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M Schuler

Publications and source records attributed to M Schuler.

At least 19 recordsLinked to original sources
PubMed1997

A critical evaluation of centromeric labeling to distinguish micronuclei induced by chromosomal loss and breakage in vitro.

The in vitro micronucleus assay in conjunction with CREST-staining and fluorescence in situ hybridization (FISH) with centromere-specific DNA probes is being increasingly utilized for the detection of clastogenic and aneuploidy-inducing agents. Although potentially powerful techniques, both methods have unique characteristics that can influence sample processing and the interpretation of results. In this article, the use of the CREST and the FISH modifications of the in vitro micronucleus assay have been used to characterize the origin of the micronuclei induced by cyclophosphamide, 4,4'-methylene-bis(2-chloroaniline), 4-nitroquinoline N-oxide and ionizing radiation in metabolically competent MCL-5 cells or a derived cell line lacking metabolic activation. Using these results and our previous experiences with these techniques, a detailed comparison including the strengths and limitations of each technique as well as potential problems in performing each assay and in analyzing the data is discussed. In spite of their limitations, our results to date indicate that CREST-staining as well as FISH with centromere-specific DNA probes can be used to accurately distinguish micronuclei formed from chromosome loss from those originating from chromosome breakage and that these techniques can be valuable complements to the in vitro micronucleus assay.

4-Nitroquinoline-1-oxide↗
PubMed1997

Induction of micronuclei, hyperdiploidy and chromosomal breakage affecting the centric/pericentric regions of chromosomes 1 and 9 in human amniotic fluid cells after treatment with asbestos and ceramic fibers.

This article describes the induction of micronuclei, hyperdiploidy and chromosome breakage in human amniotic cells in vitro by amosite, chrysotile and crocidolite asbestos, and ceramic fibers. The response of human (amniotic fluid cells) and rodent (Syrian hamster embryo fibroblasts, SHE) cells to fiber treatment was compared using the micronucleus assay. The data of the rodent studies were taken from a previous investigation (Dopp, E. et al. (1995) Environ. Health Perspect., 103, 268-271). All types of mineral fibers caused a significant increase of micronucleated cells. The kinetochore analysis revealed that all three types of asbestos and ceramic fibers yielded similar effects. Approximately 50% of the induced micronuclei were kinetochore-negative indicating formation through clastogenic events. Human amniotic cells were much less susceptible than SHE cells to the induction of micronuclei by mineral fibers. This again demonstrates that SHE cells are more susceptible to chromosomal changes than human amniotic fluid cells. The application of fluorescence in situ hybridization (FISH) with tandem DNA probes yielded more detailed information about specific structural chromosome aberrations in the 1 (cen-q12) and 9 (cen-q12) regions and about abnormal numbers of chromosomes in interphase human amniotic fluid cells. Using this FISH approach we found a statistically significant increase of chromosomal breakage in the pericentric heterochromatin regions of chromosomes 1 and 9 in interphase human amniotic cells after exposure to asbestos and ceramic fibers compared to control cells. The number of hyperdiploid cells was also significantly increased. Our results show that asbestos fibers as well as ceramic fibers are inducers of structural and numerical chromosomal aberrations in human amniotic fluid cells.

Amniotic Fluid↗
PubMed1997

[Conversion from peridural to transdermal opiate analgesia in abdominal tumor pain syndrome].

In a 32 years old patient with advanced gastric cancer epidural analgesia with local anaesthetic and morphine via a thoracic epidural catheter was required because of intractable pain and intolerable side effects of intravenous morphine. In spite of good efficacy it was decided to remove the catheter because of technical problems and the risk of infection during chemotherapy. Analgesic therapy proceeded to non-invasive transdermal fentanyl, using an intravenous fentanyl pca-pump during transition. The equipotent daily dose ratio of epidural morphine to transdermal fentanyl was calculated as 2.25:1.

Adult↗
PubMed1997

Detection of hyperdiploidy and breakage affecting the 1cen-1q12 region of cultured interphase human lymphocytes treated with various genotoxic agents.

Chromosomal aberrations are associated with cancer, birth defects, and pregnancy loss. Previous studies using banding techniques have revealed that chromosomal alterations induced in human peripheral lymphocytes by many genotoxic agents occur nonrandomly throughout the genome. One of the regions prone to breakage is the centromeric heterochromatin of chromosome 1. We have developed a fluorescence in situ hybridization (FISH) procedure using tandem DNA probes to distinguish hyperdiploidy from breakage occurring in this region. Interphase nuclei exhibiting breakage or exchanges affecting the 1cen-1q12 region can readily be distinguished from nuclei hyperdiploid for this chromosome by identifying the number and location of the hybridization signals. This hybridization approach was tested using cultured human lymphocytes treated with a series of known aneuploidy-inducing agents (colchicine, diethylstilbestrol, and vincristine sulfate), several potent clastogens (ionizing radiation, mitomycin C, and etoposide), as well as sodium arsenite and hydroquinone, agents that have been reported to have relatively weak aneuploidy-inducing and clastogenic activity. Significant increases in chromosomal alterations were seen with all agents tested and the results were generally consistent with those previously seen using standard cytogenetic techniques. Treatment with colchicine, diethylstilbestrol, and vincristine sulfate resulted in high frequencies of primarily hyperdiploid nuclei, and cells exposed to radiation, mitomycin C, and etoposide exhibited elevated frequencies of breakage affecting the 1cen-1q12 region. Sodium arsenite and hydroquinone induced relatively minor but significant increases in both hyperdiploidy and breakage. These results indicate that this tandem labeling approach can be used to distinguish aneuploidy-inducing agents from those causing breakage in interphase human cells and may be a valuable procedure for monitoring human populations exposed to genotoxic agents.

Aneuploidy↗
PubMed1996

Differential regulation of Raf isozymes by growth versus differentiation inducing factors in PC12 pheochromocytoma cells.

PC12 pheochromocytoma cells possess four known MEK activators: A-, B-, c-Raf-1 and MEKK. In order to examine whether differentiation factors or growth factors have a Raf isozyme preference for activation of the mitogenic cytoplasmic Raf-MEK-MAPK protein kinase cascade, the activation kinetics of these enzymes in response to epidermal growth factor (EGF) and nerve growth factor (NGF) were compared. An initial activation of all three Raf kinases was noticed, but only A- and B-Raf showed sustained activation by NGF, which was not seen after EGF treatment. Furthermore, expression of oncogenic versions of all three Raf kinases as well, as a potentially Raf-independent MEK activator, v-Mos, leads to activation of MAPK and to differentiation of PC12 cells. These data suggest a differential regulation of Raf kinases and that probably no alternative Raf substrates are involved in differentiation processes of PC12 cells.

Animals↗
PubMed1996

Effects of novel 3,4-bisphenylhex(3)enes on cell proliferation in malignant and normal cells.

The growth-inhibitory effect of several newly synthesized alkyl derivatives of 3,4-bisphenylhex(3)ene was studied in four tumor cell lines and three healthy primary cell systems. A marked inhibition of cell proliferation was noted in the neoplastic cells but not in the primary systems. No effect on the cytoplasmic or mitotic microtubule system but an increase in the gross level of 5-methylcytosine in nuclear DNA was observed. It is speculated that the selective growth inhibition of tumor cells is due to DNA-hypermethylation.

5-Methylcytosine↗
PubMed1996

Fiber transformation and replacement in low-frequency stimulated rabbit fast-twitch muscles.

The fast-to-slow conversion of rabbit skeletal muscles by chronic low-frequency (10 Hz, 12 h daily) stimulation involves (1) sequential fast-to-slow fiber-type transitions in the order of type IID-->type IIA-->type I, and (2) the replacement of deteriorating fast-twitch glycolytic fibers by new fibers derived from satellite cells and myotubes. These two processes were analyzed in 30- and 60-day stimulated extensor digitorum longus and tibialis anterior muscles. Fast-to-slow transforming fibers were identified by myofibrillar actomyosin histochemistry as type C fibers and immunohistochemically by their reaction with monoclonal antibodies specific to slow and fast myosin heavy chain isoforms. In situ hybridization of mRNA specific to the myosin heavy chain I isoform identified all fibers expressing slow myosin, i.e., type I and C fibers. The fraction of transforming fibers ranged between 35% and 50% in 30-day stimulated muscles. The percentage of type I fibers (20%) was threefold elevated in extensor digitorum longus muscle, but unaltered (3.5%) in tibialis anterior muscle, suggesting that fast-to-slow fiber conversion was more advanced in the former than in the latter. Fiber replacement was indicated by the finding that the fiber populations of both muscles contained 15% myotubes or small fibers with central nuclei. In situ hybridization revealed that myotubes and small regenerating fibers uniformly expressed myosin heavy chain I mRNA. Similarly, high percentages of slow-myosin-expressing myotubes and small fibers were found in 60-day stimulated muscles.

Adenosine Triphosphatases↗
PubMed1996

Immunomodulatory and hematopoietic effects of recombinant human interleukin-6 in patients with advanced renal cell cancer.

Interleukin-6 (IL-6) is a cytokine with pleiotropic biologic activities on B cells, T cells, and hematopoietic progenitors. The present study was undertaken to assess pharmacodynamic effects of subcutaneous administration of IL-6 on blood counts, immunologic parameters, and acute-phase reactants. Blood samples were taken from patients with advanced renal cell cancer participating in a phase II trial of recombinant human IL-6. Multiparameter FACS analyses of peripheral blood mononuclear cells were performed using antibodies against CD3, CD4, CD8, HLA-DR, CD56, CD28, CD38, CD19, sIgM, and sIgG. Serum levels of IL-10, soluble CD23 (sCD23), sCD25, IL-1 receptor antagonist protein (IL-1RA), soluble tumor necrosis factor (TNF) receptors (sTNF-R) p55 and p75, and soluble IL-6 receptor (sIL-6R) were detected by ELISA systems. Levels of C-reactive protein (CRP), neopterin, fibrinogen, beta 2-microglobulin, and immunoglobulins M, G, and A were measured by standard methods. In response to administration of IL-6, a significant increment in platelet counts was observed, reaching peak levels after 21 days of treatment. In contrast, leukocyte subsets remained unaffected. No change in number of immunophenotype of peripheral blood B cells, T cells, or natural killer cells could be detected following IL-6 administration. Blood levels of sCD23, IL-10, sIL-6R, neopterin, beta 2-microglobulin, and immunoglobulin subsets were not influenced by cytokine therapy. However, administration of IL-6 led to a slow increment of acute-phase reactants CRP and fibrinogen. Furthermore, the anti-inflammatory molecules sTNF-R p55 and p75 were induced by IL-6, whereas serum levels of IL-1RA remained unchanged. Finally, an increase in blood levels of sCD25 was observed. In conclusion, IL-6 in vivo predominantly acts as a regulator of inflammation and a megakaryocyte differentiation factor.

Acute-Phase Reaction↗
PubMed1995

Cytokines in the pathophysiology and treatment of chronic B-cell malignancies. A review.

Chronic B-cell malignancies are characterized by accumulation of transformed B cells of low proliferative index in lymphatic and extralymphatic tissues. Cytokines do not appear to play a role in the primary step of transformation. However, proliferation as well as inhibition of apoptosis of malignant B cells can readily be explained by cytokine effects. Clinical trials of interferons (IFN) and interleukin-2 alone or in combination have been performed in patients with hairy cell leukemia (HCL), CLL, and low- and intermediate-grade non-Hodgkin's lymphoma. While IFN alpha became standard therapy of HCL, responses in other entities were variable, ranging from 0 to 70% in selected populations. Combination of IFN and cytotoxic chemotherapy in general revealed no additional benefit as compared to chemotherapy alone. Perspectives for future clinical testing of cytokines in low-grade B-cell lymphomas are discussed.

B-Lymphocytes↗
PubMed1995

Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia.

Plasma levels of IL-1, IL-6, IL-8, IL1-RA, TNF alpha, and G-CSF were prospectively studied during 23 chemotherapy cycles of 20 patients suffering from acute myelogenous leukemia. Increased plasma levels of IL-6, IL-8, and G-CSF were observed in patients with febrile neutropenia and/or major infection. Plasma levels of IL-6, IL-1, TNF alpha and IL-1-RA measured 1 day before and 1 day after the onset of febrile episodes did not accurately predict the development of major infection. In contrast, IL-8 plasma levels were significantly higher in those patients who subsequently developed major infection. The question whether IL-8 plasma levels identify high risk or low risk patients with sufficient specificity and sensitivity has to be answered in large scale clinical trials.

Adolescent↗
PubMed1995

Advantages and limitations of using fluorescence in situ hybridization for the detection of aneuploidy in interphase human cells.

Fluorescence in situ hybridization with chromosome-specific DNA probes is being increasingly utilized for the detection of chromosome aberrations induced in vitro and in vivo by chemical and physical agents. Although potentially a powerful technique, FISH studies for aneuploidy can be heavily influenced by cellular phenomena and hybridization artifacts which make the performance and interpretation of the results difficult. As a consequence, frequently hyperdiploid frequencies are reported in the literature which are substantially higher than one would expect based upon frequencies seen in conventional metaphase analyses. In this article, a number of the potential pitfalls that we have encountered while performing FISH analyses for aneuploidy are discussed and their potential impact on the observed hybridization frequencies is described. After considering these factors, the frequencies of lymphocyte nuclei containing 3 and 4 chromosome copies are compared between metaphase values obtained from published human population studies and interphase values obtained from similar studies using FISH. It is concluded that by using caution in the evaluation of slides, interphase studies using FISH to detect hyperdiploidy and polyploidy can provide estimates of numerical alterations which closely reflect those seen during metaphase analysis using either FISH or conventional approaches. However, due to the inability of interphase analysis to distinguish hyperdiploidy from polyploidy as well as other potential problems, frequencies of aneuploid nuclei obtained using single label FISH should only be considered approximations of absolute frequencies. For additional accuracy, multi-color FISH with two or more different probes should be performed.

Aneuploidy↗
PubMed1994

Interleukins. Clinical pharmacology and therapeutic use.

With interleukins (IL), a new class of potential drugs has been introduced into clinical research. These signal peptides are involved in the regulation of many physiological and pathophysiological processes. IL-1, -2, -3, -4, -6 and -11 have been tested in clinical trials. The growth promoting, growth inhibiting or immunomodulatory activities of interleukins represent the theoretical basis for large scale clinical testing, predominantly in malignant disease. Dose-dependent effects on numbers of peripheral blood cells and recovery from bone marrow failure have been demonstrated for IL-1, -3, -6 and -11. Phase III trials are in progress to determine their value for clinical practice. However, investigations on the immunomodulatory activities proved to be more difficult. This is because key mechanisms for successful treatment of malignant disease by immunomodulation are not clearly defined and the methodology for assessment of immunostimulatory effects is not well established. Besides treatment of renal cell carcinoma and malignant melanoma with IL-2, no successful trials have been reported. However, phase I clinical trials with IL-1, IL-4 and IL-6 have just been completed. Thus, it seems too early to conclude on their therapeutic potential.

Adjuvants, Immunologic↗
PubMed1994

Parenting and early development among children of drug-abusing women: effects of home intervention.

OBJECTIVE: To evaluate the efficacy of home intervention with drug-abusing women on parenting behavior and attitudes, and on children's development. DESIGN: A randomized, clinical trial of 60 drug-abusing women recruited prenatally and randomized into an intervention (n = 31) or comparison (n = 29) group. There were no group differences in gestational age, 1-minute Apgar scores, duration of hospital stay, or neonatal abstinence score. Intervention infants were slightly heavier (P = .098) and had slightly lower 5-minute Apgar scores (P = .089). Most mothers were single, African-American, multiparous, and non-high school graduates from low income families. Approximately 40% of the women were human immunodeficiency virus (HIV)-positive, all admitted to either cocaine and/or heroin use, and 62% had a history of incarceration. Intervention and comparison group women did not differ on any background variables. INTERVENTIONS: All children received primary care in a multidisciplinary clinic. Biweekly home visits were provided by a nurse beginning before delivery and extending through 18 months of life. The intervention was designed to provide maternal support and to promote parenting, child development, the utilization of informal and formal resources, and advocacy. MEASUREMENTS: Behavioral measures included self-reported ongoing drug abuse, compliance with primary care appointments, and an observation of the child-centered quality of the home (HOME Scale). Parenting attitudes were measured by the Child Abuse Potential Inventory (CAPI) and the Parenting Stress Index. The CAPI was administered before initiating the intervention and the Parenting Stress Index was administered when the children were 3 months of age. Both scales were repeated when the children were 18 months of age. Developmental status was measured with the Bayley Scales of Infant Development administered at 6, 12, and 18 months. ANALYSES: Repeated measures multivariate analyses of variance were used to examine changes in parenting attitudes and children's development. Analyses of covariance were used to examine compliance with primary care appointments and the quality of the home. Logistic regression was used to examine ongoing drug abuse. Birth weight and maternal education were used as covariates in all analyses. To control for social desirability, the faking-good index of the CAPI was included as a covariate in analyses involving self-report measures. MAIN RESULTS: Women in the intervention group were marginally more likely to report being drug-free (P = .059) and were compliant with primary care appointments for their children (P = .069). Based on the HOME Scale, women in the intervention group were more emotionally responsive (P = .033) and provided marginally more opportunities for stimulation (P = .065). At 18 months parents reported more normative attitudes regarding parenting and more child-related stress than they had initially, but the differences were not related to intervention status. At 6 months infants in the intervention group obtained marginally higher cognitive scores (P = .099); at 12 and 18 months there were no differences. CONCLUSIONS: The findings suggest a cautious optimism regarding the efficacy of early home intervention among drug-abusing women in promoting positive behaviors. Subsequent investigations of home intervention should include larger sample sizes and more intensive options.

Adult↗
PubMed1993

Prenatal drug exposure: neurodevelopmental outcome and parenting environment.

Examined neurodevelopmental patterns and caregiving environment among 20 infants prenatally exposed to cocaine and 20 drug-free infants. The Brazelton Scale was administered 4 times. Drug-exposed infants had less optimal neurodevelopment than comparison infants at birth, but by 6 weeks only differences in autonomic stability were apparent. Neurodevelopmental performance was related positively to the child-centered quality of the environment. Though support buffered stress in both groups, the effect was more robust among drug-free mothers. Findings support the need to consider neurodevelopmental recovery and the caregiving environment in evaluations of developmental outcome among drug-exposed infants.

Developmental Disabilities↗