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Biomedical subjects

G B Hubbard

Publications and source records attributed to G B Hubbard.

At least 37 records · Page 2Linked to original sources
PubMed2000

Microstructural heterogeneity and the fracture toughness of bone.

Age-related changes in the skeleton often lead to an increase in the susceptibility of bone to fracture. The purpose of this study was to determine whether differences in material properties between the osteonal and interstitial regions of bone have an effect on bone fracture properties. Parameters such as longitudinal fracture toughness, transverse fracture toughness, porosity, interstitial microhardness, osteonal microhardness, bone density, and weight fractions of the mineral and organic phases of bone were examined as a function of age using female baboon femurs. With increasing age, the longitudinal fracture toughness decreased significantly as did transverse fracture toughness, whereas the interstitial microhardness increased. However, no significant differences in the other parameters were observed as a function of age. Using the ratio of interstitial microhardness to osteonal microhardness as a measure of the differences in the material properties in these two regions, correlation analysis revealed that the longitudinal fracture toughness of bone has a significant correlation with the microhardness ratio. Localized differences in material properties between osteonal and interstitial regions of bone increase with age; such differences may result in high stress concentrations at cement lines and facilitate longitudinal crack propagation.

Aging↗
PubMed2000

Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons.

Intracellular filamentous inclusions containing abnormally phosphorylated tau protein are hallmarks of several human neurodegenerative disorders. This study reveals tau-positive cytoskeletal abnormalities in neurons and glial cells of aged baboons. The brains of four baboons (Papio hamadryas, 20-30 yr of age) were examined using the Gallyas silver technique for neurofibrillary changes and phosphorylation-dependent anti-tau antibodies (AT8, AT100, AT270, PHF-1, TG-3). Conspicuous changes were noted in two animals, 26 and 30 yr of age. In both animals, a combination of neuronal and glial cytoskeletal pathology was seen preferentially affecting limbic brain areas, including the hippocampal formation. In the 30-yr-old animal, numerous tau-positive inclusions were seen in the granule cells of the fascia dentata. These cells even exhibited an accumulation of argyrophilic neurofibrillary tangles. The glial changes affected both astrocytes and oligodendrocytes. Tau-positive astrocytes were seen in perivascular, subpial, and subependymal locations. Tau-positive oligodendrocytes preferentially occurred in limbic fiber tracts including the entorhinal perforant path. Ultrastructurally, tau-positive straight filaments (10-14 nm) in both neurons and glial cells were revealed by anti-tau immunoelectron microscopy. This study thus indicates the potential usefulness of aged baboons for experimental investigation of neuronal and glial filamentous tau pathology. This nonhuman primate species may provide valuable information pertinent to the broad spectrum of human tauopathies.

Aging↗
PubMed2000

Effect of collagen denaturation on the toughness of bone.

The purpose of this study was to explore the relationship between the integrity of collagen and biomechanical properties of bone. In this study, age (range, 5-26 years old) and gender related changes in cortical bone samples from 33 baboon femurs (15 males and 18 females) were examined. The percentage of denatured collagen was determined using a selective digestion technique. The fracture toughness, elastic modulus, yield and ultimate strength, and energy to fracture of bone were determined in three-point bending configurations. The porosity and weight fractions of the mineral and organic phase also were measured. A two-way analysis of variance showed that age dependent changes were reflected primarily in the amount of denatured collagen, fracture toughness, energy to fracture, and elastic modulus, whereas gender had effects on the fracture toughness, elastic modulus, and porosity of bone. In addition, regression analyses indicated that the percentage of denatured collagen had an inverse correlation with the toughness of bone and a positive correlation with its elastic modulus, whereas mineral content had positive correlation with the strength and elastic modulus of bone. The results of this study suggest collagen influences the toughness of bone, whereas mineral content predominantly contributes to bone stiffness and strength.

Animals↗
PubMed2000

Cytokine expression, natural killer cell activation, and phenotypic changes in lymphoid cells from rhesus macaques during acute infection with pathogenic simian immunodeficiency virus.

We studied the innate and adaptive immune system of rhesus macaques infected with the virulent simian immunodeficiency virus isolate SIVmac251 by evaluating natural killer (NK) cell activity, cytokine levels in plasma, humoral and virological parameters, and changes in the activation markers CD25 (interleukin 2R ¿IL-2R alpha chain), CD69 (early activation marker), and CD154 (CD40 ligand) in lymphoid cells. We found that infection with SIVmac251 induced the sequential production of interferon-alpha/beta (IFN-alpha/beta), IL-18, and IL-12. IFN-gamma, IL-4, and granulocyte-macrophage colony-stimulating factor were undetected in plasma by the assays used. NK cell activity peaked at 1 to 2 weeks postinfection and paralleled changes in viral loads. Maximum expression of CD69 on CD3(-)CD16(+) lymphocytes correlated with NK cytotoxicity during this period. CD25 expression, which is associated with proliferation, was static or slightly down-regulated in CD4(+) T cells from both peripheral blood (PB) and lymph nodes (LN). CD69, which is normally present in LN CD4(+) T cells and absent in peripheral blood leukocyte (PBL) CD4(+) T cells, was down-regulated in LN CD4(+) T cells and up-regulated in PBL CD4(+) T cells immediately after infection. CD8(+) T cells increased CD69 but not CD25 expression, indicating the activation of this cellular subset in PB and LN. Finally, CD154 was transiently up-regulated in PBL CD4(+) T cells but not in LN CD4(+) T cells. Levels of antibodies to SIV Gag and Env did not correlate with the level of activation of CD154, a critical costimulatory molecule for T-cell-dependent immunity. In summary, we present the first documented evidence that the innate immune system of rhesus macaques recognizes SIV infection by sequential production of proinflammatory cytokines and transient activation of NK cytotoxic activity. Additionally, pathogenic SIV induces drastic changes in the level of activation markers on T cells from different anatomic compartments. These changes involve activation in the absence of proliferation, indicating that activation-induced cell death may cause some of the reported increase in lymphocyte turnover during SIV infection.

Animals↗
PubMed2000

Outbreak of Orthoreovirus-induced meningoencephalomyelitis in baboons.

BACKGROUND AND PURPOSE: Spontaneous viral encephalitis is rare in the baboon; yet, during a 13-month period (1993-1994), eight juvenile baboons (Papio cynocephalus spp.) developed acute, progressive nonsuppurative meningoencephalomyelitis caused by an unknown agent. Clinical signs of disease included disorientation and truncal ataxia that rapidly progressed to hemiparesis or paraparesis. Clinicopathologic findings were not remarkable and appreciable gross lesions were not seen at necropsy. Microscopic examination revealed CNS lesions that were characterized by lymphoplasmacytic perivascular cuffing, microglial nodules, demyelination, axonal degeneration, vacuolization, and hemorrhage. Subsequently, a novel syncytium-inducing mammalian orthoreovirus was isolated from the brain tissue of five baboons with clinical signs of infection. METHODS: To confirm the etiologic role of the orthoreovirus, two juvenile baboons were inoculated with the virus, then were monitored for 6 weeks. RESULTS: Lesions similar to those seen in spontaneous cases were found in the CNS, and orthoreovirus was isolated from the brain of both animals. CONCLUSION: Analysis of the outbreak indicated juvenile baboons were most susceptible to disease and the virus had a possible incubation time of 46 to 66 days, but did not indicate a source of the virus or mode of transmission.

Animals↗
PubMed1999

Cytogenetic and fertility studies of a rheboon, rhesus macaque (Macaca mulatta) x baboon (Papio hamadryas) cross: further support for a single karyotype nomenclature.

Historically, two different numbering systems have been used to describe the baboon and macaque karyotypes. However, G-banding studies and, more recently, fluorescence in situ hybridization results have shown that the two karyotypes are virtually identical. To confirm this hypothesis, cytogenetic analysis of an unusual animal, a rheboon, was undertaken. The rheboon reported here, an 18-year-old male, is the only long-term survivor of 26 pregnancies resulting from matings between female baboons (Papio hamadryas) and male rhesus macaques (Macaca mulatta). A G-banded karyotype was prepared from the rheboon and compared with the karyotypes of the two parental species. Spectral karyotyping (SKY) was carried out on the rheboon chromosomes, and the results were compared with SKY studies reported for the baboon and with CISS (chromosome in situ suppression) studies in the rhesus macaque. No differences were detected in any of the rheboon's pairs of autosomes, reinforcing the apparent identity of the two parental karyotypes. Based on these results, we argue that a single karyotyping system should be adopted for the two species. Fertility studies were initiated to determine if the rheboon is sterile, as are most hybrid animals. Two semen ejaculates were devoid of sperm. A testicular biopsy revealed hypoplasia of the seminiferous tubules with few Leydig cells and large lumena. Meiotic arrest occurred during meiosis I, resulting in absence of mature spermatozoa. Thus, the testicular and meiotic findings in the rheboon were similar to those observed in other hybrids, even though the parental karyotypes appear identical.

Animals↗
PubMed1999

Effects of iron loading on pathogenicity in hepatitis C virus-infected chimpanzees.

Elevated iron levels have been associated with raised serum alanine transaminase (ALT) levels in hepatitis C virus (HCV)-infected humans. However, it is not clear if HCV infection causes increased iron accumulation by the liver or if the severity of HCV infection is actually worsened by higher iron levels in the host. To better understand the relationship between iron and persistent HCV infections, we examined the effect of excess dietary iron on disease severity in HCV-infected chimpanzees. Iron was supplemented in the diets of four HCV-infected and two uninfected chimpanzees for 29 weeks to achieve iron loading. Iron loading was confirmed by increases in serum iron levels, percentages of transferrin saturation, ferritin levels, elevations in hepatic iron concentration (HIC), and by histological examination. The majority of HCV-infected chimpanzees had higher iron levels before iron feeding than the uninfected animals. Although various degrees of iron loading occurred in all chimpanzees, HCV-infected animals exhibited increased loading in comparison with uninfected animals. The effects of iron loading on HCV disease expression was determined by comparing disease parameters during an extended baseline period before iron loading with the period during iron loading and immediately following iron loading. Iron loading did not influence the viral load, but did exacerbate liver injury in HCV-infected chimpanzees, as evidenced by elevated ALT and histological changes. Because all chimpanzees on high iron diets experienced iron loading, but pathological effects were only observed in HCV-infected chimpanzees, HCV infection appears to increase the susceptibility of the liver to injury following iron loading. These results confirm and extend previous observations made in human populations and serve to further validate the chimpanzee model of chronic hepatitis C.

Alanine Transaminase↗
PubMed1998

Teratoma with trisomy 16 in a baboon (Papio hamadryas).

A teratoma was found during a planned cesarean section in a 10-year-old primigravida baboon. This teratoma had a female sex chromosome complement and trisomy for chromosome 16. This is the first report of a teratoma in a baboon and the first report of a chromosomal abnormality in a nonhuman primate teratoma. It is also the first case in a nonhuman primate to address the mechanism of origin. Through the use of genetic markers from human chromosomes 5, 8 and 17, the origin of the teratoma was shown to be most consistent with failure of meiosis II or endoreduplication in a mature ovum, while the trisomy for chromosome 16 originated after the formation of the tumor.

Animals↗
PubMed1998

Aged-rodent models of long-term growth hormone therapy: lack of deleterious effect on longevity.

Studies were carried out to examine the effects of long-term recombinant human growth hormone (GH) therapy on longevity in rodents. In the first study, 150 18-month-old female F344 rats were divided into three groups of 50 rats per group: Group 1, solvent vehicle; Group 2, 10 microg GH/kg body weight three times per week; Group 3, 50 microg GH/kg body weight three times per week. GH and solvent vehicle therapies were started at 18 months of age and continued until all the animals died spontaneously. Serum insulin-like growth factor (IGF)-I was measured at 18 and 29 months of age and on 3-month-old rats. Serum IGF-I level decreased between 3 and 29 months of age. GH therapy reversed the decrease in a dose-dependent manner, with the 50 microg GH dose returning the serum IGF-I level to that of 3-month-old animals. However, statistical analysis revealed no significant effect of GH therapy on median life span, 10th percentile life span, or maximum life span. Similar observations on longevity were made on aged F344 male rats and on aged Balb/c mice, even when the dose of GH was increased to 1.0 mg/kg body weight two times per week. The main pathologic lesions in control animals were nephropathy, cardiomyopathy, leukemia, and testicular interstitial cell tumor; the prevalence of these lesions was not significantly altered by GH therapy. We conclude that long-term low-dose GH therapy that includes doses in the range that is given to humans in clinical trials in GH deficiency and to revert age-related physiologic declines has no overt deleterious effects on longevity and pathology in aged rodents.

Aging↗
PubMed1998

Intratumoral toremifene therapy and tissue distribution in the baboon.

The purpose of the present study was to evaluate the tissue distribution of toremifene (TOR) in baboons following intra-tissue injections and to examine the effectiveness of intratumoral TOR therapy of baboons with various spontaneous neoplasms. Five healthy baboons (Papio sp.) were used to examine the distribution of TOR following intra-tissue injections. Twenty-three different tissue specimens were collected for HPLC analysis. In addition, four baboons with various spontaneous neoplasms (myxoma, squamous cell carcinoma, lymphosarcoma and adenocarcinoma) were treated with intratumoral TOR and their responses were evaluated. Tissue TOR distribution was also examined in these animals. In the tissue distribution study, target tissue/serum TOR concentration ratios ranged from 138 to 8873 and the target tissue/other tissue ratios ranged from 1.2 to 2428. The distribution of TOR was very favorable, with the highest concentrations outside the injection sites noted in adjacent organs. A marked response was observed in the myxoma and partial responses were observed in the other three cases. Drug level analysis data from these four animals revealed tissue concentrations similar to those seen in the TOR tissue distribution study. Intratumoral administration of TOR can achieve effective local tumor and tissue concentrations, while systemic distribution via circulation to other organs is limited.

Adenocarcinoma↗
PubMed1998

Clinical disease associated with simian agent 8 infection in the baboon.

Simian agent 8 (SA8) is an alphaherpesvirus that was first reported as a spontaneous natural infection in a captive baboon colony in 1988. It was first isolated from an African vervet monkey in 1958 and was classified as a simian agent. Simian agent 8 was later isolated from a baboon rectal swab specimen in 1969 and from an oral lesion in a vervet monkey in 1972. Restriction endonuclease analysis was used to identify the virus as SA8. In a 1-year period, 70 baboons housed in two outside 6-acre breeding corrals developed lesions principally on the genitalia and oral cavity. The incidence was the same for males and females, with recurrence rate, severity of the lesions, and duration for the lesions to resolve being greater in the female baboons. Lesions involving the mouth, tongue, and lips were most commonly observed in the juvenile population. The lesions tended to start as small multiple papules or vesicles, which advanced to large pustular or ulcerative areas. Using an every-other-day treatment regimen consisting of Nolvasan cleaning and procaine penicillin G injections, it took an average of 14 to 21 days for the lesions to resolve totally. Thirty-seven percent of the baboons with herpetic lesions experienced another episode of SA8 infection, usually within 1 year of development of the primary lesion. Several complications have been documented to be associated with SA8 infections. Partial or total vaginal obstruction is most common, leading to impaired breeding performance and pyelonephritis. A vaginal corrective surgical procedure has been developed to allow these females to return to productive breeding status within the colony. Penile urethral obstruction, also causing pyelonephritis, was observed in the male baboons. A case of sciatic neuritis was reported in a baboon that presented with self mutilation of the foot; viral isolation revealed the etiologic agent to be SA8. Four female baboons with chronic SA8 infections went on to develop perineal neoplasms. This is an economically important disease entity in captive baboons because it causes severe morbidity, decreased reproductive performance, and ultimately death in 1% of the baboon colony each year. The baboon is a promising animal model in which to study genital herpes as it relates to disease in human beings.

Alphaherpesvirinae↗
PubMed1998

Human immunodeficiency virus-2 infection in baboons is an animal model for human immunodeficiency virus pathogenesis in humans.

OBJECTIVE: To assess disease progression in baboons (Papio cynocephalus) that were infected with two human immunodeficiency virus-2 (HIV-2) isolates. METHODS: Eight baboons were inoculated intravenously with either HIV-2UC2 or HIV-2UC14 and were followed for a 2- to 7-year period of observation. RESULTS: Six of 8 baboons showed lymphadenopathy and other signs of HIV-related disease, 3 of 8 baboons had an acute phase CD4+ T-cell decline, and 2 of 5 baboons infected with the HIV-2UC2 isolate progressed to an acquired immunodeficiency syndrome-like disease. Human immunodeficiency virus-2-specific pathology in lymphatic tissues included follicular lysis, vascular proliferation, and lymphoid depletion. Both neutralizing antibodies and a CD8+ T-cell antiviral response were associated with resistance to disease. CONCLUSIONS: Disease progression and the development of acquired immunodeficiency syndrome in HIV-2-infected baboons have similarities to human HIV infections.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Low-dose ultraviolet exposure early in development can lead to widespread melanoma in the opossum model.

Suckling young of opossums (Monodelphis domestica) were exposed to ultraviolet radiation (UVR, predominantly UVB: 290-320 nm) in part to determine an optimal protocol for induction and progression of melanoma in this species. In all, 620 litters were introduced to one of seven protocols. The lowest dose (175 J/m2) administered three times a week for almost three weeks led to the highest incidence of melanotic lesions with melanoma potential (8.1%) among young (5-month-old) adults. Among 101 much older animals (> 17 months at necropsy), 43% showed metastatic melanoma to the lymph nodes and almost one-third of these had progressed to widespread dissemination. Three of the latter animals, from a total of 13 obtained so far, were selected for detailed histological examination of disseminated disease. At necropsy, all three showed widespread metastases beyond the lymph nodes to the spleen, lungs, and other distant sites. Histological changes typical of malignant melanoma included junctional activity, mitotic figures, and nerve and vessel invasion. This novel finding leads us to conclude that UVR can act as a complete carcinogen for progression to widely disseminated disease and that exposure of sucklings can lead, in old age, to widespread metastatic melanoma in this model. The results are thus not inconsistent with the view that, in humans, early exposure to sunlight might act as an initiating factor in a later progression to malignant melanoma.

Age Factors↗
PubMed1997

Tissue distribution of transdermal toremifene.

PURPOSE: Toremifene is an orally administered triphenylethylene derivative with antiestrogenic activity that is primarily used in the treatment of patients with metastatic breast cancer. The purpose of this study was to evaluate the therapeutic advantage of local (transdermal) administration of toremifene in several animal models. Local (subcutaneous and skin) versus systemic concentrations of toremifene were evaluated serially following transdermal application of the drug. With high local concentrations and minimal distribution to other organs via the circulation, topical toremifene may deliver maximal therapeutic effects to local tissue while avoiding the side effects seen with systemic therapy. METHODS: Three animal models (nude mice, baboons, and a horse) were used to examine topically administered toremifene for kinetic measurements. RESULTS: In nude mice implanted subcutaneously with MDA-MB-231 human breast tumors, topical toremifene (2.5 mg/day x 5 days) produced greater than 50-fold higher tumor concentrations compared with intraperitoneal (i.p.) administration (1.0 mg/day x 5 days). Systemic distribution in plasma, uterus, and liver was lower following topical than following i.p. administration. In nude mice inoculated subcutaneously with estrogen receptor-positive (ER +) MCF-7 human breast cancer cells, topical toremifene and 4-hydroxytoremifene (4-OH) prevented tumor growth in the presence of estradiol. In four nontumor-bearing baboons that were given transdermal toremifene, relatively high distribution of drug was noted in normal breast tissue and fat, compared with undetectable serum concentrations. Finally, a new topical formulation of toremifene (a gel preparation for human use, Orion-Farmos, Finland) achieved high local tumor toremifene concentrations in a horse melanoma, with minimal systemic distribution. CONCLUSIONS: Transdermal toremifene can achieve high local tissue concentrations with minimal systemic distribution.

Administration, Cutaneous↗
PubMed1997

Preserving the posterior superior synovial recess during allograft TMJ diskal condylar transplantation in the adult goat.

OBJECTIVE: The purpose of the study was to test the hypothesis that sparing the posterior superior synovial recess during the resection of temporomandibular joint condyle and disk would maintain a critical mass of synovium necessary to predictably achieve a successful allograft joint reconstruction. STUDY DESIGN: A group of 15 adult goats underwent unilateral resection of their temporomandibular condyle and meniscus. The fossa and posterior superior synovial recess were left intact. They were immediately reconstructed with cryogenically preserved allograft mandibular condyles and temporomandibular joint disk harvested from 15 adult donor goats. The animals were evaluated clinically and radiographically at 6 and 12 months and histologically at 12 months. RESULTS: Of the 15 animals, 13 met all the criteria to be declared a success and retained the posterior superior synovial recess. CONCLUSION: Immediate joint reconstruction using cryogenically preserved mandibular condyles and temporomandibular joint disk can have a high rate of success if the native posterior superior synovial recess remains intact.

Animals↗
PubMed1997

Spontaneous pathology of the gray short-tailed opossum (Monodelphis domestica).

The gray short-tailed opossum, Monodelphis domestica, is a newly established laboratory animal that is becoming increasingly important to biomedical research. Because little disease information is available for this species, we reviewed records for spontaneous gross and histologic lesions and microbiologic results in 150 M. domestica necropsies during an 11-year period. We identified 150 (91 female, 59 male) animals from 441 necropsy cases which were controls in experimental protocols or were members of the breeding colony. Initial statistical examinations indicated that the sample was representative of the living members of the breeding colony with respect to age, sex, and range of inbreeding. Causes of death and types of tumors were specifically evaluated. Females died earlier than males (22.6 +/- 13.0 months versus 30.9 +/- 11.9 months), but this difference was not associated readily with diet or inbreeding levels. The organ systems with the greatest lesion prevalences, in decreasing order, were the digestive, urogenital, cardiovascular, and respiratory systems. The most probable causes of all deaths were associated with the digestive system, followed by the cardiovascular and integumentary systems. The principal disease problems were rectal prolapse, congestive heart failure, and dermatitis. Neoplasia was found in 39 of the animals. The prevalence of neoplasia was greatest in the digestive system, followed by the endocrine, urogenital, integumentary, and hematopoietic systems. Pituitary adenoma was the most common neoplasm, followed by uterine leiomyoma and cutaneous lipoma. Specific microbially-induced diseases were not recognized, and endo- and ectoparasites were not found in colony-born M. domestica.

Animal Diseases↗
PubMed1997

Evaluation of a vaginal moisturizer in baboons with decreasing ovarian function.

Decrease of estrogen concentrations in postmenopausal women leads to many urogenital problems including vaginal dryness, atrophy, stenosis, itching, and irritation, along with sexual dysfunction. Systemic estrogen replacement is effective in many women but may not be effective in others because estrogen therapy may be contraindicated for medical reasons. The reproductive tract in nonhuman female primates has been used successfully as a model for a variety of research including, but not limited to, anatomy and physiology, reproduction, cancer, infectious disease, and menopause. The baboon is especially valuable because of the similarity of its menstrual cycle to women's, prior research with this animal, and its adaptability to captivity. A nonhormonal, nonsystemic, bio-adhesive vaginal moisturizer was evaluated in baboons as a possible alternative to hormonal therapy for vaginal symptoms due to a decrease in estrogen concentrations. Eight baboons with decreasing ovarian function were used in a two-part study to evaluate vaginal health with pliability, elasticity, mucosal secretion, pH, and histologic features as criteria. The first study involved a single intravaginally administered dose of test product, with evaluation at 20 min and 24 h later. The second study consisted of five doses given at 24-h intervals, with daily evaluations for 9 consecutive days. There was marked improvement in vaginal pliability, elasticity, and secretions, with decreased pH and thickness of the vaginal epithelium. These effects appeared 1 or 2 days after drug administration, reached the maximum on day 4, and mostly decreased by day 8. However, increased secretions, vaginal elasticity, and vacuolization of the epithelium in biopsy specimens persisted to the last day of observation. The study results indicate the efficacy of the test product and the value of the baboon as a model to study decreasing ovarian function and vaginal health.

Animals↗