Germline mosaicism in keratitis–ichthyosis–deafness syndrome: pre‐natal diagnosis in a familial lethal form

Sbidian E, Feldmann D, Bengoa J, Fraitag S, Abadie V, de Prost Y, Bodemer C, Hadj‐Rabia S. Germline mosaicism in keratitis–ichthyosis–deafness syndrome: pre‐natal diagnosis in a familial lethal form. Keratitis–ichthyosis–deafness (KID) syndrome is an autosomal dominant congenital ectodermal defect characterized by the association of skin lesions, hearing loss and keratitis. Most of the cases appear to be sporadic. KID syndrome is mostly related to mutations of GJB2 gene encoding connexin‐26. Recently, a lethal form of the disease during the first year of life has been reported in two unrelated Caucasian patients. This rare lethal form is caused by the G45E mutation of GJB2 gene. We here report the first pre‐natal molecular genetic diagnosis of the lethal form of KID syndrome relating to a G45E mutation. In the same family, the occurrence of this condition in three other siblings born to African non‐consanguineous healthy parents lead to perform pre‐natal diagnosis for this last pregnancy. Molecular analysis confirms the diagnosis of the lethal form of KID for the fetus. These results establish the role of germline mosaicism in KID syndrome and warrant careful genetic counseling. Furthermore, analysis of our cases and the literature allowed us to define a characteristic severe neonatal phenotype including facial dysmorphy, severe cornification with massive focal hyperkeratosis of the skin with erythroderma, dystrophic nails, complete atrichia and absence of foreskin.     

Clinical trials in amyotrophic lateral sclerosis: the tenuous past and the promising future

The past decade of research in amyotrophic lateral sclerosis has contributed to a greater understanding of the disease process, the development of relevant animal models, and the identification of several therapeutic approaches that may delay disease progression. Completed and ongoing clinical trials and the process of selecting drugs for clinical trials are presented.     

Seasonal variations of the beta-endorphin neuronal system in the mediobasal hypothalamus of the jerboa (Jaculus orientalis)

The distribution of neurons expressing beta-endorphin immunoreactivity was explored in the brain of adult jerboa during two distinct periods characterizing its reproductive cycle. A large presence of cell bodies displaying beta-endorphin immunoreactivity occured within different parts of the mediobasal hypothalamus along its rostrocaudal extent, from the retrochiasmatic area to the posterior arcuate nucleus. Quantitatively, the highest density of immunoreactive beta-endorphin neurons was noted at the medial level of the arcuate nucleus. Furthermore, a seasonal study showed that the number of IR-beta-endorphin neurons was highest in the anterior portion of the arcuate nucleus of jerboas sacrificed in autumn as compared to those sacrificed during spring-summer. Quantitatively, the number of beta-endorphin containing neurons in autumn was 200% in comparison to that found in spring-summer. These results suggest that beta-endorphin containing neuronal population especially localized in the anterior part of arcuate nucleus, exerts an inhibitory influence on the GnRH neurosecretory system in the jerboa, notably in autumn, probably via an increasing expression of its products. The results provide morphofunctional arguments in favour of inhibitory opioid control of GnRH neurons activity and hence the neuroendocrine events regulating reproduction in jerboa.     

Do platelet apoptosis, activation, aggregation, lipid peroxidation and platelet-leukocyte aggregate formation occur simultaneously in hyperlipidemia?

OBJECTIVES: The circulating lipoproteins may cause some abnormalities in platelet composition and function in hypercholesterolemia. The aim of this study was to investigate whether platelet apoptosis, platelet activation, platelet aggregation, platelet-leukocyte aggregate (PLA) formation and lipid peroxidation occur simultaneously in hyperlipidemia. DESIGN AND METHODS: Expression of GpIIb/IIIa (CD41a), P-selectin (CD62-P), platelet-bound fibrinogen (antifibrinogen), platelet membrane phosphatidylserine (PS), platelet-monocyte aggregates (mono-PLA) and platelet-neutrophil aggregates (neut-PLA) was measured in eight hyperlipidemic and eight normal subjects using flow cytometry. ADP (10 microM) was used to activate platelets. Furthermore, ADP induced platelet aggregation responses, platelet malondialdehyde (MDA) and glutathione (GSH) levels were determined. RESULTS: Before platelet activation, platelet CD62-P, antifibrinogen, annexin-V, mono-PLA, neut-PLA and platelet MDA levels as well as platelet aggregation responses in the hyperlipidemics were significantly higher than those in the controls (P<0.01, P<0.01, P<0.01, P<0.001, P<0.001, P<0.01, P<0.001, respectively), whereas GpIIb/IIIa expression and GSH levels were not different significantly (P > 0.05). In the control group, CD62-P, antifibrinogen and annexin-V levels increased significantly after ADP activation (P<0.05, P<0.05, P<0.01, respectively). In hyperlipidemic subjects, annexin-V expression increased significantly after activation (P<0.01), whereas expression of GpIIb/IIIa, CD62-P and antifibrinogen remained unchanged (P>0.05). The levels of total cholesterol (T-CHO), low density lipoprotein cholesterol (LDL-C), serum fibrinogen (S-FGN) and high density lipoprotein cholesterol (HDL-C) in patients were found to be correlated with platelet CD62-P, antifibrinogen, annexin-V, mono-PLA and MDA. CONCLUSIONS: In conclusion, it seems that in hyperlipidemia, some platelets are in an activated state in circulation, and that increased lipid peroxidation, early apoptosis, platelet-leukocytes aggregate formation and platelet aggregation altogether accompany this process.     

Effect of pupillary dilation on retinal nerve fiber layer thickness measurements using optical coherence tomography

PURPOSE: To evaluate the effect of pupillary dilation on retinal nerve fiber layer thickness (RNFL) measurements using optical coherence tomography (OCT-3). METHODS: Randomly chosen eyes of healthy individuals were scanned before and after pupillary dilation by two trained operators (R.G.O., R.V.) using OCT-3 (Carl Zeiss Meditec, Inc., Dublin, CA). Fast and regular RNFL (256 A-scans) OCT-3 protocols (software version A1.1) were used in each scanning session. RNFL thickness measurements before and after dilation were compared. RESULTS: Ten eyes of 10 subjects (6 females, 4 males) were enrolled. Mean age was 32.0 +/- 11.2 years (range, 21 to 52 years). Mean pupillary diameter before and after dilation was 2.9 +/- 0.6 mm and 7.6 +/- 0.8 mm, respectively (P < 0.0001, paired t-test). There was no significant difference in RNFL thickness measurements before and after dilation using both fast and regular RNFL protocols (P > or = 0.05 for all comparisons, paired t-test). Mean coefficients of variation for mean RNFL thickness measurements were 15.3% before and 13.7% after dilation for operator 1; and 10.8% before and 12.7% after dilation for operator 2 for the fast RNFL protocol and 11.3% versus 10.4% and 12.9 versus 11.1%, respectively, for the regular RNFL protocol. CONCLUSION: Pupillary dilation is not necessary in all subjects to obtain reproducible RNFL thickness measurements using OCT-3.     

Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women

Schizophrenia is a complex disorder with a polygenic inheritance. Catechol-O-methyltransferase (COMT) plays a significant role in the regulation of dopaminergic systems. A polymorphism at COMT Val108/158Met has been identified in association with schizophrenia. We examined the allele and genotype association of the COMT Val108/158Met polymorphism of 297 unrelated schizophrenic patients who strictly met DSM-IV criteria for schizophrenia, and 341 healthy controls. We found significant difference in allele and genotype frequencies between schizophrenic patients and controls (chi2=13.030; P=0.001). The allele frequency of the COMT-L was 45.79% in the total schizophrenic patients, and 41.50% in controls. The genotype frequency of the COM-LL was 21.2% in the total schizophrenic patients, and 11.4% in controls (OR=2.085; 95% CI=1.350-3.219; chi2=11.293; P=0.001). With a separate sex analysis, the frequency of the COMT-L allele was moderately distributed in male schizophrenia (chi2=6.177; df=2; P=0.046). The COMT-LL genotype had a 1.818-fold increased risk for schizophrenia (OR=1.818; 95% CI=1.010-3.273; chi2=4.048; P=0.044). The frequency of the COMT-L allele was even more significantly distributed in women schizophrenia (chi2=7.797; df=2; P=0.020). The COMT-LL genotype had remarkably more increased risk for schizophrenia (OR=2.456; 95% CI=1.287-4.687; chi2=7.710; P=0.005). In conclusion, our results provide strong evidence for a role of the COMT-L allele and LL genotype in the etiopathophysiology of schizophrenia with a sexual difference.