Biomedical subjects
Publications and source records attributed to J Schmidt.
In our clinic we used a frame fixator to immobilize a distal radius fracture in 7 cases. The results obtained with regard to length preservation and fracture apposition suggest that this may be a very useful, quick and easy mode of treatment.
Since 1983 we have treated 19 cases of medial neck of femur fracture by using the dynamic hip screw. A follow-up of these patients has shown bad result in 12 cases. We have abandoned the indications for implantation of DHS.
Azelastine (4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-p hthalazinone hydrochloride), a novel long-acting antiasthmatic/antiallergic drug has been demonstrated to be effective in the treatment both of asthma and of allergic rhinitis. In this paper some selected properties of azelastine are presented which might contribute to its antiasthmatic and antiallergic effect. Azelastine causes a marked inhibition of generation of oxygen radicals in alveolar macrophages. A bronchosecretolytic activity of azelastine is observed which is based on the secretion of a more liquid mucus. Furthermore, the mucociliary clearance is enhanced as demonstrated in a rabbit model. Also IL-1 generation is inhibited in vitro and in vivo. Finally, the possible tissue and cellular accumulation of azelastine in lung and alveolar macrophages resp. is discussed.
During the last few years an increased interest has been directed towards the application of a new class of cholesterol lowering substances, the HMG-CoA reductase inhibitors. Since preclinical trials with beagle dogs revealed lens opacifications, the necessity of drug safety studies arose. The paper presents the results of two drug safety studies concerning Simvastatin (45 patients) and Pravastatin (35 patients) after an application period of two years in patients with primary hypercholesterolemia type II. Besides ophthalmological examinations (every 6 month) Scheimpflug photographs of the anterior eye segment have been taken and the negatives subjected to microdensitometric image analysis. Neither the clinical parameters nor the results of Scheimpflug measurement showed drug induced changes at the eye until now. Based on these results cataractogenic side effects of the substances in question could not be proven.
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An ultrastructural study was performed on bone marrow tissue in 8 patients revealing early and late stages of so-called primary (idiopathic) myelofibrosis - osteomyelosclerosis (agnogenic myeloid metaplasia) to evaluate the constituents of the hematopoietic microenvironment (myeloid stroma). A survey of the stroma cells disclosed an overall increase, particularly in so-called undifferentiated (primitive - pluripotent), but also in transitional (fibroblastic) reticular cells and myofibroblasts. The most primitive reticular cells were characterized by their stellate aspect with elongated slender cytoplasmic processes traversing the interstitial space, and by the scarcity of organelles. The transition into a fibroblast was preceded by the appearance of branching cisternal structures of the rough endoplasmic reticulum, extensively developed Golgi fields and an abundance in mitochondria. Frequently, so-called myofibroblasts were encountered displaying bundles of filaments along the subplasmalemmal region. Extracellularly fibrillar material with an irregular cross-banding as well as microfibrils could be observed. The many vascular structures (sinusoids and capillaries) exhibited a multilayered basement membrane-like material including many fibrils and adventitial cells (pericytes, smooth muscle and transitional reticular cells) with numerous cytoplasmic processes. Undifferentiated and transitional reticular cells as well as myofibroblasts seem to form an integral part of the hematopoietic microenvironment in OMF and are assumed to play an important role for the evolution of the disease-specific myelofibrosis in this disorder.
We have examined the interactions of low (Os43 and OS48) and high (Os50/K8 and Os50/K12) metastatic cell lines derived from osteosarcomas (Os) of the Balb/c mouse with fibronectin (FN) and laminin (LN). All of these cell lines formed osteogenic tumors when transplanted subcutaneously into syngeneic mice. Os43 and Os48 cells gave rise to few metastases while the Os50/K8 and Os50/K12 cells were highly metastatic. In an in vitro chemoinvasion assay only the highly metastatic cells were able to invade a reconstituted basement membrane. Although the interactions of all cell lines with FN were quite similar, their response to LN differed considerably. Within each of the cell lines, chemotactic response to and cell spreading on LN were closely correlated. Highly metastatic Os cells migrated to and spread on LN substrates to a much greater extent than low metastatic cells. Os43 and particularly Os48 showed very much low migration to LN, similar to that of Balb/c 3T3 fibroblasts. They also spread poorly on LN, resembling the behavior of normal human bone cells which were used as a control. Thus, with these assays it is possible to distinguish the LN interactions associated with the metastatic phenotype of Os cells. The acquisition of LN recognition in tumor cells of bone origin may be related to their ability to invade and metastasize. This system may be valuable for the study of LN recognition molecules, their appearance, or changes with the metastatic phenotype.
The effect of cycloheximide (CHX) on denervation-induced acetylcholine receptor (AChR) expression was investigated in chickens one day after nerve section, using probe excess solution hybridization to quantitate AChR alpha-subunit gene transcript levels and run-on analysis to measure subunit gene activity. The increase in alpha-subunit transcripts that normally follows denervation was prevented when drug treatment was commenced 2 h before or after denervation but was not blocked when CHX administration was begun 6 h after the operation. Drug-induced reduction of transcript levels results from decreased activity of genes coding for the alpha-, delta-, and gamma-subunits; in contrast, the transcription rates of several non-receptor genes are not affected by CHX. The results suggest that the de novo synthesis of a transcriptional activator is required as a mediating event in the signalling pathway linking the plasma membrane and AChR gene expression.
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The acetylcholine receptor is a multimeric membrane protein whose expression is activated during muscle differentiation and upon denervation of adult muscle. To gain insight into the coordinate expression of receptor subunits during myogenesis we have analyzed the chick muscle receptor delta-subunit gene upstream region. The delta-subunit gene lacks canonical promoter elements (CCAAT and TATA boxes). Nuclease protection and primer extension analysis revealed that transcription starts at six major and several minor sites between -110 and -30 upstream of the translational initiation site; two sites, at positions -77 and -66, give rise to approximately 50% of all transcripts. Using nested deletions of the proximal 960 bp of the 5' flanking region of this gene we have identified a 62 bp sequence (-207 to -146) that activates transcription in a position independent manner. This enhancer-like element is activated during myotube formation; it contains two distinct functional moieties, each resembling the same 16 bp portion of the stage and tissue specific alpha-subunit gene enhancer which we have characterized previously [Wang et al. (1988) Neuron, 1, 527-534]. This common element, which also comprises several previously proposed skeletal muscle specific motifs [Buskin, J. N. and Hauschka, S. D. (1989) Mol. Cell Biol., 9, 2627-2640; Mar, J. H. and Ordahl, C. P. (1988) Proc. Natl. Acad. Sci. USA, 85, 6404-6408], may account for the coordinate expression of the two subunits. The cell specificity of the delta-subunit gene 5' flanking region is partly due to the enhancer, partly to an inhibitory element upstream of -207.
The effect of azelastine, an orally effective antiasthmatic antiallergic drug on the generation of oxygen-derived free radicals in phagocytes was investigated using different chemiluminescence-assays. The chemiluminescence (CL) of both human polymorphonuclear granulocytes (PMNL) and guinea-pig alveolar macrophages (AM) was induced either by phorbol myristate acetate (PMA) or zymosan and amplified either by lucigenin or DMNH (7-dimethylamino-naphthalene-1,2-dicarbonic-acidhydrazide). The inhibitory effect of azelastine was dependent on the inducer employed and the condition and type of cells used. Azelastine reduced PMA-induced CL concentration-dependently in both PMNL (IC30 = 3.9 microM) and AM (IC30 = 9.8 microM). In AM zymosan-induced CL was inhibited 21.7% by 10 microM azelastine, whereas in PMNL it remained unchanged up to 10 microM azelastine. Azelastine has a significantly stronger inhibitory effect (IC30 = 4.2 microM) on oxygen free radical generation in AM primed by fetal calf serum than in unprimed AM. Based on present results it is likely that azelastine inhibits oxygen-derived free radical generation by interaction with protein kinase C.
Cells of the clonal osteogenic cell line MC3T3-E1 were seeded onto a three-dimensional matrix of denatured collagen type 1 and cultured for a period of up to 8 weeks. Specimens were analyzed by histological, enzyme histochemical, immunocytochemical, and ultrastructural methods and by in situ hybridization between day 7 and day 56 after seeding. In 56-day cultures, the MC3T3-E1 cells were arranged in a three-dimensional network and formation of bone-like tissue was indicated by calcification of a newly synthesized collagen type I matrix resembling osteoid and surrounding osteocyte-like cells. The differentiating culture showed high expression of osteocalcin and alkaline phosphatase activity. NIH3T3 fibroblasts used as control cells passed through the network of the substrate forming a confluent monolayer underneath. This culture system offers a potentially powerful model for bone formation in vitro and for investigating the osteogenic potential of bone-derived cells.
The acute effects of small-volume infusion of hypertonic-hyperoncotic solutions on central hemodynamics, regional organ blood flow (RBF; 15-microns-diameter radiolabeled microspheres), and respiratory function following severe hemorrhage (MAP = 40 mm Hg for 45 min, approx 50% blood loss) were analyzed in anesthetized beagles. Treatment regimens used were: 10% Dextran 60 in 7.2% NaCl (HHS); 10% Dextran 60 in 0.9% NaCl (HDS); or 7.2% NaCl (HSS) alone, administered over 2 min in a volume equivalent to 10% of the blood loss (4 ml/kg iv). Within 5 min, cardiac output reached (HSS, HDS) or even exceeded prehemorrhage values (HHS), and MAP increased to 56% (HDS)-74% (HHS) of baseline. At the same time, RBF in kidneys (all groups), pancreas (HHS, HSS) and gastric mucosa (HHS) was completely restored, while flow in myocardium, brain, skeletal muscle, adrenal glands (all groups), and small intestine and colon (HHS) rose even above baseline values (P less than 0.05). Fractional blood flow (percentage of cardiac output) favored heart and brain in all three groups. These effects tended to persist for at least 30 min. Respiratory function was not affected by either of the three solutions, and no adverse effects were noted. Small-volume resuscitation with 7.2% saline/10% Dextran 60 provides instantaneous restitution of regional organ blood flow; it appears to result in a more uniform circulatory response than 7.2% saline or 10% Dextran 60 alone and might ensure improved organ perfusion during evacuation of patients from the accident site.
N-tropic murine leukemia viruses have been observed in connection with radiation-induced osteosarcomagenesis in BALB/c mice. We have investigated the bone disease-inducing potential of molecularly cloned, BALB/c-derived N-tropic viruses in the random-bred NMRI mouse strain. The germ-line virus and an exogenous virus isolate were found to induce high incidences of osteopetrosis and lymphomas and a lower incidence of osteomas. Two viruses derived from somatically acquired proviruses of independent radiation-induced osteosarcomas induced lower incidence of osteopetrosis and lymphomas. Nucleotide sequence analysis of the long terminal repeat regions and RNase T1 fingerprint analysis revealed only few differences between the isolates. The possible involvement of N-tropic murine leukemia viruses in radiation-induced osteosarcomagenesis in the BALB/c mouse strain is discussed.
A variety of structurally related hydroxyanthraquinones (HA) were investigated in a test battery for the evaluation of mutagenicity and cell-transforming activity. The tests were: (1) the Salmonella typhimurium mutagenicity assay, (2) the V79-HGPRT mutagenicity assay, (3) the DNA-repair induction assay in primary rat hepatocytes and (4) the in vitro transformation of C3H/M2 mouse fibroblasts. In Salmonella, most of the tested compounds were mutagenic in strain TA1537, but only a few were active in other strains. Among these were HA with a hydroxymethyl group, such as lucidin and aloe-emodin. In V79 cells, only HA with 2 hydroxy groups in the 1,3 positions (1,3-DHA, purpurin, emodin) or with a hydroxymethyl sidechain (lucidin and aloe-emodin) were mutagenic. The compounds found to be active in V79 cells were also active in the DNA-repair assay and in the C3H/M2 transformation assay. Thus, it appears that the genotoxicity of HA is dependent on certain structural requirements.
Transient visual disturbances have been noted in patients undergoing transurethral resection of the prostate. It has been suggested recently that these visual aberrations were secondary to high serum concentrations of glycine from the intravasation of irrigant solutions used during the procedure. We prospectively studied visual acuity, serum electrolytes, glucose, ammonia and glycine concentrations in 18 patients undergoing transurethral resection of the prostate. Of our patient population 22% experienced significant decreases in visual acuity. We found that all patients had significantly elevated serum glycine concentrations but that there was no correlation of visual symptomatology with serum electrolyte or glucose concentrations. Our data further suggest that impeded metabolism of glycine may be more important than the absolute serum concentration in symptomatic patients.
A patient with bilateral congenital aplasia of the deep femoral arteries is described. The condition was accompanied by aneurysms of the popliteal arteries. Besides the academic interest of such an anatomical rarity, the abnormality is of clinical importance insofar as acute ischemia of the extremity may occur in the presence of superficial femoral artery occlusion.
The cartilagenous tissue of mandibular condyles of newborn mice contains progenitor cells as well as young and mature chondrogenic cells. During in vitro cultivation of the tissue, progenitor cells undergo osteogenic differentiation and form new bone (Silbermann, M., D. Lewinson, H. Gonen, M. A. Lizarbe, and K. von der Mark. 1983. Anat. Rec. 206:373-383). We have studied the expression of genes that typify osteogenic differentiation in mandibular condyles during in vitro cultivation. RNAs of the genes for collagen type I, osteonectin, alkaline phosphatase, and bone gla protein were sequentially expressed in progenitor cells and hypertrophic chondrocytes during culture. Osteopontin expression peaked in both the early and the late phase of the differentiation process. The data indicate a distinct sequence of expression of osteoblast-specific genes during osteogenic differentiation and new bone formation in mandibular condyles.