Lack of effects on male fertility from a quadrivalent HPV vaccine in Sprague‐Dawley rats

BACKGROUND: Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases in both men and women. A recently developed quadrivalent HPV vaccine, Gardasil^®, has been shown to be highly effective in the prevention of several HPV‐mediated diseases. The objective of the present study was to evaluate the potential effects of the vaccine on male fertility including reproductive performance, sperm evaluations, and histology of the testes. In addition, anti‐HPV antibodies were measured during the study. METHODS: Group 1 (30 male rats) received the full human dose of vaccine (0.5 mL, ～200‐fold excess based on body weight) by intramuscular injection at 6 weeks, 3 weeks, and 3 days prior to cohabitation. Group 2 males received only 1 dose at 3 days prior to cohabitation. Additional groups (20 male rats each) were administered PBS or Merck Aluminum Adjuvant similarly to Group 1. Ten males in the vaccine‐treated groups were bled for immunogenicity assays after each dose. Twenty males per group were mated to untreated female rats. Cesarean sections were performed on Gestation Day 15 or 16. Cohabited males were necropsied and sperm count and motility were evaluated. RESULTS: There were no unscheduled deaths during the study and no evidence of toxicity in vaccine‐treated male rats. The vaccine induced a specific antibody response to the 4 HPV types after each injection. There were no effects on the cesarean‐section parameters of females or reproductive parameters of the cohabited male rats, including histomorphology of testes and epididymis, sperm count, and sperm motility. CONCLUSIONS: These results demonstrate that this quadrivalent HPV vaccine had no detectable adverse effects on routine measures of male fertility in rats. Birth Defects Res (Part B) 89:376–381, 2010. © 2010 Wiley‐Liss, Inc.     

Methamphetamine Self-Administration Is Associated with Persistent Biochemical Alterations in Striatal and Cortical Dopaminergic Terminals in the Rat

Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers.     

Race and the Culture of Anthropology

The number of panels on "multiculturalism" and "cultural studies" at the AAA's annual meetings has increased significantly. Many anthropologists believe that the discipline has been in the vanguard of debates on racism and multiculturalism, that it stands for precisely those issues raised in the "culture wars": the equal valuation of all cultures. Yet this is not the case.
Multiculturalism and cultural studies have emerged as counterdisciplinary formations which radically foreground race and racial identity precisely because anthropology cannot do so.     

Degradation of Alpha-, Beta-, and Gamma-Hexachlorocyclohexane by a Soil Bacterium under Aerobic Conditions

A Pseudomonas sp., isolated from sugarcane rhizosphere soil, readily metabolized not only alpha and gamma isomers of hexachlorocyclohexane, but also the thermodynamically more stable beta isomer, under aerobic conditions. Bacterial degradation of the three isomers led to the accumulation of a transitory metabolite and eventual release of covalently linked chlorine as chloride in stoichiometric amounts.     

Biogeography and genetic diversity of clinical isolates of Burkholderia pseudomallei in Sri Lanka

BackgroundMelioidosis is a potentially fatal infectious disease caused by Burkholderia pseudomallei and the disease is endemic in Southeast Asia and Northern Australia. It has been confirmed as endemic in Sri Lanka. Genomic epidemiology of B. pseudomallei in Sri Lanka is largely unexplored. This study aims to determine the biogeography and genetic diversity of clinical isolates of B. pseudomallei and the phylogenetic and evolutionary relationship of Sri Lankan sequence types (STs) to those found in other endemic regions of Southeast Asia and Oceania.MethodsThe distribution of variably present genetic markers [Burkholderia intracellular motility A (bimA) gene variants bimA_BP/bimA_BM, filamentous hemagglutinin 3 (fhaB3), Yersinia-like fimbrial (YLF) and B. thailandensis-like flagellum and chemotaxis (BTFC) gene clusters and lipopolysaccharide O-antigen type A (LPS type A)] was examined among 310 strains. Multilocus sequence typing (MLST) was done for 84 clinical isolates. The phylogenetic and evolutionary relationship of Sri Lankan STs within Sri Lanka and in relation to those found in other endemic regions of Southeast Asia and Oceania were studied using e BURST, PHYLOViZ and minimum evolutionary analysis.ResultsThe Sri Lankan B. pseudomallei population contained a large proportion of the rare BTFC clade (14.5%) and bimA_BM allele variant (18.5%) with differential geographic distribution. Genotypes fhaB3 and LPSA were found in 80% and 86% respectively. This study reported 43 STs (including 22 novel). e-BURST analysis which include all Sri Lankan STs (71) resulted in four groups, with a large clonal group (group 1) having 46 STs, and 17 singletons. ST1137 was the commonest ST. Several STs were shared with India, Bangladesh and Cambodia.ConclusionThis study demonstrates the usefulness of high-resolution molecular typing to locate isolates within the broad geographical boundaries of B. pseudomallei at a global level and reveals that Sri Lankan isolates are intermediate between Southeast Asia and Oceania.     

Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers

Inactivation of p53 is present in almost every tumor, and hence, p53-reactivation strategies are an important aspect of cancer therapy. Common mechanisms for p53 loss in cancer include expression of p53-negative regulators such as MDM2, which mediate the degradation of wildtype p53 (p53α), and inactivating mutations in the TP53 gene. Currently, approaches to overcome p53 deficiency in these cancers are limited. Here, using non–small cell lung cancer and glioblastoma multiforme cell line models, we show that two alternatively spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising exons 1 to 9β or 9γ, respectively) and that lack the C-terminal MDM2-binding domain have markedly reduced susceptibility to MDM2-mediated degradation but are highly susceptible to nonsense-mediated decay (NMD), a regulator of aberrant mRNA stability. In cancer cells harboring MDM2 overexpression or TP53 mutations downstream of exon 9, NMD inhibition markedly upregulates p53β and p53γ and restores activation of the p53 pathway. Consistent with p53 pathway activation, NMD inhibition induces tumor suppressive activities such as apoptosis, reduced cell viability, and enhanced tumor radiosensitivity, in a relatively p53-dependent manner. In addition, NMD inhibition also inhibits tumor growth in a MDM2-overexpressing xenograft tumor model. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in p53-deficient tumors bearing MDM2 overexpression or p53 mutations downstream of exon 9, subgroups that comprise approximately 6% of all cancers.