Association of malalignment, muscular dysfunction, proprioception, laxity and abnormal joint loading with tibiofemoral knee osteoarthritis - a systematic review and meta-analysis

Background: To investigate (1) the association of specific biomechanical factors with knee osteoarthritis and knee osteoarthritis development, and (2) the impact of other relevant risk factors on this association.Methods: MEDLINE, EMBASE, CINAHL and SPORTDiscus were searched up until April 2017. Studies were included if they fulfilled the following criteria: the study 1) assessed the association of a biomechanical factor with knee osteoarthritis, or knee osteoarthritis development; 2) reported on skeletal malalignment, muscular dysfunction, impaired proprioception, laxity and abnormal loading during gait; 3) was a cohort study with participants developing knee osteoarthritis and participants not developing knee osteoarthritis, or a case-control or cross-sectional study with participants with knee osteoarthritis and without knee osteoarthritis. Risk of bias was assessed with the QUIPS tool and meta-analyses were performed using random effects models.Results: Of 6413 unique studies identified, 59 cross-sectional studies were eligible for meta-analyses (9825 participants, 5328 with knee osteoarthritis). No cohort studies fulfilled the inclusion criteria. Compared with healthy controls, patients with knee osteoarthritis have higher odds of having lower muscle strength, proprioception deficits, more medial varus-valgus laxity and less lateral varus-valgus laxity. Patients with medial knee osteoarthritis have higher odds of having a higher knee adduction moment than healthy controls. Level of evidence was graded as 'very low' to 'moderate' quality. Due to large between study differences moderation of other risk factors on biomechanical risk factors could not be evaluated.Conclusions: Patients with knee osteoarthritis are more likely to display a number of biomechanical characteristics. The causal relationship between specific biomechanical factors and the development of knee osteoarthritis could not be determined as no longitudinal studies were included. There is an urgent need for high quality, longitudinal studies to evaluate the impact of specific biomechanical factors on the development of knee osteoarthritis.Trial Registration: (PROSPERO ID: CRD42015025092)

Human papilloma viruses and cervical tumours: mapping of integration sites and analysis of adjacent cellular sequences

BACKGROUND: In cervical tumours the integration of human papilloma viruses (HPV) transcripts often results in the generation of transcripts that consist of hybrids of viral and cellular sequences. Mapping data using a variety of techniques has demonstrated that HPV integration occurred without obvious specificity into human genome. However, these techniques could not demonstrate whether integration resulted in the generation of transcripts encoding viral or viral-cellular sequences. The aim of this work was to map the integration sites of HPV DNA and to analyse the adjacent cellular sequences. METHODS: Amplification of the INTs was done by the APOT technique. The APOT products were sequenced according to standard protocols. The analysis of the sequences was performed using BLASTN program and public databases. To localise the INTs PCR-based screening of GeneBridge4-RH-panel was used. RESULTS: Twelve cellular sequences adjacent to integrated HPV16 (INT markers) expressed in squamous cell cervical carcinomas were isolated. For 11 INT markers homologous human genomic sequences were readily identified and 9 of these showed significant homologies to known genes/ESTs. Using the known locations of homologous cDNAs and the RH-mapping techniques, mapping studies showed that the INTs are distributed among different human chromosomes for each tumour sample and are located in regions with the high levels of expression. CONCLUSIONS: Integration of HPV genomes occurs into the different human chromosomes but into regions that contain highly transcribed genes. One interpretation of these studies is that integration of HPV occurs into decondensed regions, which are more accessible for integration of foreign DNA

Improving the Nurse-Family Partnership in Community Practice

Evidence-based preventive interventions are rarely final products. They have reached a stage of development that warrant public investment but require additional research and development to strengthen their effects. The Nurse-Family Partnership (NFP), a program of nurse home visiting, is grounded in findings from replicated randomized controlled trials

Refined physical map of the human PAX2/HOX11/NFKB2 cancer gene region at 10q24 and relocalization of the HPV6AI1 viral integration site to 14q13.3-q21.1

BACKGROUND: Chromosome band 10q24 is a gene-rich domain and host to a number of cancer, developmental, and neurological genes. Recurring translocations, deletions and mutations involving this chromosome band have been observed in different human cancers and other disease conditions, but the precise identification of breakpoint sites, and detailed characterization of the genetic basis and mechanisms which underlie many of these rearrangements has yet to be resolved. Towards this end it is vital to establish a definitive genetic map of this region, which to date has shown considerable volatility through time in published works of scientific journals, within different builds of the same international genomic database, and across the differently constructed databases. RESULTS: Using a combination of chromosome and interphase fluorescent in situ hybridization (FISH), BAC end-sequencing and genomic database analysis we present a physical map showing that the order and chromosomal orientation of selected genes within 10q24 is CEN-CYP2C9-PAX2-HOX11-NFKB2-TEL. Our analysis has resolved the orientation of an otherwise dynamically evolving assembly of larger contigs upstream of this region, and in so doing verifies the order and orientation of a further 9 cancer-related genes and GOT1. This study further shows that the previously reported human papillomavirus type 6a DNA integration site HPV6AI1 does not map to 10q24, but that it maps at the interface of chromosome bands 14q13.3-q21.1. CONCLUSIONS: This revised map will allow more precise localization of chromosome rearrangements involving chromosome band 10q24, and will serve as a useful baseline to better understand the molecular aetiology of chromosomal instability in this region. In particular, the relocation of HPV6AI1 is important to report because this HPV6a integration site, originally isolated from a tonsillar carcinoma, was shown to be rearranged in other HPV6a-related malignancies, including 2 of 25 genital condylomas, and 2 of 7 head and neck tumors tested. Our finding shifts the focus of this genomic interest from 10q24 to the chromosome 14 site

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology