Chronic leg ulcers: beware the 'wolf in sheep's clothing!'.
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Chronic Disease↗
Biomedical subjects
J R Salisbury
Publications and source records attributed to J R Salisbury.
In vivo proton magnetic resonance spectroscopy in polymyositis and dermatomyositis: a preliminary study.
The aim of the study is to determine whether biochemical abnormalities, such as lipid, creatine and choline metabolites, are observed in the more distal muscles of polymyositis (PM) and dermatomyositis (DM) patients. 12 patients suffering from chronic active PM/DM and 9 controls underwent a combined proton magnetic resonance (MR) imaging and proton MR spectroscopy study of the calf muscle. From a combination of T1-weighted MR images and corresponding fat suppressed images, fat infiltration into the muscle of both PM and DM patients was consistently observed. Muscular atrophy with a variable distribution was also noted in all patients. The biochemical profile of the localised proton MR spectra of soleus muscle showed reduction of both 'choline' to lipid and 'creatine' to lipid ratios in chronic PM and DM patients when compared with controls.
Adipose Tissue↗
Epstein-Barr virus latent membrane protein does not inhibit differentiation and induces tumorigenicity of human epithelial cells.
Latent membrane protein (LMP) is a latent Epstein-Barr virus (EBV) protein expressed in the EBV associated malignancy, nasopharyngeal carcinoma (NPC). Properties ascribed to this protein include inhibition of epithelial cell differentiation and deregulation of epithelial cellular gene expression, and are believed to contribute to the development of NPC. Studies to evaluate the oncogenic potential of LMP in epithelial cells have not been conclusive. We carried out studies to determine the tumorigenic activity of LMP in two human epithelial cell lines, SCC12F and HaCaT; while SCC12F LMP transfectants were non-tumorigenic in severe combined immunodeficient mice, HaCaT LMP transfectants were strongly oncogenic. The tumours produced were well differentiated, keratinising squamous cell carcinomas suggesting that LMP does not inhibit epithelial cell differentiation which conflicts with a previous report by Dawson et al. (1990). To resolve this discrepancy we examined the ability of HaCaT and SCC12F LMP transfectants to differentiate in a suspension culture assay. Both lines were able to differentiate to a similar extent as parental lines and control transfectants. Our results indicate that LMP is strongly oncogenic in human epithelial cells but that inhibition of differentiation is not necessarily a mechanism by which LMP contributes to the pathogenesis of NPC.
Animals↗
Three-dimensional reconstruction of non-Hodgkin's lymphoma in bone marrow trephines.
The objective of this study was to analyse the location in the bone marrow of deposits of low-grade non-Hodgkin's lymphoma. This was achieved using computer-generated three-dimensional reconstruction techniques applied to serial tissue sections of five bone marrow trephines involved by lymphoma. For comparative purposes, previously published three-dimensional models of benign lymphoid aggregates in the bone marrow were need. The images generated by this new study showed that deposits of low-grade non-Hodgkin's lymphoma involving the bone marrow always assumed a paratrabecular pattern of infiltration at some point. This is in direct contrast to the pattern of bone marrow infiltration shown by benign lymphoid aggregates. It is concluded that location within the marrow space is a crucial factor in distinguishing between benign and low-grade malignant lymphoid infiltrates in the bone marrow.
Biopsy↗
Analysis of the T-cell receptor repertoire in human atherosclerosis.
OBJECTIVE: Analysis of T-cell receptor (TCR) beta-chain gene expression in atherosclerotic lesions of human aorta. METHODS: TCR diversity was studied using non-radioactive polymerase chain reaction for quantitative assessment of TCRBV gene transcripts, together with size and sequence analysis of the beta-chain third complementarity-determining region (CDR3). Samples represent a wide range of atheromatous histology, allowing evaluation of the T-cell repertoire at different stages of disease. RESULTS: Diverse TCRBV family usage was observed in the majority of the samples, as the 25 different TCRBV products were detected at levels exceeding background. The data also showed that TCRBV transcripts expressed in the diseased aorta tissue displayed considerable size heterogeneity and no repetition of CDR3 nucleotide motifs. CONCLUSIONS: The early presence of T-lymphocytes in the atheromatous blood vessel has been interpreted as an indication of specific immunological reactions operating during the course of the atherosclerotic process. Although a T-cell infiltrate characterized by limited usage of TCRAV genes cannot be excluded the unrestricted usage of TCRBV genes argues against a local T-cell clonal expansion in atherogenesis.
Aorta, Thoracic↗
Time-course of iron overload and biochemical, histopathological and ultrastructural evidence of pancreatic damage in hypotransferrinaemic mice.
1. The time course of iron overload of the pancreas in hypotransferrinaemic mice maintained on a standard rodent diet was compared with biochemical and histological markers of tissue damage. 2. Pancreatic iron levels increased linearly from weaning till 9 months of age [73.3 nmol/mg of tissue (SEM 9.9; n = 5) compared with 0.9 nmol/mg of tissue (SEM 0.1; n = 4) in age-matched controls] then decreased linearly till at least 18 months of age. 3. Investigation of tissue distribution of newly absorbed radioiron suggested that significant redistribution of iron from liver to pancreas (rather than direct dietary iron sources) must be invoked to explain the rate of pancreatic iron loading in hypotransferrinaemic mice. 4. Pancreatic epithelial cells first showed altered morphology at 9 months of age. At 12 months of age, the pancreatic epithelium had developed a micronodular appearance, with large numbers of acini replaced by atrophic, degenerated acinar cells. Increased collagen fibre deposition was evident by trichrome staining and by electron microscopy. Biochemical markers of pancreatitis (serum lipase, tissue pancreatitis-associated protein mRNA) were elevated before 9 months of age, whereas the levels of pancreatic amylase mRNA declined from 9 months of age. 5. The data suggest that iron loading of hypotransferrinaemic mouse pancreas proceeds up to a threshold level at 9 months of age followed by a progressive atrophy of secretory epithelium. The hypotransferrinaemic mouse pancreas is a useful model system for investigation of parenchymal cell damage by iron.
Acute-Phase Proteins↗
Iron metabolism in transgenic mice with hypoplastic anaemia due to incomplete deficiency of erythropoietin.
Iron overload is a serious complication of many forms of anaemia, arising in part from mechanisms associated with compensatory increases in erythropoiesis. To investigate other mechanisms by which anaemia itself may perturb iron metabolism, without the confounding effects of compensatory erythropoiesis, we studied transgenic mice with a partially disabling insertion in the erythropoietin gene, which manifested as incomplete erythropoietin deficiency. Mice were studied aged 7-8 weeks. Haemoglobin concentrations were 6.6 +/- 0.8 g/dl in mice homozygous for the modified erythropoietin gene, 12.9 +/- 2.2 g/dl in heterozygous mice and 14.1 +/- 1.0 g/dl in controls. Homozygous mice showed significant hepatic iron loading (2-fold increase in liver non-haem iron, compared with heterozygous mice and normal controls, with iron staining principally in the periportal hepatocytes). Absorption studies using 59Fe showed increased uptake from the lumen of an in vivo isolated duodenal segment in homozygous mice, although at this point in time overall transfer of radioiron to the circulation and other tissues (mucosal transfer) was not different from controls. These observations demonstrate that anaemia can lead to hepatic iron loading even in the absence of increased erythropoiesis, and are consistent with the possibility that anaemic hypoxia can enhance mucosal iron uptake by the duodenal enterocyte.
Absorption↗
Lymphoid infiltrates in B cell non Hodgkin's lymphoma: comparing nuclear characteristics between lymph node and bone marrow; and evaluating diagnostic features of bone marrow infiltrates in paraffin embedded tissues.
Distinguishing non Hodgkin's lymphoma from benign lymphoid aggregates in bone marrow is well recognised to be difficult. Our objective was to evaluate nuclear morphology, and to perform morphometry on benign and neoplastic lymphoid infiltrates, to establish if objective criteria were of value in the diagnosis of neoplasia. By comparing neoplastic infiltrates in bone marrow with infiltrates in lymph nodes, the validity of grading non Hodgkin's lymphoma on the basis of bone marrow histology alone was assessed. 82 cases of B cell non Hodgkin's lymphoma (44 low grade and 38 high grade), known to have both lymph node and bone marrow involvement at the time of presentation, were compared with bone marrow trephines containing reactive lymphoid infiltrates. The results suggest that in paraffin embedded tissue from bone marrow trephines, nuclear morphology, nuclear area and the nuclear contour index cannot, in most cases, be used to distinguish reactive from neoplastic lymphoid infiltrates although mean nuclear area supports a diagnosis of a neoplastic infiltrate if it can be shown that the nuclei are larger than would be expected in reactive infiltrates. Such differences are subtle and often not appreciable without the use of quantitative techniques. The frequent occurrence of discordant infiltrates in high grade lymphomas means grading of lymphoma on the basis of bone marrow appearances is often unrealistic.
B-Lymphocytes↗
Three-dimensional reconstruction of benign lymphoid aggregates in bone marrow trephines.
Distinguishing between deposits of low-grade non-Hodgkin's lymphoma and benign lymphoid aggregates in bone marrow trephine sections is a recognized problem in haematopathology. To test the hypothesis that benign lymphoid aggregates do not make contact with a trabecular surface, three-dimensional models were constructed of five serially sectioned bone marrow trephines, containing a total of 19 lymphoid aggregates known to be benign. The computer-generated images showed that benign lymphoid aggregates were located in the central marrow space and did not become paratrabecular. This suggests that a paratrabecular location may help in some cases to distinguish deposits of low-grade non-Hodgkin's lymphoma from benign lymphoid aggregates.
Aged↗
Evaluation of non-isotopic in situ hybridization for mRNA in reactive and neoplastic lymphoid cells.
An evaluation of nonisotopic in situ hybridization (NISH) for mRNA in archival lymphoid tissue was carried out and an analysis of factors affecting the final outcome was performed. A modification of the in situ reverse transcription method for RNA preservation assessment has been used and described. We have shown that, for frozen samples mRNA detection is optimal within 3 months of the biopsy being taken, while preservation declines after 1 year of storage.
Biopsy↗
Osmotic diarrhoea and skeletal muscle protein synthesis in vivo.
The pathogenic nature of the wasting seen in diarrhoea is unknown. This study measured protein synthesis in an established model of diarrhoea using lactose for seven days. Comparisons were also made with data obtained from rats fed an identical diet in which lactose was replaced by isocaloric glucose ad libitum (that is, the control diet). To account for diarrhoea induced anorexia, a third group of rats were included, which were fed identical amounts of the control diet as the rats with diarrhoea inducing diet. Comparisons of the diarrhoea induced group with rats fed the control diet ad libitum showed that diarrhoea caused a significant reduction in body weights. Type I and type II muscles showed significant reductions in protein, RNA, and DNA contents, as well as a fall in the derived parameters, RNA/DNA, protein/DNA, and RNA/protein. Fractional rates of protein synthesis (ks) were also reduced. However, synthesis rates of type I and II muscles relative to RNA (kRNA) were unchanged in these muscles in diarrhoea induced rats compared with ad libitum fed controls. In the jejunum there was an increase in the RNA/DNA ratio, and reductions in ks and kRNA. Comparisons were also made between rats with diarrhoea and rats pair fed the control diet. There were no changes in total muscle protein, RNA or DNA contents. This suggests that an important feature of body wasting in diarrhoea is the element of anorexia, which induces severe metabolic changes. The comparison between rats with diarrhoea and the pair fed group showed that histological features of the plantaris were not overtly changed, though diarrhoea caused significant reductions in RNA/DNA, protein/DNA, ks, and kRNA. Similar changes were seen for the soleus; though the reduction in ks failed to attain statistical significance. In the jejunum a comparison of diarrhoea induced rats with pair fed controls, showed increases in the ratios of RNA/DNA and protein/DNA.
Animals↗
Use of different histomorphometric parameters in the routine assessment of human skeletal muscle biopsies.
In the diagnosis of muscle biopsies it has become traditional to identify any changes in fibre size by measuring minimum fibre diameter (dmin), as past technical constraints prevented the routine measurement of other parameters. The advent of user-friendly computerised image analysis, however, has facilitated such measurements. We examined a total of 39 skeletal muscle biopsies, including normal, myopathic, myositic and neuropathic cases, to determine whether improved discrimination between normal and abnormal histology was now possible on the basis of fibre cross-sectional areas (CSA). Using a semi-automated image analysis system, measurements of dmin, CSA and fibre perimeter were made. In all case groups, the skew of the frequency distribution of area was greater than that of dmin, moreover the difference was more marked in the abnormal cases. As expected, the mean values of dmin and area were reduced in all abnormal cases. As expected, the mean values of dmin and area were reduced in all abnormal cases. The range of their values, however, was reduced in the myopathic and neuropathic cases and increased in the myositic cases. In conclusion, fibre area is a more valuable discriminator between normal and abnormal skeletal muscle than is dmin.
Histocytochemistry↗
A histomorphometric study of bone changes in thyroid dysfunction in rats.
Clinical studies in thyrotoxicosis reveal a state of high bone turnover leading, eventually, to osteoporosis. Recently there has been concern that thyroxine (T4) treatment may have a similar effect on bone. Rat models have been used to study the effects of T4 on bone, but the majority of studies have looked at the effects of T4 after only 3 weeks of treatment. The aim of this study was to evaluate histomorphometric changes in rats after 12 weeks of thyroxine overtreatment or 12 weeks of hypothyroidism compared with untreated control animals. Animals received either T4 200 micrograms/kg per day, 0.1% propylthiouracil, or vehicle for 12 weeks. Tetracycline was administered 1 week and 3 weeks prior to killing. Iliac crest bone was used for histomorphometry. Serum T4 measurements (taken at killing) confirmed hyper- and hypothyroidism in the appropriate animal groups (between group difference p < 0.001 by ANOVA). In hyperthyroid animals there was an increase in mineral apposition rate (MAR; 0.94 vs. 0.59 microns/day, p < 0.001) and mineral formation rate (MFR/BS; 0.24 vs. 0.12 x 10(-2) micron3/micron2 per day, p < 0.001) and a slight increase in eroded surfaces (ES/BS%; 1.54 vs. 1.36, p < 0.05) compared with controls, consistent with previous in vitro and in vivo observations. In hypothyroid rats there was a marked reduction in osteoid surfaces (OS/BS%; 1.7 vs. 24.8, p < 0.001) and MAR (0.3 vs. 0.59 micrograms/day, p < 0.001), a reduction in ES/BS% (0.51 vs. 1.36, p < 0.05), and an increase in cancellous bone volume (BV/TV%; 30.29 vs. 19.6, p < 0.05), suggesting that thyroid hormones are a requirement for normal bone turnover.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Genotype study of non-Hodgkin's lymphoma.
DNA from 47 patients with non-Hodgkin's lymphoma (NHL) was studied for immunoglobulin and T-cell receptor (TCR) gene rearrangements with Southern blot hybridization. In 83% of the cases the genotypic changes were consistent with immunophenotypic and morphologic examination. Two cases showed mixed genotype and 9 cases of B-cell NHL (67% of centroblastic, 36% of follicular and 33% of large cell anaplastic) showed a population of cells with TCR gamma rearrangements in addition to immunoglobulin rearranged bands. We compared the TCR gamma variable region usage in these rearrangements in B-cell NHL with T-cell NHL and reactive hyperplasia. In T-cell NHL TCR gamma variable regions located at the 3' part of the variable locus were used more often, whilst in B-cell NHL regions of the 5' portion of the locus were preferentially used. Our results confirm the genotypic heterogeneity of histologically defined subtypes of NHL.
Adult↗
3D reconstruction and quantitation of pathological tissues.
3DR techniques are under continuous development, as is the technology which supports them. Systems developed for engineering and other applications are coming within the price range of many users. Recently publications have started to appear using standard high-quality graphics workstations. As these are coming down in price, more applications will be possible. The advent of new computer technology, notably possible. The advent of new computer technology, notably highly parallel systems and chips such as the Intel i860, offer the prospect of very fast reconstructions and the software to make 3DR a routine technique. Most significant however is the continuing increase in type and numbers of scanning systems, both macroscopic and microscopic. Prior to these systems becoming available, the critical limiting factor inhibiting the wide application of 3DR was generating adequately registered, undistorted, complete sets of serial section data for the reconstruction process. The fact that scanning optical microscopes can produce such datasets easily means that the everyday use of 3DR for studies of pathology is now feasible.
Humans↗
Alcoholic muscle disease: features and mechanisms.
Approximately 50 per cent of all chronic alcohol misusers have alcoholic muscle disease. Chronic alcoholic skeletal muscle myopathy is characterized by a selective atrophy of type II fibres, so that up to 20 per cent of the entire skeletal musculature is lost. The pathogenetic mechanism for the myopathy is currently unknown but a model has been described in which various anatomically-distinct skeletal muscles are employed to reflect type I and II fibres, i.e. the soleus and plantaris, respectively. In chronic studies, rats were fed nutritionally complete liquid diets containing either ethanol or glucose (controls) for up to 6 weeks. In acute studies, rats were given single boluses of ethanol and rates of protein synthesis were examined at 2.5 h. The results show that the myopathy is due to defective skeletal muscle protein synthesis. The information gained from these studies enhances our understanding of skeletal muscle diseases characterized by preferential effects on anaerobic fibres and should be applicable to disease processes in other toxic or metabolic myopathies.
Adult↗
Primary bone lymphoma: report of an unusual case with a review of the literature.
Primary bone lymphoma is uncommon and usually involves the long bones. We report a patient with involvement of a metacarpal bone, and review the literature.
Aged↗
The effect of low molecular weight heparin on intimal hyperplasia in vein grafts.
Intimal hyperplasia due to smooth muscle cell proliferation is a well recognised cause of vascular graft failure. In experimental studies heparin and its low molecular weight derivatives can inhibit this proliferative response. This study examines the effect of subcutaneous low molecular weight heparin (LMWH) therapy on intimal hyperplasia in a model of arterial vein grafting. Twenty-four New Zealand White rabbits underwent interposition vein grafting of the carotid artery. Animals were randomly assigned to a control or treated group. Treated animals received 60 anti Xa units/kg of subcutaneous LMWH daily for 1 month. Animals were then sacrificed, graft patency assessed and the vessels then harvested for analysis of intimal hyperplasia. Intimal hyperplasia in carotid arteries and vein grafts was measured using a computerised image analysis system and was expressed as an intimal:medial area ratio. A statistically significant reduction in the degree of intimal hyperplasia seen in the arterial component of the distal anastomoses of carotid vein grafts was achieved using subcutaneous LMWH [Control 0.44 (0.37-0.55): LMWH 0.27 (0-0.37) p < 0.05]. There was no difference in the degree of intimal hyperplasia seen in the vein grafts themselves. [Control 0.21 (0-0.54): LMWH 0.23 (0-0.72)]. This study suggests that subcutaneous LMWH can inhibit the development of intimal hyperplasia in arteries undergoing vascular grafting but does not influence intimal hyperplasia within vein grafts. This has important implications for the further evaluation of antithrombotic agents following vascular surgery.
Animals↗