Tissue Plasminogen Activator–Mediated Fibrinolysis Protects against Axonal Degeneration and Demyelination after Sciatic Nerve Injury

Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin and can trigger the degradation of extracellular matrix proteins. In the nervous system, under noninflammatory conditions, tPA contributes to excitotoxic neuronal death, probably through degradation of laminin. To evaluate the contribution of extracellular proteolysis in inflammatory neuronal degeneration, we performed sciatic nerve injury in mice. Proteolytic activity was increased in the nerve after injury, and this activity was primarily because of Schwann cell–produced tPA. To identify whether tPA release after nerve damage played a beneficial or deleterious role, we crushed the sciatic nerve of mice deficient for tPA. Axonal demyelination was exacerbated in the absence of tPA or plasminogen, indicating that tPA has a protective role in nerve injury, and that this protective effect is due to its proteolytic action on plasminogen. Axonal damage was correlated with increased fibrin(ogen) deposition, suggesting that this protein might play a role in neuronal injury. Consistent with this idea, the increased axonal degeneration phenotype in tPA- or plasminogen-deficient mice was ameliorated by genetic or pharmacological depletion of fibrinogen, identifying fibrin as the plasmin substrate in the nervous system under inflammatory axonal damage. This study shows that fibrin deposition exacerbates axonal injury, and that induction of an extracellular proteolytic cascade is a beneficial response of the tissue to remove fibrin. tPA/plasmin-mediated fibrinolysis may be a widespread protective mechanism in neuroinflammatory pathologies

A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis

A key role of both coagulation and vascular thrombosis has been reported since the first descriptions of multiple sclerosis (MS). Subsequently, the observation of a close concordance between perivascular fibrin(ogen) deposition and the occurrence of clinical signs in experimental allergic encephalomyelitis (EAE), an animal model of MS, led to numerous investigations focused on the role of thrombin and fibrin(ogen). Indeed, the activation of microglia, resident innate immune cells, occurs early after fibrinogen leakage in the pre-demyelinating lesion stage of EAE and MS. Thrombin has both neuroprotective and pro-apoptotic effects according to its concentration. After exposure to high concentrations of thrombin, astrocytes become reactive and lose their neuroprotective and supportive functions, microglia proliferate, and produce reactive oxygen species, IL-1β, and TNFα. Heparin inhibits the thrombin generation and suppresses EAE. Platelets play an important role too. Indeed, in the acute phase of the disease, they begin the inflammatory response in the central nervous system by producing of IL-1alpha and triggering and amplifying the immune response. Their depletion, on the contrary, ameliorates the course of EAE. Finally, it has been proven that the use of several anticoagulant agents can successfully improve EAE. Altogether, these studies highlight the role of the coagulation pathway in the pathophysiology of MS and suggest possible therapeutic targets that may complement existing treatments

HIV Prevalence and Impact on Renutrition in Children Hospitalised for Severe Malnutrition in Niger: An Argument for More Systematic Screening

Background: In developing countries, malnutrition is a contributing factor in over 50 % of child deaths. Mortality rates are higher in underweight children, and HIV-infection is known to increase underweight. Our goals were to evaluate the prevalence of HIV among children hospitalised for severe malnutrition (SM) at the Niamey national hospital (Niger), and to compare renutrition and mortality by HIV-status. Methods: Retrospective study based on all children,5 years hospitalised for SM between January 1 st 2008 and July 1 st 2009. HIV-prevalence was the ratio of HIV+ children on the number of children tested. Duration of renutrition and mortality were described using survival curves. Results: During the study period, 477 children were hospitalised for SM. HIV testing was accepted in 470 (98.5%), of which 40 were HIV+ (HIV prevalence (95 % confidence interval) of 8.6 % (6.2–11.5)). Duration of renutrition was longer in HIV+ than HIV2 children (mean: 22 vs. 15 days; p = 0.003). During renutrition, 8 (20%) and 61 (14%) HIV+ and HIV2 children died, respectively (p = 0.81). Conclusion: Around 9 % of children hospitalised for severe malnutrition were HIV infected, while in Niger HIV prevalence i