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.

Influence of systemic inflammation on efficiency of antiplatelet therapy in PAOD patients.

Recently it was shown that inflammation adversely influences results obtained from the platelet function analyzer system, PFA-100, hypothesizing that inflammation could confound interpretation of platelet function results. We investigated the clinical relevance of these results in patients with peripheral arterial occlusive disease (PAOD), with and without signs of systemic inflammation. In 98 PAOD patients, all treated with acetyl-salicylic acid (ASA), we obtained PFA-100 values upon stimulation with epinephrine. C-reactive protein (CRP) values were investigated as indicator for systemic inflammation. Mean CRP levels were elevated in 23 patients (23%). There was no difference of mean PFA-100 results between patients with elevated CRP levels and those without. Our results indicate that the effect of ASA on platelet aggregation, as measured by the PFA-100, is not relevantly influenced in PAOD patients with elevated CRP.

Internet sex-seeking leads to acute HIV infection: a report of two cases.

The use of the internet provides a rapid medium for identifying potential sexual partners and arranging in-person meetings that often result in sex. There is growing concern that the internet facilitates the transmission of sexually transmitted diseases and HIV. We report the first two cases of acute HIV infection after internet chat room encounters. Physicians should address the potential risks to sex seekers who use the internet. HIV prevention efforts that target internet sex seekers are needed.

Final state three-body Coulomb effects in the 208Pb(8B,7Bep)208Pb Coulomb breakup reaction.

We present results of the first calculation of the double differential cross section for the 208Pb(8B,(7)Bep)208Pb Coulomb breakup reaction which treats the postdecay acceleration of the ejectiles within a genuine three-body approach. From this we conclude that, in order to minimize postdecay Coulomb acceleration effects, experiments should be performed at as small as possible scattering angles, not too low 7Be-p relative energies, and high incident energy.

Monitoring of antiplatelet therapy with the PFA-100 in peripheral angioplasty patients.

BACKGROUND: In patients suffering from peripheral arterial occlusive disease (PAOD) the risk of restenosis after percutaneous transluminal angioplasty (PTA) might be influenced by platelet mediated factors. OBJECTIVE: To look for a correlation between the effect of antiplatelet therapy and recurrence of disease after PTA by monitoring platelet function in 3-month intervals by the platelet function analyzer system, PFA-100, over a period of 1 year. PATIENTS AND METHODS: A group of 98 patients (43 females, 55 males) with PAOD, treated with aspirin (n = 52), thienopyridine (n = 34) or combination therapy of both (n = 12) were followed over a period of 12 months after elective PTA of the lower extremities with regard to occurrence of restenosis or reocclusion at the site of angioplasty, to demonstrate inhibitory effects on platelets, induced by antiplatelet therapy. RESULTS: PFA-100 proved suitable to identify 'non-responders' to antiplatelet therapy, in a 12-month follow-up period. In 'non-responders' to clopidogrel therapy, a higher incidence of restenosis or reocclusion after PTA of the lower limbs was detected compared with 'responders'. CONCLUSION: PFA-100, upon stimulation with ADP, might predict patients under clopidogrel therapy with elevated risk for the development of complications following PTA of the lower limbs. This could offer the chance to switch to an alternative therapy or adapt the dose.

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.

Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol.

AIMS: The purpose of the study was to compare the efficacy and safety of sotalol and bisoprolol in the maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation. METHODS: Patients (n=128) were randomized to sotalol (80 mg b.i.d.) or bisoprolol (5 mg x day(-1)). Patients with contraindications to beta-blockers, class III antiarrhythmic drugs or prior treatment with use of study medication for prevention of atrial fibrillation were excluded. Follow-up clinical evaluation was performed 1 day and 1 month after cardioversion and thereafter at 3-month intervals. RESULTS: There were no group differences in baseline clinical characteristics. After a follow-up of 12 months, 59% of all patients were still in sinus rhythm. The fraction remaining in sinus rhythm was calculated for the two groups by Kaplan--Meier analysis. During follow-up, 41% of patients on sotalol and 42% on bisoprolol developed atrial fibrillation (ns). In two patients (3.1%) on sotalol, life-threatening proarrhythmias (torsade de pointes tachycardias) occurred, whereas none were found in the bisoprolol group. Symptomatic bradycardias occurred in two patients on sotalol and three on bisoprolol. CONCLUSION: This study demonstrates that sotalol (160 mg x day(-1)) and bisoprolol (5 mg x day(-1)) are equally effective in maintaining sinus rhythm. Because of the side effects of sotalol, bisoprolol seems to be advantageous for maintenance of sinus rhythm after cardioversion of atrial fibrillation.

High prevalence of anal squamous intraepithelial lesions and squamous-cell carcinoma in men who have sex with men as seen in a surgical practice.

INTRODUCTION: Anal high-grade squamous intraepithelial lesions are probable invasive anal squamous-cell cancer precursors, and although unproved, treatment of high-grade squamous intraepithelial lesions may prevent progression to anal squamous-cell cancer. Men who have sex with men are often treated for benign anorectal disorders without consideration given to the possibility of concurrent high-grade squamous intraepithelial lesions or anal squamous-cell cancer. We determined the prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer in an urban surgical practice of men who have sex with men referred for treatment of anal condyloma and other benign noncondylomatous anal disorders. METHODS: One hundred thirty-one HIV-positive and 69 HIV-negative men who have sex with men referred for surgical treatment of presumed benign anorectal disease were evaluated by anal cytology, high-resolution anoscopy, and biopsy. Anal cytology and histology were reported with a modified Bethesda classification. RESULTS: One hundred fifty-seven patients (79 percent) were referred for condyloma, 4 (2 percent) for anal squamous intraepithelial lesions (anal high-grade squamous intraepithelial lesions) diagnosed by primary care providers, and 39 (19 percent) for other benign anorectal disorders. One hundred forty-three patients (93 percent) had abnormal anal cytology, with 107 (54 percent) having high-grade squamous intraepithelial lesions on cytology. Biopsy results revealed 120 patients (60.0 percent) with high-grade squamous intraepithelial lesions and 5 patients (3 percent) with invasive squamous-cell carcinoma. Four of five men with anal squamous-cell cancer were HIV positive. Fourteen men (36 percent) who have sex with men referred for noncondylomatous benign anal disorders had high-grade squamous intraepithelial lesions, and three (8 percent) had anal squamous-cell cancer. High-grade squamous intraepithelial lesions and anal squamous-cell cancer were seen most often at the squamocolumnar junction. CONCLUSIONS: Men who have sex with men referred for treatment of either condyloma or noncondylomatous benign anorectal disease had a high prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer. All men who have sex with men referred for treatment of benign anorectal disease should have high-resolution anoscopy and aggressive biopsy of all abnormal areas. Treatment of external lesions alone could miss high-grade squamous intraepithelial lesions or anal squamous-cell cancer.

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.

Carotid artery stenting: effect of learning curve and intermediate-term morphological outcome.

PURPOSE: To assess the impact of learning on the rate of success and complications of carotid stenting in a single-center, one-operator series and prospectively follow a patient cohort with regard to restenosis. METHODS: In 303 patients (mean age 70 +/- 8.8 years), 320 internal carotid arteries (ICA) were treated with carotid stenting for stenoses > or = 70%. Four groups of 80 consecutive interventions were compared with regard to primary technical success and periprocedural complications. Stent patency in follow-up was assessed using duplex scanning. RESULTS: Stenting was successful in 298 (93%) arteries. The combined neurological complications (transient ischemic attacks and all strokes) and 30-day death rate was 8.2% (n = 25), but the all stroke and 30-day death rate was 3.0% (n = 9). A significant reduction in the frequency of neurological complications after the initial 80 interventions was observed (p = 0.03), but technical success was not appreciably improved with increasing experience thereafter. Over a median 12 months (interquartile range 6 to 24), cumulative patency rates were 91%, 90%, and 91% at 6, 12, and 36 months, respectively. CONCLUSIONS: Elective carotid stenting can be performed with excellent technical success, an acceptable frequency of periprocedural complications, and good intermediate-term patency. However, our findings suggest that a larger number of interventions should be performed to overcome the negative effects of the initial learning phase.

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.

Coronary stent symmetry and vascular injury determine experimental restenosis.

OBJECTIVE: To assess the impact of stent symmetry on restenosis using the coronary overstretch sheep model. METHODS: Neointimal thickness, injury index, and percentage diameter and area stenosis were calculated by digital morphometry. The standard deviation of the angular burden was used to assess stent symmetry for each section. MATERIALS: 15 healthy Merino sheep (63-75 kg) underwent implantation of 30 slotted tube stents (7 mm). Restenosis was induced by calculated overstretch of the coronary artery. Twenty eight days after implantation, stents were excised and underwent histological examination using quantitative digital morphometry. RESULTS: The severity of vessel injury was positively correlated with neointimal thickness and with percentage diameter and area stenosis (p < 0.001). Mean neointimal thickness and mean vascular injury per cross section were strongly related to the standard deviation of angular burden, with correlation coefficients of 0.6 and 0.8, respectively (p < 0.001). CONCLUSIONS: The well known relation between vascular injury and restenosis was confirmed, and a new relation was discovered between stent asymmetry and restenosis. If these results apply to human coronary arteries, restenosis may also be dependent on the degree of asymmetric stent expansion. These results should influence the development of new stent designs to reduce asymmetric stent expansion, leading to a more homogeneous strain distribution in stented coronary segments.

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.

[Development of a radioligand assay for quantifying specific prostaglandin E1 binding in ischemic ulcers]. / Entwicklung eines Radioligandenassays zur Quantifizierung der spezifischen Prostaglandin-E1-Bindung in ischämischen Ulzera.

Ulcers of the lower extremities are of immense socioeconomical importance. Prevention and therapy of these trophic lesion are hence of great interest. In granulation tissue of ischemic ulcers Laser Doppler flow was previously shown to be higher compared to that in ischemic/adjacent skin or in ulcer without granulation tissue. Intravenous infusion of prostaglandin E1 significantly increased Laser Doppler flow. The present study was designed to test the hypothesis whether the increased baseline and prostaglandin E1-stimulated perfusion of granulation tissue is due to an increased number of prostaglandin E1-receptors in granulation tissue. Therefore, a radioligand binding assay was developed. In an initial pilot study the density of the prostaglandin E1-receptors in granulation tissue of ulcers was compared to that in ischemic/adjacent skin in 8 patients suffering from peripheral arterial occlusive disease requiring debridement or amputation of limbs because of ischemic lesions. The amount of specific binding sites detected was not significantly different between granulation tissue and ischemic/adjacent ulcer tissue. However it cannot be excluded that a possible difference might be detectable with more sensitive assays. In the future we hope to establish a more sensitive assay in order to be able to answer the initial question, whether there is a difference concerning the density of prostaglandin E1 receptor sites in granulation tissue and ischemic/adjacent skin.

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.

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.

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.