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Biomedical subjects

C Murphy

Publications and source records attributed to C Murphy.

At least 55 records · Page 3Linked to original sources
PubMed2000

An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia.

Activated protein C (APC) is a natural anticoagulant that plays a pivotal role in coagulation homeostasis. Severe inherited or acquired deficiency results in a clinical syndrome called purpura fulminans. In addition, APC also appears to have potent cytokine-modifying properties and is protective in animal models of sepsis. The dual functional properties of APC are particularly relevant to severe meningococcemia, where acquired PC deficiency is accompanied by multiorgan failure and purpura fulminans. The authors conducted an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicemia, purpura fulminans, and multiorgan failure. The morbidity and mortality were compared with predicted morbidity using the Glasgow Meningococcal Septicemia Prognostic Score. Thirty-six patients with a mean age of 12 years (range 3 months to 72 years) were enrolled in the study. The mean +/- SD for plasma PC was 18 +/- 7 IU/mL. PC was significantly lower than antithrombin or protein S and was also significantly lower than PC levels in a cohort of patients who developed meningococcemia without multiorgan failure and purpura fulminans. A total of 3 of 36 (8%) patients died, which compares favorably with predicted mortality of 18 of 36 (50%). Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the hospital, in comparison with the predicted amputation rate of 11 of 33 (30%). In conclusion, PC replacement therapy in severe meningococcal septicemia was associated with a reduction in predicted morbidity and mortality. The beneficial effect of PC replacement may reflect both the anticoagulant and anti-inflammatory properties of the PC pathway. (Blood. 2000;96:3719-3724)

Adolescent↗
PubMed2000

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice.

A physiological examination of mice harboring a null allele at the aryl hydrocarbon (Ah) locus revealed that the encoded aryl hydrocarbon receptor plays a role in the resolution of fetal vascular structures during development. Although the aryl hydrocarbon receptor is more commonly studied for its role in regulating xenobiotic metabolism and dioxin toxicity, a developmental role of this protein is supported by the observation that Ah null mice display smaller livers, reduced fecundity, and decreased body weights. Upon investigating the liver phenotype, we found that the decrease in liver size is directly related to a reduction in hepatocyte size. We also found that smaller hepatocyte size is the result of massive portosystemic shunting in null animals. Colloidal carbon uptake and microsphere perfusion studies indicated that 56% of portal blood flow bypasses the liver sinusoids. Latex corrosion casts and angiography demonstrated that shunting is consistent with the existence of a patent ductus venosus in adult animals. Importantly, fetal vascular structures were also observed at other sites. Intravital microscopy demonstrated an immature sinusoidal architecture in the liver and persistent hyaloid arteries in the eyes of adult Ah null mice, whereas corrosion casting experiments described aberrations in kidney vascular patterns.

Animals↗
PubMed2000

Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells.

The Rho-kinase inhibitor, Y-27632, inhibited in vitro chemotactic migration to bone marrow fibroblast conditioned media and metastatic growth in immune-compromised mice of highly invasive human prostatic cancer (PC3) cells. Y-27632 also reduced myosin light chain phosphorylation and markedly altered the morphology of cells that developed numerous processes containing microtubules. A strikingly different, rounded phenotype was induced by an inhibitor of myosin light chain kinase, ML9. The M(110-130) subunit of the myosin phosphatase that is regulated by Rho-kinase was present in PC3 cells that contained significantly more RhoA than the less invasive, LNCaP cells. Y-27632 also inhibited angiogenesis as measured by endothelial cell tube formation on Matrigel. We conclude that invasiveness of human prostate cancer is facilitated by the Rho/Rho-kinase pathway, and exploration of selective Rho-kinase inhibitors for limiting invasive progress of prostate cancer is warranted.

Amides↗
PubMed2000

Thermodynamic modulation of light chain amyloid fibril formation.

To obtain further insight into the pathogenesis of amyloidosis and develop therapeutic strategies to inhibit fibril formation we investigated: 1) the relationship between intrinsic physical properties (thermodynamic stability and hydrogen-deuterium (H-D) exchange rates) and the propensity of human immunoglobulin light chains to form amyloid fibrils in vitro; and 2) the effects of extrinsically modulating these properties on fibril formation. An amyloid-associated protein readily formed amyloid fibrils in vitro and had a lower free energy of unfolding than a homologous nonpathological protein, which did not form fibrils in vitro. H-D exchange was much faster for the pathological protein, suggesting it had a greater fraction of partially folded molecules. The thermodynamic stabilizer sucrose completely inhibited fibril formation by the pathological protein and shifted the values for its physical parameters to those measured for the nonpathological protein in buffer alone. Conversely, urea sufficiently destabilized the nonpathological protein such that its measured physical properties were equivalent to those of the pathological protein in buffer, and it formed fibrils. Thus, fibril formation by light chains is predominantly controlled by thermodynamic stability; and a rational strategy to inhibit amyloidosis is to design high affinity ligands that specifically increase the stability of the native protein.

Amino Acid Sequence↗
PubMed2000

Expression of the imprinted tumour-suppressor gene H19 is tightly regulated during normal haematopoiesis and is reduced in haematopoietic precursors of patients with the myeloproliferative disease polycythaemia vera.

cDNA subtraction was employed to uncover differences in gene expression between myeloproliferative polycythaemia vera (PV) and normal haematopoietic precursors. Following cDNA subtraction using mRNAs isolated from PV and normal CD34+/CD33- bone-marrow cells, expression of the tumour suppressor H19 was found to be low or absent in the PV sample. Low levels of H19 expression in PV patients were confirmed by in situ hybridization. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to examine expression in the pluripotent haematopoietic cell line FDCP-mix and single bone-marrow precursors, unambiguous IGF2 and H19 expression was demonstrated in normal haematopoietic precursors. Examination of individual bone-marrow precursors revealed that all IGF2-expressing haematopoietic precursors also co-expressed H19, indicating that H19 and IGF2 may be co-ordinately regulated during haematopoiesis. Analysis of FDCP-mix undergoing differentiation and single pluripotent and committed bone-marrow precursors revealed that the pattern of H19 expression coincided with the commitment to a single lineage. Taken together, these observations demonstrate that H19 and IGF2 are specifically expressed during haematopoiesis and that low levels of H19 expression are associated with PV and may contribute to the pathology of the disease.

Animals↗
PubMed2000

Symptoms of striatofrontal dysfunction contribute to disability in geriatric depression.

OBJECTIVE: To examine whether symptoms of striatofrontal dysfunction contribute to disability in geriatric depression. DESIGN: Cross-sectional evaluation of the relationship of specific cognitive impairments, psychomotor retardation, severity of depression, and medical burden to impairment of instrumental activities of daily living. SETTING: Inpatient and outpatient services of a psychiatric university hospital located in a suburban metropolitan area.Patients. One hundred and fifty elderly psychiatric inpatients and outpatients with major depression and cognitive function ranging from normal to moderate dementia. MEASURES: Psychomotor retardation was evaluated with the Hamilton retardation item and executive dysfunction was assessed with the initiation/perseveration (IP) domain of the Dementia Rating Scale. Disability, severity of depression and medical burden were assessed with the Instrumental Activities of Daily Living Index of the Multilevel Assessment Instrument, the Hamilton Depression Rating Scale and the Cumulative Illness Rating Scale-Geriatric, respectively. RESULTS: In the entire sample (N = 150) and in the non-demented subjects (N = 101), stepwise regression analyses revealed that IP and psychomotor retardation were associated with IADL impairment. Additionally, a 'striatofrontal component', which consisted of IP and psychomotor retardation was also significantly associated with IADL impairment in the whole sample, as well as in the non-demented patients. CONCLUSION: Clinical symptoms and neuropsychological findings associated with striatofrontal dysfunction contribute to disability in depressed elderly patients.

Activities of Daily Living↗
PubMed2000

RNA polymerase II in Cajal bodies of amphibian oocytes.

Cajal bodies (coiled bodies) are nuclear organelles that contain a variety of components required for transcription and processing of RNA. Cajal bodies in amphibian oocytes are stained by mAb H14, which recognizes the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II when the heptapeptide repeat is phosphorylated on serine-5. Oocytes were treated with the transcription inhibitor 5, 6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), which prevents phosphorylation of the CTD. Cajal bodies from oocytes that had been treated for 2-3 h with DRB no longer stained with mAb H14, but staining reappeared when the inhibitor was washed out. Epitope-tagged transcripts of two small subunits of polymerase II, RPB6 and RPB9, were injected into the cytoplasm of Xenopus and Triturus oocytes. Newly translated RPB6 and RPB9 were specifically targeted to Cajal bodies within 4 h, and Cajal bodies remained the site of highest concentration of tagged protein during the next 2 days. These data suggest that polymerase subunits pass through the Cajal bodies with a transit time no greater than a few hours. We discuss the possibility that Cajal bodies are sites of assembly or modification of the transcription machinery of the nucleus.

Animals↗
PubMed2000

MYCN oncogene and angiogenesis: down-regulation of endothelial growth inhibitors in human neuroblastoma cells. Purification, structural, and functional characterization.

Angiogenesis, the formation of new blood vessels, is seen during embryonic development and tumor progression, but the mechanisms have remained unclear. Recent data indicate that tumor angiogenesis can be induced by cellular oncogenes, leading to the enhanced activity of molecules stimulating angiogenesis. However, activated oncogenes might also facilitate angiogenesis by down-regulating endogenous inhibitors of angiogenesis. We report here that enhanced expression of the N-myc oncogene in human neuroblastoma cells down-regulates three inhibitors of endothelial cell proliferation. One of them was identified by amino acid sequencing as being identical with activin A, a developmentally-regulated protein. Down-regulation involves interaction of the N-myc protein with the activin A promoter. Work is ongoing to characterize the other two endothelial cell inhibitors. We suggest that the N-myc induced down-regulation of angiogenesis inhibitors could contribute to tumor angiogenesis.

Activins↗
PubMed2000

Event-related brain potentials to attended and ignored olfactory and trigeminal stimuli.

Event-related brain potentials (ERPs) were recorded from 26 young adults, with equal numbers of male and female subjects, using attended and ignored, olfactory and trigeminal stimuli. The amplitudes and latencies of the N1, P2, and P3 components were recorded using a single-stimulus paradigm, with an inter-stimulus interval of 60 s, employing amyl acetate as the olfactory stimulus and ammonia as the trigeminal stimulus. Subjects estimated stimulus intensity in the attend condition or continued with a visual tracking task in the ignore condition. Results indicate that olfactory information is processed 30-70 ms faster than trigeminal information for the N1 and P2 potential and 100 ms faster for the P3 ERP component. N1/P2 interpeak amplitude was greater for the trigeminal than the olfactory stimuli, and greater in the attended than ignored condition. P3 amplitude was greater in the attend than ignore condition for olfactory information processing and equivalent for trigeminal information processing. These findings suggest that neuronal resource allocation is greatest for attended stimuli and that a painful stimulus demands neuronal resources even when ignored.

Adult↗
PubMed2000

Olfactory event-related potentials and aging: normative data.

Unlike the clinical usages of evoked potentials (e.g. brain stem auditory evoked potentials for the assessment of auditory function), normative data for the olfactory event-related potential (OERP) have been unavailable. The principal objective was to establish normative data across the human life span for OERPs with a given set of parameters. Participants were 140 persons from seven age groups (16-19, 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years of age), with equal numbers of males and females, screened for nasal health and dementia. The odor stimulus was amyl acetate, presented at nasal temperature in a humidified airstream delivered by an air-dilution olfactometer at a constant flow rate, using a 60-s inter-stimulus interval. OERPs were recorded at Fz, Cz, and Pz electrode sites, amplified and averaged over trials. Amplitudes of the N1/P2 and P3 and latencies of the P2 and P3 were analyzed. Processing speed decreased at a constant rate over decades for the sensory (P2 latency) as well as cognitive (P3 latency) components. Decline in amplitude over decades was also apparent. Normative data will be useful in research on olfactory function and in clinical assessment of olfactory functional status.

Adolescent↗
PubMed2000

Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line.

Activated protein C (APC) protects against sepsis in animal models and inhibits the lipopolysacharide (LPS)-induced elaboration of proinflammatory cytokines from monocytes. The molecular mechanism responsible for this property is unknown. We assessed the effect of APC on LPS-induced tumour necrosis factor alpha (TNF-alpha) production and on the activation of the central proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in a THP-1 cell line. Cells were preincubated with varying concentrations of APC (200 microg/ml, 100 microg/ml and 20 microg/ml) before addition of LPS (100 ng/ml and 10 microg/ml). APC inhibited LPS-induced production of TNF-alpha both in the presence and absence of fetal calf serum (FCS), although the effect was less marked with 10% FCS. APC also inhibited LPS-induced activation of NF-kappaB, with APC (200 microg/ml) abolishing the effect of LPS (100 ng/ml). The ability of APC to inhibit LPS-induced translocation of NF-kappaB is likely to be a significant event given the critical role of the latter in the host inflammatory response.

Analysis of Variance↗
PubMed2000

Standardising surveillance of nosocomial infections: the HISS program. Hospital Infection Standardised Surveillance.

Standardised surveillance of nosocomial infections in Australia had not been addressed until June 1998 when the New South Wales Health Department funded the development and implementation of the first standardised surveillance system for hospital infection: the Hospital Infection Standardised Surveillance program (HISS). The introduction of a standardised surveillance system needs to balance the requirements of a Health Department and the needs of hospitals. The Health Department requires data to develop aggregated rates for the setting of thresholds for all nosocomial infections while hospitals require rates to reflect the quality of clinical care and provide data for evidence-based infection control practices. The Hospital Infection Epidemiology and Surveillance (HIES) Unit has attempted to balance these requirements using a 'sentinel surveillance' approach with standardised definitions and methodology. The HISS program utilizes eICAT software modified for its standardised requirements of data collection. To date, 10 hospitals surveyed sentinel multiple resistant organisms (MRO), eight also elected sentinel surgical procedures (SSP) and intravascular device-related bacteraemia (IVDRB) modules, and two the seasonal respiratory syncytial (RSV) and rota-virus modules in paediatric patients. The surgical site infection rates in three commonly monitored SSP were 1.8% (95% confidence interval (CI) 0.7-3.9%) for coronary artery bypass (CABG), 3.3% (95% CI 1.4-6.8%) lower segment Caesarean section (LSCS) and 7.7% (95% CI 3.4-14.6%) colorectal surgery. The rate of IVDRB was 4.7 per 1000 central venous catheter days (95% CI 2.2-8.6) and 1.1 per 1000 peripheral line-days (95% CI 0.1-3.9). Methicillin resistant Staphylococcus aureus (MRSA) accounted for 99% of all new infections diagnosed with an endemic MRO.

Adolescent↗
PubMed2000

Train of four fade in a child with stiff baby syndrome.

A case is described of a child with stiff baby syndrome who underwent open reduction and femoral shortening of congenital dislocated hip under general anaesthesia. Neuromuscular function was measured electromyographically and demonstrated a great degree of train of four fade (57%) after sevoflurane inhalational induction of anaesthesia. The response to suxamethonium (2 mg x kg(-1)) was normal. The neuromuscular response to volatile anaesthetic agents and suxamethonium may be abnormal in these children with stiff baby syndrome and intraoperative neuromuscular monitoring is recommended.

Anesthesia, General↗
PubMed2000

Should we routinely use mupirocin to prevent staphylococcal infections?

Routine use of mupirocin to prevent staphylococcal infections is controversial. We assessed attitudes and practices of healthcare professionals attending the Fourth Decennial International Conference on Nosocomial and Healthcare-Associated Infections regarding mupirocin prophylaxis. Eighty percent of participants did not use mupirocin routinely. At the end of the session, 58% indicated they would consider increased use of mupirocin.

Anti-Bacterial Agents↗
PubMed2000

Clinical study and literature review of nasal irrigation.

OBJECTIVES/HYPOTHESIS: Nasal disease, including chronic rhinosinusitis and allergic rhinitis, is a significant source of morbidity. Nasal irrigation has been used as an adjunctive treatment of sinonasal disease. However, despite an abundance of anecdotal reports, there has been little statistical evidence to support its efficacy. The objective of this study was to determine the efficacy of the use of pulsatile hypertonic saline nasal irrigation in the treatment of sinonasal disease. STUDY DESIGN: A prospective controlled clinical study. METHODS: Two hundred eleven patients from the University of California, San Diego (San Diego, CA) Nasal Dysfunction Clinic with sinonasal disease (including allergic rhinitis, aging rhinitis, atrophic rhinitis, and postnasal drip) and 20 disease-free control subjects were enrolled. Patients irrigated their nasal cavities using hypertonic saline delivered by a Water Pik device using a commercially available nasal adapter twice daily for 3 to 6 weeks. Patients rated nasal disease-specific symptoms and completed a self-administered quality of well-being questionnaire before intervention and at follow-up. RESULTS: Patients who used nasal irrigation for the treatment of sinonasal disease experienced statistically significant improvements in 23 of the 30 nasal symptoms queried. Improvement was also measured in the global assessment of health status using the Quality of Well-Being scale. CONCLUSIONS: Nasal irrigation is effective in improving symptoms and the health status of patients with sinonasal disease.

Humans↗
PubMed2000

Sinonasal disease and olfactory impairment in HIV disease: endoscopic sinus surgery and outcome measures.

OBJECTIVES: To investigate the effects of ESS (ESS) on olfactory impairment, disease-specific symptoms, and general quality of well-being In HIV+ patients with sinonasal disease. STUDY DESIGN: Study 1: Nasal cytology, rhinomanometry, nasal examination including endoscopy, disease-specific sinonasal symptoms, olfactory threshold sensitivity, and odor identification testing were performed before and after ESS in HIV+ patients with sinonasal complaints. Study 2: Quality of well-being was assessed before and after ESS in HIV+ patients with sinonasal complaints and controls. RESULTS: Significant olfactory sensitivity loss persisted for patients with chronic sinusitis after ESS, suggesting that the impairment in these patients may be due to viral disease rather than inflammation. Significant improvement in other disease-specific symptom scores (nasal obstruction, nasal congestion, headache, sinus pain, etc.) and results of the general quality of well-being assessment showed ESS to be beneficial in the extended health management of HIV illness. CONCLUSIONS: The current study indicated both olfactory dysfunction and subjective negative symptoms in HIV+ patients with chronic sinusitis. Although olfactory dysfunction remained, ESS was successful in providing marked alleviation of symptomatology in HIV+ patients with chronic sinusitis. The results support ESS as an appropriate treatment option for HIV+ patients with chronic sinusitis.

Adult↗
PubMed2000

Phenotypic differences between African and white patients with motor neuron disease: a case-control study.

There is increasing evidence that race may affect the phenotype in some neurodegenerative diseases. To investigate this in motor neuron disease a retrospective case-control study has been carried out on 15 negroid African and 45 white patients with the disease seen over 8 years. Each African was compared with three age and sex matched white patients with motor neuron disease. There were no statistically significant differences in age of onset or the mean duration of disease in the two groups. The chance of presenting with the "flail arm" variant of motor neuron disease was four times as high in the African group than the white group (odds ratio 4.33, p=0. 05, 95% confidence interval 0.99-18.92). Although no overall differences in survival were seen between the two groups, in those with the flail arm variant, four out of the six African patients had died whereas all six white arm patients were alive at the censoring date of 1 January 1999 (median follow up 38.5 months). It is concluded that race may influence the phenotype and progression of motor neuron disease.

Africa↗