Genome-wide association studies in Alzheimer disease

The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (> or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.     

Are myocardial infarction and venous thromboembolism associated? Population-based case–control and cohort studies

Introduction

Because the association of myocardial infarction (MI) and venous thromboembolism (VTE) is uncertain, we tested MI as a VTE risk factor and VTE as a predictor of MI.

Materials and Methods

Using Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE over the 13-year period, 1988–2000 (n = 1311), one to two resident controls per VTE case (n = 1511), and all residents with incident MI over the 31-year period, 1979–2010. For VTE cases and controls, we reviewed their complete medical records in the community for VTE and MI risk factors. Using conditional logistic regression we tested MI as a potential VTE risk factor, both unadjusted and after adjusting for VTE risk factors. We also followed VTE cases and controls without prior MI forward in time for incident MI through 12/31/2010, and using Cox proportional hazards modeling, tested VTE as a predictor of MI, both unadjusted and after adjusting for MI risk factors.

Results

The number (%) of MI prior to VTE among cases and controls were 75 (5.7) and 51 (3.4), respectively, and the number (%) of MI after VTE among cases and controls were 58 (4.4) and 77 (5.1), respectively. In univariate analyses, MI was significantly associated with VTE but not after adjusting for VTE risk factors. In both univariate and multivariate analyses, VTE (overall or idiopathic) was not a predictor of MI.

Conclusions

MI is not an independent risk factor for VTE, and VTE is not a predictor of MI.     

A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states

Objective:  Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania.
Methods:  After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5–20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values.
Results:  Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean ± SE changes in YMRS scores were observed on day 2 with asenapine (−3.0 ± 0.4) and olanzapine (−3.4 ± 0.4) versus placebo (−1.5 ± 0.5, both p < 0.01) and were maintained until day 21 (−10.8 ± 0.8 with asenapine, −12.6 ± 0.8 with olanzapine; both p ≤ 0.0001 versus placebo, −5.5 ± 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures.
Conclusions:  These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.     

Suicide attempt characteristics, diagnoses, and future attempts: comparing multiple attempters to single attempters and ideators

OBJECTIVE: To compare psychiatric diagnoses and future suicide attempt outcomes of multiple attempters (MAs), single attempters (SAs), and ideators. METHOD: Two hundred twenty-eight teens who reported recent ideation or a lifetime suicide attempt in a screening of 1,729 high school students completed the Adolescent Suicide Interview, which provided information on attempt number and characteristics and mood, anxiety, and substance use disorder modules of the Diagnostic Interview Schedule for Children; 191 were reinterviewed 4 to 6 years later to ascertain interval attempts and psychiatric disorder. Between screening and follow-up, 33 (17%) teens made an attempt, 12 of whom were previously classified as lifetime MAs (more than one attempt) and six as SAs. RESULTS: MAs more often met criteria for any one of the DSM diagnoses assessed at baseline (mood, anxiety, or substance use disorder; 71%), compared with SAs (39%) and ideators (41%), and at follow-up (mood, anxiety, substance use, or disruptive behavior disorder; 69%) compared with SAs (36%) (p <.05). As reported at baseline, MAs (versus SAs) more often wished to die during their attempt (53% versus 23%), less often planned their attempt for intervention (44% versus 76%), and more often regretted recovery (26% versus 7%; p <.05). Baseline MAs had significantly higher odds of making a later attempt compared to ideators (odds ratio 4.0, 95% confidence interval 1.5-10.2) and SAs (odds ratio 4.6, 95% confidence interval 1.0-20.2). No participants committed suicide during follow-up. SAs who made another attempt (versus those who did not) more often met criteria for a baseline anxiety disorder and more often wished to die during their baseline attempt. CONCLUSIONS: MAs more strongly predict later suicidality and diagnosis than SAs and ideation. Forms that assess past suicide attempts should routinely inquire about frequency of attempts. The similarity between the present findings and those of clinical samples suggests that screening may yield a representative sample of suicide attempters and ideators.     

Motor unit recruitment and bursts of activity in the surface electromyogram during a sustained contraction

Bursts of activity in the surface electromyogram (EMG) during a sustained contraction have been interpreted as corresponding to the transient recruitment of motor units, but this association has never been confirmed. The current study compared the timing of trains of action potentials discharged by single motor units during a sustained contraction with the bursts of activity detected in the surface EMG signal. The 20 motor units from 6 subjects [recruitment threshold, 35.3 +/- 11.3% maximal voluntary contraction (MVC) force] that were detected with fine wire electrodes discharged 2-9 trains of action potentials (7.2 +/- 5.6 s in duration) when recruited during a contraction that was sustained at a force below its recruitment threshold (target force, 25.4 +/- 10.6% MVC force). High-pass filtering the bipolar surface EMG signal improved its correlation with the single motor unit signal. An algorithm applied to the surface EMG was able to detect 75% of the trains of motor unit action potentials. The results indicate that bursts of activity in the surface EMG during a constant-force contraction correspond to the transient recruitment of higher-threshold motor units in healthy individuals, and these results could assist in the diagnosis and design of treatment in individuals who demonstrate deficits in motor unit activation.     

A preliminary report of the dopamine receptor D4 and the dopamine transporter 1 gene polymorphism and its association with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset psychiatric syndromes affecting 5%–10% of school-age children worldwide. Distortions in the catecholaminergic system seem to be responsible for this condition. Within this system there are several candidate genes, the dopamine receptor D₄ (DRD4) and the dopamine transporter 1 (DAT1), with common polymorphism which might be associated with ADHD. We performed a family based association study with 36 trios and 19 parent proband pairs. All diagnoses were confirmed by the “Hypescheme” diagnostic computer program. In this study we did not observe an association of ADHD with DRD4 and DAT1 polymorphism neither by the haplotype relative risk (HRR) method nor by the transmission disequilibrium test (TdT) method. The odds ratio for the DRD4 7-allele was 1.01 and 0.94 for both statistical tests, respectively, and the respective odds ratio for the DAT1 6-allele were 0.91 and 0.88.     

Characterization of a panel of monoclonal antibodies toward mouse PAI-1 that exert a significant profibrinolytic effect in vivo

Introduction

PAI-1 is the main physiological inhibitor of t-PA and u-PA. Elevated PAI-1 levels have been implicated in the pathogenesis of several thrombotic and non-thrombotic diseases. The effect of PAI-1 inhibition can be studied in mouse models, when appropriate immunological tools are available. The majority of the available monoclonal antibodies against PAI-1 have been raised against human PAI-1. Even though some of these antibodies cross-react with non-glycosylated PAI-1 from different species, these antibodies often do not cross-react sufficiently with glycosylated mouse PAI-1. Moreover, the antibodies that cross-react with glycosylated mouse PAI-1 often have decreased inhibitory properties in the presence of vitronectin. Our objective was the generation of a panel of monoclonal antibodies reacting with vitronectin-bound glycosylated mouse PAI-1.

Results

Five monoclonal antibodies revealed binding to glycosylated mouse PAI-1 and exerted a strong (i.e. 58-80% inhibition of PAI-1 activity) inhibitory effect toward mouse PAI-1. Similar inhibitory effects were seen in the presence of a 33-fold molar excess of vitronectin. The PAI-1 inhibitory potential of the antibodies in vivo was demonstrated in a thromboembolism model, in which the evaluated antibodies significantly increased the percentage of mice with normal physical activity in comparison to mice treated with negative control antibody.

Conclusions

To the best of our knowledge this is the first panel of monoclonal antibodies that can inhibit mouse PAI-1 in the presence of vitronectin and that show a profibrinolytic effect in vivo. Therefore these antibodies provide excellent immunological tools to further investigate the role of PAI-1 in mouse models.     

Head-up sleeping improves orthostatic tolerance in patients with syncope

Objectives  This study was designed to examine the effect of head-up sleeping as a treatment for vasovagal syncope in otherwise healthy patients. Treatment for syncope is difficult. Pharmacological treatments have potential side effects and, although other non-pharmacological treatments such as salt and fluid loading often help, in some cases they may be ineffective or unsuitable. Head-up sleeping may provide an alternative treatment. Methods  Twelve patients had a diagnosis of vasovagal syncope based both on the history and on early pre-syncope during a test of head-up tilting and graded lower body suction. They then underwent a period of 3–4 months of sleeping with the head-end of their bed raised by 10°, after which orthostatic tolerance (time to pre-syncope during tilt test) was reassessed. Results  Eleven patients (92%) showed a significant improvement in orthostatic tolerance (time to pre-syncope increased by 2 minutes or more). Plasma volume was assessed in eight patients and was found to show a significant increase (P < 0.05, Wilcoxon signed-rank test). There was no significant change in either resting or tilted heart rate or blood pressure after head-up sleeping. Interpretation  Head-up sleeping is a simple, non-pharmacological treatment which is effective in the majority of patients. However, it may not be tolerated by patients or bed-partners long term and whether the effects continue after cessation of treatment remains to be determined.     

Comparison of Two School-Based Smoking Prevention Programs among South African High School Students: Results of a Randomized Trial

Background  Smoking rates are projected to increase substantially in developing countries such as South Africa. Purpose  The aim of this study was to test the efficacy of two contrasting approaches to school-based smoking prevention in South African youth compared to the standard health education program. One experimental program was based on a skills training/peer resistance model and the other on a harm minimization model. Method  Thirty-six public schools from two South African provinces, KwaZulu-Natal and the Western Cape, were stratified by socioeconomic status and randomized to one of three groups. Group 1 (comparison) schools (n = 12) received usual tobacco use education. Group 2 schools (n = 12) received a harm minimization curriculum in grades 8 and 9. Group 3 schools (n = 12) received a life skills training curriculum in grades 8 and 9. The primary outcome was past month use of cigarettes based on a self-reported questionnaire. Result  Five thousand two hundred sixty-six students completed the baseline survey. Of these, 4,684 (89%) completed at least one follow-up assessment. The net change in 30-day smoking from baseline to 2-year follow-up in the control group was 6% compared to 3% in both harm minimization (HM) and life skills training (LST) schools. These differences were not statistically significant. Intervention response was significantly moderated by both gender and race. The HM intervention was more effective for males, whereas the life skills intervention was more effective for females. For black African students, the strongest effect was evident for the HM intervention, whereas the strongest intervention effect for “colored” students was evident for the LST group. Conclusion  The two experimental curricula both produced similar overall reductions in smoking prevalence that were not significantly different from each other or the control group. However, the impact differed by gender and race, suggesting a need to tailor tobacco and drug use prevention programs. More intensive intervention, in the classroom and beyond, may be needed to further impact smoking behavior.

Prevalence of headache in patients with Parkinson’s disease and its association with the side of motor symptom onset

We compared the lifetime prevalence and the prevalence of headache during the previous year in patients with Parkinson’s disease (PD) and control subjects. We also investigated the association between the side of PD symptom onset and the side of the headache. We interviewed 98 consecutive patients with an established diagnosis of PD between December 2010 and January 2012. The control group consisted of the 98 oldest sex-matched individuals from the nationwide Brazilian headache database. PD patients showed a significantly lower prevalence (40.8 %) of headache in the previous year than controls (69.4 %) (adjusted OR 0.5, CI 95 % 0.2–0.9, p = 0.03). PD patients also showed a lower prevalence of headache throughout life (74.5 %) than controls (93.9 %) (adjusted OR 0.2, CI 95 % 0.1–0.6, p = 0.01). Considering only patients who presented headache during the previous year, PD patients showed a higher association with occurrence of migraine than tension-type headache compared with controls (adjusted OR 3.3, CI 95 % 1.2–8.9, p = 0.02). The headache side was ipsilateral to the side of PD onset in 21 patients (84 %), with a concordance of 85.7 % on the left side and 81.8 % on the right side (p < 0.01). The prevalence of primary headache was significantly lower in patients with PD than controls. The predominant side of headache was ipsilateral to the side of initial motor signs of PD.