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Wandering spleen in children is a rare condition. The diagnosis is difficult, and any delay can cause splenic ischemia. An epidemiologic, semiological, and surgical diagnosis questionnaire on incidence of wandering spleen in children was sent to several French surgical teams. We report the results of this multicenter retrospective study. Fourteen cases (6 girls, 8 boys) were reported between 1984 and 2009; the age range varies between 1-day-old and 15 years; 86% were seen in the emergency department. Ninety-three percent had diffuse abdominal pain. For 57% of the cases, it was their first symptomatic episode of this type. No diagnosis was established based on the clinical results alone. All patients had presurgical imaging diagnosis. Open surgery was performed on 64% cases. Forty-three had splenectomy for splenic ischemia. Thirty-six percent had splenopexy, 14% had laparoscopic gastropexy, and 7% had spleen repositioning and regeneration. Complications were noted in 60% of the cases resulting in postsplenopexy splenic ischemia. Early diagnosis and surgery are the best guarantee for spleen preservation. Even if the choice of one technique, splenopexy or gastropexy, can be argued, gastropexy has the advantage of avoiding splenic manipulation and restoring proper physiologic anatomy. When there is no history of abdominal surgery, laparoscopy surgery seems the best procedure., (Copyright 2010 Elsevier Inc. All rights reserved.)

Loud sound exposure is a significant cause of hearing loss worldwide. We asked whether a lack of vezatin, an ubiquitous adherens junction protein, could result in noise-induced hearing loss. Conditional mutant mice bearing non-functional vezatin alleles only in the sensory cells of the inner ear (hair cells) indeed exhibited irreversible hearing loss after only one minute exposure to a 105 dB broadband sound. In addition, mutant mice spontaneously underwent late onset progressive hearing loss and vestibular dysfunction related to substantial hair cell death. We establish that vezatin is an integral membrane protein with two adjacent transmembrane domains, and cytoplasmic N- and C-terminal regions. Late recruitment of vezatin at junctions between MDCKII cells indicates that the protein does not play a role in the formation of junctions, but rather participates in their stability. Moreover, we show that vezatin directly interacts with radixin in its actin-binding conformation. Accordingly, we provide evidence that vezatin associates with actin filaments at cell-cell junctions. Our results emphasize the overlooked role of the junctions between hair cells and their supporting cells in the auditory epithelium resilience to sound trauma.

Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions. These distortions reflect nonlinear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. Because both cochlear amplification and distortion originate from the outer hair cells-one of the two types of sensory receptor cells-it has been speculated that they stem from a common mechanism. Here we show that the nonlinearity underlying cochlear waveform distortions relies on the presence of stereocilin, a protein defective in a recessive form of human deafness. Stereocilin was detected in association with horizontal top connectors, lateral links that join adjacent stereocilia within the outer hair cell's hair bundle. These links were absent in stereocilin-null mutant mice, which became progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, we conclude that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic nonlinear behaviour of the mechanoelectrical transducer channel.

Background: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons., Methods: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed., Results: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A., Conclusion: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

Usher syndrome type IIa (USH2A) combines moderate to severe congenital hearing impairment and retinitis pigmentosa. It is the most common genetic form of USH. USH2A encodes usherin, which was previously defined as a basement membrane protein. A much larger USH2A transcript predicted to encode a transmembrane (TM) isoform was recently reported. Here, we address the role of TM usherin in the inner ear. Analysis of the usherin alternative transcripts in the murine inner ear revealed the existence of several predicted TM usherin isoforms with modular ectodomains of different lengths. In addition, we identified in the usherin cytoplasmic region a predicted 24 amino acid peptide, derived from a newly defined exon that is predominantly expressed in the inner ear but not in the retina. In mouse and rat inner ears, we show that TM usherin is present at the base of the differentiating stereocilia, which make up the mechanosensitive hair bundles receptive to sound. The usherin immunolabeling is transient in the hair bundles of cochlear hair cells (HCs), but persists in mature hair bundles of vestibular HCs. Several lines of evidence support the involvement of TM usherin in the composition of the ankle links, a subset of filamentous lateral links connecting stereocilia at the base. By co-immunoprecipitation and in vitro binding assays, we establish that the usherin cytodomain can bind to whirlin and harmonin, two PDZ domain-containing proteins that are defective in genetic forms of isolated deafness and USH type I, respectively. These PDZ proteins are suitable to provide the anchoring of interstereocilia lateral links to the F-actin core of stereocilia. Our results strongly suggest that congenital deafness in USH type I and type II shares similar pathogenic mechanisms, i.e. the disruption of hair bundle links-mediated adhesion forces that are essential for the proper organization of growing hair bundles.

Deafness is a heterogeneous disorder showing different pattern of inheritance and involving a multitude of different genes. Mutations in the gene, GJB2 Gap junction type 1), encoding the gap junction protein connexin-26 on chromosome 13q11 may be responsible for up 50% of autosomal recessive nonsyndromic hearing loss cases (ARNSHL), and for 15-30% of sporadic cases. However, a large proportion (10-42%) of patients with GJB2 has only one GJB2 mutant allele. Recent reports have suggested that a 342-kb deletion truncating the GJB6 gene (encoding connexin-30), was associated with ARNSHL through either homozygous deletion of Cx30, or digenic inheritance of a Cx30 deletion and a Cx26 mutation in trans. Because mutations in Connexin-26 (Cx26) play an important role in ARNSHL and that distribution pattern of GJB2 variants differs considerably among ethnic groups, our objective was to find out the significance of Cx26 mutations in Moroccan families who had hereditary and sporadic deafness. One hundred and sixteen families with congenital deafness (including 38 multiplex families, and 78 families with sporadic cases) were included. Results show that the prevalence of the 35delG mutation is 31.58% in the family cases and 20.51% in the sporadic cases. Further screening for other GJB2 variants demonstrated the absence of other mutations; none of these families had mutations in exon 1 of GJB2 or the 342-kb deletion of GJB6. Thus, screening of the 35delG in the GJB2 gene should facilitate routinely used diagnostic for genetic counselling in Morocco.

The 2G1MycP2Tu1 cell line was obtained following transfection of human colon carcinoma cells from the SW613-S cell line with a plasmid carrying a genomic copy of the human MYC gene. 2G1MycP2Tu1 cells produce MYC mRNAs and proteins of abnormal size. In order to analyze the structure of these abnormal products, a cDNA library constructed using RNA isolated from these cells was screened with a MYC probe. Fifty clones were studied by DNA sequencing. The results indicated that a truncated copy of the MYC gene had integrated into an rDNA transcription unit in 2G1MycP2Tu1 cells. This was confirmed by northern blot analysis, PCR amplification on genomic DNA and fluorescent in situ hybridization (FISH) experiments on metaphase chromosomes. 2G1MycP2Tu1 cells produce hybrid rRNA-MYC RNA molecules that are polyadenylated and processed by splicing reactions involving natural and cryptic splice sites. These transcripts are synthesized by RNA polymerase I, as confirmed by actinomycin D sensitivity experiments, suggesting that 3' end processing and splicing are uncoupled from transcription in this case. 2G1MycP2Tu1 cells also produce another type of chimeric mRNAs consisting of correctly spliced exons 2 and 3 of the MYC gene fused to one or more extraneous 5' exons by proper splicing to the acceptor sites of MYC exon 2. These foreign exons belong to 33 different genes, which are located on 14 different chromosomes. These observations and the results of FISH and Southern blotting experiments lead us to conclude that trans-splicing events occur at high frequency in 2G1MycP2Tu1 cells.

Defects in myosin VIIa, harmonin (a PDZ domain protein), cadherin 23, protocadherin 15 and sans (a putative scaffolding protein), underlie five forms of Usher syndrome type I (USH1). Mouse mutants for all these proteins exhibit disorganization of their hair bundle, which is the mechanotransduction receptive structure of the inner ear sensory cells, the cochlear and vestibular hair cells. We have previously demonstrated that harmonin interacts with cadherin 23 and myosin VIIa. Here we address the extent of interactions between the five known USH1 proteins. We establish the previously suggested sans-harmonin interaction and find that sans also binds to myosin VIIa. We show that sans can form homomeric structures and that harmonin b can interact with all harmonin isoforms. We reveal that harmonin also binds to protocadherin 15. Molecular characterization of these interactions indicates that through its binding to four of the five USH1 proteins, the first PDZ domain (PDZ1) of harmonin plays a central role in this network. We localize sans in the apical region of cochlear and vestibular hair cell bodies underneath the cuticular plate. In contrast to the other four known USH1 proteins, no sans labeling was detected within the stereocilia. We propose that via its binding to myosin VIIa and/or harmonin, sans controls the hair bundle cohesion and proper development by regulating the traffic of USH1 proteins en route to the stereocilia.

Otospiralin is a novel protein of unknown function that is produced by non-sensory cells (fibrocytes) of the inner ear (cochlea and vestibule). We showed that downregulation of otospiralin in guinea pigs leads to deafness and we therefore hypothesized that genetic defects in the otospiralin gene could also cause deafness in humans. In this study, we cloned and localized OTOSP, the human gene for otospiralin. OTOSP spans 1630 nucleotides, contains four exons and codes for a 567-nucleotide cDNA. By fluorescence in situ hybridization and hybrid panel mapping we localized OTOSP on chromosome 2 at position q37.3. There is currently no deafness family linked to this region. We screened OTOSP for mutations in 410 unrelated patients exhibiting various levels of hearing loss. Beside intronic polymorphisms, a rare variant (Pro7Leu) was found in 4 deafness patients and 3 control individuals, indicating that this change is not involved in this condition and excluding OTOSP as a major gene for genetic deafness.

Usher syndrome type I (USH1) is the most frequent cause of hereditary deaf-blindness in humans. Seven genetic loci (USH1A-G) have been implicated in this disease to date, and four of the corresponding genes have been identified: USH1B, C, D and F. We carried out fine mapping of USH1G (chromosome 17q24-25), restricting the location of this gene to an interval of 2.6 Mb and then screened genes present within this interval for mutations. The genes screened included the orthologue of the Sans gene, which is defective in the Jackson shaker deaf mutant and maps to the syntenic region in mice. In two consanguineous USH1G-affected families, we detected two different frameshift mutations in the SANS gene. Two brothers from a German family affected with USH1G were found to be compound heterozygotes for a frameshift and a missense mutation. These results demonstrate that SANS underlies USH1G. The SANS protein contains three ankyrin domains and a sterile alpha motif, and its C-terminal tripeptide presents a class I PDZ-binding motif. We showed, by means of co-transfection experiments, that SANS associates with harmonin, a PDZ domain-containing protein responsible for USH1C. In Jackson shaker mice the hair bundles, the mechanoreceptive structures of inner ear sensory cells, are disorganized. Based on the known interaction between USH1B (myosin VIIa), USH1C (harmonin) and USH1D (cadherin 23) proteins and the results obtained in this study, we suggest that a functional network formed by the USH1B, C, D and G proteins is responsible for the correct cohesion of the hair bundle.

The authors report a rare complication of ureteroscopy for stones of the lumbar ureter: Escherichia coli spondylitis.

Usher syndrome (USH) is an autosomal recessive disorder associated with sensorineural hearing impairment and progressive visual loss attributable to retinitis pigmentosa. This syndrome is both clinically and genetically heterogeneous. Three clinical types have been described of which type I (USH1) is the most severe. Six USH1 loci have been identified. We report a Palestinian consanguineous family from Jordan with three affected children. In view of the combination of profound hearing loss, vestibular dysfunction, and retinitis pigmentosa in the patients, we classified the disease as USH1. Linkage analysis excluded the involvement of any of the known USH1 loci. A genome-wide screening allowed us to map this novel locus, USH1G, in a 23-cM interval on chromosome 17q24-25. The USH1G interval overlaps the intervals for two dominant forms of isolated hearing loss, namely DFNA20 and DFNA26. Since several examples have been reported of syndromic and isolated forms of deafness being allelic, USH1G, DFNA20, and DFNA26 might result from alterations of the same gene. Finally, a mouse mutant, jackson shaker ( js), with deafness and circling behavior has been mapped to the murine homologous region on chromosome 11.