Circulating micrornas correlate with multiple myeloma and skeletal osteolytic lesions

Multiple myeloma (MM) is the second most frequent hematological disease and can cause skeletal osteolytic lesions. This study aims to evaluate the expression of circulating microRNAs (miR-NAs) in MM patients and to correlate those levels with clinicopathological features, including bone lesions. A panel of miRNAs associated with MM onset and progression, or with bone remodeling, was analyzed in the plasma of 82 subjects (47 MM patients; 35 healthy controls). Results show that miR-16-5p, miR-20a-5p, and miR-21-5p are differently expressed between MM patients and healthy controls. Receiver operating characteristic analyses indicate that their combined expression has potential as a molecular marker (Area Under the Curve, AUC of 0.8249). Furthermore, significant correlations were found between the analyzed miRNAs and disease stage, treatment, ß2 microglobulin, serum albumin and creatinine levels, but not with calcium levels or genetic alterations. In this cohort, 65.96% of MM patients had bone lesions, the majority of which were in the vertebrae. Additionally, miR-29c-3p was decreased in patients with osteolytic lesions compared with patients without bone disease. Interestingly, circulating levels of miR-29b-3p correlated with cervical and thoracic vertebral lesions, while miR-195-5p correlated with thoracic lesions. Our findings suggest circulating miRNAs can be promising biomarkers for MM diagnosis and that their levels correlate with myeloma bone disease and osteolytic lesions.The project was supported by AO Spine-ESA Grant Award 2018 (AO Foundation); As-sociação Portuguesa Contra a Leucemia, Sociedade Portuguesa de Hematologia, AMGEN; and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-031402-R2Bone (FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation—POCI, Portugal 2020)

Genomic analysis of ERVWE2 locus in patients with multiple sclerosis: absence of genetic \ud association but potential role of human endogenous retrovirus type W elements in \ud molecular mimicry with myelin antigen

Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5' LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesisThis research was made possible by FAPESP, project number 2010/10619-0

Women’s pelvic floor muscle strength and urinary and anal incontinence after childbirth: a cross-sectional study

Abstract OBJECTIVE To analyse pelvic floor muscle strength (PFMS) and urinary and anal incontinence (UI and AI) in the postpartum period. METHOD Cross-sectional study carried out with women in their first seven months after child birth. Data were collected through interviews, perineometry (Peritron™), and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). RESULTS 128 women participated in the study. The PFMS mean was 33.1 (SD=16.0) cmH2O and the prevalence of UI and AI was 7.8% and 5.5%, respectively. In the multiple analyses, the variables associated with PFMS were type of birth and cohabitation with a partner. Newborn’s weight, previous pregnancy, UI during pregnancy, and sexual activity showed an association with UI after child birth. Only AI prior to pregnancy was associated with AI after childbirth. CONCLUSION Vaginal birth predisposes to the reduction of PFMS, and caesarean section had a protective effect to its reduction. The occurrence of UI during pregnancy is a predictor of UI after childbirth, and women with previous pregnancies and newborns with higher weights are more likely to have UI after childbirth.AI prior to pregnancy is the only risk factor for its occurrence after childbirth. Associations between PFMS and cohabitation with a partner, and between UI and sexual activity do not make possible to conclude that these variables are directly associated

Fracturing ranked surfaces

Discretized landscapes can be mapped onto ranked surfaces, where every element (site or bond) has a unique rank associated with its corresponding relative height. By sequentially allocating these elements according to their ranks and systematically preventing the occupation of bridges, namely elements that, if occupied, would provide global connectivity, we disclose that bridges hide a new tricritical point at an occupation fraction $p=p_{c}$, where $p_{c}$ is the percolation threshold of random percolation. For any value of $p$ in the interval $p_{c}< p \leq 1$, our results show that the set of bridges has a fractal dimension $d_{BB} \approx 1.22$ in two dimensions. In the limit $p \rightarrow 1$, a self-similar fracture is revealed as a singly connected line that divides the system in two domains. We then unveil how several seemingly unrelated physical models tumble into the same universality class and also present results for higher dimensions

Binding Truths: Atypical anti-GBM disease mediated by IgA anti-GBM antibodies targeting the α1 chain of type IV collagen

Anti−glomerular basement membrane (anti-GBM) disease presents with rapidly progressive glomerulonephritis, often associated with alveolar hemorrhage and characterized histologically by crescentic glomerulonephritis. Typically, there is linear deposition of Ig along the glomerular basement membrane (GBM), which, in the majority of cases, is due to IgG autoantibodies directed against the noncollagenous domain of the α3 chain of type IV collagen (α3[IV]NC1).1 Early disease recognition relies on detecting circulating IgG anti-GBM antibodies in serum samples. However, conventional assays do not detect IgA antibodies or those directed against other target antigens, including α5(IV) found in some Alport disease patients following renal transplantation.2 The presence and specificity of the antibody can be confirmed by Western blotting, usually at a reference center, although this is not routinely performed. We describe a case of anti-GBM disease mediated by IgA anti-GBM antibodies not detected by standard serological tests, and suggest a method of detection and monitoring that can be used in the right clinical context

Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission

Cytokines and intrathecal IgG synthesis were determined in the cerebrospina fluid (CSF) and sera to evaluate inflammatory activity in multiple sclerosis (MS) patients during clinical remission. Although the disease was stable, there had been a significant increase of proinflammatory cytokines such as TNF alpha and IFN gamma in the CSF and serum, with no significant changes of IL12 and IL10 production. The changes in the cytokine production patterns were associated with an increase of leukocytes in the CSF, as well as the presence of oligoclonal bands suggesting intrathecal IgG synthesis. These results suggest that even when the disease is clinically silent, one can observe inflammatory activity in these MS patients.63491491

Living biointerfaces based on non-pathogenic bacteria to direct cell differentiation

Genetically modified Lactococcus lactis, non-pathogenic bacteria expressing the FNIII7-10 fibronectin fragment as a protein membrane have been used to create a living biointerface between synthetic materials and mammalian cells. This FNIII7-10 fragment comprises the RGD and PHSRN sequences of fibronectin to bind α5β1 integrins and triggers signalling for cell adhesion, spreading and differentiation. We used L. lactis strain to colonize material surfaces and produce stable biofilms presenting the FNIII7-10 fragment readily available to cells. Biofilm density is easily tunable and remains stable for several days. Murine C2C12 myoblasts seeded over mature biofilms undergo bipolar alignment and form differentiated myotubes, a process triggered by the FNIII7-10 fragment. This biointerface based on living bacteria can be further modified to express any desired biochemical signal, establishing a new paradigm in biomaterial surface functionalisation for biomedical applications

Endotracheal intubation skill acquisition by medical students

During the course of their training, medical students may receive introductory experience with advanced resuscitation skills. Endotracheal intubation (ETI – the insertion of a breathing tube into the trachea) is an example of an important advanced resuscitation intervention. Only limited data characterize clinical ETI skill acquisition by medical students. We sought to characterize medical student acquisition of ETI procedural skill.11Presented as a poster discussion on 17 October 2007 at the annual meeting of the American Society of Anesthesiologists in San Francisco, CA.The study included third-year medical students participating in a required anesthesiology clerkship. Students performed ETI on operating room patients under the supervision of attending anesthesiologists. Students reported clinical details of each ETI effort, including patient age, sex, Mallampati score, number of direct laryngoscopies and ETI success. Using mixed-effects regression, we characterized the adjusted association between ETI success and cumulative ETI experience.ETI was attempted by 178 students on 1,646 patients (range 1–23 patients per student; median 9 patients per student, IQR 6–12). Overall ETI success was 75.0% (95% CI 72.9–77.1%). Adjusted for patient age, sex, Mallampati score and number of laryngoscopies, the odds of ETI success improved with cumulative ETI encounters (odds ratio 1.09 per additional ETI encounter; 95% CI 1.04–1.14). Students required at least 17 ETI encounters to achieve 90% predicted ETI success.In this series medical student ETI proficiency was associated with cumulative clinical procedural experience. Clinical experience may provide a viable strategy for fostering medical student procedural skills