Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on ...genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.
Current image sharing is carried out by manual transportation of CDs by patients or organization-coordinated sharing networks. The former places a significant burden on patients and providers. The ...latter faces challenges to patient privacy.
To allow healthcare providers efficient access to medical imaging data acquired at other unaffiliated healthcare facilities while ensuring strong protection of patient privacy and minimizing burden on patients, providers, and the information technology infrastructure.
An image sharing framework is described that involves patients as an integral part of, and with full control of, the image sharing process. Central to this framework is the Patient Controlled Access-key REgistry (PCARE) which manages the access keys issued by image source facilities. When digitally signed by patients, the access keys are used by any requesting facility to retrieve the associated imaging data from the source facility. A centralized patient portal, called a PCARE patient control portal, allows patients to manage all the access keys in PCARE.
A prototype of the PCARE framework has been developed by extending open-source technology. The results for feasibility, performance, and user assessments are encouraging and demonstrate the benefits of patient-controlled image sharing.
The PCARE framework is effective in many important clinical cases of image sharing and can be used to integrate organization-coordinated sharing networks. The same framework can also be used to realize a longitudinal virtual electronic health record.
The PCARE framework allows prior imaging data to be shared among unaffiliated healthcare facilities while protecting patient privacy with minimal burden on patients, providers, and infrastructure. A prototype has been implemented to demonstrate the feasibility and benefits of this approach.
Rationale
Studies have demonstrated that brain dopamine D2/D3 receptors (D2/D3R) and the reinforcing effects of cocaine can be influenced by a monkey’s position in the social dominance hierarchy.
...Objective
In this study, we manipulated the social ranks of monkeys by reorganizing social groups and assessed effects on D2/D3R availability and cocaine self-administration.
Methods
Male cynomolgus monkeys (
N
= 12) had been trained to self-administer cocaine under a concurrent cocaine-food reinforcement schedule. Previously, PET measures of D2/D3R availability in the caudate nucleus and putamen had been obtained with
18
Ffluoroclebopride during cocaine abstinence, while monkeys lived in stable social groups of four monkeys/pen. For this study, monkeys were reorganized into groups that consisted of (1) four previously dominant, (2) four previously subordinate, and (3) a mix of previously dominant and subordinate monkeys. After 3 months, D2/D3R availability was redetermined and cocaine self-administration was reexamined.
Results
D2/D3R availability significantly increased after reorganization in monkeys who were formerly subordinate, with the greatest increases observed in those that became dominant. No consistent changes in D2/D3R availability were observed in formerly dominant monkeys. Cocaine self-administration did not vary according to rank after reorganization of social groups. However, when compared to their previous cocaine self-administration data, the potency of cocaine as a reinforcer decreased in 9 of 11 monkeys.
Conclusions
These results indicate that changing the social conditions can alter D2/D3R availability in subordinate monkeys in a manner suggestive of environmental enrichment. In most monkeys, social reorganization shifted the cocaine dose-response curve to the right, also consistent with environmental enrichment.
Abstract Socially housed monkeys have been used as a model to study human diseases. The present study examined behavioral, physiological and neurochemical measures as predictors of social rank in 16 ...experimentally naïve, individually housed female cynomolgus monkeys ( Macaca fascicularis ). The two behavioral measures examined were novel object reactivity (NOR), as determined by latency to touch an opaque acrylic box placed in the home cage, and locomotor activity assessed in a novel open-field apparatus. Serum cortisol concentrations were evaluated three times per week for four consecutive weeks, and stress reactivity was assessed on one occasion by evaluating the cortisol response to adrenocorticotropic hormone (ACTH) following dexamethasone suppression. Measures of serotonin (5-HT) function included whole blood 5-HT (WBS) concentrations, cerebrospinal fluid (CSF) concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) and brain 5-HT transporter (SERT) availability obtained using positron emission tomography (PET). After baseline measures were obtained, monkeys were assigned to four social groups of four monkeys per group. The two measures that correlated with eventual social rank were CSF 5-HIAA concentrations, which were significantly higher in the animals who eventually became subordinate, and latency to touch the novel object, which was significantly lower in eventual subordinate monkeys. Measures of 5-HT function did not change as a consequence of social rank. These data suggest that levels of central 5-HIAA and measures of novel object reactivity may be trait markers that influence eventual social rank in female macaques.
The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate ...clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.
Colorectal cancers are common tumors in the United States and appropriate imaging is essential to direct appropriate care. Staging and treatment differs between tumors arising in the colon versus the ...rectum. Local staging for colon cancer is less integral to directing therapy given radical resection is often standard. Surgical options for rectal carcinoma are more varied and rely on accurate assessment of the sphincter, circumferential resection margins, and peritoneal reflection. These important anatomic landmarks are best appreciated on high-resolution imaging with transrectal ultrasound or MRI. When metastatic disease is suspected, imaging modalities that provide a global view of the body, such as CT with contrast or PET/CT may be indicated. Rectal cancer often metastasizes to the liver and so MRI of the liver with and without contrast provides accurate staging for liver metastases. This article focuses on local and distant staging and reviews the appropriateness of different imaging for both variants. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
The problem of automatic quantification of brain tissue by utilizing single-valued (single echo) magnetic resonance imaging (MRI) brain scans is addressed. It is shown that this problem can be solved ...without classification or segmentation, a method that may be particularly useful in quantifying white matter lesions where the range of values associated with the lesions and the white matter may heavily overlap. The general technique utilizes a statistical model of the noise and partial volume effect together with a finite mixture density description of the tissues. The quantification is then formulated as a minimization problem of high order with up to six separate densities as part of the mixture. This problem is solved by tree annealing with and without partial volume utilized, the results compared, and the sensitivity of the tree annealing algorithm to various parameters is exhibited. The actual quantification is performed by two methods: a classification-based method called Bayes quantification, and parameter estimation. Results from each method are presented for synthetic and actual data.< >
Statistical models of partial volume effect for systems with various types of noise or pixel value distributions are developed and probability density functions are derived. The models assume either ...Gaussian system sampling noise or intrinsic material variances with Gaussian or Poisson statistics. In particular, a material can be viewed as having a distinct value that has been corrupted by additive noise either before or after partial volume mixing, or the material could have nondistinct values with a Poisson distribution as might be the case in nuclear medicine images. General forms of the probability density functions are presented for the N material cases and particular forms for two- and three-material cases are derived. These models are incorporated into finite mixture densities in order to more accurately model the distribution of image pixel values. Examples are presented using simulated histograms to demonstrate the efficacy of the models for quantification. Modeling of partial volume effect is shown to be useful when one of the materials is present in images mainly as a pixel component.< >
The pancreas is one of the most heavily innervated peripheral organs in the body. Parasympathetic and sympathetic neurons terminate in the pancreas and provide tight control of endocrine and exocrine ...functions. The aim of this study was to determine whether the pancreas can be imaged with a radioligand that binds to specific neuroreceptors. Using fluorine-18 4-fluorobenzyltrozamicol (FBT), which binds to the presynaptic vesicular acetylcholine transporter, positron emission tomography scans were performed in four adult mice, two adult rhesus monkeys, and one adult human. In these mammals, the pancreas is intensely FBT avid, with uptake greater than in any other organ at 30, 60, and 90 min. The maximum standardized uptake value (SUV) ratios of pancreas to liver, for example, ranged from 1.4 to 1.7 in rhesus monkeys (mean 1.6; median 1.7) and from 1.9 to 4.7 (mean 3.24; median 3.02) in mice. The maximum SUV ratio of pancreas to liver in the human was 1.8. These data suggest that neuroreceptor imaging of the pancreas in vivo is feasible in animal models and humans. This imaging could allow researchers to interrogate functions under control of the autonomic nervous system in the pancreas, with applications possible in transplanted and native pancreata. Also, as beta cell function is intimately related to parasympathetic cholinergic input, FBT activity in the pancreas may correlate with insulin-producing beta cell mass. This could ultimately provide a method of in vivo imaging in animal models and humans for diabetes research.
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