Reference Charts for Fetal Cerebellar Vermis Height: A Prospective Cross-Sectional Study of 10605 Fetuses

Objective

To establish reference charts for fetal cerebellar vermis height in an unselected population.

Methods

A prospective cross-sectional study between September 2009 and December 2014 was carried out at ALTAMEDICA Fetal–Maternal Medical Centre, Rome, Italy. Of 25203 fetal biometric measurements, 12167 (48%) measurements of the cerebellar vermis were available. After excluding 1562 (12.8%) measurements, a total of 10605 (87.2%) fetuses were considered and analyzed once only. Parametric and nonparametric quantile regression models were used for the statistical analysis. In order to evaluate the robustness of the proposed reference charts regarding various distributional assumptions on the ultrasound measurements at hand, we compared the gestational age-specific reference curves we produced through the statistical methods used. Normal mean height based on parametric and nonparametric methods were defined for each week of gestation and the regression equation expressing the height of the cerebellar vermis as a function of gestational age was calculated. Finally the correlation between dimension/gestation was measured.

Results

The mean height of the cerebellar vermis was 12.7mm (SD, 1.6mm; 95% confidence interval, 12.7–12.8mm). The regression equation expressing the height of the CV as a function of the gestational age was: height (mm) = -4.85+0.78 x gestational age. The correlation between dimension/gestation was expressed by the coefficient r = 0.87.

Conclusion

This is the first prospective cross-sectional study on fetal cerebellar vermis biometry with such a large sample size reported in literature. It is a detailed statistical survey and contains new centile-based reference charts for fetal height of cerebellar vermis measurements.     

Biochemical characterization and structural analysis of a new cold-active and salt-tolerant esterase from the marine bacterium <Emphasis Type="Italic">Thalassospira</Emphasis> sp.

A gene encoding an esterase, ThaEst2349, was identified in the marine psychrophilic bacterium Thalassospira sp. GB04J01. The gene was cloned and overexpressed in E. coli as a His-tagged fusion protein. The recombinant enzyme showed optimal activity at 45 °C and the thermal stability displayed a retention of 75 % relative activity at 40 °C after 2 h. The optimal pH was 8.5 but the enzyme kept more than 75 % of its maximal activity between pH 8.0 and 9.5. ThaEst2349 also showed remarkable tolerance towards high concentrations of salt and it was active against short-chain p-nitrophenyl esters, displaying optimal activity with the acetate. The enzyme was tested for tolerance of organic solvents and the results are suggesting that it could function as an interesting candidate for biotechnological applications. The crystal structure of ThaEst2349 was determined to 1.69 Å revealing an asymmetric unit containing two chains, which also is the biological unit. The structure has a characteristic cap domain and a catalytic triad comprising Ser158, His285 and Asp255. To explain the cold-active nature of the enzyme, we compared it against thermophilic counterparts. Our hypothesis is that a high methionine content, less hydrogen bonds and less ion pairs render the enzyme more flexible at low temperatures.     

Genetic variations of NOD2 and MD2 genes in hepatitis B virus infection

Objectives: Nucleotide oligomerization domain 2 (NOD2) and myeloid differentiation protein 2 (MD-2) have crucial roles in the innate immune system. NOD2 is a member of the NOD-like receptor (NLR) family of pattern recognition receptors (PRRs), while MD-2 is a co-receptor for Toll-like receptor 4 (TLR4), which comprises another group of PRRs. Genetic variations in the NOD2 and MD-2 genes may be susceptibility factors to viral pathogens including hepatitis B virus (HBV). We investigated whether polymorphisms at NOD2 (rs2066845 and rs2066844) or at MD-2 (rs6472812 and rs11466004) were associated with susceptibility to HBV infection and advancement to related liver complications in a Saudi Arabian population. Methods: A total of 786 HBV-infected patients and 600 healthy uninfected controls were analyzed in the present study. HBV-infected patients were categorized into three groups based on the clinical stage of the infection: inactive HBV carriers, active HBV carriers, and patients with liver cirrhosis + hepatocellular carcinoma (HCC). Results: All four SNPs were significantly associated with susceptibility to HBV infection although none of the SNPs tested in NOD2 and MD-2 were significantly associated with persistence of HBV infection. We found that HBV-infected patients that were homozygous CC for rs2066845 in the NOD2 gene were at a significantly increased risk of progression to HBV-related liver complications (Odds Ratio = 7.443 and P = 0.044). Furthermore, haplotype analysis found that the rs2066844-rs2066845 C-G and T-G haplotypes at the NOD2 gene and four rs6472812-rs11466004 haplotypes (G-C, G-T, A-C, and A-T) at the MD-2 gene were significantly associated with HBV infection in the affected cohort compared to those found in our control group. Conclusion: We found that the single nucleotide polymorphisms rs2066844 and rs2066845 at NOD2 and rs6472812 and rs11466004 at MD-2 were associated with susceptibility to HBV infection in a Saudi population.     

MicroRNAs expression profiles as diagnostic biomarkers of gastric cancer: a systematic literature review

Objective: The early identification of gastric cancer (GC) represents a major clinical challenge. We conducted a systematic review of studies evaluating the miRNA expression profiling as a diagnostic tool in GC.

Methods: We performed a search of PubMed, ISI Web of Science and SCOPUS databases for studies on diagnostic miRNAs and GC, published in English up to October 2017. Eligibility criteria included case-control studies evaluating blood or tissue-based miRNA expression profiles, and incorporating at least two detection phases (screening and validation).

Results: We included 27 eligible studies, that reported on 97 deregulated miRNAs either in blood or tissue, out of which 30 were reported in at least two studies. Among 22 studies on tissue-diagnostic miRNAs, 13 consistently upregulated miRNAs (miR-214, miR-21, miR-103, miR-107, miR-196a, miR-196b, miR-7, miR-135b, miR-222, miR-23b, miR-25, miR-92 and miR-93), and six consistently downregulated miRNAs (miR-148a, miR-375, miR-133b, miR-30a, miR-193a and miR-204) were reported. Ten miRNAs with inconsistent direction of expression in tissues were identified. Among the five studies performed on blood samples, only one miRNA was consistently upregulated (miR-20a).

Conclusions: This review shows that some tissue or blood miRNAs may be considered as potential biomarkers for GC diagnosis, that urgently needs to be confirmed from large prospective studies.     

Dual Role of Mitochondrial Porin in Metabolite Transport across the Outer Membrane and Protein Transfer to the Inner Membrane

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Characterization of reemerging chikungunya virus

An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host.     

Methylglyoxal accumulation de-regulates HoxA5 expression,thereby impairing angiogenesis in glyoxalase 1 knock-down mouse aortic endothelial cells

Impaired angiogenesis leads to long-term complications and is a major contributor of the high morbidity in patients with Diabetes Mellitus (DM). Methylglyoxal (MGO) is a glycolysis byproduct that accumulates in DM and is detoxified by the Glyoxalase 1 (Glo1). Several studies suggest that MGO contributes to vascular complications through mechanisms that remain to be elucidated. In this study we have clarified for the first time the molecular mechanism involved in the impairment of angiogenesis induced by MGO accumulation.Angiogenesis was evaluated in mouse aortic endothelial cells isolated from Glo1-knockdown mice (Glo1KD MAECs) and their wild-type littermates (WT MAECs). Reduction in Glo1 expression led to an accumulation of MGO and MGO-modified proteins and impaired angiogenesis of Glo1KD MAECs. Both mRNA and protein levels of the anti-angiogenic HoxA5 gene were increased in Glo1KD MAECs and its silencing improved both their migration and invasion. Nuclear NF-?B-p65 was increased 2.5-fold in the Glo1KD as compared to WT MAECs. Interestingly, NF-?B-p65 binding to HoxA5 promoter was also 2-fold higher in Glo1KD MAECs and positively regulated HoxA5 expression in MAECs. Consistent with these data, both the exposure to a chemical inhibitor of Glo1 “SpBrBzGSHCp2” (GI) and to exogenous MGO led to the impairment of migration and the increase of HoxA5 mRNA and NF-?B-p65 protein levels in microvascular mouse coronary endothelial cells (MCECs).This study demonstrates, for the first time, that MGO accumulation increases the antiangiogenic factor HoxA5 via NF-?B-p65, thereby impairing the angiogenic ability of endothelial cells.