How frequently should patients with type 2 diabetes mellitus be screened for retinopathy?
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Adult↗
Biomedical subjects
C Murphy
Publications and source records attributed to C Murphy.
Activated protein C inhibits tumor necrosis factor and macrophage migration inhibitory factor production in monocytes.
The precise regulatory mechanisms of amplification and downregulation of the pro- and anti-inflammatory cytokines in the inflammatory response have not been fully delineated. Although activated protein C (APC) and its precursor protein C (PC) have recently been reported to be promising therapeutic agents in the management of meningococcal sepsis, direct evidence for the anti-inflammatory effect remains scarce. We report that APC inhibits in vitro the release of tumor necrosis factor (TNF) and macrophage migration inhibitory factor (MIF), two known cytokine mediators of bacterial septic shock, from lipopolysaccharide (LPS)-stimulated human monocytes. The THP-1 monocytic cell line, when stimulated with LPS and concomitant APC, exhibited a marked reduction in the release of TNF and MIF protein in a concentration-dependent manner compared to cells stimulated with LPS alone. This effect was observed only when incubations were performed in serum-free media, but not in the presence of 1-10% serum. Serum-mediated inhibition could only be overcome by increasing APC concentrations to far beyond physiological levels, suggesting the presence of endogenous serum-derived APC inhibitors. Inhibition of MIF release by APC was found to be independent of TNF, as stimulation of MIF release by LPS was unaltered in the presence of anti-TNF antibodies. Our data confirm that the suggested anti-inflammatory properties of APC are due to direct inhibition of the release of the pro-inflammatory monokine TNF, and imply that the anti-inflammatory action of APC is also mediated via inhibition of MIF release.
Cell Line↗
Speech dysfunction and body image.
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Articulation Disorders↗
Thermodynamic instability of human lambda 6 light chains: correlation with fibrillogenicity.
Certain types of human light chains have the propensity to deposit pathologically as amyloid fibrils as evidenced by the preferential association of monoclonal lambda 6 proteins with AL amyloidosis. However, the molecular features that render such proteins amyloidogenic have not been elucidated. Based upon the demonstrated relationship between the thermodynamic stability of light chains and their propensity to aggregate in vitro, we have initiated studies where the thermodynamic properties and fibrillogenic potential of two recombinant (r) V lambda 6 molecules were compared. The first protein was generated from cDNA cloned from marrow-derived plasma cells from a patient (Wil) who had AL amyloidosis and renal amyloid deposits; the second was from a patient (Jto) with multiple myeloma in whom the lambda 6 protein was deposited not as amyloid but in the form of renal tubular casts. The thermodynamic stabilities of rV lambda 6Wil and -Jto were determined from chaotropic and thermal denaturation studies. Based upon the Delta GH2O, Delta H, Delta G25 degrees C, Tm, and Cm values, the rV lambda 6Wil was less stable than its nonamyloidogenic counterpart, rV lambda 6Jto. Measurement of fibril formation using a novel in vitro fibril forming assay demonstrated that although both rV lambda 6 proteins formed fibrils in vitro, Wil had a shorter lag time and exhibited faster kinetics under physiologic conditions. Comparative amino acid sequence analyses of these two components and other lambda 6 amyloid-associated light chains revealed that the Jto protein had certain primary structural features that we posit contributed to its increased stability and thus rendered this protein nonamyloidogenic. Our studies provide the first evidence that stabilizing interactions within the V L domain can influence the kinetics of light chain fibrillogenicity.
Amino Acid Sequence↗
Oligomeric complexes link Rab5 effectors with NSF and drive membrane fusion via interactions between EEA1 and syntaxin 13.
SNAREs and Rab GTPases cooperate in vesicle transport through a mechanism yet poorly understood. We now demonstrate that the Rab5 effectors EEA1 and Rabaptin-5/Rabex-5 exist on the membrane in high molecular weight oligomers, which also contain NSF. Oligomeric assembly is modulated by the ATPase activity of NSF. Syntaxin 13, the t-SNARE required for endosome fusion, is transiently incorporated into the large oligomers via direct interactions with EEA1. This interaction is required to drive fusion, since both dominant-negative EEA1 and synthetic peptides encoding the FYVE Zn2+ finger hinder the interaction and block fusion. We propose a novel mechanism whereby oligomeric EEA1 and NSF mediate the local activation of syntaxin 13 upon membrane tethering and, by analogy with viral fusion proteins, coordinate the assembly of a fusion pore.
Adenosine Triphosphatases↗
Effects of tamoxifen and toremifene on ALDH1 and ALDH3 in human retinal pigment epithelial cells and rat liver.
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Aldehyde Dehydrogenase↗
T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism: implications for tubule formation.
Neovascularization frequently accompanies chronic immune responses characterized by T cell infiltration and activation. Angiogenesis requires endothelial cells (ECs) to penetrate extracellular matrix, a process that involves matrix metalloproteinases (MMPs). We report here that activated human T cells mediate contact-dependent expression of MMPs in ECs through CD40/CD40 ligand signaling. Ligation of CD40 on ECs induced de novo expression of gelatinase B (MMP-9), increased interstitial collagenase (MMP-1) and stromelysin (MMP-3), and activated gelatinase A (MMP-2). Recombinant human CD40L induced expression of MMPs by human vascular ECs to a greater extent than did maximally effective concentrations of interleukin-1beta or tumor necrosis factor-alpha. Moreover, activation of human vascular ECs through CD40 induced tube formation in a three-dimensional fibrin matrix gel assay, an effect antagonized by a MMP inhibitor. These results demonstrated that activation of ECs by interaction with T cells induced synthesis and release of MMPs and promoted an angiogenic function of ECs via CD40L-CD40 signaling. As vascular cells at the sites of chronic inflammation, such as atherosclerotic plaques, express CD40 and its ligand, our findings suggest that ligation of CD40 on ECs can mediate aspects of vascular remodeling and neovessel formation during atherogenesis and other chronic immune reactions.
CD40 Antigens↗
Measuring outcomes in children's rehabilitation: a decision protocol.
OBJECTIVE: To develop and test the feasibility and clinical utility of a computerized self-directed software program designed to enable service providers in children's rehabilitation to make decisions about the most appropriate outcome measures to use in client and program evaluation. DESIGN: A before-and-after design was used to test the feasibility and initial impact of the decision-making outcome software in improving knowledge and use of clinical outcome measures. SETTING: A children's rehabilitation center in a city of 50,000. PARTICIPANTS: All service providers in the children's rehabilitation center. Disciplines represented included early childhood education, occupational therapy, physical therapy, speech and language pathology, audiology, social work, and psychology. INTERVENTION: Using a conceptual framework based on the International Classification of Impairment, Disability, and Handicap (ICIDH), an outcome measurement decision-making protocol was developed. The decision-making protocol was computerized in an educational software program with an attached database of critically appraised measures. Participants learned about outcome measures through the program and selected outcome measures that met their specifications. The computer software was tested for feasibility in the children's rehabilitation center for 6 months. OUTCOME MEASURES: Knowledge and use of clinical outcome measures were determined before and after the feasibility testing using a survey of all service providers currently at the centre and audits of 30 randomly selected rehabilitation records (at pretest, posttest, and follow-up). RESULTS: Service providers indicated that the outcomes software was easy to follow and believed that the use of the ICIDH framework helped them in making decisions about selecting outcome measures. Results of the survey indicated that there were significant changes in the service providers' level of comfort with selecting measures and knowing what measures were available. Use of outcome measures as identified through the audit did not change. CONCLUSIONS: The "All About Outcomes" software is clinically useful. Further research should evaluate whether using the software affects the use of outcome measures in clinical practice.
Child↗
Loss of olfactory function in dementing disease.
Alzheimer's (AD) patients show neuropathological changes in areas of the brain central to olfactory processing, suggesting the theoretical importance and potential diagnostic utility of investigating functional changes in olfaction in these patients. Persons with Down's Syndrome who live to the fourth decade develop neuropathological changes in the brain similar to those found in AD. A series of investigations have been conducted to assess olfaction function in both patients with Alzheimer's disease and persons with Down's Syndrome. Functional testing included olfactory threshold, odor identification, odor similarity judgements, odor recognition memory, odor recall, odor fluency. Both Alzheimer's patients and persons with Down's Syndrome showed significant impairment in olfactory function, with some measures showing more impairment than others in the early stages of the disease process. Longitudinal investigation of several of the measures indicated decreased function over time consonant with falling DRS scores. Normal controls who tested positive for the APOE4 allele showed impaired odor identification compared to those who were allele negative. Patients with Huntington's Disease showed olfactory functional impairments, although the degree of impairment differed from the cortical dementias for some of these tasks. The sensitivity and specificity of these assessments will be discussed in relation to analogous assessments in other sensory modalities.
Alzheimer Disease↗
A demonstration of classical conditioning of the human eyeblink to an olfactory stimulus.
While acquisition of the eyeblink conditioned response to a variety of stimuli has been widely studied, it has yet to be established that humans will demonstrate a conditioned response to an olfactory stimulus. In this study we present data to show that humans will demonstrate a classically conditioned eyeblink response to an olfactory stimulus. Ten participants were tested in a delay conditioning procedure with an olfactory stimulus presented in a heated, humidified stream of air via an olfactometer, allowing the precise control over stimulus duration necessary for delay conditioning. Trials on which odor alone was presented were administered to four additional participants. Establishing that humans will demonstrate an eyeblink conditioned response to an olfactory stimulus will allow further exploration of the pathways involved in classical conditioning and associative learning, as well as an analysis of conditioning pathways across sensory modalities.
Adult↗
Normal aging and odor intensity effects on the olfactory event-related potential.
Olfactory event-related potentials (OERPs) were recorded in 14 young and 14 older adults, with odor strength of isoamyl acetate manipulated to assess olfactory stimulus intensity. Young participants produced significantly larger N1/P2, N2/P3 amplitudes and shorter N1, P2 and N2 latencies than older participants. Medium- and high-odor concentrations elicited significantly shorter P2 and N2 latencies than the lowest concentration for both age groups. Odor concentration appears to affect the speed of olfactory stimulus information processing regardless of age.
Adult↗
Individuals with Down's syndrome demonstrate abnormal olfactory event-related potentials.
OBJECTIVE: Recent research has demonstrated that individuals with Down's syndrome (DS) develop plaques and tangles in the brain similar to people with Alzheimer's disease. As a result, they show increased dementia and decreased olfactory functioning compared to healthy individuals. The olfactory event-related potential (OERP) has been used as an objective quantitative measure of olfactory functioning in normal and clinical populations. The present study investigated the utility of the latency and amplitude of the OERP components in examining olfactory dysfunction in DS individuals. METHODS: OERPs were recorded monopolarly at the Fz, Cz and Pz electrode sites, using amyl acetate at a 60 s inter-stimulus interval, from individuals with DS (mean age 26.0 years) and age-matched normal controls. Participants were screened for nasal health and odor thresholds were assessed. Dementia was assessed using the dementia rating scale (DRS). RESULTS: Results indicate that DS subjects have significantly longer latencies in the sensory (N1, P2, and N2) and cognitive (P3) components of the OERP than normal controls. Odor threshold was significantly associated with sensory OERP components. In addition, DS subjects with a higher level of dementia showed significantly longer P3 latencies than those with lower dementia levels. CONCLUSIONS: The study suggests that the OERP may be a useful measure of olfactory dysfunction in DS which may precede developing dementia in this population.
Adult↗
Olfactory P3 in young and older adults.
Olfactory event-related potentials (OERPs) were recorded monopolarly at the Fz, Cz, and Pz electrode sites in 16 young adults and 16 older adults to assess aging effects on the olfactory P3. Amyl acetate was used to elicit the OERPs, with an intertrial interval of 45 s. Young adults produced significantly larger P3 amplitudes and shorter P3 peak latencies than older adults. The olfactory P3 response appears to be sensitive to age-related changes in the olfactory system and may reflect cognitive slowing in the central nervous system.
Adult↗
Odor detection, learning, and memory in Huntington's disease.
We compared 7 mildly affected Huntington's disease (HD) patients to 7 age- and education-matched healthy controls (NC) on an odor detection test, the California Odor Learning Test, and the California Verbal Learning Test. Results demonstrated that odor detection sensitivity, but not group membership, accounted for significant variance in total olfactory learning. Both groups learned fewer items in the olfactory modality compared to the verbal modality, but retained a similar amount following a delay. No group differences were demonstrated for verbal recognition discriminability, but the HD group demonstrated significantly impaired odor recognition discriminability. Finally, odor detection provided excellent classification sensitivity and specificity between the patients and controls, suggesting that olfactory testing may provide a sensitive measure of the early disease process in HD.
Cognition Disorders↗
The 20% rule: a simple, instantaneous radioactivity measurement defines cure and allows elimination of frozen sections and hormone assays during parathyroidectomy.
BACKGROUND: Although primary hyperparathyroidism is a physiologic disease, surgeons rely on anatomical characteristics (gross and histologic) to determine appropriate operative decisions. After the development of radioguided parathyroidectomy, we hypothesized that the amount of radioactivity contained within resected tissue would be the only information needed to establish the nature of the tissue and to determine a cure for the disease. METHODS: A total of 1290 tissue specimens were obtained from 345 patients who had sporadic primary hyperparathyroidism. Ex-vivo radioactivity, in counts per second, was measured in parathyroid and other tissues within 3.5 hours of sestamibi injection. Background radioactivity was measured after tissue excision, and ratios were calculated. RESULTS: Lymph nodes, normal parathyroids, and fat never contained more than 2.2% of background radioactivity, whereas thyroid and hyperplastic parathyroids contained 5.5% and 7.5%, respectively, and never more than 16%. In contrast, adenomas contained 59% +/- 9% of background radioactivity (P < .000001 vs all other tissues), with a range of 18% to 136%. CONCLUSIONS: Radioactive ratios are an instantaneous measure of metabolic activity, thereby determining parathyroid function. Any excised tissue containing more than 20% of background radioactivity in a patient with a positive sestamibi scan result is a solitary parathyroid adenoma. This alleviates the need to identify other glands, obtain frozen sections, or measure serum parathyroid hormone levels intraoperatively.
Adenoma↗
Neuropsychological performance and cognitive olfactory event-related brain potentials in young and elderly adults.
The P3 event-related brain potential (ERP) reflects neuroelectric activity related to the speed of cognitive processing and allocation of attentional resources. The objective of the present study was to assess the relationship between the P3 and Slow Wave components of the olfactory event-related potential (OERP) with neuropsychological performance in young (n = 16) and elderly (n = 16) adults. OERPs were recorded monopolarly from midline electrode sites while subjects estimated the odor magnitude of each stimulus, eliciting highly reproducible P3s. Results showed that the late cognitive components (P3 amplitude, P3 latency and Slow Wave area) decline with age and that this decreased neuronal efficiency is associated with reductions in the neuropsychological performance indexed by the Trail Making Test and the California Verbal Learning Test.
Adult↗
A test of odor fluency in patients with Alzheimer's and Huntington's disease.
In the present study, an olfactory analog to the verbal fluency test was designed and administered to 40 patients with Alzheimer's disease (AD) and 11 patients with Huntington's disease (HD). Because onset of AD is typically in the sixties while onset of HD is typically in the mid-thirties, the patient groups had their own control group, an older (ONC) and younger (YNC) control group, respectively. Both control groups included 40 participants who were age- and education-matched to their respective patient group. Odor threshold, odor identification, and odor fluency measures were administered to each participant. Results of the study indicate that patients with dementia perform more poorly on all three measures of olfactory functioning. Our results suggest that tests of odor memory show differential performance in healthy and demented patients, leading to the suggestion that tests of olfactory functioning may be useful in detection and diagnosis of neurodegenerative disease.
Adult↗
Assembly of the nuclear transcription and processing machinery: Cajal bodies (coiled bodies) and transcriptosomes.
We have examined the distribution of RNA transcription and processing factors in the amphibian oocyte nucleus or germinal vesicle. RNA polymerase I (pol I), pol II, and pol III occur in the Cajal bodies (coiled bodies) along with various components required for transcription and processing of the three classes of nuclear transcripts: mRNA, rRNA, and pol III transcripts. Among these components are transcription factor IIF (TFIIF), TFIIS, splicing factors, the U7 small nuclear ribonucleoprotein particle, the stem-loop binding protein, SR proteins, cleavage and polyadenylation factors, small nucleolar RNAs, nucleolar proteins that are probably involved in pre-rRNA processing, and TFIIIA. Earlier studies and data presented here show that several of these components are first targeted to Cajal bodies when injected into the oocyte and only subsequently appear in the chromosomes or nucleoli, where transcription itself occurs. We suggest that pol I, pol II, and pol III transcription and processing components are preassembled in Cajal bodies before transport to the chromosomes and nucleoli. Most components of the pol II transcription and processing pathway that occur in Cajal bodies are also found in the many hundreds of B-snurposomes in the germinal vesicle. Electron microscopic images show that B-snurposomes consist primarily, if not exclusively, of 20- to 30-nm particles, which closely resemble the interchromatin granules described from sections of somatic nuclei. We suggest the name pol II transcriptosome for these particles to emphasize their content of factors involved in synthesis and processing of mRNA transcripts. We present a model in which pol I, pol II, and pol III transcriptosomes are assembled in the Cajal bodies before export to the nucleolus (pol I), to the B-snurposomes and eventually to the chromosomes (pol II), and directly to the chromosomes (pol III). The key feature of this model is the preassembly of the transcription and processing machinery into unitary particles. An analogy can be made between ribosomes and transcriptosomes, ribosomes being unitary particles involved in translation and transcriptosomes being unitary particles for transcription and processing of RNA.
Animals↗