A genome-wide association study of suicide severity scores in bipolar disorder

BackgroundSuicide claims one million lives worldwide annually, making it a serious public health concern. The risk for suicidal behaviour can be partly explained by genetic factors, as suggested by twin and family studies (reviewed in (Zai et al. 2012)). Recently, genome-wide association studies (GWASs) of suicide attempt on large samples of bipolar disorder (BD) patients from multiple sites have identified a number of novel candidate genes. GWASs of suicide behaviour severity, from suicidal ideation to serious suicide attempt, have not been reported for BD.MethodsWe conducted a GWAS of suicide behaviour severity in three independent BD samples:212 small nuclear families with BD probands from Toronto, Canada, 428 BD cases from Toronto, and 483 BD cases from the UK. We carried out imputation with 1000 Genome Project data as reference using IMPUTE2. Quality control and data analysis was conducted using PLINK and R. We conducted the quantitative analyses of suicide behaviour severity in the three samples separately, and derived an overall significance by a meta-analysis using the METAL software.ResultsWe did not find genome-wide significant association of any tested markers in any of the BD samples, but we found a number of suggestive associations, including regions on chromosomes 8 and 10 (p < 1e-5).ConclusionsOur GWAS findings suggest that likely many gene variants of small effects contribute collectively to the risk for suicidal behaviour severity in BD. Larger independent replications are required to strengthen the findings from the GWAS presented here.     

Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

BackgroundGlycogen synthase kinase-3 β (GSK3β) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3β is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3β becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3β (phospho-GSK3β) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3β has never been studied in humans.MethodsIn 27 patients with bipolar depression, total GSK3β and phospho-GSK3β were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group.ResultsNo differences in phospho-GSK3β or total GSK3β were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3β and total GSK3β levels. From baseline to endpoint, lithium treatment inactivated GSK3β by significantly increasing phospho-GSK3β levels (p = 0.010). Clinical improvement (baseline HAM-D — endpoint HAM-D) negatively correlated with the increase in phospho-GSK3β (p = 0.03).ConclusionThe present results show that lithium inactivates platelet GSK3β in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3β as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3β in other neuropsychiatric disorders and as a new therapeutic target per se.     

Electrical mapping in bipolar disorder patients during the oddball paradigm

Bipolar disorder (BD) is characterized by an alternated occurrence between acute mania episodes and depression or remission moments. The objective of this study is to analyze the information processing changes in BP (Bipolar Patients) (euthymia, depression and mania) during the oddball paradigm, focusing on the P300 component, an electric potential of the cerebral cortex generated in response to external sensorial stimuli, which involves more complex neurophysiological processes related to stimulus interpretation. Twenty-eight bipolar disorder patients (BP) (17 women and 11 men with average age of 32.5, SD: 9.5) and eleven healthy controls (HC) (7 women and 4 men with average age of 29.78, SD: 6.89) were enrolled in this study. The bipolar patients were divided into 3 major groups (i.e., euthymic, depressive and maniac) according to the score on the Clinical Global Impression – Bipolar Version (CGI-BP). The subjects performed the oddball paradigm simultaneously to the EEG record. EEG data were also recorded before and after the execution of the task. A one-way ANOVA was applied to compare the P300 component among the groups. After observing P300 and the subcomponents P3a and P3b, a similarity of amplitude and latency between euthymic and depressive patients was observed, as well as small amplitude in the pre-frontal cortex and reduced P3a response. This can be evidence of impaired information processing, cognitive flexibility, working memory, executive functions and ability to shift the attention and processing to the target and away from distracting stimuli in BD. Such neuropsychological impairments are related to different BD symptoms, which should be known and considered, in order to develop effective clinical treatment strategies.     

Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease

BackgroundThere is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.ObjectiveTo investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.MethodsCross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [¹¹C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.ResultsThere were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98 ± 1.01) compared to the non-diabetics (−0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).ConclusionDiabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.     

The association between daytime napping and risk of diabetes: a systematic review and meta-analysis of observational studies

ObjectiveTo investigate the association between daytime napping and prevalent/incident diabetes mellitus (DM) based on systematic review and meta-analytic data.MethodsThe electronic databases of Embase, Medline, Pubmed and Web of Science were searched. Relevant studies were extracted by two reviewers independently. The associations between daytime napping (irrespective of duration), long nap (≥1 h/day) and short nap (<1 h/day), and risk of DM were assessed according to study types. Overall estimates were pooled using either fixed- or random-effect with inverse variance meta-analysis. Heterogeneity of included studies was assessed using the I² test and possible cause of the heterogeneity was examined by meta-regression analyses.ResultsTen studies (four cross-sectional and six longitudinal cohort) comprising a total of 304,885 individuals and 20,857 cases of DM were included in the systematic review, with an average napping prevalence of 47%. Nappers were found to have increased risk of DM in both cross-sectional and cohort studies. However, significant heterogeneity was present. Long nap (≥1 h/day) was associated with both prevalent and incident DM; in particular, those with a daily nap over 1 h had a 31% increased risk of developing DM during follow-up (95% confidence interval: 2–67%). Conversely, no such association was found in individuals with short naps (<1 h/day) in cohort studies.ConclusionsLong daytime napping over 1 h per day was associated with increased risk of both prevalent and incident DM. Further studies are needed to confirm the findings.     

Characterizing the Mechanisms of Central and Peripheral Forms of Neurostimulation in Chronic Dysphagic Stroke Patients

BackgroundSwallowing problems following stroke may result in increased risk of aspiration pneumonia, malnutrition, and dehydration.Objective/hypothesisOur hypothesis was that three neurostimulation techniques would produce beneficial effects on chronic dysphagia following stroke through a common brain mechanism that would predict behavioral response.MethodsIn 18 dysphagic stroke patients (mean age: 66 ± 3 years, 3 female, time-post-stroke: 63 ± 15 weeks [±SD]), pharyngeal electromyographic responses were recorded after single-pulse transcranial magnetic stimulation (TMS) over the pharyngeal motor cortex, to measure corticobulbar excitability before, immediately, and 30 min, after real and sham applications of neurostimulation. Patients were randomized to a single session of either: pharyngeal electrical stimulation (PES), paired associative stimulation (PAS) or repetitive TMS (rTMS). Penetration-aspiration scores and bolus transfer timings were assessed before and after both real and sham interventions using videofluoroscopy.ResultsCorticobulbar excitability of pharyngeal motor cortex was beneficially modulated by PES, PAS and to a lesser extent by rTMS, with functionally relevant changes in the unaffected hemisphere. Following combining the results of real neurostimulation, an overall increase in corticobulbar excitability in the unaffected hemisphere (P = .005, F_1,17 = 10.6, ANOVA) with an associated 15% reduction in aspiration (P = .005, z = −2.79) was observed compared to sham.ConclusionsIn this mechanistic study, an increase in corticobulbar excitability the unaffected projection was correlated with the improvement in swallowing safety (P = .001, rho = −.732), but modality-specific differences were observed. Paradigms providing peripheral input favored change in neurophysiological and behavioral outcome measures in chronic dysphagia patients. Further larger cohort studies of neurostimulation in chronic dysphagic stroke are imperative.     

Increased methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of patients with generalized anxiety disorder

Previous findings on the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety disorder (GAD) are controversial, and the molecular mechanisms underlying such dysfunction remain unclear. We analyzed the methylation status of the NR3C1 1_F promoter and the expression of glucocorticoid receptor-α isoform (GRα) in peripheral blood mononuclear cells (PMBCs), the basal cortisol level in serum, and a functional neuroendocrine marker for GR sensitivity in the PMBCs in 64 patients with current GAD and 85 healthy controls. We found that patients with GAD had significantly elevated levels of morning basal serum cortisol (P < 0.0001) and diminished GR sensitivity in the PBMCs (P < 0.0001) compared with healthy controls. The overall methylation levels across NR3C1 1_F promoter (P < 0.0001) and percent methylation at each of the 5 CpG sites including CpG12, 21, 30, 31, and 32 (P < 0.001) significantly increased. Accordingly, the mRNA levels of GRα significantly decreased (P < 0.0001) in the PBMCs in patients with GAD compared with healthy controls, with the effects specific in patients without childhood traumatic experience. Moreover, both serum basal cortisol levels and GR sensitivity in the PBMCs were negatively correlated with the overall methylation levels of the NR3C1 1_F promoter (P < 0.0001) and positively correlated with GRα mRNA levels (P = 0.007) in the PBMCs. In sum, our study revealed the increased activity of the HPA axis and diminished peripheral glucocorticoid responsiveness of GR underlying episodes of GAD. Furthermore, such dysfunction of the HPA axis is associated with both increased DNA methylation of NR3C1 1_F promoter and decreased GRα expression.     

Distal muscle activity alterations during the stance phase of gait in restless leg syndrome (RLS) patients

ObjectiveTo assess if there is a circadian variation in electromyographical (EMG) muscle activity during gait in restless legs syndrome (RLS) patients and healthy control participants.MethodsGait assessment was done in 14 RLS patients and 13 healthy control participants in the evening (PM) and the morning (AM). Muscle activity was recorded bilaterally from the tibialis anterior (TA), lateral gastrocnemius (GL), rectus femoris (RF) and biceps femoris (BF) muscles.ResultsA circadian variation during the stance phase in only TA (PM > AM, p < 0.005) and BF (PM < AM, p = 0.008) activity was observed in control participants. Conversely no circadian variation was seen in any muscles in the RLS patients. RLS patients had an increased TA and GL activity (RLS > Controls, p < 0.05) during early stance and decreased GL activity (RLS < Controls, p < 0.01) during terminal stance in comparison to control participants in the evening. No other significant differences were noted between RLS patients and control participants. Activation of GL during the swing phase was noted in 79% of RLS patients and in 23% of control participants in the morning compared to 71% and 38% in the evening, respectively.ConclusionEMG muscle activity shows no circadian variation in RLS patients. Evening differences in gait muscle activation patterns between RLS patients and control participants are evident. These results extend our knowledge about alterations in spinal processing during gait in RLS. A possible explanation for these findings is central pattern generator sensitization caused by increased sensitivity in cutaneous afferents in RLS patients.     

Association between severity of untreated sleep apnoea and postoperative complications following major cardiac surgery: a prospective observational cohort study

ObjectiveTo examine whether untreated sleep apnoea is associated with prolonged Intensive Care Unit (ICU) stay and increased frequency of postoperative ICU complications, in patients undergoing major cardiac surgery.Patients/methodsAdult patients, undergoing elective coronary artery bypass grafting with or without cardiac valve surgery, between March 2013 and July 2014, were considered. We excluded patients participating in other interventional studies, those who had a tracheostomy before surgery, required emergency surgery or were due to be admitted on the day of surgery. Patients underwent inpatient overnight oximetry on the night prior to their surgery to assess for the presence of sleep apnoea. Since oximetry alone cannot differentiate obstructive from central apnoea, the results are reported as sleep apnoea which was diagnosed in patients with an arterial oxygen desaturation index (ODI) ≥ 5/h.ResultsThe primary outcome measure was length of stay (LoS) in ICU in days. The secondary outcome was a composite measure of postoperative complications in ICU. Multivariate models were developed to assess associations between ODI and the primary and secondary outcome measures, adjusting for preselected predictor variables, relative to primary and secondary outcomes. There was no significant association between ODI and ICU LoS, HR 1.0, 95% CI 0.99–1.02; p = 0.12. However we did find a significant association between ODI and postoperative complications in the ICU, OR = 1.1; 95% CI 1.02–1.17; p = 0.014. The probability of developing complications rose with higher ODI, reflecting sleep apnoea severity.ConclusionsAcknowledging the limitations of this prospective study, untreated sleep apnoea did not predict an increased length of stay in ICU but we do report an association with postoperative complications in patients undergoing major cardiac surgery.     

Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity

BackgroundVagus nerve stimulation (VNS) is currently used to treat refractory epilepsy and is being investigated as a potential therapy for a range of conditions, including heart failure, tinnitus, obesity and Alzheimer's disease. However, the invasive nature and expense limits the use of VNS in patient populations and hinders the exploration of the mechanisms involved.ObjectiveWe investigated a non-invasive method of VNS through electrical stimulation of the auricular branch of the vagus nerve distributed to the skin of the ear – transcutaneous VNS (tVNS) and measured the autonomic effects.MethodsThe effects of tVNS parameters on autonomic function in 48 healthy participants were investigated using heart rate variability (HRV) and microneurography. tVNS was performed using a transcutaneous electrical nerve stimulation (TENS) machine and modified surface electrodes. Participants visited the laboratory once and received either active (200 μs, 30 Hz; n = 34) or sham (n = 14) stimulation.ResultsActive tVNS significantly increased HRV in healthy participants (P = 0.026) indicating a shift in cardiac autonomic function toward parasympathetic predominance. Microneurographic recordings revealed a significant decrease in frequency (P = 0.0001) and incidence (P = 0.0002) of muscle sympathetic nerve activity during tVNS.ConclusiontVNS can increase HRV and reduce sympathetic nerve outflow, which is desirable in conditions characterized by enhanced sympathetic nerve activity, such as heart failure. tVNS can therefore influence human physiology and provide a simple and inexpensive alternative to invasive VNS.     

The effect of sleep duration and sleep quality on hypertension in middle-aged and older Chinese: the Dongfeng-Tongji Cohort Study

ObjectiveTo examine the independent and combined associations of sleep duration and sleep quality with hypertension in a middle-aged and older Chinese population.MethodsWe included 21,912 individuals aged 62.2 years at baseline from September 2008 to June 2010, and they were followed until October 2013. Sleep duration was self-reported and sleep quality was evaluated with questions designed according to the Pittsburgh Sleep Quality Index. Hypertension was defined as blood pressure ≥140/90 mmHg, or self-reported physician diagnosis of hypertension, or self-reported current use of antihypertensive medication.ResultsIn the cross-sectional analyses, the odds ratio of hypertension prevalence was significantly elevated (OR = 1.13, 95% CI = 1.03–1.24) in those who slept less than 7 h after adjusting for sex, age, body mass index, midday napping, cigarette smoking and sleep quality. It was particularly evident among males (OR = 1.19, 95% CI = 1.01–1.40) and individuals who were thin (OR = 2.00, 95% CI = 1.01–3.93) with full adjustment. The association was also found for sleep duration of 9∼<10 h after adjusting various covariates (OR = 1.14, 95% CI = 1.04–1.27). In addition, impaired sleep quality was only associated with hypertension in obese individuals (OR = 1.25, 95% CI = 1.02–1.50), not in other subgroups. However, no significant association was detected in any category of sleep duration or sleep quality in all models in the prospective analyses, and the results remained unchanged in the subgroup analyses of sex, age and body mass index.ConclusionsThe results of this study provide limited support for association of sleep duration and sleep quality with hypertension in middle-aged and older Chinese. Further studies are needed to confirm the results.     

Impact of adolescent peer aggression on later educational and employment outcomes in an Australian cohort

This study used prospective birth cohort data to analyse the relationship between peer aggression at 14 years of age and educational and employment outcomes at 17 years (N = 1091) and 20 years (N = 1003). Participants from the Western Australian Pregnancy Cohort (Raine) study were divided into mutually exclusive categories of peer aggression. Involvement in peer aggression was reported by 40.2% (10.1% victims; 21.4% perpetrators; 8.7% victim–perpetrators) of participants. Participants involved in any form of peer aggression were less likely to complete secondary school. Perpetrators and victim–perpetrators of peer aggression were more likely to be in the ‘No Education, Employment or Training’ group at 20 years of age. This association was explained by non-completion of secondary school. These findings demonstrate a robust association between involvement in peer aggression and non-completion of secondary school, which in turn was associated with an increased risk of poor educational and employment outcomes in early adulthood.     

Focused Ultrasound-mediated Non-invasive Brain Stimulation: Examination of Sonication Parameters

BackgroundTranscranial focused ultrasound (FUS) has emerged as a new brain stimulation modality. The range of sonication parameters for successful brain stimulation warrants further investigation.ObjectiveThe objective of this study was to examine the range of FUS sonication parameters that minimize the acoustic intensity/energy deposition while successfully stimulating the motor brain area in Sprague–Dawley rats.MethodsWe transcranially administered FUS to the somatomotor area of the rat brain and measured the acoustic intensity that caused excitatory effects with respect to different pulsing parameters (tone-burst duration, pulse-repetition frequency, duty cycle, and sonication duration) at 350 and 650 kHz of fundamental frequency.ResultsWe observed that motor responses were elicited at minimum threshold acoustic intensities (4.9–5.6 W/cm² in spatial-peak pulse-average intensity; 2.5–2.8 W/cm² in spatial-peak temporal-average intensity) in a limited range of sonication parameters, i.e. 1–5 ms of tone-burst duration, 50% of duty cycle, and 300 ms of sonication duration, at 350 kHz fundamental frequency. We also found that the pulsed sonication elicited motor responses at lower acoustic intensities than its equivalent continuous sonication.ConclusionOur results suggest that the pulsed application of FUS selectively stimulates specific brain areas-of-interest at an acoustic intensity that is compatible with regulatory safety limits on biological tissue, thus allowing for potential applications in neurotherapeutics.     

Restless legs syndrome after high-risk TIA and minor stroke: association with reduced quality of life

BackgroundRestless legs syndrome (RLS) is a movement disorder that is associated with poor quality of life and depressive symptoms in the general population. Emerging evidence suggests that RLS is closely associated with cerebrovascular disease. We assessed the effect of RLS on quality of life after stroke and transient ischemic attack (TIA).MethodsIn this single-center prospective study, we recruited patients within 14 days of high-risk TIA or minor stroke. Patients were diagnosed with RLS using a questionnaire based on the 2003 International RLS Study Group criteria, and diagnoses were confirmed by a sleep neurologist. Follow-up assessments were conducted within 2–6 months of recruitment. The outcome of quality of life was measured using the Stroke-specific Quality of Life (SS-QoL).ResultsOf the 94 patients recruited into the study, 23 (24.4%) were diagnosed with RLS: 11 were newly diagnosed with RLS and 12 had RLS preceding the index stroke/TIA. There were no significant differences in baseline characteristics between those with or without RLS. Median SS-QoL in patients with RLS was lower at baseline (p = 0.008) and at follow-up (p = 0.002). RLS patients had more depressive symptoms at follow-up (p = 0.007). Ordinal logistic regression demonstrated that RLS was negatively associated with quality of life at baseline (OR = 0.28; p = 0.010) and at follow-up (OR = 0.14; p = 0.029), independent of functional outcome and depressive symptoms.ConclusionsRLS is common after stroke or TIA and negatively affects the quality of life. Screening for RLS after cerebrovascular events may be warranted, and future research should assess whether treatment of RLS can improve post-stroke quality of life.     

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.     

Sleep duration on workdays or nonworkdays and cardiac–cerebral vascular diseases in Southern China

ObjectivesThis study aimed to assess the relationship between sleep duration on work or nonworkdays and myocardial infarction (MI) and stroke in Southern China.MethodsA cross-sectional survey was conducted among 15,364 participants of age ≥15 years in Southern China from November 2013 to August 2014. Data on self-reported duration of sleep on workdays or nonworkdays as well as history of MI and stroke were collected in the questionnaire. The subjects were examined for weight, height, waist circumference, and blood pressure. Multivariate logistic regression analyses were performed to evaluate the association of sleep duration with MI and stroke.ResultOverall, compared with a sleep duration of 6–8 h, individuals who slept <6 h on workdays and nonworkdays were associated with increased risk for MI (odds ratio [OR] = 3.17, 2.04). Furthermore, individuals who slept >8 h on workdays and nonworkdays were associated with an increased risk for stroke (OR = 1.86, 1.54). Although this association persisted in men and subjects aged <65 years, we also observed that long sleep duration on workdays was associated with MI, especially among women, and short sleep duration on nonworkdays was associated with stroke among those aged 65 years or older. Participants with abnormal sleep duration and hypertension had higher risk of MI and stroke. Sleep debt was independently associated with MI risk, but not stroke (OR = 1.40; 95% confidence interval [CI]: 1.06–1.86), specifically among men aged <65 years.ConclusionsCompared with a sleep duration of 6–8 h, both short and long sleep duration were associated with the prevalence of MI and stroke and these associations were more pronounced among hypertensive persons, and tended to vary by age and sex. Moreover, sleep debt was linked to greater MI risk among men aged <65 years. These findings suggest that we should develop a healthy biological clock.     

Measuring positive and negative aspects of youth behavior: Development and validation of the Adolescent Functioning Scale

This paper outlines the development and validation of the Adolescent Functioning Scale (AFS) in an Australian sample of parents of young people aged 11–18 years (N = 278). The AFS, a parent self-report measure, was designed to assess problem behavior and positive development in adolescents. Principal components analysis produced a 33-item measure comprising four subscales: Positive Development, Oppositional Defiant Behavior, Antisocial Behavior and Emotional Difficulties. Convergent validity was established via correlations between the AFS and established measures of adolescent functioning and parenting, and discriminant validity was shown through no association between the AFS and a measure of technology use. Internal consistency for the subscales was high (H = .82–.92 for different age groups), as was test-retest reliability (r = .77–.86). The study indicated that the AFS is a potentially valuable tool for assessing levels of problem behaviors and positive development in adolescents.     

Subclinical neurological involvement does not develop if Wilson's disease is treated early

Background & aimsWilson's disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset.MethodsThirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests.ResultsPatients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement.ConclusionsThis study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.     

Evidence for Pretreatment LICI Deficits Among Depressed Children and Adolescents With Nonresponse to Fluoxetine

BackgroundResearch suggests that alterations in gamma-aminobutyric acid receptor functioning have a role in depression. Paired-pulse transcranial magnetic stimulation (TMS) paradigms are noninvasive measures of cortical inhibitory and excitatory circuits.Objective/hypothesisThe present study examined pretreatment short-interval intracortical inhibition (SICI), long-interval cortical inhibition (LICI), and intracortical facilitation (ICF) in children and adolescents with major depressive disorder who were initiating fluoxetine treatment. The primary objective was to examine the relationship of these measures with subsequent treatment response. It was hypothesized that alterations in pretreatment GABA and glutamate mediated neurotransmission, would be associated with fluoxetine nonresponse.MethodsSixteen children and adolescents with major depressive disorder underwent paired-pulse TMS testing before beginning fluoxetine treatment. Response was prospectively characterized by scores of 1 or 2 on the Clinical Global Impression Scale and less than 40 on the Children's Depression Rating Scale-Revised after 6 weeks of fluoxetine treatment (20–40 mg/day).ResultsEight patients responded to treatment. Least-squares mean LICI values were consistently higher bilaterally for treatment nonresponders. Higher LICI values indicate less inhibition and impaired GABA_B functioning. There was no significant effect of treatment response on the measures of SICI and ICF.ConclusionsOur findings suggest that deficits in pretreatment GABA_B may be related to fluoxetine nonresponse in depressed youth. This is congruent with prior work demonstrating that GABA_B interneurons have serotonergic input and antidepressants modulate GABA_B receptors. These findings also show that TMS paradigms have utility in studying the neurophysiology and treatment of childhood mood disorders.RegistrationsCortical Excitability and Inhibition in Children and Adolescents With Major Depressive Disorder, http://www.clinicaltrials.gov/ct2/show/NCT00896090?term=cortical+excitability+and+inhibition&rank=2, NCT00896090; Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse, http://www.clinicaltrials.gov/ct2/show/NCT00612313?term=Sequential+Treatment+and+MDD&rank=1, NCT00612313.     

Association between sleep duration and the prevalence of hypertension in an elderly rural population of China

BackgroundPrevious studies have examined an association between sleep duration and hypertension, but the conclusions remain inconsistent.MethodsWe conducted a cross-sectional study in a community-based rural elderly population of Beijing, China. A total of 2397 participants (967 male and 1430 female) completed the survey. Sleep duration was assessed in a face-to-face interview and was self-reported. Hypertension was defined as systolic blood pressure (BP) ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg and/or receiving treatment for hypertension. Multiple logistic regression was used to estimate the association between gender-specific sleep duration and hypertension prevalence.ResultsOverall, no significant differences were observed among female participants and the total participants, and the differences were statistically significant only in men. After adjusting for potential confounding variables, the odds ratio (OR) and 95% confidential interval (CI) of having hypertension was 1.33 (1.00, 1.77) in men who slept for ≥9 h compared with those slept for six to eight hours per 24-h period. Furthermore, a one hour nap was associated with less likelihood of hypertension in men compared with those who did not nap, with an adjusted OR (95% CI) of 0.61 (0.41, 0.90).ConclusionIn a community-based rural elderly population of China, we found that sleep duration of six to eight hours per 24-h period and a one hour nap were significantly associated with lower risk of hypertension only among male participants after adjustment for potential confounders. Further studies are still needed to determine the relationships between 24-h, nighttime, and daytime sleep duration separately with hypertension, and to explore the biological mechanisms underlying the gender-related association.