Discovering Genotype Variants in an Infant with VACTERL through Clinical Exome Sequencing: A Support for Personalized Risk Assessment and Disease Prevention.

Congenital anomalies may have an increased risk of noncommunicable diseases (NCDs) We performed a clinical exome analysis in an infant affected by "Vertebral, Anorectal, Cardiac, Tracheoesophageal, Genitourinary, and Limb" (VACTERL) malformation association to identify potential biomarkers that may be helpful for preventing malignancy risk or other chronic processes. Among the variants, six variants that may be linked with VACTERL were identified in the exome analysis. The variants c.501G>C on OLR1 and c.-8C>G on PSMA6 were previously associated with myocardial infarction. The variants c.1936A>G on AKAP10 and c.575A>G on PON1 are linked to defects in cardiac conduction and artery disease, respectively. Alterations in metabolism were also suggested by the variants c.860G>A on EPHX2 and c.214C>A on GHRL. In addition, three variants associated with colon cancer were discovered. Specifically, the reported variants were c.723G>A on CCND1 and c.91T>A on AURKA proto-oncogenes as well as c.827A>C in the tumor suppressor PTPRJ. A further inspection identified 15 rare variants carried by cancer genes. Specifically, these mutations are located on five tumor suppressors (SDHA, RB1CC1, PTCH1, DMBT1, BCR) and eight proto-oncogenes (MERTK, CSF1R, MYB, ROS1, PCM1, FGFR2, MYH11, BRCC3) and have an allele frequency lower than 0.01 in the Genome Aggregation Database (GnomAD). We observed that the cardiac and metabolic phenotypic traits are linked with the genotype of the patient. In addition, the risk of developing neoplasia cannot be excluded a priori. Long-term surgical issues of patients with VATER syndrome could benefit from the clinical exome sequencing of a personalized risk assessment for the appearance of further disease in pubertal timing and adult age.

Th17 and Treg Balance in Children With Obesity and Metabolically Altered Status.

Background: Chronic low-grade inflammation and activation of the immune system are hallmark pathogenic mechanisms involved in metabolic dysfunction and are related to obesity. In particular, the involvement of regulatory and pro-inflammatory lymphocyte subpopulations has been reported in adults. We evaluated the Th17/Treg lymphocyte balance in obese and normal weight children, in relation with their metabolic status. Methods: We enrolled 50 pediatric patients. According to metabolic status, subjects were classified into: metabolically healthy (MH) and metabolically unhealthy (MU) groups. MU phenotype was defined as the presence of at least one of the following risk factors: blood pressure >90th percentile, glycemia>100 mg/dl, HDL cholesterol <40 mg/dl, triglycerides>100 mg/dl (<10 years) or >130 mg/dl (>10 years), impaired insulin sensitivity with HOMA-IR>97.5th percentile. Patient Treg and Th17 profiles were also evaluated. Results: Based on the presence of metabolic and/or cardiovascular pathological parameters, we classified 15 MU (30%) and 35 MH (70%) children; all MU children were obese. Analyzing the correlations between lymphocyte subpopulations and metabolic data, we noted a correlation between Th17 percentage and systolic hypertension (p = 0.01, r = -0.37); Treg/Th17 ratio and HOMA-IR (p = 0.02, r = 0.32) and systolic hypertension (p = 0.05, r = 0.30). Conclusion: Children with obesity have a high risk of developing metabolic and cardiovascular complications. The Th17/Treg lymphocyte balance appears to be involved in glycemic homeostasis and blood pressure control. Careful and early monitoring of the immune system would facilitate new early preventive strategies in pediatric metabolic diseases.

Pain assessment in animal models: do we need further studies?

In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal-dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals.