scholarly journals Genetic variation of iron-induced uroporphyria in mice

1993 ◽  
Vol 291 (1) ◽  
pp. 29-35 ◽  
Author(s):  
A G Smith ◽  
J E Francis
Keyword(s):  
Iron Concentration ◽  
Strain Differences ◽  
Inbred Strains ◽  
Optimum Level ◽  
Iron Loading ◽  
Uroporphyrinogen Decarboxylase ◽  
Liver Iron ◽  
Inbred Strains Of Mice ◽  
Iron Treatment ◽  
Cytochrome P 450

Iron overload causes inhibition of hepatic uroporphyrinogen decarboxylase (UROD) and uroporphyria in C57BL/10ScSn but not DBA/2 mice [Smith, Cabral, Carthew, Francis and Manson (1989) Int. J. Cancer 43, 492-496]. We have investigated the induction of uroporphyria in 12 inbred strains of mice 25 weeks after iron treatment (600 mg/kg) to determine if there was any correlation with the Ah locus. Under these conditions, inhibition of UROD occurred to varying degrees in Ahd mice (SWR and AKR) as well as nominally Ahb-1 (C57BL/6J, C57BL/10ScSn and C57BL/10-cc) and Ahb-2 strains (BALB/c and C3H/HeJ). Five other Ahb or Ahd strains (C57BL/Ks, A/J, CBA/J, LP and DBA/2) were unaffected. Thus there appeared to be no correlation with the Ah phenotype and this illustrated that some other variable inherited factors are involved. Comparisons between another susceptible strain, A2G, and the congenic A2G-hr/+strain (carrying the recessive hr gene) showed a modulating influence associated with the hr locus. In contrast with individual mice of inbred strains, which showed consistent responses to iron, those of the outbred MF1 strain showed a spectrum of sensitivities as might be expected for a heterogeneic stock. The rate of porphyria development was accelerated by administration of 5-aminolaevulinic acid (5-ALA) in the drinking water, but this did not overcome strain differences. Among four strains the order of susceptibility was SWR > C57BL/10ScSn > C57B1/6J > DBA/2 (the last strain was completely resistant). With degrees of iron loading greater than 600 mg of Fe/kg (1200-1800 mg of Fe/kg) C57BL/10ScSn mice (after 20 weeks) and SWR mice (after 5 weeks which included 4 weeks of 5-ALA treatment) had less inhibition of UROD and a lower uroporphyric response, showing that there was an optimum level of liver iron concentration. Studies on selected microsomal enzyme activities associated with cytochrome P-450 showed no correlation with the propensities of strains to develop porphyria. These activities included the NADPH-dependent oxidation of uroporphyrinogen I to uroporphyrin I.

Effect of transfusional iron intake on response to chelation therapy in β-thalassemia major

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 583-587 ◽  
Author(s):  
Alan R. Cohen ◽  
Ekkehard Glimm ◽  
John B. Porter
Keyword(s):  
Chelation Therapy ◽  
Iron Concentration ◽  
Chelating Agent ◽  
Thalassemia Major ◽  
Phase Iii ◽  
Iron Loading ◽  
Iron Intake ◽  
Liver Iron ◽  
Iron Stores ◽  
Using Data

The success of chelation therapy in controlling iron overload in patients with thalassemia major is highly variable and may partly depend on the rate of transfusional iron loading. Using data from the 1-year phase III study of deferasirox, including volumes of transfused red blood cells and changes in liver iron concentration (LIC) in 541 patients, the effect of iron loading on achieving neutral or negative iron balance was assessed in patients receiving different doses of deferasirox and the comparator deferoxamine. After dose adjustment, reductions in LIC after 1 year of deferasirox or deferoxamine therapy correlated with transfusional iron intake. At a deferasirox dose of 20 mg/kg per day, neutral or negative iron balance was achieved in 46% and 75% of patients with the highest and lowest transfusional iron intake, respectively; 30 mg/kg per day produced successful control of iron stores in 96% of patients with a low rate of transfusional iron intake. Splenectomized patients had lower transfusional iron intake and greater reductions in iron stores than patients with intact spleens. Transfusional iron intake should be monitored on an ongoing basis in thalassemia major patients, and the rate of transfusional iron loading should be considered when choosing the appropriate dose of an iron-chelating agent. This study is registered at http://clinicaltrials.gov as NCT00061750.

THE EFFECT OF PYRIDOXINE DEFICIENCY ON BLOOD UREA IN MICE

1958 ◽  
Vol 36 (1) ◽  
pp. 1143-1148
Author(s):  
John B. Lyon Jr. ◽  
Eugene A. Arnold ◽  
Rita Farmer
Keyword(s):  
Environmental Changes ◽  
Strain Differences ◽  
Inbred Strains ◽  
Vitamin B ◽  
Age Group ◽  
Pyridoxine Deficiency ◽  
Inbred Strains Of Mice

Blood urea levels were determined in weanling, young, and adult C57 and I strain mice fed vitamin B6-deficient or complete rations. Elevations in blood urea were found in some of the deprived groups, but they were transient, and the maxima occurred early in the deficiency, at 2 weeks. Although the I strain is more susceptible to a B6 deficiency, strain differences were found in only one age group. Increases in blood urea were also induced by simple environmental changes. It was concluded that elevations in blood urea are not directly related to a pyridoxine deficiency in these inbred strains of mice.

Consequences and management of iron overload in sickle cell disease

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 447-456 ◽  
Author(s):  
John Porter ◽  
Maciej Garbowski
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Cell Disease ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

scholarly journals STRAIN DIFFERENCES IN LOCAL HEMORRHAGIC RESPONSE (SHWARTZMAN-LIKE REACTION) OF MICE TO A SINGLE INTRADERMAL INJECTION OF BACTERIAL POLYSACCHARIDES

1957 ◽  
Vol 105 (6) ◽  
pp. 653-664 ◽  
Author(s):  
Margaret G. Kelly ◽  
Norman H. Smith ◽  
Isidore Wodinsky ◽  
David P. Rall
Keyword(s):  
Strain Differences ◽  
Inbred Strains ◽  
Blocking Agent ◽  
Intradermal Injection ◽  
F1 Hybrid ◽  
Hemorrhagic Necrosis ◽  
Inbred Strains Of Mice ◽  
Anticoagulant Drug ◽  
Shwartzman Reaction ◽  
Hemorrhagic Lesion

A survey of inbred strains of mice was made to determine whether the phenomenon of dermal hemorrhagic necrosis, as described in rabbits by Shwartzman, could be elicited in mice by bacterial polysaccharide preparations of demonstrated activity in rabbits. The polysaccharide preparations used were obtained from cultures of S. marcescens, S. typhosa, Ps. aeruginosa, and H. pertussis. Ten of the strains tested were unreactive. Three strains of mice and one F1 hybrid subline developed a hemorrhagic lesion at the site of injection of a single, relatively high intradermal dose of polysaccharide. Some increase in incidence of hemorrhagic lesions was obtained when the intradermal dose was followed in 24 hours by an intravenous injection. In the gross and microscopically, the skin lesion produced in mice resembled the Shwartzman reaction in rabbits. An adrenergic blocking agent, SY-28, and an anticoagulant drug, coumadin, both of which block the dermal Shwartzman reaction in rabbits, also blocked the hemorrhagic skin reaction in mice.

scholarly journals Variation among inbred strains of mice in adenosine 3′:5′ cyclic monophosphate levels of spermatozoa

1979 ◽  
Vol 33 (2) ◽  
pp. 129-136 ◽  
Author(s):  
Robert P. Erickson ◽  
Martin S. Butley ◽  
Susan R. Martin ◽  
Charles J. Betlach
Keyword(s):  
Cyclic Amp ◽  
High Strain ◽  
Strain Differences ◽  
Inbred Strains ◽  
Fertilization Rates ◽  
Major Histocompatibility Locus ◽  
Inbred Strains Of Mice ◽  
Histocompatibility Locus ◽  
Camp Levels ◽  
Reproducible Manner

SUMMARYSpermatozoa from inbred strains of mice were found to vary significantly for levels of cyclic AMP when extractions were performed in a reproducible manner. The F1 hybrid between high and low spermatozoal cAMP strains showed spermatozoal cAMP levels typical of the low strain. An analysis of spermatozoal cAMP in individual mice from the back-cross of the F1 to the high strain suggested that alleles at more than one locus determine strain differences in spermatozoal cAMP. The major histocompatibility locus of mice, H-2, which had been found to have an effect on liver cAMP levels did not seem to affect spermatozoal cAMP levels. t-Alleles, which appear to alter fertilization rates by effects on motility, had no apparent affects on spermatozoal cAMP.

Antioxidant Mediated Effects in a Gerbil Model of Iron Overload.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3813-3813
Author(s):  
Maya Otto-Duessel ◽  
Michelle I. Aguilar ◽  
Rex Moats ◽  
John C. Wood
Keyword(s):  
Vitamin E ◽  
Iron Uptake ◽  
Serum Iron ◽  
Iron Concentration ◽  
Iron Loading ◽  
Taurine Supplementation ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Gpx Activity

Abstract Introduction: Iron cardiomyopathy is a lethal complication of monthly blood transfusion therapy in patients with thalassemia major. Medications or nutritional supplements that could potentially reduce cardiac iron uptake or toxicity would have clinical significance. The amino acid taurine is ubiquitous in both rodent and human myocytes, but its physiologic role is poorly understood. In mice, taurine supplementation decreases cardiac iron and oxidative toxicity. Since taurine could produce these effects through a direct antioxidant action or through modulation of iron uptake via calcium channels, we compared taurine’s benefits with a combination of vitamin E and selenium in the gerbil model of iron cardiomyopathy. We hypothesized that taurine supplementation would decrease cardiac iron levels and iron toxicity in a parallel manner while vitamin/selenium would only decrease cardiac iron toxicity. Methods: Twenty-four animals were divided into four groups (control, iron, taurine, vitamin E + selenium). Supplementation was initiated 2 weeks prior to the iron loading period and continued throughout the 10 weeks of iron injection (200mg/kg/week). Taurine (12.5 g/L) and selenium (1.67g/L) were administered via drinking water, while vitamin E (400mg/gerbil/day) was injected subcutaneously daily. Post mortem assessment of heart and liver iron content, malondialdehyde (MDA) levels, glutathione peroxidase (GPx) activity, aspartate aminotransferase (AST) levels, alanine transaminase (ALT) levels, histology, serum, and enzyme analyses were performed. Results: No significant differences were found in heart and liver iron content between treatment groups, although dry-weight liver iron concentrations was increased in taurine-treated animals (p<0.03). Serum iron increased with iron loading (751 ± 66 ug/dL versus 251 ± 54 ug/dL, p < 0.001) and was further increased by taurine treatment (903 ± 136 ug/dL, p = 0.03). Iron overload increased cardiac malondialdehyde (MDA) levels and decreased heart and liver gluthathione peroxidase (GPx) activity, and increased serum AST consistent with oxidative stress. Taurine ameliorated these changes but results were significant only for liver GPx activity. Despite raising organ selenium levels, selenium and vitamin E supplementation did not improve oxidative markers (MDA, GPx) and actually worsened cardiac GPx levels. Discussion: Prior murine work suggested selective cardioprotective effects of taurine mediated, in part, through decreased cardiac iron levels. In the gerbil model, taurine improved hepatic GPx, despite increasing liver iron concentration and serum iron. Qualitatively similar behavior was observed in the heart, but values did not reach statistical significance. Therefore, taurine exhibits antioxidant behavior that is not mediated by decreasing organ iron concentration; oxidative protection was superior to the effects produced by selenium/vitamin E supplementation. The etiology of the increased liver and serum iron concentrations is unclear but probably reflects interference with spontaneous iron losses. While taurine supplementation appears promising, future studies are needed to clarify interspecies variability in its behavior.

Variation in pentobarbitone sleeping time in mice 1. Strain and sex differences

1986 ◽  
Vol 20 (2) ◽  
pp. 85-90 ◽  
Author(s):  
D. P. Lovell
Keyword(s):  
Sex Differences ◽  
Environmental Factors ◽  
Strain Differences ◽  
Inbred Strains ◽  
Genetic Differences ◽  
Strain Variation ◽  
Sleeping Time ◽  
Inbred Strains Of Mice ◽  
Designed Experiment ◽  
Pentobarbitone Sleeping Time

A set of 23 inbred strains of mice was tested for their sleeping time under sodium pentobarbitone anaesthetic. Highly significant strain differences were found. Estimates of the proportion of the variation accounted for by genetic differences ranged from 28% to 42%. In general, males slept longer than females but the size of the sex differences was not consistent across strains. Sleeping times on different test days also varied, indicating that environmental factors were affecting the results. A specially designed experiment failed to detect any differences in within-strain variation.

THE EFFECT OF PYRIDOXINE DEFICIENCY ON BLOOD UREA IN MICE

1958 ◽  
Vol 36 (11) ◽  
pp. 1143-1148 ◽  
Author(s):  
John B. Lyon Jr. ◽  
Eugene A. Arnold ◽  
Rita Farmer
Keyword(s):  
Environmental Changes ◽  
Strain Differences ◽  
Inbred Strains ◽  
Vitamin B ◽  
Age Group ◽  
Pyridoxine Deficiency ◽  
Inbred Strains Of Mice

Blood urea levels were determined in weanling, young, and adult C57 and I strain mice fed vitamin B6-deficient or complete rations. Elevations in blood urea were found in some of the deprived groups, but they were transient, and the maxima occurred early in the deficiency, at 2 weeks. Although the I strain is more susceptible to a B6 deficiency, strain differences were found in only one age group. Increases in blood urea were also induced by simple environmental changes. It was concluded that elevations in blood urea are not directly related to a pyridoxine deficiency in these inbred strains of mice.

scholarly journals CHROMOSOME MARKERS IN MUS MUSCULUS: STRAIN DIFFERENCES IN C-BANDING

Genetics ◽  
1973 ◽  
Vol 75 (4) ◽  
pp. 663-670
Author(s):  
V G Dev ◽  
D A Miller ◽  
O J Miller
Keyword(s):  
Mus Musculus ◽  
Strain Differences ◽  
Inbred Strains ◽  
F1 Hybrids ◽  
Centromeric Heterochromatin ◽  
Mitotic Chromosomes ◽  
Homologous Chromosomes ◽  
Chromosome Markers ◽  
C Banding ◽  
Inbred Strains Of Mice

ABSTRACT The mitotic chromosomes of several inbred strains of mice and a series of F1 hybrids have been analyzed by quinacrine staining and further characterized by the centromeric heterochromatin banding (C-banding). Inbred strains had the same amount of C-banding material on homologous chromosomes but showed variation in the amount on different chromosomes. F1 hybrids showed characteristics of each parent and it appears that the amount of C-banding on each chromosome is a simple inherited polymorphism. In this study 12 different chromosomes could be distinguished by their C-banding, and these can be used as normal chromosome markers.

The Effect of Supplemental Ascorbate on Defersirox Iron Chelation In the Iron-Loaded Gerbil

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2059-2059
Author(s):  
Maya Otto-Duessel ◽  
Casey Brewer ◽  
Aleya Hyderi ◽  
Jens Lykkesfeldt ◽  
Ignacio Gonzalez-Gomez ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Dextran ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Wet Weight

Abstract Abstract 2059 Introduction: Iron dextran injections are often used to induce iron overload in rodents, for the purposes of assessing iron chelation therapy. In gerbils, we have previously described that deferasirox therapy preferentially clears hepatocellular iron when compared with reticuloendothelial stores. Ascorbate deficiency, which is common in humans with iron overload, produces similar profound disparities between reticuloendothelial and parenchymal iron stores. We postulated that iron-induced ascorbate deficiency might be exaggerating reticuloendothelial iron retention in gerbils receiving deferasirox therapy. This study examined the effect of supplemental ascorbate on spontaneous iron loss and deferasirox chelation efficiency in the iron-dextran loaded gerbil. Methods: 48 female gerbils underwent iron dextran loading at 200 mg/kg/week for 10 weeks. Sixteen animals were sacrificed at 11 weeks to characterize iron loading; eight were on standard rodent chow and eight had chow supplemented with 2250 ppm of ascorbate. 32 additional animals that were not ascorbate supplemented during iron loading transitioned into the chelation phase. Half were subsequently placed on ascorbate supplemented chow and both groups were assigned to receive either deferasirox 100 mg/kg/day five days per week or sham chelation. Animals received iron chelation for twelve weeks. Liver histology was assessed using H & E and Prussian blue stains. Iron loading was ranked and graded on a five-point scale by an experienced pathologist screened to the treatment arm. Iron quantitation in liver and heart was performed by atomic absorption. Results: Table 1 one summarizes the findings. During iron dextran loading, ascorbate supplementation lowered wet weight liver iron concentration but not liver iron content suggesting primarily changes in tissue water content. Spontaneous iron losses were insignificant, regardless of ascorbate therapy. Deferasirox lowered liver iron content 56% (4.7% per week) in animals without ascorbate supplementation and 48.3% (4.0% per week) with ascorbate supplementation (p=NS). Cardiac iron loading, unloading and redistribution were completely unaffected by ascorbate supplementation. Spontaneous iron redistribution was large (1.9% – 2.3% per week). Deferasirox chelation did not lower cardiac iron to a greater degree than spontaneous cardiac iron redistribution. Histologic grading paralleled tissue wet weight iron concentrations. Ascorbate treatment lowered the rank and absolute iron score in liver during iron loading (p=0.003) and there was a trend toward lower iron scoring in sham treated animals (p=0.13). Ascorbate had no effect on histological score or relative compartment distributions of iron in deferasirox chelated animals (p=0.5). Ascorbate supplementation was sufficient to increase total plasma ascorbate levels from 25 ± 12.2 uM to 38.4 ± 11 uM at 10 weeks (p=0.03). In the liver, ascorbate increased from 1203 ± 212 nmol/g of tissue to 1515 ± 194 nmol/g of tissue (p=0.01) with supplementation. No significant change in total ascorbate was observed in the heart. Discussion: We hypothesized that ascorbate supplementation might improve reticuloendothelial iron accessibility to deferasirox by facilitating redox cycling. Although gerbils synthesize their own ascorbate, supplementation was able to raise both serum and hepatic total ascorbate levels. However, increasing ascorbate did not change either the amount or distribution of tissue iron in deferasirox-treated animals. Disclosures: Nick: Novartis: Employment. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

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