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Biomedical subjects

Stephen G Ball

Publications and source records attributed to Stephen G Ball.

31 records · Page 2Linked to original sources
PubMed2004

Relationship of neurovascular compression to central sympathetic discharge and essential hypertension.

OBJECTIVES: We planned to examine the relationship between neurovascular compression (NVC) of the rostral ventrolateral medulla (RVLM) and the magnitude of central sympathetic hyperactivity in normal subjects and in patients with untreated and uncomplicated essential hypertension (EHT). BACKGROUND: Previously it has not been possible to establish a definitive relationship between EHT and NVC of the RVLM, a location containing efferent sympathetic vasoconstrictor neurons. Furthermore, the relationship between NVC and magnitude of sympathetic nerve hyperactivity has not been adequately examined, despite the knowledge that hyperactivity varies according to EHT severity. METHODS: In 83 subjects, we used magnetic resonance imaging to detect NVC and, independently, peroneal microneurography to quantify muscle sympathetic nerve activity (MSNA), expressed as the mean frequency of multi-unit discharge (m-MSNA) and of single units (s-MSNA). Subjects were classified according to arterial pressure values into groups with normal (NT) (n = 24) or high-normal (HN) (n = 14) arterial pressure and mild (EHT-1) (n = 26) or severe (EHT-2/3) (n = 19) EHT. RESULTS: A significantly greater sympathetic activity was found in 23 subjects with NVC, compared with 60 subjects without NVC. The prevalence of NVC and the magnitude of sympathetic hyperactivity were greater in the EHT-1 group (p < 0.05) than in the other three groups. There was no significant difference in confounding variables between the groups. Although increased sympathetic activity was strongly predictive of NVC, this was not significantly related to baroreceptor sensitivity controlling the pulse interval (cardiac baroreceptor reflex sensitivity). CONCLUSIONS: Neurovascular compression of the RVLM may cause central sympathetic activation in normal and hypertensive populations and therefore has significant implications regarding the pathogenesis of EHT.

Adult↗
PubMed2004

Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA.

OBJECTIVE: Adverse atrial and ventricular myocardial remodeling is characterized by fibrosis, myocyte death or hypertrophy and fibroblast proliferation. HMG-CoA reductase inhibitors (statins) are widely prescribed cholesterol-lowering drugs that also appear to have beneficial effects on myocardial remodeling. Although statins are known to reduce myocyte hypertrophy, their effect on cardiac fibroblast proliferation is unknown. The purpose of this study was to investigate the effects of simvastatin on human atrial myofibroblast proliferation. METHODS: Cardiac myofibroblasts were cultured from biopsies of human right atrial appendage. Proliferation was quantified by cell counting and cell cycle progression determined by immunoblotting for Cyclin A. The expression, activation and intracellular localization of RhoA were investigated using immunoblotting and immunocytochemistry. RESULTS: Simvastatin (0.1-1.0 micromol/l) inhibited serum-induced myofibroblast proliferation in a concentration-dependent manner at a point upstream of Cyclin A expression. These effects were reversed by mevalonate or geranylgeranyl pyrophosphate (GGPP), but not squalene or farnesyl pyrophosphate (FPP), indicating a mechanism involving inhibition of Rho-family GTPases and independent of cholesterol synthesis. The effects of simvastatin were mimicked by inhibiting Rho geranylgeranylation or Rho-kinase activation. Furthermore, we demonstrated that simvastatin inhibited RhoA function by preventing its association with the plasma membrane and hence, its interaction with downstream effectors required for cell proliferation. CONCLUSIONS: Simvastatin reduced proliferation of cultured human atrial myofibroblasts independently of cholesterol synthesis via a mechanism involving inhibition of RhoA geranylgeranylation. Statins may therefore have an important role in preventing adverse myocardial remodeling associated with cardiac myofibroblast proliferation.

Analysis of Variance↗
PubMed2004

Direct cell contact influences bone marrow mesenchymal stem cell fate.

Adult bone marrow-derived mesenchymal stem cells (MSC) can differentiate into various cell types of mesenchymal origin, but mechanisms regulating such cellular changes are unclear. We have conducted co-culture experiments to examine whether mesenchymal stem cell differentiation is influenced by indirect or direct contact with differentiated cells. Cultured adult mesenchymal stem cells showed some characteristics of synthetic state vascular smooth muscle cells (SMC). When co-cultured with vascular endothelial cells (EC) without cell contact, they exhibited abundant well-organised smooth muscle alpha-actin (alpha-actin) filaments. Direct co-culture with endothelial cells resulted in increased smooth muscle alpha-actin mRNA and protein, yet also comprehensive disruption of smooth muscle alpha-actin filament organisation. In order to assess whether these cell contact effects on mesenchymal stem cells were cell type specific, we also analysed direct co-cultures of mesenchymal stem cells with dermal fibroblasts. However, these experiments were characterised by the appearance of abundant spindle-shaped myofibroblast-like cells containing organised smooth muscle alpha-actin filaments. Thus, direct contact with distinct differentiated cells may be a critical determinant of mesenchymal stem cell fate in blood vessels and other connective tissues.

Actin Cytoskeleton↗
PubMed2003

Premature coronary artery disease shows no evidence of linkage to loci encoding for tissue inhibitors of matrix metalloproteinases.

Tissue inhibitors of metalloproteinases (TIMP1, TIMP2, TIMP3) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been proposed that MMPs have a role in weakening the fibrous cap and subsequent plaque rupture. We hypothesized that TIMP polymorphisms could predispose to premature coronary artery disease. As a first step, we examined the relevant loci using a linkage approach. Sibling pairs recruited for the British Heart Foundation (BHF) Family Heart Study with premature coronary artery disease were examined. Two to three microsatellite markers were examined per TIMP gene. These markers were either intragenic or very close to the locus encoding for the gene. Products were analyzed by capillary gel electrophoresis. Single and multipoint linkage analysis based on the likelihood ratio test was performed using SPLINK and Mapmaker/Sibs software; 417 families were genotyped consisting of 385 sibling pairs, 27 trios, and five sets of four siblings. We were unable to detect linkage of premature coronary artery disease to loci encoding for TIMP1-3. Polymorphisms of the tissue inhibitors of MMP genes do not predispose to premature coronary artery disease in an epidemiologically significant way.

Age of Onset↗
PubMed2003

Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers--a gap in evidence-based medicine.

In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension trial also demonstrated beneficial effects of ARBs in the prevention of stroke events. The Irbesartan in Patients with Diabetes and Microalbuminuria (IRMA) study, the Irbesartan Diabetic Nephropathy Trial (IDNT), and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated significant reductions in the rate of progression of renal disease in patients receiving ARBs, independent of effects on blood pressure. These data support the use of ARBs, in addition to the standard of care, in hypertensive patients with heart failure who are intolerant of ACE inhibitors, and also provide compelling evidence for their use in patients with hypertension and type 2 diabetes.

Angiotensin II↗
PubMed2003

Chronic beta2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism.

OBJECTIVE: The aim of this study was to determine whether chronic beta-adrenergic receptor (beta-AR) stimulation induces proliferation of human cardiac fibroblasts and to investigate the mechanism(s) involved. METHODS AND RESULTS: In vitro cultures of human cardiac fibroblasts were established from biopsies of right atrial appendage. RT-PCR analysis and pharmacological studies demonstrated that these cells express predominantly the beta(2)-AR subtype coupled to activation of adenylyl cyclase and p44/42 mitogen-activated protein kinase (MAPK). Proliferation was determined by cell counting over a 6-day period in medium containing 2.5% fetal calf serum (control) or supplemented with the non-selective beta-AR agonist isoproterenol (ISO). ISO induced a concentration-dependent increase in cardiac fibroblast proliferation, which was maximal at 1 micromol/l. This increased proliferation was inhibited by the beta(2)-AR-selective antagonist ICI-118,551, but not the beta(1)-AR-selective antagonist atenolol. Direct activation of adenylyl cyclase alone (0.1-10 micromol/l forskolin) stimulated cyclic AMP production and MAPK activation, but did not induce cell proliferation. Since catecholamines are not considered to be 'classical' growth factors, we subsequently investigated whether beta(2)-AR stimulation results in secretion of growth factors that are able to stimulate proliferation in an autocrine manner. Conditioned medium obtained from cardiac fibroblasts treated with ISO for 48 h increased proliferation of parallel cultures of fibroblasts in the presence of the beta-AR antagonist alprenolol. Heat-treatment of this conditioned medium fully prevented the increase in cell proliferation, indicating that the autocrine factor(s) are heat-sensitive proteins. CONCLUSIONS: Chronic beta(2)-AR stimulation increases proliferation of human cardiac fibroblasts via a mechanism involving increased secretion of heat-sensitive growth factors.

Adrenergic beta-Agonists↗
PubMed2003

Molecular development of the pancreatic beta cell: implications for cell replacement therapy.

Conventional insulin therapy is an imperfect treatment for diabetes mellitus, often failing to match insulin with prevailing blood glucose concentration. Accordingly, there is a drive for approaches such as beta-cell replacement therapy, which is a permanent replacement for the lack of endogenous insulin production. The lack of cadaveric islets for transplantation determines that researchers must explore alternative sources of graft material. Cell engineering of non-beta cells and selective expansion of stem cells are key potential sources. The past decade has witnessed an increase in our understanding of the molecular basis of pancreas and beta-cell development. Our understanding of the molecular blueprint of how a beta cell is made and maintained is crucial to realizing the potential of cell engineering and stem cell technologies in this area. This review outlines progress in this exciting field and highlights the key role of development in guiding our appraisal of these new technologies.

Animals↗
PubMed2003

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study.

BACKGROUND: The Glycine389 variant of the beta-1 adrenergic receptor (beta1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant. AIMS: The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers. METHODS: We identified the genotype at amino acid 389 of the beta1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes. RESULTS: The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69-1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44-0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL. CONCLUSION: In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism.

Adrenergic beta-Antagonists↗
PubMed2003

A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics.

BACKGROUND: Inactivating mutations of the FSH receptor (FSHR) are a rare cause of hypergonadotrophic hypogonadism in women. Only one patient with primary amenorrhoea due to an FSHR gene mutation has been reported outside of Finland, where the prevalence of Ala189Val mutations is particularly high. METHODS AND RESULTS: Here, we describe the clinical, molecular genetic and functional characteristics associated with a novel inactivating mutation in exon 10 of the FSHR gene identified in a patient who presented with primary amenorrhoea at 17 years of age. The C to G transversion found at nucleotide 1043 causes a Pro348Arg substitution in the extracellular region of the FSHR and results in a mutant FSHR that is completely inactive in functional studies and that does not bind FSH. The proband exhibits apparent homozygosity for this recessive mutation. Her father is heterozygous for the mutation while analysis of exon 10 of the FSHR gene from her mother revealed only wild-type sequence. Chromosome painting was used to exclude deletions or rearrangements of 2p, and microsatellite markers did not show paternal uniparental isodisomy for this region. These findings suggest that the proband is hemizygous, with an inherited or de-novo microdeletion, or alternatively a de-novo gene conversion, of the accompanying FSHR allele. CONCLUSIONS: This case confirms the importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations.

Adolescent↗
PubMed2003

Benefits of blood pressure reduction in diabetic patients.

Hypertension is common among patients with type 2 diabetes mellitus, increasing their risk of cardiovascular morbidity and mortality. Such patients are also at risk of renal impairment and end-stage renal disease. Long-term, tight blood pressure control (ideally to a target of < 130/85 mmHg) in patients with type 2 diabetes is a highly effective strategy for reducing the risk of cardiovascular complications and is now embodied in the many guidelines of hypertension and diabetes management. More recent studies indicate that the choice of antihypertensive agent is also important. Drugs that block the renin-angiotensin-aldosterone system, such as the angiotensin-II receptor blockers (ARBs), may prevent the onset of diabetes and confer greater cardiovascular benefit among patients who already have this disease compared with some older antihypertensive agents. For example, in type 2 diabetic patients with renal dysfunction, ARBs exert a renal protective effect that extends beyond blood pressure reduction and may retard diabetic nephropathy. Antihypertensive therapy, together with lifestyle modification to address obesity and physical inactivity, can significantly reduce the risk of cardiovascular complications in patients with type 2 diabetes. The challenge is to achieve beneficial, hygienic measures in populations with diverse backgrounds and improve compliance with proven treatments that inevitably involve multiple drugs. Combination therapies comprising agents that offer good tolerability and do not exacerbate existing metabolic disturbances, as well as demonstrating benefit in preventing events in diabetic patients beyond blood pressure reduction itself, seem a likely way forward.

Antihypertensive Agents↗
PubMed2002

Chronic treatment with nicotine or potassium attenuates depolarisation-evoked noradrenaline release from the human neuroblastoma SH-SY5Y.

Chronic treatment, of SH-SY5Y cells, with KCl (20 mM) for 4 days decreased 100 mM KCl-evoked noradrenaline (NA) release by 50% and nicotine (100 microM)-evoked NA release by 55%. Pretreatment with the L-type calcium channel antagonist, nifedipine, prevented this inhibitory effect of chronic exposure to 20 mM KCl on NA release. In contrast pretreatment with 10 microM nicotine for 4 days had no effect on 100 mM KCl -evoked secretion and decreased nicotinic -evoked NA release by only 25%. Inclusion of nifedipine prevented the inhibition of NA release by chronic nicotine treatment. These data are discussed in relation to effects of chronic moderate, depolarisation by either K(+) or nicotine on influx of Ca(2+) via L-type voltage sensitive calcium channels.

Ganglionic Stimulants↗