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Biomedical subjects

J Ross

Publications and source records attributed to J Ross.

At least 127 records · Page 7Linked to original sources
PubMed1998

Loss of adrenergic control of the force-frequency relation in heart failure secondary to idiopathic or ischemic cardiomyopathy.

This study was designed to determine whether the force-frequency effect on myocardial contractility, known to be importantly regulated by the adrenergic nervous system in experimental animals, can be enhanced by beta-adrenergic receptor stimulation in patients with heart failure. Animal experiments have demonstrated that the positive force-frequency relation in most mammals is subject to enhancement by beta-adrenergic receptor stimulation during exercise or infusion of a beta-receptor agonist. In animal models of heart failure, this regulatory mechanism generally is lost. The response to progressive increases in heart rate to 150 to 160 beats/min by right atrial pacing before and during dobutamine infusion was studied in 3 relatively normal subjects and in 5 patients with severe dilated cardiomyopathy. Left ventricular (LV) pressure and its first derivative (LV dP/dt(max)) were measured with a micromanometer, and the time constant of LV relaxation was assessed. The slopes of the relations between heart rate and LV dP/dt(max) in control subjects were positive at baseline and the mean slope increased substantially and significantly during dobutamine infusion. In patients with heart failure, the heart rate versus LV dP/dt(max) relations were depressed and flattened without a descending limb. Dobutamine infusion shifted this relation upward slightly, without increase in mean slope, indicating lack of amplification. The rate of isovolumic relaxation significantly decreased as heart rate increased at baseline and was further shortened by dobutamine. In patients with heart failure, a depressed and flattened relation between heart rate and LV dP/dt(max) (force-frequency effect) did not show the amplification of myocardial contractility by beta-adrenergic stimulation observed in the normal heart. This abnormality in control of the force-frequency relation undoubtedly plays an important role in the impairment of cardiac function during exercise in heart failure.

Adrenergic beta-Agonists↗
PubMed1998

Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family.

p38 mitogen-activated protein (MAP) kinase activities were significantly increased in mouse hearts after chronic transverse aortic constriction, coincident with the onset of ventricular hypertrophy. Infection of cardiomyocytes with adenoviral vectors expressing upstream activators for the p38 kinases, activated mutants of MAP kinase kinase 3b(E) (MKK3bE) and MAP kinase kinase 6b(E) (MKK6bE), elicited characteristic hypertrophic responses, including an increase in cell size, enhanced sarcomeric organization, and elevated atrial natriuretic factor expression. Overexpression of the activated MKK3bE in cardiomyocytes also led to an increase in apoptosis. The hypertrophic response was enhanced by co-infection of an adenoviral vector expressing wild type p38 beta, and was suppressed by the p38 beta dominant negative mutant. In contrast, the MKK3bE-induced cell death was increased by co-infection of an adenovirus expressing wild type p38 alpha, and was suppressed by the dominant negative p38 alpha mutant. This provides the first evidence in any cell system for divergent physiological functions for different members of the p38 MAP kinase family. The direct involvement of p38 pathways in cardiac hypertrophy and apoptosis suggests a significant role for p38 signaling in the pathophysiology of heart failure.

Adenoviridae↗
PubMed1998

Selective requirement of myosin light chain 2v in embryonic heart function.

Two major myosin light chain 2 isoforms are coexpressed in the early stages of murine cardiogenesis, a cardiac ventricular isoform and a cardiac atrial isoform, each of which is tightly regulated in a muscle cell-type-specific manner during embryogenesis (Chien, K. R., Zhu, H., Knowlton, K. U., Miller-Hance, W., van Bilsen, M., O'Brien, T. X., and Evans, S. M. (1993) Annu. Rev. Physiol. 55, 77-95). We have disrupted myosin light chain 2v gene in mice and monitored in vivo cardiac function in living myosin light chain 2v -/- embryos. The mutant embryos die at approximately embryonic day 12.5. In mutant ventricles, the myosin light chain 2a protein level is increased and reaches levels comparable to the myosin light chain 2v in the ventricles of wild type littermates and is appropriately incorporated into the thick filaments of mutant embryonic hearts. However, despite the substitution of myosin light chain 2a, ultrastructural analysis revealed defects in sarcomeric assembly and an embryonic form of dilated cardiomyopathy characterized by a significantly reduced left ventricular ejection fraction in mutant embryos compared with wild type littermates. We conclude that myosin light chain 2v may have a unique function in the maintenance of cardiac contractility and ventricular chamber morphogenesis during mammalian cardiogenesis and that a chamber-specific combinatorial code for sarcomeric assembly may exist that ultimately requires myosin light chain 2v in ventricular muscle cells.

Animals↗
PubMed1998

Histological, chemical, and crystallographic analysis of four calcium phosphate cements in different rabbit osseous sites.

Four calcium phosphate cement formulations were implanted in the rabbit distal femoral metaphysis and middiaphysis. Chemical, crystallographic, and histological analyses were made at 2, 4, and 8 weeks after implantation. When implanted into the metaphysis, part of the brushite cement was converted into carbonated apatite by 2 weeks. Some of the brushite cement was removed by mononuclear macrophages prior to its conversion into apatite. Osteoclastlike cell mediated remodeling was predominant at 8 weeks after brushite had converted to apatite. The same histological results were seen for brushite plus calcite aggregate cement, except with calcite aggregates still present at 8 weeks. However, when implanted in the diaphysis, brushite and brushite plus calcite aggregate did not convert to another calcium phosphate phase by 4 weeks. Carbonated apatite cement implanted in the metaphysis did not transform to another calcium phosphate phase. There was no evidence of adverse foreign body reaction. Osteoclastlike cell mediated remodeling was predominant at 8 weeks. The apatite plus calcite aggregate cement implanted in the metaphysis that was not remodeled remained as poorly crystalline apatite. Calcite aggregates were still present at 8 weeks. There was no evidence of foreign body reaction. Osteoclastlike cell remodeling was predominant at 8 weeks. Response to brushite cements prior to conversion to apatite was macrophage dominated, and response to apatite cements was osteoclast dominated. Mineralogy, chemical composition, and osseous implantation site of these calcium phosphates significantly affected their in vivo host response.

Animals↗
PubMed1998

Distinct molecular phenotypes in murine cardiac muscle development, growth, and hypertrophy.

The onset of cardiac hypertrophy is associated with characteristic changes in myocardial gene expression that are thought to recapitulate a developmental gene program. We report here the first gene expression profile of the murine myocardium, using a rapid method of quantitative expression analysis based on real-time analytical RT-PCR. This assay was used to measure expression levels of 29 genes in (1) late stage development as represented by day 1 neonatal ventricles, (2) normal cardiac growth in 3 and 18 month old mice, and (3) cardiac hypertrophy following pressure overload by aortic constriction. For males and females normal growth is not associated with differential expression although there is elevated expression of skeletal and smooth muscle actin mRNA's in males compared to females. Using normal adult ventricles as a reference, there are many qualitative and quantitative differences between the day 1 neonatal myocardium and experimental cardiac hypertrophy. These data suggest that the response to POL involves a subset of re-expressed developmental genes together with altered expression of genes not necessarily associated with cardiac development.

Animals↗
PubMed1998

Adrenergic regulation of the force-frequency effect.

An important interaction between beta-adrenergic receptor (AR) stimulation and the myocardial contractile response to increased heart rate has only recently been identified. The effect of beta-AR stimulation to amplify the force-frequency effect is responsible for a large component of the positive inotropic effect of exercise in conscious dogs and also can be demonstrated at rest with dobutamine infusions over a range of paced heart rates. The interaction is apparent across species (dog, pig, mouse, rabbit, man). Amplification of the heart rate effect on myocardial contractility by dobutamine is lost in heart failure, which may play an important role in impaired exercise tolerance in that setting. In syndromes of chronotropic incompetence when adrenergic control is intact, it may be expected that a normal response of myocardial contractility to exercise will be achieved only when the interaction with heart rate is optimized by use of a rate-responsive cardiac pacemaker.

Adrenergic beta-Agonists↗
PubMed1998

Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia.

The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SCC). The importance of chronic inflammation and scarring in oncogenesis is well recognized. Thirty-two patients with symptomatic vulvar LS and 60 with vulvar SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar lichen simplex chronicus [LSC]) were investigated with a panel of seven tissue markers and for DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were reviewed. Of the cohort of symptomatic vulvar LS patients (mean/median age, 60 years), 9% developed VIN lesions and 21% invasive SCC; symptomatic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 years). Second and third primary tumors developed in three of these patients. Of the series of 60 patients presenting with vulvar SCCa, the clinical setting and histological features of SCCs associated with LS were significantly distinctive compared with SCCas without LS: SCCs associated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41% v 5%; P = .003), were of conventional SCCa type (85% v 57%; P = .02), were associated with a prominent fibromyxoid stromal response (46% v 10%; P = .004), were not associated with VIN 3 (SCC in situ) (5% v 67%; P = .02) and diffusely expressed tumor suppressor gene product p53 (43% v 19%; P = .01) and cytokine TGF-beta (33% v 9%; P = .05). The epidermis of vulvar LS was similar to that of acute scars and differed significantly compared with normal vulva with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P < .03), and proliferative index by PCNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells [bc]; P < .003). Vulvar LS showed significantly higher expression of p53 than all three control groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 bc; P < .008), and aneuploidy (33% v diploid controls) in the absence of VIN. Comparing LS with and without associated SCCa found significant increases in age of patients (74 v 66 years; P = .001), and DNA aneuploidy (52% v 11%; P = .0001) and no differences in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA content showed significantly elevated p53 expression (88 v 60/200 bc; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an association between LS and vulvar SCC. The phenomenon of chronic inflammation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis (sclerosis). A subset of vulvar SCCs is significantly associated with the presence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA aneuploidy. As a chronic scarring inflammatory dermatosis, vulvar LS could act as both "initiator and promoter" of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 gene may be involved early in this proposed pathway of carcinogenesis.

Adult↗
PubMed1998

Hodgkin's lymphoma in a pregnant patient with acquired immunodeficiency syndrome.

The occurrence of Hodgkin's lymphoma in pregnancy is unusual; its management poses not only medical but also ethical problems. We report the case history of a pregnant patient with acquired immunodeficiency syndrome and Hodgkin's lymphoma. Combination chemotherapy was given, with a favourable outcome for the foetus. From a review of some of the available literature, the management considerations are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Angiotensin II blockade followed by growth hormone as adjunctive therapy after experimental myocardial infarction.

BACKGROUND: Recombinant human growth hormone (rhGH) has shown beneficial effects on cardiac function after myocardial infarction (MI) in rats. High-dose angiotensin II (AT1) receptor blockade in normal rats inhibited the hypertrophic effect of growth hormone (GH), therefore we investigated whether GH effects after MI would be enhanced by giving it in sequence after remodeling had been inhibited by prior AT1 blockade (losartan, L). METHODS AND RESULTS: Rats given losartan for 10 weeks after MI followed by rhGH for 2 weeks (2 mg/kg twice a day, GH plus losartan) were compared with rats given losartan for 10 weeks followed by placebo for 2 weeks (placebo plus losartan group) and with untreated controls (n = 17-20/group). Average MI sizes and left ventricular (LV) end diastolic (ED) dimensions (echocardiography) did not differ between groups. In GH and losartan, body weight (BW) was increased but left ventricular weight (LVW)/BW was reduced, and the LV fractional shortening and LV dP/dtmax (catheter tip micromanometer) were increased compared with the control group (20.3 vs 15.4% and 5579 vs 4699 mmHg/s, respectively, P < .05). The cardiac index also was significantly increased. In the placebo plus losartan group, the LVW/BW was also reduced and the cardiac index increased versus controls. Stroke volume was increased in GH plus losartan group compared with both placebo plus losartan and controls, and the systemic vascular resistance was significantly decreased only in the GH plus losartan group. The ED posterior wall thickness (noninfarcted wall) was increased in GH plus losartan compared with both control and placebo plus losartan. Left ventricular end diastolic pressure reduction was not significant in GH plus losartan group versus controls but was reduced in placebo plus losartan group, whereas LV relaxation (tau) was improved in both groups versus control rats. Thus, persistent remodeling effects caused by prior AT1 blockade undoubtedly contributed to some responses, but short-term GH given in sequence after chronic AT1 blockade had favorable actions on the failing heart and peripheral circulation by increasing LV wall thickness with partial reversal of unfavorable remodeling, lowering of vascular resistance, improvement of LV contractility, and enhanced LV systolic function and cardiac index relatively late after experimental MI.

Angiotensin II↗
PubMed1998

Effects of growth hormone and insulin-like growth factor I in experimental heart failure.

These studies suggest that IGF-I and GH have generally favourable effects on the failing heart. They further demonstrate the ability of the severely depressed and failing heart to respond to the trophic and inotropic effects of GH. There is, however, a need for a better understanding of the mechanism of the contractility effect, the character of the hypertrophy observed (whether it is a more favourable type than that secondary to mechanical overload) and the vascular actions, both trophic and vasodilatory. In addition, the degree to which high-dose ACE inhibition or angiotensin II receptor blockade may inhibit some of these effects requires further study. Finally, it is clear that additional experimental studies and clinical trials are needed to investigate the long-term effects of GH on morbidity and mortality in heart failure, as well as the possible side-effects and other actions, such as the potential of GH to enhance skeletal muscle size and strength.

Animals↗
PubMed1998

A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet.

Mutations in the low density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia, a human disease characterized by premature atherosclerosis and markedly elevated plasma levels of LDL cholesterol and apolipoprotein (apo) B100. In contrast, mice deficient for the LDL receptor (Ldlr-/-) have only mildly elevated LDL cholesterol levels and little atherosclerosis. This difference results from extensive editing of the hepatic apoB mRNA in the mouse, which limits apoB100 synthesis in favor of apoB48 synthesis. We have generated Ldlr-/- mice that cannot edit the apoB mRNA and therefore synthesize exclusively apoB100. These mice had markedly elevated LDL cholesterol and apoB100 levels and developed extensive atherosclerosis on a chow diet. This authentic model of human familial hypercholesterolemia will provide a new tool for studying atherosclerosis.

Animals↗
PubMed1998

Stochastic kinetic analysis of developmental pathway bifurcation in phage lambda-infected Escherichia coli cells.

Fluctuations in rates of gene expression can produce highly erratic time patterns of protein production in individual cells and wide diversity in instantaneous protein concentrations across cell populations. When two independently produced regulatory proteins acting at low cellular concentrations competitively control a switch point in a pathway, stochastic variations in their concentrations can produce probabilistic pathway selection, so that an initially homogeneous cell population partitions into distinct phenotypic subpopulations. Many pathogenic organisms, for example, use this mechanism to randomly switch surface features to evade host responses. This coupling between molecular-level fluctuations and macroscopic phenotype selection is analyzed using the phage lambda lysis-lysogeny decision circuit as a model system. The fraction of infected cells selecting the lysogenic pathway at different phage:cell ratios, predicted using a molecular-level stochastic kinetic model of the genetic regulatory circuit, is consistent with experimental observations. The kinetic model of the decision circuit uses the stochastic formulation of chemical kinetics, stochastic mechanisms of gene expression, and a statistical-thermodynamic model of promoter regulation. Conventional deterministic kinetics cannot be used to predict statistics of regulatory systems that produce probabilistic outcomes. Rather, a stochastic kinetic analysis must be used to predict statistics of regulatory outcomes for such stochastically regulated systems.

Bacteriophage lambda↗
PubMed1998

Laparoscopy or open Burch colposuspension?

The laparotomy Burch has long been considered the gold standard for the repair of genuine stress incontinence. With the advent of laparoscopic Burch, many have argued that possibly this should be the new gold standard. However, when many laparoscopic bladder series were examined, there was some question of whether these should be considered Burch procedures and there is still a lack of long-term laparoscopic data.

Female↗
PubMed1998

Characterization of the HLA class I genotypes of a Venezuelan Amerindian group by molecular methods.

We have characterized the HLA class I genotypes of the Yucpa, a tribe of Venezuelan Amerindians, using molecular methods. The study was carried out on DNA extracted from unrelated individuals using low resolution ARMS-SSP typing with sequence-specific primers, high resolution typing using reference strand conformation analysis (RSCA), and for some samples sequence-based typing (SBT). The following class I alleles were found to be present in this tribe: for the HLA-A locus A*0204, A*0212, A*0213, A*2402, A*3101 and A*6801; for the B locus B*1522, B*3512, B*3905, B*3909, B*4004 and B*52012, and for C locus Cw*0102, Cw*0302/ 4, Cw*0401, Cw*0702 and Cw*1503. This is the first time these alleles have been described in this group, although all of them have previously been reported as being present in other Amerindian tribes. The study confirmed the high frequency of HLA-B39 which was previously observed in serological analysis of this tribe, and indicated that two different B*39 alleles were present in this population. The identification of the class I alleles by molecular methods for this ethnic group confirms the restricted polymorphism of the MHC molecules previously obtained by serology and has allowed a more accurate definition of the different alleles present in this population.

Alleles↗
PubMed1998

Identification of an HLA-C variant allele, Cw*0805, by sequencing based typing.

We have identified a variant HLA-C allele, Cw*0805, in DNA isolated from a blood sample used in the UK National External Quality Assessment Scheme for Histocompatibility and Immunogenetics. The DNA was initially typed by PCR-SSP and PCR-SBT as Cw*0802, 1602 with a single mismatch in exon 2 of one of the alleles. The two HLA-C alleles were separated by locus- and allele-specific PCRs and sequencing analysis showed that the Cw*0802 allele was variant in this sample, with a single mismatch in exon 2 at position 289.

Alleles↗
PubMed1998

Effects of growth hormone and IGF-I on cardiac hypertrophy and gene expression in mice.

Cardiac hypertrophic and contractile responses were studied in mice administered growth hormone (GH) and insulin-like growth factor (IGF-I) (8 mg . kg-1 . day-1), alone or in combination (IGF-I/GH), for 2 wk. Also, changes in expression of selected left ventricular (LV) genes in response to IGF-I/GH were compared with those in other forms of cardiac hypertrophy. GH or IGF-I alone at three to four times the usual dose in rats failed to produce increases in heart and LV weights and hemodynamic effects; however, IGF-I/GH was synergistic, increasing body weight and LV weights by 39 and 35%, respectively. A measure of myocardial contractility (maximal first derivative of LV pressure, catheter-tip micromanometry) was increased by 34% in the IGF/GH group, related in part to a force-frequency effect, since the heart rate increased by 21%. Other mice were treated surgically to produce pressure overload (transverse aortic constriction) or volume overload (arteriovenous fistula) for 2 wk; LV weights were then matched to those in the IGF-I/GH group, and mRNA levels of selected markers were assessed. In contrast to the increased mRNA levels of atrial natriuretic factor, alpha-skeletal actin, and collagen III generally observed in overloaded hearts, changes in IGF-I/GH-treated mice were not significant. Thus high-dose IGF-I/GH produce cardiac hypertrophy and a positive inotropic effect without causing significant changes in expression of fetal and other selected myocardial genes, suggesting that this hypertrophy may be of a more physiological type than that due to mechanical overload.

Actins↗