The effects of chemotherapeutic drugs on human monocyte-derived dendritic cell differentiation and antigen presentation.

Recent studies indicate that chemotherapeutic agents may increase the anti-tumoral immune response. Based on the pivotal role of dendritic cells (DCs) in host tumour-specific immune responses, we investigated the effect of commonly used chemotherapeutic drugs dexamethasone, doxorubicin, cisplatin and irinotecan and glucocorticoids on monocyte-derived DCs (moDCs). Dexamethasone displayed the strongest inhibitory effect on DC differentiation. The effect of cisplatin and irinotecan was moderate, while only weak effects were noticed for doxorubicin. Surprisingly, when the functional consequence of chemotherapy-treated CD14(+) monocytes and their capacity to activate CD4(+) T responders cells were investigated, cisplatin-treated monocytes gave rise to increased T cell proliferation. However, dexamethasone, doxorubicin and irinotecan-pretreated monocytes did not stimulate any increased T cell proliferation. Further investigation of this observation revealed that cisplatin treatment during DC differentiation up-regulated significantly the interferon (IFN)-ß transcript. By contrast, no effect was evident on the expression of interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, IL-6 or IFN-α transcripts. Blocking IFN-ß attenuated the cisplatin-enhanced T cell proliferation significantly. In conclusion, cisplatin treatment enhanced the immune stimulatory ability of human monocytes, a mechanism mediated mainly by the increased production of IFN-ß.

Effectiveness of the electronic medical record in cholesterol management in patients with coronary artery disease (Virtual Lipid Clinic).

This study demonstrates that the Virtual Lipid Clinic, an electronic medical record with computer-assisted cholesterol management, is associated with improved lipid management in patients with coronary artery disease. In comparison to traditional documentation methods with "pen and paper" charts, outpatient visits utilizing the electronic medical record were associated with a twofold increase in low-density lipoprotein (LDL) documentation, a threefold increase in achieving LDL goal, and a 30% increase in the use of lipid-lowering drugs.

Recruiting and retention tips and techniques.

By incorporating today's technology and common sense into their recruiting and retention efforts, businesses will update age-old practices and reduce unnecessary costs.

Effect of platelet activation on coronary collateral blood flow.

BACKGROUND: The platelet products thromboxane A2 and serotonin have been shown to cause constriction of well-developed coronary collateral vessels. This study was performed to determine whether intravascular platelet activation produced with platelet activating factor (PAF) can cause a decrease in coronary collateral blood flow. METHODS AND RESULTS: Collateral vessel growth was induced by embolization of a hollow stainless steel plug into the left anterior descending coronary artery (LAD) of adult dogs. The animals were returned to the laboratory 3 to 6 weeks later for surgical instrumentation and measurement of collateral blood flow. Collateral flow was assessed by measuring retrograde blood flow from the cannulated collateral-dependent artery. PAF (10 nmol) was injected into the left main coronary artery to allow products of platelet activation to reach collateral vessels arising from the left coronary system. PAF caused a vasoconstrictor response, which became maximal 3 minutes after injection and resulted in a 40.3+/-7.4% decrease in retrograde blood flow (32.1+/-2.1 to 19.6+/-3.2 mL/min; P<0.05). By 15 minutes after the PAF injection, both retrograde blood flow and transcollateral resistance had returned to normal. After pretreatment with the thromboxane A2 receptor antagonist SQ30, 741, the vasoconstrictor response to PAF was abolished and, in contrast to the decrease in retrograde blood flow from PAF alone, a weak vasodilator effect was unmasked. CONCLUSIONS: PAF caused a decrease in coronary collateral blood flow. This vasoconstrictor response required the participation of thromboxane A2.

Nitric oxide inhibition impairs blood flow during exercise in hearts with a collateral-dependent myocardial region.

OBJECTIVES: We sought to determine the importance of nitric oxide (NO) production in maintaining coronary blood flow during exercise in hearts with collateral-dependent myocardium. BACKGROUND: Coronary collateral vessels demonstrate endothelium-mediated NO-dependent vasodilation in response to agonists such as acetylcholine. However, the contribution of endogenous NO production to maintaining vasodilation of coronary collateral vessels during exercise has not been previously studied. METHODS: Collateral vessel growth was induced in 13 chronically instrumented dogs by intermittent 2-min occlusions, followed by permanent occlusion of the left anterior descending coronary artery (LAD). One week after permanent LAD occlusion, myocardial blood flow was measured with microspheres during rest and treadmill exercise at 6.4 km/h at a 15% grade. Measurements were then repeated after blockade of NO production with N-nitro-L-arginine (LNNA) (20 mg/kg body weight intravenously). RESULTS: LNNA caused a 62 +/- 4% (mean +/- SEM) inhibition of the coronary vasodilation produced by acetylcholine. During rest conditions, LNNA caused a slight decrease in blood flow to the collateral region (p = NS), with no change in normal zone blood flow. During exercise, LNNA caused a decrease in mean blood flow to the collateral region (from 2.24 +/- 0.19 to 1.78 +/- 0.26 ml/min per g after LNNA, p < 0.05). This decrease resulted from a near doubling of the collateral vascular resistance (p < 0.05), with a trend toward an increase in small vessel resistance in the collateral zone. LNNA also reduced myocardial blood flow to the normal region during exercise (from 2.99 +/- 0.24 to 2.45 +/- 0.28 ml/min per g, p < 0.05) as the result of a 44 +/- 13% increase in coronary vascular resistance (p < 0.05). CONCLUSIONS: NO contributes to the maintenance of coronary collateral blood flow during exercise. In contrast to the normal heart, endogenous NO production also maintains blood flow in remote myocardial regions during exercise. These results suggest that control of blood flow during exercise in normal myocardium is altered by the presence of an occluded coronary artery.

Primary angioplasty reduces risk of myocardial rupture compared to thrombolysis for acute myocardial infarction.

Although the mechanical complications of acute ventricular septal defect and acute mitral regurgitation are uncommon after acute myocardial infarction, these complications are associated with an extremely high morbidity and mortality. We hypothesized that the administration of thrombolytic drugs may result in hemorrhagic infarction as well as the potential for incomplete revascularization and thus may lead to an increased incidence of mechanical complications compared to primary angioplasty. Accordingly, we reviewed the data of the most contemporary thrombolytic and primary angioplasty trials and compared the incidence of mechanical complications among 36,303 patients treated with thrombolytics reported in the GUSTO trial to the incidence of mechanical complications among 1,295 patients treated with primary angioplasty obtained from the PAMI-1 and PAMI-2 trials. We found that angioplasty resulted in an overall 86% relative risk reduction in mechanical complications (2.20% vs. 0.31%, P < 0.001). In comparison to thrombolytic therapy, angioplasty resulted in an 82% decrease in acute mitral regurgitation (1.73% vs. 0.31%, P < 0.001) and a 100% decrease in acute ventricular septal defect (0.47% vs. 0.00%, P < 0.03). In conclusion, in patients with acute myocardial infarction, reperfusion with primary angioplasty is associated with less myocardial rupture and mechanical complications than thrombolytics. This finding may, in part, explain the improved prognosis observed in myocardial infarction patients treated with primary angioplasty.

Treatment of no-reflow in degenerated saphenous vein graft interventions: comparison of intracoronary verapamil and nitroglycerin.

No-flow has been reported after 10-15% of percutaneous interventions on degenerated saphenous vein grafts. In this prospective study of 36 degenerated saphenous vein graft lesions (32 patients), no-flow (TIMI flow < 3 in the absence of a significant lesion or dissection) occurred in 15/36 (42%) lesions. A total of 32 episodes of no-flow occurred after angioscopy (n = 14), extraction atherectomy (n = 10), balloon angioplasty (n = 2) or stent implantation (n = 6). Intragraft nitroglycerin (100-300 micrograms) alone resulted in no improvement in TIMI flow in the setting of no-reflow (TIMI flow 1.2 +/- 0.6 to 1.4 +/- 0.8, P = NS). Intragraft verapamil (100-500 micrograms) resulted in improvement in flow in all 32 episodes (TIMI flow 1.4 +/- 0.8 before, to 2.8 +/- 0.5 after verapamil, P < 0.001). Although verapamil increased TIMI flow after all episodes of no-reflow, two (6.3%) had persistent no-reflow (TIMI 1) despite verapamil, associated with non-Q wave myocardial infarction. In conclusion, treatment of no-reflow with verapamil during degenerated vein graft interventions was associated with reestablishment of TIMI 3 flow in 88% of cases. In contrast, intragraft nitroglycerin alone was ineffective for reversing no-reflow.

Vasomotor responses of newly developed coronary collateral vessels.

Well-developed coronary collateral vessels contain an abundant muscular media and can undergo active vasomotion. However, early after coronary occlusion, coronary collateral vessels are thin walled with little smooth muscle, suggesting that vasomotor capability might be limited. Consequently, this study determined whether newly developed coronary collateral vessels have active vasomotor activity and whether endothelial function in these newly developed vessels is impaired. Retrograde blood flow was measured as an index of coronary collateral blood flow approximately 2 wk after embolic occlusion of the anterior descending coronary artery of dogs. Agonists were administered into the left main coronary artery to reach collaterals originating from the left coronary system. Baseline retrograde blood flow was 25.1 +/- 2.7 ml/min and increased to 36.7 +/- 3.7 ml/min after nitroglycerin (6 micrograms.kg-1.min-1, P < 0.05). Cyclooxygenase blockade with indomethacin (5 mg/kg i.v.) decreased retrograde collateral blood flow to 16.8 +/- 2.3 ml/min (P < 0.05). Subsequent administration of acetylcholine increased retrograde flow to 29.4 +/- 3.7 ml/min (P < 0.05), indicating intact endothelium-mediated vasodilation. Inhibition of nitric oxide synthase with NG-nitro-L-arginine further decreased coronary collateral retrograde flow to 12.0 +/- 2.8 ml/min (P < 0.05) and markedly blunted the response to acetylcholine. These findings demonstrate substantial vasomotor capability even early during coronary collateral development and indicate that both nitric oxide and cyclooxygenase-dependent endothelial mechanisms are intact.

Rapid hemodynamic improvement after reperfusion during right ventricular infarction.

OBJECTIVES: This study sought to determine the effects of reperfusion on hemodynamic status and hospital course in patients with right ventricular infarction. BACKGROUND: In contrast to the relatively low risk associated with acute inferior myocardial infarction, right ventricular infarction is associated with higher in-hospital morbidity and mortality. However, the potential benefits of reperfusion in patients with right ventricular infarction are unknown. Consequently, this study evaluated the potential benefits of primary angioplasty in patients with right ventricular infarction. METHODS: Of 141 consecutive patients admitted to the hospital for inferior myocardial infarction, 27 were identified as having right ventricular involvement by electrocardiographic and hemodynamic criteria. Seventeen patients achieved patency of the infarct-related right coronary artery by primary coronary angioplasty within 24 h of hospital admission, but 10 patients did not. All patients had invasive hemodynamic monitoring at the time of hospital admission, and subsequent serial hemodynamic status and clinical events were recorded. RESULTS: Patients with successful reperfusion demonstrated improved right atrial pressure, pulmonary capillary wedge pressure and right atrial/pulmonary capillary wedge pressure ratio as early as 8 h after reperfusion, whereas patients without reperfusion had no hemodynamic improvement over 24 h. Right atrial pressure demonstrated the greatest 8-h improvement after successful reperfusion (15.4 +/- 0.8 to 8.4 +/- 0.8 mm Hg [mean +/- SD], p < 0.05) but was unchanged without reperfusion (13.7 +/- 0.9 to 13.9 +/- 0.8 mm Hg, p = NS). Additionally, persistently elevated right atrial pressure was associated with increased mortality. CONCLUSIONS: Reperfusion in the setting of right ventricular infarction leads to rapid hemodynamic improvement and may result in improved survival.

Effect of beta-adrenergic receptor blockade on blood flow to collateral-dependent myocardium during exercise.

BACKGROUND: beta-Adrenergic receptors have been identified in isolated coronary collateral blood vessels, but their functional significance in the intact heart has not been demonstrated. METHODS AND RESULTS: We measured myocardial blood flow with radioactive microspheres in normal and collateral-dependent myocardium in eight dogs trained to run on a treadmill before and after beta-adrenergic blockade with propranolol, 200 micrograms/kg, a dose that effectively inhibited the increase in coronary blood flow produced by selective beta 1- and beta 2-adrenergic agonists. Collateral vessel growth was stimulated with 2-minute intermittent occlusions of the left anterior descending artery followed by permanent occlusion. During control exercise, blood flow in the collateral zone was 38 +/- 5% less than in the normal zone. At identical levels of exercise, with heart rate maintained constant by atrial pacing, propranolol decreased mean blood flow in the collateralized myocardium from 1.93 +/- 0.17 to 1.50 +/- 0.14 mL.min-1.g-1 (P < .01), while increasing the subendocardial to subepicardial blood flow ratio from 0.78 +/- 0.11 to 0.91 +/- 0.10 (P < .05). The decrease in collateral zone blood flow in response to propranolol resulted from an increase in both transcollateral resistance from 25.9 +/- 2.3 to 35.2 +/- 4.3 mm Hg.mL-1.min.g (P < .05) and small-vessel resistance in the collateral-dependent myocardium from 30.9 +/- 4.7 to 44.0 +/- 8.8 mm Hg.mL-1.min.g (P < .07). Blood flow to the normal zone was also significantly reduced from 3.14 +/- 0.21 to 2.23 +/- 0.12 mL.min-1.g-1 (P < .01) after propranolol. CONCLUSIONS: beta-Adrenergic blockade decreased blood flow to collateral-dependent myocardium during exercise. These results indicate that beta-adrenergic receptor activation contributes to vasodilation of coronary collateral vessels during exercise.

Effect of inhibition of nitric oxide formation on coronary blood flow during exercise in the dog.

OBJECTIVE: The aim was to test the hypothesis that nitric oxide (or a related compound) contributes to the coronary vasodilatation during physiological increases of myocardial O2 consumption that occur with exercise. METHODS: Active hyperaemia associated with graded treadmill exercise and coronary reactive hyperaemia were examined in chronically instrumented awake dogs during control conditions and after administration of the nitric oxide synthase inhibitor, N-nitro-L-arginine (LNNA). RESULTS: LNNA blunted the response to intracoronary acetylcholine, with an 80(SEM 6)% decrease in the maximum acetylcholine induced coronary vasodilatation, but did not alter the response to sodium nitroprusside. Increases of myocardial oxygen requirements during treadmill exercise were associated with progressive increases of coronary blood flow. LNNA caused a significant increase in arterial pressure at rest and during exercise, and this was associated with slightly but significantly higher myocardial oxygen consumption. Coronary blood flow-during exercise was also slightly higher after LNNA, while coronary vascular resistance was unchanged. Coronary sinus PO2 was slightly but significantly lower during exercise after LNNA, indicating that coronary vasodilatation in response to the increased myocardial oxygen demands during exercise was slightly blunted by LNNA. LNNA did not alter the peak increase in blood flow during reactive hyperaemia following a 15 s coronary occlusion, but decreased the duration of the response and decreased reactive hyperaemia debt repayment from 300(56)% during control conditions to 182(36)% after LNNA (p < 0.01). CONCLUSIONS: LNNA antagonised coronary vasodilatation in response to acetylcholine and blunted coronary reactive hyperaemia, but did not substantially impair the coronary vasodilatation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support an essential role for nitric oxide in coronary resistance vessel dilatation during exercise in the dog.

Brain temperature measurements in rats: a comparison of microwave and ambient temperature exposures.

In an effort to understand microwave heating better, regional brain and core temperatures of rats exposed to microwave radiation (2450 MHz) or elevated air temperatures were measured in two studies. In general, we have found no substantial evidence for temperature differentials, or "hot spots," in the brain of these animals. In the first study, after a 30-min exposure, no temperature differences between brain regions either after microwave or ambient air exposure were found. However, a highly significant correlation between brain and core temperatures was found and this correlation was the same for both microwave and ambient air heating. In the second study, time-temperature profiles were measured in rats exposed to either 30 mW/cm2 or 36.2 degrees C. In this study, the 30-min exposure period was divided into seven intervals and the change in temperature during each period was analyzed. Only the cortex showed significantly different heating rates between the air heating and microwave heating; however, this difference disappeared after the initial 5 min of exposure.

Lethality in mice and rats exposed to 2450 MHz circularly polarized microwaves as a function of exposure duration and environmental factors.

Adult male CD-1 mice and CD rats were used to determine LD50/24 h lethality rates from exposure to 2450-MHz circularly polarized microwaves. Groups of 16 mice or six rats were exposed in each of 32 combinations of nominal power density (10, 25, 50 or 75 mW cm-2), exposure duration (1 or 4 h), and environmental temperature (20 or 30 degrees C) and relative humidity (35 or 80%). An analysis of variance probit model was used to determine the influence each variable had on the probability of death. Significant factors in lethality were nominal power density, exposure duration and environmental temperature, but not environmental relative humidity. The estimated power density (mW cm-2) required to kill 50% of the animals in 24 h is halved when the environmental temperature is increased from 20 to 30 degrees C. Similarly, only 20-25% of the power density is required when the exposure duration is increased from 1 to 4 h. The use of nominal power density as a predictor of the probability of death was more efficient than specific absorption rate estimated experimentally by twin-well calorimetry. The exposure of one mouse at a time, instead of 16, did not alter the predicted death rate.

Exposure of rats to 425-MHz (cW) radiofrequency radiation: effects on lymphocytes.

Four experiments were performed in which six pregnant rats were exposed from day 12 of pregnancy to parturition, for 4 hours a day in a temperature-controlled environment, to 425-MHz (CW) radiation, using a multimode rectangular strip transmission line. Four male pups born to each dam were subsequently irradiated under the same RF exposure condition for 20-21 days of age (2 pups) and 40-41 days of age (2 pups). Specific absorption rates (SARs) for rats of different ages were determined by twin-well calorimetry as well as from calculations of power measurements of incident, reflected, and transmitted energy. Values of SARs between 3.1 and 6.7 mW/g were obtained for rats so exposed at 425 MHz. At selected times, rats were weighed to determine if the irradiation affected growth. Two rats from each litter (4 pups) were euthanized at 20-21 and two at 40-41 days of age and blood was obtained for complete blood counts. The in vitro blastogenic response of blood and lymph-node lymphocytes was measured by 3H-thymidine incorporation into DNA following stimulation of cells with T- or B-lymphocyte mitogens. No difference was observed in the weights of irradiated compared with sham-irradiated rats. No consistent change in the peripheral blood picture was observed between irradiated and sham-irradiated rats. Significant increases in the response of lymph-node but not of blood lymphocytes from irradiated rats following stimulation with mitogens was observed in two of four experiments. These changes were observed for both T- and B-lymphocytes. In another experiment at the same frequency, six pregnant rats were irradiated for 16 hours daily from day 6 through day 19 of pregnancy. The pups born to these dams were not subsequently irradiated. These rats, born to irradiated dams, showed a similar increased response of node but not of blood lymphocytes to T-cell mitogens at 42 days of age. These results indicate that exposure to 425-MHz microwave radiation, under the conditions described, may lead to increased responsiveness of node lymphocytes to in vitro stimulation by mitogen.

Assessment of the immune responsiveness of mice irradiated with continuous wave or pulse-modulated 425-MHz radio frequency radiation.

Groups of female BALB/C mice were irradiated with 425-MHz radio frequency (RF) radiation either continuous wave (CW) or pulse modulated (PM, 1-ms pulse width, 250 pulses/s). Mice were irradiated in a rectangular strip-transmission line at average forward powers of 78, 17.7, or 5 W for CW and 17.7, 5, or 1.25 W for PM. The mean specific absorption rate, as measured using twin-well calorimetry was 7.7 W/kg for a forward power of 70 W. No differences in the mitogen-stimulated response of lymphocytes or in the primary antibody response to sheep erythrocytes or polyvinylpyrrolidone were observed between irradiated and sham-irradiated mice, nor between mice exposed to either CW or PM 425-MHz RF radiation.