1,720,996 research outputs found
Myelin damage due to local quantitative abnormalities in normal prion levels: evidence from subacute combined degeneration and multiple sclerosis
No full textCobalamin (Cbl) deficiency causes an imbalance in some cytokines and growth factors in the central nervous system and peripheral nervous system (PNS) of the rat, and in the serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients. It is conceivable that this imbalance triggers subsequent cellular events. We hypothesized that an imbalance in normal prion (PrP C) levels and/or synthesis might be involved in the pathogenesis of Cbl-D neuropathy, and demonstrated that: (1) Cbl deficiency induces excess PrPC in rat spinal cord (SC) and PNS, concomitantly with myelin damage and PNS electrophysiological abnormalities; (2) the SC increase is mediated by a local Cbl deficiency-induced excess of tumor necrosis factor-α; (3) myelinotrophic Cbl and epidermal growth factor upregulate PrPC-mRNA levels in rat SC; (4) treatment with anti-PrPC octapeptide repeat region antibodies normalizes the ultrastructure of the Cbl-D rat SC and PNS myelins, and the PNS electrophysiological abnormalities, without modifying their Cbl-D status; (5) PrPC administration to otherwise normal rats causes SC and PNS myelin lesions and PNS electrophysiological abnormalities, similar to those of Cbl-D neuropathy; (6) CSF and serum PrP C concentrations in Cbl-D patients are significantly higher than in controls; and (7) these concentrations significantly correlate with their CSF and serum Cbl concentrations. CSF PrPC concentrations are significantly lower in patients with multiple sclerosis (MS) than neurological controls, but serum PrPC concentrations in patients with non-Cbl-D anemias and CSF PrPC concentrations in patients with non-myelin-damaging neurological diseases are normal
Normal prions as a new target of cobalamin (vitamin B 12) in rat central nervous system
No full textAbstract The pathogenesis of cobalamin (Cbl)-deficient (Cbl-D) neuropathy and the role of normal prions (PrPcs) in myelin maintenance are both subjects of debate. We have demonstrated that Cbl deficiency damages myelin by increasing tumor necrosis factor (TNF)-α, and decreasing epidermal growth factor (EGF) levels in the rat central nervous system (CNS). It is known that TNF-α and EGF regulate PrPc expression in vitro, and that myelin vacuolation, reactive astrocytosis and microglial activation are common to rat Cbl-D neuropathy and some prion diseases. We have shown that Cbl deficiency leads to high levels of PrPcs [particularly the octapeptide repeat (OR) domains] in the rat CNS thereby damaging the spinal cord (SC) myelin, and that chronic intra-cerebroventricular treatment with anti-OR antibodies normalizes SC myelin morphology. We have also found that PrPc levels are increased in the SC of Cbl-D rats by the time the myelin lesions appear, and that this increase is mediated by excess myelinotoxic TNF-α and prevented by EGF treatment, which has proved to be as effective as Cbl in preventing Cbl deficiency-induced lesions. Cbl stimulates PrPc mRNA-related synthesis in Cbl-D SC and duodenum, two rat tissues that are severely affected by Cbl deficiency. New PrPc synthesis is a common effect of various myelinotrophic agents, two of which (EGF and anti-TNF-α antibodies) also stimulate PrPc mRNA-related synthesis in the SC of Cbl-D rats
Some problems of linear elasticity for cylinders in micropolar orthotropic material
No full textSome special problems for axisymmetric solids made of linearly elastic orthotropic micropolar material with central symmetry are dealt with. The first one is a hollow circular cylinder of unlimited length, subjected to internal and external uniform pressure. The second one is a hollow or solid circular cylinder of finite length, subjected to a relative rotation of the bases about its axis. In both cases, one of the axes of elastic symmetry is parallel to the ylinder axis; the other two are arbitrarily oriented in the plane of any cross-section of the solid. The elastic properties are invariant along the cylinder axis. It is shown that the two problems are governed by formally similar sets of ordinary differential equations in the kinematic fields (in-plane displacements and microrotations). In the general case, numerical solutions are derived. The solution for the cylinder subjected to radial pressure does not significantly differ from that obtained in classical elasticity, at least in terms of radial and hoop force stresses. In the case of a cylinder subjected to torsion the difference between the micropolar and the classical solutions is more pronounced. The torque induces twisting couple stresses about the cylinder axis of variable sign. Finally, size effects in terms of torsional inertia are pointed out
Relationships between cobalamin, epidermal growth factor, and normal prions in the myelin maintenance of central nervous system
No full textCobalamin (Cbl), epidermal growth factor (EGF), and prions (PrPs) are key molecules for myelin maintenance in the central and peripheral nervous systems. Cbl and EGF increase normal prion (PrP(C)) synthesis and PrP(C) levels in rat spinal cord (SC) and elsewhere. Cbl deficiency increases PrP(C) levels in rat SC and cerebrospinal fluid (CSF), and decreases PrP(C)-mRNA levels in rat SC. The administration of anti-octapeptide repeat PrP(C) region antibodies (Abs) to Cbl-deficient (Cbl-D) rats prevents SC myelin lesions and a local increase in tumor necrosis factor (TNF)-α levels, whereas anti-TNF-α Abs prevent SC myelin lesions and the increase in SC and CSF PrP(C) levels. As it is known that both Cbl and EGF regulate SC PrP(C) synthesis independently, and that Cbl regulates SC EGF synthesis, EGF may play both Cbl-independent and Cbl-dependent roles. When Cbl-D rats undergo Cbl replacement therapy, SC PrP(C) levels are similar to those observed in Cbl-D rats. In rat frontal cortex (which is marginally affected by Cbl deficiency in histological terms), Cbl deficiency decreases PrP(C) levels and the increase induced by Cbl replacement leads to their normalization. Increased nerve PrP(C) levels are detected in the myelin lesions of the peripheral neuropathy of Cbl-D rats, and CSF PrP(C) levels are also increased in Cbl-D patients (but not in patients with Cbl-unrelated neurological diseases). Various common steps in the downstream signaling pathway of Cbl, EGF, and PrP(C) underlines the close relationship between the three molecules in keeping myelin normal
Experimental and clinical evidence of the role of cytokines and growth factors in the pathogenesis of acquired cobalamin-deficient leukoneuropathy
No full textOur experimental and clinical studies have highlighted the non-coenzyme functions of cobalamin (Cbl; vitamin B12). The neuropathy of the rat central nervous system (CNS) due to Cbl deficiency is associated with increases in CNS tissue and/or cerebrospinal fluid (CSF) levels of some neurotoxic molecules, and decreases in local and/or CSF levels of some neurotrophic molecules. The increased molecules are nerve growth factor (NGF), tumor necrosis factor (TNF)-alpha, and the soluble (s)CD40:sCD40 Ligand dyad; the decreased molecules are epidermal growth factor (EGF) and interleukin-6. The morphological lesions of the CNS white matter in Cbl-deficient (Cbl-Df) rats can be prevented to the same extent by treatments replacing Cbl or the deficient neurotrophic molecules, or treatment with agents that antagonize the excess neurotoxic molecules. Patients with neurological and/or hematological manifestations of severe Cbl deficiency also have high TNF-alpha levels and low EGF levels in CSF and serum. Cbl replacement treatment corrects cytokine and growth factor abnormalities in Cbl-Df patients and Cbl-Df rats, and so Cbl-Df CNS neuropathy is also due to an imbalance in local cytokine/growth factor networks. TNF-alpha and NGF levels are also increased in Cbl-Df rat liver, which is morphologically unaffected by Cbl deficiency. The increases in TNF-alpha and NGF levels increase nuclear factor-kappaB activity levels in both the CNS and liver, and this indirect regulation supports the idea that Cbl may modulate the expression of some cytokine/growth factor genes in rat CNS and other tissues. Finally, we have tried to harmonize our pathogenetic theory of cytokine and growth factor dysregulation with the biochemical interpretation
Topology optimization of three-dimensional non-centrosymmetric micropolar bodies
No full textThe topology optimization problem for linearly elastic micropolar solids is dealt with. The constituent materials are supposed to lack in general of centro-symmetry, which means that force stresses and microcurvatures are coupled, and so are couple stresses and micropolar strains. The maximum global stiffness is taken as objective function. According to the SIMP model, the constitutive tensors are assumed to be smooth functions of the design variable, that is, the material density. Optimal material distributions are obtained for several significant three-dimensional cases. The differences respect to the optimal configurations obtained with classical Cauchy materials and centrosymmetric materials are pointed out. The influence of the constants defining the non-centrosymmetric behaviour on the optimal configurations is discussed
New pathogenesis of the cobalamin-deficient neuropathy
No full textSubacute combined degeneration (SCD) is considered the neurological counterpart of pernicious anaemia because it is the paradigmatic neurological manifestation of acquired vitamin B12 (cobalamin (Cbl)) deficiency in adulthood. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl-dependent reactions. We have identified a new experimental model, the totally gastrectomised (TGX) rat, to reproduce the key morphological features of the disease, and found new mechanisms responsible for the pathogenesis of SCD. We have demonstrated that the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumour necrosis factor (TNF)-alpha, nerve growth factor, the soluble(s) CD40:sCD40 ligand dyad, and the reduced synthesis of the neurotrophic agents, epidermal growth factor and interleukin-6. Cbl replacement treatments normalised all of these abnormalities
Cobalamin and normal prions: a new horizon for cobalamin neurotrophism.
No full textIt is known that cobalamin (Cbl) deficiency damages myelin by increasing tumor necrosis factor (TNF)-α and decreasing epidermal growth factor (EGF) levels in rat central nervous system (CNS), and affects the peripheral nervous system (PNS) morphologically and functionally. It is also known that some polyneuropathies not due to Cbl deficiency are connected with increased TNF-α levels, and that various cytokines (including TNF-α) and growth factors regulate the in vitro synthesis of normal prions (PrP Cs). Given that there is extensive evidence that PrPCs play a key role in the maintenance of CNS and PNS myelin, we investigated whether the PrPC octapeptide repeat (OR) region is involved in the pathogenesis of rat Cbl-deficient (Cbl-D) polyneuropathy. After intracerebroventricularly administering antibodies (Abs) against the OR region (OR-Abs) to Cbl-D rats to prevent myelin damage and maximum nerve conduction velocity (MNCV) abnormalities, and PrPCs to otherwise normal rats to reproduce PNS Cbl-D-like lesions, we measured PrPC levels and MNCV of the sciatic and tibial nerves. PrPC and TNF-α levels were increased in sciatic and tibial nerves of Cbl-D and saline-treated rats, and the OR-Abs normalized the myelin ultrastructure, TNF-α levels, and MNCV values of the sciatic and tibial nerves of Cbl-D rats. The same peripheral nerves of the otherwise normal PrPC-treated rats showed typical Cbl-D myelin lesions, significantly increased TNF-α levels, and significantly decreased MNCV values. These findings demonstrate that Cbl deficiency induces excess PrPCs and thereby excess OR regions, which seem to be responsible for the PNS myelin damage, as has recently been found in the case of CNS myelin damage [66]. Furthermore, excess TNF-α is also involved in the pathogenesis of Cbl-D polyneuropathy. In conclusion, we have extended the list of prion diseases by adding one caused by excess PrPCs and the polyneuropathies related to excess TNF-α
New basis of the neurotrophic action of vitamin B12
No full textOver the last few years we have reproduced all of the key morphological and biochemical features of human subacute combined degeneration in the central nervous system and peripheral nervous system of rats made cobalamin-deficient by means of total gastrectomy or a chronic cobalamin-deficient diet. We have also recently clarified the pathogenesis of experimental subacute combined degeneration induced in the rat by cobalamin deprivation. The results of our studies strongly support the notion that cobalamin plays a pivotal role in regulating the balance of the network of cytokines and growth factors in the central nervous system of the rat. We have demonstrated that cobalamin tightly regulates the central nervous system synthesis and/or the cerebrospinal fluid level of two cytokines, tumor necrosis factor-alpha and interleukin-6, and a growth factor, epidermal growth factor. Of these neuroactive agents, one, tumor necrosis factor-alpha, is neurotoxic, whereas the others are neurotrophic. Therefore, it becomes clear that cobalamin-deficient central neuropathy is caused not by the withdrawal of the vitamin, but reflects a locally increased production of neurotoxic agents, combined with the locally decreased production of neurotrophic agents
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