Citations

With the epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The influence of a perinatal obesity‐inducing diet (OID) on the development and progression of NAFLD in offspring is important but incompletely studied. Hence, we fed breeding pairs of C57BL/6J mice during gestation and lactation (perinatally) either chow or an OID rich in fat, fructose, and cholesterol (FFC). The offspring were weaned to either chow or an FFC diet, generating four groups: perinatal (p)Chow‐Chow, pChow‐FFC, pFFC‐Chow, and pFFC‐FFC. Mice were sacrificed at 10 weeks of age. We examined the whole‐liver transcriptome by RNA sequencing (RNA‐seq) and whole‐liver genome methylation by reduced representation bisulfite sequencing (RRBS). Our results indicated that the pFFC‐FFC mice had a significant increase in hepatic steatosis, injury, inflammation, and fibrosis, as assessed histologically and biochemically. We identified 189 genes that were differentially expressed and methylated in the pFFC‐FFC mice versus the pChow‐FFC mice. Gene set enrichment analysis identified hepatic fibrosis/hepatic stellate cell activation as the top canonical pathway, suggesting that the differential DNA methylation events in the mice exposed to the FFC diet perinatally were associated with a profibrogenic transcriptome. To verify that this finding was consistent with perinatal nutritional reprogramming of the methylome, we exposed pFFC‐Chow mice to an FFC diet in adulthood. These mice developed significant hepatic steatosis, injury, inflammation, and more importantly fibrosis when compared to the appropriate controls.Conclusion: Perinatal exposure to an OID primes the immature liver for an accentuated fibrosing nonalcoholic steatohepatitis (NASH) phenotype, likely through nutritional reprogramming of the offspring methylome. These data have potential clinical implications for monitoring children of obese mothers and risk stratification of children with NAFLD.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Background: Intima-media thickness (IMT) has been proposed as a measurement of subclinical atherosclerosis and has been associated with cardiovascular disease (CVD). Epicardial adipose tissue (EAT) is a fat depot between the pericardium and myocardium and has been associated with coronary atherosclerosis. The relationship between IMT and EAT thickness has not been reported before. We investigated the relationship between EAT thickness, IMT, CVD risk factors, and ideal cardiovascular health (CVH) metrics using subjects from the Kardiovize Brno 2030 cohort study, a random urban sample population in Central Europe. Methods: We studied 102 individuals (65 males) aged 25–64 years (median = 37 years) with no current or past CVD history. We measured IMT using a vascular ultrasound and EAT thickness using transthoracic echocardiography, and collected data on anthropometric factors, CVD risk factors, and CVH score. Correlation tests and multiple linear regression models were applied. Results: In the age- and gender-adjusted model, we demonstrated that, among CVD risk factors, only BMI was significantly and positively associated with EAT thickness (β = 0.182, SE = 0.082, p = 0.030), while no significant associations with IMT were evident. Although both EAT thickness and IMT were negatively correlated with CVH score (r = −0.45, p < 0.001, and r = −0.38, p < 0.001, respectively), we demonstrated that overall CVH score (β = −0.262; SE = 0.077; p = 0.001), as well as BMI (β = −1.305; SE = 0.194; p < 0.001) and blood pressure CVH metrics (β = −0.607; SE = 0.206; p = 0.004) were significantly associated with EAT thickness but not with IMT. Conclusions: Our study is important as it demonstrated for the first time that CVH is associated with EAT thickness. Interestingly, this relationship seems to be dependent on BMI and blood pressure rather than on the other CVH metrics. However, outcome-driven studies are required to confirm these findings.

Background: The prevalence of smoking among mental health and addiction (MHA) patients is 3 times higher than it is in the general population, yet this patient population has received little help to combat smoking. Considering this, psychosocial care centers (CAPS – Centros de Atenção Psicossocial) are strategic locations for integrating tobacco dependence treatment (TDT) into existing treatment activities. Methods: Our team provided an 8-hour training package to the staff of CAPS that have not been providing specialized TDT for smokers. Our curriculum included the following topics focused on the implementation of treatment for MHA smokers: management, epidemiology, medications, psychotherapy, and smoking/mental health assessment instruments. Results: Our team trained the staff of 17 CAPS units within 10 cities – which included more than 186 health professionals. There were many barriers encountered as we provided this training. A summary of problems we faced were as follows: resistance to incorporating TDT in addiction/mental health-care units, resistance to the implementation of cognitive-behavioral therapy (CBT) (psychodynamic therapy and harm reduction were preferred) and treatment for smoking is already implemented in primary care network; resistance to the use of medication in addiction treatment (a preference for psychotherapy and psychosocial approach). Conclusion: We learned a number of important lessons as we worked to improve the delivery of TDT to MHA patients in Brazil: provide clinicians an opportunity to explore how they feel/think about providing TDT to their clients at the very outset of the training, rather than focusing on a specific type of behavioral therapy for TDT (such as CBT), which some may find objectionable; use more generic descriptions of behavioral therapy such as ‘supportive counseling’; include training professionals who are open to other forms of behavioral therapy in addition to psychoanalysis and discuss the important impact that MHA units can have in improving the quality of life for their patients who smoke.

AbstractComputational fluid dynamics (CFD) has been studied as a tool for the stratification of aneurysm rupture risk. We performed CFD analysis in a patient operated on for a ruptured anterior communicating artery aneurysm. The point of rupture was identified during surgery. The aneurysm and blood vessels were segmented from computed tomography angiography to prepare a model for simulations. We found that the streamlines showed a concentrated inflow jet directed straight at the rupture point, and high wall shear stress was found at the point of rupture in the aneurysm sac. Thus specific local hemodynamics may be indicative of the aneurysm rupture site.