Associations between epigenetic aging and childhood peer victimization, depression, and suicidal ideation in adolescence and adulthood: A study of two population-based samples.

Background: Prior studies indicate that peer victimization (including bullying) is associated with higher risk for depression and suicidal ideation across the life course. However, molecular mechanisms underlying these associations remain unclear. This two-cohort study proposes to test whether epigenetic aging and pace of aging, as well as a DNA methylation marker of responsive to glucocorticoids, are associated to childhood peer victimization and later depressive symptoms, or suicidal ideation. Methods: Cohort 1: Epigenome-wide DNA methylation (EPIC array) was measured in saliva collected when participants were 10.47 years (standard deviation = 0.35) in a subsample of the Quebec Longitudinal Study of Child Development (QLSCD, n = 149 participants), with self-reported peer victimization at 6-8 years, depressive symptoms (mean symptoms, and dichotomized top 30% symptoms) and suicidal ideation at 15-17 years. Cohort 2: Epigenome-wide DNA methylation (EPIC array) was measured in blood collected from participants aged 45.13 years (standard deviation = 0.37) in a subsample of the 1958 British Birth cohort (1958BBC, n = 238 participants) with information on mother-reported peer victimization at 7-11 years, self-reported depressive symptoms at 50 years, and suicidal ideation at 45 years. Five epigenetic indices were derived: three indicators of epigenetic aging [Horvath's pan-tissue (Horvath1), Horvath's Skin-and-Blood (Horvath2), Pediatric-Buccal-Epigenetic age (PedBE)], pace of aging (DunedinPACE), and stress response reactivity (Epistress). Results: Peer victimization was not associated with the epigenetic indices in either cohort. In the QLSCD, higher PedBE epigenetic aging and a slower pace of aging as measured by DunedinPACE predicted higher depressive symptoms scores. In contrast, neither the Horvath1, or Horvath2 epigenetic age estimates, nor the Epistress score were associated with depressive symptoms in either cohort, and none of the epigenetic indices predicted suicidal ideation. Conclusion: The findings are consistent with epigenome-wide and candidate gene studies suggesting that these epigenetic indices did not relate to peer victimization, challenging the hypothesis that cumulative epigenetic aging indices could translate vulnerability to depressive symptoms and suicidal ideation following peer victimization. Since some indices of epigenetic aging and pace of aging signaled higher risk for depressive symptoms, future studies should pursue this investigation to further evaluate the robustness and generalization of these preliminary findings.

Perceived friend support buffers against symptoms of depression in peer victimized adolescents: Evidence from a population-based cohort in South Korea.

BACKGROUND: Peer victimization is associated with an increased risk for depression, but there is less evidence on how certain factors such as friend support can buffer this association. This study investigated the associations between friend support and depressive symptoms among victimized and non-victimized adolescent girls and boys from South Korea. METHODS: Participants includes 2258 students from the Korean Children and Youth Panel Survey, a nationally representative sample of middle school students in South Korea. Self-reported perceived friend support, depressive symptoms and peer victimization were measured using validated scales during middle school year 3 (mean age= 15.7 years). RESULTS: The association between peer victimization and depressive symptoms varied by sex (p for sex by peer victimization interaction<0.05). Peer victimization was more strongly associated with same year depressive symptoms in girls (ß=0.55) than boys (ß=0.24). After controlling for key confounders, including prior year mental health symptoms, higher levels of friend support were found to attenuate the association between peer victimization and depressive symptoms (p for friend support by peer victimization interaction <0.05). Peer victimization was associated with more depressive symptoms for adolescents with low and moderate friend support, but not those with high friend support. LIMITATIONS: Peer victimization, depressive symptoms, and friend support, were self-reported and measured the same year. CONCLUSIONS: Friend support protects victimized South Korean adolescents from the negative effect of peer victimization on depressive symptoms, hence contributes to closing the gap in depression between victimized and non-victimized adolescents.

Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide.

Neuregulin-1 (NRG1) and ErbB receptors have been associated with psychopathology, and NRG1-ErbB3 signaling has been shown to increase hippocampal neurogenesis and induce antidepressant-like effects. In this study, we aimed to determine whether deficits in NRG1 or ErbBs might be present in the hippocampus of suicide completers. In well-characterized postmortem hippocampal samples from suicides and matched sudden-death controls, we assessed gene expression and methylation using qRT-PCR and EpiTYPER, respectively. Moreover, in hippocampal tissues stained with cresyl violet, stereology was used to quantify numbers of granule cells and of glia. Granule cell body size was examined with a nucleator probe, and granule cell layer volume with a Cavalieri probe. Unmedicated suicides showed sharply decreased hippocampal ErbB3 expression and decreased numbers of ErbB3-expressing granule cell neurons in the anterior dentate gyrus; a phenomenon seemingly reversed by antidepressant treatment. Furthermore, we found ErbB3 expression to be significantly decreased in the dentate gyrus of adult mice exposed to chronic social defeat stress. Taken together, these results reveal novel suicidal endophenotypes in the hippocampus, as well as a putative etiological mechanism underlying suicidality, and suggest that antidepressant or NRG1 treatment may reverse a potential deficit in anterior dentate gyrus granule cell neurons in individuals at risk of dying by suicide.

Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide.

This corrects the article DOI: 10.1038/tp.2017.132.

New avenues for phase matching in nonlinear hyperbolic metamaterials.

Nonlinear optical processes, which are of paramount importance in science and technology, involve the generation of new frequencies. This requires phase matching to avoid that light generated at different positions interferes destructively. Of the two original approaches to achieve this, one relies on birefringence in optical crystals, and is therefore limited by the dispersion of naturally occurring materials, whereas the other, quasi-phase-matching, requires direct modulation of material properties, which is not universally possible. To overcome these limitations, we propose to exploit the unique dispersion afforded by hyperbolic metamaterials, where the refractive index can be arbitrarily large. We systematically analyse the ensuing opportunities and demonstrate that hyperbolic phase matching can be achieved with a wide range of material parameters, offering access to the use of nonlinear media for which phase matching cannot be achieved by other means. With the rapid development in the fabrication of hyperbolic metamaterials, our approach is destined to bring significant advantages over conventional techniques for the phase matching of a variety of nonlinear processes.

Single and repeated dosing of the converting enzyme inhibitor perindopril to normal subjects.

The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril (S9490-3) was evaluated in 18 normotensive men. In three subjects the pressor response to exogenous angiotensin I was tested. A 8 mg oral dose reduced the pressor response by greater than 80%. Single oral perindopril doses of 2, 4, 8, and 16 mg were given to groups of five subjects each. Eight and 16 mg decreased plasma ACE activity within 4 hours to less than 10% of control; 72 hours later, plasma ACE activity was still reduced by at least 40%. Doses of 4 and 8 mg po once a day were then given for 8 days to two groups of six subjects. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone, and plasma ACE activity fell significantly, whereas blood angiotensin I and plasma renin activity rose. There was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed. Thus in normotensive subjects, perindopril seems an effective, orally active, long-lasting ACE inhibitor.

Pharmacokinetics of perindopril and its metabolites in healthy volunteers.

Perindopril, an angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to its active diacid metabolite, perindoprilat and to a perindoprilat glucuronide. The pharmacokinetic parameters of perindopril, perindoprilat and perindoprilat glucuronide were evaluated after single administration to healthy volunteers (N = 12) of 8 mg of perindopril tert-butylamine salt by oral route (treatment A), by intravenous route (bolus in 5 min, treatment B) and of an equimolar dose of perindoprilat (6.1 mg) by intravenous route (infusion over 2 h, treatment C). The treatments were administered as a randomised 3-way cross-over design. Plasma samples were collected up to 96 h and urines up to 120 h. Perindopril is rapidly absorbed with an oral bioavailability of 95% and is mainly eliminated by metabolic processes. The formation of perindoprilat is slow and about 20% of the available parent drug is transformed into this metabolite. Elimination profile of perindoprilat is biphasic, with a rapid renal excretion of the free fraction and a long terminal half-life of the fraction bound to ACE. Perindoprilat glucuronide is mainly obtained from perindopril by a pre-systemic first pass metabolism.

Experience with perindopril in normal volunteers.

The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril was evaluated in normotensive men. Doses of 2 to 16 mg were given once a day for up to one week. Single oral doses of perindopril were found to blunt the pressor response to exogenous angiotensin I in a dose-dependent manner. The drug-induced ACE inhibition, as estimated by the measurement of plasma ACE activity, was maximal 4 to 8 hours post drug intake. ACE activity was still importantly reduced 24 hours after dosing. Plasma levels of angiotensin II and aldosterone decreased significantly whereas plasma renin activity and blood angiotensin I levels rose during peak ACE inhibition induced by the 4 and 8 mg doses. However, circulating levels of angiotensin II returned to baseline 24 hours after dosing, both on the first day of treatment and after one week of administration. ACE inhibition with perindopril did not affect blood pressure and heart rate in any consistent manner. There was no evidence for drug accumulation during repeated administration. The novel ACE inhibitor was well tolerated and produced no change in routine laboratory tests. The long-acting ACE inhibitor perindopril appears therefore to be effective when given orally in a dose range of 4 to 16 mg.

[Clinical evaluation: from intermediate to surrogate criteria]. / Evaluation clinique: du critère intermédiaire au critère de substitution.

The development and evaluation of new drugs often rely on surrogacy. An intermediate outcome becomes a surrogate outcome if it fulfils certain criteria, it should be easier to measure compared with the clinical outcome, a statistical relationship should exist between the clinical outcome and the surrogate outcome, a relation should exist allowing prediction of the degree of clinical effect based on the measured effect on the surrogate outcome. Development and authorization of drugs today often rely on so-called surrogate outcomes. Is this use sound? The validity of such outcomes has been reviewed in different therapeutic areas: hypertension, venous thromboembolism, AIDS, osteoporosis, hepatitis C. Based on this review, a pragmatic strategy is proposed which allows for the validation and proper use of surrogate outcomes.

[Tianeptine, an uncommon psychotropic drug]. / La tianeptine, un psychotrope original.

The pharmacological studies show that tianeptine (Stablon) is an original psychotropic drug. In classical and behavioural pharmacology, tianeptine has a novel antidepressant profile, different from other molecules and an anxiolytic effect but different from the benzodiazepines. Tianeptine does not cause sedation and sleeping troubles. In mice, tianeptine does not impair spatial memory but have facilitating effects on both working and reference memory. Tianeptine also increased the focalization of attention in cat and is active on comportmental adaptation models in stress. The electrophysiological data showed that tianeptine increases activity of the hippocampus pyramidal cells and decreases the recovery time after inhibitory substances application. Neurobiochemical studies showed that tianeptine increases serotonin uptake, in rat brain and in rat and human platelets, after acute and chronic treatment. Neuroendocrinology data showed that tianeptine decreases CRF and ACTH levels. Current research on the effect of tianeptine on acetylcholine could explain its anti-stress and memory facilitation activity.

[Colonization by Ureaplasma urealyticum and chronic lung disease in premature newborn infants under 32 weeks of gestation]. / Colonisation par Ureaplasma urealyticum et maladie pulmonaire chronique chez les nouveau-nés prématurés de moins de 32 semaines de gestation.

UNLABELLED: Colonization of the respiratory tract of premature newborn infants by genital mycoplasma is suspected to be associated with chronic lung disease. METHODS AND PATIENTS: We prospectively determined the prevalence of genital mycoplasma colonization with nasopharyngeal or endotracheal culture in preterm neonates younger than 32 weeks gestation and its possible association with the development of chronic lung disease in a prospective study. RESULTS: Fifty-nine infants were enrolled and 11 (19%) were colonized with Ureaplasma urealyticum. In the subgroup of 45 ventilated infants, seven of seven U. urealyticum-positive infants developed chronic pulmonary disease versus ten of 38 (26%) of U. urealyticum-negative infants (relative risk [RR] = 3.8; 95% confidence interval [CI] 2.2 to 6.5, P < 0.001). U. urealyticum-colonized infants had a lower median birth weight (760 vs 1,083 g, P = 0.04), a lower gestational age (26 vs 28 weeks, P = 0.03), and a higher incidence of symptomatic patent ductus arteriosus (P = 0.03). These potential confounding factors may partially explain the association between U. urealyticum and chronic pulmonary disease. However, this association remained statistically significant when the analysis was restricted to infants with birth weight of 1,000 g or less (RR = 2.3; 95% CI 1.3 to 4, P = 0.02) or to infants with a patent ductus arteriosus (RR = 2; 95% CI 1.3 to 3.1, P = 0.02). CONCLUSION: Colonization with U. urealyticum in ventilated preterm neonates younger than 32 weeks gestation is a significant risk factor of developing chronic pulmonary disease.

Peripheral haemodynamic effects of perindopril compared in patients with congestive heart failure and in normal volunteers.

The effects of perindopril, 4 mg orally, on brachial artery blood flow and diameter (pulsed Doppler) and on forearm vascular resistance were investigated and compared in six normal subjects and 10 congestive heart failure patients (New York Heart Association class III or IV). Pre-drug values of brachial artery blood flow and diameter were significantly lower in patients with congestive heart failure than in normal subjects, the reverse being true for forearm vascular resistance. In normal subjects perindopril increased brachial artery blood flow and decreased forearm vascular resistance, while in patients with congestive heart failure the same effects were observed but they were more pronounced and brachial artery diameter was increased. In patients with congestive heart failure, when perindopril effects were maximal, brachial artery blood flow remained below the baseline values of normal subjects but brachial artery diameter was normalized. Finally, there was a correlation between the drug-induced decrease in forearm vascular resistance and basal plasma noradrenaline values in all subjects taken together. These results indicate that: (1) the renin-angiotensin system plays a major role in vasoconstriction in patients with congestive heart failure; (2) this vasoconstriction affects both large arteries and arterioles; (3) perindopril is able to considerably improve peripheral haemodynamics in congestive heart failure; and (4) this improvement is linked to the initial sympathetic tone.

Effects of perindopril on renal haemodynamics and natriuresis in essential hypertension.

Renal haemodynamics and natriuresis were studied before and 6 h after oral intake of perindopril (8 mg) in eight hypertensive patients without renal failure. The patients were then treated with perindopril (8 mg per day) and renal haemodynamics were measured on the fifth day, 6 h after the morning intake. Sodium intake was controlled during the study (100 mmol sodium per day). Renal blood flow and the glomerular filtration rate were measured by the clearance method using 131I-hippuran and 125I-iothalamate, respectively. Mean blood pressure decreased from 135 to 110 after 6 h, and was 118 mmHg on the fifth day (P less than 0.001, respectively). Renal vascular resistance decreased significantly after acute drug intake from 0.19 to 0.15 arbitrary units (P less than 0.001) and on the fifth day to 0.16 arbitrary units (P less than 0.001). Renal blood flow rose from 708 to 723 after 6 h, and to 750 ml/min per 1.73 m2 on the fifth day but the change was no significant. There was no alteration in the glomerular filtration rate so that the filtration fraction decreased from 0.27 to 0.26 (after 6 h), and to 0.25 on the fifth day (P less than 0.02). Natriuresis increased after the first intake between the first and tenth hours. On the fifth day, maximum natriuresis was observed between the fourth and sixth hours. Perindopril caused strong renal vasodilation after the first intake and during the following days, with no change in the glomerular filtration rate. There was a significant decrease in the filtration fraction, indicating efferent, as well as afferent, arteriolar vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary heterologous carcinosarcoma (metaplastic carcinoma) of the urinary bladder: a clinicopathologic, immunohistochemical, and ultrastructural analysis of eight cases and a review of the literature.

BACKGROUND: Heterologous carcinosarcomas of the urinary bladder are rare neoplasms, the histogenesis of which is still disputed. METHODS: The clinicopathologic, immunohistochemical, and ultrastructural features of eight cases were analyzed. RESULTS: The patients, 5 males and 3 females, had a median age of 70 years. Gross hematuria, dysuria, and urinary tract infections were the main presenting symptoms. Tumors were solitary in all cases and located in the right wall in six cases. Tumor size ranged from 2 to 12 cm (median, 5 cm). Four patients died of disease 2, 6, 17, and 42 months postoperatively, respectively. Microscopically, the tumors consisted mostly of a varied mixture of high grade transitional cell carcinoma with chondrosarcoma, osteosarcoma, rhabdomyosarcoma, and undifferentiated spindle cell (leiomyosarcoma-like) components with occasional transitional features between one component and another. All tumors but one invaded the muscularis propria or the perivesical fatty tissue. Immunohistochemically, keratin expression was observed focally in the sarcoma component as well as the carcinoma component. Reactivity for vimentin, desmin, muscle specific actin, and S-100 protein was observed in poorly differentiated areas in addition to the expected positivity of each histologic subtype of sarcoma. Ultrastructurally, one tumor showed evidence of both epithelial and chondrosarcomatous differentiation, whereas three contained rhabdomyosarcomatous elements. CONCLUSIONS: On the basis of the current series and a review of 55 reports from the literature, primary heterologous carcinosarcoma of the urinary bladder proved to be a highly malignant type of neoplasm occurring predominantly in elderly males that was most often in an advanced stage at presentation and rapidly became lethal. Histogenetically, some heterologous carcinosarcomas should be regarded as a variant of sarcomatoid carcinoma (metaplastic carcinoma) that shows prominent heterologous differentiation.

[Anti-synthetase syndrome: a special subgroup of idiopathic inflammatory myopathies. Apropos of 3 case reports]. / Le syndrome antisynthétase: un sous-groupe particulier des myopathies idiopathiques inflammatoires. A propos de trois observations.

Anti-synthetase antibodies are found in 20 to 25% of all idiopathic inflammatory myopathies and allow identification of a syndrome associating myositis with interstitial pulmonary disease (50 to 70%), polyarthritis, Raynaud's phenomenon and mechanic's hands. Anti-Jo-1 is the most common anti-synthetase antibody. If anti-Jo-1 is present, interstitial lung disease must be looked for, because this is the most important determinant of the outcome. Treatment with high doses of corticosteroids is required. Immunosuppressive drugs are added in resistant cases or as corticosteroid-sparing agents.

Perindopril, a new angiotensin converting enzyme inhibitor--clinical pharmacological studies in healthy subjects.

Perindopril is a new angiotensin converting enzyme (ACE) inhibitor which is activated after hydrolysis in vivo to a diacid (S9780). Oral administration of perindopril (1-16 mg) to groups of 6 healthy males led to a long lasting and dose-elated inhibition of plasma ACE and rises in plasma renin activity with no evidence of accumulation of drug or effect. At higher doses there was a modest fall in blood pressure. S9780 given intravenously in doses of 1,2 or 4 mg caused an immediate inhibition of plasma ACE. The concentration of S9780 in plasma which led to 50% inhibition of plasma ACE was 1.55 +/- 1.14 ng/ml (mean +/- S.D.). Clinical trials with 2-8 mg once daily in essential hypertension are currently in progress.

Evaluation of the dose-effect relationship of a new ace inhibitor (perindopril) by an automatic blood pressure recorder.

Repeated blood pressure recordings by non-invasive devices are of better predictive value than single measurements in the evaluation of antihypertensive treatment. Such a method has been used to establish the dose-effect relationship of perindopril. After a two-week placebo run-in period, 40 patients with essential hypertension (age 56.6 +/- 1.5 years, 31 males, nine females) were treated with placebo or 2, 4 or 8 mg of perindopril once daily for one month following a randomized double-blind design. They were included if at least 75% of diastolic blood pressure recordings, made over an 8 h diurnal period using an automatic blood pressure recorder, were greater than 95 mmHg on placebo. Values (mean +/- SEM) before and after treatment were assessed using analysis of variance. These data showed a significantly greater reduction of blood pressure with 4 mg and 8 mg daily doses compared to placebo and the 2 mg daily dose. Such results were not obtained with blood pressure levels recorded by a mercury sphygmomanometer, confirming the value of an automatic blood pressure recorder as a tool in therapeutic trials.

Experience with perindopril in normal volunteers.

The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril was evaluated in normotensive men. Doses of 2 to 16 mg were given once a day for up to one week. Single oral doses of perindopril were found to blunt the pressor response to exogenous angiotensin I in a dose-dependent manner. The drug-induced ACE inhibition, as estimated by the measurement of plasma ACE activity, was maximal 4 to 8 hours post drug intake. ACE activity was still markedly reduced 24 hours after dosing. Plasma levels of angiotensin II and aldosterone decreased significantly, whereas plasma renin activity and blood angiotensin I levels rose during peak ACE inhibition induced by the 4 and 8 mg doses. However, circulating levels of angiotensin II returned to baseline values 24 hours after dosing, both on the first day of treatment and after one week of administration. ACE inhibition with perindopril did not consistently affect blood pressure and heart rate. There was no evidence for drug accumulation during repeated administration. The novel ACE inhibitor was well tolerated and produced no change in routine laboratory tests. The long-acting ACE inhibitor perindopril therefore appears to be effective when given orally in a dose range of 4 to 16 mg.