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1.  Acute inhibition of superoxide formation and Rac1 activation by nitric oxide and iloprost in human vascular smooth muscle cells in response to the thromboxane A2 analogue, U46619 
The over-production of superoxide (O2⋅−) derived from NADPH oxidase (NOX) plays a central role in cardiovascular diseases. By contrast, nitric oxide (NO) and prostacyclin (PGI2) are vasculoprotective. The effect of the NO donor, NONOate and iloprost on O2⋅− formation, p47phox and Rac1 activation in human vascular smooth muscle cells (hVSMCs) was investigated.
hVSMCs were incubated with 10 nM thromboxane A2 analogue, U46619 for 16 h, and then with apocynin (a NOX inhibitor), NONOate or iloprost for 1 h and O2⋅− measured spectrophometrically. The role of cyclic AMP and cyclic GMP was examined by co-incubation of drugs with protein kinase (PK) A and G inhibitors listed above. Rac1 was studied using pull-down assays.
NONOate and iloprost inhibited O2⋅− formation, acutely, effects blocked by inhibition of PKG and PKA, respectively. Rac1 and p47phox activation and translocation to the plasma membrane was completely inhibited by NONOate and iloprost, effects again reversed by co-incubation with PKG or PKA inhibitors.
NO and PGI2 block the acute activity of NOX in hVSMCs via the cGMP–PKG axis (for NO) and by the cAMP–PKA axis (for iloprost) through inhibition of Rac1 and p47phox translocation. These findings have implications in the pathophysiology and treatment of CVD.
PMCID: PMC2850987  PMID: 18420399
2.  Tissue inhibitor of metalloproteinase‐3 differentially binds to components of Bruch's membrane 
The British Journal of Ophthalmology  2006;90(10):1310-1315.
Sorsby's fundus dystrophy (SFD) is caused by mutations in tissue inhibitor of metalloproteinase (TIMP)‐3 and, with the exception of early onset, is similar to age‐related macular degeneration. The pathological features of this condition relate to the accumulation of TIMP‐3 in Bruch's membrane.
To compare the extracellular membrane‐binding characteristics of wild‐type and four SFD‐mutant TIMP‐3s.
COS‐7 cells were transfected with wild‐type, Ser‐181, Gly‐167, Ser‐156 and Tyr‐168 SFD‐mutant TIMP‐3 cDNA. The TIMP‐3 proteins subsequently synthesised were harvested, analysed by sodium dodecyl sulphate‐polyacrylamide gel electrophoresis, semiquantified by ELISA and used in binding assays on the basis of the retention of the wild‐type and SFD‐mutant TIMP‐3 proteins by components of Bruch's membrane.
SFD‐mutant TIMP‐3s could not be distinguished from wild‐type TIMP‐3 by the extents to which they aggregated or adhered to type‐I collagen, type‐IV collagen, fibronectin, laminin, elastin, chondroitin sulphates A, B and C, and heparin sulphate. Of these macromolecules, the wild‐type and SFD‐mutant TIMP‐3s exhibited greatest affinity for elastin and laminin.
The similarity in the physical and extracellular membrane‐binding characteristics of wild‐type and SFD‐mutant TIMP‐3s indicates that these properties are not responsible for the difference in timing of onset of SFD and age‐related macular degeneration.
PMCID: PMC1857436  PMID: 16837541
3.  Assessing elemental mercury vapor exposure from cultural and religious practices. 
Environmental Health Perspectives  2001;109(8):779-784.
Use of elemental mercury in certain cultural and religious practices can cause high exposures to mercury vapor. Uses include sprinkling mercury on the floor of a home or car, burning it in a candle, and mixing it with perfume. Some uses can produce indoor air mercury concentrations one or two orders of magnitude above occupational exposure limits. Exposures resulting from other uses, such as infrequent use of a small bead of mercury, could be well below currently recognized risk levels. Metallic mercury is available at almost all of the 15 botanicas visited in New York, New Jersey, and Pennsylvania, but botanica personnel often deny having mercury for sale when approached by outsiders to these religious and cultural traditions. Actions by public health authorities have driven the mercury trade underground in some locations. Interviews indicate that mercury users are aware that mercury is hazardous, but are not aware of the inhalation exposure risk. We argue against a crackdown by health authorities because it could drive the practices further underground, because high-risk practices may be rare, and because uninformed government intervention could have unfortunate political and civic side effects for some Caribbean and Latin American immigrant groups. We recommend an outreach and education program involving religious and community leaders, botanica personnel, and other mercury users.
PMCID: PMC1240404  PMID: 11564612
4.  Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. 
Journal of Clinical Investigation  1998;101(6):1478-1487.
Tissue inhibitors of metalloproteinases (TIMPs) are a family of closely related secreted proteins that limit matrix metalloproteinase (MMP) activity and also have direct effects on cell growth. We used the highly efficient adenoviral delivery system to overexpress individual TIMPs from the cytomegalovirus immediate early promoter in rat aortic smooth muscle cells. Overexpression of TIMP-1, -2, or -3, or a synthetic MMP inhibitor similarly inhibited SMC chemotaxis and invasion through reconstituted basement membrane. TIMP-1 overexpression did not effect cell proliferation. By contrast, TIMP-2 caused a dose-dependent reduction in proliferation, an effect not mimicked by a synthetic MMP inhibitor. TIMP-3 overexpression induced DNA synthesis, and promoted SMC death by apoptosis, a phenotype reproduced by adding TIMP-3 to uninfected cells, but not by a synthetic MMP inhibitor. Our study is the first to compare systematically the effect of overexpression of three TIMPs in any cell. We found similar effects on invasion mediated by inhibition of MMP activity, but widely divergent effects on proliferation and death through actions of TIMP-2 and -3 independent of MMP inhibition. These findings have important implications for the physiological roles of TIMPs and their use in gene therapy.
PMCID: PMC508704  PMID: 9502791
5.  Inhibition of vascular smooth muscle cell proliferation in vitro and in vivo by c-myc antisense oligodeoxynucleotides. 
Journal of Clinical Investigation  1994;93(2):820-828.
Restenosis after angioplasty is due predominantly to accumulation of vascular smooth muscle cells (VSMCs). The resistance of restenosis to pharmacological treatment has prompted investigation of genes involved in VSMC proliferation. We have examined the effect on VSMC proliferation of blocking expression of the c-myc proto-oncogene with antisense oligodeoxynucleotides, both in vitro and in a rat carotid artery injury model of angioplasty restenosis. Antisense c-myc oligodeoxynucleotides reduced average cell levels of c-myc mRNA and protein by 50-55% and inhibited proliferation of VSMCs when mitogenically stimulated from quiescence or when proliferating logarithmically (IC50 = 10 micrograms/ml). Corresponding sense c-myc, two-base-pair mismatch antisense c-myc, antisense alpha-actin or glyceraldehyde phosphate dehydrogenase oligodeoxynucleotides did not suppress c-myc expression or inhibit VSMC proliferation. Antisense c-myc inhibition was relieved by overexpression of an exogenous c-myc gene. After balloon catheter injury, peak c-myc mRNA expression occurred at 2 h. Antisense c-myc applied in a pluronic gel to the arterial adventitia reduced peak c-myc expression by 75% and significantly reduced neointimal formation at 14 d, compared with sense c-myc and gel application alone. We conclude that c-myc expression is required for VSMC proliferation in vitro and in the vessel wall. C-myc is a therefore a potential target for adjunctive therapy to reduce angioplasty restenosis.
PMCID: PMC293939  PMID: 8113414
6.  Coronary artery bypass surgery: current practice in the United Kingdom. 
Thorax  1989;44(9):721-724.
A survey of current clinical practice was carried out among the 84 consultant cardiac surgeons currently performing coronary artery bypass surgery in the United Kingdom. The 80 surgeons who returned the questionnaire performed an estimated total of 17,100 coronary artery bypass graft operations in 1987, a mean case load of 214 operations each. Sixty two of the 80 surgeons regarded the internal mammary artery as the graft conduit of choice, and seven preferred the saphenous vein. The internal mammary artery was used in 73% of bypass grafts to the left anterior descending coronary artery but in only 4% of grafts to the circumflex and right coronary systems. Contraindications to the use of the internal mammary artery included advanced age of the patient (51 surgeons), insufficient flow through the internal mammary artery (49), and endarterectomy (35). Seventy four of the 80 surgeons considered intraoperative damage to the saphenous vein to be a possible cause of vein graft failure, but there was no agreement about how it should be reduced. All surgeons advocated pharmacological measures to enhance graft patency. Dipyridamole and aspirin constituted the most popular regimen (58 surgeons), though only 28 started dipyridamole preoperatively. Warfarin was prescribed postoperatively on occasion by 22 surgeons, but 14 of these used it only after endarterectomy.
PMCID: PMC462052  PMID: 2588208
7.  Cutting down Salaries 
British Medical Journal  1900;1(2057):1382.
PMCID: PMC2506508

Results 1-7 (7)