Refinement of the HIVAN1 Susceptibility Locus on Chr. 3A1-A3 via Generation of Sub-Congenic Strains

HIV-1 transgenic mice on the FVB/NJ background (TgFVB) represent a validated model of HIV-associated nephropathy (HIVAN). A major susceptibility locus, HIVAN1, was previously mapped to chromosome 3A1-A3 in a cross between TgFVB and CAST/EiJ (CAST) strains, and introgression of a 51.9 Mb segment encompassing HIVAN1 from CAST into TgFVB resulted in accelerated development of nephropathy. We generated three sub-congenic strains carrying CAST alleles in the proximal or distal regions of the HIVAN1 locus (Sub-II, 3.02–38.93 Mb; Sub-III, 38.45–55.1 Mb and Sub-IV, 47.7–55.1 Mb, build 38). At 5–10 weeks of age, histologic injury and proteinuria did not differ between HIV-1 transgenic Sub-II and TgFVB mice. In contrast, HIV-1 transgenic Sub-III and Sub-IV mice displayed up to 4.4 fold more histopathologic injury and 6-fold more albuminuria compared to TgFVB mice, similar in severity to the full-length congenic mice. The Sub-IV segment defines a maximal 7.4 Mb interval for HIVAN1, and encodes 31 protein coding genes: 15 genes have missense variants differentiating CAST from FVB, and 14 genes show differential renal expression. Of these, Frem1, Foxo1, and Setd7 have been implicated in the pathogenesis of nephropathy. HIVAN1 congenic kidneys are histologically normal without the HIV-1 transgene, yet their global transcriptome is enriched for molecular signatures of apoptosis, adenoviral infection, as well as genes repressed by histone H3 lysine 27 trimethylation, a histone modification associated with HIV-1 life cycle. These data refine HIVAN1to 7.4 Mb and identify latent molecular derangements that may predispose to nephropathy upon exposure to HIV-1

Is vitamin D status a determining factor for metabolic syndrome? A case-control study

This study was undertaken to assess vitamin D status in nonmenopausal women with metabolic syndrome (MeS) and to evaluate its possible role in inflammation and other components of MeS. A case-control study was conducted during late fall and winter 2009–10. A total of 375 women with waist circumference (WC) ≥88 cm were examined to find 100 who met MeS criteria according to the National Cholesterol Education Program (NCEP)/Adult Treatment Panel (ATP) III criteria (NCEP/ATP III). Of those without MeS, 100 age- and residence area-matched women were selected as a control group. Anthropometric and laboratory evaluations were performed. Waist-to-hip ratio (WHR), body mass index (BMI), homeostatic model of insulin resistance (HOMA-IR) and body fat mass (FM) were also evaluated. Women with MeS had significantly higher BMI, waist circumference (WC) and FM but lower serum osteocalcin than controls. There was no significant difference in serum 25 hydroxyvitamin D (25[OH]D), intact parathyroid hormone (iPTH) or vitamin D status between the two groups. Serum highly sensitive C-reactive protein (hsCRP) concentration was significantly higher in the MeS group, compared to the controls (3.4 ± 3.3 vs 2.0 ± 1.9 mg/L, P < 0.001). The difference remained significant even after controlling for BMI (P = 0.011), WC (P = 0.014) and FM (P = 0.005). When comparison was made only in those subjects with insulin resistance (HOMA-IR > 2.4), hsCRP was still higher in the MeS group (n = 79) than in the control group (n = 61) (P < 0.001). When data were categorized according to vitamin D status, in the MeS group significantly higher plasma glucose concentrations were observed in subjects with vitamin D deficiency compared to those with insufficiency or sufficiency (104.0 ± 11.7, 83.0 ± 11.3 and 83.2 ± 9.9 mg/dL, respectively, P < 0.001). Interestingly, their WC or WHR did not show any significant difference. In stepwise regression analysis, 25(OH)D was the main predictor of both hsCRP and plasma glucose. Vitamin D status may, at least in part, be a determining factor of systemic inflammation and the related metabolic derangements of MeS

Investigating the effect of perceived authenticity, destination image and memorable experience on the intention of visiting tourists again (Case study: Ardabil city)

urban destinations can achieve a sustainable competitive advantage by increasing the number of new tourist visits. Research has shown that in the long run, attracting re-visits costs less than visiting a destination for the first time. Therefore, the sustainable growth of the tourism sector relies more on tourists who repeat their visits. Such a factor has added to the importance of the concepts affecting the re-visit of urban tourism destinations. In this research, an attempt has been made to evaluate and analyze the effect of perceived originality, destination image and memorable experience on the intention of tourists to visit Ardabil again. The present study is applied in terms of purpose and descriptive-analytical in terms of method and the statistical population of this study is incoming tourists to Ardabil in 1398. The required sample size was considered using the Cochran's formula and 384 people. The questionnaire used in the research has been made by a researcher whose indicators have been obtained and localized from related studies and backgrounds. Validity and reliability of the research model and data analysis were performed using structural equation modeling and confirmatory factor analysis in SMART PLS software. Findings showed that the perceived authenticity of tourist attractions has a positive and significant effect on the image of destinations and memorable experience. The destination image also has a positive and significant effect on the memorable experience. Finally, the findings showed that a memorable experience has a positive and significant effect on the intention to visit again

A Panel of Serum Biomarkers Differentiates IgA Nephropathy from Other Renal Diseases

Background and Objectives: There is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). In the present study, we assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN. Materials and Methods: We compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgAN patients, 79 patients with non-IgAN chronic kidney disease (CKD) controls and 106 healthy controls. Serum was collected at the time of kidney biopsy from all IgAN and CKD patients. Results: Each serum marker was significantly elevated in IgAN patients compared to CKD (P<0.001) and healthy controls (P<0.001). While 41% of IgAN patients had elevated serum Gd-IgA1 levels, 91% of these patients exhibited Gd-IgA1-specific IgG levels above the 90th percentile for healthy controls (sensitivity 89%, specificity 92%). Although up to 25% of CKD controls, particularly those with immune-mediated glomerular diseases including lupus nephritis, also had elevated serum levels of Gd-IgA1-specific IgG, most IgAN patients had elevated levels of Gd-IgA1-specific antibody of both isotypes. Serum levels of Gd-IgA1-specific IgG were associated with renal histological grading. Furthermore, there was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria (≥1.0 g/g), compared to patients with less proteinuria. Conclusions Serum levels of Gd-IgA1-specific antibodies are elevated in most IgAN patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgAN from other glomerular diseases

Case Report of a Vanished Aspirated Foreign Body; Cough may be more Helpful

Foreign body aspiration is a potentially life-threatening event especially in those who are younger than 5 years old. Aspiration could be presented as a spectrum, ranging from absolutely asymptomatic event to more sever events including choking, respiratory distress and cyanosis or even death. Although foreign bodies in lung may not be visualized on X-ray, X-ray radiography is considered as a first step in localizing aspirated foreign bodies. Bronchoscope as rigid or flexible optic fiber is the main device used in removing aspirated foreign bodies. However, in some cases, as the present case report, previous foreign bodies which were localized in lung could travel back to the mouth and be ingested. In this report, we discussed a case of foreign body aspiration in a 10 year-old girl referred to Dr. Sheikh Hospital, Mashhad, Iran, whose foreign body located in the lower lobe of the left lung returned and was ingested before bronchoscopy after some episodes of sever coughing

A Retrotransposon Insertion in the 5' Regulatory Domain of Ptf1a Results in Ectopic Gene Expression and Multiple Congenital Defects in Danforth’s Short Tail Mouse

Danforth's short tail mutant (Sd) mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2. Resequencing of this region identified an 8.5-kb early retrotransposon (ETn) insertion within the highly conserved regulatory sequences upstream of Pancreas Specific Transcription Factor, 1a (Ptf1a). This mutation resulted in up to tenfold increased expression of Ptf1a as compared to wild-type embryos at E9.5 but no detectable changes in the expression levels of other neighboring genes. At E9.5, Sd mutants exhibit ectopic Ptf1a expression in embryonic progenitors of every organ that will manifest a developmental defect: the notochord, the hindgut, and the mesonephric ducts. Moreover, at E 8.5, Sd mutant mice exhibit ectopic Ptf1a expression in the lateral plate mesoderm, tail bud mesenchyme, and in the notochord, preceding the onset of visible defects such as notochord degeneration. The Sd heterozygote phenotype was not ameliorated by Ptf1a haploinsufficiency, further suggesting that the developmental defects result from ectopic expression of Ptf1a. These data identify disruption of the spatio-temporal pattern of Ptf1a expression as the unifying mechanism underlying the multiple congenital defects in Danforth's short tail mouse. This striking example of an enhancer mutation resulting in profound developmental defects suggests that disruption of conserved regulatory elements may also contribute to human malformation syndromes

Predicting Progression of IgA Nephropathy: New Clinical Progression Risk Score

IgA nephropathy (IgAN) is a common cause of end-stage renal disease (ESRD) in Asia. In this study, based on a large cohort of Chinese patients with IgAN, we aim to identify independent predictive factors associated with disease progression to ESRD. We collected retrospective clinical data and renal outcomes on 619 biopsy-diagnosed IgAN patients with a mean follow-up time of 41.3 months. In total, 67 individuals reached the study endpoint defined by occurrence of ESRD necessitating renal replacement therapy. In the fully adjusted Cox proportional hazards model, there were four baseline variables with a significant independent effect on the risk of ESRD. These included: eGFR [HR = 0.96(0.95–0.97)], serum albumin [HR = 0.47(0.32–0.68)], hemoglobin [HR = 0.79(0.72–0.88)], and SBP [HR = 1.02(1.00–1.03)]. Based on these observations, we developed a 4-variable equation of a clinical risk score for disease progression. Our risk score explained nearly 22% of the total variance in the primary outcome. Survival ROC curves revealed that the risk score provided improved prediction of ESRD at 24th, 60th and 120th month of follow-up compared to the three previously proposed risk scores. In summary, our data indicate that IgAN patients with higher systolic blood pressure, lower eGFR, hemoglobin, and albumin levels at baseline are at a greatest risk of progression to ESRD. The new progression risk score calculated based on these four baseline variables offers a simple clinical tool for risk stratification