Intranasal Flunisolide Suppresses Pathological Alterations Caused by Silica Particles in the Lungs of Mice.

Silicosis is an occupational disease triggered by the inhalation of fine particles of crystalline silica and characterized by inflammation and scarring in the form of nodular lesions in the lungs. In spite of the therapeutic arsenal currently available, there is no specific treatment for the disease. Flunisolide is a potent corticosteroid shown to be effective for controlling chronic lung inflammatory diseases. In this study, the effect of flunisolide on silica-induced lung pathological changes in mice was investigated. Swiss-Webster mice were injected intranasally with silica particles and further treated with flunisolide from day 21 to 27 post-silica challenge. Lung function was assessed by whole body invasive plethysmography. Granuloma formation was evaluated morphometrically, collagen deposition by Picrus sirius staining and quantitated by Sircol. Chemokines and cytokines were evaluated using enzyme-linked immunosorbent assay. The sensitivity of lung fibroblasts was also examined in in vitro assays. Silica challenge led to increased leukocyte numbers (mononuclear cells and neutrophils) as well as production of the chemokine KC/CXCL-1 and the cytokines TNF-α and TGF-ß in the bronchoalveolar lavage. These alterations paralleled to progressive granuloma formation, collagen deposition and impairment of lung function. Therapeutic administration of intranasal flunisolide inhibited granuloma and fibrotic responses, noted 28 days after silica challenge. The upregulation of MIP-1α/CCL-3 and MIP-2/CXCL-2 and the cytokines TNF-α and TGF-ß, as well as deposition of collagen and airway hyper-reactivity to methacholine were shown to be clearly sensitive to flunisolide, as compared to silica-challenge untreated mice. Additionally, flunisolide effectively suppressed the responses of proliferation and MCP-1/CCL-2 production from IL-13 stimulated lung fibroblasts from silica- or saline-challenged mice. In conclusion, we report that intranasal treatment with the corticosteroid flunisolide showed protective properties on pathological features triggered by silica particles in mice, suggesting that the compound may constitute a promising strategy for the treatment of silicosis.

Prevalence of Early- and Late-Season Pest Damage to Corn in Cover Crop-Based Reduced-Tillage Organic Systems.

In organic agronomic cropping systems, the use of synthetic insecticides and transgenic varieties are prohibited and producers rely mainly on biological control, tillage, crop rotation, and other cultural practices to manage pests. We measured damage to organic corn (Zea mays L.) from multiple invertebrate pests, including slugs (Gastropoda: Mollusca), European corn borer (Ostrinia nubilalis Hübner), corn earworm (Helicoverpa zea Boddie), and fall armyworm (Spodoptera frugiperda Smith), early and late in the growing season in four cropping systems that varied in tillage frequency and intensity and in winter cover crop species. Specific management tactics included two cover crop mixtures preceding corn, the use of a roller-crimper or tillage to terminate cover crops preceding corn, and the establishment of interseeded cover crops after corn emergence. Prevalence of early-season damage was high, but severity of damage was very low and unrelated to corn yield. The proportion of corn plants affected by chewing pests early in the season was lower in plots in which tillage compared to a roller-crimper was used to terminate cover crops. Cropping system did not affect the numbers of late-season caterpillar pests or corn yield. Predation by natural enemies appeared to effectively maintain damage from chewing pests below yield-damaging levels. These results support the inclusion of winter and interseeded cover crops in organic agronomic crop rotations to gain environmental benefits without increasing risks of damage by insect pests.

Enhanced Analgesic Effects and Gastrointestinal Safety of a Novel, Hydrogen Sulfide-Releasing Anti-Inflammatory Drug (ATB-352): A Role for Endogenous Cannabinoids.

Aims: The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increase anti-inflammatory and analgesic potency. We have tested the hypothesis that an H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. Results: ATB-352 was significantly more potent and effective as an analgesic than ketoprofen and did not elicit GI damage. Pretreatment with an antagonist of the CB1 cannabinoid receptor (AM251) significantly reduced the analgesic effects of ATB-352. The CB1 antagonist exacerbated GI damage when coadministered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB1 antagonist. In vitro, ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352. Innovation: Ketoprofen is a potent analgesic, but its clinical use, even in the short term, is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H2S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting analgesic effectiveness. Conclusion: This study demonstrates a marked enhancement of the potency and effectiveness of ATB-352, an H2S-releasing derivative of ketoprofen, in part, through the involvement of the endogenous cannabinoid system. This may have significant advantages for the control and management of pain, such as in a postoperative setting.

Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial.

BACKGROUND: Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. METHODS: After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. RESULTS: All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95%CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 ± 129 pg/mL before treatment and 241 ± 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 ± 109 pg/mL before treatment, and 168 ± 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95%CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. CONCLUSION: Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02632812 . Registered 14 December 2015.

Hydrogen sulfide inhibits oxidative stress in lungs from allergic mice in vivo.

Recent studies show that endogenous hydrogen sulfide (H(2)S) plays an anti-inflammatory role in the pathogenesis of airway inflammation. This study investigated whether exogenous H(2)S may counteract oxidative stress-mediated lung damage in allergic mice. Female BALB/c mice previously sensitized with ovalbumin (OVA) were treated with sodium hydrosulfide (NaHS) 30 min before OVA challenge. Forty eight hours after antigen-challenge, the mice were killed and leukocyte counting as well as nitrite plus nitrate concentrations were determined in the bronchoalveolar lavage fluid, and lung tissue was analysed for nitric oxide synthase (NOS) activity, iNOS expression, superoxide dismutase (SOD), catalase, glutathione reductase (GR) and glutathione peroxidase (GPx) activities, thiobarbituric acid reactive species and 3-nitrotyrosine containing proteins (3-NT). Pre-treatment of OVA-sensitized mice with NaHS resulted in significant reduction of both eosinophil and neutrophil migration to the lungs, and prevented the elevation of iNOS expression and activity observed in the lungs from the untreated allergic mice, although it did not affect 3-NT. NaHS treatment also abolished the increased lipid peroxidation present in the allergic mouse lungs and increased SOD, GPx and GR enzyme activities. These results show, for the first time, that the beneficial in vivo effects of the H(2)S-donor NaHS on allergic airway inflammation involve its inhibitory action on leukocyte recruitment and the prevention of lung damage by increasing endogenous antioxidant defenses. Thus, exogenous administration of H(2)S donors may be beneficial in reducing the deleterius impact of allergic pulmonary disease, and might represent an additional class of pharmacological agents for treatment of chronic pulmonary diseases.

Role of cyclooxygenases in oedema-forming activity of bothropic venoms.

The venoms of Bothrops asper (BaV) and Bothrops jararaca (BjV), two of the most medically important poisonous snakes of Latin America, cause pronounced oedema in the victims through poorly understood mechanisms. In the present study, we examined the possible role of cyclooxygenases (COX) in the genesis of mouse paw oedema caused by BaV and BjV injections. BaV at 2.5 microg/paw and BjV at 0.75 microg/paw induced significant oedema that persisted for up to 6h following subplantar injection. Treatment with indomethacin (2 mg/kg), rofecoxib, (10 mg/kg), or dexamethasone (2 mg/kg) significantly reduced the BaV- and BjV-induced oedema formation. Treatment with SC-560 (30 mg/kg) significantly reduced the oedema formation induced by BjV but had no effect on that induced by BaV. Both venoms induced significant increases in the levels of prostaglandin E(2) (PGE(2)) and the expression of COX-1 and COX-2 in paw tissue. The peak of oedema formation and PGE(2) release correlated with marked expression of COX-2 in the paw tissue. These results demonstrate that injection of BaV and BjV results in a rapid increase in oedema formation that is, at least partially, mediated by arachidonic acid metabolites formed by COX-2. In the case of BjV, COX-1-derived prostanoids also appear to contribute significantly to the inflammatory changes.

Bothrops jararaca and Crotalus durissus terrificus venoms elicit distinct responses regarding to production of prostaglandins E2 and D2, and expression of cyclooxygenases.

Prostaglandins (PGs), synthesized by cyclooxygenases, play important roles in many pathophysiological processes including inflammation and hyperalgesia. In this study the profiles of PGE(2) and PGD(2) production secondary to injection of Bothrops jararaca venom (BjV), with inflammatory activity or Crotalus durissus terrificus venom (CdtV), with anti-inflammatory and antinociceptive properties, into mice were evaluated, and the ability of these venoms to induce expression of cyclooxygenases-1 (COX-1) and -2 (COX-2) was investigated. Intraperitoneal injection of BjV but not of CdtV induced the release and PGD(2) at 30 min and of PGE(2) from 3 up to 12 h after injection. Moreover, BjV up-regulated expression of COX-2 but not of the constitutive COX-1, suggesting that expressed COX-2 provides more substrate for synthesis of PGs by the respective terminal synthases, being the critical enzyme for PGs production in the late periods of BjV effect. In contrast, CdtV does not have any effect on constitutive COX-1 and do not induce expression of COX-2. Therefore, differences between BjV and CdtV in the ability to regulate PGs synthesis can account for their distinct effects with regard to inflammation. Moreover, inhibition of COX-2 by selective drugs may be of value to counteract the severe local inflammation induced by BjV in the victims.

Bothrops jararaca and Crotalus durissus terrificus venoms elicit distinct responses regarding to production of prostaglandins E2 and D2, and expression of cyclooxygenases

rostaglandins (PGs), synthesized by cyclooxygenases, play important roles in many pathophysiological processes including inflammation and hyperalgesia. In this study the profiles of PGE2 and PGD2 production secondary to injection of Bothrops jararaca venom (BjV), with inflammatory activity or Crotalus durissus terrificus venom (CdtV), with anti-inflammatory and antinociceptive properties, into mice were evaluated, and the ability of these venoms to induce expression of cyclooxygenases-1 (COX-1) and -2 (COX-2) was investigated. Intraperitoneal injection of BjV but not of CdtV induced the release and PGD2 at 30 min and of PGE2 from 3 up to 12 h after injection. Moreover, BjV up-regulated expression of COX-2 but not of the constitutive COX-1, suggesting that expressed COX-2 provides more substrate for synthesis of PGs by the respective terminal synthases, being the critical enzyme for PGs production in the late periods of BjV effect. In contrast, CdtV does not have any effect on constitutive COX-1 and do not induce expression of COX-2. Therefore, differences between BjV and CdtV in the ability to regulate PGs synthesis can account for their distinct effects with regard to inflammation. Moreover, inhibition of COX-2 by selective drugs may be of value to counteract the severe local inflammation induced by BjV in the victims.

COX-inhibiting nitric oxide donors (CINODs): potential benefits on cardiovascular and renal function.

The COX-inhibiting nitric oxide donors (CINODs) are a new class of agents designed for the treatment of pain and inflammation. CINODs have a multi-pathway mechanism of action that involves COX inhibition and nitric oxide donation. The anti-inflammatory and analgesic effects of COX inhibition are reinforced through inhibition of caspase-1 regulated cytokine production, while nitric oxide donation provides multiorgan protection. Whereas both conventional nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2-selective NSAIDs are associated with a variety of adverse effects on the renal system, such as hypertension and edema, CINODs may offer an improved renal safety profile. These agents are devoid of hypertensive effects in animal models and their mechanism of action suggests that they may not cause edema. CINODs also have other renal-sparing effects, being better tolerated than NSAIDs in models of kidney failure. CINODs have been shown to prevent platelet activation in vitro and exhibit anti-thrombotic activity in vivo. In animal models of ischemia/reperfusion, CINODs treatment results in improved recovery of heart contractility and reduced left ventricular end-diastolic pressure, in contrast to the effects of aspirin. The combination of improved analgesia, reduced gastrointestinal toxicity and cardiorenal protection has been established in animal models, and early clinical results suggest a favourable gastrointestinal safety profile in humans. The potential for CINODs to provide cardiorenal protection in humans is currently being investigated.

Sildenafil prevents indomethacin-induced gastropathy in rats: role of leukocyte adherence and gastric blood flow.

Nitric oxide (NO) is an important mediator of gastric mucosal defense. Sildenafil (SILD), a cyclic GMP-specific phosphodiesterase inhibitor, promotes an increase in cGMP concentrations in the gastrointestinal tract. cGMP mediates many of the biological actions of NO. We tested the hypothesis that SILD could increase mucosal defense against indomethacin-induced gastropathy in rats. SILD (1, 4 or 10 mg kg(-1), p.o.) pretreatment significantly reduced (P < 0.01) the gastric damage and the increase in gastric myeloperoxidase (MPO) activity elicited by indomethacin (20 mg kg(-1) p.o.), with the maximal effect at the dose of 10 mg kg(-1). L-NAME (3, 10 or 20 mg kg(-1), i.p.) dose dependently reversed the protective effects of SILD, an effect not seen when L-arginine (L-ARG) (200 mg kg(-1), i.p.) was co-administered with L-NAME. Indomethacin-induced leukocyte adhesion, assessed by intravital microscopy, was decreased (P < 0.01) by SILD, and this effect was reversed by L-NAME cotreatment. Indomethacin elicited a decrease in gastric blood flow and in gastric PGE2 levels. SILD was able to prevent the decrease in gastric blood flow (P < 0.01), without diminishing the inhibitory effect of indomethacin on prostaglandin synthesis. These results indicate that SILD, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy, possibly through a reduction of leukocyte adhesion and maintenance of gastric blood flow.

Nitric oxide as a regulator of inflammatory processes.

Nitric oxide (NO) plays an important role in mediating many aspects of inflammatory responses. NO is an effector molecule of cellular injury, and can act as an anti-oxidant. It can modulate the release of various inflammatory mediators from a wide range of cells participating in inflammatory responses (e.g., leukocytes, macrophages, mast cells, endothelial cells, and platelets). It can modulate blood flow, adhesion of leukocytes to the vascular endothelium and the activity of numerous enzymes, all of which can have an impact on inflammatory responses. In recent years, NO-releasing drugs have been developed, usually as derivatives of other drugs, which exhibit very powerful anti-inflammatory effects.

The epidemiology of alcohol, marijuana, and cocaine use among Mexican American, Puerto Rican, Cuban American, and other Latin American eighth-grade students in the United States: 1991-2002.

OBJECTIVES: We compared trends in and correlates of marijuana use, cocaine use, and heavy alcohol use for adolescents of Mexican American, Puerto Rican, Cuban, and other Latin American heritage in the United States. METHODS: We used/examined data from nationally representative samples of eighth-grade Hispanic students who participated in the Monitoring the Future study during the years 1991-2002 (n=24235). RESULTS: Drug use was significantly higher among boys and adolescents of almost all Hispanic ethnicities who did not live with both parents. In addition, drug use differed considerably according to ethnic group on language first spoken, parental education, urbanicity, and region. CONCLUSIONS: A better understanding of the homogeneity and heterogeneity of drug use patterns within and between Hispanic groups should assist in the development of prevention programs.

Nitric oxide as a regulator of inflammatory processes

Nitric oxide (NO) plays an important role in mediating many aspects of inflammatory responses. NO is an effector molecule of cellular injury, and can act as an anti-oxidant. It can modulate the release of various inflammatory mediators from a wide range of cells participating in inflammatory responses (e.g., leukocytes, macrophages, mast cells, endothelial cells, and platelets). It can modulate blood flow, adhesion of leukocytes to the vascular endothelium and the activity of numerous enzymes, all of which can have an impact on inflammatory responses. In recent years, NO-releasing drugs have been developed, usually as derivatives of other drugs, which exhibit very powerful anti-inflammatory effects.

Tobacco, alcohol, and illicit drug use: racial and ethnic differences among U.S. high school seniors, 1976-2000.

OBJECTIVE: This study examines differences in adolescents' use of tobacco, alcohol, and illicit drugs by racial and ethnic groups. METHODS: The authors analyzed questionnaire data from large, nationally representative samples of U.S. high school seniors to examine differences in drug use prevalence and trends among racial and ethnic groups between 1976 and 2000. RESULTS: On average, American Indian seniors showed the highest levels of tobacco, alcohol, and illicit drug use. Cuban American and white seniors also tended to have relatively high levels of substance use, followed by Mexican American and Puerto Rican seniors. Other Latin American, African American, and Asian American seniors reported the lowest levels of drug use. Most of these differences are longstanding, but some have widened and others narrowed during the past 25 years. CONCLUSION: Significant differences exist in adolescent use of tobacco, alcohol, and illicit drugs by racial and ethnic groups, and these differences have changed over time. Future research should examine these differences and seek to identify the sources and consequences of the disparities.

Glaucoma and intraocular pressure in Jamaica

Eighty-five percent of the persons aged 35 to 74 years and living in a suburban area of Kingston were examined in an ophthalmic survey to obtain data on the distribution of ocular pressure and the prevalences of the various forms of glaucoma in Jamaica. Intraocular pressures tended to rise with age and fall with successive measurements. Raised intraocular pressure was associated with myopia rather than with hypermetropia. The prevalence of chronic simple glaucoma and suspected low-tension glaucoma at 14 percent was higher in Jamaica than in the Wales.(AU)

A neurological, ophthalmological and audiological survey of a suburban Jamaican community

A neurological, opthalmological and audiological survey was conducted in a suburban Jamaican community aged 35-74 years. One aim was to determine the prevalence of signs found in the Jamaican neuropathy syndrome and their association with sensorineural hearing loss and retrobulbar neuropathy. Mean hearing levels of Jamaicans were better than those reported from a comparable Scottish population. Conductive hearing losses, including otosclerosis, were uncommon. Sensorineural loss was found in 5.0 percent of men and 11.4 percent of women; presbyacusis was a possible cause in older subjects but in many the aetiology was unknown. Noise-induced hearing loss was not an important cause of impaired hearing. Refractive errors in vision were common and many needed proper correction. Pterygia were common (15.9 percent) but less prevalent among those of predominantly African origin, suggesting a racial difference in susceptibility. The prevalence of progressive cataract rose from 3.2 percent at 35-44 years to 71.7 percent at 65-74 years and was greater in diabetics than non-diabetics. Eight cases of chronic simple glaucoma were detected, a prevalence greater than that reported in a Welsh population. Tropical amblyopia (poor visual acuity, temporal pallor and field defects) was found in eight cases. Unexplained neurological signs, possibly representing manifestations of the Jamaican neuropathy syndrome, were found in 25 subjects (4.8 percent of females and 4.0 percent of males). Sensorineural hearing losses and retrobular neuropathy were common in these than in normal subjects but also occurred separately; it is unknown to what extent they are due to the same aetiology (AU)

Auditory and ophthalmic survey results in a Jamaican suburban population

A survey of ophthalmological aural and neurolgical disease was carried out among adults age 35-74 years in August Town, a suburban community in Kingston, Jamaica. A private census showed a total population of this age group of 676. 576 (85.2 per cent) were examined ophthalmologically and 551 (81.5 per cent) audiometrically. Ophthalmic Survey: The analysis is not yet complete but provisional inspection of the results shows: (1) Pterygia was common (16 per cent) and more prevalent among those of lighter complexion, suggesting a racial difference in susceptibility. (2) The prevalence of progressive cataracts varied from 3 per cent in 35-44 age group to 75 per cent in those over 65. Cataracts were commoner in diabetics than in non-diabetics. (3) Chronic simple glaucoma as defined by raised intra-ocular pressure, typical field detects and cupping of the discs was found in four new cases. The prevalence was greater than that found in a Welsh survey but the numbers are too few for definite conclusions on relative prevalence to be reached. (4) The triad of poor visual acuity of unknown cause, field defects and pallor of the discs was found in eight patients, five of whom also had sensorineural deafness and three of whom had signs suggestive of the ataxic form of 'Jamaican neuropathy'. (5) The following cases were seen: anterior uveitis - 3, posterior uveitis - 10, diabetic retinopathy - 10, hypertensive (grade ii) - 9, hypertensive, (grade iii) - 2, senile macular degeneration - 4, myopic degeneration - 2. Audiometric survey: Conductive deafness was found in 1 per cent of the ears, compared with 6 per cent in a Scottish survey. After elimination conductive deafness, mean hearing thresholds, particular at high frequencies, were better in Jamaicans than in Scots. Jamaican men had lower thresholds (i.e. hearing better) than women whereas the reverse was found in Scotland. Sensorineural deafness (mean hearing threshold 30 or more above normal at the conversational frequencies of 500, 1,000 and 2,000 c/s) was found in one or both ears of 11 per cent of women and 5 per cent of men. The aetiology of this deafness is obscure although a proportion higher than would be expected had signs associated with "Jamaican neuropathy". No cases of deaf-mutism, Menieres syndrome or neuro-fibroma of the eight nerve were seen. One case of oto-sclerosis was diagnosed (AU)