Biomedical subjects

Peter Bauer

Publications and source records attributed to Peter Bauer.

At least 37 records · Page 2Linked to original sources

PubMed2005

Testing and estimation in flexible group sequential designs with adaptive treatment selection.

Integrating selection and confirmation phases into a single trial can expedite the development of new treatments and allows to use all accumulated data in the decision process. In this paper we review adaptive treatment selection based on combination tests and propose overall adjusted p-values and simultaneous confidence intervals. Also point estimation in adaptive trials is considered. The methodology is illustrated in a detailed example based on an actual planned study.

Austria↗

PubMed2005

The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease.

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.

Age of Onset↗

PubMed2005

Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study.

BACKGROUND: Strokes are an important cause of morbidity and mortality in young adults. However, in most cases the cause of the stroke remains unclear. Anderson-Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase and causes an endothelial vasculopathy followed by cerebral ischaemia. To determine the importance of Fabry disease in young people with stroke, we measured the frequency of unrecognised Fabry disease in a cohort of acute stroke patients. METHODS: Between February, 2001, and December, 2004, 721 German adults aged 18 to 55 years suffering from acute cryptogenic stroke were screened for Fabry disease. The plasma alpha-galactosidase activity in men was measured followed by sequencing of the entire alpha-GAL gene in those with low enzyme activity. By contrast, the entire alpha-GAL gene was genetically screened for mutations in women even if enzyme activity was normal. FINDINGS: 21 of 432 (4.9%) male stroke patients and seven of 289 (2.4%) women had a biologically significant mutation within the alpha-GAL gene. The mean age at onset of symptomatic cerebrovascular disease was 38.4 years (SD 13.0) in the male stroke patients and 40.3 years (13.1) in the female group. The higher frequency of infarctions in the vertebrobasilar area correlated with more pronounced changes in the vertebrobasilar vessels like dolichoectatic pathology (42.9%vs 6.8%). INTERPRETATION: We have shown a high frequency of Fabry disease in a cohort of patients with cryptogenic stroke, which corresponds to about 1.2% in young stroke patients. Fabry disease must be considered in all cases of unexplained stroke in young patients, especially in those with the combination of infarction in the vertebrobasilar artery system and proteinuria.

Adult↗

PubMed2005

Prospective, randomized, multicenter, double-blind placebo-controlled trial comparing adjuvant interferon alfa and isotretinoin with interferon alfa alone in stage IIA and IIB melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group.

PURPOSE: The combination of interferon alfa (IFNalpha) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB. PATIENTS AND METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFNalpha and isotretinoin (isotretinoin group; 206 patients) or IFNalpha and placebo (placebo group; 201 patients) after excision of the primary tumor. IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients < or = 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months. RESULTS: A scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility. CONCLUSION: The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.

Adolescent↗

PubMed2005

SAPS 3--From evaluation of the patient to evaluation of the intensive care unit. Part 1: Objectives, methods and cohort description.

OBJECTIVE: Risk adjustment systems now in use were developed more than a decade ago and lack prognostic performance. Objective of the SAPS 3 study was to collect data about risk factors and outcomes in a heterogeneous cohort of intensive care unit (ICU) patients, in order to develop a new, improved model for risk adjustment. DESIGN: Prospective multicentre, multinational cohort study. PATIENTS AND SETTING: A total of 19,577 patients consecutively admitted to 307 ICUs from 14 October to 15 December 2002. MEASUREMENTS AND RESULTS: Data were collected at ICU admission, on days 1, 2 and 3, and the last day of the ICU stay. Data included sociodemographics, chronic conditions, diagnostic information, physiological derangement at ICU admission, number and severity of organ dysfunctions, length of ICU and hospital stay, and vital status at ICU and hospital discharge. Data reliability was tested with use of kappa statistics and intraclass-correlation coefficients, which were >0.85 for the majority of variables. Completeness of the data was also satisfactory, with 1 [0-3] SAPS II parameter missing per patient. Prognostic performance of the SAPS II was poor, with significant differences between observed and expected mortality rates for the overall cohort and four (of seven) defined regions, and poor calibration for most tested subgroups. CONCLUSIONS: The SAPS 3 study was able to provide a high-quality multinational database, reflecting heterogeneity of current ICU case-mix and typology. The poor performance of SAPS II in this cohort underscores the need for development of a new risk adjustment system for critically ill patients.

Aged↗

PubMed2005

SAPS 3--From evaluation of the patient to evaluation of the intensive care unit. Part 2: Development of a prognostic model for hospital mortality at ICU admission.

OBJECTIVE: To develop a model to assess severity of illness and predict vital status at hospital discharge based on ICU admission data. DESIGN: Prospective multicentre, multinational cohort study. PATIENTS AND SETTING: A total of 16,784 patients consecutively admitted to 303 intensive care units from 14 October to 15 December 2002. MEASUREMENTS AND RESULTS: ICU admission data (recorded within +/-1 h) were used, describing: prior chronic conditions and diseases; circumstances related to and physiologic derangement at ICU admission. Selection of variables for inclusion into the model used different complementary strategies. For cross-validation, the model-building procedure was run five times, using randomly selected four fifths of the sample as a development- and the remaining fifth as validation-set. Logistic regression methods were then used to reduce complexity of the model. Final estimates of regression coefficients were determined by use of multilevel logistic regression. Variables selection and weighting were further checked by bootstraping (at patient level and at ICU level). Twenty variables were selected for the final model, which exhibited good discrimination (aROC curve 0.848), without major differences across patient typologies. Calibration was also satisfactory (Hosmer-Lemeshow goodness-of-fit test H=10.56, p=0.39, C=14.29, p=0.16). Customized equations for major areas of the world were computed and demonstrate a good overall goodness-of-fit. CONCLUSIONS: The SAPS 3 admission score is able to predict vital status at hospital discharge with use of data recorded at ICU admission. Furthermore, SAPS 3 conceptually dissociates evaluation of the individual patient from evaluation of the ICU and thus allows them to be assessed at their respective reference levels.

Adult↗

PubMed2005

Two-stage designs for experiments with a large number of hypotheses.

MOTIVATION: When a large number of hypotheses are investigated the false discovery rate (FDR) is commonly applied in gene expression analysis or gene association studies. Conventional single-stage designs may lack power due to low sample sizes for the individual hypotheses. We propose two-stage designs where the first stage is used to screen the 'promising' hypotheses which are further investigated at the second stage with an increased sample size. A multiple test procedure based on sequential individual P-values is proposed to control the FDR for the case of independent normal distributions with known variance. RESULTS: The power of optimal two-stage designs is impressively larger than the power of the corresponding single-stage design with equal costs. Extensions to the case of unknown variances and correlated test statistics are investigated by simulations. Moreover, it is shown that the simple multiple test procedure using first stage data for screening purposes and deriving the test decisions only from second stage data is a very powerful option.

Algorithms↗

PubMed2005

B-raf and Ha-ras mutations in chemically induced mouse liver tumors.

The mitogen-activated protein kinase signalling pathway is a central regulator of tumor growth, which is constitutively activated in chemically induced mouse liver tumors. In about 30-50% of cases this effect can be related to activation of the Ha-ras gene by point mutations, whereas in the remaining cases mutations may occur in other members within this pathway, such as Raf kinases. Recently, B-raf has been shown to be frequently mutated in human melanomas and certain other cancers, with a V599E amino-acid change representing the most predominant mutation type. We now screened 82 N-nitrosodiethylamine-induced liver tumors from C3H/He mice for mutations within the hotspot positions in the Ha-ras and B-raf genes. About 50% (39/82) of tumors showed Ha-ras codon 61 mutations and 16 tumors ( approximately 20%) harbored mutations at codon 624 of the B-raf gene, which corresponds to codon 599 in human B-raf. None of the tumors was mutated in both Ha-ras and B-raf. The high prevalence of Ha-ras and B-raf mutations in mouse liver tumors is in striking contrast to human hepatocellular cancers which very infrequently harbor mutations in the two genes. These fundamental differences between the biology of liver tumors in mice and man may be of toxicological relevance.

Animals↗

PubMed2005

New mutations in protein kinase Cgamma associated with spinocerebellar ataxia type 14.

Autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurological disorders. Point mutations in the gene encoding protein kinase Cgamma (PRKCG) are responsible for spinocerebellar ataxia 14 (SCA14). We screened for mutations in the PRKCG gene, in a large series of 284 ADCA index cases, mostly French (n=204) and German (n=48), in whom CAG repeat expansions in the known SCA genes were previously excluded. Six mutations were found that segregated with the disease and were not detected on 560 control chromosomes, including F643L (exon 18), already reported in another French kindred. Five new missense mutations were identified in exons 4 (C114Y/G123R/G123E), 10 (G360S) and 18 (V692G). All but one (V692G) were located in highly conserved regions of the regulatory or catalytic domains of the protein. All six SCA14 families were French and there was no evidence of reduced penetrance. The phenotype consisted in a very slowly progressive cerebellar ataxia with a mean age at onset of 33.5+/-14.2 years (range 15 to 60 years), occasionally associated with executive dysfunction, myoclonus, myorythmia, tremor or decreased vibration sense. SCA14 represented only 1.5% (7/454) of French ADCA families but none of the German families. It should, however, be considered in patients with slowly progressive ADCA, particularly when myoclonus and cognitive impairment are present.

Adolescent↗

PubMed2005

Younger birth cohort correlates with higher breast and ovarian cancer risk in European BRCA1 mutation carriers.

Mutations in the BRCA1 gene result in an elevated risk of breast cancer (BC) and ovarian cancer (OC). However, risk estimates vary depending on the study population and statistical methodology used, and there are indications that the birth cohort and location of the mutation influence cancer risk. We investigated the risks for BC and OC associated with BRCA1 mutations in a young cohort of female mutation carriers who were identified by molecular genetic testing and belonged to a genetically heterogeneous Central European population. The study included 106 healthy and 158 affected carriers identified at an Austrian risk evaluation center. Risk estimation employed the product limit method. The log rank test was used to compare different strata. The risk of developing cancer to age 70 was found to be 85% for BC (95% CI 75-97%) and 53% for OC (95% CI 37-68%). Female mutation carriers born in 1958 or later were subject to a significantly higher risk of BC (P=0.005; 27% vs. 46% to age 40) and OC (P=0.006; 2% vs. 8% to age 40) than those born earlier. Mutations in exon 11 were associated with lower BC risk than mutations in exons 1-10 (P=0.008) and exons 12-24 (P=0.0006). OC risk was not influenced by mutation location (P=0.86). We conclude that female BRCA1 mutation carriers should be counseled about their cohort-dependent cancer risk. Further research into variables that affect cancer risk and are amenable to modification (e.g., lifestyle-related factors) should be considered a priority.

Adult↗

PubMed2005

Alpha-synuclein and Parkinson's disease: implications from the screening of more than 1,900 patients.

Data on the frequency of alpha-synuclein mutations in Parkinson's disease (PD) are limited. Screening the entire coding region in 1,921 PD patients with denaturing high performance liquid chromatography and subsequent sequencing we only detected silent mutations (g.2654A>G, g.10151G>A, and g.15986A>T) and the c.209G>A substitution corresponding to the p.A53T mutation. These results demonstrate that mutations in the alpha-synuclein gene are rare and suggest that other factors contribute to alpha-synuclein aggregation in the majority of PD patients.

Aged↗

PubMed2005

Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease.

BACKGROUND & AIMS: A 5-fold increase of hepatic copper concentration is considered as the best available test for diagnosis of hepatic Wilson's disease (WD). However, the sensitivity and specificity of this test have never been fully investigated. METHODS: Copper content was measured by flame atomic absorption spectroscopy in 114 liver biopsies obtained at diagnosis of WD, in 219 patients with noncholestatic liver diseases (including 144 with chronic hepatitis C and 44 with nonalcoholic fatty liver disease), and in 26 without evidence of liver disease. RESULTS: Liver copper content was >250 microg/g in 95 WD patients (83.3%), between 50 and 250 microg/g in 15, and below 50 microg/g in 4. It did not correlate with age (r(2) = .003), the grade of fibrosis, or the presence of stainable copper. Liver copper content was >250 or between 50 and 250 microg/g in 3 (1.4%) and 20 (9.1%) of 219 patients with noncholestatic liver diseases, respectively. By lowering the cutoff from 250 to 75 microg/g, the sensitivity of liver copper content to diagnose WD increased from 83.3% (95% confidence interval, 75.2%-89.6%) to 96.5% (91.3%-99.1%), but the specificity decreased from 98.6% (96.0%-99.7%) to 95.4% (91.8%-97.8%). CONCLUSIONS: There is no gold standard for the diagnosis of WD. Liver copper content is a useful parameter, but a value below 250 microg/g does not exclude WD. Diagnosis requires the combination of a variety of clinical and biochemical tests.

Adenosine Triphosphatases↗

PubMed2005

PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism.

Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.2+/-5.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.2+/-9.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G>A), and two patients had known Parkin mutations (heterozygous c.734A>T and c.924C>T; heterozygous c.924C>T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A>T) and four novel PINK1 changes of unknown pathogenic significance (-21G/A; IVS1+97A/G; IVS3+38_40delTTT; c.852C>T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.

Adult↗

PubMed2005

Effect of information on reported adverse events in a placebo-controlled trial.

OBJECTIVE: Although placebo controls are a standard measure in clinical trials the mechanisms underlying placebo effects are still not fully understood. We hypothesised that information about the likelihood of receiving placebo might influence the perception of adverse effects in volunteers participating in a clinical trial. METHODS: Healthy subjects received either nifedipine 20 mg or placebo in an adaptive two-stage crossover study. Sixty subjects were randomised to a group given either correct (50% chance) or misleading (100% chance) information about the likelihood of receiving the active drug. A sum of the severity scores from visual analogue scales over all individual adverse effects was defined as the primary endpoint. RESULTS: The analysis revealed no difference in the primary endpoint between the two groups. This lack of difference may in part be attributable to a conditioning effect as on the first study day higher symptom scores were reported by the participants than on the second study day. Furthermore, the day effect seemed to arise mainly when the first day treatment was the placebo. For the placebo the day effect was clearly significant (p = 0.012), with higher scores on the first day. A further explorative finding in patients given placebo was a tendency for higher scores in the group with the misleading information (p = 0.08). Nothing of that sort was found in the analysis for active treatment. The day effect collapsed and the factor information did not show any tendency of being a potential influence. CONCLUSIONS: In the present study we did not find a statistically significant effect of misleading information on reported adverse events. The large treatment and day effects observed made it difficult to detect a potential small information effect. However, this study excluded a strong and relevant effect of information on the frequency and severity of reported adverse events.

Adult↗

PubMed2004

Overexpression of glial cell line-derived neurotrophic factor induces genes regulating migration and differentiation of neuronal progenitor cells.

The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. Mutations in components of its signaling pathway lead to severe migration deficits of neuronal crest stem cells, tumor formation, or ablation of the urinary system. In animal models of Parkinson's disease, GDNF has been recognized to be neuroprotective and to improve motor function when delivered into the cerebral ventricles or into the substantia nigra. Here, we characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and alpha-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. Axonal guidance depends on cell-surface molecules and extracellular matrix proteins. Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. Moreover, we found four key enzymes of the cholesterol-synthesis pathway to be down-regulated leading to decreased farnesyl-pyrophospate production. Many proteins are anchored by farnesyl-derivates at the cell membrane. The identification of these GDNF-regulated genes may open new opportunities for directly influencing differentiation and developmental processes of neurons.

Animals↗

PubMed2004

Wnt-5a expression in the rat neuronal progenitor cell line ST14A.

Transplantation of cells derived from embryonic stem cells is currently under investigation as a promising strategy to restore functional deficits in neurodegenerative diseases, e.g. Parkinson's disease. To generate cells suitable for transplantation, a neuronal progenitor cell line (ST14A) was derived from embryonic day 14 rat striatum by stable retroviral transfection of the temperature-sensitive SV40 large T antigen and genetically modified by transfection with constructs of the neurotrophic factors ciliary neurotrophic factor (CNTF) [CNTF-ST14A] and glial cell line-derived neurotrophic factor (GDNF) [GDNF-ST14A], respectively. In order to investigate the capacity of these cells to regulate neuronal growth and physiological differentiation, e.g. remodeling of axons and synaptogenesis, we analyzed the expression of molecules which control the cell fate during embryonic development. For the first time, we found endogenous Wnt-5a, a regulator molecule that can induce dopaminergic phenotype, by RT-PCR, Western blot and flow cytometry in the neuronal progenitor cell line ST14A and its derivatives CNTF-ST14A and GDNF-ST14A. The protein was transiently upregulated at the differentiation-inducing non-permissive temperature of 39 degrees C and it was also secreted into the culture medium. Our findings are based on in vitro investigation of artificially immortalized cell lines. However, they raise the possibility that neuronal progenitor cells that might be used to treat neurodegenerative diseases express Wnt-5a, thus promoting their potential for dopaminergic differentiation.

Animals↗

PubMed2004

The advantages and disadvantages of adaptive designs for clinical trials.

Flexible designs for clinical trials permit mid-trial design modifications, which are based on interim information from inside or outside the trial while meeting (regulatory) requirements for the control of the type I error rate. The basic principle is to combine stage standardized test statistics such as p-values or z-scores in a pre-specified way. The flexibility covers changes of sample sizes, treatment allocation ratios and the number of interim analyses, as well as the selection of treatments, doses and end points. The price to be paid is that non-standard test statistics must be used after an adaptation.

Biomedical Research↗

PubMed2004

Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7).

Mutations in the parkin gene have been identified as a common cause of autosomal recessive inherited Parkinson disease (PD) associated with early disease manifestation. However, based on linkage data, mutations in other genes contribute to the genetic heterogeneity of early-onset PD (EOPD). Recently, two mutations in the DJ1 gene were described as a second cause of autosomal recessive EOPD (PARK7). Analyzing the PARK7/DJ1 gene in 104 EOPD patients, we identified a third mutation, c.192G>C (p.E64D), associated with EOPD in a patient of Turkish ancestry and characterized the functional significance of this amino acid substitution. In the patient, a substantial reduction of dopamine uptake transporter (DAT) binding was found in the striatum using [(18)F]FP-CIT and PET, indicating a serious loss of presynaptic dopaminergic afferents. His sister, homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who is heterozygous for E64D. We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells. Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEK293 cells overexpressing wild-type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein.

Adult↗