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Biomedical subjects

Michael J Murray

Publications and source records attributed to Michael J Murray.

At least 19 recordsLinked to original sources
PubMed2006

The Fes/Fer non-receptor tyrosine kinase cooperates with Src42A to regulate dorsal closure in Drosophila.

Fes/Fer non-receptor tyrosine kinases regulate cell adhesion and cytoskeletal reorganisation through the modification of adherens junctions. Unregulated Fes/Fer kinase activity has been shown to lead to tumours in vivo. Here, we show that Drosophila Fer localises to adherens junctions in the dorsal epidermis and regulates a major morphological event, dorsal closure. Mutations in Src42A cause defects in dorsal closure similar to those seen in dfer mutant embryos. Furthermore, Src42A mutations enhance the dfer mutant phenotype, suggesting that Src42A and DFer act in the same cellular process. We show that DFer is required for the formation of the actin cable in leading edge cells and for normal rates of dorsal closure. We have isolated a gain-of-function mutation in dfer (dfergof) that expresses an N-terminally fused form of the protein, similar to oncogenic forms of vertebrate Fer. dfergof blocks dorsal closure and causes axon misrouting. We find that in dfer loss-of-function mutants beta-catenin is hypophosphorylated, whereas in dfergof beta-catenin is hyperphosphorylated. Phosphorylated beta-catenin is removed from adherens junctions and degraded, thus implicating DFer in the regulation of adherens junctions.

Adherens Junctions↗
PubMed2006

A novel methionine aminopeptidase-2 inhibitor, PPI-2458, inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo.

PURPOSE: Fumagillin and related compounds have potent antiproliferative activity through inhibition of methionine aminopeptidase-2 (MetAP-2). It has recently been reported that MetAP-2 is highly expressed in germinal center B cells and germinal center-derived non-Hodgkin's lymphomas (NHL), suggesting an important role for MetAP-2 in proliferating B cells. Therefore, we determined the importance of MetAP-2 in normal and transformed germinal center B cells by evaluating the effects of MetAP-2 inhibition on the form and function of germinal centers and germinal center-derived NHL cells. EXPERIMENTAL DESIGN: To examine the activity of PPI-2458 on germinal center morphology, spleen sections from cynomolgus monkeys treated with oral PPI-2458 were analyzed. Antiproliferative activity of PPI-2458 was assessed on germinal center-derived NHL lines in culture. A MetAP-2 pharmacodynamic assay was used to determine cellular MetAP-2 inhibition following PPI-2458 treatment. Finally, inhibition of MetAP-2 and proliferation by PPI-2458 was examined in the human SR NHL line in culture and in implanted xenografts. RESULTS: Oral PPI-2458 caused a reduction in germinal center size and number in lymphoid tissues from treated animals. PPI-2458 potently inhibited growth (GI(50) = 0.2-1.9 nmol/L) of several NHL lines in a manner that correlated with MetAP-2 inhibition. Moreover, orally administered PPI-2458 significantly inhibited SR tumor growth, which correlated with inhibition of tumor MetAP-2 (>85% at 100 mg/kg) in mice. CONCLUSIONS: These results show the potent antiproliferative activity of PPI-2458 on NHL lines in vitro and oral antitumor activity in vivo and suggest the therapeutic potential of PPI-2458 as a novel agent for treatment of NHL should be evaluated in the clinical setting.

Aminopeptidases↗
PubMed2005

Gastric ulcer development in horses in a simulated show or training environment.

OBJECTIVE: To determine whether conditions representing activities that are typical in the recreational use of horses, including transport to and from show grounds, stall confinement in unfamiliar surroundings, and light exercise, are associated with increased incidence of gastric ulcers in horses. DESIGN: Randomized controlled study. ANIMALS: 20 client-owned horses. PROCEDURE: Horses had no gastric ulcers as determined by endoscopic examination on study day -1. Ten control horses were maintained on-site with no changes in management variables. Ten horses were transported via trailer for 4 hours on day 0 to another site, placed in individual stalls, fed twice daily, and exercised twice daily for 3 days. On day 4, they were transported back to the original site via trailer for 4 hours. On day 5, endoscopic examinations were performed on all horses to assess gastric mucosa status. RESULTS: Horses that were transported and housed off-site had a significantly higher incidence of hyperkeratosis and reddening of the gastric mucosa than control horses. Two control horses and 7 transported horses developed gastric ulcers by day 5. Ulcer scores of transported horses increased significantly from day -1, whereas ulcer scores in control horses did not change significantly from day -1. CONCLUSIONS AND CLINICAL RELEVANCE: Activities that are typical in recreational use of horses were ulcerogenic, and ulcers in the gastric squamous mucosa can develop under these conditions within 6 days.

Animals↗
PubMed2004

The epithelial-mesenchymal transition of the Drosophila mesoderm requires the Rho GTP exchange factor Pebble.

Drosophila pebble (pbl) encodes a Rho-family GTP exchange factor (GEF) required for cytokinesis. The accumulation of high levels of PBL protein during interphase and the developmentally regulated expression of pbl in mesodermal tissues suggested that the primary cytokinetic mutant phenotype might be masking other roles. Using various muscle differentiation markers, we found that Even skipped (EVE) expression in the dorsal mesoderm is greatly reduced in pbl mutant embryos. EVE expression in the dorsalmost mesodermal cells is induced in response to DPP secreted by the dorsal epidermal cells. Further analysis revealed that this phenotype is likely to be a consequence of an earlier defect. pbl mutant mesodermal cells fail to undergo the normal epithelial-mesenchymal transition (EMT) and dorsal migration that follows ventral furrow formation. This phenotype is not a secondary consequence of failed cytokinesis, as it is rescued by a mutant form of pbl that does not rescue the cytokinetic defect. In wild-type embryos, newly invaginated cells at the lateral edges of the mesoderm extend numerous protrusions. In pbl mutant embryos, however, cells appear more tightly adhered to their neighbours and extend very few protrusions. Consistent with the dependence of the mesoderm EMT and cytokinesis on actin organisation, the GTP exchange function of the PBL RhoGEF is required for both processes. By contrast, the N-terminal BRCT domains of PBL are required only for the cytokinetic function of PBL. These studies reveal that a novel PBL-mediated intracellular signalling pathway operates in mesodermal cells during the transition from an epithelial to migratory mesenchymal morphology during gastrulation.

Animals↗
PubMed2004

Late-life action tremor in a southern sea otter (enhydris lutris nereis).

Although tremor is highly prevalent in human beings, there are few reports of tremor occurring in other mammals. Such tremor can further our insight into the mechanisms and anatomical basis of human tremor disorders. We report on a southern sea otter with a slowly progressive 6.5 to 8.5 Hz action tremor of late life that shared several clinical characteristics with essential tremor. The main pathological finding was in the cerebellum, where there was extensive vacuolation of Purkinje cells.

Age Factors↗
PubMed2004

Intraoperative management of aortic aneurysm surgery.

Managing the anesthesia of patients undergoing open aortic surgical repair is a great challenge. The anesthesiologist's role in myocardial,renal, and neurologic protection is crucial to the patient's overall outcome.Each case presents different challenges, and there is no one right way to manage the patient intraoperatively.

Anesthesia↗
PubMed2004

Vascular disease and inflammation.

The past decade has witnessed a dramatic shift in the understanding of the causes of atherosclerotic vascular disease. What was once considered to be a process of abnormal lipid deposition in the vascular wall is now understood to be a dynamic inflammatory process from inception through plaque growth, rupture and ultimately thrombosis. This article reviews the basic science research that supports this growing body of epidemiologic data and discusses the inflammatory markers that predict future clinical events,as well as the pharmacologic success in therapies that specifically target inflammation.

Animals↗
PubMed2004

A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women.

OBJECTIVE: To refine or redefine the traditional histologic criteria used to date the secretory phase endometrium. DESIGN: Randomized, observational study. SETTING: Academic clinical research center. PATIENT(S): One hundred and thirty healthy, regularly cycling, fertile volunteers, aged 18 to 35 years. INTERVENTION(S): Patients were randomized to undergo endometrial sampling and measurement of serum estradiol and progesterone 1 to 14 days after the midcycle urinary luteinizing hormone surge. Three gynecologic histopathologists objectively scored each tissue specimen for 32 distinct histologic features and dated the endometrium using traditional histologic criteria. MAIN OUTCOME MEASURE(S): The 32 features were evaluated for [1] temporally dependent variation, [2] the amplitude of variations in score observed across the secretory phase, and [3] interobserver variability. Additionally, traditional dating criteria were analyzed. RESULT(S): The traditional endometrial histologic dating criteria are much less temporally distinct and discriminating than originally described, due to considerable intersubject, intrasubject, and interobserver variability. Neither traditional dating criteria nor any combination of the best performing histologic features identified by our objective and systematic analyses could reliably distinguish any specific cycle day or narrow interval of days. CONCLUSION(S): Histologic endometrial dating does not have the accuracy or the precision necessary to provide a valid method for the diagnosis of luteal phase deficiency or to otherwise guide the clinical management of women with reproductive failure.

Adolescent↗
PubMed2004

Use of self-etching adhesives to seal resected apices.

The purpose of this study was to evaluate the sealing ability of four self-etching adhesives placed over blood-contaminated/uncontaminated resected root apices without root-end preparation. Extracted maxillary incisors and canines were randomly divided into four groups of 10 teeth each. After canal preparation and resection of the apex, four self-etching adhesives (Clearfil SE Bond, One-Up Bond F, Unifil Bond, and ABF) were applied over the control and contaminated surfaces. The roots were then subjected to 15 cm of water pressure to simulate periapical microleakage stress. Data were analyzed using a two-way repeated measures, ANOVA. Positive and negative controls responded as expected. Statistical analysis indicated that there were no significant differences in the sealing effectiveness among the adhesives applied to contaminated or uncontaminated groups. All contaminated groups had significantly higher leakage (p < 0.003) than their uncontaminated pairs.

Analysis of Variance↗
PubMed2004

What is taught, what is tested: findings and competency-based recommendations of the Undergraduate Medical Education Committee of the Society of Critical Care Medicine.

INTRODUCTION: Addressing an unexpected shortfall of intensivists requires early identification and training of appropriate personnel. The purpose of this study was to determine how U.S. medical students are currently educated and tested on acute care health principles. HYPOTHESIS/METHODS: A survey of critical care education with telephone follow-up was mailed to the deans of all 126 medical schools. Web site review of medical school curricula for critical care education was performed. Upon invited request, four members of the Undergraduate Medical Education Committee (UGMEC) reviewed 1,200 pool questions of step II of the U.S. Medical Licensing Examination (USMLE) given to graduating medical students for critical care content. Descriptive statistics are employed. RESULTS: Survey response rate was 49% and 88% by the second mailing with Web site review. Forty-five percent of U.S. medical schools responding had formal undergraduate critical care didactic curricula averaging 12 +/- 3 hrs: 60% were elective, 60% taught in the 4th year. Eighty percent of clinical ICU rotations offered were elective. Sixty percent of schools taught 11 key critical care procedures in the 3rd or 4th year; 17% required them to graduate. Nineteen percent of Step II USMLE questions had critical care content; 58% dealt with pulmonary or cardiac disease. CONCLUSIONS: Graduating medical students are tested (and licensed accordingly) on critical care knowledge, despite an inconsistent exposure to the discipline in medical school. The UGMEC has drafted competency-based recommendations for acute health care delivery that encourage mandatory didactic and procedural critical care training. The UGMEC recommends that critical care rotations with didactic curricula be required for undergraduate education and that acute care procedural skills be an important component of these curricula.

Clinical Competence↗
PubMed2004

Effect of omeprazole paste on intragastric pH in clinically normal neonatal foals.

OBJECTIVE: To evaluate the efficacy of omeprazole paste, a commonly used antiulcer drug, on intragastric pH in clinically normal neonatal foals. ANIMALS: 6 clinically normal foals between 5 and 14 days of age. PROCEDURE: Intragastric pH was recorded in each foal by use of a disposable antimony pH electrode with internal reference. Values for intragastric pH were recorded every 4 seconds by use of an ambulatory pH monitor. There were two 24-hour recordings of intragastric pH for each foal, with 24 hours between recordings. Foals were not administered any drugs during the first recording. Foals were administered omeprazole paste (4 mg/kg, PO) 1 hour after the start of the second recording. Mean pH was calculated for each hour of each 24-hour recording session. Hourly mean values were compared between the first and second 24-hour recordings. RESULTS: Complete data were obtained from 4 of 6 foals during the first 24-hour recording and 6 of 6 foals during the second 24-hour recording. Foals had significantly higher mean hourly intragastric pH for hours 2 to 22 following omeprazole administration, compared with corresponding hourly pH values in foals during the first recording. CONCLUSION AND CLINICAL RELEVANCE: Omeprazole paste can effectively increase intragastric pH in clinically normal neonatal foals within 2 hours after oral administration of the first dose and can be administered to neonatal foals at the rate of 4 mg/kg, PO, every 24 hours.

Administration, Oral↗
PubMed2004

Assessment of the efficacy of a single dose of a recombinant vaccine against West Nile virus in response to natural challenge with West Nile virus-infected mosquitoes in horses.

OBJECTIVE: To determine the onset of immunity after IM administration of a single dose of a recombinant canarypox virus vaccine against West Nile virus (WNV) in horses in a blind challenge trial. ANIMALS: 20 mixed-breed horses. PROCEDURE: Horses with no prior exposure to WNV were randomly assigned to 1 of 2 groups (10 horses/group). In 1 group, a recombinant canarypox virus vaccine against WNV was administered to each horse once (day 0). The other 10 control horses were untreated. On day 26, 9 treated and 10 control horses were challenged via the bites of mosquitoes (Aedes albopictus) infected with WNV. Clinical responses and WNV isolation were monitored for 14 days after challenge exposure; antibody responses against WNV after administration of the vaccine and challenge were also assessed in both groups. RESULTS: Following challenge via WNV-infected mosquitoes, 1 of 9 treated horses developed viremia. In contrast, 8 of 10 control horses developed viremia after challenge exposure to WNV-infected mosquitoes. All horses seroconverted after WNV challenge; compared with control horses, antibody responses in the horses that received the vaccine were detected earlier. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, a single dose of the recombinant canarypox virus-WNV vaccine appears to provide early protection against development of viremia after challenge with WNV-infected mosquitoes, even in the absence of measurable antibody titers in some horses. This vaccine may provide veterinarians with an important tool in controlling WNV infection during a natural outbreak or under conditions in which a rapid onset of protection is required.

Aedes↗
PubMed2004

Concentrations of gentamicin in serum and bronchial lavage fluid after once-daily aerosol administration to horses for seven days.

OBJECTIVE: To assess gentamicin concentrations in serum and bronchial lavage fluid (BLF) of horses during a 24-hour period after once-daily aerosol administration of gentamicin (GAER) for 7 days and the pattern and degree of bronchial tree inflammation associated with repeated GAER. ANIMALS: 13 healthy adult horses (9 geldings and 4 mares). PROCEDURE: The treatment group comprised 8 horses, and 5 horses were untreated control animals. Gentamicin (20 mL of gentamicin [50 mg/mL]) was administered via aerosol once daily for 7 days. Samples of serum and BLF were obtained from all horses before GAER and 0.5, 4, 8, and 24 hours after the final day of GAER. Gentamicin concentrations were determined for all samples from treated horses, and cytologic examinations were performed on all BLF samples. RESULTS: Peak median BLF gentamicin concentration detected at 0.5 hours was 2.50 microg/mL. Median serum gentamicin concentration was < 0.50 microg/mL at all time points. Significant differences were not observed in total nucleated cell counts or differential cell counts in BLF between groups at any time point. Neutrophil count in BLF for all horses was increased over baseline at 4 and 24 hours. CONCLUSIONS AND CLINICAL RELEVANCE: We did not detect evidence of gentamicin accumulation or respiratory inflammation after once-daily GAER for 7 days. This protocol appears unlikely to result in local or systemic toxicosis. Repeated daily GAER to horses appears to be a safe procedure and may have clinical use in the treatment of horses with bacterial infections of the airways.

Administration, Inhalation↗
PubMed2003

Temporal and morphologic characteristics of pinopod expression across the secretory phase of the endometrial cycle in normally cycling women with proven fertility.

OBJECTIVE: To assess the temporal and morphologic characteristics of pinopod expression on the surface of endometrium across the secretory phase, in LH-timed endometrial samples in normal, healthy women. DESIGN: Prospective, randomized study. SETTING: Academic teaching hospital. PATIENT(S): Sixty-eight healthy volunteers with proven fertility. INTERVENTION(S): Urinary LH-timed endometrial and blood sampling was performed on each subject on a randomly selected day of the secretory phase. MAIN OUTCOME MEASURE(S): Histologic dating, assessment of pinopods using scanning electron microscopy, and comparison with serum P levels. RESULT(S): Eighty-six endometrial tissue samples obtained from 68 subjects were evaluated under scanning electron microscopy. Pinopods were first observed on luteal day 5, corresponding with the onset of the midluteal phase increase in serum P levels. Pinopods persisted for the entire duration of the secretory phase, but their morphology changed as the cycle advanced. CONCLUSION(S): The present findings demonstrate that pinopods are a characteristic feature of the mid to late secretory phase endometrial epithelium, exhibit cycle-dependent changes in morphology, and are most prominent during the putative implantation interval.

Adolescent↗