Quinoxaline chemistry. Part 8. 2-[anilino]-3- [carboxy]-6(7)-substituted quinoxalines as non classical antifolate agents. Synthesis and evaluation of in vitro anticancer, anti-HIV and antifungal activity

Thirty quinoxalines bearing a substituted anilino group on position 2, a carboethoxy or carboxy group on position 3 and a trifluoromethyl group on position 6 or 7 of the heterocycle were prepared in order to evaluate in vitro anticancer activity. Preliminary screening performed at NCI showed that most derivatives exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10-5 and 10-4 molar concentrations. Interesting selectivities were also recorded between 10-8 and 10-6 M for a few compounds. One single compound exhibited good activity against Candida Albicans

Interaction between <i>Mycobacterium tuberculosis</i>, <i>Mycobacterium bovis</i>, <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> with the enteric glia and microglial cells

Background We investigated the interaction of Mycobacterium avium subspecies paratuberculosis, M. bovis and M. tuberculosis and different glial cells (enteric glial and microglial cells) in order to evaluate the infecting ability of these microorganisms and the effects produced on these cells, such as the evaluation of cytokines expression. Results Our experiments demonstrated the adhesion of M. paratuberculosis to the enteroglial cells and the induction of IL-1A and IL-6 expression; M. tuberculosis and M. bovis showed a good adhesive capability to the enteric cell line with the expression of the following cytokines: IL-1A and IL-1B, TNF-α, G-CSF and GM-CSF; M. bovis induced the expression of IL-6 too. The experiment performed with the microglial cells confirmed the results obtained with the enteroglial cells after the infection with M. tuberculosis and M. bovis, whereas M. paratuberculosis stimulated the production of IL-1A and IL-1B. Conclusion Enteroglial and microglial cells, could be the target of pathogenic mycobacteria and, even if present in different locations (Enteric Nervous System and Central Nervous System), show to have similar mechanism of immunomodulation

Specific immunoassays confirm association of <i>Mycobacterium avium</i> subsp. <i>paratuberculosis</i> with type-1 but not type-2 diabetes mellitus

Background Mycobacterium avium subspecies paratuberculosis (MAP) is a versatile pathogen with a broad host range. Its association with type-1 diabetes mellitus (T1DM) has been recently proposed. Rapid identification of infectious agents such as MAP in diabetic patients at the level of clinics might be helpful in deciphering the role of chronic bacterial infection in the development of autoimmune diseases such as T1DM. Methodology/Principal Findings We describe use of an ELISA method to identify live circulating MAP through the detection of a cell envelope protein, MptD by a specific M13 phage – fMptD. We also used another ELISA format to detect immune response to MptD peptide. Both the methods were tested with blood plasma obtained from T1DM, type-2 diabetes (T2DM) patients and non-diabetic controls. Our results demonstrate MptD and fMptD ELISA assays to be accurate and sensitive to detect MAP bacilli in a large fraction (47.3%) of T1DM patients as compared to non-diabetic controls (12.6%) and those with confirmed T2DM (7.7%). Comparative analysis of ELISA assays performed here with 3 other MAP antigen preparations, namely HbHA, Gsd and whole cell MAP lysates confirmed comparable sensitivity of the MptD peptide and the fMptD based ELISA assays. Moreover, we were successful in demonstrating positive bacterial culture in two of the clinical specimen derived from T1DM patients. Conclusions and Significance The MptD peptide/fMptD based ELISA or similar tests could be suggested as rapid and specific field level diagnostic tests for the identification of MAP in diabetic patients and for finding the explanations towards the occurrence of type-1 or type-2 diabetes in the light of an active infectious trigger

CORRELATIONS BETWEEN HEAD ROTATIONAL KINEMATICS AND BRAIN TISSUE STRAIN FOR LOW AND HIGH LEVEL FOOTBALL HELMET IMPACTS

This study examined the correlation between head angular velocity and acceleration with brain strain for low and high level impacts. Impacts at 2.4m/s (low) and 11m/s (high) were delivered to a American football helmeted Hybrid III headform using a centric/non-centric protocol. A finite element model calculated strain from headform accelerations. The lowlevel impact data were obtained from a previous subset eliciting angular responses occurring at 20g, therefore linear acceleration relationships were not examined. High correlations (r=>0.8) existed for non-centric conditions between strain with angular acceleration and velocity, while centric conditions had moderate relationships (r=0.50.68). This research demonstrates that kinematic-strain relationships are dependent on the impact event, and that a single variable may not represent strain under all conditi

Melt-Rock Interaction at Mantle Conditions: Evidences from Finero Gabbroic Dykes

The Finero Phlogopite-Peridotite (FPP) is a worldwide famous mantle massif recrystallized through several events of melt migrations. These events have enriched the FPP in hydrous phases and crustal components and have been commonly interpreted as related to a subduction/post orogenic geodynamic setting. The last of these metasomatic events has produced composite sapphirine-bearing gabbroic dykes, interpreted as the result of the interaction of channelized migrating melts with the host rock in a two-steps intrusion process. In the first step, the melt reacted with the FPP rocks and evolved by fractional crystallization of amphibole cumulates. In the second step, the evolved melt reacted with the first cumulates producing magmatic sapphirine and segregating plagioclase-rich bands containing abundant apatites at the nucleus of the dike. New data suggest, however, a more complex evolution. New O and in situ Sr isotopes on minerals suggest that the gabbroic dykes have evolved from melt(s) that progressively were contaminated by the interaction with the FPP rocks during its fractionation. The δ18O increases from 5.81‰ in orthopyroxenes at the dykes border to ~6.90‰ in cumulitic amphiboles and 8.60‰ in plagioclases. The 87Sr/86Sr values for plagioclase and coexisting apatite show isotopic disequilibrium between the two phases (plagioclases at 0.70474 ± 0.00033, n=23, and apatites at 0.70369 ± 0.00025, n=6). These isotopic variations could be explained with an AFC-like process between mantle-derived melt(s) and a crustal-enriched host (the FPP). In situ Sr isotope analyses were performed at the CIGS laboratory of the Università di Modena e Reggio Emilia using a Thermo Fisher Scientific Neptune™ coupled to a 213 nm Nd:YAG laser ablation system (New Wave Research™). During the analytical sessions a new in house plagioclase reference material for Rb-Sr systematic, named BC84, has been successfully tested and used

Epidemic of tuberculosis in a high school in Northern Sardinia

Abstract The aim of this study was to investigate the Mycobacterium tuberculosis transmission among high school student and teacher populations in a high school in Northern Sardinia. Tuberculin skin-test screening, chest-X-rays, QuantiFERON-TB Gold, microbiological examination, spoligotyping and variable numbers of tandem repeats (VNTR) analysis of M. tuberculosis isolates were performed. This study indicates the effectiveness of the epidemiological investigation

1,2,3-triazolo[4,5-h]quinolines: III: preparation and antimicrobial evaluation of 4-ethyl-4,7-dihydro-1(2)-R-1(2)H triazolo[4,5-h]quinolin-7-one-6-carboxylic acids as anti-infectives of the urinary tract

Some 4-ethyl-1(2)-R-1(2)H-4,7-dihydro-triazolo[4,5-h]-quinolin-7-one-6- carboxylic acids were prepared as novel analogues of oxolinic acid, in order to discover the influence of the annelation position of the triazole ring on the antimicrobial activity that, in some isomers triazolo[4,5-f]quinoline carboxylic acids, is selective against Escherichia coli. Some interesting side reactions in the cyclization of 1(2)-R-1(2)H-benzotriazol-4-yl-aminomethylenemalonate are also described. The biological results indicate that this type of annelation is not profitable for antimicrobial activity

"In vitro" activities of antimycobacterial agents against <i>Mycobacterium avium</i> subsp. <i>paratuberculosis</i> linked to Crohn's disease and paratuberculosis

Crohn's disease, a human disease similar to paratuberculosis in animals is the most painful and devastating disease that may involve infection with M. avium subsp. paratuberculosis (MAP), different genetic polymorphisms and an immune dysregulation syndrome. Treatment of Crohn's disease is most commonly based on 5-aminosalicylic acid (5-ASA) compounds, corticosteroids, and immunosuppressive agents. Recently, biological therapies using monoclonal antibodies against inflammatory cytokines have shown some positive results. However, all these therapies treat the symptoms not the cause of the disease

A Protocol for microbiologically safe preparation, storage, and use of autologous serum eye-drops in low-income countries

Introduction: The study aimed to investigate whether the preparation, storage, and use of autologous serum in insulin syringes is microbiologically safe. Methodology: Blood samples (10 mL) were obtained from 10 volunteers. After centrifugation, the supernatant serum was removed and distributed in 5 sterile insulin syringes for each sample; syringes were numbered 0 to 4 and labelled with the subject’s details. Syringes were immediately transported to the microbiology laboratory and stored in a refrigerator at +4°C. The “0” labelled syringes were separated from the others and 100 μl of serum from each syringe was immediately seeded on chocolate and Sabouraud agar plates, which were incubated aerobically at 37°C for 96 hours to detect any bacterial and/or fungal contamination. In the next 4 days, the same procedure was repeated for the remaining syringes: on day 1, the “1” labelled syringes were analyzed; on day 2, the “2” labelled ones, and so on. In a second experiment, blood samples were obtained from 5 different volunteers. The same procedure as above was followed, but each syringe was used for repeated cultures at 2-hour intervals, for a total of 12 cultures/day. The needle was removed and replaced for each inoculation and the syringes were stored in the refrigerator after use. Results: Under these experimental conditions, none of the cultures showed microbial growth. Conclusions: Results suggest that, under the protocol described, preparation, storage and use of undiluted autologous serum in insulin syringes is inexpensive, fast, and microbiologically safe. This is of great importance for low-income countries.</br

Rheumatoid Arthritis and Cardiovascular Risk: Retrospective Matched-Cohort Analysis Based on the RECORD Study of the Italian Society for Rheumatology

Background: Rheumatoid arthritis (RA) is associated with an increase in cardiovascular (CV) risk. This issue maybe not only explained by a genetic component, as well as by the traditional CV risk factors, but also by an underestimation and undertreatment of concomitant CV comorbidities. Method: This was a retrospective matched-cohort analysis in the Italian RA real-world population based on the healthcare-administrative databases to assess the CV risk factors and incidence of CV events in comparison with the general population. Persistence and adherence to the CV therapy were also evaluated in both groups. Results: In a RA cohort (N = 21,201), there was a greater prevalence of hypertension and diabetes with respect to the non-RA subjects (N = 249,156) (36.9 vs. 33.4% and 10.2 vs. 9.6%, respectively), while dyslipidemia was more frequent in the non-RA group (15.4 vs. 16.5%). Compared with a non-RA cohort, the patients with RA had a higher incidence of atrial fibrillation (incidence rate ratio, IRR 1.28), heart failure (IRR 1.53), stroke (IRR 1.19), and myocardial infarction (IRR 1.48). The patients with RA presented a significantly lower persistence rate to glucose-lowering and lipid-lowering therapies than the controls (odds ratio, OR 0.73 [95% CI 0.6-0.8] and OR 0.82 [0.8-0.9], respectively). The difference in the adherence to glucose-lowering therapy was significant (OR 0.7 [0.6-0.8]), conversely no statistically significant differences emerged regarding the adherence to lipid-lowering therapy (OR 0.89 [95% CI 0.8-1.0]) and anti-hypertensive therapy (OR 0.96 [95% CI 0.9-1.0]). Conclusion: The patients with RA have a higher risk of developing CV events compared with the general population, partially explained by the excess and undertreatment of CV risk factors