High rates of undiagnosed leprosy and subclinical infection amongst school children in the Amazon Region

Leprosy in children is correlated with community-level factors, including the recent presence of disease and active foci of transmission in the community. We performed clinical and serological examinations of 1,592 randomly selected school children (SC) in a cross-sectional study of eight hyperendemic municipalities in the Brazilian Amazon Region. Sixty-three (4%) SC, with a mean age of 13.3 years (standard deviation = 2.6), were diagnosed with leprosy and 777 (48.8%) were seropositive for anti-phenolic glycolipid-I (PGL-I). Additionally, we evaluated 256 household contacts (HHCs) of the students diagnosed with leprosy; 24 (9.4%) HHC were also diagnosed with leprosy and 107 (41.8%) were seropositive. The seroprevalence of anti-PGL-I was significantly higher amongst girls, students from urban areas and students from public schools (p < 0.0001). Forty-five (71.4%) new cases detected amongst SC were classified as paucibacillary and 59 (93.6%) patients did not demonstrate any degree of physical disability at diagnosis. The results of this study suggest that there is a high rate of undiagnosed leprosy and subclinical infection amongst children in the Amazon Region. The advantages of school surveys in hyperendemic areas include identifying leprosy patients at an early stage when they show no physical disabilities, preventing the spread of the infection in the community and breaking the chain of transmission.

Lupus anticoagulant: a marker for stroke and venous thrombosis in primary Sjogren's syndrome

Antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) have been described in primary Sjogren's syndrome (pSS) with controversial findings regarding aPL prevalence and their association with thrombotic events. We evaluated 100 consecutive pSS patients (American-European criteria) and 89 age-gender-ethnicity-matched healthy controls for IgG/IgM anticardiolipin (aCL), IgG/IgM anti-beta2-glycoprotein-I (a beta 2GPI), and lupus anticoagulant (LA) (positivity according to APS Sydney's criteria). Clinical analysis followed standardized interview and physical examination assessing thrombotic and nonthrombotic APS manifestations and thrombosis risk factors. aPLs were detected in 16 % patients and 5.6 % controls (p = 0.035). LA was the most common aPL in patients (9 %), followed by a beta 2GPI (5 %) and aCL (4 %). Thrombotic events occurred in five patients [stroke in two, myocardial infarction in one and deep-vein thrombosis (DVT) in four], but in none of controls (p = 0.061). Mean age at time of stroke was 35 years. Three patients with thrombotic events (including the two with stroke) had APS (Sydney's criteria) and were positive exclusively for LA. Comparison of patients with (n = 16) and without (n = 84) aPL revealed similar mean age, female predominance, and ethnicity (p > =0.387). Frequencies of livedo reticularis (25 vs. 4.8 %, p = 0.021), stroke (12.5 vs. 0 %, p = 0.024), and DVT (18.8 vs. 1.2 %, p = 0.013) were significantly higher in APL + patients. Conversely, frequencies of hypertension, dyslipidemia, diabetes, obesity, smoking, sedentarism, and hormonal contraception were similar in patients with or without aPL (p a parts per thousand yenaEuro parts per thousand 0.253). Our study identified LA as an important marker for APS in pSS, particularly for stroke in young patients, warranting routine evaluation of these antibodies and rigorous intervention in modifiable risk factors.

Antioxidant, anti-acetylcholinesterase and cytotoxic activities of ethanol extracts of peel, pulp and seeds of exotic Brazilian fruits Antioxidant, anti-acetylcholinesterase and cytotoxic activities in fruits

Ethanol extracts of powdered genipap (Genipa americana L), umbu (Spondia tuberosa A.) and siriguela (Spondia purpurea L) prepared from separate pulp, seeds and peel were investigated for their (i) antioxidant capacity, which was evaluated by various known methods; (ii) acetylcholinesterase (AChE) inhibitory activity; and (iii) cytotoxic effect on corneal epithelial cells of sheep. The highest values of total phenolic content were obtained with peel and seed extracts. Siriguela and umbu (seeds and peel) extracts displayed the highest antioxidant activities. Lipid peroxidation assays using mimetic biomembranes and mouse liver homogenates indicated that genipap pulp is a promising antioxidant. The investigation of phenols and organic acid contents revealed the presence of quercetin, citric and quinic acids, chlorogenic acid derivatives, among others, in several extracts, with the highest amount found in siriguela seeds. Genipap pulp and siriguela seed ethanol extracts presented an AChE inhibition zone similar to that of the positive control, carbachol. AChE inhibition assay with chlorogenic acid, one of the main constituents of siriguela seeds, revealed that this acid showed activity similar to that of the control physostigmine. These data suggest that these extracts are potentially important antioxidant supplements for the everyday human diet, pharmaceutical and cosmetic industries. (C) 2012 Elsevier Ltd. All rights reserved.

Anti-Atherogenic Effects of a Phenol-Rich Fraction from Brazilian Red Wine (Vitis labrusca L.) in Hypercholesterolemic Low-Density Lipoprotein Receptor Knockout Mice

Moderate wine intake (i.e., 1-2 glasses of wine a day) is associated with a reduced risk of morbidity and mortality from cardiovascular disease. The aim of this study was to evaluate the anti-atherosclerotic effects of a nonalcoholic ethyl acetate fraction (EAF) from a South Brazilian red wine obtained from Vitis labrusca grapes. Experiments were carried out on low-density lipoprotein (LDL) receptor knockout (LDLr-/-) mice, which were subjected to a hypercholesterolemic diet and treated with doses of EAF (3, 10, and 30 mg/kg) for 12 weeks. At the end of the treatment, the level of plasma lipids, the vascular reactivity, and the atherosclerotic lesions were evaluated. Our results demonstrated that the treatment with EAF at 3 mg/kg significantly decreased total cholesterol, triglycerides, and LDL plus very low-density lipoprotein levels compared with control hypercholesterolemic mice. The treatment of mice with EAF at 3 mg/kg also preserved the vasodilatation induced by acetylcholine on isolated thoracic aorta from hypercholesterolemic LDLr-/- mice. This result is in agreement with the degree of lipid deposit on arteries. Taken together, the results show for the first time that the lowest concentration of an EAF obtained from a red wine produced in southern Brazil significantly reduced the progression of atherosclerosis in mice.

In vitro Metabolism of Grandisin, a Lignan with Anti-chagasic Activity

Tetrahydrofuran lignans represent a well-known group of phenolic compounds capable of acting as antiparasitic agents. In the search for new medicines for the treatment of Chagas disease, one promising compound is grandisin which has shown significant activity on trypomastigote forms of Trypanosoma cruzi. In this work, the in vitro metabolism of grandisin was studied in the pig cecum model and by biomimetic phase I reactions, aiming at an ensuing a preclinical pharmacokinetic investigation. Although grandisin exhibited no metabolization by the pig microbiota, one putative metabolite was formed in a biomimetic model using Jacobsen catalyst. The putative metabolite was tested against T. cruzi revealing loss of activity in comparison to grandisin.

Anti-aquaporin-4 antibodies in the context of assorted immune-mediated diseases

Background and purposes: Anti-aquaporin 4 antibodies are specific markers for Devics disease. This study aimed to test if this high specificity holds in the context of a large spectrum of systemic autoimmune and non-autoimmune diseases. Methods: Anti-aquaporin-4 antibodies (NMO-IgG) were determined by indirect immunofluorescence (IIF) on mouse cerebellum in 673 samples, as follows: group I (clinically defined Devic's disease, n = 47); group II [ inflammatory/demyelinating central nervous system (CNS) diseases, n = 41]; group III (systemic and organ-specific autoimmune diseases, n = 250); group IV (chronic or acute viral diseases, n = 35); and group V (randomly selected samples from a general clinical laboratory, n = 300). Results: MNO-IgG was present in 40/47 patients with classic Devic's disease (85.1% sensitivity) and in 13/22 (59.1%) patients with disorders related to Devic's disease. The latter 13 positive samples had diagnosis of longitudinally extensive transverse myelitis (n = 10) and isolated idiopathic optic neuritis (n = 3). One patient with multiple sclerosis and none of the remaining 602 samples with autoimmune and miscellaneous diseases presented NMO-IgG (99.8% specificity). The autoimmune disease subset included five systemic lupus erythematosus individuals with isolated or combined optic neuritis and myelitis and four primary Sjogren's syndrome (SS) patients with cranial/peripheral neuropathy. Conclusions: The available data clearly point to the high specificity of anti-aquaporin-4 antibodies for Devic's disease and related syndromes also in the context of miscellaneous non-neurologic autoimmune and non-autoimmune disorders.

Base-Paired and Base-Stacked Structures of the Anti-HIV Drug Lamivudine: A Nucleoside DNA-Mimicry with Unprecedented Topology

We have prepared a DNA-mimicry of nucleosides in which the anti-HIV drug lamivudine (beta-L-2',3'-dideoxy-3'-thiacytidine, 3TC) self-assembles into a base-paired and helically base-stacked hexagonal structure. Face-to-face and face-to-tail stacked 3TC=3TC dimers base-paired through two hydrogen bonds between neutral cytosines by either N-H center dot center dot center dot O or N-H center dot center dot center dot N atoms give rise to a right-handed DNA-mimicry of lamivudine with an unusual highly symmetric hexagonal lattice and topology. In addition, a base-paired and base-stacked supramolecular architecture of lamivudine hemihydrochloride hemihydrate was also obtained as a result of our crystal screenings. This structure is formed through partially face-to-face stacked lamivudine pairs held together by protonated and neutral fragments. However, no helical stacking occurs in this structure in which lamivudine also adopts unusual conformations as the C1'-endo and C1'-exo sugar puckers and cytosine orientations intermediate between the anti and syn conformations. As a conclusion drawn from the nucleoside duplex, the hexagonal DNA-mimicry of lamivudine reveals that such double-stranded helices can be assembled without counterions and organic solvents but with higher crystallographic symmetry instead, because only water crystallizes together with lamivudine in this structure.

Age-dependent changes in rat lacrimal gland anti-oxidant and vesicular related protein expression profiles

Purpose: Anti-oxidation and exocytosis are important for maintaining exocrine tissue homeostasis. During aging, functional and structural alterations occur in the lacrimal gland (LG), including oxidative damage to proteins, lipids, and DNA. The aims of the present study were to determine in the aging LG: a) the effects of aging on LG structure and secretory activity and b) changes in the expression of oxidative stress markers. Methods: To address these goals, tear secretion composition and corneal impression cytology were compared between male Wistar rats of 2 (control) and 24 (aged) months. LG morphology and the expression levels of vitamin E and malonaldehyde (MDA) were evaluated to determine the anti-oxidant activity and lipid peroxidation, respectively. RT-PCR and western blot analysis were used for the analysis of Ras related in brain GTPase protein (Rab) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins of the secretory machinery (i.e.; Rab 3d, Rab 27, vesicle-associated membrane protein-2 (Vamp-2), and syntaxin). Results: Histological analysis of aged rats revealed a higher frequency of corneal epithelia metaplasia. In the acinar cells, organelles underwent degeneration, and lipofucsin-like material accumulated in the cytoplasm along with declines in the anti-oxidant marker vitamin E. Rab3d and Rab27b mRNA levels fell along with Rab3d protein expression, whereas syntaxin levels increased. Conclusions: These findings indicate that exocytotic and anti-oxidant mechanisms become impaired with age in the rat LG. In parallel with these structural alterations, functional declines may contribute to the pathophysiology caused by tear film modification in dry eye disease.

Lasiodiplodan, an exocellular (1 -> 6)-beta-d-glucan from Lasiodiplodia theobromae MMPI: production on glucose, fermentation kinetics, rheology and anti-proliferative activity

Lasiodiplodan, an exopolysaccharide of the (1 -> 6)-beta-d-glucan type, is produced by Lasiodiplodia theobromae MMPI when grown under submerged culture on glucose. The objective of this study was to evaluate lasiodiplodan production by examining the effects of carbon (glucose, fructose, maltose, sucrose) and nitrogen sources (KNO3, (NH4)(2)SO4, urea, yeast extract, peptone), its production in shake flasks compared to a stirred-tank bioreactor, and to study the rheology of lasiodiplodan, and lasiodiplodan's anti-proliferative effect on breast cancer MCF-7 cells. Although glucose (2.05 +/- A 0.05 g L-1), maltose (2.08 +/- A 0.04 g L-1) and yeast extract (2.46 +/- A 0.06 g L-1) produced the highest amounts of lasiodiplodan, urea as N source resulted in more lasiodiplodan per unit biomass than yeast extract (0.74 +/- A 0.006 vs. 0.22 +/- A 0.008 g g(-1)). A comparison of the fermentative parameters of L. theobromae MMPI in shake flasks and a stirred-tank bioreactor at 120 h on glucose as carbon source showed maximum lasiodiplodan production in agitated flasks (7.01 +/- A 0.07 g L-1) with a specific yield of 0.25 +/- A 0.57 g g(-1) and a volumetric productivity of 0.06 +/- A 0.001 g L-1 h(-1). A factorial 2(2) statistical design developed to evaluate the effect of glucose concentration (20-60 g L-1) and impeller speed (100-200 rpm) on lasiodiplodan production in the bioreactor showed the highest production (6.32 g L-1) at 72 h. Lasiodiplodan presented pseudoplastic behaviour, and the apparent viscosity increased at 60A degrees C in the presence of CaCl2. Anti-proliferative activity of lasiodiplodan was demonstrated in MCF-7 cells, which was time- and dose-dependent with an IC50 of 100 mu g lasiodiplodan mL(-1).

CD44(+)/CD24(-) cells and lymph node metastasis in stage I and II invasive ductal carcinoma of the breast

The presence of tumor-initiating cells (CD44(+)/CD24(-)) in solid tumors has been reported as a possible cause of cancer metastasis and treatment failure. Nevertheless, little is know about the presence of CD44(+)/CD24(-) cells within the primary tumor and metastasis. The proportion of CD44(+)/CD24(-) cells was analyzed in 40 samples and in 10 lymph node metastases using flow cytometry phenotyping. Anti-human CD326 (EpCam; FITC), antihuman CD227 (MUC-1; FITC), anti-human CD44 (APC), and anti-human CD24 (PE), anti-ABCG2 (PE), and anti-CXCR4 (PeCy7) were used for phenotype analysis. The mean patient age was 60.5 years (range, 33-87 years); mean primary tumor size (pT) was 1.8 cm (0.5-3.5 cm). The Wilcoxon or Kruskal-Wallis test was used for univariate analyses. Logistic regression was used for multivariate analysis. The median percentage of CD44(+)/CD24(-) cells within primary invasive ductal carcinomas (IDC) was 2.7% (range, 0.2-71.2). In lymph node metastases, we observed a mean of 6.1% (range, 0.07-53.7). The percentage of CD44(+)/CD24(-) cells in IDCs was not associated with age, pT, tumor grade and HER2. We observed a significantly enrichment of CD44(+)/CD24(-) and ABCG2(+) cells in ESA(+) cell population in patients with positive lymph nodes (P = 0.02 and P = 0.04, respectively). Our data suggest that metastatic dissemination is associated with an increase in tumorinitiating cells in stage I and II breast cancer.

Advanced glycated albumin impairs HDL anti-inflammatory activity and primes macrophages for inflammatory response that reduces reverse cholesterol transport

Objective: We investigated the effect of advanced glycated albumin (AGE-albumin) on macrophage sensitivity to inflammation elicited by S100B calgranulin and lipopolysaccharide (LPS) and the mechanism by which HDL modulates this response. We also measured the influence of the culture medium, isolated from macrophages treated with AGE-albumin, on reverse cholesterol transport (RCT). Methods and results: Macrophages were incubated with control (C) or AGE-albumin in the presence or absence of HDL, followed by incubations with S100B or LPS. Also, culture medium obtained from cells treated with C- or AGE-albumin, following S100B or LPS stimulation was utilized to treat naive macrophages in order to evaluate cholesterol efflux and the expression of HDL receptors. In comparison with C-albumin, AGE-albumin, promoted a greater secretion of cytokines after stimulation with S100B or LPS. A greater amount of cytokines was also produced by macrophages treated with AGE-albumin even in the presence of HDL Cytokine-enriched medium, drawn from incubations with AGE-albumin and S100B or LPS impaired the cholesterol efflux mediated by apoA-I (23% and 37%, respectively), HDL2 (43% and 47%, respectively) and HDL3 (20% and 8.5%, respectively) and reduced ABCA-1 protein level (16% and 26%, respectively). Conclusions: AGE-albumin primes macrophages for an inflammatory response impairing the RCT. Moreover, AGE-albumin abrogates the anti-inflammatory role of HDL, which may aggravate the development of atherosclerosis in DM. (C) 2012 Elsevier BM. All rights reserved.

Oócitos aparentemente maduros injetados em telófase I apresentam piores resultados de reprodução assistida

OBJETIVO: Avaliar o estágio de maturação nuclear de oócitos com o primeiro corpúsculo polar (CP) visível de pacientes inférteis submetidas à estimulação ovariana para injeção intracitoplasmática de espermatozoide (ICSI) e comparar os resultados da injeção intracitoplasmática de espermatozoide entre os oócitos em telófase I (TI) e metáfase II (MII), e entre aqueles em metáfase II com e sem fuso celular visível. MÉTODOS: Estudo prospectivo que incluiu 106 pacientes inférteis submetidas à injeção intracitoplasmática de espermatozoide. Foram incluídas pacientes com idade menor ou igual a 38 anos, hormônio folículo estimulante (FSH) basal menor que 10 mIU/mL e índice de massa corpórea (IMC) menor que 30 kg/m². Foram excluídas pacientes com doenças sistêmicas, com qualquer infecção ativa, tabagistas ou que fizeram uso de medicações hormonais e anti-inflamatórias hormonais e não hormonais nos últimos dois meses, previamente à programação para o procedimento de reprodução assistida. Os oócitos com extrusão do primeiro corpúsculo polar foram avaliados pela microscopia de polarização, imediatamente antes da realização da injeção intracitoplasmática de espermatozoide, e caracterizados quanto ao estágio de maturação nuclear (telófase I ou metáfase II). Os oócitos em metáfase II foram avaliados de acordo com a presença ou não do fuso meiótico. Foram analisadas as taxas de fertilização, clivagem e o número de embriões de boa qualidade no segundo dia (D2) de desenvolvimento. Os dados foram analisados comparativamente através do teste exato de Fisher. Em todas as análises foi considerado o nível de significância de 5% (p<0,05). RESULTADOS: O fuso meiótico de 516 oócitos foi visualizado através da microscopia de polarização. Dezessete dos 516 oócitos avaliados estavam em telófase I (3,3%) e 499 (96,7%) em metáfase II. Os oócitos injetados em telófase I apresentaram taxas de fertilização significativamente menores do que os injetados em metáfase II (53 e 78%, respectivamente) e não produziram nenhum embrião de boa qualidade no segundo dia. Comparando-se os oócitos com e sem fuso celular visível, não foi observada diferença significativa nos resultados de injeção intracitoplasmática de espermatozoide. CONCLUSÕES: Oócitos injetados em telófase I apresentaram menores taxas de fertilização quando comparados aos em metáfase II. É possível que a análise do estágio de maturação nuclear oocitária, por meio da microscopia de polarização, possa ser utilizada como fator de predição das taxas de fertilização pós-injeção intracitoplasmática de espermatozoide.

A phase I clinical trial of a new 5-valent rotavirus vaccine

We conducted a phase I, double-blind, placebo-controlled trial to evaluate a new 5-valent oral rotavirus vaccine’s safety and immunogenicity profiles. Subjects were randomly assigned to receive 3 orally administered doses of a live-attenuated human-bovine (UK) reassortant rotavirus vaccine, containing five viral antigens (G1, G2, G3, G4 and G9), or a placebo. The frequency and severity of adverse events were assessed. Immunogenicity was evaluated by the titers of anti-rotavirus IgA and the presence of neutralizing antibodies anti-rotavirus. No severe adverse events were observed. There was no difference in the frequency of mild adverse events between experimental and control groups. The proportion of seroconversion was consistently higher in the vaccine group, for all serotypes, after each one of the doses. The 5-valent vaccine has shown a good profile of safety and immunogenicity in this small sample of adult volunteers.

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.