Abstract
Acute lung injury is characterized by inflammation and respiratory failure. In this work, we evaluated the effect of Toll-like receptor 4 (TLR4)-interacting SPA4 peptide on inflammatory and ...physiological parameters in cells and in mice against lipopolysaccharide (LPS). Cellular toxicity was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Binding of SPA4 peptide was studied in cells transiently transfected with a plasmid DNA encoding TLR4. We assessed the changes in the levels of cytokines and chemokines in supernatants of cells treated with SPA4 peptide simultaneously or post-LPS challenge. The extent of lung edema, levels of cytokines and chemokines, and changes in lung histopathology, blood gas and electrolytes, and serum lactate levels, were then determined after SPA4 peptide treatment in a mouse model of acute lung inflammation and injury induced by intratracheal LPS challenge. Our results demonstrate that the SPA4 peptide is not toxic, and binds to TLR4 at the cellular level. A significant reduction was observed in secreted levels of LPS-induced cytokines and chemokines in cell-free supernatants. Correspondingly, the levels of TNF-α, IL-1β, IL-6, MIP-2, KC, and MCP-1 were reduced in bronchoalveolar lavage fluids of SPA4 peptide-treated mice. Moreover, SPA4 peptide treatment attenuated the LPS-induced pulmonary inflammation, lung edema, serum lactate, and blood gas and electrolyte parameters. Together, our results suggest that the SPA4 peptide treatment can help control lung inflammation and injury.
Buprenorphine is a common analgesic administered to rabbits and high concentration formulations can reduce handling stress without sacrificing pain relief. The objective of this study was to evaluate ...the pharmacokinetics of high concentration buprenorphine and its metabolites following multiple subcutaneous doses in the rabbit. Laboratory variables (complete blood cell count, biochemistry profile, urinalysis) were compared for drug effects and injection sites were evaluated via histopathology.
High concentration buprenorphine (HCB) was administered subcutaneously (0.24 mg/kg) to six, 17-week-old, intact female, New Zealand white rabbits (Oryctolagus cuniculus) for three doses, 24 hours apart. Two control animals received an equal volume of saline. Blood samples were collected at -72, 0, 0.33, 0.66, 1.5, 3, 6, 12, 24, 48, 72, 96, 120, and 144 hours. Buprenorphine and its metabolites were measured via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS). Blood and urine profiles were collected prior to and following HCB administration and compared within and between groups. Injection sites and major organ systems were evaluated grossly and microscopically for drug effects.
High concentration buprenorphine administered once every 24 hours for three doses had a variable accumulation index of 1.68 (1.24–2.29), reflecting variability in terminal half-life. Subsequently, the metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide had accumulation indices of 1.79 (1.25–2.77) and 1.84 (1.43–2.88), respectively. No significant laboratory changes were attributed to multiple dose drug administration. Local subcutaneous vasculitis and panniculitis were reported in rabbits receiving HCB. Ante-mortem examination did not find clinical disease, however 6 of 8 rabbits, including controls, had multifocal inflammatory changes in the liver and lungs on histopathology.
Subcutaneous high concentration buprenorphine in rabbits has substantial pharmacokinetic variability and accumulation of both the parent drug and metabolites occurs with multiple dosing regimens. Subclinical illness may have impacted these findings and is a notable study limitation. Local inflammation in subcutaneous fat at injection sites was noted in rabbits administered HCB.
High concentration buprenorphine has a quick onset of action when administered subcutaneously in the rabbit, but individual variability is notable. Subclinical inflammatory illness may prolong buprenorphine metabolism and clearance and should be considered in determining dosing regimens in rabbits, especially if disease is present or suspected. Inflammation at HCB injection sites is a drug sequela; monitoring injection sites is recommended.
A 13-year-old, castrated male Maine Coon cat was presented to Oklahoma State University Boren Veterinary Medical Teaching Hospital for yearly echocardiographic examination monitoring hypertrophic ...cardiomyopathy (HCM) diagnosed in 2003. Physical examination revealed a heart murmur and premature beats, likely related to HCM, but was otherwise unremarkable. A biochemistry profile revealed a hyperglobulinemia (6.3 g/dL). Cytologic examination of fine-needle aspirates from liver and spleen revealed increased numbers of plasma cells and mast cells, confirmed with subsequent histologic examination. Immunohistochemistry (IHC) for c-kit in the spleen and liver showed mast cells predominantly exhibiting type I staining pattern, with moderate numbers exhibiting type II pattern in spleen, and scattered cells exhibiting type II and III patterns in liver. Bone marrow cytology and core biopsy documented approximately 22% plasma cells. Cutaneous masses on the cat's left shoulder and right carpus were cytologically confirmed mast cell tumors. Serum protein electrophoresis with immunofixation confirmed an IgG monoclonal gammopathy. This is an example of 2 hematologic neoplasms occurring simultaneously in a cat. Concurrent pathologies may be overlooked if a single disease is diagnosed and suspected of causing all clinical signs. Both neoplasms were well differentiated, and neoplastic cells could have easily been interpreted as a reactive population had a full workup not been performed. Missing either diagnosis could result in a potentially lethal outcome. Eleven months after diagnoses, the cat was clinically doing well following a splenectomy and oral prednisolone and chlorambucil chemotherapy. Globulins decreased to 4.9 g/dL.
In this paper we characterize the function of Xylosyltransferase 2 (XylT2) in different tissues to investigate the role XylT2 has in the proteoglycan (PG) biochemistry of multiple organs. The results ...show that in all organs examined there is a widespread and significant decrease in total XylT activity in Xylt2 knock out mice (Xylt2−/−). This decrease results in increased organ weight differences in lung, heart, and spleen. These findings, in addition to our previous findings of increased liver and kidney weight with loss of serum XylT activity, suggest systemic changes in organ function due to loss of XylT2 activity. The
Xylt2
−/− mice have splenomegaly due to enlargement of the red pulp area and enhanced pulmonary response to bacterial liposaccharide. Tissue glycosaminoglycan composition changes are also found. These results demonstrate a role of XylT2 activity in multiple organs and their PG content. Because the residual XylT activity in the Xylt2−/− is due to xylosyltransferase 1 (XylT1), these studies indicate that both XylT1 and XylT2 have important roles in PG biosynthesis and organ homeostasis.
Purinergic P2X7 receptor is an ATP‐gated ion channel and participates in inflammation by regulating IL‐1β processing and release. Recent studies have identified the pathophysiological importance of ...P2X7 receptor in immune and neuroinflammatory diseases. However, the role of P2X7 receptor in acute lung injury is still unclear. In the present study using a two‐hit lung injury model of low dose endotoxin exposure and moderate tidal volume mechanical ventilation for 3 hours, we compared the early inflammatory response between wild‐type and P2X7−/−mice. There was a significant reduction in total bronchoalveolar lavage cell counts and neutrophil infiltration in lung tissue and lavage in P2X7−/− mice compared to wild‐type. Furthermore, myeloperoxidase from P2X7−/− mice lung homogenate was also reduced. The release of proinflammatory cytokine IL‐1β and IL‐6, but not TNF‐α from P2X7−/− mice showed a marked reduction. In parallel, transcripts of IL‐1β, IL‐6, and MCP‐1 from P2X7−/− mice failed to respond to challenge. However, TNF‐α, KC, and IL‐10 shows a similar expression pattern between wild‐type and P2X7−/−mice. Moreover, P2X7−/− mice exhibited less responsiveness to alveolar–capillary leakage, as measured by reduced bronchoalveolar lavage protein accumulation and Evans blue dye extravasion. Taken together our results support that P2X7 receptor facilitates IL‐1β and IL‐6 release and is involved in the pathogenesis of acute lung injury.
Naturally Occurring Hepatozoonosis in Coyotes from Oklahoma Kocan, A. Alan; Breshears, Melanie; Cummings, Connie ...
Journal of wildlife diseases,
1999-JANUARY, 1999, 19990101, 1999-Jan, 1999-01-00, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Nine of 16 free-ranging coyotes (Canis latrans) from central Oklahoma (USA) had naturally acquired infections of Hepatozoon americanum. Infections were confirmed by recognition of tissue stages ...closely resembling H. americanum in skeletal and cardiac muscle. At the time coyotes were collected they were infested with a variety of ticks, including adult Gulf Coast ticks (Amblyomma maculatum). We propose that the high prevalence of H. americanum in this small sample of free-ranging coyotes and the ability of these same animals to harbor adult populations of A. maculatum is an important component of the epizootiology of canine hepatozoonosis in North America.
Scope and method of study. The purpose of this study was to investigate the pathogenesis of Saimiriine herpesvirus 1 (SaHV-1) infection by characterizing the clinical disease and gross and ...microscopic lesions in experimentally infected mice. To aid in the identification of anatomic sites of viral replication and to trace viral spread in experimentally infected mice, a green fluorescent protein (GFP)-expressing recombinant strain of SaHV-1 was constructed and used in subsequent inoculation studies. Mice were inoculated intramuscularly or epidermally with ten-fold dilutions of virus and sacrificed at 14 or 21 days in endpoint studies or on sequential days in temporal studies. Serum was tested by ELISA and tissues were examined microscopically with routine stains, immunohistochemistry, and confocal microscopy. Findings and conclusions. SaHV-1 inoculation of Balb/c mice, either intramuscularly or epidermally, resulted in active infection as indicated by seroconversion, clinical disease, and gross and microscopic lesions. Mice inoculated intramuscularly initially developed skin lesions in the region of inoculation with subsequent development of paresis or paralysis of the inoculated hindlimb in animals receiving higher doses of virus. Lesions in these mice were restricted to the skin and thoracolumbar spinal cord and consisted of necrotizing dermatitis and segmental myelitis with neuronal necrosis. Mice inoculated with SaHV-1 via epidermal scarification developed a more rapidly progressive, severe disease that began in the inoculated epidermis and spread to involve thoracolumbar spinal cord, regional autonomic ganglia, and lower urinary tract. All mice receiving an infective dose of virus by this route developed ultimately fatal disease. GFP expression, indicating viral replication, corresponded with microscopic lesions and was present in keratinocytes of the epidermis, neurons of the dorsal root ganglia, spinal cord, sympathetic ganglia, and colonic myenteric plexus as well as epithelium of the lower urinary tract. SaHV-1 exhibited neurovirulence in Balb/c mice that varied significantly with the route of inoculation.
Broad-scale forest die-off associated with drought and heat has now been reported from every forested continent, posing a global-scale challenge to forest management. Climate-driven die-off is ...frequently compounded with other drivers of tree mortality, such as altered land use, wildfire, and invasive species, making forest management increasingly complex. Facing similar challenges, rangeland managers have widely adopted the approach of developing conceptual models that identify key ecosystem states and major types of transitions between those states, known as "state-and-transition models" (S&T models). Using expert opinion and available research, the development of such conceptual S&T models has proven useful in anticipating ecosystem changes and identifying management actions to undertake or to avoid. In cases where detailed data are available, S&T models can be developed into probabilistic predictions, but even where data are insufficient to predict transition probabilities, conceptual S&T models can provide valuable insights for managing a given ecosystem and for comparing and contrasting different ecosystem dynamics. We assembled a synthesis of 14 forest die-off case studies from around the globe, each with sufficient information to infer impacts on forest dynamics and to inform management options following a forest die-off event. For each, we developed a conceptual S&T model to identify alternative ecosystem states, pathways of ecosystem change, and points where management interventions have been, or may be, successful in arresting or reversing undesirable changes. We found that our diverse set of mortality case studies fit into three broad classes of ecosystem trajectories: (1) single-state transition shifts, (2) ecological cascading responses and feedbacks, and (3) complex dynamics where multiple interactions, mortality drivers, and impacts create a range of possible state transition responses. We integrate monitoring and management goals in a framework aimed to facilitate development of conceptual S&T models for other forest die-off events. Our results highlight that although forest die-off events across the globe encompass many different underlying drivers and pathways of ecosystem change, there are commonalities in opportunities for successful management intervention.
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