Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis

A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.     

Cytotoxicity and genotoxicity of nanosized and microsized titanium dioxide and iron oxide particles in Syrian hamster embryo cells

Potential differences in the toxicological properties of nanosized and non-nanosized particles have been notably pointed out for titanium dioxide (TiO(2)) particles, which are currently widely produced and used in many industrial areas. Nanoparticles of the iron oxides magnetite (Fe(3)O(4)) and hematite (Fe(2)O(3)) also have many industrial applications but their toxicological properties are less documented than those of TiO(2). In the present study, the in vitro cytotoxicity and genotoxicity of commercially available nanosized and microsized anatase TiO(2), rutile TiO(2), Fe(3)O(4), and Fe(2)O(3) particles were compared in Syrian hamster embryo (SHE) cells. Samples were characterized for chemical composition, primary particle size, crystal phase, shape, and specific surface area. In acellular assays, TiO(2) and iron oxide particles were able to generate reactive oxygen species (ROS). At the same mass dose, all nanoparticles produced higher levels of ROS than their microsized counterparts. Measurement of particle size in the SHE culture medium showed that primary nanoparticles and microparticles are present in the form of micrometric agglomerates of highly poly-dispersed size. Uptake of primary particles and agglomerates by SHE exposed for 24 h was observed for all samples. TiO(2) samples were found to be more cytotoxic than iron oxide samples. Concerning primary size effects, anatase TiO(2), rutile TiO(2), and Fe(2)O(3) nanoparticles induced higher cytotoxicity than their microsized counterparts after 72 h of exposure. Over this treatment time, anatase TiO(2) and Fe(2)O(3) nanoparticles also produced more intracellular ROS compared to the microsized particles. However, similar levels of DNA damage were observed in the comet assay after 24 h of exposure to anatase nanoparticles and microparticles. Rutile microparticles were found to induce more DNA damage than the nanosized particles. However, no significant increase in DNA damage was detected from nanosized and microsized iron oxides. None of the samples tested showed significant induction of micronuclei formation after 24 h of exposure. In agreement with previous size-comparison studies, we suggest that in vitro cytotoxicity and genotoxicity induced by metal oxide nanoparticles are not always higher than those induced by their bulk counterparts.     

Response from lieberman and colleagues

Respond on comments on Lieberman's article: Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice. Environ Health Perspect 107:161-165     

Risk selection and benefits in the Medicare+Choice program

We estimate the relation between enhanced benefits offered by the Medicare+Choice (M+C) plan in 1999 and a measure of risk selection based on inpatient encounter data. Higher risks are attracted to plans that offer outpatient drug coverage. The risk score increases by 2.2 percent for drug coverage with an annual limit less than $800 and by 3.6 percent for coverage with a limit more than $800. However, some benefits such as dental coverage were related to favorable risk selection. If M+C plans competed on the basis of benefits and premiums, as they would if they could give untaxed premium rebates, benefits that attract high risks would be underprovided.     

Trichinella infection and clinical disease

Trichinellosis is caused by ingestion of insufficiently cooked meat contaminated with infective larvae of <it>Trichinella</it> species. The clinical course is highly variable, ranging from no apparent infection to severe and even fatal disease. We report two illustrative cases of trichinellosis. Returning to Denmark a few days after having eaten roasted pork in the Republic of Serbia, a female patient suffered from severe vomiting, epigastric pain, diarrhoea, and later myalgia, generalized oedema, and prostration. A biopsy showed heavy infestation with <it>Trichinella spiralis</it>, 2000 larvae/g of muscle. Life-threatening cardiopulmonary, renal and central nervous system complications developed. The patient recovered after several months. Her husband, who also ate the pork, did not have clinical symptoms, but an increased eosinophil count and a single larva in a muscle biopsy confirmed infection. The epidemiology, clinical manifestations, diagnosis, treatment and prevention of trichinellosis are reviewed.      

The dynamic cardiac biosimulator: A method for training physicians in beating-heart mitral valve repair procedures

Objective

Previously, cardiac surgeons and cardiologists learned to operate new clinical devices for the first time in the operating room or catheterization laboratory. We describe a biosimulator that recapitulates normal heart valve physiology with associated real-time hemodynamic performance.

The CLEAR Study: A 5-day, 3-g Loading Dose of Mycophenolate Mofetil versus Standard 2-g Dosing in Renal Transplantation

Background and objectives: Adequate early mycophenolic acid (MPA) exposure is associated with lower rates of acute rejection in renal transplantation. The aim of this randomized controlled trial was to determine if higher initial mycophenolate mofetil (MMF) doses increased the proportion of patients reaching therapeutic MPA levels (30 to 60 mg·h/L) by day 5.Design, setting, participants, & measurements: De novo renal transplant patients were randomized to receive intensified dosing of MMF (1.5 g twice daily on days 1 to 5, then 1.0 g twice daily) or standard dosing (1.0 g twice daily). All recipients received tacrolimus and prednisone. Full MPA areas under the curve (AUCs) were completed on days 3 and 5, whereas a limited sampling strategy was utilized at four subsequent time points.Results: At day 5, 47.5% of the MMF 3-g arm achieved the MPA therapeutic window versus 54.4% of the MMF 2-g arm. However, MPA AUC levels were significantly higher in the 3-g arm at day 3 and 5. This resulted in a trend for fewer treated acute rejections at 6 months. Significantly more acute rejections (treated, biopsy-proven including and excluding borderline) occurred in patients with MPA AUC levels <30 mg·h/L compared with those ≥30 mg·h/L at day 5. No significant differences were seen in common adverse events.Conclusions: A limited intensified dose of MMF increased early MPA exposure and was well tolerated. Further studies are required to determine whether limited intensified MMF dosing can reduce acute rejection.Mycophenolate mofetil (MMF, CellCept^®) is an effective immunosuppressant and a key component of the immunosuppression regimen in most renal allograft recipients (1,2). A recent review and preliminary meta-analysis showed that overall graft survival is better with MMF compared with azathioprine when administered with calcineurin inhibitors (3,4). Traditionally, MMF is administered as a fixed dose without therapeutic drug monitoring (TDM). It remains unclear what role TDM of MMF has in improving graft and patient outcomes.There is a growing body of evidence supporting the utility of TDM. The drug has a large interpatient variability, with a 6-fold variation for a fixed daily dose (5). Van Gelder and his colleagues demonstrated a clear dose-effect relationship between acute rejection and 12-hour mycophenolic acid (MPA) area under the curve (AUC) exposures (6). MPA AUC values between 30 and 60 mg·h/L are proposed to be the target therapeutic window for patients treated with cyclosporine and prednisone (5). However, nearly 50% of cyclosporine-treated subjects are below the therapeutic target within the first week when administered the standard MMF dose of 2 g daily posttransplantation (7). More recently, a randomized controlled trial demonstrated that a concentration-controlled arm (dosed to achieve a mean exposure of 45 mg·h/L) resulted in significantly less rejection as compared with a standard-dosed arm (8).However, TDM is problematic given the poor correlation with any convenient single point concentration and AUC (5). Furthermore, there is some evidence that early exposure is important, with day-3 values being better predictors of acute rejection as compared with later values (7,9). Accordingly, clinicians would need to monitor exposure early and aim to intensify treatment within the first 3 days. Nonsteady-state conditions and the requirement for rapid turnaround times make TDM problematic in the early posttransplantation period. Alternatively, higher initial doses could either be given during the early critical period or until TDM can be performed. However, the safety profile of this approach is unknown. In addition, tacrolimus is now the most commonly used calcineurin inhibitor in the United States and there is limited information on MMF exposure when used in combination with tacrolimus (2,10).This study compared the ability of early, intensified, but limited-duration MMF dosing to increase the number of patients adequately exposed to MPA within the first week posttransplantation as compared with standard dosing in renal transplant recipients treated with tacrolimus.     

Hepatitis B Immunisation in Health Care Workers

Background

Hepatitis B virus (HBV) infection is an important occupational risk in health care workers (HCW). In spite of HBV vaccine availability in Armed Forces, the high prevalence of HBV infection in HCW continues to be a problem. The study was undertaken to study the HBV vaccine-compliance among HCW.

Methods

A cross-sectional study was conducted at a tertiary care hospital. HCW were requested to fill up the pre set questionnaire to assess the HBV vaccination coverage.

Result

Amongst 254 HCW, only 57.7% were vaccinated against HBV. The vaccine compliance was lowest among housekeeping professionals. The mean age at vaccination was high (30.5 years). Amongst the vaccine non-compliant subjects, 34.3% were above 30 years of age. 32.2% HCW completed primary vaccination after spending more than 10 years in the profession. Accessibility of HBV vaccine, knowledge and perception of HBV risk were important factors in vaccine non-compliance.

Conclusion

Due to low and delayed HBV vaccine-compliance, HCW continue to be at the risk of occupational HBV. Health education highlighting occupational risk of HBV, accessibility of vaccine and mandatory vaccination of HCW is recommended to increase HBV vaccine compliance among HCW.Key Words: Health care workers, Hepatitis B virus, Occupational risk, Hepatitis B vaccine