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Biomedical subjects

W G Beamer

Publications and source records attributed to W G Beamer.

At least 55 records · Page 3Linked to original sources
PubMed1997

Circulating and skeletal insulin-like growth factor-I (IGF-I) concentrations in two inbred strains of mice with different bone mineral densities.

Recent work has demonstrated differences in femoral bone mineral density between two common inbred strains of mice, C3H/HeJ (C3H) and C57BL/6J (B6), across a wide age range. To investigate one possible mechanism that could affect acquisition and maintenance of bone mass in mice, we studied circulatory and skeletal insulin-like growth factor-I (IGF-I) and femoral bone mineral density (F-BMD) by pQCT in C3H and B6 progenitor strains, as well as serum IGF-I obtained from matings between these two strains and mice bred from subsequent F1 intercrosses (F2). Serum IGF-I measured by radioimmunoassay was more than 35% higher in virgin progenitor C3H than virgin B6 at 1, 4, 8, and 10 months of age, and in 8-month-old C3H compared with B6 retired breeders (p < 0.001). In the progenitors, there was also a strong correlation between serum IGF-I and serum alkaline phosphatase (r = 0.51, p = 0.001). In the 4 month F1 females IGF-I levels and F-BMD were intermediate between C3H and B6 progenitors. In contrast, groups of F2 mice with the highest or lowest BMD also had the highest or lowest serum IGF-I (p = 0.0001). IGF-I accounted for > 35% of the variance in F-BMD among the F2 mice. Conditioned media from newborn C3H calvarial cultures had higher concentrations of IGF-I than media from B6 cultures, and cell layer extracts from C3H calvariae exhibited greater alkaline phosphatase activity than cultures from B6 calvarial cells (p < 0.0001). The skeletal content of IGF-I in C3H tibiae, femorae, and calvariae (6-14 weeks of age) was also significantly higher than IGF-I content in the same bones of the B6 mice (p < 0.05). These data suggest that a possible mechanism for the difference in acquisition and maintenance of bone mass between these two inbred strains is related to systemic and skeletal IGF-I synthesis.

Aging↗
PubMed1997

Genetic control of platelet activation in inbred mouse strains.

Platelet activation in inbred mouse strains was studied using expression of P-selectin as a marker of activated platelets. P-selectin expression in response to no added stimulus (spontaneous activation) or in response to adenosine diphosphate (ADP) and epinephrine or thrombin, was assessed using a flow cytometric assay. Wide variation in the responsiveness of different strains was observed with strains SJL and AKR in particular showing very high levels of spontaneous activation. Genetic studies suggest that this phenomenon is under control of a small number of genes and that the same loci are probably responsible for the high activation of both SJL and AKR. Bone marrow transplant experiments show that the trait is expressed in the platelet itself. Screening of SWXJ and AKXD recombinant inbred lines suggests that one of the responsible genes is located on chromosome 3.

Journal Article↗
PubMed1997

Development and progression of psoriasiform dermatitis and systemic lesions in the flaky skin (fsn) mouse mutant.

Flaky skin (fsn) mutant mice were originally described as a mouse model for psoriasis accompanied by hematological abnormalities. However, homozygous (fsn/fsn) mice develop a number of other pathological changes. Systematic evaluation of over 300 fsn/fsn and normal littermate control (+/+ or +/fsn) mice was carried out to characterize these changes. Psoriasiform skin lesions were first evident as focal epidermal hyperplasia and inflammation at 2 weeks of age. These lesions became confluent and diffuse by 3-4 weeks of age and were associated with marked dermal infiltration of lymphocytes and small numbers of neutrophils and macrophages. Mast cell numbers increased significantly in the dermis from 2 weeks of age onward. Diffuse dermal neovascularization accompanied these cutaneous changes. Systemic lesions included progressive and massive papillomatosis of the stratified squamous epithelium of the forestomach, hyperplasia and dysplasia of the glandular stomach, increased apoptosis of cecal enterocytes, renal glomerulopathy associated with immune complex and complement deposition, testicular degeneration, mixed inflammatory cell infiltrates and fibrosis around portal triads in the liver, splenomegaly due to massive erythropoiesis, and granulomatous lymphadenitis. This spontaneous mouse mutation provides a useful model for modulating neovascularization and keratinocyte hyperproliferation, especially since the cutaneous changes resemble some forms of psoriasis in humans.

Aging↗
PubMed1996

Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.

The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.

Alleles↗
PubMed1996

Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation.

Insulin-like growth factor I (IGF-I) is a potent breast cancer mitogen. Growth hormone (GH) up-regulates hepatic IGF-I gene expression and circulating IGF-I level. Tissue IGF bioactivity is influenced not only by circulating IGF-I and IGF-II levels but also by autocrine and paracrine production of these growth factors and by IGF binding proteins. There is considerable person-to-person variability in GH-IGF-I physiology. Both laboratory and epidemiological data are consistent with the hypothesis that the host GH-IGF-I axis influences breast cancer behavior, but such an effect has not been directly demonstrated. To determine whether breast cancer growth in an in vivo model is influenced by the host GH-IGF-I axis, we compared the growth of human MCF-7 breast cancer cells in control mice to that in mice homozygous for lit, a missense mutation resulting in loss of function of the pituitary GH-releasing hormone receptor and secondary suppression of GH and IGF-I. Breast cancer growth was significantly reduced in lit/lit animals compared to control hosts [tumor size (mean +/- SD) on day 39,444 +/- 82 versus 845 +/- 444 mm3, respectively; P < 0.001, Mann-Whitney U test]. These data demonstrate that in our model, host GH-IGF-I axis physiology plays a role in determining breast cancer behavior. The results a) suggest that patient-to-patient variability in GH-IGF-I physiology may contribute to the large variability between patients regarding breast cancer behavior, and b) motivate clinical trials of novel hormonal treatment strategies that target the GH-IGF-I axis.

Animals↗
PubMed1996

Strain distribution pattern for SSLP markers in the SWXJ recombinant inbred strain set: chromosomes 7 to X.

The SWXJ recombinant inbred (RI) set was developed for genetic analysis of heritable ovarian tumors. In this report we present data for 223 simple sequence length polymorphisms spanning Chromosomes (Chrs) 7-X to complete the genetic marking of this RI set. The strain distribution patterns (SDP) for these loci were combined with data from 19 other polymorphic genes, resulting in densely marked maps for Chrs 7-X. Combined with the 165 loci for Chr 1-6 reported previously (Svenson et al., Mamm. Genome 6, 867, 1995), the SWXJ RI set represents a powerful tool for mapping genes in neoplastic as well as other heritable disorders.

Animals↗
PubMed1996

Genetic variability in adult bone density among inbred strains of mice.

More than 70% of the variability in human bone density has been attributed to genetic factors as a result of studies with twins, osteoporotic families, and individuals with rare heritable bone disorders. We have applied the Stratec XCT 960M pQCT, specifically modified for small skeletal specimens, to analyses of bones from 11 inbred strains (AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, C57L/J, DBA/2J, NZB/B1NJ, SM/J, SJL/BmJ, SWR/BmJ, and 129/J) of female mice to determine the extent of heritable differences in peak bone density, pQCT scans were taken of femurs from (a) 12-month-old inbred strain females and (b) a subset of four strains (C3H/HeJ, DBA/2J, BALB/cByJ, C57BL/6J) at 2, 4, and 8 months. In addition, pQCT scans were also obtained from L5-L6 vertebrae and proximal phalanges from the same subset of four inbred strains at 12 months of age. Comparison of bone parameters among inbred strains revealed significant differences at each of the three sites investigated. Femoral and phalangeal bones differed among strains with respect to total and cortical density, mineral, and volume. Only cortical bone parameters were significantly different among strains at the vertebral site. With respect to strain differences, the highest value for any given bone parameter was found in the C3H/HeJ strain, whereas C57BL/6J values were absolutely, or statistically, the lowest. Similarly, with respect to bone sites, cortical bone density was significantly correlated among strains. On the other hand, we found that none of the femur, vertebral, or phalangeal parameters correlated with body weight, even though body weight varied by 86% among those inbred strains. The developmental studies of femurs conducted at 2, 4, and 8 months of age with C3H/HeJ, DBA/2J, BALB/cByJ, and C57BL/6J females showed differences in total density among strains at 2 months and thereafter. Adult peak bone density was typically achieved by 4 months, whereas femurs continued to lengthen for 4 to 8 months thereafter. We conclude that (1) major genetic effects on femoral, vertebral, and phalangeal bone density are detectable among inbred strains of mice; (2) cortical bone density shares common genetic regulation at the three measured sites; and (3) within the femur, genes that regulate length and density are different.

Aging↗
PubMed1995

The flaky skin (fsn) mutation in mice: map location and description of the anemia.

Flaky skin (gene symbol fsn) is an autosomal recessive mutation that causes pleiotropic effects of anemia, papulosquamous skin disorder, and gastric forestomach hyperplasia. In this report, we assign fsn to distal chromosome 17 and characterize the anemia. The decrease in hematocrit levels and red blood cell counts is significant and persists throughout life in fsn/fsn mice. There is compensatory enlargement of the heart, liver, and spleen by 8 weeks of age, whereas the thymus is less than one half normal weight. Nucleated cell counts in the peripheral blood are increased 15- to 30-fold, primarily due to an increased percentage of normoblasts. The fsn/fsn mice examined at 8 weeks of age have significantly increased reticulocyte counts and protoporphyrin levels but reduced hemoglobin concentration, suggesting possible abnormalities of hemoglobin metabolism. Erythrocyte membrane fragility is normal. Compared with normal +/? littermates, fsn/fsn mice (1) lack splenic and hepatic stores of elemental iron, (2) have the ability to transport 59Fe across the duodenal cells and into the blood, (3) have increased levels of transferrin in serum, and (4) have acute loss of urinary 59Fe. Hemolysis is indicated by increased serum bilirubin and high blood reticulocyte numbers. Collectively, the genetic, hematologic, and pathologic data indicate a severe hematologic disorder caused by homozygosity for the fsn mutation that differs from other known hematologic mutations in the mouse. The mechanism whereby fsn induces the reported pleiotropic effects has yet to be elucidated.

Anemia, Hypochromic↗
PubMed1995

Treatment with growth hormone and IGF-I in growing rats increases bone mineral content but not bone mineral density.

Human growth hormone (hGH) and insulin-like growth factor I (IGF-I) both stimulate bone formation and have been proposed as therapeutic agents for osteoporosis. We examined the effect of hGH and IGF-I alone and in combination on bone size, bone mineral content (BMC), and bone mineral density (BMD) in 10- to 12-week old growing female Sprague-Dawley rats. Sixty rats were assigned to treatment with either placebo, hGH, IGF-I, or both for 4 weeks. After 4 weeks, the right femurs and tibias were excised, and ex vivo BMC and the area of the tibia and femur were measured by dual-energy X-ray absorptiometry (DXA); volume of these bones was measured by Archimedes' principle. In addition, proximal tibial bone density was measured directly by peripheral quantitative computerized tomography (pQCT). Bone length, area, and volume in all treated groups was greater than controls. Areal bone density by DXA (BMC/area) was higher in IGF-treated rats and lower in GH-treated rats than in controls. Volumetric bone density (BMC/volume) was lower in treated groups than in controls. Measurements by pQCT confirmed that true bone density was lower in all treated groups than in controls. We conclude that treatment with hGH or IGF-I increased bone size and mineral content but decreased bone density in growing rats. Because areal correction of BMC did not adequately correct for the increased bone volume in IGF-treated rats, results of areal bone density by DXA should be interpreted with caution when treatment causes a disparity in bone size between groups.

Animals↗
PubMed1995

Survival of human prostate carcinoma, benign hyperplastic prostate tissues, and IL-2-activated lymphocytes in scid mice.

Mice, homozygous for the mutation severe combined immunodeficiency (scid) and also segregating for the mutation hypogonadal (hpg), were tested for their potential use as an in vivo model system for studying the growth of human prostate cancer and benign hyperplastic prostate tissue grafts. Fresh human prostate cancer or benign hyperplastic prostate tissue was implanted subcutaneously into androgen-replete C.B. 17 scid/scid males, and into androgen-deficient hpg/hpg scid/scid or androgen-replete +/? scid scid males. The tissue grafts grew in both androgen-replete and androgen-deficient host mice. When dihydrotestosterone (DHT) was administered at tissue grafting, both the incidence and size of the tissue grafts increased. Histology of tissue from tumors in the androgen-deficient hpg/hpg scid/scid host showed either undifferentiated tumors or adenocarcinomas with few glandular structures. These data suggest the androgen deficient environment selected for growth of androgen-independent tumor tissue. Finally, when interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes were injected into scid/scid hosts, the cells were found to survive and could be identified in the spleen of the recipient mice. These results indicate that growth of human prostate tissues and IL-2-activated lymphocytes in scid/scid mice is a viable model system for in vivo studies of prostatic disease.

Adenocarcinoma↗
PubMed1995

Strain distribution pattern for SSLP markers in the SWXJ recombinant inbred strain set: chromosomes 1 to 6.

We typed 147 simple sequence length polymorphisms in the SWXJ recombinant inbred (RI) strain set spanning Chromosomes (Chrs) 1-6. The strain distribution pattern for these loci was combined with data from 18 previously typed loci for SWXJ, resulting in new chromosome maps for this RI set, with an average density of 3.5 cM between loci. This is the first systematic effort to develop a more highly resolved genetic map for the SWXJ RI set and thereby improves the usefulness of this genetic tool for mapping genes underlying both simple and complex genetic disorders.

Animals↗
PubMed1995

Differentiating between orchiectomized rats and controls using measurements of trabecular bone density: a comparison among DXA, histomorphometry, and peripheral quantitative computerized tomography.

In studies of rat bone metabolism, trabecular bone density should be measured. Three established methods of measuring trabecular bone include trabecular bone volume by histomorphometry (BV/TV%), trabecular bone density by peripheral quantitative computerized tomography (pQCT), and areal bone density of trabecular-rich regions by dual x-ray absorptiometry (DXA). We compared the ability of these three methods to discriminate between orchiectomized (orchidectomized) rats and controls. Sixteen male Sprague-Dawley rats (400-425 g) were orchiectomized, and 16 others were controls. In vivo spine bone mineral density (BMD) was measured at the beginning of the study and again after 11 weeks. Rats were sacrificed, and ex vivo BMDs of the right femur and tibia were measured by DXA, followed by trabecular bone density of the right proximal tibia by pQCT. BT/TV% of the left proximal tibia was measured by histomorphometry. Differences between groups were detected by all three methods, but both the magnitude of the difference between groups and the variance of the measurements was much greater for histomorphometry and pQCT than for DXA. Consequently, the statistical significance for the difference between groups was comparable for all three methods. Of the sites measured with DXA, the proximal tibia had the greatest statistical significance for the difference between groups. In summary, all three methods can demonstrate the effect of orchiectomy on trabecular bone. The large differences between groups seen by histomorphometry are also seen by pQCT but not by DXA. We conclude that trabecular bone density by pQCT may be a reasonable surrogate for measurements by histomorphometry.

Absorptiometry, Photon↗
PubMed1995

Mechanisms of hormone-mediated carcinogenesis of the ovary in mice.

Experimental ovarian carcinogenesis has been investigated in inbred and hybrid strains of mice and induced by a diversity of mechanisms including X-irradiation, oocytotoxic xenobiotic chemicals, ovarian grafting to ectopic or orthotopic sites, neonatal thymectomy, mutant genes reducing germ cell populations, and aging. The mechanisms are briefly reviewed whereby disruptions in the function of graafian follicles results in a spectrum of ovarian proliferative lesions including tumors. The findings in mutant mice support the concept of a secondary (hormonally-mediated) mechanism of ovarian carcinogenesis in mice associated with sterility. Multiple pathogenetic factors that either destroy or diminish the numbers of graafian follicles in the ovary result in decreased sex hormone secretion (especially estradiol-17 beta) leading to a compensatory over-production of pituitary gonadotrophins (particularly luteinizing hormone), which places the mouse ovary at an increased risk to develop tumors. The intense proliferation of ovarian surface epithelium and stromal (interstitial) cells with the development of unique tubular adenomas in response to sterility does not appear to have a counterpart in the ovaries of women.

Animals↗
PubMed1995

Improved engraftment of human spleen cells in NOD/LtSz-scid/scid mice as compared with C.B-17-scid/scid mice.

T and B lymphocyte-deficient mice homozygous for the severe combined immunodeficiency (SCID) mutation can be immunologically engrafted with human lymphocytes. However, low levels of human peripheral blood mononuclear cell engraftment are commonly observed, impeding full use of this model. We now demonstrate that strain background in mice homozygous for the scid mutation is a strong determinant of levels of human lymphocyte engraftment. NOD/LtSz-scid/scid mice support higher levels of engraftment of both human spleen and peripheral blood mononuclear cells than do C.B-17-scid/scid mice. We observed, using human spleen cell injected scid mice, 1), high levels of engraftment of the host peripheral lymphoid tissues with human CD45+ (leukocytes), CD3+ (T cells), CD4+ (helper/inducer), and CD8+ (suppressor/cytotoxic) lymphoid cells for up to 24 weeks in NOD/LtSz-scid/scid mice; 2), migration of high numbers of human lymphocytes to peripheral lymphoid and nonlymphoid organs in NOD/LtSz-scid/scid, but not in C.B-17-scid/scid mice; 3), higher levels of serum immunoglobulin of human origin in NOD/LtSz-scid/scid mice than in C.B-17-scid/scid mice; 4), histological lesions characteristic of human anti-mouse xenoreactivity in NOD/LtSz-scid/scid mice; and 5), human origin antibodies against filarial antigens after engraftment with native human spleen cells. The use of NOD/LtSz-scid/scid mice as recipients to achieve significantly enhanced human lymphopoietic cell engraftment will now enable human immunity to be more easily studied in animal models.

Animals↗
PubMed1994

Increased B lymphopoiesis in genetically sex steroid-deficient hypogonadal (hpg) mice.

Interleukin 7 (IL-7) responsive B lineage precursors were greatly expanded in genetically hypogonadal female (HPG/Bm-hpg/hpg) mice that have a secondary deficiency in gonadal steroidogenesis. Estrogen replacement in these mice resulted in a dose-dependent reduction in B cell precursors. More modest increases were documented in genetically normal mice that were surgically castrated. These findings complement other recent observations that B lymphopoiesis selectively declines in pregnant or estrogen-treated animals. Sex steroids have long been known to influence such disparate processes as bone physiology and tumor growth, in addition to their importance for reproductive function. We now show that these hormones are important negative regulators of B lymphopoiesis.

Animals↗
PubMed1994

Influence of gonadal steroids on susceptibility to Brugia malayi in scid mice.

In the present study, we demonstrate that male scid/scid mice have higher adult worm burdens than do female scid/scid mice following equal challenge doses of infective Brugia malayi L3 larvae. Gonadectomy of four week old immature mice has no effect on worm burden in either sex, suggesting that the gender dichotomy between males and females does not depend on continued presence of endogenous gonadal steroids. The worm yield from female, but not male, mice can be increased by prepubertal oophorectomy combined with administration of either estradiol or testosterone in depot form. Our results raise the possibility that prepubertal steroid pulse(s) result(s) in physiological changes in male scid/scid mice that enhance worm growth. These studies confirm earlier reports of epidemiological data in humans suggesting a sexual dimorphism in susceptibility to filarial infection. Our data suggest that this gender difference is not due simply to the presence of adult gonadal steroids, but rather to ontogenic differentiative actions of sex steroids in the host.

Animals↗
PubMed1994

Full-thickness skin grafts from flaky skin mice to nude mice: maintenance of the psoriasiform phenotype.

Flaky skin (fsn) is an autosomal recessive mouse mutation with papulosquamous disease features similar to human psoriasis. In fsn/fsn skin, one sees marked acanthosis and hyperkeratosis with focal parakeratosis, subcorneal pustules, dermal capillary dilation, and a marked diffuse dermal infiltration of mixed inflammatory cells, predominantly lymphocytes. To determine if these pathologic features are a characteristic of the skin or a chronic autoimmune attack, we placed full-thickness skin grafts from affected homozygous (fsn/fsn) and normal littermate control (+/?) mice on the dorsal skin of genetically athymic nude (nu/nu) mice. After 10 weeks of observation, the grafts maintained the histologic phenotype of the donor animal. In the fsn/fsn grafts, there was persistence of both epidermal proliferation and dermal inflammation, characteristics of the mutation. The fsn/fsn phenotype was also confirmed by immunohistochemical evaluation for specific mouse keratinocyte marker expression. Based on tritiated thymidine uptake, we found DNA synthesis rates elevated threefold or more in fsn/fsn epidermis compared to littermate control mouse skin. Elevated rates of DNA synthesis remained a feature of the fsn/fsn grafts but not that of littermate control skin grafts. This study demonstrates that the psoriasiform phenotype of this mouse mutation can persist independent of the host thymic-derived immune system.

Animals↗