The random case of Conley's theorem: III. Random semiflow case and Morse decomposition

In the first part of this paper, we generalize the results of the author \cite{Liu,Liu2} from the random flow case to the random semiflow case, i.e. we obtain Conley decomposition theorem for infinite dimensional random dynamical systems. In the second part, by introducing the backward orbit for random semiflow, we are able to decompose invariant random compact set (e.g. global random attractor) into random Morse sets and connecting orbits between them, which generalizes the Morse decomposition of invariant sets originated from Conley \cite{Con} to the random semiflow setting and gives the positive answer to an open problem put forward by Caraballo and Langa \cite{CL}.Comment: 21 pages, no figur

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Eating disorders: from twin studies to candidate genes and beyond

Substantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way

Borna disease virus (BDV) circulating immunocomplex positivity in addicted patients in the Czech Republic: a prospective cohort analysis

<p>Abstract</p> <p>Background</p> <p>Borna disease virus (BDV) is an RNA virus belonging to the family Bornaviridae. Borna disease virus is a neurotropic virus that causes changes in mood, behaviour and cognition. BDV causes persistent infection of the central nervous system. Immune changes lead to activation of infection. Alcohol and drug dependence are associated with immune impairment.</p> <p>Methods</p> <p>We examined the seropositivity of BDV circulating immunocomplexes (CIC) in patients with alcohol and drug dependence and healthy individuals (blood donors). We examined 41 addicted patients for the presence of BDV CIC in the serum by ELISA at the beginning of detoxification, and after eight weeks of abstinence. This is the first such study performed in patients with alcohol and drug dependence.</p> <p>Results</p> <p>BDV CIC positivity was detected in 36.59% of addicted patients on day 0 and in 42.86% on day 56. The control group was 37.3% positive. However, we did not detect higher BDV CIC positivity in addicted patients in comparison with blood donors (p = 0.179). The significantly higher level of BDV CIC was associated with lower levels of GGT (gamma glutamyl transferase) (p = 0.027) and approached statistical significance with the lower age of addicted patients (p = 0.064). We did not find any association between BDV CIC positivity and other anamnestic and demographic characteristics.</p> <p>Conclusions</p> <p>In our study addicted patients did not have significantly higher levels of BDV CIC than the control group. The highest levels of BDV CIC were detected in patients with lower levels of GGT and a lower age.</p> <p>Trial registration</p> <p>This study was approved by the ethical committee of the University Hospital Medical Faculty of Charles University in Pilsen, Czech Republic (registration number 303/2001).</p

Season of birth, clinical manifestations and Dexamethasone Suppression Test in unipolar major depression

<p>Abstract</p> <p>Background</p> <p>Reports in the literature suggest that the season of birth might constitute a risk factor for the development of a major psychiatric disorder, possibly because of the effect environmental factors have during the second trimester of gestation. The aim of the current paper was to study the possible relationship of the season of birth and current clinical symptoms in unipolar major depression.</p> <p>Methods</p> <p>The study sample included 45 DSM-IV major depressive patients and 90 matched controls. The SCAN v. 2.0, Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Scale (HAS) were used to assess symptomatology, and the 1 mg Dexamethasone Suppression Test (DST) was used to subcategorize patients.</p> <p>Results</p> <p>Depressed patients as a whole did not show differences in birth season from controls. However, those patients born during the spring manifested higher HDRS while those born during the summer manifested the lowest HAS scores. DST non-suppressors were almost exclusively (90%) likely to be born during autumn and winter. No effect from the season of birth was found concerning the current severity of suicidal ideation or attempts.</p> <p>Discussion</p> <p>The current study is the first in this area of research using modern and rigid diagnostic methodology and a biological marker (DST) to categorize patients. Its disadvantages are the lack of data concerning DST in controls and a relatively small size of patient sample. The results confirm the effect of seasonality of birth on patients suffering from specific types of depression.</p

Missense mutation of Brain Derived Neurotrophic Factor (BDNF) alters neurocognitive performance in patients with mild traumatic brain injury: a longitudinal study

The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen’s d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers

The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models

A compelling association has been observed between cardiovascular disease (CVD) and depression, suggesting individuals with depression to be at significantly higher risk for CVD and CVD-related mortality. Systemic immune activation, hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, arterial stiffness and endothelial dysfunction have been frequently implicated in this relationship. Although a differential epidemiological association between CVD and depression subtypes is evident, it has not been determined if this indicates subtype specific biological mechanisms. A comprehensive systematic literature search was conducted using PubMed and PsycINFO databases yielding 147 articles for this review. A complex pattern of systemic immune activation, endothelial dysfunction and HPA axis hyperactivity is suggestive of the biological relationship between CVD and depression subtypes. The findings of this review suggest that diagnostic subtypes rather than a unifying model of depression should be considered when investigating the bidirectional biological relationship between CVD and depression. The suggested model of a subtype-specific biological relationship between depression and CVDs has implications for future research and possibly for diagnostic and therapeutic processes

The Combined Dexamethasone/CRH Test (DEX/CRH Test) and Prediction of Acute Treatment Response in Major Depression

In this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated. In 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome. Taken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response