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Biomedical subjects

C M Newman

Publications and source records attributed to C M Newman.

At least 19 recordsLinked to original sources
PubMed2005

Ultrasound-mediated delivery of TIMP-3 plasmid DNA into saphenous vein leads to increased lumen size in a porcine interposition graft model.

Progressive saphenous vein graft (SVG) narrowing and occlusion remains a major limitation of coronary artery bypass grafting and is an important target for gene therapy. Ex vivo adenoviral gene transfer of tissue inhibitor of metalloproteinase 3 (TIMP-3) reduces adverse SVG remodelling postarterialization, but concerns remain over the use of viral vectors in patients. Ultrasound exposure (USE) in the presence of echocontrast microbubbles (ECM) substantially enhances nonviral gene delivery. We investigated the effects of ultrasound-enhanced gene delivery (UEGD) of TIMP-3 plasmid on vascular remodelling in porcine SVG. Maximal luciferase activity (3000-fold versus naked plasmid alone) and TIMP-3 transgene expression in porcine vascular smooth muscle cells in vitro was achieved using USE at 1 MHz, 1.8 mechanical index (MI), 6% duty cycle (DC) in the presence of 50% (v/v) BR14 ECM (Bracco). These conditions were therefore utilized for subsequent studies in vivo. Yorkshire White pigs received carotid interposition SVG that were untransfected or had undergone ex vivo UEGD of lacZ (control) or TIMP-3 plasmids. At 28 d postgrafting, lumen and total vessel area were significantly greater in the TIMP-3 group (10.1+/-1.2 and 25.5+/-2.2 mm2, respectively) compared to untransfected (6.34+/-0.5 and 20.8+/-1.9 mm2) or lacZ-transfected (6.1+/-0.7 and 19.7+/-1.2 mm2) controls (P<0.01). These data indicate that nonviral TIMP-3 plasmid delivery by USE achieves significant biological effects in a clinically relevant model of SV grafting, and is the first study to demonstrate the potential for therapeutic UEGD to prevent SVG failure.

Animals↗
PubMed2003

Nonrealistic behavior of mean-field spin glasses.

We study chaotic size dependence of the low-temperature correlations in the Sherrington-Kirkpatrick (SK) spin glass. We prove that as temperature scales to zero with volume, for any typical coupling realization, the correlations cycle through every spin configuration in every fixed observation window. This cannot happen in short-ranged models as there it would mean that every spin configuration is an infinite-volume ground state. Its occurrence in the SK model means that the commonly used "modified clustering" notion of states sheds little light on the replica symmetry breaking (RSB) solution of SK, and, conversely, the RSB solution sheds little light on the thermodynamic structure of Edwards-Anderson models.

Journal Article↗
PubMed2002

The Brownian web.

Arratia, [Arratia, R. (1979) Ph.D. thesis (University of Wisconsin, Madison) and unpublished work] and later Toth and Werner [Toth, B. & Werner, W. (1998) Probab. Theory Relat. Fields 111, 375-452] constructed random processes that formally correspond to coalescing one-dimensional Brownian motions starting from every space-time point. We extend their work by constructing and characterizing what we call the Brownian Web as a random variable taking values in an appropriate (metric) space whose points are (compact) sets of paths. This leads to general convergence criteria and, in particular, to convergence in distribution of coalescing random walks in the scaling limit to the Brownian Web.

Journal Article↗
PubMed2002

Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography.

OBJECTIVE: Current thinking is that amiodarone-induced thyrotoxicosis (AIT) might be either iodine-induced thyrotoxicosis in latent hyperthyroidism (Type 1) or destructive thyroiditis (Type 2), and also that colour-flow Doppler sonography (CFDS) of the thyroid and serum interleukin 6 (IL-6) are tools that can classify AIT and direct treatment. To assess the validity of this thinking, our objective was to determine whether CFDS and IL-6 identified AIT subgroups with distinct features. DESIGN: Retrospective case-note audit of all patients presenting with AIT to the Endocrine Department of a UK teaching hospital over a 3-year period. To assess proportions of Type 1 vs. Type 2 AIT and to compare and contrast their clinical features. PATIENTS: 37 patients were identified with AIT (mean age 65, range 20-86 years). In 30 patients in whom AIT persisted, 25 underwent CFDS. RESULTS: In 25 patients who underwent CFDS, 10 (40%) were classified as Type 1, 10 (40%) as Type 2 and 5 (20%) as indeterminate type. In the patients classified by CFDS in whom AIT persisted, 40% of Type 1 patients were male vs. 90% of Type 2 patients. Also, free T4 tended to be lower in patients presenting with Type 1 AIT (52.1 +/- 7.5 pmol/l) compared to Type 2 (74.8 +/- 8.1 pmol/l, P = 0.08), free T3 was lower (8.8 +/- 0.9 vs. 15.6 +/- 3.0 pmol/l, P = 0.03) and the cumulative amiodarone dose was lower (66 +/- 20 vs. 186 +/- 28 g, P = 0.002). We used less prednisolone to achieve euthyroidism in patients with Type 1 AIT whereas carbimazole doses were not different and the time to euthyroidism was the same in both groups (81 +/- 21 vs. 88 +/- 13 days). IL-6 was raised in two patients with Type 1 and in one patient with Type 2 AIT. CONCLUSIONS: CFDS could characterize two distinct subtypes in patients with AIT. Conversely, IL-6 seemed to be an unhelpful test in this context.

Adult↗
PubMed2001

Aging in 1D discrete spin models and equivalent systems.

We derive exact expressions for a number of aging functions that are scaling limits of nonequilibrium correlations, R(t(w),t(w)+t) as t(w)-->infinity, t/t(w)-->theta, in the 1D homogenous q-state Potts model for all q with T = 0 dynamics following a quench from T = infinity. One such quantity is (0)(t(w));sigma-->(n)(t(w)+t)> when n/square root of ([t(w))-->z. Exact, closed-form expressions are also obtained when an interlude of T = infinity dynamics occurs. Our derivations express the scaling limit via coalescing Brownian paths and a "Brownian space-time spanning tree," which also yields other aging functions, such as the persistence probability of no spin flip at 0 between t(w) and t(w)+t.

Journal Article↗
PubMed2001

Interfaces and the question of regional congruence in spin glasses.

We present a general theorem restricting properties of interfaces between thermodynamic states and apply it to the spin glass excitations observed numerically by Krzakala and Martin and separately by Palassini and Young in spatial dimensions d = 3,4. We show that such excitations, with interface dimension d(s) < d, cannot yield regionally congruent thermodynamic states. More generally, zero density interfaces of translation-covariant excitations cannot be pinned (by the disorder) in any d but rather must deflect to infinity in the thermodynamic limit. Additional consequences concerning regional congruence in spin glasses and other systems are discussed.

Journal Article↗
PubMed2001

Ultrasound gene therapy: on the road from concept to reality.

The promise of gene therapy lies in the potential to ameliorate or cure conditions that are resistant to conventional therapeutic approaches. Progress in vascular and all other fields of gene therapy has been hampered by concerns over the safety and practicality of recombinant viral vectors and the inefficiency of current nonviral transfection techniques. This review summarizes the increasing evidence that exposure of eukaryotic cells to relatively modest intensity ultrasound, within the range emitted by diagnostic transducers, either alone or in combination with other nonviral techniques, can enhance transgene expression by up to several orders of magnitude over naked DNA alone. In combination with the flexibility and excellent clinical safety profile of therapeutic and diagnostic ultrasound, these data suggest that ultrasound-assisted gene delivery has great promise as a novel approach to improve the efficiency of many forms of nonviral gene delivery.

Genetic Therapy↗
PubMed2000

Realistic spin glasses below eight dimensions: A highly disordered view.

By connecting realistic spin glass models at low temperature to the highly disordered model at zero temperature, we argue that ordinary Edwards-Anderson spin glasses below eight dimensions have at most a single pair of physically relevant pure states at nonzero low temperature. Less likely scenarios that evade this conclusion are also discussed.

Journal Article↗
PubMed2000

Microbubble-enhanced ultrasound for vascular gene delivery.

Progress in cardiovascular gene therapy has been hampered by concerns over the safety and practicality of viral vectors and the inefficiency of current nonviral transfection techniques. We have previously reported that ultrasound exposure (USE) enhances transgene expression in vascular cells by up to 10-fold after naked DNA transfection, and enhances lipofection by up to three-fold. We report here that performing USE in the presence of microbubble echocontrast agents enhances acoustic cavitation and is associated with approximately 300-fold increments in transgene expression after naked DNA transfections. This approach also enhances by four-fold the efficiency of polyplex transfection, yielding transgene expression levels approximately 3000-fold higher than after naked DNA alone. These data indicate an important role for acoustic cavitation in the effects of USE. Ultrasound can be focused upon almost any organ and hence this approach holds promise as a means to deliver targeted gene therapy in cardiovascular conditions such as such angioplasty restenosis and in many other clinical situations.

Albumins↗
PubMed1999

Ultrasound enhances reporter gene expression after transfection of vascular cells in vitro.

BACKGROUND: Restenosis after percutaneous coronary intervention remains a serious clinical problem. Progress in local gene therapy to prevent restenosis has been hindered by concerns over the safety and efficacy of viral vectors and the limited efficiency of nonviral techniques. This study investigates the use of adjunctive ultrasound to enhance nonviral gene delivery. METHODS AND RESULTS: Cultured porcine vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) were transfected with naked or liposome-complexed luciferase reporter plasmid for 3 hours. Ultrasound exposure (USE) for 60 seconds at 1 MHz, 0.4 W/cm2, 30 minutes into this transfection period enhanced luciferase activity 48 hours later by 7.5-fold and 2. 4-fold, respectively. Luciferase activity after lipofection of ECs was similarly enhanced 3.3-fold by adjunctive USE. USE had no effect on cell viability, although it inhibited VSMC but not EC proliferation. CONCLUSIONS: Adjunctive USE was associated with enhanced transgene expression in VSMCs and ECs and reduced VSMC but not EC proliferation in vitro, which suggests that ultrasound-assisted local gene therapy has potential as an antirestenotic therapy.

Animals↗
PubMed1999

Metastable states in spin glasses and disordered ferromagnets.

We study analytically M-spin-flip stable states in disordered short-ranged Ising models (spin glasses and ferromagnets) in all dimensions and for all M. Our approach is primarily dynamical, and is based on the convergence of sigma(t), a zero-temperature dynamical process with flips of lattice animals up to size M and starting from a deep quench, to a metastable limit sigma(infinity). The results (rigorous and nonrigorous, in infinite and finite volumes) concern many aspects of metastable states: their numbers, basins of attraction, energy densities, overlaps, remanent magnetizations, and relations to thermodynamic states. For example, we show that their overlap distribution is a delta function at zero. We also define a dynamics for M=infinity, which provides a potential tool for investigating ground state structure.

Journal Article↗
PubMed1998

Apoptosis and cell proliferation after porcine coronary angioplasty.

BACKGROUND: Angioplasty initiates a number of responses in the vessel wall including cellular migration, proliferation, and matrix accumulation, all of which contribute to neointima formation and restenosis. Cellular homeostasis within a tissue depends on the balance between cell proliferation and apoptosis. METHODS AND RESULTS: Profiles of apoptosis and proliferation were therefore examined in a porcine PTCA injury model over a 28-day period. Forty-two arteries from 21 pigs, harvested at the site of maximal injury at 1, 6, and 18 hours, and 3, 7, 14, and 28 days after PTCA, were examined (n=3 animals per time point). Uninjured arteries were used as controls. Apoptosis was demonstrated by the terminal uridine nick-end labeling (TUNEL) method, transmission electron microscopy (TEM), and DNA fragmentation. Cells traversing the cell cycle were identified by immunostaining for proliferating cell nuclear antigen (PCNA). Apoptosis was not detected in control vessels at all time points nor at 28 days after PTCA. Apoptotic cells were identified at all early time points with a peak at 6 hours (5.1+/-0.26%; compared to uninjured artery, P<0.001) and confirmed by characteristic DNA ladders and TEM findings. Regional analysis showed apoptosis within the media, adventitia, and neointima peaked at 18 hours, 6 hours, and 7 days after PTCA, respectively. In comparison, PCNA staining peaked at 3 days after PTCA (7.16+/-0.29%; compared to 1.78+/-0.08% PCNA-positive cells in the uninjured artery, P<0.001). Profiles of apoptosis and cell proliferation after PTCA were discordant in all layers of the artery except the neointima. These profiles also differed between traumatized and nontraumatized regions of the arterial wall. Immunostaining with cell-type specific markers and TEM analysis revealed that apoptotic cells included vascular smooth muscle cells (VSMCs), inflammatory cells, and adventitial fibroblasts. CONCLUSIONS: These results suggest that the profile of apoptosis and proliferation after PTCA is regional and cell specific, and attempts to modulate either of these events for therapeutic benefit requires recognition of these differences.

Actins↗
PubMed1998

Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy.

Amiodarone induces predictable changes in thyroid function tests that are largely explicable in terms of the physiological effects of iodide excess and inhibition of deiodinase activity. Clinically relevant thyroid dysfunction is not uncommon during amiodarone therapy, and requires careful diagnosis and treatment. The diagnosis and management of thyrotoxicosis is probably best supervised by a specialist endocrinologist. Control of hypothyroidism can generally be achieved simply by the addition of T4 to the therapeutic regimen, ideally after an initial assessment by an endocrinologist. The frequency with which amiodarone causes thyroid and other complications serves to emphasize the need for rational prescribing and long-term cardiological follow up.

Amiodarone↗
PubMed1998

Intravascular stents: a new technique for tissue processing for histology, immunohistochemistry, and transmission electron microscopy.

BACKGROUND: Study of the vascular response to stent implantation has been hampered by difficulties in sectioning metal and tissue without distortion of the tissue stent interface. The metal is often removed before histochemical processing, causing a loss of arterial architecture. Histological and immunohistochemical sections should be 5 microns with an intact tissue stent interface. OBJECTIVES: To identify the most suitable cutting and grinding equipment, embedding resin, and slides for producing thin sections of stented arteries with the stent wires in situ for histological, immunohistochemical, and transmission electron microscopic (TEM) analyses. METHODS: 20 balloon stainless steel stents were implanted in the coronary arteries of 10 pigs. Twenty eight days later the stented arterial segments were excised, formalin fixed, embedded in five different resins (Epon 812, LR white, T9100, T8100, and JB4), and sectioned with two different high speed saws and a grinder for histological, immunohistochemical, and TEM analyses. Five stented human arteries were obtained at necropsy and processed using the best of the reported methods. RESULTS: The Isomet precision saw and grinder/polisher unit reliably produced 5 microns sections with most embedding resins; minimum section thickness with the horizontal saw was 400 microns. Resin T8100, a glycol methacrylate, enabled satisfactory sectioning, grinding, and histological (toluidine blue, haematoxylin and eosin, and trichromatic and polychromatic stains) and immunohistochemical analyses (alpha smooth muscle actin, von Willebrand factor, vimentin, proliferating cell nuclear antigen, and CD68 (mac 387)). T9100 and T8100 embedded stented sections were suitable for ultrastructural examination with TEM. Stented human arterial sections showed preserved arterial architecture with the struts in situ. CONCLUSION: This study identified the optimal methods for embedding, sawing, grinding, and slide mounting of stented arteries to achieve 5 microns sections with an intact tissue metal interface, excellent surface qualities, histological and immunohistochemical staining properties, and suitability for TEM examination. The technique is applicable to experimental and clinical specimens.

Animals↗
PubMed1997

The effect of oligonucleotides to c-myb on vascular smooth muscle cell proliferation and neointima formation after porcine coronary angioplasty.

Proto-oncogenes, including c-myb, are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN-c-myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN-c-myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c-myb mRNA and protein. Expression of another early gene, c-fos, was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN-c-myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c-myb, with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN-c-myb was 30 times less potent than unphosphorothioated AS-ODN-c-myb. PTCA induced porcine coronary artery neointima formation. c-myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN-c-myb, sense-ODN-c-myb, saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN-c-myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN-c-myb by 79% compared with saline (P < .05), 82% compared with sense-ODN-c-myb, and 63% compared with nothing (P < .10). Conclusions are as follows: (1) c-myb is expressed in VSMCs after vascular injury. (2) AS-ODN-c-myb is retained intact in VSMCs, reducing their proliferation in vitro in dose-dependent fashion, with reduction in c-myb mRNA and protein, whereas sense-ODN-c-myb is not. (3) A range of ODNs can reduce VSMC proliferation by a non-sequence-specific mechanism. (4) Phosphorothioate protection of antisense molecules may reduce their efficacy. (5) Local delivery of unmodified AS-ODN-c-myb via the Transport catheter reduces neointima formation after porcine PTCA. (6) Local delivery of fluid may exacerbate neointimal thickening.

Angioplasty, Balloon↗
PubMed1995

Osteopontin is not a marker for proliferating human vascular smooth muscle cells.

Osteopontin (OP) is a secreted glycoprotein that contains the Arg-Gly-Asp (RGD) cell-binding sequence that binds calcium and is chemotactic and adhesive for rat vascular smooth muscle cells (VSMCs). OP gene expression is upregulated in cultured rat VSMCs in vitro and after balloon carotid injury in vivo, suggesting that OP may be a marker for proliferating VSMCs in vivo and in vitro. Our in situ hybridization studies of human atherosclerotic coronary vessels, however, have shown OP mRNA expression in plaque macrophages but not VSMCs. The current study investigated OP mRNA expression in cultured human VSMCs and macrophages and in an organ culture model of neointima formation in human saphenous vein. OP mRNA expression was not detected by Northern blot analysis of total RNA from subconfluent or confluent cultures of human VSMCs of any passage maintained in normal growth medium or after stimulation with TGF beta 1 (20 ng/mL), angiotensin II (1 mumol/L), or basic fibroblast growth factor (10 mg/mL) but was just detectable after stimulation with activation vitamin D3 (1 mumol/L). In contrast, cultured human macrophages expressed high levels of OP mRNA that were not dependent on lipid loading. OP mRNA was detected in isolated foci in all layers of saphenous veins maintained in organ culture for 14 days, including <2% of neointimal cells, a distribution that paralleled that of tissue macrophages. These results suggest that OP gene expression is not a marker for proliferation of human VSMCs in vitro and highlight a fundamental difference in the biology of human and rodent VSMCs.

Arteriosclerosis↗
PubMed1994

The costs of interrupting antihypertensive drug therapy in a Medicaid population.

This research explores the association between the interruption or termination of antihypertensive drug therapy and total health care costs among non-institutionalized Medicaid patients older than age 40 who survive the first year after treatment. Multivariate regression analysis was used to estimate the statistical relationship between post-treatment costs and patient demographic characteristics, prior use of services, the type of medication used as initial therapy and whether the patient maintained continuous therapy. Paid claims data from the California Medicaid (Medi-Cal) program were used in the analysis. Total cost of health care in the first year after the initiation of drug therapy was the primary outcome variable. Components of total costs (e.g., hospital, outpatient and physician services, prescription drugs) were also investigated. Nearly 86% of new antihypertensive drug therapy patients interrupted or discontinued purchasing any form of antihypertensive medication during the first year. Patients with interrupted antihypertensive drug therapy consumed an additional $873 per patient (P < .0001) in health care during the first year, not counting a reduction in prescription drug cost of $281 (P < .0001). Increased costs were primarily due to increased hospital expenditures of $637 (P < .0002).

Adult↗