PubMed Health⌕ Search

Biomedical subjects

P Oh

Publications and source records attributed to P Oh.

At least 19 recordsLinked to original sources
PubMed2002

Health-related quality-of-life treatments for severe haemophilia: utility measurements using the Standard Gamble technique.

Prophylaxis for haemophilia improves outcomes, but at a substantial cost. Cost-utility analysis balances improvements seen in health-related quality of life (HRQoL) against costs, with the purpose of aiding healthcare decision-making. This analysis uses a measure of HRQoL known as utility. The objective of this study was to measure HRQoL (utility) values for states of health that result from on-demand therapy or prophylaxis. The HRQoL for different health states (including target joint bleeding, different intensities of prophylaxis, and indwelling intravenous catheters [ports]) was measured for healthy adults (n=30), parents of haemophilic children (n=30), and adults with haemophilia (n=28). Parents and patients rated health states similarly. Healthy adults gave the lowest ratings. The following rank, in order of HRQoL, was obtained: prophylaxis (low > medium > high) > on-demand therapy > prophylaxis with port> prophylaxis with infected port > on-demand therapy with development of a target joint. We conclude that: (1) haemophilia and its treatment reduce HRQoL; (2) prophylaxis is preferred to on-demand therapy; (3) intravenous ports substantially reduce HRQoL; (4) and an intravenous port to provide prophylaxis is preferable to on-demand therapy if a target joint develops.

Adult↗
PubMed2001

Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default.

Select lipid-anchored proteins such as glycosylphosphatidylinositol (GPI)-anchored proteins and nonreceptor tyrosine kinases may preferentially partition into sphingomyelin-rich and cholesterol-rich plasmalemmal microdomains, thereby acquiring resistance to detergent extraction. Two such domains, caveolae and lipid rafts, are morphologically and biochemically distinct, contain many signaling molecules, and may function in compartmentalizing cell surface signaling. Subfractionation and confocal immunofluorescence microscopy reveal that, in lung tissue and in cultured endothelial and epithelial cells, heterotrimeric G proteins (G(i), G(q), G(s), and G(betagamma)) target discrete cell surface microdomains. G(q) specifically concentrates in caveolae, whereas G(i) and G(s) concentrate much more in lipid rafts marked by GPI-anchored proteins (5' nucleotidase and folate receptor). G(q), apparently without G(betagamma) subunits, stably associates with plasmalemmal and cytosolic caveolin. G(i) and G(s) interact with G(betagamma) subunits but not caveolin. G(i) and G(s), unlike G(q), readily move out of caveolae. Thus, caveolin may function as a scaffold to trap, concentrate, and stabilize G(q) preferentially within caveolae over lipid rafts. In N2a cells lacking caveolae and caveolin, G(q), G(i), and G(s) all concentrate in lipid rafts as a complex with G(betagamma). Without effective physiological interaction with caveolin, G proteins tend by default to segregate in lipid rafts. The ramifications of the segregated microdomain distribution and the G(q)-caveolin complex without G(betagamma) for trafficking, signaling, and mechanotransduction are discussed.

Animals↗
PubMed2001

The role of effectors of the activin signalling pathway, activin receptors IIA and IIB, and Smad2, in patterning of tooth development.

The gene for activin betaA is expressed in the early odontogenic mesenchyme of all murine teeth but mutant mice show a patterning defect where incisors and mandibular molars fail to develop but maxillary molars develop normally. In order to understand why maxillary molar tooth development can proceed in the absence of activin, we have explored the role of mediators of activin signalling in tooth development. Analysis of tooth development in activin receptor II and Smad2 mutants shows that a similar tooth phenotype to activin betaA mutants can be observed. In addition, we identify a novel downstream target of activin signalling, the Iroquois-related homeobox gene, Irx1, and show that its expression in activin betaA mutant embryos is lost in all tooth germs, including the maxillary molars. These results strongly suggest that other transforming growth factor beta molecules are not stimulating the activin signalling pathway in the absence of activin. This was confirmed by a non-genetic approach using exogenous soluble receptors to inhibit all activin signalling in tooth development, which reproduced the genetic phenotypes. Activin, thus, has an essential role in early development of incisor and mandibular molar teeth but this pathway is not required for development of maxillary molars.

Activin Receptors, Type II↗
PubMed2001

The relationship of insulin resistance measured by reliable indexes to coronary artery disease risk factors and outcomes--a systematic review.

OBJECTIVES: To provide a qualitative and quantitative review of the published literature that examines the relationship between reliable markers of insulin resistance and coronary artery disease risk factors (plasma glucose, triglycerides, high density lipoprotein cholesterol, hypertension, obesity, low density lipoprotein size) and outcomes (as related to ischemic heart disease) in populations with and without type 2 diabetes. METHODS: The MEDLINE database was searched (January 1966 to April 2000). Additional references were identified from bibliographies of retrieved articles. The quantitative relationship between insulin resistance and coronary artery disease outcomes was estimated in individual studies by derivation of 2x2 tables. RESULTS: Of 780 publications reviewed, 28 met the inclusion criteria. Twenty publications investigated the relationship of insulin resistance markers with coronary artery disease risk factor profiles only, while eight publications primarily evaluated coronary artery disease outcomes. CONCLUSIONS: The present review suggests that populations with lower insulin resistance measured by reliable indexes are consistently associated with better overall cardiovascular risk profiles (including reduced clustering of risk factors), and improved coronary artery disease outcomes than populations with elevated insulin resistance.

Coronary Disease↗
PubMed2000

Subcellular localization of intracellular protein tyrosine phosphatases in T cells.

A high protein tyrosine phosphatase (PTPase) activity is required to maintain circulating T lymphocytes in a resting phenotype, and to limit the initiation of T cell activation. We report that 15 of the currently known 24 intracellular PTPases are expressed in T cells, namely HePTP, TCPTP, SHP1, SHP2, PEP, PTP-PEST, PTP-MEG2, PTEN, PTPH1, PTP-MEG1, PTP36, PTP-BAS, LMPTP, PRL-1 and OV-1. Most were found in the cytosol and many were enriched at the plasma membrane. Only TCPTP and PTP-MEG2 had subcellular localizations that essentially excludes them from a direct role in early T cell antigen receptor signaling events. Overexpression of 6 of the PTPases reduced IL-2 gene activation, 3 of them thereby identified as novel candidates for negative regulators of TCR signaling. Our findings expand the repertoire of PTPases that should be considered for a regulatory role in T cell activation.

Cell Membrane↗
PubMed2000

An evidence-based review of ACE inhibitors in incipient diabetic nephropathy.

Diabetic nephropathy develops in approximately 35% of diabetics and is the leading cause of end-stage renal disease in North America. End-stage renal disease is associated with increased morbidity and mortality, and a large economic burden. Treatments that can prevent or postpone diabetic nephropathy are important therapeutic advances. Interventional studies in type I diabetes and type II diabetes have demonstrated a beneficial effect of improved glycemic control and good blood pressure control in delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors have been found to be effective in delaying the progression of diabetic nephropathy in hypertensive as well as normotensive diabetics with early and advanced nephropathy. Microalbuminuria or incipient diabetic nephropathy is the earliest clinical expression of diabetic nephropathy and identifies patients at risk of further progression. Advanced or overt nephropathy is associated with a greater risk for coronary artery disease and mortality. It is possible that interventions aimed earlier in the cascade at preventing the development of overt nephropathy may result in greater clinical benefit. There is compelling evidence of the benefit of ACE inhibitors in preventing the progression of incipient diabetic nephropathy to overt diabetic nephropathy in normotensive diabetics.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Immunoisolation of caveolae with high affinity antibody binding to the oligomeric caveolin cage. Toward understanding the basis of purification.

Defining the molecular composition of caveolae is essential in establishing their molecular architecture and functions. Here, we identify a high affinity monoclonal antibody that is specific for caveolin-1alpha and rapidly binds caveolin oligomerized around intact caveolae. We use this antibody (i) to develop a new simplified method for rapidly isolating caveolae from cell and tissue homogenates without using the silica-coating technology and (ii) to analyze various caveolae isolation techniques to understand how they work and why they yield different compositions. Caveolae are immunoisolated from rat lung plasma membrane fractions subjected to mechanical disruption. Sonication of plasma membranes, isolated with or without silica coating, releases caveolae along with other similarly buoyant microdomains and, therefore, requires immunoisolations to purify caveolae. Shearing of silica-coated plasma membranes provides a homogeneous population of caveolae whose constituents (i) remain unchanged after immunoisolation, (ii) all fractionate bound to the immunobeads, and (iii) appear equivalent to caveolae immunoisolated after sonication. The caveolae immunoisolated from different low density fractions are quite similar in molecular composition. They contain a subset of key signaling molecules (i.e. G protein and endothelial nitric oxide synthase) and are markedly depleted in glycosylphosphatidylinositol-anchored proteins, beta-actin, and angiotensin-converting enzyme. All caveolae isolated from the cell surface of lung microvascular endothelium in vivo appear to be coated with caveolin-1alpha. Caveolin-1beta and -2 can also exist in these same caveolae. The isolation and analytical procedures as well as the time-dependent dissociation of signaling molecules from caveolae contribute to key compositional differences reported in the literature for caveolae. This new, rapid, magnetic immunoisolation procedure provides a consistent preparation for use in the molecular analysis of caveolae.

Animals↗
PubMed1999

Trends in clinical and economic outcomes of coronary angioplasty from 1992 to 1995: a population-based analysis.

BACKGROUND: The impact of recent developments in coronary angioplasty on the broad spectrum of patients treated in routine practice is largely undefined. Analysis of population-based data can provide insight into trends in clinical outcomes and associated costs of coronary angioplasty procedures. METHODS AND RESULTS: With the use of a comprehensive hospital discharge database covering more than 11 million Canadians, we analyzed 12,748 first-time angioplasty procedures performed from 1992 to 1995 inclusive. Patient demographics and major adverse events were recorded. With the use of forward linkage, readmissions within 12 months were classified according to procedure performed and/or most responsible diagnosis. The proportion of patients readmitted, the number of readmissions per index procedure, and diagnosis-specific readmission costs were compared by calendar year. Over the 4-year study period, there was a 21% increase in the annual volume of index procedures. There were no statistically significant differences between 1992 and 1995 in sex distribution, mean age, comorbid conditions, length of stay, or need for coronary bypass surgery related to the index procedure. The all-cause readmission rate declined from 51.6% to 47.2% between 1992 and 1995 (P <.001), primarily because of a decline in the admission rate for repeat revascularization from 24.8% to 19.6% (P <.001). The 12-month readmission cost declined by $435 (1994 Canadian dollars) per patient. CONCLUSIONS: The clinical outcomes of coronary angioplasty in a broad cohort of patients have improved in recent years. Although readmissions within 1 year of an angioplasty procedure remain common, the number related to repeat revascularization has declined, with an associated decline in downstream costs.

Aged↗
PubMed1998

In situ flow activates endothelial nitric oxide synthase in luminal caveolae of endothelium with rapid caveolin dissociation and calmodulin association.

Acute changes in pressure or shear stress induce the rapid release of nitric oxide (NO) from the vascular endothelium resulting in vasodilation. Endothelial nitric oxide synthase (eNOS) regulates this flow-induced NO secretion. The subcellular location of flow-induced eNOS activity in the endothelium in vivo as well as the mechanisms by which hemodynamic forces regulate eNOS activity are unknown. The luminal cell surface of the endothelium, which is directly exposed to circulating blood stressors, has been examined for eNOS expression and functional activity. Immunoelectron microscopy of rat lung tissue shows eNOS labeling on the endothelial cell surface primarily within caveolae. Subcellular fractionation to purify luminal endothelial cell plasma membranes and their caveolae directly from rat lungs reveals that eNOS is not only concentrated but also enzymatically active in caveolae. Increasing vascular flow and pressure in situ rapidly activates caveolar eNOS with apparent eNOS dissociation from caveolin and association with calmodulin. Hemodynamic forces resulting from increased flow appear to transmit through caveolae to release eNOS from its inhibitory association with caveolin, apparently to allow more complete activation by calmodulin and other possible effectors. These data demonstrate a physiological relevant mechanotransduction event directly in caveolae at the luminal endothelial cell surface. Caveolae may serve as flow-sensing organelles with the necessary molecular machinery to transduce rapidly, mechanical stimuli and thereby regulate eNOS activity.

Animals↗
PubMed1998

Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae.

The vascular endothelium is uniquely positioned between the blood and tissue compartments to receive directly the fluid forces generated by the blood flowing through the vasculature. These forces invoke specific responses within endothelial cells and serve to modulate their intrinsic structure and function. The mechanisms by which hemodynamic forces are detected and converted by endothelia into a sequence of biological and even pathological responses are presently unknown. By purifying and subfractionating the luminal endothelial cell plasma membrane from tissue, we show, for the first time, that not only does mechanotransduction occur at the endothelial cell surface directly exposed to vascular flow in vivo but also increased flow in situ induces rapid tyrosine phosphorylation of luminal endothelial cell surface proteins located primarily in the plasmalemmal invaginations called caveolae. Increased flow induces the translocation of signaling molecules primarily to caveolae, ultimately activating the Ras-Raf-mitogen-activated protein kinase pathway. This signaling appears to require intact caveolae. Filipin-induced disassembly of caveolae inhibits both proximal signaling events at the cell surface and downstream activation of the mitogen-activated protein kinase pathway. With the molecular machinery required for mediating rapid flow-induced responses as seen in endothelium, caveolae may be flow-sensing organelles converting mechanical stimuli into chemical signals transmitted into the cell.

Animals↗
PubMed1998

Dynamin at the neck of caveolae mediates their budding to form transport vesicles by GTP-driven fission from the plasma membrane of endothelium.

The molecular mechanisms mediating cell surface trafficking of caveolae are unknown. Caveolae bud from plasma membranes to form free carrier vesicles through a "pinching off" or fission process requiring cytosol and driven by GTP hydrolysis (Schnitzer, J.E., P. Oh, and D.P. McIntosh. 1996. Science. 274:239-242). Here, we use several independent techniques and functional assays ranging from cell-free to intact cell systems to establish a function for dynamin in the formation of transport vesicles from the endothelial cell plasma membrane by mediating fission at the neck of caveolae. This caveolar fission requires interaction with cytosolic dynamin as well as its hydrolysis of GTP. Expression of dynamin in cytosol as well as purified recombinant dynamin alone supports GTP-induced caveolar fission in a cell-free assay whereas its removal from cytosol or the addition to the cytosol of specific antibodies for dynamin inhibits this fission. Overexpression of mutant dynamin lacking normal GTPase activity not only inhibits GTP-induced fission and budding of caveolae but also prevents caveolae-mediated internalization of cholera toxin B chain in intact and permeabilized endothelial cells. Analysis of endothelium in vivo by subcellular fractionation and immunomicroscopy shows that dynamin is concentrated on caveolae, primarily at the expected site of action, their necks. Thus, through its ability to oligomerize, dynamin appears to form a structural collar around the neck of caveolae that hydrolyzes GTP to mediate internalization via the fission of caveolae from the plasma membrane to form free transport vesicles.

Animals↗
PubMed1998

Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells.

Cancer development is a multistage process that results from the step-wise acquisition of somatic alterations in diverse genes. Recent studies indicate that caveolin-1 expression correlates with the level of oncogenic transformation in NIH3T3 cells, suggesting that caveolin in caveolae may regulate normal cell proliferation. In order to better understand potential functions of caveolin-1 in cancer development, we have studied expression levels of caveolin-1 in human breast cancer cells, and have found that caveolin expression is significantly reduced in human breast cancer cells compared with their normal mammary epithelial counterparts. When the caveolin cDNA linked to the CMV promoter is transfected into human mammary cancer cells having no detectable endogenous caveolin, overexpression of caveolin-1 resulted in substantial growth inhibition, as seen by the 50% decrease in growth rate and by approximately 15-fold reduction in colony formation in soft agar. In addition, characterization of caveolin-1 expression during cell cycle progression indicates that expression of alpha-caveolin-1 is regulated during cell cycle. Furthermore p53-deficient cells showed a loss in caveolin expression. In summary, the overall expression patterns, its ability to inhibit tumor growth in culture, its regulation during the cell cycle, and the loss of expression in p53-deficient cells all are consistent with an important growth regulating function for caveolin-1 in normal human mammary cells, that needs to be repressed in oncogenic transformation and tumor cell growth.

Animals↗
PubMed1998

Changing practice and costs of carotid endarterectomy in Toronto, Canada.

BACKGROUND AND PURPOSE: During our annual audits of carotid endarterectomy (CEA) in Toronto metropolitan hospitals, we have been aware of major changes in the practice of this operation in recent years. To evaluate the effect of changing practice on costs of carotid endarterectomy, we have therefore compared the effects of changes in length of stay, complication rates, and other variables on cost during the last 3 years for which we have complete data. METHODS: We evaluated 757 consecutive patients, of whom 600 had CEA procedures in 3 teaching hospitals, and 190 procedures in 2 community hospitals in metropolitan Toronto. We estimated costs using a specially designed computer program, Transitional System Incorporated, including surgical complications, in patients admitted between January 1994 and December 1996. RESULTS: There was a significant decrease in length of stay in both groups of hospitals, mainly due to preoperative outpatient evaluation but also due to lower complication rates, which probably reflect an increase in asymptomatic surgery in both hospital groups. Costs fell from approximately $8000 per procedure to $5000 in asymptomatic patients and from approximately $10,000 to $7000 in symptomatic patients (Can $). CONCLUSIONS: Major changes in the management of patients undergoing CEA have resulted in a significant decrease in both length of hospital stay and utilization of postoperative intensive care. At the same time, complication rates have significantly fallen, although our mortality and morbidity figures remain slightly higher than those from published multicenter trials. Future changes in surgical practice in Canada, including noninvasive carotid imaging, should produce even lower costs within the next few years.

Aged↗
PubMed1997

Flotillin and epidermal surface antigen define a new family of caveolae-associated integral membrane proteins.

Caveolae are plasmalemmal microdomains that are involved in vesicular trafficking and signal transduction. We have sought to identify novel integral membrane proteins of caveolae. Here we describe the identification and molecular cloning of flotillin. By several independent methods, flotillin behaves as a resident integral membrane protein component of caveolae. Furthermore, we have identified epidermal surface antigen both as a flotillin homologue and as a resident caveolar protein. Significantly, flotillin is a marker for the Triton-insoluble, buoyant membrane fraction in brain, where to date mRNA species for known caveolin gene family members have not been detected.

3T3 Cells↗
PubMed1997

Organized endothelial cell surface signal transduction in caveolae distinct from glycosylphosphatidylinositol-anchored protein microdomains.

Regulated signal transduction in discrete microdomains of the cell surface is an attractive hypothesis for achieving spatial and temporal specificity in signaling. A procedure for purifying caveolae separately from other similarly buoyant microdomains including those rich in glycosylphosphatidylinositol-anchored proteins has been developed (Schnitzer, J. E., McIntosh, D. P., Dvorak, A. M., Liu, J., and Oh, P. (1995) Science 269, 1435-1439) and used here to show that caveolae contain many signaling molecules including select kinases (platelet-derived growth factor (PDGF) receptors, protein kinase C, phosphatidylinositol 3-kinase, and Src-like kinases), phospholipase C, sphingomyelin, and even phosphoinositides. More importantly, two different techniques reveal that caveolae function as signal transducing subcompartments of the plasma membrane. PDGF rapidly induces phosphorylation of endothelial cell plasmalemmal proteins residing in caveolae as detected by membrane subfractionation and confocal immunofluorescence microscopy. This PDGF signaling cascade is halted when the caveolar compartment is disassembled by filipin. Finally, in vitro kinase assays show that caveolae contain most of the intrinsic tyrosine kinase activity of the plasma membrane. As signal transducing organelles, caveolae organize a distinct set of signaling molecules to permit direct regionalized signal transduction within their boundaries.

Animals↗
PubMed1997

Cost considerations in the pharmacological prevention and treatment of stroke.

Stroke remains the leading cause of neurological disability and the third leading cause of death worldwide, consuming a large share of total healthcare expenditures. In this review, we discuss the cost effectiveness of stroke prevention for various risk factor-modification programmes and pharmacological interventions with aspirin (acetylsalicylic acid), ticlopidine and warfarin. Cost considerations and potential cost savings resulting from acute treatment are discussed for parenterally administered anticoagulants, such as heparin and nadroparin, and for intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; r-tPA). Patients with multiple risk factors for stroke require more aggressive prevention strategies which are associated with a greater risk of complications. The rates of complications, particularly intracerebral haemorrhage, should be kept low to achieve cost benefits for warfarin and alteplase. Reduced hospital length of stay is the key factor in the implementation of cost-effective stroke therapies. The analysis of future clinical trials of new stroke therapies should also include economic parameters, such as length of hospital stay and intensity of resource usage, to help guide formulary and therapeutic decision.

Cerebrovascular Disorders↗
PubMed1996

Role of GTP hydrolysis in fission of caveolae directly from plasma membranes.

Caveolae are specialized invaginated cell surface microdomains of undefined function. A cell-free system that reconstituted fission of caveolae from lung endothelial plasma membranes was developed. Addition of cytosol and the hydrolysis of guanosine triphosphate (GTP) induced caveolar fission. The budded caveolae were isolated as vesicles rich in caveolin and the sialoglycolipid GM1 but not glycosyl-phosphatidylinositol (GPI)-anchored proteins. These vesicles contained the molecular machinery for endocytosis and transcytosis. In permeabilized endothelial cells, GTP stimulated, whereas GTPgammaS prevented, caveolar budding and endocytosis of the cholera toxin B chain to endosomes. Thus, caveolae may bud to form discrete carrier vesicles that participate in membrane trafficking.

Animals↗