Recent evidence on the association between vitamin D and cognition in mentally healthy individuals is inconsistent. Furthermore, the link between vitamin D and cognitive ability in individuals with ...bipolar disorder has not been studied yet. Thus, we aimed to investigate the association between 25-hydroxyvitamin D (25(OH)D), 24,25 dihydroxyvitamin D (24,25(OH)2D, the vitamin D metabolite ratio (VMR) and cognition in a cohort of euthymic patients with bipolar disorder. Vitamin D metabolites were measured simultaneously by liquid-chromatography tandem mass-spectrometry in serum samples from 86 outpatients with bipolar disorder and 93 healthy controls. Neither the inactive precursor 25(OH)D, nor the primary vitamin D catabolite 24,25(OH)2D, or the vitamin D metabolite ratio were significantly associated with the domains “attention”, “memory”, or “executive function” in individuals with bipolar disorder and healthy controls. Further, no vitamin D deficiency effect or interaction group × vitamin D deficiency was found in the cognitive domain scores. In summary, the present study does not support vitamin D metabolism as a modulating factor of cognitive function in euthymic BD patients. Considering the current study’s cross-sectional design, future research should expand these results in a longitudinal setting and include additional aspects of mental health, such as manic or depressive symptoms, long-term illness course and psychopharmacological treatment.
Protein secretion plays a crucial role for bacterial pathogens, exemplified by facultative human-pathogen
, which secretes various proteinaceous effectors at different stages of its lifecycle. ...Accordingly, the identification of factors impacting on protein secretion is important to understand the bacterial pathophysiology. PglL
, a predicted oligosaccharyltransferase of
, has been recently shown to exhibit
-glycosylation activity with relaxed glycan specificity in an engineered
system. By engineering
strains to express a defined, undecaprenyl diphosphate-linked glycoform precursor, we confirmed functional
-linked protein glycosylation activity of PglL
in
. We demonstrate that PglL
is required for the glycosylation of multiple
proteins, including periplasmic chaperones such as DegP, that are required for efficient type II-dependent secretion. Moreover, defined deletion mutants and complementation strains provided first insights into the physiological role of
-linked protein glycosylation in
. RbmD, a protein with structural similarities to PglL
and other established oligosaccharyltransferases (OTases), was also included in this phenotypical characterization. Remarkably, presence or absence of PglL
and RbmD impacts the secretion of proteins via the type II secretion system (T2SS). This is highlighted by altered cholera toxin (CT) secretion, chitin utilization and biofilm formation observed in Δ
and Δ
single or double mutants. This work thus establishes a unique connection between broad spectrum
-linked protein glycosylation and the efficacy of type II-dependent protein secretion critical to the pathogen's lifecycle.
•Bipolar individuals showed deficits in ToM, measured by the reading the mind in the eyes Test, compared to healthy controls over a course of 4.5 years.•ToM deficits contribute to social and ...executive dysfunction in euthymic bipolar individuals.•First 4.5-year longitudinal study on theory of mind deficits and bipolar disorder, but with limited data.
Theory of mind (ToM) deficits, difficulties in recognizing the intentions, propensities, and beliefs of others have been shown in individuals with bipolar disorder in several studies; however, it is not yet elucidated how ToM abilities changes over the course of bipolar disorder and is related to illness symptoms. This is one of the first longitudinal studies to compare the ToM abilities of euthymic bipolar individuals and healthy controls over a four and a half years period. ToM abilities were measured using the Reading the Mind in the Eyes Test (RMET). A total of 91 euthymic bipolar individuals and 91 healthy controls were included in the analyses. Linear mixed models were used to compare ToM abilities of bipolar individuals and healthy controls. It was found that bipolar individuals scored lower on average on the RMET than healthy controls and that these RMET scores were stable over four and a half years. The results of this study suggest that ToM deficits are a stable (possibly endophenotypic) trait of bipolar disorder. This understanding can contribute to better identification, assessment, and treatment strategies for individuals with bipolar disorder, ultimately improving their overall care and outcome.
The association between severe psychiatric disorders and metabolic syndrome is well documented and goes along with a reduced life expectancy. The prevalence of medical comorbidities in individuals ...suffering from psychiatric disorders in Austria has not yet been examined; aim of this study was to analyze the prevalence of comorbid somatic disorder in individuals diagnosed with psychiatric disorders in Austria.
Patients (n = 600) with a life-time diagnosis of mood and anxiety disorders undergoing a six-week course of intensive treatment in a psychiatric rehabilitation center were recruited. Prevalent somatic and psychological conditions, anamnestic data, medical history, blood samples, clinical and psychological tests as well as medication were examined to determine somatic and psychiatric diagnoses.
Metabolic disorders were highly prevalent especially in individuals diagnosed with affective disorders, respectively in bipolar disorder. Furthermore, obesity and thyroid dysfunction were found in about 40% of individuals diagnosed with bipolar disorder in the present study. Significant gender differences were found in CVD and hypertension with higher prevalence in men, while thyroid dysfunction occurred more often in women also compared to the general female population.
Characterizing somatic comorbidity in individuals with psychiatric disorders can stimulate research to better understand possible shared etiologic factors and has public health implications for improving models of care. This could have a positive effect on the course of mental disorders, and additionally improve social integration and life expectancy. Knowledge about sex differences should be used to further improve individualized treatment of individuals with psychiatric disorders.
Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, ...mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days (
n
= 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days (
n
= 24, tachycardiomyopathy, TCM). In
n
= 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH–iPSC–CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM,
p
< 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm
2
vs. 538.9 ± 23.8 µm
2
,
p
< 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8,
p
< 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH–iPSC–CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O
2
·s
−1
·mg
−1
tissue,
p
< 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies.
Introduction: Sleep disturbances are highly prevalent across most major psychiatric disorders. Alterations in the hypothalamic-pituitary-adrenal axis, neuroimmune mechanisms, and circadian rhythm ...disturbances partially explain this connection. The gut microbiome is also suspected to play a role in sleep regulation, and recent studies suggest that certain probiotics, prebiotics, synbiotics, and fecal microbiome transplantation can improve sleep quality. Methods: We aimed to assess the relationship between gut-microbiota composition, psychiatric disorders, and sleep quality in this cross-sectional, cross-disorder study. We recruited 103 participants, 63 patients with psychiatric disorders (major depressive disorder n = 31, bipolar disorder n = 13, psychotic disorder n = 19) along with 40 healthy controls. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). The fecal microbiome was analyzed using 16S rRNA sequencing, and groups were compared based on alpha and beta diversity metrics, as well as differentially abundant species and genera. Results: A transdiagnostic decrease in alpha diversity and differences in beta diversity indices were observed in psychiatric patients, compared to controls. Correlation analysis of diversity metrics and PSQI score showed no significance in the patient and control groups. However, three species, Ellagibacter isourolithinifaciens, Senegalimassilia faecalis, and uncultured Blautia sp., and two genera, Senegalimassilia and uncultured Muribaculaceae genus, were differentially abundant in psychiatric patients with good sleep quality (PSQI >8), compared to poor-sleep quality patients (PSQI ≤8). Conclusion: In conclusion, this study raises important questions about the interconnection of the gut microbiome and sleep disturbances.
In Austria, new approaches of rehabilitation programs focus on the prevention of mental illness and offer treatment not only for acute psychiatric patients, but also for those who are at risk of ...developing a mental disorder or have recovered from one.The aim of this study was to determine the effects of a psychiatric rehabilitation program on individuals with different mood states.
600 patients with a history of affective disorder were tested at the time of admission to an Austrian inpatient psychiatric rehabilitation center. Data of extreme groups - patients who were depressed (n=59; BDI-II<9 and HAMD<8) or euthymic (n=59; BDI<18 and HAMD>19) at the time of therapy start - were analyzed. The participants completed the Maslach Burnout Inventory - General Survey, the Symptom Checklist - Revised and the Stress Coping Questionnaire at the beginning and the end of the 6-weeks rehabilitation program.
After 6 weeks, both groups showed significantly less psychiatric symptoms (BDI-II, HAMD, SCL-90, and negative coping strategies (SVF). Importantly, work-related stress symptoms ("burnout" symptoms) improved significantly in the euthymic group.
Euthymic patients seem to be able to focus on work-related stress symptoms including reduced emotional exhaustion through treatment, while currently depressed patients primarily benefit by an improvement in general psychiatric symptomatology. The results indicate the crucial role of mood state validated with standardized psychological questionnaires BDI-II and HAMD at time of admission to such programs. These findings could have implications on treatment decisions for psychiatric patients and assist in making a forecast concerning ability to recover and treatment prognosis.
Few data on the influence of vessel invasion on the progression of neuroendocrine lung tumors are available. Because of the lack of specific markers, previous studies could not reliably discriminate ...lymphatic and blood vessels. By immunostaining for podoplanin, specific for lymphatic endothelium, and CD34 antigen, we assessed lymphatic and blood vessel invasion in 120 tissue specimens of patients with neuroendocrine lung tumors. Lymphovascular invasion was correlated with clinicopathologic parameters, and its prognostic relevance was evaluated. Lymphatic vessels were identified exclusively at the tumor invasion front, whereas blood capillaries were also seen within tumors. Lymphatic vessel as well as lymphatic and blood vessel invasion was prevalent in patients with high-grade neuroendocrine tumors and advanced tumor stages, closely associated with lymph node metastases (P < 0.0001). In univariate analysis, these two invasion types correlated with decreased disease-free survival (both P < 0.0001), whereas blood vessel invasion alone did not. In multivariate analysis, only tumor grade and lymph node status remained statistically significant factors for prognosis (P = 0.016 and P < 0.0001). Our results suggest that evaluation of lymphatic vessel invasion is important in neuroendocrine lung tumors serving as a prognostic parameter for disease-free survival.
The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosine‐phosphorylation‐regulated kinases (
DYRK
s) ...autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in
DYRK
1A and related kinases. Tyrosine autophosphorylation of
DYRK
1A occurred rapidly during
in vitro
translation and did not depend on the non‐catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of
DYRK
1A is not restricted to the co‐translational autophosphorylation in the activation loop. Moreover, mature
DYRK
1A was still capable of tyrosine autophosphorylation. Point mutants of
DYRK
1A and
DYRK
2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse
DYRK
1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin‐dependent kinase‐like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both
in vitro
and in living cells. We propose a model of
DYRK
autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation.
Structured digital abstract
CLK1
and
CLK1
phosphorylate
by
protein kinase assay
(
View interaction
)
HIPK2
and
HIPK2
phosphorylate
by
protein kinase assay
(
View interaction
)
DYRK1A
phosphorylates
SF3B1
by
protein kinase assay
(
View interaction
)
DYRK1A
and
DYRK1A
phosphorylate
by
protein kinase assay
(
View interaction
)
Hot-spot microvessel density (MVD) and vascular patterns have been reported as histopathologic factors that influence prognosis in retrospective series of malignant gliomas. To investigate clinical ...utility, the authors systematically studied observer agreement on MVD and vascular patterns and the influence of repeatedly assessed data on patient outcomes in 2 independent glioblastoma series.
MVD and vascular patterns were assessed retrospectively by 5 observers in 1) a retrospectively compiled glioblastoma series that included 110 patients and 2) a glioblastoma series that included 233 patients who were treated within a randomized trial. MVD was determined in the field of greatest density ("hot-spot"). Predominantly classic or bizarre vascular patterns were determined by using a previously defined algorithm.
Observer agreement on MVD was highly variable (range of kappa values, 0.464-0.901). The worst observer agreement was achieved when both the selection of hot-spots and MVD counts were performed independently. Survival analysis did not show a consistent association between repeatedly assessed MVD and patient outcome. Observer agreement on vascular patterns was poor (kappa = 0.297). Survival analysis did not show a consistent association between repeatedly assessed vascular patterns and patient outcome.
Observer agreement on hot-spot MVD and vascular patterns in patients with glioblastoma was poor in independent assessments. MVD and vascular patterns were not associated consistently with patient outcome. Based on these findings, the authors concluded that poor observer agreement limits the clinical utility of histopathologically assessed hot-spot MVD and vascular patterns as prognostic factors in patients with glioblastoma. Improved methodologies for morphologic assessment of glioblastoma vascularization need to be identified.
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