Preclinical Development of a Novel Antileishmanial Agent OJT007: Bioanalytical Assay, in Vitro Studies and Pharmacokinetics

Current treatments for cutaneous leishmaniasis suffer from toxic side effects, high cost, parenteral administration, and drug resistance. Thus, there is a critical need to develop oral drugs for the treatment of leishmaniasis. OJT007 is a novel class of drug with potent antiproliferative effects against Leishmania Major. The purpose of this project is to conduct preclinical drug development studies for OJT007 including bioanalytical assay development, pre-formulation studies, in vitro hepatic drug metabolism and in vivo pharmacokinetics. A sensitive, specific, and reproducible ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. The separation was achieved on a UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm) using a mobile phase consisting of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as gradient elution at a flow rate of 0.4 mL/min. The mass analysis was performed with a 4000 QTRAP® mass spectrometer using multiple-ion reaction monitoring (MRM) in the positive mode, with the transition of m/z 325 → m/z 205 for OJT007 and m/z 350 → m/z 101 for voriconazole (as internal standard). Rat plasma and urine were extracted for OJT007 by protein precipitation in acetonitrile for quantification. Plasma protein binding of OJT007 was determined using the ultrafiltration method. In vitro phase I and II hepatic metabolism of OJT007 was evaluated in rat liver microsomes using standard reaction protocols. OJT007 metabolites were identified by LC-MS/MS using Q1MI, product ion, precursor ion and neutral loss scan and by β-glucuronidase hydrolysis. The OJT007 glucuronidation rates were determined by quantifying OJT007 glucuronide using UPLC, and the kinetic parameters of OJT007 were determined by measuring the initial glucuronidation rates. . Oral bioavailability of OJT007 was evaluated using a crossover study design. Serial plasma samples were collected at predetermined time points. Total urine samples were also collected from each rat for 24 hours after each dose. The pharmacokinetic parameters were calculated using Phoenix WinNonlin® 8.3 software. The intra- and inter-day precision and accuracy were within the acceptable limit of ≤20% for LLOQ and ≤15% for high, medium and low QC. The extraction recovery in rat plasma and urine samples were 95.1% and 83%, respectively. OJT007 exhibited a matrix factor in plasma and urine of 7.96% and 12.4%, respectively. The fraction of OJT007 bound to plasma protein had a mean value of 99.1%, suggesting the drug is highly bound to plasma proteins. OJT007 is glucuronidated rapidly in rat liver microsomes to form a mono-glucuronide, which was confirmed by LC-MS/MS and β-glucuronidase hydrolysis. The kinetic parameters of glucuronidation Vmax and Km were 1.125 nmol/min/mg and 10.73 μM., respectively. After intravenous administration, OJT007 displayed a bi-exponential disposition with a rapid distribution followed by a slower elimination. The mean AUC, volume of distribution, and clearance were 2.06 h.mg/L, 6.90 L/Kg and 2.30 L/hr/Kg, respectively. Following oral administration, OJT007 was rapidly absorbed with a tmax of 1.4 hours. After oral dosing the mean AUC, volume of distribution, and clearance were 0.45 h.mg/L, 78.6 L/Kg and 23.19 L/hr/Kg, respectively. Mean oral bioavailability of OJT007 in the co-solvent formulation was 10.9%. The mean percentage of OJT007 dose excreted unchanged in urine after 24 hours following intravenous and oral administration was less than 1%, suggesting OJT007 was extensively metabolized in vivo. A sensitive, specific and reproducible LC-MS/MS method was developed and validated to quantify OJT007 in rat plasma and urine. The method was successfully used for pharmacokinetic studies. This is the first time that oral bioavailability of OJT007 after oral administration in rat is determined. These results may prove valuable for further preclinical and clinical evaluation of OJT00

Fire and Earth: Native American Pottery from New Mexican Pueblos - Catalogue

Exhibition Catalogue for Fire and Earth: Native American Pottery from New Mexican Pueblos. Exhibition on view at the Bellarmine Museum of Art from June 27 - October 3, 2013. First created nearly two millennia ago, Pueblo pottery is remarkable not only for its formal beauty but also for its cultural importance. Centuries after the Anasazi (or ancestral Pueblo people) first began making potted vessels from coils of tempered earth - rubbed smooth and painted with local clays, minerals, and vegetal pigments - their successors continue to do the same. An ancestral whisper, this knowledge was (and is) passed down from artist to artist, generation after generation, ensuring the survival of both ancient pottery techniques and the cultures that birthed them. Herein lies the beauty of objects whose value is truly much more than skin deep: They embody their creators’ heritage. As material manifestations of the different Pueblos’ values and experiences, these pots bear witness to the remarkable histories of their peoples. From the establishment of fixed and settled villages to the successive waves of conquest and all that this implies, the earthenware vessels created by New Mexico’s native populations have been buffeted by the winds of change. Yet despite subtle shifts in their silhouettes and decorative elements, the pots on view in the Bellarmine Museum of Art’s Fire & Earth: Native American Pottery from New Mexican Pueblosexhibition remind us that Pueblo pottery has never strayed too far from its ancient forebears, both cultural and aesthetic; a testament to the strength of these peoples’ roots and the depth of their cultural legacies.https://digitalcommons.fairfield.edu/fireandearth-ephemera/1000/thumbnail.jp

A numerical study of squeeze-film damping in MEMS-based structures including rarefaction effects

In a variety of MEMS applications, the thin film of fluid responsible of squeeze-film dampingresults to be rarefied and, thus, not suitable to be modeled though the classical Navier-Stokes equation. Thesimplest way to consider fluid rarefaction is the introduction of a slight modification into its ordinaryformulation, by substituting the standard fluid viscosity with an effective viscosity term. In the present paper,some squeeze-film damping problems of both parallel and torsion plates at decreasing pressure are studied bynumerical solving a full 3D Navier-Stokes equation, where the effective viscosity is computed according toproper expressions already included in the literature. Furthermore, the same expressions for the effectiveviscosity are implemented within known analytical models, still derived from the Navier-Stokes equation. In allthe considered cases, the numerical results are shown to be very promising, providing comparable or evenbetter agreement with the experimental data than the corresponding analytical results, even at low air pressure.Thus, unlike what is usually agreed in the literature, the effective viscosity approach can be efficiently applied atlow pressure regimes, especially when this is combined with a finite element analysis (FE

Innovazione tecnologica nella riscossione delle sanzioni da infrazioni stradali

Il presente contributo propone un sistema innovativo di avviso telematico che informa l’utente della strada della violazione commessa e che permette il pagamento diretto della contravvenzione. Tale sistema ha come primo obiettivo la facilitazione/snellimento delle procedure per il pagamento delle contravvenzioni, rivolgendosi prettamente agli utenti “non evasori” e garantendo così introiti sicuri per l’amministrazione pubblica da trasporto privato

A Sardinian early 1st millennium BC bronze axe from Motya

An Iron Age bronze axe was found in Motya (Sicily, Italy) in a prehistoric layer dating from the 10th century BC underneath the 4th century BC patrician residency known as “Casa dei mosaici”. The axe belongs to the double-looped socketed type well known in central Mediterranean in the time span 1200-900 BC, and it is comparable with some coeval Sardinian specimens. The bronze has been characterised using the backscattering electron signal of a SEM (Scanning Electron Microscope) and EDX (Energy Dispersive X-ray Spectroscopy). The resulting composition of the metal alloy is Cu-Sn-As with an addition of Pb in some specific spots

Lise Meitner

Lise Meitner, nacque nella Vienna imperiale nel 1878 da una famiglia ebraico-galiziana. Fu una delle prime donne a conseguire il diploma e ad entrare all’Università, dopo che venne abolita la legge che privava le donne dell’istruzione. Provava molta stima per Marie Curie, in quanto possedeva una grande intelligenza e conoscenza. La Meitner aveva un obbiettivo, sfidare il mondo maschile. Non ebbe un’esistenza facile e visse in una società non pronta ad accettare l’indipendenza femminile.Lise Meitner was born in 1878 in Vienna, in a Jewish-Galician family. She was one of the first women who got the degree and who attended the University, after that the law, which deprived women of education, was lifted. She appreciated Marie Curie because of her intelligence and knowledge. Lise Meitner had a goal, challenging the male world. She did not have an easy life and she lived in a society which was not ready to accept female empowerment

To Chase or not to Chase: A Study on the Role of Mentalization and Alcohol Consumption in Chasing Behavior

Background and aims: Chasing is a behavioral marker and a diagnostic criterion for gambling disorder. Although chasing has been recognized to play a central role in gambling disorder, research on this topic is relatively scarce. This study investigated the association between chasing, alcohol consumption, and mentalization among habitual gamblers. Method: A total of 132 adults took part in the study. Participants were administered the South Oaks Gambling Screen, the Alcohol Use Disorders Identification Test, the Reflective Functioning Questionnaire, and a laboratory task assessing chasing behavior. Participants were randomly assigned to three experimental conditions (Control, Loss, and Win). To deeply investigate chasing behavior, participants were requested to indicate the reasons for stopping or continuing playing at the end of the experimental session. Results: Logistic regression analysis showed that the choice to stop or continue playing depended on experimental condition and alcohol use. Hierarchical linear regression indicated that chasing propensity was affected by experimental condition, alcohol consumption, and deficit in mentalization. The results of path analysis showed that hypermentalizing predicts chasing not only directly, but also indirectly via alcohol consumption. Conclusions: Overall, these results for the first time showed that hypermentalization plays a key role in chasing behavior over and above gambling severity. Since these findings support the idea that chasers and non-chasers are different subtypes of gamblers, clinical interventions should consider the additive role of chasing in gambling disorder

Non-typhoidal Salmonella septic arthritis in an immunocompetent child with a pharyngeal streptococcal infection

Summary We report the case of an immunocompetent child who showed monoarticular arthritis and fever, preceded by pharyngitis and arthralgias. Because group A β-hemolytic Streptococcus had been detected in the pharyngeal swab, erythromycin was given on admission. However, based on ultrasound examination, therapy with ceftriaxone and joint fluid drainage were promptly performed, and a rapid and full recovery followed. Meanwhile, Salmonella enterica infection was revealed in blood and joint fluid. Our case suggests that septic arthritis caused by a non-typhoidal Salmonella infection may occur without gastrointestinal manifestations and concomitantly with a pharyngeal streptococcal infection

A INSURREIÇÃO CONTESTADA: WILLIAM STYRON E AS CONFISSÕES DE NAT TURNER

Neste trabalho apresentamos meandros de “veracidade” no romance histórico de William Styron, As confissões de Nat Turner, levando em consideração o ponto de vista do narrador. Ao falar do negro, Styron mantém, de certa maneira, a perspectiva do branco, além de também perpetuar a distância criada pelo sistema escravista e segregacionista dos Estados Unidos da América.PALAVRAS-CHAVE: Literatura e história, William Styron, sistema escravagist

The Management of Dental Practices in the Post-COVID 19 Era: An Economic and Operational Perspective

Background: In order to protect dental teams and their patients during the COVID-19 pandemic, dentists have had to adopt several measures (operating and post-operating procedures) which may increase the total treatment time and costs relating to individual protective measures. This paper will propose a thorough analysis of operating dentistry procedures, comparing the economic performance of the activity in a dental surgery before and after the adoption of these protective measures, which are required to contain the risk of SARS-COV-2 infections. Methods: The economic analysis is articulated in three approaches. Firstly, it assesses a reduction in markup by maintaining current charges (A); alternatively, it suggests revised charges to adopt in order to maintain unvaried levels of markup (B). And the third Approach (C) examines available dental treatments, highlighting how to profitably combine treatment volumes to reduce markup loss or a restricted increase in dental charges. Results: Maintaining dental charges could cause a loss in markup, even rising to 200% (A); attempting to maintain unvaried levels of markup will result in an increase in dental charges, even at 100% (B); and varying the volumes of the single dental treatments on offer (increasing those which current research indicates as the most profitable) could mitigate the economic impact of the measures to prevent the transmission of SARS-COV-2 (C). Conclusions: The authors of this paper provide managerial insights which can assist the dentist-entrepreneur to become aware of the boundaries of the economic consequences of governmental measures in containing the virus infection