A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis

Abstract Background Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model. Methods Male Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase – MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing. Results At the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance. Conclusion The presence of a H2S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H2S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.

A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis

BACKGROUND: Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model. METHODS: Male Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase - MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing. RESULTS: At the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance. CONCLUSION: The presence of a H2S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H2S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.

Politiche di sviluppo e questione etnica. La cooperazione italiana IN Bosnia Erzegovina

The globalization process of the last twenty years has changed the world through international flows of people, policies and practices. International cooperation to development is a part of that process and brought International Organizations (IOs) and Non Governmental Organizations (NGOs) from the West to the rest of the world. In my thesis I analyze the Italian NGOs that worked in Bosnia Herzegovina (BH) to understand which development projects they realized and how they faced the ethnic issue that characterized BH. I consider the relation shaped between Italian NGOs and Bosnian civil society as an object of ethnic interests. In BH, once part of former Yugoslavia, the transition from the communist regime to a democratic country has not been completed. BH’s social conditions are characterized by strong ethnic divisions. The legacy of the early 1990s crisis was a phenomenon of ethnic identities created before the war and that still endure today. The Dayton Peace Agreement signed in 1995 granted the peace and reinforced the inter-ethnic hate between the newly recognized three principal ethnicities: Serbs, Croats and Bosniak. Through the new constitution, the institutions were characterized by division at every level, from the top to the bottom of society. Besides it was the first constitution ever written and signed outside the own country; that was the root of the state of exception that characterized BH. Thus ethnic identities culture survived through the international political involvement. At the same time ethnic groups that dominated the political debate clashed with the international organization’s democratic purpose to build a multicultural and democratic state. Ethnic and also religious differences were the instruments for a national statement that might cause the transition and development projects failure. Fifteen years later social fragmentation was still present and it established an atmosphere of daily cultural violence. Civil society suffered this condition and attended to recreate the ethnic fragmentation in every day life. Some cities became physically divided and other cities don’t tolerated the minority presence. In rural areas, the division was more explicit, from village to village, without integration. In my speech, the anthropology for development – the derivative study from applied anthropology – constitutes the point of view that I used to understand how ethnic identities still influenced the development process in BH. I done ethnographic research about the Italian cooperation for development projects that were working there in 2007. The target of research were the Italian NGOs that created a relation with Bosnian civil society; they were almost twenty divided in four main field of competences: institutional building, education, agriculture and democratization. I assumed that NGOs work needed a deep study because the bottom of society is the place where people could really change their representation and behavior. Italian NGOs operated in BH with the aim of creating sustainable development. They found cultural barricade that both institutions and civil society erected when development projects have been applied. Ethnic and religious differences were stressed to maintain boundaries and fragmented power. Thus NGOs tried to negotiate development projects by social integration. I found that NGOs worked among ethnic groups by pursuing a new integration. They often gained success among people; civil society was ready to accept development projects and overcome differences. On the other hand NGOs have been limited by political level that sustained the ethnic talk and by their representation of Bosnian issue. Thus development policies have been impeded by ethnic issue and by cooperation practices established on a top down perspective. Paradoxically, since international community has approved the political ethnic division within DPA, then the willing of development followed by funding NGOs cooperation projects was not completely successful.

Lifecycle analysis for surgery instruments at a hospital

Gli strumenti chirurgici sono importanti “devices” utilizzati come supporto indi-spensabile nella cura di pazienti negli ospedali. Essi sono caratterizzati da un intero ciclo di vita che inizia convenzionalmente nello “Store”, dove gli strumenti sterilizzati sono prelevati per essere utilizzati all’interno delle sale operatorie, e termina nuovamente nello “Store”, dove gli strumenti vengono immagazzinati per essere riutilizzati in un nuovo ciclo. Può accadere che le singole fasi del ciclo subiscano ritardi rispetto ai tempi previ-sti, non assicurando, pertanto, nelle sale operatorie, il corretto numero degli stru-menti secondo i tempi programmati. Il progetto che vado ad illustrare ha come obiettivo l’ottimizzazione del ciclo degli strumenti chirurgici all’interno di un nuovo ospedale, applicando i principi della Lean philosophy ed in particolare i metodi: “Poke Yoke, 5S e tracciabilità”. Per raggiungere tale scopo, il progetto è stato articolato come segue. In un primo momento si è osservato l’intero ciclo di vita degli strumenti nei due principali ospedali di Copenhagen (Hervel e Gentofte hospital). Ciò ha permesso di rilevare gli steps del ciclo, nonché di riscontrare sul campo i principali problemi relativi al ciclo stesso quali: bassa flessiblità, decentramento dei differenti reparti di cleaning e di store rispetto alle operation theatres ed un problema nel solleva-mento degli strumenti pesanti. Raccolte le dovute informazioni, si è passati alla fase sperimentale, in cui sono stati mappati due cicli di vita differenti, utilizzando tre strumenti di analisi: • Idef0 che consente di avere una visione gerarchica del ciclo; • Value stream Mapping che permette di evidenziare i principali sprechi del ciclo; • Simulator Tecnomatix che favorisce un punto di vista dinamico dell’analisi. Il primo ciclo mappato è stato creato con il solo scopo di mettere in risalto gli steps del ciclo e alcuni problemi rincontrati all’interno degli ospedali visitati. Il secondo ciclo, invece, è stato creato in ottica Lean al fine di risolvere alcuni tra i principali problemi riscontrati nei due ospedali e ottimizzare il primo ciclo. Si ricordi, infatti, che nel secondo ciclo le principali innovazioni introdotte sono state: l’utilizzo del Barcode e Rfid Tag per identificare e tracciare la posizione degli items, l’uso di un “Automatic and Retrievial Store” per minimizzare i tempi di inserimento e prelievo degli items e infine l’utilizzo di tre tipologie di carrello, per consentire un flessibile servizio di cura. Inoltre sono state proposte delle solu-zioni “Poke-Yoke” per risolvere alcuni problemi manuali degli ospedali. Per evidenziare il vantaggio del secondo ciclo di strumenti, è stato preso in consi-derazione il parametro “Lead time”e le due simulazioni, precedentemente create, sono state confrontate. Tale confronto ha evidenziato una radicale riduzione dei tempi (nonché dei costi associati) della nuova soluzione rispetto alla prima. Alla presente segue la trattazione in lingua inglese degli argomenti oggetto di ri-cerca. Buona lettura.

Alternative derivative expansion in Functional RG and application

We give a brief review of the Functional Renormalization method in quantum field theory, which is intrinsically non perturbative, in terms of both the Polchinski equation for the Wilsonian action and the Wetterich equation for the generator of the proper verteces. For the latter case we show a simple application for a theory with one real scalar field within the LPA and LPA' approximations. For the first case, instead, we give a covariant "Hamiltonian" version of the Polchinski equation which consists in doing a Legendre transform of the flow for the corresponding effective Lagrangian replacing arbitrary high order derivative of fields with momenta fields. This approach is suitable for studying new truncations in the derivative expansion. We apply this formulation for a theory with one real scalar field and, as a novel result, derive the flow equations for a theory with N real scalar fields with the O(N) internal symmetry. Within this new approach we analyze numerically the scaling solutions for N=1 in d=3 (critical Ising model), at the leading order in the derivative expansion with an infinite number of couplings, encoded in two functions V(phi) and Z(phi), obtaining an estimate for the quantum anomalous dimension with a 10% accuracy (confronting with Monte Carlo results).

NCX-1000, a nitric oxide-releasing derivative of UDCA, does not decrease portal pressure in patients with cirrhosis: results of a randomized, double-blind, dose-escalating study

NCX-1000 (2(acetyloxy) benzoic acid-3(nitrooxymethyl)phenyl ester) is an nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), which showed selective vasodilatory effect on intrahepatic circulation in animal models of cirrhosis. This study was aimed at testing the efficacy and tolerability of this compound in patients with cirrhosis and portal hypertension.

Clinical Outcomes Following Treatment of Non-contained Intrabony Defects with Enamel Matrix Derivative (EMD) or Guided Tissue Regeneration (GTR). A 12-month Randomized Controlled Clinical trial

The purpose of this study is to compare the healing of deep, non-contained intrabony defects (i.e., with a ?80% 1-wall component and a residual 2- to 3-wall component in the most apical part) treated with either an enamel matrix derivative (EMD) or guided tissue regeneration (GTR) after 12 months.

Healing of two and three wall intrabony periodontal defects following treatment with an enamel matrix derivative combined with autogenous bone

BACKGROUND: There are still limited data on the outcomes of regenerative periodontal surgery using a combination of an enamel matrix protein derivative (EMD) and autogenous bone (AB). AIM: To evaluate the healing of deep intrabony defects treated with either a combination EMD+AB or EMD alone. MATERIALS AND METHODS: Forty patients with advanced chronic periodontitis, with one deep intrabony defect, were randomly treated with either EMD+AB (test) or EMD (control). Clinical assessments were performed at baseline and at 1 year after treatment. The primary outcome variable was relative attachment level (RAL). RESULTS: Healing was uneventful in all patients. The test sites showed a reduction in the mean probing pocket depth (PPD) of 5.6 +/- 0.9 mm (p<0.001), a gain in the mean RAL of 4.2 +/- 1.1 mm (p<0.001) and a gain in the mean probing bone level (PBL) of 3.9 +/- 1.0 mm (p<0.001). The control group displayed a mean PPD reduction of 4.6 +/- 0.4 mm (p<0.001), a mean RAL gain of 3.4 +/- 0.8 mm (p<0.001) and a mean PBL gain of 2.8 +/- 0.8 mm (p<0.001). RAL gains of > or =4 mm were measured in 90% of the test defects and in 55% of the controls. PBL gains of > or =4 mm were obtained in 85% of the test defects and in 25% of the control ones. The test treatment resulted in statistically higher PPD reductions, RAL gains and PBL gains compared with the control (p<0.01). CONCLUSIONS: Within their limits, the present results indicate that: (i) at 1 year after surgery, both therapies resulted in statistically significant clinical improvements compared with baseline and (ii) although the combination of EMD+AB resulted in statistically significant higher soft and hard tissue improvements compared with treatment with EMD, the clinical relevance of this finding is unclear.

The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G(1)/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET.

Effect of enamel matrix derivative and parathyroid hormone on bone formation in standardized osseous defects: an experimental study in minipigs

Previous experimental studies have indicated that locally administered enamel matrix derivative (EMD) and parathyroid hormone (PTH) may have a stimulatory effect on bone formation. However, it is not clear if the positive effect of EMD is related to its effect on the periodontium as a whole or directly on the bone-forming cells. In addition, it is not known if the presentation of PTH by adding the amino acid sequence Arg-Gly-Asp (RGD) is essential for its osteopromotive effect. Local delivery of a bioactive substance at the right time and in the right concentration often constitutes a major challenge. Polyethylene glycol-based hydrogel (PEG) is a degradable vehicle developed for delivery of bioactive proteins. To enhance the mechanical stability of the PEG-bioactive substance complex, an osteoconductive bone substitute material is often needed.

On The Choice and Impacts of Innovative International Food Assistance Instruments

The rise of new food assistance instruments, including local and regional procurement, cash, and vouchers, has surpassed increase in understanding of the tradeoffs among and impacts of these options relative to traditional food aid. Response choices rarely appear to result from systematic response analyses. Further, impacts along multiple dimensions-timeliness, cost-effectiveness, local market effects, recipient satisfaction, food quality, impact on smallholder suppliers, etc.-may be competing or synergistic. No single food assistance tool is always and everywhere preferable. A growing body of evidence, including the papers in this special section, nonetheless demonstrates the clear value-added of new food assistance instruments. (C) 2013 Elsevier Ltd. All rights reserved.