Using integrated meta-omics to appreciate the role of the gut microbiota in epilepsy.

The way the human microbiota may modulate neurological pathologies is a fascinating matter of research. Epilepsy is a common neurological disorder, which has been largely investigated in correlation with microbiota health and function. However, the mechanisms that regulate this apparent connection are scarcely defined, and extensive effort has been conducted to understand the role of microbiota in preventing and reducing epileptic seizures. Intestinal bacteria seem to modulate the seizure frequency mainly by releasing neurotransmitters and inflammatory mediators. In order to elucidate the complex microbial contribution to epilepsy pathophysiology, integrated meta-omics could be pivotal. In fact, the combination of two or more meta-omics approaches allows a multifactorial study of microbial activity within the frame of disease or drug treatments. In this review, we provide information depicting and supporting the use of multi-omics to study the microbiota-epilepsy connection. We described different meta-omics analyses (metagenomics, metatranscriptomics, metaproteomics and metabolomics), focusing on current technical challenges in stool collection procedures, sample extraction methods and data processing. We further discussed the current advantages and limitations of using the integrative approach of multi-omics in epilepsy investigations.

Technological tools and strategies for culturing human gut microbiota in engineered in vitro models.

The gut microbiota directly impacts the pathophysiology of different human body districts. Consequently, microbiota investigation is an hot topic of research and its in vitro culture has gained extreme interest in different fields. However, the high sensitivity of microbiota to external stimuli, such as sampling procedure, and the physicochemical complexity of the gut environment make its in vitro culture a challenging task. New engineered microfluidic gut-on-a-chip devices have the potential to model some important features of the intestinal structure, but they are usually unable to sustain culture of microbiota over an extended period of time. The integration of gut-on-a-chip devices with bioreactors for continuous bacterial culture would lead to fast advances in the study of microbiota-host crosstalk. In this review, we summarize the main technologies for the continuous culture of microbiota as upstream systems to be coupled with microfluidic devices to study bacteria-host cells communication. The engineering of integrated microfluidic platforms, capable of sustaining both anaerobic and aerobic cultures, would be the starting point to unveil complex biological phenomena proper of the microbiota-host crosstalks, paving to way to multiple research and technological applications.

Increased transcription of transglutaminase 1 mediates neuronal death in in vitro models of neuronal stress and Aß1-42-mediated toxicity.

Alzheimer's disease (AD) is the most common cause of dementia. At the pre-symptomatic phase of the disease, the processing of the amyloid precursor protein (APP) produces toxic peptides, called amyloid-ß 1-42 (Aß 1-42). The downstream effects of Aß 1-42 production are not completely uncovered. Here, we report the involvement of transglutaminase 1 (TG1) in in vitro AD models of neuronal toxicity. TG1 was increased at late stages of the disease in the hippocampus of a mouse model of AD and in primary cortical neurons undergoing stress. Silencing of TGM1 gene was sufficient to prevent Aß-mediated neuronal death. Conversely, its overexpression enhanced cell death. TGM1 upregulation was mediated at the transcriptional level by an activator protein 1 (AP1) binding site that when mutated halted TGM1 promoter activation. These results indicate that TG1 acts downstream of Aß-toxicity, and that its stress-dependent increase makes it suitable for pharmacological intervention.

Association between Sirtuin 1 Gene rs10997870 Polymorphism and Suicide Behaviors in Bipolar Disorder.

BACKGROUND/AIMS: Suicidal behavior (SB) in bipolar disorder (BD) is a complex multifactorial event resulting from an interaction of genetic, neurobiological and psychosocial factors. Recent studies identified new possible mechanisms, suggesting a role for sirtuins (SIRTs 1-7), a family of nicotinamide adenine dinucleotide-dependent enzymes with a multifaceted role in the central nervous system. The aims of the present study were: (1) to investigate the effects of the rs10997870 SIRT1 gene variant on SB in BD; (2) to explore the effects of the same gene variant on specific depressive symptoms at the severest episode. METHODS: One hundred and eighty DSM-IV bipolar outpatients were enrolled in a naturalistic cohort study. The rs10997870 polymorphism within the SIRT1 gene was analyzed. RESULTS: An association between the GG genotype and SB was detected (lifetime: p = 0.015). Compared to other genotypes, GG carriers presented more frequently psychomotor agitation (p = 0.009) and a higher Hamilton Depression Rating Scale total score (p = 0.014) at the severest depressive episode. SB and psychomotor agitation were found to be associated with GG carriers and G allele in a multivariate analysis as well. CONCLUSION: Our findings suggest a role of the rs10997870 SIRT1 gene variant in SB amongst BD patients and its association with specific depressive symptoms. Despite a number of limitations of this exploratory study, our results may provide new insight into the mechanisms underlying SB in BD.

Clinical and genetic factors associated with suicide in mood disorder patients.

Suicidality is a continuum ranging from ideation to attempted and completed suicide, with a complex etiology involving both genetic heritability and environmental factors. The majority of suicide events occur in the context of psychiatric conditions, preeminently major depression and bipolar disorder. The present study investigates clinical factors associated with suicide in a sample of 553 mood disorder patients, recruited within the 'Psy Pluriel' center, Centre Européen de Psychologie Médicale, and the Department of Psychiatry of Erasme Hospital (Brussels). Furthermore, genetic association analyses examining polymorphisms within COMT, BDNF, MAPK1 and CREB1 genes were performed in a subsample of 259 bipolar patients. The presence or absence of a previous suicide attempt and of current suicide risk were assessed. A positive association with suicide attempt was reported for younger patients, females, lower educated, smokers, those with higher scores on depressive symptoms and higher functional disability and those with anxiety comorbidity and familial history of suicidality in first- and second-degree relatives. Anxiety disorder comorbidity was the stronger predictor of current suicide risk. No associations were found with polymorphisms within COMT and BDNF genes, whereas significant associations were found with variations in rs13515 (MAPK1) and rs6740584 (CREB1) polymorphisms. From a clinical perspective, our study proposes several clinical characteristics, such as increased depressive symptomatology, anxiety comorbidity, functional disability and family history of suicidality, as correlates associated with suicide. Genetic risk variants in MAPK1 and CREB1 genes might be involved in a dysregulation of inflammatory and neuroplasticity pathways and are worthy of future investigation.

[Efficacy of educational intervention for patients wearing peripherall inserted central catheter. A pilot study]. / Efficacia di un intervento educativo rivolto ai pazienti portatori di un catetere venoso centrale ad inserzione periferica: studio pilota.

BACKGROUND: Peripherally Inserted Central Catheter (PICC) is a central venous catheter suitable for patients who receive chemotherapy in Day Hospital regimen. The patient must be educated to a proper home management of the PICC through targeted education. AIM: To evaluate the effectiveness of a targeted educational intervention through the comparison of: indi- vidual interview, brochure paper, informative video. METHOD: Single-centre randomized controlled clinical trial with a simple three-arm comparative scheme. The study population is represented by all patients undergoing the insertion of PICC at the Oncological Day Hospital and Breast Unit in the observation period between October 2013 and February 2014. The Standard educational session is performed by the nurse positioning the PICC. PICC team consists of two nurses in possession of the first level master in venous access management. Following randomization eligible patients were divided in three groups: group A received Standard educational session; group B received the standard information and the brochure; group C received the stan- dard information and the informative video. The level of the achieved knowledge was investigated by administering targeted questionnaires. RESULTS: A total of 40 patients joined the study: a convenience sample represented by people between the ages of 18 and 75 years, in outpatient care. Statistically significant difference in key areas necessary for the proper management of PICC: when to change the dressing (p=0.001), when to wash the catheter (p=0), how to recognize signs and symptoms of infection (p=0.001), identify at-risk behaviors (p=0.005), when carrying out the inspection of the catheter's insertion site (p=0). CONCLUSIONS: The administration of a multimedial educational tool was found to be superior in efficacy compared to the only Standard educational session to increase patient's knowledges. The video appears to be more effective than the brochure. The obtained results are influenced by the small sample size and by the shortness of the follow up timing; this leads to a low generalizability of the conclusions.

Bronchial Progenitor Cells in Obstructive and Neoplastic Lung Disease: A Pilot Study.

The alteration of progenitor/stem cells present in the airway epithelium has been observed in patients with COPD. Smoking exposure induces remodeling patterns in bronchial progenitor cells (BPCs), encompassing squamous metaplasia, hyperplasia of basal and of mucus-secreting cells, and the depletion of ciliated and non-mucous secretory cells. Our aim was to assess the expression of p63 and vimentin as potential markers of airway remodeling and the regulation of stem cell populations in obstructive and neoplastic lung disease patients. A retrospective single-center observational study was conducted, including patients undergoing bronchoscopy with bronchial biopsies for suspected lung cancer. p63 and vimentin expression were evaluated via immunohistochemical analysis. There were 25 patients, of which 21 with COPD were included, and 17 were diagnosed with lung cancer. We observed that FEV1% was negatively correlated with p63+ basal cell number (r = -0.614, p = 0.019) and positively correlated with vimentin expression (r = 0.670; p = 0.008). p63 was significantly higher in biopsies from the trachea and main bronchi compared to more distal areas (p = 0.040), whereas vimentin was prevalent in the more distal areas (p = 0.042). Our preliminary data suggest the initial evidence of structural changes in BPCs among patients with COPD and lung cancer. Further research efforts are warranted to investigate additional morphologic and functional respiratory parameters in these patients.

The microbiota-gut-brain axis and epilepsy from a multidisciplinary perspective: Clinical evidence and technological solutions for improvement of in vitro preclinical models.

Epilepsy is a common neurological disease characterized by the enduring predisposition of the brain to generate seizures. Among the recognized causes, a role played by the gut microbiota in epilepsy has been hypothesized and supported by new investigative approaches. To dissect the microbiota-gut-brain (MGB) axis involvement in epilepsy, in vitro modeling approaches arouse interest among researchers in the field. This review summarizes, first of all, the evidence of a role of the MGB axis in epilepsy by providing an overview of the recent clinical and preclinical studies and showing how dietary modification, microbiome supplementations, and hence, microbiota alterations may have an impact on seizures. Subsequently, the currently available strategies to study epilepsy on animal and in vitro models are described, focusing attention on these latter and the technological challenges for integration with already existing MGB axis models. Finally, the implementation of existing epilepsy in vitro systems is discussed, offering a complete overview of the available technological tools which may improve reliability and clinical translation of the results towards the development of innovative therapeutic approaches, taking advantage of complementary technologies.

CSF cutoffs for MCI due to AD depend on APOEε4 carrier status.

Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aß42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aß42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aß42 and Aß42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis.

Asymptomatic Carriers of Presenilin-1 E318G Variant Show no Cerebrospinal Fluid Biochemical Signs Suggestive of Alzheimer's disease in a Family with Late-onset Dementia.

BACKGROUND: Presenilin-1 (PSEN-1) is a component of the γ-secretase complex involved in ß-amyloid Precursor Protein (AßPP) processing. Usually, Alzheimer's disease (AD)-linked mutations in the PSEN-1 gene lead to the early onset and increase the production of the aggregation-prone peptide Aß42. However, the PSEN-1 E318G variant has an unclear pathogenic role and is recently reported as a genetic risk factor for AD. In particular, E318G variant presence correlated with increased cerebrospinal fluid (CSF) levels of Total Tau (t-tau) and Phosphorylated Tau (p-tau). OBJECTIVE: We describe a large Italian family, which we followed from January 2003 to January 2018, with the late-onset AD and the E318G variant, with the aim of assessing E318G-associated CSF or plasma biochemical changes in biomarkers of dementia. METHOD: CSF Aß42, t-tau and p-tau, plasma Aß42 and Aß40 were assessed by ELISA tests, while CSF amyloid peptides profile was investigated by mass spectrometry. RESULTS: We did not find any changes in CSF biochemical markers (Aß42, t-tau, p-tau and amyloid peptides) of asymptomatic E318G carriers in 2010 and 2012, but plasma Aß40 was increased at the same times. From 2003 to 2018, no asymptomatic E318G carrier developed AD. CONCLUSION: Our follow-up of this family may help elucidate E318G's role in AD and globally points to a null effect of this variant.