The German guideline "Obesity in pregnancy": comparison with the international approach.

BACKGROUND: Obesity is an increasing problem, even in young women of reproductive age. Obesity has a negative impact on conception, the course of pregnancy, and neonatal outcomes. Caring for obese pregnant women has becoming an important aspect of standard prenatal care. The Guideline "Obesity and Pregnancy" of the German Society of Gynecology and Obstetrics aims to create evidence-based recommendations which can be used to improve the care of obese pregnant women. As obesity is a worldwide problem, many societies for obstetrics and gynecology have created national guidelines. METHODS: We reviewed the following guidelines for obesity and pregnancy: American College of Obstetricians and Gynecologists (ACOG) 2021, Royal College of Obstetrics and Gynecology (RCOG) 2018; AND Society of Obstetricians and Gynecologists of Canada (SOGC) 2019. These guidelines were compared to the German guideline. RESULTS: There are some variations between the guidelines, though no major contradictions exist. Disparities were found regarding the recommendations for substitution of high folic acid and Vitamin D. Furthermore, the recommended time for screening for gestational diabetes and the methods to control fetal growth differ between the guidelines. Regarding place of birth, RCOG allows delivery in midwifery-led units in the absence of other high-risk circumstances, while others request facility of care by neonatologists and medical staff trained in care of obese women. Induction of labor at term due to increased risk of intrauterine demise is mostly limited to women with a body mass index of 40 kg/m2. Only one guideline considers induction of all obese women. For intrapartum management, the majority allows tolerating of longer labor times to delivery if fetal monitoring is sufficient and fetal stress is excluded. Special encouragement of breastfeeding and healthy lifestyle is commonly recommended; only in the Canadian guideline, postpartum depression evaluation is requested due to the overall high prevalence of depression and anxiety in obese women. CONCLUSION: All guidelines consider pregnancies in obese women as high-risk pregnancies and emphasize the need for preconception counseling. There are special needs in pregnancy care and in the intrapartum and postpartum management to be observed.

[Predisposition and phenotypes of gestational diabetes]. / Prädisposition und Phänotypen des Gestationsdiabetes.

Gestational diabetes (GDM) is defined as glucose intolerance first diagnosed with a 75 gram oral glucose tolerance test based on IADPSG criteria which had been recently adopted by WHO. In industrial countries GDM is one of the most frequent pregnancy complications. In 2012, in Germany GDM had been diagnosed in 4,3 % of all births, overall 27,700 cases. GDM has to be considered as a preliminary stage of type 2 diabetes with insulin resistance and inadequate ß-cell-compensation. Additionally, adverse metabolic profile, associations with inflammatory parameters, with D vitamin metabolism, and insufficient decline of renal threshold for glucose had been identified in women with GDM. Within 10 years after GDM roughly 50 % of the women convert to overt diabetes, mostly type 2. GDM and type 2 diabetes share potential candidate genes. In about 1 % of GDM in Caucasian women a mutation in glucokinase gene had been found (GCK-MODY). Predisposition to GDM is predominantly characterized by family history of diabetes, previous GDM in pregnancies, factors of metabolic syndrome, and unfavorable life style. The probability for GDM rises with increasing mother's age and preconceptional BMI. Via fetal programming GDM dispones to offspring obesity as early as school entry. Prevention of GDM focus on regular physical exercise, normalizing body weight before conception, reducing excess intake of animal protein and soft drinks, planning of pregnancy in younger ages, and avoiding pollutant exposition as well as smoking cessation.

Sulforaphane modulates the expression of Cyp6a2 and Cyp6g1 in larvae of the ST and HB crosses of the Drosophila wing spot test and is genotoxic in the ST cross.

Constitutive overexpression of Cyp6g1 and Cyp6a2 genes in DDT-resistant line Oregon-flare of the Drosophila melanogaster wing spot test (SMART) has been reported. Cyp6g1 and Cyp6a2 expression levels were compared against the ß-actin gene in the standard (ST) and high bioactivation (HB) crosses of the Somatic Mutation and Recombination test (SMART) treated with sulforaphane or phenobarbital as the control inductor. The CYP450s' enzymatic activity was determined by overall NADH consumption. The expression levels of both genes and the CYP450s activity was higher in the HB cross. The Cyp6g1 levels were higher than those of Cyp6a2 in both crosses, but lower than the expression of ß-actin. Sulforaphane decreased Cyp6g1 in the HB cross and increased it in the ST cross; Cyp6a2 expression was inhibited in the ST cross. Sulforaphane resulted mutagenic in the ST cross, which could be related to the inhibition of Cyp6a2. Phenobarbital did not modify the Cyp6g1 levels but increased the Cyp6a2 and CYP450s basal activity. Although the transcript levels were always higher in the HB cross than in the ST, the expression of Cyp6a2 and Cyp6g1 was not constitutive and was independent one from the other. Sulforaphane modulated both genes in a differential way in each cross and, in contrast to its putative protective effect, it resulted to be mutagenic.

Follow-up of adult celiac patients: which noninvasive test reflects mucosal status most reliably?1.

UNLABELLED: SPECIFIC AUTHOR CONTRIBUTIONS: Andreas Vécsei, MD, and Ulrike Graf wrote the manuscript. All authors contributed to study design, data collection and analysis, and approved the final draft for submission. The corresponding author declares that the manuscript is submitted on behalf of all authors. BACKGROUND AND STUDY AIMS: The best mode of follow-up in celiac disease has not yet been established. The intention of this study was to clarify which noninvasive follow-up investigation - serological tests or intestinal permeability test (IPT) - correlates best with histology and whether the interval between diagnosis and follow-up affects the accuracy of these tests. PATIENTS AND METHODS: Data from adult patients with celiac disease (diagnosed between December 1989 and July 2006) followed up with biopsy, IPT, and serological tests [IgG anti-gliadin antibodies (AGA-IgG), AGA-IgA, and endomysial antibodies (EMA)] were retrieved from a computerized database. Results of noninvasive tests were compared with the persistence of villous atrophy on biopsy. Patients were divided into groups A, which comprised patients followed up within 2 years after diagnosis, and B, comprising patients followed up later than 2 years. RESULTS: Forty-seven patients were evaluable. The lactulose/mannitol (L/M) ratio had a sensitivity of 85 % and a specificity of 46.2 % for mucosal atrophy, whereas saccharose excretion showed a sensitivity of 60 % and a specificity of 52.6 %. The sensitivities of AGA-IgA and AGA-IgG were 15 % and 20 %, respectively, while specificity was 100 % for both. Validity of AGA was limited due to low number of positive results. EMA assay was 50 % sensitive and 77.8 % specific. In group A (n = 23) L/M ratio performed best in terms of sensitivity (88.9 %), whereas EMA achieved a higher specificity (71.4 %). In group B, the sensitivity of the L/M ratio decreased to 85.7 %, while the specificity of EMA increased to 91.7 %. CONCLUSIONS: In this study, none of the noninvasive tests was an accurate substitute for follow-up biopsy in detecting severe mucosal damage.

Inhibitory effects of water extract of propolis on doxorubicin-induced somatic mutation and recombination in Drosophila melanogaster.

Propolis is a substance produced by honeybees (Apis mellifera L.). Its components are strong antioxidants and free radical scavengers. The aim of this study was to evaluate the protective effects of a water extract of Brazilian green propolis (WEP) combined with the antitumor agent doxorubicin (DXR) on Drosophila melanogaster wing cells through the somatic mutation and recombination test (SMART). Two different crosses were used: The standard (ST) cross and the high bioactivation (HB) cross. The HB cross is characterized by a constitutively enhanced level of cytochrome P450 which leads to an increased sensitivity to a number of promutagens and procarcinogens. Larvae obtained from these two crosses were chronically treated with different concentrations of WEP (12.5,25.0 and 50.0 mg/mL) alone or combined with DXR (0.125 mg/mL). The results obtained with the two different crosses were rather similar. Neither toxicity nor genotoxicity were observed in WEP treated series. Simultaneous treatment with different concentrations of WEP and DXR led to a reduction in the frequency of recombination compared to the treatment with DXR alone. This anti-recombinogenic effect was proportional to the concentrations applied, indicating a dose-response correlation and can be attributed to the powerful scavenger ability of WEP.

Taxanes: the genetic toxicity of paclitaxel and docetaxel in somatic cells of Drosophila melanogaster.

In this study, the taxanes, paclitaxel and docetaxel were investigated for genotoxicity in the wing spot test of Drosophila melanogaster. These relatively new drugs are used in cancer therapy and show great promise in the treatment of a variety of cancers. Their major cellular target is the alpha,beta-tubulin dimer but, unlike other spindle poisons, they stabilize microtubules by a shift towards assembly, producing nonfunctional microtubule bundles. The Drosophila wing Somatic Mutation and Recombination Test (SMART) provides a rapid means to evaluate agents able to induce gene mutations and chromosome aberrations, as well as rearrangements related to mitotic recombination. We applied the standard version of SMART (with normal bioactivation) and a variant version with increased cytochrome P450-dependent biotransformation capacity. In the standard assay, docetaxel was found to be aneuploidogenic; this was effectively abolished by a high cytochrome P450-dependent detoxification capacity. This suggests, as previously reported, the involvement of this family of enzymes in the detoxification of docetaxel rather than in its activation. In contrast, paclitaxel was clearly non-genotoxic at the same (millimolar) concentrations as used for docetaxel in both crosses. The weak responsiveness of SMART assays to aneugenic compounds, the weaker ligand and assembly action of paclitaxel and the more rapid reversibility of the microtubules formed with this compound, may have caused the negative response observed in the present study.

Interference of tannic acid on the genotoxicity of mitomycin C, methylmethanesulfonate, and nitrogen mustard in somatic cells of Drosophila melanogaster.

The modulating effects of tannic acid (TA) on somatic mutation and mitotic recombination induced by methylmethanesulfonate (MMS), nitrogen mustard (HN2), and mitomycin C (MMC) were evaluated in the standard (ST) cross of the wing spot test in Drosophila melanogaster using co- and posttreatment protocols. It was shown that TA alone did not modify the spontaneous frequencies of single and twin spots, which means that this polyphenol neither acts as a genotoxin nor exerts any antigenotoxic effect over spontaneous DNA lesions. However, the simultaneous administration of genotoxins with TA can lead to considerable alterations of the frequencies of induced wing spots in comparison to those with administration of the genotoxins alone. In fact, TA produced a significant increase in HN2-induced wing spots with enhancements between 90 and 160%. For MMS, the enhancement was 38% in the highest TA concentration tested. In contrast, a significant protective action of this polyphenol was observed in combined treatments with MMC (64 to 99% inhibition). Moreover, the data from TA posttreatments demonstrated that this agent is not effective in exerting protective or enhancing effects on the genotoxicity of MMS, HN2, or MMC. One feasible mechanism of TA action is its interaction with the enzyme systems catalyzing the metabolic detoxification of MMS and HN2, which may also be involved in the bioactivation of MMC.

The results of assays in Drosophila as indicators of exposure to carcinogens.

Drosophila has fulfilled a dual function in the field of genetic toxicology: for use in short-term tests for identifying carcinogens and in a model for studies of the mechanisms of mutagenesis by chemicals. Until the mid-1980s, use of Drosophila in short-term tests was restricted to assays for genetic damage in germ cells, mostly in males. The largest database, on 700-750 chemicals, is available for the test for sex-linked recessive lethal (SLRL) forward mutation. The database for assays of the consequences of chromosomal breakage--reciprocal translocations and chromosome loss--is smaller, with about 100 chemicals tested. Comparative studies conducted within the US National Toxicology Program showed that SLRL is a better end-point than reciprocal translocation: of 66 chemicals (68 entries) that induced SLRL, only 28 (41%) induced reciprocal translocation. The major weakness of the SLRL assay is its low sensitivity (0.27-0.79) for mammalian genotoxins. A strength of the SLRL mutation test is its high specificity, which is close to 1. Thus, whereas a negative response in Drosophila provides little evidence for genotoxicity, a positive response (SLRL frequency > or = five times the control level) provides good evidence that a chemical is a trans-species mutagen and probably also carcinogenic to mammals. The poor performance of the SLRL test revealed in several collaborative studies led to the development of assays for recombination in somatic cells of Drosophila. Two of these tests have been evaluated for all known classes of genotoxic chemical: the mwh/flr wing spot test on more than 400 chemicals and the white/white+ eye spot test on about 220 chemicals. Of 24 carcinogens that gave negative or inconclusive test results in the SLRL assay, 22 gave positive results in one or both of the somatic systems. Their better performance in comparison with the germ-line assays is primarily the result of their low cost (5-10% of that needed for an SLRL assay), allowing use of multiple doses and protocols and the use of distinct tester strains with heterogeneity for activation of procarcinogens. For qualitative and quantitative studies on structure-activity and activity-activity relationship, only germ-line system have been used. In general, clear relationships between physico-chemical parameters (s values, O6/N7-alkylguanine ratios), carcinogenic potency in rodents and several descriptors of genotoxic activity in germ cells (from mice and Drosophila) became apparent when the following descriptors were used: (1) estimates of TD50 (lifetime doses expressed in milligrams per kilogram body weight or millimoles per kilogram body weight) from bioassays for cancer in rodents; (2) the degree of germ-cell specificity, i.e. the ability of a genotoxic agent to induce mutations at practically any stage of development of Drosophila and mouse spermatogenesis, as opposed to a more specific response in postmeiotic stages of both species; (3) the M(NER-)/M(NER+) hypermutability ratio, determined in a repair assay in Drosophila germ cells; (4) the ratio of chromosomal aberrations to SLRL in postmeiotic germ cells of Drosophila, i.e. the comparative efficiency of a carcinogen to induce these two end-points; (5) mutational spectra induced at single loci, i.e. the seven loci used in the specific-locus test in mice and the vermilion, white and rosy genes of Drosophila; and (6) the doubling doses in milligrams or millimoles per kilogram for specific locus induction in mice. On the basis of these parameters, alkylating agents were classified into three categories in terms of germ-cell specificity, which is primarily due to stage-related differences in DNA repair, clastogenic efficiency, type of mutation spectra and carcinogenic potency in rodents. The three categories allow predictions of the genotoxicity of alkylating agents but not yet for other categories of genotoxic carcinogens.

Genotoxicity testing of six insecticides in two crosses of the Drosophila wing spot test.

Among the great variety of genotoxicity assays available, the wing spot test in Drosophila melanogaster has some characteristics that make it very suited for the screening of genotoxic activity, i.e., it is an easy and inexpensive assay using a eukaryotic organism in vivo. One of the most interesting characteristics of the assay is its capacity to detect genotoxic activity of promutagens without the necessity of an exogenous metabolic activation system. In this paper we present results obtained with a recently developed high bioactivation cross of the wing spot test (NORR cross). The positive results obtained with the five well-known procarcinogens 7, 12-dimethylbenz[a]anthracene, N-nitrosopyrrolidine, p-dimethylaminoazobenzene, diethylnitrosamine and urethane clearly show that the NORR strains are similar to the other high bioactivation strains previously described, but they lack their methodological disadvantages. We have tested six insecticides, which are characterised by having contradictory results in other genotoxicity tests, using both the standard and the high bioactivation (NORR) cross. The six insecticides analysed are the pyrethroid allethrin, the methylenedioxyphenolic compound piperonyl butoxide, the chlorinated hydrocarbons dieldrin and endrin, and the organophosphates dimethoate and malathion. We obtained negative results for all six compounds. Our results show the suitability of the wing spot test for the evaluation of compounds at the first level of genotoxicity testing.

Hepatitis C virus: a high risk factor for a second primary malignancy besides hepatocellular carcinoma. Fact or fiction?

PURPOSE: Second primary malignancies occur more and more often. But the hepatocellular carcinoma (HCC) linked to a second primary cancer is not frequent. MATERIALS AND METHODS: A retrospective study focused on a second primary cancer was performed in 37 patients with HCC, aged between 46 and 81 years, 27 males and 10 females. RESULTS: 5 out of them (13.5%), 3 males and 2 females, developed a second primary neoplasm before or after HCC. In 3 cases the second malignancy was a carcinoma of the kidney, of the breast, and the prostate. The fourth patient had a Hodgkin's lymphoma before HCC. The last and most unlucky case, besides HCC, had a basal cell carcinoma, a colorectal cancer, and a bladder carcinoma. The common data of these 5 patients were the presence of anti-HCV antibodies and the positivity of the HCV RNA polymerase reaction. One patient was also HBV positive. CONCLUSION: Considering that a large number of virus has been found linked to human cancers, our results brought us to hypothesize that HCV could have played an important role not only in the development of HCC but of the second primary malignancy too. This is likely favoured by constitutional or acquired biological and molecular alterations. Tumor suppressor genes alterations have been reported to be frequently linked to cancers of kidney and breast, of colorectal and skin, of prostate, and lymphoemopoietic tissue. Now just these organs are involved in our patients in addition to the liver. Our results, if confirmed, are of a relevant interest, considering that world-wide HCC is constantly increasing for the spreading of the virus risk-factors.

Recombinagenic activity of integerrimine, a pyrrolizidine alkaloid from Senecio brasiliensis, in somatic cells of Drosophila melanogaster.

Integerrimine (ITR), a pyrrolizidine alkaloid from Senecio brasiliensis, was tested for genotoxicity using the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster. The compound was administered by chronic feeding (48 hours) of 3-day-old larvae. Two different crosses involving the markers flare (flr) and multiple wing hairs (mwh) were used, that is, the standard (ST) cross and the high bioactivation (HB) cross, which has a high cytochrome P450-dependent bioactivation capacity. In both crosses, the wings of two types of progeny were analyzed, that is, inversion-free marker heterozygotes and balancer heterozygotes carrying multiple inversions. ITR was found to be equally potent in inducing spots in a dose-related manner in the marker heterozygotes of both crosses. This indicates that the bioactivation capacity present in larvae of the ST cross is sufficient to reveal the genotoxic activity of ITR. In the balancer heterozygotes of both crosses, where all recombinational events are eliminated due to the inversions, the frequencies of induced spots were considerably reduced which documents the recombinagenic activity of ITR. Linear regression analysis of the dose response relationships for both genotypes shows that 85% to 90% of the wing spots are due to mitotic recombination.

[Neurolinguistic programming in physician-patient communication. Basic principles of the procedure--examples for application in surgery]. / Neurolinguistisches Programmieren in der Arzt-Patient-Kommunikation. Grundzüge des Verfahrens--Beispiele zur Anwendung aus der Chirurgie.

Neurolinguistic programming (NLP) is a means of improving physician-patient communication that can be learned by any doctor. The present article first describes some of the fundamentals of NLP and then provides examples taken from the field of surgery-in the first instance dealing with the treatment of painful conditions by means of trance or dissociation and, secondly, on the influencing of expectations and the restructuring (reframing) of doctrines in a patient with malignant disease.

Isolation and characterization of the MHC linked beta-type proteasome subunit MC13 cDNA.

We have cloned and analysed the second mouse MHC-linked proteasome subunit, designated MC13, which appears to be homologous to the human RING10 proteasome protein. The isolated cDNA has an ORF encoding a protein of 276 amino acids with a molecular weight of ca. 30 kDa. Sequence alignment reveals that the subunit MC13 and several other mammalian proteasome subunits are encoded by a second proteasome gene family. This second gene family encodes subunits of the beta-type, reveals striking sequence similarities with the beta-subunit of archaebacterial proteasomes and is related to, but distinct from, the genes encoding the so-called alpha-type subunits.

Genotoxicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and related compounds in Drosophila.

The potent food mutagen and carcinogen 2-amino-3-methylimidazo[4,5- f]quinoline (IQ) and the structurally related heterocyclic aromatic amines 2-aminoimidazo[4,5-f]quinoline (demethyl-IQ) and 2-amino-1-methylimidazo[4,5-f]quinoline (iso-IQ) were assayed for genotoxicity in the wing somatic mutation and recombination test (SMART) as well as in the sex-linked recessive lethal (SLRL) test in Drosophila melanogaster. In addition, 3-methyl-2-nitroimidazo[4,5-f]quinoline (nitro-IQ), 2-nitrofluorene and 1,8-dinitropyrene were also assayed in the wing spot test. IQ was clearly mutagenic in the SLRL test with highest activity in spermatids. Iso-IQ was more active than IQ whereas demethyl-IQ was inactive in this test. The same pattern of results was obtained in the wing SMART: iso-IQ produced greater than 2-fold higher frequencies of spots than IQ and demethyl-IQ was clearly negative. In addition, nitro-IQ exhibited an approximately equal genotoxic activity as IQ. 2-Nitrofluorene and 1,8-dinitropyrene were both inactive in the wing spot test. These data provide good evidence for a correlation of genotoxic effects in germinal and somatic cells, and for the practical advantage of the wing spot test in Drosophila. Moreover, the results show structure-activity relationships among the heterocyclic aromatic amines and nitro compounds similar to those found in Salmonella.

In vivo cytochrome P 450 interactions of the newly developed H+/K(+)-ATPase inhibitor pantoprazole (BY 1023/SK&F 96022) compared to other antiulcer drugs.

Almost 10% of adverse drug reactions observed in clinical patients are due to interactions of two or more therapeutic agents (18). The aim of the present study was to investigate in vivo interactions of the H2-blocker cimetidine and three newly developed H+/K(+)-ATPase inhibitors, omeprazole, lansoprazole and pantoprazole (BY 1023/SK&F 96022) with cytochrome P 450 in rats. Because diazepam is a drug used very often as comedication in ulcer patients, the duration of the effects of diazepam on muscle coordination were used to evaluate the drug interactions on metabolic enzymes. The present data indicate a clear rank order of the antiulcer drugs' potency for interaction with diazepam: 1) lansoprazole with a 50% prolongation of diazepam effect at 170 mumol/kg, 2) cimetidine and omeprazole at 281 and 288 mumol/kg, respectively and 3) pantoprazole at greater than 1000 mumol/kg. Because the three H+/K(+)-ATPase inhibitors are approximately equipotent with respect to inhibition of gastric acid secretion, it can be concluded that pantoprazole is superior to omeprazole and lansoprazole when unwanted adverse effects with drug metabolizing enzymes are considered. This may be an advantage in clinical use of the drug.

Genotoxicity of aniline derivatives in various short-term tests.

Various substituted aniline derivatives were tested for genotoxicity in several short-term tests in order to examine the hypothesis that a substitution at both ortho positions (2,6-disubstitution) could prevent genotoxicity due to steric hindrance of an enzymatic activation to electrophilic intermediates. In the Salmonella/microsome assay, 2,6-dialkylsubstituted anilines and 2,4,6-trimethylaniline (2,4,6-TMA) were weakly mutagenic in strain TA100 when 20% S9 mix was used, although effects were small compared to those of 2,4-dimethylaniline and 2,4,5-trimethylaniline (2,4,5-TMA). In Drosophila melanogaster, however, 2,4,6-TMA and 2,4,6-trichloroaniline (TCA) were mutagenic in the wing spot test at 2-3 times lower doses than 2,4,5-TMA. In the 6-thioguanine resistance test in cultured fibroblasts, 2,4,6-TMA was again mutagenic at lower doses than 2,4,5-TMA. Two methylene-bis-aniline derivatives were also tested with the above methods: 4,4'-methylene-bis-(2-chloroaniline) (MOCA) was moderately genotoxic in all 3 test systems whereas 4,4'-methylene-bis-(2-ethyl-6-methylaniline) (MMEA) showed no genotoxicity at all. DNA binding studies in rats, however, revealed that both MOCA and MMEA produced DNA adducts in the liver at levels typically found for moderately strong genotoxic carcinogens. These results indicate that the predictive value of the in vitro test systems and particularly the Salmonella/microsome assay is inadequate to detect genotoxicity in aromatic amines. Genotoxicity seems to be a general property of aniline derivatives and does not seem to be greatly influenced by substitution at both ortho positions.

Aristolochic acid is mutagenic and recombinogenic in Drosophila genotoxicity tests.

Aristolochic acid (AA) has been tested for genotoxic activity in three different assays with Drosophila melanogaster (i-iii). AA induced sex-linked recessive lethals (i) and chromosome losses (ii) in male germ cells. In a newly developed fast assay with somatic cells of larvae (iii), AA induced mutant single spots as well as twin spots. The data indicate that in addition to the mutagenic activity, AA also possesses recombinogenic activity leading to somatic recombination in mitotically active cells. The experimental labor involved to detect the genotoxic activity of AA was lowest with the somatic cell assay.