HLA-DRB1*0404 is strongly associated with high titers of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis

OBJECTIVE:To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS:The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined.RESULTS:RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025).CONCLUSIONS:The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.     

Pixel-by-Pixel Comparison of Volume Transfer Constant and Estimates of Cerebral Blood Volume from Dynamic Contrast-Enhanced and Dynamic Susceptibility Contrast-Enhanced MR Imaging in High-Grade Gliomas

BACKGROUND AND PURPOSE:Estimates of blood volume and volume transfer constant are parameters commonly used to characterize hemodynamic properties of brain lesions. The purposes of this study were to compare values of volume transfer constant and estimates of blood volume in high-grade gliomas on a pixel-by-pixel basis to comprehend whether they provide different information and to compare estimates of blood volume obtained by dynamic contrast-enhanced MR imaging and dynamic susceptibility contrast-enhanced MR imaging.MATERIALS AND METHODS:Thirty-two patients with biopsy-proved grade IV gliomas underwent dynamic contrast-enhanced MR imaging and dynamic susceptibility contrast-enhanced MR imaging, and parametric maps of volume transfer constant, plasma volume, and CBV maps were calculated. The Spearman rank correlation coefficients among matching values of CBV, volume transfer constant, and plasma volume were calculated on a pixel-by-pixel basis. Comparison of median values of normalized CBV and plasma volume was performed.RESULTS:Weak-but-significant correlation (P < .001) was noted for all comparisons. Spearman rank correlation coefficients were as follows: volume transfer constant versus CBV, ρ = 0.113; volume transfer constant versus plasma volume, ρ = 0.256; CBV versus plasma volume, ρ = 0.382. We found a statistically significant difference (P < .001) for the estimates of blood volume obtained by using dynamic contrast-enhanced MR imaging (mean normalized plasma volume, 13.89 ± 11.25) and dynamic susceptibility contrast-enhanced MR imaging (mean normalized CBV, 4.37 ± 4.04).CONCLUSIONS:The finding of a very weak correlation between estimates of microvascular density and volume transfer constant suggests that they provide different information. Estimates of blood volume obtained by using dynamic contrast-enhanced MR imaging are significantly higher than those obtained by dynamic susceptibility contrast-enhanced MR imaging in human gliomas, most likely due to the effect of contrast leakage.

Characterization of the hemodynamics of glial tumors by MR perfusion is very relevant because tumor aggressiveness and growth are associated with both endothelial hyperplasia and neovascularization.¹The 2 most common MR perfusion techniques used in clinical practice are dynamic susceptibility contrast-enhanced MR imaging (DSC–MR imaging) and dynamic contrast-enhanced MR imaging (DCE–MR imaging).² CBV is usually calculated from DSC–MR imaging data, while the volume transfer constant (K^trans) is usually obtained by using DCE–MR imaging. Both CBV and the volume transfer constant have demonstrated good discriminative power in distinguishing low- and high-grade tumors³ and utility in predicting prognosis.^4–6K^trans is defined as the volume transfer constant between plasma and interstitial space. It is often used as a synonym for permeability, but, as defined by Tofts et al,⁷ “the measured transfer constant is a potentially intractable combination of flow, permeability, and surface area.” The physiologic significance of K^trans depends on the balance between capillary permeability and blood flow in the tissue of interest. When permeability is very high, the amount of contrast that leaks out of the vessels depends on the amount of contrast that gets to the capillaries per unit of time. In this situation, K^trans is equal to the blood plasma flow per unit volume of tissue (Fig 1). In cases of low permeability, the transfer constant equals the permeability surface area product between blood plasma and the extravascular-extracellular space, per unit volume of tissue.Open in a separate windowFig 1.Schematic illustrating flow-limited contrast extravasation. Due to high permeability, the rate of leakage within the voxel depends on the amount of plasma reaching the voxel per unit of time (plasma flow). The venous blood would be “clean” of contrast.In the brain, most cases are surface area product–limited,⁷ so K^trans depends on both the leakiness of the vessels and the total surface of leaky capillaries. The problem is that the contribution of each factor to the measured K^trans is a priori unknown. The transfer constant measured in a voxel may be high due to very leaky vessels, a high number of leaky capillaries within the voxel, or a combination of both (Fig 2).Open in a separate windowFig 2.Schematic illustrating 2 voxels with similar K^trans values: the first one showing high permeability and low surface area and the second one with low permeability and high surface area.We suggest that within-voxel comparison of blood volume estimates and K^trans would provide valuable information about physiologic meaning of K^trans in high-grade gliomas. The correlation between K^trans and CBV has been previously assessed in gliomas by Law et al.⁸ Regions with maximal CBV and maximal K^trans were compared in each tumor to obtain a weak-but-positive correlation. However, they did not compare parameters of the same tumor region because their main goal was to correlate maximal values of the parameters with tumor grade. A similar approach was followed by Provenzale et al.⁹ They reported a high correlation between CBV and the degree of contrast enhancement, which was defined by the authors as a relative measure of permeability. Again the CBV and K^trans values used for comparison were obtained from different tumor regions. Results about the correlation between K^trans and CBV are, therefore, based on indirect methods and are controversial.The purpose of this study was to compare values of K^trans and CBV in high-grade gliomas on a pixel-by-pixel basis to determine whether they provide different physiologic information. The second aim was to compare estimates of blood volume obtained by DCE–MR imaging and DSC–MR imaging.     

Optimizing the management of patients with spinal myeloma disease

Myeloma is one of the most common malignancies that results in osteolytic lesions of the spine. Complications, including pathological fractures of the vertebrae and spinal cord compression, may cause severe pain, deformity and neurological sequelae. They may also have significant consequences for quality of life and prognosis for patients. For patients with known or newly diagnosed myeloma presenting with persistent back or radicular pain/weakness, early diagnosis of spinal myeloma disease is therefore essential to treat and prevent further deterioration. Magnetic resonance imaging is the initial imaging modality of choice for the evaluation of spinal disease. Treatment of the underlying malignancy with systemic chemotherapy together with supportive bisphosphonate treatment reduces further vertebral damage. Additional interventions such as cement augmentation, radiotherapy, or surgery are often necessary to prevent, treat and control spinal complications. However, optimal management is dependent on the individual nature of the spinal involvement and requires careful assessment and appropriate intervention throughout. This article reviews the treatment and management options for spinal myeloma disease and highlights the value of defined pathways to enable the proper management of patients affected by it.     

Collapsin response‐mediator protein 5 (CRMP5) phosphorylation at threonine 516 regulates neurite outgrowth inhibition

The collapsin response‐mediator proteins (CRMPs) are multifunctional proteins highly expressed during brain development but down‐regulated in the adult brain. They are involved in axon guidance and neurite outgrowth signalling. Among these, the intensively studied CRMP2 has been identified as an important actor in axon outgrowth, this activity being correlated with the reorganisation of cytoskeletal proteins via the phosphorylation state of CRMP2. Another member, CRMP5, restricts the growth‐promotional effects of CRMP2 by inhibiting dendrite outgrowth at early developmental stages. This inhibition occurs when CRMP5 binds to tubulin and the microtubule‐associated protein MAP2, but the role of CRMP5 phosphorylation is still unknown. Here, we have studied the role of CRMP5 phosphorylation by mutational analysis. Using non‐phosphorylatable truncated constructs of CRMP5 we have demonstrated that, among the four previously identified CRMP5 phosphorylation sites (T509, T514, T516 and S534), only the phosphorylation at T516 residue was needed for neurite outgrowth inhibition in PC12 cells and in cultured C57BL/6J mouse hippocampal neurons. Indeed, the expression of the CRMP5 non‐phosphorylated form induced a loss of function of CRMP5 and the mutant mimicking the phosphorylated form induced the growth inhibition function seen in wildtype CRMP5. The T516 phosphorylation was achieved by the glycogen synthase kinase‐3β (GSK‐3β), which can phosphorylate the wildtype protein but not the non‐phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin‐binding property of CRMP5. Therefore, CRMP5‐induced growth inhibition is dependent on T516 phosphorylation through the GSK‐3β pathway. The findings provide new insights into the mechanisms underlying neurite outgrowth.