Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant

The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls.As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010.10:g.43582056T?>?C; genotype TT, OR?=?17.31, P?=?1.462?×?10^?21). Previously published associations in variants in SEMA (rs11766001, NC_000007.13:g.84145202A?>?C; allele C, OR?=?2.268, P?=?0.009533) and NRG1 (rs4541858, NC_000008.10:g.32410309A?>?G; allele G, OR?=?1.567, P?=?0.015; rs7835688, NC_000008.10:g.32411499G?>?C; allele C, OR?=?1.567, P?=?0.015) were also replicated in the genome-wide association analysis. Sequencing revealed a total of 12 exonic RET rare variants. Of these, eight amino acid changing rare variants and two frameshift variants caused or possibly caused Hirschsprung disease.Only a minority of the Hirschsprung disease cases (9/30 familial; 7/75 sporadic) carried one of the rare variants. Excluding the rare variant carriers from the genome-wide association analysis did not appreciably change the association of rs2435357 with Hirschsprung disease. We estimate that approximately two thirds of the sporadic cases may be statistically attributed to the recessive action of the common non-coding RET variants. Thus, even though most cases do not carry rare RET variants, combinations of rare variants and the common non-coding RET variant cause the majority of the cases in our population.     

Ten-year experience with transcatheter and surgical aortic valve replacement in Finland

Aim: We investigated the outcomes of transcatheter (TAVR) and surgical aortic valve replacement (SAVR) in Finland during the last decade.

Methods: The nationwide FinnValve registry included data from 6463 patients who underwent TAVR or SAVR with a bioprosthesis for aortic stenosis from 2008 to 2017.

Results: The annual number of treated patients increased three-fold during the study period. Thirty-day mortality declined from 4.8% to 1.2% for TAVR (p?=?.011) and from 4.1% to 1.8% for SAVR (p?=?.048). Two-year survival improved from 71.4% to 83.9% for TAVR (p?<?.001) and from 87.2% to 91.6% for SAVR (p?=?.006). During the study period, a significant reduction in moderate-to-severe paravalvular regurgitation was observed among TAVR patients and a reduction of the rate of acute kidney injury was observed among both SAVR and TAVR patients. Similarly, the rate of red blood cell transfusion and severe bleeding decreased significantly among SAVR and TAVR patients. Hospital stay declined from 10.4?±?8.4 to 3.7?±?3.4 days after TAVR (p?<?.001) and from 9.0?±?5.9 to 7.8?±?5.1 days after SAVR (p?<?.001).

Conclusions: In Finland, the introduction of TAVR has led to an increase in the invasive treatment of severe aortic stenosis, which was accompanied by improved early outcomes after both SAVR and TAVR.

Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03385915

• Key Messages

• This study demonstrated that the introduction of transcatheter aortic valve replacement has led to its widespread use as an invasive treatment for severe aortic stenosis.

• Early and 2-year survival after transcatheter and surgical aortic valve replacement has improved during past decade.

• Transcatheter aortic valve replacement has fulfilled its previously unmet clinical needs and has surpassed surgical aortic valve replacement as the most common invasive treatment for aortic stenosis.

     

One-stage repair of cardiac and arch anomalies without circumlatory arrest

Indian Journal of Thoracic and Cardiovascular Surgery -     

腺病毒载体介导的PML生长抑制因子对前列腺癌细胞生长和致瘤能力的抑制效果

为探讨用腺病毒载体携带ＰＭＬ（ＰｒｏｍｙｅｌｏｃｙｔｉｃＬｅｕｋｅｍｉａ）基因作为前列腺癌基因治疗的可能性，应用重组人携带ＰＭＬ基因腺病毒（ＡｄＰＭＬ）感染培养的前列腺癌细胞，观察表达ＰＭＬ蛋白的癌细胞与对照组癌细胞的体外生长和裸鼠体内致瘤能力变化，对荷瘤裸鼠瘤体周围注射ＡｄＰＭＬ，观察治疗组和对照组肿瘤生长的变化。结果显示，感染ＡｄＰＭＬ的前列腺癌细胞体外生长和裸鼠体内致瘤能力明显下降，荷瘤裸鼠瘤体周围注射ＡｄＰＭＬ后肿瘤生长速度明显减慢。证实了ＰＭＬ是一种生长抑制因子，提示其可能被应用于前列腺癌的基因治疗研究     

Effect of directorial intervention on web-based student feedback

The Medical Faculty of the University of Helsinki decided to employ a web-based evaluation system as an integral and essential part of all courses beginning in the autumn term of 2006.
Objectives:  To analyse the effects of the intervention on dental students' web-based responses at the University of Helsinki, Finland.
Subjects and Methods:  A previously developed web-based tool was used for all preclinical and clinical courses from the beginning of the 2006—2007 academic year. We analysed data sets of student feedback for all courses before (2005—2006) and after (2006—2007) the intervention. We then compared the quantity and quality of the students' feedback for the six standardised questions used in the evaluation, and calculated the means and standard deviations of values obtained with a Likert scale. The students' assessments in the open questions were categorised according to key issues.
Results:  Implementation of the system resulted in a considerable increase in student feedback: the mean response rate for the preclinical phase rose from 59% (SD 15.0; range 25—80) before the intervention to 90% (SD 9.6; range 72—100) after it. In the clinical phase, the response rates more than doubled from 34% (SD 15.9; range 9—69) to 73% (SD 12.9; range 45—100). The students' assessments showed no significant change despite the marked rise in response rates. The educators' positive attitude towards the students was appreciated (4.2—4.3) whereas the general goals for the courses in the clinical phase seemed unclear to the students (3.4) ( P  < 0.05).
Conclusions:  Web-based evaluation as an integral part of all courses in the dental curriculum proved successful: shortly after the intervention, we observed a considerable increase in student feedback with no significant change in quality.     

Human oral keratinocyte E‐cadherin degradation by Candida albicans and Candida glabrata

J Oral Pathol Med (2010) 39 : 275–278 Background: E‐cadherin (E‐Cad) is a 120‐kDa adhesive protein found in adherens junctions of the digestive tract epithelium. We tested the ability of two Candida strains to degrade human E‐Cad in the Candida virulence factor perspective. Materials and methods: We set out to study oral mucosal E‐Cad degradation by clinical and reference strains of Candida albicans and Candida glabrata. We also included hyphal and secreted aspartic proteinase (Sap) mutants of C. albicans to test the effect of yeast/hyphal transition on the ability to degrade E‐Cad. The tests were performed at pH 4 and pH 6 to determine the effect of local tissue acidity on the activation of Saps. The C. albicans strains used were: CCUG 32723; clinical strain SC5314 which is known to be strongly invasive; hyphal mutants of SC5314: HLC52 (efg1/efg1), HLC54 (cph1/cph1 efg1/efg1) and JKC19 (cph1/cph1); clinical strain B1134; Sap 1–3 and Sap 4–6 mutants of SC5314. The C. glabrata strains used were ATCC 90030, and the clinical strains 5WT and G212. Results: The sonicated yeast cells of C. albicans JKC19 and SC5314, both in hyphal form, degraded E‐Cad at pH 4. The 10× concentrated growth media of the strains HLC‐52, HLC‐54, 32723 and B1134; all in yeast form, caused degradation at pH 4, HLC‐52 and HLC‐54 also at pH 6. The C. glabrata strains did not degrade E‐Cad. Conclusions: pH is a strain dependent triggering factor in activating yeast or hyphal form related Candida Saps in degrading epithelial cell associated E‐Cads.