Reproductive toxicity of emerging plasticizers, flame retardants, and bisphenols, using culture of the rat fetal testis†.

The use of bis (2-ethylhexyl) phthalate (DEHP), 2,2'4,4'-tetrabromodiphenyl ether (BDE47), and bisphenol A (BPA), as plasticizers, flame retardants, and epoxy resins, respectively, has been regulated due to their endocrine disrupting activities. Replacements for these chemicals are found in human matrices, yet the endocrine disrupting potential of these emerging contaminants is poorly characterized. We compared the effects of legacy chemicals with those of their replacements using fetal rat testis organ culture. Fetal testes sampled at gestation day 15 were grown ex vivo, and the impact was evaluated after a 3-day exposure to 10 µM of each legacy chemical; two BPA analogs (bisphenol M and bisphenol TMC); three replacements for DEHP/MEHP (2,2,4-trimethyl-1,3-pentanediol diisobutyrate, diisononyl-phthalate, and diisodecyl adipate); or two replacements for BDE47 (tributoxyethyl phosphate and isopropylated triphenyl phosphate). We showed that only BPA and MEHP significantly decrease testosterone secretions after 24 h, while BPM and BPTMC have the opposite effect. Luteinizing hormone-stimulated testosterone was reduced by BPA and MEHP but was increased by BPTMC. After exposure, testes were used for immunofluorescent staining of germ cells, Sertoli cells, and Leydig cells. Interestingly, exposures to BPM or BPTMC induced a significant increase in the Leydig cell density and surface area. A decrease in germ cell density was observed only after treatment with MEHP or BDE47. MEHP also significantly decreased Sertoli cell proliferation. These studies show that some replacement chemicals can affect testicular function, while others appear to show little toxicity in this model. These findings provide essential information regarding the need for their regulation.

Cellular senescence limits translational readthrough.

The origin and evolution of cancer cells is considered to be mainly fueled by DNA mutations. Although translation errors could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called caretakers block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretaker genes should prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the process of cellular senescence induced by oncogenes, tumor suppressors or chemotherapeutic drugs is associated with a reduction in translational readthrough (TR) measured using reporters containing termination codons withing the context of both normal translation termination or programmed TR. Senescence reduced both basal TR and TR stimulated by aminoglycosides. Mechanistically, the reduction of TR during senescence is controlled by the RB tumor suppressor pathway. Cells that escape from cellular senescence either induced by oncogenes or chemotherapy have an increased TR. Also, breast cancer cells that escape from therapy-induced senescence express high levels of AGO1x, a TR isoform of AGO1 linked to breast cancer progression. We propose that senescence and the RB pathway reduce TR limiting proteome diversity and the expression of TR proteins required for cancer cell proliferation.

"The uncertainty is what is driving me crazy": the tripartite model of uncertainty in the adolescent and young adult cancer context.

Building on scholarship indicating that uncertainty is a fundamental component of the cancer experience, this study focuses on an understudied population: adolescents and young adults (AYAs) with cancer. Because AYAs' health outcomes lag behind those of older and younger people with cancer, scholars have recommended that the subjective experiences of AYAs be better understood. Using the tripartite model of uncertainty sources as a guiding framework, we analyzed naturally occurring messages from an online discussion forum for AYA cancer survivors. The majority of messages communicating uncertainty expressed medical uncertainty regarding the complexities of understanding treatment options and sequelae. Results indicated that several overarching areas of AYA uncertainty correspond to themes reported by other cancer populations, but that some distinctive concerns arise amid the normative complexities of late adolescence and young adulthood.

Cognitive stimulation programs in healthy elderly: a review.

This literature paper investigated the efficacy of 14 cognitive intervention programs administered to healthy elderly participants. PsycINFO and PubMed databases were searched using the following terms: cognitive training, cognitive stimulation, elderly, and aging. The majority of participants (13/14 studies) were recruited in community. Nine out of 14 studies targeted memory as the principal cognitive function to train or stimulate. Face-name associations, mental imagery, paired associations, and the method of loci were the main techniques taught to participants. Improvements were observed on at least one outcome measure in each study included in this paper. Recommendations to improve cognitive interventions in the healthy elderly are proposed, such as the utilization of more robust experimental designs, the inclusion of measures of generalization of training in daily life, the assessment of instrumental activities of daily living, quality of life, and self-esteem.

Differentiation of the pattern of cognitive impairment between depressed and non-depressed patients with dementia living in long-term care facilities.

OBJECTIVE: The principal objective of this study is to examine the cognitive profile of patients with dementia plus (D+ group) and without (D- group) concomitant depression. METHOD: The D+ (N = 61) and D- (N = 89) patients were recruited in long-term care facilities. The depression status of the participants was determined using the Cornell Scale for Depression in Dementia. Cognitive functioning was assessed using the Hierarchic Dementia Scale (HDS). RESULTS: The analyses first indicated that on the total HDS score, patients of the D+ group exhibited more severe cognitive impairment compared to those of the D- group. Further analyses revealed that the difference between groups pertained to perception, attention/memory, calculation, and language functions. Moreover, secondary analyses revealed that the cognitive deficits of the D+ group were associated with behavioral (agitation and retardation, in particular), but not with mood-related, symptoms of depression. Interestingly, ideational symptoms of depression (suicide and self-depreciation, in particular) were positively correlated with cognitive impairment. CONCLUSION: These findings add to those of previous studies showing that D+ and D- patients differ not only regarding the presence or absence of depressive symptoms, but also regarding cognitive manifestations. This study thus reinforces the need to detect and treat accurately depression in dementia.

Thalamic-prefrontal cortical-ventral striatal circuitry mediates dissociable components of strategy set shifting.

The mediodorsal nuclei of thalamus (MD), prefrontal cortex (PFC), and nucleus accumbens core (NAc) form an interconnected network that may work together to subserve certain forms of behavioral flexibility. The present study investigated the functional interactions between these regions during performance of a cross-maze-based strategy set-shifting task. In Experiment 1, reversible bilateral inactivation of the MD via infusions of bupivacaine did not impair simple discrimination learning, but did disrupt shifting from response to visual cue discrimination strategy, and vice versa. This impairment was due to an increase in perseverative errors. In Experiment 2, asymmetrical disconnection inactivations of the MD on one side of the brain and PFC on the other also caused a perseverative deficit when rats were required to shift from a response to a visual cue discrimination strategy, as did disconnections between the PFC and the NAc. However, inactivation of the MD on one side of the brain and the NAc contralaterally resulted in a selective increase in never-reinforced errors, suggesting this pathway is important for eliminating inappropriate strategies during set shifting. These data indicate that set shifting is mediated by a distributed neural circuit, with separate neural pathways contributing dissociable components to this type of behavioral flexibility.

Pharmacoscintigraphic assessment of the regional drug absorption of the dual angiotensin-converting enzyme/neutral endopeptidase inhibitor, M100240, in healthy volunteers.

M100240 is the thioester of MDL 100,173, a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor currently in phase II development. The purpose of this study was to evaluate the relative bioavaibility of M100240 in various regions of the gastrointestinal tract using the Enterion capsule, a noninvasive radiocontrolled device providing targeted drug delivery, to explore the absorption characteristics of M100240 in healthy volunteers. In addition, the absolute bioavailability of an immediate-release formulation of M100240 was assessed. Pharmacokinetic data were obtained from 13 healthy subjects in an open-label, single-dose, randomized, five-period crossover study. Treatments included 25 mg M100240 administered via short intravenous infusion, oral immediate-release tablet administration, and oral Enterion capsule delivery of drug substance to the proximal small bowel, distal small bowel, and ascending colon. Each treatment was separated by a 14-day drug-free washout period. The localization of the Enterion capsule in the gastrointestinal tract was monitored using scintigraphic imaging. M100240 and MDL 100,173 plasma concentrations were quantified using a validated LC/MS/MS method, and pharmacokinetic parameters were calculated using noncompartmental methods. The estimates of relative bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the oral immediate-release tablet are approximately 94%, 97%, and 41%, respectively. M100240 is primarily absorbed throughout the proximal and distal small bowel with modest absorption in the ascending colon. The absolute bioavailability estimate of the M100240 immediate-release formulation is 49%. These data characterize the fundamental in vivo performance attributes of M100240, thereby providing an approach for optimizing prototype modified-release formulations for this compound.