Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice

Background and Aims: Increased fatty acid (FA) flux from adipose tissue to the liver contributes to the development of NAFLD. Because free FAs are key lipotoxic triggers accelerating disease progression, inhibiting adipose triglyceride lipase (ATGL)/patatin-like phospholipase domain containing 2 (PNPLA2), the main enzyme driving lipolysis, may attenuate steatohepatitis. Approach and Results: Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with methionine-choline–deficient (MCD) or high-fat high-carbohydrate (HFHC) diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis, and endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator-activated receptor (PPAR) α and PPARδ was measured. After short hairpin RNA–mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid:palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild-type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary-challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC-2 and myeloperoxidase-positive cells and low mRNA expression levels of inflammatory markers (such as IL-1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R–like endoplasmic reticulum kinase and inositol-requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. Accordingly, pretreatment of LPS-treated HepG2 cells with the PPARδ agonist GW0742 suppressed mRNA expression of inflammatory markers. Additionally, ATGL knockdown in HepG2 cells attenuated LPS/OP21-induced expression of proinflammatory cytokines and chemokines such as chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand (Ccl) 2, and Ccl5. Conclusions: Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis

Trouble with Bleeding: Risk Factors for Acute Hepatitis C among HIV-Positive Gay Men from Germany—A Case-Control Study

OBJECTIVES: To identify risk factors for hepatitis C among HIV-positive men who have sex with men (MSM), focusing on potential sexual, nosocomial, and other non-sexual determinants. BACKGROUND: Outbreaks of hepatitis C virus (HCV) infections among HIV-positive MSM have been reported by clinicians in post-industrialized countries since 2000. The sexual acquisition of HCV by gay men who are HIV positive is not, however, fully understood. METHODS: Between 2006 and 2008, a case-control study was embedded into a behavioural survey of MSM in Germany. Cases were HIV-positive and acutely HCV-co-infected, with no history of injection drug use. HIV-positive MSM without known HCV infection, matched for age group, served as controls. The HCV-serostatus of controls was assessed by serological testing of dried blood specimens. Univariable and multivariable regression analyses were used to identify factors independently associated with HCV-co-infection. RESULTS: 34 cases and 67 controls were included. Sex-associated rectal bleeding, receptive fisting and snorting cocaine/amphetamines, combined with group sex, were independently associated with case status. Among cases, surgical interventions overlapped with sex-associated rectal bleeding. CONCLUSIONS: Sexual practices leading to rectal bleeding, and snorting drugs in settings of increased HCV-prevalence are risk factors for acute hepatitis C. We suggest that sharing snorting equipment as well as sharing sexual partners might be modes of sexual transmission. Condoms and gloves may not provide adequate protection if they are contaminated with blood. Public health interventions for HIV-positive gay men should address the role of blood in sexual risk behaviour. Further research is needed into the interplay of proctosurgery and sex-associated rectal bleeding

Law defining the critical level of driver fatigue in terms of hours without sleep: Criminal justice professionals\u27 opinions and fatal accident data

The aims of the present study were to determine the support among criminal justice professionals for a law that defines the critical limit of driver fatigue in terms of 24 consecutive hours of wakefulness; and to determine how many drivers causing fatal accidents would be potentially covered by such a law. The data included an online questionnaire data collected from 325 criminal justice professionals (96 prosecutors, 129 traffic police officers, and 100 local police officers with experience in traffic surveillance and accident investigations) and the national database of fatal road accidents studied in depth (N = 1871; 2002-2008). The support for such a law was quite low among prosecutors while police officers were more in favor than against it. Only a handful of the (survived) drivers who caused a fatal accident were awake for more than 24 consecutive hours. We discuss several challenges and considerations associated with such a law

Driver fatigue and the law from the perspective of police officers and prosecutors

Even though police officers and prosecutors play a key role in traffic law application, little is known about their experiences, attitudes, and opinions regarding the complex issue of driver fatigue and the law. This paper is based on an extensive online survey collected from traffic (N = 129) and local (N = 100) police officers and prosecutors (N = 96) in the context of Finnish traffic law, which forbids driving while fatigued in an article relating to a driver's fitness to drive. While encountering fatigued drivers is very common for police officers, only a small proportion has received training about how to recognize and deal with fatigued drivers. Driving while extremely fatigued is considered rather or extremely negligent behavior by almost all respondents. Although agreement between these three groups exists regarding several issues, they disagree about whether the current law is specific enough, and whether experts might be valuable in court when discussing the possible contribution of fatigue to the cause of a crash. We discuss the application of the law and opinions about the current law formulation, experience and education, as well as general awareness and attitudes, taking into consideration the different nature of police and prosecutor work

Self-reported circumstances and consequences of driving while

Contains fulltext : 149349.pdf (publisher's version ) (Closed access)Driver surveys are indispensable sources of information when estimating the role of sleepiness in crash causation. The purpose of the study was to (1) identify the prevalence of driving while sleepy among Finnish drivers, (2) determine the circumstances of such instances, and (3) identify risk factors and risk groups. Survey data were collected from a representative sample of active Finnish drivers (N = 1121). One-fifth of the drivers (19.5%) reported having fallen asleep at the wheel during their driving career, with 15.9% reporting having been close to falling asleep or having difficulty staying awake when driving during the previous twelve months. Epworth Sleepiness Scale scores were found to be associated with both types of sleepiness-related driving instances, while sleep quality was associated only with the latter. Compared to women, men more often reported falling asleep at the wheel; the differences were somewhat smaller with respect to fighting sleep while driving during the previous twelve months. The reported discrepancy in sleepiness-related instances (high prevalence of fighting sleep while driving during the previous twelve months and lower proportion of actually falling asleep) identifies young men (⩽25 years) as one of the main target groups for safety campaigns. Approximately three-quarters of drivers who had fallen asleep while driving reported taking action against falling asleep before it actually happened. Furthermore, almost all drivers who had fallen asleep while driving offered at least one logical reason that could have contributed to their falling asleep. These data indicate some degree of awareness about driving while sleepy and of the potential pre-trip factors that could lead to sleepiness while driving, and supports the notion that falling asleep at the wheel does not come as a (complete) surprise to the driver.10 p

Alcohol Ignition Interlocks in All New Vehicles: A Broader Perspective

Objective: To discuss the implications of widespread implementation of alcohol ignition interlocks. Method: We base our discussion on data from Finland including crash statistics and surveys collected from criminal justice professionals and general driving population. Results: Alcohol ignition interlocks are an effective preventive measure against drunk driving when installed in the vehicles of convicted drunk drivers. However, once they are removed from the vehicles, drivers typically return to their habit of drinking and driving. Furthermore, for a number of reasons, the proportion of convicted drunk drivers that install an interlock in their vehicles is quite small. Therefore, many stakeholders believe that the solution to the drunk driving problem will come when interlocks become standard equipment in all new vehicles. However, drunk driving is a complex sociopsychological problem, and technology can rarely offer a solution to such complex problems. Consequently, many aspects of such interventions might be difficult to identify and include in cost-benefit analysis. Conclusion: We express caution about requiring an interlock as standard equipment in all new vehicles