Genetic association of single nucleotide polymorphisms of FZD4 and BDNF genes with retinopathy of prematurity

Background: Retinopathy of prematurity (ROP) is a multifactorial disease occurring in preterm neonates, caused by incorrect development of retinal blood vessels. It has been suggested that, in addition to gestational age, weight, and oxygen supplementation, genetic factors can play a role in the pathogenesis of ROP.

Methods: In the present prospective study, 97 neonates were enrolled based on the gestational age and weight, and genomic DNA from patients diagnosed with ROP and premature newborns without ROP was collected. The DNA sequence of protein coding and 5´and 3´ untranslated regions (UTRs) of the frizzled-4 (FZD4) gene and the genotype of the locus rs7934165:G?A (NM_170731.4: c.3 + 10976 C?T) within the brain-derived neurotrophic factor gene (BDNF) were determined.

Results: We detected a significant association between rs61749246:C?A (NM_012193.3: c.*2G?T) and ROP in a general genetic model as well as in a multiplicative model and by the Cochran-Armitage test for trend. Moreover, rs61749246 was strongly associated with ROP, requiring surgical intervention.

Conclusion: We suggest that rs61749246:C?A of the FZD4 gene is likely associated with the development of ROP. It is necessary to confirm this suggestion in larger studies.     

Importance of Body Water in the Efficacy of Convective Solute Transport in Online Hemodiafiltration

High‐volume online hemodiafiltration (OL‐HDF) has been associated with improved patient survival compared to conventional hemodialysis in recent trials, where the importance of convective volume (CV) in this benefit is noted. The purpose of this study was to determine the corporal composition parameters influencing the efficacy of CV in the removal of different molecular weight (MW) molecules. Demographic data, corporal composition parameters with bioimpedance spectroscopy, dialysis features and the reduction rates of different MW molecules in a four‐hour OL‐HDF session were collected in 61 patients. We observed a significant negative correlation of β2‐microglobulin, cystatin‐C, myoglobin and prolactin reduction rates with body surface area, weight, total body extracellular (ECW) and intracellular water (ICW), lean tissue mass and body cellular mass. The multivariable regression analysis identified ECW and ICW as the only corporal composition factors independently associated to the relative elimination of β2‐microglobulin (Beta: –0.801, P = 0.002 for ECW and Beta: –1.710, P = 0.001 for ICW), cystatin‐C (Beta: –0.656, P = 0.010 for ECW and Beta: –1.511, P = 0.004 for ICW) and myoglobin (Beta: –0.745, P = 0.014 for ECW and Beta: –2.103, P = 0.001 for ICW), in addition to CV. Prolactin reduction was only associated with ICW (Beta: –1.540, P = 0.028). When adjusting CV with ECW and ICW, only the ratio CV/ECW was an independent predictor for higher elimination of β2‐microglobulin, cystatin‐C and myoglobin. The corporal composition parameters independently associated to the reduction of medium‐sized molecules are the extracellular and intracellular water. The ratio “convective volume/extracellular water” predicts higher efficacy of convective transport. Adjusting the convective volume to patient features could be useful to monitor the efficacy of OL‐HDF and to prescribe individualized therapies.     

Subjective and Objective Measures of Dryness Symptoms in Primary Sjögren's Syndrome: Capturing the Discrepancy

Objective

To develop a novel method for capturing the discrepancy between objective tests and subjective dryness symptoms (a sensitivity scale) and to explore predictors of dryness sensitivity.

Methods

Archive data from the UK Primary Sjögren's Syndrome Registry (n = 688) were used. Patients were classified on a scale from ?5 (stoical) to +5 (sensitive) depending on the degree of discrepancy between their objective and subjective symptoms classes. Sensitivity scores were correlated with demographic variables, disease‐related factors, and symptoms of pain, fatigue, anxiety, and depression.

Results

Patients were on average relatively stoical for both types of dryness symptoms (mean ± SD ocular dryness ?0.42 ± 2.2 and ?1.24 ± 1.6 oral dryness). Twenty‐seven percent of patients were classified as sensitive to ocular dryness and 9% to oral dryness. Hierarchical regression analyses identified the strongest predictor of ocular dryness sensitivity to be self‐reported pain and that of oral dryness sensitivity to be self‐reported fatigue.

Conclusion

Ocular and oral dryness sensitivity can be classified on a continuous scale. The 2 symptom types are predicted by different variables. A large number of factors remain to be explored that may impact symptom sensitivity in primary Sjögren?s syndrome, and the proposed method could be used to identify relatively sensitive and stoical patients for future studies.

     

Late-onset islet autoimmunity in childhood: the Diabetes Autoimmunity Study in the Young (DAISY)

Aims/hypothesis

We sought to assess the frequency, determinants and prognosis for future diabetes in individuals with islet autoimmunity and whether these factors differ depending on the age of onset of islet autoimmunity.

Methods

A prospective cohort (n = 2547) of children from the general population who had a high-risk HLA genotype and children who had a first-degree relative with type 1 diabetes were followed for up to 21 years. Those with the persistent presence of one or more islet autoantibodies were categorised as early-onset (<8 years of age, n = 143, median 3.3 years) or late-onset (≥8 years of age, n = 64, median 11.1 years), and were followed for a median of 7.4 and 4.7 years, respectively. Progression to diabetes was evaluated by Kaplan–Meier analysis with logrank test. Factors associated with progression to diabetes were analysed using the parametric accelerated failure time model.

Results

Children with late-onset islet autoimmunity were more likely to be Hispanic or African-American than non-Hispanic white (p = 0.004), and less likely to be siblings of individuals with type 1 diabetes (p = 0.04). The frequencies of the HLA-DR3/4 genotype and non-HLA gene variants associated with type 1 diabetes did not differ between the two groups. However, age and HLA-DR3/4 were important predictors of rate of progression to both the presence of additional autoantibodies and type 1 diabetes. Late-onset islet autoimmunity was more likely to present with a single islet autoantibody (p = 0.01) and revert to an antibody-negative state (p = 0.01). Progression to diabetes was significantly slower in children with late-onset islet autoimmunity (p < 0.001).

Conclusions/interpretation

A late onset of islet autoimmunity is more common in African-American and Hispanic individuals. About half of those with late-onset islet autoimmunity progress to show multiple islet autoantibodies and develop diabetes in adolescence or early adulthood. Further investigation of environmental determinants of late-onset autoimmunity may lead to an understanding of and ability to prevent adolescent and adult-onset type 1 diabetes.