Biomedical subjects

D Gordon

Publications and source records attributed to D Gordon.

At least 271 records · Page 15Linked to original sources

PubMed1993

A peptide motif that recognizes A.T tracts in DNA.

The DAT1 gene of Saccharomyces cerevisiae encodes a DNA binding protein that specifically interacts with nonalternating oligo(A).oligo(T) tracts (A.T tracts). Deletion analysis of DAT1 coding information showed that the amino-terminal 36 residues are sufficient for specific DNA binding activity. Furthermore, a 35-residue synthetic peptide corresponding to amino acids 2-36 bound to A.T tracts with an equilibrium dissociation constant of 4 x 10(-10) M. Within this region the pentad Gly-Arg-Lys-Pro-Gly is repeated three times. Mutational analysis revealed that the Arg side chains are required for high-affinity binding, whereas the other pentad side chains are dispensable. Chemical interference experiments showed that the DAT1 protein interacts with the minor groove of the double helix. The data suggest that the pentad arginines interact in a cooperative manner with a repeated minor groove feature of A.T tract DNA to achieve high-affinity recognition. Amino acid similarities with other DNA binding proteins suggest that the DAT1 protein pentad represents a specialized example of a widespread motif used by proteins to recognize A.T base pairs.

Amino Acid Sequence↗

PubMed1993

Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia.

The arterial wall responds to thrombosis or mechanical injury through the induction of specific gene products that increase cellular proliferation and connective tissue formation. These changes result in intimal hyperplasia that is observed in restenosis and the early phases of atherosclerosis. Transforming growth factor beta 1 (TGF-beta 1) is a secreted multi-functional protein that plays an important role in embryonal development and in repair following tissue injury. However, the function of TGF-beta 1 in vascular cell growth in vivo has not been defined. In this report, we have evaluated the role of TGF-beta 1 in the pathophysiology of intimal and medial hyperplasia by gene transfer of an expression plasmid encoding active TGF-beta 1 into porcine arteries. Expression of TGF-beta 1 in normal arteries resulted in substantial extracellular matrix production accompanied by intimal and medial hyperplasia. Increased procollagen, collagen, and proteoglycan synthesis in the neointima was demonstrated by immunohistochemistry relative to control transfected arteries. Expression of TGF-beta 1 induced a distinctly different program of gene expression and biologic response from the platelet-derived growth factor B (PDGF B) gene: procollagen synthesis induced by TGF-beta 1 was greater, and cellular proliferation was less prominent. These findings show that TGF-beta 1 differentially modulates extracellular matrix production and cellular proliferation in the arterial wall in vivo and could play a reparative role in the response to arterial injury.

Animals↗

PubMed1993

Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.

Allograft rejection is a T cell-dependent process. Productive T cell activation by antigen requires antigen engagement of the T cell receptor as well as costimulatory signals delivered through other T cell surface molecules such as CD28. Engagement of CD28 by its natural ligand B7 can be blocked using a soluble recombinant fusion protein, CTLA4Ig. Administration of CTLA4Ig blocks antigen-specific immune responses in vitro and in vivo, and we have shown that treatment of rats with a 7-d course of CTLA4Ig at the time of transplantation leads to prolonged survival of cardiac allografts (median 30 d), although most grafts are eventually rejected. Here, we have explored additional strategies employing CTLA4Ig in order to achieve long-term allograft survival. Our data indicate that donor-specific transfusion (DST) plus CTLA4Ig can provide effective antigen-specific immunosuppression. When DST is administered at the time of transplantation followed by a single dose of CTLA4Ig 2 d later, all animals had long-term graft survival (> 60 d). These animals had delayed responses to donor-type skin transplants, compared with normal rejection responses to third-party skin transplants. Furthermore, donor-matched second cardiac allografts were well tolerated with minimal histologic evidence of rejection. These data indicate that peritransplant use of DST followed by subsequent treatment with CTLA4Ig can induce prolonged, often indefinite, cardiac allograft acceptance. These results may be clinically applicable for cadaveric organ and tissue transplantation in humans.

Abatacept↗

PubMed1993

A comparison of management patterns after acute myocardial infarction in Canada and the United States. The SAVE investigators.

BACKGROUND: There are major differences in the organization of the health care systems in Canada and the United States. We hypothesized that these differences may be accompanied by differences in patient care. METHODS: To test our hypothesis, we compared the treatment patterns for patients with acute myocardial infarction in 19 Canadian and 93 United States hospitals participating in the Survival and Ventricular Enlargement (SAVE) study, which tested the effectiveness of captopril in this population of patients after a myocardial infarction. RESULTS: In Canada, 51 percent of the patients admitted to a participating coronary care unit had acute myocardial infarctions, as compared with only 35 percent in the United States (P < 0.001). Despite the similar clinical characteristics of the 1573 U.S. patients and 658 Canadian patients participating in the study, coronary arteriography was more commonly performed in the United States than in Canada (in 68 percent vs. 35 percent, P < 0.001), as were revascularization procedures before randomization (31 percent vs. 12 percent, P < 0.001). During an average follow-up of 42 months, these procedures were also performed more commonly in the United States than in Canada. These differences were not associated with any apparent difference in mortality (22 percent in Canada and 23 percent in the United States) or rate of reinfarction (14 percent in Canada and 13 percent in the United States), but there was a higher incidence of activity-limiting angina in Canada than in the United States (33 percent vs. 27 percent, P < 0.007). CONCLUSIONS: The threshold for the admission of patients to a coronary care unit or for the use of invasive diagnostic and therapeutic interventions in the early and late periods after an infarction is higher in Canada than in the United States. This is not associated with any apparent difference in the rate of reinfarction or survival, but is associated with a higher frequency of activity-limiting angina.

Angina Pectoris↗

PubMed1993

Binding of an alpha scorpion toxin to insect sodium channels is not dependent on membrane potential.

The insect-specific Lqh alpha IT toxin resembles alpha scorpion toxins affecting mammals by its amino acid sequence and effects on sodium conductance. The present study reveals that Lqh alpha IT does not bind to rat brain membranes and possesses in locust neuronal membranes a single class of high affinity (Kd = 1.06 +/- 0.15 nM) and low capacity (Bmax = 0.7 +/- 0.19 pmol/mg protein) binding sites. The latter are: (1) distinct from binding sites of other sodium channel neurotoxins; (2) inhibited by sea anemone toxin II; (3) cooperatively interacting with veratridine; (4) not dependent on membrane potential, in contrast to the binding sites of alpha toxins in vertebrate systems. These data suggest the occurrence of (a) conformational-structural differences between insect and mammal sodium channels and (b) the animal group specificity and pharmacological importance of the alpha scorpion toxins.

Animals↗

PubMed1993

Alteration of sodium currents by new peptide toxins from the venom of a molluscivorous Conus snail.

TxIA and TxIB, peptides with 27-amino acid residues recently isolated from the molluscivorous marine snail Conus textile neovicarius, exhibit strong paralytic activity in molluscs, with no paralytic effects on athropods and vertebrates. At concentrations of 0.25-0.5 microM the toxins cause spontaneous repetitive firing and dramatic broadening of the action potential of cultured Aplysia neurons. The action potential duration partially recovers within 30 min in the presence of the toxins. Under these conditions a second toxin application does not change the spike duration. TxI-induced spike broadening occurs when potassium and calcium conductances are blocked. Voltage-clamp experiments revealed that the toxins alter the kinetics of the sodium current either by slowing down the rate of sodium current inactivation or by recruiting silent sodium channels with slower activation and inactivation kinetics. The toxins shift the voltage-dependent steady-state Na+ current inactivation curve to more positive values by 6 mV. These changes are not associated with alteration in the rate of sodium current activation, in the peak sodium current, or the sodium current reversal potential. TxI apparently represents a new class of conotoxins with an unusual phylogenic specificity and may therefore be useful as a probe for the study of molluscan neuronal sodium channels.

Animals↗

PubMed1993

Ramipril prevents impaired endothelium-dependent relaxation in arteries from rabbits fed an atherogenic diet.

Endothelium-dependent relaxation in arteries is attenuated in clinical and experimental atherosclerosis. This study investigates the endothelial preservation properties of the angiotensin converting enzyme inhibitor, ramipril, by assessing its ability to restore endothelium-dependent responsiveness in blood vessels from rabbits fed an atherogenic diet (0.25% cholesterol; 3% coconut oil; 12 weeks). Seven rabbits fed the atherogenic diet received ramipril (3 mg/kg mixed into their food daily) and 6 rabbits were maintained on the atherogenic diet alone. Control rabbits (n = 6) were fed a standard diet and did not receive ramipril. At the end of the dietary intervention, the rabbits were killed and blood was collected for measurement of the lipid profile. The thoracic aorta was isolated and half was frozen for pathologic review while the other half was cut into rings and placed in a muscle bath for measurement of isometric force development. Dose response curves to phenylephrine (10(-9) to 10(-5) M) and angiotensin II (10(-10) to 3 x 10(-7) M) were completed. There was a minimal decrease in responsiveness to phenylephrine in vessels from rabbits eating the atherogenic diet compared with controls and no significant differences in the response to angiotensin II for any of the vessels. Following contraction by phenylephrine, acetylcholine (10(-9) to 10(-5) M) and nitroglycerin (10(-10) to 10(-5) M) dose response curves were completed. Relaxation to acetylcholine in aortic rings from control rabbits was observed, although in arteries from atherogenic rabbits relaxation was attenuated. This effect was prevented in the atherogenic rabbits fed ramipril. Responsiveness to the endothelium-independent vasodilator, nitroglycerin, was similar in arteries from the three rabbit groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1993

Thrombocytopenia following administration of phenytoin, dexamethasone and cimetidine: a case report and a potential mechanism.

Cimetidine and phenytoin are useful medications often used together in patients with seizure disorders secondary to brain masses or metabolic abnormalities. We describe a case of thrombocytopenia in the setting of concurrent phenytoin, dexamethasone and cimetidine administration, and compare it with previously described cases of thrombocytopenia induced by concurrent use of phenytoin, cimetidine, and glucocorticoids. The similarities between these cases suggest mechanisms by which these agents may induce thrombocytopenia, specifically through potential downregulation of epoxide hydrolase by glucocorticoids.

Aged↗

PubMed1993

A comparison of different methods of assessing free radical activity in type 2 diabetes and peripheral vascular disease.

Increased free radical activity in diabetes mellitus may contribute to the higher prevalence and mortality from macrovascular disease in diabetic patients. To investigate this, levels of plasma antioxidants (superoxide dismutase, caeruloplasmin, plasma, and lysate thiol), diene conjugates, lipid peroxides, and chemiluminescence were measured in diabetic and non-diabetic patients with peripheral vascular disease compared with healthy control subjects. Caeruloplasmin, diene conjugate ratio, and lipid peroxides were significantly increased in patients with vascular disease but there was no difference between diabetic and non-diabetic patients. Conjugated diene ratio correlated with caeruloplasmin (r = 0.40, p < 0.02) and inversely with superoxide dismutase level (r = 0.36, p < 0.05) but there was no significant correlation between other antioxidants and diene conjugates, lipid peroxides or chemiluminescence. The relationship between different indirect measurements of free radical activity is variable but there appears to be no additive effect of diabetes on the increased free radical activity associated with vascular disease.

Aged↗

PubMed1993

Psychological factors and their relationship to diabetes control.

Thirty-nine Type 1 diabetic patients were asked to complete an Eysenck Personality Questionnaire (EPQ). A significant relationship was found between neuroticism scores and glycosylated haemoglobin concentrations (r = 0.43, p < 0.01) and also fructosamine (r = 0.45, p < 0.01). Patients with glycosylated haemoglobin concentrations greater than or equal to 10 (n = 13) had significantly higher neuroticism scores than patients with glycosylated haemoglobin results less than or equal to 8 (n = 11) (p < 0.01).

Adolescent↗

PubMed1993

Prostaglandin prophylaxis and bladder function after vaginal hysterectomy: a prospective randomised study.

OBJECTIVE: To assess the efficacy of prostaglandins in enhancing bladder function after vaginal hysterectomy. DESIGN: Prospective randomised study of women who underwent vaginal hysterectomy between November 1989 and August 1990. SETTING: Sackler School of Medicine Tel Aviv University Medical Center, Department of Obstetrics and Gynaecology 'B'. SUBJECTS: 24 women who underwent vaginal hysterectomy and anterior and posterior colporrhaphy for prolapse. INTERVENTION: Administration of prostaglandin F2 alpha 5 mg intravesically or E2 3 mg intravaginally versus 100 ml saline intravesically (control) daily, starting on the first postoperative day, until adequate spontaneous voiding was established. RESULTS: Women receiving PGE2 resumed spontaneous bladder functions earlier, required significantly fewer days catheterisation and had significantly less febrile morbidity compared to women in the control group or PGE2 group. CONCLUSIONS: Prostaglandins PGE2 intravaginally are beneficial in enhancing functions after vaginal hysterectomy [corrected].

Adult↗

PubMed1993

Cell proliferation in human arteriovenous fistulas used for hemodialysis.

The long-term patency of arteriovenous (AV) fistulas created for hemodialysis of renal-failure patients is usually measured in months, particularly when polytetrafluoroethylene (PTFE) material is interposed between the artery and vein. This is due to the rapid development of intimal hyperplastic lesions in the anastomosis region of the PTFE graft material with the vein. We studied the proliferative patterns in seven human AV fistulas removed at the time of fistula revision. Cell proliferation was determined by using an antibody to the proliferating cell nuclear antigen (PCNA), and specific cell types were identified by immunochemical reagents for smooth muscle cells, monocytes/macrophages, monocytes, lymphocytes, and endothelial cells. All venous segments exhibited a markedly hyperplastic intima. Vascularization of the intima and media by capillary-sized vessels was found. The main intimal cellular component was smooth muscle. Macrophages were usually seen around microvessels, and many also populated the perigraft region of the adventitia. In contrast to human atherosclerotic lesions, high rates of cell proliferation were observed in these fistulas. PCNA indices (percentage of cells that were PCNA positive [mean +/- SD]) were as follows: intima 17.7 +/- 11.3%, media 24 +/- 11.2%, and adventitia 20 +/- 11.6%. However, the distribution of PCNA-positive cells was not uniform. Instead, the PCNA index in microvessel-containing intimal fields was five to six times that of avascular fields (28.9 +/- 10.6% versus 4.9 +/- 4.5%, respectively, p < 0.001). Double immunolabeling revealed a large proportion of PCNA-positive microvascular endothelial cells and surrounding pericyte-like smooth muscle cells, as well as smooth muscle cells without visual connection to either microvessels or the lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy.

On the basis of animal models of arterial injury, smooth muscle cell proliferation has been posited as a dominant event in restenosis. Unfortunately, little is known about this proliferation in the human restenotic lesion. The purpose of this study was to determine the extent and time course of proliferation in primary and restenotic coronary atherectomy-derived tissue. Primary (n = 118) and restenotic (n = 100) coronary atherectomy specimens were obtained from 211 nonconsecutive patients. Immunocytochemistry for the proliferating cell nuclear antigen (PCNA) was used to gauge proliferation in the atherectomy specimens. The identity of PCNA-positive cells was then determined using immunohistochemical cell-specific markers. Eighty-two percent of primary specimens and 74% of restenotic specimens had no evidence of PCNA labeling. The majority of the remaining specimens had only a modest number of PCNA-positive cells per slide (typically < 50 cells per slide). In the restenotic specimens, PCNA labeling was detected over a wide time interval after the initial procedure (eg, 1 to 390 days), with no obvious proliferative peak. Cell-specific immunohistochemical markers identified primary and restenotic PCNA-positive cells as smooth muscle cells, macrophages, and endothelial cells. In conclusion, the findings were as follows: (1) Proliferation in primary and restenotic coronary atherectomy specimens, as indicated by PCNA labeling, occurs infrequently and at low levels. (2) The response to injury in existing animal models of angioplasty may follow a very different course of events from the clinical reality in human atherosclerotic coronary arteries and may help explain why current approaches to restenosis therapy have been ineffective.

Adult↗

PubMed1993

Carotid artery intraplaque hemorrhage and stenotic velocity.

BACKGROUND AND PURPOSE: One of the proposed mechanisms for sudden expansion of a carotid bifurcation plaque is hemorrhage within the lesion. It has been postulated that the sudden increase in plaque size will acutely reduce blood flow to the ipsilateral hemisphere and induce either a transient ischemic attack or a stroke. In this study, the relation between peak systolic velocity at the site of narrowing and its potential role in the development of intraplaque hemorrhage were investigated. METHODS: Ten patients who had carotid endarterectomy were examined by duplex Doppler sonography before surgery to determine the peak systolic velocity at the site of maximal narrowing. The excised carotid plaques were sectioned at 1-mm intervals and examined for histological evidence of intraplaque hemorrhage. The recorded peak systolic velocities in patients with intraplaque hemorrhage were compared with the velocities in cases in which no hemorrhage was identified. RESULTS: Five of the ten patients had intraplaque hemorrhage. Four of the five patients with intraplaque hemorrhage had a peak systolic velocity of > 420 cm/sec and diastolic velocities of > 160 cm/sec; none of the patients without intraplaque hemorrhage had such high values. CONCLUSIONS: Peak systolic velocity is significantly higher in patients with intraplaque hemorrhage. The specificity and sensitivity of a peak systolic velocity of > 420 cm/sec in predicting intraplaque hemorrhage remains to be determined.

Arteriosclerosis↗

PubMed1993

Recombinant platelet-derived growth factor B gene expression in porcine arteries induce intimal hyperplasia in vivo.

Platelet-derived growth factor (PDGF) B chain induces cell proliferation in vitro and is associated with arterial lesions that cause cardiovascular disease. However, it has been difficult to document the biological response to PDGF B gene expression in arteries in vivo. To determine the biologic effects of this growth factor in vivo, we have introduced an eukaryotic expression vector plasmid encoding recombinant PDGF B by direct gene transfer into porcine iliofemoral arteries using DNA liposome complexes. The presence of PDGF B plasmid DNA and expression of recombinant mRNA were confirmed by polymerase chain reaction analysis, and recombinant PDGF protein was demonstrated by immunohistochemistry. Intimal thickening was observed in porcine arteries 21 days following transfection with the recombinant PDGF B gene compared with arteries transduced with a control gene, E. coli beta-galactosidase. An eightfold increase in intimal to medial ratio was present in PDGF B gene transfected arteries compared with control transfected arteries (P = 0.001). This study suggests that expression of a recombinant PDGF B gene in vivo can play a role in the induction of intimal hyperplasia, which can lead to cardiovascular diseases.

Animals↗

PubMed1993

Type I collagen gene expression in human atherosclerosis. Localization to specific plaque regions.

Because collagen is a major component of the human atherosclerotic plaque, factors controlling collagen synthesis may have a profound influence on the volume growth of these intimal lesions. In human arteries, we compared normal vs atherosclerotic media vs intimas for type I collagen gene expression using immunocytochemistry and in situ messenger RNA hybridization with subsequent correlations with plaque topographical features. We also determined the associations of such collagen gene expression with proximity to monocyte/macrophages and T lymphocytes. Type I collagen synthesis appears to be upregulated in atherosclerotic plaques compared with their underlying medias and normal internal mammary arteries and coronary diffuse intimal thickenings. At least in established and advanced coronary and carotid plaques, type I collagen gene expression is focal and especially prevalent in fibrous cap and vascularized regions. Although macrophages and type I procollagen messenger RNA and protein are both found in atherosclerotic plaques, no apparent spatial correlation between macrophage presence and type I procollagen presence was found within these atherosclerotic intimas. Type I procollagen presence appears to be negatively associated with the spatial presence of T cells. Thus, human atherosclerotic plaques exhibit nonuniform patterns of type I collagen gene expression. Although the biochemical determinants of this focal gene expression have yet to be determined, it is conceivable that stimulatory/inhibitory cytokines and other factors (eg hemodynamics) play important roles in determining the focal nature of collagen synthesis in atherosclerosis.

Arteriosclerosis↗

PubMed1993

Chemical and electrophysiological characterization of new peptide neurotoxins from the venom of the molluscivorous snail Conus textile neovicarius: a review.

Three peptide toxins exhibiting strong paralytic activity to molluscs, but with no paralytic effects on arthropods or vertebrates, were purified from the venom of the molluscivorous snail Conus textile neovicarius from the Red Sea. The amino acid sequences of these mollusc specific toxins are: TxIA, WCKQSGEMCNLLDQNCCDGYCIVLVCT (identical to the so-called 'King Kong peptide'); TxIB, WCKQSGEMCNVLDQNCCDGYCIVFVCT; TxIIA, WGGYSTYC gamma VDS gamma CCSDNCVRSYCT (gamma = gamma-carboxyglutamate). There is a similarity of the Cys framework of these toxins to that of the omega-conotoxins; however, their net negative charges, high content of hydrophobic residues, and uneven number of Cys residues in TxIIA are highly unusual for conotoxins. When assayed on isolated cultured Aplysia neurons, all three toxins induced spontaneous repetitive firing. The TxI toxins also induced a marked prolongation of the action potential duration. Voltage clamp experiments revealed that the TxI toxins alter the kinetics of the sodium current either by slowing down the rate of sodium current inactivation, or by recruiting silent sodium channels with slower activation and inactivation kinetics. The toxins shift the voltage-dependent steady-state Na+ current inactivation curve to more positive values by 6 mV. These changes are not associated with alteration in the rate of INa+ activation, in the peak INa+, or the sodium current reversal potential. TxI represents a new class of conotoxins with an unusual phylogenic specificity and may therefore be useful as a probe for the study of voltage gated sodium channels. (This review summarizes previously published papers).

Amino Acid Sequence↗

PubMed1993

Risk factors for HIV infection among injection drug users: results of blinded surveys in drug treatment centers, King County, Washington 1988-1991.

Among injection drug users (IDUs) entering drug treatment in King County, Washington between 1988 and 1991, we investigated HIV seroprevalence in relationship to demographic, sexual, and drug-use characteristics. Eighty-two of 3,039 (2.7%) IDUs tested HIV positive. Gay or bisexual men had the highest HIV prevalence (37.1%), followed by lesbian or bisexual women (8.3%), heterosexual men (2.3%), and heterosexual women (1.5%). American Indians were more likely to be infected with HIV than were whites. Those with no permanent address were more likely to be infected than those with an address. Unexpectedly, the prevalence of HIV infection among amphetamine injectors (13.1% of 168) was higher than among those who did not report using amphetamines. After adjustment for sexual orientation, HIV prevalence was four times higher among primary amphetamine injectors and three times higher among secondary amphetamine injectors than among injectors of other drugs. The basis for the strong association observed between HIV infection and a history of injection of amphetamines is not known and should be clarified through further research that obtains more detailed information on IDUs.

Amphetamines↗