Assessing the Potential of N-Butyl-l-deoxynojirimycin (l-NBDNJ) in Models of Cystic Fibrosis as a Promising Antibacterial Agent.

Over the past few years, l-iminosugars have revealed attractive pharmacological properties for managing rare diseases including Cystic Fibrosis (CF). The iminosugar N-butyl-l-deoxynojirimycin (l-NBDNJ, ent-1), prepared by a carbohydrate-based route, was herein evaluated for its anti-inflammatory and anti-infective potential in models of CF lung disease infection. A significant decrease in the bacterial load in the airways was observed in the murine model of Pseudomonas aeruginosa chronic infection in the presence of l-NBDNJ, also accompanied by a modest reduction of inflammatory cells. Mechanistic insights into the observed activity revealed that l-NBDNJ interferes with the expression of proteins regulating cytoskeleton assembly and organization of the host cell, downregulates the main virulence factors of P. aeruginosa involved in the host response, and affects pathogen adhesion to human cells. These findings along with the observation of the absence of an in vitro bacteriostatic/bactericidal action of l-NBDNJ suggest the potential use of this glycomimetic as an antivirulence agent in the management of CF lung disease.

Phylogenomics of Acinetobacter species and analysis of antimicrobial resistance genes.

Introduction: Non-baumannii Acinetobacter species are increasingly isolated in the clinical setting and the environment. The aim of the present study was to analyze a genome database of 837 Acinetobacter spp. isolates, which included 798 non-baumannii Acinetobacter genomes, in order to define the concordance of classification and discriminatory power of 7-gene MLST, 53-gene MLST, and single-nucleotide polymorphism (SNPs) phylogenies. Methods: Phylogenies were performed on Pasteur Multilocus Sequence Typing (MLST) or ribosomal Multilocus Sequence Typing (rMLST) concatenated alleles, or SNPs extracted from core genome alignment. Results: The Pasteur MLST scheme was able to identify and genotype 72 species in the Acinetobacter genus, with classification results concordant with the ribosomal MLST scheme. The discriminatory power and genotyping reliability of the Pasteur MLST scheme were assessed in comparison to genome-wide SNP phylogeny on 535 non-baumannii Acinetobacter genomes assigned to Acinetobacter pittii, Acinetobacter nosocomialis, Acinetobacter seifertii, and Acinetobacter lactucae (heterotypic synonym of Acinetobacter dijkshoorniae), which were the most clinically relevant non-baumannii species of the A. baumannii group. The Pasteur MLST and SNP phylogenies were congruent at Robinson-Fould and Matching cluster tests and grouped genomes into four and three clusters in A. pittii, respectively, and one each in A. seifertii. Furthermore, A. lactucae genomes were grouped into one cluster within A. pittii genomes. The SNP phylogeny of A. nosocomialis genomes showed a heterogeneous population and did not correspond to the Pasteur MLST phylogeny, which identified two recombinant clusters. The antimicrobial resistance genes belonging to at least three different antimicrobial classes were identified in 91 isolates assigned to 17 distinct species in the Acinetobacter genus. Moreover, the presence of a class D oxacillinase, which is a naturally occurring enzyme in several Acinetobacter species, was found in 503 isolates assigned to 35 Acinetobacter species. Conclusion: In conclusion, Pasteur MLST phylogeny of non-baumannii Acinetobacter isolates coupled with in silico detection of antimicrobial resistance makes it important to study the population structure and epidemiology of Acinetobacter spp. isolates.

PYED-1 Overcomes Colistin Resistance in Acinetobacter baumannii.

Antibiotic resistance has become more and more widespread over the recent decades, becoming a major global health problem and causing colistin to be increasingly used as an antibiotic of last resort. Acinetobacter baumannii, an opportunistic pathogen that has rapidly evolved into a superbug exhibiting multidrug-resistant phenotypes, is responsible for a large number of hospital infection outbreaks. With the intensive use of colistin, A. baumannii resistance to colistin has been found to increase significantly. In previous work, we identified a deflazacort derivative, PYED-1 (pregnadiene-11-hydroxy-16,17-epoxy-3,20-dione-1), which exhibits either direct-acting or synergistic activity against Gram-positive and Gram-negative species and Candida spp., including A. baumannii. The aim of this study was to evaluate the antibacterial activity of PYED-1 in combination with colistin against both A. baumannii planktonic and sessile cells. Furthermore, the cytotoxicity of PYED-1 with and without colistin was assessed. Our results show that PYED-1 and colistin can act synergistically to produce a strong antimicrobial effect against multidrug-resistant populations of A. baumannii. Interestingly, our data reveal that PYED-1 is able to restore the efficacy of colistin against all colistin-resistant A. baumannii isolates. This drug combination could achieve a much stronger antimicrobial effect than colistin while using a much smaller dosage of the drugs, additionally eliminating the toxicity and resistance issues associated with the use of colistin.

Corrigendum: Case report: Pragmatic impairment in multiple sclerosis after worsening of clinical symptoms.

[This corrects the article DOI: 10.3389/fpsyg.2022.1028814.].

Case report: Pragmatic impairment in multiple sclerosis after worsening of clinical symptoms.

Pragmatics, defined as the ability to integrate language and context to communicate effectively, may be impaired in Multiple Sclerosis (MS). We present the case of a patient with active secondary progressive MS who, after a first neuropsychological assessment that evidenced only a slight pragmatic impairment, suffered a sudden worsening of her clinical conditions, treated with corticosteroids. After this clinical worsening, her pragmatic abilities declined markedly, both in comprehension and production. This worsening was accompanied by a decline only in one attention task, in the context of an overall stable cognitive functioning. We conclude that pragmatics may be a domain particularly susceptible to cognitive worsening, highlighting the importance of its assessment in clinical practice.

Resveratrol Reverts Tolerance and Restores Susceptibility to Chlorhexidine and Benzalkonium in Gram-Negative Bacteria, Gram-Positive Bacteria and Yeasts.

The spread of microorganisms causing health-care associated infection (HAI) is contributed to by their intrinsic tolerance to a variety of biocides, used as antiseptics or disinfectants. The natural monomeric stilbenoid resveratrol (RV) is able to modulate the susceptibility to the chlorhexidine digluconate (CHX) biocide in Acinetobacter baumannii. In this study, a panel of reference strains and clinical isolates of Gram-negative bacteria, Gram-positive bacteria and yeasts were analyzed for susceptibility to CHX and benzalkonium chloride (BZK) and found to be tolerant to one or both biocides. The carbonyl cyanide m-chlorophenylhydrazine protonophore (CCCP) efflux pump inhibitor reduced the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CHX and BZK in the majority of strains. RV reduced dose-dependently MIC and MBC of CHX and BZK biocides when used as single agents or in combination in all analyzed strains, but not CHX MIC and MBC in Pseudomonas aeruginosa, Candida albicans, Klebsiella pneumoniae, Stenotrophomonas maltophilia and Burkholderia spp. strains. In conclusion, RV reverts tolerance and restores susceptibility to CHX and BZK in the majority of microorganisms responsible for HAI. These results indicates that the combination of RV, CHX and BZK may represent a useful strategy to maintain susceptibility to biocides in several nosocomial pathogens.

Clinical Impact of Aspergillus fumigatus in Children with Cystic Fibrosis.

Background. The clinical relevance of Aspergillus fumigatus (Af) in cystic fibrosis (CF) is controversial. The aims of the study were to assess the prevalence of Af disease in our cohort of CF patients and evaluate whether allergic bronchopulmonary aspergillosis (ABPA) and sensitization to Af affected lung function, body mass index (BMI) and exacerbations. Methods. Clinical data and lung function of CF patients aged 6−18 years followed at the CF Centre of Parma (Italy) were recorded. Patients were classified as: patients with no signs of Af, patients sensitized or colonized by Af, patients with ABPA or patients with Aspergillus bronchitis (Ab). Results. Of 38 CF patients (14.2 years (6.2−18.8) M 23), 8 (21%) showed Af sensitization, 7 (18.4%) showed ABPA, 1 (2.6%) showed Af colonization and 1 (2.6%) showed Ab. Compared to non-ABPA, patients with ABPA had lower BMI (15.9 ± 1.6 vs. 19.7 ± 3.4, p < 0.005), lower lung function (FEV1 61.5 ± 25.9% vs. 92.3 ± 19.3%, p < 0.001) and more exacerbations/year (4.43 ± 2.44 vs. 1.74 ± 2.33, p < 0.005). Patients with Af sensitization showed more exacerbations/year than non-Af patients (3.5 ± 3.2 vs. 0.9 ± 1.2, p < 0.005). ABPA and sensitized patients had more abnormalities on chest CT scans. Conclusion. This study showed the relevant clinical impact of ABPA and Af sensitization in terms of exacerbations and lung structural damage.

MECHANISMS OF HYPNOTIC ANALGESIA EXPLAINED BY FUNCTIONAL MAGNETIC RESONANCE (fMRI).

Hypnotic-focused analgesia (HFA) was produced in 20 highly hypnotizable subjects receiving nociceptive stimulations while undergoing functional magnetic resonance imaging (fMRI). The fMRI pattern in brain cortex activation while receiving a painful stimulus was recorded both during nonhypnosis and during HFA. The scanning protocol included the acquisition of a T1-weighted structural scan, 4 functional scans, a T2-weighted axial scan, and a fluid attenuated inversion recovery (FLAIR) scan. Total imaging time, including localization and structural image acquisitions, was approximately 60 minutes. Without HFA, the subjects reported subjective presence of pain, and the cortex primary sensory areas S1, S2, and S3 were activated. During HFA, the subjects reported complete absence of subjective pain and S1, S2, and S3 were deactivated. The findings suggest that HFA may prevent painful stimuli from reaching the sensory brain cortex, possibly through a gate-control mechanism.

Multiple brain networks support processing speed abilities of patients with multiple sclerosis.

Objectives: Many people affected by multiple sclerosis (MS) experience cognitive impairment, especially decreases in information processing speed (PS). Neural disconnection is thought to represent the neural marker of this symptom, although the role played by alterations of specific functional brain networks still remains unclear. The aim is to investigate and compare patterns of association between PS-demanding cognitive performance and functional connectivity across two MS phenotypes. Methods: Forty patients with relapsing-remitting MS (RRMS) and 25 with secondary progressive MS (SPMS) had neuropsychological and MRI assessments. Multiple regression models were used to investigate the relationship between performance on tests of visuomotor and verbal PS, and on the verbal fluency tests, and functional connectivity of four cognitive networks, i.e. left and right frontoparietal, salience and default-mode, and two control networks, i.e. visual and sensorimotor. Results: Patients with SPMS were older and had longer disease history than patients with RRMS and presented with worse overall clinical conditions: higher disease severity, total lesion volume, and cognitive impairment rates. However, in both patient samples, cognitive performance across tests was negatively correlated with functional connectivity of the salience and default-mode networks, and positively with connectivity of the left frontoparietal network. Only the visuomotor PS scores of the RRMS group were also associated with connectivity of the sensorimotor network. Conclusions: PS-demanding cognitive performance in patients with MS appears mainly associated with strength of functional connectivity of frontal networks involved in the evaluation and manipulation of information, as well as the default mode network. These results are in line with the hypothesis that multiple neural networks are needed to support normal cognitive performance across MS phenotypes. However, different PS measures showed partially different patterns of association with functional connectivity. Therefore, further investigations are needed to clarify the contribution of inter-network communication to specific cognitive deficits due to MS.

Cognitive speed and white matter integrity in secondary progressive multiple sclerosis.

BACKGROUND: Processing speed (PS) deficits have been consistently observed in secondary progressive multiple sclerosis (SPMS). However, the underlying neural correlates have not been clarified yet. The present study aimed to investigate the relationship between macrostructural and microstructural white matter (WM) integrity and performance on different cognitive measures with prominent PS load. METHODS: Thirty-one patients with SPMS were recruited and underwent neurological, neuropsychological, and MRI assessments. The associations between a composite index of PS abilities and scores on various tests with prominent PS load and T1-weighted and diffusion tensor image parameters were tested. Analyses were carried out using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS). RESULTS: VBM results showed that only the semantic fluency task correlated with grey matter (GM) volume in a range of cortical and subcortical areas bilaterally as well as the corpus callosum and the superior longitudinal fasciculus. TBSS analysis revealed consistent results across all the cognitive measures investigated, showing a prominent role of commissural and frontal associative WM tracts in supporting PS-demanding cognitive operations. CONCLUSIONS: In patients with SPMS, PS abilities are mainly dependent on the degree of both macrostructural and microstructural WM integrity. Preservation of associative WM tracts that support information integration seems crucial to sustain performance in tasks requiring fast cognitive processes.

Expiratory and phonation times as measures of disease severity in patients with Multiple Sclerosis. A case-control study.

BACKGROUND: Speech disorders are common in patients with Multiple Sclerosis (MS). They can be assessed with several methods, which are however expensive, complex, and not easily accessible to physicians during routine clinic visits. This study aimed at measuring maximum phonation times, maximum expiratory times, and articulation abilities scores in patients with MS compared to healthy subjects and at investigating if any of these parameters could be used as a measure of MS progression. METHODS: 50 MS patients and 50 gender- and age-matched healthy controls were enrolled in the study. Maximum expiratory times and maximum phonation times were collected from both groups. Articulation abilities were evaluated using the articulation subtest from the Fussi assessment (dysarthria scores). MS patients were evaluated with the Expanded Disability Status Scale (EDSS). Correlations between EDSS scores and maximum expiratory times, maximum phonation times, and dysarthria scores were calculated. RESULTS: EDSS scores of MS patients ranged from 4.5 to 7.5. In MS patients, maximum expiratory times, maximum phonation times, and dysarthria scores were significantly altered compared to healthy controls. Moreover, the EDSS scores were correlated with the maximum expiratory times; the maximum expiratory times were correlated with the maximum phonation times, and the maximum phonation times were correlated with the dysarthria scores. CONCLUSIONS: As the expiratory times were significantly correlated with the EDSS scores, they could be used to measure the severity of MS and to monitor its progression.

Physical rehabilitation modulates microRNAs involved in multiple sclerosis: a case report.

This study shows that neuromuscular taping improves gait, balance, pain and ability to walk and conduct daily activities in a multiple sclerosis patient. It is the first study to identify a panel of miRNAs modulated throughout rehabilitation using neuromuscular taping in a multiple sclerosis patient.

Personality functioning in patients with a progressive course of multiple sclerosis.

This study intended to describe general personality functioning in patients with a progressive course of multiple sclerosis. 55 consecutive rehabilitation inpatients with progressive course of multiple sclerosis were assessed with a multimethod test battery: the Expanded Disability Status Scale, the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Rosenberg Self-esteem Scale, and the Rorschach Test administered and scored with Comprehensive System. The control group comprised 55 healthy participants with similar sociodemographic characteristics. Specific differences were found for both cognitive and affective aspects, as the patients with progressive course of multiple sclerosis had less positive self-image, less effective mediation processing, and an affective approach to reality. Present data illustrated the usefulness of examining patients with a progressive course of multiple sclerosis to identify abilities and difficulties in cognitive and affective patterns, and support better adaptation to relationships and the environment.

Servicios de provisión de agua potable y desag³es cloacales: regulación y control

Analiza la normativa vigente aplicable a la concesión de los servicios de provisión de agua potable y desag³es cloacales, teniendo en cuenta la necesidad de aplicar adecuados mecanismos de regulación y control. Señala los derechos y obligaciones de los principales actores del servicio, la distribución de las facultades del control y formula una propuesta para la organización y funcionamiento del ente regulador

Servicios de provisión de agua potable y desagues cloacales. Regulación y control

A partir de las disposiciones contenidas en la normativa vigente, aplicable a la Concesión de los Servicios de Provisión de Agua Potable y Desagues Cloacales y teniendo en cuenta la necesidad de aplicar adecuados mecanismos de regulación y control, se analizan los derechos y obligaciones de los principales actores del servicio concesionado, la distribución de las facultades de control correspondientes al ejercicio del Poder de Policía y se formula una propuesta para la organización y funcionamiento del Ente Regulador, que se estima adecuada para la protección del usuario como objetivo fundamental