The molecular genetics of human sleep

It has been known for many years that genetic influences account for some of the individual differences in human sleep parameters, but the underlying molecular mechanisms remain unclear. With major advances of molecular biology and the recognition of heritable sleep behaviors in humans over the past 30 years, a number of genetic variants have been identified to be associated with human sleep timing, duration and quality, both in healthy individuals and under pathological conditions. Some of these variants were further validated and characterized in animal models, shedding light on the mechanism of how these variants likely alter sleep in humans, which may provide new insights into developing more effective treatments to improve human sleep.     

Natural compulsive‐like behaviour in the deer mouse (Peromyscus maniculatus bairdii) is associated with altered gut microbiota composition

Obsessive–compulsive disorder (OCD) is a psychiatric illness that significantly impacts affected patients and available treatments yield suboptimal therapeutic response. Recently, the role of the gut–brain axis (GBA) in psychiatric illness has emerged as a potential target for therapeutic exploration. However, studies concerning the role of the GBA in OCD are limited. To investigate whether a naturally occurring obsessive–compulsive‐like phenotype in a rodent model, that is large nest building in deer mice, is associated with perturbations in the gut microbiome, we investigated and characterised the gut microbiota in specific‐pathogen‐free bred and housed large (LNB) and normal (NNB) nest‐building deer mice of both sexes (n = 11 per group, including three males and eight females). Following baseline characterisation of nest‐building behaviour, a single faecal sample was collected from each animal and the gut microbiota analysed. Our results reveal the overall microbial composition of LNB animals to be distinctly different compared to controls (PERMANOVA p < .05). While no genera were found to be significantly differentially abundant after correcting for multiple comparisons, the normal phenotype showed a higher loading of Prevotella and Anaeroplasma, while the OC phenotype demonstrated a higher loading of Desulfovermiculus, Aestuariispira, Peptococcus and Holdemanella (cut‐off threshold for loading at 0.2 in either the first or second component of the PCA). These findings not only provide proof‐of‐concept for continued investigation of the GBA in OCD, but also highlight a potential underlying aetiological association between alterations in the gut microbiota and the natural development of obsessive–compulsive‐like behaviours.     

Characterization of a Parkinson’s disease rat model using an upgraded paraquat exposure paradigm

Animal models of human diseases are crucial experimental tools to investigate the mechanisms involved in disease pathogenesis and to develop new therapies. In spite of the numerous animal models currently available that reproduce several neuropathological features of Parkinson disease (PD), it is challenging to have one that consistently recapitulates human PD conditions in both motor behaviors and biochemical pathological outcomes. Given that, we have implemented a new paradigm to expose rats to a chronic low dose of paraquat (PQ), using osmotic minipumps and characterized the developed pathologic features over time. The PQ exposure paradigm used lead to a rodent model of PD depicting progressive nigrostriatal dopaminergic neurodegeneration, characterized by a 41% significant loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc), a significant decrease of 18% and 40% of dopamine levels in striatum at week 5 and 8, respectively, and a significant 1.5‐fold decrease in motor performance. We observed a significant increase of microglia activation state, sustained levels of α‐synucleinopathy and increased oxidative stress markers in the SNpc. In summary, this is an explorative study that allowed to characterize an improved PQ‐based rat model that recapitulates cardinal features of PD and may represent an attractive tool to investigate several mechanisms underlying the various aspects of PD pathogenesis as well as for the validation of the efficacy of new therapeutic approaches that targets different mechanisms involved in PD neurodegeneration.     

Cognitive behavioral therapy reduces illness perceptions and anxiety symptoms in patients with unruptured intracranial aneurysm

The main purpose of this study was to assess the relation between cognitive behavioral therapy and possible changes in illness perceptions and anxiety in patients diagnosed with unruptured intracranial aneurysm. An observational study of an intervention with 67 patients with an unruptured intracranial aneurysm from two medical centers in a Colombian city (n = 35 on the intervention group) was carried out. To assess changes, measurements were taken at baseline and at one-year follow-up with the Beck Anxiety Inventory and the Illness Perception Questionnaire, brief version, taking into account the importance of perceptions in the process of adjusting to illness and acquiring healthy life habits. Hypotheses were tested by a structural model. The results obtained from this study showed that illness perceptions were related to anxiety levels at both time points; however, the relations were stronger before cognitive behavioral therapy (βt0 = 0.61, p < 0.01; βt1 = 0.37, p < 0.01). Cognitive behavioral therapy was found to be a moderator of changes in both illness perceptions and anxiety at the time of follow-up (β = −0.31, p < 0.01; β = −0.26, p < 0.01). The structural model suggests that cognitive behavioral therapy is associated with less anxiety (β = −0.17, p < 0.05) and better illness perceptions (β = −0.35, p < 0.01) in patients diagnosed with unruptured intracranial aneurysms.     

Dyskinesia Matters

Levodopa-induced dyskinesia (LID) represents a significant source of discomfort for people with Parkinson's disease (PD). It negatively affects quality of life, it is associated with both motor and nonmotor fluctuations, and it brings an increased risk of disability, balance problems, and falls. Although the prevalence of severe LID appears to be lower than in previous eras (likely owing to a more conservative use of oral levodopa), we have not yet found a way to prevent the development of this complication. Advanced surgical therapies, such as deep brain stimulation, ameliorate LID, but only a minority of PD patients qualify for these interventions. Although some have argued that PD patients would rather be ON with dyskinesia than OFF, the deeper truth is that patients would very much prefer to be ON without dyskinesia. As researchers and clinicians, we should aspire to make that goal a reality. To this end, translational research on LID is to be encouraged and persistently pursued. © 2019 International Parkinson and Movement Disorder Society     

经乙二醇诱导的改良型草酸钙肾结石果蝇模型

目的:通过一种改良方法构建果蝇草酸钙肾结石模型。方法:配制标准培养基和造模用培养基，空白对照组果蝇仅予标准培养基，而传统模型组和改良模型组分别从成虫期和幼虫期开始摄入含 0.5%乙二醇( EG)的造模用培养基。于偏光显微镜下观察并评估各组果蝇马氏管内成石情况，分别记录模型组成石率达 100%所花时间，并对成石率 100%时模型组间“ ++”和“ +++”所占比率进行比较；用傅立叶变换拉曼光谱仪鉴定模型组果蝇马氏管内结石成分。绘制各组果蝇生存曲线，并比较生存周期差异。结果:改良模型组和传统模型组分别在果蝇成虫日龄 14 d和 22 d，马氏管内成石率达到 100%。当改良模型组和传统模型组成石率均达到 100%时，两组“ ++”与“+++”所占比率分别为(40.5±4.4)%和(39.0±4.2)%，差异无统计学意义(P＞ 0.05)；拉曼位移的主峰主要集中在 1 462 cm-1、1 463 cm-1和 1 473 cm-1，说明模型组果蝇马氏管内结石成分均为草酸钙。空白对照组、传统模型组和改良模型组的最高寿命分别为 76 d、70 d和 68 d，中位生存时间分别为 35 d、30.5 d和 30 d，与空白对照组相比，模型组生存周期均显著缩短(P均＜ 0.01)，但传统模型组与改良模型组间差异无统计学意义( P＞ 0.05)。结论:改良型造模方法使果蝇在其幼虫期即摄入 0.5% EG，缩短了模型构建周期且具有可重复性，值得进一步研究推广。     

Study of tissue inflammatory response in different mice strains infected by dematiaceous fungi Fonsecaea pedrosoi

Background:Diseases caused by melanized fungi include mycetoma, chromoblastomycosis and phaeohyphomycosis. This broad clinical spectrum depends on the dynamic interactions between etiologic agent and host. The immune status of the host influences on the development of the disease, as, an exemple. phaeohyphomicosis is more frequently observed in immunocompromised patients.Objectives:Examine the histological inflammatory response induced by Fonsecaea pedrosoi in several different strains of mice (BALB/c, C57BL/6, Nude and SCID, and reconstituted Nude).Methods:Fonsecaea pedrosoi was cultivated on agar gel and a fragment of this gel was implanted subcutaneously in the abdominal region of female adult mice. After infection has been obtained, tissue fragment was studied histopathologically.Results:There were significant changes across the strains, with the nodular lesion more persistent in Nude and SCID mice, whereas in immunocompetent mice the lesion progressed to ulceration and healing. The histopathological analysis showed a significant acute inflammatory reaction which consisted mainly of neutrophils in the initial phase that was subsequently followed by a tuberculoid type granuloma in immunocompetent mice.Study limitations:There is no a suitable animal model for chromoblastomycosis.Conclusions:The neutrophilic infiltration had an important role in the containment of infection to prevent fungal spreading, including in immunodeficient mice. The fungal elimination was dependent on T lymphocytes. The re-exposure of C57BL/6 mice to Fonsecaea pedrosoi caused a delay in resolving the infection, and appearance of muriform cells, which may indicate that re-exposure to fungi, might lead to chronicity of infection.     

Decision-support models for empiric antibiotic selection in Gram-negative bloodstream infections

Objectives

Early empiric antibiotic therapy in patients can improve clinical outcomes in Gram-negative bacteraemia. However, the widespread prevalence of antibiotic-resistant pathogens compromises our ability to provide adequate therapy while minimizing use of broad antibiotics. We sought to determine whether readily available electronic medical record data could be used to develop predictive models for decision support in Gram-negative bacteraemia.