Biomedical subjects
G W RICHTER
Publications and source records attributed to G W RICHTER.
CRYSTALLIZATION OF BIREFRINGENT, PSEUDOCUBIC HORSE APOFERRITIN WITH CAESIUM CHLORIDE.
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ELECTROPHORETIC AND SEROLOGICAL PROPERTIES OF THE FERRITINS PRODUCED BY HELA AND KB CELLS IN CULTURES. I. COMPARISON WITH OTHER FERRITINS.
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Hypertrophy of the human heart at the level of fine structure. An analysis and two postulates.
Muscle cells in the left ventricular walls of four markedly hypertrophied human hearts (above 600 gm) were compared with muscle cells in four non-hypertrophied hearts (up to 310 gm). Blocks of tissue obtained postmortem within 6 hours were processed for light and electron microscopy under conditions suitable for good preservation of myofibrils. A lattice parameter, q(h), was defined as the number of myosin filaments per square micron in either H zones or A bands. By the use of methods of electron microscopy, q(h) was determined for perpendicular cross-sections of A bands in a large number of well preserved myofibrils of muscle cells in both groups of hearts. Statistical evaluation of the distributions of values of q(h) revealed no significant difference between the two groups. Thus, the myofilament lattices in hypertrophied cells were geometrically within normal limits. Planimetric measurements of cross-sectional areas of muscle fibers were made, using photomicrographs obtained from one representative hypertrophied heart and from one control. The size-frequency distribution of the measurements showed a marked difference between the two hearts, and confirmed the presence of hypertrophy of muscle cells. Counts of the number of myofibrils per muscle cell were determined for samples from the same two hearts, evaluated statistically, and found to be significantly higher for the hypertrophied heart. It is proposed (a) that myofibrils in hypertrophied heart muscle cells have filament lattices with geometrical arrangement and macromolecular parameters that are the same as those found in myofibrils of normal heart muscle cells; and (b) that in hypertrophy the number of myofilaments increases through formation of new myofibrils, and possibly also by addition of filaments to preexisting myofibrils.
ON FERRITIN AND ITS PRODUCTION BY CELLS GROWING.
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Activation of ferritin synthesis and induction of changes in fine structure in HeLa cells in vitro: implications for protein synthesis.
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Intranuclear aggregates of ferritin in liver cells of mice treated with saccharated iron oxide. Their possible relation to nuclear protein synthesis.
Several months following parenteral injections of saccharated iron oxide into DBA/2J mice, granules rich in iron were found in nuclei of scattered parenchymal liver cells as well as in the cytoplasm. As seen in the light microscope, the intranuclear granules were brown; most of them measured between 0.5 micro and 1 micro in cross-section. They gave positive Prussian blue tests, and were not selectively stainable with pyronine. Electron micrographs of the granules showed closely packed aggregates of ferritin molecules, occasionally in paracrystalline order. The intranuclear collections were often surrounded by bands of material of moderate opacity. Scattered ferritin molecules and collections of such molecules were also present in the cytoplasm of many liver cells, but there seemed to be no quantitative relationship between intranuclear and cytoplasmic ferritin. Liver cells from untreated control mice failed to reveal intranuclear deposits of ferritin. Although the site of origin of the intranuclear aggregates of ferritin is unknown, the findings suggest the possibility that under suitable circumstances ferritin synthesis may take place within nuclei of liver cells-perhaps induced by the presence of colloidal iron.
The nature of storage iron in idiopathic hemochromatosis and in hemosiderosis. Electron optical, chemical, and serologic studies on isolated hemosiderin granules.
Using three different methods of cells fractionation, hemosiderin granules were isolated from tissues (liver and/or spleen) of three patients. The samples were obtained from a case of idiopathic hemochromatosis, a case of thalassemia major with secondary (transfusional?) hemosiderosis, and a case of transfusional hemosiderosis associated with an unclassified anemia. Iron, nitrogen, and protein content of the hemosiderin granules varied over a wide range. Electron microscopy of sectioned granules revealed aggregates of dense particles of different shapes, with diameters ranging from 10 A to about 75 A. In some of the granules dense particles corresponding to the iron hydroxide micelles of ferritin molecules were abundant. But many of the granules contained very few of these molecules. The presence of ferritin and apoferritin in the samples of hemosiderin granules was demonstrated by means of precipitin tests in agar-gel, using rabbit antiferritin sera with known antibody nitrogen concentrations. At least three antigenic components were detected in highly purified crystalline ferritin prepared from tissues of the three patients; the hemosiderin granules contained the same antigens, but probably in much smaller quantities. Both ferritin and apoferritin molecules were extracted from hemosiderin granules, and were demonstrated in the electron microscope after suitable preparation. The solubility curve of human ferritin in solutions of (NH(4))(2)SO(4) was investigated. The results indicate that substantial quantities of ferritin or apoferritin can be lost in saline, aqueous media during isolation of hemosiderin granules from cells. It was shown by means of electron microdiffraction on selected hemosiderin granules that the dense particles represent forms of partly hydrated alpha-Fe(2)O(3). The conditions necessary for electron microdiffraction in an electron microscope precluded an exact determination of the state of hydration of the alpha-Fe(2)O(3) or of its structural relation to (FeOOH) micelles of pure ferritin in its undenatured state. The findings were considered in the light of evidence on the structure and disposition of hemosiderin in situ in cells, and on the structure of ferritin. Differences between endogenous hemosiderin and hemosiderin derived from injections of colloidal iron compounds were pointed out. The evidence indicates that in hemochromatosis and in secondary hemosiderosis much of the inorganic storage iron in liver and spleen is derived from degraded ferritin. The findings suggest that an abnormal cellular metabolic pathway of ferritin is implicated in the pathogenesis of hemochromatosis and transfusional hemosiderosis.
On the extraction and staining of ferritin.
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The cellular transformation of injected colloidal iron complexes into ferritin and hemosiderin in experimental animals; a study with the aid of electron microscopy.
As revealed by electron microscopy and electron diffraction, the physical state of ferric hydroxide micelles contained in iron-dextran, saccharated iron oxide, and hydrous ferric oxide ("ferric hydroxide") differs notably from the state of the ferric hydroxide in ferritin or hemosiderin. By virtue of this difference one can trace the intracellular transformation of colloidal iron, administered parenterally, into ferritin and hemosiderin. One hour after intraperitoneal injection of iron-dextran or saccharated iron oxide into mice, characteristic deposits were present in splenic macrophages, in sinusoidal endothelial cells of spleen and liver, and in vascular endothelial cells of various renal capillaries. Four hours after injection, small numbers of ferritin molecules were identifiable about intracellular aggregates of injected iron compounds; and by the 6th day, ferritin was abundant in close proximity to deposits of injected iron compounds. The latter were frequently situated in cytoplasmic vesicles delimited by single membranes. These vesicles were most frequently found in tissue obtained during the first 6 days after injection; and in certain of the vesicles ferritin molecules surrounded closely packed aggregates of injected material. Much unchanged ferric hydroxide was still present in macrophages and vascular endothelial cells 3 to 4 weeks after injection. While electron microscopy left no doubt about the identity of injected ferric hydroxide on the one hand, and of ferritin or hemosiderin on the other, histochemical tests for iron failed in this respect. Precipitation of ferric hydroxide (hydrous ferric oxide) from stabilized colloidal dispersions of iron-dextran was brought about in vitro by incubation with minced mouse tissue (e.g. liver), but not by incubation with mouse serum or blood. Subcutaneous injections of hydrous gel of ferric oxide into mice initially produced localized extracellular precipitates. Most of the material was still extracellular 16 days after injection, though part of it was phagocytized by macrophages near the site of injection; but apparently none reached the spleen in unaltered form. Five days after injection and thereafter, much ferritin was present in macrophages about the site of injection and in the spleen. The findings show that iron preparations widely used in therapy can be identified within cells, and that their intracellular disposition and fate can be followed at the molecular level. Considered in the light of previous work, they indicate that the characteristic structure of the ferric hydroxide micelles in molecules of ferritin is specific, and develops during the union of apoferritin with ferric hydroxide. Apparently this union does not depend upon specific cell components.
Electron microscopy of hemosiderin; presence of ferritin and occurrence of crystalline lattices in hemosiderin deposits.
Injections of hemoglobin were given to rats in order to produce hemosiderosis, and selected hemosiderin granules in sectioned cells of proximal convoluted tubules were studied by means of electron microscopy. When examined at high resolution, many of the dense particles that were present in hemosiderin granules proved to have the structure that characterizes the iron hydroxide micelles of molecular ferritin. In some hemosiderin deposits the dense particles formed lattices similar to those present in sections of crystalline ferritin. Such ordered arrangement of dense particles was encountered inside as well as outside of the cytoplasmic organelles for which the name "siderosomes" has been proposed previously, and which may be derived from mitochondria. Study of hemosiderin granules in hepatic parenchymal and reticuloendothelial cells of human beings yielded similar results. The findings confirm the inference that ferritin is a component of hemosiderin, and they indicate that some of the so called hemosiderin granules are crystals of ferritin.
A study of hemosiderosis with the aid of electron microscopy; with observations on the relationship between hemosiderin and ferritin.
Hemosiderin deposits in rats and in man were studied and compared by means of electron and light microscopy. Typical, isotropic, iron-positive hemosiderin granules were found to contain innumerable, closely packed, electron-dense particles, embedded in matter that was much less dense to electrons. Similar dense particles were often scattered diffusely through the cytoplasmic matrix of cells containing hemosiderin granules. In cells of proximal convoluted tubules of rats given repeated intraperitoneal injections of hemoglobin the hemosiderin granules contained dense particles with a mean diameter of 55 A, and with a size-frequency distribution that indicated uniformity. These particles corresponded in size to the iron micelles of ferritin molecules. There was less uniformity of particles in hemosiderin granules situated in liver and reticulo-endothelial cells of rats that had been given a diet containing ethionine. The dense aggregates representing hemosiderin granules were often situated inside discrete cytoplasmic organelles that were bordered by membranes, and sometimes contained "cristae"; and often the membranous borders were markedly disrupted. The term "sidersomes" is proposed for these specialized cytoplasmic structures which may be derivatives of mitochondria, and apparently play a part in the formation of hemosiderin. Ferritin was crystallized from the livers and kidneys of the hemosiderotic rats with ease, but could not be crystallized from comparable quantities of liver and kidney tissue of untreated control rats. Specimens from the liver and spleen of a patient with advanced hemosiderosis, obtained at an operation, were also studied. In liver and reticulo-endothelial cells many particles with diameters of about 60 A were scattered through the cytoplasmic matrix. By contrast, hemosiderin granules in the same cells contained particles that varied considerably in size. In representative granules, examined at high resolution, the size-frequency distribution of particle diameters displayed a periodicity consistent with the presence of small, uniform subunits. Electron micrographs of ferritin, isolated from the spleen of the same patient, provided confirmation for the inferences that the dense particles observed inside cells are iron micelles, and that ferritin is probably a component of hemosiderin.
Alterations in serum globulins during the formation and resorption of amyloid in rabbits.
A marked increase of the serum beta globulins was found in rabbits developing amyloidosis as a result of prolonged treatment with ribonucleate administered by subcutaneous injections. Following cessation of treatment the beta globulin levels gradually returned to normal while the gamma globulin levels rose strikingly, the changes being accompanied by a resorption of amyloid from the spleen, and probably also from the kidneys. Electrophoretic studies provided some evidence that the increase in beta globulins which accompanied the development of amyloidosis resulted from the production of a globulin not normally present in rabbit serum. A protein or protein derivative that moved as a beta globulin when subjected to filter paper electrophoresis was excreted in substantial quantities in the urine of several amyloidotic rabbits, along with much smaller quantities of substances moving as albumin, alpha and gamma globulins. Considered as a whole, the findings indicate a causal relationship between the abnormal production of circulating beta globulins and the deposition of amyloid in rabbits treated with ribonucleate. Hence it appears that a beta globulin may be directly involved in the formation of amyloid under the conditions of the experiments here reported.
Coexisting congenital stenoses of aortic and pulmonic ostia.
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Experimental hyperglobulinemia; the effect of injected ribonucleotide on serum globulin levels in rabbits undergoing immunization.
It was shown, by means of salt fractionation procedures and electrophoresis that a marked and sustained hyperglobulinemia regularly resulted when sodium ribonucleate was injected subcutaneously at frequent intervals into rabbits undergoing immunization with horse serum. The hyperglobulinemia was characterized by a large increase in the gamma globulin levels, and a slight increase in the alpha and beta globulin levels. In control experiments done concurrently, the immunization of rabbits with horse serum, accompanied by subcutaneous injections of saline instead of ribonucleate, resulted in only moderate elevations in gamma globulin levels, while injections of ribonucleate alone brought about slight elevations in all three globulin components in some of the animals. Precipitin tests showed that the rabbits immunized with horse serum and simultaneously treated with ribonucleate developed antibody titers against horse serum that were no higher than those of the immunized controls given saline instead of ribonucleate. Indeed, some of the animals treated with horse serum and ribonucleate had globulin levels that were much higher and had antibody titers that were significantly lower than were those of several rabbits receiving horse serum and saline. Injections of ribonucleate alone did not result in the formation of specific antibodies detectable by means of precipitin tests. The results made it plain that the hyperglobulinemia of the animals treated with horse serum and ribonucleate was not due to an excessive production of specific antibodies. The findings as a whole provide further evidence that nucleotides play an important role in the formation of proteins in animals, and they indicate that an abnormally increased utilization of ribonucleotides by cells capable of producing globulins may be a causative factor in the pathogenesis of hyperglobulinemia.
Parenchymatous lesions of liver and kidney of mice due to pectin.
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The resorption of amyloid under experimental conditions.
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Experimental argyrosis. VI. Electron microscopic study of ingested silver in the kidney of the rat.
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