Nonalcoholic Fatty Liver Disease and Estimated Insulin Resistance in Obese Youth: A Mendelian Randomization Analysis.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and predicts type 2 diabetes. Currently, it is uncertain whether NAFLD may directly cause IR or vice versa. OBJECTIVE: To test the hypothesis that NAFLD is causally related to IR. DESIGN AND METHODS: We performed a Mendelian randomization (MR) in 904 obese children/adolescents using an NAFLD-related genetic risk score (GRS) as an instrumental variable. We assessed NAFLD by ultrasonography and IR by homeostasis model assessment (HOMA-IR). We also interrogated the MAGIC Consortium dataset of 46 186 adults to assess the association between PNPLA3 rs738409 (ie, the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a 2-sample MR with 2 large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD). RESULTS: Nonalcoholic fatty liver disease prevalence increased by 20% for every increase in the GRS (ß-coefficient = 0.20, P < 0.001), and NAFLD was associated with ln-HOMA-IR (ß-coefficient = 0.28, P < 0.001). Thus, the expected increase in ln-HOMA-IR for every increase in the GRS (expected ß-coefficient) was 0.056 (0.28*0.20) in the case of complete NAFLD-HOMA-IR causal association, and 0.042 in the case of 75% causality. In our cohort, the GRS did not predict ln-HOMA-IR (ß-coefficient = 0.007, P = 0.75). In the MAGIC cohort, the PNPLA3 rs738409 did not associate with ln-HOMA-IR. The 2-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD. CONCLUSIONS: Our study shows that genetically-influenced NAFLD does not increase HOMA-IR, and genetically-influenced HOMA-IR does not increase the risk of NAFLD. Shared pathogenic pathways or NAFLD subtypes not "captured" by our MR design might underpin the association between NAFLD and HOMA-IR.

Wheezing preschool children with early-onset asthma reveal a specific metabolomic profile.

BACKGROUND: Many children of preschool age present with recurrent wheezing. Most of them outgrow their symptoms, while some have early-onset asthma. Aim of this prospective preliminary study was to apply a metabolomic approach to see whether biochemical-metabolic urinary profiles can have a role in the early identification of the children with asthma. METHODS: Preschool children with recurrent wheezing were recruited and followed up for 3 years, after which they were classified as cases of transient wheezing or early-onset asthma. A urine sample was collected at recruitment and analyzed using a metabolomic approach based on UPLC mass spectrometry. RESULTS: Among 34 children aged 4.0 ± 1.1 years recruited, at the end of the 3-year follow-up, 16 were classified as having transient wheezing and 16 as cases of early-onset asthma. Through a joint multivariate and univariate statistical analyses, we identified a subset of metabolomic variables that enabled the 2 groups to be clearly distinguished. The model built using the identified variables showed an AUC = 0.99 and an AUC = 0.88 on sevenfold full cross-validation (P = .002). CONCLUSIONS: Metabolomic urinary profile can discriminate preschoolers with recurrent wheezing who will outgrow their symptoms from those who have early-onset asthma. These results may pave the way to the characterization of early non-invasive biomarkers capable of predicting asthma development.

Chronic lung disease of prematurity: long-term respiratory outcome.

Chronic respiratory morbidity is a common adverse outcome of preterm birth, especially in infants who develop bronchopulmonary dysplasia (BPD), which is still a major cause of long-term lung dysfunction with a heavy burden on health care services and medical resources throughout childhood. The most severely affected patients remain symptomatic even in adulthood, and this may be influenced also by environmental variables (e.g. smoking), which can contribute to persistent obstruction of airflow. Of all obstructive lung diseases in humans, BPD has the earliest onset and probably lasts the longest. Since the prevention of BPD is an elusive goal, minimizing neonatal lung injury and closely monitoring survivors remain the best courses of action. This review describes the clinical and functional changes characteristic of the long-term pulmonary sequelae of preterm birth, focusing particularly on BPD.

Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans.

Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy. From a clinical standpoint BPD subjects are characterized by recurrent respiratory symptoms, which are very frequent during the first years of life and, although becoming less severe as children grow up, they remain more common than in term-born controls throughout childhood, adolescence and into adulthood. From a functional point of view BPD subjects show a significant airflow limitation that persists during adolescence and adulthood and they may experience an earlier and steeper decline in lung function during adulthood. Interestingly, patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations during childhood and later on, suggesting that also prematurity per se has life-long detrimental effects on pulmonary function. For the time being, little is known about the presence and nature of pathological mechanisms underlying the clinical and functional picture presented by BPD survivors. Nonetheless, recent data suggest the presence of persistent neutrophilic airway inflammation and oxidative stress and it has been suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD. This hypothesis is intriguing but more pathological data are needed. A better understanding of these pathogenetic mechanisms, in fact, may be able to orient the development of novel targeted therapies or prevention strategies to improve the overall respiratory health of BPD patients.

The effect of body cooling on respiratory system mechanics and hysteresis in rats.

Literature reports and theoretical considerations suggest that body cooling may affect respiratory mechanics in vivo. To examine this hypothesis, healthy rats were studied using the end-inflation occlusion method under control conditions and after total body cooling. Respiratory mechanics parameters, hysteresis areas, the inspiratory work of breathing, and its elastic and resistive components, were calculated. After body cooling (mean rectal temperature from 36.6 ± 0.25 to 32.1 ± 0.26 °C), the ohmic and the additional visco-elastic respiratory system resistances, the hysteresis, the total inspiratory work of breathing, and its resistive components, were all increased. No significant changes were detected for the static and dynamic respiratory system elastance mean values, and the related elastic component of the work of breathing. These data indicate that body cooling increases the mechanical inspiratory work of breathing by increasing the resistive pressures dissipation. This effect is evident even for limited temperature variations, and it is suggested that it may occur in the event of accidental or therapeutic hypothermia.

Medical professional values and education: a survey on italian students of the medical doctor school in medicine and surgery.

BACKGROUND: The values such as participation/empathy, communication/sharing, self-awareness, moral integrity, sensitivity/trustfulness, commitment to ongoing professional development, and sense of duty linked to the practice of the medical professionalism were defined by various professional oaths. AIMS: The aim of this study was to evaluate how these values are considered by the students of the degree course of medicine. MATERIALS AND METHODS: Four hundred twenty three students (254 females, 169 males) taking part of the first, fourth, and fifth years of the degree course in medicine were asked to answer seven questions. Pearson's Chi-square, Wilcoxon rank sum test, and Kruskal-Wallis test were used for the statistical analysis. RESULTS: The survey showed a high level of knowledge and self-awareness about the values and skills of medical profession. In particular, the respect, accountability, and the professional skills of competence were considered fundamental in clinical practice. However, the students considered that these values not sufficiently present in their educational experience. CONCLUSIONS: Teaching methods should be harmonized with the contents and with the educational needs to ensure a more complex patient-based approach and the classical lectures of teachers should be more integrated with learning through experience methods.