Nitrous oxide-induced predominantly motor neuropathies: a follow-up study.

OBJECTIVES: Recreational nitrous oxide (N2O) abuse is increasingly popular among youth. We report a systematic clinical, electrophysiological and biological follow-up of patients with neuropathy caused by N2O. METHODS: We retrospectively report seven patients with neuropathy attributed to N2O abuse and their comprehensive follow-up. Demographic, toxicological, clinical, biological and electrophysiological data were collected at first and second examination. Functional data were collected at the last evaluation. RESULTS: Seven patients aged 18-30, consuming more than 140 gas-filled balloons (one balloon is filled with approximately 8 g of N2O) per week for over a month, developed a severe, predominantly motor, length-dependent, progressive neuropathy over 3 to 6 weeks. Two-thirds presented associated signs of myelopathy. Distal lower limbs motor deficit and ataxia led to moderate disability. Spinal cord imaging was frequently normal. Nerve conduction studies disclosed an almost exclusively motor axonal neuropathy affecting the lower limbs with active denervation. Homocysteine plasma level was systematically elevated, whereas cobalamin plasma levels were normal in almost all patients. At short-term follow-up after intoxication discontinuation, ataxia and motor deficit only partially resolved despite vitamin B12 supplementation, while active denervation and homocysteinemia decreased. At last follow-up (median 9.2 months, IQR 7.5-10.75), mean ONLS was 2.0 (IQR 2.0-2.0). DISCUSSION: Young patients, with induced N2O motor neuropathy remain disabled after 5 to 14.5 months of gas withdrawal, despite vitamin B12 supplementation. A longer follow-up is needed to fully appraise the severity of these toxic neuropathies.

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.

Cell Therapy for Ischemic Stroke: How to Turn a Promising Preclinical Research into a Successful Clinical Story.

Stroke is a major public health issue with limited treatment. The pharmacologically or mechanically removing of the clot is accessible to less than 10% of the patients. Stem cell therapy is a promising alternative strategy since it increases the therapeutic time window but many issues remain unsolved. To avoid a new dramatic failure when translating experimental data on the bedside, this review aims to highlight the indispensable checkpoints to make a successful clinical trial based on the current preclinical literature. The large panel of progenitors/ stem cells at the researcher's disposal is to be used wisely, regarding the type of cells, the source of cells, the route of delivery, the time window, since it will directly affect the outcome. Mechanisms are still incompletely understood, although recent studies have focused on the inflammation modulation of most cells types.

MFGE8 inhibits inflammasome-induced IL-1ß production and limits postischemic cerebral injury.

Milk fat globule-EGF 8 (MFGE8) plays important, nonredundant roles in several biological processes, including apoptotic cell clearance, angiogenesis, and adaptive immunity. Several recent studies have reported a potential role for MFGE8 in regulation of the innate immune response; however, the precise mechanisms underlying this role are poorly understood. Here, we show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1ß production. MFGE8 inhibited necrotic cell-induced and ATP-dependent IL-1ß production by macrophages through mediation of integrin ß(3) and P2X7 receptor interactions in primed cells. Itgb3 deficiency in macrophages abrogated the inhibitory effect of MFGE8 on ATP-induced IL-1ß production. In a setting of postischemic cerebral injury in mice, MFGE8 deficiency was associated with enhanced IL-1ß production and larger infarct size; the latter was abolished after treatment with IL-1 receptor antagonist. MFGE8 supplementation significantly dampened caspase-1 activation and IL-1ß production and reduced infarct size in wild-type mice, but did not limit cerebral necrosis in Il1b-, Itgb3-, or P2rx7-deficient animals. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1ß production.