Variation of the N-acetyltransferase 2 gene in a Romanian and a Kyrgyz population.

As part of a project on environmental disasters in minority populations, this study aimed to evaluate differences in the sequence of N-acetyltransferase 2 (NAT2) as a metabolic susceptibility gene in yet unexplored ethnicities. Eight single nucleotide polymorphisms (SNP) in the NAT2 coding region and a variant in the 3' flanking region were analyzed in 290 unrelated Kyrgyz and 140 unrelated Romanians by SNP-specific PCR analysis. The variants 341C, 481T, and 803G were less and 857A more prevalent in Kyrgyz (P < 0.0001). The variant at site 857 indicates Asian descent. 282C>T and 590G>A showed no significant variation by ethnicity. 364G>A and 411A>T turned out to be monomorphic. Database comparisons of the NAT2 minor allele frequencies support that Romanians belong to Caucasians and Kyrgyz are in between Caucasians and East Asians. The distributions of predicted haplotypes differed significantly between the two ethnicities where the Kyrgyz showed a higher genetic diversity. The haplotype without mutations was more common in Kyrgyz (40.1% in Kyrgyz, 29.3% in Romanians). Accordingly, the imputed slow acetylator phenotype was less prevalent in Kyrgyz (35.2% versus 51.4% in Romanians). We found pronounced ethnic differences in NAT2 genotypes with yet unknown effect on the health risks for environmental or occupational exposures in minority populations.     

Gehörschäden durch Silvester-Feuerwerkskörper Befragung zur Inzidenz von Knall- und Explosionstraumata in der Bundesrepublik Deutschland zur Jahreswende 1998/99

In der Ausgabe 4/99 der HNO wurde in einer ausführlichen übersichtsarbeit die Gef?hrdung für das Geh?r durch Freizeitl?rm dargestellt [8]. Die Autoren hoben im besonderen die wachsende Zahl irreversibler Innenohrsch?den bei Kindern, Jugendlichen und jungen Erwachsenen hervor. In der Stellungnahme der Bundes?rztekammer werden mit dem Umweltbundesamt abgestimmte Pegelbegrenzungen für Diskotheken, tragbare Musikwiedergabeger?te sowie l?rmgebende Spielzeuge konkret vorgechlagen, so da? der Gesetzgeber eine klare Handhabe hat [6,7]. Feuerwerksk?rper spielen neben lauten Kinderspielzeugen, Musik bei Besuchen von Diskotheken oder Gro?veranstaltungen, tragbaren Musikabspielger?ten und Schie?l?rm eine urs?chliche Rolle für die im Freizeitbereich entstandene, l?rmbedingte Innenohrschwerh?rigkeit. Um das Ausma? der Geh?rsch?den durch Feuerwerksk?rper abzusch?tzen, wurde eine retrospektive Befragung bundesdeutscher HNO-Kliniken und HNO-Abteilungen zu Knall- und Explosionstraumata in der Silvesternacht 1998/99 durchgeführt. Die vorliegenden Ergebnisse machen die Aktualit?t der Problematik für die Pr?ventivmedizin und den weiteren Handlungsbedarf auch auf diesem Gebiet des Freizeitl?rms deutlich.     

Analysis of mdm2 and p53 Gene Alterations in Glioblastomas and its Correlation with Clinical Factors

Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with probably prognostic implications. To elucidate the involvement of murine-double-minute (mdm)2 gene amplifications and mutations of the tumor suppressor gene p53 in the tumorigenesis of malignant gliomas we analyzed a series of 75 glioblastomas. The p53 mutations occur in one-third of glioblastomas, mdm2 amplifications were found in 13% of cases. Our analysis revealed a hot spot in the p53 gene locus in codon 156, the same point mutation was detected in 4 tumor samples. None of the mdm2 amplified tumors had p53 mutations, supporting the hypothesis, that mdm2 amplifications are alternative mechanisms for p53 inactivation. Patients with p53 mutated tumors were significantly younger characterized by a mean age of 44 years. Additionally association with longer overall survival could be detected for this subgroup of patients. In our study, survival estimation revealed a significant correlation of mdm2 gene amplification with shorter survival time, and support the hypothesis, that mdm2 oncogene activation appears to occur late in tumor progression and may be characteristic as negative prognostic marker.     

Changes in the classification of carcinogenic chemicals in the work area

Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories – IIIA1, IIIA2, IIIB – be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.     

Local application of vancomycin for prophylaxis of graft infection: Release of vancomycin from antibiotic-bonded dacron grafts,toxicity in endothelial cell culture,and efficacy against graft infection in an animal model

Methicillin-resistant strains ofStaphylococcus epidermidis cause an increasing number of prosthetic infections. This prompted us to test the uptake of vancomycin in various graft materials in vitro, its influence on graft healing, and its efficacy against graft infection in pigs. Incubation of six different Dacron graft materials in a vancomycin solution (20 gm/L) was performed. Grafts were then placed in plasma, and samples were taken over 72 hours to determine vancomycin levels. Release of vancomycin ranged from 775 µg/cm² to 3691 µg/cm² after 1 hour of incubation. Gelatin-covered grafts increased release of vancomycin fourfold when incubation time was extended to 24 hours; uncovered grafts or the collagen-covered graft did not. Graft healing was not complicated when a vancomycin-bonded, gelatin-impregnated Dacron graft was implanted to replace the common femoral artery in pigs. Four weeks after implantation, histologic examination revealed normal development of neointima and perigraft scar tissue in the vancomycin-treated (n=4) and untreated (n=5) grafts. To test the efficacy of local vancomycin against graft infection, grafts were implanted in the groin of pigs and contaminated with 2 × 10⁷ colony-forming units ofStaphylococcus aureus. Four weeks after implantation, all grafts were infected in the untreated group (n=6), with abscess, nonincorporated graft, and detection ofS. aureus from the graft. In the treatment group (n=6) vancomycin was added to the contaminated grafts. As a carrier for the vancomycin, we used a resorbable gelatin-glycerol foam. All grafts healed without infection. The difference between the treated and untreated groups is statistically significant (p<0.05). We conclude that it may be effective to prevent graft infection with local application of vancomycin if an in situ replacement of infected graft (infected by gram-positive bacteria) is necessary or if there is a high risk of infection by methicillin-resistant staphylococci.     

Modulation of EAE by vaccination with T cell receptor peptides: Vβ8 T cell receptor peptide-specific CD4 lymphocytes lack direct immunoregulatory activity

Resistance to experimental autoimmune encephalomyelitis (EAE) induced by vaccination with a peptide representing amino acids 39–59 of the rat T cell receptor (TCR) Vβ8 element has been ascribed to the induction of protective antibodies and T lymphocytes, both recognizing the Vβ8 TCR peptide (TCRP) as well as Vβ8 TCR-expressing encephalitogenic lymphocytes. In this study immunization with the Vβ8 TCR peptide conferred partial resistance to active induction of EAE in three of six rats. The immunoregulatory role of TCRP-specific T cells in resistance to EAE was investigated. In vitro, D4⁺ T cell lines reactive with the Vβ8 TCRP did not respond to encephalitogenic Vβ8 TCRP-bearing cell lines nor did they impair their MBP-induced activation. In vivo, activated TCRP-specific line cells did not ameliorate actively induced EAE. The beneficial effect of Vβ8 TCRP-vaccination on the course of EAE may be due to the induction of protective antibodies. Neither before, nor during or after EAE did we observe a cellular response to the Vβ8 TCRP in lymph nodes or spleens of MBP-immunized animals. Moreover, we were not able to established TCRP-specific T cell lines from EAE rats, but from all rats immunized with the TCRP. Our data do not support the assumption that Vβ8 TCRP-reactive CD4⁺ T cells are the population operative in resistance to EAE after recovery from disease.     

Evaluation of HMG-CoA reductase inhibitors for multiple sclerosis: opportunities and obstacles

The disease-modifying agents currently used in the treatment of multiple sclerosis (MS) are not completely effective and are associated with adverse effects and high costs. Thus, alternative treatment options are highly desirable. HMG-CoA reductase inhibitors (statins), widely prescribed as cholesterol-lowering agents, may be a future treatment option for MS--either in an add-on therapy regimen or alone--as they have been shown to exhibit potent immunomodulatory effects. Several recent reports have demonstrated that HMG-CoA reductase inhibitors prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, in vitro experiments with human immune cells have shown an immunomodulatory mode of action of HMG-CoA reductase inhibitors that is comparable to that of interferon-beta, an established treatment for MS. An open-label clinical trial assessing simvastatin treatment in patients with MS revealed a significant decrease in the number and volume of new lesions, as assessed using magnetic resonance imaging, and a favourable safety profile. A large multicentre, placebo-controlled phase II clinical trial assessing atorvastatin in patients with a clinically isolated syndrome (i.e. a single clinical event that is indicative of demyelination, and that predisposes to the development MS) has recently been initiated. However, prospective placebo-controlled trials of HMG-CoA reductase inhibitors in definite MS are difficult to perform because of ethical and financial issues. Furthermore, overly optimistic reports in the popular media, as well as the often uncontrolled access to HMG-CoA reductase inhibitors by patients with MS, complicate the evaluation of HMG-CoA reductase inhibitors as a realistic future treatment option for MS.     

Differential dopaminergic modulation of executive control in healthy subjects

Rationale Executive control (EC) has different subcomponents, e.g., response inhibition (measured, for example, by the Stroop task) and working memory (WM—measured, for example, by delayed response tasks, DRT). EC has been associated with networks involving the prefrontal cortex (PFC). Moreover, there is evidence that dopamine agonists, especially those with a D1 profile, may modulate EC, since in the PFC D1 subtype receptors are more abundant.Objective This study aimed to selectively distinguish whether D1 versus D2 dopamine agonism differentially influences EC related to the inhibition of irrelevant information and WM. Because of its D1 component, we predicted that the administration of pergolide (mixed D1/D2 agonist), in comparison with bromocriptine (D2 selective agonist) and placebo, would enhance performance in both EC tasks. Using a lateralized Stroop task, we predicted a decrease in the interference effect, as well as error rates, while no increase in facilitation effects. For the DRT task, we predicted fewer error scores in the delay condition.Methods Forty male healthy subjects participated in this randomized, double-blind, placebo-controlled, crossover study.Results For the Stroop task no superiority of pergolide was found; however, with bromocriptine, decreased interference was found. No modulation of lateralization effects was shown in interference measures. Moreover, subjects on pergolide showed an absence of facilitation effects. No effects of either agonist were found for the DRT.Conclusion Our findings suggest that dopamine agonists modulate two EC tasks differently. Furthermore, there seems to be a selective modulation of different aspects of the Stroop task.     

Histological Grading in Gastric Cancer by Ming Classification: Correlation with Histopathological Subtypes, Metastasis, and Prognosis

The aim of this prospective study was to analyze Ming’s classification in correlation with other currently used classification systems of gastric cancer. In addition, we wanted to define the prognostic significance of the Ming classification system. The present study analyzed material of 117 patients with gastric carcinoma who underwent D2-gastrectomy with curative intent. All specimens were catagorized according to International Union Against Cancer (UICC) classification, World Health Organization (WHO) classification, Borrmann classification, Laurén classification, Goseki classification, Ming classification, and tumor differentiation. For analysis of correlation between the classification systems, the correlation coefficient according to Spearman was calculated. The survival curves have been calculated according to the Kaplan-Meier method. According to the Ming classification, 38.5% of the carcinomas exhibited an expanding growth pattern, and 61.5% of specimens showed an infiltrating growth pattern. The subtypes according to the Ming and Laurén classification correlated significantly (P < 0.001). WHO classification (P < 0.001), tumor differentiation (P < 0.001), and Goseki classification (P < 0.001), as well as the macroscopic classification of Borrmann (P < 0.001) and the pT and pN categories of the UICC classification exhibited a highly significant correlation with the Ming classification (P < 0.001 and 0.001, respectively). Median overall survival was 31.3 months. In Kaplan-Meier analysis, the 3-year survival rates were lower in the infiltrative tumor type when compared to the expansive tumor type according to Ming (P = 0.0847). In multivariate analysis, only the UICC system presented as an independent prognostic factor in multivariate analysis (P < 0.001). This study shows that the Ming classification correlates significantly with the currently used classification systems for gastric cancer and with the UICC staging system, especially, the pT and pN category. The 3-year survival rates were lower in the infiltrative tumor type than in the expansive tumor type according to Ming. However, the Ming classification is not an independent prognostic factor.