[Pediatric prediction models for evaluation of bone mass with DEXA].
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Absorptiometry, Photon↗
Biomedical subjects
M Alison
Publications and source records attributed to M Alison.
Permanent partial phenotypic correction and tolerance in a mouse model of hemophilia B by stem cell gene delivery of human factor IX.
Immune responses against an introduced transgenic protein are a potential risk in many gene replacement strategies to treat genetic disease. We have developed a gene delivery approach for hemophilia B based on lentiviral expression of human factor IX in purified hematopoietic stem cells. In both normal C57Bl/6J and hemophilic 129/Sv recipient mice, we observed the production of therapeutic levels of human factor IX, persisting for at least a year with tolerance to human factor IX antigen. Secondary and tertiary recipients also demonstrate long-term production of therapeutic levels of human factor IX and tolerance, even at very low levels of donor chimerism. Furthermore, in hemophilic mice, partial functional correction of treated mice and phenotypic rescue is achieved. These data show the potential of a stem cell approach to gene delivery to tolerize recipients to a secreted foreign transgenic protein and, with appropriate modification, may be of use in developing treatments for other genetic disorders.
Animals↗
Expression of beta-catenin in basal cell carcinoma.
Background beta-Catenin is a crucial member of the E-cadherin/catenin complex, which plays a major role in cell-cell adhesion. beta-Catenin is also known to be involved in signal transduction pathways. Many studies have demonstrated changes in the expression of beta-catenin in colorectal carcinomas, suggesting a role for beta-catenin in neoplastic development. Objectives Basal cell carcinoma (BCC) is a locally invasive tumour. The various subtypes show differences in biological behaviour. This study aimed to investigate the presence of differences in the immunoprofile of beta-catenin among histological variants of BCC. Methods Eighty BCCs were studied (32 nodular, 7 micronodular, 24 superficial and 17 infiltrative and morphoeic). Formalin-fixed, paraffin-embedded tissue sections were stained for beta-catenin using the avidin/biotin immunodetection technique. Results All the nodular BCCs showed membranous and weak cytoplasmic staining. Nuclear staining was seen in 15 of 32 (47%) cases, being stronger at the periphery of the nodules in 11 of 15 (73%) of these cases. In superficial BCCs the membranous staining was variable and cytoplasmic staining was increased. Nuclear staining was seen in 16 of 24 (67%) cases, being more notable at the periphery in 8 of 16 (50%) of these cases. All micronodular BCCs showed strong membranous staining, weak cytoplasmic and no nuclear staining. In the infiltrative and morphoeic BCCs membranous staining was completely lost at the advancing margins of the invading cell strands, with a marked increase in cytoplasmic staining; nuclear staining was observed in all these tumours. Conclusions The expression of beta-catenin varied between different types of BCC. Nuclear localization was most notable in the infiltrative and morphoeic variants, followed by the superficial variant, and seen least in nodular BCC. Its prominence at tumour margins suggests that this may be associated with more aggressive types of invasion.
Basal Cell Carcinoma↗
Bone marrow contributes to renal parenchymal turnover and regeneration.
In order to establish whether extra-renal cells contribute to the turnover and repair of renal tissues, this study examined kidneys of female mice that had received a male bone marrow transplant and kidney biopsies from male patients who had received kidney transplants from female donors. By using in situ hybridization to detect Y-chromosomes it could be demonstrated that circulating stem cells frequently engraft into the kidney and differentiate into renal parenchymal cells. In the human renal grafts it was confirmed that some of the recipient-derived cells within the kidney exhibited a tubular epithelial phenotype, by combining in situ hybridization with immunostaining for the epithelial markers CAM 5.2 and the lectin Ulex europaeus. Female mouse recipients of male bone marrow grafts showed co-localization of Y-chromosomes and tubular epithelial markers Ricinus communis and Lens culinaris, and a specific cytochrome P450 enzyme (CYP1A2) indicating an appropriate functional capability of clustered newly formed marrow-derived tubular epithelial cells. Y-chromosome-containing cells were observed within glomeruli, with morphology and location appropriate for podocytes. Within the murine kidney, these Y-chromosome-positive cells were negative for the mouse macrophage marker F4/80 antigen and leukocyte common antigen, but were vimentin-positive. The presence of bone marrow-derived cells was noted in both histologically normal mouse kidneys and in human transplanted kidneys suffering damage from a variety of causes. These data indicate that bone marrow cells contribute to both normal turnover of renal epithelia and regeneration after damage, and it is suggested that this could be exploited therapeutically.
Animals↗
Small fry starting to make waves.
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Aged↗
Wound healing in the liver with particular reference to stem cells.
The efficiency of liver regeneration in response to the loss of hepatocytes is widely acknowledged, and this is usually accomplished by the triggering of normally proliferatively quiescent hepatocytes into the cell cycle. However, when regeneration is defective, tortuous ductular structures, initially continuous with the biliary tree, proliferate and migrate into the surrounding hepatocyte parenchyma. In humans, these biliary cells have variously been referred to as ductular structures, neoductules and neocholangioles, and have been observed in many forms of chronic liver disease, including cancer. In experimental animals, similar ductal cells are usually called oval cells, and their association with impaired regeneration has led to the conclusion that they are the progeny of facultative stem cells. Oval cells are of considerable biological interest as they may represent a target population for hepatic carcinogens, and they may also be useful vehicles for ex vivo gene therapy for the correction of inborn errors of metabolism. This review proposes that the liver harbours stem cells that are located in the biliary epithelium, that oval cells are the progeny of these stem cells, and that these cells can undergo massive expansion in their numbers before differentiating into hepatocytes. This is a conditional process that only occurs when the regenerative capacity of hepatocytes is overwhelmed, and thus, unlike the intestinal epithelium, the liver is not behaving as a classical, continually renewing, stem cell-fed lineage. We focus on the biliary network, not merely as a conduit for bile, but also as a cell compartment with the ability to proliferate under appropriate conditions and give rise to fully differentiated hepatocytes and other cell types.
Animals↗
Liver stem cells: a two compartment system.
Hepatocytes and biliary epithelia are phenotypically very dissimilar, but share a common ancestry. Hepatocytes regenerate very efficiently, and their division potential indicates that many of them are functional stem cells. When hepatocyte-damaging agents also impair the regenerative ability of surviving hepatocytes, a potential stem cell system of biliary origin is activated to generate new hepatocytes - a reversal of ontogeny. Now both bile duct derived cells and hepatocytes can be isolated from the liver, genetically modified in vitro and returned to their in vivo origins where, after considerable population expansion, they can function as hepatocytes - paving the way for ex vivo gene therapy.
Animals↗
Wholesale hepatocytic differentiation in the rat from ductular oval cells, the progeny of biliary stem cells.
BACKGROUND/AIMS: Biliary epithelial cells (ductular oval cells) migrate into the periportal and midzonal parenchyma when hepatocyte regeneration after injury is significantly impeded. The potential of oval cells to differentiate into hepatocytes has been questioned. We have sought to resolve this issue using the modified Solt-Farber procedure in which 2-acetylaminofluorene is used to block hepatocyte regeneration in partially hepatectomized rats. METHODS: Rats received 2-acetylaminofluorene by oral gavage for 6 days before and up to 7 days after a two-thirds hepatectomy. The cellular reaction was visualized by the immunohistochemical localization of intermediate filaments cytokeratins 8 and 19 and vimentin, cytochrome P450 enzymatic proteins and alpha-foetoprotein. Expression of albumin and alpha-foetoprotein mRNA transcripts were observed in situ using antisense riboprobes. RESULTS: During the first 9 days after partial hepatectomy long strings of ductular cells spread outwards from the portal areas. These cells exhibited strong diffuse cytoplasmic staining with the anticytokeratin 8 and 19 antibodies, like authentic bile ducts, but in addition also expressed vimentin and alpha-foetoprotein (protein and mRNA)-collectively termed the "oval cell phenotype". Thereafter, these ducts rapidly vanished to be replaced by basophilic hepatocytes which lacked the oval cell phenotype, but which acquired strong expression of albumin mRNA. At 14 days after partial hepatectomy the oval cell phenotype was restricted to the peripheral margins of the newborn periportal hepatocytes, the distal tips of the oval cell ducts, and these too had disappeared within another 7 days. CONCLUSIONS: Ductular oval cells will differentiate into hepatocytes under appropriate experimental conditions.
Albumins↗
The anti-proliferative effect of plasma from rats with acute fulminant hepatic failure.
BACKGROUND: During fulminant hepatic failure (FHF) metabolites normally cleared by the liver accumulate in the circulation and cause hepatic coma. It is believed that the plasma of FHF patients has an inhibitory effect on liver regeneration. Plasma exchange was used to study the effect of plasma collected from donor FHF rats on liver regeneration in two-thirds partially hepatectomized syngeneic animals. METHODS: FHF and hepatic coma were induced in donors by administration of galactosamine at a dose of 1.85 g/kg. Plasma from donors in either grade-II or -IV coma was transfused by plasma exchange into partially hepatectomized animals 2h after resection. RESULTS: The livers from donor animals showed evidence of oval cell activation 1-2 days after galactosamine, but differentiation of oval cells to hepatocytes did not occur before the development of coma. The plasma collected from animals in grade-IV coma totally abolished regeneration in the partially hepatectomized recipients. CONCLUSION: These results support the hypothesis that metabolites present in the plasma during FHF inhibit liver regeneration.
Acute Disease↗
Soybean lectin stimulates pancreatic exocrine secretion via CCK-A receptors in rats.
Rats fed raw soy flour (RSF) show pancreatic growth due to excessive cholecystokinin (CCK) release. Soybean trypsin inhibitors are implicated, but rats fed soybean lectin also showed pancreatic growth. Therefore, we studied the effect of soybean lectin on pancreatic protein secretion in anesthetized rats. Intraduodenal administration of 30 mg of RSF stimulated a 1-h integrated rise in pancreatic protein output of 2.2 +/- 1.1 mg/h (mean +/- SE) in rats with bile pancreatic (BP) juice returned to the duodenum. Selective removal of the lectin by affinity to N-acetyl-D-galactosamineagarose abolished the response (-0.1 +/- 0.2 mg/h). Adding back the 84 micrograms of lectin restored the output of 2.2 +/- 0.9 mg/h. With BP juice returned to the duodenum, 84 micrograms of lectin required the added presence of protein and protease inhibitors to have this effect. However, when BP juice was not returned, 84 micrograms of lectin given alone produced a pancreatic response of 3.2 +/- 1.3 mg/h. Plasma CCK concentrations rose significantly from 6.6 +/- 1.9 to 14.3 +/- 2.9 pmol/l, and the pancreatic response was abolished by CCK-A receptor blockade (0.0 +/- 0.1 mg/h). We conclude that soybean lectin plays a major role in the acute stimulation of pancreatic protein secretion by RSF. The lectin releases CCK and the effect is mediated by CCK-A receptors.
Animals↗
Liver regeneration: a comparison of in situ hybridization for histone mRNA with bromodeoxyuridine labeling for the detection of S-phase cells.
We developed an in situ hybridization technique for measurement of proliferative cell numbers through detection of histone mRNA in routinely fixed, paraffin-embedded tissue sections. Histone gene expression is coordinated with the cell cycle, and the increase in expression during S-phase permits unambiguous identification of cells undergoing DNA replication. Histone mRNAs were identified in routinely processed rat liver tissue by non-isotopic in situ hybridization with digoxigenin-labeled oligonucleotide probes. Specific hybrids were detected with alkaline phosphatase-labeled anti-digoxigenin antibody and visualized by BCIP-nitroblue tetrazolium indicator substrate. Unequivocal cytoplasmic labeling was observed in various cell types in the liver remnant during the first 72 hr after a two-thirds partial hepatectomy. The spatial and temporal patterns of histone labeling were almost identical to those obtained by staining with an antibody to bromodeoxyuridine. The identification of histone mRNA appears to be a reliable marker of the S-phase fraction, a technique with the further advantage that the tissue does not have to be first exposed to a nucleotide analogue. Hence, retrospective studies are possible. The probes can be applied to human and animal cells and tissues because the nucleotide sequences of histone genes are conserved.
Animals↗
Cell behavior in the acetylaminofluorene-treated regenerating rat liver. Light and electron microscopic observations.
When hepatocyte regeneration is impaired, facultative stem cells and their descendants, also called oval cells, become activated and produce cell progeny that eventually differentiate. We have observed these cells in the rat liver after partial hepatectomy when the animals have been fed 2-acetylaminofluorene. Oval cells emerge from the portal areas and stain strongly with monoclonal antibodies raised against cytokeratins 8 and 19 and vimentin, the intermediate filament traditionally associated with mesenchymal cells. The majority of oval cells appeared to be part of a bile ductular reaction, manifest by their cytokeratin expression, and the bile duct injection of pigmented gelatin confirmed that these oval cells were essentially tortuous, arborizing duct-like structures (cholangioles) branched from and continuous with preexisting bile ducts. In situ hybridization studies showed that hepatocyte growth factor mRNA-expressing sinusoid lining cells were most numerous in the periportal areas during the period of ductular proliferation. At 1 week after partial hepatectomy, we observed morphological evidence of areas of in situ focal differentiation in the ductular structures, either to a columnar intestinal-type epithelia or to a hepatocyte phenotype, with abundant large mitochondria and membranous cytokeratin 8 immunoreactivity contrasting with the diffuse staining of the ductular cells. By following the fate of oval cells the authors conclude that in this model proliferated bile ductules represent the oval cell compartment capable of producing pluripotential progenitor cells.
2-Acetylaminofluorene↗
[Renal hyperechogenicity associated with an obstructive urologic disease in the newborn infant. A case].
A newborn infant exhibited bilateral hydronephrosis induced by uretero-pelvic junction syndrome (U.J.S.), pathological renal hyperechogenicity, and renal dysplasia at histology. Renal hyperechogenicity rapidly improved after curative surgery of the U.J.S. and therefore could not relate to dysplasia which is irreversible. The diagnostic value of renal hyperechogenicity is discussed.
Female↗
A case of progressive familial encephalopathy in infancy with calcification of the basal ganglia and chronic cerebrospinal fluid lymphocytosis.
The authors report the ninth case of progressive familial encephalopathy in infancy, with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis, as recently described by Aicardi and Goutieres. The encephalopathy appears during the first year of life with bilateral spasticity, continuing microcephaly, abnormal eye movements, and a rapid course toward a behavioral vegetative state. In every case, there is a mild lymphocytosis in the CSF and brain atrophy with calcification of the lenticular nuclei. No evidence of an infectious disease has been discovered. This syndrome constitutes a distinct type of leukodystrophy, transmitted as an autosomal recessive trait. Our case is a reminder that the presence of CSF lymphocytosis in infants, with encephalopathy and calcification of the lenticular nuclei, may be due to genetic degenerative encephalopathy.
Atrophy↗
[Bilateral nephroblastoma with aniridia].
Bilateral nephroblastoma may be associated with congenital bilateral aniridia in children. A partial deletion of the short arm of chromosome 11 has been reported in several cases of polymalformation syndrome with associated catalase deficiency. We report one case and review the recent genetic and pathogenic data.
Chromosome Deletion↗