Suitability of Yin Yang 1 transcript and protein levels for biomarker studies in B cell non-Hodgkin lymphoma.

BACKGROUND: Yin Yang 1 (YY1) is a transcription factor that plays an important role during all stages of B cell differentiation. Several studies reported upregulation of YY1 in B cell derived lymphoma, indicating that it might act as an oncogene. Furthermore, aberrant YY1 expression has been associated with survival in some entities of B cell non-Hodgkin lymphoma (B-NHL), suggesting that YY1 could be a valuable biomarker in B-NHL. However, studies are controversial and methodologically disparate, partially because some studies are based on transcript levels while others rely on YY1 protein data. Therefore, we aimed to investigate the dependence of YY1 protein levels on YY1 transcription. METHODS: A panel of human cell lines representing different B-NHL subtypes was used to test for the correlation of YY1 mRNA and protein levels which were determined by quantitative PCR and immunoblotting. To analyze YY1 mRNA and YY1 protein stability cells were treated with actinomycin-D and cycloheximide, respectively. siRNAs were transfected to knockdown YY1. Kaplan-Meier survival analyses were performed with data from published patient cohorts. Pearson's correlation analyses were assessed and statistical power was examined by Student's t-test. RESULTS: In the analyzed panel of B-NHL cell lines YY1 transcript levels do not correlate with their cellular protein amounts. YY1 protein levels were unaffected by transient block of transcription or by targeting YY1 mRNA using siRNA. Additionally, global inhibition of translation up to 48 h did not alter protein levels of YY1, indicating that YY1 is a highly stable protein in B-NHL. Furthermore, in a retrospective analysis of two different B-NHL cohorts, YY1 transcript levels had no impact on patients' survival probabilities. CONCLUSIONS: Our results point out the necessity to focus on YY1 protein expression to understand the potential role of YY1 as an oncogene and to unravel its suitability as clinical biomarker in B-NHL.

The Health Effects of Aluminum Exposure.

BACKGROUND: Aluminum is regularly taken up with the daily diet. It is also used in antiperspirants, as an adjuvant for vaccination, and in desensitization procedures. In this review, we present the scientifically documented harmful effects of aluminum on health and the threshold values associated with them. METHODS: This review is based on publications retrieved by a selective search of the PubMed and SCOPUS databases on the topic of aluminum in connection with neurotoxicity, Alzheimer's disease, and breast cancer, as well as on the authors' personal experience in occupational and environmental medicine. RESULTS: The reference values for the internal aluminum load (<15 µg/L in urine, <5 µg/L in serum) are especially likely to be exceeded in persons with occupational exposure. The biological tolerance value for occupational exposure is 50 µg of aluminum per gram of creatinine in the urine. For aluminum welders and workers in the aluminum industry, declining performance in neuropsychological tests (attention, learning, memory) has been found only with aluminum concentrations exceeding 100 µg/g creatinine in the urine; manifest encephalopathy with dementia was not found. Elevated aluminum content has been found in the brains of persons with Alzheimer's disease. It remains unclear whether this is a cause or an effect of the disease. There is conflicting evidence on carcinogenicity. The contention that the use of aluminum-containing antiperspirants promotes breast cancer is not supported by consistent scientific data. CONCLUSION: The internal aluminum load is measured in terms of the concentration of aluminum in urine and blood. Keeping these concentrations below the tolerance values prevents the development of manifest and subclinical signs of aluminum toxicity. Large-scale epidemiologic studies of the relationship between aluminum-containing antiperspirants and the risk of breast cancer would be desirable.

Unnecessary Investigations in Environmental Medicine.

BACKGROUND: Patients in environmental medicine often want a thorough diagnostic evaluation of nonspecific symptoms. Unconventional testing, as well as conventional testing for indications other than the established ones, can lead to false diagnoses and, in turn, to substantial emotional, social, and financial harm. The goal of this single-center study was to assess inappropriate diagnostic testing among the patients of a specialized university outpatient clinic for environmental medicine. METHODS: The charts of 653 consecutive outpatients seen in the institute and outpatient clinic of occupational, social, and environmental medicine in Erlangen from 2010 to 2015 were evaluated, and inappropriate diagnostic tests were assessed. RESULTS: 9% of the patients had received at least one inappropriate diagnostic test. The most common one was an inappropriate heavy-metal test (26%), followed by an inappropriately ordered hair analysis (15%) and biomonitoring in the blood or urine with an erroneous choice of the testing matrix or an erroneous interpretation of the findings (15%). Biomonitoring performed by us did not confirm the suspected environmental diagnosis in any case. Laboratory values exceeding the normal limits were rarer among these patients than in the patients for whom we considered biomonitoring to be indicated without any pretesting. CONCLUSION: An appreciable number of patients in environmental medicine were subjected to inappropriate diagnostic testing. When this happens, proper testing often needs to be done thereafter in order to confirm or refute the findings. This phenomenon should be more thoroughly assessed and quantified.

Human metabolism and renal excretion of selenium compounds after oral ingestion of sodium selenate dependent on trimethylselenium ion (TMSe) status.

An in vivo metabolism study in humans was carried out to investigate the toxicokinetics and metabolism of sodium selenate differentiating by the trimethylselenium (TMSe) status. Therefore, the changes in blood plasma concentration and the urinary excretion within 24 h of seven healthy subjects after oral administration of a dietary supplement containing sodium selenate (50 µg selenium) were analyzed. Three subjects belong to the subgroup of TMSe eliminators, and four subjects were related to the non-TMSe eliminators subgroup. The concentrations of total selenium in blood plasma and urine samples were determined by inductively coupled plasma-mass spectrometry (ICP-MS). Additionally, speciation analysis of urine samples was performed using ICP-MS coupled to a liquid chromatography system. Plasma selenium concentration changed from 82.5 ± 12.5 µg Se/L before to 85.1 ± 12.0 µg Se/L 2-3 h after supplementation. Considering the individual 24-hour background amounts of renal excreted selenium, the ingestion caused an additional excretion of 15.4 ± 3.3 µg Se/24 h (≙31.1 ± 7.6 % of the administered dose) with a maximum elimination already 2 h after exposure. The differentiated analysis revealed that in all subjects, the main elimination product (30.1 ± 6.9 % of the administered dose) was unmetabolized selenate. TMSe was only detected in the urine of the TMSe eliminators. This subgroup excreted in comparison with the non-TMSe eliminators a significantly lower amount of selenate. Only one subject metabolized selenate to a larger portion to methyl-2-acetamido-2-deoxy-1-seleno-ß-D-galactopyranoside (SeSug1) and methyl-2-amino-2-deoxy-1-seleno-ß-D-galactopyranoside (SeSug3). All other subjects showed only a minor metabolism of selenate to selenium-containing carbohydrates. By individuals, which do not excrete TMSe in urine basically, selenate is metabolized only marginally and is excreted rapidly via urine generally. In contrast, a considerable portion of this inorganic selenium compound is metabolized by individuals, which eliminate TMSe basically. An elevated metabolism may also be provided by individuals, which eliminate high levels of selenium-containing carbohydrates basically. The difference in metabolism may imply a different disposition for pharmacological or toxic effects by exposure to inorganic selenium compounds.

Human metabolism and renal excretion of selenium compounds after oral ingestion of sodium selenite and selenized yeast dependent on the trimethylselenium ion (TMSe) status.

A human in vivo metabolism study was carried out to investigate the impact of the trimethylselenium ion (TMSe) status on metabolism and toxicokinetics of sodium selenite and selenized yeast. Nine healthy human volunteers were orally exposed to 200 µg selenium as sodium selenite and seven with selenized yeast (100 µg selenium). In each intervention group, three subjects belong to TMSe eliminators. Blood samples were withdrawn before and up to 6 h after administration. Urine samples were collected before and within 24 h after administration. Total selenium (Se) was quantified in blood plasma and urine and low molecular Se species in urine. Selenium concentration in plasma increased from 84.5 ± 13.2 µg Se/L before to 97.4 ± 13.2 µg Se/L 2-3 h after selenite supplementation and 89.5 ± 12.9 µg Se/L to 92.1 ± 13.9 µg Se/L after selenized yeast intake. The oral ingestion caused an additional Se elimination via urine of 16.9 ± 10.6 µg/24 h (TMSe elim.: 10.8 ± 6.9 µg/24 h; non-TMSe elim.: 20.0 ± 11.3 µg Se/24 h) after selenite exposure and 11.8 ± 4.1 µg/24 h (TMSe elim.: 10.8 ± 4.6 µg/24 h; non-TMSe elim.: 12.6 ± 4.2 µg Se/24 h) after selenized yeast exposure. Methyl-2-acetamido-2-deoxy-1-seleno-ß-D-galactopyranoside (SeSug1) was the main metabolite in all urine samples, whereas TMSe was another main metabolite in TMSe eliminators' urine. After selenite exposure, a small amount of the dose (0.5 ± 0.2 %) was oxidized to selenate and rapidly excreted via urine. With the exception of selenite exposure in TMSe eliminators, the comparison of total Se and the sum of quantified Se species revealed a high renal portion of unidentified species. The study indicated a different metabolism of inorganic and organic Se compounds in human, but also crucial differences of Se metabolism in TMSe eliminators and non-TMSe eliminators.

S1 guideline on occupational skin products: protective creams, skin cleansers, skin care products (ICD 10: L23, L24)--short version.

Job-related hand dermatitis heads up the list of reported occupational diseases. So-called skin products - understood to mean protective creams, skin cleansers and skin care products - are used for the primary and secondary prevention of job- related hand dermatitis. In the interests of evidence-based medicine, the only preventive measures and/or occupational skin products that should be used are those whose potential uses and efficacy are underpinned by scientific research. To this end, the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (Working Group for Occupational and Environmental Dermatology, ABD) of the DDG (German Dermatological Society) and the Deutsche Gesellschaft für Arbeits- und Umweltmedizin (German Society for Occupational and Environmental Medicine, DGAUM) have summed up the latest scientific findings and recommendations in the updated guideline. The benefit of the combined application of protective creams and skin care products in the primary and secondary prevention of work-related contact dermatitis has been widely confirmed by recent clinical-epidemiological studies. The guideline clearly explains the necessity of demonstrating the efficacy of protective creams and cleansing products by means of in vivo methods in the sense of repetitive applications. Transferable standardised testing systems designed to examine the irritation potential and thus the compatibility of occupational skin cleansers and the reduction of irritation by protective skin creams have now been developed and validated by multicentre studies for skin protection creams and cleansers. The status of the current assessment of the safety of occupational skin products is also summarised.

Metal ion concentrations in body fluids after implantation of hip replacements with metal-on-metal bearing--systematic review of clinical and epidemiological studies.

INTRODUCTION: The use of metal-on-metal (MoM) total hip arthroplasty (THA) increased in the last decades. A release of metal products (i.e. particles, ions, metallo-organic compounds) in these implants may cause local and/or systemic adverse reactions. Metal ion concentrations in body fluids are surrogate measures of metal exposure. OBJECTIVE: To systematically summarize and critically appraise published studies concerning metal ion concentrations after MoM THA. METHODS: Systematic review of clinical trials (RCTs) and epidemiological studies with assessment of metal ion levels (cobalt, chromium, titanium, nickel, molybdenum) in body fluids after implantation of metalliferous hip replacements. Systematic search in PubMed and Embase in January 2012 supplemented by hand search. Standardized abstraction of pre- and postoperative metal ion concentrations stratified by type of bearing (primary explanatory factor), patient characteristics as well as study quality characteristics (secondary explanatory factors). RESULTS: Overall, 104 studies (11 RCTs, 93 epidemiological studies) totaling 9.957 patients with measurement of metal ions in body fluids were identified and analyzed. Consistently, median metal ion concentrations were persistently elevated after implantation of MoM-bearings in all investigated mediums (whole blood, serum, plasma, erythrocytes, urine) irrespective of patient characteristics and study characteristics. In several studies very high serum cobalt concentrations above 50 µg/L were measured (detection limit typically 0.3 µg/L). Highest metal ion concentrations were observed after treatment with stemmed large-head MoM-implants and hip resurfacing arthroplasty. DISCUSSION: Due to the risk of local and systemic accumulation of metallic products after treatment with MoM-bearing, risk and benefits should be carefully balanced preoperatively. The authors support a proposed "time out" for stemmed large-head MoM-THA and recommend a restricted indication for hip resurfacing arthroplasty. Patients with implanted MoM-bearing should receive regular and standardized monitoring of metal ion concentrations. Further research is indicated especially with regard to potential systemic reactions due to accumulation of metal products.

Radon in indoor spaces: an underestimated risk factor for lung cancer in environmental medicine.

BACKGROUND: Occupational medicine has long recognized radon to be a cause of lung cancer, especially among miners working under ground. Until recently, however, little scientific evidence was available about the risk to the general population caused by indoor radon. METHODS: The authors analyzed literature that they found by a selective search in the light of the recently published S1 guideline of the German Society of Occupational and Environmental Medicine (Deutsche Gesellschaft für Arbeitsmedizin und Umweltmedizin) and a recent publication of the German Commission on Radiological Protection (Strahlenschutzkommission). RESULTS: Exposure to indoor radon and its decay products is a major contributor to the radiation exposure of the general population. In Germany, the mean radiation exposure due to radon in living rooms and bedrooms is about 49 Bq/m(3). It is well documented in the scientific literature that indoor radon significantly increases the risk of lung cancer, probably in a linear dose-response relationship with no threshold. Every 100 Bq/m(3) increase in the radon concentration is estimated to increase the relative risk for lung cancer by 8% to 16%. After cigarette smoking, radon is the second main cause of lung cancer in the general population without occupational exposure. CONCLUSIONS: From the point of view of preventive environmental medicine, it is important to identify buildings with high radon concentrations, initiate appropriate measures, and minimize radon exposure, particularly in new buildings.

Human leukemia and lymphoma cell lines as models and resources.

Tumor cell lines are widely used as oncologic models and resources, forming, along with primary patient material and animal models, one of three major subjects for cancer investigation. With the advent of the Human Genome Project (HGP) and the ensuing provision of sequencing data and mapped clones, human cancer cell lines, notably those derived from leukemia-lymphoma (LL) have become increasingly productive tools for cancer gene ascertainment and characterization. Hence, the roles of putative novel cancer genes may be investigated using diverse panels of LL cell lines, both individually by PCR-based methods, and globally by transcriptional chip-profiling. Similar studies have also enabled the faithfulness with which cancer cell lines model their supposed in vivo counterparts to be quantified at last. Several recent transcriptional profiling studies indicate that of all tumor types well characterized human LL cell lines most accurately model the gene expression patterns of their corresponding primary tumors. Analysis using genomic arrays tells a similar story for the stability of chromosome rearrangements in LL cell lines. Well characterized LL cell lines also provide ideal tools for investigating the druggability of individual gene products, e.g. by measuring their transcript levels using q(uantitative)-PCR methods in cells subjected to treatments with small interfering (si)-RNAs. We provide a list of authentic, well characterized examples for prospective investigators, since many circulating cell lines have been cross-contaminated and describe DNA profiling methods which, together with classic and molecular cytogenetic analyses, inform authentication. We also review the problem of mycoplasma contamination and means for its eradication.

Hemoglobin adducts of ethylene oxide, propylene oxide, acrylonitrile and acrylamide-biomarkers in occupational and environmental medicine.

In a chemical plant, ethylene oxide (EO) and propylene oxide (PO) were used for the production of surfactants for the textile industry. Within health supervision, we investigated the internal exposure of the workers using hemoglobin adducts as parameters of biochemical effects. The 95th percentile for N-2-hydroxyethylvaline (HEV) was 1280 pmol/g globin (=29.4 microg/l blood) in blood from exposed workers compared with 100 pmol/g globin (or 2.3 microg/l) in controls. N-(R,S)-2-hydroxypropylvaline (HPV) both in workers and controls was below the detection limit (80 pmol/g globin or 2 microg/l). The levels of the adducts of acrylonitrile (ACN) and acrylamide (AA) were also determined, though they were mainly accounted for by smoking and diet. Median values of N-2-cyanoethylvaline (CEV) were below 4 pmol/g globin (or 0.1 microg/l) in non-smokers (n=24) and 131 pmol/g globin (or 3.3 microg/l) in smokers (n=38). Median values of N-2-carbamoylethylvaline (AAV) were 22 pmol/g globin (or 0.6 microg/l) in non-smokers compared with 89 pmol/g globin (or 2.4 microg/l) in smokers. Correlations were found between smoking habits and adduct levels of CEV and AAV.