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Background: Generalized joint hypermobility is an inherited collagen phenotype based on clinical assessments of joint mobility. However, there is no international consensus to define generalized joint hypermobility, both considering which joint mobility tests should be included and limits for joint hypermobility., Objectives: The primary aim of the study was to identify a subset of joint mobility tests to define generalized joint hypermobility. A further aim was to evaluate standardized limits for the classification of hypermobility in different joint types throughout the body., Methods: A total of 255 early pregnant women were included in the study. Joint mobility was measured according to a structured protocol. Correlation and principal component analysis were used to find a subset of joint mobility tests. To classify hypermobility in each joint mobility test, five different standard deviation levels plus 0.84, plus 1.04, plus 1.28, plus 1.64 and plus 2 were used, corresponding to 20%, 15%, 10%, 5% and 2.5% of the normal distribution., Results: No subset of joint mobility test could define generalized joint hypermobility. The higher the standard deviation levels, the higher the limit to classify joint hypermobility and the lower the prevalence. As a result of no subset of joint mobility tests were found to define generalized joint hypermobility, different combinations of major and minor joints in upper and lower limbs and the axial skeleton, were systematically developed. These combinations were evaluated for each standard deviation level, resulting in a prevalence of generalized joint hypermobility between 0% and 12.9% and a clear variation in how the hypermobile joint mobility tests were distributed., Conclusion: It is probably not possible to choose a subset of joint mobility tests to define GJH. In order not to overlook generalized joint hypermobility, a broader assessment of different joint types and sizes of joints appears to be needed. The prevalence of generalized joint hypermobility is dependent on joint hypermobility limit and the chosen combination of joint mobility tests., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schlager et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Molecular targeted therapy using a drug that suppresses the growth and spread of cancer cells via inhibition of a specific protein is a foundation of precision medicine and treatment. High expression of the proto-oncogene Bcl-3 promotes the proliferation and metastasis of cancer cells originating from tissues such as the colon, prostate, breast, and skin. The development of novel drugs targeting Bcl-3 alone or in combination with other therapies can cure these patients or prolong their survival. As a proof of concept, in the present study, we focused on metastatic melanoma as a model system. High-throughput screening and in vitro experiments identified BCL3ANT as a lead molecule that could interfere with Bcl-3-mediated cyclin D1 expression and cell proliferation and migration in melanoma. In experimental animal models of melanoma, it was demonstrated that the use of a Bcl-3 inhibitor can influence the survival of melanoma cells. Since there are no other inhibitors against Bcl-3 in the clinical pipeline for cancer treatment, this presents a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clinical need., (© 2024. The Author(s).)

Introduction: Pelvic girdle pain (PGP) affects approximately 50% of pregnant women. The mechanisms are multifactorial but not fully understood. Women with generalized joint hypermobility (GJH) may be vulnerable to load in the pelvic joints during pregnancy. Our aim was to investigate if women with GJH had an increased risk of PGP and higher pain intensity during and after pregnancy, compared with women with normal joint mobility. We also studied if body mass index (BMI) in early pregnancy influenced that risk., Material and Methods: A prospective cohort study of 356 women, whose data were collected by self-reports and clinical examinations in early and in late pregnancy and 9 months after childbirth. GJH was present with ≥5/9 points on the Beighton score. PGP was defined by a pain drawing and ≥1 positive test. Pain intensity was measured with a visual analogue scale (0-100 mm). We adjusted for age and origin in logistic regression and ordinal logistic regression analysis., Results: In early pregnancy, 47.1% of the women with GJH had PGP vs 32.6% of women with normal joint mobility (adjusted odds ratio [aOR] 1.76; 95% confidence interval [CI] 0.86-3.62) and had higher odds of reporting higher pain intensity (aOR 2.04; 95% CI 1.02-4.07). The odds of PGP were highest for women with GJH and BMI ≥25 kg/m 2 (aOR 6.88; 95% CI 1.34-35.27) compared with women with normal joint mobility and BMI <25 kg/m 2 . The estimated associations were weaker and not statistically significant in late pregnancy or after childbirth., Conclusions: Women with GJH did not have an increased risk of PGP during or after pregnancy but reported higher pain intensity in early pregnancy compared with women with normal joint mobility. Since women with combined GJH and BMI ≥25 kg/m 2 had the highest odds of PGP in early pregnancy, our results may suggest that health care needs to pay attention to and develop methods to reduce the risk of PGP and delay the onset of pain during pregnancy in women with this combination., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: Pelvic girdle pain in pregnancy is a major public health concern. For too many women, the pain condition causes disability and sick leave, has a negative impact on daily life, and breeds doubt in their view as mother, partner, and worker. The pathophysiology is unknown and causal treatment is lacking. Depression in pregnancy is common, undertreated, and previously associated with pelvic girdle pain with unclear causal direction., Material and Methods: A prospective inception cohort study of 356 Swedish women examined them in early and late pregnancy. Women with a positive Posterior Pelvic Pain Provocation test in early pregnancy were not included. The exposure, depressive symptoms in early pregnancy, was self-reported on the Hospital Anxiety and Depression Scale, depression part (0-21). Outcome measure in late pregnancy was a graded score on the Posterior Pelvic Pain Provocation test (0-8). Covariates for statistical adjustment were identified in a directed acyclic graph. Linear robust and logistic regression were used in the statistical analyses., Results: In early pregnancy, the 248 women with negative Posterior Pelvic Pain Provocation test had a mean score of 2.35 (± 2.3 standard deviation) on the Hospital Anxiety and Depression Scale, depression part. In a fully adjusted, multiple robust regression model a positive association was shown between Hospital Anxiety and Depression Scale score, depression part, and the Posterior Pelvic Pain Provocation test score in late pregnancy with an estimated effect of β = 0.32 (95% confidence interval [CI] 0.16-0.48, p < 0.001). Dichotomization of exposure (Hospital Anxiety and Depression Scale, depression part <8/≥8) and outcome (Posterior Pelvic Pain Provocation test score 0/>0) rendered adjusted odds ratio 1.71 (95% CI 0.38-7.7) and numbers needed to treat adjusted odds ratio 5.54 (95% CI -3.4-14.5)., Conclusions: Depressive symptoms in early pregnancy were associated with the development and intensity of pelvic girdle pain in late pregnancy. Considering the small sample size, screening and treatment for depressive symptoms in early pregnancy may enable a way to reduce and prevent disabling pelvic girdle pain in late pregnancy. Trials are needed to confirm the results., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions 1-4 . How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron-sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The assessment of generalized joint hypermobility is difficult due to differences in classification methods and in the performance of joint mobility assessment. The primary aim was to evaluate the validity of the self-reported five-part questionnaire, 5PQ, for identifying generalized joint hypermobility using the Beighton score as reference test. The secondary aim was to describe how joint angles measured in degrees included in the Beighton score varied in different cut-off levels in the self-reported 5PQ and the Beighton score., Methods: A cross-sectional validity study with a total of 301 women in early pregnancy, mean age of 31 years, were included in the study. The participants answered the self-reported 5PQ before the joint angles were measured. To standardize the joint mobility measurement, a structural protocol was used. The sensitivity, specificity, receiver operating characteristic curve, area under curve, positive- and negative predictive value, positive likelihood ratio and Spearman's rank correlation between the self-reported 5PQ ≥ 2 and the Beighton score ≥ 5 were used as main outcome measures in the validity analyses. Joint angles, measured in degrees, were calculated with means in relation to different cut-off levels., Results: There was moderate correlation between the self-reported 5PQ and the Beighton score. The highest combined sensitivity, 84.1%, as well as specificity, 61.9%, was on 5PQ cut-off level ≥ 2, with a 38% false-positive rate, a moderate area under curve, a low positive predictive value and likelihood ratio, and a high negative predictive value. The odds of a self-reported 5PQ, cut-off level ≥ 2, among women with generalized joint hypermobility, Beighton ≥5, was low indicating a low post-test probability. The mean for all joint angles measured in degrees increased with increased cut-off levels, both in the Beighton score and in the self-reported 5PQ. However, there was a significant variation for each cut-off level., Conclusions: There is uncertainty in identifying generalized joint hypermobility in young women using the self-reported 5PQ with a cut-off level of ≥2 when the Beighton score ≥ 5 is used as the reference test. The strength of the self-reported 5PQ is to rule-out women without generalized joint hypermobility.

Background: Pelvic girdle pain (PGP) is common during pregnancy but the causes remain poorly understood. Generalized joint hypermobility (GJH) is an inherited trait, with joint mobility beyond normal limits and is assumed to be related with PGP. The aim of this project was to study the association between self-reported GJH and the presence of PGP during pregnancy., Methods: In this cohort study, 4884 Swedish-speaking women were consecutively recruited at their first visit for registration in the national antenatal screening programme in Sweden. We used the five-part questionnaire (5PQ) to assess GJH and pain drawings to identify PGP. Our primary outcome was the presence of PGP during the entire pregnancy and secondary outcomes were PGP in each trimesters. We tested the associations with logistic regression analysis, and adjusted for age and ethnicity., Results: In all, 2455 (50.3%) women responded to both questionnaires. The prevalence of self-reported GJH was 28.7%. A higher proportion of women with GJH than women without GJH reported PGP during the entire pregnancy (47.9% vs. 41.0%), particularly in trimester 1 (31.6% vs. 22.0%). Thus, women with GJH also had higher odds of PGP during the entire pregnancy (adjusted odds ratio (aOR) 1.27: 95% CI 1.11-1.47) and in trimester 1 (aOR 1.54: 95% CI 1.20-1.96), but the associations were not statistically significant in trimester 2 (aOR 1.24: 95% CI 0.82-1.88) or trimester 3 (aOR 1.20: 95% CI 0.99-1.45). The odds of PGP in pregnancy increased with increasing numbers of positive answers to the 5PQ (p for linear trend < 0.001) for the entire pregnancy and in trimester 1 (p for linear trend < 0.001), but not in trimesters 2 or 3 (p = 0.13 and p = 0.06, respectively)., Conclusions: Compared to women with normal joint mobility, women with GJH had higher odds of reporting PGP during pregnancy and the odds increased with number of positive responses to the 5PQ. The associations were present in trimester 1 but did not reach statistical significance in trimester 2 and 3.

Background: Comparisons across studies of generalized joint hypermobility are often difficult since there are several classification methods and methodological differences in the performance exist. The Beighton score is most commonly used and has been tested for inter- and intra-rater reliability. The Contompasis score and the Hospital del Mar criteria have not yet been evaluated for reliability. The aim of this study was to investigate the inter- and intra-rater reliability for measurements of range of motion in joints included in these three hypermobility assessment methods using a structured protocol., Methods: The study was planned in accordance with guidelines for reporting reliability studies. Healthy adults were consecutively recruited (49 for inter- and 29 for intra-rater assessments). Intra-class correlations, two-way random effects model, (ICC 2.1) with 95% confidence intervals, standard error of measurement, percentage of agreement, Cohen's Kappa (κ) and prevalence-adjusted bias-adjusted kappa were calculated for single-joint measured in degrees and for total scores., Results: The inter- and intra-rater reliability in total scores were ICC 2.1: 0.72-0.82 and 0.76-0.86 and for single-joint measurements in degrees 0.44-0.91 and 0.44-0.90, respectively. The difference between ratings was within 5 degrees in all but one joint. Standard error of measurement ranged from 1.0 to 6.9 degrees. The inter- and intra-rater reliability for prevalence of positive hypermobility findings the Cohen's κ for total scores were 0.54-0.78 and 0.27-0.78 and in single joints 0.21-1.00 and 0.19-1.00, respectively. The prevalence- and bias adjusted Cohen's κ, increased all but two values., Conclusions: Following a structured protocol, the inter- and intra-rater reliability was good-to-excellent for total scores and in all but two single joints, measured in degrees. The inter- and intra-rater reliability for prevalence of positive hypermobility findings was fair-to-almost perfect for total scores and slight-to-almost-perfect in single joints. By using a structured protocol, we attempted to standardize the assessment of range of motion in clinical and in research settings. This standardization could be helpful in the first part of the process of standardizing the tests thus avoiding that assessment of GJH is based on chance.

The canonical Wnt signaling can be silenced either through β-catenin-mediated ubiquitination and degradation or through phosphorylation of Tcf and Lef by nemo-like kinase (NLK). In the present study, we generated NLK deficient animals and found that these mice become cyanotic shortly before death because of lung maturation defects. NLK-/- lungs exhibited smaller and compressed alveoli and the mesenchyme remained thick and hyperplastic. This phenotype was caused by epithelial activation of vascular endothelial growth factor (VEGF) via recruitment of Lef1 to the promoter of VEGF. Elevated expression of VEGF and activation of the VEGF receptor through phosphorylation promoted an increase in the proliferation rate of epithelial and endothelial cells. In summary, our study identifies NLK as a novel signaling molecule for proper lung development through the interconnection between epithelial and endothelial cells during lung morphogenesis.

Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

Posttranslational modification of different proteins via direct ubiquitin attachment is vital for mediating various cellular processes. Cylindromatosis (CYLD), a deubiquitination enzyme, is able to cleave the polyubiquitin chains from the substrate and to regulate different signaling pathways. Loss, or reduced expression, of CYLD is observed in different types of human cancer, such as hepatocellular carcinoma (HCC). However, the molecular mechanism by which CYLD affects cancerogenesis has to date not been unveiled. The aim of the present study was to examine how CYLD regulates cellular functions and signaling pathways during hepatocancerogenesis. We found that mice lacking CYLD were highly susceptible to chemically induced liver cancer. The mechanism behind proved to be an elevated proliferation rate of hepatocytes, owing to sustained c-Jun N-terminal kinase 1 (JNK1)-mediated signaling via ubiquitination of TNF receptor-associated factor 2 and expression of c-MYC. Overexpression of wild-type CYLD in HCC cell lines prevented cell proliferation, without affecting apoptosis, adhesion and migration. A combined immunohistochemical and tissue microarray analysis of 81 human HCC tissues revealed that CYLD expression is negatively correlated with expression of proliferation markers Ki-67 and c-MYC. To conclude, we found that downregulation of CYLD induces tumor cell proliferation, consequently contributing to the aggressive growth of HCC. Our findings suggest that CYLD holds potential to serve as a marker for HCC progression, and its link to c-MYC via JNK1 may provide the foundation for new therapeutic strategies for HCC patients.

Tumor suppressor gene CYLD is a deubiquitinating enzyme which negatively regulates various signaling pathways by removing the lysine 63-linked polyubiquitin chains from several specific substrates. Loss of CYLD in different types of tumors leads to either cell survival or proliferation. In this study we demonstrate that lack of CYLD expression in CYLD-/- MEFs increases proliferation rate of these cells compared to CYLD+/+ in a serum concentration dependent manner without affecting cell survival. The reduced proliferation rate in CYLD+/+ in the presence of serum was due to the binding of serum response factor (SRF) to the serum response element identified in the CYLD promoter for the up-regulation of CYLD levels. The serum regulated recruitment of SRF to the CYLD promoter was dependent on p38 mitogen-activated protein kinase (MAPK) activity. Elimination of SRF by siRNA or inhibition of p38 MAPK reduced the expression level of CYLD and increased cell proliferation. These results show that SRF acts as a positive regulator of CYLD expression, which in turn reduces the mitogenic activation of serum for aberrant proliferation of MEF cells.

The oncogenic transcription factor Myc has an established role in the regulation of stem cell self-renewal and differentiation. However, the regulation of Myc activity or expression in stem and progenitor cells is not thoroughly understood. We studied the expression and function of the Myc stabilizing protein and a newly found oncogene, cancerous inhibitor of protein phosphatase 2A (CIP2A) in mouse neural progenitor cells (NPCs). We found intensive CIP2A expression in the neurogenic areas of the developing E13 as well as of the adult mouse brain. Here we also show that retroviral overexpression of CIP2A increases and siRNA silencing of CIP2A decreases NPC self-renewal and proliferation. Differentiation of the NPCs correlates with diminished CIP2A expression although overexpression of CIP2A does not prevent differentiation of neurons and astrocytes. Lastly, we demonstrate that both Myc and CIP2A enhance each other's expression and siRNA against CIP2A in Myc-overexpressing NPCs significantly reduces the ability of Myc to increase self-renewal and proliferation thus indicating a functional connection between CIP2A and Myc in NPCs., (Copyright 2010 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Background: Knee injuries end many careers among female soccer players. The number of injuries can be anticipated to increase because of the increasing popularity of the sport worldwide and the higher incidence of knee injuries among young females compared with males., Methods: In a community-based intervention trial performed from February 1 through October 31, 2007, we sought to reduce the number of knee injuries among female soccer players aged 13 to 19 years (N = 1506), representing 97 teams from 2 Swedish counties. A physical exercise program designed exclusively for female soccer players was combined with education of athletes, parents, and coaches to increase awareness of injury risk. The training program aimed to improve motor skills, body control, and muscle activation. New acute knee injuries, diagnosed by the physician, were the main outcome measure., Results: Three knee injuries occurred in the intervention group and 13 occurred in the control group, corresponding to incidence rates of 0.04 and 0.20, respectively, per 1000 player hours. The preventive program was associated with a 77% reduction in knee injury incidence (crude rate ratio, 0.23; 95% confidence interval, 0.04-0.83). The noncontact knee injury incidence rate was 90% lower in the intervention group (crude rate ratio, 0.10; 95% confidence interval, 0.00-0.70). Adjustment for potential confounders strengthened the estimates. Forty-five of the 48 intervention teams (94%) reported a high adherence of at least 75%., Conclusion: The incidence of knee injuries among young female soccer players can be reduced by implementation of a multifaceted, soccer-specific physical exercise program including education of individual players.

Mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation of multiple mtDNA deletions in affected tissues. The majority of families with autosomal dominant progressive external ophthalmoplegia (PEO) harbour mutations in genes encoding one of three well-characterized proteins--pol gamma, Twinkle or Ant 1. Here we show that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase (COX). The disorder presented with visual failure and optic atrophy in childhood, followed by PEO, ataxia, deafness and a sensory-motor neuropathy in adult life. COX-deficient skeletal muscle fibres contained supra-threshold levels of multiple mtDNA deletions, and genetic linkage, sequencing and expression analysis excluded POLG1, PEO1 and SLC25A4, the gene encoding Ant 1, as the cause. This demonstrates the importance of OPA1 in mtDNA maintenance, and implicates OPA1 in diseases associated with secondary defects of mtDNA.