Somatic Diseases and Conditions Before the First Diagnosis of Schizophrenia: A Nationwide Population-based Cohort Study in More Than 900 000 Individuals

Objective: Schizophrenia is associated with excess physical comorbidity. Yet, to our knowledge, large studies are lacking on the associations with somatic diseases before the onset of schizophrenia. The authors conducted a nationwide study of the full spectrum of treated somatic diseases before the first diagnosis of schizophrenia. Method: Nationwide sample of the Danish population consisting of singletons (n = 954351) born 1977–1993 and followed from birth to 2009, during which period 4371 developed schizophrenia. Somatic diagnoses at all general hospital contacts (admitted or outpatient care at a somatic hospital) from 1977 to 2009 were used as exposures. The incidence rate ratio (IRR) of schizophrenia was calculated using Poisson regression adjusted for confounders. Results: Among the 4371 persons who developed schizophrenia from 1992 to 2009, a total of 4180 (95.6%) persons had a previous somatic hospital contact. A history of any somatic hospital contact was associated with an elevated risk of schizophrenia (IRR = 2.04, 95% CI = 1.77–2.37). A wide range of somatic diseases and conditions were associated with an increased risk of schizophrenia, including epilepsy (IRR = 2.26, 95% CI = 1.93–2.62), nutritional or metabolic disorders (IRR = 1.57, 95% CI = 1.39–1.77), circulatory system diseases (IRR = 1.63, 95% CI= 1.38–1.92), and brain injury (IRR = 1.58, 95% CI = 1.45–1.72). Conclusions: A wide range of potential etiological factors could have contributed to the observed associations, including genetic or physiological overlaps between conditions, and interacting immunological, behavioral, and neurodevelopmental factors.Key words: schizophrenia, risk factors, physical illness     

Quality of life in children with OCD before and after treatment

Quality of life (QoL) is a well-established outcome measure. In contrast to adult obsessive–compulsive disorder (OCD), little is known about the effects of treatment on QoL in children with OCD. This study aimed to assess QoL after cognitive behavioural therapy (CBT) in children and adolescents with OCD compared with the general population and to explore factors associated with potential changes in QoL after treatment. QoL was assessed in 135 children and adolescents (ages 7–17; mean 13 [SD 2.7] years; 48.1 % female) before and after 14 CBT sessions, using self-report and a caregivers proxy report of the Questionnaire for Measuring Health-related Quality of Life in Children and Adolescents (KINDL-R). QoL was compared with an age- and gender-matched sample from the general population. Before treatment, QoL was markedly lower in children with OCD compared with the general population. QoL improved significantly in CBT responders (mean score change 7.4), to the same range as QoL in the general population. Non-responders reported no QoL changes after treatment, except for one patient. Comorbidity, family accommodation and psychosocial functioning were not associated with changes in QoL after treatment. To our knowledge, this is the first study of the changes in QoL after treatment of paediatric OCD. The assessment of QoL beyond symptoms and function in children with OCD has been shown to be reliable and informative. The results of this study support the application of QoL assessment as an additional measure of treatment outcome in children and adolescents with OCD.     

How to Assess the Quality of Glucose Clamps? Evaluation of Clamps Performed With ClampArt,a Novel Automated Clamp Device

Background:

There are no widely accepted parameters to assess the quality of glucose clamps. Thus, we selected different parameters describing clamp quality. These parameters were then evaluated in glucose clamps carried out with ClampArt, a novel CE-marked, state-of-the-art fully automated glucose clamp device employing continuous blood glucose (BG) measurements and minute-by-minute adaptations of glucose infusion rate (GIR).

Methods:

Thirty-nine glucose clamps were performed in 10 healthy and 29 subjects with type 1 diabetes (T1DM) (total duration 583 h). ClampArt-based BG measurements were compared with those obtained with a laboratory reference method. Clamp quality was assessed by 5 parameters: (1) difference (mg/dl) of all paired BG measurements of ClampArt versus reference method (“trueness”), (2) coefficient of variation (CV, %) of ClampArt’s BG measurements at target clamp level (“precision”), (3) mean absolute relative difference (MARD, %) at target clamp level (“accuracy”), (4) difference (mg/dl) between ClampArt and target BG (“control deviation”), and (5) percentage operational time (“utility”).

Results:

ClampArt-based BG measurements showed a trueness of 1.2 ± 2.5 mg/dl. CV and MARD at target BG were 5.5 ± 2.1% and 5.3 ± 2.3%, respectively. There were only small deviations from target level (1.2 ± 1.6 mg/dl). Operational time was as high as 95.4% ± 4.1% (means ± SD).

Conclusions:

The selected parameters seem to be adequate to characterize clamp quality. The novel, fully automated clamp device ClampArt achieves high clamp quality, which in future trials should be compared with other (automated and manual) clamp methods.     

Mutational profiles of Brenner tumors show distinctive features uncoupling urothelial carcinomas and ovarian carcinoma with transitional cell histology

Brenner tumors (BT) are rare ovarian tumors encompassing benign, borderline, and malignant variants. While the histopathology of BTs and their clinical course is well described, little is known about the underlying genetic defects. We employed targeted next generation sequencing to analyze the mutational landscape in a cohort of 23 BT cases (17 benign, 2 borderline, and 4 malignant) and 3 ovarian carcinomas with transitional cell histology (TCC). Copy number variations (CNV) were validated by fluorescence in‐situ hybridization (FISH) and quantitative PCR‐based copy number assays. Additionally, we analyzed the TERT promotor region by conventional Sanger sequencing. We identified 25 different point mutations in 23 of the analyzed genes in BTs and 10 mutations in 8 genes in TCCs. About 57% percent of mutations occurred in genes involved in cell cycle control, DNA repair, and epigenetic regulation processes. All TCC cases harbored TP53 mutations whereas all BTs were negative and none of the mutations observed in BTs were present in TCCs. CNV analysis revealed recurrent MDM2 amplifications in 3 out of 4 of the malignant BT cases with one case harboring a concomitant amplification of CCND1. No mutations were observed in the TERT promoter region in BTs and TCCs, which is mutated in about 50%‐75% of urothelial carcinoma and in 16% of ovarian clear‐cell carcinomas. In conclusion, our study highlights distinct genetic features of BTs, and detection of the triplet phenotype MDM2 amplification/TP53 wt/TERT wt may aid diagnosis of malignant BT in difficult cases. Moreover, selected genetic lesions may be clinically exploitable in a metastatic setting.     

Making sense: Dopamine activates conscious self‐monitoring through medial prefrontal cortex

When experiences become meaningful to the self, they are linked to synchronous activity in a paralimbic network of self‐awareness and dopaminergic activity. This network includes medial prefrontal and medial parietal/posterior cingulate cortices, where transcranial magnetic stimulation may transiently impair self‐awareness. Conversely, we hypothesize that dopaminergic stimulation may improve self‐awareness and metacognition (i.e., the ability of the brain to consciously monitor its own cognitive processes). Here, we demonstrate improved noetic (conscious) metacognition by oral administration of 100 mg dopamine in minimal self‐awareness. In a separate experiment with extended self‐awareness dopamine improved the retrieval accuracy of memories of self‐judgment (autonoetic, i.e., explicitly self‐conscious) metacognition. Concomitantly, magnetoencephalography (MEG) showed increased amplitudes of oscillations (power) preferentially in the medial prefrontal cortex. Given that electromagnetic activity in this region is instrumental in self‐awareness, this explains the specific effect of dopamine on explicit self‐awareness and autonoetic metacognition. Hum Brain Mapp 36:1866–1877, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. .     

Interleukin‐15‐activated natural killer cells kill autologous osteoclasts via LFA‐1, DNAM‐1 and TRAIL,and inhibit osteoclast‐mediated bone erosion in vitro

Osteoclasts reside on bone and are the main bone resorbing cells playing an important role in bone homeostasis, while natural killer (NK) cells are bone‐marrow‐derived cells known to play a crucial role in immune defence against viral infections. Although mature NK cells traffic through bone marrow as well as to inflammatory sites associated with enhanced bone erosion, including the joints of patients with rheumatoid arthritis, little is known about the impact NK cells may have on mature osteoclasts and bone erosion. We studied the interaction between human NK cells and autologous monocyte‐derived osteoclasts from healthy donors in vitro. We show that osteoclasts express numerous ligands for receptors present on activated NK cells. Co‐culture experiments revealed that interleukin‐15‐activated, but not resting, NK cells trigger osteoclast apoptosis in a dose‐dependent manner, resulting in drastically decreased bone erosion. Suppression of bone erosion requires contact between NK cells and osteoclasts, but soluble factors also play a minor role. Antibodies masking leucocyte function‐associated antigen‐1, DNAX accessory molecule‐1 or tumour necrosis factor‐related apoptosis‐inducing ligand enhance osteoclast survival when co‐cultured with activated NK cells and restore the capacity of osteoclasts to erode bone. These results suggest that interleukin‐15‐activated NK cells may directly affect bone erosion under physiological and pathological conditions.     

Recruitment of activating NK‐cell receptors 2B4 and NKG2D to membrane microdomains in mammalian cells is dependent on their transmembrane regions

Membrane microdomains play an important role in the regulation of natural killer (NK) cell activities. These cholesterol‐rich membrane domains are enriched at the activating immunological synapse and several activating NK‐cell receptors are known to localize to membrane microdomains upon receptor engagement. In contrast, inhibitory receptors do not localize in these specialized membrane domains. In addition, the functional competence of educated NK cells correlates with a confinement of activating receptors in membrane microdomains. However, the molecular basis for this confinement is unknown. Here, we investigate the structural requirements for the recruitment of the human‐activating NK‐cell receptors NKG2D and 2B4 to detergent‐resistant membrane fractions in the murine BA/F3 cell line and in the human NK‐cell line NKL. This stimulation‐dependent recruitment occurred independently of the intracellular domains of the receptors. However, either interfering with the association between NKG2D and DAP10, or mutating the transmembrane region of 2B4 impacted the recruitment of the receptors to detergent‐resistant membrane fractions and modulated the function of 2B4 in NK cells. Our data suggest a potential interaction between the transmembrane region of NK‐cell receptors and membrane lipids as a molecular mechanism involved in determining the membrane confinement of activating NK‐cell receptors.