Delayed affective recovery to daily-life stressors signals a risk for depression.

OBJECTIVE: The aim of this study is to investigate the time to affective recovery from daily-life stressors between healthy controls (HC) and two groups with an increased risk for developing depression: individuals with subclinical symptoms of depression (SSD), and individuals remitted from a depressive episode with residual symptoms of depression (RRS). METHOD: The experience sampling method (ESM) was used to measure affective recovery to daily-life stressors. Affective recovery was defined as the moment that negative affect (NA) returned to baseline level following the first stressful event of the day. We assessed two different operationalizations of the baseline: NA at the moment before the stressful event (t-1), and mean-person NA. The effect of stress intensity, and cumulative stress were also assessed. RESULTS: Survival analyses showed significantly longer recovery times for the at risk groups in comparison to healthy individuals, albeit no significant difference was found between the two at risk groups (i.e. SSD and RRS). There was also an effect of cumulative stress, but not stress intensity on time to recovery in that cumulative stress resulted in significantly longer recovery times for all three groups. LIMITATIONS: The present study is limited by the ESM sampling design, assessments take place post-stress and therefore do not capture peak stress. Additionally, we are only able to assess patterns at the group level. Finally, there is a significant age difference between groups. CONCLUSION: Individuals at risk for depression display a delayed recovery to daily-life stressors when compared to healthy controls, which is not explained by differences in stress intensity or cumulative stress. Understanding what is driving this delay may help combat the development of depression.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations.

AIM: To identify the genetic aetiology of a distinct leukoencephalopathy causing acute neurological regression in infancy with apparently complete clinical recovery. METHODS: We performed trio whole genome sequencing (WGS) to determine the genetic basis of the disorder. Mitochondrial function analysis in cultured patient fibroblasts was undertaken to confirm the pathogenicity of candidate variants. RESULTS: The patient presented at 18 months with acute hemiplegia and cognitive regression without obvious trigger. This was followed by clinical recovery over 4 years. MRI at disease onset revealed bilateral T2 hyperintensity involving the periventricular and deep white matter and MR spectroscopy of frontal white matter demonstrated a lactate doublet. Lactate levels and mitochondrial respiratory chain enzyme activity in muscle, liver and fibroblasts were normal. Plasma glycine was elevated. The MRI abnormalities improved. WGS identified compound heterozygous variants in BOLA3: one previously reported (c.136C>T, p.Arg46*) and one novel variant (c.176G>A, p.Cys59Tyr). Analysis of cultured patient fibroblasts demonstrated deficient pyruvate dehydrogenase (PDH) activity and reduced quantity of protein subunits of mitochondrial complexes I and II, consistent with BOLA3 dysfunction. Previously reported cases of multiple mitochondrial dysfunctions syndrome 2 (MMDS2) with hyperglycinaemia caused by BOLA3 mutations have leukodystrophy with severe, progressive neurological and multisystem disease. CONCLUSIONS: We report a novel phenotype for MMDS2 associated with apparently complete clinical recovery and partial resolution of MRI abnormalities. We have identified a novel disease-causing variant in BOLA3 validated by functional cellular studies. Our patient's clinical course broadens the phenotypic spectrum of MMDS2 and highlights the potential for some genetic leukoencephalopathies to spontaneously improve.

Sirtuin 1 genetic variation, energy balance and colorectal cancer risk by sex and subsite in the Netherlands Cohort Study.

Sirtuin 1 (SIRT1) is an energy-sensing protein, which may affect tumorigenesis. We used SIRT1 variants as time-independent indicators of SIRT1 involvement in carcinogenesis and we studied two tagging SIRT1 variants in relation to colorectal cancer (CRC) risk. We also evaluated known energy balance-related CRC risk factors within SIRT1 genotype strata. The Netherlands Cohort Study includes 120,852 individuals and has 20.3 years follow-up (case-cohort: nsubcohort = 5000; nCRC cases = 4667). At baseline, participants self-reported weight, weight at age 20, height, trouser/skirt size reflecting waist circumference, physical activity, and early life energy restriction. SIRT1 rs12778366 and rs10997870 were genotyped in toenail DNA available for ~75% of the cohort. Sex- and subsite-specific Cox hazard ratios (HRs) showed that the rs12778366 CC versus TT genotype decreased CRC and colon cancer risks in women (HRCRC = 0.53, 95% confidence interval: 0.30-0.94) but not men. Multiplicative interactions were observed between SIRT1 variants and energy balance-related factors in relation to CRC endpoints, but the direction of associations was not always conform expectation nor specific to one genotype stratum. In conclusion, these results support SIRT1 involvement in colon cancer development in women. No conclusions could be made regarding a modifying effect of SIRT1 variants on associations between energy balance-related factors and CRC risk.

Research protocol: The initiation, design and establishment of the Global Angelman Syndrome Registry.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder affecting between 1 in 15 000 and 1 in 24 000 individuals. The condition results in severe developmental and expressive language delays, motor impairments and a unique behavioural phenotype consisting of excessive laughter, smiling and sociability. While many studies have contributed knowledge about the causes and natural history of the syndrome, large scale longitudinal studies are required to advance research and therapeutics for this rare syndrome. METHOD: This article describes the protocol for the Global Angelman Syndrome Registry, and some initial findings. Due to the rarity of AS and the variability in symptom presentation, the registry team will strive for complete case ascertainment. Parents and caregivers will submit data to the registry via a secure internet connection. The registry consists of 10 modules that cover patient demographics; developmental, diagnostic, medical and surgical history, behaviour and development, epilepsy, medications and interventions and sleep. RESULTS: Since its launch at https://angelmanregistry.info in September 2016, almost 470 individuals with AS have been signed up to the registry worldwide: 59% are from North and South America, 23% are from Europe, 17% are from the Asia Pacific region and 1% are from the Middle East or Africa. The majority of registrants are children, with only 16% aged over 20 years. Most participants indicated a chromosome deletion (76%), with fewer participants indicating a mutation, uniparental disomy or imprinting defect (20%). CONCLUSION: Findings indicate a need to consider recruitment strategies that target caregivers of older children and adults, and parents and caregivers from non-English speaking backgrounds.

Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy.

Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole-exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2.

Performance of Current Thromboembolism Risk Assessment Tools in Patients With Gastric Cancer and Validity After First Treatment.

Patients with gastric cancer (GC) are at higher risk of thromboembolism when compared to other solid tumors. We aim to determine the predictive performance of current venous thromboembolism (VTE) predictive tools and their variability and validity after first treatment. Single institution cohort of GC-treated patients (2010*15). We abstracted predictive tools, validated for VTE prediction in patient with cancer; including the Khorana Score (KRS), platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ratio (NLR). The primary outcome was CAT prediction. We included 112 patients who were predominantly men (66%), 58 (51-64)-year-olds, with adenocarcinoma (84%) and advanced disease (59%). The median follow-up was 21.3 months (9.5-42.6). The VTE occurrence was 12%. The median time from diagnosis to VTE occurrence was 59 days (36-258). In our cohort, performance status (PS; hazard ratio [HR], 8.02; 95% confidence interval [CI], 2.37-27.14; P < .01) was an independent predictor of VTE whereas KRS (univariate HR, 2.3; 95% CI, 0.7-7.4; P = .17), PLR (univariate HR, 0.8; 95% CI, 0.2-3.1; P = .8), and NLR (univariate HR, 0.8; 95% CI, 0.3-2.5; P = .8) at baseline were not associated with VTE risk. The posttreatment KRS was an independent predictor of VTE (HR, 3.69; 95% CI, 1.17-11.65; P = .25) along with PS (HR, 7.58; 95% CI, 2.27-25.33; P = .01). Posttreatment KRS appears as a valid tool to identify patients with GC at high risk of VTE after first cancer treatment.

Evidence that polygenic risk for psychotic disorder is expressed in the domain of neurodevelopment, emotion regulation and attribution of salience.

BACKGROUND: The liability-threshold model of psychosis risk predicts stronger phenotypic manifestation of the polygenic risk score (PRS) in the healthy relatives of patients, as compared with healthy comparison subjects. METHODS: First-degree relatives of patients with psychotic disorder (871 siblings and 812 parents) and healthy comparison subjects (n = 523) were interviewed three times in 6 years. Repeated measures of two psychosis phenotypes, the Community Assessment of Psychic Experiences (CAPE; self-report - subscales of positive, negative and depressive symptoms) and the Structured Interview for Schizotypy - Revised (SIS-R; clinical interview - subscales of positive and negative schizotypy), were examined for association with PRS. Interview-based lifetime rate of depressive and manic episodes were also examined, as was association with repeated measures of intelligence quotient (IQ). RESULTS: In the relatives, PRS was associated with CAPE/SIS-R total score (respectively, B = 0.12, 95% CI 0.02-0.22 and B = 0.11, 95% CI 0.02-0.20), the SIS-R positive subscale (B = 0.16, 95% CI 0.04-0.28), the CAPE depression subscale (B = 0.21, 95% CI 0.07-0.34), any lifetime affective episode (OR 3.1, 95% CI 1.04-9.3), but not with IQ (B = -1.8, 95% CI -8.0 to 4.4). In the controls, similar associations were apparent between PRS on the one hand and SIS-R total score, SIS-R positive, SIS-R negative, any lifetime affective episode and, in contrast, lower IQ (B = -8.5, 95% CI -15.5 to -1.6). CONCLUSIONS: In non-ill people, polygenic risk for psychotic disorder is expressed pleiotropically in the domain of neurodevelopment, emotion regulation and attribution of salience. In subjects at elevated genetic risk, emerging expression of neurodevelopmental alterations may create floor effects, obscuring genetic associations.

Photocatalytic photosystem I/PEDOT composite films prepared by vapor-phase polymerization.

Photosystem I (PSI) achieves photo-induced charge separation with outstanding internal quantum efficiency and has been used to improve the performance of various photoelectrochemical systems. Herein, we describe a fast and versatile technique to assemble composite films containing PSI and a chosen intrinsically conductive polymer (ICP). A mixture of PSI and a Friedel-Crafts catalyst (FeCl3) is drop cast atop a substrate of choice. Contact with ICP monomer vapor at low temperature stimulates polymer growth throughout PSI films in minutes. We assess the effects of PSI loading on the rapid vapor-phase growth of poly(3,4-ethylenedioxythiophene) (PEDOT) within and above PSI multilayer films, and characterize the resulting film's thickness, electrochemical capacitance, and photocatalytic response. Composite films generate cathodic photocurrent when in contact with an aqueous redox electrolyte, confirming retention of the photocatalytic activity of the polymer-entrapped PSI multilayer assembly.

Clinical high risk for psychosis: the association between momentary stress, affective and psychotic symptoms.

OBJECTIVE: The aim of this study was to assess associations between momentary stress and both affective and psychotic symptoms in everyday life of individuals at clinical high risk (CHR), compared to chronic psychotic patients and healthy controls, in search for evidence of early stress sensitization. It also assessed whether psychotic experiences were experienced as stressful. METHOD: The experience sampling method was used to measure affective and psychotic reactivity to everyday stressful activities, events and social situations in 22 CHR patients, 24 patients with a psychotic disorder and 26 healthy controls. RESULTS: Multilevel models showed significantly larger associations between negative affect (NA) and activity-related stress for CHR patients than for psychotic patients (P = 0.008) and for CHR compared to controls (P < 0.001). Similarly, the association between activity-related stress and psychotic symptoms was larger in CHR than in patients (P = 0.02). Finally, the association between NA and symptoms (P < 0.001) was larger in CHR than in patients. CONCLUSION: Stress sensitization seems to play a role particularly in the early phase of psychosis development as results suggest that CHR patients are more sensitive to daily life stressors than psychotic patients. In this early phase, psychotic experiences also contributed to the experience of stress.

Introducing the White Noise task in childhood: associations between speech illusions and psychosis vulnerability.

BACKGROUND: Auditory verbal hallucinations (AVH) are common during development and may arise due to dysregulation in top-down processing of sensory input. This study was designed to examine the frequency and correlates of speech illusions measured using the White Noise (WN) task in children from the general population. Associations between speech illusions and putative risk factors for psychotic disorder and negative affect were examined. METHOD: A total of 1486 children aged 11-12 years of the Copenhagen Child Cohort 2000 were examined with the WN task. Psychotic experiences and negative affect were determined using the Kiddie-SADS-PL. Register data described family history of mental disorders. Exaggerated Theory of Mind functioning (hyper-ToM) was measured by the ToM Storybook Frederik. RESULTS: A total of 145 (10%) children experienced speech illusions (hearing speech in the absence of speech stimuli), of which 102 (70%) experienced illusions perceived by the child as positive or negative (affectively salient). Experiencing hallucinations during the last month was associated with affectively salient speech illusions in the WN task [general cognitive ability: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.03-3.93]. Negative affect, both last month and lifetime, was also associated with affectively salient speech illusions (aOR 2.01, 95% CI 1.05-3.83 and aOR 1.79, 95% CI 1.11-2.89, respectively). Speech illusions were not associated with delusions, hyper-ToM or family history of mental disorders. CONCLUSIONS: Speech illusions were elicited in typically developing children in a WN-test paradigm, and point to an affective pathway to AVH mediated by dysregulation in top-down processing of sensory input.

Diabetes mellitus type 2 and subsite-specific colorectal cancer risk in men and women: results from the Netherlands Cohort Study on diet and cancer.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of colorectal cancer (CRC); however, studies differentiating between subsites of CRC are limited. We investigated how diabetes mellitus (DM) was associated with subsite-specific CRC risk in men and women. METHODS: The Netherlands Cohort Study on diet and cancer is a prospective study among 120 852 men and women aged 55-69 years old at baseline in 1986. Information on DM, anthropometric, dietary and lifestyle factors was self-reported at baseline. T2DM was defined as the diagnosis of DM after 30 years of age. Incident CRC cases were identified by record linkage with the Netherlands cancer registry and the Dutch pathology registry. After 17.3 years of follow-up, 1735 incident male CRC cases and 1321 female CRC cases were available for analyses. Subsite-specific hazard ratios (HRs) for CRC were estimated in case-cohort analyses using Cox regression. RESULTS: At baseline, 3.1% of subcohort members reported T2DM, of whom 80% were diagnosed after 50 years of age. Multivariable-adjusted models showed that the risk of proximal colon cancer was significantly increased in women with T2DM versus women without T2DM (HR=1.80, 95% confidence interval: 1.10-2.94). There was no association between T2DM and the risk of overall CRC, distal colon cancer and rectal cancer in women. In men, T2DM was not associated with overall CRC (HR=0.98, 95% confidence interval: 0.64-1.50), or with risk at any subsite. CONCLUSIONS: This prospective study showed an increased risk of proximal colon cancer in women with T2DM compared with non-T2DM women.

Effects of momentary self-monitoring on empowerment in a randomized controlled trial in patients with depression.

BACKGROUND: Interventions based on the experience sampling method (ESM) are ideally suited to provide insight into personal, contextualized affective patterns in the flow of daily life. Recently, we showed that an ESM-intervention focusing on positive affect was associated with a decrease in symptoms in patients with depression. The aim of the present study was to examine whether ESM-intervention increased patient empowerment. METHODS: Depressed out-patients (n=102) receiving psychopharmacological treatment who had participated in a randomized controlled trial with three arms: (i) an experimental group receiving six weeks of ESM self-monitoring combined with weekly feedback sessions, (ii) a pseudo-experimental group participating in six weeks of ESM self-monitoring without feedback, and (iii) a control group (treatment as usual only). Patients were recruited in the Netherlands between January 2010 and February 2012. Self-report empowerment scores were obtained pre- and post-intervention. RESULTS: There was an effect of group×assessment period, indicating that the experimental (B=7.26, P=0.061, d=0.44, statistically imprecise) and pseudo-experimental group (B=11.19, P=0.003, d=0.76) increased more in reported empowerment compared to the control group. In the pseudo-experimental group, 29% of the participants showed a statistically reliable increase in empowerment score and 0% reliable decrease compared to 17% reliable increase and 21% reliable decrease in the control group. The experimental group showed 19% reliable increase and 4% reliable decrease. CONCLUSIONS: These findings tentatively suggest that self-monitoring to complement standard antidepressant treatment may increase patients' feelings of empowerment. Further research is necessary to investigate long-term empowering effects of self-monitoring in combination with person-tailored feedback.

Effects of feeding diets based on transgenic soybean meal and soybean hulls to dairy cows on production measures and sensory quality of milk.

This experiment was conducted to determine whether feeding meal and hulls derived from genetically modified soybeans to dairy cows affected production measures and sensory qualities of milk. The soybeans were genetically modified (Event DAS-444Ø6-6) to be resistant to multiple herbicides. Twenty-six Holstein cows (13/treatment) were fed a diet that contained meal and hulls derived from transgenic soybeans or a diet that contained meal and hulls from a nontransgenic near-isoline variety. Soybean products comprised approximately 21% of the diet dry matter, and diets were formulated to be nearly identical in crude protein, neutral detergent fiber, energy, and minerals and vitamins. The experimental design was a replicated 2×2 Latin square with a 28-d feeding period. Dry matter intake (21.3 vs. 21.4kg/d), milk yield (29.3 vs. 29.4kg/d), milk fat (3.70 vs. 3.68%), and milk protein (3.10 vs. 3.12%) did not differ between cows fed control or transgenic soybean products, respectively. Milk fatty acid profile was virtually identical between treatments. Somatic cell count was significantly lower for cows fed transgenic soybean products, but the difference was biologically trivial. Milk was collected from all cows in period 1 on d 0 (before treatment), 14, and 28 for sensory evaluation. On samples from all days (including d 0) judges could discriminate between treatments for perceived appearance of the milk. The presence of this difference at d 0 indicated that it was likely not a treatment effect but rather an initial bias in the cow population. No treatment differences were found for preference or acceptance of the milk. Overall, feeding soybean meal and hulls derived from this genetically modified soybean had essentially no effects on production or milk acceptance when fed to dairy cows.

Body size, physical activity, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk.

Insulin-like growth factors (IGFs) have been associated with growth, body size, physical activity and colorectal cancer (CRC). We hypothesized that variants in IGF-related genes increase the CRC susceptibility associated with a larger body size and a lack of physical activity. We assessed this in The Netherlands Cohort Study. Participants (n = 120852) completed a baseline questionnaire on diet and cancer. ~75% returned toenail clippings. Using a case-cohort approach and 16.3 years of follow-up, toenail DNA from 3768 subcohort members and 2580 CRC cases was genotyped. We aggregated unfavorable alleles (potentially increasing CRC risk) for 18 single nucleotide polymorphisms in 8 genes into a sum score. The sum score (in tertiles) and an IGF1 19-CA repeat polymorphism (19/19, 19/non-19 and non-19/non-19 repeats) in combination with body size (mostly in tertiles) and (non-)occupational physical activity (>12, 8-12 and <8 kJ/min in the job and >90, >60-90, >30-60 and ≤30 min/day) were analyzed by Cox regression. Increasingly higher hazard ratios (HRs) for CRC were observed for a larger adult body mass index, larger trouser size and tallness in the presence of more unfavorable alleles in men. HRs (95% confidence intervals) for joint effects were 1.55 (1.06-2.25), 1.78 (1.29-2.46) and 1.48 (1.01-2.17), respectively. In women, variant repeat alleles halved CRC risk irrespective of body size and physical activity. Almost no interactions tested significant. To conclude, a larger body size was a CRC risk factor in men in the presence of an accumulation of unfavorable alleles in IGF-related genes, but interactions were generally nonsignificant.

A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: implications for prognosis.

BACKGROUND: We studied the overlap between the major (epi)genomic events microsatellite instability (MSI), the CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) in colorectal cancer (CRC), and whether specific (epi)genotypes were associated with CRC-related deaths. PATIENTS AND METHODS: Molecular analyses using tumor DNA were successful in 509 CRC cases identified within the Netherlands Cohort Study in the period 1989-1993. Follow-up for the vital status until May 2005 was 100%. RESULTS: MSI (12.6%), CIMP-only (5.3%), CIMP + CIN (13.4%), CIN-only (58.2%) and triple-negative tumors (10.6%) differed significantly regarding tumor localization, differentiation grade, initial adjuvant therapy (AT) use and genetic characteristics (P ≤ 0.03). CIMP-only, CIMP + CIN and triple-negative tumors, compared with CIN-only tumors, were significantly associated with a 3.67, 2.44 and 3.78-fold risk of CRC-related deaths after 2-year follow-up (95% confidence intervals, CIs, 1.70-7.91, 1.35-4.41 and 1.97-7.25, respectively), but not after late follow-up. MSI tumors were borderline significantly associated with a 0.40-fold risk of CRC-related deaths after late follow-up (95% CI 0.15-1.03). CONCLUSION(S): This is the first study to show that specific (epi)genotypes may hold a differential prognostic value that may vary over time. Although no specific treatment data were available, an explanation for the differential findings over time might be that (epi)genotypes modify therapy response.

Emotion recognition in psychosis: no evidence for an association with real world social functioning.

BACKGROUND: Patients with psychotic disorders show impairments in the recognition of emotions in other people. These impairments have been associated with poor social functioning as measured by self-report questionnaires, clinical interviews and laboratory-based tests of social skills. The ecological validity of these tests, however, is low. Associations were examined between emotion recognition and daily life social interactions in 50 patients diagnosed with a non-affective psychotic disorder and 67 healthy controls. METHODS: All participants were assessed with the Degraded Facial Affect Recognition Task (DFAR), a computer test measuring the recognition of emotional facial expressions. Social functioning in daily life was assessed using the Experience Sampling Method (a random time sampling technique) with focus on measures of social context and appraisal of the social situation. RESULTS: Groups differed significantly in the recognition of angry faces, whereas no differences existed for other emotions. There were no associations between emotion recognition and social functioning in daily life and there was no evidence for differential associations in patients as compared to controls. DISCUSSION: Social functioning, when assessed in an ecologically valid fashion, is not sensitive to variation in the traditional experimental assessment of emotion recognition. Real life measures of functioning should guide research linking the handicaps associated with psychosis to underlying cognitive and emotional dysregulation.

NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the ß-catenin pathway.

Nuclear factor-κB (NF-κB) inducing kinase (NIK) is a MAP3K that regulates the activation of NF-κB. NIK is often highly expressed in tumor cells, including melanoma, but the significance of this in melanoma progression has been unclear. Tissue microarray analysis of NIK expression reveals that dysplastic nevi (n=22), primary (n=15) and metastatic melanoma (n=13) lesions showed a statistically significant elevation in NIK expression when compared with benign nevi (n=30). Moreover, when short hairpin RNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model. As expected, when NIK was depleted there was decreased activation of the non-canonical NF-κB pathway, whereas canonical NF-κB activation remained intact. NIK depletion also resulted in reduced expression of genes that contribute to tumor growth, including CXCR4, c-MYC and c-MET, and pro-survival factors such as BCL2 and survivin. These changes in gene expression are not fully explained by the attenuation of the non-canonical NF-κB pathway. Shown here for the first time is the demonstration that NIK modulates ß-catenin-mediated transcription to promote expression of survivin. NIK-depleted melanoma cells exhibited downregulation of survivin as well as other ß-catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate that NIK mediates both ß-catenin and NF-κB regulated transcription to modulate melanoma survival and growth. Thus, NIK may be a promising therapeutic target for melanoma.

Cognitive alterations in patients with non-affective psychotic disorder and their unaffected siblings and parents.

OBJECTIVE: The purpose of this study was to examine a range of cognitive measures as candidate phenotypic liability markers for psychosis in a uniquely large sample of patients with psychosis, their unaffected relatives and control subjects. METHOD: Patients with non-affective psychosis (n = 1093), their unaffected siblings (n = 1044), parents (n = 911), and controls (n = 587) completed a comprehensive cognitive test battery. Cognitive functioning was compared using tests of verbal learning and memory, attention/vigilance, working memory, processing speed, reasoning and problem solving, acquired knowledge, and social cognition. Age- and gender-adjusted z-scores were compared between groups using mixed-model analyses of covariance. Clinically relevant impairment (-1 and -2 SD from control mean) was compared between subject groups. RESULTS: Patients performed significantly worse than controls in all cognitive domains (z-range -0.26 to -1.34). Siblings and parents showed alterations for immediate verbal learning, processing speed, reasoning and problem solving, acquired knowledge, and working memory (z-range -0.22 to -0.98). Parents showed additional alterations for social cognition. Prevalence of clinically relevant impairment in relatives ranged from 50% (-1 SD criterion) to 10% (-2 SD criterion). CONCLUSION: Cognitive functioning is a candidate intermediate phenotype given significant small to large alterations in patients and intermediate alterations in first-degree relatives.