Učinci intra-artikularno primijenjenog tramadola na histopatološki nalaz koljenog zgloba u štakora.

The aim of this study was to investigate the effect of intra-articular injections of saline and tramadol on the articular cartilage in rat knee joints. Twenty-five adult Wistar rats were used in this experiment. They were randomly assigned to two groups, control (n = 5) and experimental (n = 20) and the latter was subdivided into four groups (each group n = 5). Saline was administered intra-articularly into the knee joints in the controls (group 1) and tramadol with different doses was injected into the knee joints of the experimental groups. In groups 2, 3, 4 and 5 different concentrations, 0.1, 0.25, 1.0 and 2.5 mg/mL respectively, of available tramadol were administrated intra-articularly into the knee joints. The results showed that there were no pathological changes in the saline-treated control joints (P>0.05). Joints treated with tramadol displayed significantly more pathological changes than the saline joints (P0.05). Joints that received tramadol in group 3 (0.25 mg/mL) showed no significant difference as compared with control joints in all histological indices, except for cell count. Joints treated with tramadol in groups 4 and 5 revealed significant histological changes compared to control joints in all histological indices. We conclude that intra-articular tramadol in high dosages (especially 2.5 mg/mL) causes histopathological changes in rat knee joints.Cilj istraživanja bio je utvrditi učinak primjene fiziološke otopine soli i tramadola na hrskavicu koljenog zgloba štakora. U pokusu je korišteno 25 odraslih Wistar štakora koji su metodom slučajnog izbora bili podijeljeni u dvije skupine, kontrolnu (n = 5) i pokusnu (n = 20). Pokusna skupina je naknadno podijeljena u 4 podskupine po 5 štakora. Fiziološka otopina bila je unesena u koljeni zglob štakora kontrolne skupine (skupina 1), dok je tramadol bio primijenjen u različitim dozama u koljeni zglob štakora pokusnih skupina. Skupina 2 primila je 0,1 mg/mL, skupina 3 primila je 0,25 mg/mL, dok su skupine 4 i 5 primile 1,0 odnosno 2,5 mg/mL tramadola. Rezultati su pokazali da nije bilo patoloških promjena u zglobovima kontrolne skupine (P>0,05). Zglobovi u koje je bio primijenjen tramadol pokazali su značajno (P0,05) između skupine 2 koja je primila tramadol i skupine kojoj je bila primijenjena fiziološka otopina kuhinjske soli. U štakora skupine 3, kojima je u zglobove bio primijenjen tramadol u količini od 0,25 mg/mL, također nisu utvrđene značajne razlike u odnosu na kontrolnu skupinu za sve histološke pokazatelje osim za broj stanica. Primjena tramadola u zglobove štakora u skupinama 4 i 5 dovela je u usporedbi s kontrolnom skupinom do značajnih promjena svih histoloških pokazatelja. Na temelju navedenih rezultata, zaključuje se da primjena većih doza tramadola (osobito 2,5 mg/mL) u koljeni zglob štakora dovodi do histopatoloških promjena

Intracranial and subcortical volumes in adolescents with early‐onset psychosis: A multisite mega‐analysis from the ENIGMA consortium

Early‐onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early‐onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early‐onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early‐onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed‐effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = −0.39) and hippocampal (d = −0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early‐onset schizophrenia (d = −0.34) and affective psychosis (d = −0.42), and early‐onset schizophrenia showed lower hippocampal (d = −0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = −0.42). The findings demonstrate a similar pattern of brain alterations in early‐onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early‐onset psychosis

Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype-first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior

Static Spherically Symmetric Solution of (R +- {\mu}^4/R) Gravity

The static spherically symmetric solution for (R +- {\mu}^4/R) model of f(R)gravity is investigated. We obtain the metric for space-time in the solar system that reduces to the Schwarzschild metric, when {\mu} tends to zero. For the obtained metric, the deviation from Einstein gravity is very small. This result is different from the other results have been obtained by equivalence between f(R) gravity and scalar tensor theory. Also it is shown that the vacuum solution in the solar system depends on the shape of matter distribution which differ from the Einstein's gravity

Source‐based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1‐weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source‐based morphometry (SBM) pipeline (SS‐Detect) to generate structural brain patterns (SBPs) that capture co‐varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV‐SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel‐based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism

Reformacija kao proces uspostavljanja i obnavljanja odnosa s Bogom

22q11.2 deletion syndrome (22q11DS)—a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22—is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6–52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen’s d’s ranging from −0.9 to −1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia

Corrosion Behavior of A356-10 Vol.% SiC Composites Cast by Gravity and Squeeze Casting in H2SO4 Solutions

Corrosion behavior of A356-10 vol.% SiC composites cast by gravity and squeeze casting is evaluated. For this purpose, prepared samples were immersed in H2SO4 solution for 2 hrs. at open circuit potential. Tafel polarization and electrochemical impedance spectroscopy (EIS) were carried out to study the corrosion resistance of composites. The results showed that corrosion resistance of composites cast by squeeze casting is higher than that of the gravity cast composites. The micrographs of scanning electron microscope (SEM) clearly showed the squeeze casting composites exhibit a good dispersion/matrix interface when compared with composites produced by gravity casting