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Biomedical subjects

K Walsh

Publications and source records attributed to K Walsh.

At least 127 records · Page 7Linked to original sources
PubMed1999

Serving people with developmental disabilities in Medicaid managed care.

Concurrent with the sweeping changes in health care during the past decade, particularly in Medicaid financed health care, has been the reshaping of social policy toward people with developmental disabilities. The extent to which managed care entities match the themes now driving social services for people with mental retardation and other developmental disabilities (cerebral palsy, autism, etc.) is the extent to which they will be successful in serving this unique group of consumers of managed health care. The authors suggest a number of considerations for managed care organizations that increasingly serve significant numbers of this population.

Comprehensive Health Care↗
PubMed1999

Angiogenesis and gene therapy in man: dream or reality?

Preclinical studies indicate that angiogenic growth factors can stimulate the development of collateral arteries in animal models of peripheral or myocardial ischaemia, a concept termed 'therapeutic angiogenesis'. The goal of this review is to provide a brief overview of the advantages and disadvantages of gene versus recombinant protein therapy for therapeutic angiogenesis. We also discuss different options for delivering genes to patients, including plasmids and modified viral vectors. Recently, the safety and potential utility of gene therapy for ischaemic disease were demonstrated in 3 clinical trials involving the delivery of plasmid DNA encoding the 165 amino acid isoform of human vascular endothelial growth factor (phVEGF165), a factor that specifically promotes the proliferation and migration of vascular endothelial cells. Two trials involved the administration of phVEGF165 for peripheral arterial disease. In one trial, the plasmid was administered to the arterial wall from a hydrogel-coated angioplasty balloon, while a second trial examined the direct injection of phVEGF165 into the skeletal muscle of the affected limb. More recently, phVEGF165 was directly injected into ischaemic myocardium. In all these trials, it appears that administration of phVEGF165 led to improvements in tissue perfusion.

Angiogenesis Inducing Agents↗
PubMed1998

Endothelial cell apoptosis induced by oxidized LDL is associated with the down-regulation of the cellular caspase inhibitor FLIP.

Fas (CD-95/APO-1) is a death receptor that initiates an apoptotic signal when activated by its ligand, FasL. Normal vascular endothelial cells are resistant to Fas-mediated apoptosis though they express both Fas and FasL. Oxidized low density lipoprotein (OxLDL) or lysophosphatidylcholine (LPC), a major component of OxLDL, induces endothelial cell suicide by sensitizing endothelial cells to Fas-mediated apoptosis. Here, we show that endothelial cell apoptosis by OxLDL and LPC-C16:0 was dose-dependent and correlated with down-regulation of FLICE-inhibitory protein (FLIP), an intracellular caspase inhibitor. FLIP down-regulation also occurred when endothelial cells were treated with toxic doses of LPC-C18:0 or minimally modified low density lipoprotein (LDL). In contrast, FLIP was not down-regulated by native LDL, acetylated LDL, LPC-C12:0, cholesterol, or 7-ketocholesterol, which are not toxic to endothelial cells. The cytotoxicity of oxidized lipids was reversed by transfecting endothelial cells with a FLIP expression plasmid. The results demonstrate, for the first time, FLIP regulation under conditions that lead to pathological tissue destruction.

Amino Acid Sequence↗
PubMed1998

Oxidized LDL activates fas-mediated endothelial cell apoptosis.

Oxidized low density lipoproteins (OxLDL) promote chronic inflammatory responses in the vasculature that give rise to atherosclerotic plaques. Fas ligand (FasL) is naturally expressed on the vascular endothelium where it can induce apoptosis in Fas-expressing immune cells as they enter the vessel wall. Although vascular endothelial cells are normally resistant to Fas-mediated cell death, OxLDL were shown to induce apoptosis in cultured endothelial cells and endothelium of arterial explants by a process that could be inhibited with Fas L neutralizing antibodies. OxLDL-induced cell death was also reduced in the aortic endothelium cultured from gld (FasL-/-) and lpr (Fas-/-) mice as compared with wild-type mice. OxLDL acted by sensitizing endothelial cells to death signals from the Fas receptor. Thus, the ability of OxLDL to promote Fas-mediated endothelial cell suicide may be a feature that contributes to their atherogenicity.

Animals↗
PubMed1998

Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation.

When placed in the cold (4 degreesC), BALB/cByJ mice of both genders rapidly lose body temperature as compared with the control strain, C57BL/6J. This sensitivity to cold resembles that previously described for mice with a defect in nonshivering thermogenesis due to the targeted inactivation of the brown adipocyte-specific mitochondrial uncoupling protein gene, Ucp1. Genetic mapping of the trait placed the gene on chromosome 5 near Acads, a gene encoding the short chain acyl CoA dehydrogenase, which is mutated in BALB/cByJ mice. The analysis of candidate genes in the region indicated a defect only in the expression of Acads. Confirmation of the importance of fatty acid oxidation to thermogenesis came from our finding that mice carrying the targeted inactivation of the long chain acyl CoA dehydrogenase gene (Acadl) are also sensitive to the cold. Both of these mutations attenuate the induction of genes normally responsive to adrenergic signaling in brown adipocytes. These results suggest that the action of fatty acids as regulators of gene expression has been perturbed in the mutant mice. From a clinical perspective, it is important to determine whether defects in thermogenesis may be a phenotype in human neonates with inherited deficiencies in fatty acid beta-oxidation.

Acyl-CoA Dehydrogenase↗
PubMed1998

Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity.

The mRNA levels for the mitochondrial uncoupling protein (UCP1) in fat tissues of A/J and C57BL/6J inbred strains of mice varied in a regional-specific manner after stimulation of adrenergic signaling by cold exposure or treatment with a beta3-adrenergic agonist. While the differences between strains were minimal in interscapular brown fat, large differences occurred in white fat tissues, particularly in retroperitoneal fat. Among the AXB recombinant inbred strains, the Ucp1 mRNA levels varied up to 130-fold. This large induction at the mRNA level was accompanied by a corresponding increase in brown adipocytes as revealed by immunohistology with anti-UCP1 antibodies. A high capacity to induce brown fat in areas of traditional white fat had no impact on the ability to gain weight in response to high fat and sucrose diets, but did correlate with the loss of weight in response to treatment with a beta3-adrenergic agonist (CL 316,243). This genetic variation in mice provides an experimental approach to identify genes controlling the induction of brown adipocytes in white fat tissues.

Adipocytes↗
PubMed1998

Bax-mediated cell death by the Gax homeoprotein requires mitogen activation but is independent of cell cycle activity.

Tissues with the highest rates of proliferation typically exhibit the highest frequencies of apoptosis, but the mechanisms that coordinate these processes are largely unknown. The homeodomain protein Gax is down-regulated when quiescent cells are stimulated to proliferate, and constitutive Gax expression inhibits cell proliferation in a p21(WAF/CIP)-dependent manner. To understand how mitogen-induced proliferation influences the apoptotic process, we investigated the effects of deregulated Gax expression on cell viability. Forced Gax expression induced apoptosis in mitogen-activated cultures, but quiescent cultures were resistant to cell death. Though mitogen activation was required for apoptosis, neither the cdk inhibitor p21(WAF/CIP) nor the tumor suppressor p53 was required for Gax-induced cell death. Arrest in G1 or S phases of the cell cycle with chemical inhibitors also did not affect apoptosis, further suggesting that Gax-mediated cell death is independent of cell cycle activity. Forced Gax expression led to Bcl-2 down-regulation and Bax up-regulation in mitogen-activated, but not quiescent cultures. Mouse embryonic fibroblasts homozygous null for the Bax gene were refractive to Gax-induced apoptosis, demonstrating the functional significance of this regulation. These data suggest that the homeostatic balance between cell growth and death can be controlled by mitogen-dependent pathways that circumvent the cell cycle to alter Bcl-2 family protein expression.

Animals↗
PubMed1998

GATA-6 induces p21(Cip1) expression and G1 cell cycle arrest.

GATA transcription factors represent a family of highly conserved zinc finger proteins with tissue-specific expression patterns. Previous studies have shown that GATA-6 is expressed in vascular smooth muscle cells (VSMCs) and rapidly down-regulated when VSMCs are induced to proliferate. Here we investigated whether the GATA-6 transcription factor can modulate cellular proliferation. Transient transfection with a GATA-6 expression vector inhibited S-phase entry in VSMCs and in mouse embryonic fibroblasts (MEFs) lacking both p53 alleles. The GATA-6-induced growth arrest correlated with a marked increase in the expression of the general cyclin-dependent kinase (Cdk) inhibitor p21. In contrast to p53-deficient MEFs and VSMCs, MEFs null for both p21 alleles were refractory to the GATA-6-induced growth inhibition. These data demonstrate that elevated GATA-6 expression can promote the quiescent phenotype in VSMCs.

Animals↗
PubMed1998

Nitric oxide-induced downregulation of Cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells.

BACKGROUND: Nitric oxide (NO) inhibits vascular smooth muscle cell (VSMC) proliferation and neointima formation after balloon injury. However, the molecular mechanisms underlying NO-mediated growth arrest are poorly understood. In the present study, we examined the effects of the NO donors sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on cell cycle activity in VSMCs. METHODS AND RESULTS: Stimulation of quiescent rat VSMCs with serum leads to an increase in cyclin-dependent kinase (cdk)2 kinase activity that correlates with a marked induction of cyclin A protein expression. The addition of SNP or SNAP to VSMC cultures at the time of serum stimulation abrogates the induction of cdk2 activity without suppressing protein levels of cdk2 or cyclin E. These NO donors block serum-stimulated upregulation of cyclin A mRNA and protein and repress the serum induction of cyclin A promoter activity in VSMCs. CONCLUSIONS: The addition of the nitric oxide donors SNP or SNAP to mitogen-stimulated VSMCs prevents activation of cdk2, a key regulator of the G1 and S phases of the cell cycle. These NO donors do not affect the expression of cdk2 protein but block the mitogen-induced expression of cyclin A, an activating subunit of cdk2. SNP and SNAP also repress the mitogen-stimulated activation of the cyclin A promoter. These data suggest that the antiproliferative effect of NO on VSMCs results, at least in part, from the repression of cyclin A gene transcription.

Animals↗
PubMed1998

Effects of poloxamer 407 on transfection time and percutaneous adenovirus-mediated gene transfer in native and stented vessels.

UNLABELLED: Reduction in transfection time and the ability to perform gene transfer in conjunction with endovascular stent implantation constitute two important challenges for percutaneous adenovirus-mediated gene transfer to vessel walls. Studies have suggested that the use of biocompatible polyol poloxamer 407 could be useful. We first evaluated the use of poloxamer 407 for percutaneous gene transfer in nonstented rabbit iliac arteries. A 200-microl mixture of Ad-RSVbetagal or Ad-CMVLuc in either phosphate-buffered saline (PBS) or 20% poloxamer was delivered. After 3 days, gene transfection was evaluated by X-Gal staining or measurement of luciferase activity. Poloxamer use resulted in a 3- to 15-fold increase in the percentage of transfected cells (X-Gal, p = 0.001) and a 16-fold increase in protein product (luciferase activity, p = 0.03), and allowed a decrease in transfection time from 30 to 5 min with minimal reduction in transfection efficiency. We then evaluated the feasibility of percutaneous gene transfer, using Ad-RSVbetagal diluted in pure PBS or 20% poloxamer, in conjunction with stent implantation. Gene delivery was performed either immediately before (pre-) or after (post-) stent implantation. When adenoviruses were diluted in PBS, gene transfer had a low efficiency (prestent, 0.3%; poststent, 0.2%; NS). With poloxamer, the efficacy was much higher (p = 0.0001) and similar "pre" (2.2%) or "post" (1.7%) stent delivery (NS). CONCLUSIONS: (1) The use of poloxamer, rather than PBS, as a vehicle increases the efficacy of percutaneous adenovirus-mediated gene transfer and reduces transfection time; (2) gene transfer performed during stent implantation with poloxamer is feasible and achieves a significant level of gene expression. Thus percutaneous gene delivery is applicable to conventional stents and could present an attractive method by which to achieve local biological effects in a stent environment.

Adenoviruses, Human↗
PubMed1998

Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia.

BACKGROUND: Preclinical studies have indicated that angiogenic growth factors can stimulate the development of collateral arteries, a concept called "therapeutic angiogenesis." The objectives of this phase 1 clinical trial were (1) to document the safety and feasibility of intramuscular gene transfer by use of naked plasmid DNA encoding an endothelial cell mitogen and (2) to analyze potential therapeutic benefits in patients with critical limb ischemia. METHODS AND RESULTS: Gene transfer was performed in 10 limbs of 9 patients with nonhealing ischemic ulcers (n=7/10) and/or rest pain (n=10/10) due to peripheral arterial disease. A total dose of 4000 microg of naked plasmid DNA encoding the 165-amino-acid isoform of human vascular endothelial growth factor (phVEGF165) was injected directly into the muscles of the ischemic limb. Gene expression was documented by a transient increase in serum levels of VEGF monitored by ELISA. The ankle-brachial index improved significantly (0.33+/-0.05 to 0.48+/-0.03, P=.02); newly visible collateral blood vessels were directly documented by contrast angiography in 7 limbs; and magnetic resonance angiography showed qualitative evidence of improved distal flow in 8 limbs. Ischemic ulcers healed or markedly improved in 4 of 7 limbs, including successful limb salvage in 3 patients recommended for below-knee amputation. Tissue specimens obtained from an amputee 10 weeks after gene therapy showed foci of proliferating endothelial cells by immunohistochemistry. PCR and Southern blot analyses indicated persistence of small amounts of plasmid DNA. Complications were limited to transient lower-extremity edema in 6 patients, consistent with VEGF enhancement of vascular permeability. CONCLUSIONS: These findings may be cautiously interpreted to indicate that intramuscular injection of naked plasmid DNA achieves constitutive overexpression of VEGF sufficient to induce therapeutic angiogenesis in selected patients with critical limb ischemia.

Adult↗
PubMed1998

Fas ligand gene transfer to the vessel wall inhibits neointima formation and overrides the adenovirus-mediated T cell response.

Proliferation of vascular smooth muscle cells (VSMCs) in response to injury plays a key role in the pathogenesis of vascular disorders. Fas ligand (FasL) induces apoptosis in Fas-bearing cells, and its expression on activated T cells contributes to the regulation of the immune response and physiological cell turnover. Here, we show that a replication-defective adenovirus encoding FasL (Ad-FasL) induced apoptosis in Fas-bearing VSMCs. When introduced locally to balloon-injured rat carotid arteries, a well characterized model of a VSMC-derived lesion, Ad-FasL functioned as a potent inhibitor of neointima formation. In rats immunized with an empty adenoviral vector, robust T cell infiltration of the vessel wall was detected after local delivery of a beta-galactosidase-expressing virus (Ad-betagal), whereas T cell infiltrates were not detected after local delivery of Ad-FasL. Prior immunization prevented beta-galactosidase expression from Ad-betagal, whereas the expression of the FasL transgene was unaffected. When Ad-betagal and Ad-FasL were delivered together to preimmunized animals, T cell infiltration was reduced and beta-galactosidase expression was restored. These data demonstrate that Fas ligand gene transfer can effectively inhibit injury-induced vessel lesion formation and can allow adenovirus-harboring cells to evade immune destruction.

Adenoviridae Infections↗
PubMed1998

Effect of high irradiance and iron on volatile odour compounds in the cyanobacterium Microcystis aeruginosa.

The cyanobacterium, Microcystis aeruginosa was exposed to direct sunlight for 3, 6 or 9 h in media containing either low or high concentrations of iron, in order to determine any effects on the composition of volatile odour compounds (VOCs) released under photooxidative conditions. The most abundant VOCs detected included aliphatic hydrocarbons (C15-C21), naphthalene and the terpenoid compounds, beta-cyclocitral, and beta-ionone. Exposure to sunlight and low iron concentrations resulted in a decrease in beta-cyclocitral, beta-ionone, heptadecane and the total VOCs concentration after 9 h with respect to the control cultures. Six VOCs detected in the low iron cells were not detected in any of the high iron cells. However, those VOCs present in the high iron cells, in general, occurred at higher concentrations than the equivalent low iron cells after exposure to the sunlight conditions. Consequently, it was concluded that exposure to both high irradiance and high iron concentrations influenced the VOCs composition in cyanobacteria and this was interpreted to represent a cellular change during the photooxidation-promoting conditions.

Hydrocarbons↗
PubMed1998

TNFalpha regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation.

It is generally believed that the vascular endothelium serves as an inflammatory barrier by providing a nonadherent surface to leukocytes. Here, we report that Fas ligand (FasL) is expressed on vascular endothelial cells (ECs) and that it may function to actively inhibit leukocyte extravasation. TNFalpha downregulates FasL expression with an accompanying decrease in EC cytotoxicity toward co-cultured Fas-bearing cells. Local administration of TNFalpha to arteries downregulates endothelial FasL expression and induces mononuclear cell infiltration. Constitutive FasL expression markedly attenuates TNFalpha-induced cell infiltration and adherent mononuclear cells undergo apoptosis under these conditions. These findings suggest that endothelial FasL expression can negatively regulate leukocyte extravasation.

Aorta↗
PubMed1998

Hearing loss in community-dwelling older persons: national prevalence data and identification using simple questions.

OBJECTIVE: To estimate the prevalence of hearing loss among community-dwelling older persons according to clinical criteria and to develop a brief self-report screening instrument to detect hearing loss. DESIGN: Survey. SETTING: National probability sample of noninstitutionalized older persons. PARTICIPANTS: A total of 2506 persons aged 55 to 74 who participated in the National Health and Nutrition Examination Survey. MAIN OUTCOME MEASURES: Hearing loss as defined by Ventry and Weinstein (VW) criteria and by the High Frequency Pure-Tone Average (HFPTA) scale. RESULTS: Hearing loss by VW criteria was present in 14.2% and by HFPTA criteria in 35.1% of those surveyed. The prevalence increased with advancing age and was higher among men and those with less education. A logistic regression model identified six independent factors for hearing loss by VW criteria: age > or = 70 years (adjusted odds-ratio (AOR) 2.7, 95% confidence interval (95% CI) 1.6, 4.4), male gender (AOR 3.0, 95% CI 1.9, 4.8), < or = 12th grade education (AOR 3.8, 95% CI 1.8, 7.7), having seen a doctor for deafness or hearing loss (AOR 8.9, 95% CI 5.3, 14.9), unable to hear a whisper across a room (AOR 3.2, 95% CI 2.0, 5.1), and unable to hear a normal voice across a room (AOR 6.2, 95% CI 2.6, 14.9). A clinical scale based on the logistic model had 80% sensitivity and 80% specificity in predicting hearing loss using VW criteria and 59% sensitivity and 88% specificity in predicting hearing loss using HFPTA criteria. CONCLUSIONS: Hearing loss, as defined by two clinical criteria, is common and can be screened for accurately using simple questions that assess sociodemographic and hearing-related characteristics.

Aged↗
PubMed1998

The impact of patient experience on practice: the acceptability of emergency contraceptive pills in inner-city clinics.

OBJECTIVES: This article reports on a study of 119 women who sought and used emergency contraceptive pills (ECPs) at Planned Parenthood of New York City (PPNYC) clinics between June 1996 and May 1997. It focuses on their satisfaction with the method, their attitudes toward ECPs, their reactions to the service, and the impact their perceptions had on changing the provision of care. METHOD: The PPNYC clinical protocol employed the Yuzpe method and fairly conservative procedures, including restrictive screening, a pelvic examination for all new patients, and limited appointment slots. A two-part survey captured information on patient experience with ECPs. RESULTS: The largest group of respondents (40%) found out about ECPs from friends. Almost 90% of the women were using contraception before their visit to the clinic. Sixty-eight percent reported that they sought ECPs because the condom failed. In the follow-up, a majority (57%) reported that they intended to change or had changed their method of contraception--more than three-quarters to a hormonal contraceptive. While generally satisfied with the service, many respondents were cautious of more extensive distribution of ECPs. CONCLUSION: The survey results had a profound impact on services: PPNYC revised the ECP protocol, developed a staff training package, expanded its service, and planned a multidimensional public media campaign. Further research, including a closer examination of participants' cautious attitude toward unrestricted distribution of ECPs, will be needed as PPNYC expands access to ECP.

Adolescent↗