Symptoms of depression and anxiety predict mortality in elderly veterans enrolled in the UPBEAT program.
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Acute Disease↗
Biomedical subjects
R Gould
Publications and source records attributed to R Gould.
Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists.
Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.
Platelet Activation↗
Identification and characterization of novel mammalian neuropeptide FF-like peptides that attenuate morphine-induced antinociception.
The two mammalian neuropeptides NPFF and NPAF have been shown to have important roles in nociception, anxiety, learning and memory, and cardiovascular reflex. Two receptors (FF1 and FF2) have been molecularly identified for NPFF and NPAF. We have now characterized a novel gene designated NPVF that encodes two neuropeptides highly similar to NPFF. NPVF mRNA was detected specifically in a region between the dorsomedial and ventromedial hypothalamic nuclei. NPVF-derived peptides displayed higher affinity for FF1 than NPFF-derived peptides, but showed poor agonist activity for FF2. Following intracerebral ventricular administration, a NPVF-derived peptide blocked morphine-induced analgesia more potently than NPFF in both acute and inflammatory models of pain. In situ hybridization analysis revealed distinct expression patterns of FF1 and FF2 in the rat central nervous system. FF1 was broadly distributed, with the highest levels found in specific regions of the limbic system and the brainstem where NPVF-producing neurons were shown to project. FF2, in contrast, was mostly expressed in the spinal cord and some regions of the thalamus. These results indicate that the endogenous ligands for FF1 and FF2 are NPVF- and NPFF-derived peptides, respectively, and suggest that the NPVF/FF1 system may be an important part of endogenous anti-opioid mechanism.
Amino Acid Sequence↗
Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase.
Wilson disease is an autosomal recessive copper transport disorder resulting from defective biliary excretion of copper and subsequent hepatic copper accumulation and liver failure if not treated. The disease is caused by mutations in the ATP7B (WND) gene, which is expressed predominantly in the liver and encodes a copper-transporting P-type ATPase that is structurally and functionally similar to the Menkes protein (MNK), which is defective in the X-linked copper transport disorder Menkes disease. The toxic milk (tx) mouse has a clinical phenotype similar to Wilson disease patients and, recently, the tx mutation within the murine WND homologue (WND:) of this mouse was identified, establishing it as an animal model for Wilson disease. In this study, cDNA constructs encoding the wild-type (Wnd-wt) and mutant (Wnd-tx) Wilson proteins (Wnd) were generated and expressed in Chinese hamster ovary (CHO) cells. The tx mutation disrupted the copper-induced relocalization of Wnd in CHO cells and abrogated Wnd-mediated copper resistance of transfected CHO cells. In addition, co-localization experiments demonstrated that while Wnd and MNK are located in the trans-Golgi network in basal copper conditions, with elevated copper, these proteins are sorted to different destinations within the same cell. Ultrastructural studies showed that with elevated copper levels, Wnd accumulated in large multi-vesicular structures resembling late endosomes that may represent a novel compartment for copper transport. The data presented provide further support for a relationship between copper transport activity and the copper-induced relocalization response of mammalian copper ATPases, and an explanation at a molecular level for the observed phenotype of tx mice.
Adenosine Triphosphatases↗
Compliance with the school meals initiative: effect on meal programs' financial success.
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Child↗
Studies of posttranslational modifications in spiny dogfish myelin basic protein.
The objective of this investigation was to determine whether nonmammalian myelin basic protein contained charge isomers resulting from extensive posttranslational modifications as seen in mammalian MBP. Four charge isomer components from dogfish MBP have been isolated. These forms arise by phosphorylation and deamidation modifications. Components C1, C2 and C3 have been characterized. We are currently characterizing component C8. Dogfish MBP is less cationic than mammalian MBP and has about 50% lower mobility on a basic pH gel electrophoresis relative to human and to bovine MBP. The mammalian component C1, which is unmodified, is modified in the dogfish by phosphorylation. The reduced electrophoretic mobility is largely attributable to the charge reduction resulting from phosphorylation in serine 72, 83, and 120 or 121 in C1, and C3. In component C2, two or three phosphate groups were distributed among residues 134, 138 and 139. It was found that dogfish amino acid residue 30 was a lysine residue and not a glutamate residue as reported in the literature.
Amino Acid Sequence↗
Molecular cytogenetic analysis of a novel high-grade canine T-lymphoblastic lymphoma demonstrating co-expression of CD3 and CD79a cell markers.
We present the molecular cytogenetic analysis of a novel case of canine lymphoma, in a nine-year-old entire male collie cross retriever dog that presented with an enlarged prescapular lymph node. A diagnosis of high-grade lymphoblastic lymphoma was made by histological evaluation of fixed lymph node biopsy sections, whilst immunohistochemical analyses demonstrated co-expression of B- and T-cell antigens (CD79a and CD3) by 95% of lymphomatous cells. Comparative genomic hybridisation (CGH) analysis detected loss of dog chromosomes 11, 30 and 38 and gain of chromosome 36 within the lymphoma biopsy specimen. These findings correlated with direct cytogenetic analysis of tumour metaphases using whole chromosome paint probes representing each of these four chromosomes. This study represents the first report of the combined application of both direct and indirect cytogenetic techniques for the analysis of recurrent chromosome aberrations in canine cancer.
Animals↗
UPBEAT: the impact of a psychogeriatric intervention in VA medical centers. Unified Psychogeriatric Biopsychosocial Evaluation and Treatment.
BACKGROUND: The Unified Psychogeriatric Biopsychosocial Evaluation and Treatment (UPBEAT) program provides individualized interdisciplinary mental health treatment and care coordination to elderly veterans whose comorbid depression, anxiety, or alcohol abuse may result in overuse of inpatient services and underuse of outpatient services. OBJECTIVES: To determine whether proactive screening of hospitalized patients can identify unrecognized comorbid psychiatric conditions and whether comprehensive assessment and psychogeriatric intervention can improve care while reducing inpatient use. DESIGN: Randomized trial. SUBJECTS: Veterans aged 60 and older hospitalized for nonpsychiatric medical or surgical treatment in 9 VA sites (UPBEAT, 814; usual care, 873). MEASURES: The Mental Health Inventory (MHI) anxiety and depression subscales, the Alcohol Use Disorder Identification Test (AUDIT) scores, RAND 36-Item Health Survey Short Form (SF-36), inpatient days and costs, ambulatory care clinic stops and costs, and mortality and readmission rates. RESULTS: Mental health and general health status scores improved equally from baseline to 12-month follow-up in both groups. UPBEAT increased outpatient costs by $1,171 (P <0.001) per patient, but lowered inpatient costs by $3,027 (P = 0.017), for an overall savings of $1,856 (P = 0.156). Inpatient savings were attributable to fewer bed days of care (3.30 days; P = 0.016) rather than fewer admissions. Patients with 1 or more pre-enrollment and postenrollment hospitalizations had the greatest overall savings ($6,015; P = 0.069). CONCLUSIONS: UPBEAT appears to accelerate the transition from inpatient to outpatient care for acute nonpsychiatric admissions. Care coordination and increased access to ambulatory psychiatric services produces similar improvement in mental health and general health status as usual care.
Aged↗
Rate of cognitive change in Alzheimer's disease: methodological approaches using random effects models.
Subtraction of serial scores, Least Squares Estimators, and Best Linear Unbiased Predictors (BLUPs) were compared for estimating rates of cognitive change for Mini-Mental State Exam (MMSE) and Dementia Rating Scale (DRS) scores for 299 probable Alzheimer's disease patients. The BLUPs provided cleaner group estimates of subjects' intercepts and slopes and are preferred. Regression analysis of the BLUP estimates of rate of change indicated that steeper declines were associated with higher levels of education and older age at onset. These effects were much smaller than those due to estimated initial cognitive test score. Differences in longitudinal metric characteristics of the MMSE and DRS were found, with the DRS yielding more precise change estimates. We discuss modeling these longitudinal data, and discuss use of the estimates of rate of change and intercept as data in their own right.
Aged↗
Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells.
Phosphatidylinositol 3-kinase (PI3K) regulates several vital cellular processes, including signal transduction and membrane trafficking. In order to study the intracellular localization of the PI3K product, phosphatidylinositol 3-phosphate [PI(3)P], we constructed a probe consisting of two PI(3)P-binding FYVE domains. The probe was found to bind specifically, and with high affinity, to PI(3)P both in vitro and in vivo. When expressed in fibroblasts, a tagged probe localized to endosomes, as detected by fluorescence microscopy. Electron microscopy of untransfected fibroblasts showed that PI(3)P is highly enriched on early endosomes and in the internal vesicles of multivesicular endosomes. While yeast cells deficient in PI3K activity (vps15 and vps34 mutants) were not labelled, PI(3)P was found on intralumenal vesicles of endosomes and vacuoles of wild-type yeast. vps27Delta yeast cells, which have impaired endosome to vacuole trafficking, showed a decreased vacuolar labelling and increased endosome labelling. Thus PI(3)P follows a conserved intralumenal degradation pathway, and its generation, accessibility and turnover are likely to play a crucial role in defining the early endosome and the subsequent steps leading to multivesicular endosome formation.
Animals↗
Simulation of disaster recovery of a picture archiving and communications system using off-site hierarchal storage management.
The purpose of this communication is to report on the testing of the disaster recovery capability of our hierarchical storage management (HSM) system. Disaster recovery implementation is a requirement of every mission-critical information technology project. Picture archiving and communications systems (PACS) certainly falls into this category, even though the counterpart, conventional film archive, has no protection against fire, for example. We have implemented a method for hierarchical storage with wavelet technology that maximizes on-site case storage (using lossy compression), retains bit-preserved image data for legal purposes, provides an off-site backup (lossless bit-preserving wavelet transform), and provides for disaster recovery. Recovery from a natural (earthquake and subsequent fire) or technical (system crash and data loss) disaster was simulated by attempting to restore from the off-site image and database backup to clean core PACS components. The only existing loaded software was the operating system. The database application was reloaded locally, and then the database contents and image store were loaded from the off-site component of the HSM system. The following measurements were analyzed: (1) the ability to recover all data; (2) the integrity of the recovered database and image data; (3) the time to recover the database relative to the number of studies and age of the archive, as well as bandwidth between the local and remote site; and (4) the time to recover image data relative to compression ratio, number of studies, number of images, and time depth of the archive. This HSM system, which maximizes on-site storage, maintains a legal record, and provides off-site backup, also facilitates disaster recovery for a PACS.
Computer Storage Devices↗
Antiplatelet effects of MK-852, a platelet fibrinogen receptor antagonist, in healthy volunteers.
MK-852, a cyclic heptapeptide, is a potent platelet fibrinogen receptor antagonist. When administered to normal healthy male subjects by 1- and 4-hour constant rate intravenous infusions, it provides a generally well-tolerated and reversible means of inhibition of platelet function. At infusion rates of 1 microgram/kg/min for 1 hour and 0.44 microgram/kg/min for 4 hours, respectively, MK-852 extended baseline bleeding time by greater than 2.2-fold and 2.6-fold, inhibited ADP-induced platelet aggregation by 76% and 69%, and inhibited collagen-induced platelet aggregation by 65% and 67%, respectively. The pharmacokinetics of MK-852 include an elimination half-life of approximately 2 hours, total clearance of about 150 ml/min, and volume of distribution of about 18 liters. Examination of the relationship between MK-852 whole-blood concentration in vitro and inhibition of platelet aggregation showed an EC50 of about 55 ng/ml and a Hill coefficient of 1.55. The infusions were generally well tolerated, with no study drug-related changes in blood counts or biochemical profiles.
Adenosine Diphosphate↗
Direct coronal CT scanning of the neonatal chest.
BACKGROUND: The purpose of this study was to attempt to improve upon conventional coronal computed tomographic (CT) images of neonatal chest which to date have been made by reformatting thinly spaced axial images. MATERIALS AND METHODS: Nine neonates were studied by direct coronal CT scans with the patients' long axis 90 degrees to the scanning table. They were studied to further define their thoracic abnormalities detected on plain film. Spiral CT and cine scan (Imatron) were utilized. RESULTS: Congenital lung lesions such as congenital cystic adenomatoid malformation could not be diagnosed but their anatomical location could be accurately depicted, enabling easier surgical planning. The arterial supply to bronchopulmonary sequestrations was also identifiable. Tracheobronchial abnormalities such as tracheobronchus and bronchial atresia were also identifiable. Causing of air trapping, both intrinsic such as an atretic bronchus and extrinsic such as vascular compression were readily demonstrated. CONCLUSION: With neither special devices nor paraphernalia, the described method of direct coronal CT scans were both feasible and provided significant information. This technique allows for improved assessment of the tracheobronchial tree and more accurate detection, localization, and characteristics of lesions adjacent to the diaphragm.
Bronchi↗
Control of transmission of vancomycin-resistant Enterococcus faecium in a long-term-care facility.
OBJECTIVES: To describe the investigation and control of transmission of vancomycin-resistant enterococci (VRE) in a residential long-term-care (LTC) setting. OUTBREAK INVESTIGATION: A strain of vancomycin-resistant Enterococcus faecium not previously isolated in Ontario colonized five residents of a 254-bed LTC facility in Toronto. The index case was identified when VRE was isolated from a urine culture taken after admission to a local hospital. Screening of rectal swabs from all 235 residents identified four others who were colonized with the same strain of E faecium. CONTROL MEASURES: Colonized residents were cohorted. VRE precautions were established as follows: gown and gloves for resident contact, restriction of contact between colonized and noncolonized residents, no sharing of personal equipment, and daily double-cleaning of residents' rooms and wheelchairs. OUTCOME: Two colonized residents died of causes unrelated to VRE. Although bacitracin therapy (75,000 units four times a day x 14 days) failed to eradicate carriage in two of three surviving residents, both cleared their carriage within 7 weeks. Repeat rectal swabs from 224 residents (91%) 2 months after isolation precautions were discontinued and from 125 residents (51%) 9 months later identified no new cases. Total cost of investigation and control was $12,061 (Canadian). CONCLUSION: VRE may be transmitted in LTC facilities, and colonized LTC residents could become important VRE reservoirs. Control of VRE transmission in LTC facilities can be achieved even with limited resources.
Aged↗
Fractal analysis of radiographs: assessment of trabecular bone structure and prediction of elastic modulus and strength.
The purpose of this study was to determine whether fractal dimension of radiographs provide measures of trabecular bone structure which correlate with bone mineral density (BMD) and bone biomechanics, and whether these relationships depend on the technique used to calculate the fractal dimension. Eighty seven cubic specimen of human trabecular bone were obtained from the vertebrae and femur. The cubes were radiographed along all three orientations--superior-inferior (SI), medial-lateral (ML), and anterior-posterior (AP), digitized, corrected for background variations, and fractal based techniques were applied to quantify trabecular structure. Three different techniques namely, semivariance, surface area, and power spectral methods were used. The specimens were tested in compression along three orientations and the Young's modulus (YM) was determined. Compressive strength was measured along the SI direction. Quantitative computed tomography was used to measure trabecular BMD. High-resolution magnetic-resonance images were used to obtain three-dimensional measures of trabecular architecture such as the apparent bone volume fraction, trabecular thickness, spacing, and number. The measures of trabecular structure computed in the different directions showed significant differences (p<0.05). The correlation between BMD, YM, strength, and the fractal dimension were direction and technique dependent. The trends of variation of the fractal dimension with BMD and biomechanical properties also depended on the technique and the range of resolutions over which the data was analyzed. The fractal dimension showed varying trends with bone mineral density changes, and these trends also depended on the range of frequencies over which the fractal dimension was measured. For example, using the power spectral method the fractal dimension increased with BMD when computed over a lower range of spatial frequencies and decreased for higher ranges. However, for the surface area technique the fractal dimension increased with increasing BMD. Fractal measures showed better correlation with trabecular spacing and number, compared to trabecular thickness. In a multivariate regression model inclusion of some of the fractal measures in addition to BMD improved the prediction of strength and elastic modulus. Thus, fractal based texture analysis of radiographs are technique dependent, but may be used to quantify trabecular structure and have a potentially valuable impact in the study of osteoporosis.
Biomechanical Phenomena↗
Messenger RNAs for kinesins and dynein are located in neural processes.
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Animals↗
EGF-Receptor phosphorylation and signaling are targeted by H2O2 redox stress.
Inflammation of the respiratory tract is associated with the production of reactive oxygen species, such as hydrogen peroxide (H2O2) and superoxide (O2-), which contribute extensively to lung injury in diseases of the respiratory tract. The mechanisms and target molecules of these oxidants are mainly unknown but may involve modifications of growth-factor receptors. We have shown that H2O2 induces epidermal growth factor (EGF)-receptor tyrosine phosphorylation in intact cells as well as in membranes of A549 lung epithelial cells. On the whole, total phosphorylation of the EGF receptor induced by H2O2 was lower than that induced by the ligand EGF. Phosphorylation was confined to tyrosine residues and was inhibited by addition of genistein, indicating that it was due to the activation of protein tyrosine kinase (PTK). Phosphoamino acid analysis revealed that although the ligand, EGF, enhanced the phosphorylation of serine, threonine, and tyrosine residues, H2O2 preferentially enhanced tyrosine phosphorylation of the EGF receptor. Serine and threonine phosphorylation did not occur, and the turnover rate of the EGF receptor was slower after H2O2 exposure. Selective H2O2-mediated phosphorylation of tyrosine residues on the EGF receptor was sufficient to activate phosphorylation of an SH2-group-bearing substrate, phospholipase C-gamma (PLC-gamma), but did not increase mitogen-activated protein (MAP) kinase activity. Moreover, H2O2 exposure decreased protein kinase C (PKC)-alpha activity by causing translocation of PKC-alpha from the membrane to the cytoplasm. These studies provide novel insights into the capacity of a reactive oxidant, such as H2O2, to modulate EGF-receptor function and its downstream signaling. The H2O2-induced increase in tyrosine phosphorylation of the EGF receptor, and the receptor's slower rate of turnover and altered downstream phosphorylation signals may represent a mechanism by which EGF-receptor signaling can be modulated during inflammatory processes, thereby affecting cell proliferation and thus having implications in wound repair or tumor formation.
Calcium-Calmodulin-Dependent Protein Kinases↗
Prevalence of panic in patients referred for pulmonary function testing at a major medical center.
OBJECTIVE: The authors examined the prevalence and correlates of panic disorder in a group of patients who were referred for pulmonary function testing. METHOD: Patients (N = 115) were screened for the presence of panic attacks and panic disorder with a self-report questionnaire; a subgroup (N = 25) received structured diagnostic assessment. RESULTS: Of the 115 patients, 41% (N = 47) reported panic attacks and 17% (N = 20) met screening criteria for panic disorder. From the confirmed rate of panic disorder among the subgroup who received structured diagnostic assessment, the overall prevalence rate of panic disorder was estimated to be 11% and included six of the nine patients (67%) who had a diagnosis of chronic obstructive pulmonary disease. There were no significant differences between patients with and without panic in the severity of pulmonary function abnormalities or in the response to bronchodilators. However, patients with panic attacks were significantly more likely to report dyspnea at rest and irritable bowel symptoms and tended to report difficulty swallowing. CONCLUSIONS: This study suggests that panic disorder and subsyndromal panic are relatively common and may be unrecognized and inadequately treated in patients who present with respiratory symptoms.
Airway Obstruction↗