Thyrotoxicosis incidence in Switzerland and benefit of improved iodine supply.
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Dietary Supplements↗
Biomedical subjects
M Kohler
Publications and source records attributed to M Kohler.
Ki-ras gene mutations and absence of p53 gene mutations in spontaneous and urethane-induced early lung lesions in CBA/J mice.
Ki-ras and p53 genes are involved in human lung carcinogenesis; however, the role of these genes in experimental lung tumors is not well known. In our study, the CBA/J mouse strain was used to investigate the presence of Ki-ras and p53 alterations in lung carcinogenesis of spontaneous tumors and tumors induced with high and low doses of urethane (ethyl carbamate). To study the presence of these alterations in the early stages of lung carcinogenesis and in very small lung tumors, restriction fragment length polymorphism and single-strand conformation polymorphism analyses were performed on polymerase chain reaction-amplified DNA from microdissected tumoral and normal lung samples. Ki-ras gene mutations in codons 12 and 61 were detected in all types of lung lesions, even in small and preneoplastic lesions, and their incidence increased with progression from lung hyperplasias (18%) to adenomas (75%) and to carcinomas (80%). Urethane exposure, in both high and low doses, increased the incidence of Ki-ras mutations in lung tumors, especially in adenomas. The presence of Ki-ras gene mutations in very small urethane-induced lung tumors and the absence of hyperplasias among the treated-group lesions may indicate that urethane accelerates tumoral progression. No p53 mutations were detected in exons 5-8 in any of the epithelium-derived lung tumors. Only one p53 mutation in exon 5 was found in a spontaneous lymphoma. Therefore, p53 mutations do not seem to cooperate with Ki-ras gene mutations or represent an alternative molecular pathway in murine carcinogenesis.
Adenoma↗
A phase II trial of CPT-11 in recurrent squamous carcinoma of the cervix: a gynecologic oncology group study.
OBJECTIVE: To determine the response rate and associated toxicity of weekly CPT-11 in squamous carcinoma of the cervix. METHODS: From October 1994 to May 1996, the Gynecologic Oncology Group (GOG) conducted a Phase II trial in patients with recurrent squamous cervix carcinoma. The schedule employed weekly x4 intravenous CPT-11 at 125 mg/m2 followed with a 2-week rest, to be repeated until disease progression or unacceptable toxicity. Eligibility criteria were a GOG performance status of 0-2, adequate bone marrow reserve, adequate liver function, and serum creatinine <2 mg%. None of the patients had received prior chemotherapy other than radiation sensitizers. Standard GOG toxicity and response criteria were used. RESULTS: Fifty-four patients were entered into the trial. Three patients were ineligible because of wrong cell type (N = 2) or inadequate pathology material (N = 1). Two were inevaluable because of inadequate trial of drug. An additional 4 patients were inevaluable for response. Thus, 49 were evaluable for toxicity and 45 were evaluable for response. The median age of patients was 45 years (range, 29-71 years). The median number of weekly doses delivered was 7 (range, 1-46). The incidence of grade 4 neutropenia and anemia was 6.1 and 4.1%, respectively. Nineteen patients (38.8%) developed gastrointestinal (GI) toxicity including 8 with grade 3 and 11 with grade 4 severity. The overall response rate was 13.3% (6/45). There was 1 patient death from GI toxicity. There was one complete response of 8.8 months duration and 5 partial responses. CONCLUSION: OFFis schedule of CPT-11 exhibits modest activity with moderate toxicity in patients with recurrent squamous carcinoma of the cervix.
Adult↗
A comparison between the Weinberger Adjustment Inventory and the Minnesota Multiphasic Personality Inventory with incarcerated adolescent males.
Empirical work on psychopathology and delinquency requires concise and specific instruments. The Weinberger Adjustment Inventory (WAI), was correlated with the Minnesota Multiphasic Personality Inventory (MMPI) using a sample of incarcerated adolescent males (N = 178). The distress dimension of the WAI was significantly and positively associated with scales 2, 4 and 7 of the MMPI. The restraint dimension was significantly and positively associated with the Lie and K scales of the MMPI. Distress and restraint were distinct dimensions. The WAI may be a brief and helpful personality measure, determining responses to conflict and subjective stress in delinquents with poor reading skills and other special education impairments. The length of the WAI makes it especially suitable for populations such as incarcerated adolescent males who exhibit short attention spans and frequent episodes of noncompliant and resistant behavior.
Adolescent↗
Locking and unlocking of running wheel affects circadian period stability differently in three inbred strains of rats.
Running-wheel access has been shown to shorten the circadian period length (tau) of various mammalian species. Due to the close correlation between tau and the level of activity, running wheel-induced changes of the activity level are thought to be responsible for the observed changes in tau. In the present study, the influence of the running wheel on tau and the activity level was examined in three inbred strains of rats (ACI, BH, LEW). Four animals of each strain had free access to their running wheels, while the wheels of the other 4 animals of each strain were mechanically locked. These conditions were changed twice, so that each animal encountered both kinds of changes, that is, from a locked to an unlocked running wheel and vice versa. During the whole study, overall activity was measured by infrared detectors. Running-wheel access resulted in a significant increase of overall activity in strains LEW and ACI. However, significant changes of tau were observed only in LEW rats. These rats showed a significant shortening of tau after the second change of the housing conditions regardless of whether the wheel was locked or unlocked. Consequently, no causal relationship was found between changes of tau and running wheel-induced changes of overall activity. Instead, the results suggest that subtle environmental influences like locking or unlocking the running wheel affect tau in a strain-dependent manner, whereas changes in the activity level are neither necessary nor sufficient to induce changes of tau.
Animals↗
Extraction of artemisinin and artemisinic acid from Artemisia annua L. using supercritical carbon dioxide.
Artemisinin (an antimalaric compound) and its major precursor artemisinic acid, isolated as the active principles of the medicinal plant Artemisia annua L., were extracted by supercritical fluid extraction (SFE) and analyzed by supercritical fluid chromatography (SFC) using a capillary column, coupled with a flame ionization detector (FID). With optimized operating conditions, artemisinin and artemisinic acid were quantitatively extracted at a flow-rate of 2 ml min-1 in less than 20 min. The supercritical fluid was composed of carbon dioxide and 3% methanol with temperature and pressure fixed at 50 degrees C and 15 MPa, respectively. From the kinetic curves, it appears that the extraction of artemisinin is not limited by the diffusion of the analyte from the plant into the extraction fluid but rather by the elution process. These conditions avoided degradation of the analyte and gave clean extracts ready to be analyzed by SFC. The SFE-SFC-FID method was successfully applied to six samples of A. annua containing various concentrations of artemisinin and artemisinic acid. Results were compared with two conventional liquid solvent extraction processes.
Antimalarials↗
Effects of an activity-correlated feeding regime on circadian locomotor activity rhythms in LEW/Ztm rats.
The aim of the present study was to examine the possible feedback effect of activity on the circadian system in rats. The animals were housed in running wheel cages equipped with food dispensers and were forced to run for their food during parts of the study. Overall level and free-running period tau of wheel-running activity were recorded continuously to quantify the relationship between tau and the level of activity. Surprisingly, the activity-dependent feeding regime failed to increase the level of wheel-running activity and did not affect the activity pattern. Nevertheless, the period of wheel-running activity was shortened in 50% of the animals subjected to food dispensers and in 38% of the animals fed only once a day at irregular times, indicating that subtle environmental differences can affect the circadian pacemaker system without changing the level or the pattern of activity. In addition, 26% of the animals showed a shortening of tau after 3 weeks, i.e., before any change in the experimental setup. This shortening was probably caused by the access to the running wheel at the beginning of the experiment. The present results suggest that the effect on the circadian pacemaker common to both of these experimental manipulations is a change in the physiological or emotional state of the animal rather than an increase of the overall level of activity.
Animals↗
Subcutaneous soft tissue tumours at the site of implanted microchips in mice.
An experiment using 4279 CBA/J mice of two generations was carried out to investigate the influence of parental preconceptual exposure to X-ray radiation or to chemical carcinogens. Microchips were implanted subcutaneously in the dorsolateral back for unique identification of each animal. The animals were kept for lifespan under standard laboratory conditions. In 36 mice a circumscribed neoplasm occurred in the area of the implanted microchip. Females were significantly more frequently affected than male mice. An influence of age or different treatment on the s.c. tumour incidence in two mice generations could not be observed. Macroscopically, firm, pale white nodules up to 25 mm in diameter with the microchip in its center were found. Microscopically, soft tissue tumours such as fibrosarcoma and malignant fibrous histiocytoma were detected.
Animal Identification Systems↗
Spontaneous myelofibrosis in castrated and ovariectomized NMRI mice.
The histopathological appearance of myelofibrosis of the bone marrow is described in aged castrated males, ovariectomized females and in male and female control NMRI mice. The highest incidence of the lesion was observed in ovariectomized and female control mice where more than 90% of the animals were affected. The presence of myelofibrosis in the bone marrow of ovariectomized females and castrated males indicates that estrogens may not play a major role in the development of the lesion and other hormonal disturbances must also be considered.
Age Factors↗
LC/MS/MS of carbohydrates with postcolumn addition of metal chlorides using a triaxial electrospray probe.
A new technique for on-line postcolumn addition (PCA) formation and tandem electrospray mass spectrometry of carbohydrate-metal complexes is presented. A metal chloride solution is added to a carbohydrate sample directly within the ion source of the mass spectrometer. Using a triaxial electrospray probe, this technique can be applied to form carbohydrate-metal complexes on-line, without the need of previously mixing the carbohydrate and metal chloride. Two basic tasks may be accomplished: structural analysis and sensitivity enhancement. The performance of this approach is demonstrated through PCA of LiCl, NaCl, KCl, RbCl, CsCl, and CoCl2, introduced via the triaxial probe after chromatographic separation of two four-component carbohydrate mixtures. Each metal-carbohydrate complex is subsequently analyzed by on-line MS and MS/MS. This technique is used to enhance sensitivity and also, in the case of cobalt coordination, to assist in carbohydrate structural elucidation. On-line LC/MS with PCA of LiCl was achieved with as little as 1.7 pmol of oligosaccharide (average consumed amount, 1.7 pmol with 1 microL of a 10 pmol/microL carbohydrate test mixture injection).
Carbohydrates↗
Increased risk of cancer in the descendants of Syrian hamsters exposed prenatally to diethylnitrosamine (DEN).
Transmission of site-specific tumorigenicity (papillomas in larynx and trachea) of diethylnitrosamine (DEN) to the 2 subsequent generations (F1 and F2) was studied using an outbred strain (Han:AURA) of pregnant Syrian golden hamsters (P generation), which were treated i.p. with 10 mg/kg b.w. of DEN on day 12, 13 or 14 of gestation. Laryngotracheal papillomas were induced by DEN in the P and F1 generations only, while these tumours did not occur in the F2 generation. Spontaneously occurring tumours, including uterine adenocarcinomas, lymphomas, and laryngotracheal neuro-endocrine cell tumours, were observed at higher incidences among the F2 animals derived from the P generation hamsters treated with DEN only on day 13 or 14 of gestation. In the same animals, the ratio of malignant to benign tumours was considerably higher than in controls. In addition, the F2 hamsters derived from the DEN-treated P generation showed more frequent multiple organ involvement in tumorigenesis than the F2 controls. Several uncommon malignant tumours were detected in the F2 offspring, possibly the result of damage caused to germ cells by the prenatal exposure of F1 Syrian hamsters to DEN.
Animals↗
Histological changes after fractionated whole or partial irradiation of the rabbit urinary bladder.
Effects of x-irradiation on the urinary bladder of male New Zealand rabbits were studied by means of light microscopy 100 weeks after exposure. The absorbed dose was 33, 36 or 39 Gy given in 5 daily fractions administered to the whole, the cranial or the caudal part of the bladder. The changes in the epithelium and in the muscular tissue were dose-dependent while the changes in the submucosa and in the extramuscular layer were not. The transitional epithelium was generally either atrophic or hyperplastic. If dysplastic or neoplastic changes were seen, the involved areas were mostly surrounded by an apparently normally differentiated epithelium and the highly specialized superficial cells lining the bladder cavity were always present. The submucosal and muscular tissues showed fibrosis and changes in blood vessels and, sometimes also in lymph vessels.
Animals↗
Distribution of integrin cell adhesion molecules in endometrial cancer.
Integrins are ubiquitous cell adhesion molecules that are involved in maintaining normal tissue morphology and have been implicated in the behavior of certain malignancies. We examined the expression of nine integrin subunits in 38 endometrial adenocarcinomas using immunohistochemistry. The pattern of integrin expression in the cancers was compared with that seen in the endometrium of 20 normal cycling women and 7 postmenopausal women. Integrin expression was correlated with grade, stage, nodal status, depth of invasion, steroid receptor status, and histological pattern. In endometrial cancers there was an inverse relationship between the number of integrins expressed and histological grade (P = 0.011). Of the normally expressed, constitutive endometrial epithelial integrin subunits (alpha 2, alpha 3, alpha 6, and beta 4), the least frequently seen in the cancers was the alpha 3 subunit (44.7%) and the most frequently found was alpha 6 (81.6%). The alpha 5 beta 1 integrin, a fibronectin receptor normally found only on endometrial stromal cells, was seen in 17.8% of cases of these epithelial cancers. In addition, a significant association was found between the loss of the alpha 2 beta 1 integrin and the presence of lymph node metastases (P < 0.001). These data suggest that a decline in integrin expression occurs more frequently in poorly differentiated endometrial cancers and that the loss of specific integrins may be associated with metastatic nodal spread.
Adenocarcinoma↗
Modification of in vitro mouse embryogenesis by X-rays and fluorochromes.
In view of planned studies using single particle irradiation at the Institute for Medical Radiobiology (IMR), confocal microscopy will become an important tool to visualise subtle changes in embryo morphology. Therefore, the influence of X-rays and that of three different fluorochromes on the in vitro development of murine 2-cell stage embryos was investigated. Embryos of B6C3F1 mice were cultured at 32 h post-conception (pc) and treated with X-rays, acridine orange (AO), ethidium bromide (EB) or propidium iodide (PI), respectively, in various doses (0.0-3.0 Gy) or concentrations (AO: 0.05-2.00 micrograms/ml; EB and PI: 0.50-10.00 micrograms/ml). Additional experiments using combinations of AO and irradiation were performed. The embryos were cultivated for a total of 7 days and checked for their vital status by morphological endpoints such as the percentage of embryos that reached the blastocyst stage and the hatching rate. After treatment of the 2-cell embryos with AO, EB and PI, the dose-effect curves with the endpoint 'hatching rate' showed a 23-fold reduction of the ED50 for AO (0.23 microgram/ml) compared with EB (5.30 micrograms/ml). Despite the higher toxicity, AO had much better staining qualities in subtoxic concentrations than EB. PI showed no toxicity in these experiments and was used as an inverse control for embryo vitality. No synergistic modification of the radiogenic effects could be seen in combination experiments (AO+X-rays).
Acridine Orange↗
Method for the description of differences in the filamentous structure of the cytoskeleton in cultured cells.
Over the last few years in vitro cell systems have been established for toxicological investigations. These systems permit the evaluation of effects on the basis of cultured cells in order to replace animal studies. Not only qualitative assessment of cytotoxic effects, but also efforts to quantify these intracellular changes have become more and more important to objectify the results which have been obtained. The cytoskeleton, a dynamic and sensitive system, seems to be a valuable morphological parameter to gain information about the intracellular alterations of drug-influenced cells. Depending on the dose of the substance administered, the cytoskeleton shows morphological alterations in specific components, which fulfill structural as well as metabolic regulatory functions and thus provide information on possible mechanisms. Normally, microtubules as well as the intermediate filament system from 3-dimensional networks. Treatment may induce contraction or depolymerization of the filamentous proteins. These alterations, seen in immunofluorescent preparations, can be quantified by means of a 2-dimensional Fourier transformation. As there is no statistical method to compare different spectra, the spatial frequency spectrum of the Fourier components has to be transformed to a 1-dimensional array. This step is performed by measuring the optical density of localised areas in the frequency spectrum. Using this transformation it is possible to compare the Fourier spectra belonging to different treatment groups.
Animals↗
Vector analyzing power iT11 in pi d elastic scattering at 49 MeV.
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Journal Article↗
Cell growth regulation in epithelial ovarian cancer.
BACKGROUND: As in the case of other epithelial neoplasms, most ovarian cancers arise from single clones of cells that have undergone multiple genetic alterations. A comparison of normal and malignant ovarian epithelium has identified several differences in growth regulation by peptide growth factors, protooncogenes, and tumor suppressor genes. METHODS: Recent articles and abstracts have been reviewed. RESULTS: The malignant ovarian epithelial phenotype has been associated with (1) autocrine growth stimulation by transforming growth factor-alpha, (2) loss of autocrine growth inhibition by transforming growth factor-beta, (3) mutation or amplification of ras in 2-12% of cases, (4) amplification of myc in 23% of specimens, (5) expression of fms in 56% of cases with potential autocrine stimulation by macrophage colony stimulating factor, (6) paracrine stimulation by macrophage products including interleukin-1, interleukin-6 and tumor necrosis factor, (7) overexpression of c-erbB-2 (HER-2/neu) in 30% of cases, and (8) mutation with consequent overexpression of p53 in 50% of advanced ovarian cancers. A poor clinical prognosis is associated with expression or overexpression of the epidermal growth factor receptor, fms, and HER-2/neu. Antibodies against the extracellular domain of the HER-2/neu gene product p185 inhibit the growth of tumor cells that overexpress HER-2/neu and are associated with marked decreases in diacylglycerol levels. The intracellular kinase domain is required for growth inhibition. Antibodies that inhibit growth stimulate phosphorylation of intracellular substrates. Ricin A chain monoclonal antibody conjugates that react with p185 also inhibit the growth of tumor cells that overexpress p185. The intracellular kinase region is not required for immunotoxin-mediated killing. Coexpression of HER-2/neu and the epidermal growth factor receptor has been observed in 65% of epithelial ovarian cancers and in a limited number of normal tissue from a fraction of donors. CONCLUSIONS: Multiple alterations in growth factors, protooncogenes and growth factors have been detected in different epithelial ovarian cancers. Inappropriate signalling from receptor tyrosine kinases may be particularly important for ovarian oncogenesis. Drugs that affect tyrosine kinase and phosphatase activity deserve attention as potential therapeutic agents for ovarian cancer. The extracellular domains of the HER-2/neu gene product p185 and the epidermal growth factor receptor may provide useful targets for serotherapy.
Carcinoma↗
Gene structure and expression analysis of the epidermal growth factor receptor, transforming growth factor-alpha, myc, jun, and metallothionein in human ovarian carcinomas. Classification of malignant phenotypes.
This study reports the structure and expression rates of genes of the transforming growth factor-alpha (TGF-alpha) signal transduction pathway (TGF-alpha, epidermal growth factor receptor [EGF-R], jun, myc, and metallothionein [MT]) in 47 specimens of ovarian cancer and 21 nonmalignant tissues. The objective was to establish a direct correlation between the genetic activities and the malignant phenotype of the ovarian cancer. The Southern blot technique identified four samples with myc amplification and two with rearranged EGF-R genes. By using the S1 nuclease assay, the analysis of myc transcription showed a similar use of both promotors. Although the size of the investigated transcripts was unaltered, significant differences in the transcription rates were noticed in malignant tissue probes (using northern blot analysis and RNAase protection assay). The following results of messenger RNA analysis in ovarian cancer were observed: EGF-R, negative in 25%, low in 65%, and strongly positive in 10%; TGF-alpha, negative in 34%, low in 36%, and strongly positive in 30%; myc, negative in 8%, low in 64%, and strongly positive in 28%; jun, negative in 4%, low in 58%, and strong in 38%; and MT, low in 80% and strongly positive in 20%. In most nonmalignant tissues studied, no or only a low expression of TGF-alpha, EGF-R, and myc. was found. A comparison of these messenger RNA results with the clinical data from tumors showed four different subgroups of ovarian carcinomas. The results of chemotherapy were known in 32 cases. Tumors with negative or low expression rates of all investigated genes did not respond to chemotherapy; 13 of 18 tumors with high expression rates did respond. Additional signal transduction chains distinct from the TGF-alpha pathway, however, are likely to influence both the expression and activity of transcription factors and MT.
Adult↗