Re: Exact tests of equivalence and efficacy with a non-zero lower bound for comparative studies by I. S. F. Chan, Statistics in Medicine, 17, 1403-1413 (1998)
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Humans↗
Biomedical subjects
U Mansmann
Publications and source records attributed to U Mansmann.
Kaposi's sarcoma is an important risk factor for survival in HIV-infected patients independent of CD4+ cell count.
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Adult↗
Defective post-transcriptional processing of MUC2 mucin in ulcerative colitis and in Crohn's disease increases detectability of the MUC2 protein core.
Ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD) are associated with a reduction of the protective mucus layer in the large intestine; the role of this alteration in the pathogenesis of either disease is, however, not clear. To learn more about the molecular mechanism of the alteration of the mucus layer, the expression of the main intestinal mucin, MUC2, was investigated in relation to inflammation and dysplasia. Formalin-fixed, paraffin-embedded biopsies from 70 patients with UC and 16 patients with CD, and 13 biopsies from normal colonic mucosa, were used for detection of MUC2 mRNA by in situ hybridization with the SMUC41 probe, and MUC2 protein by immunohistochemistry with the antibody CCP58. The steady-state concentration of MUC2 mRNA was not affected by UC or CD. By contrast, the amount of the detectable MUC2 protein, assessed as the immunoreactive score (IRS), was significantly (p<0. 0001) increased in UC (IRS=8.0+/-3.8) and CD (8.0+/-3.7), compared with the normal colonic mucosa (IRS=2.0+/-1.5). This alteration occurred in the inactive phase of inflammation and persisted in the active phase of the disease. It was also observed during bacterial or protozoal inflammation (n=7). The IRS values did not correlate with the grade of inflammation or dysplasia. Simultaneous histochemistry with high iron diamine and immunohistochemistry indicated that the increase of detectable MUC2 is concomitant with low mucin sulphation in the same cells. These data indicate that the strong MUC2 protein staining in colonic mucosa of patients with UC or CD is due to a long-term alteration of the post-transcriptional modification of the MUC2 molecule, leading to its better detectability by the anti-MUC2 antibody CCP58. This alteration, induced by the inflammatory process, may affect the gel thickness and may contribute to a protracted autoimmune response.
Acute Disease↗
Desensitization of melanoma cells to autocrine TGF-beta isoforms.
Previous studies have suggested that transforming growth factor-beta 1 (TGF-beta1) acts as an autocrine growth inhibitor on normal human melanocytes, while melanoma cells may not respond to this stimulus. The role of other TGF-beta isoforms such as TGF-beta2 and TGF-beta3 remained less well characterized. In the present study, the mRNA and protein levels of all three isoforms of TGF-beta were analyzed in a panel of human melanoma cell lines and in cultures of normal human melanocytes in vitro. Northern analysis showed that the degree of TGF-beta1, -beta2, -beta3 mRNA expression varied considerably in melanoma cells, whereas TGF-beta expression was very low in melanocytes. In melanoma cells, secreted amounts of TGF-beta1 and TGF-beta3 were found increased in comparison to normal melanocytes: 615 pg/ml vs. 118 pg/ml and 193 pg/ml vs. 30 pg/ml (mean values). In addition, low levels of TGF-beta2 were detected (mean value: 28 pg/ml). Although TGF-beta secretion increased, the proliferation of melanoma cells was found to be only moderately inhibited by TGF-beta isoforms, in contrast to its strong antiproliferative effect on normal human melanocytes: - 15%, -11%, and -18% vs. -52%, -46%, and -50% average inhibition at 0.5 ng/ml TGF-beta1, -beta2, and -beta3, respectively. The different efficacy of TGF-beta on melanocyte and melanoma cells was highly significant (P<0.0001); in addition, TGF-beta-dependent growth inhibition of melanoma cells from primary tumors vs. cells from metastases showed a trend for further decreased response for the metastatic populations (P< or = 0.075). Measurements of DNA synthesis revealed even more pronounced differences between melanocytes (-86%, -78%, and -80% inhibition, respectively, for TGF-beta1, -beta2, and -beta3) and melanoma cells (no inhibition). Our data show loss of responsiveness of melanoma cells to the growth-inhibitory function of TGF-beta isoforms but not of melanocytes. Although melanoma cells are not growth-inhibited by all three TGF-beta isoforms, they secrete significantly higher levels of TGF-beta, as compared to melanocytes. The reduced response indicates their escape from TGF-beta surveillance with ongoing tumor progression.
Cell Division↗
[Effects of argon gas embolism during pneumoperitoneum].
In a porcine model, ten animals with a mean body weight of 18.9 (15-24) kg were exposed either to intravenous boli of 10, 20, and 30 ml argon (n = 5) or CO2 gas (n = 5). Gas embolism with argon led to increased pulmonary artery pressure (P > 0.001) and induced a decrease in end tidal CO2 (P < 0.001) and reduced cardiac output (P < 0.001) with a consecutive decrease in mean arterial pressure (P < 0.05). One animal died in cardiac shock after a 20 ml argon gas embolism and another after a 30 ml argon bolus. A third animal recovered after resuscitation with noradrenaline after a 30 ml argon bolus. Animals in the CO2 group receiving 10, 20, or 30 ml bolus neither required resuscitation nor died. Hemodynamic parameters were not affected by a 10 to 30 ml bolus of CO2 gas. Thus, gases with a low solubility in blood like argon should not be used during procedures with an increased risk of gas embolism.
Animals↗
[Comparative study of oncological outcome quality in colorectal carcinoma--ranking by surrogate endpoint?].
The data of the German Prospective Multicenter Study of the Study Group Colorectal Carcinoma (SGCRC) were analyzed with regard to interinstitutional differences in 5-year survival by statistical methods adequate for ranking and observing anonymity. Furthermore, possible so-called surrogate endpoints that allow an assessment of definite outcome after surgical treatment earlier than after 5 years were also analyzed. This requires a separate analysis for rectal and colon carcinoma patients. For rectal carcinoma, the combination of the frequency of local tumor cell spillage during tumor resection (iatrogenous tumor perforation and/or incision into or through tumor tissue) and the rate of locoregional recurrences (within 2 years after surgery) could be demonstrated as reliable surrogate endpoint. For colon carcinoma, no reliable surrogate endpoint could be found. Surgical morbidity is not an indicator of definite outcome. A very low rate of surgical mortality does not ensure satisfactory long-term results in colorectal cancer surgery.
Clinical Competence↗
Increase of segments of elastic-type blood vessel walls in fetal placental stem villi during pre-eclampsia at term.
In recent studies we described the presence of elastic-type blood vessels within trunci and rami chorii of human placental stem villi. For systemic and pulmonary hypertension it is known that elastic fibres are enhanced in arteries. The aim of our study was, therefore, to examine whether pre-eclampsia may lead to an increase of elastic tissue fibres in blood vessel walls of placental stem villi and whether there are differences in the thickness of blood vessel walls within these villi when compared to normotensive pregnant women. Twenty-six women with uncomplicated pregnancies and 25 patients with pre-eclampsia were investigated. Unfixed cryostat serial sections were processed for conventional orcein staining and for the demonstration of alpha-actin-immunoreactivity. The intensity of orcein staining of stem villus blood vessel walls was evaluated by a semiquantitative score method. Significant higher intensities of orcein staining (P<0.00001) were calculated for blood vessel walls of placentae with pre-eclampsia. The amount of thick stem villus vessels (>41 microm) increased during pre-eclampsia from 39 gestational weeks onwards. Our study demonstrates that segments of thick blood vessel walls and elastic-type vessel walls are increased in placental stem villi of patients with pre-eclampsia. This reaction may protect the fetal placental vessels and avert an increase of the fetal hypertension.
Chorionic Villi↗
Heart mitochondria in rats submitted to chronic hypoxia.
The effect of prolonged exposure to normobaric hypoxia on the mitochondria of myocard of rats exposed for several weeks to 8 and 7% O2 has been morphometrically evaluated. Twelve male Wistar rats housed in Nalgene cages (2 per cage) with a batch of six cages placed in plexiglass chambers were maintained in air/N2 mixtures containing different concentrations of O2. Six animals kept in similar cages under normoxia served as controls. When at day 60 the FIO2 was reduced to 8%, the weight increase stagnated and after the 81st test day, on which the hypoxic animals were subdivided into 8% and 7% groups the weight curve showed a decrease in the mean body weight for both groups. The arrest and the following loss of weight beyond the 85th day may be interpreted as the expression of a limit reached in the compensation capacity. In the 8%-group the shape of the mitochondria varied more markedly often with budding and furrowing of the surface. In the 7%-group bizarre shapes and wide variations in size with a decided shift towards larger mitochondria were noteworthy. While rats kept under 8% oxygen exhibited a numerical increase in myocardial mitochondria compared to controls, the mitochondria of the 7%-group were numerically reduced. The results suggest that hypoxia of 8% oxygen is compensatable, if only to some extent, by an increasing surface of mitochondrial membranes, and that further reduction of oxygen causes compensation mechanisms to fail as seen by the severe alterations of the mitochondrial population of the cardiomyocyte in the 7%-group.
Animals↗
Preoperative treatment of rectal cancer with radiation, chemotherapy and hyperthermia: analysis of treatment efficacy and heat-shock response.
Preoperative treatment of locally advanced rectal cancer with radiation, chemotherapy and hyperthermia is analyzed with regard to heat-shock response. In 23 patients with locally advanced rectal cancer (uT3/uT4), hyperthermia was administered in combination with radiotherapy and chemotherapy. In parallel, the effect of the treatment on levels of the heat-shock proteins HSP27 and inducible HSP70 in tumors and surrounding tissues was investigated by Western blotting. The patients' sera were also examined for autoantibodies against HSPs. HSP27 and inducible HSP70 were detected in most rectal tumors and surrounding tissues before and after treatment. HSP27 and inducible HSP70 levels had changed in 10 tumors after treatment. However, prior to treatment, there existed an unexpected diversity in HSP levels in the tumors and surrounding tissue. Hyperthermia doses in cumulative minutes for which 90% of the tumor is above the reference temperature (cum min T90 > or = 15 min) led to increased survival and response compared to that of a control group of patients treated without or with low-dose hyperthermia (cum min T90 < 15 min). However, there was no correlation to different expression of the HSPs. Hyperthermia as used in this setting does not lead to any sustained expression of HSPs in either the tumor or the surrounding tissue.
Antibodies↗
Effect of a silver device in preventing catheter-related infections in peritoneal dialysis patients: silver ring prophylaxis at the catheter exit study.
Catheter-related infections remain a significant cause of method failure in chronic peritoneal dialysis (PD) therapy. Given the increasing antibiotic resistance, such nonpharmacological strategies as local silver devices attract more interest. To establish whether a silver ring device (designed by Grosse-Siestrup in 1992) mounted onto the PD catheter and placed at the exit site at skin level is effective in preventing exit-site and other catheter-related infections, a prospective 12-month, multicenter, controlled study stratified by diabetes status was conducted. The study subjects were assessed by an extensive structured inventory, including a broad spectrum of control variables, such as age, body mass index (BMI), Staphylococcus aureus carrier status, catheter features, mode and quality of PD therapy, comorbidity, and psychosocial rehabilitation. Ten experienced German outpatient dialysis centers (seven adult, three pediatric) participated in the trial. All eligible patients (n=195) from the study area without catheter-related infections during the ascertainment period were included (incidental subjects undergoing PD therapy for at least 3 months). The main outcome measures were the occurrence of first exit-site infections (primary study end point), sinus tract/tunnel infection, and peritonitis. Ninety-seven patients were assigned to the silver ring and 98 patients to the control group. Baseline characteristics of age, sex, proportion of pediatric and incidental patients, S aureus carrier status, and other variables were similar in both groups. The incidence of infections in the silver ring group versus the control group was as follows: 23 of 97 versus 16 of 98 patients had exit-site infections, 12 of 97 versus 12 of 98 patients had sinus tract/tunnel infections, 16 of 97 versus 18 of 98 patients had peritonitis, respectively. Kaplan-Meier analysis for the probability of an infection-free interval showed no statistical difference (log-rank test) between the two groups. Displacement of the silver ring contributed to study termination in 6% of the study group patients, including two patients with catheter loss. Univariate analysis and multiple logistic regression identified younger age (<50 years), low serum albumin level (<35 g/L), number of previously placed PD catheters, short cuff-exit distance (<2 cm), and S aureus nasal carriage as risk factors for the development of exit-site infections. In conclusion, our study does not show any benefit of the silver ring in preventing catheter-related infections in PD patients. Thus, prevention of infection-related method failure in PD still has to rely on conventional antibiotic treatment strategies and less so on alternative methods.
Adult↗
Improvements in staging of gastric carcinoma from using the new edition of TNM classification.
AIMS: To recognize possible advantages of the 5th edition of TNM of gastric carcinoma in comparison to the former edition. METHODS: Data from Erlangen Cancer Center for 898 patients with gastric carcinoma treated surgically by total or subtotal gastrectomy with en bloc lymphadenectomy were analysed. RESULTS: The prognostic significance of TNM has been improved by the new edition as demonstrated by the likelihood ratio test. In addition, uncertainties of method in the pathological classification of regional lymph-node metastasis inherent in the 4th edition can now be avoided. CONCLUSION: The changes in the TNM classification introduced by the 5th edition are justified by data from the Erlangen Cancer Center, have methodic advantages in determining the N classification, and lead to an improvement in estimation of outcome.
Adult↗
Endolaryngeal contact pressures.
In this work, we present a new method for in vivo endolaryngeal contact pressure measurement with a miniature pressure transducer. Using this methodology, contact pressures can be measured during videoendoscopy at different locations between the artyenoids and also at various locations along the membranous vocal folds. Twenty adults with organic and functional voice disorders and two vocally healthy adults participated as subjects. Endolaryngeal contact pressure measures were made during a series of phonatory tasks varying pitch, loudness, and phonatory onset and offset. Measures were also made during nonphonatory tasks, including throat clearing, coughing, Valsalva maneuvres, and gagging. The most remarkable findings were: (1) interarytenoid contact pressures were considerably greater than intraglottal contact pressures; (2) interarytenoid contact pressures were greater for lower than higher pitches; (3) both interarytenoid and intraglottal contact pressures were remarkably large during hard glottal attack; and (4) overall, the largest endolaryngeal pressures were recorded between the arytenoids, during a thoracic fixation maneuver and during gag reflex.
Adult↗
Elevated plasma levels of transforming growth factor (TGF)-beta1 and TGF-beta2 in patients with disseminated malignant melanoma.
Overexpression of transforming growth factor-beta isoforms (TGF-beta1, -beta2, -beta3) has been previously reported in human melanoma cell lines and tumours. The aim of the present study was to evaluate the plasma levels of TGF-beta isoforms in melanoma patients. Significantly elevated levels of TGF-beta1 (4.2 x the controls, P = 0.0094) and of TGF-beta2 (1.5 x the controls, P = 0.012) but not of TGF-beta3 were measured in patients with disseminated but not locoregional melanoma. These results indicate systemic circulation of potentially immunosuppressive peptides of the TGF-beta family in end-stage melanoma patients.
Humans↗
Cutaneous hemoglobin oxygenation of different free flap donor sites.
Microsurgical skin flaps raised from various body regions show differences in vascular architecture, cutaneous capillary density, and skin perfusion. Therefore, it can be expected that oxygenation of the skin is different at the various free flap donor sites. To determine the cutaneous oxygen supply, intracapillary hemoglobin oxygenation was measured on the donor sites of the radial forearm flap, scapula, latissimus dorsi, rectus abdominis, anterolateral thigh, and osteocutaneous fibula flap on 50 healthy subjects (25 men and 25 women aged 20 to 40 years). Measurements were performed noninvasively with the Erlangen Microlightguide Spectrophotometer (EMPHO) on skin areas of 6 x 8 cm in each region under resting conditions. The hemoglobin oxygenation of the skin in all donor regions varied between a maximum of 43.94 to 58.94 percent in the scapula region and a minimum of 13.89 to 29.45 percent in the lateral calf. High oxygenation values were also found on the skin over the latissimus dorsi muscle (34.56 to 48.45 percent), followed by the distal volar forearm (29.78 to 40.30 percent), whereas paraumbilical skin and the donor sites of the lower extremities were less oxygenated. By using the Wilcoxon test, significant differences were found between all donor regions except for the anterolateral thigh and lateral calf (p = 0.05). There were no gender-specific differences. From these results, it is concluded that, on young healthy subjects, regional oxygen supply on different free flap donor sites varies significantly. This finding must be considered in the interpretation of intracutaneous or transcutaneous PO2 measurements for flap monitoring.
Adult↗
Efficacy of different methods for detection of low Cryptosporidium parvum oocyst numbers or antigen concentrations in stool specimens.
The detection of Cryptosporidium parvum oocysts in stool specimens by acid-fast (AF) stains or immunofluorescence assays (IFA) requires the presence of large numbers of oocysts. To determine whether new commercially available enzyme immunoassays (EIAs) are more sensitive alternatives, three EIAs, a direct IFA, and the modified cold Kinyoun AF stain were compared, particularly with respect to detection of low oocyst numbers or antigen concentrations. Thirty-one negative and 31 calf stool-enriched human stool specimens were tested. One EIA method detected only nine positive specimens, demonstrating a sensitivity significantly less (p < 0.0001) than that of the IFA, the AF stain, and the other two EIAs. No differences could be found with respect to specificity. In addition, serial dilutions of 28 patients' stool samples containing cryptosporidian oocysts were prepared and examined using two EIAs, IFA, and the AF stain. One EIA yielded significantly inferior results (p < 0.0001), whereas the other one and the two microscopic methods did not differ significantly in either part of the study. The results indicate that the new EIAs do not exhibit higher sensitivities for detection of Cryptosporidium parvum than the two routinely used microscopic methods. Thus, for most laboratories, the IFA or AF stain may still represent the preferred method for the diagnosis of cryptosporidiosis.
AIDS-Related Opportunistic Infections↗
Risk of invasive carcinoma in colorectal adenomas assessed by size and site.
BACKGROUND: The risk of invasive carcinoma developing in colorectal adenomas is influenced by a number of characteristics of both patients and adenomas, and the composition of the sample analysed. PATIENTS AND METHODS: Between 1978 and 1993 more than 20,000 polyps were prospectively documented at the Erlangen Registry of Colorectal Polyps, and analysed statistically by logistic regression. RESULTS: The size of the adenomas proved to be the most important factor for adenomas equal to or larger than 15 mm as compared with smaller lesions. In 5,137 diminutive adenomas (< or = 5 mm) invasive carcinoma was never found. Adenomas in the right-sided colon had a lower risk than those in the left colon or rectum, but with increasing adenoma size, the malignancy rate showed a right-sided shift. In adenomas of up to 36 mm in diameter, invasive carcinoma was found more often when they were located in the rectum or left colon while adenomas larger than 36 mm were more likely to harbour invasive carcinoma when located in the right or left colon rather than in the rectum. CONCLUSIONS: A multivariate analysis of 11,380 adenomas detected at the first total colonoscopy showed that the factors size and site, both of which can be assessed by endoscopic inspection alone, were found to enable a statistically and clinically adequate assessment of the malignancy risk.
Adenoma↗
Invasive carcinoma in colorectal adenomas: multivariate analysis of patient and adenoma characteristics.
BACKGROUND AND STUDY AIMS: The risk of invasive carcinoma developing in colorectal adenomas is influenced by a number of characteristics, relating both to the patients and to the adenomas, and by the composition of the sample analyzed. The aim of the present study was use a multivariate analysis to investigate the risk of invasive carcinoma in endoscopically and surgically removed adenomas. PATIENTS AND METHODS: Between 1978 and 1993, more than 20,000 polyps were prospectively documented at the Erlangen Registry of Colorectal Polyps. A multivariate analysis of 11,188 adenomas detected at the first total colonoscopy was carried out in order to investigate the risks associated with size and site--both of which can be assessed by endoscopic inspection alone- and the extent to which these may be modified by other patient and adenoma characteristics, with an influence on the risk of invasive carcinoma in colorectal adenomas. RESULTS: The size of the adenoma proved to be the most important influencing factor. Invasive carcinoma was never found in 5027 small adenomas (< or = 5 mm). Adenomas in the right colon had a lower risk than those in the left colon or rectum. But with increasing adenoma size, the malignancy rate showed a right-sided shift, with a significant interactive effect of size and right-sided location. However, the risk determined by the size and site of the adenoma was significantly modified by a number of patient and adenoma characteristics, including histological type, presence of multiple adenomas, and patient age and sex. CONCLUSIONS: The risk of invasive carcinoma in colorectal adenomas can only be adequately described by a complex model of the interactive effects of patient and adenoma characteristics on the main factors of size and site.
Adenoma↗
Comparative evaluation of modified trichrome and Uvitex 2B stains for detection of low numbers of microsporidial spores in stool specimens.
At present, the laboratory diagnosis of intestinal infections caused by microsporidia depends on the detection of the typical spores either with a modified trichrome stain (MTS) or by staining with fluorochromes. The purpose of the present study was (i) to compare staining with MTS (MTS method) and the staining with the fluorochrome Uvitex 2B (U2B method) with respect to their sensitivities and specificities, particularly in the presence of low numbers of spores, and (ii) to evaluate their reliabilities under routine laboratory conditions. First, 30 negative human stool specimens as well as 30 specimens enriched with a low concentration of microsporidial spores were examined. The U2B and MTS methods detected 27 and 30, of the positive samples, respectively (95% confidence intervals for sensitivity, 0.73 to 0.98 for the U2B method and 0.88 to 1.00 for the MTS method) without yielding false-positive results (95% confidence intervals for specificity, 0.88 to 1.00 for the MTS and U2B methods). In addition, analysis of serial dilutions of 17 stool specimens from AIDS patients containing microsporidia revealed comparable detection thresholds (P = 0.52) for both methods. Finally, 40 slides prepared from one stool specimen containing very few microsporidia and 40 negative slides were included in the routine diagnostic program during 1 month in order to monitor laboratory handling and run-to-run variations. Again, both methods exhibited comparable sensitivities (95% confidence intervals, 0.83 to 0.99 for the MTS method and 0.91 to 1.00 for the U2B method) and specificities (95% confidence intervals, 0.91 to 1.00 for the MTS and U2B methods). In conclusion, MTS and U2B methods are equally useful in the diagnosis of microsporidiosis. However, since detection thresholds for both methods differed considerably in all diluted stool specimens, performance of a combination of both methods may be more sensitive than the performance of only one procedure in the event of very low numbers of microsporidial spores.
AIDS-Related Opportunistic Infections↗