Mechanisms of CNS myelin inhibition: evidence for distinct and neuronal cell type specific receptor systems

Following injury to the adult mammalian central nervous system, regenerative growth of severed axons is very limited. The lack of neuronal repair is often associated with significant functional deficits, and depending on the severity of injury, may result in permanent paralysis distal to the site of injury. A detailed understanding of the molecular mechanisms that limit neuronal growth in the injured spinal cord is an important step toward the development of specific strategies aimed at restoring functional connectivity lost as a consequence of injury. While rapid progress is being made in defining the molecular identity of CNS growth inhibitory constituents, comparatively little is known about their receptors and downstream signaling mechanisms. Emerging new evidence suggests that the mechanisms for myelin inhibition are likely to be complex, involving multiple and distinct receptor systems that may operate in a redundant manner. Furthermore, the relative contribution of a specific ligand-receptor system to bring about growth inhibition may greatly vary among different neuronal cell types. Myelin-associated glycoprotein (MAG), for example, employs different mechanisms to inhibit neurite outgrowth of cerebellar, sensory, and retinal ganglion neurons in vitro. Nogo-A harbors distinct growth inhibitory regions, which employ different signaling mechanisms. The Nogo-66 receptor 1 (NgR1), a shared ligand binding component in a receptor complex for Nogo-66, MAG, and OMgp, participates in neuronal growth cone collapse to acutely presented myelin inhibitors, but is dispensable for longitudinal neurite outgrowth inhibition on substrate-bound Nogo-66, MAG, OMgp, or crude CNS myelin in vitro. Consistent with the idea of cell-type specific mechanisms for myelin inhibition, different types of CNS neurons possess very different regenerative capacities and respond differently to experimental treatment strategies in vivo. We speculate that differences in regenerative axonal growth among different fiber systems are a reflection of their intrinsic ability to elongate axons and their distinct cell surface receptor profiles to respond to the growth inhibitory extracellular milieu. The existence of cell type specific mechanisms to impair regenerative axonal growth in the CNS may have important implications for the development of treatment strategies. Depending on the fiber tract injured, different ligand-receptor systems may need to be targeted in order to elicit robust and long-distance regenerative axonal growth.     

Endomyocardial fibrosis in an adult mimicking left ventricular mass

Endomyocardial fibrosis is a rare condition that occurs primarily in tropical countries. It can often mimick a variety of other common cardiac conditions such as apical hypertrophic cardiomyopathy and Ebstein anomaly. We report a case of a left ventricular mass that at histologic examination was found to be endomyocardial fibrosis.     

Acute myeloid leukaemia presenting with mediastinal myeloid sarcoma: report of three cases and review of literature

Although myeloid sarcomas (MS) are frequently associated with acute myeloid leukaemia (AML), the occurrence of mediastinal MS is a much rarer event. The authors describe a distinct group of three AML patients with mediastinal MS and complex cytogenetics presenting at their centre over a 7-year period. Clinical features consistent with superior vena caval obstruction were noted at presentation in two of the three patients. Mediastinal mass was detected on routine chest radiography, and biopsies confirmed the diagnosis of MS. One patient relapsed after consolidation chemotherapy and died from progressive disease. Two patients underwent allogeneic haemopoietic stem cell transplant, but succumbed to transplant related complications. Review of mediastinal MS over the last 20 years shows that a significant proportion of patients have complex cytogenetic abnormalities and a poor long-term prognosis. Early and accurate diagnosis is essential and patients should be managed along the lines of high risk AML.     

Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors

A growing body of literature is demonstrating that Notch signaling is a more complex process than originally thought. Contradictory findings of notch-1 acting as an oncogene or a tumor suppressor revealed that its role is very specific to the cellular context. In this review we focus on the tumor suppressor role of Notch-1 signaling in neuroendocrine tumors (NETs) such as carcinoid and medullary thyroid cancers. NETs secrete various bioactive hormones that can cause debilitating symptoms. Surgery is the only potential curative treatment for the patients with NETs. Notch-1 signaling is absent in these tumors and activation of Notch-1 significantly reduces tumor growth in vitro. Therefore, identification of compound(s) that activate the Notch-1 pathway in NETs could be a potential strategy to treat patients with NETs.     

Histological characterization and development of mesial surface sulci in the human brain at 13–15 gestational weeks through high-resolution histology

Cellular-level anatomical data from early fetal brain are sparse yet critical to the understanding of neurodevelopmental disorders. We characterize the organization of the human cerebral cortex between 13 and 15 gestational weeks using high-resolution whole-brain histological data sets complimented with multimodal imaging. We observed the heretofore underrecognized, reproducible presence of infolds on the mesial surface of the cerebral hemispheres. Of note at this stage, when most of the cerebrum is occupied by lateral ventricles and the corpus callosum is incompletely developed, we postulate that these mesial infolds represent the primordial stage of cingulate, callosal, and calcarine sulci, features of mesial cortical development. Our observations are based on the multimodal approach and further include histological three-dimensional reconstruction that highlights the importance of the plane of sectioning. We describe the laminar organization of the developing cortical mantle, including these infolds from the marginal to ventricular zone, with Nissl, hematoxylin and eosin, and glial fibrillary acidic protein (GFAP) immunohistochemistry. Despite the absence of major sulci on the dorsal surface, the boundaries among the orbital, frontal, parietal, and occipital cortex were very well demarcated, primarily by the cytoarchitecture differences in the organization of the subplate (SP) and intermediate zone (IZ) in these locations. The parietal region has the thickest cortical plate (CP), SP, and IZ, whereas the orbital region shows the thinnest CP and reveals an extra cell-sparse layer above the bilaminar SP. The subcortical structures show intensely GFAP-immunolabeled soma, absent in the cerebral mantle. Our findings establish a normative neurodevelopment baseline at the early stage.     

Bilateral temporal bone xanthoma. Case report

Xanthoma formation is frequently seen over the subcutaneous tissue of extensor surfaces and tendons that have received minor trauma or friction in patients with hypercholesterolemia. However, temporal bone xanthomas with intracranial extension are uncommon. To the best of the authors' knowledge, this is the second report in the literature in which bilateral extension of a xanthoma is described. Xanthomas of the temporal bone are benign lesions, and complete or even partial removal is effective. The predisposing cause of the lesion should also be treated.     

A single-institution experience with the AneuRx Stent Graft for endovascular repair of abdominal aortic aneurysm

We report our experience of endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) using the modular AneuRx Stent Graft System. We retrospectively reviewed the outcomes of 113 patients who underwent EVAR with the AneuRx system performed at our institution between October 1999 and August 2003. The mean age of this group was 72.5 years, with 71% (n = 80) over the age of 70 years and 95% (n = 107) males. Aneurysm diameter ranged 4.0-9.0 cm, with 33% (n = 37) >6.0 cm. The average duration of late follow-up was 32.6 +/- 24.8 months (median = 37). Successful deployment of the modular AneuRx system was noted in all patients. There were no immediate operative conversions, deaths within 24 hr of operation, or type I or III endoleaks observed at the completion of the procedure. Thirty-day mortality was 3.5% (n = 4). Acute deployment-related complications occurred in 10% (n = 13) of patients and included misdeployment, operative bleeding, arterial perforation/dissection, and access site complications. Acute systemic complications were present in nine patients, predominantly renal and cardiac complications. An endoleak noted at any time occurred in 25% of patients, with 40% of those requiring a secondary intervention. Two patients suffered late aneurysm rupture due to a type I endoleak and graft infection. Kaplan-Meier analysis revealed 5-year freedom from secondary intervention of 72.4%; freedom from aneurysm-related death of 93.9%; and probability of survival based on all-cause mortality of 60.1%. Endovascular treatment with the modular AneuRx Stent Graft System is safe and effective, producing acceptable rates of disease-free survival and mid-term clinical outcome.