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Biomedical subjects

C Murphy

Publications and source records attributed to C Murphy.

At least 19 recordsLinked to original sources
PubMed1999

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↗
PubMed1999

Traumatic brain injury assessed with olfactory event-related brain potentials.

Olfactory event-related potentials (OERPs) were evaluated to develop an objective, quantitative assessment of sensory and cognitive olfactory loss following traumatic brain injury (TBI). Subjects included 25 TBI patients and 25 age/gender-matched healthy controls. Following standard clinical evaluation of smell function, TBI patients were divided into three groups: 12 anosmics (loss of smell), 6 hyposmics (reduced smell), and 7 normosmics (normal smell). Cognitive ability was assessed using the Trail Making Test (A and B). OERPs were recorded monopolarly from midline electrode sites using an amyl acetate stimulus with a 60-second interstimulus interval; subjects estimated the magnitude of each odor stimulus. Anosmic TBI patients were also tested with OERPs using ammonia to ensure trigeminal nerve function. Amyl acetate OERPs demonstrated that the sensory N1 and P2 amplitudes and the cognitive P3 amplitudes were absent in the anosmic TBI patients and greatly reduced in the hyposmic and normosmic TBI patients compared to healthy controls. The trigeminal OERPs from the anosmic TBI patients were within normal limits, indicating that the primary olfactory deficits were objectively measured with OERPs. The relationship between the OERPs and neuropsychologic test performance supports the cognitive loss associated with TBI. The present study lends support to the utility of OERPs as an objective tool for measuring sensory and cognitive loss after traumatic brain injury.

Adult↗
PubMed1999

Macrophage-mediated lysis of a beta-cell line, tumour necrosis factor-alpha release from bacillus Calmette-Guérin (BCG)-activated murine macrophages and interleukin-8 release from human monocytes are dependent on extracellular glutamine concentration and glutamine metabolism.

Macrophages and monocytes are cells with a large capacity for cytokine production. Cytokines produced by these cells are not preformed and released upon stimulation, but must be transcribed and translated. Although much is known concerning the regulation of the latter processes at the molecular level, the role of exogenous amino acids in the secretory process has not been actively investigated. Glutamine is utilized by macrophages at a much faster rate than any other amino acid. The role for high rates of glutamine utilization in macrophages or monocytes is not fully understood. We demonstrate here that the rates of lipopolysaccharide-stimulated tumour necrosis factor-alpha secretion from bacillus Calmette-Guérin (BCG)-activated murine peritoneal macrophages and lipopolysaccharide-stimulated interleukin-8 production from human monocytes are dependent upon extracellular glutamine concentration. We also demonstrate that potent inhibition of cytokine production can be achieved by incubating macrophages or monocytes in the presence of the glutaminase inhibitor 6-diazo-5-oxo-norleucine. On co-culture of BCG-activated macrophages and the clonal pancreatic beta-cell line BRIN-BD11, macrophage-specific beta-cell death was significantly reduced on prior exposure of macrophages to 6-diazo-5-oxo-norleucine. Thus glutamine metabolism may be essential for generation of cytotoxic products from macrophages, including tumour necrosis factor-alpha.

Animals↗
PubMed1998

Age effects on central nervous system activity reflected in the olfactory event-related potential. Evidence for decline in middle age.

A series of studies in this laboratory using the olfactory event-related potential (OERP) have examined the underlying central nervous system activity associated with age-related changes in olfactory functioning. Early (sensory) components of the OERP showed reduced amplitude and longer latency in elderly subjects, with larger effects in males. Amplitudes are already decreased in middle age. The late cognitive component, P3, showed a longer latency as well as a decreased amplitude in the elderly, with effect sizes for age significantly larger for the late component than for the early components. We report here the significantly longer latency, particularly for the P3, in middle-aged persons, suggesting age-related slowing of olfactory information processing as early as the 50s. Results suggest that the elderly brain, and indeed, the middle-aged brain shows smaller responses to odors, is less able to allocate attentional resources and slows in its olfactory cognitive processing. The OERP is a potent reflection of these changes.

Adult↗
PubMed1998

Developmental effects on odor learning and memory in children.

The child version of the California Odor Learning Test (COLT) was designed to assess cognitive functioning in impaired and healthy children. The COLT's rationale was based on two assumptions. First, measures of cognitive functioning are a good index of severity or extent of brain damage if compared between normal and clinical populations. Second, the cognitive-mediated tasks of verbal odor recall, recognition and identification were suitable to evaluate cognitive functioning. The focus of this study was to determine the COLT's ability to detect developmental differences in odor learning and memory. The participants were 51 healthy children who were twice administered the COLT with a weekly delay between tests. They were ascribed to two age-groups (7-10 and 11-15 years old) according to levels of cognitive development. The COLT employed 22 common odors and included two sessions. In the first session, children learned two sets of six odors. The first set was presented three times, the second one once, during a single learning episode. Following learning, children recalled the odors of the first set by name at free recall and category-cued recall. The second session included the following tasks: long-term free odor recall and category-cued odor recall, odor recognition-memory and verbal odor identification. A series of analyses of variance (ANOVAs, p < 0.05) with age as between-subject variable and repeated measurements on recall revealed significant differences between the two groups on the number of odors correctly recalled by name both at free recall, category-cued recall, recognition and identification. There were differences in false alarms at odor recognition between the two groups. Children from both groups benefited from a learning effect over odor trials. A gender effect was found for odor free recall at retest. These results suggest that the COLT has the potential to serve as a useful tool in the assessment of cognitive functioning in children.

Adolescent↗
PubMed1998

Abnormality of semantic network in patients with Alzheimer's disease. Evidence from verbal, perceptual, and olfactory domains.

A series of studies was initiated to model the organization of semantic memory in Alzheimer's disease (AD) patients using multidimensional scaling (MDS) and Pathfinder analyses. The resulting models (cognitive maps or semantic networks) embed studied stimuli in a coordinate space or network where distances between points are assumed to reflect psychological proximity between items. The organization of semantic networks in verbal and sensory domains were modeled based upon the frequency of the subject's choice of two concepts as most alike. Results suggested that while the organization of concepts in the semantic networks of AD patients was primarily based upon a concrete perceptual dimension in both verbal and olfactory domains, those of normal controls subjects were predominantly organized by an abstract conceptual attribute. Also, networks of AD patients were more complex and chaotic than normal, that is, they consisted of more unnecessary connections and of atypical strengths of association between concepts.

Alzheimer Disease↗
PubMed1998

Odor memory in normal aging and Alzheimer's disease.

The ability in normal elderly to verbally recall previously presented odors and to learn this task across trials was studied by applying a design which compared performance on the California Verbal Learning Test (CVLT) with an analogous odor test. Results suggest that both immediate and delayed recall of odors, both free and cued, as well as the ability to learn across trials is impaired in normal aging, perhaps more so for olfaction than for audition, which can be referred to poor use of semantic-clustering strategies and poor identification. Olfactory decline in memory in normal aging is, however, far from as affected as in Alzheimer's disease (AD). Two studies of persons with questionable AD demonstrated significant deficits in both recognition memory and identification of odors. Although further research is required, the findings from these 'pre-clinical' cases imply that performance on olfactory-mediated tasks may contribute to early diagnosis of AD.

Aged↗
PubMed1998

Very early changes in olfactory functioning due to Alzheimer's disease and the role of apolipoprotein E in olfaction.

Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by memory loss and at least one other cognitive disturbance. Early diagnosis of the disease has proved difficult and has therefore been the focus of much research. Apolipoprotein E (ApoE), a protein manufactured and distributed throughout the body, has shown specificity of binding to the beta A4 peptide, the primary component in the senile plaques of AD. Furthermore, the ApoE, epsilon 4 (epsilon 4) allele, is overrepresented in AD. These two lines of evidence suggest that ApoE, specifically the epsilon 4 allele, plays an important role in the development of AD. Further support for this hypothesis appears in neuropsychological data showing cognitive decrements in ostensibly nondemented individuals with the epsilon 4 allele, compared to those without the allele. It is also well known that olfaction is compromised in AD. Thus, the purpose of this study was twofold: (1) to examine very early changes in olfactory functioning due to AD and (2) to examine the role of ApoE in olfactory functioning in people at risk for AD by virtue of early cognitive decline. Results demonstrated changes in olfactory threshold the year immediately preceding change in diagnosis from normal control to AD. Also, in individuals with mild cognitive impairment, those with the ApoE epsilon 4 allele show poorer thresholds than those without the epsilon 4 allele.

Aged↗
PubMed1998

Apolipoprotein E status is associated with odor identification deficits in nondemented older persons.

Alzheimer's disease (AD) patients with moderate dementia show losses in olfactory threshold, odor identification and odor memory. Sensitivity and specificity of olfactory testing is significant, with the greatest power of accurate diagnosis in the more cognitively loaded olfactory tasks. In patients with very mild AD or in patients at risk for the disease because of their mild cognitive impairment, losses are apparent for odor identification, odor recognition memory and odor threshold, with the best sensitivity in the identification task. Persons who are either heterozygous or homozygous for the epsilon 4 allele of apolipoprotein E (ApoE) have an increased risk of Alzheimer's disease, although they show no dementia in the preclinical period. Evidence of olfactory dysfunction in this population might be reflective of an incipient dementing process. We have recently examined olfactory function in a group of normal elderly persons who have undergone genetic testing for the Apoe4 allele. These individuals consisted of all normal control subjects at the University of California, San Diego (UCSD) Alzheimer's Disease Research Center (ADRC) who had undergone both the genetic testing and testing for olfactory function. All had been diagnosed as normal control participants by two different neurologists who applied the National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINDS-ADRDA) criteria for dementia. Persons with a history of alcoholism, drug abuse, learning disability or neurologic or psychiatric illness (including depression) were excluded. In this population, persons with the Apoe4 allele showed significantly poorer odor identification than those without an epsilon 4 allele. Early appearance of olfactory deficits in the progression to AD in persons with the epsilon 4 allele suggests diagnostic utility in olfactory testing.

Aged↗
PubMed1998

Rapid clinical evaluation of anosmia in children: the Alcohol Sniff Test.

Smell impairment affects 1-2% of Americans and leads to frequent physician visits. Olfactory functional testing is available in chemosensory centers, but is frequently omitted in routine cranial nerve examinations. A new smell test, using the standard 70% isopropyl alcohol pad, was developed at the UCSD Nasal Dysfunction Clinic: The Alcohol Sniff Test (AST). The current study examined the reliability of the AST in children, using test-retest measures. A standard 70% isopropyl alcohol pad was moved upward 1 cm per exhalation until the participant reported detection. Test-retest reliability of the AST in children was significant, r = 0.80. The AST predictably classified children as anosmic, hyposmic or normosmic, p < 0.0001. The AST requires only 5 minutes to administer with materials readily available in any physician's office or hospital. The AST is an effective screening tool, even in children, for the average physician who can then refer patients who show less than normal function for further comprehensive testing.

2-Propanol↗
PubMed1998

EEA1 links PI(3)K function to Rab5 regulation of endosome fusion.

GTPases and lipid kinases regulate membrane traffic along the endocytic pathway by mechanisms that are not completely understood. Fusion between early endosomes requires phosphatidylinositol-3-OH kinase (PI(3)K) activity as well as the small GTPase Rab5. Excess Rab5-GTP complex restores endosome fusion when PI(3)K is inhibited. Here we identify the early-endosomal autoantigen EEA1 which binds the PI(3)K product phosphatidylinositol-3-phosphate, as a new Rab5 effector that is required for endosome fusion. The association of EEA1 with the endosomal membrane requires Rab5-GTP and PI(3)K activity, and excess Rab5-GTP stabilizes the membrane association of EEA1 even when PI(3)K is inhibited. The identification of EEA1 as a direct Rab5 effector provides a molecular link between PI(3)K and Rab5, and its restricted distribution to early endosomes indicates that EEA1 may confer directionality to Rab5-dependent endocytic transport.

Androstadienes↗
PubMed1998

Rab17 regulates membrane trafficking through apical recycling endosomes in polarized epithelial cells.

A key feature of polarized epithelial cells is the ability to maintain the specific biochemical composition of the apical and basolateral plasma membrane domains while selectively allowing transport of proteins and lipids from one pole to the opposite by transcytosis. The small GTPase, rab17, a member of the rab family of regulators of intracellular transport, is specifically induced during cell polarization in the developing kidney. We here examined its intracellular distribution and function in both nonpolarized and polarized cells. By confocal immunofluorescence microscopy, rab17 colocalized with internalized transferrin in the perinuclear recycling endosome of BHK-21 cells. In polarized Eph4 cells, rab17 associated with the apical recycling endosome that has been implicated in recycling and transcytosis. The localization of rab17, therefore, strengthens the proposed homology between this compartment and the recycling endosome of nonpolarized cells. Basolateral to apical transport of two membrane-bound markers, the transferrin receptor and the FcLR 5-27 chimeric receptor, was specifically increased in Eph4 cells expressing rab17 mutants defective in either GTP binding or hydrolysis. Furthermore, the mutant proteins stimulated apical recycling of FcLR 5-27. These results support a role for rab17 in regulating traffic through the apical recycling endosome, suggesting a function in polarized sorting in epithelial cells.

Amino Acid Sequence↗
PubMed1998

Effects of nasal-airway volume and body temperature on intranasal chemosensitivity.

Interrelations between intranasal detection sensitivity for odor (H2S) and pain (CO2), nasal-airway volume (acoustic rhinometry), and body temperature were studied in young, healthy men across the diurnal cycle. The results showed a weak but statistically significant negative correlation between nasal volume and odor threshold and a weak but positive correlation between body temperature and odor threshold.

Adult↗
PubMed1998

Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro.

Mononuclear phagocytes play an important role in atherosclerosis and its sequela plaque rupture in part by their secretion of matrix metalloproteinases (MMPs), including MMP-9. Peroxisomal proliferator-activated receptor gamma (PPARgamma), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-delta12,14-prostaglandin J2 and the antidiabetic agent troglitazone. The role of PPARgamma in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPARgamma. Normal artery specimens (n = 6) reveal minimal immunoreactive PPARgamma. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPARgamma mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPARgamma mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPARgamma with troglitazone or 15-deoxy-delta12,14-prostaglandin J2 in human monocyte-derived macrophages inhibited MMP-9 gelatinolytic activity in a concentration-dependent fashion as revealed by zymography. This inhibition correlates with decreased MMP-9 secretion as determined by Western blotting. Thus, PPARgamma is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPARgamma is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.

Arteriosclerosis↗
PubMed1998

Adult susceptibility to varicella in the tropics is a rural phenomenon due to the lack of previous exposure.

In the industrialized countries of the West, varicella is largely a childhood disease, whereas reports from tropical countries indicate a significant incidence of varicella among adults. High ambient temperature, epidemiologic interference from other viruses, and race have been blamed. We tested our hypothesis that less exposure to varicella-zoster virus (VZV) during childhood in rural areas accounts for the reported greater frequency of varicella in adults in tropical climates by comparing rates of VZV seropositivity among urban and rural adult Bengalee populations living in identical climatic conditions in India. Only 5 (3.4%) of 153 urban adults were seronegative compared with 74 (31.1%) of 246 rural adults. Ninety-six percent of urban adults were immune by the age of 25, compared with 42% in the rural group. The results suggest that higher adult susceptibility to varicella is seen only in rural areas of the Tropics and is due to reduced transmission of VZV.

Adult↗
PubMed1998

Assembly of lampbrush chromosomes from sperm chromatin.

We have examined the behavior of demembranated sperm heads when injected into the germinal vesicle (GV) of amphibian oocytes. Xenopus sperm heads injected into Xenopus GVs swelled immediately and within hours began to stain with an antibody against RNA polymerase II (Pol II). Over time each sperm head became a loose mass of chromosome-like threads, which by 24-48 h resolved into individually recognizable lampbrush chromosomes (LBCs). Although LBCs derived from sperm are unreplicated single chromatids, their morphology and immunofluorescent staining properties were strikingly similar to those of the endogenous lampbrush bivalents. They displayed typical transcriptionally active loops extending from an axis of condensed chromomeres, as well as locus-specific "landmarks. " Experiments with [3H]GTP and actinomycin D demonstrated that transcription was not necessary for the initial swelling of the sperm heads and acquisition of Pol II but was required for maintenance of the lampbrush loops. Splicing was not required at any stage during formation of sperm LBCs. When Xenopus sperm heads were injected into GVs of the newt Notophthalmus, the resulting sperm LBCs displayed very long loops with pronounced Pol II axes, like those of the endogenous newt LBCs; as expected, they stained with antibodies against newt-specific proteins. Other heterologous injections, including sperm heads of the frog Rana pipiens and the zebrafish Danio rerio in Xenopus GVs, confirm that LBCs can be derived from taxonomically distant organisms. The GV system should help identify both cis- and trans-acting factors needed to convert condensed chromatin into transcriptionally active LBCs. It may also be useful in producing cytologically analyzable chromosomes from organisms whose oocytes do not go through a typical lampbrush phase or cannot be manipulated by current techniques.

Animals↗