Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy.

PURPOSE: Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy. METHODS: Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. RESULTS: We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. CONCLUSIONS: We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy

Correlates of physical activity and sitting time in adults with type 2 diabetes attending primary health care in Oman

Abstract Background Despite evidence of the benefits of physical activity in the management of type 2 diabetes, it is poorly addressed in diabetes care. This study aimed to identify the prevalence and correlates of meeting ≥600MET-min/wk. (150 min/wk) of physical activity and sitting time in adults with type 2 diabetes in Oman. Approaches to encourage physical activity in diabetes care were explored. Methods A cross-sectional study using the Global Physical Activity Questionnaire was conducted in 17 randomly selected primary health centres in Muscat. Clinical data including co-morbidities were extracted from the health information system. Questions on physical activity preferences and approaches were included. Patients were approached if they were ≥18 years, and had been registered in the diabetes clinic for >2 years. Results The questionnaire was completed by 305 people (females 57% and males 43%). Mean age (SD) was 57 (10.8) years and mean BMI (SD) was 31.0 (6.0) kg/m2. Duration of diabetes ranged from 2 to 25 (mean 7.6) years. Hypertension (71%) and dyslipidaemia (62%) were common comorbidities. Most (58.4%) had an HbA1c ≥7% indicating poor glycaemic control (55% in males vs 61% in females). Physical activity recommendations were met by 21.6% of the participants, mainly through leisure activities. Odds of meeting the recommendations were significantly higher in males (OR 4.8, 95% CI 2.5–9.1), individuals ≤57 years (OR 3.0, 95% CI 1.6–5.9), those at active self-reported stages of change for physical activity (OR 2.2, 95% CI 1.2–4.1) and those reporting no barriers to performing physical activity (OR 2.7, 95% CI 1.4–4.9). Median (25th, 75th percentiles) sitting time was 705 (600, 780) min/d. Older age (>57 years) was associated with longer sitting time (>705 min/d) (OR 2.8, 95% CI 1.7–4.6). Preferred methods to support physical activity in routine diabetes care were consultations (38%), structured physical activity sessions (13.4%) and referrals to physical activity facilities (5.6%) delivered by a variety of health care providers. Conclusions The results suggest that intervention strategies should take account of gender, age, opportunities within daily life to promote active behaviour and readiness to change. Offering physical activity consultations is of interest to this study population, thus development and evaluation of interventions are warranted

Oral manifestations of systemic disease

While the majority of disorders of the mouth are centred upon the direct action of plaque, the oral tissues can be subject to change or damage as a consequence of disease that predominantly affects other body systems. Such oral manifestations of systemic disease can be highly variable in both frequency and presentation. As lifespan increases and medical care becomes ever more complex and effective it is likely that the numbers of individuals with oral manifestations of systemic disease will continue to rise. The present article provides a succinct review of oral manifestations of systemic disease. In view of this article being part of a wider BDJ themed issue on the subject of oral medicine, this review focuses upon oral mucosal and salivary gland disorders that may arise as a consequence of systemic disease