The contribution of cannabis use to the increased psychosis risk among minority ethnic groups in Europe.

BACKGROUND: We examined whether cannabis use contributes to the increased risk of psychotic disorder for non-western minorities in Europe. METHODS: We used data from the EU-GEI study (collected at sites in Spain, Italy, France, the United Kingdom, and the Netherlands) on 825 first-episode patients and 1026 controls. We estimated the odds ratio (OR) of psychotic disorder for several groups of migrants compared with the local reference population, without and with adjustment for measures of cannabis use. RESULTS: The OR of psychotic disorder for non-western minorities, adjusted for age, sex, and recruitment area, was 1.80 (95% CI 1.39-2.33). Further adjustment of this OR for frequency of cannabis use had a minimal effect: OR = 1.81 (95% CI 1.38-2.37). The same applied to adjustment for frequency of use of high-potency cannabis. Likewise, adjustments of ORs for most sub-groups of non-western countries had a minimal effect. There were two exceptions. For the Black Caribbean group in London, after adjustment for frequency of use of high-potency cannabis the OR decreased from 2.45 (95% CI 1.25-4.79) to 1.61 (95% CI 0.74-3.51). Similarly, the OR for Surinamese and Dutch Antillean individuals in Amsterdam decreased after adjustment for daily use: from 2.57 (95% CI 1.07-6.15) to 1.67 (95% CI 0.62-4.53). CONCLUSIONS: The contribution of cannabis use to the excess risk of psychotic disorder for non-western minorities was small. However, some evidence of an effect was found for people of Black Caribbean heritage in London and for those of Surinamese and Dutch Antillean heritage in Amsterdam.

Self-stigma, religiosity, and perceived social support in people with recent-onset psychosis in the Islamic Republic of Iran: Associations with symptom severity and psychosocial functioning.

AIMS: Most evidence on psychosocial factors in recent-onset psychosis comes from high-income countries in Europe, Australia, Canada and the USA, while these factors are likely to differ under varying sociocultural and economic circumstances. In this study, we aimed to investigate associations of self-stigma, religiosity and perceived social support with symptom severity and psychosocial functioning in an Iranian cohort of people with recent-onset psychosis (i.e. illness duration of <2 years). METHODS: We used baseline data of 361 participants (N = 286 [74%] male, mean age = 34 years [Standard Deviation = 10.0]) from the Iranian Azeri Recent-onset Acute Phase Psychosis Survey (ARAS). We included assessments of self-stigma (Internalized Stigma of Mental Illness, ISMI), religiosity (based on Stark & Glock), perceived social support (Multidimensional Scale of Perceived Social Support, MSPSS), symptom severity (Positive And Negative Syndrome Scale, PANSS) and psychosocial functioning (clinician-rated Global Assessment of Functioning Scale, GAF, and self-reported World Health Organization Disability Assessment Schedule 2.0, WHODAS 2.0). Descriptive analyses were employed to characterize the study sample. Covariate-adjusted ordinal and multivariable linear regression analyses were performed to investigate cross-sectional associations of baseline ISMI, religiosity and MSPSS with concurrent PANSS, GAF and WHODAS 2.0. RESULTS: Higher self-stigma was associated with poorer self-reported functioning (B = 0.375 [95% Confidence Interval (CI): 0.186, 0.564]) and more severe concurrent symptoms (B = 0.436 [95% CI: 0.275, 0.597]). Being more religious was associated with poorer clinician-rated functioning (OR = 0.967 [95% CI: 0.944, 0.991]), but with less severe symptoms (B = -0.258 [95% CI: -0.427, -0.088]). Stronger social support was associated with poorer clinician-rated (OR = 0.956 [95% CI: 0.935, 0.978]) and self-reported functioning (B = 0.337 [95% CI: 0.168, 0.507]). CONCLUSION: This study shows that self-stigma, religiosity and perceived social support were associated with symptom severity and clinician-rated as well as self-reported psychosocial functioning in an Iranian cohort of people with recent-onset psychosis. The findings extend previous evidence on these psychosocial factors to one of the largest countries in the Middle East, and suggest that it may be worthwhile to develop strategies aimed at tackling stigma around psychosis and integrate the role of religiosity and social support in mental ill-health prevention and therapy.

[Linguistic distance and psychosis in ethnic minorities]. / Taalachterstand en psychose onder mensen met een migratieachtergrond.

BACKGROUND: Ethnic minorities in the Netherlands face an excess psychosis risk, and understanding of causality remains limited. Linguistic disadvantage and other indicators of societal exclusion might play a role, and offer potential targets for public health interventions. AIM: To establish the contribution of linguistic disadvantage, indicators of social distance and perceived discrimination to the increased risk of psychoses in migrants and ethnic minorities. METHODS: We used the Dutch data from an international case-control study into psychotic disorders (the EU-GEI study). A first episode of psychosis was our outcome variable, and we used well-defined data on established confounders (e.g. age and sex) and indicators of ethnicity, social distance, linguistic disadvantage and perceived discrimination as our predictor variables. RESULTS: Ethnic minorities face an increased psychosis risk. This appears to be the case for both first- and second- generation migrants and so-called ‘Western’ and non-Western migrants. Though confounders and social distance appear to contribute, linguistic disadvantage appears to play a role in the excess psychosis risk in first-generation migrants. CONCLUSION: Reducing the social consequences of linguistic disadvantage or social distance might be a starting point for concrete public health interventions aimed at preventing the increased psychosis risk faced by first-generation migrants.

Genetic and psychosocial stressors have independent effects on the level of subclinical psychosis: findings from the multinational EU-GEI study.

AIMS: Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample. METHODS: Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of 'Genetic' models (solely fitted with PRS-SZ), 'Environmental' models (solely fitted with each environmental stressor), 'Independent' models (with PRS-SZ and each environmental factor), and 'Interaction' models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models. RESULTS: There were no genes-environment associations. PRS-SZ was associated with positive dimensions (ß = 0.092, R2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension. CONCLUSIONS: This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.

Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion.

BACKGROUND: Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease. METHODS AND RESULTS: Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Cx40del mice). Cx40del mice were indeed not hypertensive. The progression of atherosclerosis was increased in Cx40del mice after 5 and 10 weeks of a high-cholesterol diet, and spontaneous lesions were observed in the aortic sinuses of young mice without such a diet. These lesions showed monocyte infiltration into the intima, increased expression of vascular cell adhesion molecule-1, and decreased expression of the ecto-enzyme CD73 in the endothelium. The proinflammatory phenotype of Cx40del mice was confirmed in another model of induced leukocyte recruitment from the lung microcirculation. Endothelial CD73 is known to induce antiadhesion signaling via the production of adenosine. We found that reducing Cx40 expression in vitro with small interfering RNA or antisense decreased CD73 expression and activity and increased leukocyte adhesion to mouse endothelial cells. These effects were reversed by an adenosine receptor agonist. CONCLUSIONS: Cx40-mediated gap junctional communication contributes to a quiescent nonactivated endothelium by propagating adenosine-evoked antiinflammatory signals between endothelial cells. Alteration in this mechanism by targeting Cx40 promotes leukocyte adhesion to the endothelium, thus accelerating atherosclerosis.

Electrophysiological features of the mouse sinoatrial node in relation to connexin distribution.

OBJECTIVE: The sinoatrial (SA) node consists of a relatively small number of poorly coupled cells. It is not well understood how these pacemaker cells drive the surrounding atrium and at the same time are protected from its hyperpolarizing influence. To explore this issue on a small tissue scale we studied the activation pattern of the mouse SA node region and correlated this pattern with the distribution of different gap junction proteins, connexin (Cx)37, Cx40, Cx43 and Cx45. METHODS AND RESULTS: The mouse SA node was electrophysiologically mapped using a conventional microelectrode technique. The primary pacemaker area was located in the corner between the lateral and medial limb of the crista terminalis. Unifocal pacemaking occurred in a group of pacemaking fibers consisting of 450 cells. In the nodal area transitions of nodal and atrial waveform were observed over small distances ( approximately 100 microm). Correlation between the activation pattern and connexin distribution revealed extensive labeling by anti-Cx45 in the primary and secondary pacemaker area. Within these nodal areas no gradient in Cx45 labeling was found. A sharp transition was found between Cx40- and Cx43-expressing myocytes of the crista terminalis and the Cx45-expressing myocytes of the node. In addition, strands of myocytes labeled for Cx43 and Cx40 protrude into the nodal area. Cx37 labeling was only present between endothelial cells. Furthermore, a band of connective tissue largely separates the nodal from the atrial tissue. CONCLUSIONS: Our results demonstrate strands of Cx43 and Cx40 positive atrial cells protruding into the Cx45 positive nodal area and a band of connective tissue largely separating the nodal and atrial tissue. This organization of the mouse SA node provides a structural substrate that both shields the nodal area from the hyperpolarizing influence of the atrium and allows fast action potential conduction from the nodal area into the surrounding atrium.

Channelopathies: Kir2.1 mutations jeopardize many cell functions.

Andersen's syndrome is caused by mutations in the potassium channel Kir2.1, a major determinant of resting membrane potential. The clinical features of this disease illustrate the importance of a stable resting membrane potential for many cell functions.

Markedly reduced chronic nociceptive response in mice lacking the PAC1 receptor.

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been proposed to have a role in nociception. Here we have used the formalin test, thermal laser stimulation and mechanical von Frey stimulation to investigate possible alteration of PAC1-/- mice nociceptive behaviour. Our finding, that PAC1-/- mice have a substantial, 75% decrease in nociceptive response during the late phase, provides clear evidence that the specific PACAP-receptor PAC1 is involved in the mediation of nociceptive responses during chronic conditions such as inflammation. PAC1-/- mice had small or no changes in the response to mechanical and thermal laser stimulation. This suggests a limited, if any, involvement of PAC1 in nociception after short-lasting stimuli. Injury-induced changes in DRG neuropeptide expression were more pronounced in PAC1-/- mice, implying neuroregulatory functions of PAC1.

Fetal habituation to vibroacoustic stimulation in uncomplicated postterm pregnancies.

OBJECTIVES: Testing of fetal habituation to repeated vibroacoustic stimulation might give additional information concerning the fetal condition and central nervous system (CNS) functioning in postterm pregnancies. This study is designed to investigate whether healthy postterm fetuses are able to habituate and if so, if the habituation pattern of postterm fetuses differs from that of term fetuses. STUDY DESIGN: Twenty women with an uncomplicated pregnancy beyond 41 weeks gestational age (GA) participated, and 37 women with a GA between 37 and 40 weeks served as controls. The vibroacoustic stimulus was repeatedly applied to the maternal abdomen above the fetal legs for a period of 1s every 30s. A fetal trunk movement within 1s of stimulus application was considered a positive response. Lack of response to four consecutive stimuli indicated habituation. The habituation rate is defined as the number of stimuli applied before the fetus stopped responding. Data were compared using Mann-Whitney U test. RESULTS: Of the 18 postterm fetuses in which the presence or absence of habituation could be established, 14 habituated and four persisted in responding. Twenty-six of the 32 term fetuses, in which the presence or absence of habituation could be established, habituated and six persisted in responding. The habituation rate varied widely in postterm (median of eight stimuli, quartile ranges of 6 and 18) as well as in term fetuses (median of 9.5 stimuli, quartile ranges of 6 and 15). There was no difference in median habituation rate between postterm and term fetuses. CONCLUSION: The ongoing maturation of the CNS in the last weeks of pregnancy appears not to be reflected in the fetal habituation pattern. Furthermore, the interfetal variability in habituation of healthy postterm fetuses is such that testing of habituation appears not to be suitable for the identification of the fetus at risk for an adverse neonatal outcome.

Hypoxia in fetal lambs: a study with (1)H-MNR spectroscopy of cerebrospinal fluid.

In fetal lambs, severe hypoxia (SH) will lead to brain damage. Mild hypoxia (MH) is thought to be relatively safe for the fetal brain because compensating mechanisms are activated. We questioned whether MH, leading to mild acidosis, induces changes in cerebral metabolism. Metabolites in cerebrospinal fluid (CSF) samples, as analyzed by proton magnetic resonance spectroscopy, were studied in two groups of seven anesthetized near-term fetal lambs. In group I, SH leading to acidosis with an arterial pH <7.1 was achieved. In group II, MH with an intended pH of 7.23--7.27 was reached [start of MH (SMH)], and maintained during 2 h [end of MH (EMH)]. During SH, choline levels in CSF, a possible indicator of cell membrane damage, were increased. Both during SH and at EMH, CSF levels of lactic acid, alanine, phenylalanine, tyrosine, lysine, branched chain amino acids, and hypoxanthine were increased compared with control values and with SMH, respectively. At EMH, the hypoxanthine CSF-to-blood ratio was increased as compared with SMH. These results indicate that prolonged MH leads to energy degradation in the fetal lamb brain and may not be as safe as assumed.

The responses to repeated vibroacoustic stimulation in a fetus with trisomy 18.

Observation of the fetal movement and fetal heart rate responses to repeated vibroacoustic stimulation might be useful as a measure to assess fetal well-being. Studies of abnormal fetuses are needed to gain insight in the spectrum of possible responses to stimulation. We present a case of a fetus with trisomy 18 that failed to respond to repeated stimulation.

Gap junctions in the rabbit sinoatrial node.

In comparison to the cellular basis of pacemaking, the electrical interactions mediating synchronization and conduction in the sinoatrial node are poorly understood. Therefore, we have taken a combined immunohistochemical and electrophysiological approach to characterize gap junctions in the nodal area. We report that the pacemaker myocytes in the center of the rabbit sinoatrial node express the gap junction proteins connexin (Cx)40 and Cx46. In the periphery of the node, strands of pacemaker myocytes expressing Cx43 intermingle with strands expressing Cx40 and Cx46. Biophysical properties of gap junctions in isolated pairs of pacemaker myocytes were recorded under dual voltage clamp with the use of the perforated-patch method. Macroscopic junctional conductance ranged between 0.6 and 25 nS with a mean value of 7.5 nS. The junctional conductance did not show a pronounced sensitivity to the transjunctional potential difference. Single-channel recordings from pairs of pacemaker myocytes revealed populations of single-channel conductances at 133, 202, and 241 pS. With these single-channel conductances, the observed average macroscopic junctional conductance, 7.5 nS, would require only 30-60 open gap junction channels.

Impaired conduction in the bundle branches of mouse hearts lacking the gap junction protein connexin40.

BACKGROUND: Connexin (Cx)40 and Cx45 are the major protein subunits of gap junction channels in the conduction system of mammals. To determine the role of Cx40, we correlated cardiac activation with Connexin distribution in normal and Cx40-deficient mice hearts. METHODS AND RESULTS: Epicardial and septal activation was recorded in Langendorff-perfused adult mice hearts with a 247-point compound electrode (interelectrode distance, 0.3 mm). After electrophysiological measurements, hearts were prepared for immunohistochemistry and histology to determine Connexin distribution and fibrosis. In both wild-type and Cx40-deficient animals, epicardial activation patterns were similar. The right and left ventricular septum was invariably activated from base to apex. Histology revealed a continuity of myocytes from the common bundle to the septal myocardium. Within this continuity, colocalization was found of Cx43 and Cx45 but not of Cx40 and Cx43. Both animals showed similar His-bundle activation. In Cx40-deficient mice, the proximal bundle branches expressed Cx45 only. The absence of Cx40 in the proximal bundles correlated with right bundle-branch block. Conduction in the left bundle branch was impaired as compared with wild-type animals. CONCLUSIONS: Our data show that (1) in mice, a continuity exists between the common bundle and the septum, and (2) Cx40 deficiency results in right bundle-branch block and impaired left bundle-branch conduction.

Fetal habituation to vibroacoustic stimulation in relation to fetal states and fetal heart rate parameters.

OBJECTIVES: Fetal habituation to repeated stimulation has the potential to become a tool in the assessment of fetal condition and of the function of the fetal central nervous system (CNS). However, the influence of fetal quiescence and activity on habituation remains to be clarified. We studied habituation and the influence of fetal state and fetal heart rate (FHR) parameters on habituation in healthy term fetuses. SUBJECTS AND METHOD: We studied habituation in 37 healthy fetuses in two tests with an interval of 10 min. The vibroacoustic stimuli were applied to the maternal abdomen above the fetal legs for a period of 1 s every 30 s. A fetal trunk movement within 1 s after stimulation was defined as a positive response. Habituation rate is defined as the number of stimuli applied before an observed non-response to four consecutive stimuli. The FHR patterns (FHRP) of the 10 min observation period before and after the tests were visually classified. Fetal states were defined according to the FHRP. Baseline FHR, FHR variability and the number of accelerations were calculated in a subgroup of 25 fetuses. RESULTS: Of the 32 fetuses that responded normally during the first test, 26 habituated and six had persistent responses. The median habituation rate decreased significantly in the second test (P=0.001). There was no difference in habituation rate between fetuses that where initially in a quiet state and those in an active state. The FHR parameters before the first test and the difference between these FHR parameters before and after the test did not correlate with the habituation rate. CONCLUSIONS: Although the majority of healthy fetuses was able to habituate, the interfetal variability in habituation performance is such that testing of habituation seems not to be a sensitive tool for the assessment of the fetal CNS. This variability is neither the result of differences in fetal state nor of the various FHR parameters before testing, nor of the difference in change of FHR parameters arising from stimulation.

Atrial fibrillation in the goat induces changes in monophasic action potential and mRNA expression of ion channels involved in repolarization.

INTRODUCTION: Sustained atrial fibrillation (AF) is characterized by a marked shortening of the atrial effective refractory period (AERP) and a decrease or reversal of its physiologic adaptation to heart rate. The aim of the present study was to investigate whether the AF-induced changes in AERP in the goat are associated with changes in the atrial monophasic action potential (MAP) and whether an abnormal expression of specific ion channels underlies such changes. METHODS AND RESULTS: Following thoracotomy, MAPs were recorded from the free wall of the right atrium both before induction of AF (control) and after cardioversion of sustained AF (>2 months) in chronically instrumented goats. In control goats, MAP duration at 80% repolarization (MAPD80) shortened (P < 0.01) from 132+/-4 msec during slow pacing (400-msec interval) to 86+/-10 msec during fast pacing (180 msec). After cardioversion of sustained AF, the MAPD80 during slow pacing was as short as 67+/-5 msec (electrical remodeling). Increasing the pacing rate resulted in prolongation (P = 0.02) of the MAPD80 to 91+/-6 msec. Also, MAPD20 (20% repolarization) shortened (P = 0.05) from 32+/-4 msec (400 msec) to 14+/-7 msec (180 msec) in the control goats, whereas it prolonged (P = 0.03) from 20+/-3 msec (400 msec) to 33+/-5 msec (180 msec) in sustained AF. mRNA expression of the L-type Ca2+ channel alpha1c gene and Kv1.5 potassium channel gene, which underlie ICa and IKur, respectively, was reduced in sustained AF compared with sinus rhythm by 32% (P = 0.01) and 45% (P < 0.01), respectively. No significant changes were found in the mRNA levels of the rapid Na+ channel, the Na+/Ca2+ exchanger, or the Kv4.2/4.3 channels responsible for Ito. CONCLUSION: AF-induced electrical remodeling in the goat comprises shortening of MAPD and reversal of its physiologic rate adaptation. Changes in the time course of repolarization of the action potential are associated with changes in mRNA expression of the alpha subunit genes of the L-type Ca2+ channel and the Kv1.5 potassium channel.

Effect of low-sodium diet on uteroplacental circulation.

OBJECTIVE: To study the influence of chronic dietary sodium restriction on uteroplacental circulation. METHODS: In a randomized trial, Doppler flow velocity waveforms of the uterine and umbilical artery were studied at monthly intervals during pregnancy in 59 women on a low-sodium diet and in 68 controls. RESULTS: Pulsatility index (PI), resistance index (RI), and A/B ratio of the uterine artery were significantly lower during sodium restriction, whereas PI, RI, and A/B ratio of the umbilical artery were significantly higher. CONCLUSIONS: The lower resistance indices of the uterine artery during sodium restriction might reflect an increase in pulse pressure/impedance ratio as a result of activation of the renin-angiotensin system. The increase in umbilical artery resistance indices supports the hypothesis that fetal circulation might be altered by chronic dietary sodium restriction.

Urinary prostaglandin excretion in pregnancy: the effect of dietary sodium restriction.

INTRODUCTION: Dietary sodium restriction results in activation of the renin-angiotensin-aldosterone-system. In the non-pregnant situation renin release in response to a low sodium diet is mediated by prostaglandins. We studied the effect of dietary sodium restriction on urinary prostaglandin metabolism in pregnancy. PATIENTS AND METHODS: In a randomized, longitudinal study the excretion of urinary metabolites of prostacyclin (6-keto-PGF(1 alpha)and 2,3-dinor-6-keto-PGF(1 alpha)) and thromboxane A(2)(TxB(2)and 2,3-dinor-TxB(2)) was determined throughout pregnancy and post partum in 12 women on a low sodium diet and in 12 controls. RESULTS: In pregnancy the excretion of all urinary prostaglandins is increased. The 6-keto-PGF(1 alpha)/ TxB(2)-ratio as well as the 2, 3-dinor-6-keto-PGF(1 alpha)/ 2,3-dinor-TxB(2)-ratio did not significantly change in pregnancy. CONCLUISION Prostacyclin and thromboxane do not seem to play an important role in sodium balance during pregnancy.

Responses to vibroacoustic stimulation in a fetus with an encephalocele compared to responses of normal fetuses.

BACKGROUND: Observation of fetal movement and fetal heart rate (FHR) responses to repeated vibroacoustic stimulation (VAS) might be useful as a measure to assess fetal well-being and to assess the integrity of the fetal central nervous system (CNS). We observed the movement and FHR responses to repeated VAS of a term fetus with a serious brain anomaly as compared to responses of normal term fetuses. SUBJECTS, METHODS, RESULTS: In 37 normal term fetuses and in a term fetus with an encephalocele we studied movement and FHR response to repeated VAS. All normal fetuses responded within 1 s after stimulation with general body movement and FHR acceleration. At 36 gestational weeks, no movement or FHR responses were seen in the fetus with an encephalocele. Repetition of the test in this fetus after one week still showed no response to repeated VAS. CONCLUSION: Normal fetuses showed movement and FHR responses to external stimulation. The fetus with an encephalocele did not respond to repeated VAS with a movement or FHR acceleration. Case studies in fetuses with structural anomalies of the CNS are needed to gain insight into the spectrum of possible responses to VAS.