Changes in calcaneal trabecular bone structure assessed with high-resolution MR imaging in patients with kidney transplantation.

The purpose of this study was to use high-resolution magnetic resonance (HR-MR) imaging to analyze the trabecular bone structure of the calcaneus in patients before and after renal transplantation and to compare this technique with bone mineral density (BMD) in predicting therapy-induced bone loss and osteoporotic fracture status. HR-MR imaging (voxel size: 0.195 x 0.195 x 1 mm) was performed at 1.5 T with an axial and sagittal orientation in 48 patients after transplantation, 12 patients before renal transplantation and 20 healthy controls. Structure measures analogous to standard histomorphometry and fractal dimension were determined in these images. BMD measurements of the lumbar spine and the proximal femur were obtained in the healthy female controls and the patients. Vertebral and peripheral fracture status were determined in all patients. The structural measures app.BV/TV, Tb.Sp, Tb.Th and Tb.N showed significant differences between controls and patients (p<0.05) while fractal dimension showed no significant differences. Neither the structural measures nor BMD showed significant differences between patients before and after transplantation. Correlations between time after transplantation versus structural measures and BMD were not significant. Differences between fracture and nonfracture patients were significant for the structural measures app.BV/TV, Tb.Sp and Tb.N (axial images) as well as for app.Tb.Th (sagittal images) and spine BMD (p<0.05) but not for hip BMD. Using odds ratios the strongest discriminators between patients with and without fractures were app. BV/TV, app.Tb.Sp (axial images) and app.Tb.Th (sagittal images), even after adjustment for age and BMD. Using receiver operating characteristic analysis the highest diagnostic performance was found for a combination of BMD and structural measures. In conclusion, our results indicate that structural measures obtained from HR-MR images may be used to characterize fracture incidence in kidney transplant patients; the best results, however, are obtained using a combination of BMD and structural measures.

The beneficial effects of calcium channel blockers on long-term kidney transplant survival are independent of blood-pressure reduction.

There is a growing body of evidence suggesting that calcium channel blockers (CCB) exert beneficial effects on kidney transplant survival. However, it is not completely understood if these agents act independently of blood-pressure reduction. In the present study, the 5-yr follow-up of 45 kidney transplant recipients receiving CCB during the 60-month follow-up period was compared to that of recipients with lower blood pressure and an antihypertensive treatment without CCB. During the whole follow-up, systolic (127.4 +/- 2.5 vs. 139.4 +/- 2.1 mmHg, p < 0.05) as well as diastolic blood pressure (78.8 +/- 1.1 vs. 84.8 +/- 1.8 mmHg, p < 0.05) was higher in the group receiving CCB. Moreover, in CCB-treated recipients, a significant (p < 0.05) higher increase in proteinuria was detected (from 759 +/- 120 to 1690 +/- 359 mg/24 h vs. 180 +/- 45 to 340 +/- 45 mg/24 h). Despite higher blood pressure and higher proteinuria, the increase in serum creatinine in the group of CCB-treated recipients was significantly lower (0.01 mg/dL/month) in comparison to that of the controls (0.02 mg/dL/month, p < 0.05). Moreover, the 5-yr transplant survival was significantly higher in CCB-treated recipients (62.3 vs. 31.8%, p < 0.05). The results of the present study further support the beneficial effects of CCB in kidney transplant recipients, which are independent of blood-pressure reduction.

Glutathione S-transferase polymorphism in Parkinson's disease.

Glutathione S-transferases (GSTs) are involved in the detoxification of endogenous or exogenous toxins, which may play a role in the pathogenesis of Parkinson's disease. We genotyped the Glutathione-S-Transferase isoenzymes GSTM1 and GSTT1 by polymerase chain reaction in order to evaluate different gene polymorphisms of these isoenzymes in 149 parkinsonian and 99 control subjects. No differences appeared between both groups regarding the frequencies of the homozygous deletion of GSTM1 (odds ratio 1.021; 95% CI [0.613; 1.699], p < 0.521 Fisher's exact test) and GSTT1 (odds ratio 1.514; 95% CI [0.811; 2.824], p < 0.127). Age of onset of PD did not correlate to GSTM1 and GSTT1 polymorphisms. These results do not support the hypothesis of a possible impact of GSTM1 and GSTT1 detoxification activities in the pathogenesis of Parkinson's disease.

Haemoglobin adducts of acrylonitrile and ethylene oxide in acrylonitrile workers, dependent on polymorphisms of the glutathione transferases GSTT1 and GSTM1.

Fifty-nine persons with industrial handling of low levels of acrylonitrile (AN) were studied. As part of a medical surveillance programme an extended haemoglobin adduct monitoring [N-(cyanoethyl)valine, CEV; N-(methyl)valine. MV: N-(hydroxyethyl)valine, HEV] was performed. Moreover, the genetic states of the polymorphic glutathione transferases GSTM1 and GSTT1 were assayed by polymerase chain reaction (PCR). Repetitive analyses of CEV and MV in subsequent years resulted in comparable values (means, 59.8 and 70.3 microg CEV/1 blood; 6.7 and 6.7 microg MV/1 blood). Hence, the industrial AN exposures were well below current official standards. Monitoring the haemoglobin adduct CEV appears as a suitable means of biomonitoring and medical surveillance under such exposure conditions. There was also no apparent correlation between the CEV and HEV or CEV and MV adduct levels. The MV and HEV values observed represented background levels, which apparently are not related to any occupational chemical exposure. There was no consistent effect of the genetic GSTM1 or GSTT1 state on CEV adduct levels induced by acrylonitrile exposure. Therefore, neither GSTM1 nor GSTT1 appears as a major AN metabolizing isoenzyme in humans. The low and physiological background levels of MV were also not influenced by the genetic GSTM1 state, but the MV adduct levels tended to be higher in GSTT1- individuals compared to GSTT1 + persons. With respect to the background levels of HEV adducts observed, there was no major influence of the GSTM1 state, but GST- individuals displayed adduct levels that were about 1/3 higher than those of GSTT1 + individuals. The coincidence with known differences in rates of background sister chromatid exchange between GSTT1- and GSTT1 + persons suggests that the lower ethylene oxide (EO) detoxification rate in GSTT1- persons, indicated by elevated blood protein hydroxyethyl adduct levels, leads to an increased genotoxic effect of the physiological EO background.

Determination of extent and activity with radionuclide imaging in Erdheim-Chester disease.

Erdheim-Chester disease usually involves the diaphyseal and metaphyseal regions of tubular bones and various visceral organs. A 56-year-old woman presented with the histologically confirmed diagnosis of Erdheim-Chester disease. A Tc-99m MDP bone scan revealed the entire extent of the skeletal disease and showed unusual involvement of the epiphyses and axial skeleton. In addition to MRI, a Ga-67 citrate scan including SPECT showed extensive soft-tissue infiltration of different organs. Both Tc-99m MDP and Ga-67 scintigraphy are useful tools in determining the distribution of this rare disease.

N-Acetyltransferase 2 (NAT2) and Glutathione S-Transferase µ (GSTM1) in Bladder-cancer Patients in a Highly Industrialized Area.

The study was designed to assess occupational and non-occupational risk factors in patients with urothelial carcinomas in an area of former coal, iron, and steel industries, with special regard to the impacts of polymorphic enzymes involved in the metabolism of aromatic amines (N-acetyltransferase 2, NAT2) and of polycyclic aromatic hydrocarbons (glutathione S-transferase µ, GSTM1). Inpatients with bladder cancer (n = 179) were interviewed for occupations ever engaged in for more than six months, and for bladder cancer risk factors in general. NAT2 was phenotyped by high-pressure liquid chromatography of caffeine metabolites in urine. The NAT2 status was additionally evaluated by genotyping 88 of these patients. Eighty-nine patients were genotyped for GSTM1. Of the 179 bladder-cancer patients, 115 (64%) were slow acetylators. In 70% of the subgroup of 89 patients, GSTM1 was negative, suggesting an impact of polycyclic aromatic hydrocarbons (PAHs) in bladder-cancer carcinogenesis in the general population in this area. Contrary to an ordinary distribution of the acetylator status in underground coal miners (18 slow acetylators out of 32), GSTM1 was negative in 16 of 19 of these coal miners. Five of six coke-oven workers were slow acetylators; GSTM1 was negative in all four genotyped coke-oven workers. Twelve of 17 patients formerly exposed to colorants were slow acetylators. Distributions of NAT2 (59% slow acetylators) and GSTM1 (54% GSTM1 negative) were normal in businessmen and administrative officers among the occupationally non-exposed bladder-cancer patients. The results are consistent with the view that a slow-acetylator status and lack of the GSTM1 gene are individual risk factors for bladder cancer in persons occupationally exposed to aromatic amines and PAHs. Aromatic amines may be connected with induction of bladder cancer in persons who have been in contact with azo dyes and in coke-oven workers. PAHs may also contribute to elevated bladder-cancer risks in coke-oven workers and in underground coal miners.

Influence of polymorphisms of GSTM1 and GSTT1 for risk of renal cell cancer in workers with long-term high occupational exposure to trichloroethene.

Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTM1 and GSTT1 isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTM1 and GSTT1 genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTM1 gene (GSTT1 +) and 18 at least one functional GSTT1 gene (GSTT1 +). Among the 48 reference workers, 17 were GSTM1 + and 31 were GSTT1 +. Odds ratio for renal cell cancer were 2.7 for GSTM1 + individuals (95% CI, 1.18-6.33; P < 0.02) and 4.2 for GSTT1 + individuals (95% CI, 1.16-14.91; P < 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI.

Glutathione S-transferase GSTM1 and GSTT1 null genotypes as potential risk factors for urothelial cancer of the bladder.

One-hundred-and-thirteen patients with cancer of the urinary bladder (cases) were examined with respect to the frequency of null genotypes of the polymorphic glutathione S-transferases GSTM1 and GSTT1. The allelic background in the German population of the area was evaluated by analysing 170 newborns (controls). The frequency of GSTM1 and GSTT1 null genotypes in this population, using methods based upon internal standard controlled polymerase chain reaction (PCR), was 0.54 and 0.18 respectively. An elevated relative bladder cancer risk of GSTM1 null genotype carriers was indicated by comparison of this background with the data of the bladder cancer cases (OR = 1.81; 95% CI [1.10, 2.98]; p = 0.019). The frequencies of the GSTT1 null genotype in the total group of bladder cancer cases versus controls did not differ statistically. However, a significantly higher relative risk of bladder cancer for the GSTT1 null genotype was detected in the cases-subgroup of non-smokers (OR = 3.84; 95% CI [1.21, 12.23]; p = 0.023). Thus, the GSTT1 null genotype might represent a minor risk factor for human bladder cancer which should be further investigated.

Comparative genotyping and phenotyping of glutathione S-transferase GSTT1.

Only limited information is available so far concerning the human glutathione S-transferase isoenzyme class theta encoded by the GSTT1 gene. The aim of the study was to characterize individuals in respect to a polymorphic deletion of the GSTT1 gene and to validate these results with the phenotypical determination of the "conjugator status" according to Hallier et al. (1993). Determination of the GSTT1 genotype was done in 40 healthy adults by using an assay based on internal standard controlled polymerase chain reaction. The GSTT1-1 phenotype was determined by measuring the erythrocyte conjugating activity towards methyl chloride using a gas chromatographic assay. Genotypically, 34 individuals out of 40 were classified as GSTT1 positive; the remainder were negative. These results could be confirmed by phenotyping in all but one case. In the present study the frequency of "nonconjugators" was 15%. Our study demonstrates the reliability of the suggested PCR assay for GSTT1 genotyping which is easier to perform than the phenotyping assay and is not affected by confounding factors.