GJB2: the spectrum of deafness-causing allele variants and their phenotype

Genetic testing was completed on 1,294 persons with deafness referred to the Molecular Otolaryngology Research Laboratories to establish a diagnosis of DFNB1. Exon 2 of GJB2 was screened for coding sequence allele variants by denaturing high-performance liquid chromatography (DHPLC) complemented by bidirectional sequencing. If two deafness-causing mutations of GJB2 (encoding Connexin 26) were identified, further screening was not performed. If only a single deafness-causing mutation was identified, we screened for the g.1777179_2085947del (hereafter called del(GJB6-D13S1830); GenBank NT_024524.13) and mutations in the noncoding region of GJB2. Phenotype-genotype correlations were evaluated by categorizing mutations as either protein truncating or nontruncating. A total of 205 persons carried two GJB2 exon 2 mutations and were diagnosed as having DFNB1; 100 persons carried only a single deafness-causing allele variant of exon 2. A total of 37 of these persons were c.35delG carriers, and 51 carried other allele variants of GJB2. Persons diagnosed with DFNB1 segregating two truncating/nonsense mutations had a more severe phenotype than persons carrying two missense mutations, with mean hearing impairments being 88 and 37%, respectively (P < 0.05). The number of deaf c.35delG carriers was greater than expected when compared to the c.35delG carrier frequency in normal-hearing controls (P < 0.05), suggesting the existence of at least one other mutation outside the GJB2 coding region that does not complement GJB2 deafness-causing allele variants.     

Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

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Testicular Synovial Sarcoma:A Case Report

This paper reports a case of testicular synovial sarcoma with molecular genetic analysis.A 24-year-old male presented with painless scrotal mass.Ultrasonography showed a heterogeneous mass of 66 mm×34 mm in size involving the inguinal region.Histological examination of a surgical biopsy showed a gradeⅢmonophasic growth pattern of spindle cell proliferation.Immunohistochemical analyses indicated positive staining for pancytokeratine and epithelial membrane antigen.Cytogenetic analysis showed the presence of CYT-SSX1 mutation,and CT scan showed non-specific pleural micro-nodules with a size of 7.5 mm.The patient had an extended left orchidectomy but was lost to follow-up for 1 year.A local recurrent scrotal mass of 32 mm×25 mm,multiple inguinal lymph nodes,and increased pleural nodules,which were confirmed by histological examination,were treated with three cycles of adriamycine and ifosfamide chemotherapy,surgical resection,and radiotherapy with complete response.After 3 months,the patient developed local recurrence and pulmonary metastases that did not respond to second-line chemotherapy based on gemcitabine and paclitaxel.The patient had dyspnea at the time of this writing and chest pain,and is under third-line chemotherapy based on Deticene after 30 months of following up.This patient died on November 16,2012 after a resperatory failure and malignant plural effusion. Synovial sarcoma should be considered in the differential diagnosis of soft tissue tumor and it should be aggressively treated to improve prognosis.Although our patient has shown numerous factors of bad prognosis,he has had a relatively long survival time.     

Pathway‐Based Association Study of Multiple Candidate Genes and Multiple Traits Using Structural Equation Models

There is increasing interest in the joint analysis of multiple genetic variants from multiple genes and multiple correlated quantitative traits in association studies. The classical approach involves testing univariate associations between genotypes and phenotypes and correcting for multiple testing that results in loss of power to detect associations. In this paper, we propose modeling complex relationships between genetic variants in candidate genes and measured correlated traits using structural equation models (SEM), taking advantage of prior knowledge on clinical and genetic pathways. We adopt generalized structured component analysis (GSCA) as an approach to SEM and develop a single association test between multiple genetic variants in a gene and a set of correlated traits, taking into account all available data from other genes and other traits. The performance of this test is investigated by simulations. We apply the proposed method to the Quebec Child and Adolescent Health and Social Survey (1999) data to investigate genetic associations with cardiovascular disease‐related traits.     

Soft‐tissue tumor of the perineum: an exceptional case of bilateral perineal myoma

Perineal myomas in female are exceptional. We report the second case in literature of perineal myomas. It is a case of bilateral perineal myomas lifting the skin occurring in a female patient of 49 years old. She was operated by perineal incisions. Histopathology confirmed the fibromatous nature without signs of malignancy.     

Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques

TLR3 is a key receptor for recognition of double-stranded RNA and initiation of immune responses against viral infections. However, hyperactive responses can have adverse effects, such as virus-induced asthma. Strategies to prevent TLR3-mediated pathology are therefore desired. We investigated the effect of single-stranded DNA oligonucleotides (ssDNA-ODNs) on TLR3 activation. Human monocyte-derived dendritic cells up-regulate maturation markers and secrete proinflammatory cytokines on treatment with the synthetic TLR3 ligand polyinosine-polycytidylic acid (poly I:C). These events were inhibited in cultures with ssDNA-ODNs. Poly I:C activation of nonhematopoietic cells was also inhibited by ssDNA-ODNs. The uptake of poly I:C into cells was reduced in the presence of ssDNA-ODNs, preventing TLR3 engagement from occurring. To confirm this inhibition in vivo, we administered ssDNA-ODNs and poly I:C, alone or in combination, via the intranasal route in cynomolgus macaques. Proinflammatory cytokines were detected in nasal secretions in the poly I:C group, while the levels were reduced in the groups receiving ssDNA-ODNs or both substances. Our results demonstrate that TLR3-triggered immune activation can be modulated by ssDNA-ODNs and provide evidence of dampening proinflammatory cytokine release in the airways of cynomolgus macaques. These findings may open novel perspectives for clinical strategies to prevent or treat inflammatory conditions exacerbated by TLR3 signaling.     

Description of response to aspirin and clopidogrel in outpatients with coronary artery disease using multiple electrode impedance aggregometry

Identification of outpatients with high platelet reactivity (HPR) on antiplatelet treatment is an unmet need. The present study was conducted in healthy individuals (n = 50) and in outpatients with coronary artery disease (CAD) at a distance from the acute ischemic episode (aspirin group, n = 71; aspirin/clopidogrel group, n = 106). We studied the feasibility and the precision of whole blood multiple electrode aggregometry (MEA) after triggering platelet aggregation by arachidonic acid or adenosine diphospate (ADP). The MEA can be performed on whole blood within 2 hours after sample venipuncture. The threshold for the diagnosis of HPR is situated at 55 and 50 U for the arachidonic acid and ADP test, respectively. Frequency of HPR was 7% and 20% in aspirin and aspirin/clopidogrel groups, respectively. In 3.8% of patients in aspirin/clopidogrel group, combined HPR on aspirin and clopidogrel was found. In outpatients with CAD, use of MEA is feasible for the diagnosis of HPR.     

Association of IL-8 (-251)T/A polymorphism with susceptibility to and aggressiveness of nasopharyngeal carcinoma

Interleukin-8 (IL-8) is an angiogenic chemokine that plays a potent role in both development and progression of many human malignancies including nasopharyngeal carcinoma (NPC). In the present study, we evaluated the susceptibility and prognostic implications of the (-251) T/A genetic variation in IL-8 in NPC. We used the allele-specific polymerase chain reaction to characterize the variation of the IL-8 promoter region for 160 unrelated Tunisian patients with NPC and 169 healthy control subjects. There was a significant association between the homozygotes IL-8 (-251) AA genotype and nasopharyngeal carcinoma (OR = 2.46; P = 0.004). The presence of the IL-8 (-251) AA genotype was highly associated with elevated NPC risk for male patients. A significant association was demonstrated between the IL-8 (-251) AA genotype and the aggressive forms of NPC as defined by large tumor size, lymph node metastasis, and advanced stages. Moreover, the presence of the IL-8 (-251) AA genotype indicated a significant association with decreased overall survival. Our findings suggest that the IL-8 promoter polymorphism is associated with increased nasopharyngeal carcinoma risk, particularly in males, as well as disease progress, supporting our hypothesis for IL-8 involvement in NPC pathogenesis.     

Skeletal phenotype/genotype in progressive pseudorheumatoid chondrodysplasia

Clinical Rheumatology - Axial and extra-axial deceleration in function and progressive joint pain with subsequent development of antalgic gait associated with swellings, and stiffness of the joints...