Fatigue in neuroimmunological diseases

Journal of Neurology - Fatigue is a widespread symptom in numerous neuroimmunological diseases like multiple sclerosis (MS), myasthenia gravis, morbus Behcet, neurosarcoidosis, neuroborreliosis or...     

Recurrent genetic aberrations in thymoma and thymic carcinoma

Apart from single reported aberrant karyotypes, genetic alterations in thymic epithelial neoplasms have not been investigated so far. In this study, 12 World Health Organization classification type A thymomas (medullary thymomas), 16 type B3 thymomas (well-differentiated thymic carcinomas), and nine type C thymomas, all of them primary thymic squamous cell carcinomas, were analyzed by comparative genomic hybridization and fluorescence in situ hybridization. With the exception of one single case, type A thymomas did not reveal chromosomal gains or losses in comparative genomic hybridization. In contrast, all type B3 thymomas showed chromosomal imbalances, with gain of 1q, loss of chromosome 6, and loss of 13q occurring in 11 (69%), six (38%), and five (31%) of 16 cases, respectively. In primary thymic squamous cell carcinoma, the most frequent chromosomal losses were observed for 16q (six of nine cases, 67%), 6 (4 of 9, 44%), and 3p and 17p (three of nine each, 33%), whereas recurrent gains of chromosomal material were gains of 1q (5 of 9, 56%), 17q, and 18 (three of nine each, 33%). This study shows that the distinct histological thymoma types A and B3 exhibit distinct genetic phenotypes, whereas type B3 thymoma and primary thymic squamous cell carcinoma partially share genetic aberrations. In addition to the possible tumorigenic role, the deletion in type B3 thymoma of chromosome 6, harboring the HLA locus, might play a role in the pathogenesis of paraneoplastic autoimmunity characteristic of thymoma.     

Comparison of the results of the Weil and Helal osteotomies for the treatment of metatarsalgia secondary to dislocation of the lesser metatarsophalangeal joints

We retrospectively reviewed the outcome of 30 patients who were treated surgically for metatarsalgia resulting from dislocation of one or more lesser metatarsophalangeal (MTP) joints. We used two treatments, including an osteotomy of the metatarsal head (Weil osteotomy, N = 15) or an osteotomy of the metatarsal shaft (Helal osteotomy, N = 15). Before surgery, all patients had been treated with various nonoperative modalities for a minimum of 6 months. Between 1991 and 1993, 15 consecutive patients underwent a Helal osteotomy (22 metatarsals), and 15 consecutive patients were subsequently treated between 1994 and 1995 with a Weil osteotomy (25 metatarsals). All patients were evaluated clinically and radiographically at a mean follow-up period of 22 months (range, 12-39 months), noting especially persistent subluxation or dislocation, recurrent metatarsalgia, and transfer lesions. Patients managed with a Weil osteotomy had significantly higher satisfaction (P = 0.049), lower incidence of recurrent metatarsalgia (0 vs. 27%, P = 0.107), and fewer transfer lesions (0 vs. 41%, P = < 0.001) than those managed with a Helal osteotomy. Furthermore, those managed with the Weil procedure had a higher percentage of radiographic reduction and maintenance of the MTP joint dislocation (21 of 25, 84%; vs. 8 of 22, 36%; P = 0.002) than those managed with the Helal procedure. In the Weil group, there was also no malunion or pseudoarthrosis; in the Helal group there were five malunions and three pseudoarthroses. Although the follow-up period for the Weil osteotomy (15 months) was shorter than that for the Helal osteotomy (26 months), the former group had higher American Orthopaedic Foot and Ankle Society forefoot scores, which were significantly different from the results attained with the Helal osteotomy. A telephone update was performed on the Weil osteotomy group at an average of 27 months postsurgery, and no patient had experienced changes since the clinical follow-up. We concluded that the Weil procedure is a satisfactory method for correcting metatarsalgia caused by dislocation of the MTP joint and that, because of the high complication rate, the Helal osteotomy is not an acceptable procedure for correcting this condition.     

Lymphocyte Subpopulations,Oxidative Burst and Apoptosis in Peripheral Blood Cells of Patients with Multiple Sclerosis–Effect of Interferon-β

At present, the most efficient therapeutical treatment of multiple sclerosis (MS) is achieved by IFN-β. However, its in vivo effects remain incompletely understood. If applied parenterally, the hydrophobic IFN-β acts primarily on blood cells with probable selectivity for functionally different lymphocyte subpopulations, monocytes and granulocytes. We have investigated the expression of the activation marker interleukin-2 receptor-α (CD25) on CD3⁺ T cells, CD19⁺ B cells, foetal-type γδ⁺CD3⁺ T cells and foetal-type CD5⁺CD19⁺ B cells of the peripheral blood. In addition, the oxidative burst activity and apoptosis have been determined in mononuclear and polymorphonuclear blood cells, respectively. The study accompanied a phase III trial with IFN-β1b (BETAFERON^®, Schering). Two groups of MS patients with relapsing-remitting course of the disease have been investigated at 8 time points (days 0, 5, 15, 31, 60, 90, 180 and 270 after starting therapy): (1) verum group (n=8) with application of 8 Mill. units IFN-β1b every other day, and (2) placebo group (n=4) with application of placebo for 3 months and therapy as in (1) from day 90 onward. The main results were: (1) Activated T cells decreased until day 180 in the verum group and return thereafter to pre-treatment values, whereas in the placebo group the values remained relatively stable over the whole observation period. (2) Activated B cells increased between days 90 and 270 in both groups, i.e. after verum application in both groups. (3) Foetal-type B cells were more activated than total B and T cells with increase over time in both groups. (4) Foetal-type T cells exerted relatively stable intra-individual levels with generally low CD25 expression, but punctual CD25 peaks in both groups. (5) The spontaneous oxidative burst was higher in lymphocytes, more variable in monocytes and faster increasing in granulocytes in the verum group than in the placebo group. (6) Apoptosis of mononuclear cells and granulocytes showed similar variations in the verum and placebo groups with the exception of a selective increase over time of the proportion of granulocytes undergoing induced apoptosis in the verum group. It is concluded that IFN-β has the following main effects on the immune system of MS patients: (1) the T cell immunity is systemically and reversibly suppressed, (2) the foetal-type lymphocytes, which are responsible for the first line of defence of infections, are stimulated in the long range, (3) the oxidative burst activity is increased in lymphocytes and granulocytes and instable in monocytes, and (4) the inducibility of apoptosis in granulocytes is increased. Re-examination of the altered blood cell parameters after long-term IFN-β therapy is warranted.     

Glucocorticoid-induced formation of tight junctions in mouse mammary epithelial cells in vitro.

Phenotypically stable cultures of untransformed mouse mammary epithelial cells (denoted 31EG4) were established and utilized to investigate the lactogenic hormone (glucocorticoids, insulin, and prolactin) regulation of tight junction formation. When 31EG4 cells were grown on permeable supports for 4 days in medium containing the synthetic glucocorticoid dexamethasone and insulin, confluent cell monolayers obtained a transepithelial electrical resistance (TER) of 1000-3000 omega.cm2. In contrast, over the same time period, confluent monolayers treated with insulin or insulin and prolactin maintained a low TER (35-150 omega.cm2). Consistent with the formation of tight junctions, apical to basolateral paracellular permeability was decreased from 12% to 1% for [14C]mannitol and 3.3% to 0.3% for [3H]inulin when cells were cultured in dexamethasone. This effect of dexamethasone on TER required extracellular calcium, de novo protein synthesis, dose-dependently correlated with glucocorticoid receptor occupancy, and was not due to an increase in cell density. As shown by direct and indirect immunofluorescence microscopy, dexamethasone treatment did not modulate the production or location of filamentous actin, the tight junction protein ZO-1, or the cell adhesion protein E-cadherin. Our results suggest that glucocorticoids play a fundamental role in the function and maintenance of cell-cell contact in the mammary epithelia by inducing the formation of tight junctions.     

Clinical and histopathological correlations of fecal calprotectin release in colorectal carcinoma

AIM:To determine calprotectin release before and after colorectal cancer operation and compare it to tumor and histopathological parameters.METHODS:The study was performed on patients with diagnosed colorectal cancer admitted for operation.Calprotectin was measured in a single stool sample before and three months after the operation using an enzymelinked immunosorbent assay(ELISA).Calprotectin levels greater than or equal to 50μg/g were considered positive.The compliance for collecting stool samples was assessed and the value of calprotectin was correlated to tumor and histopathological parameters of intra-and peri-tumoral inflammation.Surgical specimens were fixed in neutral buffered formalin and stained with hematoxylin and eosin.Staging was performed according to the Dukes classification system and the 7th edition tumor node metastasis classification system.Intra-and peri-tumoral inflammation was graded according to the Klintrup criteria.Immunohistochemical quantification was performed for MPO,CD45R0,TIA-1,CD3,CD4,CD8,CD57,and granzyme B.Statistical significance was measured using Wilcoxon signed rank test,Kruskal Wallis test and Spearman’s rank correlation coefficient as appropriate.RESULTS:Between March 2009 and May 2011,80 patients with colorectal cancer(46 men and 34 women,with mean age of 71±11.7 years old)were enrolled in the study.Twenty-six patients had rectal carcinoma,29 had left-side tumors,23 had right-side tumors,and2 had bilateral carcinoma.In total,71.2%of the patients had increased levels of calprotectin before the operation(median 205μg/g,range 50-2405μg/g)and experienced a significant decrease three months after the operation(46μg/g,range 10-384μg/g,P<0001).The compliance for collecting stool samples was 89.5%.Patients with T3 and T4 tumors had significantly higher values than those with T1 and T2 cancers(P=0.022).For all other tumor parameters(N,M,G,L,V,Pn)and location,no significant difference in calprotectin concentration was found.Furthermore,the calprotectin levels and histological grading of both peri-and intra-tumoral inflammation was not correlated.Additional testing with specific markers for lymphocytes and neutrophils also revealed no statistically significant correlation.CONCLUSION:Fecal calprotectin decreases significantly after colorectal cancer operation.Its value depends exclusively on the individual T-stage,but not on other tumor or histopathological parameters.     

Results of titanium locking plate and stainless steel cerclage wire combination in femoral fractures

Background:

Some in vitro studies warn combining different metals in orthopedic surgery. The aim of this study is to determine the impact of combining titanium and stainless steel on bone healing and the clinical course of patients undergoing internal fixation of femoral fractures.

Materials and Methods:

69 patients with femoral fractures had polyaxial locking plate osteosynthesis. The locking plate was made of a titanium alloy. Two different cohorts were defined: (a) sole plating and (b) additional stainless steel cerclage wiring. Postoperative radiographs and clinical followup were performed at 6 weeks, 3 months and 12 months.

Results:

Cohorts A and B had 36 and 33 patients, respectively. Patient demographics and comorbidities were similar in both groups. In two cases in cohort A, surgical revision was necessary. No complication could be attributed to the combination of titanium and stainless steel.

Conclusion:

The combination of stainless steel cerclage wires and titanium plates does not compromise fracture healing or the postoperative clinical course.     

Tissue microarray-based screening for chromosomal breakpoints affecting the T-cell receptor gene loci in mature T-cell lymphomas

The pathogenesis of mature T-cell non-Hodgkin lymphomas (T-NHLs) is poorly understood. Analogous to B-cell lymphomas, in which the immunoglobulin (IgH) receptor loci are frequently targeted by chromosomal translocations, the T-cell receptor (TCR) gene loci are affected by translocations in a subset of precursor T-cell malignancies. In a large-scale analysis of 245 paraffin-embedded mature T-NHLs, arranged in a tissue microarray format and using improved FISH assays for the detection of breakpoints in the TCRalpha/delta, TCRbeta, and TCRgamma loci, we provide evidence that mature T-NHLs other than T-cell prolymphocytic leukaemia (T-PLL) also occasionally show a chromosomal rearrangement that involves the TCRalpha/delta locus. In particular, one peripheral T-cell lymphoma (not otherwise specified, NOS) with the morphological variant of Lennert lymphoma displayed a chromosomal translocation t(14;19) involving the TCRalpha/delta and the BCL3 loci. A second case, an angio-immunoblastic T-cell lymphoma (AILT), carried an inv(14)(q11q32) affecting the TCRalpha/delta and IgH loci. FISH signal constellations as well as concomitant comparative genomic hybridization (CGH) data were also suggestive of the occurrence of an isochromosome 7, previously described to be pathognomonic for hepatosplenic T-cell lymphomas, in rare cases of enteropathy-type T-cell lymphoma.     

C-kit overexpression is not associated with KIT gene mutations in chromophobe renal cell carcinoma or renal oncocytoma

Introduction

C-kit overexpression has previously been described in chromophobe renal cell carcinoma (cpRCC) and renal oncocytoma (RO). However, so far no KIT mutations have been found. The objective of our study was to analyse c-kit in a large cohort of renal tumors and to perform KIT mutation analysis in a subset cpRCC and RO cases with overexpression of c-kit.

Materials and methods

We studied the immunohistochemical expression of c-kit on tissue microarrays containing formalin-fixed, paraffin-embedded samples of 948 patients with renal tumors. CpRCC and RO cases with c-kit overexpression (n = 23) were analyzed for KIT mutations in exons 9, 11, 13, 14, 15, and 17.

Results

Expression of c-kit was found in 6/642 (0.9%) clear cell RCC, 3/154 (1.9%) papillary RCC, 54/69 (78.3%) cpRCC, 37/45 (82.2%) RO and 2/30 (6.7%) of other unclassified tumor types. In none of the RO and cpRCC cases analyzed, a KIT gene mutation was found.

Conclusion

C-kit expression is found in the majority of cpRCC and RO, but these tumors do not harbor the usual c-kit activating mutations. This may have implications for the use of tyrosine kinase inhibitors in patients with advanced cpRCC and c-kit expression.