Heterogeneity and Classification of Recent Onset Psychosis and Depression: A Multimodal Machine Learning Approach

Diagnostic heterogeneity within and across psychotic and affective disorders challenges accurate treatment selection, particularly in the early stages. Delineation of shared and distinct illness features at the phenotypic and brain levels may inform the development of more precise differential diagnostic tools. We aimed to identify prototypes of depression and psychosis to investigate their heterogeneity, with common, comorbid transdiagnostic symptoms. Analyzing clinical/neurocognitive and grey matter volume (GMV) data from the PRONIA database, we generated prototypic models of recent-onset depression (ROD) vs. recent-onset psychosis (ROP) by training support-vector machines to separate patients with ROD from patients with ROP, who were selected for absent comorbid features (pure groups). Then, models were applied to patients with comorbidity, ie, ROP with depressive symptoms (ROP+D) and ROD participants with sub-threshold psychosis-like features (ROD+P), to measure their positions within the affective-psychotic continuum. All models were independently validated in a replication sample. Comorbid patients were positioned between pure groups, with ROP+D patients being more frequently classified as ROD compared to pure ROP patients (clinical/neurocognitive model: χ² = 14.874; P < .001; GMV model: χ² = 4.933; P = .026). ROD+P patient classification did not differ from ROD (clinical/neurocognitive model: χ² = 1.956; P = 0.162; GMV model: χ² = 0.005; P = .943). Clinical/neurocognitive and neuroanatomical models demonstrated separability of prototypic depression from psychosis. The shift of comorbid patients toward the depression prototype, observed at the clinical and biological levels, suggests that psychosis with affective comorbidity aligns more strongly to depressive rather than psychotic disease processes. Future studies should assess how these quantitative measures of comorbidity predict outcomes and individual responses to stratified therapeutic interventions.     

CAD-CAM milled versus rapidly prototyped (3D-printed) complete dentures: An in vitro evaluation of trueness

Statement of problem

Complete dentures fabricated by computer-aided design and computer-aided manufacturing (CAD-CAM) techniques have become popular. The 2 principal CAD-CAM techniques, milling and rapid prototyping (3D printing), used in the fabrication of complete dentures have been reported to yield clinically acceptable results. However, clinical trials or in vitro studies that evaluated the accuracy of the 2 manufacturing techniques are lacking.

A plasma metabolite panel as biomarkers for early primary breast cancer detection

In recent years, metabolites have attracted substantial attention as promising novel biomarkers of various diseases. However, breast cancer plasma metabolite studies are still in their infancy. Here, we investigated the potential of metabolites to serve as minimally invasive, early detection markers of primary breast cancer. We profiled metabolites extracted from the plasma of primary breast cancer patients and healthy controls using tandem mass spectrometry (UHPLC-MS/MS and FIA-MS/MS). Two metabolites were found to be upregulated, while 16 metabolites were downregulated in primary breast cancer patients compared to healthy controls in both the training and validation cohorts. A panel of seven metabolites was selected by LASSO regression analysis. This panel could differentiate primary breast cancer patients from healthy controls, with an AUC of 0.87 (95% CI: 0.81 ~ 0.92) in the training cohort and an AUC of 0.80 (95% CI: 0.71 ~ 0.87) in the validation cohort. These significantly differentiated metabolites are mainly involved in the amino acid metabolism and breast cancer cell growth pathways. In conclusion, using a metabolomics approach, we identified metabolites that have potential value for development of a multimarker blood-based test to complement and improve early breast cancer detection. The panel identified herein might be part of a prescreening tool, especially for younger women or for closely observing women with certain risks, to facilitate decision making regarding which individuals should undergo further diagnostic tests. In the future, the combination of metabolites and other blood-based molecular marker sets, such as DNA methylation, microRNA, and cell-free DNA mutation markers, will be an attractive option.     

Tissue Distribution of Sex Steroids: Concentration of 17β-Oestradiol and Cyproterone Acetate in Selected Organs of Female Wistar Rats

Abstract: The tissue distribution of 17β-oeslradiol and cyproterone acetate was investigated after intravenous and intragastric administration to female Wistar rats by measuring the time course of the concentration of the sex steroids in plasma, liver, kidney, brain, and heart by radioimmunoassay. Test substances were administered intravenously in doses of 0.1 mg/kg each and intragastrically in doses of 10 mg/kg (17β-oestradiol) and 0.1 mg/kg (cyproterone acetate) corresponding to the expected oral bioavailability. Tissue distribution was assessed within each mode of administration by AUC_organ/ AUC_plasma-quotients (Q-values), and between both routes of administration by F-values representing (bio- and organ availability) and R-values, which express the organ load after intragastric compared to intravenous administration if the same amount of drug has been made bioavailable in the plasma after both routes (for explanation see next page). The absolute bioavailability of 17β-oestradiol after intragastric administration of 10 mg/kg was ca. 8%. The oestradiol liver load after intragastric administration was about 20 times higher than after intravenous administration, whereas the drug load of other organs was independent of the administration route. Cyproterone acetate was completely bioavailable after intragastric administration in a dose of 0.1 mg/kg. Cyproterone acetate levels and AUC-values in all organs investigated were higher when compared to the plasma with highest levels in the liver. The organ distribution of cyproterone acetate including the drug liver load was independent of the route of administration.     

Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation

T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.

Multiple sclerosis (MS) is a disabling inflammatory disease of the central nervous system (CNS) characterized by demyelination as a key pathological hallmark (1). Loss of metabolic support and axonal myelination provided by oligodendrocytes not only impairs neurotransmission but also compromises neuronal homeostasis, leading to neuroaxonal vulnerability (2, 3). Chronic demyelination is therefore considered to play a major role in the progression of neurological disability in MS (4–6). The pharmacological protection of oligodendrocytes has been discussed as a new therapeutic strategy for MS (7) and is especially appealing in light of recent results showing that oligodendrocyte damage is partially reversible (8). However, the mechanisms underlying immune-mediated oligodendrocyte injury in neuroinflammation are still only partially understood.Proinflammatory CD4⁺ T cells are considered to play a major role in neuroinflammatory processes in MS and in its animal model, experimental autoimmune encephalomyelitis (EAE) (9–11). In particular, interleukin (IL)-23–polarized T helper (Th)17 cells coexpressing T-bet and ROR-γ are considered pathogenic in both EAE (12, 13) and in MS (13–15). Interestingly, in MS subjects, reduced Th17 responses after hematopoietic stem cell transplantation (16) or the exclusion of the double-positive Th17/1 cells from the CNS compartment after treatment with natalizumab (17) is associated with a dramatic decrease in the accumulation or expansion of demyelinating lesions, while interfering with IL-17A-cytokine signaling had moderate effects on disease severity (18). The capacity of IL-23–skewed Th17 cells to destabilize the blood–brain barrier (BBB) and recruit antigen-presenting cells to the CNS compartment in neuroinflammation is well established (13, 19, 20), but it is not clear whether Th17 cells cause tissue injury themselves. Previous studies have demonstrated that activated CD4⁺ T cells can exert cytotoxicity toward human and rodent oligodendrocytes (21–23) in vitro and impair remyelination in a toxic mouse model (24). Of note, older in vitro reports, from prior to the discovery of Th17 cells, using human oligodendrocytic cell lines rather excluded a soluble cytokine mediator of adult oligodendrocyte lysis (21, 25). Therefore, our goal was to unravel the direct influence of Th17 cells on the myelin compartment in neuroinflammation.     

Apolipoprotein E polymorphism and dendritic shape in hippocampal interneurons

The apolipoprotein E genetic polymorphism exerts a well described influence on Alzheimer's disease (AD) risk, although the pathogenetic mechanism is still not clear. Increasing evidence points to a diminished neuroplasticity in apolipoprotein E varepsilon4-allele carriers. But, alternatively or additionally, developmental differences in dendritic geometry may be associated with the polymorphism. We morphometrically examined the dendritic ramification of CA1 Parvalbumin-positive GABAergic hippocampal neurons (n=571) in matched pairs of aged non-demented individuals with different apolipoprotein E genotype. We chose Parvalbumin-positive interneurons since they lack potentially confounding AD-like cytoskeletal changes. To minimize the risk of transneuronal dendritic changes due to significant deafferentation we focused on non-demented individuals. In this chosen paradigm, neither the disease-associated apolipoprotein E varepsilon4-allele nor the apolipoprotein E varepsilon2-allele had a significant impact on dendritic shape when compared to the most common allelic variant apolipoprotein E varepsilon3/3. At least with respect to the studied cell type, the data suggest that the apolipoprotein E polymorphism does not modulate the original formation of dendrites in vivo, contrary to conclusions drawn from in vitro studies on neurite outgrowth.     

High-dose tamoxifen treatment increases the incidence of multifocal tumor recurrences in glioblastoma patients

BACKGROUND: Multifocal tumor recurrences in glioblastoma patients are described in 4% - 14% of cases. Two recent studies, treating newly diagnosed glioblastoma patients with continuous high-dose tamoxifen (TAM), reported an increased incidence of multifocal tumor recurrences in 45.5% and 33% of study patients. PATIENTS AND METHODS: Fifty newly diagnosed patients with glioblastoma were treated with 3 cycles of carboplatin, continuous high-dose TAM and radiotherapy. Tumor progression was determined on follow-up MRI studies at 3-month intervals and categorized as either local or multifocal. RESULTS: Multifocal tumor recurrence was found in 16 (33%) out of 49 study patients. Compared to tumors which remained local, multifocal tumor recurrences were characterized by a significantly longer median time to tumor progression (41 vs. 23 weeks, Breslow test: p = 0.0123). Multifocal tumor recurrences were mainly observed after an initial response to the study treatment (81%), whereas local regrowth was more often associated with initial treatment failure, i.e. progressive disease (64%). CONCLUSION: The association of the pattern of tumor recurrence with the type of response to TAM treatment suggests that acquired resistance to TAM might be an important contributing mechanism in the development of multifocal glioblastoma disease.