Sleep Quality and Eating Disorder-Related Psychopathologies in Patients with Night Eating Syndrome and Binge Eating Disorders

Night eating syndrome (NES) is an eating disorder (ED) characterized by nocturnal ingestion (NI), evening hyperphagia, morning anorexia, as well as mood and sleep disturbances. This study compared subjective and objective sleep quality and ED-related psychopathologies in patients seeking treatment for ED. Method: The sample was composed of 170 women, aged 18–68, who were referred for an ED assessment from 2011 to 2020. The participants were divided into three subgroups: NES-NI only (n = 30), NES+ binge eating (BE) (including binge eating disorders or bulimia nervosa (n = 52), and BE-only (n = 88). The measures consisted of a psychiatric evaluation, objective sleep monitoring measured by an actigraph for 1 week, a subjective sleep self-report, and ED-related psychopathology questionnaires. Results: Objective sleep monitoring revealed significant group differences, with higher sleep efficiency in participants with BE-only and longer sleep durations for the NES-NI only group. Subjectively, the BE-only group described a significantly lower sleep quality than either the NES-NI only or the NES+BE groups. ED-related psychopathology was lower in the NES-NI-only group. A stepwise linear regression revealed that general psychopathology (the brief symptom inventory total score) was a significant predictor of subjective sleep quality. Conclusion: NES-NI-only was correlated with less psychopathology, but with more subjective and objective sleep disturbances. These results lend weight to the supposition that NES lies on a continuum of ED psychopathologies, and that NES-NI-only appears to be a separate entity from NES+BE and BE-only in terms of its psychopathology

Bodyweight Measures and Lifestyle Habits in Individuals with Multiple Sclerosis and Moderate to Severe Disability

Multiple sclerosis (MS) is a chronic disease marked by progressive disability and decreased mobility over time. We studied whether individuals with MS of higher disability levels will be more overweight/obese as a result of their immobility and/or recurrent steroid treatments. In a prospective study, 130 individuals with MS and significant disability were classified according to the Expanded Disability Status Scale (EDSS) score as belonging to four groups: EDSS 3.0–4.0 (n = 31, 24%), EDSS 4.5–5.5 (n = 24, 18%), EDSS = 6.0 (n = 44, 34%) and EDSS ≥ 6.5 (n = 31, 24%). Medical history, body mass index (BMI), waist circumference and the level of engagement in physical activity were obtained. The mean ± standard error age was 55.8 ± 0.5 years, disease duration 18.2 ± 1.0 years and EDSS score 5.5 ± 0.1. Disease duration, the number of steroid courses per disease duration, weight, BMI and physical activity did not differ according to the four disability groups. The mean waist circumference increased significantly with increased severity of EDSS, p = 0.03. Increased disability in individuals with MS was not correlated with disease duration, lifestyle habits or overweight/obesity. However, increased disability was associated with central obesity

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency

Aim: To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ-aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. Method: In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. Results: Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months-18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = -0.67, p < 0.001) and γ-hydroxybutyrate levels (r = -0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = -0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 μM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. Interpretation: ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA-related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD

Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants

To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders

The presence and severity of epilepsy coincide with reduced GABA and cortical excitatory markers in SSADH deficiency

Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of ɣ-aminobutyrate (GABA) catabolism. Despite the resultant hyperGABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation. Methods: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/NAA quantification, and plasma GABA-related metabolite measurements. Results: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p=0.001) and lower levels of GABA (p=0.002), γ-hydroxybutyrate (GHB) (p=0.004), and γ-guanidinobutyrate (GBA) (p=0.003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (rMT) (p=0.04). The cut-off values with the highest discriminative ability to predict seizures were age >9.2 years (p=0.001), GABA<2.57μM/L (p=0.002), GHB<143.6 (p=0.004), and GBA<0.075 (p=0.007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age, lower plasma GABA, GHB, and GBA (area under the ROC of 0.798, p=0.008). Significance: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyperGABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD

Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells

Endoplasmic reticulum stress from unfolded proteins is associated with the proliferation of pancreatic tumor cells, making the many regulatory molecules of this pathway appealing targets for therapy. The objective of our study was to assess potential therapeutic efficacy of inhibitors of unfolded protein response (UPR) in pancreatic cancers focusing on IRE1 alpha inhibitors. IRE1 alpha-mediated XBP-1 mRNA splicing encodes a transcription factor that enhances transcription of chaperone proteins in order to reverse UPR. Proliferation assays using a panel of 14 pancreatic cancer cell lines showed a dose-and time-dependent growth inhibition by IRE1 alpha-specific inhibitors (STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, toyocamycin). Growth inhibition was also noted using a clonogenic growth assay in soft agar, as well as a xenograft in vivo model of pancreatic cancer. Cell cycle analysis showed that these IRE1 alpha inhibitors caused growth arrest at either the G1 or G2/M phases (SU8686, MiaPaCa2) and induced apoptosis (Panc0327, Panc0403). Western blot analysis showed cleavage of caspase 3 and PARP, and prominent induction of the apoptotic molecule BIM. In addition, synergistic effects were found between either STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, or toyocamycin and either gemcitabine or bortezomib. Our data suggest that use of an IRE1 alpha inhibitor is a novel therapeutic approach for treatment of pancreatic cancers

Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer

We utilized three tiers of screening to identify novel therapeutic agents for pancreatic cancers. First, we analyzed 14 pancreatic cancer cell lines against a panel of 66 small-molecule kinase inhibitors and dasatinib was the most potent. Second, we performed RNA expression analysis on 3 dasatinib-resistant and 3 dasatinib sensitive pancreatic cancer cell lines to profile their gene expression. Third, gene profiling data was integrated with the Connectivity Map database to search for potential drugs. Thioridazine was one of the top ranking small molecules with highly negative enrichment. Thioridazine and its family members of phenothiazine including penfluridol caused pancreatic cancer cell death and affected protein expression levels of molecules involved in cell cycle regulation, apoptosis, and multiple kinase activities. This family of drugs causes activation of protein phosphatase 2 (PP2A). The drug FTY-720 (activator of PP2A) induced apoptosis of pancreatic cancer cells. Silencing catalytic unit of PP2A rendered pancreatic cancer cells resistant to penfluridol. Our observations suggest potential therapeutic use of penfluridol or similar agent associated with activation of PP2A in pancreatic cancers. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved