A binding study of phospholipase A2 with lecithin,lysolecithin and their tetrahedral intermediates using molecular modeling

We used molecular modeling to examine the binding of 1, 2-dioctanoyl-sn-glycero-3-phosphocholine (a lecithin), 1-octanoyl-sn-glycero-3-phosphocholine (a lysolecithin) and their tetrahedral intermediates in the catalytic site of phospholipase A₂ (PLA₂). We performed energy minimization on each complex, computed the binding energy, determined the relative binding energy among the complexes and calculated the difference in inter- and intramolecular energies of the components in the complexes. We found that the calculated orientation of the sn-1 ester bond of lysolecithin in the active site is similar to that of the sn-2 ester bond in lecithin, thus permitting PLA₂ to hydrolyze lysolecithin using the same mechanism as it uses to hydrolyze lecithin. On the other hand, the binding of lecithin is energetically more favorable by 4.5 kcal/mol than the binding of lysolecithin to the enzyme, and the binding of the lecithin tetrahedral intermediate is also energetically more favorable by 19.7 kcal/mol than the binding of the lysolecithin tetrahedral intermediate to the enzyme, which explains why lecithin is a better substrate than lysolecithin in the catalytic site. These results indicate that the activation energy for the hydrolysis of lysolecithin is higher than that for lecithin, consistent with the observed slower rate for the hydrolysis of lysolecithin.     

Influencing physician response to prenatal substance exposure through state legislation and work-place policies

Little research attention has focused on ways to encourage physician response to prenatal substance exposure. We report initial results from a study examining the impact of state laws and work-place policies on physician response by combining legal analyses and data from a national physician survey. Our findings indicate that the message that laws and policies exist usually does not reach physicians. However, when the message does come through, some physician behaviors are influenced. In particular, physicians in states with clearer policies and behavioral expectations are significantly more likely to know and understand the law than physicians in other states. Further, believing that a work-place protocol on prenatal substance exposure exists is associated with significantly increased likelihood of an active response in case vignettes portraying prenatal substance exposure. The findings suggest that state legislative behaviors may increase physician response to prenatal substance exposure, but that response depends on the nature of the policy and on efforts to disseminate it.     

Preservation of All Chordae Tendineae and Papillary Muscle During Mitral Valve Replacement with a Tilting Disc Valve

Mitral valve replacement was performed in 21 patients using a surgical technique that preserves the entire papillary muscle and chordal apparatus. With this technique, the anterior mitral leaflet is split from the center of the free edge toward the annulus. Bilateral incisions are made from the proximal end of this split to the two mitral commissures, detaching the anterior leaflet from the annulus. These two halves of the leaflet, with all chordae intact (corresponding to the anterolateral and posteromedial papillary muscles), are judiciously trimmed to remove areas of leaflet untethered by chordae tendineae and (when necessary) fibrous thickening; then swung posteriorly and sutured to the posterior mitral annulus using mattress sutures with pledgets. This surgical technique is expected to favor the preservation of left ventricular function and avoid occurrence of irreversible left ventricular dilation/dysfunction, and has been used successfully for calcific and degenerative etiologies, using both tilting disc valves and porcine bioprostheses. It is especially useful in the implantation of tilting disc and bileaflet mechanical prostheses because anterior subvalvular chordae tissue may interfere with the disc excursion and relocated to the posterior leaflet annulus.     

Symptomatic and endoscopic duodenal ulcer relapse rates 12 months following Helicobacter pylori eradication treatment with omeprazole and amoxycillin with or without metronidazole

Aim: To determine the effect of Helicobacter pylori eradication with omeprazole and amoxycillin, with or without metronidazole, on the 12-month course of duodenal ulcer disease. Methods: In a randomized, double-blind study, conducted in 19 hospitals, 105 H. pylori positive duodenal ulcer patients were healed and symptom-free following either omeprazole dual therapy (omeprazole 40 mg o.m.+amoxycillin 500 mg t.d.s., OA, eradication rate 46%, n=52) or omeprazole triple therapy (omeprazole 40 mg o.m.+amoxycillin 500 mg t.d.s.+metronidazole 400 mg t.d.s., OAM, eradication rate 92%, n=53) for 2 weeks, followed by 2 weeks of omeprazole 20 mg o.m. and a 12-month untreated follow-up period, after which time all patients were endoscoped. Endoscopic and symptomatic relapse rates, and effect on H. pylori status measured using ¹³C-urea breath test, were determined. Results: During the 12-month untreated follow-up period, the life-table endoscopic relapse rates were 12% (95% CI: 2–22%) and 2% (95% CI: 0–6%) for OA and OAM patients, respectively. By 12 months, life-table symptomatic relapse rates were 22% (95% CI: 13–37%) and 19% (95% CI: 8–30%) for OA and OAM, respectively. In the 12 months untreated follow-up period, 2/69 (3%, 95% CI: 0–7%) patients rendered H. pylori negative had an endoscopic relapse at the end of the 12-month follow-up period, compared with 5/31 (16%, 95% CI: 3–29%) patients remaining H. pylori positive (P=0.03 between H. pylori positive and negative groups). Twelve of 69 (17%, 95% CI: 8–26%) patients rendered H. pylori negative relapsed symptomatically, compared with 9/31 (29%, 95% CI: 13–45%) patients remaining H. pylori positive (P= N.S. between groups). There was a significant improvement in epigastric pain (P=0.0001), nausea and vomiting (P<0.05) between entry to the study and 1, 6 and 12 months post-treatment for both treatment groups. Conclusions: OAM eradicates H. pylori in significantly more patients than OA, but successful H. pylori eradication with either OAM or OA predisposes to low endoscopic and symptomatic relapse rates for duodenal ulcer patients when followed up for 12 months.     

CONDITIONED ETHANOL PREFERENCE IN RATS

The question of whether ethanol has intrinsically rewardingproperties, or whether, as a discriminative stimulus, it canbecome a conditioned reinforcer as a function of context associationwas examined. Paired rats consumed more of an ethanol solutionthan isolated rats over a 15 day ‘conditioning’phase and their ingestion rate was increased significantly overthe 15 day period. Furthermore, animals exposed to the solutionwith a conspecific companion during this conditioning phasesubsequently showed a marked preference for ethanol over waterthroughout a 10 day test phase (when all animals were alone)compared to those with prior experience of the solution in isolation.Both groups consumed significantly more ethanol than the controls(with no prior ethanol experience at all) during this test phase.The results suggest that the total context of initial exposureto ethanol mediate its subsequent reinforcing properties, withthe prior pleasurable context of being with a conspecific companiongeneralizing to the ethanol stimulus for the paired group.