Characterization of Coding Synonymous and Non-Synonymous Variants in ADAMTS13 Using Ex Vivo and In Silico Approaches

Synonymous variations, which are defined as codon substitutions that do not change the encoded amino acid, were previously thought to have no effect on the properties of the synthesized protein(s). However, mounting evidence shows that these “silent” variations can have a significant impact on protein expression and function and should no longer be considered “silent”. Here, the effects of six synonymous and six non-synonymous variations, previously found in the gene of ADAMTS13, the von Willebrand Factor (VWF) cleaving hemostatic protease, have been investigated using a variety of approaches. The ADAMTS13 mRNA and protein expression levels, as well as the conformation and activity of the variants have been compared to that of wild-type ADAMTS13. Interestingly, not only the non-synonymous variants but also the synonymous variants have been found to change the protein expression levels, conformation and function. Bioinformatic analysis of ADAMTS13 mRNA structure, amino acid conservation and codon usage allowed us to establish correlations between mRNA stability, RSCU, and intracellular protein expression. This study demonstrates that variants and more specifically, synonymous variants can have a substantial and definite effect on ADAMTS13 function and that bioinformatic analysis may allow development of predictive tools to identify variants that will have significant effects on the encoded protein

Predictors of Clinical Course and Outcomes of Acute Diverticulitis: The Role of Age and Ethnicity

Background and Objectives: Acute diverticulitis (AD) is the leading and most burdensome complication of colonic diverticulosis. However, risk factors for its development and predictors of its course are still poorly defined. In this regard, the association of a young age with a complicated course and worse outcome are still controversial. Moreover, little research has addressed the effect of ethnicity on the course of AD. The current study aimed to evaluate the impact of these variables on AD’s course and outcome in the diverse and unique ethnic landscape of Israel. Materials and Methods: We performed a retrospective review of the charts of patients with a radiologically confirmed diagnosis of AD. Patients’ outcomes and disease course, including hospitalization duration, complications, and recurrent episodes, were documented and compared among different age and ethnic groups. Multivariate analysis was performed to identify predictors of complicated AD. Results: Overall, 637 patients with AD were included, the majority (95%) had distal colon AD, and almost one quarter of them were aged less than 50 years. The majority of patients in the young age (<50) group were males (69.7%). Nonetheless, the rate of recurrent episodes (35.3% vs. 37.3%, p = 0.19), hospitalization duration (5 ± 4.7 vs. 6 ± 3.2, p = 0.09) and complications rate (17.3% vs. 13.7%; p = 0.16) were similar for both age groups. In the ethnicity group analysis, Arab minority patients had a first episode of AD at a significantly younger age compared to their Jewish counterparts (51.8 vs. 59.4 years, p < 0.001). However, factors such as a complicated course (16% vs. 15%; p = 0.08) and relapsing episode rates (33% vs. 38%; p = 0.36) did not differ significantly between groups. None of the variables, including young age and ethnic group, were predictors of complicated AD course in the multivariate analysis. Conclusion: AD is increasingly encountered in young patients, especially in ethnic minority groups, but neither ethnicity nor young age was associated with worse outcomes

Melanosis Coli: A Helpful Contrast Effect or a Harmful Pigmentation?

Background: Melanosis coli, a brown discoloration of colonic mucosa, is considered as a benign condition mainly observed in patients under chronic anthranoid laxatives. Recent data link this condition with an increased adenoma detection rate. Moreover, its tumorigenic potential and possible association with the development of colorectal cancer remains uncertain. We conducted this study to compare the polyp detection rate and colorectal cancer diagnosis in patients with melanosis against matched control group without melanosis. Patients and methods: A retrospective single-center study. Patients diagnosed with melanosis coli on colonoscopy over a 15-year period were included. Each melanosis coli patient was matched with three controls by age, gender, setting (inpatient/outpatient), and procedure’s indication. Polyp detection rate and diagnosis of colorectal cancer were recorded and compared between the groups before and after adjustment for bowel preparation. Results: A cohort of 718 patients with melanosis and 2154 controls were included. The polyp detection rates were 33.4% and 21.8% of melanosis and control groups, respectively ( P  < .001). Melanosis coli, however, was associated with less diagnosis of colorectal cancer than controls (0.3% vs 3.9%; P  < .001). In multivariate analysis, melanosis diagnosis on endoscopy was significantly associated with higher polyp detection rate (odds ratio [OR] = 1.986, 95% confidence interval [CI]: 1.626-2.425; P value < .01). Conclusions: Melanosis coli is not associated with increased diagnosis of colorectal cancer. It is associated, however, with enhanced polyp detection likely due to chromo-endoscopy-like effect