Abstract
Intestinal barrier derangement allows intestinal bacteria and their products to translocate to the systemic circulation.
Pseudomonas aeruginosa
(
PA
) superimposed infection in critically ...ill patients increases gut permeability and leads to gut-driven sepsis.
PA
infections are challenging due to multi-drug resistance (MDR), biofilms, and/or antibiotic tolerance. Inhibition of the quorum-sensing transcriptional regulator MvfR(PqsR) is a desirable anti-
PA
anti-virulence strategy as MvfR controls multiple acute and chronic virulence functions. Here we show that MvfR promotes intestinal permeability and report potent anti-MvfR compounds, the N-Aryl Malonamides (NAMs), resulting from extensive structure-activity-relationship studies and thorough assessment of the inhibition of MvfR-controlled virulence functions. This class of anti-virulence non-native ligand-based agents has a half-maximal inhibitory concentration in the nanomolar range and strong target engagement. Using a NAM lead in monotherapy protects murine intestinal barrier function, abolishes MvfR-regulated small molecules, ameliorates bacterial dissemination, and lowers inflammatory cytokines. This study demonstrates the importance of MvfR in
PA
-driven intestinal permeability. It underscores the utility of anti-MvfR agents in maintaining gut mucosal integrity, which should be part of any successful strategy to prevent/treat
PA
infections and associated gut-derived sepsis in critical illness settings. NAMs provide for the development of crucial preventive/therapeutic monotherapy options against untreatable MDR
PA
infections.
Pneumonia associated with a dental unit waterline Ricci, Maria Luisa, Dr; Fontana, Stefano, PhD; Pinci, Federica, BiolD ...
The Lancet (British edition),
02/2012, Letnik:
379, Številka:
9816
Journal Article
Recenzirano
L pneumophila is a Gram-negative bacterium ubiquitous in natural water environments and found also in man-made water systems; it can infect people by inhalation or microaspiration of aerosolised ...water causing a severe pneumonia known as Legionnaires' disease, mainly affecting elderly and immune-compromised patients, or a flu-like disease, known as Pontiac fever. Sources of infection have been shown to be primarily air-conditioning systems, hot-water systems, spas, and fountains.3 Significant contamination of dental unit waterlines with legionella has been widely documented.4 Serological studies have also shown a higher prevalence of antibodies to L pneumophila in dentists and dental practice staff, suggesting a potential health risk for these workers.4 However, as far as we are aware, no case of Legionnaires' disease has been associated with this source of infection.
Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of ...abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele ('altered self-allele') and create the potential for robust T cell responses.
Acute flaccid paralysis (AFP) surveillance has been adopted globally as a key strategy for monitoring the progress of the polio eradication initiative. Hereby, to evaluate the completeness of the ...ascertainment of AFP cases in Italy, a hospital-discharges based search was carried out.
AFP cases occurring between 2007 and 2016 among children under 15 years of age were searched in the Italian Hospital Discharge Records (HDR) database using specific ICD-9-CM diagnostic codes. AFP cases identified between 2015 and 2016 were then compared with those notified to the National Surveillance System (NSS).
Over a 10-year period, 4163 hospital discharges with diagnosis of AFP were reported in Italy. Among these, 956 (23.0%) were acute infective polyneuritis, 1803 (43.3%) myopathy, and 1408 (33.8%) encephalitis, myelitis and encephalomyelitis. During the study period, a decreasing trend was observed for all diagnoses and overall the annual incidence rate (IR) declined from 5.5 to 4.5 per 100,000 children. Comparing NSS with HDR data in 2015-2016, we found a remarkable underreporting, being AFP cases from NSS only 14% of those recorded in HDR. In particular, the acute infective polyneuritis cases reported to NSS accounted for 42.6% of those detected in HDR, while only 0.9% of myopathy cases and 13.1% of encephalitis/myelitis/encephalomyelitis cases have been notified to NSS. The highest AFP IRs per 100,000 children calculated on HDR data were identified in Liguria (17.4), Sicily (5.7), and Veneto (5.1) Regions; regarding the AFP notified to the NSS, 11 out of 21 Regions failed to reach the number of expected cases (based on 1/100,000 rate), and the highest discrepancies were observed in the Northern Regions. Overall, the national AFP rate was equal to 0.6, therefore did not reach the target value.
AFP surveillance data are the final measure of a country's progress towards polio eradication. The historical data obtained by the HDR have been useful to assess the completeness of the notification data and to identify the Regions with a low AFP ascertainment rate in order to improve the national surveillance system.
The prevention of nicotinamide adenine dinucleotide (NAD) biosynthesis is considered an attractive therapeutic approach against cancer, considering that tumor cells are characterized by an increased ...need for NAD to fuel their reprogrammed metabolism. On the other hand, the decline of NAD is a hallmark of some pathological conditions, including neurodegeneration and metabolic diseases, and boosting NAD biosynthesis has proven to be of therapeutic relevance. Therefore, targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD biosynthesis from nicotinamide (NAM) and nicotinic acid (NA), respectively, is considered a promising strategy to modulate intracellular NAD pool. While potent NAMPT inhibitors and activators have been developed, the search for NAPRT modulators is still in its infancy. In this work, we report on the identification of a new class of NAPRT modulators bearing the 1,2-dimethylbenzimidazole scaffold properly substituted in position 5. In particular, compounds
,
, and
emerged as the first NAPRT activators reported so far, while
behaved as a noncompetitive inhibitor toward NA (
= 338 µM) and a mixed inhibitor toward phosphoribosyl pyrophosphate (PRPP) (
= 134 µM). From in vitro pharmacokinetic studies, compound
showed an overall good ADME profile. To rationalize the obtained results, docking studies were performed on the NAPRT structure. Moreover, a preliminary pharmacophore model was built to shed light on the shift from inhibitors to activators.
Legionella pneumophila (Lp), responsible for a severe pneumonia called Legionnaires’ disease, represents an important health burden in Europe. Prevention and control of Lp contamination in warm water ...systems is still a great challenge often due to the failure in disinfection procedures. The aim of this study was to evaluate the in vitro activity of Terpinen-4-ol (T-4-ol) as potential agent for Lp control, in comparison with the essential oil of Melaleuca alternifolia (tea tree) (TTO. Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of T-4-ol were determined by broth micro-dilution and a micro-atmosphere diffusion method to investigate the anti-Lp effects of T-4-ol and TTO vapors. Scanning Electron Microscopy (SEM) was adopted to highlight the morphological changes and Lp damage following T-4-ol and TTO treatments. The greatest antimicrobial activity against Lp was shown by T-4-ol with a MIC range of 0.06–0.125% v/v and MBC range of 0.25–0.5% v/v. The TTO and T-4-ol MIC and MBC decreased with increasing temperature (36 °C to 45 ± 1 °C), and temperature also significantly influenced the efficacy of TTO and T-4-ol vapors. The time-killing assay showed an exponential trend of T-4-ol bactericidal activity at 0.5% v/v against Lp. SEM observations revealed a concentration- and temperature- dependent effect of T-4-ol and TTO on cell surface morphology with alterations. These findings suggest that T-4-ol is active against Lp and further studies may address the potential effectiveness of T-4-ol for control of water systems.
Abstract
In recent years, there has been a growing consensus that gender diversity could improve the economic and social performance of companies—although progress has been painfully slow. In Italy, ...Law n. 120/2011 has required that since 2012 the composition of corporate boards must comprise at least 1/5 women and, from 2015, 1/3 women. Here, our primary aim was to study the proportion and the progression of female directors on the boards of Italian companies over the period between 2009–2014, among a sample of 60 companies listed on the Milan Stock Exchange. We additionally studied the characteristics of the women on the companies’ boards, in order to assemble a typical profile. To do this, we verified the boards’ compositions, the number of female directors, women’s power on the boards and their levels of education. Our results confirm that Italian law has produced significant effects on the composition of corporate boards. Moreover, we found that female directors are generally of Italian ethnic origin and have high levels of education, with a master’s, and sometimes, post-master’s degree. Furthermore, female directors are more likely to be professional figures with experience—the percentages of female directors with professional qualifications as well as the percentage of female directors on boards of other companies have consistently increased during the period mentioned. Our findings provide a descriptive analysis of female directors during the period between 2009–2014, thereby presenting a picture of gender equality in the Italian context. To our knowledge, this is the first study that has focused on examining gender equality among Italian-listed companies over such a long period. Future development of this research could examine in more depth the differences between male and female presence, behaviour and characteristics on boards, as well as how these issues affect the performance of firms. This article is published as part of a collection on the role of women in management and the workplace.
RH1 incompatibility between mother and fetus can cause hemolytic disease of the fetus and newborn. In Switzerland, fetal RHD genotyping from maternal blood has been recommended from gestational age ...18 onwards since the year 2020. This facilitates tailored administration of RH immunoglobulin (RHIG) only to RH1 negative women carrying a RH1 positive fetus. Data from 30 months of noninvasive fetal RHD screening is presented. Cell-free DNA was extracted from 7192 plasma samples using a commercial kit, followed by an in-house qPCR to detect RHD exons 5 and 7, in addition to an amplification control. Valid results were obtained from 7072 samples, with 4515 (64%) fetuses typed RHD positive and 2556 (36%) fetuses being RHD negative. A total of 120 samples led to inconclusive results due to the presence of maternal or fetal RHD variants (46%), followed by women being serologically RH1 positive (37%), and technical issues (17%). One sample was typed false positive, possibly due to contamination. No false negative results were observed. We show that unnecessary administration of RHIG can be avoided for more than one third of RH1 negative pregnant women in Switzerland. This reduces the risks of exposure to a blood-derived product and conserves this limited resource to women in actual need.
PDF
