Alzheimer disease: curly fibers and tangles in organs other than brain.

The filamentous brain lesions that define Alzheimer disease (AD) consist of senile plaques and neurofibrillary tangles. Undulated pathological filaments--curly fibers or neuropil threads--also occur in the neuropil. Beta-amyloid precursor proteins are synthesized by many cells outside the central nervous system and recently, deposition of beta-amyloid-protein was reported to occur in non-neuronal tissues. In addition, increasing data claim the importance of chronic inflammation in the pathogenesis of AD. These observations suggest that AD may be a widespread systemic disorder. Here we report that pathological argyrophilic filaments with histochemical properties of amyloid showing striking morphological similarity to curly fibers and/or tangles accumulate not only in ependymal layer and in epithelial cells of choroid plexus, but also in several other organs (e.g. liver, pancreas, ovary, testis, thyroid) in AD. The ependyma, choroid plexus, and various organs of 39 autopsy cases were analyzed. In search of curly fiber and tangle-like changes in organs other than brain, 395 blocks from 21 different tissues of 24 AD cases, 5 cases with discrete or moderate AD-type changes, and 10 control cases were investigated. We found in non-neuronal cells "curly fibers" or "tangles" immunoreactive with antibodies to P component, Tau-protein, ubiquitin, fibronectin, and Apolipoprotein-E, but lacking immunoreactivity with antibodies to neurofilament proteins. Ultrastructurally they consist of densely packed straight and paired helical filaments and closely resemble neurofibrillary tangles and neuropil threads. These observations indicate that the formation of "curly fibers" and "tangles" is not unique to the central nervous system. The results suggest that AD might be a systemic disorder or that similar fibrillary changes to tangles and curly fibers may also be associated with other amyloidosis than beta-amyloidosis. Further investigations are necessary to understand the pathogenetic interest of these fibrillary changes outside the CNS.

[Ovarian carcinoid tumors: immunohistochemical and ultrastructural study of 8 cases]. / Carcinoïdes ovariens: étude immunohistochimique et ultrastructurale de 8 cas.

Eight ovarian carcinoids, 4 trabecular and 4 strumal have been studied immunohistochemically for polypeptide hormones; three of them were also examined with the electron microscope. Seven of eight cases were positive for at least one polypeptide hormone. The trabecular parts of the 4 cases of strumal carcinoid were positive for pancreatic polypeptide. As the vesicular regions of these 4 cases were positive for thyroglobulin and for pancreatic polypeptide, we suspect the existence of "hybrid" thyroid and neuroendocrine cells. The electron microscopic examination revealed: the cell in the insular carcinoid had no distinct polarization and contained electron-dense granules of varying shape; in the trabecular part of the strumal carcinoid the cells were polarized and contained round electron-dense granules.

[Disseminated lupus erythematosus without antinuclear antibodies or other autoantibodies]. / Lupus érythémateux disséminé sans anticorps antinucléaires et sans autres autoanticorps.

Antinuclear antibodies (ANA) are found in the majority of patients with systemic lupus erythematosus (SLE). We report here the only documented case, out of a series of 38 patients, in which SLE was diagnosed in spite of the fact that we failed to demonstrate any type of autoantibodies. A 25-year-old black woman presented with 6 of the 11 criteria of the American Rheumatism Association for classification of SLE, between August 1984 and April 1985, i.e. malar rash, photosensitivity, arthritis, pleurisy and pericarditis, renal insufficiency and nephrotic syndrome, anemia and leukopenia. Renal biopsy revealed mesangial glomerulonephritis, tubulonephritis and many tubuloreticular inclusions in the capillary endothelium highly suggestive of SLE. Four ANA determinations were performed during the 8 months of observation which were all negative, as were all other antibodies (anti-nDNA, -Sm, -RPN, -Ro, -La). The outcome was very favourable under prednisone and cyclophosphamide. In the rare cases of ANA negative SLE (5-10%) photosensitive dermatitis is the prominent feature and renal or central nervous system involvement is less frequent. Those patients usually have other types of autoantibodies (especially anticytoplasmic) which was not the case in our patient. This indicates that the absence of autoantibodies does not rule out SLE.

Dietary factors and medullary sponge kidneys as causes of the so-called idiopathic renal leak of calcium.

Out of 89 stone formers with idiopathic hypercalciuria, 51 remained hypercalciuric on a low calcium diet over 5 days: a renal leak of calcium could thus have been suspected in them. Dietary factors such as high sodium or high animal protein intake, and metabolic factors such as obesity with or without hyperinsulinemia, which all might account for the hypercalciuria of these patients, have been evaluated. This evaluation revealed conditions known to be associated with hypercalciuria in 37 of these 51 patients: 15 had hypercalciuria related to a high sodium intake, 7 had severe hyperuricosuria (greater than 1 g/24 h) reflecting a high animal protein intake, 20 were obese (greater than 120% of ideal weight) with (7 cases) or without (13 cases) concomitant high fasting plasma level of insulin (greater than 18 microU/ml). A careful retrospective analysis of the intravenous pyelograms disclosed medullary sponge kidneys in 8 cases which had remained undiagnosed so far. One of them was studied histologically. Only 14 out of 51 patients had an otherwise unexplained hypercalciuria on a low calcium diet. It is concluded that dietary causes appear to play a key role in 'idiopathic' hypercalciuria, that the incidence of a primary renal leak of calcium among idiopathic stone formers is much smaller than initially thought, and that this condition can hide unrecognized medullary sponge kidneys.

Idiopathic acute interstitial nephritis and uveitis in the adult. Report of 1 case and review of the literature.

In a 59-year-old female, concurrence of acute interstitial nephritis and uveitis was observed. While the clinical signs resolved after a few weeks, signs of renal tubular dysfunction persisted for 9 months, and creatinine clearance was still impaired (22 ml/min) more than 2 years after beginning of the symptoms. This is the 5th case of idiopathic interstitial nephritis with concomitant uveitis reported in adult patients. In contrast to the benign evolution observed in children, the renal function may remain impaired in adults.

[The place of kidney biopsies in the diagnosis of isolated hematuria]. / Place de la biopsie rénale dans le diagnostic des hématuries isolées.

Twenty-six patients with idiopathic hematuria, i.e. with normal intravenous pyelography, without arterial hypertension, renal failure or significant proteinuria, underwent renal biopsy in our institution between 1973 and 1981. Segmental proliferative endocapillary glomerulonephritis was diagnosed in 13 cases; in the other 13 patients the renal tissue was either normal (6) or presented only minor lesions of the mesangium (5) or interstitial tissue (2). Twenty-two patients underwent a follow-up examination after a mean of 51 months (range 12-120). The hematuria had disappeared in half of them and no patients had developed hypertension or renal failure. These results suggest that in cases of idiopathic hematuria renal biopsy is not indicated for prognostic or therapeutic reasons, though in some cases it may avoid repeated and potentially dangerous investigations.

Microvasculature of human colorectal epithelial tumors. An electron microscopic study.

The ultrastructure of the microvasculature in human colorectal adenomas and carcinomas was studied, and compared with that of normal tissue. Blood vessels in adenomas were generally of normal structure, whereas carcinoma vessels displayed a variety of structural alterations. Endothelial proliferation was frequently observed in all the eleven carcinomas examined, which confirms the reports of new vessel formation in experimental malignant tumors. The presence of fenestrations in obviously abnormal endothelium was tentatively attributed to hypoxia, vascular regression or immaturity of the cells, in spite of the fact that normal capillaries in colonic mucosa are fenestrated. Some vessels showed multilayered basement membranes, various types of activated cells containing numerous lysosomal granules, and thickened perivascular tissue. These features may be a vascular response to repeated damage or a manifestation of vascular remodelling. Dilated thin-walled vessels, which were usually found at the periphery of carcinomas, were identified as venules. Small vessels located between the closely apposed carcinoma tubules were not obviously abnormal. They were nevertheless considered to be tumor-induced vessels which had undergone differentiation. The differences in vascular morphology between adenomas and carcinomas were considered to be due to their different growth patterns, growth rates and degrees of maturity.

[Is functional demand a condition without which the pancreatic auto transplant can not survive in the dog's spleen?]. / La demande fonctionnelle est-elle une condition sine qua non à la survie de tissus pancréatiques autotransplantés dans la rate chez le chien?

Two groups of mongrel dogs underwent intrasplenic autotransplantation of pancreatic tissues prepared from the head and tail of the organ. In the first group (12), the operation was terminated by the removal of the rest of the gland. In the second group (8), total pancreatectomy was done 6-8 months after autotransplantation. The first group of dogs became spontaneously normoglycemic after ten days of moderate hyperglycemia; their insulinemia increased significantly during a glucose loading test. The second group of dogs never became normoglycemic but remained vivacious; insulin level in their splenic vein increased moderately only after glucose injection. Microscopically, exo- and endocrine pancreatic tissues were seen in the spleens of the first group of dogs; in the spleens of the second group of dogs, only a few degenerating B cells were observed. These results suggest that the temporary hyperglycemia following autotransplantation of pancreatic tissues is a functional demand: it is necessary for ultimate survival and function of transplanted B cells.

Pancreatic transplantation. Absence of diabetes in dogs after total pancreatectomy and intrasplenic autotransplantation of pancreatic tissue.

Two simple, rapid, and reproducible techniques of pancreatic tissue preparation produced favorable results after just part of the gland was autotransplanted in totally pancreatectomized animals. It is probable that the short and less traumatic treatment in vitro was responsible for the sufficient yield of viable islets. Moreover, the results show convincingly that the complete separation of endocrine from exocrine pancreas is not mandatory to insure adequate endocrine secretion. The spleen, an organ of no vital importance having a rich blood supply and belonging to the portal circulation, was a very suitable experimental implantation site, which permitted thorough evaluation of the tissue preparation techniques. These favorable results were not conditioned by the splenic tissue itself, because similar results have been obtained in dogs when the tissues were implanted into the liver via the portal vein.

Intrasplenic autotransplantation of canine pancreatic tissues. Maintenance of normoglycaemia after total pancreatectomy.

In mongrel dogs, the horizontal part of the pancreas was infiltrated with collagenase, cut in pieces, incubated with collagenase, rinsed twice by centrifugation or sedimentation, and implanted into the spleen of the same animal. The operations were terminated by the removal of the rest of the pancreas. Of 26 operated dogs, one died because of a duodenal perforation, five developed severe hyperglycaemia without remission, and 20 were long-term normoglycaemic survivors followed for up to 10 weeks. These 20 animals became spontaneously normoglycaemic in the course of the first 10 postoperative days. Later, during glucose loading tests, the pattern of blood sugar values was the same in the transplanted animals as in those of a group of non-operated dogs, but the insulin release, although immediate, attained half the control values. The plasma insulin in the splenic vein was more than seven times higher than in the peripheral circulation. Splenectomies performed in seven animals were followed by severe hyperglycaemia and death. Light and electron microscopy demonstrated the presence of the intact endocrine and exocrine pancreatic tissues in the spleens of all animals investigated. It is concluded that laborious separations of endocrine from exocrine tissue are not mandatory for ulterior endocrine function, and that in an animal larger than rodents it is possible to obtain a diabetes-preventing function after the transplantation of only a part of the gland.