IVIG blocks complement deposition mediated by anti-GM1 antibodies in multifocal motor neuropathy

The pathogenesis of multifocal motor neuropathy (MMN) has yet to be established. MMN patients often carry anti-GM1 IgM antibodies, suggesting an autoimmune process involving complement. Intravenous immunoglobulin (IVIG) is the first line treatment, but its action mechanism is unknown.

Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer

Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.

Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M (2012) Histopathology Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims:  Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results:  A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1-3 cytokeratin-immunostained, whole-slide digital scans from 50 pT1-pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants' experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding-positive cases with all methods compared to H&E-stained slides, but did not influence agreement levels. Conclusions:  An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.

T2 mapping of hip articular cartilage in healthy volunteers at 3T: a study of topographic variation

PURPOSE: To perform baseline T(2) mapping of the hips of healthy volunteers, focusing on topographic variation, because no detailed study has involved hips. T(2) mapping is a quantitative magnetic resonance imaging (MRI) technique that evaluates cartilage matrix components. MATERIALS AND METHODS: Hips of 12 healthy adults (six men and six women; mean age = 29.5 +/- 4.9 years) were studied with a 3.0-Tesla MRI system. T(2) measurement in the oblique-coronal plane used a multi-spin-echo (MSE) sequence. Femoral cartilage was divided into 12 radial sections; acetabular cartilage was divided into six radial sections, and each section was divided into two layers representing the superficial and deep halves of the cartilage. T(2) of these sections and layers were measured. RESULTS: Femoral cartilage T(2) was the shortest (-20 degrees to 20 degrees and -10 degrees to 10 degrees , superficial and deep layers), with an increase near the magic angle (54.7 degrees ). Acetabular cartilage T(2) in both layers was shorter in the periphery than the other parts, especially at 20 degrees to 30 degrees . There were no significant differences in T(2) between right and left hips or between men and women. CONCLUSION: Topographic variation exists in hip cartilage T(2) in young, healthy adults. These findings should be taken into account when T(2) mapping is applied to patients with degenerative cartilage. J. Magn. Reson. Imaging 2007;26:165-171. (c) 2007 Wiley-Liss, Inc.

Effect of multislice acquisition on T1 and T2 measurements of articular cartilage at 3T

PURPOSE: The aim of this study was to investigate the effect of magnetization transfer on multislice T(1) and T(2) measurements of articular cartilage. MATERIALS AND METHODS: A set of phantoms with different concentrations of collagen and contrast agent (Gd-DTPA(2-)) were used for the in vitro study. A total of 20 healthy knees were used for the in vivo study. T(1) and T(2) measurements were performed using fast-spin-echo inversion-recovery (FSE-IR) sequence and multi-spin-echo (MSE) sequence, respectively, in both in vitro and in vivo studies. We investigated the difference in T(1) and T(2) values between that measured by single-slice acquisition and that measured by multislice acquisition. RESULTS: Regarding T(1) measurement, a large drop of T(1) in all slices and also a large interslice variation in T(1) were observed when multislice acquisition was used. Regarding T(2) measurement, a substantial drop of T(2) in all slices was observed; however, there was no apparent interslice variation when multislice acquisition was used. CONCLUSION: This study demonstrated that the adaptation of multislice acquisition technique for T(1) measurement using FSE-IR methodology is difficult and its use for clinical evaluation is problematic. In contrast, multislice acquisition for T(2) measurement using MSE was clinically applicable if inaccuracies caused by multislice acquisition were taken into account. J. Magn. Reson. Imaging 2007;26:109-117. (c) 2007 Wiley-Liss, Inc.

Evaluation of reparative cartilage after autologous chondrocyte implantation for osteochondritis dissecans: histology, biochemistry, and MR imaging

BACKGROUND: The aim of this study was to investigate the biochemical properties, histological and immunohistochemical appearance, and magnetic resonance (MR) imaging findings of reparative cartilage after autologous chondrocyte implantation (ACI) for osteochondritis dissecans (OCD). METHODS: Six patients (mean age 20.2 +/- 8.8 years; 13-35 years) who underwent ACI for full-thickness cartilage defects of the femoral condyle were studied. One year after the procedure, a second-look arthroscopic operation was performed with biopsy of reparative tissue. The International Cartilage Repair Society (ICRS) visual histological assessment scale was used for histological assessment. Biopsied tissue was immunohistochemically analyzed with the use of monoclonal antihuman collagen type I and monoclonal antihuman collagen type II primary antibodies. Glycosaminoglycan (GAG) concentrations in biopsied reparative cartilage samples were measured by high performance liquid chromatography (HPLC). MR imaging was performed with T1- and T2-weighted imaging and three-dimensional spoiled gradient-recalled (3D-SPGR) MR imaging. RESULTS: Four tissue samples were graded as having a mixed morphology of hyaline and fibrocartilage while the other two were graded as fibrocartilage. Average ICRS scores for each criterion were (I) 1.0 +/- 1.5; (II) 1.7 +/- 0.5; (III) 0.6 +/- 1.0; (IV) 3.0 +/- 0.0; (V) 1.8 +/- 1.5; and (VI) 2.5 +/- 1.2. Average total score was 10.7 +/- 2.8. On immunohistochemical analysis, the matrix from deep and middle layers of reparative cartilage stained positive for type II collagen; however, the surface layer did not stain well. The average GAG concentration in reparative cartilage was 76.6 +/- 4.2 microg/mg whereas that in normal cartilage was 108 +/- 11.2 microg/mg. Common complications observed on 3D-SPGR MR imaging were hypertrophy of grafted periosteum, edema-like signal in bone marrow, and incomplete repair of subchondral bone at the surgical site. Clinically, patients had significant improvements in Lysholm scores. CONCLUSIONS: In spite of a good clinical course, reparative cartilage after ACI had less GAG concentration and was inferior to healthy hyaline cartilage in histological and immunohistochemical appearance and on MRI findings.

Classification of intervertebral disk degeneration with axial T2 mapping

OBJECTIVE: The aim of this study was to establish an MRI classification system for intervertebral disks using axial T2 mapping, with a special focus on evaluating early degenerative intervertebral disks. MATERIALS AND METHODS: Twenty-nine healthy volunteers (19 men, 10 women; age range, 20-44 years; mean age, 31.8 years) were studied, and axial T2 mapping was performed for the L3-L4, L4-L5, and L5-S1 intervertebral disks. Grading was performed using three classification systems for degenerative disks: our system using axial T2 mapping and two other conventional classification systems that focused on the signal intensity of the nucleus pulposus or the structural morphology in sagittal T2-weighted MR images. We analyzed the relationship between T2, which is known to correlate with change in composition of intervertebral disks, and degenerative grade determined using the three classification systems. RESULTS: With axial T2 mapping, differences in T2 between grades I and II were smaller and those between grades II and III, and between grades III and IV, were larger than those with the other grading systems. The ratio of intervertebral disks classified as grade I was higher with the conventional classification systems than that with axial T2 mapping. In contrast, the ratio of intervertebral disks classified as grade II or III was higher with axial T2 mapping than that with the conventional classification systems. CONCLUSION: Axial T2 mapping provides a more T2-based classification. The new system may be able to detect early degenerative changes before the conventional classification systems can.

Evaluation of early tissue reactions after lumbar intertransverse process fusion using CT in a rabbit

OBJECTIVE: The objective of the study was to evaluate tissue reactions such as bone genesis, cartilage genesis and graft materials in the early phase of lumbar intertransverse process fusion in a rabbit model using computed tomography (CT) imaging with CT intensity (Hounsfield units) measurement, and to compare these data with histological results. MATERIALS AND METHODS: Lumbar intertransverse process fusion was performed on 18 rabbits. Four graft materials were used: autograft bone (n = 3); collagen membrane soaked with recombinant human bone morphogenetic protein-2 (rhBMP-2) (n = 5); granular calcium phosphate (n = 5); and granular calcium phosphate coated with rhBMP-2 (n = 5). All rabbits were euthanized 3 weeks post-operatively and lumbar spines were removed for CT imaging and histological examination. RESULTS: Computed tomography imaging demonstrated that each fusion mass component had the appropriate CT intensity range. CT also showed the different distributions and intensities of bone genesis in the fusion masses between the groups. Each component of tissue reactions was identified successfully on CT images using the CT intensity difference. Using CT color mapping, these observations could be easily visualized, and the results correlated well with histological findings. CONCLUSIONS: The use of CT intensity is an effective approach for observing and comparing early tissue reactions such as newly synthesized bone, newly synthesized cartilage, and graft materials after lumbar intertransverse process fusion in a rabbit model.

Ability of dGEMRIC and T2 mapping to evaluate cartilage repair after microfracture: a goat study

OBJECTIVE: To investigate the ability of delayed gadolinium-enhanced magnetic resonance (MR) imaging of cartilage (dGEMRIC) and T2 mapping to evaluate the quality of repair tissue after microfracture. DESIGN: Twelve knees from 12 goats were studied. An osteochondral defect (diameter, 6mm; depth, 3mm) with microfracture was created in the weight-bearing aspect of both the medial and lateral femoral condyles. Goats were euthanized at 24 weeks (n=6) and 48 weeks (n=6) postsurgery. Pre-contrast R1 (R1pre) and post-contrast R1 (R1post) measurements for dGEMRIC and a pre-contrast T2 measurement for T2 mapping were performed with a 3T MR imaging system. MR imaging findings were compared with histological and biochemical assessments. RESULTS: In native cartilage, significant correlations were observed between the R1post and the glycosaminoglycan (GAG) concentration, as well as DeltaR1 (difference between the R1pre and R1post) and the GAG concentration (P<0.05). In repair tissue, a significant correlation was observed between DeltaR1 and the GAG concentration (P<0.05), but not between the R1post and the GAG concentration. In both repair tissue and native cartilage, no correlation was observed between T2 and the water concentration or between T2 and the hydroxyproline (HP) concentration. A zonal variation of T2 and a clear dependence of T2 on the angles relative to B0 were observed in native cartilage, but not in repair tissue. CONCLUSION: dGEMRIC with DeltaR1 measurement might be useful for the evaluation of the GAG concentration in repair tissue after microfracture. T2 mapping might be useful for the differentiation of repair tissue after microfracture from native cartilage; however, its potential to assess the specific biochemical markers in native cartilage as well as repair tissue may be limited.