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Objective: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA)., Methods: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1)., Results: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient., Conclusions: Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.

Purpose: To evaluate the diagnostic accuracy of contrast-enhanced FDG-PET/CT (ce-PET/CT), PET-only, and CT-only in patients with newly diagnosed and resected cutaneous malignant melanoma., Methods: A final group of 56 patients (mean age 62 years, range 23-86 years; 29 women, 27 men) were staged with ce-PET/CT after resection of the primary tumour. Histopathology as well as clinical follow-up (mean 780 days, range 102-1,390 days) served as the standards of reference. Differences between the staging modalities were tested for statistical significance with McNemar's test., Results: All imaging procedures provided low sensitivities in the detection of lymph nodes (sensitivity N-stage: PET/CT and PET-only 38.5%; CT-only 23.1%) and distant metastases (sensitivity M-stage: PET/CT 41.7%, PET-only 33.3%, CT-only 25.0%) in initial staging after resection of the primary tumour. No statistically significant differences were detected between the imaging procedures (p > 0.05). PET/CT resulted in an alteration in further treatment in two patients compared to PET-only and in four patients compared to CT-only., Conclusion: All imaging modalities had a low sensitivity on initial staging of patients with malignant melanoma. Thus, close patient follow-up must be considered mandatory.

Background: The noninvasive detection of RNA tumor markers in body fluids represents an attractive diagnostic option, but diagnostic performance of tissue-derived markers is often poorer when measured in body fluids rather than in tumors. We aimed to develop a procedure for measurement of tumor RNA in urine that would minimize donor-dependent influences on the results., Methods: RNA isolated from urinary cell pellet, cell-depleted fraction, and whole urine was quantified by reverse transcription quantitative-PCR. The donor-dependent influence of urine background on individual steps of the standardized procedure was analyzed using an external RNA standard. Using a test set of samples from 61 patients with bladder cancer and 37 healthy donors, we compared 4 putative RNA tumor markers identified in whole urine with 5 established, tissue-derived RNA tumor markers for the detection of bladder cancer., Results: Of the markers analyzed by this system, the RNA ratio of v-ets erythroblastosis virus E26 oncogene homolog 2 (avian; ETS2) to urokinase plasminogen activator (uPA) enabled the most specific (100%) and sensitive (75.4%) detection of bladder cancer from whole urine, with an area under the curve of 0.929 (95% CI 0.882-0.976)., Conclusions: The described methodology for RNA marker detection in urine appears to be clinically applicable. The ratio of ETS2 mRNA to uPA mRNA in urine is a potential marker for bladder cancer.

Purpose: PET/CT, PET+CT, and CT were compared concerning accuracies in TNM staging and malignancy detection in head and neck cancer. The impact of PET/CT compared to the other imaging modalities on therapy management was assessed., Materials and Methods: Fifty-five patients with suspected head and neck primary cancer underwent whole-body FDG-PET/CT. PET/CT and PET+CT were evaluated by a nuclear medicine physician and a radiologist; CT was evaluated by two radiologists, PET by two nuclear physicians. Histopathology served as the standard of reference. Differences between the staging modalities were tested for statistical significance by McNemar's test., Results: Overall TNM-staging and T-staging with PET/CT were more accurate than PET+CT and CT alone (p < 0.05). PET/CT was marginally more accurate than CT alone in N-staging (p = 0.04); no statistically significant difference was found when compared to PET+CT for N-staging. PET/CT altered further treatment in 13 patients compared to CT only and in 7 patients compared to PET+CT., Conclusion: Combined PET/CT proved to be partly more accurate in assessing the overall TNM-stage than CT and PET+CT. These results were based on a higher accuracy concerning the T-stage, mainly in patients with metallic implants and marginally the N-stage. Therapy decisions have been influenced in a substantial number of patients. PET/CT might be considered as a first line diagnostic tool in patients with suspected primary head and neck cancer.

Objective: To report on anatomical and visual outcomes after vitrectomy and internal limiting membrane peeling for idiopathic macular hole repair., Methods: Forty patients with stage II to IV idiopathic macular holes were randomly assigned (1:1) in a 2-arm, single-center, randomized controlled . Internal limiting membrane delamination was performed using indocyanine green (ICG) solution (n = 20) or trypan blue (TB) (n = 20). Two patients did not complete the study, for a total of 19 in each group. Follow-up examinations included Early Treatment of Diabetic Retinopathy Study visual acuity, scanning laser ophthalmoscope microperimetry, optical coherence tomography, and fluorescein angiography. Main Outcome Measure Visual acuity 3 months after surgery., Results: Visual acuity did not show a significant difference between study groups (95% confidence interval [CI], -2 to 1 lines). The rate of macular hole closures was identical (84%; 95% CI, 60% to 97%). Within-group visual recovery was significant only in the TB group. Central scotomata despite hole closure persisted in 8 patients (42%) in the ICG group and in 5 (26%) in the TB group., Conclusion: Although no statistically significant difference was detected for the primary end point, the better visual recovery in the TB group and the higher rate of persistent central scotomata in the ICG group justify a larger clinical trial. Application to Clinical Practice No statistically significant difference in visual acuity between ICG and TB in the used concentrations and application method could be proved in macular hole surgery.

Background: The Ross procedure has gained increasing interest as an attractive alternative to a prosthetic aortic valve substitute within the last decade. Because of a probably better resistance to infection as one of its advantages, the pulmonary autograft is theoretically preferable for active endocarditis., Methods: Between June 1994 and July 2003, the Ross procedure was performed using the subcoronary and inclusion technique in 296 patients (231 male, 65 female). Twenty patients had an active endocarditis of the aortic valve at the time of operation. A bicuspid valve was present in 10 patients. One patient had previous aortic valve surgery. Clinical and echocardiographic follow-up was complete., Results: Early mortality was 1, late mortality was 0. There were no recurrence of endocarditis and no neurologic events during the mean follow-up of 47.3 +/- 28.6 months. All patients were in New York Heart Association class I. Mean and maximum pressure gradient across the autograft was 3.5 +/- 2.0 and 6.5 +/- 3.4, respectively, with no autograft insufficiency in 15, 1+ in 4. Comparing postoperative with the last investigations, there were no significant changes of pressure gradients or grade of regurgitation. Mean and maximum homograft pressure gradients were 7.9 +/- 3.7 and 16.2 +/- 8.1 mm Hg, respectively, at last investigation; most patients had no or mild homograft regurgitation (0+, n = 13; 1+, n = 5; 2+, n = 1)., Conclusions: Native valve endocarditis can be treated with excellent results using the Ross procedure with the subcoronary and inclusion technique, with low mortality and morbidity rates and a very low recurrence rate of endocarditis.

Objective: The Ross procedure has gained increasing interest as an attractive alternative for aortic valve replacement. Despite its advantages, there is a certain risk of structural valve deterioration, especially of the pulmonary homograft as a result of shrinkage and subsequent stenosis predominantly at the muscular annulus. Theoretically, reduction of homograft muscle tissue could reduce this risk., Methods: From February 1996 through December 2002, a total of 238 patients (mean age 44 +/- 13.2 years) underwent the Ross procedure with the subcoronary technique with follow-up investigations before discharge and after 12 and 24 months. To estimate the importance of homograft muscle reduction within our institution-specific risk factor scale for change of transhomograft pressure gradient with time, we performed a generalized estimating equation approach, which identified homograft muscle reduction, higher body surface area in male patients, younger patient age, smaller homograft diameter, blood transfusions, and follow-up time as independent risk factors demonstrating a high beta value (-2.8638) for muscle reduction. To find out whether muscle reduction influences transhomograft pressure gradient, we compared patients with (group A, n = 39) and without (group B, n = 199) muscle reduction. The other mentioned independent risk factors were not different between groups, except for blood transfusions (group A greater than B, P < .01), indicating a negative bias for group A., Results: The maximum pressure gradient across the homograft was lower in patients with muscle reduction before discharge (4.5 +/- 2.8 mm Hg group A vs 6.2 +/- 3.8 mm Hg group B, P = .004) and after 1 (9.3 +/- 5.8 vs 13.1 +/- 8.4 mm Hg, P = .028) and 2 years (10.8 +/- 7.6 vs 13.7 +/- 7.5 mm Hg, P = .013). No significant differences were found concerning homograft insufficiency., Conclusions: We provide some evidence that transhomograft pressure gradient can be reduced significantly within the first 2 years after operation by homograft muscle reduction. Longer term follow-up is necessary to evaluate this promising operative technique further.

Context: Staging of patients with colorectal cancer often requires a multimodality, multistep imaging approach. Colonography composed of a combined modality of positron emission tomography (PET) and computed tomography (CT) provides whole-body tumor staging in a single session., Objectives: To determine the staging accuracy of whole-body PET/CT colonography compared with the staging accuracies of CT followed by PET (CT + PET) and CT alone and to evaluate the effect of PET/CT colonography on therapy planning compared with conventional staging (CT of the abdomen and thorax and optical colonoscopy)., Design, Setting, and Patients: Prospective study of 47 patients enrolled between May 2004 and June 2006 with clinical findings and optical colonoscopy that suggested primary colorectal cancer (mean [SD] age, 71 [11] years; range, 47-92 years). Patients underwent whole-body PET/CT colonography 1 day after colonoscopy. The study was conducted at a university hospital with a mean (SD) follow-up of 447 (140) days (range, 232-653 days)., Main Outcome Measures: Correct classification of overall TNM stage using PET/CT colonography compared with CT + PET and CT alone. Secondary outcome measures were the accurate assessment of T-stage, N-stage, and M-stage by PET/CT colonography compared with CT + PET and CT alone and the effect of PET/CT colonography on therapy planning., Results: Of the 47 patients with a total of 50 lesions, the overall TNM stage was correctly determined for 37 lesions with PET/CT colonography (74%; 95% confidence interval [CI], 60%-85%), 32 lesions with CT + PET (64%; 95% CI, 49%-77%), and 26 lesions with CT alone with a 0.7-cm node threshold (52%; 95% CI, 37%-66%). Compared with optimized abdominal CT staging alone, PET/CT colonography was significantly more accurate in defining TNM stage (difference, 22%; 95% CI, 9%-36%; P=.003), which was mainly based on a more accurate definition of the T-stage. Differences were not detected for defining N-stage between PET/CT colonography and CT alone with a threshold of 0.7 cm for malignant nodes but were detected with a threshold of 1 cm. Differences were not detected in defining M-stage separately or when comparing the accuracies of PET/CT colonography with CT + PET. PET/CT colonography affected consecutive therapy decisions in 4 patients (9%; 95% CI, 2.4%-20.4%) compared with conventional staging (CT alone and colonoscopy)., Conclusions: In this preliminary study, PET/CT colonography is at least equivalent to CT + PET for tumor staging in patients with colorectal cancer. Thus, PET/CT colonography in conjunction with optical colonoscopy may be a suitable concept of tumor staging for patients with colorectal cancer.

Purpose: To assess intraobserver and interobserver variability of anterior segment optical coherence tomography (AS-OCT) as an objective diagnostic tool to quantify the anterior chamber angle and opening width., Setting: University Eye Clinic, Lübeck, Germany., Methods: The anterior chamber angle and opening width were assessed in 18 eyes of 9 healthy volunteers by 2 observers. Intraobserver reproducibility was evaluated by calculating an intraclass correlation coefficient (ICC) in a mixed model. Each observer had a separate model using information from 5 scans. Interobserver variability was determined by Bland-Altman analysis. The ICC was calculated in a mixed model using a residual maximum likelihood method. The results of 3 and 5 repeated scans were evaluated to indicate the change to 1 measurement application., Results: The mean anterior chamber angle measurement was 35.9 degrees +/- 5.7 (SD) for observer A and 36.2 +/- 5.7 degrees for observer B. The ICC was 0.94 and 0.91, respectively. The mean opening width was 315 +/- 62 microm for observer A and 317 +/- 60 microm for observer B. The ICC was 0.97 and 0.93, respectively. Interobserver comparisons showed a mean difference between anterior chamber angle measurements of -0.27 +/- 1.6 degrees, a limit of agreement (LOA) interval from -3.52 to 2.98 degrees, and an ICC estimate of 0.96. The mean difference in opening width measurements was 2.40 +/- 12.40 microm, the LOA from -27.20 to 22.40 microm, and the estimated ICC 0.96. Using 1 instead of the mean of 5 measurements, the LOA range increased by 3.46 degrees for the anterior chamber angle and 30.0 microm for the opening width., Conclusion: Anterior chamber angle and opening width measurements by OCT showed low intraobserver and interobserver variability, indicating OCT is a valuable technique for quantitative assessment that provides reproducible measurements and objective documentation by different examiners.

Objectives: The application of independence estimating equations (IEE) for controlled clinical trials (CCTs) has recently been discussed, and recommendations for its use have been derived for testing hypotheses. The robust estimator of variance has been shown to be liberal for small sample sizes. Therefore a series of modifications has been proposed. In this paper we systematically compare confidence intervals (CIs) proposed in the literature for situations that are common in CCTs., Methods: Using Monte-Carlo simulation studies, we compared the coverage probabilities of CIs and non-convergence probabilities for the parameters of the mean structure for small samples using modifications of the variance estimator proposed by Mancl and de Rouen [7], Morel et al. [8] and Pan [3]., Results: None of the proposed modifications behave well in each investigated situation. For parallel group designs with repeated measurements and binary response the method proposed by Pan maintains the nominal level. We observed non-convergence of the IEE algorithm in up to 10% of the replicates depending on response probabilities in the treatment groups. For comparing slopes with continuous responses, the approach of Morel et al. can be recommended., Conclusions: Results of non-convergence probabilities show that IEE should not be used in parallel group designs with binary endpoints and response probabilities close to 0 or 1. Modifications of the robust variance estimator should be used for sample sizes up to 100 clusters for CI estimation.

Repair of diseased bicuspid aortic valves has gained increasing interest as an alternative to conventional valve replacement. Hemodynamic data at exercise have not been reported before. The aim of this study was to investigate the clinical and echocardiographic status of patients after bicuspid aortic valve repair at rest and exercise. Between 03/94 and 09/02 a reconstruction of an incompetent bicuspid aortic valve was performed in 25 patients (mean age 35+/-12.1 years, group A, mean insufficiency 2.8 preoperatively). Patients were investigated clinically and echocardiographically after 2.1+/-2.4 (0.1-8.9) years at rest and exercise and compared to 20 controls (group B). Clinical followup was complete. There were no deaths, reoperations, thromboembolic or bleeding complications. At last examination 21 patients were in NYHA class I, n=4 in NYHA class II and mean aortic valve insufficiency (AI) was 1.0 with one patient having an AI>II degrees. Maximum and mean pressure gradient (dPmax/mean) across the aortic valve at rest were 14+/-5.5/7+/-2.6 mmHg for patients of group A and 7+/-2.5/3.6+/-1.1 mmHg in group B. Mean AVA at rest was 2.6+/-0.8 (group A) vs 2.9+/-0.6 cm(2) (group B, p=0.025), valvular resistance 13.4+/-4.8 (group A) vs 13.6+/-2.9 dyn x s x cm(-5) (group B, p>0.05). All individuals were stressed up to 100 W (dPmax/mean 21+/-6.8/11+/-3.6, group A vs 11+/-2.9/6+/-1.3 mmHg, group B). 56% of group A and 85% of group B could be stressed up to 175 W with dPmax/mean 24.5+/-8.3/12+/-4.2 and 16+/-3.6/8+/-1.4 mmHg, respectively (p<0. 01). Heart rate and blood pressure behavior were comparable. Left ventricular mass regression (preoperatively 369.3+/-76.4 vs 277.3+/-80.7 g at last examination, p<0.01) was significant in group A but did not reach normal values (group B, 227.8+/-71.1; p<0.01). Bicuspid aortic valve reconstruction reduces left ventricular volume load significantly. Although residual mild subclinical obstruction and incompetence were observed, the behavior of hemodynamics at exercise was comparable to controls. The clinical relevance of these findings in long term follow-up has to be evaluated.

Purpose: To assess the accuracy of positron emission tomography/computed tomography (PET/CT) when staging different malignant diseases., Patients and Methods: This was a retrospective, blinded, investigator-initiated study of 260 patients with various oncological diseases who underwent fluorine-18-2-fluoro-2-deoxy-d-glucose PET/CT for tumor staging. CT images alone, PET images alone, PET + CT data viewed side by side, and fused PET/CT images were evaluated separately according to the tumor-node-metastasis system. One hundred forty patients with tumors not staged according to the tumor-node-metastasis system or a lack of reference standard were excluded from data analysis; 260 patients were included. Diagnostic accuracies were determined for each of the four image sets. Histopathology and a clinical follow-up of 311 (+/- 125) days served as standards of reference., Results: PET/CT proved significantly more accurate in assessing tumor-node-metastasis system stage compared with CT alone, PET alone, and side-by-side PET + CT (P < .0001). Of 260 patients, 218 (84%; 95% CI, 79% to 88%) were correctly staged with PET/CT, 197 (76%; 95% CI, 70% to 81%) with side-by-side PET + CT, 163 (63%; 95% CI, 57% to 69%) with CT alone, and 166 (64%; 95% CI, 58% to 70%) with PET alone. Combined PET/CT had an impact on the treatment plan in 16, 39, and 43 patients when compared with PET + CT, CT alone, and PET alone, respectively., Conclusion: Tumor staging with PET/CT is significantly more accurate than CT alone, PET alone, and side-by-side PET + CT. This diagnostic advantage translates into treatment plan changes in a substantial number of patients.

Purpose: To evaluate the effect of photodynamic therapy with verteporfin on the maintenance of central visual field function., Design: Randomized controlled clinical trial., Participants: Forty-six consecutive patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration including a classic component were randomly assigned. Thirty-three participants received standard verteporfin therapy, and 13 received placebo and laser treatment., Methods: The trial was performed as a single-center, double-masked study. Patients were examined before therapy and continuously in 3-month intervals during 2 years of follow-up. A scanning laser ophthalmoscope (SLO) was used to perform macular microperimetry. Absolute and relative scotomas were documented at each visit, and size was measured in square millimeters., Main Outcome Measures: The change in size of central scotoma in the verteporfin group compared with the placebo group., Results: An absolute scotoma was seen in 88%, and a relative scotoma was seen in 100% of eyes before therapy. Absolute defects were associated with the classic CNV component localized angiographically. In the verteporfin group, the absolute scotoma grew from 2.5 mm(2) at baseline to a final size of 7.3 mm(2) at month 24. In the placebo group, the mean lesion size of the absolute scotoma enlarged from an initial size of 2.7 mm(2) to 31.5 mm(2) after 24 months. The relative scotoma increased from 7.9 mm(2) at baseline to 20.8 mm(2) at month 24 in the verteporfin group, whereas a progression from 8.5 mm(2) initially to 48.3 mm(2) at the final presentation was measured in the placebo group. Statistical analysis showed that both the mean absolute and relative scotoma sizes were significantly smaller in the verteporfin group than the placebo group for all intervals from 6 to 24 months (P<0.001)., Conclusions: Documentation of macular function with SLO perimetry demonstrated a significant benefit of verteporfin therapy for the preservation of the central visual field. Absolute and relative scotoma sizes remained smaller after therapy. This may influence reading ability and visual rehabilitation.

Objectives: Clinical trials with correlated response data based on generalized estimating equations (GEE) have become increasingly popular as they require smaller samples than classical methods that ignore the clustered nature of the data. We have recently derived the recommendation to use the independence estimating equations (IEE) as primary analysis in most controlled clinical trials instead of GEE with estimated correlations. Although several approaches for sample size and power calculation have been proposed, we have shown that most of these procedures are very specific and not as general as required for designing clinical trials., Methods: We extended the previously developed SAS macro GEESIZE to overcome this restriction. Specifically, we have added the option of an independence working correlation matrix required for the IEE. Additionally, we have reformulated the hypotheses to allow for coding that includes an intercept term instead of the previously used analysis of variance coding., Results: To demonstrate the validity of GEESIZE we investigate the calculated sample sizes for specific models where closed formulae are available. For illustration, we utilize GEESIZE for planning a new trial on the treatment of hypertension and thereby exemplify its flexibility., Conclusions: We show that our freely available macro is a very general and useful tool for sample size calculation purposes in clinical trials with correlated data.

Context: Deciding on the appropriate therapy for patients with malignant diseases mandates accurate tumor staging with whole-body coverage. Magnetic resonance imaging (MRI) and a combined modality including positron emission tomography (PET) and computed tomography (CT) provide whole-body tumor staging in a single session., Objective: To determine the staging accuracies of both whole-body PET/CT and whole-body MRI for different malignant diseases., Design, Setting, and Patients: Prospective, blinded, investigator-initiated study of 98 patients (mean age, 58 years; range, 27-94 years) with various oncological diseases who underwent back-to-back whole-body glucose analog [18F]-fluorodeoxyglucose-PET/CT and whole-body MRI for tumor staging. The study was conducted at a university hospital from December 2001 through October 2002 and had a mean follow-up of 273 days (range, 75-515 days). The images were evaluated by 2 different, blinded reader teams. The diagnostic accuracies of the 2 imaging procedures were compared., Main Outcome Measures: Correct classification of the primary tumor, regional lymph nodes, and distant metastasis (overall TNM stage) using whole-body PET/CT and whole-body MRI. Secondary outcome measures were accurate assessment of T-stage, N-stage, and M-stage by the 2 imaging procedures., Results: Of 98 patients, the overall TNM stage was correctly determined in 75 with PET/CT (77%; 95% confidence interval [CI], 67%-85%) and in 53 with MRI (54%; 95% CI, 44%-64%) (P<.001). Compared with MRI, PET/CT had a direct impact on patient management in 12 patients. Results from MRI changed the therapy regimen in 2 patients compared with PET/CT. Separate assessment of T-stage (with pathological verification) in 46 patients revealed PET/CT to be accurate in 37 (80%; 95% CI, 66%-91%) and MRI to be accurate in 24 (52%; 95% CI, 37%-67%) (P<.001). Of 98 patients, N-stage was correctly determined in 91 patients with PET/CT (93%; 95% CI, 86%-97%) and in 77 patients with MRI (79%; 95% CI, 69%-86%) (P =.001). Both imaging procedures showed a similar performance in detecting distant metastases., Conclusions: The feasibility and diagnostic accuracy of the whole-body staging strategies of PET/CT and MRI are established. Superior performance in overall TNM staging suggests the use of [18F]-fluorodeoxyglucose-PET/CT as a possible first-line modality for whole-body tumor staging.

Background: Since the early 1990s, the pulmonary autograft is predominantly implanted as a freestanding root for less aortic valve regurgitation is reported. However, there is a certain risk of dilatation of the root over time potentially impairing valve function. We favor since 8 years the original subcoronary or inclusion technique to preserve the root of the patient as a restrain to dilatation., Methods and Results: Between June 1994 and May 2002 the subcoronary (n=228) and inclusion technique (n=17) were performed in 245 patients (191 male, 54 female), mean age 45.7+/-13.4 (15-70) years. The underlying aortic valve disease was an aortic insufficiency in n=83, stenosis in n=48, a combined aortic valve disease in n=111 and an acute endocarditis in n=19 patients. Previous aortic valve surgery was performed in n=23. Last follow-up investigations (within last year) including echocardiography was performed at a mean follow-up of 29.4+/-24.7 months (553.7 patient years). Hospital mortality was n=2, late mortality n=4 (all noncardiac). Two patients were lost to follow-up (99% complete clinical follow-up). Reoperations were necessary in n=7 valves (autograft: endocarditis n=1, malpositioning n=1, leaflet prolapse n=1; homograft: stenosis n=2, insufficiency n=2). Autograft insufficiency (AI) was AI 0 in n=154, AI I n=66, AI II n=8. The maximum/mean pressure gradient across the autograft was 6.6+/-3.4 (2.1 to 25.9)/3.6+/-1.8 (1.2 to 13.2) mm Hg, respectively. Homograft insufficiency was 0 in n=167, I in n=54, II in n=9, and III in n=1. Maximum and mean transhomograft pressure gradients were 11.7+/-6.8 (2.2 to 42.6)/6.2+/-3.8 (1.2 to 24.5) mm Hg. Most patients were NYHA class I (n=214), class II (n=19), class III (n=2). Significant aortic root dilatation was not observed., Conclusions: Aortic valve replacement with a pulmonary autograft in the subcoronary or inclusion technique provides excellent hemodynamics with no root dilatation at least in a mid term postoperative period. Transhomograft pressure gradients are slightly increased. Longer term results with special emphasis on the pulmonary homograft are necessary.

This report summarizes the contributions of Genetic Analysis Workshop 13 (GAW13) related to the use of covariates in genetic analysis. Seven papers are summarized, five of which analyzed the Framingham Heart Study Data, and two the simulated data. Five papers examined the role of covariates in linkage analysis, using a variety of statistical approaches including affected sibling pair analysis, conditional logistic regression, and variance components methods. One paper examined the impact of covariates on family-based association analysis. In each of these papers, the detection of genetic effects could be influenced by the incorporation of covariates. The final paper examined the role of transmission ratio distortion in the analysis of complex traits and the role of covariates in the variability in transmission ratio distortion. While each paper takes a different approach to the genetic analysis of complex traits, a common thread running through each is that the inclusion of covariates can have a substantial impact on the results of the analysis. Care must be taken to understand how the covariates are being used in each analysis, what assumptions are being made, and how these assumptions might affect the results and their interpretation. Finally, the results of Group 5 studies show that inclusion of covariates can increase the power to detect genes for complex traits, and has the potential to advance an understanding of the role of genes in these complex traits., (Copyright 2003 Wiley-Liss, Inc.)

Exposure to low-energy ultrasound shock waves (1000 impulses at a frequency of 2/sec and an energy density of 0.08 mj/mm2; peak positive/negative pressure 16/-7 MPa; pulse duration about 10 musec) led to the following alterations in the cells and tissues of stage 35 embryos of Oryzias latipes ranked according to their extent: (1) In various tissues, especially in the trunk musculature, orthodox mitochondria were transformed into condensed (= low energy) mitochondria. (2) Nuclear envelopes and sarcoplasmatic reticulum of muscle fibres as well as endoplasmatic reticulum of epidermal ionocytes were often vesicularly dilated. (3) Muscle fibres in the trunk musculature began to separate from each other. Epidermal intercellular spaces were enlarged and increased in number. (4) Destruction of vessels and haematomas were observed in the circulatory system of the yolk sac. (5) Necroses up to total disintegration were found in various organs of the body cavity (intestine, liver, spleen). The less serious alterations (1 and 2) occurred in organs completely surrounded by other tissues. Major damages (4 and 5), however, affected only organs with free outer and inner surfaces, probably explained by cavitation and jet stream phenomena within the adjacent fluids.

Background: Hereditary breast cancer has been associated with mutations in the BRCA1 and BRCA2 genes and has a natural history different from sporadic breast cancer. We investigated disease-free and overall survival for patients with a proven BRCA1 alteration., Methods: We estimated disease-free and overall survival for 49 Dutch patients from 19 consecutive families with a proven specific BRCA1 mutation and one family with strong evidence for linkage to the BRCA1 gene. We compared clinical outcome and data on tumour size, histology, axillary nodal status, contralateral breast cancer, and oestrogen-receptor and progesterone-receptor status with those of 196 patients with sporadic breast cancer, matched for age and year of diagnosis., Findings: Disease-free survival for BRCA1 and sporadic patients at 5 years was 49% (95% CI 33-64) and 51% (43-59), respectively (p=0.98). Overall survival at 5 years was 63% (47-76) and 69% (62-76), respectively (p=0.88). Recurrence and death rates did not differ significantly between groups. Hazard ratios for recurrence and death among BRCA1 patients were 1.00 (0.65-1.55) and 1.04 (0.63-1.71) relative to sporadic patients (p=0.88), and these did not differ significantly after adjustment for prognostic factors. Patients with BRCA1-associated breast cancer had twice as many progesterone-receptor-negative tumours (p<0.005) and development of contralateral breast cancer was four to five times as frequent as in the sporadic group (p<0.001)., Interpretation: We showed that disease-free and overall survival were similar for sporadic and hereditary breast cancer in the presence of different tumour characteristics, which has implications for screening prophylactic therapy, and different treatments of hereditary breast cancer.

As perioperative prophylaxis for major orthopedic operations 81 patients were given the fixed combination of ampicillin (1 g)/sulbactam (0.5 g) or cefotiam (2 g) as short infusions. The three beta-lactams were rapidly distributed into the different tissues and their pharmacokinetic profiles were found to be very similar. It was noteworthy that ampicillin, sulbactam and cefotiam penetrated within minutes, not only into skin, fat and muscles, but also into bone. Thus 0.25 h after starting the infusion the following mean concentrations were measured in bone: 21.8 +/- 10.5 mg/kg ampicillin, 4.9 +/- 2.2 mg/kg sulbactam and 19.4 +/- 10.6 mg/kg cefotiam. For a period of at least 2 h the concentrations measured in serum and in the different tissues affected by the operation (skin, fat, muscle, bone) were above the MICs for pathogens which are involved in postoperative wound infections. On the basis of pharmacokinetic data, ampicillin/sulbactam and cefotiam seem about equally suitable for perioperative prophylaxis in major orthopedic operations.

The contribution of muscarinic receptor subtypes to biliary control mechanisms is unclear. We investigated stimulated gallbladder function and release of associated hormones during M1-receptor blockade. Following a double-blind, randomized, crossover protocol, healthy volunteers each received placebo and telenzepine, a selective M1-receptor antagonist, as 2-h background infusion. Gallbladder contraction (by ultrasonography), bilirubin output, and release of cholecystokinin (CCK) and pancreatic polypeptide (PP) were assessed during increasing doses of endogenous (intraduodenal nutrient) and exogenous (hormonal) stimulation. All parameters were stimulated in a dose-dependent manner on placebo days. Contractile and secretory responses to low-dose caerulein (CCK analogue) were inhibited by 60-80% under telezepine, whereas high-dose (supraphysiological) stimulation overrode this effect. Similar inhibition was achieved during nutrient stimulation. CCK plasma levels rose during endogenous and exogenous stimulation but were unaffected by M1 blockade, whereas stimulated PP release was completely inhibited (> 100% decrease), reflecting suppressed vagal tone. Selective M1-receptor blockade inhibits the physiological response of the gallbladder in humans; this effect cannot be attributed to suppressed CCK release. Our findings support the hypothesis that CCK acts at the gallbladder via cholinergic nerves under physiological conditions. Viewed with our previous observations, nonselective antagonism of biliary function by atropine is primarily mediated through M1 muscarinic pathways.

We determined the influence of M1-muscarinic pathways in modulating temporal cycling of motor and secretory activity in the fasting upper gut. Eight healthy subjects were studied on two separate days, following a double-blind, randomized protocol. Antroduodenal motility (migrating motor complex, MMC), pancreatic exocrine secretion (amylase, lipase, trypsin, chymotrypsin), and plasma levels of associated hormones [motilin, pancreatic polypeptide (PP)] were monitored for two consecutive cycles during background infusion of placebo or telenzepine, a selective M1-muscarinic receptor antagonist. On placebo days, pancreatic enzymes and hormones cycled in synchrony with motor activity, as expected. During M1 blockade, duodenal output of each enzyme was decreased by 85-90% in phase I and by > 90% in phase III. Similarly, plasma concentrations of hormones were decreased during all phases and cycling was absent. Despite the loss of these putative influences, intestinal motility continued to cycle, albeit in an altered fashion. Intermittent phase II activity was replaced by phase I quiescence, while phase III-like fronts were diminished (contraction frequency, amplitude, propagation velocity reduced 30-60%, duration not altered) but recurred at expected intervals (cycle length 105 +/- 14 min vs 109 +/- 12 in placebo). Gastric motor activity was virtually abolished. These data suggest or extend several working hypotheses: (1) Motilin is released and/or acts via cholinergic (M1-muscarinic) pathways to initiate antral, but not duodenal, phase III activity. (2) M1 receptors mediate all components of the gastric MMC and phase II activity throughout the gut, but intestinal phase III activity arises via alternate pathways. (3) M1-muscarinic mechanisms regulate interdigestive cycling of pancreatic enzymes and PP. (4) Secretions from the endocrine/exocrine pancreas are not primary mediators of intestinal motility.

In a clinical and radiological follow up 64 Lord-endoprostheses could be controlled after a meantime of 8.5 years. The positive judgement of the patients, which is caused by the reduction of pain, is in contrast to the poor improvement of gait and mobility. Radiological findings are suspicious for a higher rate of loosening of the cup and fractures of the shaft.

The present study was designed (a) to investigate the cephalic phase of gastropancreatic secretion, antroduodenal motility, and regulatory peptide release in six healthy young men and (b) to assess its regulation by the cholinergic system and endogenous cholecystokinin. Sham feeding performed for 15 minutes induced a concurrent stimulation of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release that lasted for 30 minutes. Reappearance of interdigestive phases III was retarded in the post-sham-fed state. Atropine abolished secretory, motor, and pancreatic polypeptide responses to sham feeding and enhanced gastrin release. The cholecystokinin receptor antagonist loxiglumide did not attenuate pancreatic enzyme response but diminished antral motor response by 72% (P less than 0.05) and release of pancreatic polypeptide by 91% (P less than 0.05); it enhanced gastrin release and abolished retardation of reappearance of phase III with sham feeding. It is concluded that (a) there is a distinct cephalic phase of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release in humans that is primarily under cholinergic control and that (b) endogenous cholecystokinin is involved in antral motor, gastrin, and pancreatic polypeptide responses to sham feeding.

Not only for giving the diagnosis "Perthes' disease" but also with regard to prognostic statements the knowledge of the radiological stages of Perthes' disease is essential. The present treatise demonstrates the radiological course of Perthes' disease, how it results from the evaluation of the courses of illness of 116 patients, which were treated in the period from 1965 to 1980 at the Orthopedic University Hospital Hamburg-Eppendorf because of a genuine Perthes' disease. The following schema turned out to be appropriate to the assessment: I. Initial stage, I a Early period, I b Late period. II. Florid stage, II a Sclerosing period, II b Fragmental period, II c Osteolytic period. III. Stage of regeneration. IV. Final stage.

School sports is not only a compensation for inactivity but also training and basic experience in many kinds of sports. The stress exercised by school sports is similar to that of hobby sports. The dimension of errors in respect of excessive stress in orthopaedic diseases and the biological development--acceleration/retardation--is important for prohibiting school sports in some diseases. The indication for prohibiting school sports either completely or incompletely in the most important orthopaedic diseases in childhood, is discussed. The special importance of part prohibition or participation without any giving marks, is emphasised.