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Biomedical subjects

H J Merker

Publications and source records attributed to H J Merker.

At least 127 records · Page 7Linked to original sources
PubMed1985

Lack of severe malformations versus occurrence of marked embryotoxic effects after treatment of pregnant mice with cis-platinum.

The embryotoxic and teratogenic effects caused by the inorganic cytostatic drug cis-diamminedichloroplatinum(II) ("cis-platinum") were investigated in mice. Single doses of 2.5, 5, 10 or 20 mg cis-platinum/kg were administered to pregnant mice on day 8, 10, 12, 14 or 16 of pregnancy; on day 18, all fetuses were removed and examined for toxic phenomena and for external, skeletal and internal malformations. A dose-dependent reduction of the number of fetuses per litter, a decrease of fetal body weight, and a marked retardation of skeletal ossification processes reflected the severe embryolethal and embryotoxic influence of cis-platinum; this influence was most pronounced when the drug was applied during organogenesis, i.e. on day 8, 10 or 12 of murine pregnancy. In contrast, the incidence of malformations was surprisingly rare after treatment with cis-platinum: Neither external nor skeletal malformations appeared more frequently than in control populations; most fetal internal organs were without anomalies, however, a portion of 10-20% of the fetuses exhibited slight signs of hydrocephaly after application of cis-platinum on day 12.

Animals↗
PubMed1985

Ultrastructure and hydrolase cytochemistry of the developing marmoset yolk sac.

Yolk sacs from Callithrix jacchus were investigated light and electron microscopically as well as by qualitative light microscopic enzyme histochemistry on days 35 to 126 of gestation. The thin yolk sac wall of the early stages (day 35-41) consists of the cuboid, endodermal epithelium, the mesothelium of the exocoelom and some interposed blood vessels. The inner endodermal surface is rather smooth. At later stages, the epithelium becomes highly prismatic and forms folds which are lined by a mesenchyme and blood vessels. Microvilli and a small number of endocytotic vesicles are observed at the apices of the epithelial cells, which are interconnected by gap junctions, desmosomes and interdigitations. The cytoplasm of the epithelial cells is characterized by a well-developed rough endoplasmic reticulum, a large Golgi apparatus and glycogen deposits. Four different membrane-bordered types of inclusions can be distinguished in the cytoplasm of the epithelial cells: The type I and II inclusions are considered as secretion granules. Their increase and their localization in the cavities of the endoplasmic reticulum at later stages are ascribed to an inhibition of the intracellular transport at the onset of involution. The type III and IV inclusions may represent lysosomes and related organelles. Bile capillary-like spaces exist between the epithelial cells. The basement membrane is incomplete below the epithelium and absent around the capillaries, the endothelium of which is porous in certain areas. Aminopeptidase M is highly active in the plasmalemma and the bile capillary-like structures of the epithelium, dipeptidylpeptidase IV in the mesothelium and alkaline phosphatase in the blood vessel endothelium. Other membrane hydrolases are absent. Acid proteases, glycosidases, non-specific phosphatases and non-specific esterases can be detected stage-dependently with moderate to high activities in the yolk sac epithelium. Compared with other organs, the yolk sac structure and hydrolase equipment are similar to those of the liver and may, therefore, have similar functions, e.g. synthesis and secretion of proteins. In addition, however, the yolk sac epithelium might also be involved in resorptive processes of material from the lumen followed by lysosomal digestion. The Callithrix jacchus yolk sac starts involution on day 80 of gestation by disintegration of the cells. On day 100, this process is completed. The stage of involution which is late in comparison with other primates, e.g. man and Rhesus monkey, is ascribed to the strongly delayed development of Callithrix jacchus.

Animals↗
PubMed1985

Effect of acyclovir on mammalian embryonic development in culture.

Acyclovir [9-(2-hydroxyethoxymethyl)guanine] interfered with embryonic development in vitro when assessed with the "whole-embryo" culture technique. The "no-observed-effect level" was at 10 microM acyclovir; Minor impairment of embryonic development (retarded development of ear anlagen) was observed in vitro at 25 microM acyclovir in the culture medium. At high concentrations (100 or 200 microM) development of the ear anlagen was largely inhibited. At concentrations of 50 microM acyclovir or higher, additional disturbances of embryonic differentiation in vitro became obvious, resulting in gross structural abnormalities, especially of the brain (telencephalon); Histological examinations confirmed and extended these observations: at 100 microM acyclovir alterations of the neuroepithelium of the ventricles were pronounced, the telencephalon had developed poorly or was almost completely absent, and necroses were seen in the ear anlagen, the maxillary branch and within the somites; In a limb bud culture (mouse embryos, starting with day 11 of gestation) acyclovir interfered with the differentiation of cartilaginous bone anlagen at concentrations of 200 microM and more in the culture medium. A concentration of 100 microM induced no significant effect. Thus, this organ culture system is less sensitive to the action of acyclovir when compared with whole-embryo culture; Contrary to the results achieved with acyclovir, physiological nucleosides (2'-deoxyguanosine and 2'-deoxyadenosine) did not interfere with embryonic development in vitro even at the highest concentration tested (500 microM).

Abnormalities, Drug-Induced↗
PubMed1985

Enzyme cytochemistry combined with electron microscopy, pharmacokinetics, and clinical chemistry for the evaluation of the effects of steady-state valproic acid concentrations on the mouse.

A number of organs from adult female mice were investigated after continuous application of the anticonvulsant drug valproic acid (VPA) by enzyme cytochemistry, light and electron microscopy, pharmacokinetics and clinical chemistry. VPA plasma levels were maintained between 55 micrograms/ml and 67 micrograms/ml for three days following subcutaneous implantation of drug reservoirs. Effects detectable by enzyme cytochemical or electron microscopical means were mainly observed in liver, kidney, thymus and spleen. A strict concentration-dependency of drug effects could not be found. In the liver, the activities of some surface-membrane hydrolases were increased at the biliary pole; the activities of other hydrolases were decreased or unchanged. Electron microscopically, number and length of microvilli of hepatocytes were increased and many of them showed fat inclusions, mitochondrial swellings and autophagic vacuoles. In some of the proximal convoluted tubules of the kidney, the reaction product originating from microvillous and lysosomal hydrolases was diffusely distributed and its amount lowered. This was paralleled by tubular cells with an increased number of fat droplets and swollen mitochondria or destroyed tubular cells, as demonstrated by electron microscopy. Additionally, peritubular endothelial cells were arranged in a garland-like pattern. Alkaline phosphatase was activated in the straight portion of the proximal tubules. Increased glucose, creatinine and total protein concentrations and increased gamma-glutamyl transpeptidase and alkaline phosphatase activities in the urine reflected well the damage of the proximal renal tubules. Cortical and medullary morphology varied considerably in the thymus. In extreme cases, the cortical zone was either reduced in size or the medulla showed a cortex-like structure or vice versa (inverted type of thymus). The thymic cortical reticular cells showed increased aminopeptidase A activity accompanied by a generalized aminopeptidase M and alkaline phosphatase reaction. Our data indicate that--in addition to the liver--also the kidney, thymus and spleen are target organs of VPA-induced toxicity in the mouse.

Alkaline Phosphatase↗
PubMed1985

Basement membrane formation and lung cell differentiation in vitro.

In high density cultures of mouse fetal lung cells, so-called "mass cultures", development of organoid structures, formation of a basement membrane (BM), and differentiation of pneumocytes type II occur accompanied by synthesis and secretion of lamellar bodies. The relationship between the formation of a BM, on the one hand, and morphogenesis as well as differentiation of pneumocytes type II, on the other hand, has been investigated by use of antibodies against BM components in the lung mass culture. It is shown here that anti-laminin antibodies prevented BM formation, but morphogenesis and pneumocyte differentiation occurred as in untreated cultures. Short-term treatment with the antibody revealed that the BM is formed only during the first 2 to 3 days in vitro. Already formed BM could not be removed by anti-laminin. Anti-collagen type IV antibodies showed no effect in the lung mass culture except for a stronger staining of the BM. Anti-BM-1 antibodies caused no changes in morphogenesis, cell differentiation and BM formation either, but the mesenchymal intercellular space exhibited a dark staining, which is probably due to antigen-antibody complexes. The results obtained with anti-laminin antibodies indicate that a BM is not necessary for lung cell differentiation in vitro.

Animals↗
PubMed1984

Effect of magnesium injection on foetal development.

Pregnant rats were subcutaneously injected twice daily with 1.5 ml 150 mmol/l MgCl2 beginning at day 5 of gestation. By this treatment development of foetal liver and pancreas was enhanced. In the foetal liver, there was a precocious glycogenolysis combined with a precocious development of the smooth endoplasmic reticulum (ER) and an irregular arrangement of the rough ER. In the pancreas, the development of secretory granules was enhanced. In alizarin red-stained and cleared specimens, the foetal skeleton was less calcified. The injected Mg2+ remained extracellular. Altered hormonal secretion and/or an altered activity of the regulatory enzymes of glycogen metabolism induced by the increased extracellular Mg2+ concentration are discussed as possible mechanisms for enhanced foetal liver development.

Animals↗
PubMed1984

The significance of cell contacts for the differentiation of the skeletal blastema.

Isolated limb bud cells from day-11 and day-12 mouse embryos served to investigate the significance of adhesion and contact formation for triggering cartilage differentiation in the blastema. In monolayer culture at low cell density, fibroblastlike cells developed which produced collagen type I and pro III as well as fibronectin. In mass culture at high cell density, however, cartilage tissue formed whose matrix contained collagen type II and cartilage-specific proteoglycans. Other experiments showed that the existence of an overgrowth phenomenon and a cartilage-inducing factor is not the reason for differentiation differences. An increased adhesion tendency and the occurrence of gap junctions speak for changes in the cell membrane during blastema formation. These notions are supported by investigations using fluorochrome-labelled lectins which show that sugar chains with terminal galactosyls only exist during the blastemal stage. It is assumed that adhesion gives the signal for chondrogenesis. The differentiation signal is then stabilized and passed on through cellular communication via gap junctions. After the onset of chondrogenesis, the cell membrane changes again and the gap junction-containing segments are incorporated and disaggregated.

Animals↗
PubMed1984

Membrane alterations in magnesium-deficiency-induced malignant T cell lymphoma.

Malignant T cell lymphoma cells induced in the thymus by chronic Mg deficiency showed a less ruffled surface in the scanning electron microscope, particularly after intraperitoneal transplantation. Their content of phosphatidylserine and phosphatidylinositol was increased. The content of phosphatidylcholine, cholesterol and the cholesterol/phospholipid ratio, and thus membrane microviscosity, were decreased. The activity of phospholipid methyltransferase I and II was reduced. In parallel to these alterations, 45Ca2+ influx and efflux as well as 45Ca2+ content in mitochondria, microsomes and cytosol of lymphoma cells were enhanced.

Animals↗
PubMed1983

Effects of the cytostatic drug cis-platinum on the developing neocortex of the mouse.

The effects of the new cytostatic drug cis-diamminedichloroplatinum(II) (cis-platinum) on the developing neocortex of NMRI mouse embryos or fetuses were investigated using light- and electron-microscopic methods. Single doses of 20 mg cis-platinum/kg were applied intraperitoneally on day 10, 11, . . ., or 16 of gestation. After treatment on day 10 or 11-i.e., during the phase of organogenesis-no morphological alterations could be detected in the neuroepithelium. However, after treatment on day 12 or later, the mitotic activity was markedly reduced and a great number of cells had become necrotic within 12-24 h after application of the drug. At the ultrastructural level, the development of necroses began with a condensation of the chromatin, culminating in the formation of large condensation plaques and shrinkage and fragmentation of the cytoplasm. The observed necroses can be classified according to Schweichel and Merker as type I necroses. It is argued that the apparent teratogenic inefficiency of cis-platinum on days 10 and 11 of murine pregnancy is caused by the inability of cis-platinum to pass the placental barrier at this stage of pregnancy.

Animals↗
PubMed1983

Production and formation of the basement membrane in embryonic tissues of the mouse. An electron-microscopic study.

Mouse embryos (strain NMRI) of days 9 + 2h, 9 + 12h, 10 + 2h, 10 + 12h, 11 + 2h, 12 + 2h, 13 + 2h, and 14 + 2h were fixed (i) in 3% glutaraldehyde + 3% paraformaldehyde, (ii) in 1% glutaraldehyde + 1% tannic acid, or (iii) in 1% glutaraldehyde + 1.5% ruthenium red. The electronmicroscopic picture of the basement membrane (BM) changed depending on the fixative used. Addition of tannic acid led to a higher staining intensity of glycoproteins, whereas after ruthenium red proteoglycans were more heavily stained. The BM around the neural tube and around the epithelial tubules in the lung anlage were investigated electron microscopically. After fusion, the BM in the dorsal regions of the neural tube is missing; on days 9-10 it is, however, reformed. Between days 11 and 13 wide gaps in the BM of the lung anlage occur at the growth buds of the epithelial tubes, which are bridged on late day 13. In the basal parts of these two epithelial types membrane-bordered granules of different density occur singly or in groups. It is postulated that these structures contain BM-material and represent secretion granules. After secretion, BM-material is first bound to the cell membrane. This process is important for the initiation of the formation of the BM. Further growth, however, proceeds via lateral aggregation (self-assembly). Thus, intercellular gaps are bridged independent of the cell membrane. The process of lateral aggregation may also explain deviations from the normal course of the BM.

Animals↗
PubMed1982

Development and properties of malignant lymphoma induced by magnesium deficiency in rats.

Female wistar rats were fed on an Mg-deficient diet. After 8 to 10 weeks, the thymus glands were strongly degenerated and the number of lymphocytes was reduced, especially in the cortex. Thymus degeneration was associated with a decreased rate of DNA, RNA, and protein biosynthesis and necrosis and phagocytosis of lymphocytes. The degeneration was normalized after feeding on an Mg-rich diet. After 10 or 11 weeks of Mg deficiency, local cell proliferations of immature lymphocytes with a great number of free ribosomes were found in some thymus glands. The local cell proliferations developed into infiltrating tumors without metastases. In lymphoma cells the Na+ and Ca2+ content, the turnover of cellular Na+ and K+, and the aerobic production of CO2 and lactate were increased.

Animals↗
PubMed1982

Basement membrane alterations after treatment with trypsin, hyaluronidase or collagenase.

A transplantable rodent tumor producing multiple layers of basement membrane was used to study the effects of trypsin, hyaluronidase and collagenase on basement membranes. Treatment with trypsin resulted in an increase in the distance between adjacent lamellae and a loss of granular structures. Treatment with hyaluronidase separated basement membrane layers only in the outer lamellae, whereas collagenase resulted in extensively folded sheets which consisted predominantly of granules. From these findings it may be concluded that the granular structures represent the morphological equivalent of glycoproteins which are interlinked by a collagenous filamentous network. Hence, the BM represents a functional unit of proteoglycans, glycoproteins and collagen.

Animals↗
PubMed1982

Morphological alterations in epithelial cells of the mouse gallbladder 30 hours after treatment with lithogenic diet.

Mice were fed a gallstone inducing diet. Thirty hours after treatment, distinct morphological alterations in the gallbladder epithelium occurred. The most striking effect was the short-term appearance of large cisternae, which emerge as a result of coalescence of dilated cavities of the rough endoplasmic reticulum. At the same time, an increased storage of small granular material was observed. These alterations did not appear after treatment lasting for less or more than thirty hours. The development started with an enlargement of the endoplasmic cavities, whereas the Golgi apparatus did not seem to undergo transformations; therefore, a transport stop of the secretory products of the epithelial cells must be located at the connection between both organelles. The formation of the endoplasmic cisternae seemed to be caused by a reversible block of the intracellular transport pathway of the secretion products.

Animals↗
PubMed1982

[Extraction of synaptosomes from the cortex of Göttinger minipigs].

The present paper describes the enrichment of synaptosomes from the cortex of a laborytory animal, which is especially suitable for this purpose, the laboratory mini pig. Great importance is attributed to a reproducible preparation and subcellular fractionation. After this standardized preparation procedure, the synaptosomal and mitochondrial fractions are inspected electron microscopically.

Animals↗
PubMed1982

The influence of colchicine on the cytotoxic effect of hydroxyurea in the embryonic spinal cord of the mouse.

The development of necroses and the course of the mitotic index in the embryonic spinal cord of 10-day-old mouse embryos (NMRI) were investigated between 1.5 h and 4 h after either an intraperitoneal application of 500 mg/kg hydroxyurea (HU) or 1 mg/kg colchicine or a simultaneous application of both substances. One h and 30 min after colchicine application, the mitotic index of the neuroepithelial cells had decreased (5.22%; control 7.7%). Subsequently, the mitotic index increased, reaching a maximum of 10.35% 2 h and 30 min after colchicine application. Between 1 h and 30 min and 4 h after HU application, the mitotic index decreased from 4.6% to 0.61% (control 7.7%). First necroses of neuroepithelial cells were observed 1 h and 50 min after HU application. 4 h after HU treatment, 34.38% of the neuroepithelial cells were necrotic. After simultaneous application of HU and colchicine, the decrease of the mitotic index was similar to the decrease after HU application alone. No necroses were observed in the embryonic spinal cord during a 4 h period after simultaneous application of HU and colchicine. After colchicine, as well as after simultaneous HU and colchicine application, the shape of the nuclei of the neuroepithelial cells changed from oval to round and the chromatin was condensed. Mechanisms for the inhibition of the cytotoxic but not the cytokinetic effects of HU by colchicine are discussed.

Animals↗