Hydroxyurea Therapy in UK Children with Sickle Cell Anaemia – A Single Centre Experience

Despite the demonstrated efficacy of hydroxyurea therapy, children with sickle cell anaemia in the United Kingdom (UK) are preferentially managed with supportive care or transfusion. Hydroxyurea is reserved for children with severe disease phenotype. This is in contrast to North America and other countries where hydroxyurea is widely used for children of all clinical phenotypes. The conservative UK practice may in part be due to concerns about toxicity, in particular marrow suppression with high doses, and growth in children. We monitored 37 paediatric patients with sickle cell anaemia who were treated with hydroxyurea at a single UK treatment centre. Therapy was well tolerated and mild transient cytopenias were the only toxicity observed. Comparative analysis of patients receiving ≥26mg/kg/day versus <26 mg/kg/day demonstrates increasing dose has a significant positive effect on foetal haemoglobin (29.2% v 20.4%, p=0.0151), mean cell volume (94.4 v 86.5, p=0.0183) and reticulocyte count (99.66 x109/L v 164.3x109/L, p=0.0059). Marrow suppression was not a clinical problem with high dose treatment, haemoglobin 92.25 g/L v 91.81 g/L (ns), neutrophil count 3.3 x109/L v 4.8 x109/L (ns) and platelet count 232.4 x109/L v 302.2 x109/L (ns). Normal growth rates were maintained in all children. Good adherence to therapy was a significant factor in reducing hospitalisations This study demonstrates the effectiveness and safety in practice of high dose hydroxyurea as a disease modifying therapy which we advocate for all children with sickle cell anaemia

Transgenic mice overexpressing human TNF-α experience early onset spontaneous intervertebral disc herniation in the absence of overt degeneration

Abstract There is a well-established link between cytokine expression and the progression of intervertebral disc degeneration. Among these cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are the most commonly studied. To investigate whether systemic hTNF-α overexpression affects intervertebral disc health, we studied the spine phenotype of Tg197 mice, a widely used hTNF-α transgenic line. These mice were studied at 12–16 weeks of age using comprehensive histochemical and immunohistological analysis of the spinal motion segment. Micro-CT analysis was performed to quantify vertebral trabecular bone architecture. The Tg197 mice evidenced spontaneous annular tears and herniation with increased vascularity in subchondral bone and significant immune cell infiltration. The full-thickness annular tear without nucleus pulposus (NP) extrusion resulted in neutrophil, macrophage, and mast cell infiltration into the disc, whereas the disc with full-thickness tear and pronounced NP herniation showed additional presence of CD4+ and CD8+ T cells. While the observed defects involved failure of the annular, endplate, and vertebral junction, there were no obvious alterations in the collagen or aggrecan content in the NP and annulus fibrosus or the maturity of collagen fibers in Tg197 mice. Despite elevated systemic inflammation and pronounced loss of trabecular bone in the vertebrae, intact Tg197 discs were healthy and showed an increase in NP cell number. The NP cells in intact discs preserved expression of phenotypic markers: CAIII, Glut1, and Krt19. In conclusion, elevated systemic TNF-α increases the susceptibility of mice to spontaneous disc herniation and possibly radiculopathy, without adversely affecting intact intervertebral disc health