A Novel Role for the Histone Demethylase JMJD3 in Mediating Heroin-induced Relapse-Like Behaviors.

BACKGROUND: Epigenetic changes, leading to long-term neuroadaptations following opioid exposure are not well understood. We examined how histone demethylase JMJD3 in the nucleus accumbens (NAc) influences heroin seeking after abstinence from self-administration. METHODS: Male Sprague-Dawley rats were trained to self-administer heroin. Western blotting and qPCR were performed to quantify JMJD3 and bone morphogenetic protein (BMP) pathway expression in the NAc (n = 7-11/group). Pharmacological inhibitors or viral expression vectors were microinfused into the NAc to manipulate JMJD3 or the BMP pathway member SMAD1 (n = 9-11/group). The RiboTag capture method (n = 3-5/group) and viral vectors (n = 7-8/group) were used in male transgenic rats to identify the contributions of D1- and D2-type medium spiny neurons (MSN) in the NAc. Drug-seeking was tested by cue-induced response previously paired with drug infusion. RESULTS: Levels of JMJD3 and phosphorylated SMAD1/5 in the NAc were increased after 14 days of abstinence from heroin self-administration. Pharmacological and virus-mediated inhibition of JMJD3 or the BMP pathway attenuated cue-induced seeking. Pharmacological inhibition of BMP signaling reduced JMJD3 expression and histone 3 lysine 27 trimethylation (H3K27me3) levels. JMJD3 bidirectionally affected seeking: expression of the wild type increased whereas expression of a catalytic dead mutant decreased cue-induced seeking. JMJD3 expression was increased in D2+ but not D1+ MSNs. Expression of the mutant JMJD3 in D2+ neurons was sufficient to decrease cue-induced heroin seeking. CONCLUSIONS: JMJD3 mediates persistent cellular and behavioral adaptations underlying heroin relapse and this activity is regulated by the BMP pathway.

Effects of escitalopram on sleep problems in patients with major depression or generalized anxiety disorder.

INTRODUCTION: Disturbed sleep is a key symptom in major depressive disorder (MDD) and generalized anxiety disorder (GAD). First-line antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs), may have different effects on sleep. METHODS: Data from 22 randomized, controlled trials comparing escitalopram with SSRIs, SNRIs, or placebo in the treatment of adult MDD or GAD were included. Both last observation carried forward (LOCF) and repeated measurements (MMRM) were used to analyze the sleep item of the Montgomery Åsberg Depression Rating Scale (MADRS) or Hamilton Anxiety Rating Scale (HAM-A) after 8 weeks of treatment. Sleep-related treatment-emergent adverse events were also compared across groups. RESULTS: For patients with MDD (n = 5133), the treatment difference on MADRS item 4 ("reduced sleep") was significantly in favor of escitalopram versus placebo (LOCF [P = 0.0017] and MMRM [P = 0.0002]), versus SSRIs (LOCF [P = 0.0020] and MMRM [P < 0.0031]), and versus SNRIs (LOCF [P = 0.0002] and MMRM [P = 0.0352]). For the 53% of patients with MDD who suffered from sleep problems at baseline (baseline MADRS item 4 score ≥ 4), the improvement in sleep symptoms was significantly in favor of escitalopram versus placebo (LOCF [P = 0.0022] and MMRM [P < 0.0005]), versus SSRIs (LOCF [P = 0.0001] and MMRM [P = 0.0002]), and versus SNRIs (LOCF [P < 0.0067] but not MMRM [P > 0.0787]). For patients with GAD (n = 2052) the treatment difference in sleep symptoms measured by HAM-A item 4 ("insomnia") was significantly in favor of escitalopram versus placebo (LOCF [P = 0.0005] and MMRM [P < 0.0001]), but not different to paroxetine or venlafaxine. The same pattern was seen for the large proportion (67%-82%) of GAD patients reporting sleep problems at baseline (baseline HAM-A item 4 score ≥ 2). In MDD, the rate of insomnia as an adverse event after escitalopram was higher than placebo, similar to SSRIs, and lower than SNRIs. CONCLUSIONS: Additional research assessing the comparative effects of antidepressants with polysomnography is needed. In the interim, from a clinical perspective, escitalopram appears to be beneficial for the treatment of sleep problems in MDD and GAD.

Coronary artery plaque burden does not affect left ventricular diastolic function in asymptomatic adults with normal ejection fraction.

BACKGROUND: Coronary artery disease (CAD) is commonly cited as a mechanism underlying diastolic dysfunction. However, the association of CAD without ischemia and left ventricular (LV) diastolic dysfunction has not been convincingly demonstrated in asymptomatic patients. The objective of this study was to determine if such a relation exists using coronary artery calcium score (CACS) as a surrogate for coronary atherosclerosis burden. METHODS: Consecutive eligible patients with normal ejection fraction who underwent CACS assessment, echocardiography, and stress testing with negative results for obstructive CAD between August 2006 and September 2007 were included in this retrospective study. Clinical variables were collected from the medical record. Diastolic function classification was based on established echocardiographic guidelines recommended by the American Society of Echocardiography. Statistical analysis was used to identify predictors of CACS. RESULTS: A total of 349 subjects (302 men) aged 58 ± 6 years were studied. Risk factors included hyperlipidemia (n = 202 [58%]), hypertension (n = 127 [36%]), impaired fasting glucose (n = 78 [22%]), and diabetes (n = 21 [6%]). Left atrial volume index was weakly correlated with CACS (r = 0.26, P < .001). There was no significant relationship between CACS and LV diastolic function grade in the entire group (P = .14) or in a subgroup of younger patients (n = 140) who matched the ages qualifying for premature CAD (P = .17). After stepwise elimination multivariate analysis, five variables independently predicted CACS: age (P < .001), hyperlipidemia (P < .001), LA volume index (P < .001), male gender (P = .01), and LV posterior wall thickness (P = .03). CONCLUSIONS: In asymptomatic patients with normal LV ejection fraction and negative cardiac stress test results, CACS does not correlate with LV diastolic function as defined by established Doppler echocardiographic criteria. In the absence of ischemia, postinfarction LV remodeling, or previous coronary artery bypass surgery, CAD does not appear be a cause of LV diastolic dysfunction in asymptomatic patients.

Acute and transient psychosis in old age and the subsequent risk of dementia: a nationwide register-based study.

AIM: Using the unique Danish psychiatric and somatic health registers, we investigated the rate of subsequent dementia in patients with late-onset acute and transient psychosis. METHODS: By linkage of the psychiatric and the somatic nationwide registers of all patients with in- or outpatient hospital contact in Denmark, we included all patients with a first ever contact during the period 1 January 1994 to 31 December 2001 with one of the main index diagnoses: late-onset acute and transient psychosis or osteoarthritis. Data on the general population were also included. The first diagnosis of dementia for each individual at discharge or at outpatient contact was established. Poisson regression models were used to compare the cohorts of patients with dementia as the outcome of interest. RESULTS: Using a cut-off age of 60 years, 8062 individuals were included. Significant associations were found between a subsequent diagnosis of dementia and the index diagnosis, age and calendar time. Overall, the rate ratio for developing dementia in late-onset acute and transient psychosis compared to osteoarthritis patients was 10.86 (95% confidence intervals, 8.42 and 14.00, respectively), however, the magnitude of the rate ratio varied according to sex, age, duration since diagnosis and calendar time. Compared to the general population, the rate ratio was 8.12 (95% confidence intervals, 6.77 and 9.74, respectively). CONCLUSION: The present study has established that subjects with late-onset acute and transient psychosis are at 11 times higher risk of subsequently getting a diagnosis of dementia compared to patients with osteoarthritis, and at 8 times higher risk compared to the general population.

Association between consistent purchase of anticonvulsants or lithium and suicide risk: a longitudinal cohort study from Denmark, 1995-2001.

BACKGROUND: Prior studies suggest anticonvulsants purchasers may be at greater risk of suicide than lithium purchasers. METHODS: Longitudinal, retrospective cohort study of all individuals in Denmark purchasing anticonvulsants (valproic acid, carbamazepine, oxcarbazepine or lamotrigine) (n=9952) or lithium (n=6693) from 1995-2001 who also purchased antipsychotics at least once (to select out nonpsychiatric anticonvulsant use). Poisson regression of suicides by medication purchased (anticonvulsants or lithium) was conducted, controlling for age, sex, and calendar year. Confounding by indication was addressed by restricting the comparison to individuals prescribed the same medication: individuals with minimal medication exposure (e.g., who purchased only a single prescription of anticonvulsants) were compared to those individuals with more consistent medication exposure (i.e., purchasing > or = 6 prescriptions of anticonvulsants). RESULTS: Demographics and frequency of anticonvulsant, lithium, or antipsychotic use were similar between lithium and anticonvulsant purchasers. Among patients who also purchased antipsychotic at least once during the study period, purchasing anticonvulsants more consistently (> or = 6 prescriptions) was associated with a substantial reduction in the risk of suicide (RR=0.22, 95% CI=0.11-0.42, p<0.0001), similar to patients consistently purchasing lithium (RR=0.27, 95% CI=0.12-0.62, p=0.006). Absolute suicide risks of consistent anticonvulsant and consistent lithium purchasers were similar. LIMITATIONS: Lack of information about diagnoses and potential confounders, as well as other covariates that may differ between minimal and consistent medication purchasers, are limitations to this study. CONCLUSIONS: In this longitudinal study of anticonvulsant purchasers likely to have psychiatric disorders, consistent anticonvulsant treatment was associated with decreased risk of completed suicide.

Stratification for smoking in case-cohort studies of genetic polymorphisms and lung cancer.

The risk estimates obtained in studies of genetic polymorphisms and lung cancer differ markedly between studies, which might be due to chance or differences in study design, in particular the stratification/match of comparison group. The effect of different strategies for stratification and adjustment for smoking on the estimated effect of polymorphisms on lung cancer risk was explored in the case-cohort design. We used an empirical and a statistical simulation approach. The stratification strategies were: no smoking stratification, stratification for smoking status and stratification for smoking duration. The study base was a prospective follow-up study with 57,053 participants. In the simulation approach the glutathione S-transferase T1 null polymorphism, as a model of any polymorphism, was added to simulated data in two different ways, assuming either absence or presence of association with smoking. In the empirical approach the risk estimates of the investigated polymorphisms differed between the three different stratification strategies. Simulated data with neither stratification nor adjustment for smoking resulted in low biases and narrow confidence intervals (CI) in the absence of a genotype-smoking association and markedly higher biases in the presence of a genotype-smoking association. In study designs stratified by smoking, low biases and narrow CI spans were found, regardless of a genotype-smoking association. Stratification for smoking seems to be advantageous in case-cohort studies of genetic polymorphisms and lung cancer.

Late and very-late first-contact schizophrenia and the risk of dementia--a nationwide register based study.

OBJECTIVE: To examine whether late and very-late first-contact schizophrenia carry a risk for later development of dementia. METHODS: By linkage of the psychiatric and the somatic nation-wide registers of all out- and in-patients with hospital contact in Denmark, we identified all patients with first ever contact during the period from January 1994 to December 2001 with one of the index main diagnoses: late (age >or=40) and very-late first-contact (age >or=60) schizophrenia. First contact osteoarthritis patients as well as data on the general population were used as controls. The first diagnosis of dementia for each individual at discharge or at out-patient contact was established. The probability of getting a dementia diagnosis is estimated using Poisson regression models with dementia as the outcome of interest. RESULTS: Twelve thousand six hundred and sixteen and 7,712 individuals were included in the late and very-late sample, respectively. Follow-up time was between 3.00 and 4.58 years. The rate ratio (RR) of developing dementia in late and very-late first-contact schizophrenia compared to osteoarthritis patients were 3.47 (95%CI: 2.19-5.50) and 3.15 (95%CI: 1.93-5.14), respectively. Compared to the general population the RR were 2.36 (95%CI: 1.54-3.62) and 2.21 (95%CI: 1.39-3.50), respectively. CONCLUSION: schizophrenic patients with late- and very-late first-contact with the psychiatric hospital system are at two to three times higher risk of subsequently getting a diagnosis of dementia compared to patients with osteoarthritis and compared to the general population.

Factors that affect the social well-being of children with cochlear implants.

The aim of the study was to identify factors associated with the level of social well-being for cochlear implanted children and to estimate effect-related odds ratios for the children's well-being. Another aim was to analyse associations between speech and language level and the level of social well-being. Data relate to 167 children with cochlear implants. In structural interviews, parents rated their children's level of social well-being regarding the degree of their child's personal-social adjustment. Five different factors were considered. Logistic regression models and proportional odds models were used to analyse the relationship between the considered factors and the assessments. The analyses showed that the communication mode at home was the most highly associated factor. A statistically significant association was found between the level of social well-being and speech understanding, speech production and vocabulary. Children who were exposed to a spoken language had considerably better odds of having a high level of social well-being compared to children with a mixture of spoken language and sign support or sign language.

Mood-stabilizing pharmacological treatment in bipolar disorders and risk of suicide.

OBJECTIVES: This study investigated the association between continued mood-stabilizing treatment (lithium and anticonvulsants) in bipolar disorder (BD) and the risk of suicide. METHODS: Using linkage of national registers, the association between continued mood-stabilizing treatment and suicide was investigated among all patients discharged nationwide from hospital psychiatry as an in- or outpatient in a period from 1995 to 2000 in Denmark with a diagnosis of BD. RESULTS: A total of 5,926 patients were included in the study and among these 51 patients committed suicide eventually during the study period. Although the rate of suicide was higher during periods when patients purchased anticonvulsants (293 suicides per 100,000 person-years) than during periods with lithium (136 suicides per 100,000 person-years), the suicide rate decreased with the number of prescriptions in a rather similar way for patients first treated with lithium and patients first treated with anticonvulsants: patients who continued treatment with mood-stabilizing drugs had a decreased rate of suicide compared to patients who purchased mood stabilizers once only [rate ratio for anticonvulsants = 0.28, 95% confidence interval (CI) = 0.19-0.41; rate ratio for lithium = 0.20, 95% CI = 0.10-0.38]. Further, the rate of suicide decreased consistently with the number of additional prescriptions. Switch to or augmentation with lithium to patients initiated on anticonvulsants was associated with a significantly reduced rate of suicide (rate ratio = 0.28, 95% CI = 0.20-0.40), whereas a switch to or augmentation with anticonvulsants to patients first started on lithium showed no additional effect on the suicide rate. CONCLUSIONS: Although continued treatment with anticonvulsants and continued treatment with lithium was associated with a rather similar reduction in the rate of suicide, the results suggest that treatment with lithium may have some superiority in relation to prevention of suicide.

Functional implications of short-term retinal detachment in porcine eyes: study by multifocal electroretinography.

PURPOSE: The aim of the study was to determine the type and magnitude of detectable changes in pig multifocal electroretinography (mfERG) induced by the vitreoretinal surgical procedures necessary to gain access to the subretinal space. METHODS: Twenty pigs underwent posterior segment surgery. Six animals had a vitrectomy (V), six had in addition a retinal bleb detachment (V + B); five had in addition a retinal diathermia on the bleb (V + B + D) and three received a retinotomy in the diathermized retinal area (V + B + D + R). mfERG evaluation was performed at baseline and 1 and 6 weeks postoperatively. Selected eyes were enucleated for histological evaluation. RESULTS: The retinal detachments blebs all reattached spontaneously. All four surgical sequences resulted in slight, non-significant changes in the mfERG peaks. A trend towards an amplitude reduction of the mfERG peaks N1, P1 and N2 were observed within the first postoperative week. After 6 weeks, all amplitudes had normalized. Of the implicit times only that of peak N1 (after retinal diathermia) was prolonged significantly at 1 week (P = 0.037). However, it returned to the preoperative level after 6 weeks. Histologically, the retinal detachment bleb was characterized by transient double layering of the retinal pigment epithelium (RPE) and loss photoreceptor outer segments. CONCLUSION: Access to the subretinal space in pigs can be gained without permanent detectable changes in the mfERG. A short-term retinal detachment was found to cause only reversible electrophysiological and histological changes in the outer retina, which suggests that this procedure is tolerated well in the porcine retina. The size of the known destructive lesion (retinotomy) was too small to be detected, given the spatial resolution of the mfERG method applied. In the future, the presented protocol can be used to assess the functional outcome of surgery and transplantation in the subretinal space in pigs.

The multifocal electroretinogram (mfERG) in the pig.

PURPOSE: To establish a method allowing multifocal electroretinography (mfERG) recording with simultaneous fundus monitoring on anaesthetized pigs. In addition we characterize the peaks of the porcine mfERG trace, and compare the visual streak area with the optic nerve head, a known non-response area. Finally we illustrate the feasibility of the method by performing mfERG after an induced laser burn in the visual streak. METHODS: Fifteen pigs underwent mfERG recordings at baseline, and after 1 and 6 weeks of observation. One pig was evaluated before and after retinal diode laser treatment in the visual streak. RESULTS: The porcine mfERG trace appears similar to the human mfERG trace, and can be described by three peaks named N1, P1 and N2. Significantly faster implicit time was found in the visual streak regarding N1 (P < 0.001) than in areas outside the visual streak. Amplitudes of all three peaks were increased in the visual streak (P < 0.005). The laser-treated area was characterized by a response similar to what is found at the location of the optic nerve head. CONCLUSION: Porcine mfERG is similar in appearance to the human response and can be described by the same three peaks. Significantly higher amplitudes of all three peaks are found in the visual streak when compared to the optic nerve head and inferior retina. We have detected the functional deficit caused by a laser burn at the size of 3 x 3 mm.

Continued antidepressant treatment and suicide in patients with depressive disorder.

Antidepressant use in Denmark, as in many developed countries, has substantially increased during recent years, coinciding with a decreasing suicide rate. In a nationwide observational cohort study with linkage of registers of all prescribed antidepressants and recorded suicides in Denmark from 1995 to 2000, we investigated the relation between continued treatment with antidepressants and suicide in a population of all patients discharged from hospital psychiatry with a diagnosis of depressive disorder. Patients discharged from hospital psychiatry with a diagnosis of depressive disorder had a highly increased rate of suicide. Those who continued treatment with antidepressants had a decreased rate of suicide compared with those who purchased antidepressants once (rate ratio: 0.31, 95% confidence interval: 0.26-0.36). Further, the rate of suicide decreased consistently with the number of prescriptions. On individualized data from a cohort of patients with a known history of depressive disorder, continued antidepressant treatment was associated with reduced risk of suicide.