Early maternal deprivation reduces prepulse inhibition and impairs spatial learning ability in adulthood: No further effect of post-pubertal chronic corticosterone treatment

Prolonged maternal deprivation leads to long-term alterations in hypothalamic–pituitary–adrenal (HPA) axis activity, disturbances of auditory information processing and neurochemical changes in the adult brain, some of which are similar to that observed in schizophrenia. Here we report the adult behavioural effects of maternal deprivation (12 h on postnatal days 9 and 11) in Wistar rats on paradigms of auditory information processing (prepulse inhibition), sensitivity to dopamimetics (amphetamine-induced hyper-locomotion) and cognition (T-maze delayed alternation and Morris water-maze). In addition, we examined the long-lasting effect of chronic 21-day corticosterone treatment during the post-pubertal period (i.e., postnatal days 56–76) on each of these behavioural paradigms in maternally deprived and control rats. Behavioural testing commenced 2 weeks after the termination of corticosterone treatment. Maternal deprivation led to a significant reduction in PPI and impaired spatial learning ability in adulthood, but did not affect the behavioural response to amphetamine. Post-pubertal chronic corticosterone treatment did not have any major long-lasting effects on any of the behavioural measures in either maternally deprived or control rats. Our findings further support maternal deprivation as an animal model of specific aspects of schizophrenia.

Neurodevelopmental animal models of schizophrenia: Effects on prepulse inhibition

Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

A developmental cascade model of behavioral sleep problems and emotional and attentional self-regulation across early childhood

This paper documents the longitudinal and reciprocal relations among behavioral sleep problems, emotional and attentional self-regulation in a population sample of 4109 children participating in the Growing Up in Australia: The Longitudinal Study of Australian Children (LSAC) – Infant Cohort. Maternal reports of children’s sleep problems and self-regulation were collected at five time points from infancy to 8-9 years of age. Longitudinal structural equation modeling supported a developmental cascade model in which sleep problems have a persistent negative effect on emotional regulation, which in turn contributes to ongoing sleep problems and poorer attentional regulation in children over time. Findings suggest that sleep behaviors are a key target for interventions that aim to improve children’s self-regulatory capacities.

Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke

One hundred seventy-six consecutive patients treated with IV tissue plasminogen activator (tPA) for acute ischemic stroke were examined prospectively, and orolingual angioedema was found in nine (5.1%; 95% CI 2.3 to 9.5). The reaction was typically mild, transient, and contralateral to the ischemic hemisphere. Risk of angioedema was associated with angiotensin-converting enzyme inhibitors (relative risk [RR] 13.6; 95% CI 3.0 to 62.7) and signs on initial CT of ischemia in the insular and frontal cortex (RR 9.1; 95% CI 1.4 to 30.0).

Auditory context effects in picture naming investigated with event-related fMRI

Naming an object entails a number of processing stages, including retrieval of a target lexical concept and encoding of its phonological word form. We investigated these stages using the picture-word interference task in an fMRI experiment. Participants named target pictures in the presence of auditorily presented semantically related, phonologically related, or unrelated distractor words or in isolation. We observed BOLD signal changes in left-hemisphere regions associated with lexical-conceptual and phonological processing, including the midto-posterior lateral temporal cortex. However, these BOLD responses manifested as signal reductions for all distractor conditions relative to naming alone. Compared with unrelated words, phonologically related distractors showed further signal reductions, whereas only the pars orbitalis of the left inferior frontal cortex showed a selective reduction in response in the semantic condition. We interpret these findings as indicating that the word forms of lexical competitors are phonologically encoded and that competition during lexical selection is reduced by phonologically related distractors. Since the extended nature of auditory presentation requires a large portion of a word to be presented before its meaning is accessed, we attribute the BOLD signal reductions observed for semantically related and unrelated words to lateral inhibition mechanisms engaged after target name selection has occurred, as has been proposed in some production models.

Responses to an in-basket activity: The role of work stress, behavioral control, and informational control

This study was undertaken to examine the main and interactive effects of work stress and work control on levels of adjustment. Work stress, behavioral control, and informational control were manipulated in an experimental setting in which participants (N = 192) completed an in-basket activity. Although minimal support was found for the main and interactive effects of objective work stress, behavioral control, and informational control on adjustment, analyses involving the subjective measures of these variables revealed strong support for the proposal that work stress, behavioral control, and informational control would exert main effects on adjustment. There was also evidence that subjective levels of behavioral control buffered the negative effects of subjective work stress on positive mood, subjective task performance, and task satisfaction.

Gene regulation by translational inhibition is determined by Dicer partnering proteins

MicroRNAs (miRNAs) are small regulatory RNAs produced by Dicer proteins that regulate gene expression in development and adaptive responses to the environment1,​2,​3,​4. In animals, the degree of base pairing between a miRNA and its target messenger RNA seems to determine whether the regulation occurs through cleavage or translation inhibition1. In contrast, the selection of regulatory mechanisms is independent of the degree of mismatch between a plant miRNA and its target transcript5. However, the components and mechanism(s) that determine whether a plant miRNA ultimately regulates its targets by guiding cleavage or translational inhibition are unknown6. Here we show that the form of regulatory action directed by a plant miRNA is determined by DRB2, a DICER-LIKE1 (DCL1) partnering protein. The dependence of DCL1 on DRB1 for miRNA biogenesis is well characterized7,​8,​9, but we show that it is only required for miRNA-guided transcript cleavage. We found that DRB2 determines miRNA-guided translational inhibition and represses DRB1 expression, thereby allowing the active selection of miRNA regulatory action. Furthermore, our results reveal that the core silencing proteins ARGONAUTE1 (AGO1) and SERRATE (SE) are highly regulated by miRNA-guided translational inhibition. DRB2 has been remarkably conserved throughout plant evolution, raising the possibility that translational repression is the ancient form of miRNA-directed gene regulation in plants, and that Dicer partnering proteins, such as human TRBP, might play a similar role in other eukaryotic systems.

Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition

The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is one of the most frequently activated signaling pathways in prostate cancer cells, and loss of the tumor suppressor PTEN and amplification of PIK3CA are the two most commonly detected mechanisms for the activation of these pathways. Aberrant activation of PI3K/Akt/mTOR has been implicated not only in the survival and metastasis of prostate cancer cells but also in the development of drug resistance. As such, selective inactivation of this pathway may provide opportunities to attack prostate cancer from all fronts. However, while preclinical studies examining specific inhibitors of PI3K or mTOR have yielded promising results, the evidence from clinical trials is less convincing. Emerging evidence from the analyses of some solid tumors suggests that a class of dual PI3K/mTOR inhibitors, which bind to and inactivate both PI3K and mTOR, may achieve better anti-cancer outcomes. In this review, we will summarize the mechanisms of action of these inhibitors, their effectiveness when used alone or in combination with other chemotherapeutic compounds, and their potential to serve as the next generation therapies for prostate cancer patients, particularly those who are resistant to the frontline chemotherapeutic drugs.

Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides

The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, −OCl) generated by the myeloperoxidase (MPO)–H2O2–Cl− system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79–86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 µM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl-substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89–99% decreased rate of reduction) and activated human neutrophils (62–75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed.

High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2)

Background Matrix metalloproteinase-2 (MMP-2) is an endopeptidase that facilitates extracellular matrix remodeling and molecular regulation, and is implicated in tumor metastasis. Type I collagen (Col I) regulates the activation of MMP-2 through both transcriptional and post-transcriptional means; however gaps remain in our understanding of the involvement of collagen-binding ?1 integrins in collagen-stimulated MMP-2 activation. Methods Three ?1 integrin siRNAs were used to elucidate the involvement of ?1 integrins in the Col I-induced MMP-2 activation mechanism. ?1 integrin knockdown was analyzed by quantitative RT-PCR, Western Blot and FACS analysis. Adhesion assay and collagen gel contraction were used to test the biological effects of ?1 integrin abrogation. MMP-2 activation levels were monitored by gelatin zymography. Results All three ?1 integrin siRNAs were efficient at ?1 integrin knockdown and FACS analysis revealed commensurate reductions of integrins ?2 and ?3, which are heterodimeric partners of ?1, but not ?V, which is not. All three ?1 integrin siRNAs inhibited adhesion and collagen gel contraction, however only the siRNA showing the greatest magnitude of ?1 knockdown inhibited Col I-induced MMP-2 activation and reduced the accompanying upregulation of MT1-MMP, suggesting a dose response threshold effect. Re-transfection with codon-swapped ?1 integrin overcame the reduction in MMP-2 activation induced by Col-1, confirming the ?1 integrin target specificity. MMP-2 activation induced by TPA or Concanavalin A (Con A) was not inhibited by ?1 integrin siRNA knockdown. Conclusion Together, the data reveals that strong abrogation of ?1 integrin is required to block MMP-2 activation induced by Col I, which may have implications for the therapeutic targeting of ?1 integrin.

Inhibition by poly(acrylic acid) and morphological changes in calcium carbonate and calcium carbonate/calcium sulfate crystallization on silica fibers

An intrinsic exposed core optical fiber sensor (IECOFS) made from fused silica was used to monitor the crystallization of calcium carbonate (CaCO3) and CaCO3/calcium sulfate (CaSO4) composite at 100 and 120 °C in the absence and presence of low-molar-mass (Mn ≤ 2000) poly(acrylic acid) (PAA) with different end groups. The IECOFS responded only to deposition and growth processes on the fiber surface rather than changes occurring in the bulk of the solution. Hexyl isobutyrate-terminated PAA (Mn = 1400) and hexadecyl isobutyrate-terminated PAA (Mn = 1700) were the most effective species in preventing CaCO3 deposition. Phase transformation from vaterite to aragonite/calcite decreased with increasing hydrophobicity of the PAA end group. Low-molar-mass PAA at 10 ppm showed very significant inhibition of CaCO3/CaSO4 composite formation for all end groups investigated.

Predictors of condom use behaviour among male street labourers in urban Vietnam using a modified Information-Motivation-Behavioral Skills (IMB) model

HIV risk in vulnerable groups such as itinerant male street labourers is often examined via a focus on individual determinants. This study provides a test of a modified Information-Motivation-Behavioral Skills (IMB) model to predict condom use behaviour among male street workers in urban Vietnam. In a cross-sectional survey using a social mapping technique, 450 male street labourers from 13 districts of Hanoi, Vietnam were recruited and interviewed. Collected data were first examined for completeness; structural equation modelling was then employed to test the model fit. Condoms were used inconsistently by many of these men, and usage varied in relation to a number of factors. A modified IMB model had a better fit than the original IMB model in predicting condom use behaviour. This modified model accounted for 49% of the variance, versus 10% by the original version. In the modified model, the influence of psychosocial factors was moderately high, whilst the influence of HIV prevention information, motivation and perceived behavioural skills was moderately low, explaining in part the limited level of condom use behaviour. This study provides insights into social factors that should be taken into account in public health planning to promote safer sexual behaviour among Asian male street labourers.

Adolescent sexual behavioral intentions measurement: A gender approach in the Colombian Caribbean region [Medición de la Intención en la Actividad Sexual en Adolescentes: una Aproximación de Acuerdo al Género del Caribe Colombiano]

The study of 1777 male and female adolescent students of 11-19 years in the Colombian Caribbean had two objectives: development and validation of two reproductive health intention scales and analyze gender differences. The pilot of the scale consisted of 8 items and was reduced to 6, to check the reliability and validity using factor analysis and principal components with VARIMAX rotation yielded two factors: Intention and Intention Risk Protection, explained between 69.4% and 70% respectively. In the male Protection Intent (M = 3.87 and SD = 1.29) and risk (M = 2.56 and SD = 1.18) obtained an alpha between 0.74 and 0.86, and in Protection of Intent to female (M = 3.49 and SD = 1.35) and risk (M = 1.50 and SD = 0.89) ranged between 0.78 and 086. In conclusion, the reliability and structural stability are adequate and there are gender differences in the scales.

Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells

Hydantoin derivatives possess a variety of biochemical and pharmacological properties and consequently are used to treat many human diseases. However, there are only few studies focusing on their potential as cancer therapeutic agents. In the present study, we have examined anticancer properties of two novel spirohydantoin compounds, 8-(3,4-difluorobenzyl)-1'-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-2',5'-dione (DFH) and 8-(3,4-dichlorobenzyl)-1'-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-dione (DCH). Both the compounds exhibited dose- and time-dependent cytotoxic effect on human leukemic cell lines, K562, Reh, CEM and 8ES. Incorporation of tritiated thymidine ([H-3) thymidine) in conjunction with cell cycle analysis suggested that DFH and DCH inhibited the growth of leukemic cells. Downregulation of PCNA and p-histone H3 further confirm that the growth inhibition could be at the level of DNA replication. Flow cytometric analysis indicated the accumulation of cells at subG1 phase suggesting induction of apoptosis, which was further confirmed and quantified both by fluorescence-activated cell sorting (FACS) and confocal microscopy following annexin V-FITC/propidium iodide (PI) staining. Mechanistically, our data support the induction of apoptosis by activation of the mitochondrial pathway. Results supporting such a model include, elevated levels of p53, and BAD, decreased level of BCL2, activation and cleavage of caspase 9, activation of procaspase 3, poly (ADP-ribosyl) polymerase (PARP) cleavage, downregulation of Ku70, Ku80 and DNA fragmentation. Based on these results we discuss the mechanism of apoptosis induced by DFH and its implications in leukemia therapy. (C) 2008 Elsevier Inc. All rights reserved.

The treatment of recurrent abdominal pain in children : a controlled comparison of cognitive-behavioral family intervention and standard pediatric care

This study describes the results of a controlled clinical trial involving 44 7- to 14-year-old children with recurrent abdominal pain who were randomly allocated to either cognitive-behavioral family intervention (CBFI) or standard pediatric care (SPC). Both treatment conditions resulted in significant improvements on measures of pain intensity and pain behavior. However, the children receiving CBFI had a higher rate of complete elimination of pain, lower levels of relapse at 6- and 12-month follow-up, and lower levels of interference with their activities as a result of pain and parents reported a higher level of satisfaction with the treatment than children receiving SPC. After controlling for pretreatment levels of pain, children's active self-coping and mothers' caregiving strategies were significant independent predictors of pain behavior at posttreatment.