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J W Halliday

Publications and source records attributed to J W Halliday.

At least 37 records · Page 2Linked to original sources
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

The endocytic pathway for H-ferritin established in live MOLT-4 cells by laser scanning confocal microscopy.

We have established the intracellular destination of the putative immunoregulatory protein, human recombinant H (heavy)-ferritin, in the transformed T-cell line MOLT-4, by laser scanning confocal microscopy of live cells. A series of confocal images was collected over a 60 min time course using indirect immunofluorescence of H-ferritin and transferrin, their respective monoclonal antibodies, and fluorescein isothiocyanate (FITC)-labelled IgG. A marked drop in FITC fluorescence after 40 min of H-ferritin internalization, indicative of an acidic environment, and co-localization with tetramethylrhodamine isothiocyanate-labelled-dextran strongly suggests that H-ferritin is transferred to the lysosome. In contrast, transferrin was observed to return to the cell surface. Electron microscopy confirmed that H-ferritin was transferred to the lysosome. The receptor-mediated endocytosis and lysosomal delivery of H-ferritin may thus potentiate its putative immunoregulatory activity.

Endocytosis↗
PubMed1994

Isolation of CA dinucleotide repeats close to D6S105; linkage disequilibrium with haemochromatosis.

The gene for hereditary haemochromatosis (HC) is linked to HLA-A and D6S105 on chromosome 6p. Both markers have also been reported to display linkage disequilibrium with the disease. However, their physical localization relative to one another has not been established. We demonstrate by fluorescent in situ hybridisation that D6S105 lies at least 1-2 Mb telomeric of HLA-A. The haemochromatosis critical region extending from proximal of HLA-A to distal of D6S105 is therefore large. To improve the genetic resolution in this region more highly polymorphic markers are required. We have therefore isolated three novel CA dinucleotide repeats close to D6S105. A linkage disequilibrium study, with two of these microsatellites, in HC patients and controls lends support to the conclusion that D6S105 is a close marker to the haemochromatosis gene.

Alleles↗
PubMed1994

Pathways of intracellular trafficking and release of ferritin by the liver in vivo: the effect of chloroquine and cytochalasin D.

We have previously shown that the clearance of exogenous ferritin and the release of endogenous ferritin into both serum and bile are altered by the microtubular inhibitor colchicine. In this study we further examined the role of the lysosome-endosome pathway in ferritin metabolism. We examined the effect of the lysosomotropic agent chloroquine and the microtubular inhibitor cytochalasin D on the uptake and release of ferritin by normal and iron-loaded rats under basal conditions and in the presence of an exogenous tissue ferritin load. Either chloroquine (50 mg/kg body wt) or cytochalasin D (0.9 microgram/100 gm body wt/min) was administered to normal and iron-loaded rats at zero time. Rats were also infused with either saline solution or rat liver ferritin containing a trace amount of 125I-ferritin. The clearance of 125I-ferritin from the circulation was not affected by chloroquine or cytochalasin D either in normal or in iron-loaded rats; however, both chloroquine and cytochalasin D decreased the serum ferritin concentration in normal rats to 39% +/- 9% and 22% +/- 7% of the baseline serum ferritin levels, respectively, implying that both drugs inhibited the release of endogenous ferritin in normal rats. In iron-loaded rats both chloroquine and cytochalasin D decreased the biliary ferritin concentration to 11% +/- 1% and 37% +/- 4% of the baseline ferritin levels, respectively, and the 125I protein-bound counts per minute in the bile to 50% of the control result. This finding is consistent with an inhibitory effect of both drugs on the biliary excretion of endogenous ferritin and the intracellular transport of exogenous ferritin, respectively. In the presence of an exogenous tissue ferritin load, there was no detectable inhibitory effect of either drug on the biliary excretion of either endogenous or exogenous ferritin. These results provide the following evidence: (a) the receptor-mediated endocytosis of ferritin is not dependent on functioning lysosomes or microfilaments; (b) the release of endogenous ferritin into the serum of normal rats and the bile of iron-loaded rats is a chloroquine-sensitive, microfilament-dependent process; (c) the biliary excretion of trace amounts of exogenous ferritin is dependent on both chloroquine-sensitive vesicles and microfilaments; and (d) increased levels of exogenous ferritin are excreted directly into the bile by way of a second microfilament-independent, chloroquine-insensitive pathway. This study provides support for a physiological mechanism for the release of ferritin from the liver.

Alanine Transaminase↗
PubMed1993

Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases.

BACKGROUND: Although liver cancer arises frequently in the course of genetic hemochromatosis (GH), it has not been previously studied in a large series of patients with well-defined GH. METHODS: The bioclinical and pathological data from 1 cholangiocarcinoma and 53 hepatocellular carcinomas (HCCs) complicating GH in 32 untreated and 22 de-ironed patients are reported. RESULTS: This study (1) adds three new well-documented cases of HCC in noncirrhotic but only fibrotic hemochromatotic liver, (2) shows the high prevalence (83%) of proliferative and often dysplastic (70%) iron-free foci in the nontumorous liver of untreated patients, and (3) emphasizes the significant increase of cirrhosis (81% vs. 28%) and of associated noniron-related risk factors, mainly chronic alcoholism (48% vs. 25%) and tobacco smoking (50% vs. 18%) in patients with HCC compared with matched hemochromatotic patients without HCC. CONCLUSIONS: These data (1) suggest that iron-free foci may be markers of an early stage of HCC in GH and (2) supply the basis for defining a cost-effective policy for the screening of HCC in GH patients.

Female↗
PubMed1993

Spontaneous apoptosis in NS-1 myeloma cultures: effects of cell density, conditioned medium and acid pH.

Apoptosis is a form of cell death which plays an important role in many biological processes including the regulation of B and T lymphocyte functions. We report here the spontaneous development of extensive apoptosis in cultures of the NS-1 mouse myeloma cell line following overgrowth. The apoptosis was identified by both its ultrastructural features and its DNA fragmentation pattern. High cell density and conditioned medium, but not acid pH, were found to be major inducers of apoptosis in this experimental system.

Animals↗
PubMed1993

Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients.

Sublobular nodules of hepatocytes free of iron or exhibiting much less iron than the surrounding parenchyma, referred to in this study as iron-free-foci, are frequently found in the livers of patients with genetic hemochromatosis complicated by hepatocellular carcinoma. To test the hypothesis that such nodules are preneoplastic lesions, iron-free foci were sought in the initial liver biopsy specimens of 185 patients with untreated and uncomplicated genetic hemochromatosis. Iron-free foci were found in 14 (7.6%) patients, all men, aged from 38 to 76 yr, with heavy iron overload and with fibrosis or cirrhosis. Twelve patients with iron-free foci were followed for 0.9 to 15 yr (7 +/- 6 yr). In six (50%), HCC developed, compared with 2 (8%) from a control group consisting of 24 patients without IFF matched according to age, sex, degree of fibrosis, liver iron amount and follow-up duration. The mean number of iron-free foci per iron-free foci-positive specimen was 3.2 +/- 2.1. Ten patients had dysplastic aspects in their iron-free foci, and four had intrahepatocytic iron-positive inclusions at the periphery of iron-free foci. Proliferative cell nuclear antigen was positive in 75% of iron-free foci and in 24% +/- 21% of hepatocyte nuclei in iron-free foci. This study clearly demonstrates that iron-free foci are proliferative lesions and strongly suggests that such nodules are preneoplastic foci. Therefore the finding of IFF in the initial liver biopsy specimen from a patient with genetic hemochromatosis should lead to regular screening for hepatocellular carcinoma.

Adult↗
PubMed1993

Localization of the hemochromatosis gene close to D6S105.

The hemochromatosis (HC) gene is known to be linked to HLA-A (6p21.3); however, its precise location has been difficult to determine because of a lack of additional highly polymorphic markers for this region. The recent identification of short tandem repeat sequences (microsatellites) has now provided this area with a number of markers with similar polymorphic index to the HLA serological polymorphisms. Using four microsatellites--D6S105, D6S109, D6S89, and F13A--together with the HLA class I loci HLA-A and HLA-B in 13 large pedigrees clearly segregating for HC, we have been able to refine the location of the HC gene. We identified no recombination between HC and HLA-A or D6S105, and two-point analyses placed the HC gene within one centimorgan (cM) of HLA-A and D6S105 (HLA-A maximum of the lod score [Zmax] of 9.90 at recombination fraction [theta] of 0.0, and D6S105 Zmax of 8.26 at theta of 0.0). The markers HLA-B, D6S109, D6S89, and F13A were separated from the HC locus by recombination, defining the centromeric and telomeric limits for the HC gene as HLA-B and D6S109, respectively. A multipoint map constructed using HLA-B, HLA-A, and D6S109 indicates that the HC gene is located in a region less than 1 cM proximal to HLA-A and less than 1 cM telomeric of HLA-A. These pedigree data indicate an association between HC and specific alleles at HLA-A and D6S105 (i.e., HLA-A3 and D6S105 allele 8).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Effect of chronic iron overload on procollagen gene expression.

The pathogenesis of hepatic fibrosis and cirrhosis in genetic hemochromatosis may involve a direct effect of excess iron on collagen synthesis in the liver. To investigate this theory, we measured procollagen messenger RNA levels (types I, III and IV) in the livers of rats in which we produced chronic parenchymal iron overload by feeding them dietary carbonyl iron (2.5%, wt/wt) for up to 18 mo. This feeding resulted in predominantly parenchymal iron deposition in a periportal distribution similar to that seen in genetic hemochromatosis. Increased amounts of collagen fibrils were observed in iron-loaded livers on electron microscopy; all iron-loaded livers showed some periportal fibrosis. Although very high hepatic iron concentrations (range = 340 to 1,100 mumol/gm dry wt) were achieved in the carbonyl iron-loaded rats, we saw no consistent difference between steady-state messenger RNA levels for procollagens types I, III and IV in control and iron-loaded livers examined at five different time points up to 18 mo. Messenger RNA levels of the cytokine transforming growth factor-beta 1, which has been implicated as having a role in the production of extracellular matrix proteins, were also measured. No significant differences were observed between iron-loaded and control livers. These results suggest that excess parenchymal iron does not have a direct effect on the expression of the procollagens or transforming growth factor-beta 1 genes in iron-loaded livers and that factors other than, or in addition to, iron are necessary for fibrosis to occur.

Animals↗
PubMed1993

Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: a study of 192 cases.

The biochemical hepatic iron index, defined as the ratio of hepatic iron concentration (expressed as micromoles per gram dry weight) to age permits accurate prediction of genetic status in patients with genetic hemochromatosis. However, the hepatic iron concentration is not always available. Therefore a histological hepatic iron index, defined as the ratio of total histological iron score (range = 0 to 60) to age, was evaluated in a total of 192 Australian and French patients with genetic hemochromatosis. These subjects had been classified previously as heterozygotes (n = 18) or homozygotes (n = 174) according to clinical and familial data only. Biochemical hepatic iron index and histological hepatic iron index were well correlated (Spearman's test: rho = 0.75, p < 0.0001). Both were significantly (p < 0.0001) increased in homozygotes (respectively, 6.7 +/- 3.8 [range = 1.2 to 22.6] and 0.62 +/- 0.28 [range = 0.14 to 1.5]) compared with heterozygotes (respectively, 1 +/- 0.4 [range = 0.45 to 1.6] and 0.08 +/- 0.05 [range = 0 to 0.14]). The histological hepatic iron index was less than 0.15 in all heterozygotes and greater than 0.15 in all but two homozygotes. These data show that the age-dependent nature of iron accumulation can also be accommodated by calculating the histological hepatic iron index and that histological study is an accurate means of predicting the genetic status of hemochromatosis patients when hepatic iron concentration is not available.

Adult↗
PubMed1993

Concordance of iron storage in siblings with genetic hemochromatosis: evidence for a predominantly genetic effect on iron storage.

Phenotypic concordance between siblings has been demonstrated in some inherited conditions, and such data provide strong evidence that the severity of disease is affected by genetic factors. We assessed the concordance of liver iron stores between siblings in 22 sibling pairs (15 same-sex pairs and 7 opposite-sex pairs) with genetic hemochromatosis. In this study population a wide range was found in the hepatic iron concentration and the hepatic iron index (32 to 833 mumol/gm dry wt and 1.65 to 14.4, respectively), which could not be accounted for by differing exposure to the environmental factors that influence iron stores. Despite the large variation of hepatic iron concentration within the group, siblings of identical sex had accumulated similar amounts of liver iron. A highly significant correlation for hepatic iron concentration (r = 0.81) and hepatic iron index (r = 0.70) was found between siblings of the same sex. The hepatic iron concentration and the hepatic iron index of one sibling was less than 50% of the other in only three same-sex sibling pairs. In each instance, reasons existed (blood donation, age at diagnosis and human leukocyte antigen nonidentity) for this discordance. In six of the seven opposite-sex pairs, the woman had lower hepatic iron stores than her male sibling, consistent with previous studies on the extent of iron overload in women and its modification by physiological blood loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Distribution of body water in patients with cirrhosis: the effect of liver transplantation.

We compared total body water and intracellular-extracellular distribution of body water between male patients with mild liver disease without ascites (n = 9), male patients with severe liver disease and gross ascites (n = 6) and a group of age-, sex-, height- and weight- matched controls (n = 6). In addition, we documented the effects of liver transplantation on intracellular, extracellular and total body water in 12 patients (6 men and 6 women) by means of deuterium oxide dilution and whole-body potassium counting. We saw no significant difference in total body water between the healthy controls, patients without ascites and patients with ascites (46.5 +/- 9.2 kg, 45.4 +/- 6.6 kg and 50.4 +/- 5.1 kg, respectively), although, as expected, extracellular water was increased in patients with ascites compared with healthy controls and cirrhotic patients without ascites (36.9 +/- 6.5 kg vs. 25.4 +/- 4.4 kg, p = 0.005; and 36.9 +/- 6.5 kg vs. 27.0 +/- 5.3 kg, p = 0.002, respectively). We found no difference between non-ascitic patients and healthy controls (25.4 +/- 4.4 kg vs. 27.0 +/- 5.3 kg). However, intracellular water was significantly reduced in patients with severe liver disease compared with that in controls (13.6 +/- 3.3 kg vs. 21.5 +/- 4.2 kg, p = 0.005) or patients without ascites (13.6 +/- 3.3 kg vs. 18.3 +/- 2.9 kg, p = 0.01). The reduction of intracellular water appears to be due to loss of body cell mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Characterization of the ferritin receptors of human T lymphoid (MOLT-4) cells.

We have previously demonstrated that distinct binding sites exist for human recombinant H ferritin (HrHF) and human liver ferritin (HLF) on human T lymphoid cells (MOLT-4). This study demonstrates that these binding sites have the characteristics of receptors specific for HrHF, and the binding characteristics and internalization of HrHF to MOLT-4 cells have now been examined. Iodinated HrHF was displaced by an excess of unlabeled HrHF. Heavy ferritin was the major subunit bound with only a small amount of light-ferritin binding, consistent with our immunofluorescence studies. Scatchard plot analysis of the competitive binding data for HrHF revealed an association constant of 6.3 to 6.7 x 10(7) L/mol with approximately 6000 to 15,000 receptor sites per MOLT-4 cell. Internalization of HrHF was demonstrated with pronase. Chloroquine substantially reduced the uptake of HrHF. Release of internalized HrHF was not observed when cells were rewarmed to 37 degrees C. These results indicate that HrHF is internalized by a mechanism consistent with receptor-mediated endocytosis, with possible involvement of the lysosome. The internalized HrHF remains associated with the cell. Although lymphoid cell growth and differentiation were not examined in this study, the presence of the demonstrated receptors may indicate a regulatory role for heavy ferritin in such cells.

Binding, Competitive↗
PubMed1992

Effect of cell proliferation on H-ferritin receptor expression in human T lymphoid (MOLT-4) cells.

We have previously demonstrated the presence of receptors specific for human recombinant H ferritin (HrHF) on human T lymphoid cells (MOLT-4), and changes in receptor number and binding affinity with growth and cell cycling have now been examined. Specific binding of HrHF was maximal in MOLT-4 cells harvested during exponential growth with the cells in the DNA synthesis phase of the cell cycle. Specific binding decreased progressively to the plateau phase of growth with the cells in the resting phase of the cell cycle. Scatchard analysis of the competitive binding data for HrHF demonstrated that this decrease in binding was associated with a reduction in receptor number, from 42,140 per cell to 10,306 per cell. Receptor binding affinity increased only minimally over this period, from 7.1 x 10(7) L/mol to 14.9 x 10(7) L/mol. These results indicate that growth- and cell cycle-induced changes in H-ferritin receptor expression are primarily associated with changes in receptor number rather than receptor binding affinity. The present study demonstrates that the expression of this receptor is associated with the proliferative status of the cell and suggests that the H-ferritin receptor may mediate the putative regulatory role of H-ferritin.

Cell Cycle↗