Biomedical subjects

Christopher Murphy

Publications and source records attributed to Christopher Murphy.

7 recordsLinked to original sources

PubMed2006

Natriuretic peptides differentially attenuate thrombin-induced barrier dysfunction in pulmonary microvascular endothelial cells.

Previous studies have described a protective effect of atrial natriuretic peptide (ANP) against agonist-induced permeability in endothelial cells derived from various vascular beds. In the current study, we assessed the effects of the three natriuretic peptides on thrombin-induced barrier dysfunction in rat lung microvascular endothelial cells (LMVEC). Both ANP and brain natriuretic peptide (BNP) attenuated the effect of thrombin on increased endothelial monolayer permeability and significantly enhanced the rate of barrier restoration. C-type natriuretic peptide (CNP) had no effect on the degree of thrombin-induced monolayer permeability, but did enhance the restoration of the endothelial barrier, similar to ANP and BNP. In contrast, the non-guanylyl cyclase-linked natriuretic peptide receptor specific ligand, cyclic-atrial natriuretic factor (c-ANF), delayed the rate of barrier restoration following exposure to thrombin. All three natriuretic peptides promoted cGMP production in the endothelial cells; however, 8-bromo-cGMP alone did not significantly affect thrombin modulation of endothelial barrier function. ANP and BNP, but not CNP or c-ANF, blunted thrombin-induced RhoA GTPase activation. We conclude that ANP and BNP protect against thrombin-induced barrier dysfunction in the pulmonary microcirculation by a cGMP-independent mechanism, possibly by attenuation of RhoA activation.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2005

PKCdelta regulates endothelial basal barrier function through modulation of RhoA GTPase activity.

We have shown that PKCdelta enhanced microvascular endothelial basal barrier function, correlating with elevated RhoA GTPase activity and increased focal contact formation. In the current study, we investigated signaling pathways important in PKCdelta modulation of barrier function in unstimulated endothelial cell monolayers by assessing the effects of PKCdelta inhibition in endothelial cells (EC) derived from rat pulmonary artery (PAEC) and epididymus (FPEC). Rottlerin exposure or Ad PKCdeltadn infection significantly enhanced monolayer permeability in both EC. Immunofluorescence analyses demonstrated fewer stress fibers and focal contacts in rottlerin-treated or Ad PKCdeltadn-infected EC; yet, PKCdelta inhibition caused no significant changes in microtubule structures. These changes correlated with a reduction in both focal adhesion kinase (FAK) and RhoA GTPase activities. Microfilament stabilization significantly attenuated the focal contact and barrier disruptive effects of rottlerin. FAK overexpression did not blunt the effects of rottlerin-induced barrier dysfunction or stress fiber and focal contact disruption. Conversely, GFP-linked dominant active RhoA overexpression protected EC from stress fiber and focal contact disruption induced by both rottlerin exposure and overexpression of PKCdelta dominant negative protein. Additionally, PKCdelta immunoprecipitated with p190RhoGAP and p120RasGAP, modulators of RhoA activity. Thus, PKCdelta may regulate basal endothelial barrier function by stabilizing microfilaments and focal contacts by regulating RhoA GTPase activity through upstream modulators, p190RhoGAP and p120RasGAP.

Actin Cytoskeleton↗

PubMed2005

Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study.

Bardet-Biedl syndrome (BBS) and Laurence-Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype-phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1-68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co-ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype-phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs.

Adolescent↗

PubMed2004

Executive dysfunction, heart disease burden, and remission of geriatric depression.

This study investigated the relationship of executive impairment and heart disease burden to remission of major depression among elderly patients. A total of 112 elderly subjects suffering from major depression received treatment with citalopram at a target daily dose of 40 mg for 8 weeks. Diagnosis was assigned using the Research Diagnostic Criteria and the DSM-IV Criteria after an interview with the Schedule for Affective Disorders and Schizophrenia. Executive dysfunction was assessed with the Initiation/Perseveration subscale of the Dementia Rating Scale (DRS) and the Color-Word Stroop test. Medical burden, including heart disease burden, was rated with the Cumulative Illness Rating Scale, and disability with Philadelphia Multilevel Instrument. Both abnormal initiation/perseveration and abnormal Stroop scores were associated with low remission rates of geriatric depression. Similarly, heart disease burden and baseline severity of depression also predicted low remission rates. The relationship of heart disease burden to remission was not mediated by executive dysfunction. Impairment in other DRS cognitive domains, disability, medical burden unrelated to heart disease did not significantly influence the outcome of depression in this sample. Executive dysfunction and heart disease burden constitute independent vulnerability factors that increase the risk for chronicity of geriatric depression. The findings of this study provide the rationale for investigation of the role of specific frontostriatal-limbic pathways in predisposing to geriatric depression or worsening its course.

Aged↗

PubMed2003

Expression of glucosamine trisaccharides on the rat uterine surface is altered by clomiphene citrate. III. Relationship with implantation regimes and pregnancy.

The present study further elucidates the complex effects of a commonly-prescribed fertility drug upon a target organ in an animal model. In the human condition, its effects are rarely observed without the influence of endogenous ovarian hormones. The aim of the study was to investigate how the administration of a single dose of clomiphene citrate (CC) given prior to an implantation-priming sequence of ovarian hormones would affect the expression of surface oligosaccharides and membrane architecture of uterine epithelium. Ovariectomized rats were given a single dose of either 0.25 mg or 1.25 mg of CC prior to a hormone-priming regime of progesterone (P4) for 3 days with a single additional administration of oestradiol 17beta (E2) on day 3. Animals were killed 24 h after final treatment. Uterine tissue was labelled with the lectin Phytolacca americana conjugated with avidin, subsequently labelled with biotinylated ferritin and prepared for transmission electron microscopy. Results indicate that CC, when administered prior to the implantation hormone-priming regime, is able to act as a super oestrogen and upregulates expression of oligosaccharides on the plasma membrane surface and increases the density and length of microvilli on the surface of the cells when compared with other treatment regimes. Understanding of the effects of CC at the uterine level at the time of implantation enables manipulation of uterine receptivity to control fertility and to improve the outcome of assisted reproductive procedures.

Animals↗

PubMed2002

Refractive error and visual outcome after cataract extraction.

PURPOSE: To determine the range of biometry prediction error of the postoperative refraction and the visual outcome after cataract surgery. SETTING: Postgraduate teaching hospital. METHODS: Refraction and visual outcomes were recorded prospectively for a consecutive case series of 1817 cataract procedures. Complete preoperative and postoperative data were available for 1676 eyes (92.4%). The paired mean error of the difference between the predicted and achieved refraction, the percentages falling within +/-0.50 diopter (D), +/-1.00 D, and +/-2.00 D, and the values that contained 99% of data points were then calculated. The number that achieved a final Snellen visual acuity of 6/12 was determined in all eyes and in eyes without preoperative ocular comorbidity. This analysis was repeated in 1265 eyes that received a single intraocular lens (IOL) design (C10UB/C11UB) after phacoemulsification through a clear corneal incision. RESULTS: The paired mean error of the difference between the predicted and achieved postoperative refraction in all eyes was -0.32 D +/- 1.05 (SD); 72.3% of eyes were within +/-1.00 D of the planned refraction, with bounds of 99% of observation of +2.92 D and -3.98 D. In the single IOL group, the paired mean error was -0.32 +/- 0.94 D; 74.2% of eyes fell within +/-1.00 D of the planned refraction, with bounds of 99% of observation of +2.54 D and -3.81 D. Axial length did not determine the magnitude of the biometry prediction error. At discharge from the service, 86.9% of all eyes and 95.4% of eyes without preoperative ocular comorbidity achieved a final corrected Snellen acuity of 6/12. CONCLUSION: These data provide benchmark information that can be used to monitor clinical practice.

Aged↗

PubMedDate not supplied

Intervention programs for perpetrators of intimate partner violence: conclusions from a clinical research perspective.

In this article, the authors consider the empirical status of batterer intervention programs (BIPs) for male perpetrators of intimate partner violence (IPV). Recent reviews have reported only small average effect sizes for BIPs, with the small number of randomized trials showing little benefit of BIP attendance in preventing future abuse. The most widely adopted BIP intervention model has little empirical justification to support this dominance, yet states with standards governing the content of BIPs often mandate this approach as a contingency for state funding. Little data exist concerning the moderators and mediators of BIP effects on IPV recidivism, and a variety of factors threaten to impede future design advancements, including "turf" battles regarding the causes of IPV and limited funding outlets. Given this discouraging summary, the authors argue that research efforts concerning BIP effectiveness should borrow the design strategies and programmatic research efforts that have proven successful in psychotherapy research, in which significant advances have been made with regard to the evaluation and validation of empirically supported treatments for a wide variety of mental health problems. They conclude by calling for a new generation of IPV researchers to work across professional boundaries in a multidisciplinary manner to design the sophisticated evaluation studies that funding agencies would readily support, and that would provide the substantive answers to the many IPV-related public health questions that remain.

Battered Women↗