. SUBJECTS: Male domestic piglets (4-24 kg). INTERVENTIONS: Eleven piglets (4-8 kg), which represented a patient <1 yr old, and ten piglets (16-24 kg), which represented a pediatric patient between the ages of 2 and 8 yrs, were anesthetized, intubated, and mechanically ventilated. Ventricular fibrillation was induced and maintained for 30 secs, and a predetermined shock was then delivered to defibrillate. Following defibrillation, the animal was permitted to stabilize hemodynamically for 4 mins. Fifty shocks were applied to each animal using a randomization schedule based on a predetermined permutation of 50. The 50 shocks were 25 shocks for each rectilinear biphasic and biphasic truncated exponential waveforms, comprising five shocks at five energy settings. Each group of five shocks was fixed at a predetermined energy value, depending on the body weight of the animal. Dose-response curves were constructed using logistic regression. Aortic pressure, electrocardiogram, left ventricular pressure, and left ventricular pressure value of 40 mm Hg were continually measured. MEASUREMENTS AND MAIN RESULTS: Dose-response curves determined defibrillation thresholds at 50% (D50) and 90% (D90) probability of success. The rectilinear biphasic waveform defibrillated with <90% of the D50 and D90 energies required for a biphasic truncated exponential waveform. The rectilinear biphasic waveform also successfully defibrillated with significantly less energy per body weight and per heart weight compared with a biphasic truncated exponential waveform. CONCLUSIONS: The rectilinear biphasic waveform has superior defibrillation performance compared with a biphasic truncated exponential waveform in a piglet defibrillation model for young children.     

Association between tetracycline or doxycycline and hepatotoxicity: a population based case-control study

BACKGROUND AND OBJECTIVE: An FDA Working Group, along with representatives of PhRMA and the American Association for the Study of Liver Diseases, as well as the Institute of Medicine Report 'To Err is Human: Building a Safer Health Care System' have suggested that post-marketing drug surveillance is a important method to decrease adverse drug events. While tetracyclines are known to cause hepatotoxicity, no post-marketing drug surveillance studies have examined the risk of developing hepatotoxicity with tetracyclines. Therefore, the objective of this study is to determine the difference in risk of hepatotoxicity in patients receiving doxycycline or tetracycline using California Medicaid claims. METHODS: This study used a retrospective, matched case-control study using California Medicaid claims data. The cases were defined as recipients who had at least one diagnosis of hepatotoxicity any time from 1 July 1999 to 31 December 2001. One control was identified for each case, matched on age, gender and race. Logistic regression was used to determine the adjusted odds ratio (OR) and 95% confidence intervals for current users and past users of tetracycline and doxycycline. Covariates controlled for in the analysis were age, use of other hepatotoxic drugs, renal dysfunction, pregnancy, and alcohol or illicit drug use. RESULTS: A total of 3377 cases of hepatotoxicity were identified. Current users and past users of tetracycline had a statistically significant increased risk of developing hepatotoxicity (current use OR 3.70, 95% CI 1.19-11.45; past use OR 2.72, 95% CI 1.26-5.85). Current users or past users of doxycycline did not have an increased risk of developing hepatotoxicity (current use OR 1.49, 95% CI 0.61-3.62; past use OR 1.74, 95% CI 0.99-3.06). Tetracycline was commonly used for acne, acute bronchitis and upper respiratory infections. Doxycycline was commonly used for acute bronchitis, vaginitis and acne. DISCUSSION AND CONCLUSION: Doxycycline was potentially less hepatotoxic than tetracycline. Doxycycline could potentially be a safe substitute for tetracycline, when appropriate.     

Hair Mercury and Fish Consumption in Residents of O‘ahu,Hawai‘i

Recent studies have established that men are susceptible to cardiotoxicity from methylmercury exposure, which also poses risks to the pregnant woman. Hair samples were obtained and questionnaires for methylmercury exposure assessment were administered to 110 adults (57 men, 53 women) throughout O‘ahu, Hawai‘i during December 2010 to January 2011. Hair samples were analyzed for total mercury with a direct mercury analyzer. Men ≥ 46 years had a median of 2.0 µg/g, which was above the reference dose of 1 µg/g, as compared to younger men with a median 1.0 µg/g (P < 0.05). Hair concentrations from older women had a median of 1.2 µg/g of mercury compared to 0.6 µg/g for younger women. Additionally, 38% of women of childbearing age had a Hazard Index > 1.0. This indicates that both men and women were at risk for excessive methylmercury exposure. In the final regression model, male gender, age > 45 years, length of residency > 10 years in Hawai‘i, and fish consumption frequency > 1 meal per week were significant factors in increased hair mercury levels. Following safe fish consumption practices allows residents to reap health benefits of fish consumption without excessive toxicant exposure.