Biomedical subjects

Thomas Lang

Publications and source records attributed to Thomas Lang.

At least 37 records · Page 2Linked to original sources

PubMed2005

Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C.

Peginterferon plus ribavirin is standard therapy for adults with chronic hepatitis C. As no data are available for children, the aim of the study was to evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in chronically infected children. Genotypes, alanine aminotransferase levels, and different routes of viral transmission were considered. In an open-labeled, uncontrolled pilot study, 62 children and adolescents (range, 2-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 microg/kg body weight once per week plus oral ribavirin (15 mg/kg x day) for 48 weeks. Sixty-one patients completed the study. Twenty-three children discontinued therapy after 6 months according to study protocol. Sustained viral response was documented in 22 (47.8%)of 46 patients with genotype 1, in 13 (100%) of 13 with genotype 2 or 3, in 1 of 2 with genotype 4, in 19 (70.4%) of 27 children with parenteral, in 12 (48%) of 25 with vertical, and in 5 of 9 with unknown route of infection. Overall, treatment was well tolerated. Nevertheless, some side effects were present in all treated patients. Eighty-three percent had leucopenia, but only 3 individuals required dose reduction and 10.3% developed thyroid autoantibodies and thyroid dysfunction. In conclusion, combination treatment of peginterferon alfa-2b with ribavirin showed encouraging results and was well tolerated in children and adolescents with chronic hepatitis C. Weekly dosing of peginterferon alfa-2b is a considerable advance for this age group. The treatment is not approved for children. Further controlled trials are needed.

Adolescent↗

PubMed2005

Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics.

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa-2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent-to-treat population. Children receiving interferon alfa-2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple-dose interferon alfa-2b and ribavirin peak and trough concentrations and area-under-the-curve were similar between children and adults. In conclusion, interferon alfa-2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus.

Adolescent↗

PubMed2005

Soluble cathepsin K: a novel marker for the prediction of nontraumatic fractures?

We sought to evaluate serum concentrations of cathepsin K in peripheral blood and to determine whether they correlated with bone-mineral density (BMD) and the incidence of nontraumatic fractures. We took blood samples from 162 patients (101 with osteoporosis, 48 with osteopenia) and 13 healthy controls, then conducted quantitative measurements of cathepsin K using a commercially available enzyme-linked immunosorbent assay. Cathepsin K concentrations were correlated with the incidence of nontraumatic fracture, BMD, markers of bone turnover (alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, parathyroid hormone, and C-telopeptide). The correlations between cathepsin K concentrations in subjects without fractures and in those with multiple nontraumatic fractures were statistically significant ( t = -2.1, degrees of freedom = 107, P = .036). The cathepsin K levels of controls and patients with osteoporosis were significantly different ( t = -3.7, degrees of freedom = 58.9, p>0.0001) These results suggest that the serum level of cathepsin K could serve as a marker for fracture prediction and BMD.

Adult↗

PubMed2005

Ethoxyresorufin-O-deethylase (EROD) activity in dab (Limanda limanda) as biomarker for marine monitoring.

GOAL, SCOPE AND BACKGROUND: Ethoxyresorufin-O-deethylase (EROD) is a well-accepted marker for biological effects in fish and is, therefore, part of numerous monitoring programmes. EROD activity was measured in livers of dab (Limanda limanda) from the German Bight (North Sea) from 1995 to 2003. The aim of the present long-term study was (a) time trend monitoring of EROD activity of dab from the German Bight and (b) to elucidate the needs for a successful application of EROD activity as an early warning system. METHODS: EROD activities were determined fluorimetrically in dab liver microsomes, using resorufin as an external standard. The limit of detection (LD) and the limit of quantification (LQ) were calculated. Results were referred to protein concentrations. RESULTS AND DISCUSSION: EROD activities of 610 female dab caught in different seasons between January 1995 and August 2003 were analyzed individually. Activities varied from < LD to 1768 pmol/(min mg protein) and showed an annual cycle as well as significant differences between the years. Highest EROD activities were observed in early summer and lowest activities during the winter period. In autumn 2002, significantly elevated EROD activities were detected, possibly related to effects of the River Elbe flood event. Two scenarios with different EROD baseline data are presented to discuss the prerequisites for the use of EROD as a monitoring tool. The comparison of these scenarios underlines the importance of appropriate season-specific baseline data. CONCLUSION: The use of EROD as an early warning tool for contaminant effects in dab in the German Bight has different prospects during the year, because, due to the high background variability, elevated EROD activities are less easy to detect in spring/ summer than during the remaining times of the year. RECOMMENDATION AND OUTLOOK: The availability of site-specific data on the EROD baseline level, its random variation and its annual cycle is a necessary prerequisite for monitoring. If monitoring is to be carried out only for a limited time period of the year, a season with low background variability in EROD activity (autumn) should be chosen to avoid the need for a compensation of the temperature-triggered shift in sexual cycles and the resulting changes in EROD activity.

Animals↗

PubMed2005

Uroflow nomogram for male adolescents.

PURPOSE: Uroflowmetry is well established for investigating lower urinary tract symptoms. Current nomograms are based on sample sizes limited to 8 men of the same age. We generated percentile curves for the maximum urinary flow rate (Qmax) in relation to voided volume in male adolescents in a large homogenous healthy group. MATERIALS AND METHODS: A total of 348 males who were 18 years old were investigated, excluding probands with a urological history. Only samples with a voided volume of 150 cc or more were included. One micturition was obtained per proband to determine Qmax, the average urinary flow rate, time to Qmax and volume. Resulting curves were compared with nomograms for children and adults. RESULTS: Average voided volume +/- SD was 262 +/- 91.9 cc (range 151 to 664). Qmax was 28.4 +/- 9.7 cc per second (range 11.4 to 76) with an average urinary flow rate of 18.6 +/- 5.5 cc per second (range 4 to 44), a micturition time of 16.9 +/- 6.8 seconds (range 7 to 48) and a mean time to Qmax of 7.8 +/- 4.1 seconds (range 1 to 25). A total of 341 probands had a Qmax of more than 15 cc per second, while only 7 showed a Qmax of less than 15 cc per second. At up to 350 cc Qmax increased with volume, followed by a plateau phase at 350 to 550 cc and a Qmax decrease at higher volumes. CONCLUSIONS: Voiding volumes in a large homogenous adolescent group demonstrated optimal Qmax at voiding volumes between 350 and 550 cc with a decrease at higher volumes. Therefore, uroflow studies in adolescent males should be interpreted with caution at volumes less than 350 and more than 550 cc.

Adolescent↗

PubMed2005

Multi-centre investigation on reference ranges for ROTEM thromboelastometry.

Reagent-supported thromboelastometry (TEM) with the ROTEM Whole Blood Haemostasis Analyser is an enhancement of thromboelastography, a method that is increasingly used for the point of care monitoring of acute perioperative bleeding disorders. We investigated the reference ranges of two activated tests (INTEM and EXTEM) and a test analysing specifically the fibrin component of coagulation (FIBTEM) in a multi-centre approach. The reference ranges obtained for the clotting time (CT), clot formation time (CFT), alpha angle (ALP), maximum clot firmness (MCF) and clot lysis parameters were comparable from centre to centre. INTEM: CT equals; 137-246 s, CFT equals; 40-100 s, MCF equals; 52-72 mm. EXTEM: CT equals; 42-74 s, CFT equals; 46-148 s, MCF equals; 49-71 mm. FIBTEM: MCF equals; 9-25 mm. ROTEM whole blood coagulation correlated weakly with a trend towards enhanced coagulation in females compared with males and in advanced age. The repeatability (within-run imprecision) of the results was dependent on the test with the following coefficients of variation: 1-5% (clot firmness, alpha angle), 3-12% (CT, CFT), 6-13% (FIBTEM clot firmness). Citrated blood samples were stable for ROTEM analysis stored within 6 h from drawing. In summary, the data showed that ROTEM thromboelastometry yields consistent values between centres and that providing general orientating reference ranges seems to be possible.

Age Factors↗

PubMed2005

Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz.

The present study investigated CYP2B6 genetic variability by sequencing genomic DNA samples of African-American, Ghanaian, Taiwanese, Japanese and Korean subjects throughout all exons and exon-intron boundaries. The most common nonsynonymous single nucleotide polymorphisms (SNPs) were 15631G > T (Q172H) and 18053A > G (K262R, together defining allele 2B6*6), both of which had frequencies close to 50% in Ghanaians and 30% in African-Americans. These SNPs have recently been shown to affect efavirenz pharmacokinetics and response in HIV patients. Eight new missense mutations (76A > T [T26S], 83A > G [D28G], 85C > A, 86G > C [both R29T], 15618C>T [T168I], 18038G > A [D257N], 21034C > T [R336C], 21498C > A [P428T]), three new silent mutations and two new intronic SNPs defining six novel alleles (*17A and B, *18, *19, *20, *21) were identified. Heterologous expression in COS-1 cells revealed pronounced reduction in expression and/or bupropion hydroxylase activity for variants T168I, D257N, R336C and P428T, whereas the triple mutant 2B6.17 (T26S, D28G, R29T) appeared to be functionally normal. These data extend the CYP2B6 knowledge base and should be particularly relevant for anti-HIV-therapy with efavirenz.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles.

The human microsomal cytochrome P450, CYP2B6, is involved in the biotransformation of several clinically important drugs. By complete sequence analysis of the human CYP2B6 gene coding regions in selected Caucasian DNA samples, we identified the five novel missense mutations 62A>T (Q21L in exon 1), 136A>G (M46V in exon 1), 12820G>A (G99E in exon 2), 13076G>A (R140Q in exon 3), and 21388T>A (I391N in exon 8). The recently described but functionally uncharacterized variant 13072A>G (K139E) was also observed. Haplotype analysis indicated the presence of at least six novel alleles that code for the protein variants CYP2B6.10 (Q21L, R22C), CYP2B6.11 (M46V), CYP2B6.12 (G99E), CYP2B6.13 (K139E, Q172H, K262R), CYP2B6.14 (R140Q), and CYP2B6.15 (I391N). Heterologous expression in COS-1 cells revealed comparable levels of CYP2B6 apoprotein and bupropion hydroxylase activity for CYP2B6.1 (wild type) and CYP2B6.10, whereas all other variants exhibited reduced expression and/or function. The three amino acid changes M46V, G99E, and I391N resulted in almost unmeasurable (M46V) or undetectable (G99E and I391N) enzyme activity, despite the presence of residual protein. The K139E change led to completely abolished protein expression; as a consequence, no function was detected. Expression in insect cells by recombinant baculoviruses confirmed these results and demonstrated the virtual absence of incorporated heme in these protein variants. The collective allele frequency of the four very low or null activity variants M46V, G99E, K139E, and I391N was 2.6% in a Caucasian study population. These data provide further insight into the genetic variability of CYP2B6 and demonstrate the existence of phenotypic null alleles in this gene.

Alleles↗

PubMed2004

Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight.

UNLABELLED: We measured cortical and trabecular bone loss using QCT of the spine and hip in 14 crewmembers making 4- to 6-month flights on the International Space Station. There was no compartment-specific loss of bone in the spine. Cortical bone mineral loss in the hip occurred primarily by endocortical thinning. INTRODUCTION: In an earlier study, areal BMD (aBMD) measurements by DXA showed that cosmonauts making flights of 4- to 12-month duration on the Soviet/Russian MIR spacecraft lost bone at an average rate of 1%/month from the spine and 1.5%/month from the hip. However, because DXA measurements represent the sum of the cortical and trabecular compartments, there is no direct information on how these bone envelopes are affected by spaceflight. MATERIALS AND METHODS: To address this, we performed a study of crewmembers (13 males and 1 female; age range, 40-55 years) on long-duration missions (4-6 months) on the International Space Station (ISS). We used DXA to obtain aBMD of the hip and spine and volumetric QCT (vQCT) to assess integral, cortical, and trabecular volumetric BMD (vBMD) in the hip and spine. In the heel, DXA was used to measure aBMD, and quantitative ultrasound (QUS) was used to measure speed of sound (SOS) and broadband ultrasound attenuation (BUA). RESULTS AND CONCLUSIONS: aBMD was lost at rates of 0.9%/month at the spine (p < 0.001) and 1.4-1.5%/month at the hip (p < 0.001). Spinal integral vBMD was lost at a rate of 0.9%/month (p < 0.001), and trabecular vBMD was lost at 0.7%/month (p < 0.05). In contrast to earlier reports, these changes were generalized across the vertebrae and not focused in the posterior elements. In the hip, integral, cortical, and trabecular vBMD was lost at rates of 1.2-1.5%/month (p < 0.0001), 0.4-0.5%/month (p < 0.01), and 2.2-2.7%/month (p < 0.001), respectively. The cortical bone loss in the hip occurred primarily by cortical thinning. Calcaneal aBMD measurements by DXA showed smaller mean losses (0.4%/month) than hip or spine measurements, with SOS and BUA showing no change. In summary, our results show that ISS crewmembers, on average, experience substantial loss of both trabecular and cortical bone in the hip and somewhat smaller losses in the spine. These results do not support the use of calcaneal aBMD or QUS measurements as surrogate measures to estimate changes in the central skeleton.

Absorptiometry, Photon↗

PubMed2004

More interventions do not necessarily improve outcome in critically ill patients.

OBJECTIVE: The organizational structure of health care facilities has been shown to affect outcome in critically ill patients. We evaluated the association between structures, treatments and outcomes in a large cohort of critically ill patients. DESIGN: Prospective multicentre cohort study. PATIENTS AND SETTING: A total of 26,186 patients consecutively admitted to 31 intensive care units (ICUs) in Austria from January 1998 through December 2000. MEASUREMENTS AND RESULTS: The ICUs were divided into three groups according to the size and function of the hospital: community hospitals and specialized trauma centers (group A); central referral hospitals (group B); and teaching hospitals (group C). Group C patients exhibited a significantly higher risk-adjusted mortality (O/E ratio). Although severity of illness at admission in groups B and C was similar, group C patients received significantly more invasive diagnostic and therapeutic interventions throughout their ICU stay: For 7 of 10 invasive interventions identified, odds ratios for group C vs group B patients were significantly increased, even after adjustment for age, gender, severity of illness and reason for admission (odds ratios 1.2-13.1; all 95% CIs >1). Risk-adjusted multivariate analysis confirmed that six of these invasive interventions were independently associated with mortality. Furthermore, nurse-to-patient ratios did not differ between groups, leading to a significantly increased nursing workload in group C ICUs. CONCLUSIONS: Several invasive interventions were independently associated with increased mortality. Our results provide strong evidence that this association was responsible in part for the increased risk-adjusted mortality in group C patients.

Adult↗

PubMed2004

BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by a cholestatic pattern of liver damage, also observed in hereditary or acquired dysfunction of the canalicular membrane transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein type 3 (MDR3, ABCB4). Controversy exists whether a genetically determined dysfunction of BSEP and MDR3 plays a pathogenic role in PBC and PSC. Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3. Sequencing spanned approximately 10,000 bp including promoter and coding regions as well as 50-350 bp of flanking intronic regions. In all, 46 and 45 variants were identified in BSEP and MDR3, respectively. No differences between the groups were detected either in the total number of variants (BSEP: control group: 37, PBC: 37, PSC: 31; and MDR3: control group: 35; PBC: 32, PSC: 30), or in the allele frequency of the common variable sites. Furthermore, there were no significant differences in haplotype distribution and linkage disequilibrium. In conclusion, this study provides an analysis of BSEP and MDR3 variant segregation and haplotype structure in a Caucasian population. Although an impact of rare variants on BSEP and MDR3 function cannot be ruled out, our data do not support a strong role of BSEP and MDR3 genetic variations in the pathogenesis of PBC and PSC.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2004

Computed axial tomography-MIBI image fusion for preoperative localization in primary hyperparathyroidism.

BACKGROUND: An imaging-guided unilateral surgical approach in patients with primary hyperparathyroidism (HPTH) requires reliable preoperative localization procedures. Using present imaging techniques, 60% to 80% of patients with primary HPTH can be treated successfully with limited surgery. Thus, further improvement of diagnostic accuracy is required. Computed axial tomography (CAT)-MIBI image fusion was introduced as a new technique for localizing enlarged parathyroid glands. We describe the new method and present its first results. METHODS: Six consecutive patients with primary HPTH underwent CAT-MIBI image fusion for preoperative parathyroid localization. CAT and technetium-99m-sestamibi scan were performed separately. The patient's head and neck were fixed with the noninvasive Vogele-Bale-Hohner Head Holder (VBH HeadFIX; Medical Intelligence, Schwabmünchen, Germany) and the BodyFIX (Medical Intelligence) vacuum cushion. Radiographic and scintigraphic markers were mounted at the head holder and the patient. CAT and MIBI images were fused by overlaying radiographic markers using a commercial software and workstation. RESULTS: In 5 patients, localization and dimension of the solitary adenomas were exactly predicted. In 1 patient with multiglandular disease (3 enlarged glands), CAT-MIBI image fusion was not able to predict multiple gland involvement. However, in a retrospective analysis of the localization study, the other two enlarged parathyroid glands could be correctly identified regarding their site and size. CONCLUSIONS: First results of CAT-MIBI image fusion are promising. The new technique provides a higher image resolution and better delimitation of enlarged parathyroid glands and adjacent anatomic structures than conventional scintigraphic methods.

Aged↗

PubMed2004

Treatment with raloxifene for 2 years increases vertebral bone mineral density as measured by volumetric quantitative computed tomography.

Volumetric quantitative computed tomography (vQCT), using multiple thin-slice acquisition, measures three-dimensional volumetric bone mineral density (BMD, mg/cm3). vQCT is often used to measure BMD of lumbar vertebrae and may detect early changes in trabecular, cortical, or integral BMD that extend beyond the technical limits of areal dual X-ray absorptiometry (DXA) BMD measurements. The objective of this study was to determine the effect of 2 years of raloxifene (RLX) treatment on several volumetric BMD measures in a subset of postmenopausal women (n=58) enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Patients in this study were randomized to one of three treatment groups: placebo (n=21), RLX 60 mg/day (n=17), or RLX 120 mg/day (n=20), and all patients received daily calcium (500 mg) and vitamin D (400-600 IU) supplementation. Data from the raloxifene treatment groups were pooled for each analysis. Following 2 years of raloxifene treatment, there was a significant percent change from baseline in the vQCT regions of interest (ROIs) of midintegral BMD, total trabecular BMD, and total integral BMD (P<0.05) compared to placebo, while there was no significant change in the spinal DXA BMD measurement. These data provide the first longitudinal assessment by vQCT of changes in vertebral bone density after 2 years of treatment with raloxifene. vQCT appears to be a valuable technique for measuring the effects of raloxifene treatment in this population of postmenopausal women with osteoporosis.

Absorptiometry, Photon↗

PubMed2004

Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder associated with increased risk of intrauterine fetal death and prematurity. There is increasing evidence that genetically determined dysfunction in the canalicular ABC transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) might be risk factors for ICP development. This study aimed to (i). describe the extent of genetic variability in BSEP and MDR3 in ICP and (ii). identify new disease-causing mutations. Twenty-one women with ICP and 40 women with uneventful pregnancies were recruited between April 2001 and April 2003. Sequencing of BSEP and MDR3 spanned 8-10 kb per gene and comprised the promoter region and 100-350 bp of the flanking intronic region around each exon. DNA sequencing of polymerase chain reaction fragments was performed on an ABI3700 capillary sequencer. MDR3 promoter activity of promoter constructs carrying different ICP-specific mutations was studied using reporter assays. A total of 37 and 51 variant sites were detected in BSEP and MDR3, respectively. Three non-synonymous sites in codons for evolutionarily conserved amino acids were specific for the ICP collective (BSEP, N591S; MDR3, S320F and G762E). Furthermore, four ICP-specific splicing mutations were detected in MDR3 [intron 21, G(+1)A; intron 25, G(+5)C and C(-3)G; and intron 26, T(+2)A]. Activity of the mutated MDR3 promoter was similar to that observed for the wild-type promoter. Our data further support an involvement of MDR3 genetic variation in the pathogenesis of ICP, whereas analysis of BSEP sequence variation indicates that this gene is probably less important for the development of pregnancy-associated cholestasis.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2004

Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver.

AIMS: To determine the genetic variability of multidrug resistance protein 3 (MRP3). METHODS: Genomic DNA samples from 103 Caucasians were systematically screened for genetic variations to find a potential relationship with hepatic MRP3 expression. Sequencing comprised all 31 exons, approximately 100 bp of the flanking intronic regions and 2 kb of the 5' UTR. RESULTS: In total, 51 mutations were identified. Fifteen SNPs were located in the coding exons of MRP3, six of which are nonsynonymous mutations. SNPs 39G>C (allele frequency: 0.5%, located in exon 1), 202C>T (1.6%, exon 2), 1037C>T (0.5%, exon 9), 1537C>A (0.5%, exon 12), 3890G>A (5.2%, exon 27) and 4267G>A (0.6%, exon 29) resulted in Lys13Asn, His68Tyr, Ser346Phe, Gln513Lys, Arg1297His and Gly1423Arg amino acid substitutions, respectively. A splice site mutation (1339-1G>T) was found at the intron 10-exon 11 boundary. To evaluate, whether mutations in the MRP3 gene correlate with human hepatic MRP3 expression, we analyzed the genetic variants in Caucasian liver samples, whose MRP3 mRNA (n = 84) and protein (n = 50) expression has been determined by real time quantitative PCR and Western Blot, respectively. We found a significant correlation of a polymorphism in the 5' promoter region (-211C>T) of MRP3 with mRNA expression. Individuals homozygous and heterozygous for the -211C>T promoter polymorphism had significantly lower MRP3 transcript levels compared to wild-type individuals (P < 0.05). Accordingly, electrophoretic mobility shift assay demonstrated that -211C>T polymorphism affected the binding of nuclear factors. CONCLUSIONS: Multiple genetic polymorphisms of MRP3 exist in Caucasians. The -211C>T promoter polymorphism appears to be associated with altered hepatic MRP3 mRNA expression.

Alternative Splicing↗

PubMed2004

High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1).

This study aimed to characterize possible relationships between polymorphisms in the drug transporter genes organic anion transporting polypeptide-C (OATP-C, SLCO1B1), OATP-B (SLCO2B1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and multidrug resistance transporter (MDR1, ABCB1) and the pharmacokinetics of pravastatin. We studied 41 healthy Caucasian volunteers who had previously participated in pharmacokinetic studies with pravastatin. Six volunteers had a very high pravastatin AUC value and were defined as outliers according to statistical criteria. The OATP-C gene was sequenced completely in all subjects, and they were also genotyped for selected single nucleotide polymorphisms (SNP) in the OATP-B, MDR1 and MRP2 genes. Of the six outliers, five were heterozygous for the OATP-C 521T>C (Val174Ala) SNP (allele frequency 42%) and three were heterozygous for a new SNP in the promoter region of OATP-C (-11187G>A, allele frequency 25%). Among the remaining 35 subjects, two were homozygous and six were heterozygous carriers of the 521T>C SNP (allele frequency 14%, P = 0.0384 versus outliers) and three were heterozygous carriers of the -11187G>A SNP (allele frequency 4%, P = 0.0380 versus outliers). In subjects with the -11187GA or 521TC genotype, the mean pravastatin AUC0-12 was 98% (P = 0.0061) or 106% (P = 0.0034) higher, respectively, compared to subjects with the reference genotype. These results were substantiated by haplotype analysis. In heterozygous carriers of *15B (containing the 388A>G and 521T>C variants), the mean pravastatin AUC0-12 was 93% (P = 0.024) higher compared to non-carriers and, in heterozygous carriers of *17 (containing the -11187G>A, 388A>G and 521T>C variants), it was 130% (P = 0.0053) higher compared to non-carriers. No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs.

Adult↗

PubMed2004

Improving risk adjustment in critically ill trauma patients: the TRISS-SAPS Score.

OBJECTIVES: To test (a) the prognostic performance of TRISS and SAPS II scoring systems in a large sample of trauma patients admitted to Austrian ICUs, and (b) the hypothesis that the prognostic performance of TRISS could be improved by adding SAPS II. METHODS: Prospective multicenter cohort study comprising 5,538 trauma patients out of 35,637 patients admitted to 31 ICUs in Austria over a 4-year period. RESULTS: Separately, TRISS and SAPS II showed lack of calibration in the cohort of trauma patients. The database was then split into two equal samples, development and validation. Using the development sample, a new scoring system was developed, with vital status at hospital discharge as the dependent variable and TRISS and SAPS II as independent variables. The prognostic performance of the new TRISS-SAPS system was then assessed in the validation cohort: Both, discrimination (as shown by area under the ROC curve), and calibration (using Hosmer-Lemeshow goodness-of-fit statistics) was excellent. CONCLUSIONS: We improved risk adjustment in critically ill trauma patients by combining TRISS and SAPS II. This new scoring system might aid in evaluating and comparing specialized trauma ICUs.

APACHE↗

PubMed2003

Reliability of a standardized reading chart system: variance component analysis, test-retest and inter-chart reliability.

BACKGROUND: The purpose of this study was to analyze statistically the test-retest and inter-chart reliability of three standardized Radner Reading Charts with respect to reading acuity, maximum reading speed, critical print size and LogRAD/LogMAR ratio and to quantitatively identify the sources of variability. METHODS: At two testing sessions (3 to 4 weeks apart), 36 volunteers read monocularly all three Radner Reading Charts in randomized order (orthogonal Latin square design). The subjects were grouped according to their distance LogMAR visual acuity (group 1, 0.1 or better; group 2, 0.12-0.4; group 3, 0.42-0.8). Based on these 216 reading tests, crude correlations were calculated between the two testing sessions and between the three charts, and "variance component analyses" were performed for all variables. RESULTS: For all visual acuity groups and variables, the test-retest and the inter-chart reliability was high. The variance component analyses showed that the differences between individuals predominantly influenced the variance, whereas the effect of the test replication was low. The three charts caused minimal variability, indicating equality for clinical examinations. CONCLUSION: The standardized Radner Reading Charts provide clinically reliable and reproducible results for individuals with normal eyesight and for patients with visual impairment. These findings indicate that reading test systems, which consider the current international standards for visual acuity measurements (EN ISO 8596, NAS-NRC) and the psychophysical requirements for controlling optical item interactions, can provide reliable measures for clinical and scientific analyses of reading performance.

Aged↗