The geometry of antisymplectic involutions, I

We study fixed loci of antisymplectic involutions on projective hyperkahler manifolds of K3([n])-type. When the involution is induced by an ample class of square 2 in the Beauville-Bogomolov-Fujiki lattice, we show that the number of connected components of the fixed locus is equal to the divisibility of the class, which is either 1 or 2

Predicting sudden death in patients with mild to moderate chronic heart failure

Objectives: To explore the relation between non-invasive measures of cardiac function and sudden cardiac death, as well as the development and utility of an index integrating these variables to identify patients at increased risk of this mode of death. Design: UK-HEART (United Kingdom-heart failure evaluation and assessment of risk trial) was a prospective study conducted between December 1993 and April 2000. The study was specifically designed to identify non-invasive markers of death and mode of death among patients with chronic heart failure. Setting: 8 UK general hospitals. Main outcome measures: Death and mode of death. Results: 553 patients aged a mean (SD) of 63 (10) years, in New York Heart Association functional class 2.3 (0.02), recruited prospectively. After 2365 patient-years’ follow up, 201 patients had died (67 suddenly). Predictors of sudden death were greater cardiothoracic ratio, QRS dispersion, QT dispersion corrected for rate (QTc) across leads V1–V6 on the 12 lead ECG, and the presence of non-sustained ventricular tachycardia. The hazard ratio and 95% confidence intervals (CI) of sudden death for a 10% increase in cardiothoracic ratio was 1.43 (95% CI 1.20 to 1.71), for a 10% increase in QRS dispersion 1.11 (95% CI 1.04 to 1.19), for the presence of non-sustained ventricular tachycardia 2.03 (95% CI 1.27 to 3.25), and for a 10% increase in QTc dispersion across leads V1–V6 1.03 (95% CI 1.00 to 1.07) (all p < 0.04). An index derived from these four factors performed well in identifying patients specifically at increased risk of sudden death. Conclusions: Results show that an index derived from three widely available non-invasive investigations has the potential to identify ambulant patients with chronic heart failure at increased risk of sudden death. This predictive tool could be used to target more sophisticated investigations or interventions aimed at preventing sudden death

Vascular effects of apelin in vivo in man

ObjectivesThis study was designed to establish the direct vascular effects of apelin in vivo in man.BackgroundApelin is the endogenous ligand for the previously orphaned G-protein–coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation.MethodsVascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a “nitric oxide clamp” (nitric oxide synthase inhibitor, L-NG-monomethylarginine [8 μmol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo.ResultsAlthough sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr1)apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr1)apelin-13–mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7).ConclusionsAlthough having no apparent effect on venous tone, apelin causes nitric oxide–dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis

Loss of lag-response curvilinearity of indices of heart rate variability in congestive heart failure

BACKGROUND: Heart rate variability (HRV) is known to be impaired in patients with congestive heart failure (CHF). Time-domain analysis of ECG signals traditionally relies heavily on linear indices of an essentially non-linear phenomenon. Poincaré plots are commonly used to study non-linear behavior of physiologic signals. Lagged Poincaré plots incorporate autocovariance information and analysis of Poincaré plots for various lags can provide interesting insights into the autonomic control of the heart. METHODS: Using Poincaré plot analysis, we assessed whether the relation of the lag between heart beats and HRV is altered in CHF. We studied the influence of lag on estimates of Poincaré plot indices for various lengths of beat sequence in a public domain data set (PhysioNet) of 29 subjects with CHF and 54 subjects with normal sinus rhythm. RESULTS: A curvilinear association was observed between lag and Poincaré plot indices (SD1, SD2, SDLD and SD1/SD2 ratio) in normal subjects even for a small sequence of 50 beats (p value for quadratic term 3 × 10(-5), 0.002, 3.5 × 10(-5 )and 0.0003, respectively). This curvilinearity was lost in patients with CHF even after exploring sequences up to 50,000 beats (p values for quadratic term > 0.5). CONCLUSION: Since lagged Poincaré plots incorporate autocovariance information, these analyses provide insights into the autonomic control of heart rate that is influenced by the non-linearity of the signal. The differences in lag-response in CHF patients and normal subjects exist even in the face of the treatment received by the CHF patients

Fire Simulation and Cardiovascular Health in Firefighters

BACKGROUND: Rates of myocardial infarction in firefighters are increased during fire suppression duties, and are likely to reflect a combination of factors including extreme physical exertion and heat exposure. We assessed the effects of simulated fire suppression on measures of cardiovascular health in healthy firefighters. METHODS: In an open-label randomized crossover study, 19 healthy firefighters (age, 41±7 years; 16 males) performed a standardized training exercise in a fire simulation facility or light duties for 20 minutes. After each exposure, ex vivo thrombus formation, fibrinolysis, platelet activation, and forearm blood flow in response to intra-arterial infusions of endothelial-dependent and -independent vasodilators were measured. RESULTS: After fire simulation training, core temperature increased (1.0±0.1°C) and weight reduced (0.46±0.14 kg, P<0.001 for both). In comparison with control, exposure to fire simulation increased thrombus formation under low-shear (73±14%) and high-shear (66±14%) conditions (P<0.001 for both) and increased platelet-monocyte binding (7±10%, P=0.03). There was a dose-dependent increase in forearm blood flow with all vasodilators (P<0.001), which was attenuated by fire simulation in response to acetylcholine (P=0.01) and sodium nitroprusside (P=0.004). This was associated with a rise in fibrinolytic capacity, asymptomatic myocardial ischemia, and an increase in plasma cardiac troponin I concentrations (1.4 [0.8–2.5] versus 3.0 [1.7–6.4] ng/L, P=0.010). CONCLUSIONS: Exposure to extreme heat and physical exertion during fire suppression activates platelets, increases thrombus formation, impairs vascular function, and promotes myocardial ischemia and injury in healthy firefighters. Our findings provide pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction in firefighters. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01812317

Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters

Background: Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. Methods: In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m3 particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4–6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. Results: Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P &lt; 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P &gt; 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P &lt; 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P &gt; 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P &gt; 0.05 for all). Conclusions: Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.Originally included in thesis in manuscript form.</p

Chow motives associated to certain algebraic Hecke characters

Shimura and Taniyama proved that if USD A USD is a potentially CM abelian variety over a number field USD F USD with CM by a field USD K USD linearly disjoint from F, then there is an algebraic Hecke character USD \lambda _A USD of USD FK USD such that USD L(A/F,s)=L(\lambda _A,s) USD. We consider a certain converse to their result. Namely, let USD A USD be a potentially CM abelian variety appearing as a factor of the Jacobian of a curve of the form USD y^e=\gamma x^f+\delta USD. Fix positive integers USD a USD and USD n USD such that USD n/2 < a \leq n USD. Under mild conditions on USD e, f, \gamma , \delta USD, we construct a Chow motive USD M USD, defined over USD F=\mathbb{Q}(\gamma ,\delta )USD, such that USD L(M/F,s) USD and USD L(\lambda _A^a\overline {\lambda }_A^{n-a},s) USD have the same Euler factors outside finitely many primes

Infusion of Mg in Humans Acutely Reduces Serum Insulin Levels: a Pilot Study

Background: infusion of Mg for therapeutic purposes is still a matter for debate. Dosages vary considerably, yet subclinical effects on normal physiology are largely ignored. In human and animal models, interactions between Mg and insulin exist, thus we have investigated the effect of infusing Mg on serum insulin, ionised Mg (Mg2+) and Ca (Ca2+) and plasma glucose in human volunteers. Methods: six male volunteers were infused with magnesium sulphate (MgSO4) dissolved in normal saline, using a high-dose loading- bolus, followed by a lower-level maintenance- period. Findings: serum Mg2+ rose rapidly throughout the bolus infusion, declined during the maintenance phase, but remained higher than pre-infusion levels throughout the experimental period; serum Ca2+ rose when serum Mg2+ was highest. Infusion of MgSO4 had no effect on heart rate or blood pressure, but caused a rapid, pronounced drop in circulating fasting insulin (p &lt; 0.0005), which slowly recovered to basal values during the course of the maintenance infusion. A slight, transient rise in plasma glucose (p &lt; 0.05) concomitant with the decline in serum insulin was also observed. Interpretation: it is possible that the effect of Mg2+ on insulin may have been due to antagonism of Ca2+ entry in pancreatic beta-cells, the insulin decline causing a subsequent rise in circulating glucose levels. We suggest that these effects of MgSO4 infusions should be considered where the aim is to achieve high doses of blood Mg2+ levels by clinical intervention.sch_die1 ISIS-4: ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 1995;345:669-685. 2 MAGIC Trial: Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial. Lancet 2002;360:1189-1196. 3 Muir KW, Lees KR, Ford I, Davis S: Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet 2004;363:439-445. 4 Wong GK, Poon WS, Chan MT, Boet R, Gin T, Ng SC, Zee BC: Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial. Stroke 2010;41:921-926. 5 Rukshin V, Santos R, Gheorghiu M, Shah PK, Kar S, Padmanabhan S, Azarbal B, Tsang VT, Makkar R, Samuels B, Lepor N, Geft I, Tabak S, Khorsandhi M, Buchbinder N, Eigler N, Cercek B, Hodgson K, Kaul S: A prospective, nonrandomized, open-labeled pilot study investigating the use of magnesium in patients undergoing nonacute percutaneous coronary intervention with stent implantation. J Cardiovasc Pharmacol Ther 2003;8:193-200. 6 Tiryakioglu O, Demirtas S, Ari H, Tiryakioglu SK, Huysal K, Selimoglu O, Ozyazicioglu A: Magnesium sulphate and amiodarone prophylaxis for prevention of postoperative arrhythmia in coronary by-pass operations. J Cardiothorac Surg 2009;4:8. 7 Collaborative Eclampsia Trial: Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. 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Exp Physiol 2003;88:533-540. 13 Blendea MC, Orbai P, Dragotoiu G, Duncea I, Hazi G, Dumitru E, Gozariu L: Effects of parenteral pharmacological magnesium loading on insulin secretion in experimental thyrotoxicosis. Magnesium Research 1999;12:31-35. 14 Gow IF: Measurement of ionised magnesium in HEPES-buffered serum samples. Anal Chim Acta 2001;432:143-149. 15 Bergmeyer H: Reagents for enzymatic analysis; in Bergmeyer HU GK, (ed): Methods of Enzymatic Analysis. Weinheim, Verlag Chemie, 1974, pp 494-495. 16 Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP: The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984;310:1221-1225. 17 Cruikshank DP, Pitkin RM, Reynolds WA, Williams GA, Hargis GK: Effects of magnesium sulfate treatment on perinatal calcium metabolism. I. Maternal and fetal responses. Am J Obstet Gynecol 1979;134:243-249. 18 Cruikshank DP, Pitkin RM, Donnelly E, Reynolds WA: Urinary magnesium, calcium, and phosphate excretion during magnesium sulfate infusion. Obstet Gynecol 1981;58:430-434. 19 Eisenbud E, LoBue CC: Hypocalcemia after therapeutic use of magnesium sulfate. Arch Intern Med 1976;136:688-691. 20 Gough IR, Balderson GA, Lloyd HM, Galligan J, Willgoss D, Fryar BG: The effect of intravenous magnesium sulphate on parathyroid function in primary hyperparathyroidism. World J Surg 1988;12:463-469. 21 Siggaard-Andersen O: Blood pH, carbon dioxide, oxygen, and calcium-ion; in Siggaard-Andersen O, (ed): Proceedings of the Fifth Meeting of the IFCC Expert Panel on pH and Blood Gases. Copenhagen, Private Press, 1981, p 163. 22 Kroll MH, Elin RJ: Relationships between magnesium and protein concentrations in serum. Clin Chem 1985;31:244-246. 23 Fogh-Andersen N, Bjerrum PJ, Siggaard-Andersen O: Ionic binding, net charge, and Donnan effect of human serum albumin as a function of pH. Clin Chem 1993;39:48-52. 24 Barbagallo M, Gupta RK, Bardicef O, Bardicef M, Resnick LM: Altered ionic effects of insulin in hypertension: role of basal ion levels in determining cellular responsiveness. J Clin Endocrinol Metab 1997;82:1761-1765. 25 Barbagallo M, Gupta RK, Resnick LM: Cellular ionic effects of insulin in normal human erythrocytes: a nuclear magnetic resonance study. Diabetologia 1993;36:146-149. 26 Curry DL, Bennett LL, Grodsky GM: Requirement for calcium ion in insulin secretion by the perfused rat pancreas. Am J Physiol 1968;214:174-178. 27 Iseri LT, French JH: Magnesium: nature's physiologic calcium blocker. Am Heart J 1984;108:188-193. 28 Devis G, Somers G, Van Obberghen E, Malaisse WJ: Calcium antagonists and islet function. I. Inhibition of insulin release by verapamil. Diabetes 1975;24:247-251. 29 Sambandam N, Abrahani MA, St PE, Al-Atar O, Cam MC, Rodrigues B: Localization of lipoprotein lipase in the diabetic heart: regulation by acute changes in insulin. Arterioscler Thromb Vasc Biol 1999;19:1526-1534. 30 Wolfe RR: Substrate utilization/insulin resistance in sepsis/trauma. Baillieres Clin Endocrinol Metab 1997;11:645-657. 31 Kohno H, Koyanagi T, Kasegawa H, Miyazaki M: Three-day magnesium administration prevents atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2005;79:117-126. 32 Haenni A, Johansson K, Lind L, Lithell H: Magnesium infusion improves endothelium-dependent vasodilation in the human forearm. Am J Hypertens 2002;15:10-15. 33 Apan A, Buyukkocak U, Ozcan S, Sari E, Basar H: Postoperative magnesium sulphate infusion reduces analgesic requirements in spinal anaesthesia. Eur J Anaesthesiol 2004;21:766-769. 34 Woods KL, Fletcher S: Long-term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1994;343:816-819. 35 Ravn HB, Lassen JF, Bergenhem N, Kristensen AT: Intravenous magnesium does not influence the activity of the coagulation cascade. Blood Coagul Fibrinolysis 2001;12:223-228. 36 Falck G, Lundgaard H, Jareld T, Skarra S, Arbo I, Gunnes S, Jynge P: Effect of magnesium infusion on bleeding time in healthy male volunteers. Scand J Clin Lab Invest 1999;59:425-430. 37 Thwaites CL, Yen LM, Loan HT, Thuy TT, Thwaites GE, Stepniewska K, Soni N, White NJ, Farrar JJ: Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial. Lancet 2006;368:1436-1443.24pub2558pub