Pre-implantation alcohol exposure induces lasting sex-specific DNA methylation programming errors in the developing forebrain.

BACKGROUND: Prenatal alcohol exposure is recognized for altering DNA methylation profiles of brain cells during development, and to be part of the molecular basis underpinning Fetal Alcohol Spectrum Disorder (FASD) etiology. However, we have negligible information on the effects of alcohol exposure during pre-implantation, the early embryonic window marked with dynamic DNA methylation reprogramming, and on how this may rewire the brain developmental program. RESULTS: Using a pre-clinical in vivo mouse model, we show that a binge-like alcohol exposure during pre-implantation at the 8-cell stage leads to surge in morphological brain defects and adverse developmental outcomes during fetal life. Genome-wide DNA methylation analyses of fetal forebrains uncovered sex-specific alterations, including partial loss of DNA methylation maintenance at imprinting control regions, and abnormal de novo DNA methylation profiles in various biological pathways (e.g., neural/brain development). CONCLUSION: These findings support that alcohol-induced DNA methylation programming deviations during pre-implantation could contribute to the manifestation of neurodevelopmental phenotypes associated with FASD.

Developmental genome-wide DNA methylation asymmetry between mouse placenta and embryo.

In early embryos, DNA methylation is remodelled to initiate the developmental program but for mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution DNA methylation maps of mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryonic and placental DNA methylation patterns. We show that the asymmetry occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri-implantation stages, the de novo methyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially compensate in the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principal de novo methyltransferase, the compensatory DNA methylation mechanism of DNMT3B on DMRs becomes less effective.

A syndemic including cigarette smoking and sexual risk behaviors among a sample of MSM in Shanghai, China.

OBJECTIVES: We explored possible correlates of cigarette smoking and their associations with levels of smoking among a sample of Chinese men who have sex with men (MSM). We also explored the syndemic associations of substance use and psychosocial problems on sexual risk behaviors. METHODS: Cross-sectional data collection from 404 MSM in Shanghai, China. RESULTS: MSM exhibit a high prevalence of smoking (66.3%). Both light and heavy smoking were associated with alcohol and drug use, depression, intimate partner violence, sexual attitudes, and gay identity (though the associations for light smokers were moderate compared to those for heavy smokers). CONCLUSIONS: Our findings indicate the presence of a health syndemic among MSM, and suggest that smoking prevention and cessation and other substance abuse interventions should be integrated into efforts preventing sexual risk behaviors among MSM.

[Palliative care: profile of medical practice in the Quebec city region]. / Les soins palliatifs. Profil de pratique des médecins de la région de Québec.

OBJECTIVE: To describe the palliative care provided by physicians in the Quebec city region and to identify factors that affect its delivery. DESIGN: Mailed survey. SETTING: Quebec city region. PARTICIPANTS: General practitioners in active clinical practice. MAIN OUTCOME MEASURES: Physicians' personal and professional characteristics and their palliative care practice (volume of work, source of requests for follow-up care, place of delivery of care, resources used, difficulties, encountered). RESULTS: Of the 476 physicians (67%) who responded to our survey, 295 (62%) provided palliative care. Of these, 70% saw no more than two patients requiring palliative care per month, and 55% devoted no more than 2 hours per week to this aspect of patient care. Most (76%) provided palliative care in a variety of settings (private office, home, institution). Home care teams working out of local community health centres are the resource physicians drew upon most frequently (69%). The main difficulties encountered were a lack of clinical expertise, scheduling home care, and providing patients and families with emotional support. CONCLUSION: Most physicians in the Quebec city region provided palliative care occasionally. This care could be improved by removing various logistical and professional barriers.

Inflammatory and hormonal measures predict neuropsychological functioning in systemic lupus erythematosus and rheumatoid arthritis patients.

Abnormalities of inflammatory and hormonal measures are common in SLE patients. Although cognitive dysfunction has been documented in SLE patients, the biological mechanism of these deficits has not been clarified. The goal of this study was to explore the relationship between inflammatory and hormonal activity and measures of learning, fluency, and attention in systemic lupus erythematosus patients without neuropsychiatric symptoms (non-CNS-SLE), patients with rheumatoid arthritis (RA), and healthy controls (HC). Fifteen non-CNS-SLE patients, 15 RA patients and 15 HC participants similar in age, education, and gender (female) were compared on tests of cognition, depression, and plasma levels of interleukin-6 (IL-6), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and cortisol. Non-CNS-SLE patients demonstrated lower learning and poorer attention. Furthermore, non-CNS-SLE and RA patients had significantly lower levels of DHEA and DHEA-S than HC participants. Hierarchical regression analysis demonstrates that DHEA-S and IL-6 accounts for a unique portion of the variance in subject performance on measures of learning and attention after controlling for depression and corticosteroid treatment. This data highlights the value of hierarchical analyses with covariates, and provides evidence in humans of a relationship between peripheral cytokine levels and cognitive function.

Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat-driven transcription and a possible implication of SHP-1.

Although protein tyrosine phosphatase (PTP) inhibitors used in combination with other stimuli can induce interleukin 2 (IL-2) production in T cells, a direct implication of nuclear factor of activated T cells (NFAT) has not yet been demonstrated. This study reports that exposure of leukemic T cells and human peripheral blood mononuclear cells to bis-peroxovanadium (bpV) PTP inhibitors markedly induce activation and nuclear translocation of NFAT. NFAT activation by bpV was inhibited by the immunosuppressive drugs FK506 and cyclosporin A, as well as by a specific peptide inhibitor of NFAT activation. Mobility shift assays showed specific induction of the NFAT1 member by bpV molecules. The bpV-mediated NFAT activation was observed to be important for the up-regulation of the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) and the IL-2 promoter; NFAT1 was demonstrated to be particularly important in bpV-dependent positive action on HIV-1 LTR transcription. The active participation of p56(lck), ZAP-70, p21(ras), and calcium in the bpV-mediated signaling cascade leading to NFAT activation was confirmed, using deficient cell lines and dominant-negative mutants. Finally, overexpression of wild-type SHP-1 resulted in a greatly diminished activation of NFAT by bpV, suggesting an involvement of SHP-1 in the regulation of NFAT activation. These data were confirmed by constitutive NFAT translocation observed in Jurkat cells stably expressing a dominant-negative version of SHP-1. The study proposes that PTP activity attenuates constitutive kinase activities that otherwise would lead to constant NFAT activation and that this activation is participating in HIV-1 LTR stimulation by PTP inhibition.

Effect of MPTP-induced denervation on basal ganglia GABA(B) receptors: correlation with dopamine concentrations and dopamine transporter.

We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of (125)I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evaluated using (3)H-CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABA(B(1a+b)), GABA(B(1a)), GABA(B(1b)), GABA(B(2)) subunits. In monkeys, (125)I-CGP64213 and selective probes for GABA(B(1a+b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, (125)I-RTI-121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABA(B) receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of (3)H-CGP54626 binding (-10%) and of the expression of GABA(B(1a+b)) mRNA (-13%). The decrease of the expression of GABA(B(1a+b)) mRNA was correlated with dopamine content, (125)I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, (125)I-CGP64213 binding (-40%), GABA(B(1a+b)) mRNA (-69%) and GABA(B(2)) mRNA (-66%) were also significantly decreased in the SNpc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA(B) receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease.

Increased tumor necrosis factor-alpha production by peripheral blood leukocytes from TCDD-exposed rhesus monkeys.

Previous work has shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Studies also suggest that immune mechanisms participate in TCDD-mediated toxicity and the pathogenesis of endometriosis. Thirteen years after TCDD treatment was terminated, we characterized the phenotypic distribution of peripheral blood mononuclear cells (PBMC) from TCDD-exposed and -unexposed rhesus monkeys and determined the ability of these cells to produce cytokines and exert cytolytic activity against NK and T-cell-sensitive cell lines. We also determined whether elevated serum levels of TCDD, dioxin-like PHAH congeners, and triglycerides correlated with changes in PBMC phenotype or function. For all animals, TCDD exposure correlated with increased PBMC tumor necrosis factor-alpha (TNF-alpha) secretion in response to stimulation by T-cell mitogen and decreased cytolytic activity against NK-sensitive target cells. Furthermore, increased production of this cytokine by PHA-stimulated leukocytes was associated with elevated serum triglyceride levels. Leukocyte TNF-alpha secretion in response to viral antigen and PBMC production of interferon gamma (IFNgamma), IL-6, and IL-10 following exposure to mitogen or antigen were unaffected by previous TCDD treatment. Although TCDD exposure was not associated with changes in PBMC surface antigen expression, elevated serum concentrations of TCDD, 1,2,3,6,7,8-hexachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl correlated with increased numbers of CD3+/CD25- and CD3-/CD25+ leukocytes and enhanced secretion of TNF-alpha by mitogen-stimulated PBMC. These findings indicate that TCDD-exposed rhesus monkeys with endometriosis exhibit long-term alterations in systemic immunity associated with elevated serum levels of specific PHAH congeners.

Profile of endometriosis in the aging female rhesus monkey.

BACKGROUND: A retrospective analysis was conducted on necropsy records from a large rhesus monkey colony to evaluate the age-related prevalence of endometriosis. METHODS: A total of 314 records collected over a 15-year period were analyzed, yielding 66 monkeys with histologically verified endometriosis and 248 control subjects. RESULTS: The analyses demonstrated that the incidence of endometriosis increases progressively across the life span, ultimately impacting 21-45% of aged monkeys over 20 years of age. CONCLUSIONS: Because mild disease is often not diagnosed premortem, the endocrine and immune sequelae of endometriosis may be a potential confound in even nonreproductive research with aging primates. Prior research-related events influence the occurrence and severity of endometriosis in these long-lived animals, and specifically could have contributed to the high prevalence of endometriosis in this particular monkey colony.

Surgical and psychological stressors differentially affect cytolytic responses in the rhesus monkey.

Four experiments were conducted in aged rhesus monkeys to investigate how physical and psychological stressors influence the lymphocyte cytolytic responses against two target cell lines. An initial analysis of the lytic activity of various cell subsets against K562 and RAJI target cell lines suggested that both CD3+CD8+ and several CD3- subsets were responsible for lysis of the K562 cells. The RAJI cell line, in contrast, was killed primarily by CD3-subsets. To explore the implications of this differential mediation of lysis, cytolytic activity was evaluated after a physical challenge (surgery), a psychological disturbance (social separation), and in vitro incubation of lymphocytes with cortisol. The minor surgical procedure-laparoscopic examination-resulted in a significant decrease in lymphocyte cytolytic responses against both target cells 1 week postsurgery. In contrast, psychological disturbance elicited by changes in social relations caused a dual response, differentially affecting the lysis of either K562 or RAJI cells, dependent upon the type of behavioral reaction. Incubation of lymphocytes with cortisol in vitro indicated that lysis of both targets could be affected by corticosteroids, but the high concentration required (10(-6) M) suggested that the in vivo inhibition of cytotoxicity may not have been mediated by adrenocortical activation. Overall, the results highlight the value of utilizing multiple target cell systems in the analysis of cytolytic activity, especially in studies using nonhuman primates.

Abuse-related posttraumatic stress disorder: evidence for chronic neuroendocrine activation in women.

The following study tested the hypothesis that women with post-traumatic stress disorder (PTSD) related to childhood sexual abuse would display elevated norepinephrine-to-cortisol ratios similar to that found in male combat veterans diagnosed with PTSD. Twenty-four-hour urine samples were collected from 28 women: 11 women with PTSD who experienced childhood sexual abuse (PTSD+), 8 women who experienced childhood sexual abuse without PTSD (PTSD-), and 9 nonabused controls. All urine samples were tested for creatinine, total catecholamines, free-cortisol, and 17-ketosteroid levels. Psychological testing validated that the PTSD+ group was significantly elevated on all three subscales of the Impact of Events Scale. Both abused groups (PTSD+ and PTSD-) showed a tendency for polyuria, and the PTSD+ group showed a tendency towards obesity. Thus, neuroendocrine values (micrograms/day) were adjusted by creatinine clearance rates (creatinine mg/day/kg body weight). The corrected values indicated that the PTSD+ group had significantly elevated daily levels of norepinephrine, epinephrine, dopamine, and cortisol. However, because of the parallel elevation in cortisol, the norepinephrine-to-cortisol ratio was not significantly elevated in the PTSD+ diagnosed women in contrast to the findings reported for male PTSD patients. This discrepancy may reflect an important gender difference, an interaction between gender and age at onset of the traumatic experience (childhood abuse in females vs. combat experience in young adult males), or physiological variation related to phase of the disorder.

Self-discrepancy and natural killer cell activity: immunological consequences of negative self-evaluation.

The study tested whether self-discrepancy theory could account for changes in natural killer (NK) cell activity after exposure to self-referential stimuli. Anxious, dysphoric, and control Ss were pretested and 1 month later covertly exposed to their own self-guides as well as those of another S. Blood samples were drawn for analysis of NK cytotoxicity and cortisol. The dysphoric Ss manifested the greatest actual:ideal discrepancy, whereas the anxious Ss manifested the greatest actual:ought discrepancy. Content analysis of written responses showed that activating discrepancies induced specific negative states; priming discrepancies also increased cortisol for the anxious Ss. NK activity was lower after self-referential priming for both distressed groups, particularly the anxious Ss. The control Ss showed a trend toward increased NK activity after self-referential priming. The study represents the 1st experimental demonstration that negative self-evaluation can alter immune responses.

[Psychological factors in falls in elderly patients]. / Le problème psychologique de la chute chez la personne âgée.

This article recognizes the high incidence and prevalence of falls in the elderly. Psychological factors can play a definite role as part of the etiology. The fall can be a depressive signal or a cry for help from a demoralized elderly patient. The authors stress the importance of recognizing the depressive syndrome of the elderly. Psychological consequences of the falls are reviewed at three different levels. For the elderly, the consequences are frequently a fear that can lead to a sharp decrease in functional capacity. For the family, the fall can lead to the institutionalization of the elderly or a very restrictive surveillance. For the family physician, the fall is frequently perceived as an emergency that leads to immediate unwarranted admission. A rational approach, with education and guidelines, is proposed and can render this traumatic experience less dramatic at these three different levels.