Effect of age on susceptibility to azoxymethane-induced colonic aberrant crypt foci formation in C57BL/6JNIA mice

To determine the effect of age on susceptibility to azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation and its underlying mechanism, young and old mice were injected with AOM weekly for 4 or 5 weeks and euthanized 5 or 6 weeks later. Given the same (12 or 15) mg/kg body weight dose of AOM, old mice had significantly more ACF than young mice. However, given the same total dose of AOM (to avoid confounding effect of higher dose to heavier old mice), at a low total dose (1.5 mg) there was no age difference, but at higher total doses (1.8 and 2.2 mg) young mice had significantly more ACF than old mice. These results indicate that the age-related susceptibility to AOM differs depending on whether administration of the carcinogen is based on weight or total dose. These age differences are not due to variations in cyclooxygenase-2 expression, cell proliferation, or AOM hydroxylase activity.     

Brain Gray and White Matter Volume Loss Accelerates with Aging in Chronic Alcoholics: A Quantitative MRI Study

Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.     

Parent's anxiety links household stress and young children's behavioral dysregulation

Young children rely heavily on their caregivers to gain information about the environment, especially during times of duress. Therefore, considering parental assessments of behavior in the context of stressful environments may better facilitate our understanding of the longstanding association between early environmental stressors and changes in child behavior and physiology. Confirming many previous reports, a higher degree of household stress exposure was associated with elevated mental health symptoms in 2‐ to 6‐year‐old children (N = 115; anxiety and externalizing behaviors), which were verified in a subset of children with laboratory‐based behaviors (N = 46). However, these associations were mediated by parental anxiety symptoms, which were also associated with increased cortisol levels in children. A closer look at the stressors indicated that it was the adult‐targeted, and not the child‐targeted, stressors that correlated most with children's behavior problems. These results highlight the importance of considering the mediating effect of parents, when examining associations between household stress and young children's behavioral development.     

Effect of a 12-week weight management program on the clinical characteristics and dietary intake of the young obese and the contributing factors to the successful weight loss

BACKGROUND/OBJECTIVES

The objectives were to investigate the effect of a 12-wk intervention with behavioral modification on clinical characteristics and dietary intakes of young and otherwise healthy obese and to identify factors for successful weight loss. The goal was to lose 0.5 kg per week by reducing 300-500 kcal/day and by increasing physical activities.

SUBJECTS AND METHODS

Forty four obese subjects (BMI > 25) and 19 normal weight subjects (BMI 18.5-23) finished the 12-week intervention. Obese subjects participated in 5 group educations and 6 individual counseling sessions. Normal weight subjects attended 6 individual counseling sessions for evaluations of dietary intake and exercise pattern. Anthropometric and clinical characteristics and 3-day dietary records were evaluated at baseline and week12.

RESULTS

Weight and serum triglyceride and free fatty acid concentrations in obese group decreased significantly with intervention. Intakes of energy, fat, and cholesterol decreased significantly in the obese. Active participation, realistic weight loss goal setting, and weight gain after high school graduation not during childhood were identified as key factors for successful weight loss.

CONCLUSIONS

The 12-week intervention with behavioral modification resulted in reduced energy and fat intakes and led to significant weight loss and improvements of clinical characteristics in the obese. The finding that those who became obese during childhood lost less weight indicates the importance of ''early'' intervention.     

Synthesis of new piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction

Two series of piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives were prepared via a Buchwald–Hartwig cross-coupling reaction and then evaluated for their ability to inhibit the drug efflux activity of CaCdr1p and CaMdr1p transporters of Candida albicans overexpressed in a Saccharomyces cerevisiae strain. In the initial screening of twenty-nine piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives, twenty-three compounds behaved as dual inhibitors of CaCdr1p and CaMdr1p. Only four compounds showed exclusive inhibition of CaCdr1p or CaMdr1p. Further biological investigations were developed and for example, their antifungal potential was evaluated by measuring the growth of control yeast cells (AD1-8u⁻) and efflux pump-overexpressing cells (AD-CDR1 and AD-MDR1) after exposition to variable concentrations of the tested compounds. The MIC₈₀ values of nineteen compounds ranging from 100 to 901 μM for AD-CDR1 demonstrated that relative resistance index (RI) values were between 8 and 274. In comparison, only seven compounds had RI values superior to 4 in cells overexpressing Mdr1p. These results indicated substrate behavior for nineteen compounds for CaCdr1p and seven compounds for CaMdr1p, as these compounds were transported via MDR transporter overexpressing cells and not by the AD1-8u⁻ cells. Finally, in a combination assay with fluconazole, two compounds (1d and 1f) have shown a synergistic effect (fractional inhibitory concentration index (FICI) values ≤ 0.5) at micromolar concentrations in the AD-MDR1 yeast strain overexpressing CaMdr1p-protein, indicating an excellent potency toward chemosensitization.

Two series of piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives were prepared via a Buchwald–Hartwig cross-coupling reaction and then evaluated for their ability to inhibit the drug efflux activity of two Candida albicans transporters.     

Increased activation of the fear neurocircuitry in children exposed to violence

Most studies investigating the effect of childhood trauma on the brain are retrospective and mainly focus on maltreatment, whereas different types of trauma exposure such as growing up in a violent neighborhood, as well as developmental stage, could have differential effects on brain structure and function. The current magnetic resonance imaging study assessed the effect of trauma exposure broadly and violence exposure more specifically, as well as developmental stage on the fear neurocircuitry in 8‐ to 14‐year‐old children and adolescents (N = 69). We observed reduced hippocampal and increased amygdala volume with increasing levels of trauma exposure. Second, higher levels of violence exposure were associated with increased activation in the amygdala, hippocampus, and ventromedial prefrontal cortex during emotional response inhibition. This association was specifically observed in children younger than 10 years. Finally, increased functional connectivity between the amygdala and brainstem was associated with higher levels of violence exposure. Based on the current findings, it could be hypothesized that trauma exposure during childhood results in structural changes that are associated with later risk for psychiatric disorders. At the same time, it could be postulated that growing up in an unsafe environment leads the brain to functionally adapt to this situation in a way that promotes survival, where the long‐term costs or consequences of these adaptations are largely unknown and an area for future investigations.     

Differential cingulate and caudate activation following unexpected nonrewarding stimuli

This study examined the effects of varying the predictability of nonrewarding events on behavior and neural activation using a rapid mixed-trial functional magnetic resonance imagery (fMRI) design. Twelve adult subjects were scanned with echo planar imaging during performance of a visual detection task where the probability of events (target and nontarget) varied. This task included expected and unexpected nonrewarding events (expected target, unexpected nontarget, and omission of target) in a design that closely parallels studies of dopamine function and reward processing in the alert monkey. We predicted that activation in dopamine-rich areas of the forebrain would behave like the animal literature shows that dopamine neurons in the midbrain behave. Specifically, we predicted increased activity in these regions when an unexpected event occurred and decreased activity when an expected event was omitted. Two main regions, the anterior cingulate and dorsal striatum, showed this pattern. The response in these regions was distinguished by enhanced anterior cingulate activity following the occurrence of an unexpected event and greater suppression of caudate activity following the omission of an expected event. These results suggest that neural activity within specific dopamine-rich brain regions can be modulated by violations in the expectation of nonrewarding events and that the direction of the modulation depends on the nature of the violations.     

Alterations of beta-adrenoceptor responsiveness in postischemic myocardium after 72 h of reperfusion

To determine the effect of a completely developed reperfused myocardial infarction model on beta-adrenoceptor responsiveness, we induced a 90-min regional ischemia followed by 72 h of reperfusion in dog hearts. Regional myocardial blood flow was determined after 60 min of ischemia using radioactive microspheres. beta-adrenoceptor density was reduced in the ischemic endocardium (95+/-16 fmol/mg) and epicardium (160+/-13 fmol/mg) compared to the nonischemic region (304+/-21 fmol/mg). beta-adrenoceptor density in the ischemic endocardium varied with the degree of collateral blood flow measured (r2=0.79, P<0.05); this relation was the opposite of that in the ischemic epicardium (r2=0.77, P<0.05). Higher levels of tissue catecholamines and G protein-coupled receptor kinase 2 (GRK2) were observed in the ischemic epicardium as compared to nonischemic tissue. Forskolin-induced adenylyl cyclase activities were depressed in both ischemic regions as compared to nonischemic region, correlating with a reduction in regional myocardial blood flow. Using forskolin stimulation as covariate, no difference in isoproterenol-induced adenylyl cyclase activity was identified in the different regions. It is concluded that cAMP production induced by beta-adrenoceptor activation is dependent upon adenylyl cyclase enzyme activity rather than beta-adrenoceptor density in the ischemic myocardium. However, the density of the beta-adrenoceptor in the viable ischemic regions can be modified by the presence of GRK2 and tissue catecholamines, an index of regional sympathetic efferent postganglionic nerve terminal activity.