Nonhuman primates are a valuable model for osteoarthritis. Osteoarthritis has been extensively studied in nonhuman primates in both naturally occurring and induced disease states. However, little ...published information describes naturally occurring osteoarthritis of the coxofemoral joints
of nonhuman primates. We report a case of naturally occurring coxofemoral joint osteoarthritis in a rhesus macaque. This case radiographically resembled hip dysplasia reported in other species and demonstrated a rapid progression in severity of lameness, with accompanying loss of muscle mass
in the affected limb. We excised the femoral head and neck to alleviate the pain that accompanied the osteoarthritis. Physical therapy was initiated, and dual-energy X-ray absorptiometry and video recordings were performed to evaluate the macaque's response to surgical intervention. By 3 mo
postoperatively, the macaque had regained full use of the affected limb.
Background Strongyloides infection may result in clinical disease or confound experimental protocols that utilize non‐human primates. There is presently a Strongyloides fulleborni infection rate of ...approximately 27% in the Tulane National Primate Research Center's breeding colonies despite the routine therapeutic and prophylactic use of ivermectin.
Methods A study was conducted to determine if moxidectin treatment offers advantages to the intestinal parasite control program. A total of 150 rhesus macaques (Macaca mulatta) that were removed from the breeding colonies due to illness were selected for the study. The animals were randomly assigned to treatment groups with 75 receiving ivermectin and 75 receiving moxidectin. Egg counts were performed on fecal samples collected pre‐ and post‐treatment.
Results Both treatments resulted in decreases in the number of eggs/g in the post‐treatment sample as compared with the pre‐treatment sample; however, no significant difference was found between treatment groups.
Conclusions With the data demonstrating a similar efficacy in both ivermectin and moxidectin treated macaques, the benefit of moxidectin treatment relates to biosafety and topical application.
Abstract only
Chronic alcohol consumption, HIV infection, and anti‐retroviral therapy (ART) have independently been shown to impair whole body insulin responsiveness. Previous studies from our group ...have shown that skeletal muscle of CBA administered SIV‐infected (CBA/SIV) male rhesus macaques has upregulated ubiquitin‐proteasome pathway activity, enhanced pro‐inflammatory cytokine, and suppressed IGF‐I expression at end stage SIV infection. These findings suggest that CBA may impair insulin‐mediated anabolic responses at end‐stage disease. Whether systemic and skeletal muscle metabolic alterations are present at earlier time points of SIV infection or are affected by ART administration was not known. In this study, we tested the hypothesis that CBA decreases whole body insulin sensitivity and insulin signaling in the skeletal muscle during the asymptomatic stage of SIV infection in male rhesus macaques and proposed that this would be further aggravated by ART. CBA or sucrose (SUC) was administered intragastrically for 3 mos prior to inoculation with SIVmac251 and continued until necropsy. At 2.5 mos. post‐SIV infection, daily administration of ART (tenofovir and emtricitabine) was initiated in half of the SUC/SIV and CBA/SIV macaques. Frequently sampled intravenous glucose tolerance tests were performed to analyze glucose‐insulin dynamics, including acute insulin response to glucose (AIRg), disposition index (DI), and insulin sensitivity index, using a homeostatic model. One week prior to necropsy, a controlled feeding protocol was performed with infusion of a Carnation breakfast supplement (9.283 mL/kg/h) beginning 1.5 hours after CBA or SUC administration, continued for one hour, followed by a quadriceps femoris biopsy. One week after the feeding protocol, fasted‐state muscle biopsy was collected. At study endpoint (14 mo CBA, 11 mo SIV) CBA/SIV macaques had a significantly reduced (p<0.05) AIRg and DI and circulating levels of adiponectin, relative to SUC/SIV macaques, irrespective of ART status. Western blot analysis of fasted‐and fed‐state skeletal muscle samples revealed a statistically significant increase in fed‐state PTP1B, a negative regulator of insulin signaling, in CBA/SIV relative to SUC/SIV macaques and irrespective of ART status. These findings suggest that CBA impairs insulin‐mediated effects in CBA/SIV macaques and warrant future studies elucidating the specific alterations in the insulin signaling cascade that are modulated by CBA.
Support or Funding Information
The work was supported by National Institutes of Health (NIH) grants: P60AA09803, T32AA07577, and F30AA024030‐01A1.
Abstract only
Chronic binge alcohol (CBA) accentuates skeletal muscle (SKM) wasting at terminal stage of simian immunodeficiency virus (SIV) infection. The purpose of this study was to identify ...differentially regulated genes that may contribute to SKM in CBA SIV‐infected macaques (CBA/SIV) vs. sucrose‐fed SIV‐infected macaques (SUC/SIV). Transcriptome of SKM samples obtained at necropsy (~10 mo post‐SIV) from CBA and sucrose‐SIV‐infected macaques were compared using Illumina Custom algorithm to compare the level of gene expression (p‐value filter of ≤ 0.05, either ≥ 3‐fold change or ≤ 0.35‐fold change). A total of 836 genes were shown to be differentially regulated between the SUC/SIV and CBA/SIV animals. Further filtering of the gene pool revealed 21 significantly upregulated and 26 significantly downregulated genes that were examined through literature searches based on their functional consequences as they relate to muscle wasting. Five of the 21 upregulated genes (
HP, CCL‐2, SELE, TIMP‐1,
and
PAPPA
) and six of the 26 downregulated genes (
ATP2B2, PP1R3C, TAOK1, PVALB, APLN, ESR1
) were selected for further analysis based their relevance to mechanisms underlying muscle wasting. Verification of the selected genes through quantitative real‐time PCR and Western blot analysis followed by
in vitro
functional assays will confirm their contribution to the mechanisms underlying accentuated skeletal muscle wasting in CBA SIV‐infected macaques.
Supported by:
AA‐07577, AA‐09803, AA‐11290.
Identification of transmitted/founder simian immunodeficiency virus (SIV) envelope sequences responsible for infection may prove critical for understanding HIV/SIV mucosal transmission. We used ...single genome amplification and phylogenetic analyses to characterize transmitted/founder SIVs both in the inoculum and in immunized-infected rhesus monkeys. Single genome amplification of the SIVsmE660 inoculum revealed a maximum diversity of 1.4%. We also noted that the consensus sequence of the challenge stock differed from the vaccine construct in 10 amino acids including 3 changes in the V4 loop. Viral env was prepared from rhesus plasma in 3 groups of 6 immunized with vesicular stomatitis virus (VSV) vectors and boosted with Semliki forest virus (SFV) replicons expressing (a) SIVsmE660 gag-env (b) SIVsmE660 gag-env plus rhesus GM-CSF and (c) control influenza hemagglutinin protein. Macaques were immunized twice with VSV-vectors and once with SFV vector and challenged intrarectally with 4000 TCID50. Single genome amplification characterized the infections of 2 unprotected animals in the gag-env immunized group, both of which had reduced acute plasma viral loads that ended as transient infections indicating partial immune control. Four of 6 rhesus were infected in the gag-env + GM-CSF group which demonstrated that GM-CSF abrogated protection. All 6 animals from the control group were infected having high plasma viral loads. We obtained 246 full-length envelope sequences from SIVsmE660 infected macaques at the peak of infection and determined the number of transmitted/founder variants per animal. Our analysis found that 2 of 2 gag-env vaccinated but infected macaques exhibited single but distinct virus envelope lineages whereas rhesus vaccinated with gag-env-GM-CSF or HA control exhibited both single and multiple env lineages. Because there were only 2 infected animals in the gag-env vaccinated rhesus compared to 10 infected rhesus in the other 2 groups, the significance of finding single env variants in the gag-env vaccinated group could not be established.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To examine the chronic effects of alcohol on learning, 2 groups (−ETOH, +ETOH) of young male rhesus monkeys trained to respond under a task with acquisition and performance components received ...ethanol 4 consecutive days per week for 12 months via an intragastric catheter. Cumulative dose‐effect curves for both flunitrazepam (0.056–0.56 mg/kg, i.m.) and ketamine (1.8–10 mg/kg, i.m.) were determined in each group before and after chronic ethanol. During the three days of the week when ethanol was not administered, little or no disruptions were observed in either response rate or the percentage of errors (accuracy) in either component compared to control subjects. During the two days of testing during ethanol administration, modest disruptions in response rate and percent errors occurred in the acquisition components; the disruptions were larger on the initial day than on the second day. When cumulative doses of flunitrazepam and ketamine were administered in the absence of ethanol, dose‐dependent decreases in response rate and accuracy occurred in both components. Over time, however, chronic ethanol administration shifted the dose‐effect curves for flunitrazepam to the right, whereas the curves for ketamine were unchanged. These results indicate that chronic alcohol administration may produce larger changes in GABA(A) receptor function than NMDA receptor function in monkeys.
Supported by USPHS AA09803.
With a few exceptions, most studies on tropospheric ozone (O3) variability during and following the COrona VIrus Disease (COVID-19) economic downturn focused on high-emission regions or urban ...environments. In this work, we investigated the impact of the societal restriction measures during the COVID-19 pandemic on surface O3 at several high-elevation sites across North America and western Europe. Monthly O3 anomalies were calculated for 2020 and 2021, with respect to the baseline period 2000–2019, to explore the impact of the economic downturn initiated in 2020 and its recovery in 2021. In total, 41 high-elevation sites were analyzed: 5 rural or mountaintop stations in western Europe, 19 rural sites in the western US, 4 sites in the western US downwind of highly polluted source regions, and 4 rural sites in the eastern US, plus 9 mountaintop or high-elevation sites outside Europe and the United States to provide a “global” reference. In 2020, the European high-elevation sites showed persistent negative surface O3 anomalies during spring (March–May, i.e., MAM) and summer (June–August, i.e., JJA), except for April. The pattern was similar in 2021, except for June. The rural sites in the western US showed similar behavior, with negative anomalies in MAM and JJA 2020 (except for August) and MAM 2021. The JJA 2021 seasonal mean was influenced by strong positive anomalies in July due to large and widespread wildfires across the western US. The polluted sites in the western US showed negative O3 anomalies during MAM 2020 and a slight recovery in 2021, resulting in a positive mean anomaly for MAM 2021 and a pronounced month-to-month variability in JJA 2021 anomalies. The eastern US sites were also characterized by below-mean O3 for both MAM and JJA 2020, while in 2021 the negative values exhibited an opposite structure compared to the western US sites, which were influenced by wildfires. Concerning the rest of the world, a global picture could not be drawn, as the sites, spanning a range of different environments, did not show consistent anomalies, with a few sites not experiencing any notable variation. Moreover, we also compared our surface anomalies to the variability of mid-tropospheric O3 detected by the IASI (Infrared Atmospheric Sounding Interferometer) satellite instrument. Negative anomalies were observed by IASI, consistent with published satellite and modeling studies, suggesting that the anomalies can be largely attributed to the reduction of O3 precursor emissions in 2020.
Liver failure causes breakdown of the Blood CNS Barrier (BCB) leading to damages of the Central-Nervous-System (CNS), however the mechanisms whereby the liver influences BCB-integrity remain elusive. ...One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BCB-integrity. To study BCB-integrity, we developed light-sheet imaging for three-dimensional analysis. We show that liver- or muscle-specific knockout of Hfe2/Rgmc induces BCB-breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits in mice. Soluble HFE2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells, triggering BCB-disruption. HFE2 administration in female mice with experimental autoimmune encephalomyelitis, a model for multiple sclerosis, prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BCB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BCB-dysfunction.
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