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Dietary deficiency of docosahexaenoic acid (C22:6 n-3; DHA) is linked to the neuropathology of several cognitive disorders, including anxiety. DHA, which is essential for brain development and protection, is primarily obtained through the diet or synthesized from dietary precursors, however the conversion efficiency is low. Curcumin (diferuloylmethane), which is a principal component of the spice turmeric, complements the action of DHA in the brain, and this study was performed to determine molecular mechanisms involved. We report that curcumin enhances the synthesis of DHA from its precursor, α-linolenic acid (C18:3 n-3; ALA) and elevates levels of enzymes involved in the synthesis of DHA such as FADS2 and elongase 2 in both liver and brain tissues. Furthermore, in vivo treatment with curcumin and ALA reduced anxiety-like behavior in rodents. Taken together, these data suggest that curcumin enhances DHA synthesis, resulting in elevated brain DHA content. These findings have important implications for human health and the prevention of cognitive disease, particularly for populations eating a plant-based diet or who do not consume fish, a primary source of DHA, since DHA is essential for brain function and its deficiency is implicated in many types of neurological disorders.

BackgroundOlder human immunodeficiency virus (HIV)-1 transgenic rats are a model for HIV-1 associated neurocognitive disorders (HAND). They show behavioral changes, neuroinflammation, neuronal loss, and increased brain arachidonic acid (AA) enzymes. Aspirin (acetylsalicylate, ASA) inhibits AA oxidation by cyclooxygenase (COX)-1 and COX-2.HypothesisChronic low-dose ASA will downregulate brain AA metabolism in HIV-1 transgenic rats.MethodsNine month-old HIV-1 transgenic and wildtype rats were given 42 days of 10mg/kg/day ASA or nothing in drinking water; eicosanoids were measured using ELISAs on microwaved brain extracts.ResultsBrain 15-epi-lipoxin A4 and 8-isoprostane concentrations were significantly higher in HIV-1 transgenic than wildtype rats; these differences were prevented by ASA. ASA reduced prostaglandin E2 and leukotriene B4 concentrations in HIV-1 Tg but not wildtype rats. Thromboxane B2, 15-HETE, lipoxin A4 and resolvin D1 concentrations were unaffected by genotype or treatment.ConclusionChronic low-dose ASA reduces AA-metabolite markers of neuroinflammation and oxidative stress in a rat model for HAND.

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

ObjectiveSalsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.MethodsA randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.ResultsIn those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01).ConclusionsFindings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation.

We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.

BackgroundAccumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population.MethodsThe effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer.ResultsThe effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50-65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period.ConclusionsProphylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit-harm profile; longer use is likely to have greater benefits. Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test effectiveness of Helicobacter pylori screening-eradication before starting aspirin prophylaxis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs worldwide. NSAIDs are used for a variety of conditions including pain, rheumatoid arthritis, and musculoskeletal disorders. The beneficial effects of NSAIDs in reducing or relieving pain are well established, and other benefits such as reducing inflammation and anticancer effects are also documented. The undesirable side effects of NSAIDs include ulcers, internal bleeding, kidney failure, and increased risk of heart attack and stroke. Some of these side effects may be due to the oxidative stress induced by NSAIDs in different tissues. NSAIDs have been shown to induce reactive oxygen species (ROS) in different cell types including cardiac and cardiovascular related cells. Increases in ROS result in increased levels of oxidized proteins which alters key intracellular signaling pathways. One of these key pathways is apoptosis which causes cell death when significantly activated. This review discusses the relationship between NSAIDs and cardiovascular diseases (CVD) and the role of NSAID-induced ROS in CVD.

ObjectivesTo determine the rate of magnetic resonance imaging (MRI)-detected noncystic white matter injury (WMI) in a prospective cohort of premature newborns, and to evaluate its associations with changes in clinical predictors of WMI over the study period.Study designA prospective cohort of premature newborns (

Although Andre Robert's historic article on "gastric cytoprotection" in 1979 introduced this new name and concept, gastroprotective drugs (e.g. sofalcone, sucralfate), which prevent and/or accelerate healing of gastric ulcers without inhibiting acid secretion, were known in Japan before or around that time. But since Robert's studies were solely focused on prostaglandins (PG), they became the center of gastrointestinal research for more than 30 years. As endogenous products, PG were implicated in mediating the gastroprotective effect of other drugs such as sofalcone and sucralfate, despite that the cyclooxygenase inhibitor indomethacin diminished but never abolished gastroprotection by other drugs. Another group of endogenous substances, that is, sulfhydryls (SH), investigated in parallel with PG, also seem to play a mechanistic role in gastroprotection, especially since SH alkylators like N-ethylmaleimide counteract virtually any form of gastroprotection. In Robert's terms of "prevention of chemically induced acute mucosal lesions," so far no single mechanism could explain the beneficial effects of diverse protective agents, but I argue that these two endogenous substances (i.e. PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG and histamine, because as mediators of acute inflammation, they increase vascular permeability (VP), and SH scavenge free radicals. This is contrary to the search for a single mechanism of action, long focused on enhanced secretion of mucus and/or bicarbonate that may contribute but cannot explain all forms of gastroprotection. Nevertheless, based on research work of the last 30 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated: it's a complex but orderly and evolution-based physiologic response of the gastric mucosa under pathologic conditions. Namely, one of the first physiologic defense responses of any organ is inflammation that starts with rapid vascular changes (e.g. increased VP and blood flow), followed by cellular events (e.g. infiltration by acute and chronic inflammatory cells). Thus, PG and histamine, by increasing VP create a perivascular edema that dilutes and delays toxic agents reaching the subepithelial capillaries. Otherwise, damaging chemicals may induce severe early vascular injury resulting in blood flow stasis, hypoxia, and necrosis of surrounding epithelial and mesenchymal cells. In this complex response, increased mucus and/or bicarbonate secretion seem to cause luminal dilution of gastrotoxic chemicals that is further reinforced by a perivascular, histodilutional component. This mechanistic explanation would encompass the protective actions of diverse agents as PG, small doses of histamine, motility stimulants, and dilute irritants (i.e. "adaptive cytoprotection"). Thus, although markedly increased VP is pathologic, slight increase in VP seems to be protective, that is, a key element in the complex pathophysiologic response during acute gastroprotection. Over the years, "gastroprotection" was also applied to accelerated healing of chronic gastroduodenal ulcers without reduction of acid secretion. The likely main mechanism here is the binding of angiogenic growth factors (e.g. basic fibroblast growth factor, vascular endothelial growth factor) to the heparin-like structures of sucralfate and sofalcone. Thus, despite intensive research of the last 30 years, gastroprotection is incompletely understood, and we are still far away from effectively treating Helicobacter pylori-negative ulcers and preventing nonsteroidal anti-inflammatory drugs-caused erosions and ulcers in the upper and lower gastrointestinal tract; hence "gastric cytoprotection" research is still relevant.

Although Andre Robert's historic article on "gastric cytoprotection" in 1979 introduced this new name and concept, gastroprotective drugs (e.g. sofalcone, sucralfate), which prevent and/or accelerate healing of gastric ulcers without inhibiting acid secretion, were known in Japan before or around that time. But since Robert's studies were solely focused on prostaglandins (PG), they became the center of gastrointestinal research for more than 30 years. As endogenous products, PG were implicated in mediating the gastroprotective effect of other drugs such as sofalcone and sucralfate, despite that the cyclooxygenase inhibitor indomethacin diminished but never abolished gastroprotection by other drugs. Another group of endogenous substances, that is, sulfhydryls (SH), investigated in parallel with PG, also seem to play a mechanistic role in gastroprotection, especially since SH alkylators like N-ethylmaleimide counteract virtually any form of gastroprotection. In Robert's terms of "prevention of chemically induced acute mucosal lesions," so far no single mechanism could explain the beneficial effects of diverse protective agents, but I argue that these two endogenous substances (i.e. PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG and histamine, because as mediators of acute inflammation, they increase vascular permeability (VP), and SH scavenge free radicals. This is contrary to the search for a single mechanism of action, long focused on enhanced secretion of mucus and/or bicarbonate that may contribute but cannot explain all forms of gastroprotection. Nevertheless, based on research work of the last 30 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated: it's a complex but orderly and evolution-based physiologic response of the gastric mucosa under pathologic conditions. Namely, one of the first physiologic defense responses of any organ is inflammation that starts with rapid vascular changes (e.g. increased VP and blood flow), followed by cellular events (e.g. infiltration by acute and chronic inflammatory cells). Thus, PG and histamine, by increasing VP create a perivascular edema that dilutes and delays toxic agents reaching the subepithelial capillaries. Otherwise, damaging chemicals may induce severe early vascular injury resulting in blood flow stasis, hypoxia, and necrosis of surrounding epithelial and mesenchymal cells. In this complex response, increased mucus and/or bicarbonate secretion seem to cause luminal dilution of gastrotoxic chemicals that is further reinforced by a perivascular, histodilutional component. This mechanistic explanation would encompass the protective actions of diverse agents as PG, small doses of histamine, motility stimulants, and dilute irritants (i.e. "adaptive cytoprotection"). Thus, although markedly increased VP is pathologic, slight increase in VP seems to be protective, that is, a key element in the complex pathophysiologic response during acute gastroprotection. Over the years, "gastroprotection" was also applied to accelerated healing of chronic gastroduodenal ulcers without reduction of acid secretion. The likely main mechanism here is the binding of angiogenic growth factors (e.g. basic fibroblast growth factor, vascular endothelial growth factor) to the heparin-like structures of sucralfate and sofalcone. Thus, despite intensive research of the last 30 years, gastroprotection is incompletely understood, and we are still far away from effectively treating Helicobacter pylori-negative ulcers and preventing nonsteroidal anti-inflammatory drugs-caused erosions and ulcers in the upper and lower gastrointestinal tract; hence "gastric cytoprotection" research is still relevant.

Background and Study Aims: Deep learning (DL) for video capsule endoscopy (VCE) is an emerging research field. It has shown high accuracy for the detection of Crohn's disease (CD) ulcers. Non-steroidal anti-inflammatory drugs (NSAIDS) are commonly used medications. In the small bowel, NSAIDs may cause a variety of gastrointestinal adverse events including NSAID-induced ulcers. These ulcers are the most important differential diagnosis for small bowel ulcers in patients evaluated for suspected CD. We evaluated a DL network that was trained using CD VCE ulcer images and evaluated its performance for NSAID ulcers.Patients and Methods: The network was trained using CD ulcers and normal mucosa from a large image bank created from VCE of diagnosed CD patients. NSAIDs-induced enteropathy images were extracted from the prospective Bifidobacterium breve (BIf95) trial dataset. All images were acquired from studies performed using PillCam SBIII. The area under the receiver operating curve (AUC) was used as a metric. We compared the network's AUC for detecting NSAID ulcers to that of detecting CD ulcers.Results: Overall, the CD training dataset included 17,640 CE images. The NSAIDs testing dataset included 1,605 CE images. The DL network exhibited an AUC of 0.97 (95% CI 0.97–0.98) for identifying images with NSAID mucosal ulcers. The diagnostic accuracy was similar to that obtained for CD related ulcers (AUC 0.94–0.99).Conclusions: A network trained on VCE CD ulcers similarly identified NSAID findings. As deep learning is transforming gastrointestinal endoscopy, this result should be taken into consideration in the future design and analysis of VCE deep learning applications.

Objective: To evaluate the influence of surgery start time (SST) and other patient‐ and therapy‐related variables on the risk for early implant failure (EIF) in an academic setting. Material and Methods: Data were extracted from the electronic health records of 61 patients who had at least one EIF and 140 age‐ and gender‐matched, randomly selected, non‐EIF controls. Bivariate and multivariable analyses were performed to identify relevant associations between EIF and different variables, such as SST. Results: Incidence of EIF was not significantly associated with SST (HR: 1.9 for afternoon implant placement, 95% CI: 0.9–3.9; p =.105). Other factors that were associated with a significantly increased risk for EIF in a multivariable model were pre‐placement ridge augmentation (HR: 7.5, 95% CI: 2.2–25.1; p =.001), intra‐operative complications (HR: 5.9, 95% CI: 2.2–16.3; p <.001), simultaneous soft tissue grafting (HR: 5.03, 95% CI: 1.3–19.5; p =.020), simultaneous bone grafting (HR: 3.7, 95% CI: 1.6–8.8; p =.002), and placement with sedation (HR: 3.4, 95% CI: 1.5–7.5; p =.002). Conclusions: While SST was not associated with the occurrence of EIF in our cohort, other variables, such as ridge augmentation prior to implant placement, simultaneous bone or soft tissue grafting, intra‐operative complications, implant placement with sedation, and number of implants in the oral cavity, were associated with an increased risk for this adverse event. [ABSTRACT FROM AUTHOR]

According to various side effects of medication in low back pain, respecting conservative therapy, owing to the widespread use of laser therapy in recent decades, related therapeutic outcomes were different and contradictory. The current study aimed at comparing the effect of non-steroidal drugs and laser therapy with different doses in patients with acute low back pain. The current randomized, placebo-controlled study was conducted on 65 patients randomly assigned to four groups. In group 1(N = 20), only drug therapy and in group 2(N = 15), laser therapy (3 J/cm 2) in addition to medication was administrated to the patients. For group 3(N = 15), a therapeutic plan similar to that of group 2 was given; however, the laser dose was 6 J/cm 2. Finally, drug therapy plus placebo laser therapy was applied to group 4(N = 15). Pain was compared among the groups using visual analogue scale and Oswestry low back pain disability questionnaire. Significant difference between baseline pain scores and those of the weeks 1, 2, 3, and 4 of laser therapy in all intervention groups. Also, the results of the intergroup analyses showed a significant difference between group 1 compared with groups 2 and 3. There was a significant ODI difference between the groups after laser therapy. Findings showed that laser therapy plus drug therapy in comparison with drug therapy alone was a more effective method to relieve pain and disability in patient with acute low back pain; however, evidence to support this finding is still inadequate. [ABSTRACT FROM AUTHOR]

Background: Potentially inappropriate prescribing (PIP) is common in older adults and known to be associated with polypharmacy and multimorbidity. Less is known about the prevalence and causes of PIP in middle-aged adults.Aim: To determine the prevalence and predictors of PIP in middle-aged adults.Design and Setting: A repeated cross-sectional study was conducted using primary care data in London.Method: PIP was defined using the PRescribing Optimally in Middle-aged People's Treatments (PROMPT) criteria. Prescribing and demographic data were extracted from Lambeth DataNet (LDN), a pseudonymised database of all patients registered at general practices in Lambeth, for those aged 45-64 years prescribed ≥1 medicines in each year from 2014-2019 (n = 46 633-52 582). Prevalence and trends over 6 years were investigated, including the association of PIP with polypharmacy, multimorbidity, deprivation, sex, and age.Results: The prevalence of PIP decreased from 20% in 2014 to 18% in 2019. The most prevalent PROMPT criteria in 2019 were the use of ≥2 drugs from the same pharmacological class (7.6%), use of non-steroidal anti-inflammatory drugs for >3 months (7.1%) and use of proton pump inhibitors above recommended maintenance dosages for >8 weeks (3.1%). Over the study period, the prevalence of multimorbidity increased (47-52%) and polypharmacy remained stable (27%). Polypharmacy, multimorbidity, deprivation, and age were independently associated with PIP. Sex was the only variable not associated with PIP.Conclusion: Almost one-fifth of middle-aged adults prescribed medicines are exposed to PIP, as defined by the PROMPT criteria. This is likely to be linked with exposure to avoidable adverse drug events. The PROMPT criteria may provide a useful aid in interventions to optimise prescribing. [ABSTRACT FROM AUTHOR]

The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window. [ABSTRACT FROM AUTHOR]

ObjectiveTo examine the use of medical management, uterus-preserving surgery (UPS), and complementary treatments among women with uterine fibroids.Study designProspective cohort study of 933 premenopausal women ages 31-54 years with symptomatic fibroids who participated in the Study of Pelvic Problems, Hysterectomy, and Intervention Alternatives (SOPHIA) for an average of 4.3 years (SD 2.5 years). Incident use of fibroid treatments was determined through annual interviews. Linear regression models were used to compare changes in fibroid-related symptoms among women who underwent UPS versus those who did not undergo surgery.ResultsParticipants were racially and ethnically diverse, with a mean age of 43 years. During study follow-up, 531 participants (57%) did not undergo UPS or hysterectomy, 250 (27%) had at least one UPS, and 152 (16%) underwent hysterectomy. Complementary and alternative treatments were commonly used, including exercise (45%), diet (34%), herbs (37%), and acupuncture (16%): participants reported significant symptom improvement and few side effects with these interventions. In multivariable linear regression models, women who did not undergo surgery during the study reported improvement in dyspareunia (p

The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risks of cancers at several sites in some studies; however, we recently reported no association between their use and total cancer risk in women in a prospective study. Here we examine the association between NSAIDs and total and site-specific cancer incidence in the large, prospective Women's Health Initiative (WHI). Women (129,013) were recruited to participate in the WHI at 40 US clinical centers from 1993 to 1998 and followed prospectively. After 9.7 years of follow-up, 12,998 incident, first primary, invasive cancers were diagnosed. NSAID use was systematically collected at study visits. We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs use and total and site-specific cancer risk. Relative to non-use, consistent use (i.e., use at baseline and year 3 of follow-up) of any NSAID was not associated with total cancer risk (HR 1.00, 95% CI: 0.94-1.06). Results for individual NSAIDs were similar to the aggregate measure. In site-specific analyses, NSAIDs were associated with reduced risks of colorectal cancer, ovarian cancer, and melanoma. Our study confirms a chemopreventive benefit for colorectal cancer in women and gives preliminary evidence for a reduction of the risk of some rarer cancers. NSAIDs' benefit on cancer risk was therefore limited to specific sites and not evident when total cancer risk was examined. This information may be of importance when NSAIDs are considered as chemopreventive agents.

ObjectivesTo examine whether older adults taking nonsteroidal anti-inflammatory drugs (NSAIDs) decreased the underuse of gastroprotective agents over time.DesignBefore-and-after study.SettingHealth, Aging and Body Composition Study.ParticipantsDaily users of a NSAID (prescription and over the counter (OTC)) at visits in 2002-03 (preperiod; n = 404) and 2006-07 (postperiod; n = 172). The sample had a mean ± standard deviation age of 78.2 ± 2.7 at the preperiod visit and 81.9 ± 2.7 at the postperiod visit. The majority were white and female and had 12 or more years of education.MeasurementsUnderusers were defined as persons taking nonselective NSAIDs who were at risk of peptic ulcer disease (PUD; because of current warfarin or glucocorticoid use or history of PUD) and not using a proton pump inhibitor (PPI) or persons taking cyclooxygenase 2 (COX-2) selective NSAIDs and aspirin who were at risk of PUD (having at least one risk factor) and not using a PPI.ResultsDaily NSAID use decreased from 17.6% to 11.3% (P < .001), and gastroprotective agent underuse decreased from 23.5% to 15.1% (P = .008). Controlling for important covariates, having prescription insurance was somewhat protective against underuse in the preperiod (adjusted odds ratio (AOR) = 0.78, 95% confidence interval (CI) = 0.46-1.34; P = .37), but more so and significantly in the postperiod (AOR = 0.41, 95% CI = 0.18-0.93; P = .03). Having prescription insurance was more protective in the post- than in the preperiod (less gastroprotective agent underuse; adjusted ratio of OR = 0.53, 95% CI = 0.22-1.29; P = .16), but this increased protection was not statistically significant.ConclusionIn older daily NSAID users at high risk of PUD, having prescription insurance and adequate gastroprotective use was more common in the post- than in the preperiod.

The effect of acanthoic acid analogs on the response to proinflammatory challenge was investigated. Some pimarane diterpenes are known activators of the LXRαβ nuclear receptors, but we show here that they also exert a rapid, potent, and selective activation of the p110γ and p110δ subunits of PI3K. Combination of these effects results in an important attenuation of the global transcriptional response to LPS in macrophages. PI3K/Akt activation leads to inhibition of the LPS-dependent stimulation of IKK/NF-κB and p38 and ERK MAPKs. Macrophages from LXRαβ-deficient mice exhibited an inhibition of these pathways similar to the corresponding wild-type cells. Silencing or inhibition of p110γ/δ suppressed the effect of these diterpenes (DTPs) on IKK/NF-κB and MAPKs signaling. Taken together, these data show a multitarget anti-inflammatory mechanism by these DTPs including a selective activation of PI3K isoenzymes.

In animal models of experimental cerebral malaria (ECM), neuropathology is associated with an overwhelming inflammatory response and sequestration of leukocytes and parasite-infected RBCs in the brain. In this study, we explored the effect of vitamin D (VD; cholecalciferol) treatment on host immunity and outcome of ECM in C57BL/6 mice during Plasmodium berghei ANKA (PbA) infection. We observed that oral administration of VD both before and after PbA infection completely protected mice from ECM. VD administration significantly dampened the inducible systemic inflammatory responses with reduced circulating cytokines IFN-γ and TNF and decreased expression of these cytokines by the spleen cells. Meanwhile, VD also resulted in decreased expression of the chemokines CXCL9 and CXCL10 and cytoadhesion molecules (ICAM-1, VCAM-1, and CD36) in the brain, leading to reduced accumulation of pathogenic T cells in the brain and ultimately substantial improvement of the blood-brain barriers of PbA-infected mice. In addition, VD inhibited the differentiation, activation, and maturation of splenic dendritic cells. Meanwhile, regulatory T cells and IL-10 expression levels were upregulated upon VD treatment. These data collectively demonstrated the suppressive function of VD on host inflammatory responses, which provides significant survival benefits in the murine ECM model.

ObjectiveTo determine whether prehospital nonsteroidal anti-inflammatory drug (NSAID) use may lead to a reduced incidence of trauma-induced coagulopathy (TIC) in severely injured patients.BackgroundTIC is present in up to a quarter of severely injured trauma patients and is linked to worse outcomes after injury. Evidence linking TIC to inflammation has emerged; however, the mechanism behind this association is still under investigation. NSAIDs are commonly used anti-inflammatory drugs, but their effects on TIC and outcomes after injury are largely unexplored.MethodsWe performed a secondary analysis of the Inflammation and the Host Response to Injury Large Scale Collaborative Program (Glue Grant) data set. Prehospital medications and comorbidities were analyzed by logistic regression analysis for association with TIC as defined by laboratory (international normalized ratio >1.5) or clinical (transfusion >2 units of fresh frozen plasma or >1 pack of platelets in 6 hours) parameters.ResultsPrehospital NSIAD use was independently associated with a 72% lower risk of TIC and was the only medication among 15 analyzed to retain significance in the model. Stepwise logistic regression also demonstrated that preadmission use of NSAIDs was independently associated with a 66% lower risk of clinically significant coagulopathy. These findings were independent of comorbid conditions linked to NSAID use.ConclusionsNSAID use before admission for severe injury is associated with a reduced incidence of TIC. These findings provide further evidence to a potential leak between TIC and inflammation.

The loss of β-cell function and β-cell death are key features of diabetes. A range of mechanisms are thought to contribute to β-cell loss, including islet amyloid formation by the neuropancreatic hormone amylin (islet amyloid polypeptide, IAPP). Islet amyloid deposition also contributes to the failure of islet transplants. There are no therapeutic strategies for the treatment or prevention of islet amyloidosis. Aspirin and the nonsteroid anti-inflammatory drug (NSAID) ketoprofen, at clinically relevant doses, have been proposed to inhibit amyloid formation by amylin and thus may hold promise for treatment of islet amyloidosis. These compounds are potentially attractive given the importance of inflammation in islet amyloidosis and given the fact that there are no anti-islet amyloid agents in the clinic. We show that aspirin, even in 20-fold excess, has no effect on the kinetics of amyloid formation by amylin as judged by thioflavin-T binding, right angle light scattering, and transmission electron microscopy, nor does it alter the morphology of resulting amyloid fibrils. Aspirin showed no ability to disaggregate preformed amylin amyloid fibrils under the conditions of these studies, 25 °C and pH 7.4. Ketoprofen is similarly ineffective at inhibiting amylin amyloid formation. The compounds do, however, interfere with circular dichroism- and Congo Red-based assays of amylin amyloid formation. This study highlights the importance of using multiple methods to follow amyloid formation when screening inhibitors.

Salicylates from plant sources have been used for centuries by different cultures to treat a variety of ailments such as inflammation, fever and pain. A chemical derivative of salicylic acid, aspirin, was synthesised and mass produced by the end of the 19th century and is one of the most widely used drugs in the world. Its cardioprotective properties are well established; however, recent evidence shows that it can also act as a chemopreventive agent. Its antithrombotic and anti-inflammatory actions occur through the inhibition of cyclooxygenases. The precise mechanisms leading to its anticancer effects are not clearly established, although multiple mechanisms affecting enzyme activity, transcription factors, cellular signalling and mitochondrial functions have been proposed. This review presents a brief account of the major COX-dependent and independent pathways described in connection with aspirin's anticancer effects. Aspirin's unique ability to acetylate biomolecules besides COX has not been thoroughly investigated nor have all the targets of its primary metabolite, salicylic acid been identified. Recent reports on the ability of aspirin to acetylate multiple cellular proteins warrant a comprehensive study to investigate the role of this posttranslational modification in its anticancer effects. In this review, we also raise the intriguing possibility that aspirin may interact and acetylate cellular molecules such as RNA, and metabolites such as CoA, leading to a change in their function. Research in this area will provide a greater understanding of the mechanisms of action of this drug.

BackgroundConclusive data about cardiovascular toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for cardiovascular events in postmenopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 when compared with cox-1 inhibition.Methods and resultsPostmenopausal women enrolled in the Women's Health Initiative were classified as regular users or nonusers of nonaspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total cardiovascular disease defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (eg, celecoxib), nonselective agents with cox-2>cox-1 inhibition (eg, naproxen), and nonselective agents with cox-1>cox-2 inhibition (eg, ibuprofen) with the primary outcome. Overall, 160 801 participants were available for analysis (mean follow-up, 11.2 years). Regular NSAID use at some point in time was reported by 53 142 participants. Regular NSAID use was associated with an increased hazard for cardiovascular events versus no NSAID use (hazard ratio [HR], 1.10; 95% confidence interval, 1.06-1.15; Pcox-1 inhibition (HR, 1.17; 1.10-1.24; Pcox-2 inhibition (HR, 1.01; 0.95-1.07; P=0.884 and ibuprofen only: HR, 1.00; 0.93-1.07; P=0.996).ConclusionsRegular use of selective cox-2 inhibitors and nonselective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for cardiovascular events. Nonselective agents with cox-1>cox-2 inhibition were not associated with increased cardiovascular risk.Clinical trial registration urlwww.clinicaltrials.gov. Unique identifier: NCT00000611.

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in the gene encoding dystrophin (DYS). Tumor necrosis factor (TNF) has been implicated in the pathogenesis since short-term treatment of mdx mice with TNF blocking drugs proved beneficial; however, it is not clear whether long-term treatment will also improve long-term outcomes of fibrosis and cardiac health. In this investigation, short and long-term dosing studies were carried out using the TNF blocking drug Remicade and a variety of outcome measures were assessed. Here we show no demonstrable benefit to muscle strength or morphology with 10mg/kg or 20mg/kg Remicade; however, 3mg/kg produced positive strength benefits. Remicade treatment correlated with reductions in myostatin mRNA in the heart, and concomitant reductions in cardiac and skeletal fibrosis. Surprisingly, although Remicade treated mdx hearts were less fibrotic, reductions in LV mass and ejection fraction were also observed, and these changes coincided with reductions in AKT phosphorylation on threonine 308. Thus, TNF blockade benefits mdx skeletal muscle strength and fibrosis, but negatively impacts AKT activation, leading to deleterious changes to dystrophic heart function. These studies uncover a previously unknown relationship between TNF blockade and alteration of muscle growth signaling pathways.

Medication overuse is not uncommon among children and adolescents with primary headache disorders. Medication overuse in adults is associated with increased headache frequency and reduced effectiveness of acute and preventive medications. These issues probably exist in children. While withdrawal of overused medications is generally recommended, it may not result in improved headache frequency in all patients. This review summarizes what is known about predicting the response to medication withdrawal. Strategies for managing children and adolescents with medication overuse are also offered.

We measured serum dBPA in non-pregnant and pregnant female rhesus monkeys, fetuses and amniotic fluid. dBPA was administered by a daily oral bolus or sc implantation of Silastic capsules; both resulted in daily average serum unconjugated dBPA concentrations of

Identification of maternal environmental factors influencing preterm birth risks is important to understand the reasons for the increase in prematurity since 1990. Here, we utilized a health survey, the US National Health and Nutrition Examination Survey (NHANES) to search for personal environmental factors associated with preterm birth. 201 urine and blood markers of environmental factors, such as allergens, pollutants, and nutrients were assayed in mothers (range of N: 49-724) who answered questions about any children born preterm (delivery

Backgrounds and aimsWe studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury.MethodsIntestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. L-Alanine (L-Ala) and inosine 5'-monophosphate (IMP) were co-administered ig after the treatment.ResultsIndomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or L-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and L-Ala + IMP further accelerated intestinal ulcer healing.ConclusionDPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.

Post-operative pain management following rumen surgery is not common practice. We examined the effect of providing the pain medication ketoprofen to dairy cattle following the first stage of a rumen cannulation surgery, which involves an incision in the body wall and exteriorizing and clamping the rumen. The results of this study provide clear evidence that the first stage of the surgery was painful and ketoprofen at the time of and 24 h following surgery, alleviated some, but not all, of the post-surgical pain. Pain mitigation should be included when performing flank surgery in cattle.

BackgroundKawasaki disease, the most common cause of acquired heart disease in developed countries, is a self-limited vasculitis that is treated with high doses of intravenous immunoglobulin. Resistance to intravenous immunoglobulin in Kawasaki disease increases the risk of coronary artery aneurysms. We assessed whether the addition of infliximab to standard therapy (intravenous immunoglobulin and aspirin) in acute Kawasaki disease reduces the rate of treatment resistance.MethodsWe undertook a phase 3, randomised, double-blind, placebo-controlled trial in two children's hospitals in the USA to assess the addition of infliximab (5 mg per kg) to standard therapy. Eligible participants were children aged 4 weeks-17 years who had a fever (temperature ≥38·0°C) for 3-10 days and met American Heart Association criteria for Kawasaki disease. Participants were randomly allocated in 1:1 ratio to two treatment groups: infliximab 5 mg/kg at 1 mg/mL intravenously over 2 h or placebo (normal saline 5 mL/kg, administered intravenously). Randomisation was based on a randomly permuted block design (block sizes 2 and 4), stratified by age, sex, and centre. Patients, treating physicians and staff, study team members, and echocardiographers were all masked to treament assignment. The primary outcome was the difference between the groups in treatment resistance defined as a temperature of 38·0°C or higher at 36 h to 7 days after completion of the infusion of intravenous immunoglobulin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00760435.Findings196 patients were enrolled and randomised: 98 to the infliximab group and 98 to placebo. One patient in the placebo group was withdrawn from the study because of hypotension before receiving treatment. Treatment resistance rate did not differ significantly (11 [11·2%] for infliximab and 11 [11·3%] for placebo; p=0·81). Compared with the placebo group, participants given infliximab had fewer days of fever (median 1 day for infliximab vs 2 days for placebo; p

BackgroundThe effectiveness of the nonsteroidal anti-inflammatory drug ketorolac in reducing pulmonary morbidity after rib fractures remains largely unknown.MethodsA retrospective cohort study was conducted spanning January 2003 to June 2011 assessing pneumonia within 30 days and potential adverse effects of ketorolac among all patients with rib fractures who received ketorolac

BackgroundUse of some non-steroidal anti-inflammatory drugs (NSAIDs) has been linked to an increased risk of stroke. However, information on the impact of NSAID use on functional outcomes from stroke is limited.MethodsUsing women enrolled in the Women's Healthy Study who were free of a history of stroke or TIA at baseline, a prospective cohort study was performed to examine the impact of NSAID use on functional outcomes from stroke. Women were classified as NSAID non-user (

BackgroundRegular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive.MethodsWe analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided.ResultsAspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (

Objective: To evaluate the effects of administering diclofenac and ketoprofen, as well as the effects of environmental oxygen pressure variation on mandibular bone regeneration. Methods: Thirty-six guinea pigs were distributed into two equal groups. Mandibular bone defects were performed on both groups. Group A was monitored under oxygen pressure at altitude (3320msl, 107mm Hg). Group B was monitored at sea level oxygen pressure (150msl, 157mm Hg). Each group was subdivided into 3 equal groups (A1, A2, A3 and B1, B2, B3). Subgroups A1 and B1 were given diclofenac; subgroups A2 and B2 ketoprofen; subgroups A3 and B3 NaCl. Bone regeneration was evaluated histologically on days 15 and 30. Results: After 15 days in the group controlled at sea level, the level of osteoblasts presented by the control subgroup was significantly higher (28.00±2.65) compared to the diclofenac subgroup (16.00±6.25) and to the ketoprofen subgroup (18.00±4.36); (p=0.041). After 15 days in the group controlled at altitude, the level of osteoblasts was significantly higher in the control subgroup (38.00±5.29) compared to the diclofenac subgroup (21.67±6.35) and to the ketoprofen subgroup (19.33±2.52); p=0.007. After 30 days in the group at sea level there was no difference found in the cell counting; p>0.05. After 30 days in the group controlled at altitude, the level of osteoblast was significantly higher in the control subgroup (58.00±4.58) compared to the diclofenac subgroup (34.33±4.73) and the ketoprofen subgroup (34.00±11.14); (p=0.003). Conclusion: The administration of diclofenac and ketoprofen produced lower mandibular bone regeneration, the effect being significantly more negative at sea level.

Abstract Background A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue. Diffuse TGCT (D-TGCT) most commonly develops in the knee, followed by the hip, ankle, elbow, and shoulder. Surgical removal is the only effective treatment option for the patients. However, a local recurrence rate as high as 47% has been reported. Recently, we revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. It plays an important role in the differentiation of adipocytes from precursor cells and exhibits antitumorigenic effects on certain malignancies. Therefore, we are conducting this investigator-initiated clinical trial to evaluate whether zaltoprofen is safe and effective for patients with D-TGCT or unresectable localized TGCT (L-TGCT). Methods This study is a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with D-TGCT or L-TGCT. For the treatment group, zaltoprofen 480 mg/day will be administered for 48 weeks; the placebo group will receive similar dosages without zaltoprofen. Twenty participants in each group are needed in this trial (40 participants total). The primary outcome is the progression-free rate at 48 weeks after treatment administration. “Progression” is defined as any serious events (1. Repetitive joint swelling due to hemorrhage, 2. Joint range of motion limitation, 3. Invasion of adjacent cartilage or bone, 4. Severe joint space narrowing, 5. Increase in tumor size) requiring surgical interventions. We hypothesize that the zaltoprofen group will have a higher progression-free rate compared to that of the placebo group at 48 weeks. Discussion This is the first study to evaluate the efficacy of zaltoprofen in patients with D-TGCT or unresectable L-TGCT. We believe that the results of this trial will validate a novel treatment option, zaltoprofen, to stabilize disease progression for TGCT patients. Trial registration University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000025901) registered on 4/01/2017.

Abstract Introduction Low back pain is a common problem worldwide causing deterioration of health and quality of life. Low back pain is often associated with muscle spasm. We investigated the combined effect of muscle relaxants and pain killers for low back pain. Methods In this open-label, prospective, multicenter study, patients with acute low back pain received a single tablet of either the fixed dose combination of chlorzoxazone 500 mg and ibuprofen 400 mg (manufacturer: Dr. Reddy’s Laboratories, India) (C + I group) or ibuprofen 400 mg (I group) thrice daily for up to 7 days. Primary outcomes were improvement in pain by Visual Analogue Scale (VAS) and Summed Pain Intensity Difference (SPID) at 3 and 7 days post-treatment. Results A total of 406 patients were included in this study. When compared to baseline, the absolute mean change in VAS scores on Day 7 was 62.39 ± 18.78 and 57.34 ± 16.29 in the C + I and I groups, respectively (P = 0.0001). In the C + I and I groups, the mean SPID at Days 3 and 7 were 51.27 ± 24.44 and 47.80 ± 22.91, and 300.82 ± 92.40 and 277.16 ± 81.83, respectively. No deaths or serious adverse events were reported. Common adverse events included gastritis, stomach pain, fever, cold, and headache. At the end of the study, excellent to good response was reported in 94.08% and 77.33% of patients in the C + I and I groups, respectively. Excellent to good tolerability was observed in 96.05% and 89.65% patients in the two groups, respectively. Conclusion Fixed dose combination of chlorzoxazone and ibuprofen demonstrated superior efficacy than ibuprofen monotherapy in acute low back pain. Both drugs were well-tolerated and should be considered as judicious therapeutic options in patients with acute low back pain. Trial Registration This trial is registered with Clinical Trial Registry of India—CTRI/2016/10/007348. Funding Dr. Reddy’s Laboratories Ltd.

Bisphenol A (BPA) poses potential risks to reproduction and development. However, the mechanism of BPA's effects on early embryonic development is still unknown. Embryonic stem cells (ESC) and embryoid bodies (EB) provide valuable in vitro models for testing the toxic effects of environmental chemicals in early embryogenesis. In this study, mouse embryonic stem cells (mESC) were acutely exposed to BPA for 24h, and general cytotoxicity and the effect of BPA on pluripotency were then evaluated. Meanwhile, mouse embryoid bodies (mEB) were exposed to BPA up to 6 days and their differentiation capacity was evaluated. In mESC and mEB, we found that BPA up-regulated pluripotency markers (Oct4, Sox2 and Nanog) at mRNA and/or protein levels. Moreover, BPA increased the mRNA levels of endodermal markers (Gata4,Sox17) and mesodermal markers (Sma,Desmin), and reduced the mRNA levels of ectodermal markers (Nestin,Fgf5) in mEB. Furthermore, microRNA(miR)-134, an expression inhibitor of pluripotency markers including Oct4, Sox2 and Nanog, was decreased both in BPA-treated mESC and mEB. These results firstly indicate that BPA may disturb pluripotency in mESC and differentiation of mEB, and may inhibit ectodermal lineage differentiation of mEB while miR-134 may play a key role underlying this effect.

Recently the relationship between oxidative stress and aging has been brought into question. It has been suggested that while oxidative events may play a role in the progression of age-related pathologies, it is not relevant to aging processes not involving specific diseases associated with senescence. The evidence in support of this concept is largely based on studies with the roundworm, Caenorhabditis elegans (C. elegans) that has been extensively used as a model system to study aging. This commentary evaluates data derived from C. elegans and documents that the preponderance of evidence from this species supports the role of pro-oxidant events as being a significant contributor to normal aging. Possible reasons for some anomalous findings conflicting with this concept, are discussed.

The expansion of regulatory T cells (Treg ) controls inflammation in children with acute Kawasaki disease (KD). Blockade of tumour necrosis factor (TNF)-α is an emerging therapy for KD patients with refractory inflammation, but there is concern that this therapy could impede the host immune regulation. To define the effect of TNF-α blockade, we conducted ex-vivo immune-monitoring in KD subjects who participated in a randomized, double-blind, placebo-controlled clinical trial of the addition of infliximab to standard intravenous immunoglobulin (IVIG) therapy. We enumerated circulating myeloid and plasmocytoid dendritic cells (DC), regulatory T cells (Treg ) and memory T cells (Tmem ) in 14 consecutive, unselected KD patients (seven treated with IVIG, seven with IVIG + infliximab) at three time-points: (i) acute phase prior to treatment, (ii) subacute phase and (iii) convalescent phase. Myeloid DC (mDC), but not plasmacytoid DC (pDC), were numerous in the peripheral blood in acute KD subjects and decreased in the subacute phase in both IVIG(-) and IVIG (+)  infliximab-treated groups. The co-stimulatory molecule for antigen presentation to T cells and CD86 decreased in mDC from acute to subacute time-points in both treatment groups, but not in the single patient who developed coronary artery aneurysms. We also defined tolerogenic mDC that expand in the subacute phase of KD not impaired by infliximab treatment. Treg and Tmem expanded after treatment with no significant differences between the two groups. Treatment of KD patients with infliximab does not adversely affect generation of tolerogenic mDC or the development of T cell regulation and memory.

The objective was to assess the effects of non‐steroidal anti‐inflammatory drugs (NSAIDs) on head and neck cancer (HNC) outcomes. A systematic review was conducted following the PRISMA guidelines. The MEDLINE and the Cochrane Central Register databases were searched. Risk of bias was assessed by the Cochrane Collaboration's tool and by the Newcastle‐Ottawa Scale. Meta‐analyses were performed with the RevMan software. Seventeen articles met the inclusion criteria. Quality scores for observational studies ranged between 5 and 8 stars and the RCT was assessed as high risk of bias. NSAIDs use was associated with a 13% risk reduction of HNC (OR: 0.87 95% CI 0.77–0.99). NSAIDs use was associated with a 30% reduced cancer‐specific mortality and with a 40% decreased risk on disease‐recurrence. NSAIDs may have a modest protective effect on HNC risk and a positive impact on cancer‐specific survival and disease‐recurrence. The findings do not support a protective role of aspirin on HNC outcomes. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs, including lowdose aspirin, cause morbidity related to gastric and duodenal mucosal damage, so the primary prevention of NSAID-induced gastrointestinal toxicity is a relevant clinical issue. The prostaglandin E analogue, misoprostol, H2 receptor antagonists and proton pump inhibitors were evaluated as prophylactic therapies for patients using NSAIDs. In addition, selective COX-2 inhibitors are another strategy for reducing NSAIDrelated gastroduodenal toxicity. Several strategies to prevent ulcers in patients requiring prolonged nonsteroidal anti-inflammatory drugs or low-dose aspirin have concluded that the risk of gastroduodenal toxicity is related to risk factors, the status of the patient's Helicobacter pylori and the specific type and dose of NSAIDs. The ability to modify the risk depends on the clinical environment, although it is preferable to use NSAIDs with the least potential for GI toxicity, all NSAIDs are associated with an increased GI risk. [ABSTRACT FROM AUTHOR]

Background: As nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids have similar effects, steroids can be avoided to reduce adverse effects. This study aimed to compare the differences in symptom improvement after subacromial injection of steroids or NSAIDs. Methods: Sixty patients with rotator cuff syndrome for at least 3 months were enrolled and divided into steroid and NSAID groups. The steroid group received a mixture of 1 mL of triamcinolone acetonide (40 mg/mL) and 1 mL of lidocaine hydrochloride 2%, while the NSAID group received a mixture of 1 mL of Ketorolac Tromethamine (30 mg/mL) and 1 mL of lidocaine hydrochloride 2%. The patients were assessed before and at 3, 6, and 12 weeks after the procedure. Shoulder scores from visual analog scale (VAS), American Shoulder and Elbow Surgeons (ASES), and University of California Los Angeles (UCLA) were used for evaluation. Results: Both groups showed improvements in the clinical outcomes. Overall VAS, ASES, and UCLA scores improved from 6.9, 32.7, and 16.0 before the procedure to 2.0, 1.2, and 1.1; 81.5, 87.6, and 88.5; and 29.7, 31.8, and 32.0 at weeks 3, 6, and 12 weeks after the procedure, respectively. Twenty-six patients (86.7%) in the steroid group and 28 (93.3%) in the NSAID group reported satisfactory treatment outcomes. There were no significant differences in the outcomes between the two groups (p=0.671). Conclusions: Subacromial injection of NSAIDs for rotator cuff tendinitis with shoulder pain had equivalent outcomes with those of steroid injection at the 12-week follow-up. [ABSTRACT FROM AUTHOR]

Mefenamic acid (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug, is metabolized into the chemically-reactive MFA-1-O-acyl-glucuronide (MFA-1-O-G), MFA-acyl-adenylate (MFA-AMP), and the MFA-S-acyl-coenzyme A (MFA-CoA), all of which are electrophilic and capable of acylating nucleophilic sites on biomolecules. In this study, we investigate the nonenzymatic ability of each MFA acyl-linked metabolite to transacylate amino and thiol functional groups on the acceptor biomolecules Gly, Tau, l-glutathione (GSH), and N-acetylcysteine (NAC). In vitro incubations with each of the MFA acyl-linked metabolites (1 μM) in buffer under physiologic conditions with Gly, Tau, GSH, or NAC (10 mM) revealed that MFA-CoA was 11.5- and 19.5-fold more reactive than MFA-AMP toward the acylation of cysteine-sulfhydryl groups of GSH and NAC, respectively. However, MFA-AMP was more reactive toward both Gly and Tau, 17.5-fold more reactive toward the N-acyl-amidation of taurine than its corresponding CoA thioester, while MFA-CoA displayed little reactivity toward glycine. Additionally, mefenamic acid-S-acyl-glutathione (MFA-GSH) was 5.6- and 108-fold more reactive toward NAC than MFA-CoA and MFA-AMP, respectively. In comparison with MFA-AMP and MFA-CoA, MFA-1-O-G was not significantly reactive toward all four bionucleophiles. MFA-AMP, MFA-CoA, MFA-1-O-G, MFA-GSH, and mefenamic acid-taurine were also detected in rat in vitro hepatocyte MFA (100 μM) incubations, while mefenamic acid-glycine was not. These results demonstrate that MFA-AMP selectively reacts with the amino functional groups of glycine and lysine nonenzymatically, MFA-CoA selectively reacts nonenzymatically with the thiol functional groups of GSH and NAC, and MFA-GSH reacts with the thiol functional group of GSH nonenzymatically, all of which may potentially elicit an idiosyncratic toxicity in vivo.

Controlled release of nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen could be beneficial for the treatment of inflammatory diseases while reducing the side effects resulting from their continuous use. Novel biodegradable polyesters solely comprised of biocompatible components (e.g., tartaric acid, 1,8-octanediol, and ibuprofen or naproxen as pendant groups) have been synthesized using tin(II) 2-ethylhexanoate as catalyst at 130 °C and subsequently characterized to determine their structures and physicochemical properties. The polymers release the free drug (ibuprofen or naproxen) in vitro in a controlled manner without burst release, unlike the release rates achieved when the drugs are encapsulated in other polymers. These new biomaterials are not cytotoxic toward mouse fibroblasts up to 0.10 mg/mL. The drugs retain their chemical structure following hydrolytic degradation of the polymer, suggesting that bioactivity is preserved.

ImportanceBack pain treatment is costly and frequently includes overuse of treatments that are unsupported by clinical guidelines. Few studies have evaluated recent national trends in guideline adherence of spine-related care.ObjectiveTo characterize the treatment of back pain from January 1, 1999, through December 26, 2010.Design, setting, and patientsUsing nationally representative data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, we studied outpatient visits with a chief symptom and/or primary diagnosis of back or neck pain, as well as those with secondary symptoms and diagnoses of back or neck pain. We excluded visits with concomitant "red flags," including fever, neurologic symptoms, or cancer. Results were analyzed using logistic regression adjusted for patient and health care professional characteristics and weighted to reflect national estimates. We also present adjusted results stratified by symptom duration and whether the health care professional was the primary care physician (PCP).Main outcomes and measuresWe assessed imaging, narcotics, and referrals to physicians (guideline discordant indicators). In addition, we evaluated use of nonsteroidal anti-inflammatory drugs or acetaminophen and referrals to physical therapy (guideline concordant indicators).ResultsWe identified 23,918 visits for spine problems, representing an estimated 440 million visits. Approximately 58% of patients were female. Mean age increased from 49 to 53 years (P

ObjectiveNerve growth factor (NGF) is a key regulator of nociceptive pain and thus appears to be an interesting target molecule for an innovative class of analgesic medication. We set out to review the principles of neurogenic inflammation and results of anti-NGF regimens in animal studies as well as clinical trials with patients with back pain and osteoarthritis (OA).DesignWe searched using Google Scholar Search and Pubmed as well as through conference reports for articles and abstracts related to NGF and clinical trials using anti-NGF regimens. We report on efficacy findings and adverse events (AEs) related to these agents in this review.ResultsWe identified five full articles and eight abstract reports relating to anti-NGF agents studied for use in back pain and in OA.ConclusionsAnti-NGF agents either alone or in combination with non-steroidal anti-inflammatory agents (NSAIDs) were more efficacious for the treatment of pain in a number of trials of knee and hip pain compared to NSAIDs alone. However, adverse effects that included rapidly progressive OA and joint replacement were more common in patients treated with anti-NGF and NSAIDs than either treatment alone. Anti-NGF treatment related neurologic symptoms including paresthesias, and potentially other types of adverse effects were usually transient but warrant additional investigation.

The mechanisms underlying the anti-inflammatory and antihypertensive effects of long-chain ω-3 polyunsaturated fatty acids (ω-3 PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid epoxyeicosatrienoic acids also exhibit antihypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may lower the blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for 3 weeks in a murine model of angiotensin-II-dependent hypertension. Also, because EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of an sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II, increased the blood pressure, further increased the renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (ie, prostaglandins and MCP-1), downregulated an epithelial sodium channel, and upregulated angiotensin-converting enzyme-2 message and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering systolic blood pressure and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by upregulation of angiotensin-converting enzyme-2 in angiotensin-II-dependent hypertension.

A newly recognized primary cause of the obesity epidemic is the developmental programming effects of infants born to mothers with obesity or gestational diabetes, intrauterine growth-restricted newborns, and offspring exposed to environmental toxins including bisphenol A. The mechanisms which result in offspring obesity include the programming of the hypothalamic appetite pathway and adipogenic signals regulating lipogenesis. Processes include nutrient sensors, epigenetic modifications, and alterations in stem cell precursors of both appetite/satiety neurons and adipocytes which are modulated to potentiate offspring obesity. Future strategies for the prevention and therapy of obesity must address programming effects of the early life environment.