Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) frequently results from synergism between chemical and infectious liver carcinogens. Worldwide, the highest incidence of HCC is in regions endemic for the foodborne contaminant aflatoxin B1 (AFB1) and hepatitis B virus (HBV) infection. Recently, gut microbes have been implicated in multisystemic diseases including obesity and diabetes. Here, the hypothesis that specific intestinal bacteria promote liver cancer was tested in chemical and viral transgenic mouse models. METHODS: Helicobacter-free C3H/HeN mice were inoculated with AFB1 and/or Helicobacter hepaticus. The incidence, multiplicity and surface area of liver tumours were quantitated at 40 weeks. Molecular pathways involved in tumourigenesis were analysed by microarray, quantitative real-time PCR, liquid chromatography/mass spectrometry, ELISA, western blot and immunohistochemistry. In a separate experiment, C57BL/6 FL-N/35 mice harbouring a full-length hepatitis C virus (HCV) transgene were crossed with C3H/HeN mice and cancer rates compared between offspring with and without H hepaticus. RESULTS: Intestinal colonisation by H hepaticus was sufficient to promote aflatoxin- and HCV transgene-induced HCC. Neither bacterial translocation to the liver nor induction of hepatitis was necessary. From its preferred niche in the intestinal mucus layer, H hepaticus activated nuclear factor-kappaB (NF-kappaB)-regulated networks associated with innate and T helper 1 (Th1)-type adaptive immunity both in the lower bowel and liver. Biomarkers indicative of tumour progression included hepatocyte turnover, Wnt/beta-catenin activation and oxidative injury with decreased phagocytic clearance of damaged cells. CONCLUSIONS: Enteric microbiota define HCC risk in mice exposed to carcinogenic chemicals or hepatitis virus transgenes. These results have implications for human liver cancer risk assessment and prevention.

Effect of proteasome inhibitors with different chemical structures on the ubiquitin-proteasome system in vitro.

Proteasome inhibitor therapeutics (PITs) have the potential to cause peripheral neuropathy. In a mouse model of PIT-induced peripheral neuropathy, the authors demonstrated that ubiquitin-positive multifocal protein aggregates with nuclear displacement appear in dorsal root ganglion cells of animals that subsequently develop nerve injuries. This peripheral-nerve effect in nonclinical models has generally been recognized as the correlate of grade 3 neuropathy in clinical testing. In differentiated PC12 cells, the authors demonstrated perturbations correlative with the development of neuropathy in vivo, including ubiquitinated protein aggregate (UPA) formation and/or nuclear displacement associated with the degree of proteasome inhibition. They compared 7 proteasome inhibitors of 3 chemical scaffolds (peptide boronate, peptide epoxyketone, and lactacystin analog) to determine if PIT-induced peripheral neuropathy is modulated by inhibition of the proteasome (ie, a mechanism-based effect) or due to effects independent of proteasome inhibition (ie, an off target or chemical-structure-based effect). The appearance of UPAs was assayed at IC(90) +/- 5% (90% inhibition concentration +/- 5%) for 20S proteasome inhibition. Results show that each of the investigated proteasome inhibitors induced identical proteasome-inhibitor-specific ubiquitin-positive immunostaining and nuclear displacement in PC12 cells. Other agents--such as paclitaxel, cisplatin, and thalidomide, which cause neuropathy by other mechanisms--did not cause UPAs or nuclear displacement, demonstrating that the effect was specific to proteasome inhibitors. In conclusion, PIT-induced neuronal cell UPA formation and nuclear displacement are mechanism based and independent of the proteasome inhibitor scaffold. These data indicate that attempts to modulate the neuropathy associated with PIT may not benefit from changing scaffolds.

[Results of laparoscopic treatment of infertility]. / Wyniki laparoskopowego leczenia nieplodnosci.

This paper sums up the results of treatment with laparoscopy the patients suffering from infertility of unknown reason. Laparoscopy was performed in 75 patients and only in 21.3% of cases the reason of infertility remained unclear. In most of infertile women (90%) different factors of infertility were revealed--among them the most important turned out adhesions in the adnexal area (37%) and polycystic ovaries (32%). The most often performed procedures during laparoscopy were adhesiolysis and electrical cauterization ("drilling") of ovaries. 20% of patient become pregnant and delivered successfully. In operated patients only 2 complications were noted (one of anesthetic origin). The results confirmed that laparoscopy is essential element in infertility diagnostics and treatment.

[The effectiveness of the pimafucin 100 mg pill for intravaginal treatment of vaginal candidiasis]. / Ocena skutecznosci terapeutycznej preparatu "Pimafucin" 100 mg, globulki dopochwowe w leczeniu drozdzakowych zapalen pochwy.

The aim of this multicentre prospective study was assessing the effectiveness of intravaginal treatment of vaginal candidiasis with Pimafucin 100 mg ovule. Success was obtained among 81% pregnant and 86% nonpregnant women. The negative predictive factors were intensive patients complains: pruritus or soreness.

[Indicators of the identity of aspirates from the oral cavity of newborn infants and the amniotic fluid: pH, protein levels and the activity of trypsin inhibitor]. / Wskazniki identycznosci aspiratu z jamy ustnej noworodka z wodami plodowymi: pH, stezenie bialka, aktywnosc inhibitora trypsyny.

The aim of the study was to establish the biochemical identity as regards pH, protein content and trypsin inhibitor activity between the aspirate from the various sites of the newborn oral cavity and the amniotic fluid. It has been found that only correctly collected aspirate from the oral cavity without any admixture of the subepiglottic or gastric content is identical with amniotic fluid. Measurement of trypsin inhibitor activity in the improperly collected aspirate with pH below 5 must not be performed. The examination of the correctly sampled aspirates from the newborn oral cavity could be a source of the new early information regarding survival and the clinical condition of the newborn.

[Prenatal monitoring of fetal heart activity and the course of labor and the state of the newborn infant]. / Przedporodowe monitorowanie czynnosci serca plodu a przebieg porodu i stan noworodka.

In the paper practical importance of cardiotocographic interpretation of records carried out during pregnancy is discussed as well as the importance of antepartum monitoring of foetal heart rate. 1944 records of 663 pregnant women were analysed. Observations of basic frequency of foetal heart rate, oscillation and heart rate response to foetal movements and uterine contractions were made. Taking into consideration these criteria the records were classified as: reactive, nonreactive and combined (reactive and nonreactive) patterns. Among 663 cases there were 544 reactive patterns, 73 combined with predominance of reactive ones, 34 combined with predominance of nonreactive ones and 12 nonreactive patterns. Comparison of separate types of records with Apgar test in the 1 st, 3 rd, and 5 th minute shows that low Apgar score (below 7) is mainly related to the group of nonreactive and combined records with predominance of nonreactive patterns. Apgar score is above 7 in the group of reactive and combined patterns with predominance of reactive pattern. Comparison of the types of records to the kinds of delivery termination shows that in predominately nonreactive pattern there was 50-55% of operational deliveries in predominately reactive pattern groups however 24%. Therefore repeating reactive pattern in antepartum monitoring records is the evidence of good foetal state and this state most probably will not be disturbed during labour. Repeating nonreactive pattern with decreasing oscillation is the evidence of increased foetal distress.

Comparative pharmacokinetics of paracetamol in men and women considering follicular and luteal phases.

The pharmacokinetics of paracetamol administered in a single dose were investigated and compared in young male and female subjects, considering follicular and luteal phase of the menstrual cycle. The mean AUC for paracetamol in the blood of female subjects was significantly increased by 39% and 51%, respectively, taking into account the follicular and luteal phase, in comparison with the AUCs of male volunteers. The peak plasma concentration revealed significantly higher values in women in both phases, by 48% and 66%, respectively. The time to reach the peak concentration was shorter by 8% in follicular phase than in males. The difference was statistically insignificant. Elimination constant decreased in follicular phase by 15% and in luteal phase by 21% in comparison with males (the difference--statistically insignificant). The paracetamol half-life was longer (although not significantly) in women than in men: in follicular phase by 29 min, i.e. 15%, and in luteal phase by 65 min, i.e. 33%. The apparent volume of distribution was found to be significantly lower in the female group by 35% and 40% in follicular and luteal phase, respectively. Comparing data obtained in the follicular and luteal phase, it was shown that the AUC was larger, peak plasma concentration was higher and biological half-life was longer in luteal phase. It is likely that the differences in some pharmacokinetic parameters between men and women, as well as in women considering both phases of menstrual cycle, might be of clinical significance.

[Sulfamethoxazole concentration in the homogenate of the human embryo]. / Stezenie sulfametoksazolu w homogenacie ludzkiego jaja plodowego.

The investigations on the extent of placental drug transfer has conventionally been based on determining drug concentration in cord blood at delivery. There is, however, data that levels in cord blood at delivery may provide misleading information on the extent of drug transfer in utero. It is due to the fact that not every drug reaches the fetus in pharmacologically active form. Hence, the evaluation of placental drug transfer requires determination of free drug concentration in fetal tissues. Seven women with indications for interruption of pregnancy for social reasons have taken Biseptol 480--Polfa (400 mg sulfamethoxazole and 80 mg trimethoprim) for 4-5 days before the operation. Each woman received 1,92 g of drug (4 tablets) a day in two divided doses. In the tissues obtained during abortion, the concentration of sulfamethoxazole was estimated by the modified method of Bratton and Marchall . The obtained results show that in the first trimester of gestation sulfamethoxazole crosses human placental barrier; it is detectable in embryo in a great amount. This fact indicates that administration of Biseptol to the pregnant mother may be harmful for the embryo. Our investigations have not permitted yet on for the statement that there is the correlation between the sulfamethoxazole concentration and week of gestation during the first trimester.