Longitudinal associations between alcohol use, smoking, genetic risk scoring and symptoms of depression in the general population: a prospective 6-year cohort study.

BACKGROUND: Alcohol consumption, smoking and mood disorders are leading contributors to the global burden of disease and are highly comorbid. Yet, their interrelationships have remained elusive. The aim of this study was to examine the multi-cross-sectional and longitudinal associations between (change in) smoking and alcohol use and (change in) number of depressive symptoms. METHODS: In this prospective, longitudinal study, 6646 adults from the general population were included with follow-up measurements after 3 and 6 years. Linear mixed-effects models were used to test multi-cross-sectional and longitudinal associations, with smoking behaviour, alcohol use and genetic risk scores for smoking and alcohol use as independent variables and depressive symptoms as dependent variables. RESULTS: In the multi-cross-sectional analysis, smoking status and number of cigarettes per day were positively associated with depressive symptoms (p < 0.001). Moderate drinking was associated with less symptoms of depression compared to non-use (p = 0.011). Longitudinally, decreases in the numbers of cigarettes per day and alcoholic drinks per week as well as alcohol cessation were associated with a reduction of depressive symptoms (p = 0.001-0.028). Results of genetic risk score analyses aligned with these findings. CONCLUSIONS: While cross-sectionally smoking and moderate alcohol use show opposing associations with depressive symptoms, decreases in smoking behaviour as well as alcohol consumption are associated with improvements in depressive symptoms over time. Although we cannot infer causality, these results open avenues to further investigate interventions targeting smoking and alcohol behaviours in people suffering from depressive symptoms.

[Patient with a long history of disease in whom service dog contributed to recovery]. / Hulphond als geslaagde contextuele interventie voor herstel.

We describe a patient who reached recovery, after purchasing a dog and training it into an assistance dog. The patient has a long lasting (over 30 years) history in mental health care and was diagnosed with autism spectrum disorder, posttraumatic stress disorder and borderline personality disorder. All these years the patient did not reach symptomatic improvement or personal or social recovery. The patient suffered from severe emotional instability, feeling misunderstood, sleeping disorder because of nightmares and traumatic re-experiences, feeling unsafe and externalisation. There were repeated conflicts and periodical rejection of caregivers. A range of interventions and support options were offered. Medication intake was considerable aiming for sedation and numbness. After a second opinion an assistance dog was suggested. Two years after the purchase of the dog, her mood had improved, anxiety decreased, she slept better and stopped all medication. She feeled safe. Conflicts with others were reduced, she had some social contacts and the intensity of care had been reduced considerably.

[Use of the Triangle of Care Card and its influence on the cooperation with caregivers and clients]. / Gebruik van Triadekaart en invloed op de samenwerking met naastbetrokkenen.

BACKGROUND: Although there is consensus on the importance of involving informal caregivers of people with severe mental illness, interventions are needed to support this. AIM: To explore whether the use of the 'Triangle of Care Card', an instrument developed to help strengthen the role of care-givers in their contact with workers, increases quality of cooperation and care. METHOD: Three outpatient mental health teams and twelve teams for supported housing started working with the card. Information from files and questionnaires were used to monitor change and compare this with the changes during the same year in ten other teams. RESULTS: Use of the Triangle of Care Card was sparse. When it was used, a broader range of subjects were discussed, including the needs of caregivers. Also, clients were more involved. In teams where the card was introduced, the clients' networks became more apparent and there was an increase in face-to-face meetings with members of this network. CONCLUSION: Introduction of the Triangle of Care Card leads to change in the involvement of caregivers. However, implementation is problematic and therefore the increase in quality of the cooperation with caregivers and quality of care is yet small.

Resuscitation with an AED: putting the data to use.

The increased use of the automated external defibrillator (AED) contributes to the rising survival rate after sudden cardiac arrest in the Netherlands. When used, the AED records the unconscious person's medical data (heart rhythm and information about cardiopulmonary resuscitation), which may be important for further diagnosis and treatment. In practice, ethical and legal questions arise about what can and should be done with these 'AED data'. In this article, the authors advocate the development of national guidelines on the handling of AED data. These guidelines should serve two purposes: (1) to safeguard that data are handled carefully in accordance with data protection principles and the rules of medical confidentiality; and (2) to ensure nationwide availability of data for care of patients who survive resuscitation, as well as for quality monitoring of this care and for related scientific research. Given the medical ethical duties of beneficence and fairness, existing (sometimes lifesaving) information about AED use ought to be made available to clinicians and researchers on a structural basis. Creating a national AED data infrastructure, however, requires overcoming practical and organisational barriers. In addition, further legal study is warranted.

Analysis of microRNA expression in brush cytology specimens improves the diagnosis of pancreatobiliary cancer.

BACKGROUND/OBJECTIVES: Malignant pancreatobiliary strictures are in many cases clinically indistinguishable and present a major problem to endoscopy specialists. Intraductal sampling procedures such as brush cytology are commonly used for diagnosis with a sensitivity that is low for a diagnostic test used in daily clinical practice. MicroRNA (miR) alterations detected in many cancers are disease-specific, which can be utilized in clinical applications. The aim of the present study was to analyze whether determination of miR expression levels in intraductal brush cytology specimens is a feasible approach to improve the diagnosis of pancreatobiliary cancer. METHODS: Brush cytology specimens have been collected during endoscopic retrograde cholangio-pancreatography (ERCP) and analyzed by routine cytology and ancillary miR assays. Total RNA was extracted using the miRNeasy Mini Kit and the expression of miRs frequently dysregulated in pancreatobiliary cancer (miR-16, miR-21, miR-196a, miR-221) were analyzed by quantitative real-time PCR using RNU6B as internal control. RESULTS: Routine cytology resulted in no false positive diagnoses, however, the combined sensitivity remained at 53.8%. Expression (ΔCt values) of miR-16 (p = 0.0039), miR-196a (p = 0.0003) and miR-221 (p = 0.0049) showed a clear statistical significance between malignant and benign pancreatobiliary specimens (n = 35). Malignancy could be detected combining routine cytology and the miR-196a single marker expression levels with a sensitivity of 84.6% (92.9% in biliary strictures) with no false positives. CONCLUSIONS: The results offer the first direct demonstration that microRNAs are readily detectable in brush cytology specimens obtained during ERCP, and have the potential to help the cytological diagnosis of pancreatobiliary malignancy.

No differences in olanzapine- and risperidone-related weight gain between women and men: a meta-analysis of short- and middle-term treatment.

OBJECTIVE: A plethora of data deriving from single studies as well as meta-analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions. METHOD: A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression. RESULTS: Data of 26 studies were used in the present analysis because sufficient data were available only for olanzapine, risperidone and the no-medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences. CONCLUSION: The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported.

The functional and clinical relevance of childhood trauma-related admixture of affective, anxious and psychosis symptoms.

OBJECTIVE: Previous work has shown that across different patient samples, patients with childhood trauma are more likely to have co-occurrence of affective, anxious and psychosis symptoms than non-traumatized patients. However, the clinical relevance of trauma-related admixture remains to be established. METHOD: We examined patients with mood disorder (NEMESIS-2; n = 1260), anxiety disorder (NEMESIS-2; n = 896) or psychotic disorder (GROUP; n = 532) in terms of symptom profiles, quality of life (QOL) and social functioning. RESULTS: Results showed that mood disorder patients with both trauma and co-occurrence of affective, anxious and psychosis symptoms had a lower QOL (B-12.6, 95% CI -17.7 to -7.5, P < 0.001), more help-seeking behaviour [odds ratio (OR) 2.5, 95% CI 1.1-5.7, P = 0.031] and higher prevalence of substance use disorders (OR 7.8, 95% CI 1.1-58.0, P = 0.044), compared with patients without trauma history and symptom admixture (Trauma-/CL-). Similar results were found in patients with an anxiety disorder. Traumatized patients with a psychotic disorder and admixture showed lower QOL (B-0.6, 95% CI -0.9 to -0.4, P < 0.001), higher prevalence of drug disorders (OR 2.2, 95% CI 1.2-3.9, P = 0.008) and lower global assessment of functioning (B-12.8, 95% CI -17.1 to -8.5, P < 0.001) than Trauma-/CL- patients. CONCLUSION: Stratification according to childhood trauma exposure thus identifies a phenotype characterized by admixture of affective, anxiety and psychotic symptoms that, when combined, has clinical relevance. Identification of functionally meaningful aetiological subgroups may aid clinical practice.

Childhood trauma is associated with a specific admixture of affective, anxiety, and psychosis symptoms cutting across traditional diagnostic boundaries.

BACKGROUND: Meta-analyses link childhood trauma to depression, mania, anxiety disorders, and psychosis. It is unclear, however, whether these outcomes truly represent distinct disorders following childhood trauma, or that childhood trauma is associated with admixtures of affective, psychotic, anxiety and manic psychopathology throughout life. METHOD: We used data from a representative general population sample (NEMESIS-2, n = 6646), of whom respectively 1577 and 1120 had a lifetime diagnosis of mood or anxiety disorder, as well as from a sample of patients with a diagnosis of schizophrenia (GROUP, n = 825). Multinomial logistic regression was used to assess whether childhood trauma was more strongly associated with isolated affective/psychotic/anxiety/manic symptoms than with their admixture. RESULTS: In NEMESIS-2, largely comparable associations were found between childhood trauma and depression, mania, anxiety and psychosis. However, childhood trauma was considerably more strongly associated with their lifetime admixture. These results were confirmed in the patient samples, in which it was consistently found that patients with a history of childhood trauma were more likely to have a combination of multiple symptom domains compared to their non-traumatized counterparts. This pattern was also found in exposed individuals who did not meet criteria for a psychotic, affective or anxiety disorder and who did not seek help for subclinical psychopathology. CONCLUSIONS: Childhood trauma increases the likelihood of a specific admixture of affective, anxiety and psychotic symptoms cutting across traditional diagnostic boundaries, and this admixture may already be present in the earliest stages of psychopathology. These findings may have significant aetiological, pathophysiological, diagnostic and clinical repercussions.

Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1): implications for GLP-1 measurements in clinical studies.

AIMS: To evaluate the performances of commercially available glucagon-like peptide-1 (GLP-1) assays and the implications for clinical studies. METHODS: Known concentrations (5-300 pmol/l) of synthetic GLP-1 isoforms (GLP-1 1-36NH2, 7-36NH2, 9-36NH2, 1-37, 7-37 and 9-37) were added to the matrix (assay buffer) supplied with 10 different kits and to human plasma, and recoveries were determined. Assays yielding meaningful results were analysed for precision and sensitivity by repeated analysis and ability to discriminate low concentrations. Endogenous GLP-1 levels in clinical samples were assessed using three commercial kits. RESULTS: The USCN LIFE assay detected none of the GLP-1 isoforms. The active GLP-1 enzyme-linked immunosorbent assays (ELISAs) from Millipore and DRG appeared identical and were specific for intact GLP-1 in buffer and plasma. The Meso Scale Discovery (MSD) total GLP-1 kit detected all six GLP-1 isoforms, although recovery of non-active forms was incomplete, especially in plasma. Millipore total GLP-1 ELISA kit detected all isoforms in buffer, but mainly amidated forms in plasma. The Alpco, Phoenix and Bio-Rad kits detected only amidated GLP-1, but the Alpco kit had a limited measurement range (30 pmol/l), the Phoenix kit had incomplete recovery in plasma and the Bio-Rad kit was insensitive (detection limit in plasma 40 pmol/l). The pattern of postprandial GLP-1 responses in clinical samples was similar between the kits tested, but the absolute concentrations measured varied. CONCLUSIONS: The specificity and sensitivity of commercially available kits for the analysis of GLP-1 levels vary considerably. This should be taken into account when selecting which assay to use and when comparing data from different studies.

Does social defeat mediate the association between childhood trauma and psychosis? Evidence from the NEMESIS-2 Study.

OBJECTIVE: Based on theoretical considerations and animal studies, mediation of 'social defeat' (SD) in the association between childhood trauma (CT) and psychosis was investigated. METHOD: Trained interviewers administered a structured interview assessing CT, psychotic experiences and other psychopathology in 6646 participants in the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). RESULTS: Childhood trauma was associated with psychotic experiences making up the extended psychosis phenotype (EPP), as well as with a diagnosis of psychotic disorder (PD). Similarly, CT was associated with a priori selected items indexing SD (discouraged, hopeless, worthless, loss of self-confidence, low self-esteem, better off dead, suicidal thoughts) and with a measure of affective dysregulation (AD), which in turn were also associated with psychosis. While SD and AD individually acted as mediators in the association between CT and EPP, only SD acted as a mediator in the association between CT and PD. Cannabis use did not mediate the association between CT and EPP or PD. CONCLUSION: The present results suggest a developmental model implicating SD as an important mediator in the link between childhood adverse experiences and later development of psychotic experiences. The combined mediation by SD and AD is compatible with an 'affective pathway' to early psychosis.

Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.

Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.

Genetic studies in congenital anterior midline cervical cleft.

Congenital anterior midline cervical cleft (CAMCC) is a rare anomaly, with less than 100 cases reported. The cause of CAMCC is unknown, but genetic factors must be considered as part of the etiology. Three cases of CAMCC are presented. This is the first genetic study of isolated CAMCC. Conventional cytogenetics, array-comparative genomic hybridization (CGH) and whole exome sequencing were performed, including a search of relevant syndromes in the Online Mendelian Inheritance in Man (OMIM) database. Array CGH indicated a loss of the PAPPA gene in one of the patients, while exome sequencing showed a mutation in SIX5 in another patient. Both aberrations were inherited from unaffected parents. These results most likely imply that the identified mutations are not disease-causing, although they may be contributing factors if CAMCC has a polygenic inheritance.

[The new curriculum for the University Training Course in Psychiatry in South Limburg and for the Mental Health Services in Eindhoven]. / Het vernieuwde cursorische onderwijs van de universitaire opleiding psychiatrie Zuid-Limburg en GGZ Eindhoven.

BACKGROUND: The curriculum for the Academic Training Course in Psychiatry in South- Limburg (UOP-ZL) needed to be modernised. There were widely differing views about the purpose and function of psychiatry and about the structure of the curriculum. Trainees failed to attend regularly because of their daily duties. AIM: Following discussion about the need for modernisation of the course in Psychiatry (HOOP), the UOP-ZL curriculum was thoroughly revised and updated. METHOD: Further development of HOOP, a careful study of the teaching material and discussion among members of UOP-ZL and the Mental Health Service in Eindhoven, led to the development of more unified views about psychiatry and produced the ingredients for a revised curriculum for training in psychiatry. RESULTS: In the early stages of their course, trainees are introduced to some basic principles; these include understanding the mechanisms for dimensions of affect, motivation, salience and cognition from a biological, cognitive and ecological perspective, and perceiving the relationship between these factors and normal and abnormal behaviour. The course is a mix of problem based learning and interactive classroom teaching and is delivered by clinical and scientific experts. Every two weeks the trainees in each year-group are given a whole day 'free' (i.e. free of normal duties) when they are required to attend classed and lectures. CONCLUSION: The two main results of the new curriculum are: diagnosis-related teaching has been replaced by an approach based on explanatory mechanisms for dimensional psychopathology and dysfunction, and the tuition provided is both problem-based and interactive and is given by expert teachers.

Beyond Tier Three: Individualized Levels of Support During Headsprout® Early Reading Instruction for Children with Autism Spectrum Disorder.

We previously conducted a series of conceptual replications to parse out which-and to what degree-adaptations and individualized supports were needed for children to access and learn early reading skills using Headsprout®. Here we developed a systematic decision-making process for providing levels of support to individuals with autism who require additional instruction in order to access and/or advance through Headsprout®. Using a series of single-case AB, ABC, and multiple-baseline designs we examined strategies from our previous research and additional strategies iteratively developed during the study on six students with autism, all of whom demonstrated progression through Headsprout® and increased reading skills. We provide practical implications for teachers and suggestions to research these supports with other computer-based programs.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

[Rapid tranquillisation; review of the literature and recommendations]. / Acute ingrijpmedicatie; literatuuroverzicht en aanbevelingen.

BACKGROUND: In The Netherlands, no guidelines exist for rapid tranquillisation in the context of acute agitation, excitement or aggression secondary to a psychiatric disorder. AIM: To generate an overview of medication regimes suitable for rapid tranquillisation. METHOD: A literature search was conducted focussing on the effect of medical interventions in acute excitement, agitation or aggression. Primary outcome measurements were tranquillity, being calm, sedation, or asleep within two hours. Secondary outcome measures were frequency of re-administration and adverse side effects. RESULTS: Haloperidol appears as effective as lorazepam; haloperidol in combination with lorazepam does not have added value to lorazepam or haloperidol alone. Dehydrobenzperidol, risperidone, olanzapine and aripiprazole are comparable in effectiveness to lorazepam or haloperidol. Haloperidol in combination with promethazine is associated with a more rapid onset of effect than lorazepam, haloperidol or olanzapine. Midazolam is faster than the combination of haloperidol and promethazine, but requires more frequent re-administration of medication and increases the risk for respiratory depression. The literature on quetiapine was insufficient. The level of evidence, however, is modest. CONCLUSION: Haloperidol in combination with promethazine, and olanzapine, are effective in psychotic agitation, although haloperidol plus promethazine has a more rapid onset of effect faster; lorazepam is effective in non-psychotic agitation, aggression or excitement as well as in acute agitation of unknown origin.

Public perception and awareness of waste management from Benin City.

Poor waste management is increasingly becoming a major challenge for municipalities, globally. Unlike previous waste management studies in Nigeria, this study examines the implications of waste management to regional greenhouse gas emissions based on awareness levels and perception of urban inhabitants. Benin City was divided into four residential zones: core, intermediate, suburban, and planned estates. Blocking was utilized to collect data from a total of 2720 randomly selected inhabitants through a self-administered survey. Results reveals low awareness level in terms of indiscrimination dumping of waste, thereby promoting sustainable mitigation and adaptation measures region-wide. It is imperative to integrate various aspects of regional government services such as infrastructure, urban planning and development, socioeconomics, public health, and regulation enforcement. Waste management policy is strengthened via working groups, community, and regional authorities.

Implementing early intensive behavioral intervention in community settings.

LAY ABSTRACT: Although research shows early intensive behavioral intervention can be very beneficial for children with autism spectrum disorder when delivered in university or private intervention centers, little is known about the best way to provide early intensive behavioral intervention within the broader community. The Michigan State University Early Learning Institute was developed to address challenges with providing early intensive behavioral intervention in community settings, with an emphasis on serving children and families on Medicaid. This short report describes the approach taken by the Early Learning Institute and reports data regarding enrollment and utilization among Medicaid families. Results suggest the model has potential to be used within community settings and that children on Medicaid are likely to consistently attend their treatment sessions.

Tumor repolarization by an advanced liposomal drug delivery system provides a potent new approach for chemo-immunotherapy.

Immunosuppressive cells in the tumor microenvironment allow cancer cells to escape immune recognition and support cancer progression and dissemination. To improve therapeutic efficacy, we designed a liposomal oxaliplatin formulation (PCL8-U75) that elicits cytotoxic effects toward both cancer and immunosuppressive cells via protease-mediated, intratumoral liposome activation. The PCL8-U75 liposomes displayed superior therapeutic efficacy across all syngeneic cancer models in comparison to free-drug and liposomal controls. The PCL8-U75 depleted myeloid-derived suppressor cells and tumor-associated macrophages in the tumor microenvironment. The combination of improved cancer cell cytotoxicity and depletion of immunosuppressive populations of immune cells is attractive for combination with immune-activating therapy. Combining the PCL8-U75 liposomes with a TLR7 agonist induced immunological rejection of established tumors. This combination therapy increased intratumoral numbers of cancer antigen-specific cytotoxic T cells and Foxp3- T helper cells. These results are encouraging toward advancing liposomal drug delivery systems with anticancer and immune-modulating properties into clinical cancer therapy.

Long-term unit recording from somatosensory neurons in the spinal ganglia of the freely walking cat.

A new technique has been developed for stable, long-term recording from groups of individual primary afferent neurons in the freely walking cat. A number of fine, flexible wires are inserted into dorsal root ganglia via a small laminotomy in the lumbar spine. The cut end of each wire can record stable and separable action potentials from one to three dorsal root ganglion neurons; each unit has typically held for 1 to 4 days. A broad range of myelinated somatosensory afferent (conduction velocities of 30 to 120 meters per second) have been studies during locomotion. Most cutaneous and proprioceptive afferent studied have been sensitive monitors of complex combinations of step-cycle components, and their firing patterns would often have been difficult to predict from existing information.