The association of HLA-DRB1 and HLA-DQB1 alleles with genetic susceptibility to multiple sclerosis in the Slovak population

Objective: The aim of the present study was to assess the association between HLA-DRB1 and -DQB1 allele groups with the genetic predisposition to multiple sclerosis (MS) in the Caucasian Central European Slovak population.

Methods: A total of 282 unrelated patients with sporadic MS were enrolled in this case-control study. HLA-DRB1 and HLA-DQB1 allele groups were genotyped using a polymerase chain reaction with sequence-specific primers. The DRB1 and DQB1 allele carrier frequencies, genotypes and haplotype frequencies were compared between MS cases and healthy controls.

Results: Positive association with MS was found for alleles HLA-DRB1*15 (OR = 3.64; Pcor = 6.9x10–11), DRB1*03 (after elimination of carriers of DRB1*15, OR = 2.8; Pcor = 0.0029), DQB1*06 (OR = 1.99; Pcor = 7.0x10–4), genotypes HLA-DRB1*15/*15 (OR = 7.6; Pcor = 0.001) and DQB1*06/*06 (OR = 3.81; Pcor = 4.0x10–4) and for haplotype DRB1*15-DQB1*06 (OR = 3.03; Pcor = 0.001). Carriage of alleles DRB1*07 (OR = 0.53; Pcor = 0.04), DRB1*13 (OR = 0.39; Pcor = 4.0x10–4), DQB1*03 (OR = 0.46; Pcor = 1.0x10–4), genotypes HLA-DRB1*13/*11 (OR = 0.12; Pcor = 0.004), DQB1*05/*03 (OR = 0.39; Pcor = 0.035), DQB1*03/*03 (OR = 0.38; Pcor = 0.029) and haplotypes DRB1*13-DQB1*06 (OR = 0.47; Pcor = 0.0128) and DRB1*11-DQB1*03 (OR = 0.58; Pcor = 0.0352) was found to be protective against MS development.

Discussion: This is the first study performed to analyse the association of HLA-DRB1/DQB1 with susceptibility to MS in Slovakia. The results of our study confirm that HLA class II alleles, genotypes and haplotypes are associated with MS risk.     

Diagnosis of co-morbid axis-I psychiatric disorders among women with newly diagnosed,untreated endocrine disorders

Abstract

Objectives. To determine the prevalence of major depressive disorder (MDD) and other selected axis-I disorders among women with newly diagnosed, untreated endocrine disorders. Methods. Two hundred and eighteen consecutive women, aged 18–65, with newly diagnosed, untreated endocrine disorders were referred for potential diagnosis of co-morbid axis-I disorders with the use of the Structured Clinical Interview for Axis I-Patient Edition (SCID-P). The SCID-P was re-administered after 12 weeks. Results. At baseline, 64 (29.3%) women met criteria for at least one axis-I disorder. Women who were diagnosed with hyperthyroidism were more likely to meet criteria for generalized anxiety disorder and panic disorder than women without hyperthyroidism. Nine of 154 (5.8 %) women who did not meet criteria for an axis-I disorder at baseline met criteria for at least one axis-I disorder during follow-up. Among them, the presence of diabetes mellitus was statistically correlated with a higher probability of developing major depressive disorder at follow-up. Conclusions. Although preliminary, our findings are consistent with previous studies and suggest an increased prevalence of MDD and other axis-I disorders among women with newly diagnosed endocrine disorders, providing further evidence suggesting that women with endocrine abnormalities may be at increased risk of depression and/or anxiety disorders.     

中国人群人类白细胞抗原A、B和DRB1基因测序分型中模棱两可等位基因的鉴别

背景：人类白细胞抗原基因测序分型中，当某些等位基因间的差异碱基位于测序范围外时，无法得到清晰的等位基因结果。 目的：分析中国人群人类白细胞抗原A、B、DRB1基因测序分型中模棱两可等位基因的分布规律，探讨其在中华骨髓库大样本人类白细胞抗原 A、B、DRB1基因的测序分型中的解决方案。 设计、时间及地点：采用随机抽样方法对研究样本进行人类白细胞抗原A、B、DRB1基因的测序分型，并对其中的模棱两可等位基因进行验证性实验，于2006-01/2008-06在深圳市血液中心完成。 材料：658名深圳骨髓库汉族供者乙二胺四乙酸盐抗凝血5 mL。 方法：采用聚合酶链式反应--测序分型方法对658名深圳骨髓库供者的人类白细胞抗原A、B和DRB1基因进行高分辨分型，并采用针对相应位点的高分辨聚合酶链式反应-序列特异性引物方法对其中由于碱基差异位于检测区外而产生的模棱两可等位基因进行鉴别。 主要观察指标：模棱两可等位基因的分布及确认。 结果：658份标本中，人类白细胞抗原A、B和DRB1三个基因座的模棱两可等位基因分别为9个(2种)、140个(5种)、406个(8种)，占等位基因总数的14.06%(555/3 948)。高分辨聚合酶链式反应-序列特异性引物鉴定结果显示，中国报道的DRB1*1401被全部确认为DRB1*1454；12例B*0705/B*0706中，有1例被确认为B*0706，其他13种等位基因的鉴定结果分别为A*6801、A*7402、B*2705、B*3501、B*4402、B*5801、DRB1*0101、DRB1*0406 、DRB1*0803、DRB1*1101、DRB1*1201、DRB1*1302 和DRB1*1502。 结论：在中华骨髓库大样本人类白细胞抗原基因的测序分型中可以应用直接鉴别的方法区分模棱两可等位基因，但在临床移植前的高分辨确认试验中则需要采用实验方法进行精确分型。     

Psychometric evaluation of a Dutch version of the Mini PAS‐ADD for assessing psychiatric disorders in adults with different levels of intellectual disability

Background People with intellectual disabilities (ID) have an increased vulnerability to develop psychiatric problems. Moreover, the early recognition and the accurate diagnosis of psychiatric disorders in the population of persons with ID are challenging. Method A Dutch version of the Mini PAS‐ADD, which is a screening instrument for identification of mental health problems in people with ID, was evaluated in terms of internal consistency, interinformant reliability, item grouping and criterion validity based on a large‐scale random sample (n = 377) and a clinical sample (n = 99) of adults with ID. Results The Dutch version of the Mini PAS‐ADD showed moderate internal consistency, and moderate concordance among informants. Both aspects of the reliability were comparable for different levels of ID. A factor analysis largely confirmed the scale structure. Concurrent validity with the Reiss Screen for Maladaptive Behavior was high for the Depression, Psychosis and Autism scale. The outcome of the criterion‐validity analysis indicated high specificity. The sensitivity for specific psychiatric disorders by the corresponding scales was moderate, but the general sensitivity for the presence of psychopathology on the basis of any of the scales was satisfying. Conclusions The present research reconfirmed the use of the Mini PAS‐ADD as a primary screening device for the identification of mental health problems among people with ID.     

A systematic review of the clinical efficacy of transcranial direct current stimulation (tDCS) in psychiatric disorders

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique, which can be used to selectively disrupt patterns of neural activity that are associated with symptoms of mental illness. tDCS has been implemented in numerous therapeutic trials across a range of patient populations, with a rapidly increasing number of studies being published each year. This systematic review aimed to evaluate the efficacy of tDCS in the treatment of psychiatric disorders. Four electronic databases were searched from inception until December 2015 by two independent reviewers, and 66 eligible studies were identified. Depression was the most extensively researched condition, followed by schizophrenia and substance use disorders. Data on obsessive compulsive disorder, generalised anxiety disorder, and anorexia nervosa were also obtained. The quality of included studies was appraised using a standardised assessment framework, which yielded a median score corresponding to “weak” on the three-point scale. This improved to “moderate” when case reports/series were excluded from the analysis. Overall, data suggested that tDCS interventions comprising multiple sessions can ameliorate symptoms of several major psychiatric disorders, both acutely and in the long-term. Nevertheless, the tDCS field is still in its infancy, and several methodological and ethical issues must be addressed before clinical efficacy can truly be determined. Studies probing the mechanisms of action of tDCS and those facilitating the definition of optimised stimulation protocols are warranted. Furthermore, evidence from large-scale, multi-centre randomised controlled trials is required if the transition of this therapy from the laboratory to the clinic is to be considered.     

Ability of the mini-mental state examination to discriminate diagnostic entities in a psychogeriatric population

The Mini-Mental State Examination (MMSE) is widely used in clinical practice. A standardized MMSE (SMMSE) was used to differentiate those patients with dementia or delirium from those with functional psychiatric disorders. Seventy psychogeriatric patients from Royal Park Psychiatric Hospital were interviewed. The SMMSE and the Hamilton Rating Scale for Depression (HRSD) were administered at two time points, 3 weeks apart. The study found that the SMMSE did differentiate those with dementia or delirium from those with functional psychiatric disorders. However, caution should be exercised when interpreting SMMSE results in community settings.     

DSM-III-R personality disorders in outpatients with non-bipolar depression: The frequency in a sample of Japanese and the relationship to the 4-month outcome under adequate antidepressant therapy

Summary We investigated the frequency of personality disorders (PDs) and the relationship between the pressence of PD and the 4-month outcome of depression under adequate antidepressant therapy in a Japanese sample of 96 outpatients with non-bipolar major depression. The diagnosis of PD was made using a structured interiew method (the Structured Clinical Interview for DSM-III-R Personality Disorders) and after severe depressive symptoms were reduced. Any one kind of PD was found in 54.2% of the saple. The most frequent was avidant (34–4%), obsessived-compulsive (22.9%), narcisstic (18.8%), and dependent (16.7%) PDs. The frequencies of these PDs in our study except narcisstic PD, were about the same as those reported in previous studies with a matched setting for the PD diagnosis. Compared with patients without PD, a worse outcome was found in patients with PD, especially patients with multiple PDs from multiple PD clussters. There was no evidence that a specific PD or PD cluster especially worsens the outcome of depression.     

Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression.

BACKGROUND: Major depressive disorder (MDD) is often complicated by anxiety symptoms, and anxiety disorders occur in approximately 30% of mood cases. This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal (HPA) axis response to stress in patients with MDD. METHODS: Untreated subjects with pure MDD (n = 15), MDD with comorbid anxiety disorders (n = 18), and pure anxiety disorders (n = 15) were recruited by advertising. Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 48). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for adrenocorticotropic hormone (ACTH) and cortisol assay. RESULTS: When all depressed patients (n = 33) were compared with their matched control subjects (n = 33), they showed a significantly greater ACTH response to the stressor; however, this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders. A similar but nonsignificant effect was observed in the cortisol response. Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST. All patient groups showed similar levels of TSST-induced anxiety. CONCLUSIONS: Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression.     

Patients with a first episode of schizophrenia spectrum psychosis and their pathways to psychiatric hospital care in South Germany

Abstract.Background: Several first-episode studies of schizophrenia suggest that many patients experience psychotic symptoms for a long time before receiving appropriate treatment. To reduce the time of untreated psychosis, it is necessary to know the patients pathways to psychiatric care. This study was designed to examine patients help-seeking contacts and the delays on their pathways to psychiatric care in Germany.Method: Sixty-six patients with first episode of schizophrenia spectrum psychosis were assessed by the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS) and were interviewed about their helpseeking contacts before psychiatric admission.Results: In contrast to other findings of long duration of untreated psychosis (DUP), 53% of our patients were admitted after 8 weeks (median) of untreated positive symptoms, although the mean value of 71 weeks corresponds well with the results of other studies. There were important differences in DUP depending on which kind of statistical parameter (median or mean) was used. In contrast to studies from other countries, only 18% of our patients had their first contact with a general practitioner. However, this was the fastest way to psychiatric admission. No differences were found between patients with short (< 1 year) and long (> 1 year) DUP in the duration of time from the first help-seeking contact up to admission.Conclusion: In Germany, a large number of mental health professionals in private practice or different services of psychosocial contact facilities exist in every region and general practitioners are not so important as a link to psychiatric care, although they seem to be functioning well if it is necessary. Therefore, programs designed to reduce the delay of treatment should focus less on general practitioners than on other health services.     

The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5α-dihydroprogesterone in psychiatric disorders

Allopregnanolone (3α,5α-TH PROG) and 5α-dihydroprogesterone (5α-DH PROG), the two most important neuroactive steroids synthesized in the brain, potently modulate neuronal activity by allosterically regulating GABA action at GABA_A receptors or by changing specific GABA_A receptor subunit gene expression, respectively. We recently reported [Proc. Natl. Acad. Sci. USA 95 (1998) 3239] that in patients with severe depression there is a decrease in the CSF levels of 3α,5α-TH PROG, which is normalized by treatment with drugs (i.e. fluoxetine) that improve psychopathology. The mechanism by which fluoxetine and other selective serotonin reuptake inhibitors normalize 3α,5α-TH PROG CSF levels appears to involve a direct stimulation of 3α-hydroxysteroidoxidoreductase (3α-HSD), an enzyme that catalyses the reduction of 5α-DH PROG into 3α,5α-TH PROG. Here, we propose the use of socially-isolated mice that have a downregulation of 3α,5α-TH PROG and of 5α-DH PROG expression to establish a model to study the behavioral consequences of this deficiency. After 4–6 weeks of isolation, these mice exhibit increased anxiety and aggressive behavior and also a decreased response to the administration of GABA-mimetic drugs. In these mice, the decrease in 3α,5α-TH PROG is selectively normalized by the use of fluoxetine in doses that reduce behavioral abnormalities. In addition, the expression of 5α-reductase Type I mRNA and protein was lower in socially-isolated mice than that in group-housed mice whereas 3α-HSD mRNA expression remained unchanged. The results of these studies may enable us to design drugs that specifically affect neurosteroidogenic enzymatic activities and may provide an efficacious treatment for the psychopathologies associated with psychiatric disorders.     

β-Amyloid precursor protein (βAPP) in human gut with special reference to the enteric nervous system

The distribution of the β-amyloid precursor protein (βAPP) in the human gastrointestinal tract, from esophagus trough rectum, was studied using immunoblotting, as well as combined immunohistochemical and image analysis (optic microdensitometry) techniques. The study was focused on the enteric nervous system. βAPP was detected by means of a monoclonal antibody (22C11), which recognizes all βAPP isoforms as well as βAPP-like proteins. Immunoblotting revealed two main protein bands, one corresponding to full-length βAPPs (estimated molecular masses of 97–115 kDa); the other corresponded to a protein with estimated molecular masses of 55 kDa. Specific, βAPP immunoreactivity (IR) was found in the submucous and myenteric plexuses localized in the supporting glial cells rather than in neurons. Differences were encountered neither in the localization nor in the intensity of immunostaining among different segments of the gastrointestinal tract. Moreover, no age-dependent changes were found.,βAPP IR was also regularly observed in blood vessels, primarily labelling endothelial cells. Our results provide evidence for the occurrence of βAPP in human gastrointestinal tract of healthy people in both neuronal and nonneuronal tissues. Whether or not these findings have functional or clinical relevance remains to be clarified in future studies.     

Mean pressures and flows in the human intracranial system as determined by mathematical simulations of a steady-state infusion test

Abstract

In order to understand the fluid dynamics within the human intracranial system, the relatively small flow of extracellular fluid into, and out of, the interstitial brain tissue must be determined. Due to the magnitude of these flows, it is difficult to measure them clinically. Through a steady-state infusion simulation run on a mathematical model, values for these small flows may be calculated based on clinical data regarding the conductance of cerebrospinal fluid outflow. In this way, the mathematical model allows information to be obtained regarding these small mean flows, as well as the remaining mean flows and mean pressures throughout the Intracranial space, with minimal reliance on data from intrusive procedures. [Neurol Res 2000; 22: 809-814]     

Detecting functional nodes in large-scale cortical networks with functional magnetic resonance imaging: a principal component analysis of the human visual system

This study aimed to demonstrate how a regional variant of principal component analysis (PCA) can be used to delineate the known functional subdivisions of the human visual system. Unlike conventional eigenimage analysis, PCA was carried out as a second-level analysis subsequent to model-based General Linear Model (GLM)-type functional activation mapping. Functional homogeneity of the functional magnetic resonance imaging (fMRI) time series within and between clusters was examined on several levels of the visual network, starting from the level of individual clusters up to the network level comprising two or more distinct visual regions. On each level, the number of significant components was identified and compared with the number of clusters in the data set. Eigenimages were used to examine the regional distribution of the extracted components. It was shown that voxels within individual clusters and voxels located in bilateral homologue visual regions can be represented by a single component, constituting the characteristic functional specialization of the cluster(s). If, however, PCA was applied to time series of voxels located in functionally distinct visual regions, more than one component was observed with each component being dominated by voxels in one of the investigated regions. The model of functional connections derived by PCA was in accordance with the well-known functional anatomy and anatomical connectivity of the visual system. PCA in combination with conventional activation mapping might therefore be used to identify the number of functionally distinct nodes in an fMRI data set in order to generate a model of functional connectivity within a neuroanatomical network.     

Pet study of [11C] β-CIT binding to monoamine transporters in the monkey and human brain

The cocaine congener β-CIT has been labeled with ¹¹C for positron emission tomographic (PET) studies of the dopamine transporter. In the present autoradiographic study on human' brain sections and PET study on monkey and human [¹¹C]β-CIT accumulated markedly in the striatum. [¹¹C]β-CIT binding in the striatum was selective to the dopamine transporter. The binding in the thalamus was on an intermediate level and was displaced by compounds having affinity for norepinephrine and serotonin transporters. The neocortical binding was on a low level and could be displaced only by citalopram, a serotonin uptake inhibitor. A high dose of cocaine intravenously (7 mg/kg) induced a 50% occupancy of specific [¹¹C]β-CIT binding to the dopamine transporter in the striatum. This dose is much higher than the doses of 0.25-0.5 mg/kg i.v. for cocaine arousal in human subjects. The finding indicates that cocaine arousal may be induced at a low dopamine transporter occupancy of a few percent. [¹¹C]β-CIT should be a useful radioligand to explore cocaine actions in humans and to follow the pathophysiological process in vivo by PET in neurodegenerative diseases of the striatum. © 1994 Wiley-Liss, Inc.     

Predictive factors for the outcome of emotional and/or behavioural disorders in 18- to 48-month-old children after parent-child psychotherapy: Protocol of a European prospective cohort study

ObjectivesSeveral studies have shown that in young children, behavioural and/or emotional disorders are more difficult to manage than regulatory disorders. Moreover, data are lacking on outcome predictive factors. This article presents a short synthesis of previous research about outcome predictive factors in child psychiatry. It also describes the protocol of a longitudinal observational European multicentre study the main objective of which was to identify predictive factors of behavioural and emotional disorder outcome in toddlers after parent-child psychotherapy. The secondary objectives were to study predictive factors of the outcome in parents (anxiety/depression symptoms) and parent-child relationship.MethodIn order to highlight medium-effect size, 255 toddlers (age: 18 to 48 months) needed to be included. Outcomes will be assessed by comparing the pre- and post-therapy scores of a battery of questionnaires that assess the child's symptoms, the parents’ anxiety/depression, and the parent-child relationship. Multivariate linear regression analysis will be used to identify predictive factors of the outcome among the studied variables (child age and sex, socio-economic status, life events, disorder type, intensity and duration, social support, parents’ psychopathology, parents’ attachment, parent-child relationships, therapy length and frequency, father's involvement in the therapy, and therapeutic alliance).Expected results and conclusionThis study should allow identifying some of the factors that contribute to the outcome of externalizing and internalizing disorders, and distinguishing between pre-existing and treatment-related variables. It should also help to identify children at higher risk of poor outcome who require special vigilance on the part of the therapist. It should confirm the importance of therapeutic alliance.Trial registrationID-RCB 2008-A01088-47.