The Ciliogenic Transcription Factor RFX3 Regulates Early Midline Distribution of Guidepost Neurons Required for Corpus Callosum Development

The corpus callosum (CC) is the major commissure that bridges the cerebral hemispheres. Agenesis of the CC is associated with human ciliopathies, but the origin of this default is unclear. Regulatory Factor X3 (RFX3) is a transcription factor involved in the control of ciliogenesis, and Rfx3–deficient mice show several hallmarks of ciliopathies including left–right asymmetry defects and hydrocephalus. Here we show that Rfx3–deficient mice suffer from CC agenesis associated with a marked disorganisation of guidepost neurons required for axon pathfinding across the midline. Using transplantation assays, we demonstrate that abnormalities of the mutant midline region are primarily responsible for the CC malformation. Conditional genetic inactivation shows that RFX3 is not required in guidepost cells for proper CC formation, but is required before E12.5 for proper patterning of the cortical septal boundary and hence accurate distribution of guidepost neurons at later stages. We observe focused but consistent ectopic expression of Fibroblast growth factor 8 (Fgf8) at the rostro commissural plate associated with a reduced ratio of GLIoma-associated oncogene family zinc finger 3 (GLI3) repressor to activator forms. We demonstrate on brain explant cultures that ectopic FGF8 reproduces the guidepost neuronal defects observed in Rfx3 mutants. This study unravels a crucial role of RFX3 during early brain development by indirectly regulating GLI3 activity, which leads to FGF8 upregulation and ultimately to disturbed distribution of guidepost neurons required for CC morphogenesis. Hence, the RFX3 mutant mouse model brings novel understandings of the mechanisms that underlie CC agenesis in ciliopathies

Associated tears of the lateral meniscus in anterior cruciate ligament injuries: risk factors for different tear patterns

BACKGROUND: The pattern of lateral meniscus tears observed in anterior cruciate ligament (ACL)-injured subjects varies greatly and determines subsequent management. Certain tear patterns with major biomechanical consequences should be repaired in a timely manner. Knowledge about risk factors for such tears may help to identify patients in the early posttraumatic phase and subsequently may improve clinical results. METHODS: A database of 268 patients undergoing primary ACL reconstruction was used to identify all patients with isolated ACL tears and patients with an associated tear of the lateral meniscus. Patients who underwent surgery >6 months after the injury were excluded. Based on the arthroscopic appearance of the lateral meniscus, patients were assorted to one of three groups: ‘no tear,’ ‘minor tear,’ and ‘major tear.’ Tear patterns defined as major included root tears, complete radial tears, and unstable longitudinal tears including bucket-handle tears. Univariate analysis was performed by comparing the three groups with regard to gender, age, height, weight, BMI, type of injury (high-impact sport, low-impact sport, and not sports related), and mechanism of injury (non-contact vs. contact). Multivariate logistic regression was carried out to identify independent risk factors for minor and major meniscal tears and to calculate odds ratios (OR). RESULTS: Two hundred fifteen patients met the inclusion and exclusion criteria. Of those, 56% had isolated ACL tears, 27% had associated minor tears, and 17% had associated major tears of the lateral meniscus. Univariate analysis revealed significant differences between the three groups for gender (p = 0.002), age groups (p = 0.026), and mechanism of injury (p < 0.001). A contact injury mechanism was a risk factor for minor tears (OR: 4.28) and major tears (OR: 18.49). Additional risk factors for major tears were male gender (OR: 7.38) and age <30 years (OR: 5.85). CONCLUSION: Male patients, patients <30 years, and particularly patients who sustained a contact injury have a high risk for an associated major lateral meniscus tear. Special attention is therefore necessary in those patients and early referral to magnetic resonance imaging and/or arthroscopy is recommended to allow meniscus repair in a timely manner

Physical activity in older age: perspectives for healthy ageing and frailty.

Regular physical activity helps to improve physical and mental functions as well as reverse some effects of chronic disease to keep older people mobile and independent. Despite the highly publicised benefits of physical activity, the overwhelming majority of older people in the United Kingdom do not meet the minimum physical activity levels needed to maintain health. The sedentary lifestyles that predominate in older age results in premature onset of ill health, disease and frailty. Local authorities have a responsibility to promote physical activity amongst older people, but knowing how to stimulate regular activity at the population-level is challenging. The physiological rationale for physical activity, risks of adverse events, societal and psychological factors are discussed with a view to inform public health initiatives for the relatively healthy older person as well as those with physical frailty. The evidence shows that regular physical activity is safe for healthy and for frail older people and the risks of developing major cardiovascular and metabolic diseases, obesity, falls, cognitive impairments, osteoporosis and muscular weakness are decreased by regularly completing activities ranging from low intensity walking through to more vigorous sports and resistance exercises. Yet, participation in physical activities remains low amongst older adults, particularly those living in less affluent areas. Older people may be encouraged to increase their activities if influenced by clinicians, family or friends, keeping costs low and enjoyment high, facilitating group-based activities and raising self-efficacy for exercise

Estimating glenoid width for instability-related bone loss: A CT evaluation of an MRI formula

© 2014 The Author(s). Background: Determining the magnitude of glenoid bone loss in cases of shoulder instability is an important step in selecting the optimal reconstructive procedure. Recently, a formula has been proposed that estimates native glenoid width based on magnetic resonance imaging (MRI) measurements of height (1/3 3 glenoid height + 15 mm). This technique, however, has not been validated for use with computed tomography (CT), which is often the preferred imaging modality to assess bone deficiencies. Purpose: The purpose of this project was 2-fold: (1) to determine if the MRI-based formula that predicts glenoid width from height is valid with CT and (2) to determine if a more accurate regression can be resolved for use specifically with CT data. Study Design: Descriptive laboratory study. Methods: Ninety normal shoulder CT scans with preserved osseous anatomy were drawn from an existing database and analyzed. Measurements of glenoid height and width were performed by 2 observers on reconstructed 3-dimensional models. After assessment of reliability, the data were correlated, and regression models were created for male and female shoulders. The accuracy of the MRI-based model\u27s predictions was then compared with that of the CT-based models. Results: Intra- and interrater reliabilities were good to excellent for height and width, with intraclass correlation coefficients of 0.765 to 0.992. The height and width values had a strong correlation of 0.900 (P\u3c.001). Regression analyses for male and female shoulders produced CT-specific formulas: for men, glenoid width = 2/3 3 glenoid height + 5 mm; for women, glenoid width = 2/3 3 glenoid height 1 3 mm. Comparison of predictions from the MRI- and CT-specific formulas demonstrated good agreement (intraclass correlation coefficient = 0.818). The CT-specific formulas produced a root mean squared error of 1.2 mm, whereas application of the MRI-specific formula to CT images resulted in a root mean squared error of 1.5 mm. Conclusion: Use of the MRI-based formula on CT scans to predict glenoid width produced estimates that were nearly as accurate as the CT-specific formulas. The CT-specific formulas, however, are more accurate at predicting native glenoid width when applied to CT data. Clinical Relevance: Imaging-specific (CT and MRI) formulas have been developed to estimate glenoid bone loss in patients with instability. The CT-specific formula can accurately predict native glenoid width, having an error of only 2.2% of average glenoid width