Biomedical subjects
Publications and source records attributed to Peter Collins.
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We investigated whether one of the main estrogenic metabolites of the postmenopausal agent, tibolone (Org OD14), exerts direct cardiac actions in a similar way to 17beta-estradiol. 3alpha-OH-tibolone (40 microM) decreased both cell shortening and Ca2+ transient amplitude of field-stimulated (1 Hz, 37 degrees C) guinea-pig ventricular myocytes. These effects were still observed in cells that had been incubated with the specific estrogen receptor antagonist, ICI 182,780 (C(32)H(47)F(5)O(3)S), suggesting an estrogen receptor-independent mechanism of action. In addition, 3alpha-OH-tibolone inhibited the L-type Ca2+ current and shortened action potential durations (APD). This mechanism may contribute to a potential cardiovascular action of tibolone.
OBJECTIVES: The soy-isoflavone, genistein, appears to be cardioprotective partly through direct actions on the heart, although the relative benefits between men and women are not fully known. The purpose of the present study was to determine whether gender influences the acute electrophysiological actions of genistein at the level of isolated cardiac myocytes and to elucidate the mechanisms involved. METHODS: Left ventricular myocytes, isolated from weight-matched male and female guinea-pigs and rats, were field stimulated at a rate of 1 Hz in a superfusion chamber (37 degrees C). The effects of acute application of genistein on cell shortening and the Ca(2+) transients were measured. Electrophysiological recordings were performed using single electrode voltage-clamp. RESULTS: Genistein increased cell contraction and the Ca(2+) transients in a concentration-dependent manner in myocytes from male guinea-pigs [by 54+/-11% and 22+/-4%, respectively (mean+/-S.E.M., p<0.001, n=18) at 40 microM], while having no significant corresponding effect in those from females. In contrast, genistein increased both parameters in myocytes obtained from male and female rats. The changes in guinea-pigs occurred despite inhibition of the L-type Ca(2+) current in both sexes (n>23, p<0.001). In order to explain these observations, we measured sarcoplasmic reticulum (SR) Ca(2+) contents by integrating the Na(+)/Ca(2+) exchanger currents (I(NCX)) following rapid caffeine application. Genistein increased I(NCX) integrals by 27% in males (n=12, p<0.01) and 20% in females (n=14, p<0.01). The increased SR Ca(2+) load in males, but not females, could be related to an impaired ability of the Na(+)/Ca(2+) exchanger to extrude Ca(2+). CONCLUSIONS: We have demonstrated novel, gender-related differences in the acute cardiac actions of genistein, which can be attributed to actions at distinct points of the intracellular Ca(2+) cycle. Our results suggest that genistein may afford greater cardioprotection in females than in males.
BACKGROUND: The effect of the use of coronary-artery bypass surgery without cardiopulmonary bypass and cardiac arrest ("off pump") on graft patency remains uncertain. We undertook a prospective, randomized, controlled study to compare graft-patency rates and clinical outcomes in off-pump surgery with conventional, "on-pump" surgery. METHODS: We randomly assigned 50 patients to undergo on-pump coronary-artery bypass grafting and 54 to undergo off-pump surgery. Surgical and anesthetic techniques were standardized for both groups. Clinical outcomes and troponin T levels were measured. Three months later, the patients underwent coronary angiography, including quantitative analysis. RESULTS: The mean age of the patients was 63 years, and 87 percent were men. The on-pump group received a mean of 3.4 grafts, and the off-pump group 3.1 (P=0.41). There were no deaths. There was no significant difference in the median postoperative length of stay between the two groups (seven days in each group). The area under the curve of troponin T levels was higher during the first 72 hours in the on-pump group than in the off-pump group (30.96 hr x microg per liter vs. 19.33 hr x microg per liter, P=0.02). At three months, 127 of 130 grafts were patent in the on-pump group (98 percent), as compared with 114 of 130 in the off-pump group (88 percent, P=0.002). The patency rate was higher for all graft territories in the on-pump group than in the off-pump group. CONCLUSIONS: In this randomized study, off-pump coronary surgery was as safe as on-pump surgery and caused less myocardial damage. However, the graft-patency rate was lower at three months in the off-pump group than in the on-pump group, and this difference has implications with respect to the long-term outcome.
AIMS: To compare the impact of oestrogen, gynaecological history, social support, life events and family history of CHD on psychosocial morbidity in syndrome X, CHD patients and healthy controls. METHODS AND RESULTS: 100 female syndrome X (60 +/- 9 years), 100 female CHD (65 +/- 9 years) and 100 healthy female volunteers (61 +/- 10 years) completed the hospital anxiety and depression scale (HADS), health anxiety questionnaire (HAQ), a demographic information scale, life events scale, family history of CHD, menopausal, menstrual and gynaecological history. A 17beta-oestradiol sample was taken. Syndrome X patients had higher levels of life interference (p < 0.05) and HADS anxiety (p < 0.05) than CHD patients, and higher levels of all HADS and HAQ scales than controls (p < 0.01). Syndrome X patients with a large social network had lower HADS anxiety (p < 0.05), health worry (p < 0.05), life interference (p < 0.01) and total HAQ (p < 0.01). Social network (p = 0.003), divorced/separated or widowed status (p = 0.005), HRT (p = 0.008) and HADS anxiety score (p < 0.001) accounted for 41.9% of the variance in HAQ scores in syndrome X. Oestrogen was unrelated to the HADS or HAQ for any group. CONCLUSION: Syndrome X patients suffered higher levels of psychological morbidity in comparison to CHD patients and controls. Life events and social network size were related to health anxiety, general anxiety and depression in women with syndrome X.
BACKGROUND: Surgical preparation of coronary conduits may affect early and long-term patency through endothelial and smooth muscle injury. We investigated the effect of hydrostatic distention on the in vitro endothelial function and contractile properties of the human radial artery. METHODS: Human radial arteries were harvested and distended to physiologic pressure or suprasystemic pressure (>300 mm Hg) by using heparinized whole blood for 2 minutes. Distal segments were retrieved and prepared into 3-mm rings. These were mounted and stretched to optimum resting tension in oxygenated Krebs solution at 37 degrees C. Contraction responses to potassium, norepinephrine, and serotonin and relaxation responses to acetylcholine and nitroprusside were evaluated. Undistended radial artery segments were used as controls. RESULTS: Vasocontraction to all 3 contractile agonists was significantly different between groups. The radial artery subjected to suprasystemic pressure distention achieved the lowest percentage of maximum contraction (potassium, P <.001; norepinephrine, P <.05; serotonin, P <.05). The median effective concentration was also significantly reduced in this group, indicating increased sensitivity to all 3 agonists. Receptor-mediated contractility was significantly reduced in both distended groups when compared with controls. Relaxation to acetylcholine and nitroprusside was significantly reduced in the suprasystemic pressure-distended group, which had a tendency to vasospasm when exposed to a physiologic concentration of acetylcholine (10(-6) mol/L). Median effective concentrations for both acetylcholine and nitroprusside were not different between groups. CONCLUSIONS: Excessive distention of the radial artery leads to a significant reduction in vasoreactivity, which may be attributed to a disruption of the vascular endothelium and media, with a propensity for graft spasm with exposure to acetylcholine.
Previous studies in acquired haemophilia A have reported on cohorts of patients referred to specialist centres or were retrospective surveys of specialist centre experience. This may have resulted in the literature representing a more severe group of patients than seen in routine haematological practice. We report on a consecutive, unselected cohort of all patients in south and west Wales who presented with acquired haemophilia A between 1996 and 2002. There were 18 patients, an incidence of 1.34/million/year. Compared with previously reported cohorts our patients were older, with a median age of 70 years, and less likely to have an underlying diagnosis (27%). The bleeding phenotype was less severe, with only 27% having life or limb threatening bleeds and 41% required no haemostatic treatment. One patient died of bleeding, but three died of complications related to immunosuppression. Response to immunosuppression was high compared with other series, with 88% of treated patients attaining an undetectable inhibitor and normal factor VIII level. These data suggest that previously reported cohorts may represent more severely affected patients and, whilst guidelines for treatment based on these assumptions may be valid for severely affected patients, they may not be universally applicable.
Fasciola hepatica secretes cathepsin L proteases that facilitate the penetration of the parasite through the tissues of its host, and also participate in functions such as feeding and immune evasion. The major proteases, cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) are members of a lineage that gave rise to the human cathepsin Ls, Ks and Ss, but while they exhibit similarities in their substrate specificities to these enzymes they differ in having a wider pH range for activity and an enhanced stability at neutral pH. There are presently 13 Fasciola cathepsin L cDNAs deposited in the public databases representing a gene family of at least seven distinct members, although the temporal and spatial expression of each of these members in the developmental stage of F. hepatica remains unclear. Immunolocalisation and in situ hybridisation studies, using antibody and DNA probes, respectively, show that the vast majority of cathepsin L gene expression is carried out in the epithelial cells lining the parasite gut. Within these cells the enzyme is packaged into secretory vesicles that release their contents into the gut lumen for the purpose of degrading ingested host tissue and blood. Liver flukes also express a novel multi-domain cystatin that may be involved in the regulation of cathepsin L activity. Vaccine trials in both sheep and cattle with purified native FheCL1 and FheCL2 have shown that these enzymes can induce protection, ranging from 33 to 79%, to experimental challenge with metacercariae of F. hepatica, and very potent anti-embryonation/hatch rate effects that would block parasite transmission. In this article we review the vaccine trials carried out over the past 8 years, the role of antibody and T cell responses in mediating protection and discuss the prospects of the cathepsin Ls in the development of first generation recombinant liver fluke vaccines.
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Genistein, a phytoestrogen found abundantly in soy products, is thought to be cardioprotective, partly through its ability to act as a natural Ca2+ channel antagonist. However, the precise nature and significance of such direct cardiac actions remain obscure. We investigated the hypothesis that genistein exerts important additional actions on cardiac excitation-contraction coupling (ECC). Genistein acutely increased cell shortening and the Ca2+ transient in field stimulated guinea-pig ventricular myocytes despite potently inhibiting the L-type Ca2+ current, I(Ca,L). The specific phosphotyrosine phosphatase inhibitor, bpV(phen), diminished the stimulatory effects of genistein on myocyte contractility, suggesting that the mechanism partly involved tyrosine kinase inhibition. Genistein increased sarcoplasmic reticulum (SR) Ca2+ load as measured with a caffeine pulse in Na+-free/ Ca2+-free solution. Furthermore, in the continued presence of caffeine, genistein increased the time constant of decline of the caffeine-induced Ca2+ transient, implying impaired sarcolemmal Na+/Ca2+ exchanger function. Tetanization studies in intact myocytes revealed that 43% of cells exhibited increased myofilament Ca2+ sensitivity in the presence of genistein. These findings demonstrate novel cardiac actions of genistein on the SR Ca2+ load, Na+/Ca2+ exchanger, and myofilament Ca2+ sensitivity, which result in an overall increase in myocyte contractility and consequently the gain of ECC.
BACKGROUND: There is little information on the effects of radial artery harvesting on postoperative forearm function and blood flow. We evaluated the early changes in forearm neural sensation, circumference, grip power, cyclical exercise fatigue, and blood flow after radial artery harvesting for coronary artery bypass graft (CABG) surgery. METHODS: Twenty-three patients with negative Allen's test of the nondominant forearm were recruited preoperatively and underwent assessment of bilateral forearm function (soft touch and pin-prick neural sensation, circumference, handgrip power, cyclical exercise fatigue) and blood flow measurements (forearm plethysmography). All vasoactive drugs were stopped 24 hours before assessments. Identical follow-up assessments were conducted (mean +/- SEM) 3.4 +/- 0.4 months postoperatively. RESULTS: At the time of postoperative assessment all harvested forearm wounds were healed. There was no reduction of postoperative soft touch sensation but in 3 patients objective pinprick sensation was reduced in the distribution of the lateral antebrachial cutaneous nerve of the harvested forearms. Postoperative forearm circumference (p < 0.05) and grip power (p < 0.05) were significantly reduced in both forearms, however cyclical exercise fatigue was improved in both forearms. Preoperative and postoperative forearm blood flow at rest and in exercise-induced ischemic reperfusion were not significantly different in both forearms. CONCLUSIONS: In patients with a negative Allen's test, harvesting of the radial artery does not adversely affect subsequent forearm function or blood flow to a clinically significant degree.
A panel of 10 clinical isolates of herpes simplex virus (HSV) deficient in the expression of thymidine kinase (TK) and phenotypically resistant to aciclovir was characterized. Sequence analysis revealed a variety of mutations in TK (nucleotide substitutions, insertions and deletions), most of which resulted in truncated TK polypeptides. In line with previous reports, the most common mutation was a single G insertion in the 'G-string' motif. One HSV-1 isolate and two HSV-2 isolates appeared to encode full-length polypeptides and, in each case, an amino acid substitution likely to be responsible for the phenotype was identified. Pathogenicity was determined using a zosteriform model of HSV infection in BALB/c mice. The majority of isolates appeared to show impaired growth at the inoculation site compared with wild-type virus. They also showed poor replication in the peripheral nervous system and little evidence of zosteriform spread. One exception was isolate 4, which had a double G insertion in the G-string but, nevertheless, exhibited zosteriform spread. These studies confirmed that TK-deficient viruses display a range of neurovirulence with respect to latency and zosteriform spread. These results are discussed in the light of previous experience with TK-deficient viruses.
A clinical isolate of herpes simplex virus type 1 that is aciclovir resistant but neurovirulent in mice was described previously. The mutation in this virus is a double G insertion in a run of seven G residues that has been shown previously to be a mutational hotspot. Using a sensitive assay, it has been demonstrated that preparations of this virus are able to induce low but consistent levels of thymidine kinase (TK) activity. However, this activity results from a high frequency mutational event that inserts a further G into the 'G-string' motif and thus restores the TK open reading frame. Passage of this virus through the nervous system of mice results in the rapid selection of the TK-positive variant. Thus, this variant is the major component in virus reactivated from latently infected ganglia. Mutation frequency appears to be influenced by the genetic background of the virus.
Soy-derived isoflavones appear to possess cardioprotective properties, although the precise nature of this protection and the particular isoflavones responsible remain unclear. We hypothesized that isoflavones may differ in their cardiac actions in view of their varying affinities for the estrogen receptor and differences in ability to inhibit tyrosine kinase. We investigated the direct effects of three closely related isoflavones, genistein, daidzein, and equol (a metabolite of daidzein formed by gut microflora), on the contractile function of isolated guinea pig ventricular myocytes. Genistein (10 and 40 microM) significantly increased cell shortening and the Ca(2+) transient (measured using indo-1). In contrast, equivalent concentrations of equol produced the opposite effect, decreasing cell shortening and the Ca(2+) transient, whereas daidzein was without effect. The opposing actions of genistein and equol were still observed in the presence of the specific estrogen receptor antagonist ICI 182,780 (10 microM). However, the stimulatory actions of genistein were markedly reduced in the presence of the potent phosphotyrosine phosphatase inhibitor, bpV(phen). Both genistein and equol significantly inhibited the peak L-type Ca(2+) current. We conclude that genistein and equol affect the contractile function of ventricular myocytes in opposing ways despite a common initial action of Ca(2+) current antagonism. These differences occur independently of the estrogen receptor but may be partly related to the unique actions of genistein as a tyrosine kinase inhibitor. Furthermore, isoflavone metabolites, such as equol, may be more biologically active than their precursors and have a greater role in cardioprotection than previously realized.
In 0.22 caliber rimfire ammunition, the primer often contains lead or lead and barium compounds. As residues from these primers do not contain lead, barium, and antimony, they cannot be uniquely classified as gunshot residue (GSR) under ASTM designation E 1588-95. In many types of 0.22 caliber rimfire ammunition, the cartridge contains a primer sensitized with glass. In this paper we describe a previously unreported type of GSR particle consisting of glass fused with other primer components. As there appear to be few potential environmental or occupational sources of particles composed of lead and barium compounds fused to glass, particularly borosilicate glass, these particles may have high evidential value. Scanning electron microscopy with energy dispersive X-ray detection (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMS) were evaluated for the characterization of glass-containing GSR particles. The occurrence of glass-containing GSR particles was established in the residue from various brands of 0.22 caliber ammunition, and several sub-types were identified.
The Raloxifene Use for The Heart (RUTH) trial is a randomized, placebo-controlled, double-blind trial designed to determine whether raloxifene 60 mg/day compared with placebo lowers the risk of coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI) and reduces the risk of invasive breast cancer in women at risk for a major coronary event. Raloxifene is a selective estrogen receptor modulator that improves cardiovascular risk factors, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. Between June 1998 and August 2000, 10,101 women were enrolled at 187 sites in 26 countries. Approximately half of the women had documented coronary heart disease (CHD) (n = 5,031); the remainder had multiple CHD risk factors that increased their risk for a CHD event (n = 5,070). The mean age of participants was 68 years (39% were >70 years old), and did not differ between those with documented CHD and those at increased CHD risk. Most women were Caucasian (84%); 60% had a body mass index >/=27 kg/m(2), 46% had diabetes mellitus, 78% had systemic hypertension, and 14% had low-density lipoprotein cholesterol >160 mg/dl. Compared with women at increased CHD risk, women with documented CHD had higher cardiovascular risk scores, a higher prevalence of abnormal electrocardiograms, greater use of cardiovascular medications, were more likely to have had cardiac rehabilitation, and were more likely to have previously used estrogen or oral contraceptives, but had a slightly lower prevalence of CHD risk factors such as smoking, obesity, diabetes mellitus, and systemic hypertension, and had lower serum levels of total and low-density lipoprotein cholesterol. The RUTH cohort is the largest group of postmenopausal women at increased risk of CHD events ever assembled in a clinical trial, and is the first trial designed to determine the effect of a selective estrogen receptor modulator on the risk of CHD events.
BACKGROUND: Depot medroxyprogesterone acetate (DMPA) inhibits proliferation of ovarian follicles, resulting in anovulation and a decrease in circulating estrogen; the latter action is potentially disadvantageous to cardiovascular health. We therefore investigated the vascular effects of long-term contraceptive DMPA in young women. METHODS AND RESULTS: Endothelium-dependent (hyperemia-induced flow-mediated dilatation [FMD]) and -independent (glyceryl trinitrate [GTN]) changes in brachial artery area were measured using cardiovascular magnetic resonance in 13 amenorrheic DMPA users (>1 year use; mean age 29+/-4 years) and in 10 controls (mean age 30+/-4 years, P=0.25) with regular menstrual cycles after validation of the technique. FMD and GTN responses were measured just before repeat MPA injection and 48 hours later (n=12) in DMPA users and during menstruation and midcycle (n=9) in controls. Serum-estradiol levels (S-estradiol) were measured at both visits. FMD was reduced in DMPA users compared with controls during menstruation (1.1% versus 8.0%, respectively P<0.01) without differences in GTN responses. S-estradiol levels in DMPA users were significantly lower than in controls during menstruation (58 versus 96 pmol/L, P<0.01). High levels of circulating MPA 48 hours after injection were not linked to an additional impairment in FMD (2.0% versus 3.1%, P=0.23). Estradiol levels were significantly correlated to FMD (r=0.43, P<0.01). CONCLUSIONS: Endothelium-dependent arterial function measured by cardiovascular magnetic resonance is impaired in chronic users of DMPA, and hypoestrogenism may be the mechanism of action. DMPA might adversely affect cardiovascular health, and in particular its use in women with cardiovascular disease should be additionally evaluated.
OBJECTIVES: The study was done to determine whether radial artery applanation tonometry can be used as a noninvasive method of assessing global endothelial function. BACKGROUND; It is known that beta(2)-receptor stimulation results in endothelial release of nitric oxide. Furthermore, for over a century glyceryl trinitrate (GTN) has been known to markedly affect the arterial pressure waveform, even in the absence of significant blood pressure (BP) changes. Therefore, it was hypothesized that the change in the peripheral pressure waveform, as measured using tonometry and quantified using the augmentation index (AIx) and in response to Salbutamol (Salb), would allow assessment of global endothelial function. METHODS: The study contained three parts. In the first study, Salb (400 microg) was administered to 11 healthy subjects via inhalation after either intravenous N-omega-nitro-monomethyl-L-arginine (L-NMMA) (3 mg/kg over 5 min) or control solution (normal saline) in the supine, rested, fasted condition. The BP, heart rate and waveform responses were recorded each 5 min following Salb for 20 min. Next, GTN was given and responses recorded 5 min later. In the second study, both the reproducibility of Salb and the GTN responses were assessed in 9 subjects studied twice on separate days. In the third study, the Salb and GTN responses of 12 subjects with angiographic coronary artery disease (CAD) were compared with 10 age-matched control subjects with no atherosclerotic risk factors. RESULTS: After control infusion, AIx decreased following Salb, from 50.8 +/- 4.3% to 44.8 +/- 4.2%, a change of -11.8 +/- 3.7%, p < 0.01. After L-NMMA, AIx did not significantly change following Salb (54.2 +/- 5.1% vs. 52.9 +/- 5.3%, -2.0 +/- 3.1%). The GTN-induced decreases in AIx were similar after either infusion (35.1 +/- 3.3% vs. 36.5 +/- 3.3%). Reproducibility of Salb-induced changes in AIx between studies performed on separate days was good (r = 0.80, p < 0.01). Salb-induced changes in AIx in CAD patients were significantly less compared to control subjects (-2.4 +/- 1.9% vs. -13.2 +/- 2.4%, respectively, p < 0.002). The GTN-induced changes were not significantly different (-27.6 +/- 4.2 vs. -38.9 +/- 4.4%, p = 0.07). CONCLUSIONS: The peripheral arterial pressure waveform is sensitive to beta(2)-stimulation. Changes are related to nitric oxide release, are reproducible and can distinguish between clinical subject groups. Arterial waveform changes following Salb may thus provide a noninvasive method of measuring "global" arterial endothelial function.