ILB® attenuates clinical symptoms and serum biomarkers of oxidative/nitrosative stress and mitochondrial dysfunction in patients with Amyotrophic Lateral Sclerosis

Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB®. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients' clinical conditions, indicating a response to ILB® treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes

The interplay among psychopathology, personal resources, context-related factors and real-life functioning in schizophrenia: stability in relationships after 4 years and differences in network structure between recovered and non-recovered patients

Improving real-life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses previously explored, by using network analysis, the interplay among illness-related variables, personal resources, context-related factors and real-life functioning in a large sample of patients with schizophrenia. The same research network has now completed a 4-year follow-up of the original sample. In the present study, we used network analysis to test whether the pattern of relationships among all variables investigated at baseline was similar at follow-up. In addition, we compared the network structure of patients who were classified as recovered at follow-up versus those who did not recover. Six hundred eighteen subjects recruited at baseline could be assessed in the follow-up study. The network structure did not change significantly from baseline to follow-up, and the overall strength of the connections among variables increased slightly, but not significantly. Functional capacity and everyday life skills had a high betweenness and closeness in the network at follow-up, as they had at baseline, while psychopathological variables remained more peripheral. The network structure and connectivity of non-recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other's activation, contributing to poor outcome in schizophrenia. Early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia

The interplay among psychopathology, personal resources, context-related factors and real-life functioning in schizophrenia: stability in relationships after 4 years and differences in network structure between recovered and non-recovered patients

Improving real-life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses previously explored, by using network analysis, the interplay among illness-related variables, personal resources, context-related factors and real-life functioning in a large sample of patients with schizophrenia. The same research network has now completed a 4-year follow-up of the original sample. In the present study, we used network analysis to test whether the pattern of relationships among all variables investigated at baseline was similar at follow-up. In addition, we compared the network structure of patients who were classified as recovered at follow-up versus those who did not recover. Six hundred eighteen subjects recruited at baseline could be assessed in the follow-up study. The network structure did not change significantly from baseline to follow-up, and the overall strength of the connections among variables increased slightly, but not significantly. Functional capacity and everyday life skills had a high betweenness and closeness in the network at follow-up, as they had at baseline, while psychopathological variables remained more peripheral. The network structure and connectivity of non-recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other's activation, contributing to poor outcome in schizophrenia. Early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia

Functional characterization of the gonococcal polyphosphate pseudo-capsule

Neisseria gonorrhoeae is an exclusively human pathogen able to evade the host immune system through multiple mechanisms. Gonococci accumulate a large portion of phosphate moieties as polyphosphate (polyP) on the exterior of their cells, however its function has not been yet clarified. Although its polyanionic nature has suggested that it may form a protective shield on the cell surface, its role has remained controversial. Taking advantage of a recombinant His-tagged polyP-binding protein, the presence of a polyP pseudo-capsule in gonococcus was demonstrated. Interestingly, the polyP shield was found to be strain specific. To investigate its functional role in host immune evasion, such as resistance to serum bactericidal activity, phagocytosis and antimicrobial peptides, the enzymes involved in polyP metabolism were genetically deleted, generating mutants with altered polyP external production. To this regard, mutants not expressing polyP on their surface, became sensitive to complement-mediated killing in presence of normal human serum. Conversely, naturally serum sensitive strains did not display polyP pseudo-capsule and could reverse their phenotype in the presence of exogenous polyP. Resistance to phagocytic killing was assessed by using differentiated HL60, a validated cell model for gonococcus-neutrophils interaction. Results exhibited a significant increase in viability of strains shielded with polyP in comparison to those lacking it on their surface. Interestingly, the addition of exogenous polyP restored bacterial survival. Finally, the presence of polyP pseudo-capsule was critical also in the protection from antibacterial activity of cationic antimicrobial peptide, like the cathelicidin LL-37. Indeed, results evidenced that the minimum bactericidal concentration was significantly lower in strains lacking polyP than in those harboring the pseudo-capsule, a condition that overturned after the complementation with exogenous polyP. Taken together, data presented have suggested an essential role of polyP pseudo-capsule in the gonococcal pathogenesis, paving the way to a new perspective on gonococcal biology and new treatments

Long-term adaptation of Daphnia to toxic environment in Lake Orta: the effects of short-term exposure to copper and acidification

Because of its 80-year history of heavy pollution and re-colonization, Lake Orta provides a good opportunity for investigating the response of zooplankton organisms to heavy metals and acidification as well as the mechanisms involved. After the recent establishment of Daphnia galeata Sars, and the detection of an extremely low clonal diversity of Lake Orta population, we carried out a study to investigate the lethal tolerance to ionic copper, as well as to acidity, and the impact of newborn Daphnia exposure to sublethal concentrations of copper for their later development and reproduction. We conducted acute toxicity tests to estimate the EC50 for ionic copper and tolerance to low pH, as well as life table experiments. Tolerance to ionic copper was high, three times that reported in literature. An increased mortality soon after exposure to low pH confirmed a high sensitivity to acidity and explained the success of the species in Lake Orta only after pH recovery. An analysis of reproductive and demographic parameters revealed that D. galeata Sars was stressed at concentrations of ionic copper only twice higher than those presently recorded in the lake (i.e., ca 3 μg L-1). An increased cumulative number of eggs produced by each female were in fact counterbalanced by an increasing abortion rate, which resulted in an unaltered or lower intrinsic rate of population increase. Our results are likely due to the strong selective pressure, more than physiological processes (acclimation), in a polluted area in which only specific adapted clones are able to grow, confirming the results previously obtained on Lake Orta's D. obtusa Kurz population. The reproductive response and the relatively low within treatment variability suggest that clone specificity, rather than physiological acclimation, was the driving force. The low variability confirmed results previously obtained from life tables experiments on Lake Orta's D. obtusa clone. Overall, our results suggest that, despite the chemical recovery, Lake Orta may be regarded as highly vulnerable to biodiversity loss

Functional characterization of the gonococcal polyphosphate pseudo-capsule.

Neisseria gonorrhoeae is an exclusively human pathogen able to evade the host immune system through multiple mechanisms. Gonococci accumulate a large portion of phosphate moieties as polyphosphate (polyP) on the exterior of the cell. Although its polyanionic nature has suggested that it may form a protective shield on the cell surface, its role remains controversial. Taking advantage of a recombinant His-tagged polyP-binding protein, the presence of a polyP pseudo-capsule in gonococcus was demonstrated. Interestingly, the polyP pseudo-capsule was found to be present in specific strains only. To investigate its putative role in host immune evasion mechanisms, such as resistance to serum bactericidal activity, antimicrobial peptides and phagocytosis, the enzymes involved in polyP metabolism were genetically deleted, generating mutants with altered polyP external content. The mutants with lower polyP content on their surface compared to the wild-type strains, became sensitive to complement-mediated killing in presence of normal human serum. Conversely, naturally serum sensitive strains that did not display a significant polyP pseudo-capsule became resistant to complement in the presence of exogenous polyP. The presence of polyP pseudo-capsule was also critical in the protection from antibacterial activity of cationic antimicrobial peptide, such as cathelicidin LL-37. Results showed that the minimum bactericidal concentration was lower in strains lacking polyP than in those harboring the pseudo-capsule. Data referring to phagocytic killing resistance, assessed by using neutrophil-like cells, showed a significant decrease in viability of mutants lacking polyP on their cell surface in comparison to the wild-type strain. The addition of exogenous polyP overturned the killing phenotype of sensitive strains suggesting that gonococcus could exploit environmental polyP to survive to complement-mediated, cathelicidin and intracellular killing. Taken together, data presented here indicate an essential role of the polyP pseudo-capsule in the gonococcal pathogenesis, opening new perspective on gonococcal biology and more effective treatments

Use of POCUS in Chest Pain and Dyspnea in Emergency Department: What Role Could It Have?

Chest pain and dyspnea are common symptoms in patients presenting to the emergency room (ER); oftentimes it is not possible to clearly identify the underlying cause, which may cause the patient to have to return to the ER. In other cases, while it is possible to identify the underlying cause, it is necessary to perform a large number of tests before being able to make a diagnosis. Over the last twenty years, emergency medicine physicians have had the possibility of using ultrasound to help them make and rule out diagnoses. Specific ultrasound tests have been designed to evaluate patients presenting with specific symptoms to ensure a fast, yet complete, evaluation. In this paper, we examine the role of ultrasound in helping physicians understand the etiology behind chest pain and dyspnea. We analyze the different diseases and disorders which may cause chest pain and dyspnea as symptoms and discuss the corresponding ultrasound findings

Strategies to Tackle Antimicrobial Resistance: The Example of Escherichia coli and Pseudomonas aeruginosa

Traditional antimicrobial treatments consist of drugs which target different essential functions in pathogens. Nevertheless, bacteria continue to evolve new mechanisms to evade this drug-mediated killing with surprising speed on the deployment of each new drug and antibiotic worldwide, a phenomenon called antimicrobial resistance (AMR). Nowadays, AMR represents a critical health threat, for which new medical interventions are urgently needed. By 2050, it is estimated that the leading cause of death will be through untreatable AMR pathogens. Although antibiotics remain a first-line treatment, non-antibiotic therapies such as prophylactic vaccines and therapeutic monoclonal antibodies (mAbs) are increasingly interesting alternatives to limit the spread of such antibiotic resistant microorganisms. For the discovery of new vaccines and mAbs, the search for effective antigens that are able to raise protective immune responses is a challenging undertaking. In this context, outer membrane vesicles (OMV) represent a promising approach, as they recapitulate the complete antigen repertoire that occurs on the surface of Gram-negative bacteria. In this review, we present Escherichia coli and Pseudomonas aeruginosa as specific examples of key AMR threats caused by Gram-negative bacteria and we discuss the current status of mAbs and vaccine approaches under development as well as how knowledge on OMV could benefit antigen discovery strategies