Gastrointestinal and eating problems in SCN1A-related seizure disorders.

OBJECTIVE: Our study aimed to describe the prevalence and characteristics of gastrointestinal and eating problems in Dravet syndrome (DS) and other SCN1A-related seizure disorders and to determine the association between the occurrence of gastrointestinal and eating problems and core features of DS. METHODS: Gastrointestinal and eating problems were assessed with a questionnaire in a Dutch cohort of participants with an SCN1A-related seizure disorder. Associations between the number of gastrointestinal and eating problems and core features of DS, seizure severity, level of intellectual disability, impaired mobility, behavioral problems, and use of anti-seizure medication, were explored by multivariate ordinal regression analyses. Symptoms were divided into the categories dysphagia-related, behavioral, and gastrointestinal, and were assessed separately. RESULTS: One hundred sixty-nine participants with an SCN1A-related seizure disorder, of whom 118 (69.8%) with DS and 51 (30.2%) with Generalized Epilepsy with Febrile Seizures Plus / Febrile Seizures (GEFS+/FS), the non-DS phenotype, were evaluated. Gastrointestinal and eating problems were highly prevalent in DS participants, 50.8% had more than three symptoms compared to 3.9% of non-DS participants. Of participants with DS, 17.8% were fully or partly fed by a gastric tube. Within the three different symptom categories, the most prevalent dysphagia-related symptom was drooling (60.7%), distraction during mealtimes (61.4%) the most prevalent behavioral symptom, and constipation and loss of appetite (both 50.4%) the most prevalent gastrointestinal symptoms. DS participants who use a wheelchair (odds ratio (OR) 4.9 95%CI (1.9-12.8) compared to walking without aid), who use ≥3 anti-seizure medications (ASM) (OR 5.9 95%CI (1.9-18.2) compared to <3 ASM) and who have behavioral problems (OR 3.0 95%CI (1.1-8.1) compared to no behavioral problems) had more gastrointestinal and eating problems. CONCLUSION: Gastrointestinal and eating problems are frequently reported symptoms in DS. Distinguishing between symptom categories will lead to tailored management of patients at risk, will improve early detection, and enable a timely referral to a dietitian, behavioral expert, and/or speech therapist, ultimately aiming to improve the quality of life of both patients and caregivers.

Glucocorticoid Receptor (GR) antagonism as disease-modifying treatment for MDD with childhood trauma: protocol of the RESET-medication randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone. METHODS: The RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology-Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained. DISCUSSION: The RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. TRIAL REGISTRATION: The trial protocol has been registered 01-02-2022 on ClinicalTrials.gov with ID "NCT05217758".

Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene.

Several de novo variants in the KIF1A gene have been reported to cause a complicated form of hereditary spastic paraplegia. Additional symptoms include cognitive impairment and varying degrees of peripheral neuropathy, epilepsy, decreased visual acuity, and ataxia. We describe four patients (ages 10-18 years), focusing on their mobility and gait characteristics. Two patients were not able to walk without assistance and showed a severe abnormal gait pattern, crouch gait. At examination, severe contractures were found.In addition to describing the different phenotypes with specific attention to gait in our cases, we reviewed known KIF1A mutations and summarized their associated phenotypes.We conclude that mobility and cognition are severely affected in children with spastic paraplegia due to de novo KIF1A mutations. Deterioration in mobility is most likely due to progressive spasticity, muscle weakness, and the secondary development of severe contractures, possibly combined with an additional progressive polyneuropathy. Close follow-up and treatment of these patients are warranted.

Depression, telomeres and mitochondrial DNA: between- and within-person associations from a 10-year longitudinal study.

Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross-sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B=-4.2; P=0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B=-0.8; P=0.548). Further, we found no between-person (B=-0.2; P=0.744) or within-person (B=0.4; P=0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn.

Alstroemeria yellow spot virus (AYSV): a new orthotospovirus species within a growing Eurasian clade.

An orthotospovirus distinct from all other orthotospoviruses was isolated from naturally infected alstroemeria plants. Disease symptoms caused by this virus mainly consisted of yellow spots on the leaves based on which the name alstroemeria yellow spot virus (AYSV) was coined. A host range analysis was performed and a polyclonal antiserum was produced against purified AYSV ribonucleoproteins which only reacted with the homologous antigen and not with any other (established or tentative) orthotospovirus from a selection of American and Asian species. Upon thrips transmission assays the virus was successfully transmitted by a population of Thrips tabaci. The entire nucleotide sequence of the M and S RNA segments was elucidated by a conventional cloning and sequencing strategy, and contained 4797 respectively 2734 nucleotides (nt). Simultaneously, a next generation sequencing (NGS) approach (RNAseq) was employed and generated contigs covering the entire viral tripartite RNA genome. In addition to the M and S RNA nucleotide sequences, the L RNA (8865 nt) was obtained. The nucleocapsid (N) gene encoded by the S RNA of this virus consisted of 819 nucleotides with a deduced N protein of 272 amino acids and by comparative sequence alignments to other established orthotospovirus species showed highest homology (69.5% identity) to the N protein of polygonum ringspot virus. The data altogether support the proposal of AYSV as a new orthotospovirus species within a growing clade of orthotospoviruses that seem to share the Middle East basin as a region of origin.

Recognizing critically ill children with a modified pediatric early warning score at the emergency department, a feasibility study.

Pediatric Early Warning Scores were developed to monitor clinical deterioration of children admitted to the hospital. Pediatric Early Warning Scores could also be useful in the Emergency Department to quickly identify critically ill patients so treatment can be started without delay. To determine if a newly designed, fast, and easy to use Modified Pediatric Early Warning Score can identify critically ill children in the Emergency Department. We conducted a retrospective observational study in the Emergency Department of an urban district hospital in Rotterdam, the Netherlands. Patients < 16 years attending the Emergency Department with an internal medical problem were included. Immediate intensive care unit admission was used as a measure for critically ill children. During the study period 2980 children attended the Emergency Department, ten (0.4%) of them required immediate intensive care unit admission. The Modified Pediatric Early Warning Score can identify critically ill children in the general pediatric Emergency Department population (area under the ROC curve 0.82). A sensitivity of 80% and specificity of 85% show potential to rule out critical illness in children visiting the Emergency Department when these results are validated in a larger population. A model containing both the Modified Pediatric Early Warning Score and the Manchester Triage System did not perform significantly better than the Manchester Triage System alone but did show a positive tendency in favor of the model containing the Modified Pediatric Early Warning Score and Manchester Triage System, area under the ROC curve 0.89 [95% CI 0.77-1.00] versus area under the ROC curve 0.82 [95% CI 0.68-0.95].Conclusions: In this feasibility study, the Modified Pediatric Early Warning Score could be a fast and easy to use tool to identify critically ill children in the general pediatric Emergency Department population. The effectiveness of the Modified Pediatric Early Warning Score may be optimized if combined with triage systems such as the Manchester Triage System. A larger prospective study is needed to confirm our results. What is known: • Pediatric Early Warning Scores can identify children who are in need for immediate intensive care unit admission at the Emergency Department. • Pediatric Early Warning Scores can be time-consuming, contain subjective parameters or parameters which are difficult to obtain in a reliable and standardized method. What is new: • We introduce a simplified, manageable and smartly designed Pediatric Early Warning Score on a pocket card based on an existing and previously investigated Pediatric Early Warning Score. • In this feasibility study the diagnostic performance of the Modified Pediatric Early Warning Score to predict immediate intensive care unit admission in the Emergency Department is in line with the original Pediatric Early Warning Scores but has to be validated on a larger scale.

Probiotic survival during a multi-layered tablet development as tested in a dynamic, computer-controlled in vitro model of the stomach and small intestine (TIM-1).

The aim of the research was to develop a galenical formulation for the combination of the three probiotic strains Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3 and Bifidobacterium bifidum MF 20/5 that would lead to the presence of a high amount of viable cells in the small intestine, the presumed site of action of these strains. This was tested in a validated, dynamic in vitro model of the stomach and small intestine (TIM-1), simulating human adults after intake of a meal. Experiments were performed both in the gastric compartment of the model, as well as in the complete system (stomach + small intestine). Survival of the strains in an unformulated probiotic powder after transit through the gastric compartment was 5·3% for the bifidobacteria and 1% for L. gasseri. After transit through the complete gastrointestinal tract, this dropped to 2% for bifidobacteria and 0·1% for Lactobacillus. After several rounds of optimization, an enteric-coated tablet was developed that increased the delivery of viable cells reaching the small intestine to 72% (gastric survival) for bifidobacteria, and 53% (gastric) for L. gasseri. Also survival in the small intestine increased by about an order of magnitude. The final galenical formulation was tested in two applications: adults and elderly, both of which have their own physiological parameters. These experiments corroborated the results obtained in the development phase of the project. In conclusion, the developed enteric coating led to a 20- to 40-fold increase in the delivery of viable cells to the small intestine. SIGNIFICANCE AND IMPACT OF THE STUDY: Predictive GI in vitro models are very helpful and reliable tools for the development of new galenical formula containing probiotics, and in the current example helped to deliver >10-fold higher numbers of viable cells to the small intestine, presumably leading to improved functionality of the strains.

Leukocyte telomere length and personality: associations with the Big Five and Type D personality traits.

Backgrounds Accelerated cellular ageing, which can be examined by telomere length (TL), may be an overarching mechanism underlying the association between personality and adverse health outcomes. This 6-year longitudinal study examined the relation between personality and leukocyte telomere length (LTL) across time among adults with a wide age-range. METHODS: Data from the Netherlands Study of Depression and Anxiety were used and included patients with a depression and/or anxiety disorder and healthy controls. Overall, 2936 persons (18-65 years, 66% female) had data on LTL at baseline and 1883 persons had LTL at 6-year follow-up. The Big Five personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) and Type D personality were assessed. RESULTS: Neuroticism was negatively (B = -2.11, p = 0.03) and agreeableness was positively (B = 3.84, p = 0.03) related to LTL measured across two time points, which became just non-significant after adjusting for somatic health, lifestyle factors, and recent life stress (B = -1.99, p = 0.06; and B = 3.01, p = 0.10). Type D personality was negatively (B = -50.16, p < 0.01) related to LTL across two time points, which still remained statistically significant after full adjustment (B = -47.37, p = 0.01). Associations did not differ by age, gender, and current psychiatric status. CONCLUSIONS: The Big Five traits high neuroticism and low agreeableness, and Type D personality were associated with shorter LTL measured across a 6-year period. Associations with the Big Five traits became non-significant after controlling for somatic health, lifestyle factors, and recent life stress, yet similar trends were observed. Type D personality remained independently associated with shorter LTL after full adjustment.

Microencapsulation increases survival of the probiotic Lactobacillus plantarum IS-10506, but not Enterococcus faecium IS-27526 in a dynamic, computer-controlled in vitro model of the upper gastrointestinal tract.

AIM: To test the effect of microencapsulation on the survival of two probiotic strains isolated from Dadih, Indonesian fermented buffalo milk, in a dynamic, computer-controlled in vitro model of the upper gastrointestinal (GI) tract (TIM-1), simulating human adults. METHODS AND RESULTS: Free or microencapsulated probiotics, Lactobacillus plantarum IS-10506 or Enterococcus faecium IS-27526, resuspended in milk were studied for survival in the complete TIM-1 system (stomach + small intestine) or in the gastric compartment of TIM-1 only. Hourly samples collected after the ileal-caecal valve or after the pylorus were plated on MRS agar (for Lactobacillus) or S&B agar (for Enterococcus). Survival of the free cells after transit through the complete TIM-1 system was on average for the E. faecium and L. plantarum 15·0 and 18·5% respectively. Survival of the microencapsulated E. faecium and L. plantarum was 15·7 and 84·5% respectively. The free cells were further assessed in only the gastric compartment of TIM-1. E. faecium and L. plantarum showed an average survival of 39 and 32%, respectively, after gastric passage. CONCLUSION: There is similar sensitivity to gastric acid as well as survival after complete upper GI tract transit of free cells, but microencapsulation only protected L. plantarum. SIGNIFICANCE AND IMPACT OF STUDY: Survival of microencapsulated L. plantarum IS-10506 is increased compared to free cells in a validated in vitro model of the upper GI tract. It increases its use as an ingredient of functional foods.

Consensus Paper: Cerebellum and Emotion.

Over the past three decades, insights into the role of the cerebellum in emotional processing have substantially increased. Indeed, methodological refinements in cerebellar lesion studies and major technological advancements in the field of neuroscience are in particular responsible to an exponential growth of knowledge on the topic. It is timely to review the available data and to critically evaluate the current status of the role of the cerebellum in emotion and related domains. The main aim of this article is to present an overview of current facts and ongoing debates relating to clinical, neuroimaging, and neurophysiological findings on the role of the cerebellum in key aspects of emotion. Experts in the field of cerebellar research discuss the range of cerebellar contributions to emotion in nine topics. Topics include the role of the cerebellum in perception and recognition, forwarding and encoding of emotional information, and the experience and regulation of emotional states in relation to motor, cognitive, and social behaviors. In addition, perspectives including cerebellar involvement in emotional learning, pain, emotional aspects of speech, and neuropsychiatric aspects of the cerebellum in mood disorders are briefly discussed. Results of this consensus paper illustrate how theory and empirical research have converged to produce a composite picture of brain topography, physiology, and function that establishes the role of the cerebellum in many aspects of emotional processing.