Agmatine as a novel candidate for rapid-onset antidepressant response

Major depressive disorder (MDD) is a disabling and highly prevalent mood disorder as well as a common cause of suicide. Chronic stress, inflammation, and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD. Although conventional antidepressants are widely used in the clinic, they can take weeks to months to produce therapeutic effects. The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD. However, the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use. Therefore, agmatine, an endogenous glutamatergic modulator, has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway, similar to ketamine. However, recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota, which have been shown to play a crucial role in the pathophysiology of MDD, may also participate in the antidepressant-like effects of both ketamine and agmatine. This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies. Considering the anti-inflammatory properties of agmatine, it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state. Moreover, the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.     

Interoception Primes Emotional Processing: Multimodal Evidence from Neurodegeneration

Recent frameworks in cognitive neuroscience and behavioral neurology underscore interoceptive priors as core modulators of negative emotions. However, the field lacks experimental designs manipulating the priming of emotions via interoception and exploring their multimodal signatures in neurodegenerative models. Here, we designed a novel task that involves interoceptive and control-exteroceptive priming conditions followed by post-interoception and post-exteroception facial emotion recognition (FER). We recruited 114 participants, including healthy controls (HCs) as well as patients with behavioral variant frontotemporal dementia (bvFTD), Parkinson''s disease (PD), and Alzheimer''s disease (AD). We measured online EEG modulations of the heart-evoked potential (HEP), and associations with both brain structural and resting-state functional connectivity patterns. Behaviorally, post-interoception negative FER was enhanced in HCs but selectively disrupted in bvFTD and PD, with AD presenting generalized disruptions across emotion types. Only bvFTD presented impaired interoceptive accuracy. Increased HEP modulations during post-interoception negative FER was observed in HCs and AD, but not in bvFTD or PD patients. Across all groups, post-interoception negative FER correlated with the volume of the insula and the ACC. Also, negative FER was associated with functional connectivity along the (a) salience network in the post-interoception condition, and along the (b) executive network in the post-exteroception condition. These patterns were selectively disrupted in bvFTD (a) and PD (b), respectively. Our approach underscores the multidimensional impact of interoception on emotion, while revealing a specific pathophysiological marker of bvFTD. These findings inform a promising theoretical and clinical agenda in the fields of nteroception, emotion, allostasis, and neurodegeneration.SIGNIFICANCE STATEMENT We examined whether and how emotions are primed by interoceptive states combining multimodal measures in healthy controls and neurodegenerative models. In controls, negative emotion recognition and ongoing HEP modulations were increased after interoception. These patterns were selectively disrupted in patients with atrophy across key interoceptive-emotional regions (e.g., the insula and the cingulate in frontotemporal dementia, frontostriatal networks in Parkinson''s disease), whereas persons with Alzheimer''s disease presented generalized emotional processing abnormalities with preserved interoceptive mechanisms. The integration of both domains was associated with the volume and connectivity (salience network) of canonical interoceptive-emotional hubs, critically involving the insula and the anterior cingulate. Our study reveals multimodal markers of interoceptive-emotional priming, laying the groundwork for new agendas in cognitive neuroscience and behavioral neurology.     

Randomized clinical trial comparing monolithic and veneered zirconia three-unit posterior fixed partial dentures in a complete digital flow: three-year follow-up

Clinical Oral Investigations - To evaluate and to compare the clinical performance and survival rate of posterior monolithic and veneered zirconia fixed partial dentures (FPDs). Sixty 3-unit...     

Prostate cancer incidence in men with prostate-specific antigen below 3 ng/mL: The Finnish Randomized Study of Screening for Prostate Cancer

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves overdetection of low-risk disease with potential adverse effects. We evaluated PCa incidence among men with PSA below 3 ng/mL and no PCa diagnosis at the first screening round of the Finnish Randomized Study of Screening for PCa. Follow-up started at the first screening attendance and ended at PCa diagnosis, emigration, death or the common closing date (December 2016), whichever came first. Cox regression analysis was used to estimate hazard ratios and their confidence intervals (CI). Among men with PSA <3 ng/mL, cumulative PCa incidence was 9.1% after 17.6 years median follow-up. Cumulative incidence was 3.6% among men with baseline PSA 0 to 0.99 ng/mL, 11.5% in those with PSA 1.0 to 1.99 ng/mL and 25.7% among men with PSA 2 to 2.99 ng/mL (hazard ratio 9.0, 95% CI: 7.9-10.2 for the latter). The differences by PSA level were most striking for low-risk disease based on Gleason score and EAU risk group. PSA values <1 ng/mL indicate a very low 20-year risk, while at PSA 2 to 2.99 ng/mL risks are materially higher, with 4- to 5-fold risk for aggressive disease. Using risk-stratification and appropriate rescreening intervals will reduce screening intensity and overdetection. Using cumulative incidence of clinically significant PCa (csPCa) as the criterion, rescreening intervals could range from approximately 3 years for men with initial PSA 2 to 2.99 ng/mL, 6 years for men with PSA 1 to 1.99 ng/mL to 10 years for men with PSA <1 ng/mL.     

数据之美——聚焦全球器官捐献发展趋势

器官移植术是20世纪出现的针对器官功能衰竭的最有效治疗方法，每年拯救全球超过12万例患者。但供器官短缺的现状，与器官移植技术和辅助药物的发展不匹配，制约了器官移植事业的发展。我国自2015年起已成为全球器官捐献和移植大国之一，2017年公民逝世后器官捐献数量超过5 000例，占全球捐献总量的15%以上。黄洁夫教授总结的器官捐献与移植"中国模式"得到了世界卫生组织、国际移植界的高度重视和充分肯定。本文通过整理全球及各国的器官捐献与移植数据，剖析全球现状与发展趋势，进一步探索我国公民器官捐献的影响因素并提出针对性的应对策略，以期实现我国器官捐献和移植的"自给自足"。