Resistance-minimizing strategies for introducing a novel antibiotic for gonorrhea treatment: a mathematical modeling study.

Background: Gonorrhea is a highly prevalent sexually transmitted infection and an urgent public health concern due to increasing antibiotic resistance. Only ceftriaxone remains as the recommended treatment in the U.S. The prospect of approval of new anti-gonococcal antibiotics raises the question of how to deploy a new drug to maximize its clinically useful lifespan. Methods: We used a compartmental model of gonorrhea transmission in the U.S. population of men who have sex with men to compare strategies for introducing a new antibiotic for gonorrhea treatment. The strategies tested included holding the new antibiotic in reserve until the current therapy reached a threshold prevalence of resistance; using either drug, considering immediate and gradual introduction of the new drug; and combination therapy. The primary outcome of interest was the time until 5% prevalence of resistance to both the novel drug and to the current first-line drug (ceftriaxone). Findings: The reserve strategy was consistently inferior for mitigating antibiotic resistance under the parameter space explored. The reserve strategy was increasingly outperformed by the other strategies as the probability of de novo resistance emergence decreased and as the fitness costs associated with resistance increased. Combination therapy tended to prolong the development of antibiotic resistance and minimize the number of annual gonococcal infections. Interpretation: Our study argues for rapid introduction of new anti-gonococcal antibiotics, recognizing that the feasibility of each strategy must incorporate cost, safety, and other practical concerns. The analyses should be revisited once robust estimates of key parameters-likelihood of emergence of resistance and fitness costs of resistance for the new antibiotic-are available. Funding: U.S. Centers for Disease Control and Prevention (CDC), National Institute of Allergy and Infectious Diseases.

Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A.

Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.

Subclinical hypervitaminosis A in rat: measurements of bone mineral density (BMD) do not reveal adverse skeletal changes.

We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

An enantioselective route to paeonilactone A via palladium- and copper-catalyzed reactions.

We herein report on a formal total synthesis of paeonilactone A involving palladium-, copper-, and enzyme-catalyzed reactions starting from 1,3-cyclohexadiene. The key step in the synthesis, a palladium(II)-catalyzed 1,4-oxylactonization of a conjugated diene, simultaneously introduces two of the oxygen substituents required for the target molecule. The synthesis also includes our recently developed copper(I)-catalyzed cross-coupling reaction between dienyltriflates with Grignard reagents, introducing one of the methyl groups present in the target molecule. This new approach toward paeonilactone A allows complete control of all four stereogenic centers and is the first enantioselective route toward paeonilactone A starting from an achiral substrate.