Mesenchymal stem cells (MSCs) are multipotent cells capable of developing along the chondrogenic, osteogenic and adipogenic lineages. As such, they have received interest as a potential cell source for tissue engineering strategies. Cartilage is an avascular tissue and thus resides in a microenvironment with reduced oxygen tension. The aim of this study was to examine the effect of a low oxygen environment on MSC differentiation along the chondrogenic route. In MSCs exposed to chondrogenic growth factors, transforming growth factor-beta and dexamethasone, in a hypoxic environment (2% oxygen), the induction of collagen II expression and proteoglygan deposition was significantly greater than that observed when cells were exposed to the chondrogenic growth factors under normoxic (20% oxygen) conditions. The transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha), is a crucial mediator of the cellular response to hypoxia. Following exposure of MSCs to hypoxia (2% oxygen), HIF-1alpha translocated from the cytosol to the nucleus and bound to its target DNA consensus sequence. Similarly, hypoxia evoked an increase in phosphorylation of both AKT and p38 mitogen activated protein kinase, upstream of HIF-1alpha activation. Furthermore, the PI3 kinase/AKT inhibitor, LY294002, and p38 inhibitor, SB 203580, prevented the hypoxia-mediated stabilisation of HIF-1alpha. To assess the role of HIF-1alpha in the hypoxia-induced increase in chondrogenesis, we employed an siRNA knockdown approach. In cells exposed to HIF-1alpha siRNA, the hypoxia-induced enhancement of chondrogenesis, as evidenced by upregulation of collagen II, sox-9 and proteoglycan deposition, was absent. This provides evidence for HIF-1alpha being a key mediator of the beneficial effect of a low oxygen environment on chondrogenesis.

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Background: Cycad palms are commonly used in landscaping and ingestion by dogs can cause disease or death. Objectives: Determine the morbidity and case fatality of cycad palm toxicosis in dogs from Louisiana, and examine putative prognostic factors.Animals: Thirty-four client-owned dogs with confirmed cycad palm toxicosis between 2003 and 2010. Methods: Retrospective cohort study. Search of all medical records for animals with cycad palm toxicosis.Results: Seventeen of 34 (50%) dogs died or were euthanized as a direct consequence of cycad intoxication. There were no differences in presenting signs and physical examination findings between survivors and nonsurvivors. Nonsurvivors had higher serum alanine transaminase activity (median 196 U/L; range 16-4,123 versus 113.5; 48-1,530) and total bilirubin concentration (0.5 mg/dL; 0.1-6.2 versus 0.25; 0-1.7) upon presentation, and their initial serum concentrations of albumin (2.9 g/dL; 1.4-4.1 versus 3.3; 2.2-3.9) were lower than those of survivors. Nadir serum albumin concentration was also lower in nonsurvivors (1.9; 1.4-3.7 versus 3.2; 1.8-3.5). A higher proportion of nonsurvivors had prolonged coagulation times, prothrombin time. and partial thromboplastin time. In a multivariate model, administration of charcoal at initial presentation was associated with longer survival (heart rate [HR] 0.019, 95% CI 0.001-0.644), while high serum aspartate aminotransferase activity was a negative prognostic factor (HR 118.2,826).Conclusions and Clinical Importance: Cycad intoxication is associated with a higher case fatality than previously published. Several laboratory parameters might help differentiating potential nonsurvivors from survivors. Administration of charcoal as part of the emergency treatment appears to have a protective effect.

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Friedreich’s ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25–39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich’s ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich’s ataxia and discuss the pitfalls and risk of misdiagnosis.