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Biomedical subjects

D Gordon

Publications and source records attributed to D Gordon.

At least 235 records · Page 13Linked to original sources
PubMed1995

Effect of mechanical forces on growth and matrix protein synthesis in the in vitro pulmonary artery. Analysis of the role of individual cell types.

The effect of mechanical stimuli on pulmonary artery growth and matrix tissue synthesis (and how individual cell types in the vessel wall respond to such stimuli) is incompletely characterized. Rabbit pulmonary arteries were placed in tissue culture medium and subjected to varying magnitudes of stretch or hydrostatic pressure (separately) for 4 days. The rate of protein synthesis in smooth muscle cells (by quantitative autoradiography) was positively related to the magnitude of stretch, as were the percentage of procollagen type I-positive cells and the rate of cell replication. In adventitial fibroblasts, stretch increased the rate of replication but not of protein synthesis. Hydrostatic pressure had little or no effect on the variables measured in either smooth muscle cells or fibroblasts. Stretch also increased the rate of elastin and collagen synthesis in the whole pulmonary artery segment, and after 4 days of stretch, the contents of actin and elastin were increased. Removal of the endothelium did not affect stretch-induced protein, collagen, or elastin synthesis but augmented stretch-induced smooth muscle replication. These data suggest that in the intact pulmonary artery, stretch, but not pressure, can stimulate hypertrophy and hyperplasia in smooth muscle cells and hyperplasia in fibroblasts. Matrix protein synthesis and accumulation are also increased by stretch. Neither stretch-mediated growth nor matrix protein synthesis required endothelium in this model.

Animals↗
PubMed1995

Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-resistant or insulin-sensitive?

Insulin resistance in black Americans with non-insulin-dependent diabetes mellitus (NIDDM) is found in only 60% of those with a body mass index (BMI) of < 30 kg/m2, suggesting that NIDDM can occur independent of peripheral insulin resistance. When insulin resistance is present, it is not necessarily correlated with obesity. Numerous studies have shown that increased amounts of intra-abdominal adipose tissue are associated with various metabolic abnormalities. We therefore investigated whether the occurrence of insulin resistance in black NIDDM men could be explained by the pattern of body adipose tissue distribution rather than total adiposity. Twenty-two near-normoglycemic black men (fasting plasma glucose [mean +/- SD] = 104 +/- 10 mg/dl, HbA1c = 4.6 +/- 0.78%, age 48.9 +/- 9.2 years, and BMI 26.5 +/- 2.4 kg/m2) were studied. The euglycemic insulin clamp with 1 mU.kg-1.min-1 insulin infusion and D-[3-3H]glucose was used to measure insulin action. Whole-body computed tomography with 22 scans was used to determine body composition. Total body adipose tissue was 19.6 +/- 7.51, and the percentage of body fat was 27 +/- 7. Glucose disposal ranged from 2.5 to 8.1 mg.kg-1.min-1 (10 men were insulin-sensitive and 12 were insulin-resistant). There was a strong inverse correlation between glucose disposal and the proportion of total adipose tissue in the intra-abdominal region (r = -0.78, P < 0.001), while there was no correlation between glucose disposal and total muscle volume, BMI, total adipose tissue volume, or total subcutaneous adipose tissue volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1995

A new method for studying plaque morphology.

A histologic method was developed for three-dimensional (3-D) analysis of atherosclerotic plaques removed from the carotid bifurcation during endarterectomy. By sectioning the plaque at frequent intervals (0.5 to 1.0 mm), it is possible to obtain important information on plaque constituents with regard to their volume and distribution within the lesion. These data from each section are combined with those from other sections and displayed in a 3-D format for the entire length of the lesion. The tissues making up each of the 10 carotid plaques were outlined and digitized for each histologic section by position along the lesion. From the areas outlined a 3-D model was created by a computer-aided design program. Quantitative information on tissue distribution within the plaque was measured. Fibrous tissue constituted between 35% and 70% of plaque volume; loose necrosis from 0.5% to 30% of the plaque and thrombus occupied, at a maximum, 10% even though if was present in six of the 10 plaques. To investigate the distribution of constituents about the long axis, measurements were also made from each of the four quadrants of each section. The reproducibility of the measurements of three sets of sections at 10-mm separation showed that estimates of the amount of some constituents were very reproducible whereas others had considerable variation related to the small volume they occupied within the lesion. By generating a complete 3-D reproduction of the contents of atherosclerotic plaques, it may be possible to identify those features of the plaque that are most responsible for the development of ischemic events.

Arteriosclerosis↗
PubMed1995

Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression.

The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein that is required for the assembly and secretion of apoB-containing lipoproteins. In this study, four factors that modulate lipid and lipoprotein metabolism were tested for their ability to regulate MTP levels in HepG2 cells. Of the factors tested, only insulin (> or = 10(-9) M), and high concentrations of glucose (> 30 mM) were found to decrease MTP large subunit mRNA levels. Oleate and glucagon had no effect on MTP mRNA levels. The insulin effect was dose- and time-dependent and was mediated through the insulin receptor. In addition, insulin also decreased protein disulfide isomerase (the small subunit of MTP) mRNA levels, although to a lesser extent. Due to the slow turnover rate of MTP (t1/2 = 4.4 days), short-term insulin treatment (24 h) did not change MTP activity levels, indicating that the regulation of MTP mRNA levels by insulin is unrelated to insulin's acute inhibition of apoB secretion in HepG2 cells. In summary, MTP mRNA levels are acutely regulated by insulin in HepG2 cells; however, sustained changes in MTP mRNA levels would be required to affect MTP protein levels.

Carrier Proteins↗
PubMed1995

Active proliferation of different cell types, including lymphocytes, in human atherosclerotic plaques.

Cell proliferation, an important mechanism of atherosclerotic plaque growth, occurs among smooth muscle, inflammatory cell, and other cell types. We have identified different topographical patterns of cell proliferation in human carotid plaques, based on cell type. Cell proliferation was determined with an antibody to the proliferating cell nuclear antigen (PCNA), combined with cell type-specific antibodies. Despite low levels of overall proliferative activity, the intima displayed more proliferative activity than the underlying media (1.61 +/- 0.35% in intima versus 0.05 +/- 0.03% in media; P < 0.01). The preponderant proliferative cell type in the intima was the monocyte/macrophage (46.0% of PCNA-positive cells), with a minority being smooth muscle alpha-actin-positive (9.7%), microvascular endothelial (14.3%), and T cells (13.1%). Smooth muscle cells were the dominant proliferating cell type in the media (44.4% of PCNA-positive cells versus 20% endothelial cells, 13.0% monocyte/macrophages, and 14.3% T cells). Within the plaque, foam-cell-rich regions mostly displayed proliferation among macrophages (66.5%), whereas in vascularized fields PCNA positivity was almost equally shared by endothelial cells (23.8%), monocyte/macrophages (26.3%), smooth muscle alpha-actin-positive cells (14.0%), and to a lesser extent, T cells (8.2%). Logistic and linear regression analyses also demonstrated that location in foam-cell-rich regions was a significant predictor of proliferation only among monocyte/macrophages, whereas location in vascularized regions was a good predictor of PCNA positivity among both inflammatory and noninflammatory cells. These different patterns of cell type proliferation suggest possibly different distributions of putative responsible growth regulatory factors in human atherosclerosis.

Animals↗
PubMed1995

Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery.

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation following arterial injury plays a critical role in a variety of vascular proliferative disorders, including atherosclerosis and restenosis after balloon angioplasty. In this study, we tested the hypothesis that localized arterial infection at the time of balloon angioplasty with an adenovirus (ADV-tk) encoding the herpes simplex virus thymidine kinase gene (HSV-tk), followed by systemic ganciclovir administration, can inhibit VSMC proliferation and neointima formation in a well-characterized model of arterial injury and restenosis. MATERIALS AND METHODS: The left carotid arteries of 31 male Sprague-Dawley rats were subjected to balloon angioplasty and immediately infected with 2 x 10(9) pfu of either ADV-tk or a control adenovirus that does not encode a recombinant protein (ADV-delta E1). Twenty-four hours after injury, animals from each experimental group were randomized to receive a course of systemic ganciclovir (ADV-tk/+GC, ADV delta E1/+GC) or saline (ADV-tk/-GC, ADV-delta E1/-GC). VSMC DNA synthesis was measured by 5'-bromodeoxuridine (BrdU) incorporation 2-4 days after balloon injury. The extent of restenosis, expressed as the neointima to media (I/M) area ratio was determined by digital planimetry 20 days after balloon injury in each of the four treatment groups. Immunohistochemistry using a mAb to von Willebrand factor (vWF) was used to determine the effects of ADV-tk infection and ganciclovir treatment on re-endothelialization of the carotid arteries 20 days following balloon angioplasty. RESULTS: Forty-one percent of the medial VSMCs in the ADV-tk/-GC arteries were labeled with BrdU 4 days after balloon injury. In contrast, ADV-tk infected animals that were treated with systemic ganciclovir (ADV-tk/+GC) displayed a 40% reduction in BrdU-staining medial VSMCs (p < 0.03). I/M area ratios of the three control groups were 1.17 +/- 0.18 (ADV-tk/-GC, n = 5), 1.15 +/- 0.10 (ADV-delta E1/+GC, n = 6), and 0.91 +/- 0.08 (ADV-delta E1/-GC, n = 6). These differences were not statistically significant (p > 0.05). In contrast, the ADV-tk/+GC animals (n = 6) displayed an I/M area ratio of 0.49 +/- 0.13 which was significantly lower than that seen in each of the three control groups (p < 0.02). None of the treated animals showed evidence of significant organ toxicity at autopsy. A regenerated endothelium was observed in the ADV-tk/+GC animals 20 days after balloon injury. CONCLUSIONS: Localized arterial infection with ADV-tk at the time of balloon angioplasty followed by systemic ganciclovir therapy reduces VSMC proliferation and neointimal expansion in the rat carotid artery injury model. Moreover, combined treatment with ADV-tk and systemic ganciclovir does not result in systemic toxicity and appears to selectively eliminate proliferating VSMCs, while preserving the capacity of the injured arterial segments to re-endothelialize within 3 weeks of injury. Taken together, these results support the feasibility of using this gene therapy approach for the treatment of human vascular proliferative disorders.

Adenoviridae↗
PubMed1995

An analysis of the paper-based health record: information content and its implications for electronic patient records.

An analysis of paper-based charting was carried out at Sunnybrook Health Sciences Center as a prelude to developing a strategic plan to implement an electronic patient record. A relational model of the Sunnybrook paper chart was developed, describing each of its forms in terms of specific data fields. Three hundred and forty nine different forms are in current use at Sunnybrook, containing 64 types of data fields such as Patient Demographics, Vital Signs, and Doctor's Orders. The extent of data field duplication at the level of hospital forms was significant. A Patient Demographics field was present on all forms and on all pages of a patient's chart, as would be expected. Twenty seven other fields were duplicated on more than ten different forms, including Working Diagnosis which was present on 110 forms, History of Past Illness on 42 forms, and History of Present Illness on 32 forms. Current Medications were recorded on 32 forms and Allergy fields were present on 29 separate forms. Only five data fields of the total 64 were present on only one form. The duplication of data fields within complete patient charts was then examined to confirm that data field duplication was occurring within the actual healthcare delivery process. Using the relational model of the charting system, 143 acute care in-patient encounters were abstracted into the database. The charts were selected randomly from each of the hospital inpatient services. The numbers and types of forms within each chart were recorded, amounting to 18,654 physical pages and using 165 of the different forms. The average in-patient encounter within the model was 130.4 pages long, with a minimum of 27 pages, a maximum of 559 pages, and containing on average 25.8 different forms. The duplication of data fields within actual charts followed a pattern similar to the duplication found on the forms. Initial diagnosis was present on an average of 20.4 pages within the charts, with a minimum of 2 pages and a maximum of 152 pages containing this data field. Other frequently occurring data fields included History of Past Illness present on an average of 12.2 pages per chart, History of present illness on 10.2 pages per chart, and allergies on an average of 9.1 pages per chart. The results obtained through the examination of Sunnybrook charts should be generalizable to most paper-based systems. This study did not measure the workload associated with duplicating chart data. however, the magnitude of the duplication seen in this study leaves little doubt that significant amounts of time could be saved with appropriate modification of health care delivery processes. Multiple copies of the same data field within a database are referred to as aliases of each other. This study demonstrates that hospital charts contain many copies of the same information, such as medication lists, allergies etc. Due to manual replication of data fields, there is no mechanism to ensure that each copy of a data element within a chart actually contains the same information. This aliasing of data through manual duplication compromises the integrity of data within paper-based charts. Decisions and therapy based upon contradictory or inaccurate data are likely to lead to inefficient or erroneous care delivery; this has significant implications for hospital liability and quality of patient care. A growing recognition of the costs and risks of data replication within paper-based charting systems is driving the healthcare industry toward Electronic Patient Record systems. Better quality patient care data, provided by computerized records, is likely to be necessary but not sufficient to improving the efficiency and effectiveness of the healthcare system. Intelligent application of this information will be essential.

Medical Records↗
PubMed1995

Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM.

OBJECTIVE: We investigated the relationship of liver fat to visceral adipose tissue, serum triglyceride levels and glucose disposal. DESIGN: Cross-sectional, prospective. SUBJECTS: 21 lean to moderately obese black NIDDM men (mean +/- s.d. age 48.9 +/- 9.4 years, body mass index 26.3 +/- 2.4, fasting plasma glucose 104 +/- 10 mg/dl, HBA1C 4.6 +/- 0.8% and body fat 26 +/- 6%) with no evidence of liver disease or alcohol abuse. Eleven were insulin-sensitive (glucose disposal > 5.5 mg/kg/min) and ten were insulin-resistant subjects during euglycemic insulin clamps. MEASUREMENTS: Body composition and liver density were determined by whole body computed tomography using 22 scans. Liver fat score was defined as 100 minus the absolute liver density. Glucose disposal was measured during 1 mU/kg/min euglycemic insulin clamp with 3-3H glucose. RESULTS: Visceral adipose tissue volume was 3.54 +/- 1.87 litres. The liver fat score was 48.8 +/- 5.0 (not in the range of clinical hepatic steatosis). Glucose disposal ranged from 2.5 to 8.1 mg/kg/min. The liver fat score was correlated with visceral/total adipose tissue ratio (r = 0.65, P = 0.001) and to fasting serum triglyceride levels (r = 0.47, P = 0.032). Fasting serum triglyceride levels were related to visceral adipose tissue (r = 0.52, P = 0.016). Liver fat was inversely related to glucose disposal (r = -0.42, 1 tail P = 0.036). CONCLUSIONS: In non-insulin-dependent diabetes mellitus, liver fat may contribute to insulin resistance and be a link between visceral adipose tissue mass and serum triglyceride levels.

Adipose Tissue↗
PubMed1994

Elastin expression in a model of acute arterial graft rejection.

Elastin is an important component of normal blood vessels and the extracellular matrix of atherosclerotic plaques, but its role in intimal thickening in the arteries of transplanted organs has not been defined. We have looked at elastin gene expression (by in situ mRNA hybridization) in an animal model using an abdominal aortic transplant between 2 strains of rats disparate for MHC class I antigens. The normal aortic wall of adult rats lacks elastin mRNA. Aortic allografts at 7 days after transplantation exhibit increased elastin mRNA in the medial vascular smooth muscle cells. This medial elastin mRNA expression is present only until 20 days after transplantation, and at later times, only the juxtaluminal cells of the neointima express elastin mRNA. Stainable elastin is detectable only in regions that previously demonstrated high levels of elastin mRNA. Combined in situ hybridization and immunocytochemistry reveals that most elastin mRNA-expressing cells in the media are alpha-actin-positive smooth muscle cells. In the neointima, elastin mRNA-expressing cells do not stain with antibodies to either smooth muscle alpha-actin or macrophage proteins. This cell population may represent a "synthetic" phenotype of vascular smooth muscle cell lacking alpha-actin protein. We presume there is immune cell-mediated injury leading to a vascular smooth muscle cell response and part of the vascular smooth muscle cell response may be increased elastin mRNA expression and elastin deposition in the allografts.

Actins↗
PubMed1994

New mollusc-specific alpha-conotoxins block Aplysia neuronal acetylcholine receptors.

Two mollusc-specific neurotoxic peptides from the venom of the molluscivorous snail Conus pennaceus are described. These new toxins block acetylcholine receptors (AChR) of cultured Aplysia neurons. Bath application of 0.5-1 microM toxin induces 5-10-mV membrane depolarization, which recovers to the control level within 1-3 min in the presence of the toxin. This response is blocked by 1 mM hexamethonium. Concomitantly with the transient depolarization, the toxins block approximately 90% of the depolarizing responses evoked by brief iontophoretic application of acetylcholine. The pharmacology and amino acid sequences of the toxins (alpha PnIA, GCCSLPPCAANNPDYC-NH2; alpha PnIB, GCCSLPPCALSNPDYC-NH2) enable their classification as novel alpha-conotoxins. The sequences differ from those of previously described alpha-conotoxins in a number of features, the most striking of which is the presence of a single negatively charged residue in the C-terminal loop. This loop contains a positively charged residue in piscivorous venom alpha-conotoxins. In contrast to other alpha-conotoxins, which are selective for vertebrate skeletal muscle nicotinic ACh receptors, these Conus pennaceus toxins block neuronal ACh receptors in molluscs. As such they are new probes which can be used to define subtypes of ACh receptors, and they should be useful tools in the study of structure-function relationships in ACh receptors.

Amino Acid Sequence↗
PubMed1994

Gene therapy for vascular smooth muscle cell proliferation after arterial injury.

Accumulation of vascular smooth muscle cells as a consequence of arterial injury is a major feature of vascular proliferative disorders. Molecular approaches to the inhibition of smooth muscle cell proliferation in these settings could potentially limit intimal expansion. This problem was approached by introducing adenoviral vectors encoding the herpesvirus thymidine kinase (tk) into porcine arteries that had been injured by a balloon on a catheter. These smooth muscle cells were shown to be infectable with adenoviral vectors, and introduction of the tk gene rendered them sensitive to the nucleoside analog ganciclovir. When this vector was introduced into porcine arteries immediately after a balloon injury, intimal hyperplasia decreased after a course of ganciclovir treatment. No major local or systemic toxicities were observed. These data suggest that transient expression of an enzyme that catalyzes the formation of a cytotoxic drug locally may limit smooth muscle cell proliferation in response to balloon injury.

Adenoviridae↗
PubMed1994

Direct gene transfer for the understanding and treatment of human disease.

Direct gene transfer has been used to develop molecular genetic interventions for acquired diseases in several animal models. Through the use of intravascular catheters or anatomically localized injection of DNA liposome complexes, specific tissues can be transduced with recombinant genes. Several promising applications of this method for the study of vascular biology have been demonstrated by direct gene transfer into arteries in vivo. Delivery, via catheter, of genes that modulate the thrombogenic or proliferative properties of vascular cells may someday provide therapy for stenotic lesions of atherosclerosis or following angioplasty. Cancer is another acquired disorder in which direct gene transfer may improve the efficacy of treatment. Introduction of class I MHC or cytokine genes with antitumor or immunostimulatory effects have demonstrated promise in animal models. Direct transfer of an allogeneic class I MHC gene into tumors in vivo induces a CD8+ CTL response against weak antigens on poorly immunogenic tumors. The efficacy of this antitumor response can be augmented to induce regression of actively growing established tumors. Additional strategies, such as intratumoral delivery of combinations of multiple cytokine and MHC genes, may serve to improve the antitumor response. A clinical gene therapy protocol is underway to analyze the safety and efficacy of DNA liposome-mediated gene transfer in humans. Development of improved gene delivery systems and introduction of recombinant genes into visceral tumors by intravascular catheter will extend the application of direct gene transfer to immunotherapy of malignancies. These clinical trials of direct gene transfer will help to develop new treatment strategies for human diseases.

Animals↗
PubMed1994

A new neurotoxin receptor site on sodium channels is identified by a conotoxin that affects sodium channel inactivation in molluscs and acts as an antagonist in rat brain.

The peptide conotoxin TxVIA is selectively toxic to molluscs and slows sodium current inactivation in mollusc neurons. Here we show that TxVIA binds with high affinity to new sites on sodium channels in both mollusc and rat central nervous systems, despite its lack of toxicity to vertebrates. Furthermore, TxVIA protects from the toxic effects of Conus striatus toxin in rat brain. The TxVIA binding site differs from other neurotoxin receptor sites affecting sodium channel inactivation in that binding is not voltage-dependent and undergoes negative allosteric modulation by veratridine. TxVIA therefore represents a novel category of sodium channel probes, designated delta-conotoxins. TxVIA is shown to discriminate between sodium channels in different phyla by activity but not by binding, thus providing a lead for the study of structural elements affecting gating modes of sodium channels.

Animals↗
PubMed1994

Basic fibroblast growth factor in the early human burn wound.

The role of endogenous growth factors in normal wound healing is not clear. Most of the data on growth factors in healing wounds have been obtained from the application of recombinant exogenous growth factors to animal and human wounds. We describe the immunolocalization of basic fibroblast growth factor (bFGF) in the injured dermis of skin from patients with partial and full-thickness burns. Three antibodies demonstrate an extracellular staining pattern of bFGF corresponding to areas of tissue injury that was most intense in specimens collected between 4 and 11 days post-burn injury. In contrast, bFGF staining appeared markedly decreased by Postburn Day 17 and was more consistent with uninjured tissue in a 30-day-old burn that had virtually reepithelialized. Basic FGF staining in the non-burned skin from the same patients was restricted to the dermal capillary basement membranes and the sweat glands, which is consistent with other reports of immunoreactive bFGF localization in normal adult skin. The immunohistochemical results were confirmed with Western immunoblots of the same tissue. The major band at 16.5 kDa, which is within the recognized range of the bFGF molecule's several forms, was detected in both burned and unburned tissue from the same patient. These findings support the hypothesis that bFGF is a presynthesized mediator that is stored in either the cells or extracellular matrix, is released locally from sites of direct injury, and may be important in early wound healing.

Blotting, Western↗
PubMed1994

Echolucent regions in carotid plaque: preliminary analysis comparing three-dimensional histologic reconstructions to sonographic findings.

This study compares sonographic and histologic findings within defined spatial regions in carotid artery plaque, using computer generated three-dimensional reconstructions. Twenty-four patients (14 asymptomatic, 10 symptomatic) with angiographically documented 70% to 99% carotid artery stenosis were examined with ultrasonic B-mode imaging prior to endarterectomy. Using a standardized protocol for instrument set-up and scanning technique, echolucent regions in the plaque were identified. After endarterectomy, each plaque was sectioned at 0.5 to 1.0 millimeter increments throughout its length. Sites containing intraplaque hemorrhage, cholesterol clefts, foam cells, necrotic cores, dense calcification and speckled calcification were identified. These areas were outlined on a template, digitized and imported into a computer program that created three-dimensional reconstructions of the histologic findings. Each carotid plaque was divided into quadrants for analysis: (1) lateral wall proximal to the common carotid bifurcation (flow divider); (2) medial wall proximal to the flow divider; (3) lateral wall distal to the flow divider; and (4) medial wall distal to the flow divider. The odds of finding intraplaque hemorrhage, foam cells, necrotic cores and speckled calcification were significantly higher in quadrants with an echolucent region identified by ultrasonography (odds ratio (95% confidence interval) for intraplaque hemorrhage = 3.5 (1.4-8.6); foam cells = 4.0 (1.6-9.9); necrotic cores = 3.2 (1.2-8.4); speckled calcification = 4.0 (1.6-9.8). This preliminary analysis demonstrates the potential of these newly developed techniques for comparing ultrasonic imaging to histology.

Aged↗