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Biomedical subjects

B Bolon

Publications and source records attributed to B Bolon.

At least 19 recordsLinked to original sources
PubMed2006

Isoflurane leakage from non-rebreathing rodent anaesthesia circuits: comparison of emissions from conventional and modified ports.

Chronic exposure to low levels of fluorocarbon-based waste anaesthetic gas (WAG) has been linked to a multitude of human health problems. We have shown that isoflurane exhaust from passive gas-scavenging canisters is often quite high when using conventional rodent anaesthesia protocols and equipment. Another likely source of WAG build-up in rodent procedure rooms is leakage at the interface between the breathing circuit and the animal's face. We evaluated this possibility using three non-rebreathing circuits: traditional Bain, modified Bain, and Mapleson (type E). For the Mapleson E circuit, a conical rodent facemask was attached and used in one of two configurations: normal aperture, or aperture modified with a latex diaphragm (cut from an unpowdered surgical glove) to reduce the orifice diameter and tighten the seal. Adult female Sprague-Dawley rats were anaesthetized with isoflurane (5% for induction, 2% or 3.5% for maintenance) in oxygen (2 L/min for induction, 1 L/min for maintenance). Isoflurane leakage was assessed by real-time spectrophotometry. In 94% of the trials, three configurations - traditional Bain, modified Bain, and Mapleson E with unmodified mask - permitted isoflurane leakage approaching or exceeding 100 ppm at the face/port interface. In contrast, the Mapleson circuit with diaphragm-modified mask emitted significantly (P<or=0.0003) less isoflurane (peak of 9.5+/-1.7 ppm [mean+/-standard error]). These data indicate that (1) WAG leakage from standard rodent non-rebreathing circuits is substantial, and that (2) a simple, rapid, and economical modification to a conventional rodent facemask can significantly reduce WAG exposure to workers performing many rodent anaesthesia procedures in one session.

Air Pollutants, Occupational↗
PubMed2004

Osteoclast numbers in Lewis rats with adjuvant-induced arthritis: identification of preferred sites and parameters for rapid quantitative analysis.

This study defined the best site for quantifying osteoclasts in male Lewis rats with mycobacteria-induced adjuvant arthritis. Hind paw sections of normal and arthritic rats (n = 6 per group) taken 7 days after disease onset were stained for osteoclasts using an anti-human cathepsin K primary antibody. Erosions and osteoclasts were assessed using semiquantitative scores (entire section) and quantitative measures (in calcaneus, navicular tarsal, and tibia). Bone area in arthritic rats was significantly reduced (P </= 0.05) by 39-55%, with the greatest decrease in the tarsal. Osteoclasts in arthritic rats were significantly increased (P </= 0.05) relative to normal in calcaneus (sevenfold), tarsal (194-fold), and tibia (threefold). The most useful quantitative indices were bone area and total osteoclasts, both defined as a percentage of total area measured. Semiquantitative scores for bone erosion and osteoclasts paralleled the quantitative indices. These data show that the navicular tarsal is the most sensitive site at which to assess arthritis in rats with this variant of adjuvant-induced arthritis.

Animals↗
PubMed2004

Interleukin-1beta and tumor necrosis factor-alpha produce distinct, time-dependent patterns of acute arthritis in the rat knee.

Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) synergistically induce and sustain arthritis. Two competing hypotheses of arthritis induction are 1) that TNF preferentially mediates inflammation, whereas IL-1 impels bone destruction, or 2) that either cytokine controls the entire process. In this study, these propositions were tested in two experiments by instilling IL-1beta or TNF-alpha into one knee of Lewis rats (n = 6/group) to incite arthritis, after which semiquantitative scores for inflammation, bone resorption, osteoclasts, and cartilage integrity were acquired. In the induction study, IL-1beta or TNF-alpha (3, 10, or 30 micro g) was given once to incite arthritis. After 2 days, IL-1beta induced significant, dose-dependent increases in inflammation (mild to marked), bone resorption (minimal to moderate), and osteoclasts (minimal to moderate). In contrast, TNF-alpha induced minimal to mild inflammation but had little impact on resorption or osteoclasts. Both IL-1 and TNF (>/=10 micro g) yielded mild cartilage degeneration. Most lesion scores in TNF-treated rats were significantly lower than those in animals given the same dose of IL-1beta. In the persistence study, rats were injected once with IL-1 or TNF (10 micro g) and maintained for 2, 3, or 7 days. IL-1beta significantly enhanced inflammation (all 3 days), bone resorption (days 2 and 3), osteoclasts (days 2 and 3), and cartilage matrix loss (days 2 and 3), whereas TNF-alpha augmented inflammation (days 2 and 3) and cartilage degeneration (day 2) but not bone resorption or osteoclasts. Thus, both IL-1beta and TNF-alpha can launch inflammation, but IL-1beta drives skeletal destruction.

Animals↗
PubMed2002

Duration of bone protection by a single osteoprotegerin injection in rats with adjuvant-induced arthritis.

Daily osteoprotegerin (OPG) injection for 7 or more days prevents bone loss for 3 weeks in rats with adjuvant-induced arthritis (AdA). The present experiments defined the duration of bone protection in AdA provided by a single OPG bolus. Male Lewis rats received OPG at the onset or peak of clinical disease, after which bone mineral density (BMD), erosions, and osteoclasts were evaluated. An OPG bolus (4 mg/kg subcutaneously) at onset eliminated osteoclasts, preserved BMD for 7 days, and prevented bone erosions for 4 days. In contrast, an OPG bolus (1, 3, 10, or 30 mg/kg intravenously) given at the peak of disease eradicated osteoclasts in a dose-dependent manner but had no impact on bone integrity due to extensive pre-existing bone loss. These data indicate that one OPG injection will inhibit joint erosions for several days, and confirm that bone-sparing therapy must be initiated early in disease to protect joint integrity.

Animals↗
PubMed2001

Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis.

Osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast formation, function, and survival. The current studies employed a mouse ovariectomy (OVX) model of estrogen deficiency to investigate gene therapy with OPG as a means of preventing osteoporosis. Young adult females injected with a recombinant adenoviral (Ad) vector carrying cDNA of either full-length OPG or a fusion protein combining the hOPG ligand-binding domain with the human immunoglobulin constant domain (Ad-hOPG-Fc) developed serum OPG concentrations exceeding the threshold needed for efficacy. However, elevated circulating OPG levels were sustained for up to 18 months only in mice given Ad-hOPG-Fc. Administration of Ad-hOPG-Fc titers between 10(7) and 10(9) pfu yielded dose-dependent increases in serum OPG. Mice subjected to OVX or sham surgery followed by immediate treatment with Ad-hOPG-Fc had significantly more bone volume with reduced osteoclast numbers in axial and appendicular bones after 4 weeks. In contrast, animals given OVX and either a control vector or vehicle had significantly less bone than did comparably treated sham-operated mice. This study demonstrates that a single adenoviral gene transfer can produce persistent high-level OPG expression and shows that gene therapy to provide sustained delivery of OPG may prove useful in treating osteoporosis.

Adenoviridae↗
PubMed2001

Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease.

Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).

Animals↗
PubMed2000

Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration.

Phosphoinositide 3-kinases (PI3Ks) regulate fundamental cellular responses such as proliferation, apoptosis, cell motility, and adhesion. Viable gene-targeted mice lacking the p110 catalytic subunit of PI3Kgamma were generated. We show that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells. PI3Kgamma-deficient neutrophils exhibited severe defects in migration and respiratory burst in response to heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) agonists and chemotactic agents. PI3Kgamma links GPCR stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase, and extracellular signal-regulated kinases 1 and 2. Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst.

Animals↗
PubMed2000

Anti-interleukin-1 and anti-tumor necrosis factor-alpha synergistically inhibit adjuvant arthritis in Lewis rats.

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play dominant roles in mediating the progression of many inflammatory joint diseases, including rheumatoid arthritis in humans, collagen-induced arthritis in mice and rats, and adjuvant arthritis in rats. Blockade of either cytokine partially controls these diseases. The present study investigated the value of combination anti-cytokine therapy in arthritis: the efficacy of IL-1 receptor antagonist (IL-1ra) and 30 kDa polyethylene glycol (PEG)-conjugated soluble TNF receptor type I (PEG sTNF-RI) given together was assessed in Lewis rats with adjuvant arthritis. Administration of either IL-1ra or PEG sTNF-RI partially alleviated joint inflammation, loss of bone mineral density, and loss of body weight. In contrast, combination of these anti-cytokine treatments exhibited a synergistic capacity to inhibit these changes, even when combining doses of IL-1ra and PEG sTNF-RI that did not affect lesion severity when used alone. Statistical analysis of these adjuvant arthritis data using the isobologram method proved that IL-1ra and PEG sTNF-RI were clearly synergistic in inhibiting inflammation, loss of bone mineral density, loss of body weight, and histopathologic parameters of inflammation and joint destruction. These results suggest that treating autoimmune arthritic diseases with combinations of anti-IL-1 and anti-TNF molecules will achieve superior efficacy compared to the use of a single class of anti-cytokine agent and may allow for dose reductions that could prove useful in minimizing potential side effects.

Animals↗
PubMed1999

Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.

Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T cells is induced by antigen receptor engagement, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.

Animals↗
PubMed1999

Retinoic acid acts during peri-implantational development to alter axial and brain formation.

All-trans retinoid acid (RA) induces a stereotypic spectrum of stage-specific malformations in vertebrate conceptuses. The present work evaluated the anatomic and biochemical effects of exposure to RA in mouse embryos at a peri-implantational stage of development - gestational day (GD) 5. The RA receptors (RARs) beta and gamma, the retinoid X receptors (RXRs) alpha and beta, and the cellular retinoid acid binding proteins (CRABPs) I and II were detected by RT-PCR in both control and treated individual GD 5 decidua/embryo complexes 3 h after RA injection, indicating the presence of the mRNAs coding for the proteins that mediate the effects of RA. In contrast, the RAR alpha mRNA was detected in some but not all decidua/embryo complexes, both control and treated, suggesting that its expression is initiated at approximately GD 5, while RXR gamma mRNA was not detected. Examination of the control and RA-exposed embryos on GD 10, 12, or 17 showed that greater than 50% of the RA-exposed embryos were adversely affected, many with defects found only after serial histopathological examination. The malformations were localized primarily in the central nervous system, the branchial arches, and their derivatives. These terata included excessive folding and elevation of the neural tube floor plate, exencephaly (with detachment of the cephalic neuroepithelium and rarefied cephalic mesenchyme), persistent patency of Rathke's pouch, small trigeminal ganglia, neural diverticula (chiefly from the spinal cord), and/or various optic and otic defects. Unexpectedly, limb reduplications were not apparent in RA-exposed fetuses. Those litters examined on GD 17 had a high percentage of resorbed or malformed implantations, and the few apparently normal fetuses were developmentally delayed with respect to bone ossification. These data confirm that the development of neural- and neural crest-derived structures are severely disrupted by RA exposure prior to initial specification of the neural plate and suggest that many of the proteins that regulate RA signaling are available in early vertebrate embryos at this developmental stage.

Abnormalities, Drug-Induced↗
PubMed1999

Wiggler-field effects on the space-charge waves of a Raman free-electron laser.

An analysis of the propagation of a space-charge wave through the wiggler and axial magnetic fields of a free-electron laser is presented. The relativistic electron beam is contained within and only partially fills a cylindrical metallic waveguide. A theory is developed using lab-frame Maxwell and fluid equations in a form which is equivalent to the electrostatic approximation in the beam frame. The computational method of determining the dispersion relation is described and some numerical results are presented which illustrate effects arising from the wiggler and the partially filled waveguide.

Journal Article↗
PubMed1999

Haematology and serum chemistry parameters of the pregnant rat.

This study describes the baseline haematology and serum chemistry values found in non-pregnant, pregnant (gestational days [GD] 2-21) and lactating (postnatal days 1-9) Sprague Dawley rats (n = 3-10/day) from the NCTR breeding colony of Crl:COBS CD(SD)BR strain. Maternal body weights on GD0 ranged from 250 to 300 g. Multiple analytes were measured in both whole blood and serum of dams. Amniotic fluid, fetal serum, and postnatal pup serum analyte values were also acquired. Maternal blood was collected from the heart under subterminal carbon dioxide (CO2) anaesthesia. Most pregnant dam blood values were not appreciably different from values for non-pregnant dams until near term; near-term values for some analytes (red blood cells, haemoglobin, haematocrit, mean corpuscular haemoglobin concentration, alkaline phosphatase, albumin, total protein, glucose, total bilirubin, sodium, and chloride) decreased but returned to near-normal values soon after delivery. The most dramatic change was a three-fold elevation of serum triglyceride levels near term with a subsequent decrease at birth. Most serum chemistry analytes measured in progeny increased after birth except for alkaline phosphatase, calcium and potassium levels which decreased.

Amniotic Fluid↗
PubMed1998

Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless.

Fgf-10-deficient mice (Fgf-10(-/-)) were generated to determine the role(s) of Fgf-10 in vertebrate development. Limb bud initiation was abolished in Fgf-10(-/-) mice. Strikingly, Fgf-10(-/-) fetuses continued to develop until birth, despite the complete absence of both fore- and hindlimbs. Fgf-10 is necessary for apical ectodermal ridge (AER) formation and acts epistatically upstream of Fgf-8, the earliest known AER marker in mice. Fgf-10(-/-) mice exhibited perinatal lethality associated with complete absence of lungs. Although tracheal development was normal, main-stem bronchial formation, as well as all subsequent pulmonary branching morphogenesis, was completely disrupted. The pulmonary phenotype of Fgf-10(-/-) mice is strikingly similar to that of the Drosophila mutant branchless, an Fgf homolog.

Animals↗
PubMed1998

Cytologic features of a meningioma in a dog.

Meningiomas are one of the most common nervous system tumors in dogs. They are mostly solitary, benign, intracranial tumors of the transitional type. Tentative diagnosis can usually be made on historical data, clinical and neurological signs, and radiographs, with an antemortem diagnosis confirmed by exploratory surgery and histologic evaluation of biopsy. The literature contains many reports of the gross, histological and ultrastructural morphology of canine meningiomas, but little on the cytologic features of these tumors. This report describes the cytologic appearance of an intracranial meningioma in a 9-year-old Miniature Schnauzer.

Journal Article↗
PubMed1998

FGF-18, a novel member of the fibroblast growth factor family, stimulates hepatic and intestinal proliferation.

The fibroblast growth factors (FGFs) play key roles in controlling tissue growth, morphogenesis, and repair in animals. We have cloned a novel member of the FGF family, designated FGF-18, that is expressed primarily in the lungs and kidneys and at lower levels in the heart, testes, spleen, skeletal muscle, and brain. Sequence comparison indicates that FGF-18 is highly conserved between humans and mice and is most homologous to FGF-8 among the FGF family members. FGF-18 has a typical signal sequence and was glycosylated and secreted when it was transfected into 293-EBNA cells. Recombinant murine FGF-18 protein (rMuFGF-18) stimulated proliferation in the fibroblast cell line NIH 3T3 in vitro in a heparan sulfate-dependent manner. To examine its biological activity in vivo, rMuFGF-18 was injected into normal mice and ectopically overexpressed in transgenic mice by using a liver-specific promoter. Injection of rMuFGF-18 induced proliferation in a wide variety of tissues, including tissues of both epithelial and mesenchymal origin. The two tissues which appeared to be the primary targets of FGF-18 were the liver and small intestine, both of which exhibited histologic evidence of proliferation and showed significant gains in organ weight following 7 (sometimes 3) days of FGF-18 treatment. Transgenic mice that overexpressed FGF-18 in the liver also exhibited an increase in liver weight and hepatocellular proliferation. These results suggest that FGF-18 is a pleiotropic growth factor that stimulates proliferation in a number of tissues, most notably the liver and small intestine.

3T3 Cells↗
PubMed1997

Differential follicle counts as a screen for chemically induced ovarian toxicity in mice: results from continuous breeding bioassays.

Ovaries from National Toxicology Program Reproductive Assessment by Continuous Breeding (RACB) bioassays were used to directly compare differential ovarian follicle counts and reproductive performance for 15 chemicals. Ovaries of 10 animals per group from 16 studies in CD-1 mice and 1 study each in C3H and C57BL/6 mice were sectioned serially at 6 microm. Counts of small, growing, and antral follicles were obtained in every 10th section. For all follicle types, younger mice had more follicles than older mice, and CD-1 mice had more follicles than age-matched animals from either inbred strain. The in-life portion of the RACB protocols demonstrated that 9 of 15 chemicals altered reproductive outcome in one or both sexes of mice, with six agents affecting females (R. E. Morrissey et al., 1989, Fundam. Appl. Toxicol. 13, 747-777). Three of six female toxicants [2,2-bis(bromoethyl)-1,3-propanediol, BPD; ethylene glycol monomethyl ether, EGME; methoxyacetic acid, MAA] significantly decreased counts of small and/or growing follicles by 33 to 92% in CD-1 mice; EGME also reduced follicle counts in the other strains. Follicle counts were decreased in progeny of animals treated with EGME or its active metabolite, MAA. For BPD, reductions in follicle numbers were proportional to dose. In CD-1 mice, female toxicants di-N-hexyl phthalate, propantheline bromide, and tricresyl phosphate reduced reproductive performance but not follicle numbers. Counts were not affected by toxicants for which the susceptible sex could not be determined (bisphenol A, ethylene glycol, oxalic acid). Altered follicle counts without apparent reproductive impairment occurred in CD-1 mice at lower doses of BPD but were not observed for nontoxic chemicals. These data suggest that differential follicle counts (1) are a quantifiable endpoint of ovarian injury in conventional bioassays, and (2) in some instances, may provide a more sensitive indicator of female reproductive toxicity than fertility.

Age Factors↗
PubMed1997

Characterization of cellular response to silicone implants in rats: implications for foreign-body carcinogenesis.

Foreign-body (FB) carcinogenesis is a classic model of multistage tumour development in rodents. Previous studies have demonstrated that the physical characteristics of the implant, and not the chemical composition, are the critical determinants of tumour development. The recent controversy over silicone breast implants has raised questions regarding the potential carcinogenicity of lifetime tissue exposure to silicone products. The present study was designed to determine whether the inflammatory and fibrotic reactions associated with silicone implants are due to a non-specific foreign-body reaction or whether these responses reflect the unique chemical composition of silicone. F344 rats were implanted subcutaneously with one of three biomaterials: silicone elastomer (Group 1); impermeable cellulose acetate filters (Group 2, positive control); or porous cellulose acetate filters (Group 3, negative control). The silicone and cellulose implants of Groups 1 and 2 have been previously shown to induce fibrosarcomas in rodents, whereas the porous cellulose acetate implants of Group 3 have been shown to be non-carcinogenic. One week and two months after implantation, the pericapsular tissues were evaluated using histopathological and in situ immunohistochemical analyses. Endpoints included expression of leucocyte antigens CD4 (T helper/inducer), CD8 (T suppressor/cytotoxic) and CD11 b/c (macrophage), proliferating cell nuclear antigen (PCNA) as an indicator of proliferation, and in situ end-labelling (ISEL) of 3'OH DNA strand breaks as an indicator of DNA damage and apoptosis. The results indicated that the acute and chronic cellular responses to silicone (Group 1) were not different from impermeable cellulose filters (Group 2) of identical size and shape, suggesting that these responses were not unique to silicone. The inflammatory response to the carcinogenic cellulose and silicone implants (Groups 1 and 2) was attenuated and associated with the formation of a thick fibrotic capsule. In contrast, the porous cellulose filters (Group 3) induced a markedly different cellular response in which the inflammatory reaction was more extensive, prolonged and associated with minimal fibrosis. Within the fibrotic capsule surrounding the tumorigenic implants, but not the non-tumorigenic implants, cell proliferation and apoptotic cell death were increased and associated with persistent DNA strand breaks. Taken together, the results suggest that the micrometre-scale surface morphology of the implant determines the nature of the subsequent cellular response which may predispose to tumour development. Further, these studies serve to emphasize the critical importance of appropriate physical controls in studies designed to evaluate carcinogenic or autoimmune manifestations associated with silicone implants in order to rule out the contribution of the chronic foreign-body reaction.

Acute Disease↗