Light and Electron Microscopical Studies of the Renal Lesion in Dogs With Pyometra

Kidney biopsies from 23 bitches with pyometra and an entire kidney from four pyometra bitches were examined by light microscopy. Kidney tissue was also taken from three bitches at different intervals after ovariohysterectomy for pyometra. All the pyometra bitches had membranous glomerulonephritis or mixed proliferative and membranous glomerulonephritis. Two of the bitches had intraglomerular hyaline nodules resembling those seen in conjunction with diabetes in human beings. The degree of glomerular damage could be correlated with the reduction in glomerular filtration rate determined by function tests. The proximal tubules generally contained numerous hyaline droplets but the degree of this change could not be correlated to the degree of glomerular damage. A yellow pigment, a lipofuscin, was regularly present in the proximal tubules as well as epithelial proliferation and mitoses. Focal atrophy of tubules also occurred, presumably because of obliteration of glomeruli. The cortical interstitium contained collections of mature and immature plasma cells, often surrounding the glomeruli. When the kidneys from three bitches were examined after ovariohysterectomy for pyometra, the glomerular damage in two had regressed to leave only slight thickening of the capillary walls. In the third bitch, examined only 14 days after ovariohysterectomy, healing was partial. Kidney tissue from five bitches was also examined by electron microscopy. The glomerular endothelial cells were swollen and the basement membrane was grealy thickened. With more severe degrees of glomerular damage, an electron-dense material was deposited along the inner surface of the basement membrane and the swollen mesangial cells contained numerous inclusions. There was focal fusion of the foot processes of the glomerular epithelial cells; in one bitch with heavy proteinuria, the fusion was widespread. The proximal tubules contained numerous protein absorption droplets representing resorbed protein. The tubular basement membrane at all levels was thickened. Because of similarities with some other types of renal damage (nephrotoxic nephritis in dogs and acute proliferative glomerulonephritis in human beings), the possibility is broached that the renal lesion in pyometra is the result of an immunobiological process.     

Cytologic, ultrastructural and immunologic features of intracytoplasmic hyaline bodies in fine needle aspirates of hepatocellular carcinoma

Intracytoplasmic hyaline bodies in malignant cells from an aspirate of a liver mass are suggestive of hepatocellular carcinoma. Such inclusions were studied by light and electron microscopy and by immunocytochemistry in fine needle aspirates from five cases of hepatocellular carcinoma. Seen by light microscopy, the inclusions were round or ovoid and were surrounded by a prominent halo. By both light and electron microscopic immunocytochemistry, the hyaline bodies showed negative staining for alpha-fetoprotein, alpha-1-antitrypsin and cytokeratin. Ultrastructurally, they were not membrane bound and were composed of filamentous, finely granular material, resembling the early stages of Mallory bodies.     

Topographical localization of lipofuscin pigment in the brain of the aged fat‐tailed dwarf lemur (Cheirogaleus Medius) and grey lesser mouse lemur (Microcebus Murinus): Comparison to iron localization

The present study was undertaken to explore the distribution of lipofuscin in the brain of cheirogaleids by autofluorescence and compare it to other studies of iron distribution. Aged dwarf (Cheirogaleus medius) and mouse (Microcebus murinus) lemurs provide a reliable model for the study of normal and pathological cerebral aging. Accumulation of lipofuscin, an age pigment derived by lipid peroxidation, constitutes the most reliable cytological change correlated with neuronal aging. Brain sections of four aged (8–15 year old) and 3 young (2–3 year old) animals were examined. Lipofuscin accumulation was observed in the aged animals but not in the young ones. Affected regions include the hippocampus (granular and pyramidal cells), where no iron accumulation was observed, the olfactory nucleus and the olfactory bulb (mitral cells), the basal forebrain, the hypothalamus, the cerebellum (Purkinje cells), the neocortex (essentially in the pyramidal cells), and the brainstem. Even though iron is known to catalyse lipid oxidation, our data indicate that iron deposits and lipofuscin accumulation are not coincident. Different biochemical and morphological cellular compartments might be involved in iron and lipofuscin deposition. The nonuniform distribution of lipofuscin indicates that brain structures are not equally sensitive to the factors causing lipofuscin accumulation. The small size, the rapid maturity, and the relatively short life expectancy of the cheirogaleids make them a good model system in which to investigate the mechanisms of lipofuscinogenesis in primates. Am. J. Primatol. 49:183–193, 1999. © 1999 Wiley‐Liss, Inc.     

Cytologic features of hyalinizing trabecular adenoma of the thyroid

OBJECTIVE: To clarify the cytologic findings of hyalinizing trabecular adenoma (HTA) in order to reduce erroneous diagnoses of papillary carcinoma. STUDY DESIGN: Review of aspiration cytologic smears of 16 HTA cases and comparison with those of 20 papillary carcinoma cases. RESULTS: The smears from HTA were slightly cellular, and 5 of 16 cases were insufficient for evaluation. Vague, curved nuclear palisading, radiating arrangement surrounding hyaline materials and yellow bodies were observed in 9 (81.8%) of 11 cases that had sufficient material. The tumor cells were mainly spindled; elongated, polygonal and stellate cells were also seen. In 9 of 11 cases, tumor cells with cytoplasmic processes were occasionally observed. The cytoplasm was faintly stained and somewhat filamentous. The cell border was indistinct. Neither papillary nor follicular structures were seen. Intranuclear cytoplasmic inclusions were identified in 100% of HTA and 75% of papillary carcinomas. The incidences of nuclear grooves in HTA and papillary carcinoma were 81.8% and 100%, respectively. CONCLUSION: Cytologic findings indicating HTA are vague, curved nuclear palsiading; radiating arrangement surrounding hyaline material; elongated cells; cell processes; ill-defined cell border; faintly stained and filamentous cytoplasm; yellow bodies; and hyaline material in the background. All are useful cytologic characteristics in distinguishing HTA from papillary carcinoma. A lack of papillary architecture and sheetlike arrangement may also suggest HTA rather than papillary carcinoma.     

Spontaneous lesions in beagle dogs used in toxicity studies

Spontaneous histopathologic lesions were examined in 276 young beagle dogs (8 to 15 months old) used in toxicity studies. Mononuclear cell infiltration in the liver was observed with the highest incidence (more than 95%). Calcium deposition in the kidney, mononuclear cell infiltration in the salivary glands, pigmentation in the spleen, and cortical atrophy in the thymus were seen with relatively high incidences (more than 30%). The incidence of mononuclear cell infiltration in the gallbladder, vacuolization of the tubular epithelium in the kidney, and vacuolization of the zona glomerulosa cell in the adrenal gland showed differences between the sexes. No abnormalities were seen in the spinal cord, sternum, and femur. Although most lesions observed are considered to be age-related, several were considered to be due to congenital anomalies observed in some organs.     

An in vitro model for Lewy body-like hyaline inclusion/astrocytic hyaline inclusion: induction by ER stress with an ALS-linked SOD1 mutation

Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) containing mutant Cu/Zn superoxide dismutase 1 (SOD1) are morphological hallmarks of familial amyotrophic lateral sclerosis (FALS) associated with mutant SOD1. However, the mechanisms by which mutant SOD1 contributes to formation of LBHI/Ast-HI in FALS remain poorly defined. Here, we report induction of LBHI/Ast-HI-like hyaline inclusions (LHIs) in vitro by ER stress in neuroblastoma cells. These LHI closely resemble LBHI/Ast-HI in patients with SOD1-linked FALS. LHI and LBHI/Ast-HI share the following features: 1) eosinophilic staining with a pale core, 2) SOD1, ubiquitin and ER resident protein (KDEL) positivity and 3) the presence of approximately 15-25 nm granule-coated fibrils, which are morphological hallmark of mutant SOD1-linked FALS. Moreover, in spinal cord neurons of L84V SOD1 transgenic mice at presymptomatic stage, we observed aberrant aggregation of ER and numerous free ribosomes associated with abnormal inclusion-like structures, presumably early stage neuronal LBHI. We conclude that the LBHI/Ast-HI seen in human patients with mutant SOD1-linked FALS may arise from ER dysfunction.     

Effect of dose of estradiol and age of animals on intranuclear inclusions in mammotrophs of the Mongolian gerbil.

Intranuclear inclusions have been examined in mammotrophs of the Mongolian gerbil. No inclusions were identified in nuclei of newborn females, although inclusions were seen in the pituitary gland of young mature females. The number of inclusions in retired breeders was similar to that in young females. Estradiol benzoate increased the number of inclusions, although 10 mug/day for 5 or 14 days induced more inclusions than 5 or 100 mug for 14 days; significantly fewer inclusions were seen with the higher dose (2.81 +/- 0.10 inclusions per field for 10 mug and 2.19 +/- 0.01 inclusions for 100 mug). Significantly fewer inclusions were present at 3 and 4 weeks. The reduced number of inclusions may be attributable at least in part to cellular hypertrophy of mammotrophs which was especially prominent. Vacuolar inclusions predominated at 3 and 4 weeks and there were fewer membranous types than at previous times.     

Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.     

Exposure to Thiodan results in lipofuscin accumulation in hepatocytes of the freshwater catfish Tandanus tandanus

We investigated the effect of time after pulse exposure to 1.0 microg l(-1) endosulfan (applied as Thiodan) on endosulfan residues in the liver and ultrastructural changes in the hepatocytes of the freshwater catfish Tandanus tandanus. Time after exposure did not affect the mean residue level in the liver. After exposure to endosulfan, residues in the liver were 227.47 microg kg(-1) after 1 d and 282.83 microg kg(-1) after 28 d; residues in the bile were 313.97 microg kg(-1) after 1 d and 334.53 microg kg(-1) after 28 d. At the end of 28 d exposure, lipofuscin was present in up to 69% of hepatocytes of fish containing residues of endosulfan, but absent from control fish. There was a statistically significant increase in the percentage of pyknotic nuclei and altered rough endoplasmic reticulum 28 d after exposure. The mean percentage of cells with altered endoplasmic reticulum ranged from 12.93% (Day 1) to 7.50% (Day 28) for control fish, while for exposed fish it increased from 14.30% (Day 1) to 35.00% (Day 28). The mean percentage of cells with pyknotic nuclei increased from 1.1 to 2.1% in control fish and from 3.8 to 9.6% in exposed fish. Other ultrastructural changes included increased ultrastructural heterogeneity, progressive vacuolation and fractionation of rough endoplasmic reticulum, accumulation of lysosomes and residual bodies, intranuclear inclusions and pseudoinclusions, membrane whorls and myelinated bodies. Protracted senescence was one of the main features of endosulfan toxicity to T. tandanus hepatocytes.     

Cytopathological effects of estradiol on the arcuate nucleus of the female rat. A possible mechanism for pituitary tumorigenesis.

Large subcutaneous doses (2 mg/21 days) of estradiol valerate (EV) given over several months will induce a prolactin and growth hormone-secreting pituitary tumor in female rats. The medial basal hypothalami (MBHs) of such EV-treated animals were examined at different time intervals with light and electron microscopes to determine whether EV affects the MBH and to relate any observed effects to the process of tumorigenesis. The MBHs of extensively treated rats exhibited profound glial and neuronal changes. The filament content of astrocytes was greatly increased and large dense pleomorphic inclusions filled both astrocytic perikarya and processes. Degenerating neuronal elements have been observed in the neuropil of extensively treated animals. Dark cells identified as M cells were seen to engage in phagocytosis and were loaded with dense inclusions. Some neurons in MBH contained large quantities of lipofuscin that was different in appearance from that of normal females of the same age. The glial reaction developed gradually. At earlier stages of EV treatment there were fewer reactive glia and these contained fewer inclusions. Myelin figures often occurred in these early inclusions. Reactive glia in EV-treated rats did not appear in the preoptic area, dorsomedial nucleus or lateral hypothalamus but were found in ventromedial nucleus. Retired breeders and starvation-stressed rats resembled normal controls. These pathological changes in MBH may result from a direct effect of EV on the hypothalamus. It is possible that, in addition to its effects on the hypophysis, EV suppresses or injures hypophysiotropic cells in MBH, thus releasing pituitary chromophobes from inhibitory hypothalamic influences. This could result in hypersecretion and neoplasia.     

Plasmodium falciparum: studies on mature exoerythrocytic forms in the liver of the chimpanzee, Pan troglodytes

Mature exoerythrocytic forms (EEF) of Plasmodium falciparum from the chimpanzee were examined by light- and transmission electron microscopy from a liver biopsy taken on Day 6 after sporozoite inoculation. Infectivity of the sporozoites obtained from whole mosquitoes which were membrane fed on cultured gametocytes was about 4-6%. In comparison, salivary gland sporozoites added to human hepatocytes in vitro had only a developmental percentage of 0.02 to 0.05% at Day 5. The EEF found in the liver biopsy were not all at the same stage of development. Immature compact parasites were seen simultaneously with stages with fully formed merozoites, indicating a rapid final maturation or asynchrony. At Day 7.5, large numbers of rings were already seen in the peripheral blood, indicating a duration of the liver development of P. falciparum in the chimpanzee of about 5.5-6 days. The process of merogony at the fine structural level was comparable to that described for rodent and other primate parasites in vivo. Compared to the fine structure of EEF in vitro in cultured human hepatocytes, the parasites described here were much more advanced in development. There appeared to be some cell infiltration with collagen deposition around the intracellular parasite; however, no marked degeneration of EEF was observed.     

An outbreak of adenovirus type 7 infection in children in Montreal

Thirteen infants and children with adenovirus type 7 infection proved by virus isolation are described. High fever, cough and dyspnea were the most frequent findings; in infants under 1 year of age wheezing was common. Four patients required artificial ventilation. Lobar collapse, consolidation and hyperinflation were frequent radiologic findings. None of the symptoms responded to antibiotic therapy or bronchodilator drugs. Three patients died (mortality rate of 23%). Pathologic findings were compatible with adenovirus type 7 pneumonia, and were characterized by a necrotizing bronchitis and bronchiolitis, patchy alveolar fibrinopurulent exudate and hyaline membrane formation. Some intra-alveolar epithelial cells showed strikingly abnormal nuclei and rare typical halo-outlined intranuclear inclusions were seen. Only one of eight survivors had evidence of significant chronic chest disease.     

EFFECTS OF SELENIUM DEFICIENCY ON THE MORPHOLOGY AND ULTRASTRUCTURE OF THE COASTAL MARINE DIATOM THALASSIOSIRA PSEUDONANA (BACILLARIOPHYCEAE)1,2

The effects of selenium deficiency on the siliceous and nonsiliceous components of the planktonic marine diatom Thalassiosira pseudonana (Hust.) Hasle and Heimdal (clone 3H) are examined using light and electron microscopy. Selenium deficiency induces elongation along the pervalvar axis initially as a result of chain formation caused by the failure of sibling cells to separate and subsequently by cell elongation via the production of hyaline girdle bands. In Se-deficient cultures cell elongation involves the blockage of both mitotic and cytokinetic components of cell division. Selenium deficiency results in ultrastructural alterations in the reticular membrane system and in mitochondrial and chloroplast membranes. Various types of inclusions are seen in vacuolar areas and the accumulation of lipid reserves is evident in Se-deficient cells. These results provide indirect evidence for a metabolic Se requirement in this algal species.     

From Mallory to Mallory-Denk bodies: what, how and why?

Frank B. Mallory described cytoplasmic hyaline inclusions in hepatocytes of patients with alcoholic hepatitis in 1911. These inclusions became known as Mallory bodies (MBs) and have since been associated with a variety of other liver diseases including non-alcoholic fatty liver disease. Helmut Denk and colleagues described the first animal model of MBs in 1975 that involves feeding mice griseofulvin. Since then, mouse models have been instrumental in helping understand the pathogenesis of MBs. Given the tremendous contributions made by Denk to the field, we propose renaming MBs as Mallory-Denk bodies (MDBs). The major constituents of MDBs include keratins 8 and 18 (K8/18), ubiquitin, and p62. The relevant proteins and cellular processes that contribute to MDB formation and accumulation include the type of chronic stress, the extent of stress-induced protein misfolding and consequent proteasome overload, a K8-greater-than-K18 ratio, transamidation of K8 and other proteins, presence of p62 and autophagy. Although it remains unclear whether MDBs serve a bystander, protective or injury promoting function, they do serve an important role as histological and potential progression markers in several liver diseases.     

Qualitative and quantitative models relating otolith zone deposition to growth and condition in sexually mature male and female capelin (Mallotus villosus)

Summary Correspondence analysis (CA) is used to examine the relationship between months, between selected body components/organs and between months and components/organs for male and female capelin from 12 to 37 months of age in Balsfijorden, northern Norway (69°21N:19°06E). The CA profiles have been used to quantify condition with regard to age and season. The major features determining the condition of fish depositing hyaline or opaque otolith zones are itemized using CA, and the data modelled by Multiple Regression (MR) using a cosine curve incorporating the chief mass variables with linear age-dependency. The highest proportion of fish having outer opaque zones are found from ca. June to October, whilst the highest proportion with exterior hyaline zones are found from ca. December to May. There is a clear annual cycle in the deposition of opaque and hyaline otolith zones in both sexes, but there is a significant difference in phase of ca. 12 days between the sexes. There is a significant trend for decreasing proportions of fish having outermost opaque otolith zones with increasing age; this trend is similar in both sexes. The mean level and amplitude of the cycles are similar in both sexes. On the other hand, CA shows a 12-month cycle of storage and utilization of body materials with obvious differences between sexes. In the female protein in the fillet plays a more dominant role than lipid in the fillet in accounting for anabolic and catabolic variations in mass, whereas in the male the opposite is true. Sexual maturation is negatively correlated with fillet (somatic) growth. Variations in stomach weight (with contents) and otolith zone deposition are not significantly correlated. Nevertheless, in both sexes there is a clear positive correlation between stomach weight and liver protein and lipid implying an association between stomach weight and feeding activity. In females, however, maximum liver condition is more positively correlated with exponential ovarian growth, probably through mobilization of lipoproteins for eggs. Qualitative (CA) and quantitative (MR) models have related changes in growth and condition to the type of otolith zone deposited. The fillet of capelin is the major somatic growth site. As CA indicates a negative correlation between fillet reserves and gonad maturation, and the best MR models describing the cycle of otolith zone deposition in males and females (accounting for 93% and 70% respectively of the variation) underlined and quantified the interplay between somatic and gonad growth, it is implicit that the energy balance of the fish will be an important determinant of otolith zone deposition in sexually maturing and mature capelin.     

Coxiella burnetii infection in C.B-17 scid-bg mice xenotransplanted with fetal bovine tissue

Two from a group of approximately 50 C.B-17 scid-bg mice were examined because of lethargy, dehydration, and rough coat. Three months prior to development of clinical signs of disease, mice of this study had been surgically implanted with fetal bovine liver, thymus, and lymph node. At necropsy, marked splenomegaly and mild hepatomegaly were observed in both animals. Large areas of necrosis and inflammation, with associated intracytoplasmic granular basophilic inclusions, were observed in histologic sections of multiple organs. Aerobic and anaerobic culturing of the liver yielded negative results. Six months after the initial case, four more reconstituted scid-bg mice from a different fetal donor had identical clinical, gross, and histologic signs of disease. To determine whether the basophilic inclusions represented an infective agent, 4-month-old immune-naive C.B-17 scid-bg mice were inoculated intraperitoneally with a liver and spleen homogenate from an affected mouse. Two weeks after inoculation, mice developed clinical signs of disease and lesions identical to those seen in the signal mice. On ultrastructural examination of the liver, pleomorphic bacteria were found in large cytoplasmic vacuoles of hepatocytes. Bacterial DNA was amplified from the liver, using primers that amplify a segment of the 16S rRNA gene from many bacterial species. Sequencing of the polymerase chain reaction (PCR) product revealed gene sequence identical to that of Coxiella burnetii, the agent of Q-fever. These results highlight the need to consider infective agents of the donor species when working with xenografted animals.     

EFFECTS OF SELENIUM DEFICIENCY ON THE MORPHOLOGY AND ULTRASTRUCTURE OF THE COASTAL MARINE DIATOM THALASSIOSIRA PSEUDONANA (BACILLARIOPHYCEAE)1,2

The effects of selenium deficiency on the siliceous and nonsiliceous components of the planktonic marine diatom Thalassiosira pseudonana (Hust.) Hasle and Heimdal (clone 3H) are examined using light and electron microscopy. Selenium deficiency induces elongation along the pervalvar axis initially as a result of chain formation caused by the failure of sibling cells to separate and subsequently by cell elongation via the production of hyaline girdle bands. In Se-deficient cultures cell elongation involves the blockage of both mitotic and cytokinetic components of cell division. Selenium deficiency results in ultra-structural alterations in the reticular membrane system and in mitochondrial and chloroplast membranes. Various types of inclusions are seen in vacuolar areas and the accumulation of lipid reserves is evident in Se-deficient cells. These results provide indirect evidence for a metabolic Se requirement in this algal species.     

Ozone ameliorates age-related oxidative stress changes in rat liver and kidney: Effects of pre- and post-ageing administration

The ageing process is known to be accompanied by increased oxidative stress and compromised antioxidant defenses. Controlled ozone administration has been shown to be effective in various pathophysiological conditions with an underlying oxidative burden. However, its effect on the biochemical alterations associated with the ageing process has been rarely studied. Therefore, the present work was carried out to study the role of ozone in counteracting the state of oxidative stress associated with ageing in rat liver and kidneys using two experimental models. In the pre-ageing model, ozone was administered prior to the onset of ageing at adulthood and continued after the start of the ageing process (3-month-old rats until the age of 15 months). While in the post-ageing model, ozone was administered after ageing has begun and lasted for one month (14-month-old rats until the age of 15 months). The pre-ageing ozone administration effectively reduced lipid and protein oxidation markers, namely, malondialdehyde and protein carbonyl levels and decreased lipofuscin pigment deposition in rat liver and kidneys. Moreover, it significantly restored hepatic and renal reduced glutathione (GSH) contents and normalized cytosolic hepatic glutathione peroxidase activity. Similar but less pronounced effects were observed in the post-ageing ozone-treated group. Nevertheless, in the latter model ozone administration failed to significantly affect liver and kidney lipofuscin levels, as well as kidney GSH contents. These data provide evidences for potentially positive effects of pre-ageing ozone therapy in neutralizing chronic oxidative stress associated with ageing in rat liver and kidneys.     

High-voltage electron microscopy of human diploid fibroblasts during ageing in vitro. Morphometric analysis of mitochondria

Since recent studies have suggested a diminished mitochondrial functional capacity in late-passage ('old') compared to early-passage ('young') normal fibroblasts and fibroblasts from the Hutchinson-Gilford (progeria) syndrome of premature ageing, we analysed whole-cell preparations on the high voltage electron microscope to look for mitochondrial and related defects. All strains examined showed considerable heterogeneity in cell size and intracellular morphology. Mitochondria were readily seen in all cells, predominantly as long slender rods with frequent branching, but occasional circular and saccular forms were also evident. Various parameters of mitochondrial mass including mean number, weight, and total length of mitochondria per cell weight tended to increase in old and progeria cells, but only the former attained statistical significance due to the heterogeneity and consequent variance. A significant finding was the decreased width of mitochondria in old and progeria cells. Cystic blebs were evident in mitochondria of some cells with an apparent increase in old and progeria fibroblasts. These blebs appeared to be due to weakening of the inner membrane, allowing dilatation of the outer membrane which otherwise appeared intact. The number of osmiophilic inclusions per cell weight, particularly lipofuscin granules and autophagic vacuoles, was significantly increased in old and progeria cells. In conclusion, despite some morphological changes, mitochondria of old and progeria cells maintain a structurally and bioenergetically adequate mass compatible with continued cellular viability.     

Recent advances in research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations: neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Of all patients with ALS, approximately 5%-10% of them are familial and most of the others are sporadic. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. FALS is neuropathologically classified into two subtypes: classical FALS in which degeneration is restricted to only motor neurons and FALS which is characterized by the degeneration of the posterior column in addition to the lesion of the motor neuron system. The neuronal Lewy body-like hyaline inclusion (LBHI) is a characteristic neuropathological marker of mutant SOD1-linked FALS with posterior column involvement. Inclusions similar to the neuronal LBHIs have been discovered in astrocytes in certain patients with FALS exhibiting SOD1 gene mutations. The purpose of this review is to discuss the novel neuropathological significance of the astrocytic hyaline inclusions (Ast-HIs) and neuronal LBHIs in brain tissues from individuals with the posterior-column-involvement-type FALS with SOD1 gene mutations. In hematoxylin and eosin preparations, both Ast-HIs and neuronal LBHIs are eosinophilic inclusions and sometimes show eosinophilic cores with paler peripheral halos. Immunohistochemically, both inclusions are intensely positive for SOD1. At the ultrastructural level, both inclusions consist of approximately 15-25 nm-sized granule-coated fibrils and granular materials. Immunoelectron microscopically, these abnormal granule-coated fibrils and granular materials are positive for SOD1. Therefore, the FALS disease process originating from SOD1 gene mutations occurs in astrocytes as well as neurons and is involved in the formation of both inclusions.