Small Number Of Secretory Granules Research Articles

Histological, Topographical and Ultrastructural Organization of Different Cells Lining the Olfactory Epithelium of Red Piranha, Pygocentrus nattereri (Characiformes, Serrasalmidae)

Abstract The structural characterization of the olfactory epithelium in Pygocentrus nattereri Kner, 1858 was studied with the help of light as well as scanning and transmission electron microscope. The oval shaped olfactory rosette consisted of 26–28 primary lamellae radiated from midline raphe. The olfactory epithelium of each lamella was well distributed by sensory and non-sensory epithelium. The sensory epithelium contained morphologically distinct ciliated and microvillous receptor cells, supporting cells and basal cells. The non-sensory epithelium was made up of labyrinth cells, mucous cells and stratified epithelial cells. According to TEM investigation elongated rod emerging out from dendrite end of the receptor cells in the free space. The dendrite process of microvillous receptor cells contained microvilli. The supporting cells had lobular nucleus with clearly seen electron dense nucleolus. The apex of the ciliated non-sensory cells was broad and provided with plenty of kinocilia. Basal cells provided with oval nucleus and contained small number of secretory granules. The mucous cells were restricted to the non-sensory areas and the nuclei situated basally and filled with about two-third of the vesicles. The functional significance of various cells lining the olfactory epithelium was discussed with mode of life and living of fish concerned.

Multistep differentiation of GH-producing cells from their immature cells

In order to study GH cell differentiation, we used the clonal cell lines called MtT/E and MtT/S cells, which were derived from a rat mammotrophic pituitary tumor. Although MtT/E cells are non-hormone-producing ones, Pit-1 protein is present in their nuclei, which suggests that MtT/E cells are progenitor cells of the Pit-1 cell lineage and have the potential to differentiate into hormone-producing cells. On the other hand, MtT/S cells produce GH; however, the responsiveness to GH-releasing hormone (GHRH) is weak and only a small number of secretory granules are present in their cytoplasm, which suggests that MtT/S cells are premature GH cells. In order to differentiate into GH cells from MtT/E cells as a progenitor cell, we examined several differentiation factors and found that retinoic acid (RA) induced the differentiation of MtT/E cells into GH-producing cells. RA-induced GH cells partially matured with the glucocorticoid treatment; however, the responsiveness to GHRH on GH secretion was incomplete. In order to elucidate the mechanism underlying full differentiation of GH cells, we used MtT/S cells. We treated MtT/S cells with glucocorticoid and found that they differentiated into mature GH cells with many secretory granules in their cytoplasm and they responded well to GHRH. These results suggested that MtT/E and MtT/S cells are progenitor or premature GH cells, and show different responses to differentiation factors. Our data also suggested that GH cells differentiate from their progenitor cells through multistep processes.

Amplification of exocytosis by Ca2+‐induced Ca2+ release in INS‐1 pancreatic β cells

Functional coupling between Ca(2+)-induced Ca(2+) release (CICR) and quantal exocytosis in 5-hydroxytryptamine-loaded INS-1 beta cells was assessed through the use of carbon fibre amperometry in combination with Fura-2. CICR was evoked by the glucagon-like-peptide-1 (GLP-1) receptor agonist exendin-4 (Ex-4) and was accompanied by quantal secretory events appearing as amperometric current spikes time-locked to the increase of [Ca(2+)](i). The action of Ex-4 was reproduced by treatment with caffeine, and the source of Ca(2+) serving as a stimulus for exocytosis originated from ryanodine and thapsigargin-sensitive Ca(2+) stores. Two distinct patterns of exocytosis occurred within 5 s following the initiation of CICR. Non-summating exocytosis (NS-type) was defined as multiple asynchronous current spikes, and the half-height duration of each spike was 12-48 ms. Summating exocytosis (S-type) was defined as a cluster of spikes. It generated a macroscopic current, the half-height duration of which was 243-682 ms. The release charge of S-type exocytosis was 3.2-fold greater than that of NS-type when measured 2 s following the initiation of secretion. NS-type exocytosis was observed frequently under conditions in which the basal Ca(2+) concentration ([Ca(2+)](B)) was low (75-150 nM), whereas S-type exocytosis predominated under conditions in which the [Ca(2+)](B) was elevated (200-275 nM). Depolarization-induced Ca(2+) influx triggered NS-type exocytosis in most cells tested, irrespective of [Ca(2+)](B). It is concluded that CICR is a highly effective stimulus for exocytosis in INS-1 cells. The increase of [Ca(2+)](i) that accompanies CICR stimulates the asynchronous release of a small number of secretory granules under conditions of low [Ca(2+)](B). When [Ca(2+)](B) is slightly elevated, CICR targets a much larger pool of secretory granules that undergo summating exocytosis. The transition from NS-type to S-type exocytosis may represent an amplification mechanism for Ca(2+)-dependent exocytosis.

Alterations in the integument ofArmadillidium vulgaremasculinized by implantation of androgenic glands

Summary Alterations in the integument of masculinized females of Armadillidium vulgare caused by the implantation of androgenic glands from normal males involve both pigment cells and epidermal cells with respect to the intracellular structure and the ommochrome content. Epidermal cells beneath the cuticle of masculinized females are thicker than those of normal females, having a number of small secretory granules and well developed rough endoplasmic reticulum in the cytoplasm. As a result of epidermal cell thickening, pigment cells are more widely separated from the cuticle in masculinized females than in normal females. The ommochrome content in the integument of masculinized females, which was initially the same as that of normal females, increased with each postoperative stage and coincided with that of male integument by the fourth postoperative stage. The observations suggest that the slate grey color characteristic of the male body, shown during masculinization of females after the implantation of ...

Immunocytochemical Localization of Relaxin in Human Corpora Lutea: Cellular and Subcellular Distribution and Dependence on Reproductive State1

Relaxin is one of the hormones present during pregnancy and it is synthesized primarily by corpora lutea (CL). Other reproductive tissues including CL of the menstrual cycle may also synthesize this hormone. Very little is known, however, about the cellular and subcellular distribution of relaxin in human CL and dependence of luteal relaxin on the reproductive state. The light and electron microscope immunocytochemical studies described here were undertaken to obtain this information using antisera to porcine and human relaxin. Immunostaining was found in large luteal cells (17-30 microns) but not in small luteal cells (7-16 microns) or in nonluteal cells in any of the reproductive states or in human hepatocytes. Luteal immunostaining was low in early luteal phase; it increased progressively, reaching the highest level in late luteal phase, and then decreased greatly in corpora albicantia. Term pregnancy CL contained similar immunostaining as early luteal phase CL. Mid luteal phase CL contained more immunostained cells than late luteal phase CL, but the late luteal phase CL contained a greater amount of immunostaining per cell than mid luteal phase CL. The immunogold particles due to relaxin were primarily present in secretory granules and to a small extent in rough endoplasmic reticulum. Quantitation revealed that secretory granules contained a much higher number of gold particles than did rough endoplasmic reticulum. These two organelles from late luteal phase CL contained greater numbers of gold particles than those from mid luteal phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Subcellular distribution of secretogranins I and II in GH3 rat tumoral prolactin (PRL) cells as revealed by electron microscopic immunocytochemistry.

The GH3 rat pituitary cell line which secretes prolactin (PRL) is characterized by the paucity and small size of secretory granules. We looked for the presence, in these cells and in normal PRL cells, of two acidic tyrosine-sulfated proteins which are widely distributed in dense-core secretory granules of endocrine and neuronal cells, secretogranins I and II, using immunofluorescence and electron microscope immunoperoxidase techniques. Both secretogranins were detected in secretory granules of GH3 cells and of normal cells. Moreover, with our pre-embedding approach, secretogranins were localized within some RER cisternae and within all sacules of the Golgi stacks in both PRL cell models. A few small vesicles, large dilated vacuolar or multivesicular structures, and some lysosome-like structures were also immunoreactive. Double localization of secretogranins and PRL performed on GH3 cells by immunofluorescence indicated that all cells contained secretogranins I and II, whereas only 50-70% of the cells contained PRL. Moreover, in the case of hormone treatment known to increase the number of secretory granules, most if not all mature secretory granules were immunoreactive for secretogranins, whereas in certain cells some of the granules were apparently not immunoreactive for PRL. These immunocytochemical observations show that GH3 cells, which under normal conditions form only a small number of secretory granules, produce secretogranins and package them into these granules.

Ultrastructure and Atrial Natriuretic Peptide(ANP)-like Immunoreactivity of Cardiocytes in the Larval, Metamorphosing and Adult Specimens of the Japanese Toad, Bufo japonicus formosus: toad/atrial natriuretic peptide(ANP)-like material/immunohistochemistry/immunocytochemistry/RIA.

The distribution of an atrial natriuretic peptide (ANP)-like material in the cardiocytes of larval, metamorphosing, and adult specimens (both breeding and non-breeding) of the toad, Bufo japonicus formosus, was studied immunohistochemically, ultrastructurally and immunocytochemically. Histochemically, ANP-immunoreaction was positive in the atrium and ventricle in stage 33 larvae, while negative in the ventricle in stage 40 larvae. In adult toads, the reaction was stronger in the right than in the left atrium but quite weak in the ventricles, particularly those of non-breeding specimens. Electron microscopy indicated a very small number of secretory granules in the atrial and ventricular cardiocytes of embryos as early as the limb-bud stage (stage 28), and as development proceeded, the number of these granules increased rapidly in atrial but not in ventricular cardiocytes. In metamorphosing animals, a small population of larger granules (200-250 nm) was noted next to those of ordinary size (the median, 110 nm) in the same cell. In adult toads, granules of about 120 nm and 200 nm in median size were found in the same cell. Postembedding immunogold staining consistently indicated ANP-immunoreactivity in these granules in atrial and ventricular cardiocytes. The plasma content of immunoreactive ANP was considerably higher in breeding (20.5 ± 5.9 pg/ml) than in non-breeding toads (5.4 ± 1.7 pg/ml). These results are discussed in relation to presently available data on the physiological role of ANP.

Fine structure of supporting elements of the small pit organ in the far eastern catfish,silurus asotus

The small pit organ of the catfish,Silurus asotus, was examined by electron microscopy. On the basis of their fine structures and positions in the organ, five types of cells were distinguished: 1) receptor cell (RC), 2) granular (supporting) cell (GC), 3) non-granular (supporting) cell (NGC), 4) mantle cell (MC), and 5) channel cell (CC). Both GCs and NGCs were located between the RCs in the sensory epithelium and had similar fine structures except for striking differences in their apical cytoplasm. The GC contained numerous secretory granules and scattered tonofilaments. By contrast, the NGC was characterized by abundant tonofilaments in their apical cytoplasm where only a small number of secretory granules were counted. The NGC always occurred in direct contact with RCs, whereas the GC never did so. The MCs, forming the outermost part of the organ, were characterized by numerous tonofilaments in the cytoplasm and resembled the ordinary epidermal cells in their fine structure. The CCs lined the duct of the organ, and contained electron dense cytoplasm and rather degenerative organelles. Presumably the GCs contribute to secretion of the mucous substance to the ampullary lumen, whereas the NGCs deal with nutrition and insulation for the RCs.

The fine structure of the female reproductive tract of adult Loa loa

Weber P. 1987. The fine structure of the female reproductive tract of adult Loa loa. International Journal for Parasitology 17: 927–934. The wall of the female reproductive tract of Loa loa was studied by electron microscopy. The wall is composed of a monolayered epithelium covered by a basal lamina. The epithelium of the ovary has a moderately developed basal labyrinth, abundant organelles, and a few secretory granules. In the oviduct, the basal lamina intrudes septa-like into the epithelium. Abundant myofilaments are attached to it. Microvilli cover the luminal cell border. The seminal receptacle contains few muscle cells in its basal lamina. It shows a highly developed spongy zone at its luminal surface. The uterine epithelium contains glycogen deposits and lipid droplets. In its anterior parts it shows a highly developed basal labyrinth and an abundance of secretory granules. The vagina has several layers of muscle cells in the basal lamina. Its epithelium contains few organelles, a small number of secretory granules, and is devoid of storage deposits.

Differential subcellular localization of ACTH and alpha-MSH in corticotropes of the rat anterior pituitary.

Specific antisera to alpha-melanotropin (alpha-MSH) and corticotropin (ACTH 1-39) were used to obtain immunocytochemical evidence for the differential localization of alpha-MSH and ACTH in the secretory granules of corticotropes of rat anterior pituitary. The specificity of the antisera was established by binding 131I-labeled alpha-MSH and ACTH 1-39 to their respective antisera. Double-labeling immunocytochemistry (for alpha-MSH, ferritin; for ACTH, colloidal gold) was performed. Some secretory granules were labeled with ferritin particles (alpha-MSH), whereas others contained gold particles (ACTH). Only a few granules showed both ACTH and alpha-MSH. In typical corticotropes (stellate in form with a small number of secretory granules aligned along the cell periphery) only some of the secretory granules that were labeled with anti-ACTH serum were also immunoreactive to anti-alpha-MSH. In atypical corticotropes (polygonal in shape and containing a large number of secretory granules) almost all of the immunoreactive ACTH secretory granules were also positive to anti-alpha-MSH serum. An intermediate type of corticotrope was observed containing a small number of secretory granules, almost all of which were labeled with anti-alpha-MSH. Thus, rat anterior pituitary corticotropes may be classified into three types according to the distribution and content of alpha-MSH. The light-microscopic immunocytochemistry provided similar results.

Isolation of a purified mitochondrial fraction from viable clonal insulin-producing cells (RINm5F) by Percoll density gradient centrifugation.

A Percoll density gradient was employed for selecting large numbers of viable insulin-producing RINm5F cells. Homogenates of these cells were then subjected to gradient centrifugation and two clearly visible bands were obtained. The light fraction was essentially composed of mitochondria banded at a density of about 1.06 g/ml. The heavier fraction banded at 1.09 to 1.10 g/ml and contained lysosomes and a small number of secretory granules. The distribution of Percoll particles was restricted to the extracellular space and there was no adsorption to any membrane structures. The distribution pattern of marker enzymes for the mitochondria and lysosomes was similar to that of normal pancreatic beta-cells. With the use of a Percoll density gradient it was thus possible to isolate a purified mitochondrial fraction from viable RINm5F cells.

Fine structural aspects on the renewal and development of surface mucous cells and glandular cells of the gastric body of the adult golden hamster.

By light and electron microscopic autoradiography using 3H-thymidine, the renewal and development of surface mucous cells and glandular cells in the gastric body were studied in normal young adult golden hamsters. The isthmus and neck regions of the gastric gland are composed of immature surface mucous cells, immature parietal cells, young parietal cells and mucous neck cells. It is presumed that the stem cell having the potency of differentiating into various kinds of cells is not present in the gastric mucosa of the adult golden hamster. Immature surface mucous cells, located in the isthmus region and capable of synthesizing DNA, contain abundant free ribosomes and a small number of secretory granules. The secretory granules increase in number as the cells ascend towards the gastric surface, forming a thick granule zone in the cell apex. The cells further contain small electron lucent vesicles which are likely involved in the formation of glycocalyx. The immature parietal cells in a low differentiated state, possessing the DNA synthesizing ability, are rarely found in the isthmus. They show collapsed intracellular canaliculi with long microvilli and contain numerous free ribosomes but smooth tubular elements are difficult to recognize. Some of the mucous neck cells located in the isthmus to neck region and capable of synthesizing DNA, are characterized by abundant free ribosomes, a few elements of rough endoplasmic reticulum relatively well developed Golgi apparatus and a few dense secretory granules. Mature surface mucous cells contain abundant secretory granules filling an apical granule zone. They are fated to be degenerated, and extruded into the gastric lumen. This is considered to be a holocrine process. The middle and basal regions of the gland consist mainly of chief cells, parietal cells and endocrine cells. A few of the chief cells in the middle part of the gastric gland also have the activity of synthesizing DNA. Some of the immature cells in the isthmus region, and mature glandular cells in the bottom of the gland are degenerated and phagocytosed by neighboring epithelial cells. This paper also records the occurrence of smooth muscle fibers in the lamina propria, extending from the muscularis mucosae to the basal part of the degenerated surface epithelium.

Glycoprotein synthesis in the mucous cells of the vascularly perfused rat stomach. III. Mucous cells of the antrum and the duodenal glands.

Labeled leucine, serine, galactose, glucosamine, fucose, and sulfate were administered to rat stomachs in a vascular perfusion system. Sections of gastric fundus and antrum, and of the duodenal glands, were studied by light-microscopic autoradiography. The rate of incorporation of radioactive label in the various mucous cell types of the antrum and of the duodenal glands was measured by counting the silver grains over each cell type and comparing this rate with that of the surface mucous cells of the fundus. The following major observations were made: The patterns of incorporation in the mucous cells on the surface and in the pits of the antrum did not differ essentially from those of the surface mucous cells of the fundus. On the contrary, the incorporation patterns of the surface mucous cells of the fundus differed considerably from those of the mucous cells of the antral glands and from the mucous cells of the duodenal glands. The mucous cells of the antral glands showed a lower incorporation rate of amino acids and of (amino) sugars, especially of galactose and glucosamine, but a higher incorporation rate of sulfate. The mucous cells of the duodenal glands showed a considerably higher rate of incorporation for serine, but a lower rate for glucosamine. No differences were seen for leucine, galactose, and sulfate. The relatively low synthetic activity of the mucous cells of antral glands correlates well with the various amounts of RER, Golgi system, and secretory granules, found in these cells, and with the histochemical staining characteristics of their mucous granules. The mucous cells of the duodenal glands are characterized by typical parallel arrays of their numerous RER cisternae and by a low number of small secretory granules.

On the chromaffin cells in dog adrenal medulla; with special reference to the small granule chromaffin cells (SGC cells).

Small granule chromaffin cells (SGC cells) were identified in the adrenal medulla of adult dogs. They were small in size and usually showed a high nucleo-cytoplasmic ratio. Cytoplasmic projections were occasionally observed in some of these cells. They contained a variable number of small secretory granules with diameters ranging from 70 to 300 nm, but mostly from 100 to 200 nm. The densities of the secretory granules were variable, ranging from highly dense to less dense. These adrenal SGC cells were rich in free ribosomes and polysomes, but were relatively poor in other cell organelles. Chromaffin cells which were intermediate in their characteristics (IM cells) between the SGC cells and the typical A and N cells were also identified. These IM cells contained both highly electron dense and less dense granules in various proportions. The IM cells were classified into two subgroups, according to the proportions of adrenaline type granules and noradrenaline type granules. One group resembled A cells (IM-A cells) and the other resembled N cells (IM-N cells). Light microscopic histochemical studies of A cells stained with the ammoniacal silver solution demonstrated that they contained a small number of darkly stained granules. Electron microscopic cytochemistry revealed that the electron dense granuls in the SGC cells, IM cells and A cells reacted positively with both the potassium dichromate solution at pH 4.1 and the ammoniacal silver solution.

Cytological Changes of Siperstein's Corticotrophs Following Thyroidectomy

Anterior pituitaries of male rats were electron-microscopically observed 12hr, 1, 3, 5, 7 and 14 days after thyro-parathyroidectomy in order to investigate the origin and destiny of Siperstein's corticotrophs (S-cells). The formation of a reticular framework by the folliculo-stellate cells may result from the general disaggregation of the solid mass of follicular cells with the pseudolumen into which microvilli project, by losing the junctional complex and pseudolumen. The S-cells, characterized by a row of secretory granules along the cytoplasmic membrane, have properties identical with those of the free agranular folliculo-stellate cells. The star-like shape, numerous ribosomes and polysomes, and elongated narrow rough endoplasmic reticulum, are common characteristics of both cells. Within 12hr to 5 days, the free or reticular folliculo-stellate cells appear in large numbers, and minute secretory granules about 50nm in diameter develop sporadically at their margins. In the course of the 5 days, secretory granules tend to increase in number and grow in size, measuring 100-200nm in diameter. However, the degree of granulation varied considerably from cell to cell during the same interval without complete equilibration with the time course after thyroidectomy. Detection of various transitional cells between folliculo-stellate cells and S-cells suggests that the former may be a stem cell of the latter. Concurrently with hypergranulation, some S-cells hypertrophy and develop a prominent Golgi apparatus, sometimes engulfing a part of the adjacent cell. The other S-cells, however, udergo degranulation associated with excessive vesiculation despite the formation of a circular arrangement of the closed Golgi lamellae. Within 7 days, there are some large vesiculated cells of stellate shape resembling the TX-cells, in which a small number of secretory granules whose diameter was reduced to 50-100nm, remain distributed along the cytoplasmic membrane. Within 14 days, the big TX-cells often appear, being characterized by the deposit of granules in the small cisternae and by the closure of Golgi lamellae which are in the circular arrangement. They are still stellate in shape, being extraordinarily enlarged to an extent 5-6 times that of an acidophil. In addition to the thyroidectomy cells (TX-cells) which are believed to result from the so-called thyrotrophs, the other developmental process of TX-cells in association with the folliculostellate cells was observed in this study. The two kinds of TX-cells are intrinsically different in their fine structures. It is postulated in this study that the folliculostellate cell is a progenitor of the S-cell which is destined to be transformed into the TX-cell, and that the S-cell, for this reason, represents a kind of basophil.

Structural changes of pancreatic islets in genetically obese rats.

Light and electron microscopic observations were performed on pancreatic islets from genetically obese rats, (Zucker, “fatty”), from 5 to 52 weeks of age. At 5 weeks of age, islets were moderately hypertrophied. After that age, hypertrophy of islets became more prominent, until 24 weeks of age, with accompanying degranulation of B cells. The plasma insulin level also continued to increase during this period, but the glucose level was normal. Degranulated B cells contained a highly developed Golgi complex, numerous vesiculated, granular, endoplasmic reticulum and a small number of secretory granules, but no glycogen deposits. Emiocytosis and microtubule formation were very remarkable with these B cells. Frequently, mixed or intermediate cells, such as exocrine-endocrine or ductural-endocrine cell, were observed in pancreas with hypertrophied islets. At 52 weeks of age, both the plasma insulin and triglyceride levels decreased. In the pancreas, there were observed proliferation of fibrous tissue and well granulated B cells in hypertrophied islets. Hence, in fatty rats, pancreatic islets were in an active state during the period of development of obesity and hyperlipaemia (from 5 to 24 weeks of age). These correlates of obesity and hyperinsulinism disappeared at 52 weeks of age.

HISTOCHEMISTRY OF THE ZINC IN THE PANCREATIC ISLETS OF GENETICALLY DIABETIC YELLOW KK MICE: HETEROGENEITY OF B GRANULES

In fed yellow KK mice, the pancreatic B cells showed severe degranulation and diminished content of zinc. In these islets, there were observed small number of secretory granules which could be classified into pale granules and dense granules with their electron densities. Both granules underwent emiocytosis. Zinc was detected in cores of dense granules as fine precipitates of silver sulfide. The pancreatic islets from 14 hours fasted mice were heavily granulated but still low in zinc reaction. By electron microscopy, B cells were filled with pale granules with very low zinc contents. Fortyeight hours fasted mice showed granulated and zinc-rich islets. In their B cells, many dense granules could be observed.These findings suggest conversion of pale granules into dense ones, on which zinc plays some role. Furthermore, it is likely that premature granules undergo secretion without being matured into dense granules in animals with hyperinsulinemia.

Immunohistologic, cytochemical and electron-microscopic investigations in Zollinger-Ellison-syndrome

One malignant extrapancreatic tumor detected in a case of Zollinger-Ellison syndrome was investigated by immunofluorescent, cytochemical and electron-microscope methods. Gastrin was demonstrated radioimmunologically in extracts of parapancreatic lymph node metastases. Only a minority of tumor cells showed specific immunofluorescence with anti-gastrin serum. This corresponds to the small number of secretory granules and can be interpreted as a high secretory activity. The cytochemical reactions correlated to the pancreatic D cell and in some cases to the antral G cell.

Histologic and ultracytochemical studies on thyroid medullary carcinoma. Diagnostic significance of argyrophil secretory granules.

Morphological, histochemical, and ultracytochemical characteristics on eight cases of thyroid medullary carcinoma are described. Solid-alveolar, streaming, ribbon, and rosette patterns characterized the histology of thyroid medullary carcinoma. Tumor cells were argyrophilic, and there were scattered numbers of ganglion cell-like tumor cells with well-impregnated dendritic processes. Ultracytochemically, it was demonstrated that the secretory granules of tumor cells contained argyrophil chemical substance closely related to polypeptide hormone (thyrocalcitonin). We consider these morphological and cytochemical characteristics as additional evidence indicating that thyroid medullary carcinoma arises from the parafollicular cells derived from the neural crest. The amount of amyloid showed a close relation to the number of secretory granules. In a case with a small number of secretory granules, amyloid deposition was not demonstrated. We stress the diagnostic significance of argyrophil secretory granules in establishing a diagnosis of thyroid medullary carcinoma, even in cases without amyloid deposits.