A patient with primary human immunodeficiency virus infection who presented with acute rhabdomyolysis.

Primary human immunodeficiency virus (HIV) infection is usually symptomatic, and infected patients can present with a variety of symptoms. We describe a 51-year-old man who presented at our hospital with acute self-limited rhabdomyolysis and who was found to have primary HIV infection. Our case and other reports suggest that a diagnosis of primary HIV infection needs to be considered for patients who present with acute rhabdomyolysis.

Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase.

Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.

Episodes of high coarse particle concentrations are not associated with increased mortality.

Fine particle concentration (i.e., particles <2.5 microm in aerodynamic diameter; PM2.5), but not coarse particle concentration, was associated with increased mortality in six U.S. cities. Others criticized this result, arguing that it could result from differences in measurement error between the two size ranges. Fine particles are primarily from combustion of fossil fuel, whereras coarse particles (i.e., particles between 2.5 and 10 microm in aerodynamic diameter) are all crustal material, i.e., dust. One way to determine if coarse particles are a risk for mortality is to identify episodes of high concentrations of coarse, but not fine, particles. Spokane, Washington, is located in an arid area and is subject to occasional dust storms after crops have been harvested. Between 1989 and 1995, we identified 17 dust storms in Spokane. The 24-hr mean PM10 concentration during those storms was 263 microg/m3. Using control dates that were the same day of the year in other years (but with no dust storm on that day) and that had a mean PM10 concentration of 42 microg/m3, we compared the rate of nonaccidental deaths on the episode versus nonepisode days. There was little evidence of any risk [relative risk (RR) = 1.00; 95% confidence interval (CI), 0.81-1.22] on the episode days. Defining episode deaths as those occurring on the same or following day as the dust storm produced similar results (RR = 1.01; CI, 0.87-1.17). Sensitivity analyses, which tested more extensive seasonal control, produced smaller estimates. We conclude that coarse particles from windblown dust are not associated with mortality risk.

Total synthesis of taxol.

Taxol, a substance originally isolated from the Pacific yew tree (Taxus brevifolia) more than two decades ago, has recently been approved for the clinical treatment of cancer patients. Hailed as having provided one of the most significant advances in cancer therapy, this molecule exerts its anticancer activity by inhibiting mitosis through enhancement of the polymerization of tubulin and consequent stabilization of microtubules. The scarcity of taxol and the ecological impact of harvesting it have prompted extension searches for alternative sources including semisynthesis, cellular culture production and chemical synthesis. The latter has been attempted for almost two decades, but these attempts have been thwarted by the magnitude of the synthetic challenge. Here we report the total synthesis of taxol by a convergent strategy, which opens a chemical pathway for the production of both the natural product itself and a variety of designed taxoids.