Demographic, Reproductive, and Dietary Determinants of Perfluorooctane Sulfonic (PFOS) and Perfluorooctanoic Acid (PFOA) Concentrations in Human Colostrum.

To determine demographic, reproductive, and maternal dietary factors that predict perfluoroalkyl substance (PFAS) concentrations in breast milk, we measured perfluorooctane sulfonic (PFOS) and perfluorooctanoic acid (PFOA) concentrations, using liquid chromatography-mass spectrometry, in 184 colostrum samples collected from women participating in a cohort study in Eastern Slovakia between 2002 and 2004. During their hospital delivery stay, mothers completed a food frequency questionnaire, and demographic and reproductive data were also collected. PFOS and PFOA predictors were identified by optimizing multiple linear regression models using Akaike's information criterion (AIC). The geometric mean concentration in colostrum was 35.3 pg/mL for PFOS and 32.8 pg/mL for PFOA. In multivariable models, parous women had 40% lower PFOS (95% CI: -56 to -17%) and 40% lower PFOA (95% CI: -54 to -23%) concentrations compared with nulliparous women. Moreover, fresh/frozen fish consumption, longer birth intervals, and Slovak ethnicity were associated with higher PFOS and PFOA concentrations in colostrum. These results will help guide the design of future epidemiologic studies examining milk PFAS concentrations in relation to health end points in children.

Contamination of vegetation growing on soils and substrates in the unhygienic region of Central Spis (Slovakia) polluted by heavy metals.

The present paper aims at clarifying the long-term impact of mining activities on the contamination of biotic components of the environment. The research was conducted in during 2011-2014 at selected locations of the cadastral territory of former mining towns of Central Spis (Slovakia) with different ecosystems of permanent grassland, mine waste sites and bankside vegetation. The results of the analysis showed that considerably dominant species at contaminated locations such as Betula pendula, Silene vulgaris, Geranium sylvaticum, Petasites hybridus, Mentha longifolia could absorb high quantities of heavy metals. The observed contents of heavy metals, especially zinc, copper and mercury in plants significantly exceeded the threshold values determined by law. The highest contamination as compared to the threshold values was found in young plants of Betula pendula in the Slovinky tailing pond site, in which zinc content exceeded the threshold value 852 times. Excess of copper content also exceeded the threshold value 271 times. The highest concentration of mercury in all of the surveyed sites was observed in dry matter of Betula pendula in the area of heap in the Por?c Valley, where threshold value was 184 times higher. Statistically significant locations similar in relation to the characteristic species and monitored heavy metals was recorded on the locations of tailing pond and heap as the most important centres of contamination with the following dominant species Betula pendula, Pinus silvestris and Agrostis capilaris.

Ofatumumab added to dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia: Results from a phase II study.

The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue. An important treatment option is the use of high-dose corticosteroids. The purpose of this clinical trial was to determine the efficacy and toxicity of an ofatumumab-dexamethasone (O-Dex) combination in relapsed or refractory CLL. The trial was an open-label, multicenter, nonrandomized, Phase II study. The O-Dex regimen consisted of intravenous ofatumumab (Cycle 1: 300 mg on day 1, 2,000 mg on days 8, 15, and 22; Cycles 2-6: 1,000 mg on days 1, 8, 15, and 22) and oral dexamethasone (40 mg on days 1-4 and 15-18; Cycles 1-6). The O-Dex regimen was given until best response, or a maximum of six cycles. Thirty-three patients (pts) were recruited. Twenty-four (73%) pts completed at least three cycles of therapy. The remaining nine pts were prematurely discontinued owing to Grade 3/4 infections (seven pts), disease progression (one pt), or uncontrollable diabetes mellitus (one pt). Overall response rates/complete remissions (ORR/CR) were achieved in 22/5 pts (67/15%). The median progression-free survival (PFS) was 10 months. In pts with p53 defects (n = 8), ORR/CR were achieved in 5/2 pts (63/25%) with a median PFS of 10.5 months. The median overall survival (OS) was 34 months. The Grades 3-5 infectious toxicity in 33% of pts represented the most frequent side effect during the treatment period. In conclusion, the O-Dex regimen shows a relatively high ORR and CR with promising findings for PFS and OS. The study was registered at www.clinicaltrials.gov (NCT01310101).

Polychlorinated biphenyls and selected organochlorine pesticides in serum of Slovak population from industrial and non-industrial areas.

The concentrations of indicator polychlorinated biphenyls (PCBs No. 28, 52, 101, 138, 153 and 180) and organochlorine pesticides (HCB, p,p'-DDE and p,p'-DDT) in 121 blood serum specimens collected from non-occupationally exposed adults living in contaminated and comparison areas were determined using high-resolution gas chromatography/electron capture detection (HRGC/ECD). The sum of the serum concentrations of the three most abundant PCB congeners (No. 138, 153 and 180) found in participants (N = 81) living in industrial areas near incinerators, metallurgical and chemical plants (Krompachy, Kosice, Nemecka and Sala) was significantly higher (p < 0.001) than in participants living in villages and towns without known sources causing persistent organic pollutant (POP) contamination (N = 40). Similarly, significant differences were observed for p,p'-DDE (p < 0.0001) and p,p'-DDT (p < 0.002). However, a Mann-Whitney U test between groups showed that the difference for HCB was not statistically significant (p = 0.089). Age was positively correlated with the sum of PCBs (No. 138, 153 and 180), HCB and the sum of p,p'-DDE and p,p'-DDT (p < 0.01 for all).

Fludarabine with cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with poor-risk chronic lymphocytic leukemia.

Allogeneic stem cell transplantation (SCT) is a treatment option for patients with poor-risk chronic lymphocytic leukemia (CLL). Sequential use of chemotherapy and reduced-intensity conditioning has been proposed to improve the treatment outcomes. Fludarabine (30 mg/m(2)/day) and cytarabine (2 g/m(2)/day) for 4 days (combination of fludarabine with cytarabine; FAraC) were used for cytoreduction. After 3 days of rest, reduced intensity conditioning (RIC) was carried out consisting of 4 Gy total body irradiation, 10-20 mg/kg/day antithymocyte globulin for 3 days, and 40-60 mg/kg/day cyclophosphamide for 2 days. The median time of neutrophil engraftment was 16 days. The most frequent toxicities were grades III/IV infections in 12 of 15 cases and gastrointestinal toxicities in 8 of 15 cases. Remission (complete remission + partial remission) was achieved in 14 of 15 patients (93 %), minimal residual disease negativity according to flowcytometric analysis was observed in 10 patients. Nonrelapse mortality after 1 and 2 years was 7 and 13 %, respectively. After the median follow-up from SCT of 30 months, 80 % of patients were alive (12/15), three patients have died, and three relapses occurred. The FAraC-RIC protocol seems to be a promising approach to the treatment of poor-risk CLL with a high response rate of 93 % and favorable progression-free survival and overall survival of 70 and 85 % at 2 years after SCT, respectively. Other prospective clinical trials are needed to confirm the results of this novel therapeutic strategy.

Cluster Modeling of Environmental and Occupational Health and Safety Management Systems for Integration Support.

Many organizations around the world recognize the complementarity of public and environmental health and focus their attention on the effective management of both health and environmental risks. For this purpose, they often use the international standards ISO 14001 and ISO 45001. However, when a company intends to implement multiple standards simultaneously, the challenge of overlapping increases. Therefore, the objective of article is to analyze the requirements and documented information of two management system standards: environmental management systems (EMS), according to ISO 14001, and occupational health and safety management systems (OH&S), according to ISO 45001. A combination of content analysis and clustering methods was used to conduct the research. Visualization of the interrelationships between the requirements of the standards was done using TouchGraph Navigator. The outputs of the analysis can serve managers in the integrated implementation of these management systems as well as auditors during the review and check process when formulating recommendations for the improvement of management systems. Integrated implementation comes with multiple benefits, including reduced bureaucracy and management costs, a simplified certification process, improved internal management, and facilitation of continuous improvement.

The influence of mutational status and biological characteristics of acute myeloid leukemia on xenotransplantation outcomes in NOD SCID gamma mice.

PURPOSE: This study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival. METHODS: Mutations in 19 genes as well as leukemia- and patient-related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45+ cells) and engraftment latency. Leukemia-related characteristics were additionally analyzed in an extended group of 68 samples that included the 47 de novo samples, and additional 21 samples from refractory and relapsed cases. Engraftment outcomes were compared with overall and event-free survival of the patients. RESULTS: For the 47 de novo samples, no single mutation influenced engraftment, whereas the NPM1 mut /DNMT3A mut co-mutation was associated with higher engraftment ability. NPM1 mut /FLT3-ITD neg had lower engraftment intensity. Among leukemia-related characteristics, a complex karyotype was associated with higher engraftment intensity. Among patient-related characteristics, higher cytogenetic risk was associated with higher engraftment intensity, and failure to achieve clinical remission was associated with shorter engraftment latency. In the extended group of 68 samples, white blood count was associated with higher engraftment ability, and the presence of a complex karyotype was associated with higher engraftment intensity. Association with patient overall survival was seen only for engraftment intensity. CONCLUSIONS: The engraftment of AML was influenced by mutation-interactions and other AML characteristics, rather than by single mutated genes, and engraftment intensity best reflected clinical penetrance of AML.

Fish from industrially polluted freshwater as the main source of organochlorinated pollutants and increased frequency of thyroid disorders and dysglycemia.

In a certain area of Michalovce district in East Slovakia, heavy industrial pollution by polychlorinated biphenyls (PCBs) developed in 1955-1984 and very high PCB levels in environmental and human samples are still persisting. Recently, a total of 2045 adults from this and the surrounding background pollution area have been examined using questionnaire data, thyroid volume by ultrasound (ThV), urinary iodine and serum levels of 15 PCB congeners, hexachlorobenzene (HCB), 2,2'-2-bis(4-chlorobiphenyl)-1,1-dichloroethylene (DDE), 2,2'-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), alpha-, beta- and gamma-hexachlorocyclohexane (HCH), thyrotropin (TSH), free thyroxine (FT4), anti-thyroperoxidase antibodies (TPOab) and fasting glucose. As based on our previous findings of strikingly high level of PCBs in fish from high pollution area (e.g. mean level of 375430 ng/g lipid) and considerably lower, but still relatively high level in background pollution area (e.g. mean PCB level of 5150 ng/g), the information on the frequency of fish meals and approximate annual consumption of fish from local waters was obtained by questionnaires. The association of contaminated fish consumption with very high blood levels of PCBs, DDE and HCB and increased ThV as well as with increased frequency of positive TPOab, high values of FT4 and impaired fasting glucose (IFG) was found. These associations were also confirmed in 16 marital pairs from high pollution area with very high PCB level in both members associated with high fish consumption. It was concluded that, due to persistent heavy pollution of waters, soil and food chain namely by PCBs, but also by pesticides (e.g. DDE and HCB) resulting from their previous extensive use in agriculture, the fish from local waters still remains the most important source of these toxic pollutants which results in considerable adverse health effects.

Thyroid ultrasound volume, structure and function after long-term high exposure of large population to polychlorinated biphenyls, pesticides and dioxin.

We examined 2,046 adults (834 males and 1,212 females aged 20-75 years) from polluted district in East Slovakia (POLL) and two neighboring upstream and upwind located districts of background pollution (BCGR). By ultrasound we estimated the thyroid volume (ThV), hypoechogenicity (HYE), nodules and cysts. Serum levels of thyrotropin (TSH), thyroperoxidase antibodies (TPOab) and thyroglobulin were estimated by electrochemiluminiscent assay and these of 15 PCB congeners, p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane by high-resolution gas chromatography. In 320 subjects also selected hydroxylated and methylsulfonated PCB metabolites, polychlorinated dibenzo-dioxins (PCDDs), -furans (PCDFs), five dioxin-like coplanar and eight mono-ortho PCB congeners were estimated. Urinary iodine was measured by automatic microplate method. Reciprocal positive association was found between three major POPs (PCBs, DDE and HCB), the levels of these and also PCDDs plus PCDFs in polluted area being considerably higher than in background pollution area. ThV in groups of males and females from POLL with high PCBs level was significantly higher (p<0.001 by t-test) then in age and sex matched groups from BCGR with low PCBs level. In 1,048 males and females aged <60 years with serum PCBs level >1,000 ng g(-1) lipid (median=1,756 ng g(-1)) a significant effect of age on ThV was found (p<0.01 by ANOVA), while in 921 respective subjects with PCBs level <1,000 ng g(-1) (median=661 ng g(-1)) it was not. These findings supported the view on the additional effect of PCBs on ThV other than that of age. Since the urinary iodine in both districts showed optimal range, any interfering effect of unsatisfactory iodine intake on ThV may be excluded. The frequency of autoimmune thyroiditis signs such as HYE, increased serum level of TPOab and TSH resulting in subclinical or overt thyroid hypofunction was positively associated with sex, age and organochlorine levels. The increase of such frequency in males with POPs levels was much more abrupt than that in females. No considerable differences in the frequency of thyroid nodules as related to PCBs level were found.

Possible effects of persistent organochlorinated pollutants cocktail on thyroid hormone levels and pituitary-thyroid interrelations.

In polluted district of Michalovce in East Slovakia (POLL) and two districts with background pollution (BCGR) 2046 adults (834 males and 1212 females aged 20-75 years) were examined. Serum levels of thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (TT3) and antithyroperoxidase antibodies (TPOab) were estimated by electrochemiluminiscent assay and also these of 15 polychlorinated biphenyl congeners (PCBs), p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane were measured by high resolution gas chromatography/mass spectrometry. In addition, also dioxins, furans, coplanar- and mono-ortho-PCBs as well as selected hydroxylated and methylsulphonated PCBs and DDE metabolites were measured by appropriate methods based on gas chromatography/mass spectrometry principle. In POLL significantly higher levels of all organochlorines were found than these in BCGR. When pooled values from both areas were stratified in terms of PCBs level and treated as continuous variables, positive association of PCBs with FT4 and TT3 was found, the latter two being also mutually associated. However, within the category of PCBs level <530 ng/glipid (n=232) the association between PCBs and both the FT4 (p<0.09) and TT3 (p<0.03) was negative and any association of these was not found within the category of PCBs level of 531-1000 ng/g (n=691). In contrast, in the category of 531-2000 ng/g (n=1307) positive association appeared between PCBs and FT4 (p<0.001) as well as TT3 (p<0.05). Highly significant association of PCBs with FT4 (p<0.001) was further found in the categories with PCBs level of 1001-101414 ng/g (n=1307) and 2001-101414 (n=1123), while significant association with TT3 was observed only in the category of 531-2000 ng/g. Such findings suggest possible threshold level in positive effect of PCBs on FT4 and TT3 level which seems to be individual and located somewhere around the PCBs level of 1000 ng/g. However, highly significant negative association of both FT4 and TT3 with TSH was found in each of above indicated PCBs categories. Considerable difference in FT4 and TT3 level between large groups of subjects with the same range of PCBs level was also found suggesting different individual susceptibility to the effects of organochlorines. Among a total of 26 cases from POLL with very low TSH level (<0.5 mU l(-1)) 13 cases showed very high level of PCBs, FT4 and TT3, thus supporting a hypothesis on a novel sporadic form of high PCBs related peripheral subclinical hyperthyroidism possibly resulting from the long-term disruption of equilibrium between bound and free thyroxine in plasma by high PCBs level followed by a striking inhibition of TSH release from the pituitary.

Dioxin-like and non-dioxin-like PCBs in human serum of Slovak population.

In the present study, non-ortho, mono-ortho and other ortho-substituted PCB congeners were analysed in individual blood serum samples taken from healthy adults (196 males and 119 females) in the polluted area of the Michalovce district and in the background area of the Stropkov/Svidnik districts in Eastern Slovakia by high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS). The samples from general population living in villages and towns of two regions were taken between August 2001 and February 2002 within the project of the EC's 5th Framework Programme (PCBRISK, ). The medians of dioxin-like PCBs (dl-PCBs)--expressed as TEQs on lipid basis--of all males (24.7 pg g(-1) lipid) and females (21.4 pg g(-1) lipid) were comparable, but there was a significant difference between both of the areas studied. In the district of Michalovce, the medians of males (47.3 pg g(-1) lipid) and females (41.1 pg g(-1) lipid) were 2.3 times higher than in the area of the Stropkov/Svidnik districts. The medians of total non-dioxin-like PCB concentration were 1,835 and 1,033 ng g(-1) lipid in males and females, respectively. The data show a trend toward higher concentrations of both dl- and non-dioxin-like PCBs in the older age groups. The substantial increase was observed for the 60+ age group. PCB-126 was the most abundant non-ortho congener. PCBs-118 and 156 were the predominant mono-ortho congeners. They were quantitated in all samples analysed. Congeners 153, 138(+163), 180 and 170(+190) were the main contributors to total non-dioxin-like PCB concentrations. Mean mutual ratio HexaCBs:HeptaCBs:OctaCBs in the non-dioxin-like group was 37:50:1. The results of this study represent the overall information about the congener distribution of dioxin-like and non-dioxin-like PCBs in human serum blood of adult Slovaks.

Serum PCBs and organochlorine pesticides in Slovakia: age, gender, and residence as determinants of organochlorine concentrations.

We measured organochlorine concentrations of 15 polychlorinated biphenyl congeners and six organochlorine pesticides (PCB28, 52, 101, 123(+149), 118, 114, 153, 105, 138(+163), 167, 156(+171), 157, 180, 170, 189, alpha-, beta-, gamma-HCH, HCB, p,p'-DDT and p,p'-DDE) in 2047 subjects from contaminated and background areas of eastern Slovakia. Data were collected in 2001 and analyzed by high-resolution gas chromatography with electron capture detection in 2002-2003. Elevated levels persist in subjects from Michalovce district, site of former production facility, after almost 20-years since the end of the PCB manufacturing. Sum of 15 PCB congeners was 3105 ng/g of lipid in the Michalovce district versus 871 ng/g of lipid for subjects from the background districts of Svidnik and Stropkov. Relatively high concentration in children from the Michalovce district, sum PCB = 766 ng/g of lipid versus 372 ng/g of lipid in children from background area suggest ongoing exposure from environmental reservoirs and contaminated food. Consistent differences between genders in both contaminated and background areas are reported here. Levels in males are about 20% higher in both districts. Levels of organochlorine pesticides, particularly of DDT metabolite DDE and hexachlorobenzene are also elevated in the Michalovce district, reflecting intensive use of pesticides in agriculture in the past. About 30% decrease in serum organochlorine levels was observed in comparison with our earlier samples collected in 1998. These results suggest that contamination with PCBs still remains a source of relatively high environmental exposure for subjects in the Michalovce district.

Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on cytochrome P450 1A1 and 1B1 gene expression in blood.

BACKGROUND: In the risk assessment of PCDDs, PCDFs, and dioxin-like (DL) PCBs, regulatory authorities support the use of the toxic equivalency factor (TEF)-scheme derived from a heterogeneous data set of the relative effect potency (REPs) estimates. OBJECTIVES: We sought to determine REPs for dioxin-like compounds (DLCs) using expression of cytochrome P450 (CYP) 1A1 and 1B1 mRNA in human peripheral blood mononuclear cells representing two different pathways. METHODS: We used a sex and age adjusted regression-based approach comparing the strength of association between each DLC and the cytochrome P450 (CYP) 1A1 and 1B1 mRNA expression in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. RESULTS: We calculated REPs based on CYP1A1 expression for 4 PCDDs, 8 PCDFs, and 1 PCB congener, and based on CYP1B1 expression for 5 PCDFs and 11 PCB congeners. REPs from CYP1A1 correlated with REPs previously derived from thyroid volume (ρ=0.85; p<0.001) and serum FT4 (ρ=0.77; p=0.009). The 13 log REPs from CYP1A1 correlated with log WHO-TEFs (r=0.63; p=0.015) and 11 log PCB REPs with PCB consensus toxicity factors (CTFs) for compounds with WHO-TEFs (r=0.80; p=0.003). The complete set of derived 56 log REPs correlated with the log CTFs (r=0.77; p=0.001) and log WHO-TEFs (r=0.81; p<0.001). CONCLUSIONS: REPs calculated from thyroid and cytochrome P450 endpoints realistically reflect human exposure scenarios because they are based on human chronic and low-dose exposures. While the CYP 1A1 seems more suitable for toxicity evaluation of PCDD/Fs, the CYP 1B1 is more apt for PCDFs and PCBs and reflects different pathways.

PCDDs, PCDFs and dioxin-like PCBs in food of animal origin (Slovakia).

The levels of 17 toxic polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and 12 non-ortho and mono-ortho polychlorinated biphenyls (PCBs) in 73 foodstuff samples of animal origin collected from shops and small farms in selected districts of Slovak Republic are presented in this paper. The concentrations expressed as WHO-TEQ in analysed samples ranged for PCDDs/PCDFs from 0.25 pg/g fat in pork to 75 pg/g fat in cod liver. The TEQ concentrations of non-ortho PCBs were between 0.007 and 181 pg/g fat and mono-ortho PCBs between 0.0083 and 66.5 pg/g fat. The mean concentrations in freshwater fish and imported species of marine fish were 0.089 pg TEQ/g fresh weight for PCDDs/PCDFs, 0.17 pg TEQ/g fresh weight for non-ortho PCBs and 0.034 pg TEQ/g fresh weight for mono-ortho PCBs. The mean total concentration of PCDDs/PCDFs and dioxin-like PCBs in samples of infant milk formula imported from EU countries was 0.98 pg TEQ/g fat.

Detection of minimal residual disease in mantle cell lymphoma-establishment of novel eight-color flow cytometry approach.

BACKGROUND: Minimal residual disease (MRD) detection is an essential tool for therapy response assessment in a considerable number of hematooncologic disorders, including mantle cell lymphoma (MCL). Flow cytometry (FCM) ranks among the most effective approaches, which allows rapid sample processing and compete successfully with highly sensitive molecular methods like polymerase chain reaction. Because FCM is ordinarily applied to detect MRD in B-lineage diseases like chronic lymphocytic leukemia, a similar method could be used in MCL. We decided to test our novel eight-color FCM approach in MCL MRD detection. METHODS: Using an eight-color FCM protocol designed by us, the expression of 24 selected surface antigens in a cohort of 30 patients with newly diagnosed leukemic MCL and 20 normal controls were compared to establish markers that can reliably distinguish normal B-lymphocytes from the MCL population. The sensitivity of the designed protocol was tested using serial dilution studies. RESULTS: Although MCL presents high immunophenotypic variability, the combination of CD20/23/5/19/200/62L/3/45 seems to be very favorable in flow cytometric MRD measurement. CONCLUSIONS: Our eight-color FCM protocol could easily detect MRD in MCL patients, and reaches a sensitivity of up to 2 × 10(-4) .

Simple reaction time in 8-9-year old children environmentally exposed to PCBs.

Simple reaction time (SRT) has been studied in children exposed to polychlorinated biphenyls (PCBs), with variable results. In the current work we examined SRT in 146 boys and 161 girls, aged 8.53 ± 0.65 years (mean ± SD), exposed to PCBs in the environment of eastern Slovakia. We divided the children into tertiles with regard to increasing PCB serum concentration. The mean ± SEM serum concentration of the sum of 15 PCB congeners was 191.15 ± 5.39, 419.23 ± 8.47, and 1315.12 ± 92.57 ng/g lipids in children of the first, second, and third tertiles, respectively. We created probability distribution plots for each child from their multiple trials of the SRT testing. We fitted response time distributions from all valid trials with the ex-Gaussian function, a convolution of a normal and an additional exponential function, providing estimates of three independent parameters µ, σ, and τ. µ is the mean of the normal component, σ is the standard deviation of the normal component, and τ is the mean of the exponential component. Group response time distributions were calculated using the Vincent averaging technique. A Q-Q plot comparing probability distribution of the first vs. third tertile indicated that deviation of the quantiles of the latter tertile from those of the former begins at the 40th percentile and does not show a positive acceleration. This was confirmed in comparison of the ex-Gaussian parameters of these two tertiles adjusted for sex, age, Raven IQ of the child, mother's and father's education, behavior at home and school, and BMI: the results showed that the parameters µ and τ significantly (p ≤ 0.05) increased with PCB exposure. Similar increases of the ex-Gaussian parameter τ in children suffering from ADHD have been previously reported and interpreted as intermittent attentional lapses, but were not seen in our cohort. Our study has confirmed that environmental exposure of children to PCBs is associated with prolongation of simple reaction time reflecting impairment of cognitive functions.

NOD/SCID IL2Rγ-null mouse xenograft model of human p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma using permanent cell lines.

Xenograft models represent a promising tool to study the pathogenesis of hematological malignancies. To establish a reliable and appropriate in vivo model of aggressive human B-cell leukemia and lymphoma we xenotransplanted four p53-mutated cell lines and one ATM-mutated cell line into immunodeficient NOD/SCID IL2Rγ-null mice. The cell lines MEC-1, SU-DHL-4, JEKO-1, REC-1, and GRANTA-519 were transplanted intraperitoneally or subcutaneously and the engraftment was investigated using immunohistochemistry and flow cytometry. We found significant differences in engraftment efficiency. MEC-1, JEKO-1 and GRANTA-519 cell lines engrafted most efficiently, while SU-DHL-4 cells did not engraft at all. MEC-1 and GRANTA-519 massively infiltrated organs and the whole intraperitoneal cavity showing very aggressive growth. In addition, GRANTA-519 cells massively migrated to the bone marrow regardless of the transplantation route. The MEC-1 and GRANTA-519 cells can be especially recommended for in vivo study of p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma, respectively.

PSC 833 modulation of multidrug resistance to paclitaxel in cultured human ovarian carcinoma cells leads to apoptosis.

BACKGROUND: Multidrug resistance (MDR) modulator PSC 833 has been shown to modulate multidrug resistance in Pg-p-positive human ovarian carcinoma cells A2780/ADR. Co-treatment of A2780/ADR cells with paclitaxel (PTX) and PSC 833 resulted in the restoration of PTX-sensitivity comparable to that in parental A2780 cells. RESULTS: The flow cytometry experiments presented here showed PTX-(A2780) and PTX plus PSC 833 (A2780/ADR)-induced cell accumulation in the G2/M-phase of the cell cycle with concomitant appearance of apoptotic cells with sub-G0 (hypodiploid) DNA content. Furthermore, these events were accompanied by the appearance of poly(ADP-ribose) polymerase (PARP) cleavage, up-regulation of Bax, p53 and p21WAF1/CIP1 proteins and internucleosomal DNA fragmentation. Interestingly, we did not detect any significant alterations in Bcl-xL, CD95/Fas and Fas-L protein levels. CONCLUSION: These results demonstrate the PSC 833 reduced the Pg-p-mediated multidrug resistance in human ovarian carcinoma cells to PTX-induced apoptosis in vitro.

Case-control study of PCBs, other organochlorines and breast cancer in Eastern Slovakia.

This case-control study was designed to investigate association between polychlorinated biphenyls (PCBs) and risk of breast cancer in an area of high environmental exposure in the Michalovce district of eastern Slovakia. Incident breast cancer cases from the Michalovce district diagnosed between May 1997 and May 1999 were recruited through the Oncology Department of the District Hospital. A total of 15 individual PCB congeners, 2,2'-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), and hexachlorobenzene (HCB) were measured in the serum of 24 breast cancer patients and 88 population controls in 1998-1999. The median levels of total PCBs were similar in cases (2586 ng/g of lipid) and controls (2682 ng/g of lipid). Higher serum levels (highest vs. lowest tertile) of total PCBs (odds ratio (OR)=0.42, 95% CI 0.10-1.82, p-for trend=0.31), group 1 congeners (OR=0.37, 95% CI 0.10-1.43, P-for trend=0.02), group 2 congeners (OR=0.32, 95% CI 0.07-1.56, P-for trend=0.60), and group 3 congeners (OR=0.49, 95% CI 0.12-2.04, P-for trend=0.51) were inversely associated with risk of breast cancer. Higher serum levels of DDE (OR=3.04, 95% CI 0.65-14.3, P-for trend=0.10) were positively associated with risk of breast cancer, while there was no association for DDT (OR=1.19, 95% CI 0.27-5.23, P-for trend=0.68), and an inverse association for HCB (OR=0.45, 95% CI 0.06-3.19, P-for trend=0.67). While generally not statistically significant, PCB and HCB levels were inversely associated with risk of breast cancer in this highly exposed population. DDE, but not DDT, was positively associated with risk.