A New Synthetic Conduit for the Treatment of Peripheral Nerve Injuries.

BACKGROUND: Peripheral nerve defects (PND) often cause lifelong physical disability, and the available treatment options are often not satisfactory. PND are usually bridged with an autologous nerve transplant or a nerve guidance conduit (NGC), when coaptation as preferred technique is not possible. The aim of this experimental study was to determine the effectiveness of a novel NGC for regeneration in the treatment of PND. MATERIALS AND METHODS: A conduit made of gelatin with an innovative interior structure was tested for the repair of a 6-mm gap versus direct microsurgical suture repair without gap. RESULTS: We found that bridging the defect with this conduit was as effective as direct microsurgical coaptation without a defect. CONCLUSIONS: This nerve conduit, effective in bridging neural defects, appears as an alternative to autologous nerve grafts, avoiding the problems related to nerve graft harvesting, host-donor differences in diameter, mismatches in number and pattern of fascicles, cross-sectional shape and area, and morbidity of the donor area.

The WHO Grade I Collagen-forming Meningioma Produces Angiogenic Substances. A New Meningioma Entity.

BACKGROUND: Meningiomas arise from arachnoid cap cells, the so-called meningiothelial cells. They account for 20-36% of all primary intracranial tumours, and arise with an annual incidence of 1.8-13 per 100,000 individuals/year. According to their histopathological features meningiomas are classified either as grade I (meningiothelial, fibrous/fibroblastic, transitional/mixed, psammomatous, angiomatous, microcystic, secretory and the lympholasmacyterich sub-type), grade II (atypical and clear-cell sub-type) or grade III (malignant or anaplastic phenotype). CASE REPORT: A 62-year-old female patient presented to the hospital because of progressive obliviousness and concentration difficulties. In the magnetic resonance imaging (MRI) of the brain, an occipital convexity-meningioma was found in the left hemisphere, which was subsequently resected. Within the tumour tissue there were multiple spheroid precipitates, i.e. secretion products that turned out to consist of collagen. Part of the tumour cells displayed positive reactions for vasogenic substances, namely for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Correspondingly, the diagnosis "WHO Grade I collagen-forming meningioma" seems to be most appropriate. CONCLUSION: The "WHO Grade I collagen-forming meningioma" reported herein produces collagen and angiogenic substances. To the best of our knowledge, no such entity has been reported on in previous literature. We propose this collagen-producing meningioma as a novel WHO grade I meningioma sub-type.

New synthetic prosthesis for peripheral nerve injuries: an experimental pilot study.

INTRODUCTION: Even the most modern technology has failed to induce satisfactory functional regeneration of traumatically severed peripheral nerves. Delayed neural regeneration and in consequence, slower neural conduction seriously limit muscle function in the area supplied by the injured nerve. This study aimed to compare a new nerve coaptation system involving an innovative prosthesis with the classical clinical method of sutured nerve coaptation. Besides the time and degree of nerve regeneration, the influence of electrostimulation was also tested. METHODS: The sciatic nerve was severed in 14 female Göttingen minipigs with an average weight of 40.4 kg. The animals were randomized into 2 groups: One group received the new prosthesis and the other underwent microsurgical coaptation. In each group, according to the randomization a part of the animals received postoperative electrostimulation. Postoperative monitoring and the stimulation schedule covered a period of 9 months, during which axonal budding was evaluated monthly. RESULTS: The data from the pilot study indicate that results with the nerve prosthesis were comparable with those of conventional coaptation. CONCLUSION: The results indicate that implantation of the nerve prosthesis allows for good and effective neural regeneration. This new and simple treatment option for peripheral nerve injuries can be performed in any hospital with surgical facilities as it does not involve the demanding microsurgical suture technique that can only be performed in specialized centers.

Medullomyoblastoma: a case report and literature review of a rare tumor entity.

BACKGROUND: Medullomyoblastoma (MMB) is a very rare medulloblastoma (MB) variant consisting of primitive neuroectodermal cells intermixed with cells featuring myogenic differentiation. MMBs are a subtype of primitive neuroectodermal neoplasm (PNET) predominantly occurring in children. CASE REPORT: We describe a case of a one-year-old girl who presented with headache, emesis and ataxia. The symptoms had started seven weeks before hospital admission. Magnet resonance imaging of the brain was performed, and revealed a lesion with a maximal diameter of 5 cm, located in the cerebellum close to the vermis. Histologically, the poorly-differentiated lesion was diagnosed as a type of PNET, but it was the immunohistochemical staining that assured the diagnosis of MMB. RESULTS: Immunohistochemistry and interphase fluorescence in situ hybridization (I-FISH) were performed on formalin-fixed paraffin-embedded tissue. FISH did not reveal any amplification of CMYC or NMYC. No nuclear expression of ß-catenin was detectable. DISCUSSION: Since MMB is a very rare tumor entity, standard treatment today is the same as that for conventional MB due to the lack of larger study series. Some authors assume that MMBs behave especially aggressive in comparison to conventional MBs. Therefore, new treatment regimes should be tested to optimize the prognosis of MMB. Further data is needed to determine the differences between MB and MMB.

Quantitative short-tandem repeat analysis of recipient-derived cells as an additional tool for diagnosing cardiac allograft rejection.

BACKGROUND: Diagnosis of cardiac allograft rejection is currently based on histologic exploration of endomyocardial biopsies. Moderate interobserver reproducibility in the estimation of number and distribution of inflammatory cells leads to disagreements in the assignment of rejection grades. Short-tandem repeat (STR) analysis is routinely used after hematopoietic stem-cell transplantation to determine the proportions of donor cells. We compared the amount of recipient-derived cells with the histopathologic grade of rejection in cardiac allografts to determine whether this method might be useful for the assessment of rejection episodes. METHODS: One hundred forty-three endomyocardial biopsies from 18 patients were investigated for the percentage of recipient-derived cell content by polymerase chain reaction-based STR analysis and correlated with rejection grades determined according to the International Society for Heart and Lung Transplantation grading system. Y-chromosome chromogene in situ hybridization was performed in gender-mismatched (female-to-male) heart transplants to explore the influence of cardiomyocyte cell chimerism. RESULTS: The mean percentages of recipient-derived cells associated with various degrees of rejection were 13% in grade 0, 24% in grade 1A, 29% in grade 1B, 35% in grade 2, and 50% in grade > or =3A. Samples lacking signs of rejection (grade 0) had a significantly lower (P<0.001) amount of recipient-derived cells than higher degrees of rejections. Chromogene in situ hybridization analysis revealed that the recipient-derived cells were mainly inflammatory. CONCLUSIONS: The results of STR-analysis indicate that rejection is correlated with a higher proportion of recipient-derived cells. This assessment is observer independent and may thus represent an additional diagnostic tool for the assessment of rejection and management of immunosuppressive treatment.

Tumefactive demyelinating lesions: conventional and advanced magnetic resonance imaging.

In rare instances, demyelinating disorders present with radiological features that mimic a brain tumour. This often leads to biopsy, which--apart from carrying significant morbidity--frequently turns out as nondiagnostic or dispensable. We therefore set out to assess the contribution of repeated conventional magnetic resonance imaging (MRI), 1H-MR spectroscopy and magnetization transfer imaging in establishing a correct diagnosis of tumefactive demyelinating lesions (TDLs). We studied two females and one male, who presented with TDLs that led to brain biopsy in two cases, for up to three years. TDLs were characterized by the following features: (a) delayed or absent response to high-dose steroids together with progressive lesion growth over several weeks; (b) late or sparse enhancement, ill-defined borders, signal inhomogeneity and considerable concomitant oedema; and (c) normalization of initial increases in lipid and lactate peaks within three to four weeks, followed by persistent, marked reductions of the neuronal marker NAA and MTR values around or below 30%. These imaging characteristics reflected the histological correlate of marked demyelination in the absence of significant inflammation. MRI techniques thus appear to have the potential to establish a correct diagnosis of this subtype of TDLs. Awareness of these possibilities might obviate the need for biopsy at least in some cases in future.

Fluorescent in situ hybridization on isolated tumor cell nuclei: a sensitive method for 1p and 19q deletion analysis in paraffin-embedded oligodendroglial tumor specimens.

In oligodendroglial neoplasms, losses of chromosomal material at 1p and 19q associate with chemosensitivity and prolonged survival. Thus, 1p/19q testing is increasingly proposed for use in brain tumor diagnosis and prognostic assessment. Fluorescent in situ hybridization (FISH) is a classic technique for investigation of 1p/19q status in paraffin-embedded tissues. A major limitation of this method is truncation of tumor cell nuclei complicating assessment of hybridization results. In our study, we analyzed 1p and 19q status in a series of 79 oligodendroglial neoplasms (49 oligodendrogliomas, 30 oligoastrocytomas, WHO: 57 Grade II, 22 Grade III tumors) and controls (gliotic brain tissue: n = 4, diffuse low-grade astrocytoma: n = 4) using FISH on isolated whole tumor cell nuclei, prepared as cytospin preparations, thus bypassing the problem of nuclear truncation. For interpretation of FISH results, we used consensus criteria as defined by the SIOP-Europe Neuroblastoma Study Group for analysis of peripheral neuroblastic tumors. FISH yielded interpretable results in 98.7% for 1p and 92.1% for 19q. Chromosome 1p/19q alterations comprised deletions (1p: 79.5%, 19q: 80%) and imbalances (1p: 11.5%, 19q: 12.9%). 1p aberrations were more frequent in oligodendroglioma than in oligoastrocytoma (100% versus 75.9%, P =.001). The frequency of 1p/19q alterations was not significantly different in WHO Grade II or Grade III tumors or in primary and recurrent tumors. We conclude that FISH on isolated cell nuclei, with application of the SIOP Europe Neuroblastoma consensus criteria, is a sensitive method for detection and interpretation of 1p and 19q aberrations in paraffin-embedded tissue specimens of oligodendroglial neoplasms.

Computerized heart allograft-recipient monitoring: a multicenter study.

Computerized heart allograft recipient monitoring (CHARM) is a unique concept of patient surveillance after heart transplantation (HTx), based on the evaluation of intramyocardial electrograms (IEGMs) recorded non-invasively with telemetric pacemakers. Previous open, single-center studies had indicated a high correlation between CHARM results and clinical findings. The present study was initiated to assess the suitability of CHARM for monitoring the absence of rejection in a blind, multicenter context. During the HTx procedure, telemetric pacemakers and two epimyocardial leads were implanted in 44 patients at four European HTx centers. IEGMs during pacing were recorded and transferred via the Internet to the CHARM computer center, for automatic data processing and extraction of diagnostically relevant information, i.e., the maximum slew rate of the descending part of the repolarization phase of the ventricular evoked response (VER T-slew). The study period comprised the first 6 months after HTx, during which the transplant centers were blind to the CHARM results. A single threshold diagnosis model was prospectively defined to assess the ability of the VER T-slew to indicate clinically significant rejection, which was defined as an endomyocardial biopsy (EMB) grade greater than or equal to 2, according to the grading system of the International Society for Heart and Lung Transplantation. All EMB slides from three centers were reviewed blind by the pathologist of the fourth center in order that agreement among the histological diagnoses at the various centers could be assessed. Totals of 839 follow-ups and 366 EMBs were obtained in 44 patients. Thirty-seven patients were alive at the end of the study period. Age at HTx, EMB grade distribution, and rejection prevalence varied significantly between the centers. Review of the EMB results showed considerable differences with respect to classification of significant rejection. Comparison of average VER T-slew values with and without rejection in the 15 patients who exhibited both states revealed significantly lower values under the influence of rejection (97+/-13% vs 79+/-15%, P<0.0001). Twenty out of the 25 cases with significant rejection were correctly identified by VER T-slew values below a threshold of 98% (sensitivity =80%, specificity =50%, negative predictive value =97%, positive predictive value =11%; P<0.0005). Of the EMBs, 48% could have been saved if the diagnosis model had been used to indicate the need for EMB. A high negative predictive value for the detection of cases with significant rejection has been obtained in a prospective, blind, multicenter study. The presented method can, therefore, be used to supplement patient monitoring after HTx non-invasively, in particular to indicate the need for EMBs. In centers with patient management similar to the ones who participated in the study, this may allow a reduction in the number of surveillance EMBs.

Influence of nerve stump transplantation into a vein on neuroma formation.

The objective of this animal study was to investigate the influence of nerve stump transposition into a vein on neuroma formation. In 24 rats the femoral nerve was severed and the proximal nerve stump was transposed into the lumen of the femoral vein on one side. On the other side, the nerve was severed and left in place. The distal nerve stump was shortened to knee level on both sides. In group 1, the bloodstream was released; in group 2, the segment of the femoral vein containing the nerve stump was excluded from circulation. Histological assessment was performed 8 months later. There were significant differences between the treatment and control sides with respect to neuroma size, endoneural architecture, neural-tissue-to-connective-tissue ratio, and myelination of axons. These data suggest that nerve transposition into a vein could inhibit the formation of classic neuroma.

p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases.

Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation.