Repair of symptomatic paraesophageal hernias in elderly (>70 years) patients results in sustained quality of life at 5 years and beyond.

BACKGROUND: Paraesophageal hernias (PEHs) involve herniation of stomach and/or other viscera into the mediastinum. These commonly occur in the elderly and can severely limit quality of life. Short term outcomes of repaired PEH demonstrated low morbidity and significant improvement in quality of life, but long-term data for all patients, especially the elderly, are lacking. METHODS: Retrospective chart review of a prospectively collected database of patients aged 70 or greater with a symptomatic PEH repaired 5+ years ago. Quality of life data were assessed preoperatively, at 12-24 months, and at 5+ years using QOLRAD, GERD-HRQL, and DSS. RESULTS: We identified 137 patients who met the age criteria, with 69 patients undergoing surgery 5+ years ago. With ten patients were lost to follow-up, 59 patients were analyzed, including 24 males and 35 females. Median age at repair was 77 years. There were two 90-day mortalities, with one occurring within 30 days of surgery. Patients alive at evaluation had a median age of 74 years and were followed a median 7.4 years. From baseline, QOLRAD improved from 4 to 6.5, GERD-HRQL improved from 11 to 5, and swallowing improved from 11 to 38. During follow-up, 21 patients died. Deceased patients lived a median of 4 years after repair, with a median age at repair of 80 years. At a median time follow-up of 2 years, this group's QOLRAD improved from 5.1 to 7, GERD-HRQL improved from 16 to 4, and swallowing improved from 14.5 to 35. CONCLUSIONS: In elderly patients with symptomatic PEH undergoing surgical repair more than 5 years ago, there was sustained improvement in quality of life. This justifies surgical repair of symptomatic PEH in elderly patients.

Identification of potent inhibitors of the chicken soluble epoxide hydrolase.

In vertebrates, soluble epoxide hydrolase (sEH) hydrolyzes natural epoxy-fatty acids (EpFAs), which are chemical mediators modulating inflammation, pain, and angiogenesis. Chick embryos are used to study angiogenesis, particularly its role in cardiovascular biology and pathology. To find potent and bio-stable inhibitors of the chicken sEH (chxEH) a library of human sEH inhibitors was screened. Derivatives of 1(adamantan-1-yl)-3-(trans-4-phenoxycyclohexyl) urea were found to be very potent tight binding inhibitors (KI <150pM) of chxEH while being relatively stable in chicken liver microsomes, suggesting their usefulness to study the role of EpFAs in chickens.

Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability.

Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 µg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high cLogP's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with cLogP and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.

Toxicology in the fast lane: application of high-throughput bioassays to detect modulation of key enzymes and receptors.

BACKGROUND: Legislation at state, federal, and international levels is requiring rapid evaluation of the toxicity of numerous chemicals. Whole-animal toxicologic studies cannot yield the necessary throughput in a cost-effective fashion, leading to a critical need for a faster and more cost-effective toxicologic evaluation of xenobiotics. OBJECTIVES: We tested whether mechanistically based screening assays can rapidly provide information on the potential for compounds to affect key enzymes and receptor targets, thus identifying those compounds requiring further in-depth analysis. METHODS: A library of 176 synthetic chemicals was prepared and examined in a high-throughput screening (HTS) manner using nine enzyme-based and five receptor-based bioassays. RESULTS: All the assays have high Z' values, indicating good discrimination among compounds in a reliable fashion, and thus are suitable for HTS assays. On average, three positive hits were obtained per assay. Although we identified compounds that were previously shown to inhibit a particular enzyme class or receptor, we surprisingly discovered that triclosan, a microbiocide present in personal care products, inhibits carboxylesterases and that dichlone, a fungicide, strongly inhibits the ryanodine receptors. CONCLUSIONS: Considering the need to rapidly screen tens of thousands of anthropogenic compounds, our study shows the feasibility of using combined HTS assays as a novel approach toward obtaining toxicologic data on numerous biological end points. The HTS assay approach is very useful to quickly identify potentially hazardous compounds and to prioritize them for further in-depth studies.