Myocardial stunning is associated with impaired calcium uptake by sarcoplasmic reticulum.

Myocardial stunning (temporary post-ischaemic contractile dysfunction) may be caused by oxidative stress and/or impaired myocyte calcium homeostasis. Regional myocardial stunning was induced in open-chest pigs (segment shortening reduced to 68.3+/-4.7% of baseline) by repetitive brief circumflex coronary occlusion (I/R). Reduced glutathione was depleted in stunned myocardium (1.34+/-0.06 vs. 1.77+/-0.11 nmol/mg, p=0.02 vs. remote myocardium) indicating regional oxidant stress, but no regional differences were observed in protein-bound 3-nitrotyrosine or S-nitrosothiol content. Repetitive I/R did not affect myocardial quantities of the sarcolemmal sodium-calcium exchanger, L-type channel, SR calcium ATPase and phospholamban, or the kinetics of ligand binding to L-type channels and SR calcium release channels. However, initial rates of oxalate-supported (45)Ca uptake by SR were impaired in stunned myocardium (41.3+/-13.5 vs. 73.0+/-15.6 nmol/min/mg protein, p=0.03). The ability of SR calcium ATPase to sequester cytosolic calcium is impaired in stunned myocardium. This is a potential mechanism underlying contractile dysfunction.

The ABC-Pyramid Atmospheric Research Observatory in Himalaya for aerosol, ozone and halocarbon measurements.

In this work we present the new ABC-Pyramid Atmospheric Research Observatory (Nepal, 27.95 N, 86.82 E) located in the Himalayas, specifically in the Khumbu valley at 5079 m a.s.l. This measurement station has been set-up with the aim of investigating natural and human-induced environmental changes at different scales (local, regional and global). After an accurate instrumental set-up at ISAC-CNR in Bologna (Italy) in autumn 2005, the ABC-Pyramid Observatory for aerosol (physical, chemical and optical properties) and trace gas measurements (ozone and climate altering halocarbons) was installed in the high Khumbu valley in February 2006. Since March 2006, continuous measurements of aerosol particles (optical and physical properties), ozone (O3) and meteorological parameters as well as weekly samplings of particulate matter (for chemical analyses) and grab air samples for the determination of 27 halocarbons, have been carried out. These measurements provide data on the typical atmospheric composition of the Himalayan area between India and China and make investigations of the principal differences and similarities between the monsoon and pre-monsoon seasons possible. The study is carried out within the framework of the Ev-K2-CNR "SHARE-Asia" (Stations at High Altitude for Research on the Environment in Asia) and UNEP-"ABC" (Atmospheric Brown Clouds) projects. With the name of "Nepal Climate Observatory-Pyramid" the station is now part of the Observatory program of the ABC project.

[Symptomatic SUNCT with cerebral abscess and subdural empyema]. / Syndrome SUNCT symptomatique d'abcès et d'empyème cérébraux.

SUNCT syndrome is a rare form of a primary headache disorder, although secondary causes, particularly posterior fossa abnormalities, are well known. We report a new case in a 67-year-old man suffering SUNCT syndrome secondary to pyogenic cerebral abscess and empyema localized in the convexity portion of the right frontal lobe.

Absolute blood flow and oxygen consumption in stunned myocardium in patients with coronary artery disease.

OBJECTIVES: In patients with coronary artery disease (CAD), we sought to demonstrate normal myocardial blood flow (MBF) and myocardial oxygen consumption (MMRO(2)) to post-ischemic myocardium that exhibited reversible dysfunction and the relation between the severity of the dysfunction and the preceding ischemia. BACKGROUND: In animal models of stunning, MBF and MMRO(2) are normal or near normal, and the severity of stunning is related to the degree of the preceding ischemia. METHODS: Myocardial blood flow and MMRO(2) were measured using positron emission tomography and oxygen 15-labelled water (H(2)(15)O) and oxygen 15-labelled oxygen ((15)O(2)), respectively, in 14 patients with CAD and normal left ventricular (LV) function. Global ejection fraction and regional LV systolic function (SF) were measured using quantitative echocardiography during and after dobutamine-induced ischemia. RESULTS: Ejection fraction and SF were reduced 30 min after dobutamine (both: p < 0.01) but recovered by 120 min. Myocardial blood flow (ml/min per g) to regions with reversible LV dysfunction was normal at baseline and during dysfunction (0.88 [0.82 to 0.99] and 1.09 [0.75 to 1.37], respectively, p = NS) as was MMRO(2) (ml/min per 100 g) (16.64 [10.16 to 16.18] and 11.68 [8.43 to 15.30] respectively, p = NS). Left ventricular dysfunction was related to stenosis severity and peak MBF. Regions were divided into those subtended by a stenosis of <50%, 50% to 80% and >80% luminal diameter. Systolic function 30 min after dobutamine was 93.9% (83.4% to 104.4%) (p = NS), 85.4% (80.0% to 90.9%) and 67.4% (56.2% to 78.7%) (both: p < 0.001), respectively. Peak MBF was 2.0 (1.71 to 2.31), 1.75 (1.65 to 1.85) (p = 0.01 compared with <50%) and 1.47 (1.33 to 1.60) (p = 0.03 compared with 50% to 80% and p = 0.002 compared with <50%), respectively. CONCLUSIONS: In patients with CAD, dobutamine produces prolonged, but reversible, LV dysfunction when MBF is normal, confirming stunning. This stunning is related to the severity of the coronary stenosis and the reduction in peak MBF. Myocardial oxygen consumption to stunned myocardium is normal.

Effect of enhanced external counterpulsation on dobutamine-induced left ventricular wall motion abnormalities in severe chronic angina pectoris.

We studied the effect of enhanced external counterpulsation (EECP) in 23 consecutive patients with stable angina pectoris who had a positive dobutamine stress echocardiogram. After EECP, stress-induced wall motion score (WMS) improved by > or =2 grades in 43% of the patients (n = 10); the average improvement was 5.3 +/- 3.8 compared with -0.6 +/- 3.0 in the remaining 13 patients (p = 0.007). The diastolic/systolic augmentation ratio increased by 217% in response to the full course of EECP (p = 0.0002) among patients with improved WMS, and by 71% (p = 0.004) among the other patients; the increase was greater among patients with improved WMS than among patients with no improvement (p = 0.01). After EECP, Canadian Cardiovascular Society angina class improved from 3.1 +/- 0.6 to 2.2 +/- 0.7 (p <0.0001) in the entire group and exercise capacity increased by 73 seconds (p = 0.0002) in patients who were able to exercise (n = 18).

Drug treatment of stable angina pectoris in the elderly: defining the place of calcium channel antagonists.

Chronic stable angina pectoris (CSAP) resulting from coronary artery disease (CAD) is common in elderly patients, and significantly reduces their quality of life. Myocardial revascularisation procedures in this age group entail significant risks, largely related to comorbidities rather than advanced age itself. Coronary artery anatomy is more likely to be technically unsuitable for revascularisation and angina more resistant to drug treatment. Therefore, elderly patients often take combinations of antianginal drugs. Calcium channel antagonists (CCAs) are effective antianginal drugs first introduced for clinical use in the late 1970's. They reduce myocardial ischaemia by both causing vasodilatation of coronary resistance vessels and reducing cardiac workload (negative inotropic effect). However, adverse effects related to abrupt arterial vasodilatation limited the tolerability of these short acting 'first generation' drugs (nifedipine, verapamil and diltiazem). Furthermore, short acting nifedipine may occasionally increase both the frequency of angina pectoris and mortality in patients with CAD. Since then, long acting formulations of first generation agents and new chemical entities (second and third generation drugs) have been developed. These are well tolerated and effective at attenuating both myocardial ischaemia and the frequency and severity of angina pectoris in most patients with stable CAD. Current guidelines on the drug treatment of CSAP propose that beta-adrenoceptor antagonists (beta-blockers) should be used as first line medication primarily for their prognostic benefits, and that CCAs need only be introduced if beta-blockers are not tolerated, contraindicated or ineffective. Despite this, there is a wealth of evidence from clinical trials that demonstrate equal antianginal efficacy for CCAs and beta-blockers. The presence of chronic heart failure and prior myocardial infarction are clear indications for the use of beta-blockers in preference to CCAs for the treatment of CSAP. However, in patients with both CSAP and hypertension, second and third generation CCAs may offer prognostic benefits of similar magnitude to those provided by beta-blockers. Therefore, antianginal drug therapy must be tailored to the individual needs and comorbidities of each elderly patient.

[Control of hypertension and blood lactate during exercise. Comparison of central antihypertensive agents with the cardio-selective beta blockers metoprolol and atenolol]. / Contrôle de l'hypertension artérielle et lactatémie à l'effort. Comparaison des antihypertenseurs centraux avec les bêtabloquants cardio-sélectifs métoprolol et aténolol.

To assess whether betablockers (BB) would better control blood pressure than central antihypertensive drugs (CAD) clonidine or alpha methyldopa in hypertensive patients during exercise, comparable triangular ergometric bicycle exercises were performed by the same patients while their hypertension had been controlled at rest either with CAD or BB. Blood pressure, heart rate and blood lactate before and during exercise were compared in II patients treated with metoprolol and CAD, and in 12 other patients treated with atenolol and CAD. Systolic and diastolic blood pressure on exercise were significantly lower with BB than with CAD. Heart rate and rate-pressure product were always lower with BB than with CAD. Blood lactate increase was greater with BB than with CAD. The work capacity was greater with atenolol than with CAD, but comparable between metoprolol and CAD.

[Multiple sclerosis and Leber's hereditary optic neuropathy mitochondrial DNA mutations]. / Sclérose en plaques et mutations de l'ADN mitochondrial associées à la maladie de Leber.

Multiple sclerosis (MS) has long been known to be associated with Leber's hereditary optic neuropathy (LHON), a disease caused by mitochondrial DNA (mtDNA) mutations. We have investigated the possible involvement of LHON mtDNA point mutations in MS. The study covered a group of 75 unrelated Caucasian patients, with the relapse-remitting or primary progressive form of MS, and a control group of 75 volunteers (matched for age, gender and ethnic origin). Mitochondrial DNA from each subject was examined for 4 primary LHON mutations (at nucleotide positions 3460, 4160, 11778 and 14484) and 7 secondary LHON mutations (at nucleotide positions 4216, 4917, 5244, 7444, 13708, 15257 and 15812) by means of restriction site polymorphism and sequencing techniques. None of the primary LHON mutations were detected in the MS patients or in the controls, whereas the proportion of individuals with secondary LHON mutations was identical (27 p. cent) in the two groups. A combination of 2 or 3 homoplasmic mutations, defining mtDNA haplogroups, was found in the majority of cases. Haplogroups J, T and X were not particularly associated with MS. The frequency of the 13708 mutation alone (haplogroup X), or associated with the 4216 mutation (haplogroup J), was somewhat higher (p=0.059) in the subgroup of MS patients with optic neuritis (ON). ON was the initial symptom in all but one of the patients with haplogroups J or X. No other correlation was found between MS phenotypes and mtDNA genotypes. Our observations confirm previous reports that neither primary nor secondary LHON mutations are involved in the development of MS. However, MS patients with haplogroups J or X appear to have a moderately higher risk of developing optic neuritis. Thus, a specific mtDNA background may be a predisposing genetic factor for optic nerve damage in MS patients.

Recommendations for the management of patients after heart valve surgery.

Approximately 50,000 valve replacement operations take place in Europe annually and almost as many valve repair procedures. Previous European guidelines on management of patients after valve surgery were last published in 1995 and were limited to recommendations about antithrombotic prophylaxis. American guidelines covering the broader topic of the investigation and treatment of patients with valve disease were published in 1998 but devoted relatively little space to post-surgical management. This document represents the consensus view of a committee drawn from three European Society of Cardiology (ESC) Working Groups (WG): the WG on Valvular Heart Disease, the WG on Thrombosis, and the WG on Rehabilitation and Exercise Physiology. In almost all areas of patient management after valve surgery, randomized trials and meta-analyses do not exist. Such randomized trials as do exist are very few in number, are narrowly focused with small numbers, have limited general applicability, and do not lend themselves to meta-analysis because of widely divergent methodologies and different patient characteristics. Recommendations are therefore almost entirely based on non-randomized studies and relevant basic science.

Evidence that stunning can be cumulative in man.

Myocardial stunning and hibernation are two entities that have become increasingly recognised as clinically important causes of reversible left ventricular (LV) dysfunction. Their occurrence is important as resting myocardial dysfunction, which was once thought to be irreversible, may recover if ischaemia is lessened or abolished. Recent evidence has suggested that cumulative stunning can occur in man and may in fact be responsible for the phenomenon of hibernation. In this chapter we will review the evidence supporting the occurrence of cumulative stunning in man.

Ischaemic myelopathy following aortic surgery or traumatic laceration of the aorta.

Paraplegia is one of the major complications following repair of aortic aneurysms or congenital malformations and from trauma of the aorta. In a series of 12 surviving patients we describe the clinical features as well as the evolution and pathophysiology of ischaemic lesions of the spinal cord. The clinical characteristics: loss of tendon reflexes, preservation of light touch sensation and bladder function, and the special topography of pin prick impairment, suggest involvement of the central grey matter. This lesion of the grey matter is incomplete in most of the patients and tends to extend for 2-10 segments. In some cases it can extend downward to the conus resulting in complete flaccid paraplegia. On follow-up we have observed limited improvement in most cases. No patient has recovered fully. Except in cases of traumatic laceration, where symptoms existed before surgery, paraplegia followed surgical repair in all other cases. Ischaemia can be related to the duration and the site of crossclamping of the aorta. Clamping above the left subclavian artery and/or a ligation of the intercostal arteries without previous visualisation of the spinal cord arteries can be dangerous. Other factors such as the phenomena of revascularisation and the presence of free radicals are discussed. These could explain delayed postischaemic spinal cord hypoperfusion.

The pathologic and immunologic response to inhaled trimellitic anhydride in rats.

Trimellitic anhydride (TMA) is a chemical intermediate used in the paint and plastics industry. Inhalation of TMA can induce four types of syndromes in TMA workers; three are immunologically based whereas the fourth, an irritant syndrome, is nonimmunologic. To evaluate the potential inhalation hazard of TMA under controlled conditions, Sprague-Dawley rats were exposed 6 hr/day via inhalation to target concentrations of 0, 10, 30, 100, and 300 micrograms/m3 for varying durations. Two sets of rats received either 5 or 10 exposures and were terminated. A third set received 10 exposures, and was held 12 days and terminated. A fourth set received 10 exposures, and was held 12 days, challenged with a single 6-hr exposure, and terminated. A fifth set received 10 exposures, and was held 12 weeks and terminated. There were no effects after 5 exposures; however, after 10 exposures the following parameters were increased in a concentration-related manner: absolute and relative lung weights, external hemorrhagic lung foci, alveolar macrophage accumulation, alveolar hemorrhage, pneumonitis, and lung and mediastinal lymph node nonspecific IgG and complement (C3). The rats exposed and rested 12 days were nearly recovered from these effects; however, rats rested 12 days and subsequently challenged exhibited lesions similar to those seen immediately following exposure. Exposed rats rested 12 weeks were completely normal in all of the above parameters. The timing and nature of the lung lesions, along with the presence of lung IgG and complement, are consistent with some of the known aspects of TMA-induced lesions in humans, and are reflective of results obtained from other hypersensitivity pneumonitis models.

Reducing the number of rabbits in the Draize eye irritancy test: a statistical analysis of 155 studies conducted over 6 years.

The Draize eye irritancy test in rabbits has been the focus of recent efforts to reduce the use of live animals in toxicity testing. A suitable alternative is not yet available; therefore, we studied the adequacy of reducing the number of rabbits used per test. Data generated from 6-rabbit eye irritation tests of 155 various materials were used to determine the ability of irritation scores from all possible combinations of 5-, 4-, 3-, or 2-rabbit subsets to predict the Draize score derived from six rabbits. There are 930, 2325, 3100, and 2325 possible combinations of 155 studies for the 5-, 4-, 3-, and 2-rabbit subsets, respectively. We classify materials using a four-level adjectival rating system based on (among other factors) the Draize score. Comparisons indicated that 5-, 4-, 3-, and 2-rabbit scores were in 98, 96, 94, and 91% agreement, respectively, with the classification assigned on the basis of the 6-rabbit score. The correlation coefficients for randomly selected subsets of 5-, 4-, 3-, and 2-rabbit scores versus the Draize score for six rabbits were 0.998, 0.996, 0.992, and 0.984, respectively. This study confirms the findings of an earlier report by De Sousa et al. (1984), and indicates that a high level of accuracy can be obtained with reduced numbers of rabbits per test.

A model of immunologic lung injury induced by trimellitic anhydride inhalation: antibody response.

We studied lung injury induced in Sprague-Dawley rats by trimellitic anhydride (TMA) inhalation. Groups of 40 male and 20 female rats were exposed to TMA by inhalation at target concentrations of 0, 10, 30, 100, and 300 micrograms/m3, 6 hours per day, 5 days per week, for 2 weeks. Rats in each exposure group were sacrificed after 10 exposures or rested for 12 days and either sacrificed or received a 6-hour TMA challenge at their initial exposure levels and sacrificed at 24 hours. At each sacrifice, serum antibody to radiolabeled trimellityl rat serum albumin (RSA-TM) was measured by an ammonium sulfate technique, and lung pathology was determined. After 10 days of exposure, external hemorrhagic lung foci were directly related to the exposure concentration of TMA. Serum antibody binding of RSA-TM correlated with exposure concentration, hemorrhagic lung foci, and lung weight. There was healing of lung lesions 12 days after exposure with a return of lung lesions only 18 hours after the 6-hour inhalation challenge. A correlation between serum antibody to RSA-TM, hemorrhagic foci, and lung weight existed after challenge. This model clarifies two clinical entities observed in exposed workers, the late respiratory systemic and the pulmonary disease-anemia syndromes.

Immunocytochemical evidence for inducible nitric oxide synthase and cyclooxygenase-2 expression with nitrotyrosine formation in human hibernating myocardium.

BACKGROUND: Myocardial hibernation may result from repetitive episodes of transient ischaemia leading to prolonged dysfunction. Inducible nitric oxide synthase (iNOS) expression has been demonstrated in animals following brief, non-lethal ischaemia-reperfusion injury. We therefore, hypothesised that in human hibernating myocardium: 1). iNOS would be present; 2). the reaction of nitric oxide and superoxide would form the strong oxidant peroxynitrite; 3) that this process would be accompanied by the expression of cyclooxygenase-2 (Cox-2) which interacts with NOS and whose products could further affect myocardial function. METHOD AND RESULTS: In sixteen patients with coronary artery disease (CAD), left ventricular biopsies were obtained from chronically dysfunctional segments subtended by a stenotic artery (> 75 %) and shown to be viable by (18)F-fluorodeoxyglucose positron emission tomography. Comparison was made with myocardial biopsies (n = 8) from normally contracting myocardium in patients undergoing coronary surgery, from unused transplant donors and at post-mortem. Regional wall motion score improved in all patients 6 months post-revascularisation (from 2.7 +/- 0.7 to 1.5 +/- 0.5; p < 0.001), confirming hibernation. Immunocytochemistry localized reactivity to iNOS, Cox-2 and nitrotyrosine (a marker of peroxynitrite formation) to cardiomyocytes from hibernating segments. No difference in reactivity to endothelial NOS was seen between hibernating and control cardiomyocytes. CONCLUSION: Cox-2 and iNOS are co-expressed in hibernating myocardium with nitrotyrosine suggesting nitric oxide production and peroxynitrite formation. We propose that this is secondary to ischaemia-reperfusion and that the products of these enzymes may have consequences for myocardial contractile function and survival.