The biological correlates of childhood trauma in first episode psychosis

Objective To overview biological mechanisms connecting childhood trauma to the development of psychosis. Methods We reviewed the evidence regarding biological correlates associated with childhood trauma in individuals affected by first episode psychosis (FEP) in terms of: 1) Hypothalamic-pituitary- adrenal (HPA) axis & cytokines levels; 2) gene 7 environment interaction, epigenetic and gene expression modifications and 3) metabolic biomarkers. Results Childhood trauma and early psychosis even when explored separately were found associated with several biological correlates. Regarding the immune system activity, in terms of both HPA axis functioning and cytokines levels, FEP patients exposed to childhood trauma showed 1) a less reactive HPA axis, characterized by a blunted cortisol awakening response, and higher serum levels of Tumor necrosis Factor-\u3b1 (TNF-\u3b1) and C-reactive protein (CRP) in comparison with patients without childhood trauma. Genetics and epigenetics were also proven significantly different in traumatized FEP in comparison with non-exposed individuals. Specifically, first 2) the Val/Val genotype at the Val158Met polymorphism in the COMT gene, the A allele at rs4713916 and rs9296158 single nucleotide polymorphisms (SNPs) and the TT homozygosis at rs1360780 SNP in the FKBP5 gene were demonstrated to be risk factors for psychosis in traumatized individuals. Second, childhood trauma in FEP was proven significantly associated with global DNA hypo-methylation and lower BDNF gene expression. Finally, regarding metabolic changes associated with childhood trauma in FEP 3) higher levels of glycated hemoglobin and higher c-peptide and insulin levels were proven in patients exposed to childhood trauma in comparison with those without childhood trauma. Conclusions This review has given evidence regarding associations between childhood trauma and its biological correlates in first episode psychosis. Nonetheless, future studies are warranted to investigate putative biological mediators and their temporal sequence in order to elucidate developmental trajectories

Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia

Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9, whereas a knock-in strain carrying the p.A221D variant was already available. Like null mutants, homozygous knock-in animals showed increased egg laying and were hypersensitive to aldicarb, an inhibitor of acetylcholinesterase, suggesting excessive neurotransmitter release by different classes of motor neurons. Automated analysis of C. elegans locomotion indicated that goa-1 mutants move faster than control animals, with more frequent body bends and a higher reversal rate and display uncoordinated locomotion. Phenotypic profiling of heterozygous animals revealed a strong hypomorphic effect of both variants, with a partial dominant-negative activity for the p.A221D allele. Finally, caffeine was shown to rescue aberrant motor function in C. elegans harboring the goa-1 variants; this effect is mainly exerted through adenosine receptor antagonism. Overall, our findings establish a suitable platform for drug discovery, which may assist in accelerating the development of new therapies for this devastating condition, and highlight the potential role of caffeine in controlling GNAO1-related dyskinesia

When ring makes the difference: coordination properties of Cu2+/Cu+ complexes with sulfur-pendant polyazamacrocycles for radiopharmaceutical applications

Three polyazamacrocyclic ligands, i.e. 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclotridecane (TRI4S) and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetrazacyclotetradecane (TE4S), were considered as potential chelators for the medically relevant copper radioisotopes. The ligands have been synthesized through facile, single-step reactions, and their acidity constants have been measured in aqueous solution at 25 degrees C. The kinetic, thermodynamic, electrochemical and structural properties of their Cu2+ and Cu+ complexes were investigated in aqueous solution at 25 degrees C using spectroscopic (UV-Visible, EPR, NMR) and electrochemical techniques (pH-potentiometric titrations, cyclic voltammetry and electrolysis). TACD3S was demonstrated to be unable to stabilize Cu2+, whereas for TRI4S and TE4S the formation of stable monocupric (CuL2+) and monocuprous (CuL+) complexes was detected. TRI4S coordinates Cu(2+)via a [4N] and a [4N]S array of donor atoms while with TE4S only the latter geometry exists. The thermodynamic stability and the kinetic inertness of the copper complexes formed by TACD3S, TRI4S and TE4S were compared with those previously reported for 1,4,7,10-tetrakis-[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclododecane (DO4S) to unravel the influence of the ring size and the nitrogen donor array on the copper chelation properties of these sulfur-rich macrocycles. The copresence of four nitrogen atoms is an essential feature to allow effective copper coordination when a 12-member ring is employed, as the Cu2+-DO4S complexes were far more stable than those of Cu2+-TACD3S. Furthermore, the larger ring size of TRI4S and TE4S, when compared to DO4S, progressively increases the rate of the Cu2+ complexation reactions but decreases the thermodynamic stability of the Cu2+ complexes. Despite this, the ability of TRI4S and TE4S to stably accommodate both copper oxidation states makes them very attractive for application in nuclear medicine as they could avoid the demetallation after the biologically triggered Cu2+/Cu+ reduction

Relationship between pulmonary function and physical performance among community-living people: results from Look-up 7+ study

Background: While respiratory muscle strength is recognized to decline with aging process, the relationship between sarcopenia and pulmonary function remains to be studied. The present study was undertaken to provide a better insight into the comprehension of the relationship between pulmonary function and muscle function (strength and physical performance) using an unselected sample of subjects assessed during the Longevity Check-up 7+ project. Methods: Look-up 7+ is an ongoing cross-sectional survey started in June 2015 and conducted in unconventional settings (i.e. exhibitions, malls, and health promotion campaigns) across Italy. Candidate participants are eligible for enrolment if they are at least 18 years of age and provide written informed consent. Muscle strength was assessed by handgrip strength test, and physical performance was evaluated by chair stand test. Spirometer analysis was performed using the AirSmart system, and the largest forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and peak expiratory flow (PEF) values were collected. Results: The mean age of 925 subjects participating in the Longevity check-7+ surveys and receiving the spirometer evaluation was 55.6 years (range from 18 to 98 years), and 501 (54%) were women. Overall, both in male and female participants, FVC, FEV1 and PEF positively correlated with handgrip strength and chair stand tests. The receiver operator characteristic curve analysis revealed that the areas under the curves for FVC, FEV1, and PEF were 0.79, 0.80 and 0.80, respectively. Conclusions: The results clearly show that pulmonary function was positively associated with handgrip strength and chair stand tests. Based on this observation, muscle strength, physical performance, and pulmonary function should be recommended as the method of choice for the early detection of individuals at risk of probable sarcopenia and at the same time to better characterized the severity of sarcopenia status

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia

Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy

Co-existence of acute myeloid leukemia with multilineage dysplasia and Epstein-Barr virus-associated T-cell lymphoproliferative disorder in a patient with rheumatoid arthritis: a case report

Rheumatoid arthritis (RA) is an autoimmune disease mediated by inflammatory processes mainly at the joints. Recently, awareness of Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD) has been heightened for its association with methotraxate usage in RA patients. In the contrary, acute myeloid leukemia with multilineage dysplasia (AML-MLD) has never been documented to be present concomitantly with the above two conditions. In this report we present a case of an autopsy-proven co-existence of AML-MLD and EBV-associated T-LPD in a patient with RA

Normative values of muscle strength across ages in a ‘real world’ population: results from the longevity check-up 7+ project

Background: Low muscle strength is a powerful predictor of negative health-related events and a key component of sarcopenia. The lack of normative values for muscle strength across ages hampers the practical appraisal of this parameter. The aim of the present study was to produce normative values for upper and lower extremity muscle strength across a wide spectrum of ages, in a large sample of community-dwellers recruited in the Longevity check-up (Lookup) 7+ project. Methods: Lookup 7+ is an ongoing project that started in June 2015 and conducted in unconventional settings (i.e. exhibitions, malls, and health promotion campaigns) across Italy with the aim of fostering the adoption of healthy lifestyles in the general population. Candidate participants are eligible for enrolment if they are 18+&nbsp;years and provide written informed consent. Upper and lower extremity muscle strength is assessed by handgrip strength and five-repetition chair-stand [5&nbsp;×&nbsp;sit-to-stand (STS)] tests, respectively. Cross-sectional centile and normative values for handgrip strength and 5&nbsp;×&nbsp;STS tests from age 18 to 80+&nbsp;years were generated for the two genders. Smoothed normative curves for the two tests were constructed for men and women using the lambda-mu-sigma method. Results: From 1 June 2015 to 30 May 2019, 11&nbsp;448 participants were enrolled. The mean age of participants was 55.6&nbsp;years (standard deviation: 11.5&nbsp;years; range: 18–98&nbsp;years), and 6382 (56%) were women. Normative values for handgrip strength and the 5&nbsp;×&nbsp;STS test, both absolute and normalized by body mass index, were obtained for men and women, stratified by age groups. Values of upper and lower extremity muscle strength across ages identified three periods in life: an increase to peak in young age and early adulthood (18–24&nbsp;years), preservation through midlife (25–44&nbsp;years), and a decline from midlife onwards (45+&nbsp;years). Conclusions: Our study established age-specific and gender-specific percentile reference values for handgrip strength and the 5&nbsp;×&nbsp;STS test. The normative curves generated can be used to interpret the assessment of muscle strength in everyday practice for the early detection of individuals with or at risk of sarcopenia