Redox homeostasis as a target for new antimycobacterial agents

Despite early treatment with antimycobacterial combination therapy, drug resistance continues to emerge. Maintenance of redox homeostasis is essential for Mycobacterium avium (M. avium) survival and growth. The aim of the present study was to investigate the antimycobacterial activity of two pro-glutathione (pro-GSH) drugs that are able to induce redox stress in M. avium and to modulate cytokine production by macrophages. Hence, we investigated two molecules shown to possess antiviral and immunomodulatory properties: C4-GSH, an N-butanoyl GSH derivative; and I-152, a prodrug of N-acetyl-cysteine (NAC) and β-mercaptoethylamine (MEA). Both molecules showed activity against replicating M. avium, both in the cell-free model and inside macrophages. Moreover, they were even more effective in reducing the viability of bacteria that had been kept in water for 7 days, proving to be active both against replicating and non-replicating bacteria. By regulating the macrophage redox state, I-152 modulated cytokine production. In particular, higher levels of interferon-gamma (IFN-γ), interleukin 1 beta (IL-1β), IL-18 and IL-12, which are known to be crucial for the control of intracellular pathogens, were found after I-152 treatment. Our results show that C4-GSH and I-152, by inducing perturbation of redox equilibrium, exert bacteriostatic and bactericidal activity against M. avium. Moreover, I-152 can boost the host response by inducing the production of cytokines that serve as key regulators of the Th1 response

Non-Functional Jaw Muscular Activity in Patients with Disorders of Consciousness Revealed by A Long-Lasting Polygraphy

The presence of involuntary, non-functional jaw muscle activity (NFJMA) has not yet been assessed in patients with disorders of consciousness (DOC), although the presence of bruxism and other forms of movement disorders involving facial muscles is probably more frequent than believed. In this work, we evaluated twenty-two prolonged or chronic DOC patients with a long-lasting polygraphic recording to verify NFJMA occurrence and assess its neurophysiological patterns in this group of patients. A total of 5 out of 22 patients showed the presence of significant NFJMA with electromyographic patterns similar to what can be observed in non-DOC patients with bruxism, thus suggesting a disinhibition of masticatory motor nuclei from the cortical control. On the other hand, in two DOC patients, electromyographic patterns advised for the presence of myorhythmia, thus suggesting a brainstem/diencephalic involvement. Functional, non-invasive tools such as long-lasting polygraphic recordings should be extended to a larger sample of patients, since they are increasingly important in revealing disorders potentially severe and impacting the quality of life of DOC patients

Aberrant DNA methylation profiles of inherited and sporadic colorectal cancer

Background: Aberrant DNA methylation has been widely investigated in sporadic colorectal carcinomas (CRCs), and extensive work has been performed to characterize different methylation profiles of CRC. Less information is available about the role of epigenetics in hereditary CRC and about the possible clinical use of epigenetic biomarkers in CRC, regardless of the etiopathogenesis. Long interspersed nucleotide element 1 (LINE-1) hypomethylation and gene-specific hypermethylation of 38 promoters were analyzed in multicenter series of 220 CRCs including 71 Lynch (Lynch colorectal cancer with microsatellite instability (LS-MSI)), 23 CRCs of patients under 40 years in which the main inherited CRC syndromes had been excluded (early-onset colorectal cancer with microsatellite stability (EO-MSS)), and 126 sporadic CRCs, comprising 28 cases with microsatellite instability (S-MSI) and 98 that were microsatellite stable (S-MSS). All tumor methylation patterns were integrated with clinicopathological and genetic characteristics, namely chromosomal instability (CIN), TP53 loss, BRAF, and KRAS mutations. Results: LS-MSI mainly showed absence of extensive DNA hypo-and hypermethylation. LINE-1 hypomethylation was observed in a subset of LS-MSI that were associated with the worse prognosis. Genetically, they commonly displayed G:A transition in the KRAS gene and absence of a CIN phenotype and of TP53 loss. S-MSI exhibited a specific epigenetic profile showing low rates of LINE-1 hypomethylation and extensive gene hypermethylation. S-MSI were mainly characterized by MLH1 methylation, BRAF mutation, and absence of a CIN phenotype and of TP53 loss. By contrast, S-MSS showed a high frequency of LINE-1 hypomethylation and of CIN, and they were associated with a worse prognosis. EO-MSS were a genetically and epigenetically heterogeneous group of CRCs. Like LS-MSI, some EO-MSS displayed low rates of DNA hypo-or hypermethylation and frequent G:A transitions in the KRAS gene, suggesting that a genetic syndrome might still be unrevealed in these patients. By contrast, some EO-MSS showed similar features to those observed in S-MSS, such as LINE-1 hypomethylation, CIN, and TP53 deletion. In all four classes, hypermethylation of ESR1, GATA5, and WT1 was very common. Conclusions: Aberrant DNA methylation analysis allows the identification of different subsets of CRCs. This study confirms the potential utility of methylation tests for early detection of CRC and suggests that LINE-1 hypomethylation may be a useful prognostic marker in both sporadic and inherited CRCs

Engagement of CD99 activates distinct programs in Ewing sarcoma and macrophages

Ewing sarcoma (EWS) is the second most common pediatric bone tumor. The EWS tumor microenvironment is largely recognized as immune-cold, with macrophages being the most abundant immune cells and their presence associated with worse patient prognosis. Expression of CD99 is a hallmark of EWS cells, and its targeting induces inhibition of EWS tumor growth through a poorly understood mechanism. In this study, we analyzed CD99 expression and functions on macrophages and investigated whether the concomitant targeting of CD99 on both tumor and macrophages could explain the inhibitory effect of this approach against EWS. Targeting CD99 on EWS cells downregulated expression of the "don't eat-me" CD47 molecule but increased levels of the "eat-me" phosphatidyl serine and calreticulin molecules on the outer leaflet of the tumor cell membrane, triggering phagocytosis and digestion of EWS cells by macrophages. In addition, CD99 ligation induced reprogramming of undifferentiated M0 macrophages and M2-like macrophages toward the inflammatory M1-like phenotype. These events resulted in the inhibition of EWS tumor growth. Thus, this study reveals what we believe to be a previously unrecognized function of CD99, which engenders a virtuous circle that delivers intrinsic cell death signals to EWS cells, favors tumor cell phagocytosis by macrophages, and promotes the expression of various molecules and cytokines, which are pro-inflammatory and usually associated with tumor regression. This raises the possibility that CD99 may be involved in boosting the antitumor activity of macrophages

Lifelong bilingualism and mechanisms of neuroprotection in Alzheimer dementia.

Lifelong bilingualism is associated with delayed dementia onset, suggesting a protective effect on the brain. Here, we aim to study the effects of lifelong bilingualism as a dichotomous and continuous phenomenon, on brain metabolism and connectivity in individuals with Alzheimer's dementia. Ninety-eight patients with Alzheimer's dementia (56 monolinguals; 42 bilinguals) from three centers entered the study. All underwent an [18F]-fluorodeoxyglucose positron emission tomography (PET) imaging session. A language background questionnaire measured the level of language use for conversation and reading. Severity of brain hypometabolism and strength of connectivity of the major neurocognitive networks was compared across monolingual and bilingual individuals, and tested against the frequency of second language life-long usage. Age, years of education, and MMSE score were included in all above mentioned analyses as nuisance covariates. Cerebral hypometabolism was more severe in bilingual compared to monolingual patients; severity of hypometabolism positively correlated with the degree of second language use. The metabolic connectivity analyses showed increased connectivity in the executive, language, and anterior default mode networks in bilingual compared to monolingual patients. The change in neuronal connectivity was stronger in subjects with higher second language use. All effects were most pronounced in the left cerebral hemisphere. The neuroprotective effects of lifelong bilingualism act both against neurodegenerative processes and through the modulation of brain networks connectivity. These findings highlight the relevance of lifelong bilingualism in brain reserve and compensation, supporting bilingual education and social interventions aimed at usage, and maintenance of two or more languages, including dialects, especially crucial in the elderly people

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders