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1.  Determination of aromatic amines in human urine using comprehensive multi-dimensional gas chromatography mass spectrometry (GCxGC-qMS) 
Aromatic amines are an important class of harmful components of cigarette smoke. Nevertheless, only few of them have been reported to occur in urine, which raises questions on the fate of these compounds in the human body. Here we report on the results of a new analytical method, in situ derivatization solid phase microextraction (SPME) multi-dimensional gas chromatography mass spectrometry (GCxGC-qMS), that allows for a comprehensive fingerprint analysis of the substance class in complex matrices. Due to the high polarity of amino compounds, the complex urine matrix and prevalence of conjugated anilines, pretreatment steps such as acidic hydrolysis, liquid–liquid extraction (LLE), and derivatization of amines to their corresponding aromatic iodine compounds are necessary. Prior to detection, the derivatives were enriched by headspace SPME with the extraction efficiency of the SPME fiber ranging between 65 % and 85 %. The measurements were carried out in full scan mode with conservatively estimated limits of detection (LOD) in the range of several ng/L and relative standard deviation (RSD) less than 20 %. More than 150 aromatic amines have been identified in the urine of a smoking person, including alkylated and halogenated amines as well as substituted naphthylamines. Also in the urine of a non-smoker, a number of aromatic amines have been identified, which suggests that the detection of biomarkers in urine samples using a more comprehensive analysis as detailed in this report may be essential to complement the approach of the use of classic biomarkers.
Graphical Abstractᅟ
PMCID: PMC4281360  PMID: 25142049
Aromatic amines; Human urine; Bladder cancer; Comprehensive multidimensional gas chromatography; Solid phase micro-extraction (SPME); Ionic liquid columns
2.  Effectiveness of a primary care based complex intervention to promote self-management in patients presenting psychiatric symptoms: study protocol of a cluster-randomized controlled trial 
BMC Psychiatry  2014;14:2.
Anxiety, Depression and Somatoform (ADSom) disorders are highly prevalent in primary care. Managing these disorders is time-consuming and requires strong commitment on behalf of the General Practitioners (GPs). Furthermore, the management of these patients is restricted by the high patient turnover rates in primary care practices, especially in the German health care system.
In order to address this problem, we implement a complex, low-threshold intervention by an Advanced Practice Nurse (APN) using a mixture of case management and counseling techniques to promote self-management in these patients. Here we present the protocol of the “Self-Management Support for Anxiety, Depression and Somatoform Disorders in Primary Care” (SMADS)-Study.
The study is designed as a cluster-randomized controlled trial, comparing an intervention and a control group of 10 primary care practices in each case. We will compare the effectiveness of the intervention applied by an APN with usual GP-care. A total of 340 participants will be enrolled in the study, 170 in either arm. We use the Patient Health Questionnaire-German version (PHQ-D) as a screening tool for psychiatric symptoms, including patients with a score above 5 on any of the three symptom scales. The primary outcome is self-efficacy, measured by the General Self-Efficacy Scale (GSE), here used as a proxy for self-management. As secondary outcomes we include the PHQ-D symptom load and questionnaires regarding coping with illness and health related quality of life. Outcome assessments will be applied 8 weeks and 12 months after the baseline assessment.
The SMADS-study evaluates a complex, low threshold intervention for ambulatory patients presenting ADSom-symptoms, empowering them to better manage their condition, as well as improving their motivation to engage in self-help and health-seeking behaviour. The benefit of the intervention will be substantiated, when patients can enhance their expected self-efficacy, reduce their symptom load and engage in more self-help activities to deal with their everyday lives. After successfully evaluating this psychosocial intervention, a new health care model for the management of symptoms of anxiety, depression and somatoform disorders for ambulatory patients could emerge, supplementing the work of the GP.
Trial registration Identifier: NCT01726387
PMCID: PMC3898061  PMID: 24387048
General practitioner; Advanced practice nurse; Primary care; Self-Management; Anxiety; Depression; Somatization; Somatic symptom disorder; Cluster-randomized clinical trial; Health services research; Supplementary nursing care
3.  Depression Treatment with Duloxetine and Reduction of Inability to Work 
Data on inability to work from an observational study in patients treated with duloxetine for major depressive disorder in clinical practice in Germany were collected. Ability to work was compared between baseline and up to 6 months after initiation of duloxetine. All patients with a working status at baseline other than retired or retired early were included. 2,825 patients were analyzed, 54.8% were able to work at baseline increasing to 83.8% at 6 months. Of those patients unable to work at baseline, 72.7% were able to work after 6 months. A relevant reduction of inability to work was also found for patient subgroups with moderate to severe pain at baseline and those with and without MDD pretreatment. As inability to work is one of the main cost drivers for depressive patients in Germany, the reduction of inability to work could potentially result in considerable cost savings for health insurance companies and society.
PMCID: PMC3419398  PMID: 22919474
4.  Influence of social support on cognitive change and mortality in old age: results from the prospective multicentre cohort study AgeCoDe 
BMC Geriatrics  2012;12:9.
Social support has been suggested to positively influence cognition and mortality in old age. However, this suggestion has been questioned due to inconsistent operationalisations of social support among studies and the small number of longitudinal studies available. This study aims to investigate the influence of perceived social support, understood as the emotional component of social support, on cognition and mortality in old age as part of a prospective longitudinal multicentre study in Germany.
A national subsample of 2,367 primary care patients was assessed twice over an observation period of 18 months regarding the influence of social support on cognitive function and mortality. Perceived social support was assessed using the 14-item version of the FSozU, which is a standardised and validated questionnaire of social support. Cognition was tested by the neuropsychological test battery of the Structured Interview for the Diagnosis of Dementia (SIDAM). The influence of perceived support on cognitive change was analysed by multivariate ANCOVA; mortality was analysed by multivariate logistic and cox regression.
Sample cognitive change (N = 1,869): Mean age was 82.4 years (SD 3.3) at the beginning of the observation period, 65.9% were female, mean cognition was 49 (SD 4.4) in the SIDAM. Over the observation period cognitive function declined in 47.2% by a mean of 3.4 points. Sample mortality (N = 2,367): Mean age was 82.5 years (SD 3.4), 65.7% were female and 185 patients died during the observation period. Perceived social support showed no longitudinal association with cognitive change (F = 2.235; p = 0.135) and mortality (p = 0.332; CI 0.829-1.743).
Perceived social support did not influence cognition and mortality over an 18 months observation period. However, previous studies using different operationalisations of social support and longer observation periods indicate that such an influence may exist. This influence is rather small and the result of complex interaction mechanisms between different components of social support; the emotional component seems to have no or only a limited effect. Further research is needed to describe the complex interactions between components of social support. Longer observation periods are necessary and standardised operationalisations of social support should be applied.
PMCID: PMC3364867  PMID: 22433223
5.  Quality of life and hormone use: new validation results of MRS scale 
The Menopause Rating Scale is a health-related Quality of Life scale developed in the early 1990s and step-by-step validated since then. Recently the MRS scale was validated as outcomes measure for hormone therapy. The suspicion however was expressed that the data were too optimistic due to methodological problems of the study. A new study became available to check how founded this suspicion was.
An open post-marketing study of 3282 women with pre- and post- treatment data of the self-administered version of the MRS scale was analyzed to evaluate the capacity of the scale to detect hormone treatment related effects with the MRS scale. The main results were then compared with the old study where the interview-based version of the MRS scale was used.
The hormone-therapy related improvement of complaints relative to the baseline score was about or less than 30% in total or domain scores, whereas it exceeded 30% improvement in the old study. Similarly, the relative improvement after therapy, stratified by the degree of severity at baseline, was lower in the new than in the old study, but had the same slope. Although we cannot exclude different treatment effects with the study method used, this supports our hypothesis that the individual MRS interviews performed by the physician biased the results towards over-estimation of the treatment effects. This hypothesis is underlined by the degree of concordance of physician's assessment and patient's perception of treatment success (MRS results): Sensitivity (correct prediction of the positive assessment by the treating physician) of the MRS and specificity (correct prediction of a negative assessment by the physician) were lower than the results obtained with the interview-based MRS scale in the previous publication.
The study confirmed evidence for the capacity of the MRS scale to measure treatment effects on quality of life across the full range of severity of complaints before treatment. The difference of the relative improvement after therapy between the old and current study as well as the observed different sensitivity/specificity is – as a matter of probability – more likely to be caused by a bias introduced by the different application of the MRS scale than by real differences in the efficacy of the therapy. A randomized clinical trial would be needed to test the impact of the latter. The message for future studies is: The MRS scale should be only used as self-administered tool where the suggestive effect of questions raised by health professionals ("therapeutic optimism") can be largely excluded.
PMCID: PMC1482687  PMID: 16737531
6.  Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials 
BMJ : British Medical Journal  2005;331(7512):321-327.
Objectives Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents.
Data sources The terms “donepezil”, “rivastigmine”, and “galantamine”, limited by “randomized-controlled-trials” were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language.
Study selection All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality.
Results 22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale—cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws—for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation.
Conclusion Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.
PMCID: PMC1183129  PMID: 16081444
7.  A New Amidohydrolase from Bordetella or Alcaligenes Strain FB188 with Similarities to Histone Deacetylases 
Journal of Bacteriology  2004;186(8):2328-2339.
The full-length gene encoding the histone deacetylase (HDAC)-like amidohydrolase (HDAH) from Bordetella or Alcaligenes (Bordetella/Alcaligenes) strain FB188 (DSM 11172) was cloned using degenerate primer PCR combined with inverse-PCR techniques and ultimately expressed in Escherichia coli. The expressed enzyme was biochemically characterized and found to be similar to the native enzyme for all properties examined. Nucleotide sequence analysis revealed an open reading frame of 1,110 bp which encodes a polypeptide with a theoretical molecular mass of 39 kDa. Interestingly, peptide sequencing disclosed that the N-terminal methionine is lacking in the mature wild-type enzyme, presumably due to the action of methionyl aminopeptidase. Sequence database searches suggest that the new amidohydrolase belongs to the HDAC superfamily, with the closest homologs being found in the subfamily assigned acetylpolyamine amidohydrolases (APAH). The APAH subfamily comprises enzymes or putative enzymes from such diverse microorganisms as Pseudomonas aeruginosa, Archaeoglobus fulgidus, and the actinomycete Mycoplana ramosa (formerly M. bullata). The FB188 HDAH, however, is only moderately active in catalyzing the deacetylation of acetylpolyamines. In fact, FB188 HDAH exhibits significant activity in standard HDAC assays and is inhibited by known HDAC inhibitors such as trichostatin A and suberoylanilide hydroxamic acid (SAHA). Several lines of evidence indicate that the FB188 HDAH is very similar to class 1 and 2 HDACs and contains a Zn2+ ion in the active site which contributes significantly to catalytic activity. Initial biotechnological applications demonstrated the extensive substrate spectrum and broad optimum pH range to be excellent criteria for using the new HDAH from Bordetella/Alcaligenes strain FB188 as a biocatalyst in technical biotransformations, e.g., within the scope of human immunodeficiency virus reverse transcriptase inhibitor synthesis.
PMCID: PMC412110  PMID: 15060035
8.  The Aging Males' Symptoms (AMS) scale: Update and compilation of international versions 
The interest of clinical research in aging males increased in recent years and thereby the interest to measure health-related quality of life (HRQoL) and symptoms of aging men. The Aging Males' Symptoms scale (AMS) became the most commonly used scale to measure HRQoL and symptoms in aging males in many countries worldwide. The aim of this paper is to review the current state of the instrument particularly concerning versions of the scale in different languages in the light of the quality of the translation process.
AMS versions available
Most of the translations were performed following international methodological recommendations for linguistic & cultural adaptation of HRQoL instruments. Mainly the English version was used as source language for the translation into Dutch, Spanish, Portuguese, Italian, Swedish, and Japanese (attached as additional PDF-files). Preliminary versions that were derived only from forward translations are of secondary quality and available in Finnish, Flemish, and Russian. It is recommended to complete the translation process for the latter languages before using them in international studies.
Translations in process
The AMS scale is in the process of consensus finding of two existing French versions, and the versions in the Korean, Thai, and Indonesian languages have not yet been completed in the translation process.
The AMS scale is obviously a valuable tool for assessing health related quality of life in aging men, because it is used worldwide. It is a standardized scale according to psychometric norms. Most of the currently available language versions were translated following international standards for linguistic and cultural translation of quality of life scales. Assistance is offered to help interested parties in the translation process.
PMCID: PMC155679  PMID: 12747807
AMS; Aging Males Symptoms; Quality of Life; Questionnaires; International AMS Versions
9.  Mosaic chromosomal aberrations in synovial fibroblasts of patients with rheumatoid arthritis, osteoarthritis, and other inflammatory joint diseases 
Arthritis Research  2001;3(5):319-330.
Chromosomal aberrations were comparatively assessed in nuclei extracted from synovial tissue, primary-culture (P-0) synovial cells, and early-passage synovial fibroblasts (SFB; 98% enrichment; P-1, P-4 [passage 1, passage 4]) from patients with rheumatoid arthritis (RA; n = 21), osteoarthritis (OA; n = 24), and other rheumatic diseases. Peripheral blood lymphocytes (PBL) and skin fibroblasts (FB) (P-1, P-4) from the same patients, as well as SFB from normal joints and patients with joint trauma (JT) (n = 4), were used as controls. Analyses proceeded by standard GTG-banding and interphase centromere fluorescence in situ hybridization. Structural chromosomal aberrations were observed in SFB (P-1 or P-4) from 4 of 21 RA patients (19%), with involvement of chromosome 1 [e.g. del(1)(q12)] in 3 of 4 cases. In 10 of the 21 RA cases (48%), polysomy 7 was observed in P-1 SFB. In addition, aneusomies of chromosomes 4, 6, 8, 9, 12, 18, and Y were present. The percentage of polysomies was increased in P-4. Similar chromosomal aberrations were detected in SFB of OA and spondylarthropathy patients. No aberrations were detected in i) PBL or skin FB from the same patients (except for one OA patient with a karyotype 45,X[10]/46,XX[17] in PBL and variable polysomies in long-term culture skin FB); or ii) synovial tissue and/or P-1 SFB of normal joints or of patients with joint trauma. In conclusion, qualitatively comparable chromosomal aberrations were observed in synovial tissue and early-passage SFB of patients with RA, OA, and other inflammatory joint diseases. Thus, although of possible functional relevance for the pathologic role of SFB in RA, these alterations probably reflect a common response to chronic inflammatory stress in rheumatic diseases.
PMCID: PMC64845  PMID: 11549374
osteoarthritis; rheumatoid arthritis; spondylarthropathy; synovial fibroblasts; trisomy/polysomy 7
10.  Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture — primary culture cells markedly differ from fourth-passage cells 
Arthritis Research  2000;3(1):72-76.
To reduce culture artifacts by conventional repeated passaging and long-term culture in vitro, the isolation of synovial fibroblasts (SFB) was attempted from rheumatoid arthritis (RA) synovial membranes by trypsin/collagenase digest, short-term in vitro adherence (7 days), and negative isolation using magnetobead-coupled anti-CD14 monoclonal antibodies. This method yielded highly enriched SFB (85% prolyl-4-hydroxylase+/74% Thy-1/CD90+ cells; <2% contaminating macrophages; <1% leukocytes/endothelial cells) that, in comparison with conventional fourth-passage RA-SFB, showed a markedly different phenotype and significantly lower proliferation rates upon stimulation with platelet-derived growth factor and IL-1β. This isolation method is simple and reliable, and may yield cells with features closer to the in vivo configuration of RA-SFB by avoiding extended in vitro culture.
PMCID: PMC17827  PMID: 11178129
isolation; phenotype/function; primary culture; rheumatoid arthritis; synovial fibroblasts

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