Does subclinical rejection contribute to chronic rejection in renal transplant patients?

Renal allograft biopsies have traditionally been performed in the setting of acute graft dysfunction. However, several groups have performed graft biopsies at times of stable graft function, and more recently, after treatment of rejection episodes. Surprisingly, unequivocal histologic criteria for acute rejection have been demonstrated in a high proportion of these protocol biopsies. The Winnipeg Transplant Group has documented the high prevalence of clinically silent inflammatory infiltrates in early protocol biopsies, and demonstrated their inflammatory and cytotoxic potential by immunohistochemical and molecular biological techniques. Furthermore, in a randomized trial, our group has demonstrated that subclinical rejection, if untreated, is associated with the development of early chronic pathology and late graft dysfunction. In this overview, we will summarize the early data on subclinical allograft inflammation, present the experience of the Winnipeg Transplant Group, and discuss the possible implications of subclinical rejection on the development of chronic rejection.

Mucosal calcified nodule of the hard palate in an infant: case report and review of the literature.

Pathological calcifications of skin manifest as small or large deposits of calcium in the dermis and subcutaneous tissues. One form of these conditions is described as subepidermal calcified nodule seen on the facial skin of young children without any underlying connective tissue disease or any abnormality in calcium or phosphorus metabolism. The oral cavity is rarely affected. Recently, two cases were reported in the oral mucosa and the term "mucosal calcified nodule" was coined for such an entity. We report another case of such a process involving the oral mucosa of a 5-month-old infant who presented with an enlarging lesion at the junction of the hard and soft palate.

[Ultrastructural changes in the gastric mucosa in chronic gastritis in children]. / Modificari ultrastructurale ale mucoasei gastrice în gastrita cronica a copilului.

Studying a series of 30 children with chronic gastritis (diagnosed by optic fiber gastroscopy and by mucosal biopsy), authors have founded important changes of the superficial mucosa and gastric glands. The histologic changes could explain the well-known functional alterations in chronic gastritis. They discussed also a possible immuno-pathogenic mechanism for these mucosal ultrastructural changes.

Do nematosomes play a role in the formation of paired helical filaments (PHF) in dorsal root ganglia (DRG) of rats?

The lack of a suitable animal model for Alzheimer research continues to be an impediment to the elucidation of the pathogenesis of the histological features of this condition, including PHF. Chronic ethanol intoxication induces the formation of PHF in young rats. Abnormalities in number and subcellular distribution of nematosomes in DRG of rats subject to chronic ethanol feeding has been noted by us. We present evidence that a vitamin A deficient diet promotes the formation of PHF and nematosomes in DRG of rats chronically intoxicated with ethanol. Three groups of young male Wistar BR rats were implanted with a gastrostomy cannula and infused with the following liquid diet: first group received 30% of total calories as corn oil, 32% ethanol, 25% protein with the balance as dextrose; 5% lard was substituted for the corn oil in the second group; the third group received 25% corn oil and was maintained in a vitamin A deficient state. Control animals were pair-fed the diet and isocaloric in dextrose with the experimental animals' alcohol intake. Animals were sacrificed at approximately 150 days and DRG were fixed in situ with a solution containing 2% paraformaldehyde and 2% glutaraldehyde. The increased number of nematosomes in all ethanol treated rats was prominent and more so in animals with a vitamin A deficient diet. A large amount of lipofuscin was usually associated with these thread-like structures which were of several types. Nematosomes commonly enclosed neurofibrillary tangles of PHF in animals treated with the ethanol-vitamin A deficient diet. PHF were rarely observed in other animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of passive transfer of human anti-myelin-associated glycoprotein IgM in marmoset.

Adult and one week old marmosets were injected intravenously within a one month period or intraperitoneally within a 6 week period respectively, with monoclonal IgM having an anti-myelin associated glycoprotein antibody activity. No clinical or electrophysiological abnormalities could be detected in experimental animals. However, indirect immunofluorescence studies showed IgM deposition in close contact to myelin sheaths. Minor but distinct alterations of nerves were found in the adult: the enlargement of Schmidt-Lanterman incisures seen in electron microscopy could explain the decrease of the proportion of fibers of small diameter found by morphometry of semi-thin section, and the reduction of the mean internodal length in fibers of a given diameter seen in teased nerve fibers studies.

Immaturity of muscle fibers in the congenital form of myotonic dystrophy: its consequences and its origin.

Skeletal muscle maturation is impaired in children with congenital myotonic dystrophy. This immaturity is characterized at the light microscopy level by an abnormal presence of myotubes, small fascicles of muscle fibers, thin myofibers, and delayed muscle fiber type differentiation with a peripheral halo lacking mitochondrial oxidative enzyme activity. At an ultrastructural level, the characteristics are a paucity of myofibrils with a peripheral rim devoid of mitochondria and myofibrils in the fibers. In time the muscle is able to gain a certain degree of maturity as shown in one of our cases who had two successive muscle biopsies. The muscle, however, never becomes normal but retains discrepancies in fiber size and fiber type distribution and shows some fiber necrosis. Maturation of the motoneurons is normal, which may explain necrosis of immature muscle fibers. In an experimental study carried out to look for evidence of a circulatory factor in mothers of children with congenital myotonic dystrophy, it was found that sera from these mothers administered intra-peritoneally to newborn rats does in fact impair muscle maturation, whereas rats injected similarly with sera from control women showed normal muscle maturation.

Alteration of neuronal cytoskeletal organization in dorsal root ganglia associated with pyridoxine neurotoxicity.

The pathogenesis of the sensory neurotoxicity arising from high doses of pyridoxine is obscure. Beagle dogs were fed 200 mg pyridoxine/kg per day and killed at 4, 10, 14 and 16 days. Dorsal root ganglia (DRG) and their processes were processed for electron microscopy and teased-fiber preparation following perfusion of anesthetized animals with heparinized saline and a fixative solution of 3% paraformaldehyde, 1% glutaraldehyde. Four days after initiation of treatment a striking accumulation of neurofilament (NF) in proximal unmyelinated axons of the DRG was observed. Domains of altered NF cytoskeleton consisting of well-demarcated zones of higher packing density and anomalous orientation were observed, mainly in the myelinated part of the DRG segment. In addition, aggregates of microtubules (MT) were noted. In the cyton the Golgi complexes were abundant and the Nissl bodies together with the NF appeared increased in numbers. At 10 days NF and MT aggregations were readily apparent in both perikarya and proximal cell processes. This phenomena was diminished in the 14- and 16-day-treated animals and retrogressive histological features appeared in the soma and in axons. Degeneration of NF with subsequent reduction in size of the axonal swellings and axonal breakdown with phagocytosis were prominent in central and peripheral processes of DRG. Cytons distended by NF were less prominent. Necrotizing changes, evidenced by disruption of the soma with the proliferation of satellite cells, were present. These results indicate that an early morphological correlate of pyridoxine neurotoxicity is the accumulation of NF with MT-NF dissociation in the unipolar process of the DRG in the absence of extensive vacuolization, and that the observed cytoskeletal disruption may be related to an increased rate of NF protein synthesis together with mechanical obstruction of transport phenomena.

[A case of acute sensory and autonomic neuropathy with regression]. / Un cas de neuropathie aiguë sensitive et végétative sévère régressive.

The authors report the case of a 24 year old man with no previous disease who presented with a severe autonomic neuropathy. This included major gastrointestinal dysfunction characterised by decreased peristalsis without distension and paralysis of the gall bladder, and orthostatic hypotension with a normal cardiac tachycardia reflex. There was an associated sensory neuropathy affecting heat sensitivity without motor dysfunction and an increased CSF protein content. The proprioceptive nerve fibre conduction was decreased but another nerve conduction was normal initially. The mesenteric plexuses examined during sigmoidectomy performed for peritonitis due to multiple bowel perforations caused by fecoliths, showed no significant changes. Peripheral nerve biopsy revealed massive rarefaction of myelinated fibres which were of small diameter, and of the unmyelinated fibres, mainly due to axonal degeneration. Only two similar cases with incomplete recovery were found in the literature. In our case, a complete recovery was observed. The cause of the condition is unknown.

Schwann cell marker defined by a monoclonal antibody (224-58) with species cross-reactivity. I. Cellular localization.

We have demonstrated by indirect immunofluorescence the cellular localization of a monoclonal antibody (mAb 224-58), produced after immunization of a mouse with human central nervous system (CNS) myelin. Serologically, mAb 224-58 was found to be specific for 3'-sulfomonogalactosylglycolipids, namely 3'-sulfogalactosylceramide (SGC) and 3'-sulfogalactosyl 1-O-alkyl ether 2-O-acylglycerol (seminolipid). This mAb did not bind to SGC-containing tissues such as kidney, liver, spleen, or brain, nor to muscle. However mAb 224-58 did stain positively mouse, rat, and human peripheral nerve sections. In these latter sections, mAb 224-58 was bound to Schwann cell bodies and processes. The specificity of mAb 224-58 for Schwann cells was ascertained on teased rat sciatic nerves and rat Schwann cell cultures. Cells positive for mAb 224-58 were also positive for laminin, and negative for Thy 1-1 antigens both in teased fibers and Schwann cell cultures. In addition, in teased nerve preparations, mAb 224-58-positive cells were also galactosylceramide (GalC)- and SGC-positive. Isolated Schwann cells also expressed 224-58 antigen, even after prolonged time in culture. On testis sections, which contain both SGC and seminolipid, the SGC-positive cells, i.e., the spermatogonia, were always 224-58-negative. But the other germinal cells were 224-58-positive. This suggests that although 224-58 does not discriminate between SGC and seminolipid in serological tests, these lipids in their naturally occurring membrane acquire a spatial configuration that renders them distinguishable to their respective antibody.

[Chloroquine neuromyopathies: 4 cases during antimalarial prevention]. / Neuromyopathies à la chloroquine: 4 cas au cours d'une prophylaxie anti-paludéenne.

Four cases of chloroquine neuropathy presented two points of particular interest: 1) these were all young women with strictly prophylactic doses of chloroquine (100 mg/24 h); two patients showed pronounced loss of weight; 2) signs of myogenic lesions were apparent in only one patient whereas clinical and electric signs of neurogenic involvement were observed in all 4 cases. Biopsy in 3 patients (muscle in one and muscle and nerve in two) failed to show characteristic vacuoles; in one case mild segmental demyelinization was present. A favorable course was obtained in all cases after discontinuation of chloroquine, with dramatic recovery from the motor deficit. Pharmacokinetic studies in 1 patient showed abnormally high chloroquine levels at initial assay with slow elimination after its discontinuation.

The cerebro-hepato-renal (Zellweger) syndrome: lamellar lipid profiles in adrenocortical, hepatic mesenchymal, astrocyte cells and increased levels of very long chain fatty acids and phytanic acid in the plasma.

Clinical, radiological, histological and biochemical aspects of two cases of cerebro-hepato-renal syndrome (CHRS) are reported. CT scan disclosed a demyelinating process and gyral abnormalities reflecting the observed neuropathological findings. Trilamellar and lamellar inclusions were found in brain astrocytes, hepatic mesenchymal and adrenal cells. The morphologic features of these inclusions are similar to those observed in childhood adrenoleukodystrophy, neonatal adrenoleukodystrophy and infantile Refsum's disease. In the two CHRS patients, increased plasma levels of very long chain fatty acids (C26:1, C26:0) and phytanic acid were in the same range as those observed in seven other instances of neonatal adrenoleukodystrophy. The presence of increased plasma levels of phytanic acid in these disorders suggests that phytanate oxidase activity is, at least, partially located in peroxisomes.

[Polyneuropathy during treatment with carbimazole]. / Polyneuropathie au cours d'un traitement par le carbimazole.

A patient developed polyneuropathy during carbimazole treatment for thyrotoxicosis. Electrophysiological data and a neuromuscular biopsy suggested a combined axonal and demyelinative lesion together with microvasculitis. Physiopathological hypotheses are discussed.

Drug induced hepatitis.

During the last decade an increased incidence of the adverse reactions to drugs with liver involvement was found. The liver lesions produced by drugs constituted a constant concern. We followed the course of liver disease produced by tuberculostatics, cytostatics, antidepressive, antibiotics, narcotics, antirheumatics, by biochemical, immunological and morphological investigations (needle biopsy of the liver with optical and electronic microscopy). The pattern of the damage to the liver ranges from minimal functional changes to severe aspects with cytolysis and cholestasis. Hypersensitivity to drugs (cutaneous eruption, rash, fever, eosinophilia) were observed only in three cases. The cholestatic clinical form was the most frequently encountered, raising problems of differential diagnosis with acute viral hepatitis and obstructive jaundice. Clinical evolution of drug induced hepatic lesions is favourable as soon as the administration of drug is arrested. Chronic evolution, as reported in the literature when the administration of hepatotoxic drug is continued, was noted only in one patient who was using Chlorpromazine.

Involvement of phosphate-modified ATP analogs in the reactions of oxidative phosphorylation.

Various analogs of adenosine 5'-triphosphate with a modified terminal phosphate group have been tested in energy-requiring reactions with intact mitochondria and submitochondrial particles. It is shown that the fluorophosphate analog ATP(gamma F) is a strong inhibitor of mitochondrial respiration and of energy requiring reactions which involve the participation of high energy intermediates, generated aerobically by the respiratory chain. On the other hand, ATP(gamma F) does not affect the ATPase activity of intact or disrupted mitochondria and is less effective in inhibiting ATP-driven reactions. The imidophosphate analog AMP-P(NH)P also inhibits the partial reactions of oxidative phosphorylation, but does not affect ATP synthesis from ADP and Pi. In contrast to ATP(gamma F), it is strong inhibitor of both soluble and membrane-bound mitochondrial ATPases. The biological implication of the complementary effects of ATP(gamma F) and AMP-P(NH)P on mitochondria-catalysed reactions is discussed while suggesting the use of such nucleotide analogs as specific tools for the study of ATP-forming and ATP-utilizing reactions in mitochondria.

Fractionation of human liver mitochondria: enzymic and morphological characterization of the inner and outer membranes as compared to rat liver mitochondria.

The fractionation of human liver mitochondria into inner membrane, outer membrane and matrix material is reported. Compared with rat, human liver mitochondria are more fragile. Fractionation can be achieved in only 2 steps, a digitonin treatment for removal of the outer membrane and centrifugation of the inner membrane plus matrix particles through a linear sucrose gradient resulting in purified inner membranes and matrix.