Oxygen-induced enzyme release: early events and a proposed mechanism.

Rat hearts perfused for 60 min with hypoxic Krebs-Henseleit medium were fixed and examined by light and electron microscopy at 0, 0.5, 1, 2, 5 and 15 min after reoxygenation. The earliest structural changes seen at 0.5 to 2 min were contracture of myocardial cells with separation of sarcomere attachments to intercalated discs and Z-bands. These separations were followed by focal, and later, diffuse mitochondrial and cytoplasmic swelling. Creatine phosphokinase release from hearts could be detected by 0.5 min, but did not peak until 2 min after reoxygenation. The observed temporal sequence of events suggests that contracture of cells precedes enzyme release and massive cell swelling. It is postulated that when oxygen-supported contracture occurs, stretching and rupture of cell sarcolemmal membranes occurs in dyskinetic regions of cells left unsupported by sarcomere detachments.     

A proposed mechanism for the self-splicing of proteins.

Intervening protein sequences, called inteins, are intronlike elements that are removed posttranslationally, apparently by self-splicing. The conserved and essential residues of precursor proteins consist of an asparagine as the last residue of the intein and a hydroxyl- or thiol-containing residue immediately following both splice junctions. Evidence for a branched intermediate has been reported [Xu, M.-Q., Southworth, M., Mersha, F., Hornstra, L. & Perler, F. (1993) Cell 75, 1371-1377]; however, the chemical nature of the branched structure is unclear. I propose a mechanism that includes the formation of a branched structure, provides an explanation for the reversal of branch formation observed at high pH, and accounts for each of the essential amino acids. The branched structure is formed by nucleophilic attack of the asparagine side chain on the N-terminal splice junction. The nature of this branched structure is a distinguishing feature of the model and can be experimentally tested.     

Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up.

Mortality rates are considerably higher in chronic ischemic heart disease (IHD) patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those who are nondiabetics. The relationship between different types of antihyperglycemic pharmacological therapy and mortality rate in this NIDDM population is uncertain. We aimed to examine the survival in NIDDM patients with IHD using various types of oral antidiabetic treatments over a 5-year follow-up period. The study sample comprised 11,440 patients with a previous myocardial infarction and/or stable anginal syndrome, aged 45-74 years, who were screened, but not included in the Bezafibrate Infarction Prevention study. Among them, 9,045 were nondiabetics and 2,395 diabetics. The diabetic patients were divided into four groups on the basis of their therapeutic regimen at screening: diet alone (n = 990), sulfonylureas (n = 1,041), metformin (n = 78) and a combination of a sulfonylurea and metformin (n = 266). All NIDDM groups were similar with regard to age, gender, hypertension, smoking, heart failure, angina and prior myocardial infarction. Crude mortality rate was lower in the nondiabetic group (11.21 vs. 21.8%; p < 0.001). In the diabetic group, mortality was 18.5% for patients on diet alone, 22.5% for those on sulfonylureas, 25.6% for patients on metformin, and 31.6% for the combined sulfonylurea/metformin group (p < 0.01). When analyzing age-adjusted mortality rate and actuarial survival curves, the lowest mortality was found in patients on diet alone and the highest in patients on metformin (alone or in combination with sulfonylureas). After adjustment for variables connected with long-term prognosis, the use of metformin was associated with increased relative risk (RR) for all-cause mortality of 1.42 (95% CI 1.10-1.85), whereas the use of sulfonylureas alone was not [RR 1.11 (95% CI 0.90-1.36)]. NIDDM patients with IHD using metformin, alone or in combination with sulfonylureas, exhibited a significantly increased mortality. Until the results of problem-oriented prospective studies on oral control of NIDDM will be available, alternative therapeutic approaches should be investigated in these patients.     

Myocardial dysfunction in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality.

OBJECTIVE--To assess cardiac structure and function in patients with treated hypopituitarism and to determine their relation to the degree of growth hormone deficiency and body composition pattern. DESIGN--26 patients with treated hypopituitarism were studied by cross sectional and Doppler echocardiography and by exercise testing. The results were analysed and their relation to the degree of growth hormone deficiency and body composition determined. SETTING--All tests were performed in the department of cardiology and the unit of metabolic medicine at a tertiary referral centre. PATIENTS--Patients with hypopituitarism referred for endocrine assessment. MAIN OUTCOME MEASURES--Left ventricular mass, left ventricular diastolic function, and exercise capacity in patients with hypopituitarism and their relation to growth hormone deficiency. RESULTS--Mean (SD) serum concentration of insulin-like growth factor 1 (IGE-1), a measure of growth hormone deficiency, was 82.4 (45) micrograms/l. Lean body mass calculated by measuring total body potassium was 50 (9) kg. All patients had a normal left ventricular mass index and a normal left ventricular ejection fraction. Eight patients had abnormal left ventricular diastolic function. There was a significant correlation between IGF-1 and left ventricular mass (r = 0.45, p less than 0.02). Lean body mass was also significantly correlated with left ventricular mass (r = 0.78, p less than 0.0001) and left ventricular diastolic function (r = -0.63, p less than 0.01). The mean exercise duration was 8.6 (3.6) minutes. There was a significant correlation between serum IGF-1 and the rate-pressure product on exercise (r = 0.47, p less than 0.01). Seven patients had planar ST segment depression greater than 0.1 mV during exercise testing. In five of these patients there was rapid resolution of ST segment depression immediately after exercise. Two patients developed considerable ST segment depression, and subsequent coronary angiography showed normal coronary arteries. Exercise-induced ST segment depression was not related to the severity or duration of growth hormone deficiency or serum cholesterol concentration. CONCLUSIONS--This study suggests that left ventricular mass and the rate-pressure product are related to the degree of growth hormone deficiency, that left ventricular diastolic dysfunction is frequently seen in hypopituitarism, and that these patients may have ischaemic-like ST segment changes during exercise testing. These findings may explain the increased cardiovascular mortality in patients with hypopituitarism and may also have implications for growth hormone replacement therapy in adults.     

The superior QRS axis in ostium primum ASD: a proposed mechanism.

The influence of abnormal hemodynamics, ventricular hypertrophy, and right bundle branch block on the AQRS was studied pre- and post-operatively in 29 patients with OPSD. The AQRS markedly diminishes with the surgical correction of abnormal hemodynamics and the subsequent resolution of RVH or BVH. With the persistence of ventricular hypertrophy postoperatively or the surgical induction of RBBB, the AQRS either remains unchanged or, in the latter instance, becomes more superior and rightward. The dependence of the superior AQRS on these factors suggests that a left anterior hemiblock is not responsible for this AQRS. In OPSD early activation of the posterobasal region of the left ventricle through an abnormally short posterior fascicle results in a minimal superior AQRS which is then exaggerated in the presence of abnormal hemodynamics, ventricular hypertrophy, or RBBB. Thus, the superior AQRS in OPSD with associated RBBB does not represent a true bifascicular block and has a different natural history and clinical significance.     

Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up.

BACKGROUND: A sulfonylurea--usually glyburide--plus metformin constitute the most widely used oral antihyperglycemic combination in clinical practice. Both medications present undesirable cardiovascular effects. The issue whether the adverse effects of each of these pharmacologic agents may be additive and detrimental to the prognosis for coronary patients has not yet been specifically addressed. HYPOTHESIS: This study was designed to examine the survival in type 2 diabetics with proven coronary artery disease (CAD) receiving a combined glyburide/metformin antihyperglycemic treatment over a long-term follow-up period. METHODS: The study sample comprised 2,275 diabetic patients, aged 45-74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition, 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253). RESULTS: The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%), 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time-related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow-up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long-term follow-up, with a time-related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all-cause mortality of 1.53 (95% confidence interval [CI] 1.20-1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02-1.45) and HR 1.26 (95% CI 0.81-1.96), respectively. Conclusions: We conclude that after a 7.7-year follow-up, monotherapy with either glyburide or metformin in diabetic patients with CAD yielded a similar outcome and was associated with a modest increase in mortality. However, time-related mortality was markedly increased when a combined glyburide/metformin treatment was used.     

Experience with flecainide for the treatment of cardiac arrhythmias in children

We treated 22 children, aged 3 days to 16 years 6 months (medium11 years 1 month), with flecainide for a variety of aryhythmiaswhere a Class I agent was indicated in 16, conventional antiarrhythmictreatment had failed. Structural heart disease was present innine. The arrhythmia was paroxysmal re-entry atrioventriculartachycardia in five and frequent ventricular extrasystoles (withcouplets) in three. Sinas rhythm was achieved in all four childrenwho received flecainide during tachycardia (three received intravenousflecainide during tachycardia (three received intravenous flecainide,one oral). During follow-up of 3–24 months (median 12months), arrhythmia control was obtained in 13 children (59%).Combination therapy was used in seven of these; with digoxinin four and a beta blocker in three. Flecainide doses used inthis study ranged from 1–11 mg kg^–1 day^–1(median 4 mg kg^–1 day^–1), 25–297 mg m^–2day^–1).The medium, pre-dose flecainide concentration inthose responding to therapy was 225 µgl^–1 and inthose failing to respond was 417 µgl^–1. An arrhythmogeniceffect occured in one child.     

Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial

This report examines whether in the Cardiac Arrhythmia Suppression Trial death and cardiac arrest from encainide, flecainide and moricizine during the titration phase and from encainide and flecainide during the follow-up phase were related to presence (Q-wave acute myocardial infarction [Q-AMI]) or absence (non-Q-AMI) of pathologic Q waves. In all, 2,371 patients (70% with Q-AMI, 26% with non-Q-AMI, and 4% unknown) entered the titration phase, starting 117 ± 163 days after index AMI and lasting for an average of 21 days. For the titration phase, no significant differences existed between Q-AMI and non-Q-AMI patients for death and cardiac arrest rate, ventricular premature complex suppression rate, and nonrandomization rate. A total of 1,498 patients entered the follow-up phase of an average of 10 months (starting 129 ± 158 days after the index AMI), and were randomized to encainide or flecainide, or their matching placebos. In the placebo group, non-Q-AMI patients had a significantly lower rate of death and cardiac arrest than Q-AMI patients (1.0 and 4.6%, respectively; P = 0.04). Encainide and flecainide significantly elevated death and cardiac arrest rate in both non-Q-AMI patients (8.7%, p < 0.01) and Q-AMI patients (7.8%, P = 0.04). The relative risk for encainide or flecainide over placebo in the non-Q-AMI patients was 8.7, which was significantly higher than 1.7 observed for the Q-AMI patients (p = 0.03). None of the baseline characteristics had any significant interaction with encainide or flecainide.

In conclusion, during the relatively early post-AMI period, therapy with encainide, flecainide or moricizine resulted in similar rates of ventricular premature complex suppression and death/cardiac arrest between non-Q-AMI and Q-AMI groups. In contrast, during the late postmyocardial infarction period, therapy with encainide or flecainide was associated with a much steeper increase in death/cardiac arrest rate in the non-Q-AMI group than in the Q-AMI group.     

Myocardial injury in critically ill patients: relation to increased cardiac troponin I and hospital mortality

OBJECTIVE: To examine the relationship between myocardial injury, assessed by cardiac troponin I (cTnI) levels, and outcome in selected critically ill patients without acute coronary syndromes or cardiac dysfunction. DESIGN AND SETTING: Prospective, observational study in the emergency ICU of a university teaching hospital. POPULATION: Over a 6-month period, 217 consecutive patients admitted to the ICU were studied. METHODS AND RESULTS: cTnI assays were performed in all patients on admission to the ICU. The incidence of myocardial injury, defined by cTnI level > 0.1 ng/mL, was 32% (69 of 217 patients). Overall mortality was 27% (58 of 217 patients). Patients with myocardial injury had a mortality rate of 51%, compared with only 16% mortality for those without myocardial injury (p < 0.001). The hospital mortality rate was highest among older patients (71 +/- 14% vs 58.5 +/- 20%, p < 0.0001) and patients with higher simplified acute physiology scale (SAPS) II score (62 +/- 25% vs 37 +/- 17%, p < 0.0001). Mechanical ventilation was associated with higher in-hospital death (50% vs 31%, for patients who died in the hospital vs those who were discharged alive; p = 0.03). Elevated blood levels of cTnI were found to be independently associated with hospital mortality, regardless of the presence of SAPS II score and mechanical ventilation, in the logistic regression analysis (odds ratio, 2.09; 95% confidence interval, 1.06 to 4.11; p = 0.01). CONCLUSIONS: This study demonstrates the high frequency of myocardial injury (32%) in critically ill patients without acute coronary syndromes or cardiac dysfunction on admission to ICU. Myocardial injury is an independent determinant of hospital mortality. Assessment of myocardial injury on admission to ICU would make it possible to identify patients at increased risk of death.     

Concentrations of amiodarone and flecainide in plasma and saliva--indications for the active transport of flecainide

Only the free protein-unbound drug concentration in plasma is pharmacologically active. The concentration of some drugs in saliva is equal to the free drug level. We compared concentrations (in plasma before, 30 and 60 min after the morning dose, in saliva before, 30, 60, 90 and 120 min after the morning dose) of amiodarone (n = 8, 2 x 200 mg orally per day) and flecainide (n = 16, 2 x 100 mg) administered as chronic antiarrhythmic treatment. Drug levels were measured by "high performance liquid chromatography". Results: Just prior to the first morning dose, amiodarone concentrations in plasma were 1.0-2.9 (2.0 +/- 0.6) micrograms/ml, in saliva 0.02-0.25 micrograms/ml; flecainide in plasma 80-560 (316 +/- 163) ng/ml, in saliva 630-3700 (1749 +/- 963) ng/ml. After the morning dose we found maximal flecainide plasma levels of 462 +/- 203 and saliva levels of 3218 +/- 2857 ng/ml. The highest flecainide concentrations in the saliva (13,400 and 11,300 ng/ml) were found in two patients 30 and 60 min after the morning dose. Flecainide, but not amiodarone, is excreted actively in the saliva, probably indicating an enteroenteric circulation. This should be considered to reduce life-threatening flecainide intoxications by gastric and intestinal lavage and suction. The concentration of flecainide in the saliva does not represent the non-protein-bound free drug level in the plasma.     

耐多药结核病报告:对治疗转归中“失败”定义的建议

耐多药结核患者并不是一个齐同的人群的。他们有些人从来没有接受过抗结核治疗,有一些人使用过一线抗结核药,还有一些人接受过二线抗结核药治疗。在报告的患者中,耐多药结核病的疗程长短不一。Burgos和他的同事报告了痰培养阴转时间的中位数是14.6周,但是最长可达3.4年~3。     

Effect of encainide,ODE, MODE,and flecainide on ADP/5-HT Induced platelet aggregation and in the anesthetized dog coronary artery stenosis-occlusion model of intravascular thrombosis

Encainide is a class 1C antiarrhythmic agent that is indicated for the treatment of life-threatening arrhythmias, such as sustained ventricular tachycardia. Furthermore, encainide possesses a moderate degree of antiserotonin activity, which was quantitated in this present study by determining displacement of [3H]spiperone binding from rat cortical 5-HT2 binding sites. The Ki for encainide in this model was 66.1 nM, compared to 2.6 nM for ketanserin. Two encainide metabolites, ODE and MODE, were also active, but were weaker than encainide. Additionally, these agents were found to inhibit platelet aggregation induced in vitro in human platelet-rich plasma by the combination of ADP and serotonin. In view of the fact that serotonin is one of a variety of humoral factors capable of activating blood platelets and has been recently implicated as playing a role in certain thrombotic syndromes, encainide, along with its two principal human metabolites, ODE and MODE, and another class 1C antiarrhythmic, flecainide, were evaluated in an in vivo model of intravascular thrombosis. Intraduodenal doses of 1 mg/kg of either encainide, ODE, or MODE significantly inhibited thrombosis in a canine model of coronary artery stenosis-occlusion.     

Clinical significance of silent ischaemia and implications for treatment: role of radionuclide techniques.

Radionuclide techniques have added substantial information to aid detection and heighten the clinical significance of silent ischaemia. While non-invasive assessment of myocardial perfusion, metabolism and wall motion have increased the knowledge of the pathophysiology of silent ischaemia, radioisotope techniques may provide information far beyond that obtained by electrocardiographic criteria alone. Whether patients with silent ischaemia should be treated can only be inferred from indirect evidence suggested by preliminary trials. Only randomized, controlled, clinical trials will yield the definite answers as to the effects of treatment on clinical outcome.     

Oral flecainide in the treatment of refractory arrhythmias. Long-term follow-up of 98 patients

Oral flecainide was administered to 98 patients with arrhythmias regarded as resistant to other antiarrhythmic agents: quinidines (82), propafenone (40), beta-blockers (30), amiodarone alone (38) or combined with a class I compound (19). Therapeutic effectiveness was assessed on clinical date, repeated Holter recordings (64 patients), exercise tests (8) and electrophysiological exploration (15). Mean follow-up was 11.7 +/- 11 months; the patients treated have now been followed up for 18.2 +/- 12 months (range: 7-58 months). Fifty-three patients had atrial arrhythmia (fibrillation or flutter in 45, atrial tachycardia in 8). Flecainide was effective in 26 patients (49%) and ineffective in 27 (51%). There was no significant difference in dosage between these 2 groups: 231 +/- 62 mg/day and 265 +/- 61 mg/day respectively. Paroxysms of re-entrant junctional tachycardia were controlled in 6 of the 8 cases observed. Eleven patients presented with Wolff-Parkinson-White syndrome: treatment was successful in the 3 patients with atrial fibrillation and in 8 of the 10 patients with orthodromic reciprocating rhythms. Among 30 patients with episodes of ventricular tachycardia, 9 (30%) responded to flecainide and 21 (70%) failed to respond. Flecainide reduced the repetitive forms by more than 90% in 7/15 patients and suppressed exercise-induced ventricular tachycardia in 2/8 patients. Fifteen out of 18 patients had ventricular tachycardia reproducible by programmed stimulation; under flecainide, the ventricular tachycardia spontaneously recurred in 4 cases, was provoked by stimulation in 5 other cases, was more easily inducible in 3 cases and was not inducible in a sustained manner in the last 3 cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term survival after permanent pacemaker implantation: analysis of predictors for increased mortality.

AIMS: To determine long-term time-related survival and evaluate risk factors for increased mortality in patients following their first permanent pacemaker implantation. METHODS AND RESULTS: Analysis of patient records from implant to follow-up. Patient-specific time-lines were constructed to date of last review or death. Observed survival was estimated by event-free analysis using the Kaplan-Meier method. Expected survival was derived from age- and gender-matched cohorts. Risk factors for mortality were sought using the multivariate Cox proportional hazards method and risk ratios estimated. Eight hundred and thirty-three patients underwent implantation of their first permanent pacemaker from April 1992 to January 1994, and were locally followed up. Survival data were available for 803 (96.4%) patients (median age, 77.3 years [5th to 95th centile range: 53.5 to 89 5 years]) and follow-up was complete in 94.8%. At implant. dual-chamber systems were implanted in 443 (55.1%). single-chamber ventricular systems in 321 (40.0%), and single-chamber-atrial systems in 39 (4.9%). Observed survival after implantation was significantly worse than expected (P<0.001). Independent predictors of increased mortality were: age at implant (risk ratio [RR] 1.06: 95% confidence interval [CI] 1.01 to 1.12). VVI pacing mode (RR 1.64; 95% CI 1.34 to 1.93), cardiomyopathy (RR 5.86; 95% CI 4.86 to 6.86), male gender (RR 1.27; 95% CI 1.22 to 1 32) and valvular heart disease (RR 2.01: 95% CI 1.98 to 2.04). CONCLUSIONS: At the end of follow-up, mortality was much higher than expected. In this typical pacemaker population. age at implant and VVI pacing mode were independently associated with increased mortality with accompanying heart disease having the greatest individual impact.     

A review of the evidence for and against increased mortality in hypothyroidism

The lifetime risk of overt hypothyroidism is around 5%, and this disease is usually preceded by subclinical hypothyroidism, which has an even higher prevalence (estimated to be up to 9%). Hypothyroidism has been linked with cardiac dysfunction, atherosclerosis, hypertension and coagulopathy. Intuitively, this increased morbidity is expected to shorten patients' lifespan, but definitive data are lacking on whether either of these hypothyroid states (particularly overt hypothyroidism) increase mortality. Study findings are inconsistent and, overall, the pooled data do not demonstrate increased mortality in patients with either subclinical or overt hypothyroidism. However, none of the available studies was adequately designed to answer this question. This Review discusses major shortcomings in those studies, such as population dissimilarities, hypothyroid state classification and misclassification, the inclusion of nonthyroidal illness, drug interference from concurrent therapies, serious comorbidities (for example, cardiovascular disease), differences in duration of follow-up and the number of levothyroxine-treated individuals. Taken together, the data exhibit little evidence of systematic bias and no strong scientific proof of increased mortality related to either subclinical or overt hypothyroidism. Future studies, however, should take the above-mentioned shortcomings and potential genetic confounding into consideration.