Frontal and subcortical contribution to visual hallucinations in dementia with Lewy bodies and Parkinson’s disease

Objectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson’s disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia.

Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones.

Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH.

Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.     

Histamine-4 receptor antagonist ameliorates Parkinson-like pathology in the striatum

Growing evidence indicates that microglia activation and a neuroinflammatory trigger contribute to dopaminergic cell loss in Parkinson’s disease (PD). Furthermore, increased density of histaminergic fibers and enhanced histamine levels have been observed in the substantia nigra of PD-postmortem brains. Histamine-induced microglial activation is mediated by the histamine-4 receptor (H₄R). In the current study, gene set enrichment and pathway analyses of a PD basal ganglia RNA-sequencing dataset revealed that upregulation of H₄R was in the top functional category for PD treatment targets. Interestingly, the H₄R antagonist JNJ7777120 normalized the number of nigrostriatal dopaminergic fibers and striatal dopamine levels in a rotenone-induced PD rat model. These improvements were accompanied by a reduction of α-synuclein-positive inclusions in the striatum. In addition, intracerebroventricular infusion of JNJ7777120 alleviated the morphological changes in Iba-1-positive microglia and resulted in a lower tumor necrosis factor-α release from this brain region, as well as in ameliorated apomorphine-induced rotation behaviour. Finally, JNJ7777120 also restored basal ganglia function by decreasing the levels of γ-aminobutyric acid (GABA) and the 5-hydroxyindoleactic acid to serotonin (5-HIAA/5-HT) concentration ratios in the striatum of the PD model. Our results highlight H₄R inhibition in microglia as a promising and specific therapeutic target to reduce or prevent neuroinflammation, and as such the development of PD pathology.     

An evolutionary analysis of nitric oxide reductase gene norV in enterohemorrhagic Escherichia coli O157

A novel virulence gene, norV, that encodes nitric oxide (NO) reductase, was examined to investigate the emergence of enterohemorrhagic Escherichia coli (EHEC) O157 subgroup C clusters 2 and 3 from subgroup C cluster 1. Deletion of norV occurred at a point between cluster 1 and cluster 2 just after or at the same time that an stx2 bacteriophage, which retains Shiga toxin 2 gene, was inserted into wrbA, which encodes a novel multimeric flavodoxin-like protein, in EHEC O157. Sensitivity of NO to anaerobic growth was correlated with the deletion of norV in all EHEC O157 individuals tested. The C467A mutation of fimH, which encodes minor component of type 1 fimbriae, occurred within cluster 1, not as a transition from cluster 1 to cluster 2, indicating that there is a cluster 1 minority branch that leads to cluster 2. These data refine the evolutionary history of an emerging EHEC O157.     

Prevalence of rheumatic heart disease in patients with recurrent tonsillitis and elevated anti-streptolysin O titers

IntroductionPatients with elevated anti-streptolysin O (ASO) titers (ASOT) and recurrent tonsillitis episodes are known to be at higher risk for rheumatic heart disease (RHD). However, there is no data regarding prevalence of RHD in this high risk population. In this study, we aimed to screen ambulatory patients with elevated ASOT and recurrent tonsillitis episodes using echocardiography for identification of RHD. We hypothesized that prevalence of RHD is higher in this patient group compared to general population.Methods102 patients (10.33 ± 4.01 years, 50.98% female) who were diagnosed with recurrent tonsillitis and had elevated ASOT were included this study. Echocardiographic evaluation was performed by an experienced cardiologist.ResultsEchocardiographic examination revealed definite RHD in 2/102 (1.96%) patients and borderline RHD in 3/102 (2.94%) patients.ConclusionOur study demonstrates a high prevalence of RHD in patients with recurrent tonsillitis episodes and high ASOT. Screening with echocardiography is beneficial to improve the detection rates of subclinical RHD in such high-risk populations.     

Epstein-Barr Virus–Related Post-Transplant Lymphoproliferative Disorders in Cystic Fibrosis Lung Transplant Recipients: A Case Series

Background

Solid organ transplantation is associated with a higher risk of Epstein-Barr virus (EBV)–related lymphoproliferative disease due to immunosuppressive regimen. Little evidence is currently available on post-transplant lymphoproliferative disorders (PTLDs) in the lung transplant (LuTx) setting, particularly in cystic fibrosis (CF) recipients.

5-氮杂-2'-脱氧胞苷对涎腺腺样囊性癌细胞系细胞MGMT和hMLH1基因表达的影响

目的 观察5-氮杂-2’-脱氧胞苷(5-aza-2-deoxycytidine,5-Aza-CdR)对体外培养人涎腺腺样囊性癌(salivary adenoid cystic carcinoma,SACC)细胞系细胞O6-甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyhransferase,MGMT)和人类mutL同源物1(homo sapiens mutL homolog 1,hMLH1)基因表达的影响,探讨DNA甲基转移酶抑制剂应用于SACC治疗的可行性及机制.方法 用不同浓度5-Aza-CdR分别处理体外培养SACC-83和SACC-LM细胞作为药物处理组,以药物处理浓度0 μmol/L为对照组.甲基噻唑基四唑法确定5-Aza-CdR的半数抑制浓度(half maximal inhibitory concentration of a substance,IC50)；实时聚合酶链反应和反转录聚合酶链反应检测用药后细胞中MGMT和hMLH1 mRNA表达水平.结果 药物处理细胞24 h后细胞形态发生变化,并且随时间延长变化愈加显著.5-Aza-CdR对SACC-83和SACC-LM细胞的IC50分别为(11.816±0.023)、(5.751± 0.049) μmol/L.经5-Aza-CdR处理后,SACC-83和SACC-LM细胞中MGMT和hMLH1 mRNA表达增高1～5倍,MGMT和hMLH1在药物处理组与对照组之间的表达差异有统计学意义(P＜0.01).结论 5-Aza-CdR可改变细胞形态,上调MGMT和hMLH1 mRNA的表达,其机制可能与5-Aza-CdR反转MGMT、hMLH1基因DNA启动子区高甲基化状态有关.     

A Review of: “ Handbook of Adaptive Designs in Pharmaceutical and Clinical Development,by A. Pong and S.-C. Chow (Eds.)”

In practice, there exist many disease processes with three ordinal disease classes; for example, in the detection of Alzheimer’s disease (AD) a patient can be classified as healthy (disease-free stage), mild cognitive impairment (early disease stage), or AD (full disease stage). The treatment interventions and effectiveness of such disease processes will depend on the disease stage. Therefore, it is important to develop diagnostic tests with the ability to discriminate between the three disease stages. Measuring the overall ability of diagnostic tests to discriminate between the three classes has been discussed extensively in the literature. However, there has been little proposed on how to select clinically meaningful thresholds for such diagnostic tests, except for a method based on the generalized Youden index by Nakas et al. (2010). In this article, we propose two new criteria for selecting diagnostic thresholds in the three-class setting. The numerical study demonstrated that the proposed methods may provide thresholds with less variability and more balance among the correct classification rates for the three stages. The proposed methods are applied to two real examples: the clinical diagnosis of AD from the Washington University Alzheimer’s Disease Research Center and the detection of liver cancer (LC) using protein segments.