Mini Review: Linkages between Essential Tremor and Parkinson\u27s Disease?

Essential tremor (ET) and Parkinson’s disease (PD) are two of the most common movement disorders. Tremors are the primary symptoms of ET and of some PD patients, the two are often mistaken for each other. Especially since there are no available differentiate tests for the tremor of ET or PD, the early diagnoses mainly based on clinical assessments of medical symptoms, family and medication history, and examination by physicians. There is increasing evidence suggesting an association between ET and PD, such as a similar tremor frequency, overlapping resting tremors (a typical PD tremor), postural tremors (mainly in ET patients) in both ET and PD patients, and many ET patients develop PD later in life. Although it is difficult to make a differential diagnosis of ET and tremor-dominant PD based on clinical assessment, recent developments of objective measurements, such as brain imaging, neuropathology, and genetic analysis, has opened a helpful window for distinguishing ET from PD. In this mini review, we included literatures of ET and PD studies and discussed various advanced methods for differential diagnosis between ET and PD such as neuroimaging, genetic markers, tremor intensity and frequency, and drug-responses

Sex Differences in Antidepressant Effect of Sertraline in Transgenic Mouse Models

The main purpose of this study is to explore sex differences in the antidepressant effect of sertraline in genetic knockout or overexpression estrogen-synthesizing enzyme aromatase (Ar) gene mouse models in the forced swim test (FST). Our results demonstrated a significant reduction of depression-like behavior in the mice with overexpression of brain aromatase (Thy1-Ar) compared to sex- and age-matched Ar+/− mice or wild type control mice. Using HPLC analysis, we also found an association between the brain estrogen-related antidepressive behavior and the regulation of serotonin (5-HT) system. Interestingly, a single dose administration of sertraline (10 mg/kg, i.p.) induced reduction of immobility time was found in all genotypes, except male Ar+/− mice. While the underlying mechanisms of sex-specific response on antidepressive effect of sertraline remain to be investigated, our data showed that female mice appear to be more sensitive to sertraline-induced changes of 5-HT system than male mice in the prefrontal cortex (PFC) and the hippocampus (HPC). Further investigation of sex-specific effect of brain estrogen on antidepressant is needed

Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease

We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI

The Clinical Importance of Campylobacter concisus and Other Human Hosted Campylobacter Species

Historically, Campylobacteriosis has been considered to be zoonotic; the Campylobacter species that cause human acute intestinal disease such as Campylobacter jejuni and Campylobacter coli originate from animals. Over the past decade, studies on human hosted Campylobacter species strongly suggest that Campylobacter concisus plays a role in the development of inflammatory bowel disease (IBD). C. concisus primarily colonizes the human oral cavity and some strains can be translocated to the intestinal tract. Genome analysis of C. concisus strains isolated from saliva samples has identified a bacterial marker that is associated with active Crohn's disease (one major form of IBD). In addition to C. concisus, humans are also colonized by a number of other Campylobacter species, most of which are in the oral cavity. Here we review the most recent advancements on C. concisus and other human hosted Campylobacter species including their clinical relevance, transmission, virulence factors, disease associated genes, interactions with the human immune system and pathogenic mechanisms

Virtual Planning and 3D printing modeling for mandibular reconstruction with fibula free flap

This study was to evaluate the use of virtual planning and 3D printing modeling in mandibular reconstruction and compare the operation time and surgical outcome of this technique with conventional method. Between 2014 and 2017, 15 patients underwent vascularized fibula flap mandibular reconstruction using virtual planning and 3D printing modeling. Titanium plates were pre-bent using the models and cutting guides were used for osteotomies. 15 patients who underwent mandibular reconstruction using fibula flap without aid of virtual planning and 3D printing models were selected as control group. The operation time was recorded and compared in two groups. Accuracy of reconstruction was measured by superimposing the preoperative image onto the postoperative image of mandible. The selected bony landmark, distance and angle were measured. The mean total operation time and reconstruction time were 1.60±0.37 and 5.54±0.50 hours in computer-assisted group, respectively; These were 2.58±0.45 and 6.54±0.70 hours in conventional group, respectively. Both operation time and reconstruction time were shorter in computer-assisted group. The difference between the preoperative and postoperative intercondylar distances, intergonial angle distances, anteroposterior distances and gonial angles were 2.92±1.15 and 4.48±1.41mm, 2.93±1.19 and 4.79±1.48mm, 4.31±1.24 and 5.61±1.41mm, 3.85±1.68° and 5.88±2.12° in the computer-assisted and conventional group, respectively. The differences between the preoperative and postoperative mandible is smaller in the computer-assisted group. Virtual planning and 3D printing modeling have the potential to increase mandibular reconstruction accuracy and reduce operation time. we believe that this technology for mandibular reconstruction in selected patients will become a used method and improve the quality of reconstruction

Participation and Division of Labor in User-Driven Algorithm Audits: How Do Everyday Users Work together to Surface Algorithmic Harms?

Recent years have witnessed an interesting phenomenon in which users come together to interrogate potentially harmful algorithmic behaviors they encounter in their everyday lives. Researchers have started to develop theoretical and empirical understandings of these user driven audits, with a hope to harness the power of users in detecting harmful machine behaviors. However, little is known about user participation and their division of labor in these audits, which are essential to support these collective efforts in the future. Through collecting and analyzing 17,984 tweets from four recent cases of user driven audits, we shed light on patterns of user participation and engagement, especially with the top contributors in each case. We also identified the various roles user generated content played in these audits, including hypothesizing, data collection, amplification, contextualization, and escalation. We discuss implications for designing tools to support user driven audits and users who labor to raise awareness of algorithm bias

Examination of the Anaerobic Growth of Campylobacter concisus

Campylobacter concisus is an oral bacterium that is associated with intestinal diseases. C. concisus was previously described as a bacterium that requires H2-enriched microaerobic conditions for growth. The level of H2 in the oral cavity is extremely low, suggesting that C. concisus is unlikely to have a microaerobic growth there. In this study, the anaerobic growth of C. concisus was investigated. The growth of fifty-seven oral C. concisus strains and six enteric C. concisus strains under various atmospheric conditions including anaerobic conditions with and without H2 was examined. The atmospheric conditions were generated using commercially available gas-generation systems. C. concisus putative virulence proteins were identified using mass spectrometry analysis. Under anaerobic conditions, 92% of the oral C. concisus strains (52/57) and all six enteric strains grew without the presence of H2 and the presence of H2 greatly increased C. concisus growth. An oral C. concisus strain was found to express a number of putative virulence proteins and the expression levels of these proteins were not affected by H2. The levels of H2 appeared to affect the optimal growth of C. concisus. This study provides useful information in understanding the natural colonization site and pathogenicity of C. concisus

Pathogenic Mutations Differentially Regulate Cell-to-Cell Transmission of α-Synuclein

Recent studies suggest that the cell-to-cell spread of pathological α-synuclein (α-syn) plays important roles in the development of Parkinson’s disease (PD). PD patients who carry α-syn gene mutations often have an earlier onset and more severe clinical symptoms and pathology than sporadic PD cases who carry the wild-type (WT) α-syn gene. However, the molecular mechanism by which α-syn gene mutations promote PD remains unclear. Here, we hypothesized that pathogenic mutations facilitate the intercellular transfer and cytotoxicity of α-syn, favoring an early disease onset and faster progression. We investigated the effects of eight known pathogenic mutations in human α-syn (A18T, A29S, A30P, E46K, H50Q, G51D, A53E, and A53T) on its pathological transmission in terms of secretion, aggregation, intracellular level, cytotoxicity, seeding, and induction of neuroinflammation in SH-SY5Y neuroblastoma cells, cultured rat neurons, and microglia, and the rat substantia nigra pars compacta. We found that 2 of the 8 mutations (H50Q and A53T) significantly increased α-syn secretion while 6 mutations (A18T, A29S, A30P, G51D, A53E, and E46K) tended to enhance it. In vitroα-syn aggregation experiments showed that H50Q promoted while G51D delayed aggregation most strongly. Interestingly, 3 mutations (E46K, H50Q, and G51D) greatly increased the intracellular α-syn level when cultured cells were treated with preformed α-syn fibrils (PFFs) compared with the WT, while the other 5 had no effect. We also demonstrated that H50Q, G51D, and A53T PFFs, but not E46K PFFs, efficiently seeded in vivo and acutely induced neuroinflammation in rat substantia nigra pars compacta. Our data indicate that pathogenic mutations augment the prion-like spread of α-syn at different steps and blockade of this pathogenic propagation may serve as a promising therapeutic intervention for PD

Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer's mice

The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid β protein (Aβ)–induced neuronal death. However, the function of TNFR1 in Aβ plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1−/−) inhibits Aβ generation and diminishes Aβ plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced β-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-κB pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Aβ plaque formation. Thus, TNFR1 is a novel therapeutic target for AD