Biomedical subjects

C R Brown

Publications and source records attributed to C R Brown.

At least 37 records · Page 2Linked to original sources

PubMed2000

Evaluation of selection on cliff swallows.

Estimates of the intensity of selection based on measurements of the living and the dead require knowledge of the fraction of the original population dying. We apply recently developed methods (Blanckenhorn et al. 1999) to estimate the intensity of selection in a population of cliff swallows. In this population the fraction of individuals dying was unknown, but certainly high. The inferred selection is very strong and impossible to achieve if the original population is assumed to have followed a normal distribution. We consider several alternative explanations for this result including measurement biases, undetected immigration, and sampling biases. Of these, sampling biases are perhaps the most likely. We conclude that the intensity of selection on the swallows was probably strong, but its absolute magnitude is unknown.

Animals↗

PubMed2000

Intrinsic susceptibility of rhesus macaque peripheral CD4(+) T cells to simian immunodeficiency virus in vitro is predictive of in vivo viral replication.

Previous studies with simian immunodeficiency virus (SIV) infection of rhesus macaques suggested that the intrinsic susceptibility of peripheral blood mononuclear cells (PBMC) to infection with SIV in vitro was predictive of relative viremia after SIV challenge. The present study was conducted to evaluate this parameter in a well-characterized cohort of six rhesus macaques selected for marked differences in susceptibility to SIV infection in vitro. Rank order relative susceptibility of PBMC to SIVsmE543-3-infection in vitro was maintained over a 1-year period of evaluation. Differential susceptibility of different donors was maintained in CD8(+) T-cell-depleted PBMC, macrophages, and CD4(+) T-cell lines derived by transformation of PBMC with herpesvirus saimiri, suggesting that this phenomenon is an intrinsic property of CD4(+) target cells. Following intravenous infection of these macaques with SIVsmE543-3, we observed a wide range in plasma viremia which followed the same rank order as the relative susceptibility established by in vitro studies. A significant correlation was observed between plasma viremia at 2 and 8 weeks postinoculation and in vitro susceptibility (P < 0.05). The observation that the two most susceptible macaques were seropositive for simian T-lymphotropic virus type 1 may suggests a role for this viral infection in enhancing susceptibility to SIV infection in vitro and in vivo. In summary, intrinsic susceptibility of CD4(+) target cells appears to be an important factor influencing early virus replication patterns in vivo that should be considered in the design and interpretation of vaccine studies using the SIV/macaque model.

Animals↗

PubMed2000

Wide range of viral load in healthy african green monkeys naturally infected with simian immunodeficiency virus.

The distribution and levels of simian immunodeficiency virus (SIV) in tissues and plasma were assessed in naturally infected African green monkeys (AGM) of the vervet subspecies (Chlorocebus pygerythrus) by limiting-dilution coculture, quantitative PCR for viral DNA and RNA, and in situ hybridization for SIV expression in tissues. A wide range of SIV RNA levels in plasma was observed among these animals (<1,000 to 800,000 copies per ml), and the levels appeared to be stable over long periods of time. The relative numbers of SIV-expressing cells in tissues of two monkeys correlated with the extent of plasma viremia. SIV expression was observed in lymphoid tissues and was not associated with immunopathology. Virus-expressing cells were observed in the lamina propria and lymphoid tissue of the gastrointestinal tract, as well as within alveolar macrophages in the lung tissue of one AGM. The range of plasma viremia in naturally infected AGM was greater than that reported in naturally infected sooty mangabeys. However, the degree of viremia in some AGM was similar to that observed during progression to AIDS in human immunodeficiency virus-infected individuals. Therefore, containment of viremia is an unlikely explanation for the lack of pathogenicity of SIVagm in its natural host species, AGM.

Animals↗

PubMed2000

Comparative efficacy of recombinant modified vaccinia virus Ankara expressing simian immunodeficiency virus (SIV) Gag-Pol and/or Env in macaques challenged with pathogenic SIV.

Prior studies demonstrated that immunization of macaques with simian immunodeficiency virus (SIV) Gag-Pol and Env recombinants of the attenuated poxvirus modified vaccinia virus Ankara (MVA) provided protection from high levels of viremia and AIDS following challenge with a pathogenic strain of SIV (V. M. Hirsch et al., J. Virol. 70:3741-3752, 1996). This MVA-SIV recombinant expressed relatively low levels of the Gag-Pol portion of the vaccine. To optimize protection, second-generation recombinant MVAs that expressed high levels of either Gag-Pol (MVA-gag-pol) or Env (MVA-env), alone or in combination (MVA-gag-pol-env), were generated. A cohort of 24 macaques was immunized with recombinant or nonrecombinant MVA (four groups of six animals) and was challenged with 50 times the dose at which 50% of macaques are infected with uncloned pathogenic SIVsmE660. Although all animals became infected postchallenge, plasma viremia was significantly reduced in animals that received the MVA-SIV recombinant vaccines as compared with animals that received nonrecombinant MVA (P = 0.0011 by repeated-measures analysis of variance). The differences in the degree of virus suppression achieved by the three MVA-SIV vaccines were not significant. Most importantly, the reduction in levels of viremia resulted in a significant increase in median (P < 0.05 by Student's t test) and cumulative (P = 0.010 by log rank test) survival. These results suggest that recombinant MVA has considerable potential as a vaccine vector for human AIDS.

Animals↗

PubMed1999

Effects of nasal O2 on sleep-related disordered breathing in ambulatory patients with stable heart failure.

OBJECTIVE: The purpose of this study was 1) to determine the effects of nasal O2 on periodic breathing, arterial oxyhemoglobin desaturation and nocturnal ventricular arrhythmias in patients with heart failure and 2) determine the characteristics of patients whose periodic breathing will be reversed by O2 administration; our hypothesis was that patients with more severe periodic breathing and desaturation, will respond more favorably to oxygen. DESIGN: Prospective study. SETTING: Referral sleep laboratory of a Department of Veterans Affairs Medical Center. PARTICIPANTS: 36 ambulatory male patients with heart failure whose initial polysomnograms showed periodic breathing with fifteen or more episodes of apnea (A) and hypopnea (H) per hour (AH index, AHI) were treated with nasal O2 during the subsequent full night polysomnography. INTERVENTIONS: Oxygen. MEASUREMENTS AND RESULTS: Arterial blood gases and hydrogen ion concentrations were measured, and cardiac radionuclide ventriculography, Holter monitoring, and polysomnography were done. The studies were scored blindly. Treatment with O2 resulted in a significant reduction in AHI (49+/-19 vs 29+/-29, means+/-SD), central apnea index (28+/-23 vs 13+/-18 per hour), and the percent of total sleep time below an arterial oxyhemoglobin saturation of 90% (23+/-21% vs 0.8+/-2.3%). In spite of virtual normalization of saturation with O2 therapy, the number of ventricular arrhythmias during sleep did not change significantly. In 39% of the patients (14 out of 36), O2 therapy resulted in reversal of central sleep apnea (defined by a reduction in AHI to less than 15/hr). In this group, the AHI decreased by 78% which was significantly (p=0.0001) more than improved (22%) in AHI of the remaining patients (n=22). The main differences between baseline characteristics of the two groups was a significantly higher mean PaCO2 in patients who did respond fully to O2 (39.3+/-5.4 vs 36.1+/-4.2 mm Hg, p=0.03). In both groups, however, O2 administration resulted in significant and similar improvement in arterial oxyhemoglobin saturation (saturation <90%, percent total sleep time 0.1+/-0.3% vs 1+/-3%). CONCLUSION: In patients with stable heart failure, administration of nasal O2 significantly improves periodic breathing and virtually eliminates clinically significant arterial oxyhemoglobin desaturation. The beneficial effects of O2, however, may be modulated by the level of arterial PCO2. Acute O2 therapy has important benefits on sleep apnea and nocturnal arterial oxyhemoglobin desaturation in heart failure patients. Long term benefits of O2 therapy in heart failure and sleep apnea need to be determined.

Aged↗

PubMed1999

Osmoregulation and water balance in the springhare (Pedetes capensis).

Springhares are large rodents that live in arid and semi-arid regions of Africa. We deprived springhares of water for periods of up to 7 days to determine what physiological adaptations. If any, enable them to survive in and regions without drinking. During water deprivation, springhares lost up to 30% body weight and produced a mean maximum urine concentration of 2548 mosmol kg-1 with a maximum of 3076 mosmol kg-1 in an individual animal. Haematocrit and plasma sodium and potassium concentrations were well regulated throughout water deprivation at 47.5 +/- 3.8% and 132.6 +/- 7.4 mmol l-1 and 3.5 +/- 0.7 mmol l-1, respectively, while plasma osmolality increased slightly from 293 +/- 12.5 mosmol kg-1 to 324 +/- 7.3 mosmol kg-1. Springhares thus appeared to be good osmoregulators and were able to maintain plasma volume during 7 days of water deprivation. In addition to the production of a relatively concentrated urine, water loss was limited by the lowered solute load and faecal water loss achieved by a reduction in food consumption and by the production of very dry faeces. These abilities, together with a favourable burrow microclimate and nocturnal activity pattern, enable them to survive in arid regions.

Adaptation, Physiological↗

PubMed1999

Comparative metabolism, thermoregulation and morphology in two populations of vlei rats (Otomys irroratus).

The Hogsback (32 degrees 33S 26 degrees 57E) and Alice (32 degrees 47S 26 degrees 50E), Eastern Cape, South Africa, are separated by only 24 km but by 1000 m in altitude and fall into different climatic regions. Thermal responses (energy expenditure and body temperature) to ambient temperature were measured in a population of vlei rats (Otomys irroratus) from each of the two localities. We predicted that animals from the colder Hogsback would show differences in their thermal physiology and morphology consistent with better cold-resistance. Basal metabolic rates of the Hogsback population were slightly, but not significantly, higher than the Alice population (23.9 J g-1 h-1 vs 22.3 J g-1 h-1), but the slope of the regression between energy expenditure and ambient temperature below the thermal neutral zone was significantly lower (-1.28 vs -1.60). Body temperature, although quite variable in both populations, was not significantly influenced by ambient temperature in the Hogsback population, whereas that of Alice animals was. Fur length was longer and relative size of the ears and tail was smaller in the Hogsback population, which probably accounted for the slightly lower minimum thermal conductance (1.79 J g-1 h-1 degree C-1 vs 1.91 J g-1 h-1 degree C-1) in the Hogsback population. Vlei rats from the two sites also have different karyotypes that correlate with climate but there is insufficient evidence at present to suggest that the different karyotypes and the physiological parameters measured are adaptive.

Animals↗

PubMed1999

Development of body temperature regulation in ostrich chicks.

Information in the literature indicates that young ostrich chicks, despite being precocial, are poor thermoregulators and may take between 8 and 12 weeks to develop efficient homeothermy. We measured the body temperatures (Tb) of young ostrich chicks (1 to 10 d) at ambient temperatures between 13 degrees and 28 degrees C under controlled conditions in the laboratory and under typical farm-rearing conditions to assess their ability to thermoregulate. Even 1-d-old ostriches could maintain a Tb above 36 degrees C at temperatures of 20 degrees C and older chicks maintained typical adult Tb at ambient temperatures of 13 degrees C in a constant temperature room. Chicks from 2-d-old could maintain adult T(b)s outdoors under a wide range of ambient temperatures and weather conditions. We conclude that ostrich chicks have well developed homeothermy soon after hatching and that some of the higher rearing temperatures recommended in the literature are unnecessary. In appropriate climates, chicks can be allowed outdoors soon after hatching provided they are not exposed to unfavourable weather conditions. Thermoregulation is, however, energetically expensive and thermoregulatory behaviour such as huddling may compete with other important activities like feeding.

Analysis of Variance↗

PubMed1999

Development of lyme arthritis in mice deficient in inducible nitric oxide synthase.

Nitric oxide (NO) is a powerful antimicrobial agent and an important regulatory molecule of the innate immune response. To determine if NO has a role in experimental Lyme disease, arthritis-resistant DBA/2J and arthritis-susceptible C3H/HeJ mice were bred to be genetically deficient for inducible NO synthase (iNOS). Following footpad injection of Borrelia burgdorferi, arthritis was similar between iNOS-deficient and control animals regardless of their genetic background. Histologic examination and arthritis severity scores of ankles revealed no differences in arthritis development between iNOS-deficient and control animals. Despite being deficient in a key antimicrobial agent, iNOS-deficient mice had tissue levels of B. burgdorferi similar to those in control mice. Thus, NO does not have a critical role in susceptibility to Lyme arthritis through tissue damage via an overexuberant inflammatory response, nor is it required in resistance through the clearance of spirochetes from tissues.

Animals↗

PubMed1999

Genetic control of experimental lyme arthritis in the absence of specific immunity.

Host genetics play an important role in determining resistance or susceptibility to experimental Lyme arthritis. While specific immunity appears to regulate disease resolution, innate immunity appears to regulate disease severity. Intradermal infection with Borrelia burgdorferi yields severe arthritis in C3H/He (C3H) mice but only minimal arthritis in BALB/c mice. Intradermal infection of immunodeficient C3H SCID mice also results in severe arthritis, but arthritis of only moderate severity in BALB/c SCID mice. In the present study, we examined immunodeficient recombinase-activating gene-knockout (RAG-1(-/-)) (RAG-) mice from resistant C57BL/6 (B6) and DBA/2 (DBA) mouse strains. B. burgdorferi-infected B6 RAG- and DBA RAG- mice had little or no ankle swelling, a low occurrence of inflammatory infiltrates in tibiotarsal joints, and low arthritis severity scores in comparison to RAG+ and RAG- BALB/c or C3H mice. Few differences in spirochete DNA levels in ankles of resistant and susceptible RAG- mice were seen. These data suggest that resistance to arthritis development following B. burgdorferi infection is not necessarily dependent on an acquired immune response and can occur despite the presence of high spirochete burden. Thus, genes expressed outside the specific immune response can be central regulators of experimental arthritis.

Animals↗

PubMed1999

Experimental lyme arthritis in the absence of interleukin-4 or gamma interferon.

Genetic resistance and susceptibility to experimental Lyme arthritis have been linked with the production of interleukin-4 (IL-4) or gamma interferon (IFN-gamma), respectively. To determine the absolute requirement for these cytokines in disease outcome, we compared arthritis development in wild-type, IL-4-deficient (IL-4 degrees ), and IFN-gamma-deficient (IFN-gamma degrees ) mice. While susceptible C3H mice developed swelling of ankle joints during the second week of infection, this swelling was exacerbated in C3H IFN-gamma degrees mice. Their arthritis severity scores at day 21, however, were similar. Resolution of arthritis was also similar between C3H and C3H IFN-gamma degrees mice. Arthritis-resistant DBA mice did not develop ankle swelling during the experimental period. There were no differences in ankle swelling or arthritis severity scores between control DBA mice and DBA IL-4 degrees mice at any of the time points tested. While the presence of spirochetes in various tissues was similar among all strains at day 21, DBA IL-4 degrees mice had a higher presence of spirochetes in blood, heart, and spleen than the DBA, C3H, and C3H IFN-gamma degrees mice did at day 60. DBA IL-4 degrees mice also had impaired ability to produce Borrelia-specific antibody responses, especially immunoglobulin G1. Thus, while IFN-gamma and IL-4 are not absolutely required for arthritis susceptibility or resistance, the production of IL-4 does appear to play an important role in Borrelia-specific antibody production and spirochete clearance.

Animals↗

PubMed1999

Protection of macaques against intrarectal infection by a combination immunization regimen with recombinant simian immunodeficiency virus SIVmne gp160 vaccines.

We previously reported that immunization with recombinant simian immunodeficiency virus SIVmne envelope (gp160) vaccines protected macaques against intravenous challenge by the cloned homologous virus E11S but that this protection was only partially effective against the uncloned virus, SIVmne. In the present study, we examine the protective efficacy of this immunization regimen against infection by a mucosal route. We found that the same gp160-based vaccines were highly effective against intrarectal infection not only with the E11S clone but also with the uncloned SIVmne. Protection against mucosal infection is therefore achievable by parenteral immunization with recombinant envelope vaccines. Protection appears to correlate with high levels of SIV-specific antibodies and, in animals protected against the uncloned virus, the presence of serum-neutralizing activities. To understand the basis for the differential efficacies against the uncloned virus by the intravenous versus the intrarectal routes, we examined viral sequences recovered from the peripheral blood mononuclear cells of animals early after infection by both routes. We previously showed that the majority (85%) of the uncloned SIVmne challenge stock contained V1 sequences homologous to the molecular clone from which the vaccines were made (E11S type), with the remainder (15%) containing multiple conserved changes (the variant types). In contrast to intravenously infected animals, from which either E11S-type or the variant type V1 sequences could be recovered in significant proportions, animals infected intrarectally had predominantly E11S-type sequences. Preferential transmission or amplification of the E11S-type viruses may therefore account in part for the enhanced efficacy of the recombinant gp160 vaccines against the uncloned virus challenge by the intrarectal route compared with the intravenous route.

Animals↗

PubMed1999

Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies.

The role of antibody in protection against human immunodeficiency virus (HIV-1) has been difficult to study in animal models because most primary HIV-1 strains do not infect nonhuman primates. Using a chimeric simian/human immunodeficiency virus (SHIV) based on the envelope of a primary isolate (HIV-89.6), we performed passive-transfer experiments in rhesus macaques to study the role of anti-envelope antibodies in protection. Based on prior in vitro data showing neutralization synergy by antibody combinations, we evaluated HIV immune globulin (HIVIG), and human monoclonal antibodies (MAbs) 2F5 and 2G12 given alone, compared with the double combination 2F5/2G12 and the triple combination HIVIG/2F5/2G12. Antibodies were administered 24 h prior to intravenous challenge with the pathogenic SHIV-89.6PD. Six control monkeys displayed high plasma viremia, rapid CD4(+)-cell decline, and clinical AIDS within 14 weeks. Of six animals given HIVIG/2F5/2G12, three were completely protected; the remaining three animals became SHIV infected but displayed reduced plasma viremia and near normal CD4(+)-cell counts. One of three monkeys given 2F5/2G12 exhibited only transient evidence of infection; the other two had marked reductions in viral load. All monkeys that received HIVIG, 2F5, or 2G12 alone became infected and developed high-level plasma viremia. However, compared to controls, monkeys that received HIVIG or MAb 2G12 displayed a less profound drop in CD4(+) T cells and a more benign clinical course. These data indicate a general correlation between in vitro neutralization and protection and suggest that a vaccine that elicits neutralizing antibody should have a protective effect against HIV-1 infection or disease.

AIDS Vaccines↗

PubMed1998

Simian immunodeficiency virus of African green monkeys is apathogenic in the newborn natural host.

Several studies have demonstrated that newborn animals are more susceptible to disease development following infection with retroviruses than adults. Adult African green monkeys (AGMs) infected with SIVagm do not develop AIDS-like disease and the objective of the study was to determine whether experimental infection of newborn AGMs with SIVagm would result in pathogenesis. Neonatal AGMs were found to have a higher percentage of circulating CD4+ lymphocytes than adults (62% versus 14%) and therefore a higher potential pool of target cells for SIVagm infection. However, no differences in the in vitro replication kinetics of SIVagm in peripheral blood mononuclear cells of adult or neonatal AGMs could be observed. In vivo, the neonatal AGMs became viremic at the earliest two months after inoculation whereas the adult AGMs had evidence of virus replication already 2 to 6 weeks after infection. None of the animals developed AIDS-like symptoms upon infection. In the heterologous cynomolgus macaque host, a newborn infected with SIVagm developed early high virus loads and died two months after birth with AIDS-like histopathologic features. It would therefore appear that in contrast to the situation with many other retroviruses, newborn AGMs are no more permissive to SIVagm infection than are adults.

Aging↗

PubMed1998

Control of Leishmania major by a monoclonal alpha beta T cell repertoire.

Little is known regarding the diversity of the host T cell response that is required to maintain immunologic control of microbial pathogens. Leishmania major persist as obligate intracellular parasites within macrophages of the mammalian host. Immunity is dependent upon activation of MHC class II-restricted T cells to an effector state capable of restricting growth and dissemination of the organisms. We generated alpha-beta Leishmania-specific (ABLE) TCR transgenic mice with MHC class II-restricted T cells that recognized an immunodominant Leishmania Ag designated LACK. Naive T cells from ABLE mice proliferated in vitro after incubation with recombinant LACK or with Leishmania-parasitized macrophages and in vivo after injection into infected mice. Infected ABLE mice controlled Leishmania infection almost as well as wild-type mice despite a drastic reduction in the T cell repertoire. ABLE mice were crossed to mice with disruption of the TCR constant region alpha gene to create animals with a single alpha beta T cell repertoire. Although mice deficient in all alpha beta T cells (TCR-C alpha 0 mice) failed to control L. major, mice with a monoclonal alpha beta T cell repertoire (ABLE TCR-C alpha 0 mice) displayed substantial control. The immune system is capable of remarkable efficiency even when constrained to recognition of a single epitope from a complex organism.

Amino Acid Sequence↗

PubMed1998

Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification.

The viral accessory protein Vpx is required for productive in vitro infection of macrophages by simian immunodeficiency virus from sooty mangabey monkeys (SIV(SM)). To evaluate the roles of Vpx and macrophage infection in vivo, we inoculated pigtailed macaques intravenously or intrarectally with the molecularly cloned, macrophage tropic, acutely pathogenic virus SIV(SM) PBj 6.6, or accessory gene deletion mutants (deltaVpr or deltaVpx) of this virus. Both wild-type and SIV(SM) PBj deltaVpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplification of infection and dissemination was observed for wild-type virus, but not for SIV(SM) PBj deltaVpx, which also showed considerable impairment of the overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIV(SM) Pbj deltaVpx intravenously or intrarectally, the deltaVpx mutant was at a strong competitive disadvantage. Vpx-dependent viral amplification at local sites of initial infection, perhaps through a macrophage-dependent mechanism, may be a prerequisite for efficient dissemination of infection and pathogenic consequences after exposure through either mucosal or intravenous routes.

Animals↗

PubMed1998

Activation of natural killer cells in arthritis-susceptible but not arthritis-resistant mouse strains following Borrelia burgdorferi infection.

Infection of susceptible mouse strains with Borrelia burgdorferi, the agent of Lyme disease, results in the development of arthritis. Components of the innate immune system may be important mediators of this pathology. To investigate the potential role of NK cells in development of experimental Lyme arthritis, we examined their activation in vivo in both resistant and susceptible mouse strains. Following inoculation of B. burgdorferi into the footpad, lymph node NK cells from susceptible C3H/HeJ (C3H) mice produced more gamma interferon than NK cells from resistant DBA/2J mice. Lymph node cells from susceptible C3H and AKR mice also had increased ability to lyse YAC-1 target cells 2 days following infection. Antibody depletion of NK cells from susceptible mice, however, did not alter the development of arthritis following B. burgdorferi challenge. In addition, NK cell depletion had little effect on spirochete burden. Thus, there is a marked activation of NK cells in susceptible mouse strains following infection. Although NK cells are not absolutely required for arthritis, events occurring prior to NK cell activation might be important in mediating pathology in experimental Lyme disease.

Animals↗

PubMed1998

Clearance of Borrelia burgdorferi may not be required for resistance to experimental lyme arthritis.

Infection of inbred mouse strains with Borrelia burgdorferi results in the development of experimental Lyme arthritis. The degree of arthritic pathology has been suggested to correlate with the level of spirochete burden within tissues. To investigate this further, we infected resistant DBA/2 (DBA) and susceptible C3H/HeJ (C3H) mice in the hind footpads and monitored arthritis development for 21 days. To quantitate levels of spirochetes within tissues, we created a competitive PCR molecule containing modified ospA and fla gene segments. C3H mice developed severe arthritis of the tibiotarsal joints, while DBA mice developed only mild inflammation throughout the experimental period. At day 21, when the gross size and histologic composition of ankles revealed significant differences in arthritis between the strains, there was little difference in levels of spirochete DNA as determined by competitive PCR. Cultures of ankle tissue at day 21 were also uniformly positive in both C3H and DBA animals and contained relatively similar levels of spirochetes. These results indicate that the presence of spirochetes in the ankles of experimental animals is not sufficient for arthritis development. Since arthritic and nonarthritic animals can harbor relatively equal spirochete burdens yet retain their distinct phenotypic outcomes, an aberrant or overly exuberant immune response may be an additional requirement for pathology in arthritis-prone mice.

Animals↗