Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis

BackgroundCystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR.MethodsThis multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport.ResultsIn the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was ?3.0 mV (?6.6; 0.6) at day 15, ?4.1 mV (?7.8; ?0.4, p = .04) at day 26 (end of treatment) and ? 3.7 mV (?8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile.ConclusionsIn F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity.     

Diffuse large and small bowel necrosis in catastrophic antiphospholipid syndrome

The catastrophic variant is an accelerated form of the antiphospholipid syndrome resulting in multiorgan failure because of multiple small vessel occlusions. We report a case of catastrophic antiphospholipid syndrome in a patient with subacute cutaneous lupus erythematosus and ischemic bowel, who presented with acute abdominal pain due to diffuse right colon and small bowel necrosis requiring large resection, associated with acute respiratory distress syndrome, thrombocytopenia and disseminated intravascular coagulation. Histopathological examination of resected tissues showed diffuse arteriolar and venous thrombosis but no vasculitis, and mesenteric artery lumen severely narrowed by intimal fibrosis. The patient died 15 days after admission despite treatment with anticoagulation, steroids, continuous hemofiltration and plasma exchange. Ischemic bowel and diffuse intestinal necrosis may be secondary to the antiphospholipid syndrome, and a high level of suspicion and an early diagnosis are required.     

Place des thérapies comportementales dans la prise en charge des insomnies

Insomnia is among the most common health complaints in medical practice and the most prevalent of all sleep disorders. Generally, hypnotics and sedative drugs are widespread used, despite new knowledge in medical literature. Chronic insomnia can be a symptom, a syndrome and co morbid disorder. Its diagnostic relies on subjective reports from patient and sleep diary. Different subtypes of insomnia are defined: prolonged sleep latency (sleep onset insomnia), difficulties in maintaining sleep (sleep maintenance insomnia), early insomnia or a mix of different sleep complaints (mixed insomnia). Beside nights complaints, diurnal consequences are reported, include fatigue, mood disruption impaired attention… First, identification and treatment of primary psychiatric disorders or medical conditions or specific sleep disorders (apnea syndrome or periodic limb movement) are essential and associated with sleep hygiene (therapeutic education). If this first step is not sufficient, behavioral therapy (BT) (stimulus control and sleep restriction) or cognitive-behavioral therapy (CBT) of insomnia have demonstrated considerable efficacy within randomized clinical trials. Other techniques exist: relaxation, biofeedback… But CBT or BT is gold standard. Nevertheless, treatment of insomnia is an individual course of care.     

Antagonism by exifone,a new cognitive enhancing agent,of the amnesias induced by four benzodiazepines in mice

Exifone is a novel compound proposed for treating cognitive decline associated with age and shows corrective effects in animal models of memory dysfunction. The present experiments examined the antagonism by exifone of the amnesias induced in mice in a passive avoidance test by four benzodiazepines: bromazepam, diazepam, lorazepam and triazolam. Subsequent experiments investigated the specificity of exifone's antagonism of benzodiazepine-induced amnesia by examining its interaction with the effects of the benzodiazepines in the staircase test (anxiolytic/sedative activity) and the electroshock test (anticonvulsant activity). The results indicated that exifone clearly antagonised the amnesias induced by the four benzodiazepines, but was without intrinsic effects in the staircase or electroshock test and did not antagonise the effects of the benzodiazepines in these two tests. These results suggest that exifone might be useful for decreasing the amnesias induced by commonly used benzodiazepines without affecting their anxiolytic or anticonvulsant activity.Adlone^c: marketed by Laboratoires Pharmascience, F-92400 Courbevoie, France     

Expression of collapsin response mediator proteins 1, 2 and 5 is differentially regulated in newly generated and mature neurons of the adult olfactory system

Collapsin-response mediator proteins (CRMPs) are highly expressed in the developing brain where they take part in several aspects of neuronal differentiation. CRMPs are still present postnatally, but their function remains speculative in the adult brain. We studied the expression and localization of CRMP1, CRMP2 and CRMP5 in two areas of the nervous system with persistent neurogenesis in adult mice, the olfactory mucosa and the olfactory bulb. In the olfactory mucosa, we have established that CRMP expression is restricted to postmitotic cells of the olfactory neurons lineage. CRMP5 is coexpressed with growth associated protein of 43 kDa (GAP43) in immature olfactory neurons and is down-regulated in olfactory marker protein-positive mature neurons. In contrast, CRMP1 and CRMP2 persist at all stages of differentiation from immature GAP43-positive to fully mature olfactory neurons. In the olfactory bulb, CRMP1, CRMP2 and CRMP5 are abundant in neuronal progenitors of the subependymal layer and in differentiating interneurons. In both areas, the subcellular distribution of CRMP1 or CRMP2 is different in mature vs. immature neurons, suggesting that these proteins are sequentially involved in various cellular events during neuronal lifetime. The variations of CRMP expression following axotomy are consistent with their differential localization and functional involvement in immature vs. mature neurons of the olfactory system. Our data bring new insight to the putative functions of CRMPs within areas of the adult nervous system with permanent neurogenesis, some related to differentiation of newly generated neurons but others occurring in mature neurons with a limited lifespan.     

Respiratory chain deficiency in a female with Aicardi-Goutières syndrome

Aicardi-Goutières syndrome (AGS) is an early-onset progressive encephalopathy characterized by calcifications of the basal ganglia, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level of CSF interferon (INF)-alpha. We report a female with mitochondrial respiratory chain deficiency fulfilling the criteria of AGS. Disease onset was in the first year of age with seizures and psychomotor regression. To date, at 4 years of age, she presents a severe encephalopathy, increased INF-alpha in the CSF, and calcifications of basal ganglia on computerized tomography. Cerebral magnetic resonance imaging showed bilateral and symmetric hypersignal of the posterior white matter. A complex I deficiency of the mitochondrial respiratory chain was found in skeletal muscle, which was associated with a complex IV deficiency in cultured skin fibroblasts. The question of whether this oxidative phosphorylation deficiency is primary or secondary in AGS is open to debate. We suggest giving consideration to systematic evaluation of the mitochondrial respiratory chain in skeletal muscle and skin fibroblasts of other AGS patients.     

Lipopolysaccharide and TNFalpha regulate the expression of GDNF,neurturin and their receptors

Inflammatory processes in the brain may trigger specific neuroprotective responses in glial cells. Here, we show that bacterial lipopolysaccharide strongly up-regulates glial derived neurotrophic factor (GDNF) mRNA while it down-regulates that of neurturin. Tumor necrosis factor alpha (TNFalpha) had different effects since it stimulated neurturin expression without enhancing GDNF mRNA. Interestingly, both lipopolysaccharide and TNFalpha triggered a significant decrease in the expression of the GDNF receptor, GFRalpha1, in glial cells. While the significance of such down-regulation during inflammatory processes remains to be characterised, the differential regulation of GDNF and neurturin following lipopolysaccharide and TNFalpha treatments suggest specific neuroprotective responses of glial cells in case of bacterial infection, trauma, transplantation or neurodegenerative diseases.