Discussion of "Optimal test procedures for multiple hypotheses controlling the familywise expected loss" by Willi Maurer, Frank Bretz, and Xiaolei Xun.

We provide commentary on the paper by Willi Maurer, Frank Bretz, and Xiaolei Xun entitled, "Optimal test procedures for multiple hypotheses controlling for the familywise expected loss." The authors provide an excellent discussion of the multiplicity problem in clinical trials and propose a novel approach based on a decision-theoretic framework that incorporates loss functions that can vary across multiple hypotheses in a family. We provide some considerations for the practical use of the authors' proposed methods as well as some alternative methods that may also be of interest in this setting.

Circulating serum CK level vs. muscle impairment for in situ monitoring burden of disease in Mdx-mice.

BACKGROUND: Duchenne muscular dystrophy (DMD) consists of a lack in the expression of the subsarcolemmal protein dystrophin causing progressive muscle dysfunction. Among the widely applied animal models in DMD research is the C57BL/1010ScSn-Dmdmdx mouse, commonly referred to as the "mdx mouse". The potential benefit of novel interventions in this model is often assessed by variables such as functional improvement, histological changes, and creatine kinase (CK) serum levels as an indicator for the extent of in situ muscle damage. OBJECTIVE: Our objective was to determine to what extent the serum CK-level serves a surrogate for muscle dysfunction. METHODS: In this trial mdx mice were subjected to a four-limb wire-hanging test (WHT) to assess the physical performance as a reference for muscle function. As CK is a component of the muscle fiber cytosol, its serum activity is supposed to positively correlate with progressing muscle damage. Hence serum CK levels were measured to detect the degree of muscle impairment. The functional tests and the serum CK levels were analyzed for their specific correlation. RESULTS: Although physical performance decreased during the course of the experiment, latency to fall times in the WHT did not correlate with the CK level in mdx mice. CONCLUSION: Our data suggests that the serum CK activity might be a critical parameter to monitor the progression of muscle impairment in mdx mice. Further this study emphasizes the complexity of the DMD phenotype in the mdx mouse, and the care with which isolated parameters in this model should be interpreted.

Coordinate expression of N-myc 2 and insulin-like growth factor II in precancerous altered hepatic foci in woodchuck hepatitis virus carriers.

Over 50% of the hepatocellular carcinomas (HCCs) arising in the livers of woodchucks with persistent woodchuck hepatitis virus (WHV) infection contain integrations of WHV DNA within, or immediately adjacent to, a unique and functional N-myc 2 retroposon [G. Fourel et al., Nature (Lond.), 347: 294-298, 1990; Y. Wei et al., J. Virol., 66: 5265-5276, 1992]. The integrations are believed to activate the expression of N-myc 2 by an enhancer insertion mechanism [Y. Wei et al., J. Virol., 66: 5265-5276, 1992]. Since the fetal growth factor insulin-like growth factor II (IGF-II) is also expressed in woodchuck HCCs [X. X. Fu et al., J. Virol., 62: 3422-3430, 1988; D. Yang and C. E. Rogler, Carcinogenesis (Lond.), 12: 1893-1901, 1991] we sought to determine the earliest stage in hepatocarcinogenesis at which overexpression of N-myc and IGF-II could be detected. The earliest precancerous lesions so far identified in woodchucks are altered hepatic foci (AHFs) [K. Abe et al., Jpn. J. Cancer Res., 79: 466-472, 1988; H. Popper et al., Hepatology (Baltimore), 1: 91-98, 1981]. Using in situ hybridization, we have demonstrated that both the N-myc and IGF-II genes are coordinately overexpressed in nearly all AHFs in precancerous woodchuck livers. In contrast, WHV replication was either repressed or undetectable in the same AHFs. The use of probes selective for N-myc 2 versus N-myc 1 (the normal mammalian homologue) revealed nearly exclusive expression of N-myc 2 in AHFs. Cells within AHFs were generally slow growing, as determined by frequency of histone III-expressing hepatocytes; however, a few fast-growing AHFs, with growth rates nearly equivalent to those of HCCs, were identified. Furthermore, very highly elevated N-myc 2 or IGF-II expression was detected in a few subregions within AHFs which otherwise exhibited a uniformly moderate expression, suggesting that selection for higher levels of N-myc or IGF-II expression may occur within AHFs. These data suggest that coordinate expression of N-myc 2 and IGF-II and repression of WHV replication may be functionally involved in the development of AHFs and that cells expressing very high levels of N-myc and IGF-II may be selectively enriched as AHFs progress to HCC, since high levels of N-myc and IGF-II are common in HCCs.

Inhibition of neointima formation after experimental coronary artery stenting: a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost.

BACKGROUND: To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and nonbiodegradable polymers have been proposed to serve as sustained-release drug carriers. METHODS AND RESULTS: In both a sheep and a pig model, we examined the vascular response to standard and high-pressure implantation of coronary Palmaz-Schatz stents coated with a 10-microm layer of polylactic acid (MW 30 kDa) releasing recombinant polyethylene glycol (r-PEG)-hirudin and the prostacyclin analogue iloprost, both drugs with antithrombotic and potentially antiproliferative effects. Study observation time was 28 days. Between the corresponding stent groups, no differences were observed with regard to preplacement and postplacement implantation parameters. The morphometric analysis demonstrated that the coating was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (P<0.02) in the standard-pressure model (sheep) and by 24.8% (P<0.02) in the overstretch pig model compared with uncoated control stents without inducing a local inflammatory response. CONCLUSIONS: The results from this study demonstrate beneficial effects of a polymeric stent coating with polylactic acid releasing r-PEG-hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury. Future studies are proposed to investigate the integration of other substances to further enhance the potential of the stent coating on reducing neointimal formation.

Endovascular irradiation from beta-particle-emitting gold stents results in increased neointima formation in a porcine restenosis model.

BACKGROUND: Recent studies have shown that ionizing radiation reduces neointima formation after balloon angioplasty and stent implantation in experimental models of restenosis and first clinical trials. The objective of this study was to determine the dose distribution of a new beta-particle-emitting radioactive gold stent and to evaluate the dose-dependent vascular response in the coronary overstretch pig model. METHODS AND RESULTS: Sixteen Göttinger minipigs underwent placement of 11 nonradioactive and 36 beta-particle-emitting stents with activity levels of 10.4+/-0.6, 14.9+/-2.4, 22.8+/-1.3, 35.8+/-2. 8, and 55.4+/-5.3 microCi of (198)Au. Three months after implantation, the percent area stenosis, neointimal thickness, neointimal area, and vessel injury were analyzed by quantitative histomorphometry. The lifetime radiation doses at a depth of 1 mm were 3.3+/-0.2, 4.7+/-0.5, 7.2+/-0.4, 11.4+/-0.9, and 17.6+/-1.7 Gy for the different activity groups. No dose-response relationship was observed in the radioactive stents with respect to percent area stenosis (P=0.297), mean neointimal thickness (P=0.82), or mean neointimal area (P=0.65). Significantly lower neointima formation and less luminal narrowing was seen in the control group than in the beta-particle-emitting stents (P<0.001). Multilinear regression analysis revealed that only radioactivity made a significant independent contribution to the degree of percent area stenosis (P<0. 001). CONCLUSIONS: Neointima formation in pigs is markedly increased by beta-particle-emitting stents with (198)Au as the radioisotope. This study provides evidence that dosages of 3 to 18 Gy of low-dose-rate beta-particle irradiation via endovascular stents cause pronounced luminal narrowing in the animal model at 3 months.

Influence of balloon pressure during stent placement in native coronary arteries on early and late angiographic and clinical outcome: A randomized evaluation of high-pressure inflation.

BACKGROUND: High-pressure dilatation is considered a better stent placement strategy, but this has not yet been proved by appropriately designed studies. The objective of this randomized trial was to assess the role of high-pressure dilatation in the early and late outcome of patients undergoing coronary stent placement. METHODS AND RESULTS: Consecutive patients with coronary stent placement were randomly assigned to high- (15 to 20 atm, 468 patients) or low- (8 to 13 atm, 466 patients) balloon-pressure dilatation. The primary end point of the study was the event-free survival at 1 year. Secondary end points were the incidence of stent thrombosis at 30 days and angiographic restenosis (>/=50% diameter stenosis) at 6 months. The incidence of stent thrombosis was 1.7% in the high-pressure and 1.9% in the low-pressure group (relative risk 0.89; 95% CI 0.30 to 2.56). During the first 30 days, although there was no significant difference in the incidence of Q-wave myocardial infarction, the incidence of non-Q-wave infarction was 6.4% in the high-pressure and 3.4% in the low-pressure group (relative risk 1. 87; 95% CI 1.02 to 3.42). The restenosis rate was 30.4% in the high-pressure and 31.4% in the low-pressure group (relative risk 0. 97; 95% CI 0.75 to 1.26). Event-free survival at 1 year was not significantly different between the groups, with 78.8% in high-pressure patients and 75.5% in patients assigned to low-pressure dilatation (hazard ratio 0.85; 95% CI 0.65 to 1.11). CONCLUSIONS: The systematic use of high-balloon-pressure inflation (15 to 20 atm) during coronary stent placement is not associated with any significant influence on the 1-year outcome of patients undergoing this intervention.

Marked reduction in atrial defibrillation thresholds with repeated internal cardioversion.

OBJECTIVES: This study was performed to assess the atrial defibrillation threshold in patients with recurrent atrial fibrillation (AF) using repeated internal cardioversion. BACKGROUND: Previous studies in patients with chronic AF undergoing internal cardioversion have shown this method to be effective and safe. However, current energy requirements might preclude patients with longer-lasting AF from being eligible for an implantable atrial defibrillator. METHODS: Internal shocks were delivered via defibrillation electrodes placed in the right atrium (cathode) and the coronary sinus (anode) or the right atrium (cathode) and the left pulmonary artery. After cardioversion, patients were orally treated with sotalol (mean 189 +/- 63 mg/day). Eighty consecutive patients with chronic AF (mean duration 291 +/- 237 days) underwent internal cardioversion, and sinus rhythm was restored in 74 patients. Eighteen patients underwent repeated internal cardioversion using the same electrode position and shock configuration after recurrence of AF (mean duration 34 +/- 25 days). RESULTS: In these 18 patients, the overall mean defibrillation threshold was 6.67 +/- 3.09 J for the first cardioversion and 3.83 +/- 2.62 J for the second (p = 0.003). Mean lead impedance was 55.6 +/- 5.1 ohms and 57.1 +/- 3.7 ohms, respectively (not significant). For sedation, 6.7 +/- 2.9 mg and 3.9 +/- 2.2 mg midazolam were administered intravenously (p = 0.003), and the pain score (0 = not felt, 10 = intolerable) was 5.1 +/- 1.9 and 2.7 +/- 1.8 (p = 0.001). Uni- and multivariate analyses revealed only the duration of AF before cardioversion to be of relevance, lasting 175 +/- 113 days before the first and 34 +/- 25 days before the second cardioversion in these 18 patients (p = 0.002). CONCLUSIONS: If the duration of AF is reduced, a significant reduction in defibrillation energy requirements for internal cardioversion ensues. This might extend the group of patients eligible for an implantable atrial defibrillator despite relatively high initial defibrillation thresholds.

Low energy intracardiac cardioversion after failed conventional external cardioversion of atrial fibrillation.

OBJECTIVES: This study was designed to evaluate the efficacy of intracardiac cardioversion in patients with chronic atrial fibrillation after unsuccessful external cardioversion. BACKGROUND: Previous studies in patients with atrial fibrillation undergoing intracardiac cardioversion have suggested that intracardiac cardioversion is highly effective and safe. However, the characteristics of patients who benefit most from this invasive technique are unknown. METHODS: We prospectively studied 25 consecutive patients with chronic atrial fibrillation (11 +/- 9 months). All patients had undergone at least three attempts at conventional external transthoracic cardioversion by means of paddles in an anteroposterolateral position applying energies up to 360 J without success. Intracardiac shocks were delivered by an external defibrillator through defibrillation electrodes placed in the right atrium and coronary sinus or in the right atrium and left pulmonary artery. After conversion, all patients were treated orally with sotalol (mean 194 +/- 63 mg/day). RESULTS: Internal cardioversion was successful in 22 of 25 patients at a mean defibrillation threshold of 6.5 +/- 3.0 J. Mean lead impedance was 56.4 +/- 7.4 omega. No severe complications were observed. At a mean follow-up of 15 +/- 12 months, 12 (55%) of the patients treated successfully remained in sinus rhythm. CONCLUSIONS: In patients with failed external cardioversion, internal cardioversion offers a new option for restoring sinus rhythm. Intracardiac cardioversion is an effective and safe method and can be easily performed in patients with minimal sedation.

Coronary stent placement in patients with acute myocardial infarction: comparison of clinical and angiographic outcome after randomization to antiplatelet or anticoagulant therapy.

OBJECTIVES: The Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial is a randomized comparison of combined antiplatelet with anticoagulant therapy after coronary Palmaz-Schatz stent placement. The objective of this study was to compare early and late clinical and angiographic outcome in a subgroup of patients with stent placement for acute myocardial infarction. BACKGROUND: Stenting has become a treatment option for acute myocardial infarction, but it is not known which antithrombotic regimen is more adequate after stent implantation. METHODS: One hundred twenty-three patients with successful stenting after acute myocardial infarction were randomized to receive aspirin plus ticlopidine (n = 61) or intense anticoagulant therapy (n = 62). Six-month repeat angiography was performed in 101 (86.3%) eligible patients. RESULTS: During the first 30 days after stenting, patients with antiplatelet therapy had a significantly lower clinical event rate (3.3% vs. 21.0%, p = 0.005) and stent vessel occlusion rate (0% vs. 9.7%, p = 0.03) and a trend to fewer cardiac events (1.6% vs. 9.7%, p = 0.12). After 6 months, the survival rate free of recurrent myocardial infarction was higher in patients with antiplatelet therapy (100% vs. 90.3%, p = 0.03), and the rate of stent vessel occlusion was lower (1.6% vs. 14.5%, p = 0.02). Both groups had comparable restenosis rates (26.5% vs. 26.9%, p = 0.87). CONCLUSIONS: This study demonstrates that combined antiplatelet therapy after stent placement in patients with acute myocardial infarction is associated with an overall better clinical and angiographic outcome than anticoagulant therapy.

p-Hydroxyphenylacetaldehyde, the major product of tyrosine oxidation by the activated myeloperoxidase system can act as an antioxidant in LDL.

The oxidative modification of low density lipoprotein (LDL) may play a significant role in atherogenesis. HOCl generated by the myeloperoxidase/H2O2/Cl- system of activated neutrophils may be operative in vivo making LDL atherogenic. Tyrosine has been found to be oxidized by HOCl to p-hydroxyphenylacetaldehyde (p-HA) capable of modifying phospholipid amino groups in LDL. As an amphiphatic phenolic compound, p-HA may have the potential to act as an antioxidant in the lipid phase of LDL. The present results show that (a) tyrosine exerts a protective effect on LDL modification by HOCl, (b) p-HA could act as antioxidant associated with the lipoprotein preventing cell- and transition metal ion-mediated LDL oxidation and (c) p-HA was able to scavenge free radicals.

Atorvastatin improves blood rheology in patients with familial hypercholesterolemia (FH) on long-term LDL apheresis treatment.

To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia (FH) on regular LDL apheresis, we prospectively studied the rheological variables fibrinogen, plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit and platelet aggregation in 12 patients (two homozygous, ten heterozygous) before and during treatment with atorvastatin. Baseline values of red cell aggregation and whole blood viscosity were increased in FH patients on regular LDL apheresis compared with healthy controls (P<0.05), whereas fibrinogen, plasma viscosity and hematocrit were similar in the two groups. Treatment with atorvastatin reduced red cell aggregation (P<0.01), whole blood viscosity (P<0.01), plasma viscosity (P<0.01) and platelet aggregation (P<0.05), but caused a slight increase in plasma fibrinogen (by 5%; P<0.01). Our findings suggest that atorvastatin improves blood rheology in patients with FH on regular LDL-apheresis. This improvement in blood flow properties may contribute to the well-known beneficial effects of atorvastatin on cardiovascular risk in patients with severe hyperlipidemia and atherosclerotic vascular disease.

Improved small intestinal preservation after lazaroid U74389G treatment and cold storage in University of Wisconsin solution.

The small intestine (SI) is highly sensitive to oxygen free radical-induced injury. The most common preservation solution, University of Wisconsin (UW) solution, does not adequately prevent free radical-induced injury. Lazaroids, and U74389G in particular, are a new class of compound that are potent inhibitors of superoxide-mediated lipid peroxidation. We studied the added influence of U74389G to 18-hr cold preservation of rat SI in UW solution. Three groups of rats were studied. In group 1, SI was excised and reperfused immediately. In group 2, SI was stored in UW solution at 4 degrees C for 18 hr. In group 3, U74389G was given to the SI graft before storage and again before reperfusion. Blood reperfusion of the grafts was achieved via connection to the superior mesenteric artery and portal vein of support rats. Functional recovery was assessed using a maltose tolerance test. Weight changes were calculated and histologic studies done. After 30 and 60 min of reperfusion, maltose uptake in group 3 was significantly better than that of the group 2, and returned to control levels. Significantly more tissue swelling was noted in group 3 over control, but the magnitude was less than that of group 2. Less transmural necrosis and villous blunting were noted in group 3 versus group 2; the appearance of the mucosa in group 3 approached that of group 1. We conclude that the use of U74389G treatment in addition to cold storage in UW solution improves recovery of graft function and minimizes morphologic damage to the small intestinal mucosa.

Antithrombogenic coating of stents using a biodegradable drug delivery technology.

To reduce the thrombogenic properties of coronary artery stents, a biodegradable polylactic acid (PLA) stent coating with an incorporated thrombin inhibitor and a platelet aggregation inhibitor has been developed. In an ex vivo human stasis model, its effect on platelets, plasmatic coagulation and its release characteristics were studied using whole blood. Bare steel and bare gold-surface stents were compared to steel and gold-surface stents coated with PLA (30 kDa) containing 5% polyethyleneglycol (PEG)-hirudin and 1% iloprost, with an empty tube as control. Markers of activated coagulation (prothrombin fragment F1-2 and thrombin-antithrombin III complex, TAT), were assayed and the release of drugs from the coating was assessed by aPTT and collagen-induced platelet aggregation. Bare steel and gold stents were completely covered by a blood clot, and high levels of coagulation markers (F1-2 fragment and TAT) were detected. No differences in the thrombogenic properties were found between bare gold or steel stents. Coated stents were free of blood clots and only minor elevations of markers were detected. Release data from in-vitro studies over 90 days showed a gradual release of the drugs with an initial exponential release characteristic for PEG-hirudin, slow release of iloprost and a 10% degradation of the PLA carrier. This drug releasing biodegradable coating effectively reduced thrombus formation independent of the metallic surface.

What is the ideal rate-adaptive sensor for patients with implantable cardioverter defibrillators: lessons from cardiac pacing.

The development of implantable pacemakers in the clinical setting mirrors the implementation of advanced technical possibilities. In the United States, 83% of all pacemakers implanted in 1996 had rate response as a programmable option. A variety of sensors have been proposed and used for rate control. Among today's many concepts, accelerometer-controlled pacing is the most widely used rate-adaptive principle. Although the use of a second sensor is currently of proven benefit for only a limited number of patients, the concept of closed-loop pacing--implementing a negative feedback between pacing rate and the control signal--merits further investigation. This is of special importance in defibrillator patients whose myocardial contractility is generally limited. These patients are most sensitive to pacing rates that are too high for a given metabolic situation. The integration of rate-adaptive pacing into defibrillators is a natural consequence of the technical evolution.

Effect of electrode position on outcome of low-energy intracardiac cardioversion of atrial fibrillation.

The aim of this study was to evaluate the new method of low-energy, catheter-based intracardiac cardioversion in patients with chronic atrial fibrillation (AF) and to compare 2 different lead positions. Accordingly, we prospectively studied 80 consecutive patients with chronic AF (9.8 +/- 7.9 months) who were randomly assigned to undergo internal cardioversion either via defibrillation electrodes placed in the right atrium and coronary sinus (coronary sinus group) or via defibrillation electrodes placed in the right atrium and left pulmonary artery (pulmonary artery group). Intracardiac shocks were delivered by an external defibrillator synchronized to the QRS complex. After conversion, all patients were treated orally with sotalol (mean daily dose, 189 +/- 63 mg/day). For conversion to sinus rhythm, the overall mean energy requirement was 5.6 +/- 3.1 J. In the coronary sinus group, cardioversion was achieved in 35 of 38 patients at a mean energy level of 4.1 +/- 2.3 J (range 1.0 to 9.9), and in the pulmonary artery group in 39 of 42 patients with 7.2 +/- 3.1 J (range 2.5 to 14.8). Although there was no difference with regard to success rate, the energy differed significantly between the 2 groups (p < 0.01). Mean lead impedance was 56.4 +/- 7.0 omega and 54.6 +/- 8.5 omega, respectively (p = NS). No serious complications were observed in either lead group. At a mean follow-up of 14.2 +/- 7.0 months, 54% and 56%, respectively, of patients who had been converted successfully remained in sinus rhythm. Thus, low-energy biphasic shocks delivered between the right atrium and coronary sinus or pulmonary artery are equally effective for cardioversion of patients with chronic AF. The energy requirements for conversion from a pulmonary artery electrode position are higher than for the coronary sinus position.

Intrinsic heart rate response as a predictor of rate-adaptive pacing benefit.

OBJECTIVE: More than half of the pacemaker systems now being implanted can be rate adaptively paced. Our objective was to determine which patients benefit from rate-adaptive pacing in terms of improvement in maximum performance and aerobic capacity. METHODS: Thirty patients with implanted accelerometer-driven, rate-adaptive pacemakers underwent a standardized, ergospirometrically and maximally symptoms = limited cardiopulmonary exercise (CPX) stress test with both rate-adaptive and fixed-rate stimulation in a randomized order. The patients were divided into three groups depending on the intrinsic heart rate achieved during maximum workload: group 1 achieved < or = 90 beats per minute (bpm), group 2 achieved 90 to < or = 110 bpm, and group 3 achieved > 110 bpm. RESULTS: Group 1 demonstrated a significant increase (p < or = 0.01) in maximum oxygen uptake from 16.4 +/- 5.6 mL/kg/min with fixed-rate pacing to 23.2 +/- 11.1 mL/kg/min (+ 41.5%) with rate-adaptive pacing. At the anaerobic threshold, oxygen uptake significantly increased (p < or = 0.01) from 11.8 +/- 2.7 mL/kg/min to 15.7 +/- 5 mL/kg/min (+33.1%). Group 2 patients showed an increase in maximum oxygen uptake from 23.3 +/- 5.4 mL/kg/min to 25.3 +/- 4.9 mL/kg/min (+8.5%, p < or = 0.05) as well as an increase in oxygen uptake at the anaerobic threshold from 15.9 +/- 2.6 mL/kg/min to 18.1 +/- 2.9 mL/kg/min (+13.8%, p < or = 0.05) with rate-adaptive pacing. Group 3 demonstrated no significant difference between the two pacing methods (from 25.6 +/- 9.4 mL/kg/min to 25.9 +/- 9.3 mL/kg/min and from 15.8 +/- 5.5 mL/kg/min to 16.3 +/- 6 mL/kg/min). No difference in maximum oxygen uptake and in oxygen uptake at the anaerobic threshold was evident among the three groups when paced rate adaptively (not significant). CONCLUSION: The second-generation, accelerometer controlled rate-adaptive pacemakers used in testing enabled a stress-oriented heart rate increase and an age- and gender-dependent adequate matching of maximum performance. The benefit from a rate-adaptive system to the patient increases as his or her chronotropic reserve limitation became more pronounced.

Evaluation of a new treadmill exercise protocol.

STUDY OBJECTIVES: To confirm that a newly drafted treadmill exercise protocol designed on a theoretical basis to span a range of 0 to 200 W with approximately 25-W increments by alteration of either speed or grade from one stage to the next should correspond to a standard bicycle protocol consisting of 25-W steps. DESIGN: Randomized, crossover study to compare both exercise test modes. STUDY PARTICIPANTS: Twenty-one consecutive healthy volunteers. INTERVENTIONS: Subjects underwent both exercise tests until either exhaustion or completion of the respective protocol, and cardiopulmonary exercise parameters were assessed during either of them. For comparison, correlation coefficients (r) were calculated. RESULTS: Exercise tolerance time was 9% higher on the treadmill (p<0.05). Ten subjects completed the bicycle program, whereas 18 subjects did so on the treadmill. With both protocols, there were comparably linear increases in heart rate (r=0.885), oxygen uptake (r=0.925), oxygen uptake per body weight (r=0.944), carbon dioxide output (r=0.937), and minute ventilation (r=0.914). For the 2-min stage duration, a plateau in oxygen uptake was achieved with neither protocol. The ventilatory equivalent for oxygen, which is not linear, showed its minimum at comparable workloads, at the point of surpassing the anaerobic threshold. Correlation of oxygen pulse was fair (r=0.896). CONCLUSIONS: There was an excellent correlation of the parameters with respect to both measured values at identical workloads and slopes of both protocols, thus enabling comparability of treadmill and bicycle ergometry. Due to its practical handling, the new protocol may facilitate acceptance, especially when used for elderly or disabled patients.

Control of pacemaker rate by impedance-based respiratory minute ventilation.

Several studies have shown that the capability for exercise can be increased in patients with pacemakers by means of adjusting the rate. Respiration is one of the parameters considered for rate control. The aim of our study was to determine how respiratory parameters such as ventilation, tidal volume, and respiratory rate are capable of controlling the pacemaker rate, especially when measured indirectly by means of impedance plethysmography. We examined four volunteers and eight patients with implanted cardiac pacemakers using bicycle ergometry at increasing work loads. We recorded heart rate, uptake of oxygen, and ventilation directly (by pneumotachygraphy) and indirectly (by chest wall impedance plethysmography). A good correlation of directly to indirectly measured ventilation (r = 0.8687) was found. Our study suggests that respiratory minute volume is more appropriate for rate control of physiologic pacemakers than tidal volume or respiratory rate alone. Measurement by means of impedance plethysmography is sufficiently precise to be used for this purpose. Further studies must be conducted as to the optimum realization within an implantable device.

Inf lammatory Mass with Fibrinoid Necrosis of Vessels Caused by Methylene Blue Marking of a Colonic Polyp.

Methylene blue is a relatively non-toxic dye that is used in a variety of procedures including the marking of margins and skin flaps, identifying sinus and fistulous tracts, localizing islet cell tumors, and marking colonic polyps. It has been used intravascularly for the labeling of arteriovenous malformations or to find small bleeding sites. Few adverse effects have been reported with its use. We report an unusual case of an inflammatory mass secondary to transmural injection of methylene blue that resulted in fibrinoid necrosis of arterial media mimicking a necrotizing vasculitis.

Treatment of acute left heart failure using dobutamine and intraaortic counterpulsation. Animal experiments and first clinical experiences.

Ten anesthetized mongrel dogs had a left anterolateral thoracotomy; the left anterior descending coronary artery was then ligated. After 60 min five animals each were treated either with dobutamine (4 microgram/min/kg; for 10 min), or with dobutamine and intraaortic counterpulsation. Combined treatment of cardiogenic shock proved superior. Those five dogs had significantly lower heart rates and dp/dt/p-values. Due to IABP the non-ischemic parts of the left ventricle were better perfused; there was no difference in treatment with regard to ischemic parts. The combined treatment was successfully inaugurated in two patients with cardiogenic shock.