Optical sectioning microscopes with no moving parts using a micro-stripe array light emitting diode.

We describe an optical sectioning microscopy system with no moving parts based on a micro-structured stripe-array light emitting diode (LED). By projecting arbitrary line or grid patterns onto the object, we are able to implement a variety of optical sectioning microscopy techniques such as grid-projection structured illumination and line scanning confocal microscopy, switching from one imaging technique to another without modifying the microscope setup. The micro-structured LED and driver are detailed and depth discrimination capabilities are measured and calculated.

High speed optically sectioned fluorescence lifetime imaging permits study of live cell signaling events.

We present a time domain optically sectioned fluorescence lifetime imaging (FLIM) microscope developed for high-speed live cell imaging. This single photon excited system combines wide field parallel pixel detection with confocal sectioning utilizing spinning Nipkow disc microscopy. It can acquire fluorescence lifetime images of live cells at up to 10 frames per second (fps), permitting high-speed FLIM of cell dynamics and protein interactions with potential for high throughput cell imaging and screening applications. We demonstrate the application of this FLIM microscope to real-time monitoring of changes in lipid order in cell membranes following cholesterol depletion using cyclodextrin and to the activation of the small GTP-ase Ras in live cells using FRET.

Determinants of systemic availability of oral hydralazine in heart failure.

Short-term therapy with oral hydralazine can favorably affect abnormal hemodynamics in patients with congestive heart failure, but the range of dosage is large. To investigate whether this variability in effective dose is a result of altered systemic availability, we studied 10 patients with congestive heart failure. Bioavailability (F) was calculated as the ratio of the blood AUC for a single 75 mg oral dose to the AUC of a 0.3 mg/kg iv dose. Acetylation capability was determined by sulfamethazine metabolic clearance (CLsmz). The F value in six subjects with CLsmz greater than 100 ml/min was 9.9% +/- 6.0% (means +/- SD) and was lower than the value of 26.2% +/- 13.0% (P less than 0.05) in the four patients with CLsmz less than 60 ml/min. Thus acetylation ability is an important consideration during low-dose hydralazine therapy (less than or equal to 225 mg/day). The clearance of the single intravenous dose of hydralazine averaged 29.5 +/- 8.0 ml/min/kg, which is not different than that reported in populations without heart failure. After oral dosage titration to induce maximum hemodynamic changes, the dose-normalized hydralazine AUC rose from 53.5 +/- 50.5 to 247.2 +/- 213.4 min/L X 10(3). Thus large oral doses of hydralazine result in disproportionate increases in systemic availability compatible with saturation of the first-pass effect or systemic clearance. In the doses required for maximum hemodynamic effects in our patients (225 to 3000 mg/day), this saturation phenomenon was a prominent determinant of systemic availability.

Hemodynamic effects of N-acetylprocainamide in heart disease.

In six normal subjects and 6 patients with primary cardiomyopathy, left ventricular performance was evaluated at rest and during isometric handgrip exercise after 4 days of oral N-acetylprocainamide (NAPA) at each of the three dosage levels (3, 4, 5, and 6 gm/day). Changes in heart rate, blood pressure, and echocardiographic performance indices were noted during isometric exercise, but no effect of NAPA could be demonstrated. In five additional patients with ventricular dysrhythmias due to cardiac diseases, NAPA was given by vein until dysrhythmias were controlled and then a maintenance infusion was continued for 48 hr. Continuous ECG recordings showed excellent dysrhythmia control in four of the five patients, but no effect of NAPA on heart rate, blood pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, or cardiac output was demonstrated, either at the peak of initial infusion (serm NAPA 27 +/- 6.7 microgramsm/ml) or at steady state during the maintenance infusion (16 +/- 4.5 microgramm/ml). We conclude that NAPA by vein and mouth in clinically appropriate doses should be safe in patients with the reduced left ventricular performance due to cardiac disease.

Prognostic value of exercise-induced ventricular ectopic activity for mortality after acute myocardial infarction.

To evaluate the importance of ventricular ectopic activity on the predischarge treadmill exercise test for predicting mortality in patients after acute myocardial infarction (AMI), 163 patients with uncomplicated AMI were studied using symptom limited low-level treadmill exercise testing and 24-hour ambulatory electrocardiographic monitoring before hospital discharge. All patients were followed for at least 2 years or until recurrent AMI, coronary artery bypass grafting or death. Seventeen patients (10%) died during the follow-up period, 15 patients (9%) had recurrent AMI and 45 patients (28%) underwent bypass surgery. Ventricular ectopic activity was the only single treadmill abnormality that predicted subsequent cardiac death; angina pectoris, electrocardiographic ST-segment depression and a hypotensive blood pressure response did not. The mortality rate in the 20 patients with exercise-induced ventricular ectopic activity was 25%, compared with 8% in those without (p less than 0.004). Furthermore, in this patient population, exercise-induced ventricular ectopic activity was a much better predictor of cardiac death than that detected by ambulatory monitoring. Thus, ventricular ectopic activity on the predischarge treadmill exercise test is an important risk factor for death after AMI.

Miscoding of hospital discharges as acute myocardial infarction: implications for surveillance programs aimed at elucidating trends in coronary artery disease.

The current decline in coronary artery disease mortality (CAD) may be a result of a declining population risk or of a declining case-fatality rate. Information on incidence trends for myocardial infarction (MI) could be used to distinguish between these 2 possibilities. Hospital discharge codes for MI (ICDCM-410) could be used as a convenient proxy for incidence trends, provided that coding of hospital discharges is sufficiently accurate. To evaluate the accuracy of medical records coding of patients signed out with an acute MI code (ICDCM-410), we compared them to an independent cardiology surveillance study of all patients with acute MI admitted to a large county teaching hospital. Over a 12-month period, 110 patients were coded as ICDCM-410 by medical records, but only 67 of these were detected by cardiology surveillance. The charts of the 43 patients not detected by surveillance were reviewed. In none of the 43 was evidence of acute MI found. In 28 of the 43, the discharge summaries listed rule out MI or status post-MI readmitted for further diagnostic workup, but were miscoded as ICDCM-410. Twelve of the 43 patients had cardiac arrests but were coded as ICDCM-410, even though there was no evidence of MI. Therefore, erroneous coding of patients as acute MI (ICDCM-410) may conceal a true downward trend in the incidence of CAD.

Exercise testing early after myocardial infarction: predictive value for subsequent unstable angina and death.

Recently, modified treadmill exercise testing before hospital discharge has been reported to be safe in patients after uncomplicated myocardial infarction. Accordingly, the frequency of treadmill exercise-induced abnormalities and their prognostic value were evaluated in 130 patients with uncomplicated myocardial infarction. Seventy-eight patients (60 percent) had one or more treadmill exercise-induced abnormalities; 42 had S-T segment depression, 35 had angina and 17 had an inadequate blood pressure response. During the mean follow-up period of 11 months, 27 patients experienced unstable angina, 12 had a recurrent myocardial infarction and 10 died of cardiac causes. Compared with patients with no exercise-induced abnormality, patients with S-T segment depression, angina pectoris or an inadequate blood pressure response had a significantly greater (p < 0.001) incidence of all cardiac events during the follow-up period. Furthermore, unstable angina pectoris was significantly more frequent (p < 0.005) in patients with S-T segment depression or angina pectoris. Finally, when the patients with ischemic treadmill abnormalities were combined with the patients exhibiting an inadequate blood pressure response, they had a statistically greater (p < 0.005) incidence of cardiac death than that of patients with no treadmill abnormalities. Therefore, these three abnormalities during modified treadmill exercise testing before hospital discharge identify patients with uncomplicated myocardial infarction who are at risk for a future cardiac event.

Positive inotropic and vasodilator effects of MDL 17,043 in patients with reduced left ventricular performance.

To assess the potential positive inotropic properties of the drug MDL 17,043, 10 patients were studied who had impaired left ventricular (LV) performance and who were undergoing diagnostic cardiac catheterization (LV ejection fraction 16 to 46%). MDL 17,043 was given in repeated i.v. doses of 0.5 mg/kg every 15 minutes until a maximal effect was observed or a total dose of 3 mg/kg was attained. Cardiac output increased from 3.5 +/- 1.0 to 5.3 +/- 0.7 liters/min (p less than 0.005); pulmonary artery wedge pressure decreased from 22 +/- 4 to 9 +/- 5 mm Hg (p less than 0.001); and total systemic resistance decreased from 2,335 +/- 1,147 to 1,310 +/- 365 dyne cm-5 (p less than 0.025). Also, maximal LV dP/dt increased from 1,011 +/- 301 to 1,243 +/- 330 mm Hg/s (p less than 0.001). No significant changes in heart rate, systemic blood pressure, routine blood chemistries, complete blood counts or platelet counts were observed. Thus, MDL 17,043 has hemodynamic effects consistent with positive inotropic and vasodilating properties in patients with reduced LV performance. Because this agent is effective orally, further evaluation in patients with overt congestive heart failure is warranted.

Prognostic value of electrocardiographic exercise testing and noninvasive assessment of left ventricular ejection fraction soon after acute myocardial infarction.

To determine the relative value of clinical findings, results of low-level treadmill electrocardiographic (ECG) exercise testing and left ventricular (LV) ejection fraction (EF) for predicting cardiac events in the year after an acute myocardial infarction (AMI), 72 patients who had had an uncomplicated AMI were studied with either radionuclide angiography or 2-dimensional echocardiography to assess LVEF and a low-level treadmill exercise test before hospital discharge. All patients were followed for 1 year. Nineteen patients (26%) had at least 1 cardiac event: coronary artery bypass grafting (11 patients), recurrent AMI (6 patients) or cardiac death (6 patients). Multiple logistic regression analysis revealed that total cardiac events were predicted by exercise ECG ST-segment depression or angina, prior AMI, ventricular ectopic activity during exercise and digoxin therapy (cumulative r = 0.58, p less than 0.001). Coronary artery bypass grafting was predicted by exercise ECG ST-segment depression or angina (r = 0.29, p = 0.01). Recurrent AMI was predicted by exercise ECG ST-segment depression or angina, prior AMI and ventricular ectopic activity during exercise (cumulative r = 0.49, p less than 0.001). Cardiac death was predicted by an LVEF of 40% or less (r = 0.38, p = 0.01). The presence of both an LVEF of 40% or less and ECG ST-segment depression on treadmill exercise testing defined a subgroup of patients with a high incidence of early cardiac death (33%).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative predictive value of ST-segment depression or angina during early and repeat postinfarction exercise tests.

To determine the relative value of electrocardiographic (ECG) ST-segment depression alone compared to angina alone for predicting multivessel coronary artery disease during early and repeat postinfarction exercise tests, we evaluated 93 postmyocardial infarction patients with modified treadmill exercise tests prior to hospital discharge (mean 14 +/- 2 days), and 36 of these 93 patients with repeat exercise tests at six weeks following infarction. It was concluded that angina alone or angina irrespective of the presence of ST-segment depression are better predictors of multivessel coronary artery disease than ECG ST-segment depression alone, and the persistence of ischemic abnormalities during repeat treadmill exercise tests following infarction is useful for confirming the presence of multivessel coronary artery disease.

Detection of bacteraemia by the continuously monitoring BacT/Alert system.

AIMS: To analyse a continuously monitoring blood culture system with respect to the time to detection of various groups of organisms, their clinical importance, and the relative efficacy of the aerobic and anaerobic bottles. METHODS: Four thousand blood cultures were monitored and the information relating to the positive cultures was noted and analysed. RESULTS: Four hundred and seventy seven blood cultures were detected as positive, 81% (387/477) of which were detected within 48 hours. The most pathogenic organisms were detected in the shortest period, less pathogenic later and those generally regarded as contaminants last. Clinically important isolates were also detected earlier. Many positive blood cultures were detected in only one bottle of the set, even those regarded as clinically important. CONCLUSIONS: The management of continuously monitoring blood culture systems could be improved by considering time to detection trends. Clinicians should be aware of the relatively rapid detection of clinically important, positive blood cultures in relation to patient treatment.

N-acetylprocainamide kinetics during intravenous infusions and subsequent oral doses in patients with coronary artery disease and ventricular arrhythmias.

The kinetics of N-acetylprocainamide (NAPA) were studied in 5 patients (all men, mean age = 62) with coronary artery disease and ventricular arrhythmias during loading infusions of 0.22-0.45 mg/kg/min, prolonged (19-48 hrs) intravenous infusions 2.5-5.2 mg/min, and in 4 of the patients, during subsequent oral doses 1.5-3 g every 8 hrs. Serum, concentrations of NAPA were determined by high-performance liquid chromatography. The individual concentration-time profiles could, with one exception, be described by a two-compartment, open, kinetic model with apparent first-order elimination. The kinetic variables were: initial distribution volume (Vc) 0.20 +/- 0.11 l/kg (mean +/- SD); steady-state distribution volume (Vss) 1.58 +/- 0.55 l/kg; distributional clearance (Cle) 133 +/- 23 ml/(kg X hr); absorption rate constant (Ka) 0.354 +/- 0.173 hr-1; and fraction of dose reaching systemic circulation (F) 1.00 +/- 0.14. The data for one patient who had received increasing oral dosages of 1.5, 2, 2.5 and 3 g every 8 hours resulted in systematic underprediction of observed concentrations at the two highest oral dosing rates. This suggests the possibility of some degree of nonlinearity or time-dependent change in the kinetic behavior of NAPA. Only low concentrations of procainamide, less than 1 mg/L, were found at the end of the infusions.

Absolute bioavailability and dose proportionality of betaxolol in normal healthy subjects.

The absolute bioavailability and dose proportionality of betaxolol [(+/-)-1-(p-[2-cyclopropylmethoxy)ethyl]phenoxy]-3- (isopropylamino)-2-propanol hydrochloride], a cardioselective beta-adrenergic antagonist effective in the treatment of angina and hypertension, was studied in 12 healthy male subjects using a four-way crossover Latin Square design. Each subject received a 10-mg iv dose administered by constant-rate infusion over a period of 30 min and three oral doses (10, 20, and 40 mg). Blood and urine were collected over a 48-h period and analyzed for betaxolol using gas-liquid chromatography with electron capture detection. Maximum concentrations occurred 3-4 h after the dose. The maximum mean (+/- SD) blood concentrations normalized to the 10-mg oral dose were 21.6 +/- 3.7, 21.1 +/- 3.7, and 22.5 +/- 4.0 micrograms/L following the 10-, 20-, and 40-mg doses, respectively. A significant lag time of 10-80 min was observed after oral doses but was not related to dose size. The terminal slope (ts), absolute bioavailability (F), and renal clearance (CLr) were likewise not affected to an important degree by dose (ts: 0.043 +/- 0.006, 0.044 +/- 0.005, 0.046 +/- 0.006 h-1; F: 0.88 +/- 0.08, 0.82 +/- 0.06, 0.84 +/- 0.07; CLr: 0.68 +/- 0.22, 0.69 +/- 0.19, 0.65 +/- 0.22 mL/min kg). Unlike many beta-adrenergic antagonists, betaxolol has a long half-life (13-20 h) and high and consistent bioavailability (70-90%), and its disposition is independent of the size of the administered dose.

Altered beta adrenergic receptor function in subjects with symptomatic mitral valve prolapse.

Individuals with mitral valve prolapse (MVP) frequently show symptoms of a hyperadrenergic state. beta adrenergic receptor characteristics were compared in the lymphocytes of subjects with symptomatic MVP and control subjects during rest and exercise. At rest, the proportion of receptors binding agonist with high affinity, as determined from isoproterenol competition for (-)[125I]-iodopindolol binding sites, was greater in MVP subjects than in controls. With exercise, the proportion of high-affinity receptors in MVP subjects decreased to control levels. Isoproterenol stimulation of lymphocyte 3',5'-cyclic adenosine monophosphate (cyclic AMP) also was greater in MVP subjects than in controls at rest, but not during exercise. Plasma catecholamine concentrations in MVP subjects were normal during both rest and exercise. Unlike exercise, isoproterenol infusion elicited clinical manifestations of increased adrenergic responsiveness in MVP subjects. The beta receptor in exercised MVP subjects exhibited unusually high affinity agonist binding (i.e. a lower dissociation constant KH than in either the same subjects at rest or exercised controls) and also abnormal coupling to the stimulatory guanine nucleotide-binding regulatory protein (GS) of adenylate cyclase, as reflected by the inability of guanine nucleotide to convert the receptor to a low-affinity state. These findings suggest that functional alteration of the beta adrenergic receptor, in the absence of abnormal plasma catecholamine levels, might contribute to the hyperadrenergic state of MVP subjects at rest. However, desensitization of high affinity beta receptors or altered receptor-GS coupling might preserve normal adrenergic responsiveness during exercise.

Spotlight article: thrombolysis in unstable angina: randomized double-blind trial of t-PA and placebo. Circulation 1992;85: 150-7. (Freeman MR, Langer A, Wilson RF, Morgan CD, Armstrong PW.).

This is a well-written and executed study that indicates that infusion of t-PA in patients with unstable angina does not decrease in-hospital cardiac events and, in fact, may worsen myocardial perfusion. The small sample size requires further study replication.

Captopril in the treatment of chronic CHF.

Captopril is an effective oral drug that helps break the cycle of CHF. Improvements in symptomatology, functional capacity and exercise tolerance are seen with long-term therapy. Captopril is an important addition to the present drug therapy of CHF.

Acute congestive heart failure: pharmacologic intervention.

Acute CHF is a highly unstable condition that requires immediate pharmacologic intervention. Mechanisms that are normally used to control the release of neurohormones are impaired in CHF. Therapeutic interventions produce hemodynamic and clinical benefits in part by restoring a balance of the neurohormonal system. This balance is achieved by interfering with actions of vasoconstriction and potentiating the effects of vasodilation and contractility. To maintain an optimal healing atmosphere, the patient's individualized needs for social support and spiritual beliefs must be considered. How the patient perceives his or her illness may also impact patient hemodynamics and outcomes.