Validating the NIH LDL-C equation for provincial implementation in Alberta.

BACKGROUND: LDL-C, a cardiovascular disease risk assessment biomarker, is commonly calculated using the Friedewald equation. The NIH equation overcomes several limitations of the Friedewald equation. Consistent with the Canadian Society of Clinical Chemists (CSCC) lipid reporting recommendations, we assessed the NIH LDL-C equation in Alberta prior to its provincial implementation. METHODS: 1-year (01/01/2021-12/31/2021) of lipid results (n = 1,486,584 after data cleaning) were obtained from five analytical instrument groups used across Alberta. Analyses were performed on all data and after separating by age, analytical instrument group, and fasting status. The correlation between Friedewald- and NIH-calculated LDL-C and between Friedewald- and NIH-calculated LDL-C difference and each lipid parameter, was determined. The frequency of unreportable/inaccurate LDL-C results was compared between the two equations. The concordance between the two equations and with non-HDL-C was determined at LDL-C thresholds. Lastly, LDL-C calculated by Friedewald, NIH, and Martin-Hopkins equations was compared to density-gradient ultracentrifugation. RESULTS: Friedewald- and NIH-calculated LDL-C exhibit the strongest correlation when triglycerides ≤ 4.52 mmol/L. The difference between Friedewald- and NIH-calculated LDL-C increases with decreasing LDL-C concentration. The NIH equation yields fewer inaccurate results (0.35 % vs. 22.0 %). The percent agreement between equations was > 96 % at all LDL-C thresholds, suggesting most patients will not require treatment changes. NIH-calculated LDL-C exhibited better agreement with non-HDL-C when triglycerides ≤ 9.04 mmol/L and better correlated with LDL-C measured by ultracentrifugation (r2 = 0.926 vs. 0.775 (Friedewald) and 0.863 (Martin-Hopkins)). Results were consistent across age, analytical instrument group, and fasting status. CONCLUSIONS: Our findings demonstrate the benefits of implementing the NIH equation across Alberta.

European consensus statement on expert colposcopy.

BACKGROUND: Following the publication of the European consensus statement on standards for essential colposcopy in 2020, the need for standards relating to more complex and challenging colposcopy practice was recognised. These standards relate to colposcopy undertaken in patients identified through cervical screening and tertiary referrals from colposcopists who undertake standard colposcopy only. This set of recommendations provides a review of the current literature and agreement on care for recognised complex cases. With good uptake of human papillomavirus (HPV) immunisation, we anticipate a marked reduction in cervical disease over the next decade. Still, the expert colposcopist will continue to be vital in managing complex cases, including previous cervical intraepithelial neoplasia (CIN)/complex screening histories and multi-zonal disease. AIMS: To provide expert guidance on complex colposcopy cases through published evidence and expert consensus. MATERIAL & METHODS: Members of the EFC and ESGO formed a working group to identify topics considered to be the remit of the expert rather than the standard colposcopy service. These were presented at the EFC satellite meeting, Helsinki 2021, for broader discussion and finalisation of the topics. RESULTS & DISCUSSION: The agreed standards included colposcopy in pregnancy and post-menopause, investigation and management of glandular abnormalities, persistent high-risk HPV+ with normal/low-grade cytology, colposcopy management of type 3 transformation zones (TZ), high-grade cytology and normal colposcopy, colposcopy adjuncts, follow-up after treatment with CIN next to TZ margins and follow-up after treatment with CIN with persistent HPV+, and more. These standards are under review to create a final paper of consensus standards for dissemination to all EFC and ESGO members.

[Leber hereditary optic neuropathy]. / Nasledstvennaia opticheskaia neiropatiia Lebera.

Leber hereditary optic neuropathy is characterized by bilateral, painless loss of vision in children and young adults (generally up to 25 years old). Since its first description in 1871, the understanding of its etiology and pathogenesis has improved considerably. The article considers Leber neuropathy from the points of view of ophthalmology, neurology and molecular genetics, and presents data on experimental treatment methods, one of which is undergoing clinical trial.

Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding.

Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.

Variation of HLA class II genes in the Nganasan and Ket, two aboriginal Siberian populations.

Allelic frequencies at the three most polymorphic loci of the HLA class II region (DRB1, DQA1 and DQB1) were determined in the Nganasan and Ket, the remnants of the two most ancient groups in the Lower Yenisey River/Taimyr Peninsula region in northern Siberia. By single-stranded conformational polymorphism typing, verified by sequencing, 19 HLA-DRB1-DQA1-DQB1 haplotypes and 15 HLA-DRB1, seven DQA1 and 11 DQB1 alleles were found. The most frequent alleles were DRB1*1301 (23.5%), DQA1*0103 (29.4%), *0501/03/05 (29.4%), and DQB1*0301/09 (32.4%) in the Ket, and DRB1*0901 (25%), DQA1*0301 (39.6%), and DQB1*0301/09 (37.5%) in the Nganasan. The distribution patterns and comprehensive phylogenic analysis based on the haplotype frequencies of 17 Siberian populations suggest that the founders of both the Ket and the Nganasan came from Palaeolithic populations in the Altai-Sayan Upland.

The Rossmann fold of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a nuclear docking site for antisense oligonucleotides containing a TAAAT motif.

The subcellular localisation of oligodeoxynucleotides (ODN) is a major limitation for their use against nuclear targets. In this study we demonstrate that an antisense ODN directed against cytosolic phospholipase A(2) (cPLA2) mRNA is efficiently taken up and accumulates in the nuclei of endothelial cells (HUVEC), human monocytes and HeLa cells. Gel shift experiments and incubation of cells with oligonucleotide derivatives show that the anti-cPLA2 oligo binds a 37 kDa protein in nuclear extracts. The TAAAT sequence was identified as the major binding motif for the nuclear protein in competition experiments with mutated ODNs. Modification of the AAA triplet resulted in an ODN which failed to localise in the nucleus. Moreover, inserting a TAAAT motif into an ODN localising in the cytosol did not modify its localisation. The 37 kDa protein was purified and identified after peptide sequencing as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). It was shown by confocal microscopy that GAPDH co-localises with anti-cPLA2 ODN in the nucleus and commercial GAPDH effectively binds the oligo. Competition experiments with increasing concentration of NAD(+) co-factor indicate that the GAPDH Rossmann fold is a docking site for antisense oligonucleotides containing a TAAAT motif.