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L W Powell

Publications and source records attributed to L W Powell.

At least 73 records · Page 4Linked to original sources
PubMed1996

A 4.5-megabase YAC contig and physical map over the hemochromatosis gene region.

We have constructed a yeast artificial chromosome (YAC) contig over the candidate hemochromatosis gene region. This contig comprises 16 YACs from the CEPH, Washington University, and ICI YAC libraries and covers 4.5 Mb at 6p21.3-6p22. The complete contig has been restriction mapped, enabling the precise relationship between the YACs to be determined and the mapping of a total of 12 STSs. Nine of these are highly polymorphic STSs that are closely linked to hemochromatosis; this series includes D6S265 and D6S1260, which comprise the most proximal and distal markers linked to HC. This is the first YAC contig that spans the hemochromatosis candidate region, and it provides valuable resource material for the cloning of this and other genes in the region distal to the MHC class I complex.

Base Sequence↗
PubMed1996

Haemochromatosis--a clinical update.

Haemochromatosis is now known to be a common genetic disorder, with a carrier rate of about 1 in 10 in populations of Northern European origin. With early diagnosis and treatment, life expectancy is normal, yet it remains underdiagnosed.

Biopsy↗
PubMed1996

Effect of the microtubular inhibitor vinblastine on ferritin clearance and release in the rat.

We have previously demonstrated that colchicine inhibits ferritin clearance from the circulation of normal and iron-loaded rats and stimulates endogenous ferritin release into both the serum and bile of iron-loaded rats. The aim of the present study was to determine the effect of vinblastine on ferritin clearance and release in normal and iron-loaded rats. Vinblastine was administered at either 1 or 10 mg/kg to both normal and iron-loaded rats, infused over a 5 h period with either a rat liver ferritin or saline solution. Serum and biliary ferritin levels were determined every 30 min. After 5 h, 90% of the infused ferritin was cleared from the circulation in the absence of vinblastine. Low-dose vinblastine decreased ferritin uptake 10-20% in iron-loaded rats. High-dose vinblastine inhibited ferritin clearance by 25% in normal rats and 20-40% in iron-loaded rats. Vinblastine administration caused a 2-3-fold increase in the serum ferritin concentration and a 3-5-fold peak in biliary ferritin levels. Thus, vinblastine caused the release of endogenous ferritin into both the serum and bile of iron-loaded rats in the presence of a ferritin load. We therefore conclude that disturbed microtubule function accounts for the observed inhibition of ferritin uptake and intracellular transport; however, the mechanism of increased ferritin release remains unclear.

Animals↗
PubMed1996

Factors influencing disease expression in hemochromatosis.

Genetic hemochromatosis is one of the most common inherited disorders in Caucasian populations. The disease frequency in Caucasian populations in Australia, Europe, and the United States is 1:300-400. The basic genetic defect remains unknown, although the hemochromatosis gene is closely linked to histocompatibility antigen (HLA) A, thus allowing early diagnosis in members of affected families. Many factors-environmental, genetic, and nongenetic in nature-influence the degree of iron loading in affected individuals. In particular, pathologic and physiologic blood loss and blood donation influence iron stores in hemochromatosis. The iron concentration in the liver is an important determinant of survival because a hepatic iron concentration in excess of 400 mumol/g dry weight is usually associated with cirrhosis. Patients with cirrhosis secondary to hemochromatosis are at risk of heptocellular carcinoma and complications of portal hypertension. The combination of improved awareness of the condition and the use of HLA typing to identify affected family members has led to earlier diagnosis and therapy, and to an improvement in overall survival.

Gene Expression↗
PubMed1995

Flucloxacillin associated cholestatic hepatitis. An Australian and Swedish epidemic?

The clinico-pathological entity of flucloxacillin-associated cholestatic hepatitis is described and the recognition and documentation of cholestasis associated with flucloxacillin and with related isoxazolyl-penicillins (cloxacillin, dicloxacillin) is examined on an international basis, with particular reference to Australia. Data were obtained from the literature, from the Australian adverse drug reaction monitoring agency and from the Collaborative Centre for International Drug Monitoring (World Health Organisation) in Sweden. Approximately 600 cases of flucloxacillin-associated cholestatic hepatitis were collected, as well as 164 cases associated with other isoxazolyl penicillins. Jaundice and pruritus may first appear several weeks after administration of the drug has ceased and typically are severe and protracted. Liver tests may be abnormal for months after symptomatic recovery. Death is uncommon. Liver pathology shows centrizonal bile stasis with portal tract inflammation and variable loss of bile ducts. Approximately 1 in 15,000 users of flucloxacillin will develop the reaction. Increasing age (> 55 years) and prolonged intake (> 14 days) are particular risk factors. Cholestasis associated with cloxacillin/dicloxacillin appears to be similar in nature but is less well defined. Recognition and reporting of the reaction have been uncommon in the United Kingdom inter alia and high in Sweden and Australia, although estimates of risk have been similar. In Australia, the remarkably high rate of reports appears to be the result of sustained publicity for the reaction. There is only a trickle of reports of cholestatic hepatitis in association with the use of cloxacillin and dicloxacillin from the USA and Canada. The high level of awareness of the reaction and consequential regulatory action so far have not resulted in a diminution of its occurrence in Australia.

Australia↗
PubMed1995

Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene.

Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been identified. The aim of this study was to look for clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metabolism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two copies, one copy, and no copies of the ancestral haplotype). We also examined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. These analyses indicate that (i) HC patients with two copies of the ancestral haplotype show significantly more severe expression of the disorder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the presence of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency.

Adult↗
PubMed1995

Haplotype analysis in Australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis.

Hemochromatosis (HC), an inherited disorder of iron metabolism, shows a very strong founder effect in Australia, with the majority of patients being of Celtic (Scots/Irish) origin. Australian HC patients thus provide an ideal group in which to examine HC-gene-region haplotypes, to analyze the extent of linkage disequilibrium and genetic heterogeneity in HC. We have analyzed chromosomes from 26 multiply affected HC pedigrees, and we were able to assign HC status unambiguously to 107 chromosomes--64 as affected and 43 as unaffected. The haplotypes examined comprise the following highly polymorphic markers: the serological marker HLA-A and the microsatellites D6S248, D6S265, HLA-F, and D6S105. All show highly significant allelic association with HC and no evidence of separation from the disease locus by recombination. Analysis identified a predominant ancestral haplotype comprising alleles 5-1-3-2-8 (marker order: D6S248-D6S265-HLA-A-HLA-F-D6S105), present in 21 (33%) of 64 affected chromosomes, and exclusively associated with HC (haplotype relative risk 903). No other common haplotype was significantly associated with HC. Haplotype analysis in Australian HC patients thus provides strong evidence for (a) the introduction of HC into this population on an ancestral haplotype, (b) a common mutation associated with HC in Australian patients, and (c) a candidate HC-gene region extending between and including D6S248 and D6S105.

Australia↗
PubMed1994

Body composition in nonalcoholic cirrhosis: the effect of disease etiology and severity on nutritional compartments.

BACKGROUND/AIMS: Previous studies of body composition in cirrhosis have either measured only one body compartment, used alcoholic subjects, or not corrected body composition for physical characteristics. The aim of this study was to perform a detailed analysis of body composition in subjects with nonalcoholic cirrhosis. METHODS: Simultaneous measurements of total body potassium and total body water were performed and values of body cell mass and body fat were corrected for physical characteristics. RESULTS: Child's class C patients had a significantly lower mean total body potassium index (i.e., percent observed value/expected value) and body fat index than class A or B patients. Eighty-one percent of class C patients had simultaneous reductions in body fat and body cell mass, and 71% of patients with class A disease had a significant reduction in either or both compartments. Nine patients showed the pattern of tissue loss seen with short-term starvation. Fourteen patients showed the pattern of tissue loss seen in physiological stress. CONCLUSIONS: Severe liver disease is characterized by significant reductions in body fat and body cell mass, most class A patients have a significant reduction in some nutritional compartments, and the pattern of tissue loss may reflect mechanisms of tissue wasting.

Adipose Tissue↗
PubMed1994

The endocytosis of transferrin by rat intestinal epithelial cells.

BACKGROUND/AIMS: The transferrin receptor is a prominent protein on the basal and lateral membranes of intestinal epithelial cells, yet little is known of the function of the receptor in the intestine. The aim of the present study was to determine whether intestinal transferrin receptors were capable of facilitating transferrin internalization. METHODS: Using the rat as an experimental model, the uptake of radiolabeled transferrin by cells isolated from different regions along the crypt-villus axis of the proximal small intestine was studied. RESULTS: An intestinal epithelial cell fraction highly enriched in crypt cells bound most radiolabeled transferrin. Cells in this fraction were able to internalize transferrin and recycle it back to the cell surface. A high affinity, saturable pathway of transferrin uptake by these cells predominated at transferrin concentrations below 0.3 mumol/L, whereas at higher concentrations, most uptake was via a nonsaturable process. Intravenously injected radiolabeled transferrin could be detected within intestinal crypt cells, indicating that these cells are able to internalize transferrin in vivo. CONCLUSIONS: These data suggest that intestinal crypt cells have an active transferrin/transferrin receptor system. Transferrin may play an important role in iron delivery to and/or as a growth factor for the rapidly proliferating intestinal epithelium.

Animals↗
PubMed1994

Establishment of a cell line from a hepatocellular carcinoma from a patient with hemochromatosis.

We describe the establishment and characterization of a novel hepatoma cell line. This cell line, designated RBHF-1, was established from a hepatocellular carcinoma of a 67-yr-old man with a history of genetic hemochromatosis. At this writing, the cells have been maintained in RPMI-1640 tissue-culture medium and fetal calf serum without any additional supplements for 30 mo. The cells form colonies on soft agar and are not tumorigenic in nude mice. The cell line is polymorphic and displays characteristics of mature hepatocytes by synthesizing albumin, alpha 2-macroglobulin, fibronectin and alpha-fetoprotein. Cytogenetic analysis shows multiple chromosomal aberrations, with a consistent deletion in the long arm and deletions or rearrangements in the short arm of chromosome 1. There is no evidence for hepatitis B or hepatitis C virus infection of the cell line. The cells contain no detectable intracellular iron after staining with Perls' stain. Unlike other hepatoma cell lines, there is no detectable binding of epidermal growth factor to RBHF-1 cells. This is the first cell line to be established from a patient with hemochromatosis, and it provides a potentially important model for the study of hepatocyte transformation in association with iron overload.

Aged↗