Skin biopsy is a minimally invasive procedure and has been used in the evaluation of non-myelinated, but not myelinated nerve fibres, in sensory neuropathies. We therefore evaluated myelinated nerves in skin biopsies from normal controls and patients with Charcot-Marie-Tooth (CMT) disease caused by mutations in myelin proteins. Light microscopy, electron microscopy and immunohistochemistry routinely identified myelinated dermal nerves in glabrous skin that appeared similar to myelinated fibres in sural and sciatic nerve. Myelin abnormalities were observed in all patients with CMT. Moreover, skin biopsies detected potential pathogenic abnormalities in the axolemmal molecular architecture previously undetected in human neuropathies. Finally, myelin gene expression at both mRNA and protein levels was evaluated by real-time PCR and immunoelectron microscopy. Peripheral myelin protein 22 (PMP22) was increased in CMT1A (PMP22 duplication) and decreased in patients with hereditary neuropathy with liability to pressure palsies (PMP22 deletion). Taken together, our data suggest that skin biopsy may in certain circumstances replace the more invasive sural nerve biopsy in the morphological and molecular evaluation of inherited and other demyelinating neuropathies.
Objective The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability. Methods Utilizing Pmp22+/− mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. Results We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain–containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. Interpretation Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.
Charcot-Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot-Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot-Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot-Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot-Marie-Tooth disease type 1A.
Objective: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases.Methods: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n 5 10), CMT type 2A (CMT2A, n 5 3), hereditary neuropathy with liability to pressure palsies (n 5 3), and healthy controls (n 5 21). Additional patients without a genetically confirmed subtype (n 5 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated.Results: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 6 3.3 percent units) and CMT2A (31.5 6 1.9 percent units) relative to controls (37.2 6 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p 5 0.01 for genetically confirmed patients only, p 5 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels. Charcot-Marie-Tooth (CMT) diseases are a group of inherited neuropathies that affect motor and sensory nerves. A majority of CMT phenotypes can be classified as primary demyelination/dysmyelinating (CMT1) or primary axonal (CMT2) neuropathies.1,2 CMT type 1A (CMT1A z 80% of CMT1 cases 3,4 ) arises from duplication of the peripheral myelin protein 22 (PMP22) gene 5,6 and results in dysmyelination and secondary axonal loss. 7 CMT type 2A (CMT2A z 35% of CMT2 cases 8 ) is caused by missense mutations in the gene that encodes for mitofusin 2 9 and leads to primary axonal degeneration. 8 Although the pathologic features of CMT1A/CMT2A are different, length-dependent axonal loss occurs in both and is predictive of outcomes.
In contemporary society, industrialization and rising of terrorism threats highlight the necessity and importance of structural protection against accidental and intentionally malicious blast loads. Consequences of these extreme loading events are known to be catastrophic, involving personnel injuries and fatalities, economic loss and immeasurable social disruption. These impacts are generated not only from direct explosion effects, that is, blast overpressure and primary or secondary fragments, but also from the indirect effects such as structural collapse. The latter one is known to be more critical leading to massive losses. It is therefore imperative to enlighten our structural engineers and policy regulators when designing modern structures. Towards a better protection of concrete structures, efforts have been devoted to understanding properties of construction materials and responses of structures subjected to blast loads. Reliable blast resistance design requires a comprehensive knowledge of blast loading characteristics, dynamic material properties and dynamic response predictions of structures. This article presents a state-of-the-art review of the current blast-resistant design and analysis of concrete structures subjected to blast loads. The blast load estimation, design considerations and approaches, dynamic material properties at high strain rate, testing methods and numerical simulation tools and methods are considered and reviewed. Discussions on the accuracies and advantages of these current approaches and suggestions on possible improvements are also made.
Vaccines have shown great success in treating and preventing tumors and infections, while adjuvants are always demanded to ensure potent immune responses. Polyethylenimine (PEI), as one of the well-studied cationic polymers, has been used as a transfection reagent for decades. However, increasing evidence has shown that PEI-based particles are also capable of acting as adjuvants. In this paper, we briefly review the physicochemical properties and the broad applications of PEI in different fields, and elaborate on the intracellular processes of PEI-based vaccines. In addition, we sum up the proof of their in vivo and clinical applications. We also highlight some mechanisms proposed for the intrinsic immunoactivation function of PEI, followed by the challenges and future perspectives of the applications of PEI in the vaccines, as well as some strategies to elicit the desirable immune responses.
As the phenomenon of transdifferentiation is uncommon, our successful transdifferentiation rates of BMSCs to mature hepatocytes prove the superiority of the C-PLGA scaffold in providing a suitable environment for such a differentiation. This material can possibly be used as a bioscaffold for liver tissue engineering in future clinical therapeutic applications.
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