Development and characterization of sub-100 ps photomultiplier tubes.

We describe the evaluation of a microchannel plate (MCP) photomultiplier tube (PMT), incorporating a 3 µm pore MCP and constant voltage anode and cathode gaps. The use of the small pore size results in PMTs with response functions of the order of 85 ps full-width-half-maximum, while the constant electric field across the anode and cathode gaps produces a uniform response function over the entire operating range of the device. The PMT was characterized on a number of facilities and employed on gas Cherenkov detectors fielded on various deuterium tritium fuel (DT) implosions on the Omega Laser Facility at the University of Rochester. The Cherenkov detectors are part of diagnostic development to measure Gamma ray reaction history for DT implosions on the National Ignition Facility.

Enhancement of adenoviral gene transfer to adult rat cardiomyocytes in vivo by immobilization and ultrasound treatment of the heart.

Direct injection of adenoviral vectors into ventricular myocardium in vivo produces local transfection of cells including cardiomyocytes. The use of vectors coexpressing GFP with the gene of interest allows subsequent identification of transfected myocytes isolated from the heart some days later, and examination of their function in cell bath experiments. We have injected vectors for antisense to phospholamban, or a control virus for expression of GFP only, into adult rat heart in vivo and then removed the heart and isolated ventricular myocytes 7 days later. Brief immobilization of the ventricle during and after injection using a haemoclip increased the number of transfected rod-shaped, viable myocytes from 1.7 +/- 0.8% (n = 8) to 5.6 +/- 0.8% (n = 9). This was further increased to 13.2 +/- 1.1% (n = 8) by the application of ultrasound pulses to the site before and after injection. Phospholamban antisense increased contraction amplitude and accelerated myocyte relengthening or decline of the Ca(2+) transient in transfected myocytes, while GFP control did not. Qualitative and quantitative effects of phospholamban downregulation were comparable between in vivo and in vitro transfections. This technique will have a number of uses, including production of transfected myocytes without the problem of culture-induced changes in contractility.

Comparison of two aspirin doses on ischemic stroke in post-myocardial infarction patients in the warfarin (Coumadin) Aspirin Reinfarction Study (CARS).

The Coumadin Aspirin Reinfarction Study demonstrated that combination treatment with fixed dose warfarin (1 or 3 mg) + aspirin 80 mg was not superior to aspirin 160 mg alone after myocardial infarction for reducing nonfatal reinfarction, nonfatal stroke, and cardiovascular death. In this analysis, we examined the importance of aspirin dose in the protection against the secondary end point of ischemic stroke. The comparison arms for this analysis were warfarin 1 mg + aspirin 80 mg versus aspirin 160 mg. In the Coumadin Aspirin Reinfarction Study, 2,028 patients were randomized to aspirin 80 mg plus warfarin 1 mg, and 3,393 were randomized to aspirin 160 mg alone. A predictive model for ischemic stroke was developed using the Cox proportional-hazards model. A reduced Cox proportional-hazards model was developed to test for the effect of aspirin dose on ischemic stroke in predefined subgroups. The incidence of ischemic stroke was lower in patients treated with aspirin 160 mg than in patients treated with aspirin 80 mg + warfarin 1 mg (0.6% vs 1.1%; p = 0.0534). Age, previous stroke or transient ischemic attack, and aspirin dose were independent predictors of ischemic stroke. In addition, the highest risk patients, those with Q-wave myocardial infarction and male patients, appeared to receive greater benefit from aspirin 160 mg than from aspirin 80 mg + warfarin 1 mg. The results of this secondary analysis suggest that aspirin 160 mg is more effective than aspirin 80 mg + warfarin 1 mg in preventing ischemic stroke in post-myocardial infarction patients.

Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up.

OBJECTIVES: This study explored the association between the initiation of hormone replacement therapy (HRT) and early cardiac events (<1 year) in women with a recent myocardial infarction (MI). BACKGROUND: Observational studies have linked postmenopausal hormone use with a reduced risk of death from heart disease. However, a recent randomized trial of HRT found no long-term benefit, primarily due to an increase in cardiac events in the first year. METHODS: The Coumadin Aspirin Reinfarction Study (CARS) database contains information on HRT use and menopausal status for women with a recent MI. We classified the 1,857 postmenopausal women in CARS as prior/current HRT users if they took HRT before enrollment, new users if they began HRT during the study period or never users. We assessed the incidence of cardiac events (death, MI, unstable angina [UA]) during follow-up. RESULTS: In our cohort, 28% (n = 524) used HRT at some point. Of these, 21% (n = 111) began HRT after their MI. New users had a higher incidence of death/MI/UA (41% vs. 28%, p = 0.001) during follow-up than never users, largely due to a higher incidence of UA (39% vs. 20%, p = 0.001). After adjustment, new users still had a significantly higher risk of death/MI/UA than never users during follow-up (relative risk [RR] = 1.44 [1.05-1.99]). Prior/current users had no excess risk of the composite end point after adjustment. Users of estrogen/progestin had a lower incidence of death/MI/UA during follow-up than users of estrogen only (RR = 0.56 [0.37-0.85]). CONCLUSIONS: Postmenopausal women who initiated HRT after a recent MI had an increased risk of cardiac events largely due to excess UA during follow-up.

Lack of compensatory enlargement at sites of coronary vasospasm: identification by ultrasound and successful treatment with stenting.

The case of a young man with spontaneous vasospasm at two sites in his left anterior descending coronary artery is described. Intravascular ultrasound demonstrated mild eccentric atherosclerosis with smaller total artery cross-sectional area (defined as the external elastic membrane) compared with reference segments. Impaired compensatory enlargement (remodeling) in response to mild atherosclerosis may derive from one or more biologic mechanisms that are also responsible for vasospasm. This characteristic is easily identified by intravascular ultrasound. In this case, coronary stenting of the vasospastic sites led to excellent long-term control of symptoms more than 1 year after intervention.

Technique for routine use of heparin bonded circuits with a reduced anticoagulation protocol.

The use of heparin-bonded cardiopulmonary bypass circuits (HBCs) with reduced anticoagulation protocol during cardiac surgery attenuates some of the adverse pathophysiologic responses to cardiopulmonary bypass (CPB). The strategies of how to maximize improvements in clinical outcomes using this technique are still debated. This article describes in detail a comprehensive approach to strategies developed at Boston Medical Center and the West Roxbury Veteran Affairs Medical Center in over 4000 cases in which HBC with a reduced anticoagulation protocol is used routinely. Important elements of this technique include elimination of cardiotomy reservoir during coronary artery bypass graft surgery (CABG), autologous blood priming, normothermic CPB, and precise heparin and protamine titration. Adaptation and variation in this technique to specific clinical situations is also highlighted.

Heparin-bonded cardiopulmonary bypass circuits reduce bleeding and transfusion requirements in proximal aortic surgery.

BACKGROUND: Methods to improve hemostasis in aortic surgery continue to evolve. Use of heparin-bonded cardiopulmonary bypass circuits (HBC) has been shown previously to effectively reduce bleeding and improve outcomes in coronary and valve operations. OBJECTIVE: To evaluate the impact of HBC on bleeding and transfusion requirements in proximal aortic surgery. METHODS: Data on 140 consecutive patients undergoing 144 operations of the proximal aorta were collected. Between July 1987 and July 1994, conventional cardiopulmonary bypass circuits (CONV) were used (n = 53). In July 1994, we switched to "tip-to-tip" HBC (n = 91). This study compared clinical outcomes and transfusion requirements between these two groups. RESULTS: Indications for surgery, baseline characteristics, and operative profile of the study groups were similar. Overall operative mortality and reoperation for bleeding were 9% and 13%, respectively. Compared with CONV, use of HBC was associated with decreased mortality (3% vs 18%, p = 0.004), reoperation for bleeding (7% vs 24%, p = 0.005), and hospital length of hospital stay (10 +/- 11 vs 20 +/- 30 days, p = 0.002). Although the incidence of allogeneic blood transfusion was similar (HBC 75% vs CONV 87%, p = 0.12), the magnitude of blood products utilization was much lower in the HBC group (total blood products per patient: 24 +/- 29 vs 49 +/- 47 donor units, p = 0.0002). In the multivariate analyses, use of HBC was identified as an independent predictor of reduced mortality, morbidity, and reduced magnitude of allogeneic blood transfusions. CONCLUSION: Use of HBC in proximal aortic surgery resulted in reduced bleeding and blood transfusion, improving clinical outcomes. Undoubtedly, multiple factors account for the overall improved results. However, use of HBC is an important component of an overall blood conservation strategy.

Functional alterations in adult rat myocytes after overexpression of phospholamban with use of adenovirus.

An increased phospholamban (PLB)-to-sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) ratio has been suggested to contribute to the slowing of relaxation in failing human ventricle. We have used an adenoviral vector carrying the sequence for PLB to increase this ratio in isolated adult rat ventricular myocytes, and we have examined the functional consequences. With use of adenoviral vectors, the PLB content of adult rat myocytes was increased 2.73-fold, with SERCA2a levels unchanged. Maximum contraction amplitude of PLB-overexpressing myocytes was decreased to 6.9 +/- 0.3% shortening compared with 11.2 +/- 0.8% for 24-h controls (Con; P < 0.001, 5 preparations, 103 myocytes). Maximum rates of shortening and relengthening were also significantly decreased. Ca(2+) transient amplitudes were slightly depressed, and time to 50% decay of the transients was significantly increased: 237 +/- 18 (n = 14 myocytes) and 432 +/- 32 ms in Con and PLB (n = 15) myocytes, respectively (P < 0.001). The amount of Ca(2+) in the sarcoplasmic reticulum stores was reduced by 21% (P < 0.05). Relaxation was significantly slower in PLB than in Con myocytes when the Na(+)/Ca(2+) exchanger was blocked but not when sarcoplasmic reticulum Ca(2+) uptake was inhibited. Adenovirus infection with Ad.RSV.PLB was therefore able to produce functional changes in adult cardiac myocytes within 24 h, consistent with overexpression of PLB and similar to those seen in failing human heart.

Heparin-bonded circuit with low systemic anticoagulation in a patient with heparin-induced thrombocytopenia: a case report.

Heparin-induced thrombocytopenia (HIT) in patients undergoing open heart surgery has been reported with increasing frequency. Several strategies have been suggested to approach this difficult problem. However, the syndrome is still associated with significant morbidity and mortality. We describe an 82-year-old male with HIT who underwent coronary artery bypass grafting utilizing a heparin-bonded cardiopulmonary bypass circuit with very low systemic anticoagulation. Only one unit of packed red blood cells was transfused. The patient recovered uneventfully. This strategy is safe and effective, and, therefore, should be considered in patients with HIT.

The role of cAMP in the frequency-dependent changes in contraction of guinea-pig cardiomyocytes.

OBJECTIVES: beta-Receptor desensitisation, low basal cAMP, and a negative force-frequency relationship are characteristic changes in human heart failure. Isolated cardiomyocytes from noradrenaline-treated guinea pigs also show these features. We tested the hypothesis that low basal cAMP underlies the loss of contractile response to increasing stimulation frequency in this model. METHODS: Isolated cardiomyocytes were obtained from noradrenaline-treated (NA) and sham-operated (SHAM) guinea pigs. They were stimulated from 0.1-2 Hz and contraction amplitude was monitored with a video edge-detection system. RESULTS: NA cells had less positive amplitude-frequency responses (AFR) compared to SHAMs at 2 mM (P = 0.002, n = 17), or midrange Ca2+ concentrations (EC40-EC60) (P < 0.001, n = 13). When the cAMP agonist, 8-CPT-cAMP (CPT, 10 microM) or high Ca2+ (above EC75) was added to NA cells the AFR was normalised to that of SHAM myocytes (NA vs. SHAM P = ns). In control experiments the cAMP antagonists, Rp-cAMPS (Rpc) and Rp-8-CPT-cAMPS (Rp8, 100 microM), blocked the positive inotropic effects of CPT at 0.5 Hz (control pD2 = 4.36 +/- 0.06, Rp8 pD2 = 3.68 +/- 0.08, P < 0.0001), n = 6 paired). Rpc (100 microM) completely but reversibly blocked the effect of maximal isoprenaline in control experiments (P < 0.0001). Neither antagonist reduced the AFR compared to time-matched controls (P = ns, n = 6). Blockade of SERCA2a with thapsigargin resulted in a significant reduction in the AFR (ANOVA P < 0.0001). CONCLUSIONS: The results are consistent with sarcoplasmic reticulum (SR) function being a more important determinant of the amplitude-frequency relationship than tonic levels of cAMP under basal conditions. Reversal of AFR depression by CPT may result from stimulation of SR Ca2+ uptake.

Effect of anticoagulation protocol on outcome in patients undergoing CABG with heparin-bonded cardiopulmonary bypass circuits.

BACKGROUND: We have demonstrated that the use of heparin-bonded cardiopulmonary bypass circuits (HBCs) combined with a lower anticoagulation protocol as an adjunct to an integrated blood conservation strategy decreases the incidence and magnitude of homologous transfusion and improves clinical outcome in patients undergoing primary coronary artery bypass grafting. It is not known whether it is the lower anticoagulation protocol that influences outcome in patients treated with HBCs. Furthermore, the thrombogenic risk of using lower anticoagulation with HBCs still is debated. METHODS: To answer these questions, a prospective randomized study was conducted in which 244 patients undergoing primary coronary artery bypass grafting were treated with HBCs and randomized to undergo either a full (activated clotting time, > 450 seconds) or a lower (activated clotting time, > 250 seconds) anticoagulation protocol. In addition to clinical outcome, levels of thrombin generation markers during and after cardiopulmonary bypass were assessed in a consecutive subset of 58 patients (full anticoagulation profile = 28, lower anticoagulation profile = 30) by measuring thrombin-antithrombin complexes and prothrombin fragment 1.2. Levels of these markers also were correlated with the activated clotting time during cardiopulmonary bypass. RESULTS: Preoperative and intraoperative risk profiles and other characteristics were similar in both groups, with more than 60% of patients undergoing nonelective operation. Compared with the full anticoagulation protocol group, patients in the lower anticoagulation protocol group were less likely to require blood products (24.2% versus 35.8%, respectively; p = 0.047) and received substantially fewer homologous donor units (0.50 +/- 0.92 versus 1.08 +/- 2.10 U, respectively; p = 0.005). Clinical outcomes were uniformly outstanding (but similar) in both treatment groups, with a modest reduction in the length of the hospital stay in the lower anticoagulation protocol group (5.26 +/- 1.23 versus 5.63 +/- 1.73 days, respectively; p = 0.05). The use of HBCs with a lower anticoagulation protocol was not associated with any adverse clinical events. Thrombin generation increased during cardiopulmonary bypass in both treatment groups, but was unrelated to the anticoagulation protocol or the activated clotting time (r2 = 0.03). No differences between the full and lower anticoagulation protocol groups were noted in the number of microemboli detected by transcranial Doppler analyses during cardiopulmonary bypass (n = 40) or in the postoperative neurologic and neuropsychologic outcomes (n = 30). CONCLUSIONS: This study definitively demonstrates that, when used appropriately, patients who are treated with HBCs and a lower anticoagulation protocol have a lower incidence and magnitude of homologous transfusion and are not at any added risk for clinical, hematologic (thrombin-antithrombin complex and fragment 1.2 measurements), or microscopic (transcranial Doppler analyses) thromboembolic complications or for neurologic or neuropsychologic deficits.

Comparison of risk profile and outcomes in patients undergoing surgical and catheter-based revascularization.

BACKGROUND: The effects of the randomized revascularization trials and improved strategies and techniques for coronary artery bypass graft (CABG) surgery and percutaneous transluminal catheter-based revascularization (PTCR) on current patient selection and clinical outcomes are unknown. METHODS: We evaluated a concurrent, contemporary (1995 to 1997), and consecutive group of patients undergoing CABG (n = 982) or PTCR (n = 939) in a single institution that participated in the Bypass Angioplasty Revascularization Investigation (BARI) trial. Results are presented as percent or mean +/- SD. Compared to PTCR, patients undergoing CABG were older (66.2+/-10.7 vs. 62.0+/-11.8 years, p<0.05) with a higher incidence of hypertension (73.3% vs. 52.4%, p<0.05), diabetes (32.5% vs. 23.1%, p<0.05), active smoking (67.8% vs. 27.2%, p<0.05), prior myocardial infarction (MI)(66.8% vs. 28.5%, p<0.05), peripheral vascular disease (19.8% vs. 7.7%, p<0.05), prior cerebrovascular accident (CVA)/transient ischemic attack (TIA) (6.4% vs. 2.8%, p<0.05), and a lower ejection fraction (48.7%+/-14.5% vs. 55.3%+/-11.7%, p<0.05). The presenting functional class and incidence of female gender were similar for both revascularization strategies. RESULTS: Compared to patients undergoing CABG, those undergoing PTCR were more likely to have single or two vessel coronary artery disease (88.6% vs. 23.1%, p<0.001) and had fewer vessels revascularized per patient (1.08+/-0.30 vs. 3.5+/-0.98, p<0.001). Outcomes were comparable for CABG and PTCR with a similar incidence of death (1.0% vs. 0.9%, NS), renal insufficiency (0.7% vs. 0.6%, NS), and CVA/TIA (0.9% vs. 0.3%, NS). Patients undergoing CABG had a higher incidence of pulmonary complications (5.2% vs. 1.0%, p<0.05), a lower incidence of periprocedural MI (1.1% vs. 4.1%, p<0.05) and major complication (5.9% vs. 9.4%, p<0.05), but longer hospital stays (6.5+/-5.1 vs. 3.1+/-2.6 days, p<0.05). CONCLUSIONS: Despite higher clinical and angiographic risk profiles in patients undergoing CABG, clinical results, morbidity, and mortality were comparable to those of PTCR. With evolving techniques, continued reevaluation of indications and outcomes are necessary.

Gender differences in presentation, management, and cardiac event-free survival in patients with syncope.

In a MEDLINE search of published English studies (1966 to 1996), no prior study was identified that examined gender-based differences in the management and prognosis of patients admitted with syncope. We studied 109 consecutive patients (48 women) admitted with syncope at the Massachusetts General Hospital (1989 to 1990). All patients underwent Holter monitoring, signal-averaged electrocardiography, and echocardiography according to study protocol. Follow-up was 100% complete (10 +/- 4 months). Women were older (74 +/- 2 vs 66 +/- 2 years, p <0.01) and less likely to have premonitory symptoms when compared with men (46% vs 66%, p <0.05). A greater proportion of men had left ventricular ejection fractions of <0.40 (18% vs 0%, p <0.01), abnormal signal-averaged electrocardiograms (28% vs 8%, p <0.01), and a cardiac cause for syncope (49% vs 25%, p <0.01). Although referral for diagnostic electrophysiologic testing was >3 times as frequent for men compared with women (20% of men vs 6% of women, p <0.05), this difference was not significant after adjustment for age, ventricular arrhythmia, and referral for coronary angiography. During follow-up, 21% of men versus 6% of women (p <0.05) had cardiac events (recurrent syncope, myocardial infarction, or sudden death). Cardiac event-free survival rates were worse for men (p = 0.045). Thus, we have identified gender-based differences in the clinical presentation of syncope for hospital admission. Left ventricular dysfunction and an abnormal signal-averaged electrocardiogram occur more frequently in men. Men are more likely to have cardiac syncope and worse cardiac event-free survival when compared with women.

The effect of alterations to action potential duration on beta-adrenoceptor-mediated aftercontractions in human and guinea-pig ventricular myocytes.

Aftercontractions induced by beta-adrenoceptor stimulation in human and guinea-pig cardiomyocytes may be related to changes in action potential duration (APD). We investigated the effects of altering APD during the occurrence of isoproterenol-induced aftercontractions, using the KATP channel openers cromakalim and lemakalim or the action potential voltage clamp technique, in guinea-pig and human ventricular cardiomyocytes. Contractile responses were measured at 32 degrees C using a video-based edge-detection system. In guinea-pig myocytes, action potentials, Indo-1 fluorescence and contraction were measured at 22 degrees C. Isoproterenol (< or = 12 nM) had variable effects on APD but induced aftercontractions, the majority (14/19 cells) of which occurred during the action potential. Short action potentials were produced using K+ channel openers. These compounds reduced or completely abolished the isoproterenol-induced aftercontractions. Increasing isoproterenol in the presence of K+ channel opener restored the main contraction to a level similar to or above those with isoproterenol alone, but without the reappearance of aftercontractions. When cells were stimulated to contract under action potential voltage clamp, isoproterenol-induced aftercontractions were abolished by voltage clamping with action potentials of short duration. It was possible to induce aftercontractions in some cells without application of isoproterenol if voltage clamp-imposed action potentials of very long duration were used. These aftercontractions were also abolished by shortening action potential duration. We conclude that K+ channel openers or the imposition of action potentials of short duration can dissociate positively inotropic beta-adrenoceptor stimulation from aftercontraction formation and that action potentials of long duration can be pro-arrhythmic.

Twenty-four hour nurse practitioner service in the accident and emergency department.

This paper discusses the introduction of a 24-h nurse practitioner service in a major accident and emergency department and monitors it over a 3-month period. The paper provides a description of the activities of the nurse practitioners and a critical evaluation of their role. It shows that every major accident and emergency department can set up a 24-h nurse practitioner scheme and the organization of such a scheme can be very simple. This is the first article to look at a 24-h service.