A peptide inhibitor of cholesteryl ester transfer protein identified by screening a bacteriophage display library

We screened a bacteriophage display library of random decapeptides to identify peptide inhibitors of cholesteryl ester transfer protein (CETP). After affinity selection against CETP, bacteriophage-infected Escherichia coli were plated at clonal density and 36 random clones were isolated. Analysis of the relevant portion of the bacteriophage DNA from a group of 12 clones that had a relatively high affinity for CETP revealed that the corresponding amino acid sequences of the displayed peptides exhibited an. Xaa-Arg-Met-Arg-Tyr-Xaa composite motif. Based on those results, decapeptides from this group were synthesized and one of them, DPI (NH₂-VTWRMWYVPA-COOH), inhibited CETP-catalyzed transfer of cholesteryl esters and triglycerides. Amino- and carboxy-terminal truncations of DPI demonstrated that the original decapeptide could be reduced to a pentapeptide without loss of either its ability to bind to CETP or its ability to inhibit CETP-mediated lipid transfer. That pentapeptide, NH₂-WRMWY-COOH (WRMWY, PNU-107368E), binds directly to CETP and its inhibition is consistent with that of a competitive inhibitor of CETP with a K_i of 164 μm . WRMWY or modified versions of this peptide may be useful in studying the interactions between CETP and plasma lipoproteins.     

Could activated charcoal be used to adsorb intraduodenal Methyl tert-butyl ether spillage during its use in the dissolution of gallstones?

Methyl tert-butyl ether (MTBE) is becoming more frequently used in the non-surgical removal of cholesterol gallstones. However, during its introduction into the biliary tract, some spillage can occur and subsequent systemic absorption has been reported to lead to a variety of side effects. We have carried out in vitro experiments to assess the ability of activated charcoal to adsorb MTBE. A 10% aqueous suspension of activated charcoal was mixed with MTBE and its adsorption was estimated subsequently by gas chromatography. Adsorption varied from 38% at an activated charcoal: MTBE ratio of 1:1, to 96% at a ratio of 8:1. Only 3.2% of the adsorbed MTBE could be desorbed by resuspending the sedimented activated charcoal: MTBE complex in an equivalent volume of fresh distilled water. The results indicate that a single dose of activated charcoal (greater than 12 g) may be effective in minimizing systemic absorption of MTBE spilt during gallstone dissolution.     

Toward understanding the use of dental services by the elderly

Predictors of dental service use were examined among a statewide sample of 776 noninstitutionalized Massachusetts residents who were older than 70 years of age. Dependent variables were use of any dental services (41% had used at least one service within 12 months) and use of those for preventive care (25%). Use of dental services by older adults was negatively influenced by older age and lower level of education, and positively affected by greater perceived need for dental treatment. Medi-caid coverage was associated with lower use of dental services. Because Medicaid reimburses for dental services in Massachusetts, ability to pay did not seem to be a critical determinant in this population.     

Effects of a Selective Al-Adenosine Receptor Agonist on Heart Rate and Heart Rate Variability During Permanent Atrial Fibrillation

Background: Mean heart rate and irregularity of the rate, i.e., heart rate variability (HRV), are two aspects of heart rate during atrial fibrillation (AF). An important goal of AF therapy is to control mean heart rate during exercise; the determinants of HRV during AF remain poorly known although its prognostic value has been established. Objectives: To investigate the effects of a stable, long-acting, selective A1-adenosine receptor agonist, SDZ WAG994, on heart rate during exercise and on HRV. Methods: In a multicenter, double-blind, randomized, placebo-controlled, parallel group study, patients with permanent AF performed a symptom-limited exercise test and underwent 24-hour ECG monitoring on day 1 during treatment with placebo, and on day 2 during treatment with either placebo or 2 mg SDZWAG994 orally. Changes in mean heart rate during exercise and changes in HRV indices between day 1 and day 2 were compared between the two groups. Results: Thirty-two patients (64 ± 8 years; 81% male; 25% in NYHA Class II; 38% with no structural heart disease) were included in the study. During active treatments, heart rate remained unchanged at rest and increased significantly during exercise. A significant daytime increase in short-term HRV indices (DpNN50 = 4.5% P = 0.01; DrMSSD = 6% P = 0.03; DSDNN Index = 6% P = 0.02) occurred during active treatment. Conclusions: Selective A1-adenosine receptor agonism with SDZ/WAG994 limits the increase in mean heart rate during exercise in patients with AF. In addition, this agonist selectively increases short-term HRV indices, suggesting that pNN50, rMSSD, and SDNN reflect vagal influences during AF.     

Punishment as a factor in preventing alcohol-related accidents

As a humanitarian and economic ‘bad’, infliction of punishment requires justification in terms of compensating achievements, as well as moral appropriateness. In the context of road accidents, there is evidence that increasing the certainty and swiftness of threatened punishment may deter risky behavior, although increasing the severity of the threat seems ineffective. These effects may be generalizable to other kinds of accidents, but empirical evidence is lacking. A further possibility for the justifiable use of punishment is in its application to negligent service of alcohol.     

Treatment of Lentigo Maligna with Imiquimod before Staged Excision

BACKGROUND Imiquimod 5% cream has demonstrated effectiveness in the treatment of lentigo maligna (LM) in several small studies. None of the studies to date have included posttreatment surgical removal to confirm negative histologic margins.
OBJECTIVE The aim of this retrospective analysis was to assess the efficacy of topical imiquimod in LM by circumferentially examining vertically oriented sections from a geometrically designed "picture frame" margin as well as bread-loafed sections of the central portion after staged excisions of imiquimod-treated lesions of LM.
METHODS Forty patients with biopsy-confirmed LM were treated five times a week for 3 months with 5% imiquimod cream before staged excision. Tazarotene 0.1% gel was added when no clinical signs of erythema developed with imiquimod alone after 1 month (10 patients). After the course of topical therapy, patients were assessed for clinical and complete histologic clearance after staged excision.
RESULTS A total of 33 of 40 patients had a complete clinical response as determined by the absence of remaining clinical lesion on physical examination. Upon histologic review, 30 of 40 patients had no evidence of LM whereas 10 of 40 harbored residual disease. One patient was found to have histologic evidence of invasion after completing the topical protocol. After a mean follow-up of 18 months (range, 12–34 months) and after complete surgical excision of the treatment site, none of the imiquimod-treated patients had evidence of recurrence.
CONCLUSIONS Imiquimod appears to be an effective adjunctive treatment for LM but does not qualify as a replacement therapy for surgery.     

Failure to Predict Development of Atrioventricular Block with Electrophysiological Testing Supplemented by Ajmaline

Electrophysiological tests supplemented by pharmacological stress of atrioventricular conduction with ajamaline failed to predict the development of atrioventricular block in a patient with bifascicular block and no organic heart disease.     

Vaccination with‘concealed’antigens: myth or reality?

Cattle infested with the tick Boophilus microplus produce antibodies to intrinsic membrane glycoproteins of the tick, as well as to Bm86, a well characterized antigen from the tick gut. Several factors explain how cattle could produce antibody to such antigens, which one would expect to be 'concealed' from the host's immune system, during natural infestation. It has been shown that the carbohydrate determinants on many tick glycoproteins are cross-reactive immunologically and that the reaction of bovine antibodies with intrinsic membrane glycoprotein is at least partially blocked by low molecular weight carbohydrate. Further, antisera from cattle exposed to ticks react with a glycosylated, native Bm86 but not with a non-glycosylated, recombinant Bm86. Thus the reaction of concealed antigens with antibodies produced as a result of tick infestation appears to be due to a relatively non-specific reaction with carbohydrate determinants on tick glycoprotein. Evidence is also presented that antibodies directed against carbohydrate determinants of Bm86 are not protective. Care must therefore be exercised in interpreting the results of antibody reaction with glycoproteins in such complex organisms.