Segmental conduction abnormalities and myelin thickenings in Val102/fs null mutation of MPZ gene

The authors report in patients with Val102/fs null mutation a possibly age dependent variability of clinical and electrophysiologic phenotype, segmental conduction abnormalities mainly in ulnar nerves at the elbow, and excessive myelin foldings and thickenings. The authors hypothesize that myelin thickenings at the paranodal region, in concurrence with compression at usual entrapment sites or minor repetitive trauma, may induce segmental conduction abnormalities.     

Vascular inflammation in central nervous system diseases: adhesion receptors controlling leukocyte-endothelial interactions

Leukocyte trafficking from the blood into the tissues represents a key process during inflammation and requires multiple steps mediated by adhesion molecules and chemoattractants. Inflammation has a detrimental role in several diseases, and in such cases, the molecular mechanisms controlling leukocyte migration are potential therapeutic targets. Over the past 20 years, leukocyte migration in the CNS has been investigated almost exclusively in the context of stroke and MS. Experimental models of ischemic stroke have led to the characterization of adhesion molecules controlling leukocyte migration during acute inflammation, whereas EAE, the animal model of MS, has provided similar data for chronic inflammation. Such experiments have led to clinical trials of antileukocyte adhesion therapy, with consistently positive outcomes in human subjects with MS, showing that interference with leukocyte adhesion can ameliorate chronic inflammatory CNS diseases. This review summarizes our current understanding of the roles of adhesion molecules controlling leukocyte-endothelial interactions in stroke and MS, focusing on recently discovered, novel migration mechanisms. We also discuss the growing evidence suggesting a role for vascular inflammation and leukocyte trafficking in neurodegenerative diseases such as AD. Moreover, we highlight recent findings suggesting a role for leukocyte-endothelial interactions in the pathogenesis of seizures and epilepsy, thus linking endothelial activation and leukocyte trafficking to neuronal electrical hyperactivity. These emerging roles for leukocytes and leukocyte adhesion mechanisms in CNS diseases provide insight into the mechanisms of brain damage and may contribute to the development of novel therapeutic strategies.     

Histamine regulates autoreactive T cell activation and adhesiveness in inflamed brain microcirculation

Histamine may contribute to the pathology of MS and its animal model EAE. We explored the effects of histamine and specific HR agonists on activation and migratory capacity of myelin-autoreactive T cells. We show that histamine in vitro inhibits proliferation and IFN-γ production of mouse T cells activated against PLP(139-151). These effects were mimicked by the H1R agonist HTMT and the H2R agonist dimaprit and were associated with reduced activation of ERK½ kinase and with increased levels of cell cycle inhibitor p27Kip-1, both involved in T cell proliferation and anergy. H1R and H2R agonists reduced spontaneous and chemokine-induced adhesion of autoreactive T cells to ICAM-1 in vitro and blocked firm adhesion of these cells in inflamed brain microcirculation in vivo. Thus histamine, through H1R and H2R, inhibits activation of myelin-autoreactive T cells and their ability to traffic through the inflamed BBB. Strategies aimed at interfering with the histamine axis might have relevance in the therapy of autoimmune disease of the CNS.     

Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush

Mesenchymal stem cells (MSCs) represent a promising therapeutic approach in nerve tissue engineering. To date, the local implantation of MSC in injured nerves has been the only route of administration used. In case of multiple sites of injury, the systemic administration of cells capable of reaching damaged nerves would be advisable. In this regard, we found that an intravenous administration of adipose-derived MSC (ASC) 1 week after sciatic nerve crush injury, a murine model of acute axonal damage, significantly accelerated the functional recovery. Sciatic nerves from ASC-treated mice showed the presence of a restricted number of undifferentiated ASC together with a significant improvement in fiber sprouting and the reduction of inflammatory infiltrates for up to 3 weeks. Besides the immune modulatory effect, our results show that ASC may contribute to peripheral nerve regeneration because of their ability to produce in culture neuroprotective factors such as insulin-like growth factor I, brain-derived neurotrophic factor, or basic fibroblast growth factor. In addition to this production in vitro, we interestingly found that the concentration of glial-derived neurotrophic factor (GDNF) was significantly increased in the sciatic nerves in mice treated with ASC. Since no detectable levels of GDNF were observed in ASC cultures, we hypothesize that ASC induced the local production of GDNF by Schwann cells. In conclusion, we show that systemically injected ASC have a clear therapeutic potential in an acute model of axonal damage. Among the possible mechanisms promoting nerve regeneration, our results rule out a process of trans-differentiation and rather suggest the relevance of a bystander effect, including the production of in situ molecules, which, directly or indirectly through a cross-talk with local glial cells, may modulate the local environment with the down-regulation of inflammation and the promotion of axonal regeneration.     

Cellular fate of oligonucleotides when delivered by nanocapsules of poly(isobutylcyanoacrylate).

Dual-labeled phosphorothioate oligonucleotides were encapsulated in the internal aqueous core of poly(isobutylcyanoacrylate) nanocapsules with high yields. Intracellular distribution of naked and encapsulated oligomers was assessed on cultured vascular smooth muscle cells using cell fractionation and confocal microscopy methods. The results showed that cell uptake and more interestingly, nuclear accumulation of oligonucleotides were importantly enhanced when the oligonucleotides were associated to the nanocapsules as compared to the naked oligomers. These results suggested an efficient capacity of this polymeric carrier to deliver its payload to the cytosol and nucleus of smooth muscle cells.     

Monitoring of intracranial pressure

A very small fiberoptic catheter initially developed as an intravascular pressure sensor was incorporated into a system to be used as an intracranial pressure (ICP) monitor. 13 patients with intracranial hypertension have been studied with this probe. The clinical experience confirmed the safety, accuracy and reliability of the device. The monitor has functioned very well, and there have been no complications except for two breakages of optic fiber as a result of nursing manoeuvres. This new device can be placed into the ventricular, subdural and epidural space. Camino System appears to offer advantages over other monitors presently in use.     

Pseudotumor cerebri. Lumboperitoneal shunt in long lasting cases.

The Authors report three cases of pseudotumor cerebri with noteworthy visual defect. Lumboperitoneal shunt enables good recovery where there was no atrophy of the optic nerve and demonstrated its usefulness also in serious situations.