Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next-generation sequencing

BackgroundThe extremely high genetic heterogeneity of hearing loss due to diverse group of genes encoding proteins required for development, function, and maintenance of the complex auditory system makes the genetic diagnosis of this disease challenging. Up to now, 121 different genes have been identified for nonsyndromic hearing loss (NSHL), of which 76 genes are responsible for the most common forms of NSHL, autosomal recessive nonsyndromic hearing loss (ARNSHL).MethodsAfter excluding mutations in the most common ARNSHL gene, GJB2, by Sanger sequencing, genetic screening for a panel of genes responsible for hereditary hearing impairment performed in 9 individuals with ARNSHL from unrelated Iranian consanguineous pedigrees.ResultsOne compound heterozygote and eight homozygote variants, of which five are novel, were identified: CDH23:p.(Glu1970Lys), and p.(Ala1072Asp), GIPC3:p.(Asn82Ser), and (p.Thr41Lys), MYO7A:p.[Phe456Phe]; p.[Met708Val], and p.(Gly163Arg), TECTA:p.(Leu17Leufs*19), OTOF:c.1392+1G>A, and TRIOBP:p.(Arg1068*). Sanger sequencing confirmed the segregation of the variants with the disease in each family.ConclusionFinding more variants and expanding the spectrum of hearing impairment mutations can increase the diagnostic value of molecular testing in the screening of patients and can improve counseling to minimize the risk of having affected children for at risk couples.     

Biologic risk factors for low birthweight in Al Ain,United Arab Emirates

A prospective study of biological factors for low birthweight (LBW) among UAE nationals in the Al Ain Medical District was undertaken from 15 January 1992 to 14 January 1993, using a case control method. All 293 mothers of LBW infants and an equal number of mothers of the next normal weight infants born after the LBW infant were studied. Of the 3,485 live births, 293 (8.4%) were LBW (less than 2,500 g). Maternal age less than 25 years, lighter weight at booking, nulliparity, first cousin marriage and short interpregnancy interval (IPI) of 3 months or less significantly increased the risk of LBW in this population. After adjusting for other biologic confounders, only low maternal weight and short IPI significantly increased the risk of LBW. Modification of these biologic risk factors would help to reduce the incidence of LBW among the UAE population. © 1996 Wiley-Liss, Inc.     

Effects of Aging Torque Controllers on Screw Tightening Force and Bacterial Micro-Leakage on the Implant-Abutment Complex

Aim: We assess the accuracy of torque controllers after several aging processes and the bacterial leakage on implant-abutment complexes (IAC). Methods: A total of 12 spring-type and 12 friction-type torque controllers and 48 IAC (24 conical and 24 hexagonal connections) were evaluated. Chemical, mechanical, temperature, and pressure-aging methods were applied individually to replicate clinical use. Torque controller accuracy was analyzed before and after aging using a calibrated gauge. To assess bacterial leakage, the IAC were suspended in a bacterial medium for 24 h. Direct Contact Test (DCT) and Polymerase Chain Reaction Test (RT-PCR) analyzed the infiltration of F. nucleatum and P. gingivalis into the IAC micro-gap. Results: A significant decrease in torque after 10 days of aging was found. The spring-type torque controller was affected the most, regardless of the aging method (P < 0.05). PCR results indicated that all groups exhibited significantly more bacterial leakage, regardless of the method used (P < 0.05). The conical IAC demonstrated more bacterial leakage of P. gingivalis compared with the hexagonal IAC (P = 0.07). DCT found bacterial growth in the IAC only before aging and was not identified after aging. Conclusion: Aging affects torque accuracy. A reduction in force was noticed after 10 days. The conical IAC exhibits more bacterial leakage, although this was not statistically significant.     

Validation of LittlEARS® Early Speech Production Questionnaire in Arabic-speaking children with normal hearing

Objectives:To validate an Arabic version of the LittlEARS^® Early Speech Production Questionnaire (LEESPQ), which assesses the early development of speech and language in infants between 0 and 18 months, in Arabic-speaking children with normal hearing in Saudi Arabia.Methods:This is a cross-sectional study conducted in the city of Riyadh, Saudi Arabia between September and December 2020. Parents completed the LEESPQ regarding their child’s speech production development. To assess the ability of normal hearing children aged 0-18 months in developing speech and language production, a norm curve has been generated based on the standardized values that were calculated from the Arabic normal-hearing data set.Results:A total of 198 questionnaires were analyzed. The total score on the LEESPQ correlated with age, gender, and bilingualism. A norm curve for early speech production in children with normal hearing was created.Conclusion:The Arabic version of LEESPQ appears to be a valid questionnaire that can be used in the assessment of early language and speech development of Arabic-speaking children with normal hearing in the age range of 0-18 months. The Arabic version of the LEESPQ might also be a useful tool to detect developmental delays and hearing disorders in young children.     

Molecular Mechanisms Involved in Intrarenal Renin-Angiotensin and Alternative Pathways in Diabetic Nephropathy - A Review

Uncontrolled or chronic hyperglycemia causes kidney failure induced by the dysfunction of biomolecules and upregulation of inflammatory cytokines and growth factors. The reninangiotensin system (RAS) is incorporated in the regulation of renal hemodynamics. In a healthy state, local RAS is independent of systemic RAS. However, in pathological conditions such as chronic hyperglycemia, angiotensin II (Ang II) increases locally and causes tissue damage, mainly through the induction of oxidative stress, inflammation, and upregulation of some growth factors and their receptors. Such tissue events may cause disruption of the glomerular filtration barrier, thickening and hypertrophy of the glomerular basement membrane, microvascular hyperpermeability, proteinuria, and finally decrease in the glomerular filtration rate (GFR). Reduced GFR causes the kidney to sense falsely a low blood pressure condition and respond to it by stimulating systemic and local RAS. Therefore, patients with diabetic nephropathy (DN) suffer from chronic hypertension. In contrast to local RAS, there are alternative pathways in the kidney that act protectively by reducing tissue Ang II. Such autoregulatory and protective mechanisms are weakened in chronic kidney disease. Previously, it was presumed that systemic RAS inhibitors such as ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) could prevent renal damage by controlling blood pressure and proteinuria. However, the progression of renal failure to end-stage renal disease (ESRD), despite such treatments, indicates the presence of factors other than Ang II. This review highlights the molecular mechanism in renal disease and discusses pharmaceutical and therapeutic approaches.     

Searching for prognostic biomarkers for small renal masses in the urinary proteome

Renal cell carcinoma (RCC) is frequently diagnosed incidentally as an early-stage small renal mass (SRM; pT1a, ≤4 cm). Overtreatment of patients with benign or clinically indolent SRMs is increasingly common and has resulted in a recent shift in treatment recommendations. There are currently no available biomarkers that can accurately predict clinical behavior. Therefore, we set out to identify early biomarkers of RCC progression. We employed a quantitative label-free liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) proteomics approach and targeted parallel-reaction monitoring to identify and validate early, noninvasive urinary biomarkers for RCC-SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤4 cm) cases, 30 progressive and 26 nonprogressive clear cell RCC (ccRCC)-SRM cases, in addition to 26 healthy controls. We identified six proteins, which displayed significantly elevated expression in clear cell RCC-SRMs (ccRCC-SRMs) relative to healthy controls. Proteins C12ORF49 and EHD4 showed significantly elevated expression in ccRCC-SRMs compared to renal oncocytoma (≤4 cm). Additionally, proteins EPS8L2, CHMP2A, PDCD6IP, CNDP2 and CEACAM1 displayed significantly elevated expression in progressive relative to nonprogressive ccRCC-SRMs. A two-protein signature (EPS8L2 and CCT6A) showed significant discriminatory ability (areas under the curve: 0.81, 95% CI: 0.70–0.93) in distinguishing progressive from nonprogressive ccRCC-SRMs. Patients (Stage I–IV) with EPS8L2 and CCT6A mRNA alterations showed significantly shorter overall survival (p = 1.407 × 10⁻⁶) compared to patients with no alterations. Our in-depth proteomic analysis identified novel biomarkers for early-stage RCC-SRMs. Pretreatment characterization of urinary proteins may provide insight into early RCC progression and could potentially help assign patients to appropriate management strategies.     

Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients

neurogenetics - Evidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described...     

The Clinical and Prognostic Implications of Pluripotent Stem Cell Markers Expression and Their Correlation with the WNT signal pathway in Hepatocellular Carcinoma

Objectives: This study aimed to investigate the expression of SOX2, SOX9, p53, and β-catenin in hepatocellular carcinoma (HCC) and their correlation with clinicopathological parameters of prognostic importance. Materials and Methods: Seventy-five patients were enrolled in this study. All patients had full clinical and follow-up data and available paraffin blocks. Immunohistochemical analysis was performed and correlated with clinicopathological factors and patient survival. Results: We detected the positive expression of SOX2, SOX9, p53, and β-catenin in 76%, 50.7%, 50.7%, and 77.9% of HCC specimens respectively. All studied markers showed a significant increase in the expression in tumor tissue specimens compared to non-tumor tissue. Both SOX2 and SOX9 expressions were significantly associated with adverse prognostic factors in HCC. Significant positive correlations were found between SOX2 and SOX9 and both p53 and β-catenin expression (r= 0.528, 0.485 and; r = 0.253, 0.327, respectively; p < 0.0001 for both of them). Regarding survival, we found that HCC patients with positive SOX2 and SOX9 expressions had significantly shorter overall survival (p=0.0001, each). Additionally, larger tumor size, tumor grade, high stage, tumor multiplicity, presence of cirrhosis, tumor necrosis, high p53 expression, and positive β-catenin expression were independent predictors of worse survival. A multivariate Cox analysis revealed that tumor grade, stage, p53, and SOX2 expression were independent predictors of unfavorable prognosis in overall survival (p=0.0001, p=0.0001,p=0.033; and p=0.003, respectively). Conclusions: Our findings might provide an insight into SOX2 and SOX9’s role in HCC and suggest that SOX2 might be targeted for HCC therapy.     

Comparison of Clinical and Echocardiographic Outcomes After Surgical Redo Mitral Valve Replacement and Transcatheter Mitral Valve-in-Valve Therapy

Objectives

There are minimal data regarding clinical outcomes and echocardiographic findings after transcatheter mitral valve-in-valve replacement (TMVR) compared with redo surgical mitral valve replacement (SMVR).