Biomedical subjects
Publications and source records attributed to E Richter.
Improved rendering and segmentation techniques lead to a new quality of 3D reconstructions of the Visible Human. Using these we have implemented an interactive atlas of anatomy and radiology of the inner organs.
PURPOSE: Long-term activation of immunocompetent cells of the bladder wall as well as case reports of systemic infections some months or years after intravesical bacillus Calmette-Guerin (BCG) therapy imply that mycobacteria may persist in the body. Therefore. we investigated the fate of BCG in patients after uncomplicated intravesical instillation therapy. MATERIAL AND METHODS: A total of 49 patients were included in the study, from whom various numbers of specimens were used for mycobacterial culture and molecular biological detection techniques. In 23 patients who received a total of 128 instillations urine, sputum, venous blood and bladder biopsies were screened for BCG by acid-fast staining and culture at different times before and after instillation. From 16 of the 23 patients and from an additional 26 a total of 180 bladder biopsies obtained at intervals 3 to 30 months after instillation were screened for mycobacterial 16S ribosomal DNA by a nested polymerase chain reaction protocol. RESULTS: No viable BCG was found in venous blood or in 127 of 128 sputum specimens before and 2 hours after instillation. Two of 56 bladder biopsies were culture positive. In urine BCG was detected in 96.4% of the specimens after 2 hours and in 67.9% after 24 hours after instillation. The number of positive specimens decreased and it was 27.1% on day 7 immediately before the next instillation. In 14 of 44 bladder biopsies (31.8%) mycobacterial ribosomal DNA was found within 1 week after the sixth instillation. A positive polymerase chain reaction was evident up to 24 months in between 4.2% and 37.5% of the investigated biopsies. After 30 months no ribosomal DNA was evident in the 6 samples available for testing. CONCLUSIONS: Nontraumatic intravesical instillation of BCG is not accompanied by systemic mycobacterial spread. Local persistence during the instillation course is evident since viable BCG is commonly found in the urine. Long lasting and persistent BCG DNA in the bladder wall may account for long-term immuno-activation. However, the remaining BCG may be a possible source of late systemic infections.
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Nicotine and its major metabolite cotinine inhibit alpha-hydroxylation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) suggesting that an alternative pathway of NNK metabolism and elimination, biliary excretion of the O-glucuronide of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL-Gluc) may be enhanced. To verify the possible role of cotinine on biliary elimination of NNK and its metabolites, bile duct cannulated rats were administered a single i.p. dose of 50 mg/kg [56sup;-3 H]-NNK with or without i.p. co-administration of 5 mg/kg cotinine or nicotine. Cotinine significantly reduced cumulative bile flow and biliary elimination of NNK-derived radioactivity within six hours to 42 and 27 percent, respectively. The pattern of NNK metabolites in bile was unchanged. Nicotine had a similar inhibitory effect on bile flow. This result constitutes the first experimental evidence that cotinine inhibits bile flow. In rats, biliary elimination of NNK is reduced accordingly which may lead to an increased carcinogen burden in the body. In humans, inhibition of bile flow by tobacco alkaloids may contribute to the appetite suppressing effect of tobacco products.
BACKGROUND: Retention of caffeine was observed in patients with alcoholic liver cirrhosis and impaired liver function. Cotinine, the major metabolite of nicotine, is transformed by microsomal N-oxidation to secondary metabolites. The aim of this study was to investigate if impaired liver function leads to a retention of cotinine in a similar way to caffeine retention. Furthermure the influence of smoking on cotinine and caffeine plasma levels was studied. METHODS: 91 smokers and 12 nonsmokers with alcoholic liver cirrhosis were subdivided according to their smoking habits. Cotinine plasma levels and fasting caffeine concentrations were measured by a gaschromatographic method. Concentrations of conjugated bile acids were measured by RIA. 10 healthy smokers and 11 nonsmokers were used as a control group. RESULTS: Mean plasma cotinine concentrations found in slight smokers (200 +/- 155 ng/ml), intermediate smokers (384 +/- 223 ng/ml) and heavy smokers (430 +/- 266 ng/ml) with alcoholic liver cirrhosis were significantly higher than in healthy, smoking volunteers with slight, intermediate, and heavy smoking (101 +/- 14; 274 +/- 112; 345 +/- 85 ng/ml) (p <0.01) respectively. In nonsmokers with alcoholic liver cirrhosis plasma cotinine (44 +/- 25 ng/ml) was significantly elevated compared to healthy nonsmokers (27 +/- 19 ng/ml) (p <0.01). - Fasting caffeine plasma levels in patients with alcoholic liver cirrhosis (4.00 +/- 5. 20 microg/ml) were significantly higher than in healthy volunteers (0.91 +/- 0.42 microg/ml) (p <0.01). A decrease of plasma levels was observed in correlation to the amount of smoking in patients with alcoholic cirrhosis (slight smokers: 7.67 +/- 8.54 microg/ml, intermediate smokers: 3.35 +/- 2.91 microg/ml and heavy smokers: 2. 48 +/- 2.68 microg/ml). Conjugated bile acids were elevated in patients with alcoholic liver cirrhosis to 32,56 +/- 38,24 mmol/l. CONCLUSIONS: Increased cotinine plasma levels in smokers and nonsmokers with alcoholic liver cirrhosis demonstrate a cotinine retention in patients with impaired liver function. The inducing effect of smoking is shown by a decrease of fasting caffeine plasma concentrations.
The pharmacokinetics of in vitro metabolism of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; concentration range 0.03-250 microM) and its proximal metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; 0.04-250 microM), were determined in Syrian golden hamster liver, lung, and kidney tissue slices in organ culture under identical experimental conditions. In the lung, a target organ for NNK animal carcinogenesis, total NNK metabolism was relatively low (maximum 23%) and oxidative metabolism by alpha-hydroxylation to DNA-reactive intermediates accounted for 13-31% of metabolism. The liver, a non-target organ for NNK carcinogenesis, showed the highest capacity to metabolise NNK (total metabolism 80%), and alpha-hydroxylation accounted for 12-25% of metabolism. The kidney, another non-target organ, also showed a low capacity for NNK metabolism (maximum 32%) and alpha-hydroxylation accounted for <3% of metabolism. Detoxification of NNK by pyridyl N-oxidation was similar in lung (5-22%) and liver (5-23%), and negligible in kidney (<2%), while carbonyl reduction of NNK to NNAL was greatest in the kidney (95-100%), followed by liver (59-79%) and lung (47-81%). NNAL is devoid of biological activity in the hamster and total metabolism was about tenfold lower than that of NNK in all tissues (<13% liver; <4% lung and kidney). In the liver, alpha-hydroxylation was the predominant pathway of NNAL metabolism at almost all concentrations (31-68% of total metabolism), whereas N-oxidation prevailed in the kidney (47-68%). In the lung, a concentration dependent decrease in the relative amount of alpha-hydroxylation (23-72%) with increasing NNAL concentrations occurred at the expense of N-oxidation (25-72%). Little or no metabolism of NNAL back to NNK was evident in any tissue.
Nicotine, the principal alkaloid in tobacco, is generally accepted to be responsible for most neuropharmacological effects due to tobacco use. Little is known about the action of cotinine, the major metabolite from nicotine, at neuronal structures. To evaluate the mode of action of cotinine at neuronal receptors, its effect on the surface compound potential of the sympathetic superior cervical ganglion (SCG) of the mouse was studied. The modulation of nicotine induced surface potentials by cotinine was tested. It was found that 2-min applications of cotinine (0.1-30 mmol/l) induced concentration dependent depolarizations at the SCG (EC(50)=1.7 mmol/l) which were followed by hyperpolarizations and weak afterdepolarizations. The intrinsic activity of cotinine compares to that induced by much lower concentrations of nicotine (EC(50)=21 micromol/l). These cotinine effects may be mediated at least in part by nicotine impurities which were found by capillary electrophoresis to be 0.1 and 0.8% in different batches of cotinine. Continuous application of 300 micromol/l cotinine shifted the concentration-response curve of nicotine to the right and reduced (IC(50)=302 micromol/l) the effects of submaximal nicotine concentrations (30 micromol/l). This effect could not be mimicked by continuous application of a nicotine concentration (0.3 micromol/l) equivalent to the lower impurity in cotinine. Therefore, the antagonistic action of cotinine at peripheral neuronal nicotinic receptors is at least in part independent of nicotine impurity. The observed antagonistic effect of cotinine at nicotinic receptors likely contributes to the neuropharmacological effects of smoking.
Therapeutic drug monitoring is essential in HIV-patients undergoing highly active antiretroviral therapy (HAART). Saquinavir (SQV) is used alone or in combination with ritonavir (RTV) or nelfinavir (NLF), respectively, in the context of the HAART drug regimen. The achievable SQV concentration range in clinical practice remains to be elucidated. A non-randomized prospecitve clinical trial 19 patients (group I) receiving SQV (1x600 mg/d Invirase or Fortovase), 29 patients (group II) receiving SQV (2x600 mg/d Fortovase) plus RTV (2x400 mg/d Norvir), and 21 patients (group III) receiving SQV (2x600 mg/d Fortovase) plus NLF (2x750 mg/d Viracept) was conducted to determine SQV plasma concentrations. SQV levels were determined as trough levels during routine outpatient visits. Analysis was performed by HPLC with UV detection. The lowest SQV plasma levels were found in group I (95% CI 89-177 ng/ml). Significantly higher SQV levels were found in group III (combination with NLF) ranging from 242 to 398 ng/ml (95% CI) and in group II (combination with RTV) ranging from 1354 to 1747 ng/ml (95% CI). The IC 50% of 54 ng/ml was not reached in at least one sample during the study (mean duration of study 16+/-10 months) in 14/19 patients of group I, 9/29 patients in group II and 13/21 patients in group III, respectively. A positive correlation between patient compliance, defined by SQV levels in the 95% CI of the used combination, and the HIV RNA plasma level was found. The presented data confirm that therapy with SQV alone may not be effective, since trough levels are near the lower limit of antiretroviral efficacy. Although the combination of SQV with NLF results in higher SQV plasma concentrations in a bid regimen, in more than 60% of the patients SQV concentrations below IC 50 level were detected during the twelve-months study period. The combination of SQV with RTV yields the highest SQV-trough levels. SQV concentrations below the IC 50 were seen in only 31% of patients with the SQV/RTV combination. In conclusion, therapeutic drug monitoring allows an efficient surveillance of patients compliance. In addition, therapeutic drug monitoring represents a valuable tool for management of HAART in patients receiving a complex comedication or suffering from advanced liver disease.
PURPOSE: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT '91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. METHODS AND MATERIALS: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). RESULTS: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70+/-0.08; for patients with residual disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1: 0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3 disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). CONCLUSIONS: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.
The recently reported formation of highly ordered traces by migrating cells has been studied on L929 fibroblasts in time lapse experiments by means of interference reflection microscopy (IRM) as well as by conventional microscopy. Formation of pronounced traces on glass substrates correlates to migration after cell division, and the trace arrangement on the substrate depends on migration velocity: slow migration results in a highly branched, broad, and relatively short trace, while fast migration yields a slim and long trace with few branches. IRM-irradiation caused cessation of locomotion and trace formation and accelerated degradation of existing traces. Traces consist of cord-like cytoplasmic strands, which contain F-actin filaments and they seem to be enveloped by a membrane. It is supposed that cell traces are homologous to filopodia. Traces arise mainly from non-retracted filopodia at the rear margin of the migrating cell. The branches within the traces are the result of the repeated stretching out of a backwardly directed lamellipodium. They arise from the formation of new filopodia that emerge at the actin ribs of the lamellipodium.
High levels of haemoglobin (Hb) adducts from 4-aminobiphenyl (4-ABP), a proven human carcinogen, have been reported in untreated animals from different laboratories fed various commercial standard diets. Therefore, the impact of dietary modifications on 4-ABP Hb adducts was investigated. Female Sprague-Dawley rats were fed a regular standard diet or three different test diets for 4 weeks. 4-ABP Hb adducts were significantly lower in rats on vegetable-based test diets #2 (596+/-183 pg/g Hb, P = 0.028) and #3 (537+/-48 pg/g Hb, P = 0.009) compared with controls (974+/-154 pg/g Hb). Cereal-based test diet #1 (1080+/-388 pg/g Hb) had no influence on the basal Hb adduct levels determined before the start of the experiment (1054+/-163 pg/g Hb). In conclusion, the body burden of rats with 4-ABP could be significantly reduced by dietary modifications.
The purpose of this study was to investigate the value of bone scintigraphy including single-photon emission tomography (SPET) and semiquantitative analysis for the assessment of graft viability following microvascularized bone transplantation. We evaluated 60 scintigraphic studies of 36 patients with 39 bone grafts. Thirty-four investigations were performed 6-11 days (early bone scans) and 26 up to 11 months (late bone scans) after mandibular reconstruction. After administration of 550 MBq technetium-99m methylene diphosphonate, planar scintigrams and a SPET study were performed. The data were reconstructed iteratively. Scans were evaluated visually and semiquantitatively by a region of interest technique using the ratio between transplant and cranium (T/C). Patients with uncomplicated healing showed a T/C ratio >1.0 in early and late bone scans. In cases with necrosis, the T/C ratio was below 1.0 when performing early bone scans. However, in late bone scans, some patients with necrosis showed a slightly increased uptake and a T/C ratio >1.0. The data demonstrate that as early as 6-11 days after mandibular reconstruction, increased tracer uptake proves that the surgery has been successful and indicates a normal healing process. Especially in the early bone scans no false-positive or false-negative results were observed and the T/C ratio clearly differentiated between vital and non-vital bone grafts. At later times false-positive findings could be observed; these were, however, rare because of the significantly higher tracer uptake of the healthy grafts when compared with completely or partially necrotic transplants.
Serum albumin level has been implicated as a prognostic factor in various cancers, however it has not been studied in early stage prostate cancer. We examine the clinical prognostic value of the readily available pretreatment albumin level as a marker for determining staging and prognosis for men undergoing radical prostatectomy. A retrospective review was performed on 354 patients who underwent a radical prostatectomy at a tertiary facility from 15 April, 1990 until 3 December, 1996 who had a pretreatment serum albumin within 6 months prior to surgery. Albumin levels were analyzed and compared to the values of standard prognostic factors to assess the ability of albumin to predict pathological stage and serological recurrence by PSA level after radical prostatectomy. Albumin level was not of value in predicting serological disease recurrence, but interestingly was an independent prognostic factor in predicting risk of nonorgan-confined disease (T3 or T4). Our data also showed that, as expected, grade and pretreatment PSA levels were independent predictors of pathological stage. Albumin appears to be of clinical utility to augment assessment of pretreatment pathological stage. However, it is not of value in predicting serological disease recurrence following radical prostatectomy. Further study in other cohorts and in using additional analysis such as neural networks is indicated. Prostate Cancer and Prostatic Diseases (2000) 3, 186-190
BACKGROUND: This prospective study was conducted to gain experience as to whether it is technically possible to produce autologous RBCs in additive solution from cord blood (CB), to optimize the blood supply for preterm infants. STUDY DESIGN AND METHODS: CB was collected from 47 infants with a mean (+/- SD) birth weight of 1717 (+/- 699) g. Whenever possible, RBC components were prepared by standard centrifugation using a six-bag system. All samples were put in sterility testing quarantine for 5 days, and a maximum storage of 14 days from collection to transfusion was specified. The babies were given either the autologous RBCs or standard allogeneic RBC concentrates, if autologous blood was not available. RESULTS: In 81 percent of the samples, autologous RBC components could be processed (vol, 7-87 mL; Hct, 31-82%). But within the group of extremely low birth weight infants (body weight <1000 g), a mean CB net volume of only 37 mL was collected, and the RBC preparation was successful only in exceptional cases. Three CB samples (8.6%) tested positive in sterility testing. Of the 47 infants, 21 were treated with a total of 62 allogeneic and 4 autologous RBC transfusions. Most infants with a body weight over 1400 g did not need any RBC transfusion. CONCLUSION: The preparation of autologous RBCs from the CB of preterm infants is technically possible in principle. However, major concerns must be raised as to whether such preparations are of benefit in ensuring safe care of neonates with blood components, with respect to the high rate of bacterial contamination and the limited availability in babies with low birth weight.
UNLABELLED: The aim of this study was to investigate the results of different volume-dependent target doses on clinical outcome 6 months after radioiodine therapy (RITh) and its correlation with post therapeutic thyroid volumes (Vpost) in patients with Graves' disease. This analysis was designed to determine factors improving the results of radioiodine therapy without increasing target doses generally, as has been recommended recently. We studied consecutive data from 102 patients with Graves' disease, who had initial radioiodine therapy between 1991 and 1995. The 131I activities were calculated according to the formula of Marinelli. In addition to the normal calculation individual target doses were adjusted to the thyroid volumes of each patient before therapy. For statistical evaluation, the patients were divided into three subgroups of comparable sample sizes: Group I included those with a thyroid volume <15 ml before therapy. Group II included those ranging from a 15-25 ml volume before therapy and group III included those with thyroid volumes >25 ml. Laboratory thyroid parameters and thyroid volumes were measured in those groups before and 6 months after therapy. RESULTS: Analysis of all patients revealed a significantly higher rate of hypothyroidism (54%) and fewer cases of hyperthyroidism (15%) six months after therapy in cases with Vpost smaller than 8 ml. The median Vpost needed to achieve an optimum therapeutic success rate (rate of eu- or hypothyroidism) was smaller than 5 ml in group I and smaller than 10 ml in group II. Therapeutic success was associated with different target doses in each group, 150,220 and 260 Gy for groups I, II, and III respectively. CONCLUSIONS: Post therapeutic thyroid volumes correlated significantly with clinical outcome six months after therapy. An adjustment of the target doses based on thyroid volumes before therapy will lead to an appropriate reduction of thyroid volumes. Thus, in the individual case clinical outcome could be improved without applying higher target doses in all patients. This would ensure a better utilization of limited resources in medical care e.g. through a shorter hospital stay.
Factors determining the in vivo replication of the opportunistic pathogen Mycobacterium genavense are largely unknown. Following intravenous injection of a patient isolate, M. genavense could not be recovered by culture or detected by PCR in the livers or spleens of infected BALB/c mice. In contrast, M. genavense was found to chronically persist and multiply in the livers and spleens of intravenously infected syngeneic gamma-interferon-gene-deficient (GKO) mice as evidenced by acid-fast stains of infected tissues and recovery by both PCR and liquid culture following organ homogenization. In GKO mice, M. genavense elicited a chronic inflammatory response, resulting in marked splenomegaly and extensive lymphadenopathy. Granulomatous lesions in the livers of GKO mice were diffuse, were composed of monocytes, neutrophils, and CD3(+) cells, and were histochemically negative for inducible nitric oxide synthase.
The variations in biochemical as well as molecular characteristics among several members of the Mycobacterium tuberculosis complex that are not M. tuberculosis have been assessed to facilitate an unambiguous species identification. Altogether, 96 M. tuberculosis complex strains including 52 M. bovis isolates and 44 M. africanum isolates were analyzed by spoligotyping. The strains could be clustered into five spoligotype groups. All M. bovis isolates showed the typical absence of the spacers 39 to 43 and typical biochemical properties. However, within these strains we found a group of strains that had a spoligotype pattern which is clearly defined by the additional absence of spacers 3 to 16 and that were uncommonly susceptible to pyrazinamide (PZA). This spoligotype pattern has previously been described as being typical for a caprine genotype because of its predominant isolation from sheep and goats. Due to the clinical importance of PZA resistance, we propose two M. bovis subtypes: M. bovis subtype bovis, which is resistant to PZA, and M. bovis subtype caprae, which is susceptible to PZA. Two additional strains that clustered in group 3 showed biochemical and genetic properties typical for M. bovis and were also sensitive to PZA; thus, they may represent a third PZA-susceptible M. bovis subtype. The M. africanum isolates could be clustered into two spoligotype groups which can be differentiated from M. bovis by hybridization to spacers 39 to 43. These groups correspond to the previously described M. africanum subtypes I and II and can be clearly distinguished from each other by spoligotyping and resistance to thiophen-2-carboxylic acid hydrazide. Our results demonstrate that spoligotyping is a useful tool for differentiation of M. bovis and M. africanum. Moreover, we describe two PZA-susceptible M. bovis subtypes and describe a method that facilitates an unambiguous differentiation of the two M. africanum subtypes.
The stability of IS6110 restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis strains in actual transmission chains has been assessed by analyzing the variability of IS6110 RFLP patterns of strains in fingerprint clusters that have been confirmed by classical epidemiological data. Forty susceptible and 35 drug-resistant (including 17 multidrug-resistant) M. tuberculosis strains obtained from 75 patients living in Germany have been analyzed. The epidemiological relationship among strains within the fingerprint clusters has been verified by family contacts (14 clusters) or by contact tracing of the public health offices (7 clusters). The time spans between the first and the last isolate of one cluster ranged from less than 1 to 29 months. Of the 75 strains only 1 showed a one-band variation when compared to the other nine isolates grouped in the same cluster, corresponding with a rate of change of approximately 1.9% per possible transmission (one index patient per cluster was subtracted from the total number of isolates). These results confirm a high degree of stability of IS6110 RFLP patterns of transmitted M. tuberculosis strains. Furthermore, the data presented indicate that isolates with identical IS6110 DNA fingerprint patterns are a good indicator for the rate of recent transmission in a study population.