Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways,accumulation of α-synuclein,and apoptotic cell death in aged mice

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson''s disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2^−/− mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2^−/− kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy–lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson''s disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time.     

Radiosynthesis and in vivo evaluation of fluorinated huprine derivates as PET radiotracers of acetylcholinesterase

IntroductionDeveloping positron emission tomography (PET) radiotracers for non-invasive study of the cholinergic system is crucial to the understanding of neurodegenerative diseases. Although several acetylcholinesterase (AChE) PET tracers radiolabeled with carbon-11 exist, no fluorinated radiotracer is currently used in clinical imaging studies. The purpose of the present study is to describe the first fluorinated PET radiotracer for this brain enzyme.MethodsThree structural analogs of huprine, a specific AChE inhibitor presenting high affinity towards AChE in vitro, were synthesized and labeled with fluorine-18 via a mesylate/fluoro-nucleophilic aliphatic substitution: ([¹⁸ F]-FHUa, [¹⁸ F]-FHUb and [¹⁸ F]-FHUc). Initial biological evaluation included in vitro autoradiography in rat with competition with an AChE inhibitor at different concentrations, and microPET-scan on anesthetized rats. In vivo PET studies in anesthetized cat focused on [¹⁸ F]-FHUa.Results and ConclusionsAlthough radiosynthesis of these huprine analogs was straightforward, they showed poor brain penetration potential, partially reversed after pharmacological inhibition of P-glycoprotein. These results indicated that current huprine analogs are not suitable for PET mapping of brain AChE receptors, but require physicochemical modulation in order to increase brain penetration.     

Resection of hepatocellular carcinoma with tumor thrombus in the major vasculature. A European case-control series

Tumor thrombus in major vasculature is a frequent finding with a poor long-term prognosis in patients with hepatocellular carcinoma (HCC). The utility of surgical resection is still controversial. This study compared morbidity and survival after resection for HCC with and without tumor thrombus. Data of 108 patients who underwent major hepatic resection for HCC were prospectively recorded. Patients were divided into two groups. The venous thrombectomy (VT) group included 26 patients who had HCC with tumor thrombus in the portal or hepatic veins. The matched control group included 82 patients who had HCC without tumor thrombus. Surgical technique, early outcome, and late survival were analyzed in each group. Multivariate analysis was performed to assess the prognostic value of this feature. Surgical technique was comparable in the VT and control group with regard to extent of hepatectomy, procedure duration, and transfusion requirements. Early postoperative outcome was also comparable. Actuarial survival at 1, 3, and 5 years was 38%, 20%, and 13%, respectively, in the VT group (median: 9 months) versus 74%, 56%, and 33%, respectively, in the control group (median: 41 months). In the subgroup of patients with tumor thrombus limited to the portal vein, actuarial survival at 1, 3, and 5 years was 50%, 26%, and 17%, respectively, (median: 12 months) and two patients lived longer than 5 years. Multivariate analysis showed that incomplete resection, alphafetoprotein level greater than 100 N, more than two tumor nodules, and tumor thrombus in major vasculature were independent factors of poor prognosis. Survival after resection for HCC with tumor thrombus in the major vasculature is poorer than after resection for HCC without tumor thrombus. However, an aggressive surgical strategy can provide significant survival with comparable morbidity in selected cases, that is, tumor thrombus located in the portal vein only and expected complete resection of the lesions.     

A phase I,randomized, double‐blind,placebo‐controlled,single‐ and multiple dose escalation study evaluating the safety,pharmacokinetics and pharmacodynamics of VX‐128, a highly selective Nav1.8 inhibitor,in healthy adults

Selective inhibition of certain voltage‐gated sodium channels (Na_vs), such as Na_v1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Na_v1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Na_v1.8 inhibitors as pain treatments.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selective sodium channel (Na_v) inhibitors have been proposed as an alternative to opioids for pain management. Their potential, however, has yet to be confirmed, as none of the multiple selective Na_v inhibitors that have been investigated for pain management has reached the market.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We investigated the safety, tolerability, and initial analgesic effects of VX‐128, a novel and highly selective Na_v1.8 inhibitor, in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This is the first study to describe clinical data obtained on the highly selective Na_v1.8 inhibitor VX‐128, and the first to report analgesic effects of this selective Na_v inhibitor in humans. VX‐128 administered as a single dose was well‐tolerated, but dose‐limiting skin rashes occurred after multiple doses resulting in a premature study halt. Although the study had a parallel design and was not necessarily powered to detect pharmacodynamic effects, nociceptive test results suggest that VX‐128 leads to dose‐dependent analgesic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings substantiate research that is performed on evaluating selective Na_v1.8 inhibitors as treatment for pain, and suggests that the cold pressor‐ and pressure pain models are suitable to evaluate selective Na_v1.8 inhibitors.     

Gender Differences in the Relationships between Perceived Stress,Eating Behaviors,Sleep, Dietary Risk,and Body Mass Index

Background: Obesity is a growing epidemic among university students, and the high levels of stress reported by this population could contribute to this issue. Singular relationships between perceived stress; engagement in restrained, uncontrolled, and emotional eating; sleep; dietary risk; and body mass index (BMI) have been reported in the current body of literature; however, these constructs interact with each other, and the complex relationships among them are infrequently examined. Therefore, the aim of the present study was to explore the complex relationships between these constructs using mediation and moderation analyses stratified by gender. Methods: A cross-sectional study, enrolling university students from the United States (U.S.), the Netherlands, South Korea, Malaysia, Ireland, Ghana, and China, was conducted between October 2020 and January 2021 during the COVID-19 pandemic. Perceived stress; maladaptive eating behaviors including restrained, uncontrolled, and emotional eating; sleep duration and quality; dietary risk; and BMI were assessed using validated questionnaires, which were distributed through an online platform. Results: A total of 1392 students completed the online survey (379 male, 973 female, and 40 who self-identified as “other”). Uncontrolled and emotional eating mediated the relationship between perceived stress and dietary risk for both males and females; higher sleep quality weakened this relationship among female students but not males. Emotional eating mediated the relationship between perceived stress and BMI for both males and females, but higher sleep quality weakened this relationship only among females. Conclusions: Our findings suggest that students in higher education are likely to benefit from interventions to reduce uncontrolled and emotional eating. Programs that improve sleep quality, especially during highly stressful periods, may be helpful.     

The Role of GJD2(Cx36) in Refractive Error Development

Refractive errors are common eye disorders characterized by a mismatch between the focal power of the eye and its axial length. An increased axial length is a common cause of the refractive error myopia (nearsightedness). The substantial increase in myopia prevalence over the last decades has raised public health concerns because myopia can lead to severe ocular complications later in life. Genomewide association studies (GWAS) have made considerable contributions to the understanding of the genetic architecture of refractive errors. Among the hundreds of genetic variants identified, common variants near the gap junction delta-2 (GJD2) gene have consistently been reported as one of the top hits. GJD2 encodes the connexin 36 (Cx36) protein, which forms gap junction channels and is highly expressed in the neural retina. In this review, we provide current evidence that links GJD2(Cx36) to the development of myopia. We summarize the gap junctional communication in the eye and the specific role of GJD2(Cx36) in retinal processing of visual signals. Finally, we discuss the pathways involving dopamine and gap junction phosphorylation and coupling as potential mechanisms that may explain the role of GJD2(Cx36) in refractive error development.     

Delinquency and drug use among adolescents and emerging adults: The role of aggression,impulsivity, empathy,and cognitive distortions

Risk behaviors are well known to be higher in adolescents and emerging adults. Drug use and delinquency present several common predictive factors. The aim of the present study was to assess the contribution of individual factors (aggression, impulsivity, empathy, and cognitive distortions) to delinquent behaviors, alcohol use and cannabis consumption among adolescents and emerging adults. Participants were between 15 and 25 years of age (M = 18.64 years, SD = 2.61); 325 were adolescents (15–18 years of age, M = 16.56, SD = 1.11, 56.31% of women) and 283 were emerging adults (19–25 years, M = 21.03, SD = 1.62, 50.88% of women). They completed self-report validated questionnaires. Multiple regression analyses showed that all individual factors significantly predicted delinquency. Impulsivity and empathy significantly predicted alcohol use. Concerning cannabis use, impulsivity is the only significantly associated predictor. Moderation analysis showed that specific associations were stronger in adolescents, whereas others were stronger in emerging adults. All these variables explained 69% of the variance of delinquency, 31% of the variance of alcohol use, and 18% of the variance of cannabis use. This model demonstrated acceptable goodness-of-fit criteria. These results may have implications for prevention and intervention.