Probiotics in autism spectrum disorders: a systematic review of clinical studies and future directions.

CONTEXT: It is hypothesized that gut dysbiosis, a typical feature of patients with autism spectrum disorder (ASD), could be involved in the origin of this neurodevelopmental disorder. Therefore, the use of probiotics to restore gastrointestinal (GI) equilibrium might be a promising therapeutic strategy due to its capacity to balance the gut-brain axis and behavioral responses. OBJECTIVE: To summarize current knowledge on the use of probiotics to treat core clinical ASD symptoms and concomitant GI signs, compare the design of published studies with those of ongoing trials, assess the near future of this field, and provide recommendations for improving novel studies. DATA SOURCES: The literature search was conducted in February 2020 and updated in March 2021, using a broad range of bibliographic and clinical trial-specific databases. DATA EXTRACTION: Data were extracted using a standardized form, and articles reporting on 28 clinical studies (already published or still ongoing) were included. The risk of bias in clinical studies was evaluated using the Cochrane Collaboration Risk of Bias Assessment tool for randomized trials and the Risk of Bias in Nonrandomized Studies-Interventions tool for nonrandomized trials. RESULTS: The results suggest that probiotics improve ASD-like social deficits, GI symptoms, and gut microbiota profile. However, inconsistencies among studies and their methodological limitations make it difficult to draw any conclusions regarding the efficacy of probiotics in ASD. This review provides specific suggestions for future research to improve the quality of the studies. CONCLUSIONS: Although ongoing studies have improved designs, the available knowledge does not permit solid conclusions to be made regarding the efficacy of probiotics in ameliorating the symptoms (psychiatric and/or GI) associated with ASD. Thus, more high-quality research and new approaches are needed to design effective probiotic strategies for ASD.

Invasive disease caused simultaneously by two different serotypes of Streptococcus pneumoniae: a microbiological appreciation.

We report a clinical case of a child with an invasive pneumococcal disease caused by two different pneumococcal serotypes that belonged to different sequence types. She was a 15-month-old girl with pneumonia and pleural effusion in which S. pneumoniae colonies with different morphologies grew, one from the blood culture (characteristic greyish appearance) and the other from the pleural fluid (mucoid appearance). The isolate from blood was serotype 22 F (ST698/CC698/GPSC61), while the isolate from the pleural fluid was serotype 3 (ST180/CC180/GPSC12). The patient fully recovered after treatment with intravenous ampicillin followed by oral amoxicillin.

A Novel Localization of METTL7A in Bergmann Glial Cells in Human Cerebellum.

Methyltransferase-like protein 7A (METTL7A) is a member of the METTL family of methyltransferases.Little information is available regarding the cellular expression of METTL7A in the brain. METTL7A is commonly located in the endoplasmic reticulum and to a lesser extent, in the lipid droplets of some cells. Several studies have reported altered protein and RNA levels in different brain areas in schizophrenia. One of these studies found reduced protein levels of METTL7A in the cerebellar cortex in schizophrenia and stress murine models. Since there is limited information in the literature about METTL7A, we characterized its cellular and subcellular localizations in the human cerebellum using immunohistochemical analysis with laser confocal microscopy. Our study reveals a novel METTL7A localization in GFAP-positive cells, with higher expression in the end-feet of the Bergmann glia, which participate in the cerebrospinal fluid-brain parenchyma barrier. Further 3D reconstruction image analysis showed that METTL7A was expressed in the contacts between the Bergmann glia and Purkinje neurons. METTL7A was also detected in lipid droplets in some cells in the white matter. The localization of METTL7A in the human cerebellar glia limitans could suggest a putative role in maintaining the cerebellar parenchyma homeostasis and in the regulation of internal cerebellar circuits by modulating the synaptic activity of Purkinje neurons.

Analysis of networks in the dorsolateral prefrontal cortex in chronic schizophrenia: Relevance of altered immune response.

The dorsolateral prefrontal cortex (DLPFC) has a crucial role in cognitive functioning and negative symptoms in schizophrenia. However, limited information of altered protein networks is available in this region in schizophrenia. We performed a proteomic analysis using single-shot liquid chromatography-tandem mass spectrometry of grey matter of postmortem DLPFC in chronic schizophrenia subjects (n = 20) and unaffected subjects (n = 20) followed by bioinformatic analysis to identify altered protein networks in schizophrenia (PXD024939 identifier in ProteomeXchange repository). Our results displayed a proteome profile in the DLPFC of 1989 proteins. 43 proteins were found significantly altered in schizophrenia. Analysis of this panel showed an enrichment of biological processes implicated in vesicle-mediated transport, processing and antigen presentation via MHC class II, intracellular transport and selenium metabolism. The enriched identified pathways were MHC class II antigen presentation, vesicle-mediated transport, Golgi ER retrograde transport, Nef mediated CD8 downregulation and the immune system. All these enriched categories were found to be downregulated. Furthermore, our network analyses showed crosstalk between proteins involved in MHC class II antigen presentation, membrane trafficking, Golgi-to-ER retrograde transport, Nef-mediated CD8 downregulation and the immune system with only one module built by 13 proteins. RAB7A showed eight interactions with proteins of all these pathways. Our results provide an altered molecular network involved in immune response in the DLPFC in schizophrenia with a central role of RAB7A. These results suggest that RAB7A or other proteins of this network could be potential targets for novel pharmacological strategies in schizophrenia for improving cognitive and negative symptoms.

Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models: Relationship to Cognitive Deficits in Schizophrenia.

Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia.

Evolution of Antimicrobial Susceptibility to Penicillin in Invasive Strains of Streptococcus pneumoniae during 2007-2021 in Madrid, Spain.

The use of pneumococcal conjugate vaccines has affected the epidemiology and distribution of Streptococcus pneumoniae serotypes causing Invasive Pneumococcal Disease (IPD). The aim of this study was to analyze the evolution of the phenotypical profiles of antimicrobial susceptibility to penicillin (PEN) in all IPD strains isolated in Madrid, Spain, during 2007-2021. In total, 7133 invasive clinical isolates were characterized between 2007 and 2021. Levels of PENR and PNSSDR were 2.0% and 24.2%, respectively. In addition, 94.4% of all the PENR belonged to four serotypes, including 11A (33.6%), 19A (30.8%), 14 (20.3%) and 9V (9.8%). All the strains of serotype 11A, which is a non-PCV13 serotype, were detected after the year 2011. Serotypes 6C, 15A, 23B, 24F, 35B, 19F, 16F, 6B, 23F, 24B, 24A, 15F and a limited number of strains of serogroups 16 and 24 (non-typed at serotype level) were associated with PNSSDR (p < 0.05). PNSSDR strains of non-PCV13 serotypes 11A, 24F, 23B, 24B, 23A and 16F were more frequent from 2014 to 2021. The changes in S. pneumoniae serotype distribution associated with the use of conjugate vaccines had caused in our region the emergence of non-PCV13 pneumococcal strains with different PENR or PNSSDR patterns. The emergence of serotype 11A resistant to penicillin as the most important non-PCV13 serotype is a worrisome event with marked relevance from the clinical and epidemiological perspective.

Distribution of Multidrug-Resistant Invasive Serotypes of Streptococcus pneumoniae during the Period 2007-2021 in Madrid, Spain.

After the systematic use of conjugate vaccines, the invasive pneumococcal disease (IPD) was included into the Madrid Notifiable Diseases Surveillance System through an Epidemiological Surveillance Network. Furthermore, Streptococcus pneumoniae was included in the Spanish Plan of Antibiotic Resistance. The aim of this study was to analyse the multidrug-resistant (MDR) phenotype distribution among invasive strains of Streptococcus pneumoniae isolated during 2007-2021 from usually sterile clinical samples in Madrid, Spain. A total number of 7133 invasive pneumococcal isolates were studied during the period from February 2007 to December 2021. Serotyping was characterised using the Pneumotest-Latex and by the Quellung reaction. Antibiotic susceptibility testing to penicillin (PEN), erythromycin (ERY), and levofloxacin (LVX) was performed using the E-test according to the EUCAST guidelines and breakpoints. Combination of non-susceptibility to PEN at standard dosing regimen (PNSSDR), resistance to ERY (ERYR) and to LVX (LVXR) was considered to be multidrug-resistant at standard dosing regimen of penicillin (MRPSDR), whereas the combination of resistance to PEN (PENR), ERYR, and LVXR was considered multidrug-resistant (MDR). The number of MDRPSDR and or MDR strains in the entire population (n = 7133) during the complete period (2007-2021) were 51 (0.7%) and 6 (0.1%), respectively. All MDRPSDR and/or MDR strains belonged to nine serotypes: 19A (n = 13), 15A (n = 12), 9V (n = 12), 14 (n = 7), 24F (n = 3), 15F (n = 1), 19F (n = 1), 6B (n = 1) and 6C (n = 1). Only two serotypes (9V and 19A) were found among MDR strains, and most of them (5/6) belonged to serotype 9V. Only 12.4% of the strains typified as serotype 9V were MDRPSDR and only 5.2% as MDR. The levels of pneumococcal MDRPSDR and/or MDR in this study were low and all six MDR strains were isolated between 2014 and 2018. These results reinforce the importance of monitoring the evolution of non-susceptible serotypes including those with MDR in the coming years, especially after the introduction of new conjugate vaccines of a broader spectrum.

Cross-Sectional Analysis of Risk Factors for Outbreak of COVID-19 in Nursing Homes for Older Adults in the Community of Madrid.

INTRODUCTION: Nursing homes for older adults have been hot spots for SARS-CoV-2 infections and mortality. Factors that facilitate COVID-19 outbreaks in these settings need to be assessed. METHODS: A retrospective cross-sectional study of a cohort of residents and workers in nursing homes taking occasion of a point seroprevalence survey was done in the Community of Madrid. Factors related to outbreaks in these facilities were analyzed. RESULTS: A total of 369 nursing homes for older adults, making a population of 23,756 residents and 20,795 staff members, were followed from July to December 2020. There were 54.2% SARS-CoV-2 IgG+ results in residents and in 32.2% of workers. Sixty-two nursing homes (16.8%) had an outbreak during the follow-up. Nursing homes with outbreaks had more residents than those without (median number of 81 [IQR, 74] vs. 50 [IQR, 56], p < 0.001). Seropositivity for SARS-CoV-2 was lower in facilities with versus without outbreaks, for residents (42.2% [IQR, 55.7] vs. 58.7% [IQR, 43.4], p = 0.002) and for workers (23.9% [IQR, 26.4] vs. 32.8% [IQR, 26.3], p = 0.01). For both residents and staff, the number of infections in outbreaks was larger in centers with lower, as compared with intermediate or high seroprevalence. The size of the facility did not correlate with the number of cases in the outbreak. Taking the incidence of cases in the community as a time-dependent variable (p = 0.03), a Cox analysis (HR [95% CI], p) showed that intermediate or high seroprevalence among residents in the facility was related to a reduction of 55% (0.45 [0.25-0.80], p = 0.007) and 78% (0.22 [0.10-0.48], p < 0.001) in the risk of outbreaks, respectively, as compared with low sero-prevalence. Also, as compared with smaller, medium (1.91 [1.00-3.65], p = 0.05) or large centers (4.57 [2.38-8.75], p < 0.001) had more respective risk of outbreaks. CONCLUSIONS: The size of the facility and the seroprevalence among residents in nursing homes, and the incidence of infections in the community, are associated with the risk of outbreaks of COVID-19. Facilities with greater proportion of seropositives had smaller number of cases. Monitoring of immunity in nursing homes may help detect those at a greater risk of future cases.

Developmental regulation of epithelial cell cuboidal-to-squamous transition in Drosophila follicle cells.

Epithelial cells form continuous membranous structures for organ formation, and these cells are classified into three major morphological categories: cuboidal, columnar, and squamous. It is crucial that cells transition between these shapes during the morphogenetic events of organogenesis, yet this process remains poorly understood. All three epithelial cell shapes can be found in the follicular epithelium of Drosophila egg chamber during oogenesis. Squamous cells (SCs) are initially restricted to the anterior terminus in cuboidal shape. They then rapidly become flattened to assume squamous shape by stretching and expansion in 12 â€‹h during midoogenesis. Previously, we reported that Notch signaling activated a zinc-finger transcription factor Broad (Br) at the end of early oogenesis. Here we report that ecdysone and JAK/STAT pathways subsequently converge on Br to serve as an important spatiotemporal regulator of this dramatic morphological change of SCs. The early uniform pattern of Br in the follicular epithelium is directly established by Notch signaling at stage 5 of oogenesis. Later, ecdysone and JAK/STAT signaling activities synergize to suppress Br in SCs from stage 8 to 10a, contributing to proper SC squamous shape. During this process, ecdysone signaling is essential for SC stretching, while JAK/STAT regulates SC clustering and cell fate determination. This study reveals an inhibitory role of ecdysone signaling in suppressing Br in epithelial cell remodeling. In this study we also used single-cell RNA sequencing data to highlight the shift in gene expression which occurs as Br is suppressed and cells become flattened.

Humoral and Cellular Response after mRNA Vaccination in Nursing Homes: Influence of Age and of History of COVID-19.

Background: Most residents and staff in nursing homes have received full vaccination. Factors related to the immune response to vaccination might be related to the risk of future severe COVID-19 and may guide the need for vaccine boosters. Design: Nursing homes that were tested in a point survey in July-October 2020 were again analyzed after a vaccination campaign in June-July 2021. Immune responses according to IgG against nucleocapsid and spike antigens, and CD4 and CD8 interferon-gamma release assay against spike antigens, were evaluated. Results: A total of 1973 subjects were tested (61.7% residents, 48.3% staff), with a mean (SD) follow-up of 46.4 (3.6) weeks between assessments. More than half of residents and more than a third of staff had evidence of COVID-19 before vaccination; 26.9% and 22.7% had seroreversion of IgG-N, and 8.9% and 4.6% had IgG-N seroconversion at second assessment, respectively. Up to 96.8% of residents and 98.1% of workers had positive IgG-S after a mean of 19.9 (2.1) weeks after vaccination. In residents with vs without a history of COVID-19, IgG-S titers were 4.11 (0.54) vs. 2.73 (0.74) logAU/mL (p < 0.001); in workers these titers were 3.89 (0.61) vs. 3.15 (0.64) logAU/mL (p < 0.001). Linear regression analysis showed that younger age (OR: −0.03 per 10 years-older [95% CI, −0.04 to −0.02], p < 0.001) and evidence of COVID-19 (OR: 1.14 [95% CI, 1.08 to 1.20], p < 0.001) are associated with greater IgG-S titers after vaccination. A direct association was found between IgG-S titers and the intensity of IFN-gamma response against spike antigens. Conclusions: Waning of humoral response and reinfection seems to be more frequent in older as compared to younger adults, although cellular responses shortly after vaccination are comparable between these groups. Younger age and prior COVID-19 are related to greater humoral response after vaccination against SARS-CoV-2.

Rendimiento del ensayo de amplificación mediada por transcriptasa (TMA) Procleix SARS-CoV-2 para el diagnóstico de COVID-19 en “pools” de muestras nasofaríngeas. Pequeño estudio piloto / Performance of the Procleix SARS-CoV-2 transcriptase-mediated amplification (TMA) assay for the diagnosis of COVID-19 in nasopharyngeal sample pools. Small pilot study

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A Pilot Study for the Evaluation of an Interferon Gamma Release Assay (IGRA) To Measure T-Cell Immune Responses after SARS-CoV-2 Infection or Vaccination in a Unique Cloistered Cohort.

Assessment of T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens may be of value to determine long-lasting protection to breakthrough infections or reinfections. Interferon gamma release assay is a validated method to test cellular immunity in mycobacterial infections and has been proposed for patients with SARS-CoV-2 infection or vaccination. Quantitative IgG to spike and qualitative IgG to nucleocapsid antigens were determined by chemiluminescence microparticle immunoassay using the Architect platform (Abbott), and interferon gamma release assays against two Qiagen proprietary mixes of SARS-CoV-2 spike protein (antigen 1 and antigen 2) were performed for a selected group of subjects. A total of 121 subjects in a cloistered institution after a COVID-19 outbreak was studied. IgG spike levels and interferon gamma concentrations were highest among subjects after two doses of vaccine, followed by patients with a longer history of past COVID-19 and no vaccination. The best cutoff for the interferon gamma assay was 25 IU/L for all subgroups of individuals and the two sets of SARS-CoV-2 antigens studied. Testing T-cell response may be of clinical utility to determine immunity after exposure to SARS-CoV-2 antigens, with the interferon gamma concentration of 25 IU/L as the best cutoff either after infection or vaccination.

Age-Dependent Serotype-Associated Case-Fatality Rate in Invasive Pneumococcal Disease in the Autonomous Community of Madrid between 2007 and 2020.

The aim of this study was to investigate the serotype-associated fatality rate in cases of invasive pneumococcal disease (IPD) in the Spanish region of Madrid between 2007 and 2020. Serotyping was performed by Pneumotest Latex and the Quellung reaction using commercial antisera. Case-fatality rate was estimated as the ratio between the number of deaths at hospital discharge and the number of cases attributable to each serotype. To evaluate the association measures, the odds ratios with a 95% confidence interval were calculated. Twenty five pneumococcal serotypes were associated to mortality and comprised 87.8% of the total number of isolates characterized. Serotypes 8, 3, 19A, 1, 7F, 22F, 12F, and 11A were the most prevalent (≥3% each). Serotypes 31, 11A, and 19F were significantly associated to high case-fatality rates (>20% each). The lower significantly associated case-fatality rate (<10% each) was found in serotypes 5, 1, 12B, 7F, 12F, 8, 33, and 10A. The serotypes with higher mortality levels (≥0.04 per 100,000 population) were 11A (fatality 24.0%), 3 (fatality 18.7%), 19A (fatality 12.5%), and 8 (fatality 7.2%). Serotype 3 was worrisome because it is associated with important fatality levels combined with very high incidence and mortality rates. Serotype 11A also showed a high fatality with marked incidence and mortality levels. Some few frequent serotypes as 31, 19F, and 15A despite its high fatality had low levels of mortality. By contrast other serotypes as 8 showing low fatality had high mortality ranges because it shows a wide extended distribution. Finally, common serotypes, such as 1 and 5, presented small mortality length, due to their low case-fatality rates.

Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology.

BACKGROUND: The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). METHODS: This work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. RESULTS: In the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. CONCLUSIONS: Thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.