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Biomedical subjects

S Bauer

Publications and source records attributed to S Bauer.

At least 19 recordsLinked to original sources
PubMed2000

Nested case-control study of leukemia among a cohort of persons exposed to ionizing radiation from nuclear weapon tests in kazakhstan (1949-1963).

PURPOSE: A unique opportunity for epidemiological studies of cancer and other health effects of radiation exposures exists around the Semipalatinsk Nuclear Test Site in Kazakhstan. The present study is the first analysis of leukemia risk among the residents of downwind settlements exposed to radioactive fallout from atmospheric nuclear weapon tests (1949-1963) and followed up from 1960 to 1998.METHODS: Within the cohort of 10,000 exposed subjects a case-control study was nested, including 22 leukaemia cases (except chronic lymphoid leukemia) and 132 controls individually (1:6 ratio) matched by birth year and sex. Leukemia deaths were identified by death certificates and diagnoses were verified by hospital records. The individual dose including internal and external exposure assessment was estimated according to the residency and age at exposure. All odds ratios were adjusted for ethnicity (Russian or Kazakh) as an independent variable.RESULTS: The median dose of exposure for all subjects was 0.89 Sv ranging from 0.01 to 5.71 Sv. A nearly two-fold increased risk of leukemia was found (OR = 1.91; 95% CI = 0.38 to 9.67) for persons exposed to doses of >2.0 Sv as compared to those exposed to <0.5 Sv, but no increase in risk with the dose was found for those exposed to doses lower than 2 Sv. Detailed evaluation of dose-response showed an excess relative risk for leukemia of 10% per 1 Sv of additional exposure.CONCLUSIONS: Our findings suggest that there is an increased risk of leukemia among those exposed to >2 SV as compared to those exposed to <0.5 Sv, but this could have been a chance finding due to the small number of cases and low statistical power.

Journal Article↗
PubMed2000

Characterization of abundance and diversity of lactic acid bacteria in the hindgut of wood- and soil-feeding termites by molecular and culture-dependent techniques.

Lactic acid bacteria have been identified as typical and numerically significant members of the gut microbiota of Reticulitermes flavipes and other wood-feeding lower termites. We found that also in the guts of the higher termites Nasutitermes arborum (wood-feeding), Thoracotermes macrothorax, and Anoplotermes pacificus (both soil-feeding), lactic acid bacteria represent the largest group of culturable carbohydrate-utilizing bacteria (3.6-5.2x10(4) bacteria per gut; 43%-54% of all colonies). All isolates were coccoid and phenotypically difficult to distinguish, but their enterobacterial repetitive intergenic consensus sequence (ERIC) fingerprint patterns showed a significant genetic diversity. Six different genotypes each were identified among the isolates from R. flavipes and T. macrothorax, and representative strains were selected for further characterization. By 16S rRNA gene sequence analysis, strain RfL6 from R. flavipes was classified as a close relative of Enterococcus faecalis, whereas strain RfLs4 from R. flavipes and strain TmLO5 from T. macrothorax were closely related to Lactococcus lactis. All strains consumed oxygen during growth on glucose and cellobiose; oxygen consumption of these and other isolates from both termite species was due to NADH and pyruvate oxidase activities, but did not result in H2O2 formation. In order to assess the significance of the isolates in the hindgut, denaturing gradient gel electrophoresis was used to compare the fingerprints of 16S rRNA genes in the bacterial community of R. flavipes with those of representative isolates. The major DNA band from the hindgut bacterial community was further separated by bisbenzimide-polyethylene glycol electrophoresis, and the two resulting bands were sequenced. Whereas one sequence belonged to a spirochete, the second sequence was closely related to the sequences of the Lactococcus strains RfLs4 and TmLO5. Apparently, those isolates represent strains of a new Lactococcus species which forms a significant fraction of the complex hindgut community of the lower termite R. flavipes and possibly also of other termites.

Animals↗
PubMed2000

Progressive liver calcifications in neonatal coxsackievirus infection.

Coxsackievirus group B can cause a severe systemic disease in the perinatal period. Severe manifestations like meningitis, encephalitis, hepatitis, and myocarditis have been previously reported. A case of a twin neonate infected by coxsackievirus group B is described, who developed progressive extensive hepatic calcifications demonstrated by ultrasound and computed tomography with follow-up. Hepatic calcifications in coxsackievirus infection have not been previously reported.

Calcinosis↗
PubMed2000

Unusual regulation of cyclin D1 and cyclin-dependent kinases cdk2 and cdk4 during in vivo mitotic stimulation of olfactory neuron progenitors in adult mouse.

The molecular mechanisms underlying cell cycle control in neuronal progenitors have been investigated with adult mouse olfactory epithelium as a model system. Odor receptive neurons of mammalian olfactory epithelium are short-lived and renewed in the adult by mitotic division of intrinsic neuronal progenitors. Ablation of the synaptic target, olfactory bulb, induces sequentially extensive apoptosis of sensory neurons and then stimulation of progenitor proliferation, peaking at 36 h and 4 days, respectively, postlesion. Known molecular effectors of G1 phase entry have been assessed on protein extracts of olfactory organs sampled at various postbulbectomy times in adult mice. The decay of betaIII-tubulin and olfactory marker protein levels and the rise of proliferating cell nuclear antigen (PCNA) levels, starting 1 and 3 days, respectively, postlesion, provided the kinetic frame of neuronal dynamics. Cyclin D1, cyclin E, and cyclin-dependent kinase cdk2 levels, low in olfactory organ of intact mice, increased 3 days after bulbectomy in parallel with PCNA levels; cdk4 content was initially high and unaffected by lesioning. Western blots of the known cdk inhibitors revealed proliferation-related decreases of p18, p21, and p27 from high expression in intact organs. Immunoprecipitation of cdk2 and cdk4 fractions of protein extracts at 4 days postlesion (mitotic reaction peak) versus control, followed by cyclin D1 immunoblotting, and vice versa, revealed that levels of both cyclin D1/cdk2 and cyclin D1/cdk4 complexes, as well as their kinase activities, were dramatically increased after lesion. In vivo proliferation of olfactory neuronal lineage cells thus involves functional binding of cyclin D1 with cdk2 and cdk4, with differential activation mechanisms for cdk2 and cdk4. In addition, the RT-PCR-detected cyclin D1 mRNA level remained unaffected after bulbectomy, which indicated that the cyclin D1 rise should involve posttranscriptional mechanisms in this in vivo neuronal system. These observations are discussed, along with their relevance to cell cycle control and to olfactory neuron dynamics.

Age Factors↗
PubMed2000

Primary gastric B-cell lymphoma: results of a prospective multicenter study. The German-Austrian Gastrointestinal Lymphoma Study Group.

BACKGROUND & AIMS: Appropriate management of primary gastric lymphoma is controversial. This prospective, multicenter study aimed to evaluate the accuracy of endoscopic biopsy diagnosis and clinical staging procedures and assess a treatment strategy based on Helicobacter pylori status and tumor stage and grade. METHODS: Of 266 patients with primary gastric B-cell lymphoma, 236 with stages EI (n = 151) or EII (n = 85) were included in an intention-to-treat analysis. Patients with H. pylori-positive stage EI low-grade lymphoma underwent eradication therapy. Nonresponders and patients with stage EII low-grade lymphoma underwent gastric surgery. Depending on the residual tumor status and predefined risk factors, patients received either radiotherapy or no further treatment. Patients with high-grade lymphoma underwent surgery and chemotherapy at stages EI/EII, complemented by radiation in case of incomplete resection. RESULTS: Endoscopic-bioptic typing and grading and clinical staging were accurate to 73% and 70%, respectively, based on the histopathology of resected specimens. The overall 2-year survival rates for low-grade lymphoma did not differ in the risk-adjusted treatment groups, ranging from 89% to 96%. In high-grade lymphoma, patients with complete resection or microscopic tumor residuals had significantly better survival rates (88% for EI and 83% for EII) than those with macroscopic tumor residues (53%; P < 0.001). CONCLUSIONS: There is a considerable need for improvement in clinical diagnostic and staging procedures, especially with a view toward nonsurgical treatment. With the exception of eradication therapy in H. pylori-positive low-grade lymphoma of stage EI and the subgroup of locally advanced high-grade lymphoma, resection remains the treatment of choice. However, because there is an increasing trend toward stomach-conserving therapy, a randomized trial comparing cure of disease and quality of life with surgical and conservative treatment is needed.

Adult↗
PubMed2000

Promoter elements and transcription factors involved in differentiation-dependent human chorionic gonadotrophin-alpha messenger ribonucleic acid expression of term villous trophoblasts.

Differentiation of primary villous cytotrophoblasts into syncytia is associated with increasing production of alpha and beta human CG subunits, which is predominantly governed at the level of messenger RNA expression. Here, we present a detailed study on the mechanisms involved in the differentiation-dependent regulation of the trophoblast-specific CGalpha gene promoter. Site-directed mutations in each of the five DNA-elements of the composite enhancer were performed to investigate the contribution of the individual regulatory sequences to the overall transcriptional activity of the promoter at two different stages of trophoblast in vitro differentiation. We show that deletion of one cyclic AMP response element (CRE) did not affect CGalpha promoter activity in cytotrophoblasts; however, it reduced transcription by 33% in differentiating cultures. Removal of both CREs almost abolished transcription at early and later stages of in vitro differentiation. Upon mutation the enhancer elements alphaACT, JRE, and CCAAT significantly decreased luciferase reporter transcription; however their contribution to the total promoter activity did not change during in vitro differentiation. Contrary to that, mutated TSE diminished promoter activity by 19% during 12 and 48 h of cultivation but reduced luciferase expression by 78% between 48 and 84 h of differentiation. In electrophoretic mobility shift assay, the TSE interacted with activating protein (AP)-2alpha in both primary trophoblasts and choriocarcinoma cells. While CRE-interacting proteins were detectable 12 h after isolation, the TSE-binding complex did not appear before 36 h of in vitro differentiation. During syncytium formation increasing protein expression of activating transcription factor (ATF)-1, cAMP response element-binding protein (CREB)-1, and AP-2alpha was observed on Western blots. Moreover, phosphorylated CREB-1 and ATF-1 accumulated between 24 and 78 h of trophoblast cultivation. By fluorescence immunohistochemistry, we show that CREB-1 was predominantly expressed in syncytiotrophoblasts, whereas ATF-1 and AP-2alpha localized to the syncytium and some cytototrophoblasts as well as to stromal and endothelial cells of the placental villus. Phosphorylated CREB-1/ATF-1 and the coactivator protein CBP were primarily detected in syncytial nuclei, suggesting the presence of functional, cAMP-dependent transcriptional complexes in the differentiated tissue. In agreement to the in vivo situation, phosphorylated CREB-1/ATF-1 were observed in nuclei of the differentiated trophoblast cultures. The activity of the CGalpha promoter as well as CREB-1/ATF-1 phosphorylation increased upon elevation of cAMP levels and overexpression of the catalytic subunit of protein kinase A. Additionally, we demonstrate that overproduction of the enzyme enhanced protein expression and binding of AP-2alpha to the TSE. We conclude that differentiation-dependent transcription of the CGalpha gene in villous trophoblasts is mainly governed by increasing expression of AP-2alpha and PKA-dependent phosphorylation of CREB-1 and ATF-1.

Activating Transcription Factor 1↗
PubMed2000

Sibling vesicoureteral reflux in multiple gestation births.

BACKGROUND: Vesicoureteral reflux (VUR) is the most commonly inherited disease of the genitourinary tract. Although the majority of evidence supports a genetic cause, the tendency for this condition to spontaneously improve over time has made it difficult to determine the actual mode of transmission. We report the incidence of VUR in siblings of multiple gestation births and for the first time compare the relative incidence of reflux between identical and fraternal twins. METHODS: A database consisting of all radionuclide cystograms and voiding cystourethrograms performed between the years 1986 and 1996 was searched for multiple gestation births. The medical records of each patient were evaluated for age at presentation, zygosity, reflux grade, and time to resolution. Children with secondary causes of VUR (eg, posterior urethral valves) were excluded. Triplets were treated as 2 pairs of twins for statistical analysis. RESULTS: Forty-six pairs met the inclusion criteria (31 dizygotic and 15 monozygotic). Overall, 23 (50%) of 46 siblings of index cases had demonstrable VUR. Comparison of VUR prevalence between identical and nonidentical twins was revealing with 80% (12/15) of identical twins and 35% (11/31) of fraternal twins having VUR. When only the youngest individuals in each group were considered, 100% (7/7) of the monozygotics and 50% (5/10) of the dizygotics demonstrated this trait. CONCLUSIONS: High concordance for VUR in identical twin siblings supports a genetic basis for the transmission of this disease. Results obtained from fraternal twin siblings provides convincing evidence that this trait is transmitted in an autosomal dominant fashion.

Child↗
PubMed2000

Systemic and local immunomodulatory effects of intravesical BCG therapy in patients with superficial urinary bladder carcinomas.

PURPOSE: The aim of the present study was to elucidate whether only local, or also systemic immunomodulatory effects may be induced by intravesical BCG therapy of superficial urinary bladder cancer. MATERIALS AND METHODS: A total of 37 patients with stages Ta to T1b superficial transitional cell bladder carcinomas received 6 weekly BCG instillations after transurethral resection of the tumor. In a first group of 19 patients blood was taken before each BCG instillation and 6 weeks after the last one. In a second group of 18 patients blood and urine was taken before and 2, 6, and 24 hours after each BCG instillation. In the mitogen-stimulated whole blood cell cultures and in the urine samples the levels of the cytokines IL-1beta, IL-2, IL-10, TNF-alpha and IFN-gamma were determined by enzymoimmunological tests. Additionally, in all plasma and urine samples the levels of TNF-p75-receptor (TNF-p75-R) were measured. RESULTS: Comparison of ex vivo leukocyte cytokine production in the blood cell cultures of the patients of group I revealed no significant change in the levels of the cytokines. In contrast, TNF-p75-R plasma levels increased significantly during the experimental time of 12 weeks (p < or =0.01). In the blood cell cultures of the group II patients a different daytime variation of cytokine production was seen, compared to the 19 healthy controls. After BCG instillation the normal peak cytokine production in the evening was suppressed. A significant rise in plasma TNF-p-75-R levels was measured 24 hours after BCG instillation (p < or =0.05). In the urine of these patients significantly higher levels of all measured cytokines and TNF-p75-R were observed 6 to 24 hours after the instillation. CONCLUSIONS: The results suggest that besides the well known local immune activation, BCG instillation also leads to a modulation of peripheral immune mechanisms.

Adjuvants, Immunologic↗
PubMed1999

Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.

Cytotoxicity, Immunologic↗
PubMed1999

An activating immunoreceptor complex formed by NKG2D and DAP10.

Many immune receptors are composed of separate ligand-binding and signal-transducing subunits. In natural killer (NK) and T cells, DAP10 was identified as a cell surface adaptor protein in an activating receptor complex with NKG2D, a receptor for the stress-inducible and tumor-associated major histocompatibility complex molecule MICA. Within the DAP10 cytoplasmic domain, an Src homology 2 (SH2) domain-binding site was capable of recruiting the p85 subunit of the phosphatidylinositol 3-kinase (PI 3-kinase), providing for NKG2D-dependent signal transduction. Thus, NKG2D-DAP10 receptor complexes may activate NK and T cell responses against MICA-bearing tumors.

Amino Acid Sequence↗
PubMed1999

Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB.

Human MHC class I-related molecules, MICA and MICB, are stress-induced antigens that are recognized by a subset of gamma delta T cells expressing the variable region Vdelta1. This functional association has been found to be limited to intestinal epithelium, where these T cells are prevalent and where MICA and, presumably, MICB are mainly expressed. However, increased frequencies of Vdelta1 gamma delta T cells have been observed in various epithelial tumors; moreover, MICA/B are expressed on diverse cultured epithelial tumor cells. With freshly isolated tumor specimens, expression of MICA/B was documented in many, but not all, carcinomas of the lung, breast, kidney, ovary, prostate, and colon. In tumors that were positive for MICA/B, the frequencies of Vdelta1 gamma delta T cells were significantly higher than in those that were negative. Vdelta1 gamma delta T cell lines and clones derived from different tumors recognized MICA/B on autologous and heterologous tumor cells. In accord with previous evidence, no constraints were observed in these interactions, such as those imposed by specific peptide ligands. Thus, MICA/B are tumor-associated antigens that can be recognized, in an apparently unconditional manner, by a subset of tumor-infiltrating gamma delta T cells. These results raise the possibility that an induced expression of MICA/B, by conditions that may be related to tumor homeostasis and growth, could play a role in immune responses against tumors.

Cytotoxicity, Immunologic↗
PubMed1999

Immunotherapy of human tumors with T-cell-activating bispecific antibodies: stimulation of cytotoxic pathways in vivo.

Bispecific monoclonal antibodies (Bi-mAbs) specific for a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes represent one of the most successful experimental strategies for the immunotherapy of cancer. We report that the in vivo administration of both alpha-CD3/CD30 and alpha-CD28/CD30 Bi-mAbs results in the specific activation of xenotransplanted, resting human T cells infiltrating the CD30-positive Hodgkin's tumor. Bi-mAb treatment resulted in enhanced expression of cytokines such as interleukin 1beta, interleukin 2, tumor necrosis factor type alpha, and activation markers including Ki-67, CD25, and CD45RO in tumor-infiltrating lymphocytes. This antigen-dependent, local T-cell stimulation led to the activation of the cytolytic machinery in T lymphocytes, determined by the up-regulation of mRNA-encoding perforin and the cytotoxic serine-esterases granzymes A and B. The Bi-mAb-induced generation of CTLs depended on the presence of the CD30 antigen and the combined application of both Bi-mAbs. Our findings suggest that the combined application of T-cell-activating Bi-mAbs is able to achieve a tumor site-specific activation of the T-cell cytolytic machinery in vivo. The fact that these cytotoxic cells do not home in tumor-associated antigen-negative tissue and do not enter circulation might explain our previous observations (C. Renner et al., Blood, 87: 2930-2937, 1996) of a high cure rate in preclinical models even at an advanced stage of disease.

Animals↗
PubMed1999

A registry for exposure and population health in the Altai region affected by fallout from the Semipalatinsk nuclear test site.

A registry of the rural population in the Altai region exposed to fallout from nuclear tests at the Semipalatinsk test site (STS) was established more than four decades after the first Soviet nuclear explosion on August 29, 1949. Information about individuals living in an exposed and a control area was collected using all available local sources, such as kolkhoz documentation, school registries, medical treatment records and interviews with residents. As a result, a database comprising an exposed group of 39 179 individuals from 53 Altai region villages, 6769 external and 3303 internal controls was compiled. For several settlements, effective dose estimates reached the level of 1.5 Sv, while the average effective dose estimate in the exposed group was 340 mSv. Dosimetric data, vital status information and health records gathered at rayon and village medical facilities are held in the registry. Cause-of-death information for deceased residents is obtained from death registration forms archived at the Altai region vital statistics office. At present, a follow-up of approximately 40% of the population exposed in 1949 has been done. More will be added by searching for migrants to the larger towns of the Altai region, i.e. Barnaul, Rubtsovsk and Biisk. In order to assess the influence of radiation exposure, analytical studies with a case-control design for stomach and lung cancer are currently being prepared. The number of known cases is sufficient to detect an odds ratio of 1.5 at the 95% confidence level. Epidemiological studies in populations affected by fallout from STS may be equally important to the atomic bomb survivors' study for the direct quantification of radiation effects. The range of exposure rates experienced will extend the acute high-dose-rate findings from Hiroshima/Nagasaki towards acute and protracted lower exposures, which are more relevant for radiation protection issues.

Environmental Exposure↗
PubMed1999

Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients.

OBJECTIVE: The mutual drug-drug interaction potential of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin and cyclosporine (INN, ciclosporin) in kidney transplant recipients receiving individual immunosuppressive treatment was evaluated with respect to pharmacokinetic behavior of either drug and tolerability of concomitant use. METHODS: Plasma and urine concentrations of cerivastatin and its major metabolites were determined after administration of 0.2 mg single-dose cerivastatin to 12 kidney transplant recipients (9 men and 3 women) who were receiving stable individual cyclosporine treatment (mainly 200 mg twice a day). These results were compared with the single-dose pharmacokinetic results obtained from a healthy control group (n = 12, age-comparable men). Cerivastatin steady-state pharmacokinetics were evaluated in the same patients during continued immunosuppressive treatment 4 to 6 weeks later, after a 7-day treatment of 0.2 mg cerivastatin once a day. Cyclosporine steady-state concentration-time profiles were determined in blood with monoclonal (EMIT [enzyme multiplied immunoassay technique] assay, parent drug specific) and polyclonal antibodies (FPIA [fluorescence polarization immunoassay] assay, cyclosporine plus metabolites) during cerivastatin cotreatment and compared with predosing data. RESULTS: Coadministration of 0.2 mg cerivastatin once a day to the kidney transplant recipients treated with individual doses of cyclosporine and other immunosuppressive agents resulted in a 3- to 5-fold increase in cerivastatin and metabolites plasma concentrations. Cerivastatin and metabolites elimination half-lives were unaffected, and no accumulation occurred during multiple-dosing conditions. Cerivastatin had no influence on steady-state blood concentrations of cyclosporine or cyclosporine metabolites in these patients. The concomitant use of both drugs was well tolerated. CONCLUSIONS: Cerivastatin and metabolites plasma concentrations were significantly increased in kidney transplant recipients treated with cyclosporine and other immunosuppressive agents. Displacement from the main site for cerivastatin distribution-the liver-by cyclosporine-inhibited liver transport processes may explain the decrease in both metabolic clearance and volume of distribution for cerivastatin and metabolites.

Adult↗
PubMed1999

Commissioning of a micro multi-leaf collimator and planning system for stereotactic radiosurgery.

PURPOSE: A computer controlled micro multi-leaf collimator, m3 mMLC, has been commissioned for conformal, fixed-field radiosurgery applications. Measurements were made to characterise the basic dosimetric properties of the m3, such as leaf transmission, leakage and beam penumbra. In addition, the geometric and dosimetric accuracy of the m3 was verified when used in conjunction with a BrainSCAN v3.5 stereotactic planning system. MATERIALS AND METHODS: The m3 was detachably mounted to a Varian Clinac 2100C accelerator delivering 6 MV X-rays. Leaf transmission, leakage, penumbra and multiple, conformal fixed field dose distributions were measured using calibrated film in solid water. Beam data were collected using a diamond detector in a scanning water tank and planned dose distributions were verified using LiF TLDs and film. A small, shaped phantom was also constructed to confirm field shaping accuracy using portal images. RESULTS: Mean transmission through the closed multi-leaves was 1.9 +/- 0.1% and leakage between leaves was 2.8 +/- 0.15%. Between opposing leaves abutting along the central beam-axis transmission was approximately 15 +/- 3%, but was reduced to a mean of 4.5 +/- 0.6% by moving the abutmen position 4.5 cm off-axis. Beam penumbrae were effectively constant as a function of increasing square field size and asymmetric fields and was seen to vary non-linearly when shaped to diagonal, straight edges. TMR, OAR and relative output beam data measurements of circular m3 fields were comparable to conventional, circular stereotactic collimators. Multiple, conformal field dose distributions were calculated with good spatial and dosimetric accuracy, with the planned 90% isodose curves agreeing with measurements to within 1-2 mm and to +/- 3% at isocentre. Portal films agreed with planned beams eye-view field shaping to within 1 mm. CONCLUSIONS: The m3 micro multi-leaf collimator is a stable, high precision field-shaping device suitable for small-field, radiosurgery applications. Dose distributions can be accurately calculated by a planning system using only a few beam data parameters.

Brain↗
PubMed1999

Crystal structure of the MHC class I homolog MIC-A, a gammadelta T cell ligand.

The major histocompatibility complex (MHC) class I homolog MIC-A functions as a stress-inducible antigen that is recognized by a subset of gammadelta T cells independent of beta2-microglobulin and bound peptides. Its crystal structure reveals a dramatically altered MHC class I fold, both in detail and overall domain organization. The only remnant of a peptide-binding groove is a small cavity formed as the result of disordering a large section of one of the groove-defining helices. Loss of beta2-microglobulin binding is due to a restructuring of the interaction interfaces. Structural mapping of sequence variation suggests potential receptor binding sites on the underside of the platform on the side opposite of the surface recognized by alphabeta T cell receptors on MHC class I-peptide complexes.

Crystallography, X-Ray↗
PubMed1999

Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin.

AIMS: The genetically polymorphic cytochrome P450 enzyme CYP2C9 metabolizes many important drugs. We studied the frequency of the amino acid variants cysteine144 (CYP2C9*2 ) and leucine359 (CYP2C9*3 ) in a Turkish population and the correlation between genotype and phenotype using phenytoin as probe drug. METHODS: CYP2C9 alleles *2 and *3 were measured in 499 unrelated Turkish subjects by PCR and restriction fragment length pattern analysis. Phenotyping was performed in a subgroup of 101 volunteers with a single oral dose of 300 mg phenytoin and concentration analysis in serum drawn 12 h after dosage. RESULTS: CYP2C9 allele frequencies in 499 unrelated Turkish subjects were 0.794 for CYP2C9*1, 0.106 for CYP2C9*2 and 0. 100 for CYP2C9*3. Mean phenytoin serum concentrations at 12 h after dosage were 4.16 mg l-1 (95% CI 3.86-4.46) in carriers of the genotype CYP2C9*1/1, 5.52 mg l-1 (4.66-6.39) in CYP2C9*1/2, and 5.65 mg l-1 (4.86-6.43) in CYP2C9*1/3. These differences were significant and accounted for 31% of total variability in phenytoin trough levels. Mean 12 h concentration ratios of 5-(para-hydroxyphenyl)-5-phenylhydantoin/phenytoin (p-HPPH/P) were 0. 43 (0.39-0.47) for CYP2C9*1/1 compared with 0.26 (0.21-0.31) for CYP2C9*1/2, 0.14 (0.13-0.14) for CYP2C9*2/2, 0.21 (0.18-0.24) for CYP2C9*1/3, and 0.02 for CYP2C9*3/3; all mutant genotypes were significantly different compared with CYP2C9*1/1. CONCLUSIONS: Frequency of the two CYP2C9 variants in Turkish subjects was in a similar range as in other Caucasian populations. A significant proportion of the interindividual variability in phenytoin trough levels is explained by the genotypes. The 12 h serum concentrations after a single phenytoin dose may be used for routine phenotyping of CYP2C9 mediated metabolic clearance and the p-HPPH/P ratios may be even more sensitive indicators of CYP2C9 activity.

Alleles↗