Responses to Medical Treatment in 192 Patients with Pancreatic Neuroendocrine Neoplasms Referred to the Copenhagen Neuroendocrine Tumour Centre in 2000-2020.

BACKGROUND: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. AIM: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. METHODS: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). RESULTS: Median OS was 36 (95% CI: 26-46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9-9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1-7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). CONCLUSION: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide.

Outlook for 615 Small Intestinal Neuroendocrine Tumor Patients: Recurrence Risk after Surgery and Disease-Specific Survival in Advanced Disease.

BACKGROUND: Small intestinal neuroendocrine tumors (siNET) are one of the most common neuroendocrine neoplasms. Radical surgery is the only curative treatment. METHOD: We utilized a single-center study including consecutive patients diagnosed from 2000 to 2020 and followed them until death or the end of study. Disease-specific survival and recurrence-free survival (RFS) were investigated by Cox regression analyses with the inclusion of prognostic factors. Aims/primary outcomes: We identified three groups: (1) disease specific-survival in the total cohort (group1), (2) RFS and disease-specific survival after intended radical surgery (group2), (3) disease specific-survival in patients with unresectable disease or residual tumor after primary resection (group3). RESULTS: In total, 615 patients, with a mean age (SD) 65 ± 11 years were included. Median (IQR) Ki-67 index was 4 (2-7)%. Median disease-specific survival in group1 was 130 months. Median RFS in group2 was 138 months with 5- and 10-year RFS rates of 72% and 59% with age, plasma chromogranin A (p-CgA) and Ki-67 index as prognostic factors. The ten year disease-specific survival rate in group2 was 86%. The median disease-specific survival in group3 was 85 months with age, Ki-67 index, p-CgA and primary tumor resection as prognostic factors. When proliferation was expressed by WHO grade, no difference was observed between G1 vs. G2 for any of the primary outcomes. CONCLUSIONS: Recurrence rates remained high 5-10 years after surgery (group2) supporting long-term follow-up. Median disease-specific survival in patient with unresectable disease (group3) was 7 years, with a favorable impact of primary tumor resection. Our data does not support the current grading system since no significant prognostic information was detected in G1 vs. G2 tumors.

Trauma exposure and diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) posttraumatic stress disorder among Danish adults: Implications of narrow and broad operationalizations of criterion A.

OBJECTIVE: Posttraumatic stress disorder (PTSD) has long been recognized as a debilitating psychiatric disorder. The definition of Criterion A has been a topic of controversy, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and International Classification of Diseases, 11th version have opted for a narrow and a broad approach to the gatekeeper criterion, respectively. The aim of this study was to test the implications of a narrow (DSM-5) versus broad (including psychologically threatening events) Criterion A for endorsement of a probable PTSD diagnosis and symptom severity. METHOD: The study was based on a cross-sectional survey conducted in March 2021 among the general population of adult Danish residents in Denmark, ranging in age between 18 and 79 years (n = 1,033). RESULTS: Psychologically threatening events did not lead to a statistically significant increase in probable PTSD diagnoses, but psychologically threatening events were independently related to probable PTSD risk and severity. Controlling for other potentially traumatizing events and demographic factors, psychologically threatening events were the strongest risk factor for higher symptom severity. We found probable PTSD rates higher but comparable to other Scandinavian countries such as Norway and Sweden. CONCLUSION: Exposure to psychologically threatening events is an important factor in explaining probable PTSD risk and severity although not independently leading to a significant increase in probable PTSD rates. Probable rates of DSM-5 PTSD are higher than Danish official estimates in a random sample of the Danish adult population (6.8%-6.9% compared to 1%). The generalizability of study findings is limited by nonrepresentativity, the use of self-report measures, and assessment during the COVID-19 lockdown. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychotherapy for difficult-to-treat depression.

A large patient subgroup (15-35%) with difficult-to-treat depression (DTD) differs from patients with non-DTD in both psychopathological complexity and the effect of treatment. This review investigates how the effect of psychotherapy is lower than for non-TRD, possibly related to differing personal characteristics. Psychotherapies such as the cognitive behavioral analysis system of psychotherapy, mindfulness-based cognitive therapy, and schema therapy are promising yet understudied treatment options. In clinical practice, awareness of potential DTD in patients is important to tailor treatment in a timely manner.

The Danish Trauma Database for Refugees (DTD): A Multicenter Database Collaboration-Overcoming the Challenges and Enhancing Mental Health Treatment and Research for Refugees.

Mental health of trauma-affected refugees is an understudied area, resulting in inadequate and poorer treatment outcomes. To address this, more high-quality treatment studies that include predictive analyses, long-term evaluations, cultural adaptations, and take account for comorbidities, are needed. Moreover, given the complex intertwining of refugees' health with post-migration stressors and other social factors, it is crucial to examine the social determinants of refugee mental health. The Danish Trauma Database for Refugees (DTD) is a multicenter research database uniting six national centers that provide outpatient treatment for trauma-affected refugees. Through the database, we collect clinical and sociodemographic data from approximately 1200 refugees annually and will merge the database with Danish population register data. The purpose of the DTD is two-fold; clinical and research. The DTD offers data-driven guidance for routine clinical treatment planning of the individual patient, as well as exceptional research opportunities for testing treatment interventions in clinical settings, with larger sample sizes, and more representative heterogeneity of the population. Complex analyses of risk and protective factors, barriers, access to treatment, and societal and transgenerational aspects of trauma are possible with the DTD. This conceptual paper introduces the DTD, the historical background, the development process and implementation strategy, and the associated challenges with developing and running a multicenter database. Most importantly, it highlights the clinical and research potential of the DTD for advancing the understanding and treatment of trauma-affected refugees.

Recurrence-Free Survival and Disease-Specific Survival in Patients with Pancreatic Neuroendocrine Neoplasms: A Single-Center Retrospective Study of 413 Patients.

INTRODUCTION: The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial. AIM: To investigate prognostic factors for recurrence-free survival and disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3). METHOD: A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors. RESULTS: 413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21-34) months, and tumor size was 1.0 (0.8-1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31-102) months, median tumor size 2 (1.2-3.4) cm, median Ki-67 index 5 (3-10)%, the 5-year recurrence rate was 21%. Tumor size (p < 0.001), Ki-67 index (p = 0.02), and location in the pancreatic head (p < 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6-46) months, median tumor size 4.2 (2.6-7.0) cm, Ki-67 index 17 (9-64)%, the median disease-specific survival was 22 (6-75) months-99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (p = 0.029), plasma chromogranin A (p = 0.014), and proliferation, expressed by grade (p = 0.001) and Ki-67 index (p < 0.001), were risk factors. CONCLUSION: Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection.

Cross-cultural validity of the WHO-5 Well-Being Index and Euthymia Scale: A clinimetric analysis.

BACKGROUND: The assessment of psychological well-being and euthymia represents an emerging issue in clinical psychology and psychiatry. Rating scales and indices such as the 5-item version of the World Health Organization Well-Being Index (WHO-5) and the Euthymia Scale (ES) were developed but insufficient attention has been devoted to the evaluation of their cross-cultural validity. This is the first study using Clinimetric Patient-Reported Outcome Measures (CLIPROM) criteria to assess cross-cultural validity and sensitivity of five different versions of the WHO-5 and ES. METHODS: A multicenter cross-sectional study involving a total of 3762 adult participants from different European (i.e., Italy, Poland, Denmark) and non-European (i.e., China, Japan) countries was conducted. Item Response Theory models (Mokken and Rasch analyses) were applied. RESULTS: Mokken coefficients of scalability were found to range from 0.42 to 0.84. The majority of the versions of the WHO-5 fitted the Rasch model expectations. Paired t-tests revealed that the Italian and Danish WHO-5 versions were unidimensional. Person Separation Reliability indices showed that the Polish, Danish, and Japanese ES versions could reliably discriminate between subjects with different levels of euthymia. LIMITATIONS: A convenience sampling was used, thus limiting the generalizability of study findings. In addition, no measures of negative mental health were administered. CONCLUSIONS: WHO-5 can be used in international studies for cross-cultural comparisons since it covers transcultural components of subjective well-being. Findings also suggest that the ES can be used as a cross-cultural screening tool since it entailed the clinimetric property of sensitivity.

Substance-induced psychosis as a risk factor for unipolar depression or anxiety disorders-A nationwide register-based prospective cohort study.

BACKGROUND: Substance-induced psychosis has previously been linked to increased incidence of schizophrenia and bipolar disorder. We aimed to investigate if substance-induced psychosis is associated with increased risk of depression or anxiety. METHODS: We conducted a nationwide prospective register-based cohort study from 1994 to 2017, including all individuals with substance-induced psychosis, and age-and-sex matched controls without substance-induced psychosis. We investigated time to either depression or anxiety, as well as time to depression and time to anxiety, in stratified Cox regression models. RESULTS: We included 5,557 individuals with substance-induced psychosis and 55,562 controls. Substance-induced psychosis was associated with increased risk of either depression or anxiety (HR=7.05, 95% CI 6.71-7.41), depression (HR=5.40, 95% CI 4.77-6.11), or anxiety (HR=7.05, 95% CI 5.99-8.31). Analyses of individual types of substance-induced psychosis revealed similar hazard ratios across substances. Associations between substance-induced psychosis and depression or anxiety were stronger in people without preceding alcohol or substance use disorders. While strongest shortly after incident substance-induced psychosis, the increased incidence of depression and anxiety remained more than double over the full period of follow-up. LIMITATIONS: Only psychiatric disorders treated either in psychiatric inpatient or outpatient units, supplemented with information on psychiatric medication, was available. Exact times of onset were similarly unknown, and only dates of first treatment were available. CONCLUSIONS: Substance-induced psychosis is a strong predictor of later onset of depression or anxiety. Regardless of whether this association is causal, this highlights the need for increased monitoring and possibly improved treatment of patients with substance-induced psychosis.

Level of alexithymia as a measure of personality dysfunction in avoidant personality disorder.

BACKGROUND AND OBJECTIVES: Avoidant Personality Disorder (AvPD) is considered a mild to moderate personality disorder. However, few studies have focused on the heterogeneity of AvPD in terms of symptoms and severity. In the current study we set out to replicate and extend earlier findings showing that there is variation among patients with AvPD in terms of alexithymia and, further, that this variation is especially associated with specific facets of personality functioning and is not explained by measures of depression, symptom severity, or co-occurring personality disorder traits. METHOD: We used intake data from a sample of AvPD patients (n = 56) who had been treated in similar outpatient services. Alexithymia was measured using the Toronto Alexithymia Scale (TAS-20). Patients filled out questionnaires that were analysed using linear regression models. RESULTS AND CONCLUSIONS: Using well-established cut-off points for low, intermediate and high levels of alexithymia we found an almost equal distribution of alexithymia groups in our sample. Alexithymia was associated with higher personality dysfunction on twelve out of sixteen facets of personality functioning. For eight of these personality facets the alexithymia total score explained significant variance even after controlling for self-reported depression, symptom severity and clinician ratings of personality disorder. Results suggest that AvPD is heterogeneous and that alexithymia may be important as an indicator of severity of specific personality dysfunction.

What is the right sequencing approach? Solo VS extended family analysis in consanguineous populations.

BACKGROUND: Testing strategies is crucial for genetics clinics and testing laboratories. In this study, we tried to compare the hit rate between solo and trio and trio plus testing and between trio and sibship testing. Finally, we studied the impact of extended family analysis, mainly in complex and unsolved cases. METHODS: Three cohorts were used for this analysis: one cohort to assess the hit rate between solo, trio and trio plus testing, another cohort to examine the impact of the testing strategy of sibship genome vs trio-based analysis, and a third cohort to test the impact of an extended family analysis of up to eight family members to lower the number of candidate variants. RESULTS: The hit rates in solo, trio and trio plus testing were 39, 40, and 41%, respectively. The total number of candidate variants in the sibship testing strategy was 117 variants compared to 59 variants in the trio-based analysis. We noticed that the average number of coding candidate variants in trio-based analysis was 1192 variants and 26,454 noncoding variants, and this number was lowered by 50-75% after adding additional family members, with up to two coding and 66 noncoding homozygous variants only, in families with eight family members. CONCLUSION: There was no difference in the hit rate between solo and extended family members. Trio-based analysis was a better approach than sibship testing, even in a consanguineous population. Finally, each additional family member helped to narrow down the number of variants by 50-75%. Our findings could help clinicians, researchers and testing laboratories select the most cost-effective and appropriate sequencing approach for their patients. Furthermore, using extended family analysis is a very useful tool for complex cases with novel genes.

The PTSD help app in a Danish PTSD population: research protocol of a randomized controlled feasibility trial.

BACKGROUND: Due to an increase in PTSD patients seeking help in the Danish mental health sector and the addition of Complex PTSD to the ICD-11, there is a need to increase efficiency of existing treatments for PTSD. mHealth interventions have been shown to reduce PTSD symptoms. Therefore, the implementation of a mHealth intervention designed for psychiatric PTSD patients as a therapy add-on may improve treatment outcome. No study to date has explored the effects of mHealth interventions for PTSD in the Danish mental health sector, the feasibility and effect of this type of intervention needs testing. METHODS: The study is an investigator-initiated randomized controlled feasibility trial investigating the clinical mHealth tool PTSD help combined with care as usual (CAU) compared to CAU for adults with PTSD. Seventy patients will be recruited and receive either the mHealth intervention combined with CAU or CAU alone. The primary feasibility outcome is the proportion of eligible patients that participate in the study until the end assessment. Secondary outcome data consists of the fraction of compliant patients in the experimental group and exploratory data on PTSD help on PTSD symptom severity, level of psychological distress, sleep quality, dissociation symptoms, therapy readiness, quality of life, disability levels, and recovery. DISCUSSION: This study may help increase our knowledge of possible benefits of, as well as potential barriers to, the implementation of mHealth tools in the psychiatric sector. It may also provide a cost-efficient means to increase therapy outcomes and decrease the duration of suffering for PTSD patients in the psychiatric sector. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (ID: NCT03862703) https://clinicaltrials.gov/ct2/show/NCT03862703 on the 27 of February 2019 and has been approved by the Danish Data Protection Agency (journal number: VD-2018-200 ISuite number 6443). Referring to the committee law §2, the National Committee on Health Research Ethics (DNVK) [H-18024180] decided that the study could proceed without approval as the use of PTSD help did not constitute a health science intervention according to Danish health science legislation.

Cortical Response to Fat Taste.

We sense fat by its texture and smell, but it is still unknown whether we also taste fat despite evidence of both candidate receptors and distinct fat taste sensations. One major reason fat is still not recognized as a basic taste quality is that we first need to demonstrate its underlying neural activity. To investigate such neural fat taste activation, we recorded evoked responses to commercial cow milk products with 0.1%, 4%, and 38 % fat via high-density electroencephalography (EEG) from 24 human participants. The experimental design ensured that the products would only be discriminable via their potential fat taste; all stimuli were carefully controlled for differences in viscosity, lubrication, odor, temperature, and confounding tastes (sweetness, acidity, and "off-taste") and were delivered directly onto the tongue using a set of computer-controlled syringe pumps. Advanced topographical pattern analysis revealed different neural activation to the milk products 85-134 ms after stimulus onset, which, as expected, best discriminated the two milk fat extremes (0.1% and 38% fat). Notably, this time period has previously been shown to also encode basic taste qualities, such as sweet or salty. By adding to the evidence of cortical fat taste processing in response to staple food, our finding not only substantiates that we taste fat but also highlights its potential relevance during our everyday lives with possible large-scale impacts on motivational eating behavior to explain overconsumption of energy-dense foods.

EEG discrimination of perceptually similar tastes.

Perceptually similar stimuli, despite not being consciously distinguishable, may result in distinct cortical brain activations. Hypothesizing that perceptually similar tastes are discriminable by electroencephalography (EEG), we recorded 22 human participants' response to equally intense sweet-tasting stimuli: caloric sucrose, low-caloric aspartame, and a low-caloric mixture of aspartame and acesulfame K. Time-resolved multivariate pattern analysis of the 128-channel EEG was used to discriminate the taste responses at single-trial level. Supplementing the EEG study, we also performed a behavioral study to assess the participants' perceptual ability to discriminate the taste stimuli by a triangle test of all three taste pair combinations. The three taste stimuli were found to be perceptually similar or identical in the behavioral study, yet discriminable from 0.08 to 0.18 s by EEG analysis. Comparing the participants' responses in the EEG and behavioral study, we found that brain responses to perceptually similar tastes are discriminable, and we also found evidence suggesting that perceptually identical tastes are discriminable by the brain. Moreover, discriminability of brain responses was related to individual participants' perceptual ability to discriminate the tastes. We did not observe a relation between brain response discriminability and calorie content of the taste stimuli. Thus, besides demonstrating discriminability of perceptually similar and identical tastes with EEG, we also provide the first proof of a functional relation between brain response and perception of taste stimuli at individual level.

A clinimetric analysis of a BPRS-6 scale for schizophrenia severity.

OBJECTIVE: A restricted Brief Psychiatric Rating Scale (BPRS-6) with the six schizophrenia specific items from the Positive and Negative Syndrome Scale (PANSS) has been investigated. These six items from the PANSS have recently been found to have both clinical validity and 'unidimensionality' in measuring the severity of schizophrenic states. The primary objective of this study was to evaluate the clinical validity of the BPRS-6. The secondary objective was to evaluate the 'unidimensionality' of the BPRS-6 by an 'item response theory' model. METHODS: The BPRS-6 was scored independently by two psychiatrists and two psychologists while viewing six open-ended videotaped interviews in patients with a DSM-III diagnosis of schizophrenia. The interviews were conducted by Heinz E. Lehmann, an experienced psychiatrist. They were focused on the psychopathology that contributed most to the 'severity' of the patient's clinical state. RESULTS: The BPRS-6 with three positive symptoms (delusions, conceptual disorganisation, hallucinations) and three negative symptoms (blunted affect, emotional withdrawal, poverty of speech) was found to be clinically valid and captured the variables that contribute most to the severity of schizophrenia. The BPRS-6 was also found to have acceptable 'unidimensionality' (coefficient of homogeneity 0.45) and inter-rater reliability (inter-class-coefficient 0.81). CONCLUSION: The BPRS-6 was found to capture the information that translates into the severity of schizophrenia. It has also acceptable psychometric validity.

Bitter taste masking of enzyme-treated soy protein in water and bread.

BACKGROUND: Bioactive protein hydrolysates are often very bitter. To overcome this challenge, xylitol, sucrose, α-cyclodextrin, maltodextrin and combinations of these were tested systematically as bitter-masking agents of an enzyme-treated soy protein in an aqueous model and in a bread model. Sensory descriptive analysis was used to reveal the bitter-masking effect of the taste-masking blends on the enzyme-treated soy protein. RESULTS: In water, xylitol, sucrose and maltodextrin reduced bitterness significantly, whereas α-cyclodextrin did not. No significant difference was observed in bitterness reduction between xylitol and sucrose. Both reduced bitterness significantly more than maltodextrin. No interactions between the taste-masking agents affecting bitterness reduction were found. Clearer bitter-masking effects were seen in the aqueous model compared with the bread model. The bitter-masking effects of α-cyclodextrin and maltodextrin were similar between water and bread. The effect of xylitol and sucrose on bitterness suppression varied between the systems. In water, bitterness was negatively correlated with sweetness. In bread, bitterness was negatively correlated with freshness, and maltodextrin significantly reduced bitterness of the enzyme-treated soy protein and increased freshness. CONCLUSION: Bitter-masking effects were generally more discernible in the aqueous model compared with the bread model. © 2018 Society of Chemical Industry.

Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families.

Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.

Novel mutation in the CHST6 gene causes macular corneal dystrophy in a black South African family.

BACKGROUND: Macular corneal dystrophy (MCD) is a rare autosomal recessive disorder that is characterized by progressive corneal opacity that starts in early childhood and ultimately progresses to blindness in early adulthood. The aim of this study was to identify the cause of MCD in a black South African family with two affected sisters. METHODS: A multigenerational South African Sotho-speaking family with type I MCD was studied using whole exome sequencing. Variant filtering to identify the MCD-causal mutation included the disease inheritance pattern, variant minor allele frequency and potential functional impact. RESULTS: Ophthalmologic evaluation of the cases revealed a typical MCD phenotype and none of the other family members were affected. An average of 127 713 variants per individual was identified following exome sequencing and approximately 1.2 % were not present in any of the investigated public databases. Variant filtering identified a homozygous E71Q mutation in CHST6, a known MCD-causing gene encoding corneal N-acetyl glucosamine-6-O-sulfotransferase. This E71Q mutation results in a non-conservative amino acid change in a highly conserved functional domain of the human CHST6 that is essential for enzyme activity. CONCLUSION: We identified a novel E71Q mutation in CHST6 as the MCD-causal mutation in a black South African family with type I MCD. This is the first description of MCD in a black Sub-Saharan African family and therefore contributes valuable insights into the genetic aetiology of this disease, while improving genetic counselling for this and potentially other MCD families.

HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia.

Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.

Heart structure-specific transcriptomic atlas reveals conserved microRNA-mRNA interactions.

MicroRNAs are short non-coding RNAs that regulate gene expression at the post-transcriptional level and play key roles in heart development and cardiovascular diseases. Here, we have characterized the expression and distribution of microRNAs across eight cardiac structures (left and right ventricles, apex, papillary muscle, septum, left and right atrium and valves) in rat, Beagle dog and cynomolgus monkey using microRNA sequencing. Conserved microRNA signatures enriched in specific heart structures across these species were identified for cardiac valve (miR-let-7c, miR-125b, miR-127, miR-199a-3p, miR-204, miR-320, miR-99b, miR-328 and miR-744) and myocardium (miR-1, miR-133b, miR-133a, miR-208b, miR-30e, miR-499-5p, miR-30e*). The relative abundance of myocardium-enriched (miR-1) and valve-enriched (miR-125b-5p and miR-204) microRNAs was confirmed using in situ hybridization. MicroRNA-mRNA interactions potentially relevant for cardiac functions were explored using anti-correlation expression analysis and microRNA target prediction algorithms. Interactions between miR-1/Timp3, miR-125b/Rbm24, miR-204/Tgfbr2 and miR-208b/Csnk2a2 were identified and experimentally investigated in human pulmonary smooth muscle cells and luciferase reporter assays. In conclusion, we have generated a high-resolution heart structure-specific mRNA/microRNA expression atlas for three mammalian species that provides a novel resource for investigating novel microRNA regulatory circuits involved in cardiac molecular physiopathology.

Eysenck's Two Big Personality Factors and Their Relationship to Depression in Patients with Chronic Idiopathic Pain Disorder: A Clinimetric Validation Analysis.

Aim. The clinimetric aspects of Eysenck's two big personality factors (neuroticism and extraversion) were originally identified by principal component analysis but have been insufficiently analysed with item response theory models. Their relationship to states of melancholia and anxiety was subsequently analysed. Method. Patients with chronic idiopathic pain disorder were included in the study. The nonparametric item response model (Mokken) was compared to the coefficient alpha to validate the anxiety and depression subscales within the neuroticism scale and the extraversion and introversion subscales within the extraversion scale. When measuring states of depression and anxiety, the Melancholia Scale and the Hamilton Anxiety Scale were used. Results. We identified acceptable subscales of anxiety and depression in the Eysenck factor of neuroticism and extraversion versus introversion subscales within the Eysenck factor of extraversion. Focusing on the item of "Does your mood often go up and down?" we showed a statistically significant association with melancholia and anxiety for patients with a positive score on this item. Conclusion. Within the Eysenck factor of neuroticism it is important to differentiate between the anxiety and depression subscales. The clinimetric analysis of the Eysenck factor of extraversion identified valid subscales.