Former Foster System Youth: Perspectives on Transitional Supports and Programs

The Journal of Behavioral Health Services & Research - Youth aging out of the foster care system have well-documented challenges when transitioning to adulthood. Multiple transition services...     

Surgery is a safe,effective first-line treatment modality for noninvasive prolactinomas

Pituitary - Dopamine agonists (DAs) have long been the recommended first-line treatment for prolactinoma. Given the remarkable developments in surgical techniques, however, surgery is on the rise....     

Malaria-infected mice are cured by a single dose of novel artemisinin derivatives

We disclose here for the first time the curative activity of a new generation of trioxane dimers, designed logically and prepared easily from the natural trioxane artemisinin in only four or five chemical steps that would be easily accomplished also on a manufacturing scale. Four of these trioxane dimers cure malaria-infected mice after only a single subcutaneous dose, and two other dimers cure after three oral doses.     

Persons Who Failed to Obtain Colorectal Cancer Screening Despite Participation in an Evidence-Based Intervention

In a previous report, we demonstrated the efficacy of an educational intervention focused on increasing colorectal cancer screening rates among African Americans. Despite participating in the intervention, however, nearly two-thirds of participants did not seek and receive screening. Participants were African-Americans over age 49 (N = 257) who had not been screened for colorectal cancer according to guidelines. At baseline, participants completed tests measuring fatalism, perceived stress, self-esteem, attitudes/benefits/barriers, social support, and social network diversity. Those who completed the educational intervention were followed up by telephone to learn if they had been screened. We compared the scores on the psychometric tests of the participants who had been screened against the scores of those who had not. Only the mean scores on the attitudes, benefits, and barriers scale distinguished participants who had been screened from those who had not (p = 0.0816 on bivariate testing and p = 0.0276 in the logistic regression model). Social interaction among participants or social cognitive learning may have played a role in determining which participants were screened, but we were not able to demonstrate this. The major factor distinguishing participants who were not screened was their attitude toward screening at baseline. There is a subset of African Americans who are persistently resistant to screening, and their perspective in this regard must be addressed if colorectal cancer disparities are to be reduced.     

Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance

Insulin resistance is a cornerstone of obesity-related complications such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of serotonin (5-hydroxytryptamine [5-HT]) signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in epididymal white adipose tissue, resulting in increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone-sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.     

Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661

PSI-353661, a phosphoramidate prodrug of 2′-deoxy-2′-fluoro-2′-C-methylguanosine-5′-monophosphate, is a highly active inhibitor of genotype 1a, 1b, and 2a HCV RNA replication in the replicon assay and of genotype 1a and 2a infectious virus replication. PSI-353661 is active against replicons harboring the NS5B S282T or S96T/N142T amino acid alterations that confer decreased susceptibility to nucleoside/tide analogs as well as mutations that confer resistance to non-nucleoside inhibitors of NS5B. Replicon clearance studies show that PSI-353661 was able to clear cells of HCV replicon RNA and prevent a rebound in replicon RNA. PSI-353661 showed no toxicity toward bone marrow stem cells or mitochondrial toxicity. The metabolism to the active 5′-triphosphate involves hydrolysis of the carboxyl ester by cathepsin A (Cat A) and carboxylesterase 1 (CES1) followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the elimination of phenol and the alaninyl phosphate metabolite, PSI-353131. Histidine triad nucleotide-binding protein 1 (Hint 1) then removes the amino acid moiety, which is followed by hydrolysis of the methoxyl group at the O⁶-position of the guanine base by adenosine deaminase-like protein 1 (ADAL1) to give 2′-deoxy-2′-fluoro-2′-C-methylguanosine-5′-monophosphate. The monophosphate is phosphorylated to the diphosphate by guanylate kinase. Nucleoside diphosphate kinase is the primary enzyme involved in phosphorylation of the diphosphate to the active triphosphate, PSI-352666. PSI-352666 is equally active against wild-type NS5B and NS5B containing the S282T amino acid alteration.     

Malaria-infected mice are cured by oral administration of new artemisinin derivatives

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6-7 postinfection. At only 3 x 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14-17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials.