Into the Blue: First in Man Data on Diving Physiology in Fontan Patients.

Swimming and diving are popular recreational activities. As congenital heart disease, especially patients with univentricular hearts after Fontan palliation are thought to have reduced physiologic capacities for compensation of submersion-associated physiologic demands, current guidelines put restraints on this group of patients. Although these restrictions on doctoral advice place a significant burden on affected patients, it is especially interesting that these guideline recommendations are merely based on physiologic assumptions, i.e., expert consensus. A recent study by Paech et al. presented the first in vivo data on the effects of immersion in Fontan patients, stating no major adverse events in their study group as well as comparable physiologic adaption as reported in the literature for healthy people. Yet, submersion was not reflected in this study, and the current study therefore aimed to conduct a first study for the evaluation of the effects of submersion and apnea diving in Fontan patients. A control group of healthy adults as well as patients recruited from the Heart Center Leipzig, Department of pediatric cardiology underwent a standardized diving protocol including a static as well as dynamic apnea phase. Physiologic data were recorded. This study presents the first structured data on diving physiology in Fontan patients compared to healthy probands. There were no adverse events. The physiologic response to diving seems to be comparable between healthy probands and Fontan patients. Although, healthy probands did reach a much better performance, the basic mechanisms of physiologic adaption seem comparable.

[The Course of E-Cigarette Use in Adolescence: A Cohort Study over 18 Months]. / Der Verlauf des E-Zigarettenkonsums im Jugendalter: Eine Kohortenstudie über 18 Monate.

AIM: Description of adolescent e-cigarette use over time. METHOD: In 2017 and 2019, 261 adolescents from North Rhine-Westphalia who had used e-cigarettes at least once a month (mean age: 14.9 years; 33.5 % female) took part in a questionnaire study. RESULTS: In 2017, 84 adolescents (32.2 %) reported exclusive e-cigarette use (single users), 177 adolescents were classified as dual users (67.8 %) because they consumed a tobacco product (conventional cigarette and/or hookah) in addition to e-cigarettes. During the observation period of 18 months, 83 adolescents (31.8 %) quit nicotine products altogether. Dual users quit nicotine less often than single users (N = 39 or 22.0 % vs. N = 44 or 52.4 %, p < 0.001). Seven single users (8.3 %) did not change their behavior, 11 began to use tobacco exclusively (13.1 %), another 22 (26.2 %) started dual use. Seventy-eight dual users (44.1 %) did not change their behavior, 57 (32.1 %) switched to tobacco use only, 3 dual users (1.7 %) stopped tobacco use, but continued to use e-cigarettes. Taken together, at the end of the study, 10 (5.6 %) of the remaining 178 adolescents consumed only e-cigarettes, while 168 (94.4 %) smoked tobacco or were dual-users. CONCLUSIONS: More than two thirds of all young e-cigarette users and more than three quarters of dual users also used nicotine products 18 months later. The remaining consumers showed a less frequent stay or switch to single use, instead a more frequent use of tobacco or dual use.

[Lung transplantation : Histomorphological diagnosis and clinical aspects]. / Lungentransplantation : Histomorphologische Diagnostik und klinische Aspekte.

The function of pulmonary allografts is regularly impaired by alloimmune reactions with quite variable clinical outcomes, different involved effector cells and molecules, as well as affected anatomical compartments. Acute rejection of grafts after lung transplantation (LuTx) is not only associated with the subsequent development of acute graft dysfunction, but can also contribute - among other immunological and nonimmunological factors - to the development of chronic lung allograft dysfunction (CLAD), which is the main reason for the limited long-term survival after LuTx. In addition to ACR and analogous to other solid organ transplants, the importance of antibody-mediated (humoral) rejection (AMR) in LuTx has also been recognized. There are currently no specific laboratory, radiological, or clinical tests available for either ACR or AMR. Only by the synoptic examination of histopathological changes and interpretation against the background of microbiological, virological, serological, and functional findings, can adequate sensitivity and specificity be achieved in the diagnostics of rejection. In this article, the current criteria for histopathological diagnostics of rejection following LuTx are summarized and the most important differential diagnoses are discussed.

Controlling the Self-Injection Threshold in Laser Wakefield Accelerators.

Controlling the parameters of a laser plasma accelerated electron beam is a topic of intense research with a particular focus placed on controlling the injection phase of electrons into the accelerating structure from the background plasma. An essential prerequisite for high-quality beams is dark-current free acceleration (i.e., no electrons accelerated beyond those deliberately injected). We show that small-scale density ripples in the background plasma are sufficient to cause the uncontrolled (self-)injection of electrons. Such ripples can be as short as ∼50 µm and can therefore not be resolved by standard interferometry. Background free injection with substantially improved beam characteristics (divergence and pointing) is demonstrated in a gas cell designed for a controlled gas flow. The results are supported by an analytical theory as well as 3D particle in cell simulations.

[Universal newborn hearing screening : Definition of uniform parameters by the Association of German Hearing Screening Centers as a requirement for nationwide evaluation with valid results]. / Universelles Neugeborenen-Hörscreening : Definition einheitlicher Parameter durch den Verband Deutscher Hörscreening-Zentralen (VDHZ) als Voraussetzung für eine flächendeckende Evaluation mit validen Ergebnissen.

BACKGROUND: Since 2009, all newborns in Germany have been entitled to universal neonatal hearing screening (UNHS). UNHS with tracking of test results leads to earlier detection of hearing disorders. The Association of German Hearing Screening Centers (Verband Deutscher Hörscreening-Zentralen, VDHZ) was founded to promote nationwide tracking, validity and quality control of UNHS results. OBJECTIVES: A comparable data structure in the different screening centers, with uniform definitions of primary parameters is essential for the nationwide evaluation of UNHS results. To address the question of whether a data structure with comparable definitions already exists or still has to be created, the existing structures and primary parameter definitions in the hearing screening centers should be investigated and compared. METHODS: A survey was conducted in all hearing screening centers to assess how data on the primary UNHS parameters defined in pediatric guidelines was gathered. In the case of discrepancies, uniform definitions were created. Finally, the practicability of these definitions was evaluated. RESULTS: Due to differing definitions of primary parameters, some of the data were not comparable between the individual centers. Therefore, uniform definitions were created in a consensus process. In the centers, the screening method, the two-step first screening and the result of the first screening now correspond to these uniform definitions. Other parameters, e.g. the total number of newborns, still vary widely, rendering the comparison of screening rates almost impossible. CONCLUSION: Valid evaluation of UNHS not only requires nationwide establishment of hearing screening centers, but also unified data structures and parameter definitions.

Hydrogen sensor based on metallic photonic crystal slabs.

We present a hydrogen sensor based on metallic photonic crystal slabs. Tungsten trioxide (WO(3)) is used as a waveguide layer below an array of gold nanowires. Hydrogen exposure influences the optical properties of this photonic crystal arrangement by gasochromic mechanisms, where the photonic crystal geometry leads to sharp spectral resonances. Measurements reveal a change of the transmission depending on the hydrogen concentration. Theoretical limits for the detection range and sensitivity of this approach are discussed.

The role of duplex ultrasonography in the diagnosis of lower-extremity deep vein thrombosis in non-hospitalized patients.

AIM: The aim of this study is to reassess the diagnostic evaluation using duplex scanning in non-hospitalized patients, suspected of having deep vein thrombosis (DVT) of the lower limbs. METHODS: In a period of 4 years, 589 patients suspected of having DVT of the lower limbs were submitted to duplex scanning for diagnostic confirmation. The patient complaints were pain, edema or color alteration of the extremity, associated with a risk factor or not. The time span between the beginning of symptoms and the ultrasound was considered as well, with the examination being conducted only on the member that presented the signs or symptoms, or on both in case of suspicion of pulmonary embolism. This study features 203 male patients and 386 female patients, aged 19 to 93. RESULTS: In Group I, of the 139 patients who displayed acute venous thrombosis (N=77), 55.4% had at least one associated risk factor; in Group II, of the 96 patients with chronic thrombosis (N=72), 75% had an associated risk factor that predominated the previous history of illness; and in Group III, in 354 patients without DVT, 161 of them (45.5%) featured some associated risk factor. CONCLUSION: It was concluded that duplex scanning is a useful tool for offering a prompt and efficient diagnosis of venous thrombosis as well as displaying alterations in adjacent structures, thus facilitating the differential diagnostic with other conditions, although in many patients (32.7%) the examination was done unnecessarily, with irrelevant clinical signs and in the absence of any evident risk factor.

Multilayer perceptron tumour diagnosis based on chromatography analysis of urinary nucleosides.

Nucleosides in human urine are of interest as a biochemical marker for cancer, acquired immune deficiency syndrome (AIDS) and the whole-body turnover of RNAs. A reversed-phase high-performance liquid chromatography (RP-HPLC) method with photodiode-array detection was used to quantitatively analyze urinary normal and modified nucleosides. 55 persons with malignant tumors of various types, 13 persons with benign tumors and 41 healthy controls were investigated within a clinical intervention study. Artificial neural networks (ANN) have been used as a practical pattern recognition tool to distinguish cancer patients from healthy persons. Using a multilayer perceptron (MPL), a specificity of 85%, and a sensitivity of 97% in differentiation between tumor patients and healthy persons was achieved. The differentiation between benign and malignant tumors had a sensitivity of 60% and a specificity of 84%. These results verify the usefulness of ANN and the RP-HPLC method for tumor recognition in agreement with existing studies.

IGF-II serum levels are normal in children with Silver-Russell syndrome who frequently carry epimutations at the IGF2 locus.

CONTEXT: Epigenetic mutations of 11p15 encompassing IGF2 are present in short children with Silver-Russell syndrome (SRS) with high frequency (31-50%). It has been speculated that these mutations characterized by demethylation of ICR1 cause diminished IGF2 expression. OBJECTIVE: We aimed to determine the prevalence of pathologically low IGF-II serum levels in children with SRS. SUBJECTS: SRS was defined by birth weight or length below the 3rd percentile, lack of postnatal catch-up growth, and the presence of two of the following characteristics: typical face, relative macrocephaly, and skeletal asymmetry. Serum samples of 30 patients were available. Mean age was 5.4 +/- 2.1 yr. METHODS: The serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2, and IGFBP-3 were measured by RIA and compared with age-related reference values and with serum concentrations measured in age- and gender-matched controls born small for gestational age (SGA), but lacking major dysmorphic features. Analysis of genomic DNA was possible in a subgroup of children with SRS: the methylation status of the ICR1 locus on 11p15 and the parental origin of chromosome 7 were analyzed in 9 and 23 children, respectively. RESULTS: Demethylation of ICR1 was found in 44% and uniparental disomy in 17% of the tested children with SRS. The median IGF-II serum level in SRS was 441 microg/liter (range, 238-875). This was significantly higher than in the SGA controls: 387 microg/liter (range, 265-596) (P < 0.03), but below the median value of the age-related reference, which was 532 microg/liter. The four children with SRS and ICR1 demethylation had high-normal and normal IGF-II serum levels that were higher than the levels of their SGA controls. IGF-I, IGFBP-2, and IGFBP-3 serum levels were not different between the SRS children and their SGA controls. CONCLUSIONS: Our data render it unlikely that demethylation of ICR1 on 11p15 does cause diminished IGF-II serum levels in children with SRS. This observation does not exclude deficient IGF-II action before birth.

Comparison of cytochrome P450- and peroxidase-dependent metabolic activation of the potent carcinogen dibenzo[a,l]pyrene in human cell lines: formation of stable DNA adducts and absence of a detectable increase in apurinic sites.

The potent carcinogen dibenzo[a,l]pyrene (DB[a,l]P) has been reported to form both stable and depurinating DNA adducts upon activation by cytochrome P450 enzymes and/or cellular peroxidases. Only stable DB[a,l]P-DNA adducts were detected in DNA after reaction of DB[a,I]P-11,12-diol-13,14-epoxides in solution or cells in culture. To determine whether DB[a,l]P can be activated to metabolites that form depurinating adducts in cells with either high peroxidase (human leukemia HL-60 cell line) or cytochrome P450 activity (human mammary carcinoma MCF-7 cell line), cultures were treated with DB[a,l]P for 4 h, and the levels of stable adducts and apurinic (AP) sites in the DNA were determined. DNA samples from DB[a,l]P-treated HL-60 cells contained no detectable levels of either stable adducts or AP sites. MCF-7 cells exposed to 2 microM DB[a,l]P for 4 h contained 4 stable adducts per 10(6) nucleotides, but no detectable increase in AP sites. The results indicate that metabolic activation of DB[a,l]P by cytochrome P450 enzymes to diol epoxides that form stable DNA adducts, rather than one-electron oxidation catalyzed either by cytochrome P450 enzymes or peroxidases to form AP sites, is responsible for the high carcinogenic activity of DB[a,l]P.

Fjord- and bay-region diol-epoxides investigated for stability, SOS induction in Escherichia coli, and mutagenicity in Salmonella typhimurium and mammalian cells.

The fjord-region diol-epoxides of benzo(c)phenanthrene combine high mutagenic and carcinogenic activity with low chemical reactivity. To study whether this is a unique property of these compounds or a more general characteristic of fjord-region diol-epoxides, we have synthesized the anti- and syn-diastereomers of r-9,t-10-dihydroxy-11,12-oxy-9,10,11,12-tetrahydrobenzo(c)chrysene and r-11-t-12-dihydroxy-13,14-oxy-11,12,13,14-tetrahydrobenzo(g)chrysene. These compounds as well as the anti- and syn-diastereomers of the fjord-region diol-epoxides of benzo(c)phenanthrene and of the bay-region diol-epoxides of phenanthrene, chrysene, and benzo(a)pyrene were investigated for their half-lives in a physiological buffer, for their mutagenicity in Salmonella typhimurium (reversion of the his- strains TA97, TA98, TA100, and TA104), for induction of SOS response in Escherichia coli (SOS chromotest in strain PQ37) and for their mutagenicity in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). All six of the investigated fjord-region diol-epoxides were more stable in physiological buffer at 37 degrees C (t1/2 greater than 2 h) than the six bay-region diol-epoxides (t1/2 = 0.011 to 1.2 h). The half-lives correlated negatively with the calculated delta Edeloc values for the formation of the benzylic carbocations, and were consistently shorter for the syn- than for the corresponding anti-diastereomer. All fjord-region diol-epoxides showed extraordinarily high activity in all six genotoxicity assays used. In mammalian cells, the anti-diol-epoxide of benzo(c)chrysene was 8.6 and 12 times more active than the anti-diol-epoxides of benzo(c)phenanthrene and benzo(a)pyrene, respectively, which were the most potent mutagens among the reference compounds. The other three newly available fjord-region diol-epoxides were also markedly more mutagenic in mammalian cells than the reference compounds. Whereas the syn-diastereomers of the simple bay-region diolepoxides were clearly less mutagenic in mammalian cells than the corresponding anti-diastereomers, the differences in potency between diastereomers were small for the fjord-region diol-epoxides. In conclusion, the diol-epoxides of benzo(c)phenanthrene are not unique in their high biological activities. The two newly available diastereomeric pairs of fjord-region diol-epoxides of benzo(g)- and benzo(c)chrysene proved to be even more active. For one of them, the diol-epoxides of benzo(g)chrysene, the delta Edeloc value for the formation of the benzylic carbocation is lower than for the benzo(c)phenanthrene diol-epoxides, for the other it is higher.

The potent carcinogen dibenzo[a,l]pyrene is metabolically activated to fjord-region 11,12-diol 13,14-epoxides in human mammary carcinoma MCF-7 cell cultures.

Dibenzo[a,l]pyrene (DB[a,l]P), an environmental hydrocarbon and very potent carcinogen in rodent bioassays, could be activated to DNA-binding intermediates in cells through formation of three different regioisomeric bay- or fjord-region diol-epoxides or other more highly oxidized metabolites. The mechanism of metabolic activation of DB[a,l]P in the human mammary carcinoma cell line MCF-7 was elucidated by analyzing the DB[a,l]P-DNA adducts formed by [35S]phosphorothioate postlabeling, immobilized boronate chromatography, and high-performance liquid chromatography. Six DB[a,l]P-DNA adducts were detected. Comparison with those formed in cells by DB[a,l]P-11,12-diol and by reaction of DNA with syn- and anti-(benzylic hydroxyl and epoxide oxygen cis and trans, respectively) DB[a,l]P-11,12-diol-13,14-epoxide (DB[a,l]PDE) demonstrated that all DB[a,l]P-DNA adducts in MCF-7 cells were formed by these diol-epoxide isomers. Cellular DNA contained large amounts of two syn- and one anti-DB[a,l]PDE-DNA adducts and small amounts of one syn- and two anti-DB[a,l]PDE-DNA adducts. The ability of human cells to activate DB-[a,l]P to its fjord-region 11,12-diol 13,14-epoxides suggests that environmental exposure to DB[a,l]P could pose a risk for humans.

The K-region trans-8,9-diol does not significantly contribute as an intermediate in the metabolic activation of dibenzo[a,l]pyrene to DNA-binding metabolites by human cytochrome P450 1A1 or 1B1.

Metabolic activation of the K-region trans-8,9-diol of the highly carcinogenic hexacyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) by human cytochrome P-450 (P450) 1A1 and 1B1 was investigated in Chinese hamster V79 cell lines expressing human P450 1A1 or 1B1. P450 1A1 and 1B1 are the major P450s involved in metabolic activation of polycyclic aromatic hydrocarbons in human cells. The major DNA adducts formed by metabolism of DB[a,l]P in cultures expressing P450 1A1 or 1B1 resulted mainly from the fjord region (-)-anti-DB[a,l]P-11,12-diol 13,14-epoxide [(-)-anti-DB[a,l]PDE] and, to a lesser extent, (+)-syn-DB[a,l]PDE. In V79 cells expressing human P450 1A1, high amounts of as yet unidentified highly polar DNA adducts are formed in addition to the DNA adducts derived from DB[a,l]PDEs. Human P450 1A1 has been found to metabolize DB[a,l]P on its K-region to the trans-8,9-diol, and it has been proposed that the DNA binding of the parent compound in P450 1A1-expressing tissues may be partially mediated by activation of the K-region trans-8,9-diol to form bis-diol epoxides. V79 cells expressing human P450 1A1 or 1B1 formed only low amounts of DNA adducts after treatment with high doses of the K-region trans-8,9-diol. None of the adducts formed were identical to the main adducts formed in the same cell lines by metabolic activation of DB[a,l]P or (-)-DB[a,l]P-trans-11,12-diol. These results demonstrate that the K-region trans-8,9-diol does not significantly contribute to the genotoxicity of the very potent carcinogen DB[a,l]P in human cells or tissues expressing P450 1A1 or 1B1.

Mutagenic and cell-transforming activities of triol-epoxides as compared to other chrysene metabolites.

The syn- and anti-isomers of the bay-region diol-epoxides of chrysene and of 3-hydroxychrysene and their metabolic precursors have been investigated for mutagenicity in Salmonella typhimurium (reversion to histidine prototrophy) and V79 Chinese hamster cells (acquirement of resistance to 6-thioguanine) and for transforming activity in M2 mouse prostate cells. Other known and potential chrysene metabolites have been included in mutagenicity experiments. Direct mutagenic activity in S. typhimurium TA 100 exhibited, in order of potency, anti-triol-epoxide greater than syn-triol-epoxide greater than anti-diol-epoxide greater than syn-diol-epoxide greater than chrysene 5,6-oxide much greater than chrysene-1,2-quinone, chrysene-3,4-quinone, and chrysene 5,6-quinone. Chrysene, the six isomeric chrysenols, and the trans-dihydrodiols [trans-1,2-dihydroxy-1,2-dihydrochrysene (chrysene-1,2-diol), trans-3,4-dihydroxy-3,4-dihydrochrysene, trans-5,6-dihydroxy-5,6-dihydrochrysene, and 9-hydroxy-trans-1,2-dihydroxy-1,2-dihydrochrysene (9-hydroxychrysene-1,2-diol)] were inactive per se but were activated to mutagens in the presence of reduced nicotinamide adenine dinucleotide phosphate-fortified postmitochondrial fraction (S9 mix) of liver homogenate from Arochlor 1254-treated rats. Chrysene, 3-hydroxychrysene, chrysene-1,2-diol, and 9-hydroxychrysene-1,2-diol were activated efficiently; the other compounds were activated weakly. In S. typhimurium TA 98, the mutagenic activities of the chrysene derivatives were weak in comparison with those in the strain TA 100. trans-3,4-Dihydroxy-3,4-dihydrochrysene (in the presence of S9 mix) was the most efficacious mutagen in strain TA 98. The relative mutagenic potencies of the directly active compounds differed from the results obtained in strain TA 100, in that in strain TA 98 the anti-diol-epoxide was more mutagenic than the triol-epoxides and chrysene 5,6-oxide was more mutagenic than syn-diol-epoxide and syn-triol-epoxide. In V79 cells, the order of mutagenic potency was: anti-triol-epoxide greater than anti-diol-epoxide greater than syn-triol-epoxide greater than syn-diol-epoxide greater than chyrsene 5,6-oxide greater than chrysene-1,2-diol (in the presence of S9 mix) greater than 9-hydroxychrysene-1,2-diol (in the presence of S9 mix) greater trans-3,4-dihydroxy-3,4-dihydrochrysene in the presence of S9 mix). Chrysene, 3-hydroxychrysene, 5-hydroxychrysene, and 6-hydroxychrysene showed no mutagenic effects in V79 cells, either in the presence or absence of S9 mix.(ABSTRACT TRUNCATED AT 400 WORDS)

Unrepaired fjord region polycyclic aromatic hydrocarbon-DNA adducts in ras codon 61 mutational hot spots.

The fjord region diol-epoxide metabolites of polycyclic aromatic hydrocarbons display stronger tumorigenic activities in rodent studies than comparable bay region diol-epoxides, but the molecular basis for this difference between fjord and bay region derivatives is not understood. Here we tested whether the variable effects of these genotoxic metabolites of polycyclic aromatic hydrocarbons may result from different DNA repair reactions. In particular, we compared the repairability of DNA adducts formed by bay region benzo[a]pyrene (B[a]P) diol-epoxides and the structurally similar but significantly more tumorigenic fjord region diol-epoxide metabolites of benzo[c]phenanthrene (B[c]Ph). For that purpose, we incorporated both types of polycyclic aromatic hydrocarbon adducts into known hot spot sites for carcinogen-induced proto-oncogene activation. Synthetic DNA substrates were assembled using a portion of human N-ras or H-ras that includes codon 61, and stereospecific B[a]P or B[c]Ph adducts were synthesized on adenine N6 at the second position of these two ras codon 61 sequences. DNA repair was determined by incubating the site-directed substrates in human cell extracts, followed by electrophoretic visualization of radiolabeled oligonucleotide excision products. These cell-free assays showed that all tested bay region B[a]P-N6-dA adducts are removed by the human nucleotide excision repair system, although excision efficiency varied with the particular stereochemical configuration of each B[a]P residue. In contrast, all fjord region B[c]Ph-N6-dA adducts located in the identical sequence context and with exactly the same stereochemical properties as the corresponding B[a]P lesions were refractory to the nucleotide excision repair process. These findings indicate that the exceptional tumorigenic potency of B[c]Ph or related fjord region diol-epoxides may be attributed, at least in part, to slow repair of the stable base adducts deriving from the reaction of these compounds with DNA.

The nucleotide excision repair protein XPC is essential for bulky DNA adducts to promote interleukin-6 expression via the activation of p38-SAPK.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants, and many are potent carcinogens. Benzo[a]pyrene (B[a]P), one of the best-studied PAHs, is metabolized ultimately to the genotoxin anti-B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE triggers stress responses linked to gene expression, cell death and survival. So far, the underlying mechanisms that initiate these signal transduction cascades are unknown. Here we show that BPDE-induced DNA damage is recognized by DNA damage sensor proteins to induce activation of the stress-activated protein kinase (SAPK) p38. Surprisingly, the classical DNA damage response, which involves the kinases ATM and ATR, is not involved in p38-SAPK activation by BPDE. Moreover, the induction of p38-SAPK phosphorylation also occurs in the absence of DNA strand breaks. Instead, increased phosphorylation of p38-SAPK requires the nucleotide excision repair (NER) and DNA damage sensor proteins XPC and mHR23B. Interestingly, other genotoxins such as cisplatin (CDDP), hydrogen peroxide and ultraviolet radiation also enhance XPC-dependent p38-SAPK phosphorylation. In contrast, anti-benzo[c]phenanthrene-3,4-dihydrodiol-1,2-epoxide, the DNA adducts of which are not properly recognized by NER, does not trigger p38-SAPK activation. As a downstream consequence, expression and secretion of the pro-inflammatory cytokine interleukin-6 is induced by BPDE and CDDP in vitro and by CDDP in the murine lung, and depends on XPC. In conclusion, we describe a novel pathway in which DNA damage recognition by NER proteins specifically leads to activation of p38-SAPK to promote inflammatory gene expression.

Induction of gene expression of xenobiotic metabolism enzymes and ABC-transport proteins by PAH and a reconstituted PAH mixture in human Caco-2 cells.

It was shown recently that in epithelial Caco-2 cells the food contaminant benzo[a]pyrene (B[a]P) is metabolized and B[a]P-sulfate metabolites were transported out of the cells. The aim of this study was to investigate whether B[a]P and other polycyclic aromatic hydrocarbons (PAH) such as chrysene, phenanthrene, benzo[k]fluoranthene (B[k]F), dibenzo[a,l]pyrene (DB[a,l]P), and pyrene alone or in a mixture in a ratio as they occur in tobacco smoke have effects on gene expression of intestinal cytochrome P450 enzymes (CYP), Phase II enzymes and ATP-binding cassette (ABC)-transport proteins in the human Caco-2 cells. B[a]P induced its own metabolism. Treatment of the Caco-2 cells with B[a]P, chrysene, B[k]F, or DB[a,l]P induced mRNA expression of CYP1A1 and CYP1B1 specifically as measured by RT-PCR. In contrast, the mRNA expression of the microsomal epoxide hydrolase (mEH) was not affected by PAH. The gene expression of the Phase II enzymes UDP-glucuronosyltransferase 1A6 (UGT1A6) and UGT1A7 was also induced by these PAH but treatment with them had no effect on gene expression of sulfotransferases (SULT) at all. Of the ABC-transport proteins, MDR1 mRNA expression was induced by treatment with carcinogenic PAH, whereas MRP2 mRNA expression was not changed. The mixture of PAH also induced CYP1A1, CYP1B1, UGT1A6, and UGT1A7 mRNA expression. We conclude that B[a]P, chrysene, B[k]F, and DB[a,l]P have specific effects on intestinal CYP1A1, CYP1B1, UGT1A6, and UDP1A7 mRNA expression but no effects on the expression of SULT.

The importance of small saphenous vein reflux on chronic venous disease clinic.

AIM: It is estimated that between 5% to 20% of the adult population in developed countries is affected by chronic venous insufficiency (CVI), thus being the most frequent vascular disorder. Recent studies show that, in most CVI patients, their junctions are competent and the correlated superficial reflux is present along the saphenous vein. Objective of the study was to correlate the presence and distribution of reflux in the saphenous vein with the signs and symptoms of CVI, through CEAP, in female patients. METHODS: Record review of patients with CVI signs and symptoms who underwent clinical and ultrasound examinations in order to classify them according to CEAP. The sample was divided into three groups according to the presence of saphenous vein insufficiency: Group I-SSV, Group II-GSV, and Group III-SSV and GSV. RESULTS: A total of 312 lower limbs of 259 female patients aged between 15 and 85 years were examined. The most prevalent clinical classes in the three groups were C2 (44.55%) and C3 (46.48%). Four patterns of reflux were identified in isolated SSV, with the highest incidence of proximal reflux (69.23%). SPJ impairment was most likely to occur in clinical cases of greater severity. Five patterns of reflux were identified in GSV, with the proximal one the most prevalent (64.42%). CONCLUSION: There is a correlation between the clinical severity of CVI and the reflux along the SSV in association with GSV; the risk of moderate to high clinical severity in group III was 3.6 times higher than in group I and 4.6 times higher than group II.

The impact of obesity on venous insufficiency.

Association between chronic venous disease and obesity has recently been studied, with indications that it may worsen in obese patients. The aim of study was to correlate clinical classes of chronic venous disease according to Clinical Etiology Anatomy Pathophysiology (CEAP) classification and body mass index, as well as to compare the severity of chronic venous disease in obese and nonobese patients. This retrospective cross-sectional prevalence study was conducted at the Maringá State University and Belczak Vascular Center along a period of 2 years, consisting of a random sample of 482 patients with complaints compatible with chronic venous disease. Data obtained from patient's files included gender, age, weight and height (for calculating body mass index), and clinical class (C) of chronic venous disease according to CEAP classification. Statistical analysis included Spearman's correlation coefficient, Chi-square test (for comparing frequencies), and Student's t-test (for comparing means). Significant positive correlation between body mass index and clinical classes was established for women (0.43), but not for men (0.07). Obesity (body mass index : ≥ : 30.0) was significantly more frequent in patients with chronic venous disease in clinical classes 3 (p < 0.001) and 4 (p = 0.002) and less frequent in patients with chronic venous disease in clinical class 1 (p < 0.001). This study evidenced significant correlation between body mass index and clinical classes of chronic venous disease in women, but not in men. It also corroborated the negative impact of obesity on the clinical severity of chronic venous disease.