Statins and non-alcoholic fatty liver disease

Dear Editor, In April 9 issue, van den Berg et al1 report interesting results on the indication for lipid‐lowering treatment in a large cohort with suspected non‐alcoholic fatty liver disease (NAFLD) within the population‐based Lifelines Cohort Study. Fatty liver index (FLI) ≥60 was used as a proxy of NAFLD and the NAFLD fibrosis score (NFS) to identify the NAFLD patients with suspected advanced fibrosis. Cardiovascular disease (CVD) risk was established by the 2016 European society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines for the Management of Dyslipidemias.2 Subjects with FLI ≥ 60 (suspected NAFLD) had an increased 10‐ year predicted cardiovascular risk compared to those with FLI < 60 with an approximately 2 times higher need for statin therapy based on CVD risk prediction and their LDL cholesterol level. Subjects with a FLI ≥ 60 were more likely to be classified with type 2 diabetes, Metabolic Syndrome (MetS), history of CVD and impaired renal function. Interestingly, estimated 10‐year very high cardiovascular risk was approximately 4 times higher in subjects with a NFS > 0.676 compared to those with the absence of advanced fibrosis. Finally, indication for statin treatment was positively associated with a FLI ≥ 60 after controlling for age, sex, current smoking, impaired renal function, and the presence of MetS and its individual components. The above results have an even greater relevance if we consider that all the subjects who were already on statin therapy were subtracted from the analysis. These findings may have an important clinical relevance and emphasize the need for effective treatment with statins in patients with NAFLD. Indeed, accumulating evidence suggests that CVD, rather than liver disease, dictates the outcomes in NAFLD.3 Besides, in most subjects NAFLD constitutes the hepatic component of MetS and numerous patients have atherogenic dyslipidemia. This study further supports the results of a previous study by our group where under prescription of statins in patients with NAFLD was observed.4 In fact, mild liver enzyme elevation remains a concern and despite its proven efficacy and safety,5 statin administration is sometimes limited by the worry about related side effects. Indeed, there is a tendency of general physicians to discourage statin use in patients with baseline elevation of serum liver enzymes and/ or to discontinue medication when minor alterations were appreciated. Of note, in our study, statin under‐use was high also in patients at very high CV risk such as those with a previous CV event. This study by van den Berg et al further stresses the issue of under prescription of statins in people with NAFLD and indication for treatment, based on CV risk class and low‐density lipoprotein cholesterol target according to ESC/EAS guidelines

“Ruminant Placental Adaptation in Early Maternal Undernutrition: An Overview”

Correct placental development during early gestation is considered the main determinant of fetal growth in late pregnancy. A reduction in maternal nourishment occurring across the early developmental window has been linked to a wide range of pregnancy disorders affecting placental transport capacity and consequently the fetal nutrient supply line, with long-term implications for offspring health and productivity. In livestock, ruminant species specifically experience maternal undernutrition in extensive systems due to seasonal changes in food availability, with significant economic losses for the farmer in some situations. In this review, we aim to discuss the effects of reduced maternal nutrition during early pregnancy on placental development with a specific focus on ruminant placenta physiology. Different types of placental adaptation strategies were examined, also considering the potential effects on the epigenetic landscape, which is known to undergo extensive reprogramming during early mammalian development. We also discussed the involvement of autophagy as a cellular degradation mechanism that may play a key role in the placental response to nutrient deficiency mediated by mammalian target of rapamycin, named the mTOR intracellular pathway

Cocaine self-administration in the mouse: A low- cost, chronic catheter preparation

Intravenous drug self-administration is the most valid animal model of human addiction because it allows volitional titration of the drug in the blood based on an individual’s motivational state together with the pharmacokinetic properties of the drug. Here we describe a reliable low-cost mouse self-administration catheter assembly and protocol that that can be used to assess a variety of drugs of abuse with a variety of protocols. We describe a method for intravenous catheter fabrication that allows for efficient and long-lasting intravenous drug delivery. The intravenous catheters remained intact and patent for several weeks allowing us to establish stable maintenance of cocaine acquisition. This was followed by a dose response study in the same mice. For collaborators interested in premade catheters for research please make a request at www.neuro-cloud.net/nature-precedings/pomerenze

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting

Long-term prediction of adherence to continuous positive air pressure therapy for the treatment of moderate/severe obstructive sleep apnea syndrome

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is a highly effective treatment for obstructive sleep apnea syndrome (OSAS). However, poor adherence is a limiting factor, and a significant proportion of patients are unable to tolerate CPAP. The aim of this study was to determine predictors of long-term non-compliance with CPAP. METHODS: CPAP treatment was prescribed to all consecutive patients with moderate or severe OSAS (AHI ≥15 events/h) (n = 295) who underwent a full-night CPAP titration study at home between February 1, 2002 and December 1, 2016. Adherence was defined as CPAP use for at least 4 h per night and five days per week. Subjects had periodical follow-up visits including clinical and biochemical evaluation and assessment of adherence to CPAP. RESULTS: Median follow-up observation was 74.8 (24.2/110.9) months. The percentage of OSAS patients adhering to CPAP was 41.4% (42.3% in males and 37.0% in females), and prevalence was significantly higher in severe OSAS than in moderate (51.8% vs. 22.1%; p < 0.001; respectively). At multivariate analysis, lower severity of OSAS (HR = 0.66; CI 95 0.46-0.94) p < 0.023), cigarette smoking (HR = 1.72; CI 95 1.13-2.61); p = 0.011), and previous cardiovascular events (HR = 1.95; CI 95 1.03-3.70; p = 0.04) were the only independent predictors of long-term non-adherence to CPAP after controlling for age, gender, and metabolic syndrome. CONCLUSIONS: In our cohort of patients with moderate/severe OSAS who were prescribed CPAP therapy, long-term compliance to treatment was present in less than half of the patients. Adherence was positively associated with OSAS severity and negatively associated with cigarette smoking and previous cardiovascular events at baseline

Solid CO_2 in low-mass young stellar objects: Comparison between Spitzer and laboratory spectra

Context. Solid interstellar CO_2 is an abundant component of ice dust mantles. Its ubiquity towards quiescent molecular clouds, as well as protostellar envelopes, has recently been confirmed by the IRS (InfraRed Spectrograph) aboard the Spitzer Space Telescope. Although it has been shown that CO_2 cannot be efficiently formed in the gas phase, the CO_2 surface formation pathway is still unclear. To date several CO_2 surface formation mechanisms induced by energetic (e.g., UV photolysis and cosmic ray irradiation) and non-energetic (e.g., cold atom addition) input have been proposed. Aims. Our aim is to investigate the contribution of cosmic ray irradiation to the formation of CO_2 in different regions of the interstellar medium (ISM). To achieve this goal we compared quantitatively laboratory data with the CO_2 bending mode band profile observed towards several young stellar objects (YSOs) and a field star by the Spitzer Space Telescope. Methods. All the experiments presented here were performed at the Laboratory for Experimental Astrophysics in Catania (Italy). The interstellar relevant samples were all irradiated with fast ions (30−200 keV) and subsequently annealed in a stainless steel high vacuum chamber (P < 10^(-7) mbar). Chemical and structural modifications of the ice samples were monitored by means of infrared spectroscopy. Laboratory spectra were then used to fit some thirty observational spectra. Results. A qualitative analysis shows that a good fit can be obtained with a minimum of two components. The choice of the laboratory components is based on the chemical-physical condition of each source. A quantitative analysis of the sources with known visual extinction (A_V) and methanol abundances highlights that the solid carbon dioxide can be efficiently and abundantly formed after ion irradiation of interstellar ices in all the selected YSOs in a time compatible with cloud lifetimes (3 × 10^7 years). Only in the case of field stars can the expected CO_2 column density formed upon energetic input not explain the observed abundances. This result, to be confirmed along the line of sight to different quiescent clouds, gives an indirect indication that CO_2 can also be formed in an early cloud stage through surface reactions induced by non-energetic mechanisms. In a later stage, when ices are exposed to higher UV and cosmic ray doses, the CO_2 total abundance is strongly affected by energetic formation mechanisms. Conclusions. Our results indicate that energetic processing of icy grain mantles significantly contribute to the formation of solid phase interstellar CO_2