Psychosis commonly develops in adolescence or early adulthood. Youths at clinical high risk (CHR) for psychosis exhibit similar, subtle symptoms to those with schizophrenia (SZ). Malfunctioning ...neurotransmitter systems, such as glutamate, are implicated in the disease progression of psychosis. Yet, in vivo imaging techniques for measuring glutamate across the cortex are limited. Here, we use a novel 7 Tesla MRI glutamate imaging technique (GluCEST) to estimate changes in glutamate levels across cortical and subcortical regions in young healthy individuals and ones on the psychosis spectrum. Individuals on the psychosis spectrum (PS; n=19) and healthy young individuals (HC; n=17) underwent MRI imaging at 3 and 7 T. At 7 T, a single slice GluCEST technique was used to estimate in vivo glutamate. GluCEST contrast was compared within and across the subcortex, frontal, parietal and occipital lobes. Subcortical (χ
(1)=4.65, P=0.031) and lobular (χ
(1)=5.17, P=0.023) GluCEST contrast levels were lower in PS compared with HC. Abnormal GluCEST contrast levels were evident in both CHR (n=14) and SZ (n=5) subjects, and correlated differentially, across regions, with clinical symptoms. Our findings describe a pattern of abnormal brain neurochemistry early in the course of psychosis. Specifically, CHR and young SZ exhibit diffuse abnormalities in GluCEST contrast attributable to a major contribution from glutamate. We suggest that neurochemical profiles of GluCEST contrast across cortex and subcortex may be considered markers of early psychosis. GluCEST methodology thus shows promise to further elucidate the progression of the psychosis disease state.
Substantial leaps in the understanding of quantum systems have been driven by exploring geometry, topology, dimensionality and interactions in ultracold atomic ensembles
. A system where atoms evolve ...while confined on an ellipsoidal surface represents a heretofore unexplored geometry and topology. Realizing an ultracold bubble-potentially Bose-Einstein condensed-relates to areas of interest including quantized-vortex flow constrained to a closed surface topology, collective modes and self-interference via bubble expansion
. Large ultracold bubbles, created by inflating smaller condensates, directly tie into Hubble-analogue expansion physics
. Here we report observations from the NASA Cold Atom Lab
facility onboard the International Space Station of bubbles of ultracold atoms created using a radiofrequency-dressing protocol. We observe bubble configurations of varying size and initial temperature, and explore bubble thermodynamics, demonstrating substantial cooling associated with inflation. We achieve partial coverings of bubble traps greater than one millimetre in size with ultracold films of inferred few-micrometre thickness, and we observe the dynamics of shell structures projected into free-evolving harmonic confinement. The observations are among the first measurements made with ultracold atoms in space, using perpetual freefall to explore quantum systems that are prohibitively difficult to create on Earth. This work heralds future studies (in orbital microgravity) of the Bose-Einstein condensed bubble, the character of its excitations and the role of topology in its evolution.
The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with ...magnetic resonance imaging (MRI) and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1042 youths (ages 11-23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF at rest was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state functional MRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.
This study explores autistic women’s experiences of eating disorder services. Estimates suggest that 20%–30% of women in treatment for anorexia nervosa display diagnostic features characteristic of ...autism. Research suggests that autistic individuals’ needs are not being met by standard anorexia nervosa treatments. In the current study, in-depth interviews were conducted with 15 autistic women with experience of anorexia nervosa, 12 parents of autistic women with anorexia nervosa, and 11 eating disorder healthcare professionals. Using thematic analysis, three overarching themes were identified: misunderstanding autism and autistic traits, one treatment does not fit all, and improving accessibility and engagement within services. We found that there were diverse barriers facing autistic women when in treatment for anorexia nervosa, and these were accentuated by a lack of autism understanding within eating disorder services. Future research should focus on developing interventions that are tailored to the specific needs of autistic individuals with anorexia nervosa.
Lay Abstract
This study explores autistic women’s experiences of eating disorder services. About 20%–30% of people with anorexia nervosa are also autistic, and current treatments seem not to work as well for them. We interviewed 15 autistic women with experience of anorexia nervosa, 12 parents of autistic women with anorexia nervosa, and 11 healthcare professionals working in eating disorder services. We asked autistic women and parents about their experiences of eating disorder services, and we asked healthcare professionals about their experiences treating autistic women with anorexia nervosa. Participants’ views were represented by three overall themes: misunderstanding autism and autistic traits, one treatment does not fit all, and improving accessibility and engagement within services. We found that autistic women face many barriers when in treatment for anorexia nervosa, often because of a lack of autism understanding within eating disorder services. Future research should look at developing anorexia nervosa treatments that can specifically help autistic individuals.
These limitations are being addressed by a four-year project initiated in October 2009 as part of the National Science Foundation Cyber-Enabled Discovery and Innovation program, led by the authors of ...this article, called the Knowledgebase of Interatomic Models (KIM). The project consists of two stages, each of which would constitute a signifi cant contribution to atomistic computational materials science.
Background: Mutations of the transforming growth factor β (TGFβ) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). ...Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. Objective: To investigate kindreds presenting with both pulmonary hypertension and HHT. Methods: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. Results: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. Conclusions: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.
Within clinical small animal practice, diagnosis of both chronic kidney disease and acute kidney injury is common. To assess renal function, measurement of glomerular filtration rate is considered ...the gold standard. Currently, routine tests of kidney function include surrogate markers of glomerular filtration rate such as serum creatinine, and urea, each with their own limitations, whilst urine protein to creatinine ratio gives an indication of glomerular and tubular handling of protein, and urine specific gravity information about urine concentrating ability by the kidney. These parameters are used together with historical and physical examination data to give a diagnosis of kidney disease following which creatinine, proteinuria and blood pressure are used to stage chronic kidney disease and, together with urine output, grade acute kidney injury according to the International Renal Interest Society. However, there has been much concern that creatinine is insensitive when used to indicate early decline in renal function and this has highlighted the need for additional methods of diagnosing and monitoring these patients, with the potential to allow earlier therapeutic intervention. Symmetric dimethylarginine is a novel biomarker, which has been shown to perform as a surrogate marker of glomerular filtration rate in small animals. This article will review current research on symmetric dimethylarginine and the ways in which it may be utilised in small animal practice; current research supports the use of symmetric dimethylarginine as a screening test for detection of early chronic kidney disease according to International Renal Interest Society guidelines, but further research is required in to the usefulness of symmetric dimethylarginine as a tool for monitoring disease and the effect of non‐renal influences.
Systematic Discovery of Multicomponent Therapeutics Borisy, Alexis A.; Elliott, Peter J.; Hurst, Nicole W. ...
Proceedings of the National Academy of Sciences - PNAS,
06/2003, Letnik:
100, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of ...medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of ≈120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans, yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-α in human primary peripheral blood mononuclear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.
In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor ...exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.
We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety.
In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms.
This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.
The combined effects of the in ovo injection of commercial Marek's disease vaccine (MDV) and various levels of 25-hydroxyvitamin D3 (25OHD3) on the hatch variables, immunological measurements, and ...gene expression of Ross 708 hatchling broilers were investigated. A total of 5 in ovo injection treatments that were applied at 18 d of incubation (doi) included: 1) noninjected (control); or a 50 μL solution volume of 2) MDV alone; or MDV combined with 3) 0.6 μg of 25OHD3; 4) 1.2 μg of 25OHD3; or 5) 2.4 μg of 25OHD3. At hatch, hatchability of set and live embryonated eggs, hatchling body weight, hatch residue analysis, serum IgY and alpha-1 acid glycoprotein (AGP) concentrations, and the expression of genes related to immunity (INFα, INFβ, INFγ, TLR-3, and TLR-21) and vitamin D3 activity (1 α-hydroxylase, 24 hydroxylase, and vitamin D receptor) were determined. No significant treatment differences were observed for hatchability of set and live embryonated eggs, or for serum IgY and AGP concentrations. However, hatchling body weight was higher when MDV was combined with either 1.2 or 2.4 μg of 25OHD3 than when MDV was provided alone or in combination with 0.6 μg of 25OHD3. Also, in comparison to the noninjected treatment group, the expression of the genes for 1 α-hydroxylase and 24 hydroxylase was improved when MDV was combined with either 1.2 or 2.4 μg of 25OHD3. Lastly, expression of the genes linked to viral detection (TLR-3) and antibody production (INF-β) was increased in those treatments that contained any level of 25OHD3. These results indicate that in comparison to controls, the effects of MDV were observed to be greater on hatchling BW and splenic gene expression when it was administered in combination with the 1.2 or 2.4 μg doses of 25OHD3. Further research is needed to determine the posthatch effects of the administration of various levels of 25OHD3 in combination with MDV.
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