Integrated dataset of screening hits against multiple neglected disease pathogens

New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.     

The gene expression profile of preclinical autoimmune arthritis and its modulation by a tolerogenic disease-protective antigenic challenge

Introduction  

Autoimmune inflammation is a characteristic feature of rheumatoid arthritis (RA) and other autoimmune diseases. In the natural course of human autoimmune diseases, it is rather difficult to pinpoint the precise timing of the initial event that triggers the cascade of pathogenic events that later culminate into clinically overt disease. Therefore, it is a challenge to examine the early preclinical events in these disorders. Animal models are an invaluable resource in this regard. Furthermore, considering the complex nature of the pathogenic immune events in arthritis, microarray analysis offers a versatile tool to define the dynamic patterns of gene expression during the disease course.     

Effects of spermatozoa during in vitro meiosis progression in the porcine germinal vesicle oocytes

We have investigated the effect of co-culture with porcine spermatozoa on in vitro maturation of porcine germinal vesicle (GV) oocytes before fertilization. Most oocytes were arrested at the first prophase of meiosis when oocytes were cultured in TCM 199 alone, but the proportion of oocytes that reached metaphase II was significantly elevated by co-incubation with spermatozoa in vitro. The oocyte maturation effect was observed with intact and parts of spermatozoa (head and tail) collected from adult swine (regardless of source). However, gonocytes from the newborn porcine testis were not able to enhance in vitro maturation of porcine germinal vesicle oocytes. Interestingly, the oocyte maturation effect by spermatozoa was not decreased with heat treatment, but the maturation effect of oocyte treatment disappeared with exposure to detergent in sperm suspension. Porcine spermatozoa were also observed to stimulate meiosis of oocytes, which was maintained at meiotic arrest using dibutyryl cyclic AMP or forskolin. The study suggests that (i) membrane of porcine spermatozoa contains a substance(s) that can enhance in vitro maturation of oocytes prior to fertilization, (ii) the putative meiosis-enhancing substance(s) of spermatozoa from adult testes retains the oocyte maturation effect during transportation of spermatozoa through epididymis, and (iii) the putative meiosis-enhancing substance(s) is able to overcome the inhibitory effect of dibutyryl cyclic AMP or forskolin by inducing germinal vesicle breakdown of porcine cumulus-oocyte complexes maintained in meiotic arrest.     

Antimicrobial Resistance, Virulence Genes, and Genetic Lineages of Staphylococcus pseudintermedius in Healthy Dogs in Tunisia

Nasal swabs of 100 healthy dogs were obtained in 2011 in Tunisia and tested for Staphylococcus pseudintermedius recovery. Antimicrobial resistance profile and virulence gene content were determined. Multilocus-sequence-typing (MLST) and SmaI-pulsed-field gel electrophoresis (PFGE) were investigated. S. pseudintermedius was recovered in 55 of the 100 tested samples (55 %), and one isolate per sample was further studied. All 55 S. pseudintermedius isolates were susceptible to methicillin (MSSP) but showed resistance to the following antimicrobials (% resistant isolates/resistance gene): penicillin (56.4/blaZ), tetracycline (40/tetM), trimethoprim-sulfamethoxazole (23.7), fusidic acid (9), kanamycin (3.7/aph(3´)-Ia), erythromycin-clindamycin (1.8/erm(B)), streptomycin (1.8/ant(6)-Ia), chloramphenicol (1.8) and ciprofloxacin (1.8). The following toxin genes were identified (% of isolates): lukS/F-I (98.2), expA (5.5), se-int (98.2), sec _canine (1.8), siet (100), sea (5.5), seb (3.6), sec (10.9), sed (54.5), sei (5.5), sej (29.1), sek (3.6), ser (9.1), and hlg _v (38.2). Ten different sequence-types were detected among 11 representative MSSP isolates: ST20, ST44, ST69, ST70, ST78, ST100, ST108, ST160, ST161, and ST162, the last three ones revealing novel alleles or allele combinations. Eleven different PFGE-patterns were identified in these isolates. The nares of healthy dogs could be a reservoir of antimicrobial resistant and virulent MSSP, highlighting the presence of the recently described exfoliating gene expA and several enterotoxin genes.     

The Increased Risk of Road Crashes in Attention Deficit Hyperactivity Disorder (ADHD) Adult Drivers: Driven by Distraction? Results from a Responsibility Case-Control Study

Background and Objective

Both distractions (external and internal) and attention-deficit/hyperactivity disorder (ADHD) are serious risk factors for traffic crashes and injuries. However, it is still unknown if ADHD (a chronic condition) modifies the effect of distractions (irregular hazards) on traffic crashes. The objective of this study was to assess the effects of distractions and ADHD on traffic crash responsibility.

Methods

A responsibility case-control study was conducted in the adult emergency department of Bordeaux University Hospital, France. Subjects were recruited among drivers injured in a motor vehicle crash between April 2010 and August 2011. Responsibility levels were estimated using a standardized method. Frequencies of exposures were compared between drivers responsible and drivers not responsible for the crash. Independent risk factors were identified using a multivariate logistic regression including test interactions between distractions and ADHD.

Results

A total of 777 subjects were included in the analysis. Factors associated with responsibility were distraction induced by an external event (adjusted OR (aOR)  = 1.47; 95% confidence interval (CI) [1.06–2.05]), distraction induced by an internal thought (aOR = 2.38; CI: [1.50–3.77]) and ADHD (aOR = 2.18 CI: [1.22–3.88]). The combined effect of ADHD and external distractions was strongly associated with responsibility for the crash (aOR = 5.79 CI: [2.06–16.32]). Interaction assessment showed that the attributable proportion due to the interaction among participants with both exposures was 68%.

Discussion

Adults with ADHD are a population at higher risk of being responsible for a road traffic crash when exposed to external distractions. This result reinforces the need to diagnose adult ADHD and to include road safety awareness messages delivered by the physician. Developing advanced driver assistance systems devoted to the management of attention lapses is also increasingly relevant for these drivers.     

Recovery of soil streptomycetes from arid habitats in Jordan and their potential to inhibit multi-drug resistant <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> pathogens

A total of 161 different Streptomyces isolates were recovered from 5 soil samples representing the driest habitats of Jordan. These were then characterized and assessed for their antagonistic activity against four clinical multi-drug resistant Pseudomonas aeruginosa test pathogens. Results indicated that only 3 strains out of 139 and 6 out of 22 isolated at 27°C and 45°C, respectively, were active against at least three strains of pathogenic Pseudomonas. However, three Streptomyces strains (J_2b, J₄, and J₁₂) that were isolated at 45°C inhibited all of the tested pathogens with an inhibition zone ranging between 5 and 16 mm in diameter. Data obtained from comparing the inhibition activity of these unique Streptomyces strains toward multi-resistant Pseudomonas pathogens with standard used antibiotics revealed that these isolates produce possible different inhibitory bioactive compounds other than the standard antibiotics.     

Association of Genetic Variants of MTHFR,ENPP1, and ADIPOQ with Myocardial Infarction in Egyptian Patients

The study aimed to investigate the association between MTHFR C677T, ENPP1 K121Q, and ADIPOQ 45 T/G gene polymorphisms and incidence of myocardial infarction (MI) in Egyptian patients. The study included 60 unrelated patients suffering from their first MI and 60 unrelated controls. Patients were recruited from Kasr-El Eini hospital, Cairo University. The previously mentioned polymorphisms were determined in all participants by PCR–RFLP. There was no significant difference in the distribution of genotypes and alleles of MTHFR C677T between groups. In contrast, significant difference was found in the distributions of genotypes and alleles of ENPP1 K121Q and ADIPOQ 45 T/G between MI patients and controls (P = 0.01, P = 0.004, P = 0.009, P = 0.001, respectively). Univariate analysis revealed that 121Q ENPP1 and 45 G ADIPOQ alleles were associated with the increased risk of MI (OR = 3; 95 % CI = 1.45–6.2; P = 0.004 and OR = 5.8; 95 % CI = 1.92–17.54; P = 0.001, respectively). The mutant homozygous genotypes of MTHFR, ENPP1, and ADIPOQ were more prevalent in diabetic hypertensive MI patients than it was among non-diabetic normotensive MI patients. Regarding the coagulation profile, INR (P = 0.009) and PC % (P = 0.022) were significantly different among the three genotypes of MTHFR C677T. The 677 T, 121 Q, and 45G variants were associated with MI in Egyptian patients; however, more studies are needed to determine the possible protective effect for these polymorphisms in our population.     

Effect of exogenous circulating anti-bPL antibodies on bovine placental lactogen measurements in foetal samples

Background  

The involvement of placental lactogen (PL) in the regulation of foetal growth has been investigated in different species by in vivo immunomodulation techniques. However, when circulating antibodies are present together with the hormone, the procedure for hormonal measurement becomes considerably complex. The aim of this study was the immunoneutralization of bovine placental lactogen (bPL) concentrations in bovine foetal circulation by direct infusion of rabbit anti-bPL purified immunoglobulins (IgG) via a foetal catheter (in vivo study). The ability of a RIA based on guinea pig anti-bPL antiserum, for the measurement of bPL concentrations in samples containing exogenous rabbit anti-bPL immunoglobulins, was also analyzed in in vitro and in vivo conditions.     

Short‐term effect of selectivity change in a trawling fishery in the Western Mediterranean

The change of mesh size or shape as a management measure to improve selectivity as proposed by the EU should be assessed using actual fishery data, despite being tested experimentally in previous studies. This work was conducted to evaluate the consequences of inserting either a 40‐mm square‐mesh or a 50‐mm diamond‐mesh (instead of the traditional 40‐mm diamond‐mesh) at codends in commercial Spanish trawlers. Landings in terms of biomass, income and catch composition were compared under commercial conditions. Four métiers were identified in the fishery: European hake (Merluccius merluccius), red mullet (Mullus barbatus), red shrimp (Aristeus antennatus) and Norway lobster (Nephrops norvegicus). No significant differences were observed in biomass or income owing to the new mesh in either European hake or red mullet. In contrast, the total biomass of the red shrimp métier and the biomass of the Norway lobster, Nephrops norvegicus, were significantly higher after the selectivity change. Regarding the catch composition, only the European hake métier showed slight – but not significant – changes after using the new mesh. Considering these results, there was no short‐term effect (substantial biological or economic loss) as previous studies had expected. This could possibly be related to a higher performance of the new gear that may compensate for the lower retention of small sizes.