Neutral metallated and meso-substituted porphyrins as antimicrobial agents against gram-positive pathogens.

Staphylococcus aureus is a bacterial pathogen that causes severe infections among humans. The increasing emergence of antibiotic resistance necessitates the development of new strategies to combat the spread of disease. One approach is photodynamic inactivation using porphyrin photosensitizers, which generate superoxide and other radicals in the presence of light, causing cell death via the oxidation of proteins and lipids. In this study, we analyzed a novel library of meso-substituted and metallated porphyrins for activity against multidrug-resistant S. aureus. From a library of 251 compounds, 51 showed antimicrobial activity, in three discrete classes of activity: those that functioned only in light, those that had toxicity only in darkness, and those that displayed activity regardless of illumination. We further demonstrated the broad-spectrum activity of these compounds against a variety of pathogens, including Bacillus anthracis, Enterococcus faecalis, and Escherichia coli. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) analyses of lead compounds (XPZ-263 and XPZ-271) revealed strong activity and killing towards methicillin-resistant S. aureus (MRSA) strains. An analysis of mutation frequencies revealed low incidences of resistance to lead compounds by E. coli and MRSA. Finally, an exploration of the underlying mechanism of action suggests that these compounds do not depend solely upon light-induced radical generation for toxicity, highlighting their potential for clinical applications.

Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction.

BACKGROUND: After an acute myocardial infarction, it is important to determine the risk of a subsequent coronary event. We studied the prognostic value of myocardial ischemia detected by ambulatory electrocardiographic (ECG) monitoring in patients who had recently had an acute myocardial infarction. METHODS: Five to seven days after acute myocardial infarction, 406 patients underwent 48-hour ambulatory ECG monitoring, with submaximal exercise testing before discharge and measurement of the left ventricular ejection fraction within 28 days after infarction. Death, nonfatal myocardial infarction, and admission to the hospital because of unstable angina were the principal end points recorded during the one-year follow-up period. RESULTS: The overall incidence of myocardial ischemia detected by ambulatory ECG monitoring was 23.4 percent. The mortality rates at one year were 11.6 percent among the patients with ischemia and 3.9 percent among those without ischemia (P = 0.009); 3.9 percent among the patients with a positive exercise test, 3.0 percent among those with a negative exercise test, and 16.4 percent among those in whom an exercise test was not performed (P < 0.001); and 3.6 percent among the patients with an ejection fraction greater than 50 percent, 3.5 percent among those with an ejection fraction between 35 and 50 percent, and 18.2 percent among those with an ejection fraction below 35 percent (P = 0.001). Using multiple logistic regression, we found that no diagnostic test performed after myocardial infarction provided additional prognostic information beyond that provided by the standard clinical variables used to predict the risk of death. When nonfatal myocardial infarction and admission to the hospital because of unstable angina were also included as outcome variables, ambulatory monitoring for ischemia was the only test that contributed significantly to the model. For the patients with ischemia detected by ambulatory monitoring, as compared with those who did not have evidence of ischemia, the odds ratio was 2.3 (95 percent confidence interval, 1.2 to 4.5) for death or nonfatal myocardial infarction (P = 0.009) and 2.8 (95 percent confidence interval, 1.6 to 4.8) for death, nonfatal myocardial infarction, or admission to the hospital because of unstable angina (P < 0.001). CONCLUSIONS: Myocardial ischemia detected by ambulatory ECG monitoring is common early after acute myocardial infarction and provides prognostic information beyond that available from standard clinical information.

Does it matter how coronary projections are combined to assess restenosis following PTCA?

Three methods were used to combine measurements from biplane coronary views to assess restenosis following PTCA. The first 153 patients from the EMPAR trial with 118 measurable coronary stenoses were chosen for this study. The mean difference between the RAO and LAO projections used was 88 +/- 22 degrees (S.D.). There was no systematic difference in coronary dimensions between RAO and LAO views for the group. Coronary restenosis was primarily defined as loss of 50% or more of the luminal diameter gain from the procedure. The ratio of luminal loss to gain was calculated for each stenosis using (Method 1) only the lesser diameter of the two views, (Method 2) an average of the two views and, (Method 3) a calculated cross-sectional coronary lumen area. Rates of restenosis calculated in this way ranged between 36 and 44% amongst the three methods, which was not significantly different. However, individual coronary lesions might be classified as either restenosed or not by this formula, depending on which method was used to integrate the biplane coronary measurements.

Anaphylactoid reaction during an infusion of recombinant tissue-type plasminogen activator for acute myocardial infarction.

Potentially life-threatening immediate hypersensitivity reactions are extremely rare among patients treated with thrombolytic agents for suspected acute myocardial infarction. A patient who developed a severe reaction during an infusion of recombinant tissue-type plasminogen activator is described. Potential causal mechanisms for the reaction could be related either to nonmedicinal additives or complement activation. Implications for treatment in the setting of acute myocardial infarction are discussed.

Management of the patient following coronary thrombolysis.

Myocardial salvage can be maximized by the early institution of thrombolytic therapy and aspirin. Certain patients may benefit from the administration of intravenous heparin, beta blockers, or nitroglycerin. The routine use of percutaneous transluminal coronary angioplasty (PTCA) or calcium-channel blockers does not appear to be warranted. Recurrent myocardial ischemia should be vigorously treated with medical therapy and there may be value in cardiac catheterization, followed by PTCA or bypass surgery, depending upon the extent of myocardium at risk and the underlying coronary anatomy. Long-term morbidity and mortality may be reduced by instituting aspirin and beta blockers as well as by modifying risk factors. There is no evidence for the long-term benefit from any calcium-channel blocker. Oral anticoagulation may be warranted in those patients with a mural thrombus, congestive heart failure, or atrial fibrillation. ACE inhibitors may be of value in the presence of left ventricular dysfunction and certainly in the presence of symptomatic congestive heart failure. Antiarrhythmic therapy is generally indicated only for symptomatic or life-threatening arrhythmias. Residual myocardial ischemia should be sought by exercise testing, and those patients with poor exercise tolerance generally warrant cardiac catheterization in consideration for revascularization.

MRI detection of myocardial perfusion changes by gadolinium-DTPA infusion during dipyridamole hyperemia.

To detect abnormal regional myocardial coronary flow reserve, serial spin-echo MR tomograms of four control dogs and six with a partial balloon occlusion of the left anterior descending (LAD) coronary artery were acquired before and after dipyridamole infusion and during the paramagnetic effect of a bolus plus infusion of gadolinium-DTPA. Microsphere myocardial blood flow was measured for correlation with serial regional changes in MR signal intensity. Significant difference in gadolinium-enhanced MR signal intensity existed between the hypoperfused LAD and the hyperemic left circumflex perfusion beds (46 +/- 22% vs 78 +/- 29% above baseline, respectively; P less than 0.05). The percentage changes in gadolinium-enhanced MR signal and microsphere myocardial blood flow were significantly correlated (r2 = 0.93).

Gated blood pool tomography: a technology whose time has come.

Tomographic gated blood pool imaging is a natural extension of the technologies of planar gated blood pool scanning and rotating Anger camera single photon emission computed tomography (SPECT). The high photon flux, optimum 140 keV energy, and volume sampling of tomography permit reconstruction of the data in any perspective. The true three-dimensional nature of this process allows the evaluation of regional wall motion of all the cardiac chambers, unencumbered by overlapping structures. The heart can be viewed from any angle, including a long axis, short axis, apical four chamber, and a true inferior view. In addition to evaluation of regional wall motion, precise determination of chamber volumes and ejection fractions is possible. Early clinical experience has demonstrated the superiority of tomographic gated blood pool imaging over planar blood pool imaging for precisely defining subtle functional abnormalities. The enormous amount of data generated by this procedure taxes the capacity of most nuclear medicine computer systems. However, the availability of 32-bit processors and large amounts of image memory in new machines should ultimately reduce this processing time to less than ten minutes. The combination of complete visualization and quantitation suggests that a renaissance for blood pool imaging is on the horizon.

Fatty acid analogue accumulation: a marker of myocyte viability in ischemic-reperfused myocardium.

A 3-methyl substituted radioiodinated long chain fatty acid analogue was evaluated as an agent for the noninvasive detection of altered fatty acid uptake in reperfused, postischemic myocardium. This iodinated fatty acid analogue, 15-(para-iodophenyl)-3-methyl pentadecanoic acid, was given intravenously at 3 hours of reperfusion following 15 minutes (Group 1, n = 5 dogs) or 60 minutes (Group 2, n = 5 dogs) of left anterior descending coronary artery occlusion. Myocardial blood flow (MBF) was measured during occlusion and reperfusion with radiolabeled microspheres administered via the left atrium. Paired ultrasonic subendocardial crystals were placed in the ischemic perfusion bed to assess regional left ventricular systolic function at baseline, during ischemia and reperfusion. Electron microscopic analysis and staining with triphenyltetrazolium chloride (TTC) was performed. Groups 1 and 2 dogs had similar (p = NS) myocardial blood flows during occlusion. TTC positive 1 g endocardial segments from Group 1 (n = 98) and Group 2 (n = 71) had 37% greater fatty acid analogue activity (0.26 +/- 0.04 vs. 0.19 +/- 0.09 percent injected dose per gram; p less than 0.05) compared with TTC negative segments from Group 2 dogs (n = 37). When fatty acid analogue activity was related to near simultaneous reperfusion blood flow, this ratio was 27% greater (p less than 0.05) in TTC positive segments (0.38 +/- 0.1) compared with TTC negative (0.30 +/- 0.16) segments, and 9% greater than normal (0.35 +/- 0.09; p less than 0.05). While ischemic regions from both Groups 1 and 2 dogs became similarly dyskinetic during occlusion (systolic shortening, -11 +/- 6 vs. -11 +/- 2%; p = NS), TTC negative segments remained akinetic (= 1 +/- 7%) at 3 hours of reperfusion while TTC positive zones had recovered partial systolic function (8 +/- 22%). Electron microscopy confirmed the presence of reversible ultrastructural changes in TTC positive regions. A 60-minute occlusion, 3-hour reperfusion model adapted for in vivo single photon emission computed tomography showed a similar excess of 123I fatty acid activity over flow when compared to perfusion (as measured with 201Tl) in the ischemic border zone of 4/4 canine myocardial infarcts. We conclude that the accumulation of this non-beta-oxidized fatty acid analogue noninvasively identifies zones of discordance between fatty acid and flow distribution that are characteristic of ischemically "stunned" but viable myocardium.

Continuous monitoring of left ventricular function by an ambulatory radionuclide detector in patients with coronary artery disease.

Global left ventricular function and a modified V5 electrocardiographic (ECG) lead were continuously monitored by a radionuclide recorder in 12 normal subjects and 39 patients with coronary artery disease while the subjects were performing various daily activities. The ambulatory studies revealed that walking on a level surface caused 11 of 12 normal subjects and 18 of 32 patients to increase their left ventricular ejection fraction by greater than 6% units. A transient decrease in left ventricular ejection fraction (6 to 18%) lasting greater than or equal to 1 min was observed on 36 occasions in 16 patients with coronary artery disease; 12 episodes were accompanied by chest pain or shortness of breath and 24 were asymptomatic. Electrocardiographic ST segment depression suggestive of ischemia was recorded in 6 of the 12 symptomatic and 5 of the 24 asymptomatic episodes. In 10 of the 12 symptomatic episodes, left ventricular ejection fraction began to decrease 30 to 90 s before the onset of symptoms. These studies suggest that continuous monitoring of both left ventricular function and the ECG may permit stratification of episodes of ST depression suggesting ischemia by the degree of left ventricular dysfunction they produce.

Prognostic importance of thallium uptake by the lungs during exercise in coronary artery disease.

We studied the value of thallium imaging as compared with clinical and exercise-test variables in predicting cardiac events occurring over five years in 525 consecutive patients referred for thallium-exercise testing in 1979. Follow-up was obtained on 467 patients (89 percent). There were 105 cardiac events--25 cardiac deaths, 33 myocardial infarctions, and 47 coronary bypass procedures. A Cox survival analysis identified increased thallium uptake by the lungs, a marker of left ventricular dysfunction during exercise, as the best predictor of a cardiac event (relative risk ratio = 3.5; 95 percent confidence interval, 2.2 to 5.4). The next most powerful predictors were a history of typical angina, a previous myocardial infarction, and ST-segment depression during exercise (relative risk ratios = 2.1, 1.8, and 1.7, respectively). No combination of variables made up for the loss in prognostic power when the variable of increased thallium uptake by the lungs was removed from the model. Cardiac events occurred over five years in 10 (5 percent) of 192 patients with a normal thallium scan, 41 (25 percent) of 163 patients with an abnormal thallium scan but normal thallium activity in the lungs, and 54 (67 percent) of 81 patients with increased thallium uptake by the lungs (P less than 0.0001). We conclude that increased uptake of thallium by the lungs during exercise predicts a high risk of subsequent cardiac events.

Myocardial uptake and clearance of thallium-201 in normal subjects: comparison of dipyridamole-induced hyperemia with exercise stress.

Thallium-201 uptake and clearance after dipyridamole infusion may differ from that after exercise stress because the hemodynamic effects of these two interventions are different. In this study of normal volunteers, thallium kinetics after dipyridamole (n = 13) were determined from three serial image sets (early, intermediate and delayed) and from serial blood samples and compared with thallium kinetics after exercise (n = 15). Absolute myocardial thallium uptake was greater after dipyridamole compared with exercise (p less than 0.0001), although the relative myocardial distribution was similar. The myocardial clearance (%/h) of thallium was slower after dipyridamole than it was after exercise. Comparing dipyridamole and exercise, the differences in clearance were large from the early to the intermediate image (anterior, -11 +/- 17 versus 24 +/- 5, p = 0.0005; 50 degrees left anterior oblique, -7 +/- 11 versus 15 +/- 8, p = 0.004; 70 degrees left anterior oblique, 3 +/- 9 versus 21 +/- 6, p = 0.001). In contrast, the differences in clearance were small from the intermediate to the delayed image (anterior, 15 +/- 4 versus 20 +/- 2, p = 0.025; 50 degrees left anterior oblique, 15 +/- 4 versus 19 +/- 3, p = 0.13; 70 degrees left anterior oblique, 15 +/- 3 versus 18 +/- 2, p = 0.047). Thallium uptake and clearance in the liver, splanchnic region and spleen were greater after dipyridamole (p less than 0.001). Blood thallium levels were greater after dipyridamole (p less than 0.05) and cleared more slowly (p = 0.07). Thus, myocardial thallium-201 uptake and clearance after dipyridamole infusion differ from thallium kinetics after exercise. This difference is, in part, related to associated differences in extracardiac and blood kinetics. Diagnostic criteria for the detection of abnormal thallium-201 clearance must be specific for the type of intervention.

Cardiac response to daily activities and exercise in normal subjects assessed by an ambulatory ventricular function monitor.

The cardiac response to a variety of daily activities was assessed in 18 healthy adult subjects (mean age 31 years, range 21 to 39) with an ambulatory ventricular function monitor (VEST), which records serial beat-to-beat radionuclide and electrocardiographic data. The VEST was positioned and calibrated using data recorded during a multigated blood pool scan. It was worn for an average of 3.0 +/- 1.1 hours, while the subjects performed the following activities: sitting quietly (baseline); standing in place; walking; climbing stairs; bicycle or treadmill exercise; eating; sitting in a room at 4 degrees C for 20 minutes; and urinating. To calculate ejection fraction (EF), relative end-diastolic counts, relative cardiac output and heart rate, the beat-to-beat data were averaged over 15 to 30 seconds. Compared with baseline, standing increased EF by 0.03 +/- 0.04 and decreased end-diastolic volume by 10.9 +/- 4.7%. Walking and climbing stairs increased EF by 0.10 +/- 0.05 and 0.18 +/- 0.09, respectively, and increased end-diastolic volume by 7.8 +/- 5.3% and 12.8 +/- 4.3% (p less than 0.001). Eating increased EF by 0.02 +/- 0.03 and decreased end-diastolic volume by 11.3 +/- 6.1% (p less than 0.001). Cold stimuli and urinating decreased EF by 0.05 +/- 0.04 and 0.03 +/- 0.04, respectively (p less than 0.001 and less than 0.05). Serial left ventricular function monitoring during graded bicycle and treadmill exercise revealed a rapid increase in EF in the early stages of exercise, with no further change in the late stages. Heart rate and systolic blood pressure increased progressively with each successive stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved left ventricular performance during exercise with verapamil or nifedipine in patients with chronic stable angina.

To examine the effects of chronic oral therapy with verapamil, 120 mg three times a day, and nifedipine, 20 mg four times daily, on left ventricular ejection fraction and regional wall motion at rest and exercise, 10 patients with chronic stable angina pectoris underwent serial rest and exercise radionuclide angiography. Pre drug control study revealed a resting left ventricular ejection fraction (LVEF) of 0.62 +/- 0.08, falling to 0.54 +/- 0.12 at peak exercise (p less than 0.05). Wall motion score deteriorated from a resting value of 13.8 +/- 2.3 to 10.6 +/- 1.8 (p less than 0.01) with exercise. Patients were subsequently randomized to verapamil or nifedipine for 4 weeks each in an open-labeled crossover design. Rest and exercise radionuclide angiography were repeated at the end of each 4-week period. Neither verapamil nor nifedipine had a significant effect on resting LVEF (verapamil LVEF = 0.61 +/- 0.10, nifedipine LVEF = 0.64 +/- 0.02). Likewise, they had no significant effect on resting wall motion score (verapamil = 14.2 +/- 2.2, nifedipine = 14.4 +/- 1.6). Both verapamil and nifedipine significantly increased LVEF at peak exercise (verapamil = 0.63 +/- 0.09, nifedipine = 0.65 +/- 0.08, p less than 0.05 vs pre drug control) and improved peak exercise wall motion score (verapamil = 13 +/- 1.9, nifedipine = 13.8 +/- 1.6, p less than 0.05 vs pre drug control). Both drugs significantly reduced maximal ST depression at peak exercise and prolonged exercise duration. Episodes of angina and nitroglycerin use were also significantly reduced. In summary, verapamil and nifedipine improved left ventricular performance at exercise in patients with angina pectoris.

Multigated blood-pool tomography: new method for the assessment of left ventricular function.

A technique for the semiautomatic calculation of left ventricular volumes from multigated blood-pool tomograms (MGBPT) was tested in a series of 12 patients undergoing contrast ventriculography within 48 hr of gated tomography. The parameters necessary for the calculation of volume were developed in a chest phantom study performed with a series of 99mTc-filled balloons representing the right and left ventricles. The images were analyzed for volume using a percentage of peak count-threshold of the left ventricular balloon. This technique resulted in a correlation of r = 0.99 of the calculated to the true phantom volumes (y = 0.87x + 27.4, p less than 0.01, s.e.e. = 7.87 ml). The patient studies were recorded at 16 frames/cardiac cycle at each of 60 angles over a 360 degree rotation. Reconstructed data were presented in an endless loop cine format producing a set of sequential "beating tomographic slices" in the transverse, apical four-chamber, short-axis, and long-axis oblique views. Measurements of end systolic volume (y = 0.79x + 30, r = 0.93, p less than 0.001, s.e.e. = 24 ml), end-diastolic volume (y = 0.63x + 60, r = 0.94, p less than 0.0001, s.e.e. = 20 ml) and ejection fraction (y = 0.88x - 0.02, r = 0.92, p less than 0.001, s.e.e. = 0.08) determined from the semiautomated volume method correlated well with those determined by left ventricular contrast angiography. A qualitative comparison of MGBPT, planar imaging, and left ventricular angiography in 12 patients revealed that the visual assessment of wall motion using the 16-frame tomographic slices had significant advantages over planar and single plane angiographic data in the identification of inferior, basal, and septal wall motion abnormalities as well as the extent of involvement by aneurysm formation. A quantitative comparison of wall motion in the long-axis oblique view of the MGBPT to the RAO 30 degree ventriculogram (y = 0.74x + 8.7, r = 0.82, p less than 0.0001, s.e.e. = 14%) confirmed the qualitative similarity of these two views. We conclude that MGBPT is promising as a method for accurately measuring left ventricular volumes and assessing regional wall motion.

Interlaboratory testing of the transferability of a candidate reference method for total cholesterol in serum.

In 1975 the Centers for Disease Control, in cooperation with the American Association for Clinical Chemistry Cholesterol Reference Method Study Group, began an investigation to develop a reference method for total cholesterol. Five potential reference methods were compared with the definitive method developed by the National Bureau of Standards before the chemical method of Abell et al. (J Biol Chem 1952;195:357-66) was selected as the recommended reference method. Because acceptance of a proposed reference method depends so greatly on the method's capability for transfer to other laboratories by written specifications and instructions, a transferability testing study was designed and conducted with 14 laboratories. The study consisted of preliminary testing of readiness of equipment, reagents, and personnel followed by transferability testing with eight runs on 10 serum pools. Laboratoires that did not meet readiness specifications had higher CVs in the transferability testing. The study demonstrated that the proposed method permits laboratories to attain a CV of less than 1.5% for one laboratory and of less than 3.0% among laboratories. The mean percent bias value was less than 1.0% for six of the 14 laboratories, less than 1.5% for 12, and less than 3.0% for all 14 laboratories.

Accuracy and comparability of long-term measurements of cholesterol.

Laboratories of the Lipid Research Clinics Program (LRC) maintained the accuracy of their measurements of total cholesterol by using seven pooled serum calibrators supplied by the Centers for Disease Control (CDC). Over the 11-year life of the LRC, each calibrator was prepared in succession and a target value was assigned by the CDC reference method for cholesterol. The results of a special experiment in which six of the seven calibrators were analyzed simultaneously demonstrated that the target values were accurately assigned. Deviations of the target values from the experimental means ranged from zero to 1.7% of the original target value. The experiment revealed no evidence of drift in the bias of the reference method over the life of LRC and demonstrated the accuracy, consistency, and the comparability of the values assigned to the successive calibrator pools used by the LRC laboratories during more than eight years. It demonstrated the reliability of a reference method and the suitability of frozen serum pools for maintaining an accurate measurement base for serum cholesterol.