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The American Journal of Pathology Apr 2019Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve...
Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signaling. Sclerostin, encoded by Sost gene, is the main negative regulator of the proformative and antiresorptive role of the Wnt signaling pathway in the skeleton. It was hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids, and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and nonconvulsive death. Detailed histopathologic analysis in a wide range of tissues identified peracute hemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials that explore the use of antisclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients who might otherwise benefit from antisclerostin antibody treatment.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bone Density; Bone Diseases, Metabolic; Cardiac Tamponade; Disease Models, Animal; Female; Genetic Markers; Glucocorticoids; Haploinsufficiency; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Wnt Signaling Pathway
PubMed: 30664862
DOI: 10.1016/j.ajpath.2018.12.007 -
Porcine Health Management 2019In 2007 African swine fever (ASF) arrived at a Black Sea harbour in Georgia and in 2014 the infection reached the European Union (EU), where it still expands its... (Review)
Review
In 2007 African swine fever (ASF) arrived at a Black Sea harbour in Georgia and in 2014 the infection reached the European Union (EU), where it still expands its territory. ASF is a fatal viral disease affecting domestic pigs and wild boar of all ages with clinical presentations ranging from per-acute to chronic disease, including apparently asymptomatic courses. Until the detection of the first case inside the EU, infections in the current epidemic were mainly seen among pig farms with generally low biosecurity, and with incidental spill over to the wild boar population. In the EU, however, the infection survived locally in the wild boar population independently from outbreaks in domestic pigs, with a steady and low prevalence. Apart from the wild boar population and the habitat, the current epidemic recognizes humans as the main responsible for both long distance transmission and virus introduction in the domestic pig farms. This underlines the importance to include social science when planning ASF-prevention, -control, or -eradication measures. Based on experiences, knowledge and data gained from the current epidemic this review highlights some recent developments in the epidemiological understanding of ASF, especially concerning the role of wild boar and their habitats in ASF epidemiology. In this regard, the qualities of three epidemiological traits: contagiousity, tenacity, and case fatality rate, and their impact on ASF persistence and transmission are especially discussed.
PubMed: 30637117
DOI: 10.1186/s40813-018-0109-2 -
Journal of the American Veterinary... Oct 2018OBJECTIVE To determine the prevalence of depressed pelvic limb reflexes and changes in those reflexes over time in dogs with acute thoracolumbar myelopathy. DESIGN...
OBJECTIVE To determine the prevalence of depressed pelvic limb reflexes and changes in those reflexes over time in dogs with acute thoracolumbar myelopathy. DESIGN Prospective study. ANIMALS 34 dogs. PROCEDURES Dogs with acute pelvic limb paralysis caused by acute noncompressive nucleus pulposus extrusion (ANNPE), fibrocartilaginous embolism (FCE), or compressive intervertebral disk herniation (IVDH) within the T3-L3 spinal cord segments were enrolled in the study. Dogs with depressed or absent pelvic limb withdrawal reflexes as determined by 2 examiners were classified as affected and underwent additional testing to rule out multifocal lesions. Pelvic limb reflexes of affected dogs were reassessed every 12 hours until they returned to normal. Neurologic examinations were performed at 4 and 8 weeks after initial examination for some dogs. RESULTS Compressive IVDH, ANNPE, and FCE were diagnosed in 30, 1, and 3 dogs, respectively. Nine (5 with compressive IVDH and all 4 with FCE or ANNPE) of 34 (26%) dogs were classified as affected. Patellar reflexes were depressed in 2 of 9 affected dogs. The median time required for withdrawal reflexes to return to normal was 60 hours (range, 12 to 156 hours). Onset duration of paralysis was negatively associated with the odds of a dog being classified as affected. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that dogs with focal thoracolumbar spinal cord lesions, especially those with peracute onset of paralysis, can develop transient depression of pelvic limb reflexes. Awareness of this phenomenon is important for veterinarians to accurately localize lesions and develop appropriate diagnostic plans and prognoses.
Topics: Animals; Dog Diseases; Dogs; Female; Hindlimb; Male; Paralysis; Reflex; Spinal Cord Diseases; Spinal Cord Injuries
PubMed: 30272519
DOI: 10.2460/javma.253.8.1022 -
Journal of Cerebral Blood Flow and... Dec 2019Intracerebral hemorrhage (ICH) is an important stroke subtype, but preclinical research is limited by a lack of translational animal models. Large animal models are...
Intracerebral hemorrhage (ICH) is an important stroke subtype, but preclinical research is limited by a lack of translational animal models. Large animal models are useful to comparatively investigate key pathophysiological parameters in human ICH. To (i) establish an acute model of moderate ICH in adult sheep and (ii) an advanced neuroimage processing pipeline for automatic brain tissue and hemorrhagic lesion determination; 14 adult sheep were assigned for stereotactically induced ICH into cerebral white matter under physiological monitoring. Six hours after ICH neuroimaging using 1.5T MRI including structural as well as perfusion and diffusion, weighted imaging was performed before scarification and subsequent neuropathological investigation including immunohistological staining. Controlled, stereotactic application of autologous blood caused a space-occupying intracerebral hematoma of moderate severity, predominantly affecting white matter at 5 h post-injection. Neuroimage post-processing including lesion probability maps enabled automatic quantification of structural alterations including perilesional diffusion and perfusion restrictions. Neuropathological and immunohistological investigation confirmed perilesional vacuolation, axonal damage, and perivascular blood as seen after human ICH. The model and imaging platform reflects key aspects of human ICH and enables future translational research on hematoma expansion/evacuation, white matter changes, hematoma evacuation, and other aspects.
Topics: Animals; Cerebral Hemorrhage; Disease Models, Animal; Female; Humans; Image Processing, Computer-Assisted; Male; Neuroimaging; Sheep; White Matter
PubMed: 30239258
DOI: 10.1177/0271678X18802119 -
Frontiers in Veterinary Science 2018Ischemic cerebrovascular disease (CVD) is a relatively common condition in dogs but infrequent in cats, with acute or peracute onset of non-progressive neurological...
Ischemic cerebrovascular disease (CVD) is a relatively common condition in dogs but infrequent in cats, with acute or peracute onset of non-progressive neurological signs. Cerebellar artery infarction appears to be very uncommon in cats, with only two cases reported affecting the rostral cerebellar artery (RCA). This study aims to report for the first time the neurological signs, magnetic resonance imaging (MRI) findings and outcome in three cats diagnosed with presumed caudal cerebellar artery (CCA) infarction. Unique presentation of vestibular signs associated with CCA in three cats and similarities between dogs and humans are discussed.
PubMed: 30027093
DOI: 10.3389/fvets.2018.00155 -
The Canadian Veterinary Journal = La... Jul 2018A 1-year-old neutered male Labrador retriever mixed breed dog was referred for peracute onset of ataxia and seizures. Hematocrit at presentation was 84%. Magnetic...
A 1-year-old neutered male Labrador retriever mixed breed dog was referred for peracute onset of ataxia and seizures. Hematocrit at presentation was 84%. Magnetic resonance imaging of the brain revealed a lesion in the right caudate nucleus consistent with infarction. Postmortem findings were consistent with polycythemia vera and presumed secondary cerebral infarction.
Topics: Animals; Ataxia; Brain; Cerebral Infarction; Dog Diseases; Dogs; Magnetic Resonance Imaging; Male; Polycythemia Vera; Seizures
PubMed: 30026622
DOI: No ID Found -
Antiviral Research Aug 2018Rift Valley fever virus (RVFV) is a mosquito-borne pathogen endemic to sub-Saharan Africa and the Arabian Peninsula. There are no approved antiviral therapies or...
Rift Valley fever virus (RVFV) is a mosquito-borne pathogen endemic to sub-Saharan Africa and the Arabian Peninsula. There are no approved antiviral therapies or vaccines available to treat or prevent severe disease associated with RVFV infection in humans. The adenosine analog, galidesivir (BCX4430), is a broad-spectrum antiviral drug candidate with in vitro antiviral potency (EC of less than 50 μM) in more than 20 different viruses across eight different virus families. Here we report on the activity of galidesivir in the hamster model of peracute RVFV infection. Intramuscular and intraperitoneal treatments effectively limited systemic RVFV (strain ZH501) infection as demonstrated by significantly improved survival outcomes and the absence of infectious virus in the spleen and the majority of the serum, brain, and liver samples collected from infected animals. Our findings support the further development of galidesivir as an antiviral therapy for use in treating severe RVFV infection, and possibly other related phleboviral diseases.
Topics: Adenine; Adenosine; Animals; Antiviral Agents; Disease Models, Animal; Injections, Intramuscular; Injections, Intraperitoneal; Liver; Mesocricetus; Purine Nucleosides; Pyrrolidines; Rift Valley Fever; Rift Valley fever virus; Spleen; Survival Analysis; Treatment Outcome
PubMed: 29864447
DOI: 10.1016/j.antiviral.2018.05.013 -
Journal of Orthopaedic Research :... Feb 2018No disease-modifying osteoarthritis (OA) drugs are available to prevent posttraumatic osteoarthritis (PTOA). Mitochondria (MT) mediate the pathogenesis of many...
UNLABELLED
No disease-modifying osteoarthritis (OA) drugs are available to prevent posttraumatic osteoarthritis (PTOA). Mitochondria (MT) mediate the pathogenesis of many degenerative diseases, and recent evidence indicates that MT dysfunction is a peracute (within minutes to hours) response of cartilage to mechanical injury. The goal of this study was to investigate cardiolipin-targeted mitoprotection as a new strategy to prevent chondrocyte death and cartilage degeneration after injury. Cartilage was harvested from bovine knee joints and subjected to a single, rapid impact injury (24.0 ±1.4 MPa, 53.8 ± 5.3 GPa/s). Explants were then treated with a mitoprotective peptide, SS-31 (1µM), immediately post-impact, or at 1, 6, or 12 h after injury, and then cultured for up to 7 days. Chondrocyte viability and apoptosis were quantified in situ using confocal microscopy. Cell membrane damage (lactate dehydrogenase activity) and cartilage matrix degradation (glycosaminoglycan loss) were quantified in cartilage-conditioned media. SS-31 treatment at all time points after impact resulted in chondrocyte viability similar to that of un-injured controls. This effect was sustained for up to a week in culture. Further, SS-31 prevented impact-induced chondrocyte apoptosis, cell membrane damage, and cartilage matrix degeneration.
CLINICAL SIGNIFICANCE
This study is the first investigation of cardiolipin-targeted mitoprotective therapy in cartilage. These results suggest that even when treatment is delayed by up to 12 h after injury, mitoprotection may be a useful strategy in the prevention of PTOA. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-10, 2018.
PubMed: 29469223
DOI: 10.1002/jor.23882 -
Diseases of Aquatic Organisms Jan 2018The challenge of identifying cause of death in discarded bycaught marine mammals stems from a combination of the non-specific nature of the lesions of drowning, the...
The challenge of identifying cause of death in discarded bycaught marine mammals stems from a combination of the non-specific nature of the lesions of drowning, the complex physiologic adaptations unique to breath-holding marine mammals, lack of case histories, and the diverse nature of fishing gear. While no pathognomonic lesions are recognized, signs of acute external entanglement, bulging or reddened eyes, recently ingested gastric contents, pulmonary changes, and decompression-associated gas bubbles have been identified in the condition of peracute underwater entrapment (PUE) syndrome in previous studies of marine mammals. We reviewed the gross necropsy and histopathology reports of 36 cetaceans and pinnipeds including 20 directly observed bycaught and 16 live stranded animals that were euthanized between 2005 and 2011 for lesions consistent with PUE. We identified 5 criteria which present at significantly higher rates in bycaught marine mammals: external signs of acute entanglement, red or bulging eyes, recently ingested gastric contents, multi-organ congestion, and disseminated gas bubbles detected grossly during the necropsy and histologically. In contrast, froth in the trachea or primary bronchi, and lung changes (i.e. wet, heavy, froth, edema, congestion, and hemorrhage) were poor indicators of PUE. This is the first study that provides insight into the different published parameters for PUE in bycatch. For regions frequently confronted by stranded marine mammals with non-specific lesions, this could potentially aid in the investigation and quantification of marine fisheries interactions.
Topics: Animals; Caniformia; Cause of Death; Cetacea; Conservation of Natural Resources; Drowning; Female; Fisheries; Male
PubMed: 29384478
DOI: 10.3354/dao03189 -
PloS One 2017Rift Valley fever phlebovirus (RVFV) causes high rates of abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or blindness in humans....
Rift Valley fever phlebovirus (RVFV) causes high rates of abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or blindness in humans. Viral transmission occurs via mosquito vectors in endemic areas, which necessitates regular vaccination of susceptible livestock animals to prevent the RVF outbreaks. Although ZH501 strain has been used as a challenge strain for past vaccine efficacy studies, further characterization of other RVFV strains is important to optimize ruminant and nonhuman primate RVFV challenge models. This study aimed to characterize the virulence of wild-type RVFV strains belonging to different genetic lineages in outbred CD1 mice. Mice were intraperitoneally infected with 1x103 PFU of wild-type ZH501, Kenya 9800523, Kenya 90058, Saudi Arabia 200010911, OS1, OS7, SA75, Entebbe, or SA51 strains. Among them, mice infected with SA51, Entebbe, or OS7 strain showed rapid dissemination of virus in livers and peracute necrotic hepatitis at 2-3 dpi. Recombinant SA51 (rSA51) and Zinga (rZinga) strains were recovered by reverse genetics, and their virulence was also tested in CD1 mice. The rSA51 strain reproduced peracute RVF disease in mice, whereas the rZinga strain showed a similar virulence with that of rZH501 strain. This study showed that RVFV strains in different genetic lineages display distinct virulence in outbred mice. Importantly, since wild-type RVFV strains contain defective-interfering RNA or various genetic subpopulations during passage from original viral isolations, recombinant RVFV strains generated by reverse genetics will be better suitable for reproducible challenge studies for vaccine development as well as pathological studies.
Topics: Animals; Cell Line; Disease Models, Animal; Dose-Response Relationship, Immunologic; Female; Liver; Mice; Rift Valley fever virus; Serial Passage; Spleen; Viral Vaccines; Virulence
PubMed: 29267298
DOI: 10.1371/journal.pone.0189250