Ketorolac effectively inhibits ureteral contractility in vitro

INTRODUCTION: The use of ketorolac in the management of painful symptoms associated with urinary stones is well supported in the literature; however, the gastric and renal adverse effects limit the dose and duration of administration. As a nonselective cyclooxygenase inhibitor, ketorolac can act locally to help control renal colic by inhibiting smooth muscle contractions and inflammation. We sought to confirm ketorolac's inhibition of ureteral contractility and determine a dose response relationship to identify an effectiveness range. MATERIALS AND METHODS: Porcine ureter strips attached to force displacement transducers were suspended in organ tissue baths that contained aerated Krebs buffer. Tissues equilibrated for 1 hour, and a spontaneous contractility rate was established. Tissues were incubated with a concentration-response curve of ketorolac (0.1 nM-10 microM) for 90 minutes and compared with indomethacin (1 muM) and dimethyl sulfoxide (DMSO) 0.1%. Contractility rates were recorded on a polygraph and analyzed for changes over exposure time. RESULTS: Ketorolac inhibition of ureteral contractility was dose dependent. At 90 minutes, the average percent decrease from the spontaneous contraction rate for 0.1 nM ketorolac was 18.2%; 1 nM, 34.3%; 10 nM, 56.0%; 100 nM, 69.9%; 1 microM, 88.7%; and 10 microM, 98.3%. Ureteral contractility was significantly reduced by 1 microM ketorolac (39.0%; P = 0.016) at 15 minutes when compared with DMSO. In addition, 1 microM ketorolac was not significantly different at any time point from any of the higher doses studied. CONCLUSION: Ketorolac inhibition of stretch-induced ureteral contractility is concentration-dependent between 1 nM and 1 microM. Local administration of ketorolac at these doses may be useful during the management of stones while at the same time limiting the risk for adverse effects.     

Comparison of azithromycin and clarithromycin in triple therapy regimens for the eradication of Helicobacter pylori

OBJECTIVE: We sought to compare an azithromycin-based regimen with an already established clarithromycin-based regimen in the eradication of Helicobacter pylori infection. METHODS: A prospective, randomized, blinded comparative analysis was performed on 56 patients with upper GI symptoms who presented to the Gastroenterology Department at the Naval Medical Center Portsmouth. All patients had documented H. pylori infection on endoscopy via rapid urease test and histopathology. Patients were randomized to a treatment arm, which consisted of bismuth, clarithromycin, amoxicillin, and lansoprazole (B-LAC) or one consisting of bismuth, azithromycin, amoxicillin, and lansoprazole (B-LAA). To assess eradication, patients then received repeat endoscopy at 8 wk from entrance into the study. Rapid urease test and histopathology were again used to evaluate infection. Patients recorded all side effects. Comparison between the two groups was made using the chi2 method. RESULTS: Of the 56 patients included in the study, 27 went on to receive B-LAC, whereas 29 received B-LAA. The per protocol eradication rate was 84.6% with B-LAC and 55.5% with B-LAA (p = 0.021). Under intention to treat analysis, the eradication rates for B-LAC and B-LAA were 81% and 52%, respectively (p = 0.019). There was a significant difference between the two groups in number of subjects using nonsteroidal anti-inflammatory drugs (NSAIDs) (p = 0.013) and a trend toward a difference in histamine-2 (H2) blocker use (p = 0.066). Taking these two variables into account, a logistical regression was performed and continued to show a significant superiority in the B-LAC regimen (p = 0.03). CONCLUSIONS: The results of our study suggest that B-LAC is superior to B-LAA in the eradication of Helicobacter pylori. Our results also suggest that B-LAA is not a suitable regimen in the treatment of H. pylori because of its substandard eradication rate.     

Validity of standard gamble estimated quality of life in acute venous thrombosis

Introduction

The standard gamble is considered the ‘gold standard’ technique for measuring quality of life. We recently used the standard gamble to estimate quality of life in acute venous thrombosis, and found unexpected variability in the responses. The current study aimed to explore the reasons for variability by comparing the standard gamble technique in patients with acute venous thrombosis to other quality of life measurement tools.

Materials and Methods

Thrombosis clinic patients treated for venous thrombosis were eligible to participate. Patients evaluated their current health state by performing a standard gamble interview, reporting on a visual analogue scale, completing the SF-36 and disease specific questionnaires (PEmb-Qol and VEINES-QOL/Sym). Validity was assessed by correlating the standard gamble utilities with the other methods. Test-retest reliability, responsiveness and acceptability were also assessed.

Results

Forty-four patients were interviewed, with 16 attending for a repeat interview. The median standard gamble utility was 0.97 (0.84-1.0), SF-6D 0.64 (0.59 - 0.80) and visual analogue score 70 (60 - 80). Participants with pulmonary embolism had lower standard gamble estimates than those with deep vein thrombosis. There was good discriminant validity in that the standard gamble estimates were not associated with risk taking behavior, negative outlook, sex or education. Test-retest reliability with the standard gamble was moderate and there was evidence of a ceiling effect.

Conclusions

Standard gamble utilities are higher than other methods of measuring quality of life in venous thrombosis. The choice of utility values adopted in studies will impact on future economic studies.     

Opposing roles of membrane and soluble forms of the receptor for advanced glycation end products in primary respiratory syncytial virus infection

Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.     

The Cogency of Risk Assessments

Preventive detention schemes rely on assessments of risk carried out by forensic practitioners. Corrective services departments and other organs of the state inevitably present the approaches they adopt and the tools they employ in this endeavour as being “best practice” and “evidence based”. Typically these assessments are conducted according to a bureaucratic template and are based on a selected suite of tests that are heavily biased towards actuarial assessment. The validity of this approach is gravely suspect as is the failure of many forensic professionals to properly identify the diagnostic accuracy/inaccuracy of the tests and methods they rely upon in conducting risk assessments. This article iterates the methodological and evidentiary problems with risk assessment of sexual offenders. It is concluded that common extant approaches lack scientific objectivity and fail to provide the courts with cogent evidence. As a result of these errors in investigatory processes miscarriages of justice are inevitable.     

Increased Act1/IL-17R expression in Hirschsprung’s disease

Purpose

Hirschsprung’s disease-associated enterocolitis (HAEC) is the most common cause of morbidity and mortality in Hirschsprung’s disease (HSCR). Altered intestinal epithelial barrier function is implicated in the pathogenesis of HAEC. IL-17 is a proinflammatory cytokine that plays a crucial role in host defense against microbial organisms in the development of inflammatory diseases. Act1 is an essential adaptor molecule required for the IL-17-mediated inflammatory responses via interaction with IL-17 receptor (IL-17R). We designed this study to investigate the hypothesis that Act1/Il-17R expression is upregulated in HSCR.

Methods

We investigated Act1 and IL17R expression in ganglionic andaganglionic bowel of HD patients (n = 10) and controls (n = 10). qPCR, Western blotting and confocal immunofluorescence were performed.

Main results

qPCR and Western blot analysis revealed that Act1 and IL17R are strongly expressed in the aganglionic and ganglionic colon of patients with HSCR. Act1 and IL17R expression was significantly increased in HSCR specimens compared to controls (p < 0.05). Confocal microscopy revealed a markedly increased expression of Act1 and IL17R in the colonic epithelium of patients with HSCR compared to controls.

Conclusion

To our knowledge, we report, for the first time, the expression of Act1 in the human colon. The increased expression of Act1 and Il-17 in the aganglionic and ganglionic bowel in HSCR may result in IL-17-mediated increased inflammatory response leading to the development of HAEC