Variant type and position predict two distinct limb phenotypes in patients with GLI3-mediated polydactyly syndromes

Introduction: Pathogenic DNA variants in the GLI-Kruppel family member 3 (GLI3) gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-Type 4 (PPD4) and Pallister-Hall syndrome. Out of these, Pallister-Hall is a different entity, but the distinction between Greig syndrome and PPD4 is less evident. Using latent class analysis (LCA), our study aimed to investigate the correlation between reported limb anomalies and the reported GLI3 variants in these GLI3-mediated polydactyly syndromes. We identified two subclasses of limb anomalies that relate to the underlying variant. Methods: Both local and published cases were included for analysis. The presence of individual limb phenotypes was dichotomised and an exploratory LCA was performed. Distribution of phenotypes and genotypes over the classes were explored and subsequently the key predictors of latent class membership were correlated to the different clustered genotypes. Results: 297 cases were identified with 127 different variants in the GLI3 gene. A two-class model was fitted revealing two subgroups of patients with anterior versus posterior anomalies. Posterior anomalies were observed in cases with truncating variants in the activator domain (postaxial polydactyly; hand, OR: 12.7; foot, OR: 33.9). Multivariate analysis supports these results (Beta: 1.467, p=0.013 and Beta: 2.548, p<0.001, respectively). Corpus callosum agenesis was significantly correlated to these variants (OR: 8.8, p<0.001). Conclusion: There are two distinct phenotypes within the GLI3-mediated polydactyly population: Anteriorly and posteriorly orientated. Variants that likely produce haploinsufficiency are associated with anterior phenotypes. Posterior phenotypes are associated with truncating variants in the activator domain. Patients with these truncating variants have a greater risk for corpus callosum anomalies

Vectorial secretion of interleukin-8 mediates autocrine signalling in intestinal epithelial cells via apically located CXCR1

BACKGROUND: In the intestinal mucosa, several adaptations of TLR signalling have evolved to avoid chronic inflammatory responses to the presence of commensal microbes. Here we investigated whether polarized monolayers of intestinal epithelial cells might regulate inflammatory responses by secreting IL-8 in a vectorial fashion (i.e. apical versus basolateral) depending on the location of the TLR stimulus. RESULTS: In the Caco-2 BBE model of polarized villus-like epithelium, apical stimulation with TLR2 and TLR5 ligands resulted in the apical secretion of IL-8. The CXCR1 receptor for IL-8 was expressed only on the apical membrane of Caco-2 BBE cells and differentiated epithelial cells in the human small intestine and colon. Transcriptome analyses revealed that Caco-2 BBE cells respond to stimulation with IL-8 supporting the hypothesis that IL-8 induces G protein-coupled receptor signalling. CONCLUSIONS: These results show that IL-8 induces autocrine signalling via an apical CXCR1 in Caco-2 BBE intestinal epithelial cells and that this receptor is also expressed on the apical surface of differentiated human intestinal epithelial cells in vivo, suggesting an autocrine function for IL-8 secreted in the lumen

Cartilage intermediate layer protein 1 (CILP1): a novel mediator of cardiac extracellular matrix remodelling

Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r2¿=¿0.83) and non-structural (e.g. TGFB3 r2¿=¿0.75) ECM proteins. Gene enrichment analysis further underscored the involvement of CILP1 in human cardiac ECM remodelling and TGFß signalling. Myocardial CILP1 protein levels were significantly elevated in human infarct tissue and in aortic valve stenosis patients. CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Cardiac fibroblasts were found to be the primary source of cardiac CILP1 expression. Recombinant CILP1 inhibited TGFß-induced ¿SMA gene and protein expression in cardiac fibroblasts. In addition, CILP1 overexpression in HEK293 cells strongly (5-fold p¿<¿0.05) inhibited TGFß signalling activity. In conclusion, our study identifies CILP1 as a new cardiac matricellular protein interfering with pro-fibrotic TGFß signalling, and as a novel sensitive marker for cardiac fibrosis

Preoperative Indicators of the Effectiveness of Surgical Release in Patients with de Quervain Disease:A Prospective Cohort Study

Background: A significant proportion of patients report persistent pain after surgical release for de Quervain disease (DQ). This study aimed to investigate the effectiveness of a surgical release for DQ and to identify the preoperative factors associated with pain after a surgical release for DQ. Methods: This prospective cohort study included 707 patients who underwent surgical release and completed a visual analogue scale questionnaire (VAS; range 0 to 100). We used a paired t test to analyze the effectiveness of the surgical release on pain at 3 months postoperatively compared with the preoperative measure. A hierarchical multivariable linear regression model was created to investigate the contribution of patient-related and disease-related characteristics to postoperative pain. Results: All VAS domains showed improvement after surgical release. On average, the mean VAS pain decreased by 44 points (95% CI, 42, 46). Smoking (B = 6.37; P &lt; 0.01), younger age (B = -0.35; P &lt; 0.01), longer duration of complaints (B = 0.13; P &lt; 0.01), concomitant surgery (B = 14.40; P &lt; 0.01), and higher VAS pain scores at intake (B = 0.15; P &lt; 0.01) were associated with worse VAS pain scores postoperatively. Together, the variables explained 11% of the variance in mean VAS pain score at 3 months follow-up. Conclusions: This study confirms that surgical treatment for DQ significantly reduces patient-reported pain. Smoking, younger age, concomitant surgery, duration of complaints, and higher VAS pain scores at intake are associated with worse patient-reported pain 3 months after surgical release. However, the small effects suggest that these factors should not be considered the only important factors. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.</p

Patient-Reported Outcomes and Function after Surgical Repair of the Ulnar Collateral Ligament of the Thumb

Purpose: The purpose of this study was to report prospectively collected patient-reported outcomes of patients who underwent open thumb ulnar collateral ligament (UCL) repair and to find risk factors associated with poor patient-reported outcomes. Methods: Patients undergoing open surgical repair for a complete thumb UCL rupture were included between December 2011 and February 2021. Michigan Hand Outcomes Questionnaire (MHQ) total scores at baseline were compared to MHQ total scores at three and 12 months after surgery. Associations between the 12-month MHQ total score and several variables (i.e., sex, injury to surgery time, K-wire immobilization) were analyzed. Results: Seventy-six patients were included. From baseline to three and 12 months after surgery, patients improved significantly with a mean MHQ total score of 65 (standard deviation [SD] 15) to 78 (SD 14) and 87 (SD 12), respectively. We did not find any differences in outcomes between patients who underwent surgery in the acute (&lt;3 weeks) setting compared to a delayed setting (&lt;6 months). Conclusions: We found that patient-reported outcomes improve significantly at three and 12 months after open surgical repair of the thumb UCL compared to baseline. We did not find an association between injury to surgery time and lower MHQ total scores. This suggests that acute repair for full-thickness UCL tears might not always be necessary. Type of study/level of evidence: Therapeutic II.</p

Carbohydrate mouth rinse: does it improve endurance exercise performance?

It is well known that carbohydrate (CHO) supplementation can improve performance in endurance exercises through several mechanisms such as maintenance of glycemia and sparing endogenous glycogen as well as the possibility of a central nervous-system action. Some studies have emerged in recent years in order to test the hypothesis of ergogenic action via central nervous system. Recent studies have demonstrated that CHO mouth rinse can lead to improved performance of cyclists, and this may be associated with the activation of brain areas linked to motivation and reward. These findings have already been replicated in other endurance modalities, such as running. This alternative seems to be an attractive nutritional tool to improve endurance exercise performance

The Angio-Fibrotic Switch of VEGF and CTGF in Proliferative Diabetic Retinopathy

BACKGROUND: In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring. METHODS/PRINCIPAL FINDINGS: VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment. CONCLUSIONS/SIGNIFICANCE: CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy

Intestinal fatty-acid binding protein and gut permeability responses to exercise

Purpose Intestinal cell damage due to physiological stressors (e.g. heat, oxidative, hypoperfusion/ischaemic) may contribute to increased intestinal permeability. The aim of this study was to assess changes in plasma intestinal fatty acid-binding protein (I-FABP) in response to exercise (with bovine colostrum supplementation, Col, positive control) and compare this to intestinal barrier integrity/permeability (5 h urinary lactulose/rhamnose ratio, L/R). Methods In a double-blind, placebo-controlled, crossover design, 18 males completed two experimental arms (14 days of 20 g/day supplementation with Col or placebo, Plac). For each arm participants performed two baseline (resting) intestinal permeability assessments (L/R) pre-supplementation and one post-exercise following supplementation. Blood samples were collected pre- and post-exercise to determine I-FABP concentration. Results Two-way repeated measures ANOVA revealed an arm?×?time interaction for L/R and I-FABP (P?<?0.001). Post hoc analyses showed urinary L/R increased post-exercise in Plac (273% of pre, P?<?0.001) and Col (148% of pre, P?<?0.001) with post-exercise values significantly lower with Col (P?<?0.001). Plasma I-FABP increased post-exercise in Plac (191% of pre-exercise, P?=?0.002) but not in the Col arm (107%, P?=?0.862) with post-exercise values significantly lower with Col (P?=?0.013). Correlations between the increase in I-FABP and L/R were evident for visit one (P?=?0.044) but not visit two (P?=?0.200) although overall plots/patterns do appear similar for each. Conclusion These findings suggest that exercise-induced intestinal cellular damage/injury is partly implicated in changes in permeability but other factors must also contribute

Laxative effects of partially defatted flaxseed meal on normal and experimental constipated mice

<p>Abstract</p> <p>Background</p> <p>Constipation is a very common health problem in the world. Intake of sufficient amount of dietary fibers is a cornerstone in the prevention and treatment of constipation. As a traditional medicine, flaxseed has been used to treat constipation for centuries, but the controlled trials are rare. The purpose of the present study was to assess that whether partially defatted flaxseed meal (PDFM) has the potential role to facilitate fecal output in normal and experimental constipated mice.</p> <p>Methods</p> <p>After supplemented with 2.5%, 5% and 10% (w/w) PDFM (L-, M- and H -PDFM) for 14 days, the constipation models of mice were induced by atropine-diphenoxylate. The small intestinal transit rates, start time of defecation, amount of defecation and wet weight of feces were researched in normal and constipation model mice.</p> <p>Results</p> <p>M- and H-PDFM significantly increase small intestinal transit rates in constipation model mice. All dose of PDFM markedly shortened the start time of defecation and M- and H-PDFM significantly increase stool frequency and weight in both normal and constipation model mice.</p> <p>Conclusions</p> <p>PDFM may be a useful laxative to facilitate fecal output in normal and constipation conditions.</p