Evaluation of trace metal fluxes to soils in hinterland of Porto Marghera, industrial zone: comparisons with direct measurements in the Lagoon of Venice

Trace metal (As, Cd, Cr, Ni, Hg, Pb) concentrations in soil samples collected around the Porto Marghera (Italy) industrial district (2-40 km) near the city of Venice were compared with direct measurements of atmospheric deposition measured at comparable distances from the same source. Concentrations of Cd and Pb in soils decreased exponentially with increasing distance from the source; less clear signals were detected for As, Cr and Ni. Significant differences were found among the soils, which were partially resolved when applying normalisation to their clay contents. Preliminary comparisons of fluxes of Cd and Pb derived from soil with direct deposition measurements show increasing values with longer integration times. Annual Cd and Pb flux values of one year of direct deposition were 5 to 10 times lower than mean annual fluxes derived from soils, integrating 50 to 100 years. Values range from ~ 0.1-0.4 to 1-2 mg m -2 yr -1 for Cd, and from 3-18 to 50-100 mg m -2 yr -1 for Pb. These results fit information on “historical” emission trends as recorded in sediments of the lagoon

Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35ES0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria

Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease

BACKGROUND: Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD. METHODOLOGY/PRINCIPAL FINDINGS: We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls. CONCLUSIONS: Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD

Guideline on management of the acute asthma attack in children by Italian Society of Pediatrics

Background: Acute asthma attack is a frequent condition in children. It is one of the most common reasons for emergency department (ED) visit and hospitalization. Appropriate care is fundamental, considering both the high prevalence of asthma in children, and its life-threatening risks. Italian Society of Pediatrics recently issued a guideline on the management of acute asthma attack in children over age 2, in ambulatory and emergency department settings. Methods: The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was adopted. A literature search was performed using the Cochrane Library and Medline/PubMed databases, retrieving studies in English or Italian and including children over age 2 year. Results: Inhaled f2 agonists are the first line drugs for acute asthma attack in children. Ipratropium bromide should be added in moderate/severe attacks. Early use of systemic steroids is associated with reduced risk of ED visits and hospitalization. High doses of inhaled steroids should not replace systemic steroids. Aminophylline use should be avoided in mild/moderate attacks. Weak evidence supports its use in life-threatening attacks. Epinephrine should not be used in the treatment of acute asthma for its lower cost / benefit ratio, compared to \u3b22 agonists. Intravenous magnesium solphate could be used in children with severe attacks and/or forced expiratory volume1 (FEV1) lower than 60% predicted, unresponsive to initial inhaled therapy. Heliox could be administered in life-threatening attacks. Leukotriene receptor antagonists are not recommended. Conclusions: This Guideline is expected to be a useful resource in managing acute asthma attacks in children over age 2

Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients with COVID-19 Pneumonia: A Randomized Clinical Trial

Importance: Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. Objective: To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. Design, Setting, and Participants: This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (Pao2/Fio2) ratio between 350 and 200 mm Hg were eligible. Interventions: Patients in the experimental group received intravenous high-titer CP (≥1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. Main Outcomes and Measures: The primary outcome was a composite of worsening respiratory failure (Pao2/Fio2ratio <150 mm Hg) or death within 30 days from randomization. Results: Of the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P =.54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P =.04). Conclusions and Relevance: In patients with moderate to severe COVID-19 pneumonia, high-titer anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04716556

Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic

PMEL is a pigment cell-specific protein that forms physiological amyloid fibrils upon which melanins ultimately deposit in the lumen of the pigment organelle, the melanosome. Whereas hypomorphic PMEL mutations in several species result in a mild pigment dilution that is inherited in a recessive manner, PMEL alleles found in the Dominant white (DW) chicken and Silver horse (HoSi)—which bear mutations that alter the PMEL transmembrane domain (TMD) and that are thus outside the amyloid core—are associated with a striking loss of pigmentation that is inherited in a dominant fashion. Here we show that the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes, suggesting that they inhibit melanin production and/or melanosome integrity. A secondary mutation in the Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartments and thus averts DW–associated pigment loss; a secondary mutation found in the Dun chicken likely dampens a HoSi–like dominant mutation in a similar manner. We propose that the DW and HoSi mutations alter the normally benign amyloid to a pathogenic form that antagonizes melanosome function, and that the secondary mutations found in the Smoky and Dun chickens revert or dampen pathogenicity by functioning as null alleles, thus preventing the formation of aberrant fibrils. We speculate that PMEL mutations can model the conversion between physiological and pathological amyloid

Evidence for Sub-Haplogroup H5 of Mitochondrial DNA as a Risk Factor for Late Onset Alzheimer's Disease

BACKGROUND: Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD. METHODOLOGY/PRINCIPAL FINDINGS: We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls. CONCLUSIONS: Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD