Several lines of evidence suggest that fluctuations in endogenous levels of the γ-aminobutyric acid (GABA)ergic neurosteroid allopregnanolone (ALLO) represent one mechanism for regulation of GABAergic inhibitory tone in the brain, with an ultimate impact on behavior. Consistent with this idea, there was an inverse relationship between ALLO levels and symptoms of anxiety and depression in humans and convulsive activity in rodents during alcohol withdrawal. Our recent studies examined activity and expression of 5α-reductase (Srd5a1), the rate-limiting enzyme in the biosynthesis of ALLO, during alcohol withdrawal in mice selectively bred for high chronic alcohol withdrawal (Withdrawal Seizure-Prone, WSP) and found that Srd5a1 was down-regulated in the cortex and hippocampus over the time course of dependence and withdrawal. The purpose of the present studies was to extend these findings and more discretely map the regions of Srd5a1 expression in mouse brain using radioactive in situ hybridization in WSP mice that were ethanol naïve, following exposure to 72 h ethanol vapor (dependent) or during peak withdrawal. In naïve animals, expression of Srd5a1 was widely distributed throughout the mouse brain, with highest expression in specific regions of the cerebral cortex, hippocampus, thalamus, hypothalamus, and amygdala. In dependent animals and during withdrawal, there was no change in Srd5a1 expression in cortex or hippocampus, which differed from our recent findings in dissected tissues. These results suggest that local Srd5a1 mRNA expression in WSP brain may not change in parallel with local ALLO content or withdrawal severity.
ethanol; neurosteroid; GABA; convulsion; in situ hybridization
This study compared the incidence of cardiovascular disease (CVD) and acute myocardial infarction (AMI) between native Danes and immigrants born in Turkey, Pakistan and the former Yugoslavia. Furthermore, we examined whether different indicators of socioeconomic status (SES), such as employment, income and housing conditions influenced potential differences.
In this registry-based follow-up study individuals were identified in a large database that included individuals from two major regions in Denmark, corresponding to about 60% of the Danish population. Incident cases of CVD and AMI included fatal and non-fatal events and were taken from registries. Using Cox regression models, we estimated incidence rates at 5-year follow-up.
Immigrant men and women from Turkey and Pakistan had an increased incidence of CVD, compared with native Danish men. In the case of AMI, a similar pattern was observed; however, differences were more pronounced. Pakistanis and Turks with a shorter duration of residence had a lower incidence, compared with those of a longer residence. Generally, no notable differences were observed between former Yugoslavians and native Danes. In men, differences in CVD and AMI were reduced after adjustment for SES, in particular, among Turks regarding CVD. In women, effects were particularly reduced among Yugoslavians in the case of CVD and in Turks in the case of CVD and AMI after adjustment for SES.
In conclusion, country of birth-related differences in the incidence of CVD and AMI were observed. At least some of the differences that we uncovered were results of a socioeconomic effect. Duration of residence also played a certain role. Future studies should collect and test different indicators of SES in studies of CVD among immigrants.
We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis.
Hormones secreted from the pituitary gland regulate important processes such as development, growth and metabolism, reproduction, water balance, and body pigmentation. Synthesis and secretion of pituitary hormones are regulated by different factors from the hypothalamus, but also through feedback mechanisms from peripheral organs, and from the pituitary itself. In the European eel extensive attention has been directed towards understanding the different components of the brain-pituitary-gonad axis, but little is known about the regulation of upstream processes in the pituitary gland. In order to gain a broader mechanistic understanding of the eel pituitary gland, we have performed RNA-seq transcriptome profiling of the pituitary of prepubertal female silver eels. RNA-seq reads generated on the Illumina platform were mapped to the recently assembled European eel genome. The most abundant transcript in the eel pituitary codes for pro-opiomelanocortin, the precursor for hormones of the melanocortin system. Several genes putatively involved in downstream processing of pro-opiomelanocortin were manually annotated, and were found to be highly expressed, both by RNA-seq and by qPCR. The melanocortin system, which affects skin color, energy homeostasis and in other teleosts interacts with the reproductive system, has so far received limited attention in eels. However, since up to one third of the silver eel pituitary’s mRNA pool encodes pro-opiomelanocortin, our results indicate that control of the melanocortin system is a major function of the eel pituitary.
Various inflammatory biomarkers show prognostic potential for multiple sclerosis (MS)-risk after clinically isolated syndromes. However, biomarkers are often examined singly and their interrelation and precise aspects of their associated pathological processes remain unclear. Clarification of these relationships could aid the appropriate implementation of prognostic biomarkers in clinical practice.
To investigate the interrelation between biomarkers of inflammation, demyelination and neurodegeneration in acute optic neuritis and to assess their association to measures of MS risk.
Material and Methods
A prospective study at a tertiary referral centre from June 2011 to December 2012 of 56 patients with optic neuritis as a first demyelinating symptom and 27 healthy volunteers. Lumbar puncture was performed within 28 (median 16) days of onset. CSF levels of CXCL13, matrix metalloproteinase (MMP)-9, CXCL10, CCL-2, osteopontin and chitinase-3-like-1, myelin basic protein (MBP) and neurofilament light-chain (NF-L) were determined. MS-risk outcome measures were dissemination in space (DIS) of white matter lesions on cerebral MRI, CSF oligoclonal bands and elevated IgG-index.
In the interrelation analysis the biomarkers showed close correlations within two distinct groups: Biomarkers of leukocyte infiltration (CXCL13, MMP-9 and CXCL10) were strongly associated (p<0.0001 for all). Osteopontin and chitinase-3-like-1 were also tightly associated (p<0.0001) and correlated strongly to tissue damage markers (NF-L and MBP). The biomarkers of leukocyte infiltration all associated strongly with MS-risk parameters, whereas CHI3L1 and MBP correlated with MRI DIS, but not with CSF MS-risk parameters and osteopontin and NF-L did not correlate with any MS-risk parameters.
Our findings suggest two distinct inflammatory processes: one of leukocyte infiltration, represented by CXCL13, CXCL10 and MMP-9, strongly associated with and potentially predicting MS-risk; the other represented by osteopontin and CHI3L1, suggesting tissue damage-related inflammation, potentially predicting residual disabilities after attack and perhaps cumulative damage over time. These hypotheses should be further addressed in follow-up studies.
Individuals with 22q11.2 deletion syndrome (22q11.2DS) evince a 30% incidence of schizophrenia. We compared the white matter (WM) of 22q11.2DS patients without schizophrenia to a group matched healthy controls using Tract-Based-Spatial-Statistics (TBSS). We found localized reduction of Fractional Anisotropy (FA) and Axial Diffusivity (AD; measure of axonal integrity) in WM underlying the left parietal lobe. No changes in Radial Diffusivity (RD; measure of myelin integrity) were observed. Of note, studies in chronic schizophrenia patients report reduced FA, no changes in AD, and increases in RD in WM. Our findings suggest different WM microstructure in 22q11.2DS than in patients with schizophrenia.
22q11.2 deletion syndrome (22q11.2DS); schizophrenia; Diffusion Tensor Magnetic Resonance Imaging (DT-MRI); fractional anisotropy (FA); axial and radial diffusivity; Tract-Based Spatial Statistics (TBSS)
RarA is an AraC-type regulator in Klebsiella pneumoniae, which, when overexpressed, confers a low-level multidrug-resistant (MDR) phenotype linked to the upregulation of both the acrAB and oqxAB efflux genes. Increased rarA expression has also been shown to be integral in the development of tigecycline resistance in the absence of ramA in K. pneumoniae. Given its phenotypic role in MDR, microarray analyses were performed to determine the RarA regulon. Transcriptome analysis was undertaken using strains Ecl8ΔrarA/pACrarA-2 (rarA-expressing construct) and Ecl8ΔrarA/pACYC184 (vector-only control) using bespoke microarray slides consisting of probes derived from the genomic sequences of K. pneumoniae MGH 78578 (NC_009648.1) and Kp342 (NC_011283.1). Our results show that rarA overexpression resulted in the differential expression of 66 genes (42 upregulated and 24 downregulated). Under the COG (clusters of orthologous groups) functional classification, the majority of affected genes belonged to the category of cell envelope biogenesis and posttranslational modification, along with genes encoding the previously uncharacterized transport proteins (e.g., KPN_03141, sdaCB, and leuE) and the porin OmpF. However, genes associated with energy production and conversion and amino acid transport/metabolism (e.g., nuoA, narJ, and proWX) were found to be downregulated. Biolog phenotype analyses demonstrated that rarA overexpression confers enhanced growth of the overexpresser in the presence of several antibiotic classes (i.e., beta-lactams and fluoroquinolones), the antifungal/antiprotozoal compound clioquinol, disinfectants (8-hydroxyquinoline), protein synthesis inhibitors (i.e., minocycline and puromycin), membrane biogenesis agents (polymyxin B and amitriptyline), DNA synthesis (furaltadone), and the cytokinesis inhibitor (sanguinarine). Both our transcriptome and phenotypic microarray data support and extend the role of RarA in the MDR phenotype of K. pneumoniae.
The giant water bug (Abedus herberti) is a large flightless insect that is a keystone predator in aridland aquatic habitats. Extended droughts, possibly due to climate change and groundwater pumping, are causing once-perennial aquatic habitats to dry, resulting in serious conservation concern for some populations. A. herberti also exhibits exclusive male parental care, which has made it a model organism for studying mating systems evolution. Here we describe 17 novel polymorphic microsatellite loci developed for A. herberti. Number of alleles per locus ranged from 2 to 15, and average observed and expected heterozygosities were 0.579 and 0.697, respectively. These loci can successfully resolve both population genetic structure among sites separated by 3–100 km (FST = 0.08–0.21, P < 0.0001), and divergent mating strategies within local populations, making them highly useful for conservation genetics studies of this vulnerable species.
Hemiptera; Stream ecology; Mating systems; Polygyny; Population genetics
The subcutaneous implantable cardioverter-defibrillator (S-ICD) has recently been approved for commercial use in Europe, New Zealand and the United States. It is comprised of a pulse generator, placed subcutaneously in a left lateral position, and a parasternal subcutaneous lead-electrode with two sensing electrodes separated by a shocking coil. Being an entirely subcutaneous system it avoids important periprocedural and long-term complications associated with transvenous implantable cardioverter-defibrillator (TV-ICD) systems as well as the need for fluoroscopy during implant surgery. Suitable candidates include pediatric patients with congenital heart disease that limits intracavitary lead placements, those with obstructed venous access, chronic indwelling catheters or high infection risk, as well as young patients with electrical heart disease (e.g., Brugada Syndrome, long QT syndrome, and hypertrophic cardiomyopathy). Nevertheless, given the absence of intracavitary leads, the S-ICD is unable to offer pacing (apart from short-term post-shock pacing). It is therefore not suitable in patients with an indication for antibradycardia pacing or cardiac resynchronization therapy, or with a history of repetitive monomorphic ventricular tachycardia that would benefit from antitachycardia pacing. Current data from initial clinical studies and post-commercialization “real-life” case series, including over 700 patients, have so far been promising and shown that the S-ICD successfully converts induced and spontaneous ventricular tachycardia/ventricular fibrillation episodes with associated complication and inappropriate shock rates similar to that of TV-ICDs. Furthermore, by using far-field electrograms better tachyarrhythmia discrimination when compared to TV-ICDs has been reported. Future results from ongoing clinical studies will determine the S-ICD system’s long-term performance, and better define suitable patient profiles.
Implantable cardioverter-defibrillator; Subcutaneous; Sudden death; Ventricular tachycardia; Ventricular fibrillation
AAV vectors have shown great promise for clinical gene therapy (GT), but pre-existing human immunity against the AAV capsid often limits transduction. Thus, testing promising AAV-based GT approaches in an animal model with similar pre-existing immunity could better predict clinical outcome. Sheep have long been used for basic biological and preclinical studies. Moreover, we have re-established a line of sheep with severe hemophilia A (HA). Given the impetus to use AAV-based GT to treat hemophilia, we characterized the pre-existing ovine humoral immunity to AAV. ELISA revealed naturally-occurring antibodies to AAV1, AAV2, AAV5, AAV6, AAV8, and AAV9. For AAV2, AAV8, and AAV9 these inhibit transduction in a luciferase-based neutralization assay. Epitope mapping identified peptides that were common to the capsids of all AAV serotypes tested (AAV2, AAV5, AAV8 and AAV9), with each animal harboring antibodies to unique and common capsid epitopes. Mapping using X-ray crystallographic AAV capsid structures demonstrated that these antibodies recognized both surface epitopes and epitopes located within regions of the capsid that are internal or buried in the capsid structure. These results suggest that sheep harbor endogenous AAV, which induces immunity to both intact capsid and to capsid epitopes presented following proteolysis during the course of infection. In conclusion, their clinically relevant physiology and the presence of naturally-occurring antibodies to multiple AAV serotypes collectively make sheep a unique model in which to study GT for HA, and other diseases, and develop strategies to circumvent the clinically important barrier of pre-existing AAV immunity.
Serum markers of inflammation are candidate biomarkers in multiple sclerosis (MS). ω-3 fatty acids are suggested to have anti-inflammatory properties that might be beneficial in MS. We aimed to explore the relationship between serum levels of inflammation markers and MRI activity in patients with relapsing remitting MS, as well as the effect of ω-3 fatty acids on these markers.
We performed a prospective cohort study in 85 relapsing remitting MS patients who participated in a randomized clinical trial of ω-3 fatty acids versus placebo (the OFAMS study). During a period of 24 months 12 repeated magnetic resonance imaging (MRI) scans and nine serum samples were obtained. We measured 10 inflammation markers, including general down-stream markers of inflammation, specific markers of up-stream inflammatory pathways, endothelial action, and matrix regulation.
After Bonferroni correction, increasing serum levels of CXCL16 and osteoprotegerin were associated with low odds ratio for simultaneous MRI activity, whereas a positive association was observed for matrix metalloproteinase (MMP) 9. CXCL16 were also associated with low MRI activity the next month, but this was not significant after Bonferroni correction. In agreement with previously reported MRI and clinical results, ω-3 fatty acid treatment did not induce any change in the inflammation markers.
Serum levels of CXCL16, MMP-9, and osteoprotegerin reflect disease activity in MS, but are not affected by ω-3 fatty acid treatment. CXCL16 could be a novel biomarker and potential predictor of disease activity in MS.
We recently described that the autoimmune, central nervous system disease, multiple sclerosis (MS), is genetically associated with the human endogenous retroviral locus, HERV-Fc1, in Scandinavians. A number of dominant human genes encoding factors that restrict retrovirus replication have been known for a long time. Today human restriction genes for retroviruses include amongst others TRIMs, APOBEC3s, BST2 and TREXs. We have therefore looked for a role of these retroviral restriction genes in MS using genetic epidemiology. We here report that markers in two TRIMs, TRIM5 and TRIM22 and a marker in BST2, associated statistically with the risk of getting MS, while markers in or near APOBEC3s and TREXs showed little or no effect. This indicates that the two TRIMs and BST2 influence the risk of disease and thus supports the hypothesis of a viral involvement.
Assembly effectors are small molecules that induce inappropriate virus capsid assembly to antiviral effect. To identify attributes of hepatitis B virus (HBV) assembly effectors, assembly reaction products (normal capsid, noncapsid polymer, intermediates, and free dimeric core protein) were quantified in the presence of three experimental effectors: HAP12, HAP13, and AT-130. Effectors bound stoichiometrically to capsid protein polymers, but not free protein. Thermodynamic and kinetic effects, not aberrant assembly, correlate with maximal antiviral activity.
Recent evidence suggests that GABAA receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit containing extrasynaptic GABAA receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analogue) and gaboxadol (THIP; a GABAA receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited access self-administration procedures. In separate studies, the effects of GAN (0 – 10 mg/kg) and THIP (2 – 16 mg/kg) were tested in C57BL/6J male mice provided with two-hour access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 minutes of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABAA receptor activation in ethanol reinforcement.
The possibility that retroviruses play a role in multiple sclerosis (MS) has long been considered; accumulating findings suggest this to be most likely in the form of human endogenous retroviruses (HERVs). A genetic test series of fifty endogenous retroviral loci for association with MS in Danes showed SNP markers near a specific endogenous retroviral locus, HERV-Fc1 located on the X-chromosome, to be positive. Bout Onset MS was associated with the HERV-Fc1 locus, while a rarer form, Primary Progressive MS, was not. Moreover, HERV-Fc1 Gag RNA in plasma was increased 4-fold in patients with recent history of attacks, relative to patients in a stable state and to healthy controls.
Finally, genetic variations in restriction genes for retroviruses influence the risk of MS, providing further support for a role of retroviral elements in disease.
We speculate that endogenous retroviruses may activate the innate immune system in a variety of ways, involving the host proteins, TRIMs, TLRs, TREXs and STING. Observations in HIV-positive patients suggest that antiretroviral drugs can curb MS. Thus, these new findings regarding the etiology and pathogenesis of MS, suggest alternative ways to challenge autoimmune diseases.
Multiple sclerosis; Endogenous retroviruses; HERV-Fc1; TRIM; BST2; Genetic association
Spinal stenosis and degenerative spondylolisthesis share many symptoms and the same treatment, but their causes remain unclear. Bone mineral density has been suggested to play a role. The aim of this study was to investigate differences in spinal bone density between spinal stenosis and degenerative spondylolisthesis patients. 81 patients older than 60 years, who underwent DXA-scanning of their lumbar spine one year after a lumbar spinal fusion procedure, were included. Radiographs were assessed for disc height, vertebral wedging, and osteophytosis. Pain was assessed using the Low Back Pain Rating Scale pain index. T-score of the lumbar spine was significantly lower among degenerative spondylolisthesis patients compared with spinal stenosis patients (−1.52 versus −0.52, P = 0.04). Thirty-nine percent of degenerative spondylolisthesis patients were classified as osteoporotic and further 30% osteopenic compared to only 9% of spinal stenosis patients being osteoporotic and 30% osteopenic (P = 0.01). Pain levels tended to increase with poorer bone status (P = 0.06). Patients treated surgically for symptomatic degenerative spondylolisthesis have much lower bone mass than patients of similar age treated surgically for spinal stenosis. Low BMD might play a role in the development of the degenerative spondylolisthesis, further studies are needed to clarify this.
The single coat protein (CP) of bacteriophage Qβ self assembles into T=3 icosahedral virus-like particles (VLPs), of interest for a wide range of applications. These VLPs are very stable, but identification of the specific molecular determinants of this stability is To investigate these determinants along with manipulations that confer more capabilities to our VLP material, we manipulated the CP primary structure to test the importance of various stabilizing interactions. Optimization of a procedure to incorporate fused CP subunits allowed good control over the average number of covalent dimers in each VLP. We confirmed that the disulfide linkages are the most important stabilizing elements for the capsid and that acidic conditions significantly enhance the resistance of VLPs to thermal degradation. Inter-dimer interactions were found to be less important for VLP assembly than intra-dimer interactions. Finally, a single point mutation in the CP resulted in a population of smaller VLPs in three structural forms.
Virus-like particles; mutation; virus stability; self-assembly
Virus-like particles (VLPs) have proven to be versatile platforms for chemical and functionalization for a variety of purposes in biomedicine, catalysis, and materials science. We here the simultaneous modification of the bacteriophage Qβ VLP with a metalloporphyrin derivative photodynamic therapy and a glycan ligand for specific targeting of cells bearing the CD-22 receptor. This application benefits from the presence of the targeting function and the delivery of a high local concentration of singlet oxygen-generating payload.
Virus-like particles; photodynamic therapy; cell targeting
The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25–10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (Cmax) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.
Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of
a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being
Sydenham chorea (SC). Our aim was to develop an animal model that resembled the
behavioral, pharmacological, and immunological abnormalities of SC and other
streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen
exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive
behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker
haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs
that are used to treat motor symptoms and compulsions in streptococcal-related
neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the
striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and
glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of
SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with
tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling
in SK-N-SH neuronal cells, as previously found with sera from SC and related
neuropsychiatric disorders. Our new animal model translates directly to human disease and
led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat
model as well as in SC and other streptococcal-related neuropsychiatric disorders.
streptococcus group A (GAS); Sydenham chorea (SC); PANDAS; dopamine; animal model; autoimmunity
Syncytin-1 and envPb1 are two conserved envelope genes in the human genome encoded by single loci from the HERV-W and -Pb families, respectively. To characterize the role of these envelope proteins in cell–cell fusion, we have developed lentiviral vectors that express short hairpin RNAs for stable knockdown of syncytin-1 and envPb1. Analysis of heterotypic fusion activity between trophoblast-derived choriocarcinoma BeWo cells, in which syncytin-1 and envPb1 are specifically silenced, and endothelial cells demonstrated that both syncytin-1 and envPb1 are important to fusion. The ability to fuse cells makes syncytin-1 and envPb1 attractive candidate molecules in therapy against cancer. Our available vectors may help eventually to decipher roles for these genes in human health and/or disease.
To investigate age-related changes in sleepiness symptoms associated
with sleep disordered breathing (SDB).
Wisconsin Sleep Cohort participants were assessed with
polysomnography, Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency
Test (MSLT). SDB was defined as an apnea/hypopnea index≥15
events/hour, sleepiness as ESS≥10 and MSLT≤5 minutes. Odds
ratios were calculated using generalized estimating equations associating
sleepiness with SDB, and conditional logistic regression examining changes
in longitudinal sleepiness status (ESS only). Models were, a priori,
stratified by gender.
ESS was measured in 1281 participants and MSLT in 998, at multiple
time points (ESS n=3695; MSLT n=1846). Significant interactions were found
between SDB and age in men, but not women. The odds ratios (OR) modeled for
sleepiness in a 40 year old male with SDB were significant, compared to a
male without SDB (OR: ESS 2.1; MSLT 2.9); however, these associations were
not significant at 60 years. The within-subject odds ratio for sleepiness
was also significant at 40 years (OR: 3.4), but not at 60 years.
The age-related reductions in the association between sleepiness and
SDB may have clinical implications for the diagnosis and treatment of SDB in
older people since sleepiness is often used as a therapeutic marker.
Sleep disordered breathing; Obstructive sleep apnea; Aging; Sleepiness
Anecdotal and biographical reports have long suggested that bipolar disorder is more common in people with exceptional cognitive or creative ability. Epidemiological evidence for such a link is sparse. We investigated the relationship between intelligence and subsequent risk of hospitalisation for bipolar disorder in a prospective cohort study of 1,049,607 Swedish men. Intelligence was measured on conscription for military service at a mean age of 18.3 years and data on psychiatric hospital admissions over a mean follow-up period of 22.6 years was obtained from national records. Risk of hospitalization with any form of bipolar disorder fell in a stepwise manner as intelligence increased (p for linear trend <0.0001). However, when we restricted analyses to men with no psychiatric comorbidity, there was a ‘reversed-J’ shaped association: men with the lowest intelligence had the greatest risk of being admitted with pure bipolar disorder, but risk was also elevated among men with the highest intelligence (p for quadratic trend = 0.03), primarily in those with the highest verbal (p for quadratic trend=0.009) or technical ability (p for quadratic trend <0.0001). At least in men, high intelligence may indeed be a risk factor for bipolar disorder, but only in the minority of cases who have the disorder in a pure form with no psychiatric comorbidity.
To examine the use of selective serotonin reuptake inhibitors (SSRIs) among Danish women of childbearing age according to lifestyle factors.
The Central Denmark Region.
4234 women (71.5% of the invited women) aged 25–44 years who participated in a public health survey in 2006.
Prevalence and prevalence ratios (PRs) of current and former SSRI use among women characterised by selected lifestyle factors. We obtained information on SSRI use through linkage to the Aarhus University Prescription Database covering all pharmacies in the region.
Of the 4234 women in the study, 161 (3.8%) were current SSRI users, 60 (1.4%) were recent users, 223 (5.3%) were former users and 3790 (89.5%) were never users. Current use of SSRIs was more prevalent in obese women than in non-obese women (PR 1.5, 95% CI 1.0 to 2.3), in current smokers compared with non-current smokers (PR 1.6, 95% CI 1.1 to 2.2), in women who drank more than seven alcoholic drinks weekly compared with women who drank seven or fewer drinks weekly (PR 1.8, 95% CI 1.2 to 2.8) and in women with an unhealthy diet compared with women with a healthy diet (PR 1.7, 95% CI 1.2 to 2.6). Prevalence of former use of SSRIs was similarly increased except in those with an unhealthy diet (PR 1.1, 95% CI 0.8 to 1.7). SSRI use did not differ according to participation in regular physical activity.
Women with an unhealthy lifestyle were about 1.5-fold more likely to be current or former users of SSRIs than those with a healthy lifestyle. These findings may be useful for quantitative assessment of the contribution of lifestyle factors to uncontrolled confounding in studies of SSRI use in pregnancy.
MENTAL HEALTH; PUBLIC HEALTH
Exposure to early life stress may profoundly influence the developing brain in lasting ways. Neuropsychiatric disorders associated with early life adversity may involve neural changes reflected in EEG power as a measure of brain activity and disturbed sleep. The main aim of the present study was for the first time to characterize possible changes in adult EEG power after postnatal maternal separation in rats. Furthermore, in the same animals, we investigated how EEG power and sleep architecture were affected after exposure to a chronic mild stress protocol. During postnatal day 2–14 male rats were exposed to either long maternal separation (180 min) or brief maternal separation (10 min). Long maternally separated offspring showed a sleep-wake nonspecific reduction in adult EEG power at the frontal EEG derivation compared to the brief maternally separated group. The quality of slow wave sleep differed as the long maternally separated group showed lower delta power in the frontal-frontal EEG and a slower reduction of the sleep pressure. Exposure to chronic mild stress led to a lower EEG power in both groups. Chronic exposure to mild stressors affected sleep differently in the two groups of maternal separation. Long maternally separated offspring showed more total sleep time, more episodes of rapid eye movement sleep and higher percentage of non-rapid eye movement episodes ending in rapid eye movement sleep compared to brief maternal separation. Chronic stress affected similarly other sleep parameters and flattened the sleep homeostasis curves in all offspring. The results confirm that early environmental conditions modulate the brain functioning in a long-lasting way.