Does treatment response to ambrisentan vary by pulmonary arterial hypertension severity? Implications for clinicians and for the design of future clinical trials.

BACKGROUND: Recent clinical trials in pulmonary arterial hypertension have included World Health Organization functional classes I and II patients. However, the impact of baseline functional class and other measures of severity on outcomes has not been evaluated in detail. METHODS: Outcomes at 12 weeks for patients grouped by functional class, haemodynamics, brain natriuretic peptide (BNP) level and 6-min walk distance (6MWD) were evaluated for patients in the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter Efficacy Study 1 and 2 (ARIES)-1 and 2 pivotal trials of ambrisentan, a once-daily oral endothelin-1 antagonist. Long-term outcomes in the ARIES-E extension study were also evaluated. RESULTS: At 12 weeks, ambrisentan-treated patients with both early and late functional class showed similar improvement in 6MWD relative to placebo. However, patients with more severe disease tended to have greater improvement in 6MWD after grouping by other measures of severity. This included higher baseline BNP level, shorter baseline 6MWD and more severe baseline haemodynamics (p < 0.05 for BNP and p = NS for other comparisons, analysed as interaction terms). During long-term open label follow-up, maintenance of 6MWD improvement, freedom from clinical worsening and survival were also numerically worse for patients who were functional class III/IV at baseline. CONCLUSIONS: Patients with both less severe and more severe PAH benefited from ambrisentan therapy vs. placebo in 12-week clinical trials and during long-term follow up, but greater improvement vs. placebo was seen for those with higher BNP levels.

Nanocrystalline forsterite for biomedical applications: synthesis, microstructure and mechanical properties.

Forsterite (Mg2SiO4) because of its exceptionally high fracture toughness which is close to that of cortical bones has been nominated as a possible successor to calcium phosphate bioceramics. Recent in vitro studies also suggest that forsterite possesses good bioactivity and promotes osteoblast proliferation as well as adhesion. However studies on preparation and sinterability of nanocrystalline forsterite remain scarce. In this work, we use a solid-state reaction with magnesium oxide (MgO) and talc (Mg3Si4(OH)2) as the starting precursors to synthesize forsterite. A systematic investigation was carried out to elucidate the effect of preparatory procedures including heat treatment, mixing methods and sintering temperature on development of microstructures as well as the mechanical properties of the sintered forsterite body.

Sensitivity of Mycosphaerella fijiensis from Banana to Trifloxystrobin.

An ascospore germination method was developed and validated to assess the sensitivity of bulk samples of Mycosphaerella fijiensis to trifloxystrobin. Using this method, the sensitivity of 142 ascospore samples from banana plantations not treated with strobilurins was analyzed to establish a baseline of pathogen sensitivity. A bulk method was utilized for monitoring purposes because it avoids potential complications due to the isolation and propagation of single-spore isolates and enables the testing of larger samples. Following intensive use of strobilurins (6 to 11 applications per year) over 4 years, under conditions of high disease pressure and the absence of sanitary measures at a development site in Costa Rica, bulk samples with 50% effective concentration (EC50) resistance factors (RFs) in excess of 500 compared with the mean baseline sensitivity were detected. Single-ascospore isolates derived from spores germinating at the discriminatory dose of 3 µg/ml were also resistant, suggesting that the frequency of resistant individuals in bulk samples could be estimated from the relative numbers of ascospores growing at this dose. The resistance of selected isolates was confirmed in planta. In vitro tests with four resistant and two sensitive single-ascospore isolates collected from different locations and times indicated possible cross-resistance of trifloxystrobin to azoxystrobin, famoxadone, and fenamidone, but not to propiconazole.

Invasive cervical cancer in human immunodeficiency virus-infected and uninfected hospital patients.

OBJECTIVE: To compare the prevalence of invasive cervical cancer in women with, and in women without, human immunodeficiency virus (HIV) infection, so as to evaluate the inclusion of invasive cervical cancer in the AIDS surveillance case definition. METHODS: The Sentinel Hospital Surveillance System for HIV Infection collected data and serum specimens that remained after clinical testing of persons who received inpatient or outpatient care at 14 hospitals with high HIV prevalence. We analyzed data on invasive cervical cancer obtained from medical record review and HIV serostatus from white, black, and Hispanic women in the age groups 20-34, 35-44, and 45-54 years. RESULTS: In 1994 and 1995, 2684 (6.6%) of the 40,524 women sampled were HIV infected. Of the HIV-positive women, 28 had invasive cervical cancer (10.4 per 1000 women) and of the HIV-negative women, 236 had invasive cervical cancer (6.2 per 1000 women, relative risk [RR] 1.7, 95% confidence interval [CI] 1.1, 2.5). The prevalence of invasive cervical cancer was higher for HIV-positive than for HIV-negative black women aged 20-34 (RR 3.8; CI 1.7, 8.5) and Hispanic women aged 20-34 (RR 7.3; CI 1.4, 37.1) and 35-44 (RR 3.9; CI 1.1, 14.7) years. Twenty-six of the 28 cases of invasive cervical cancer in HIV-positive women were in women known to be HIV-positive during admission. CONCLUSION: The prevalence of invasive cervical cancer was higher for women who were HIV positive than for women who were HIV negative. This lends support to the inclusion of invasive cervical cancer in the revision of the surveillance case definition for AIDS in 1993.

Cross-reactivity of monovalent and polyvalent Trimeresurus antivenoms with venoms from various species of Trimeresurus (lance-headed pit viper) snake.

Trimeresurus bite is a serious medical problem in Asia. However, at present only a few monospecific Trimeresurus antivenoms are available. Investigation of the cross-neutralization capacity of three Trimeresurus antivenoms indicates that the antivenoms exhibit broad cross-reactivity. A polyvalent Trimeresurus antivenom was also found to be effective in neutralization of the haemorrhagic, necrotizing and thrombin-like activities of heterologous Trimeresurus venoms.

Radioimmunoassays for cannabinoids.

The simplicity, sensitivity, and specificity of radioimmunoassay have made it an attractive procedure for the analysis of delta-9-tetrahydrocannabinol (THC) in biological fluids or tissues. The presence of closely related compounds such as metabolites may interfere with radioimmunoassay results. Appropriate design of immunogens may diminish such interference. This work has been directed towards the use of the amyl side chain for linking cannabinoid compounds to proteins to form immunogens. Although the amyl side chain is metabolized to some extent, the metabolites are not quantitatively significant in most cases. 5'-Carboxy-delta-8-THC and 5'-carboxy-delta-9-THC were linked to bovine serum albumin. Immunization of rabbits with the resulting conjugates resulted in the formation of antisera with high selectivity for delta-9-THC vs. its carboxylic acid metabolite, 11-nor-9-carboxy-delta-9-THC. Delta-8-THC radioligands (4',5'-tritium and 5'-iodine-125) could be used with these antisera for analysis of delta-9-THC in plasma. Sensitivity with tritium-labeled material is about 2.5 ng/ml. 5'-Oxo-11-nor-9-carboxy-delta-8-THC was used to prepare an immunogen which led to the generation of an antiserum highly specific for 11-nor-9-carboxy-delta-9-THC. This antiserum and iodine-125-5'-iodo-11-nor-9-carboxy-delta-8-THC were used to develop a highly specific assay for 11-nor-9-carboxy-delta-9-THC in plasma.