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Introduction: Lifelong aspirin therapy is recommended after a TIA or stroke, but dyspeptic symptoms frequently lead to non-adherence. Clinicians often recommend that daily doses be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric coated aspirin tablets. Hypothesis: We evaluated whether food interferes with bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. Methods: This was a randomized, open label, crossover study in 20 healthy volunteers. Participants fasted for ≥10 hours prior to randomization; if assigned to “fasting” they then received the single 650 mg dose of PL-ASA. If they were randomized to “fed”, they first ate a standard high-fat meal and were dosed 30 minutes later. After a washout period of 10 days each participant crossed over to the other arm and was again dosed with a 650 mg dose of PL-ASA. The primary outcome was the comparison of PK parameters of the primary metabolite salicylic acid (SA) between fasting and fed states. Results: Mean age of participants was 36.8 years and 55% were male. The primary SA PK parameters of AUC 0-t and AUC 0- infinity in the fed state were within 88.7% and 88.8% of concentrations in the fasting state consistent with bio-equivalence (FDA guidance >80%). Mean peak SA concentration was about 25% lower and occurred about 1.5 hours later in the fed state (Figure). Conclusions: Food had a modest effect on the time required to reach peak SA concentration and on the actual peak SA levels after PL-ASA administration, but did not impact the extent of exposure (area under the curve) compared with intake in a fasting state. These data demonstrate that PL-ASA may be co-administered with food without significant variability in absorption, a recognized limitation of coated aspirin formulations.

Dry eye is a common, multifactorial disease currently diagnosed by a combination of symptoms and signs. However, the subjective symptoms of dry eye poorly correlate to the current gold standard for diagnostic tests, reflecting the need to develop better objective tests for the diagnosis of dry eye. This review considers the role of ocular surface matrix metalloproteinase 9 (MMP-9) in dry eye and the implications of a novel point-of-care test that measures MMP-9 levels, InflammaDry (RPS, Sarasota, FL) on choosing appropriate therapeutic treatments.

Purpose To compare dry eye (DE) symptoms and signs in subjects who tested positive versus those who tested negative for ocular surface matrix metalloproteinase 9 ( MMP-9 ) using the InflammaDry point-of-care test (RPS, Sarasota, FL). Methods In this cross-sectional study, individuals seen in the Miami Veterans Affairs eye clinic with DE symptoms, as evidenced by DE questionnaire 5 ( DEQ5 ) ≥6, were given standardized questionnaires to assess DE symptoms and ocular and non-ocular pain complaints. Also, a complete evaluation was conducted to measure ocular surface signs of DE. MMP-9 testing was performed using the InflammaDry once in each eye, per the manufacturer's instructions. The main outcome measure was a comparison of DE symptoms and signs in MMP-9 positive versus negative subjects. Results Of 128 subjects, 50 (39%) were positive for MMP-9 for InflammaDry testing in either eye. No statistically significant differences in mental health indices, DE symptoms, or ocular surface signs were seen in subjects based on MMP-9 status. Conclusion In our population, there was no difference in the DE profile by both symptoms and signs between those testing positive versus negative for MMP-9 on the ocular surface. This suggests that clinical exam alone cannot predict patients with clinically significant inflammation.

Dry eye (DE) is a common disease whose symptoms of pain (described as discomfort, burning, and dryness) and blurry vision negatively impact quality of life.1 We previously demonstrated that approximately 1 in 6 United States (US) veterans carried a diagnosis of DE and that environmental factors (air pollution coupled with weather conditions) affected the occurrence of DE.2 By integrating health care data from the National Veterans Administration (VA) database and environmental data from the National Climatic Data Center (NCDC) and National Aeronautics and Space Administration (NASA), we found that air pollution and atmospheric pressure were the two most influential risk factors for DE. Building on this information, we subsequently used the same dataset to assess occurrence of DE by season. This analysis was performed to formally quantify the clinical impression that DE has a seasonal pattern. Patient information All patients seen in a VA eye clinic July 5, 2006 through July 4, 2011 were included in this retrospective analysis. DE cases were defined as those who had an ICD-9 code for DE (375.15) and used medication or underwent a procedure for the condition. The Miami VA Institutional Review Board approved this study, which was conducted in accordance with the principles of the Declaration of Helsinki. Findings During the study period, there were a total of 3.41 million visits to a VA eye clinic within the continental US. In total, 17.4% of veterans (95% confidence interval (CI) ±1.24) were diagnosed with DE. Looking at the distribution of cases, a clear seasonal pattern is evident (Figure 1 available at http://aaojournal.org), with the highest period prevalence of DE in winter and spring (18.7%±0.98 and 18.5%±4.16 respectively) and lowest prevalence in summer (15.3%±0.82). Furthermore, there was a higher monthly variation in the occurrence of DE during the spring season as compared to winter months, with a standard error of mean 4.16% in spring versus 0.98% in winter. The highest prevalence of DE occurred in April (20.9% ± 0.14). Interestingly, the year round prevalence of DE in Miami was higher than the national average by approximately 3.2% (p

OBJECTIVE:: Depot medroxyprogesterone acetate (DMPA) reversibly reduces bone mineral density. To estimate the extent to which DMPA might increase fracture risk we undertook a retrospective cohort study of fractures in DMPA users and users of non-DMPA contraceptives using the General Practice Research Database. METHODS:: Eligible women were aged younger than 50 years at the qualifying first contraceptive prescription. The DMPA users were classified by DMPA exposure (cumulative and time of last dose) based on prescription records. All incident fractures were included; fracture incidence and risk factors before starting contraceptive use (DMPA or other) also were estimated. RESULTS:: We identified 11822 fractures in 312395 women during 1722356 person-years of follow-up. Before contraceptive use started DMPA users had higher fracture risk than nonusers (incidence rate ratio 1.28 95% confidence interval [CI] 1.07-1.53). After DMPA started crude fracture incidence was 9.1 per 1000 person-years for DMPA users and 7.3 for nonusers (crude incidence rate ratio 1.23 95% CI 1.16-1.30). Fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after or before 1.08 95% CI 0.92-1.26). There was little confounding by age or other factors that could be measured. Fracture incidence was 9.4 per 1000 person-years in low-exposure DMPA users and 7.8 per 1000 in high-exposure DMPA users. The DMPA users had higher fracture risk than nonusers at the start of contraceptive use with no discernible induction period. CONCLUSION:: Although DMPA users experienced more fractures than nonusers this association may be the result of confounding by a pre-existing higher risk for fractures in women who chose DMPA for contraception. LEVEL OF EVIDENCE:: II.

As survival of transplant recipients improves, long-term complications become more important. We reviewed epidemiologic literature on real-world risks of de novo neoplasia post-transplant. We searched the Medline/PubMed, Cochrane, and Embase databases for population-based studies on risk of neoplasia from 1998 to 2005. Selection criteria included: solid organ transplants, neoplastic outcomes, n > 500 subjects, age > or = 18 yr, and study design. Of 187 abstracts, 64 met criteria for study size, age range, topic, and design. We classified the articles by quality of reporting on components of cohort studies. Twelve of 64 studies reported cohort eligibility and exclusion criteria, defined time at risk, and ascertained incident neoplasms. Twenty-one studies reported prevalence of neoplasms for unspecified time periods, and only eight incidence studies reported person yr at risk. Three studies of all types of neoplasms in kidney recipients reported incidence ranging from 11.0 to 17.3 cases per 1000 person yr. Two studies of post-transplant lymphoproliferative disorders reported incidence of 0.4 to 2.5 cases per 1000 person yr in kidney recipients. More precise estimation of risks and rates, better description of study population, and more attention to confounding in comparisons of rates would make studies more meaningful. Reports should adhere to established guidelines for presenting methods and results in epidemiologic studies.

Summary Background Chronic use of NSAIDs is associated with gastrointestinal (GI) toxicity that increases with age. Aim To evaluate the GI safety and therapeutic efficacy of ibuprofen chemically associated with phosphatidylcholine (PC) in osteoarthritic (OA) patients. Methods A randomized, double-blind trial of 125 patients was performed. A dose of 2400 mg/day of ibuprofen or an equivalent dose of ibuprofen-PC was administered for 6 weeks. GI safety was assessed by endoscopy. Efficacy was assessed by scores of analgesia and anti-inflammatory activity. Bioavailability of ibuprofen was pharmacokinetically assessed. Results Ibuprofen-PC and ibuprofen provided similar bioavailability/therapeutic efficacy. In the evaluable subjects, a trend for improved GI safety in the ibuprofen-PC group compared with ibuprofen that did not reach statistical significance was observed. However, in patients aged >55 years, a statistically significant advantage for ibuprofen-PC treatment vs. ibuprofen in the prevention of NSAID-induced gut injury was observed with increases in both mean Lanza scores and the risk of developing >2 erosions or an ulcer. Ibuprofen-PC was well tolerated with no major adverse events observed. Conclusion Ibuprofen-PC is an effective osteoarthritic agent with an improved GI safety profile compared with ibuprofen in older OA patients, who are most susceptible to NSAID-induced gastroduodenal injury.

Summary Background Gastrointestinal side effects are commonly associated with opioid treatment for pain. Aim To understand gastrointestinal side effects associated with opioid treatment. Methods This study was a population-based survey of adults in the US who use opioids to manage pain unrelated to cancer. Participants were recruited from an existing Web-enabled panel and a supplemental panel of individuals who previously indicated an interest in participating in Web-based surveys. Results Overall, 2055 individuals participated in the main phase of the survey. Fifty-seven per cent of participants reported having had constipation that they associated with opioid treatment, and 49% reported constipation in the previous 4 weeks. Thirty-six per cent of participants reported new or worsening constipation in the previous 4 weeks. Thirty-three per cent of participants reported constipation as their most bothersome symptom associated with opioid treatment, 13% reported nausea, 11% abdominal pain and 10% gas. Seventy-three per cent of the participants who reported any GI symptoms did not change the dosage level or frequency of use of opioids because of adverse events, which may be explained by the fact that 72% of participants used over-the-counter laxatives and 12% a prescription laxative. Conclusion Constipation is a frequent and significant event occurring with opioid use.

Background/Aims: The effect of inflammatory skin diseases on pregnancy has been incompletely characterized. We sought to estimate the incidence of pregnancy and pregnancy outcomes among women with inflammatory skin diseases. Methods: Cohort study of women with atopic dermatitis (AD), psoriasis, other inflammatory skin diseases, and comparison group, followed for pregnancies and pregnancy outcomes. Results: There were 3,131 pregnancies among 64,773 woman-years (4.8/100) in women with skin diseases, and 2,592 pregnancies among 59,826 woman-years (4.3/100) in the comparison group. The age-standardized incidence of pregnancy was similar to the comparison group [rate ratio (RR) = 1.2, 95% confidence interval (CI) 1.0–1.4 for AD, RR = 1.1, 95% CI 1.0–1.2 for psoriasis, and RR = 1.1, 95% CI 1.0–1.1 for other]. Spontaneous abortion was also similar to the comparison group (RR = 1.2 for AD, 95% CI 1.0–1.4, RR = 1.1, 95% CI 1.0–1.2 for psoriasis, and RR = 1.1, 95% CI 1.0–1.1 for other). Conclusions: Our results suggest little effect of skin disease on incidence or outcome of pregnancy.

Summary Background The effect of low-dose aspirin on endoscopic ulcer incidence in cyclo-oxygenase-2-selective inhibitor or non-selective non-steroidal anti-inflammatory drug users remains controversial. Aim To compare prospectively the incidence of endoscopic ulcers in healthy subjects receiving low-dose aspirin plus celecoxib or naproxen. Methods In this double-blind, placebo-controlled, 1-week study, subjects (50–75 years) were randomized to receive aspirin 325 mg o.d. plus either celecoxib 200 mg o.d., naproxen 500 mg b.d., or placebo. Baseline and end of study endoscopies were performed. The primary end point was incidence of one or more gastric and duodenal ulcers. Results A lower incidence of gastric and duodenal ulcers was seen in celecoxib/aspirin-treated subjects (19%) vs. naproxen/aspirin (27%; RR: 0.63, 95% CI: 0.44–0.92). Both naproxen/aspirin and celecoxib/aspirin groups demonstrated a higher incidence of gastric and duodenal ulcers vs. placebo/aspirin (8%; RR: 3.7, 95% CI: 1.8–7.6 and RR: 2.6, 95% CI: 1.2–5.8, respectively). Conclusions Fewer endoscopic ulcers were observed in patients treated with celecoxib/aspirin vs. naproxen/aspirin. However, celecoxib/aspirin was associated with a significantly higher incidence of gastric and duodenal ulcers than aspirin alone. Further studies are required to determine the generalizability of these findings in the aspirin users and to determine the appropriate strategy to minimize risk in susceptible patients.

Objective: This study evaluated the overall safety and tolerability of once-weekly (OW) alendronate 70 mg oral solution (OS) versus OW placebo OS. Methods: Postmenopausal, osteoporotic women were enrolled at 51 centers in the United States in a 6-month double-blind, randomized trial. Patients were randomized (1:1) to OW alendronate 70 mg OS or placebo OS. The primary end point was the proportion of patients reporting any upper gastrointestinal (UGI) adverse event (AE) at 6 months. Secondary end points included mean percentage change in urinary N-telopeptide of type I human collagen (NTx) and serum bone-specific alkaline phosphatase (BSAP) at 6 months. Results: Initially, 454 women were enrolled; 392 (86.3%) completed the study. The mean (SD) age was 65.2 (10) years, and the mean (SD) time since menopause was 19.1 (12) years. The proportion of patients experiencing any UGI AE was significantly higher with alendronate OS (23.7%) compared with placebo solution (15.3%), with a treatment difference of 8.3% (95% CI, 0.8%–15.8%; P = 0.024). The proportion of patients experiencing any esophageal AE was 4.0% with alendronate and 3.0% with placebo (treatment difference, 1.0% [95% CI, −2.7% to 4.8%]). In addition, 4.5% of alendronate and 8.7% of placebo patients discontinued the study due to any clinical AE, and 3.3% of alendronate and 1.8% of placebo patients discontinued due to a UGI AE (difference, 1.5% [95% CI, −1.5% to 4.4%]). Alendronate OS produced significantly greater reductions in both NTx and BSAP than placebo (differences, −47.5% and −38.7%, respectively [both, P Conclusions: In this 6-month study, patients receiving OW alendronate 70 mg OS had a higher rate of UGI AEs than placebo patients. However, rates of serious UGI AEs, discontinuations due to UGI AEs, and esophageal AEs were similar between groups. UGI AEs in the study were generally mild to moderate in severity and did not result in treatment discontinuation. In addition, OW alendronate 70 mg OS significantly reduced biochemical markers of bone turnover.

Summary Background : The ideal duration of Helicobacter pylori treatment in the United States and whether eradication therapy is as successful in nonulcer dyspepsia as in peptic ulcer disease are controversial topics. Aim : This study compared the efficacy of 3-, 7- and 10-day triple therapies with rabeprazole to a 10-day omeprazole control triple therapy for the eradication of Helicobacter pylori in patients with and without peptic ulcer disease in the United States. Methods : This was a multicentre, double-blind, randomized, parallel-group trial. A total of 803 patients with H. pylori infection (determined by [13C]urea breath test and rapid urease test or culture) received either rabeprazole 20 mg b.d., amoxicillin 1000 mg b.d., and clarithromycin 500 mg b.d. for 3, 7, or 10 days, or 10 days of omeprazole 20 mg b.d. with the same antibiotic regimen (control). H. pylori status was assessed by [13C]urea breath test ≥6 weeks after completing treatment. Results : In intent-to-treat patients, the eradication percentages achieved for the rabeprazole-based treatments were: 3-day, 27% (95% confidence interval: 21%–34%); 7-day, 77% (95% confidence interval: 71%–83%); and 10-day, 78% (95% confidence interval: 72%–84%). The eradication percentage with the 10-day omeprazole-based treatment was 73% (95% confidence interval: 67%–79%). There was no statistically significant difference between the 7-day rabeprazole-based regimen and the 10-day rabeprazole- and omeprazole-based regimens. Conclusions : Seven-day therapy with rabeprazole, clarithromycin, and amoxicillin is similar in efficacy to 10-day therapies and had similar efficacy in patients with and without ulcer disease.

Objective Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding. Methods All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk. Results A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with β-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%. Conclusions Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.

Background: ABT-229 is a potent motilin agonist without significant antibiotic activity. It has been shown to improve gastric emptying in humans and to increase lower oesophageal sphincter pressure in cats. Aim: To assess the efficacy of four different doses of ABT-229 (1.25 mg, 2.5 mg, 5 mg, 10 mg b.d.) compared to placebo in the treatment of gastro-oesophageal reflux disease, and to determine its safety in patients with gastro-oesophageal reflux disease. Methods: In a double-blind, multicentre study, 324 patients with heartburn were randomized to receive four different doses of ABT-229 or placebo for 8 weeks. The efficacy was evaluated by Patient Symptom Questionnaire, daily diary, endoscopy and global evaluation of efficacy. Results: There were no statistically significant improvement scores for any of the ABT-229 treatment groups vs. the placebo group in any of the efficacy parameters. Reflux symptom scores were significantly worse after treatment in the dyspeptic group. ABT-229 appeared to be well tolerated and safe in total daily doses up to 20 mg. Conclusion: ABT-229 appears to have limited, if any, clinical utility in the treatment of gastro-oesophageal reflux disease.

Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo.Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo.The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference = -0.22-0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions.Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Background: Bisphosphonates are effective treatments for osteoporosis. Since some primary amino bisphosphonates are associated with oesophageal injury, we conducted a study of the upper gastrointestinal effects of risedronate, a pyridinyl bisphosphonate. Methods: Healthy, postmenopausal women received risedronate 5 mg (n=26), aspirin 2600 mg (n=27), or placebo (n=27) daily for 14 days and underwent endoscopy at baseline, Day 8 and Day 15. Results: Oesophageal erosions were noted in one subject in the aspirin group, two in the placebo group, and none in the risedronate group, and an ulcer in one aspirin-treated subject. Gastric erosions and ulcers were observed most frequently in the aspirin group. Gastric ulcers were noted in eight subjects in the aspirin group, one in the placebo group, and none in the risedronate group (P=0.010, placebo vs. aspirin; P=0.002, risedronate vs. aspirin). Duodenal erosions and ulcers were observed in the aspirin group only. Gastroduodenal erosion scores of three or more occurred more frequently in the aspirin than in the risedronate and placebo groups (P

Bisphosphonates are effective treatment for osteoporosis, but upper gastrointestinal injury associated with some compounds has caused concern. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, and alendronate, a primary amino bisphosphonate. Esophageal and gastroduodenal injury assessed by endoscopy scores was a secondary endpoint.Healthy, postmenopausal women (n = 515) received 5 mg risedronate (n = 255) or 10 mg alendronate (n = 260) for 2 weeks. At baseline and on days 8 and 15, subjects underwent endoscopy and evaluator-blinded assessment of the esophageal, gastric, and duodenal mucosa.Gastric ulcers were observed during the treatment period in 9 of 221 (4.1%) evaluable subjects in the risedronate group compared with 30 of 227 (13.2%) in the alendronate group (P0.001). Mean gastric endoscopy scores for the risedronate group were lower than those for the alendronate group at days 8 and 15 (P/= 0.001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at days 8 and 15. Esophageal ulcers were noted in 3 evaluable subjects in the alendronate group, compared with none in the risedronate group, and duodenal ulcers were noted in 1 evaluable subject in the alendronate group and 2 in the risedronate group.At doses used for the treatment of osteoporosis, risedronate was associated with a significantly lower incidence of gastric ulcers than alendronate. These findings confirm that bisphosphonates differ in their potential to damage the gastroesophageal mucosa.

The use of NSAIDs constitutes a significant risk for gastrointestinal bleeding and other ulcer complications. However, if they prove clinically effective in relieving arthritic symptoms, the new COX-2 selectively inhibiting NSAIDs may ultimately solve the problem of gastrointestinal toxicity with NSAIDs.

Background and Objectives: Oropharyngeal carcinoma tends to be aggressive and deeply infiltrative of nearby sites, with an high incidence of lymphnode metastases. The last treatment decision generally depends on the stage of the lesion and the patient's general status. Oropharyngeal tumor is generally treated by integrated treatments. Methods: We retrospectively studied 115 patients with locally advanced oropharyngeal tumors treated in our institution with combined therapies compare the results in two differents groups of patients (surgery plus radiotherapy and chemotherapy plus radiotherapy). Results: The 3-year overall survival rate in patients who underwent surgery plus radiotherapy was 82% and in those who underwent chemotherapy plus radiotherapy was 49%. Conclusion: The results suggest that surgery followed by radiotherapy seems to be the best treatment in the case of locally advanced oropharyngeal tumor.

Purpose: Serious, although rare, ventricular arrhythmias and deaths have been reported in patients taking cisapride monohydrate. Without quantification of the risk involved, it is impossible to develop rational therapeutic guidelines. Subjects and Methods: Arrhythmic events (sudden deaths and other events compatible with serious ventricular arrhythmias) were sought among 36,743 patients prescribed cisapride in the United Kingdom and Saskatchewan, Canada. Prescriptions and cases were identified from computerized medical claims data and physicians' office records. We compared rates of events between periods of recent cisapride use and nonrecent use, using cohort analysis. Potential confounding factors, including concomitant treatment with agents that inhibit CYP3A4 metabolism or that prolong the QT interval, were assessed in a nested case-control study. Results: In the cohort analysis, the incidence of the arrhythmic events was 1.6 times greater (95% confidence interval [CI]: 0.9 to 2.9) in periods of recent use. With adjustment for clinical history, use of CYP3A4 inhibitors, and use of drugs that prolong the QT interval, the odds ratio for cisapride and cardiac outcomes was 1.0 (95% CI: 0.3 to 3.7). There was no identifiable increase in risk when cisapride was dispensed at about the same time as QT-prolonging drugs or CYP3A4 inhibitors. QT- prolonging agents were associated with a 2.5-fold increase in the risk of arrhythmic events (95% CI: 1.1 to 5.8). Conclusions: Serious rhythm disorders were not associated with cisapride use, although the upper confidence bounds do not rule out an increase in risk.

Background : Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxy- genase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. Aim : To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. Methods Healthy subjects (n = 170; age range 18–54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score ≥ 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. Results The percentage of subjects who developed a mucosal score ≥ 2 in the MK-0966 group (12%) was significantly lower (P

Background. The combination of ranitidine bismuth citrate (RBC) and clarithromycin (CLR) was compared with each treatment alone for the eradication of H. pylori and healing of duodenal ulcers in patients infected with H. pylori. Methods. This two-phase, randomized, double-blind, placebo-controlled, multicenter study evaluated 203 patients with an active duodenal ulcer treated with either (1) RBC 400 mg BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; (2) RBC 400 mg BID for 4 weeks plus placebo TID for the first 2 weeks; (3) placebo BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; or (4) placebo BID for 4 weeks plus placebo TID for the first 2 weeks. Patients with healed ulcers after treatment entered a 24-week observation phase for the assessment of H. pylori and ulcer relapse. Results. Four-week ulcer healing rates were higher with RBC + CLR (71%) and RBC alone (66%) compared with placebo (15%;p < 0.05) and CLR alone (49%). H. pylori eradication rates were significantly higher with RBC + CLR (86%) compared with RBC alone (0%, p < .001) or CLR alone (24%, p < .001). Ulcer recurrence rates after 6 months were lower in patients eradicated of H. pylori infection (17%) compared with patients who remained infected (43%). All treatments were well tolerated. Conclusions. Ranitidine bismuth citrate plus clarithromycin is a simple, convenient, and well-tolerated dual therapy regimen that is effective in eradicating H. pylori and healing duodenal ulcers in patients infected with H. pylori. The eradication of H. pylori in patients with healed ulcers significantly reduces the rate of ulcer relapse.

Objectives: This single-center, double-blind, randomized study assessed the effect of alendronate 5 and 10 mg on the gastroduodenal mucosa. Methods: Overall, 95 postmenopausal women without a recent history of major upper gastrointestinal (GI) disease and not taking gastric-irritant drugs, were screened with an upper GI endoscopy. Fourteen women (15% of the total) were found to have baseline endoscopic gastric and/or duodenal abnormalities, including mucosal hemorrhages (n = 4), erosions (n = 11), and ulcers (n = 3). Two additional women had baseline esophageal abnormalities. Thus, 79 postmenopausal women (mean age 51 yr, range 41–64 yr), free of esophageal, gastric and/or duodenal erosions or ulcer, were enrolled. Subjects received placebo, alendronate 5 mg/day or 10 mg/day, or aspirin 650 mg q.i.d. for 14 days. Endoscopy was repeated on Day 8 and on Day 15. Gastric and duodenal mucosae were graded separately using a 5-point scale for erosive mucosal injury. Results: The proportions of subjects with a gastric or duodenal erosion score ≥ 2 (presence of at least one mucosal erosion) on either Day 8 or 15 were four of 22 (18.2%) in the placebo group; four of 22 (18.2%) in the alendronate 5 mg group; five of 21 (23.8%) in the alendronate 10 mg group; and 14 of 14 (100.0%) in the aspirin group. Thirty-five of 76 (46%) subjects were H. pylori -positive (Pyloritek test), and were equally distributed across treatment groups. Conclusions: Alendronate 5 and 10 mg/day for 2 wk was associated with a lower incidence of gastric erosions than aspirin. The incidence of gastric erosions in the alendronate groups did not differ significantly from the placebo group. In this study, unlike aspirin, alendronate did not induce gastric erosions.

Nonsteroidal anti-inflammatory drug (NSAID)associated injury to the gastrointestinal tract is now a well-established fact. Indeed, studies have shown a prevalence of peptic ulcer in 20 –25% of patients taking these agents. The incidence of gastrointestinal bleeding, perforation, or obstruction in these patients is 1–3%, indicating that approximately one out of every 10 NSAID-associated peptic ulcers becomes complicated (ie, development of hemorrhage, perforation, or obstruction). These complications occur most often in well-defined, high-risk patients, primarily those who are elderly, those who have a history of gastrointestinal disease, and those who are receiving high-dose or multiple-drug regimens. The evaluation of any mucosal-protective agent is extremely difficult. For example, what end-point should be measured to determine efficacy: hemorrhages and erosions in healthy volunteers, peptic ulcers in volunteers or patients, or complication rates in patients taking NSAIDs? It is now generally agreed by most investigators that hemorrhages seen in short-term healthy volunteer studies are of little use. In a study from our laboratory evaluating the ability of the H2-receptor antagonist cimetidine to prevent naproxen-induced gastric injury, it was shown that the antagonist prevented hemorrhages but had no effect on the occurrence of erosions or peptic ulcers. This finding suggests that hemorrhages are acid dependent and are unrelated to more important lesions. Erosions, on the other hand, are probably more significant lesions in short-term healthy volunteer studies, and trials evaluating the prevention of these lesions by various agents are often predictive of findings in arthritic patients during long-term studies. Erosions may therefore be useful as a positive screening mechanism for new prophylactic agents. Healthy volunteer studies have shown that sucralfate is generally ineffective in preventing erosions and ulcers, that H2-receptor antagonists prevent erosions and ulcers in the duodenum but not in the stomach, and that misoprostol prevents both gastric and duodenal erosions and ulcers. –7 Longer-term studies in arthritic patients using ulcer as the end point have demonstrated essentially the same findings. –13 The use of ulcer as an end-point in these longer-term patient studies is justified by the fact that the major complications of NSAID use are those associated with peptic ulcer disease; erosions are found in a high percentage of patients taking NSAIDs chronically, but they are not associated with complications. Studies evaluating sucralfate have shown that it is essentially ineffective in preventing any type of NSAID-associated peptic ulcer disease. Two large, multicenter studies evaluating the H2-receptor antagonist ranitidine, 150 mg twice daily, in the prevention of NSAID-associated peptic ulcer have shown that this agent is significantly better than placebo in the prevention of duodenal ulcer, whereas it has no effect on the prevention of gastric ulcer. However, a recent study has shown that the H2-receptor antagonist famotidine, in addition to preventing duodenal ulcer, significantly reduces the incidence of gastric ulcer when given at high dose in patients receiving chronic NSAID therapy, when compared with placebo. Finally, numerous studies in arthritic patients have shown that misoprostol prevents both gastric and duodenal ulcers in patients taking NSAIDs, –12 although the side-effects caused by misoprostol sometimes prevent its use.

Objective. To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting. Methods. Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group-model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person-year. Results. The average individual cost rate of arthritis-related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898). Conclusion. RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.

Although eradication of Helicobacter pylori cures duodenal ulcer, some patients are not infected and others are treatment failures. This randomized, double-blind, placebo-controlled study assessed the value of treatment with low-dose lansoprazole in preventing duodenal ulcer recurrence. One hundred eighty-six patients with endoscopic documentation of healed duodenal ulcer received 15 mg/day lansoprazole or placebo for 12 months or until ulcer recurred. Endoscopy results, symptom assessment, and fasting serum gastrin levels were obtained at multiple time points. Densities of E, EC, and G cells were assessed by biopsy when the ulcer recurred or at the final visit. Time to ulcer recurrence was significantly longer (P 12 months) compared to placebo (median

We thank Dr Curry for an accurate summary1 of our study entitled ‘Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture’.2 Nevertheless, we do not recommend more selective use of depot medroxyprogesterone acetate (DMPA) on account of fracture risk, as we believe that this recommendation would reduce access to an effective, safe contraceptive without actually reducing fracture risk. As we reported, in those subjects with at least 6 months of pre-DMPA medical history (176 pre-treatment fractures …

Objective: We assessed the net effect on risk of death for within-label use of acetaminophen and the two nonaspirin alternative oral non-prescription analgesics available in the U.S. (ibuprofen and naproxen sodium) in relation to upper gastrointestinal hemorrhage, liver failure, and renal failure. Methods: For each drug we obtained estimates of recent general-population prevalence of use and the number of deaths in the US from acute liver injury, acute renal failure, and gastrointestinal hemorrhage for the years 2006-2008 in the population age 20 years or older. We searched the literature and reviewed all informative epidemiologic studies to obtain estimates of the relative risks for each analgesic-endpoint combination. From the estimates of prevalence, relative risk and total one-year risk for the U.S. population, we back-calculated the risk among unexposed, using it as a benchmark from which we could obtain the change in absolute risk related to using each analgesic. Results: Under most assumptions for the relative risks among the different analgesics, acetaminophen use carried the smallest absolute increase in risk, the best estimate being about 35 deaths per million in one year. The comparable estimated increased risk of death related to use of ibuprofen or naproxen sodium was 64 deaths for ibuprofen and 118 deaths for naproxen sodium per million person-years respectively. Conclusions: When non-prescription analgesics are used according to labeled instructions, acetaminophen use appears likely to be associated with smaller combined risks for upper gastrointestinal hemorrhage, liver disease, and renal disease than is use of ibuprofen or naproxen sodium.

Background—No estimate exists of the incidence of pelvic inflammatory disease (PID) after the occurrence of a recent bout of sexually transmitted disease (STD). Methods—We used a computerized data file of prescriptions and medical encounters from the Fallon Community Health Plan to estimate the incidence rate of pelvic inflammatory disease (PID) among women with a recently treated episode of gonorrhea or chlamydia (STD). First we identified women with presumed gonorrhea or chlamydia on the basis of a combination of diagnostic codes for cervicitis, vulvovaginitis or Bartholin's abscess, and a computer record of a prescription for doxycycline. We then followed these women to estimate the incidence rate of PID after their treatment for gonorrhea or chlamydia. We estimated the number of cases of pelvic inflammatory disease in this cohort by selecting all women with an International Classification of Diseases (ICD) code of 614.9 entered for either an outpatient or inpatient diagnosis. Results—We estimated the overall risk of PID to be about 9% during the 1-year period following treatment for gonorrhea or chlamydia, with a steep rise in risk coming within the first 45 days. Conclusion—The risk of PID in the year after an episode of treated STD is high, but the highest period of risk is in the first few weeks. The shape of the risk curve indicates that some PID cases may result from treatment-resistant infections, or possibly from untreated reinfections.

Data bases that are created to administer health care benefits and to record financial aspects of medical care in the United States are useful for epidemiologic research in certain circumstances. Case finding and verification in such records is complex and rarely described in detail in research reports because of space limitations. This report describes portmarketing surveillance for peptic ulcer, upper gastrointestinal hemorrhage and hepatic dysfunction in 68, 180 people who took non-steroidal anti-inflammatory drugs (NSAIDs), by using an automated data base together with review of selected medical records. Cases included both mild diseases treated on an outpatient basis and more severe illnesses that required hospital admission. Using computer programs we identified 9642 subjects who had at least one insurance claim suggesting a possible case event. We manually reviewed chronological profiles of their insurance claims, to select 833 subjects for medical record reviews, of whom 152 were verified as cases. Our algorithms for case identification were sensitive, but not very specific. If we had restricted our manual review to people who had at least five relevant claims during the study period, we would have avoided 42% of the reviewing workload and lost only 5% of the cases.

Background — A small number of published reports have provided estimates of incidence rates of symptomatic liver dysfunction in NSAID users, and most information has pertained to cases admitted to the hospital. Methods — We studied members of a health maintenance organization who were age 20 to 64 years in 1989–1991. Beginning with health insurance claims data for over 68,000 users of NSAIDs, and obtaining abstracts of medical records of potential cases, we ascertained the frequency of liver function abnormalities, including only cases with documented symptoms treated either as outpatients or hospital inpatients. Results — Overall, symptomatic liver dysfunction was rare, with 25 cases confirmed in the cohort of 68,028 people (0.37 cases per 1000 users of NSAIDs). For people who received a prescription NSAID in the previous six months, the crude incidence rate was 24 cases in 46,636 person-years, or 0.51 per 1000 person-years. For people who did not have a prescription NSAID in the previous six months, the crude incidence rate was 1 case in 13,303 person-years, or 0.075 per 1000 person-years. Of the 25 confirmed cases, 19 (76%) had alanine aminotransferase and/or aspartate aminotransferase at least 1.5 times the upper limit of normal values; the remaining six had abnormal results but of lesser magnitude. In five cases (20%) physician's notes document that a diagnosis of drug-induced hepatic dysfunction was considered. Only 3 (12%) of the 25 cases were admitted to the hospital. Conclusion — Although symptomatic liver dysfunction was relatively more frequent during the six months following NSAID use than at later times, the overall risk was low. Given the limitations of the available data, the apparent association with NSAID use may be confounded by other causes of liver dysfunction that could not be fully evaluated, such as other hepatotoxic medications, viral infections, or other medical conditions.

Objective To describe the monitoring of liver function for patients using nonsteroidal anti-inflammatory drugs (NSAIDs), we reviewed the patterns of liver function testing in a medium-sized health maintenance organization. Methods We examined the interval between start of therapy and first performance of a liver function test during courses of therapy of the NSAIDs diclofenac sodium, naproxen and naproxen sodium, and piroxicam. For comparison, we also studied courses of lovastatin as a "positive control," in which the anticipated frequency of liver function testing was high. Results The frequency of liver function tests in patients using NSAIDs was generally low, although testing was more common in patients who used diclofenac. The probability of liver function testing was higher for patients treated in recent calendar years, for patients treated by rheumatologists, for patients who previously used NSAIDs, and for patients who had undergone a liver function test sometime in the 6 months preceding the onset of therapy. Conclusion Physicians ordered liver function tests less frequently than recommended, but the observed testing patterns appear rational in light of the very low reported frequency of serious hepatic disease in large, monitored populations of patients using NSAIDs.

The public health status of the United States is in a critical state. Rates of overweight and obese children are on the rise in nearly every community in the nation, and obesity is quickly becoming a global problem as well. While there are many biological, cultural, and psychological factors that play into the rising rates, social factors as a cause of decreasing health are often overlooked. The “built environment,” or each community’s living, working, and eating spaces, plays a large role in determining the actions taken by individuals in a community. In this study, the built environments of two socioeconomically different neighborhoods in Nashville, Tennessee, are analyzed. The resulting data is compared to Tennessee state health census reports to posit that a decreased quality of food and physical activity related built environments parallels a rise in chronic health problems.

This study compared spontaneous bone healing and regeneration obtained with deproteinised bovine graft in residual cavities after mandibular cyst enucleation using computed tomography (CT) Dentascan.Eighty patients with a radiological diagnosis of mandibular cyst underwent surgical enucleation. Patients were divided into a control group (spontaneous healing, 40 patients) and a test group (deproteinised bovine graft, 40 patients). All patients underwent follow-up CT Dentascan 12 months after the procedure. For each residual cavity, apical-coronal and mesial-distal distance, average pixel intensity and volume were calculated and results compared between two groups using the t test.The control group showed mean volume, apical-coronal and mesial-distal distance of 703.2 ± 185.3 mm(3), 28.6 ± 9.4 mm and 25 ± 2.84 mm, respectively. In the test group, values were 738.2 ± 189.2 mm(3), 27.5 ± 3.6 mm and 25.3 ± 2.97 mm, respectively. There was no statistically significant difference between groups. Average pixel intensity was 1,102.8 ± 124.3 in the test group and 624.9 ± 133.3 in the control group, with a significant difference between groups (p0.0001).The significantly higher average pixel intensity observed in the test group demonstrates the cavalue of treatment with biomaterials to obtain earlier bone regeneration.

Compared with nonselective NSAIDs, cyclooxygenase (COX)-2-selective inhibitors have been associated with a lower incidence of gastroduodenal ulcers (in short-term endoscopic studies) and ulcer complications (in long-term trials).The aim of this study was to compare the effects of valdecoxib 20 mg BID and naproxen 500 mg BID, administered for 6.5 days, on the upper gastrointestinal (UGI) mucosa of healthy older subjects (aged 65-75 years) as assessed by UGI endoscopy.In this multicenter, double-blind, active-comparator, placebo-controlled, parallel-group study, eligible subjects who were free of NSAID or COX-2-selective inhibitor use for 2 weeks and who had normal UGI mucosa (mucosal grading score of 0, based on endoscopic evaluation of both the stomach and duodenum) were randomized. Serologic testing for Helicobacter pylori antibodies was conducted at baseline. No antiulcer medications were permitted. The primary end point was the incidence of gastroduodenal ulcers (gastric or duodenal mucosal grading score of 7, as indicated by any lesion with unequivocal depthor =3 mm in diameter) after 6.5 days of blinded treatment with valdecoxib, naproxen, or placebo. Secondary end points were incidence of gastric ulcers, duodenal ulcers, and gastroduodenal erosions/ulcers, and the incidence ofor =11 gastroduodenal erosions/ulcers. All documented adverse events were self-reported by subjects or were observed by investigators.Sixty-one patients were randomized to receive valdecoxib, 60 to naproxen, and 60 to placebo. Mean (SD) subject age was 68.8 (3.25) years in the valdecoxib group, 68.6 (2.76) years in the naproxen group, and 68.6 (3.14) years in the placebo group (P = NS). In the valdecoxib and naproxen groups, 47.5% and 58.3% of subjects were female, respectively, compared with 56.7% of the placebo group (P = NS). Valdecoxib and placebo were associated with significantly lower incidences of gastroduodenal ulcers than naproxen (1.6% [1 gastroduodenal ulcer/61 patients] and 1.7% [1/59], respectively, vs 22.0% [13/59]; P0.001). Compared with naproxen, both valdecoxib and placebo were associated with significantly lower incidences of gastric (1.6% [1/61] and 1.7% [1/59] vs 15.3% [9/59]; both, P0.03) and duodenal ulcers (0% [0/61] and 0% [0/59] vs 8.5% [5/59]; both,P0.03). In all cases, the incidence of ulcers with valdecoxib was not significantly different from placebo. Results were similar for any erosions/ulcers, and when analyzed by H pylori status. The number of adverse events was low in each group.In these healthy older subjects (aged 65-75 years), valdecoxib 20 mg BID was associated with a significantly lower rate of gastroduodenal, gastric, and duodenal ulcers than naproxen 500 mg BID, even after 6.5 days of therapy.

The bisphosphonate class of drugs are now utilized extensively in the treatment of patients with osteoporosis and Paget’s disease. Gastrointestinal (GI) adverse effects, especially those associated with esophageal injury, have been of increasing concern to clinicians. Studies in humans and animals have shown that the mucosal erosion and ulceration seen with bisphosphonates is a result of direct contact with these agents. Numerous endoscopic studies in healthy volunteers and postmenopausal women have also demonstrated the potential of bisphosphonates to cause stomach and duodenal ulcers. However, serious GI adverse events have not been noted in several large efficacy trials. Esophageal injury has for the most part been avoided by appropriate administration instructions, and gastroduodenal injury appears to be an acute phenomenon not associated with significant complications, except in certain high-risk situations, for example in the presence of existing distal esophageal disease or motility disorders, or with concurrent use of nonsteroidal anti-inflammatory drugs or anticoagulants. From the standpoint of GI safety, the bisphosphonates are well tolerated and not associated with serious adverse events.

Activation of the capsaicin receptor (VR1 or TRPV1) in bronchial epithelial cells by capsaicinoids and other vanilloids promotes pro-inflammatory cytokine production and cell death. The purpose of this study was to investigate the role of TRPV1-mediated calcium flux from extracellular sources as an initiator of these responses and to define additional cellular pathways that control cell death. TRPV1 antagonists and reduction of calcium concentrations in treatment solutions attenuated calcium flux, induction of interleukin-6 and 8 gene expression, and IL-6 secretion by cells treated with capsaicin or resiniferatoxin. Most TRPV1 antagonists also attenuated cell death, but the relative potency and extent of protection did not directly correlate with inhibition of total calcium flux. Treatment solutions with reduced calcium content or chelators had no effect on cytotoxicity. Inhibitors of arachidonic acid metabolism and cyclo-oxygenases also prevented cell death indicating that TRPV1 agonists disrupted basal arachidonic acid metabolism and altered cyclo-oxygenase function via a TRPV1-dependent mechanism in order to produce toxicity. These data confirm previous results demonstrating calcium flux through TRPV1 acts as a trigger for cytokine production by vanilloids, and provides new mechanistic insights on mechanisms of cell death produced by TRPV1 agonists in respiratory epithelial cells.

Objective—To compare concentrations of 3-methyleneindolenine (3MEIN) in lung tissues obtained from feedlot cattle that died as a result of acute interstitial pneumonia (AIP) and cattle that died as a result of other causes and to compare blood concentrations of 3MEIN in healthy feedlot cattle and feedlot cattle with AIP.Study Population—Blood samples and lung tissues collected from 186 cattle housed in 14 feedlots in the western United States.Procedure—Samples of lung tissues were collected during routine postmortem examination and submitted for histologic, microbiologic, and toxicologic examination. Blood samples were collected from cattle with clinical manifestations of AIP and healthy penmates. Histologic diagnoses were categorized as AIP, bronchopneumonia (BP), control samples, and other disorders. Concentrations of 3MEIN were determined in lung tissues and blood samples, using an ELISA.Results—Concentrations of 3MEIN in lung tissues were significantly greater in AIP and BP samples, compared with control samples. Absorbance per microgram of protein did not differ between BP and AIP samples. Blood concentrations of 3MEIN were significantly greater in cattle with AIP, compared with healthy cattle or cattle with BP. Odds of an animal with AIP being a heifer was 3.1 times greater than the odds of that animal being a steer.Conclusion and Clinical Relevance—Increased pulmonary production of 3MEIN may be an important etiologic factor in feedlot-associated AIP. (Am J Vet Res2001;62:1525–1530)

Speech restoration after circumferential pharyngolaryngectomy with free jejunal repair for advanced tumors of the hypopharyngo-esophageal tract remains a difficult problem to solve. We report here the results of secondary voice restoration in six patients who received a Provox 2 type prosthesis and intensive speech therapy after circumferential pharyngolaryngectomy with free jejunum repair. No patient had operative or post-operative complications due to insertion of the prosthesis. No patient had to have the prosthesis removed during the follow-up (8 to 14 months). Analysis of some acoustic parameters of voice (fundamental frequency, waveform perturbations) and qualitative characteristics of speech (intelligibility, pleasantness and acceptability) demonstrated that all the patients were able to produce satisfactory speech after tracheojejunum puncture and speech therapy and were satisfied with their own ability to communicate. Our results are reassuring and we therefore advise that in patients undergoing free jejunum flap reconstruction of the hypopharyngo-esophageal tract voice restoration should be attempted by placing a voice prosthesis through a secondary tracheo-esophageal puncture and providing intensive speech training.

We used automated health insurance claims records of a New England insurer to assess the relation between salmeterol and severe nonfatal asthma. We identified 61,712 members who received a beta-agonist from January 1, 1993 to August 31, 1995, including 2, 708 recipients of salmeterol. Compared with recipients of other beta-agonists, future salmeterol recipients had higher rates of asthma hospitalization and dispensings of asthma medications during the year before they received salmeterol. We selected as a comparison group 3,825 recipients of sustained-release theophylline. We defined a baseline period as the year before the start of the follow-up period, and we characterized patients according to age, sex, calendar period, presence of baseline hospitalizations for asthma, presence of chronic obstructive pulmonary disease (COPD), and baseline dispensings of asthma medications. After adjusting for baseline factors, incidence rates of severe asthma in the salmeterol group were not elevated for emergency care (rate ratio estimate [RR] = 0.69, 95% confidence intervals [CI] = 0.42, 1.11), hospitalization (RR = 1.09, 95% CI = 0.60, 1.98), or intensive care unit (ICU) stays (RR = 0.81, 95% CI = 0.25, 2.62). We conclude that salmeterol was prescribed preferentially to high-risk patients and, after adjusting for baseline risk, salmeterol recipients did not have a greater risk than theophylline recipients of severe nonfatal asthma.

BackgroundTreatment with amoxicillin plus omeprazole results in disappointing cure rates of Helicobacter pylori infection. The minimal inhibitory concentration of lansoprazole for H. pylori in vitro is lower than that for omeprazole, prompting interest in treatment with amoxicillin plus lansoprazole. Materials and Methods.H. pylori-infected patients with endoscopically documented duodenal ulcer either currently or within the past year were randomized to 14 days of (1) lansoprazole, 30 mg bid, plus amoxicillin, 1 gm tid; (2) lansoprazole, 30 mg tid, plus amoxicillin, 1 gm tid; (3) lansoprazole, 30 mg tid alone; or (4) amoxicillin, 1 gm tid alone. Endoscopy was done at enrollment and at 4 to 6 weeks after completion of treatment or for recurrent symptoms. H. pylori status was assessed by culture and histology. Ulcer prevalence was evaluated at follow-up endoscopy. Results.Two hundred sixty-two patients met enrollment criteria and were treated. By per-protocol analysis, H. pylori infection was cured in 57% of those treated with lansoprazole twice daily plus amoxicillin and in 67% of those treated with lansoprazole three times daily plus amoxicillin, compared with 0% treated with lansoprazole alone or amoxicillin alone (p < .001 for dual therapy versus either monotherapy). Amoxicillin resistance was not observed. At follow-up endoscopy, ulcer prevalence was 17% in patients treated with lansoprazole twice daily plus amoxicillin, 23% in those treated with lansoprazole three times daily plus amoxicillin, 33% in those treated with lansoprazole alone, and 35% in those treated with amoxicillin alone (p= .024; lansoprazole twice daily plus amoxicillin versus amoxicillin alone). Conclusions.Treatment with amoxicillin plus lansoprazole, 30 mg tid, led to cure of H. pylori infection in 67% of patients with active or recently healed duodenal ulcer.

This single-blind crossover trial compared the effects of single oral doses of two antacids on esophageal and gastric pH in subjects with heartburn. Gastric and esophageal pH were assessed in 83 subjects from 1 h before to 4 h after a refluxogenic meal. Subjects received two chewable tablets of a high-potency aluminum/magnesium hydroxide [Al(OH)3/Mg(OH)2] formulation (Mylanta Double-Strength(TM)) or a calcium carbonate [CaCO3] formulation (Tums E-X(TM)), or placebo 1 h after the meal. Both antacid formulations significantly increased esophageal pH, as compared with placebo. Onset of action was faster with the Al(OH)3/Mg(OH)2 formulation than with the CaCO3 in 41 subjects, slower in 13 subjects, and identical in 29 subjects. Area under the esophageal pH--time curves after dosing were significantly greater for Al(OH)3/Mg(OH)2 than for CaCO3 (p < 0.05) and significantly greater for CaCO3 than for placebo (p < 0.05). The duration of Al(OH)3/Mg(OH)2 action in the esophagus was 82 min and 60 min for CaCO3 (p < 0.05). In the stomach, only Al(OH)3/Mg(OH)2 increased gastric pH compared with placebo. After ingestion of calcium carbonate, gastric pH usually remained at or below placebo values, a finding consistent with a calcium carbonate-induced "acid rebound." The duration of Al(OH)3/Mg(OH)2 action in the stomach was 26 min. These findings demonstrate the efficacy and relative superiority of this particular aluminum/magnesium hydroxide formulation compared with the calcium carbonate preparation at increasing esophageal and gastric pH. However, the magnitude and duration of action of both antacids on esophageal pH, in contrast to minimal effects on gastric pH, suggest strongly that the lower esophagus is the primary site of antacid activity in relief of heartburn.

The first endoscopic observation of gastric mucosal injury due to aspirin occurred in 1938 [1]. Subsequently, numerous anecdotal observations of similar injury were reported in the medical literature. The advent of fibreoptic endoscopy and photography in the 1960s made it much easier to evaluate the effects of aspirin and other non-steroidal anti-inflammatory agents (NSAIDs) on the gastric and duodenal mucosa. In 1975 we reported the first double-blind controlled endoscopic study of mucosal injury due to these agents [2]. In that study, we developed a 0 to 4 grading system which primarily dealt with mucosal haemorrhages and ulcer. In recent years, improved fibreoptic bundles and more sophisticated photographic and video-endoscopic techniques have led us to appreciate the incidence and significance of erosions as well as haemorrhages and ulcers. At the present time, there is a huge body of well-controlled endoscopic studies in the literature evaluating this injury both in normal volunteers and patients [3]. Most of these studies utilize the 0 to 4 rating scale, however, many other scoring systems have also been employed. At the present time, it is generally felt that erythema and mucosal haemorrhages are of no clinical significance. The significance of erosions depends upon their numbers and depth and whether or not they ultimately develop into ulcers. Ulcers are always highly clinically significant, since, without the ulcer lesion, the complications of haemorrhage and perforation, and the therapy-limiting occurrence of intractable pain cannot occur.