Invited Article: Conflicts of interest for authors of American Academy of Neurology clinical practice guidelines.

BACKGROUND: Clinical practice guidelines (CPGs) shape clinical care worldwide but are prone to potential error and bias due to conflicts of interest (COI). OBJECTIVE: To explore the extent and scope of American Academy of Neurology (AAN) guideline author reported COI and implications for management; and to review process of AAN guideline COI management to highlight challenges, establish comparative benchmarks, and identify areas to be improved. METHODS: Authors of AAN clinical practice guidelines with an active membership panel completed a COI reporting form. Authors were asked to report current interests including the 1 year prior to the date of completing the form. Interests include personal income relationships (consulting, speaker's bureaus, advisory boards), equity (stocks/stock options), patent/royalties, research, clinical practice, fiduciary interest in a company, and expert testimony. Comparisons were made between the two committees that oversee CPG development at the AAN: the Quality Standards Subcommittee (QSS) and the Therapeutics and Technology Assessment (TTA) Subcommittee. RESULTS: There were 50 CPG with an average of 8.5 authors per CPG. There were a total of 425 available authors, 351 of whom completed a COI reporting form (83% response rate). Forty-six of the 50 guidelines had at least one author with a COI. The most commonly reported COIs were research-related (45% of authors), clinical practice-related (42%), and personal income relationships (33%). Authors of QSS guidelines were more likely to have personal income COIs with pharmaceutical and medical device companies (39% vs 24%, p < 0.01), whereas authors of TTA guidelines were more likely to have clinical practice-related COIs (50% vs 38%, p < 0.05). A minority of authors had individual COIs exceeding >$25,000 or had multiple interests (>10) that overlapped with content of the guidelines. CONCLUSION: Conflicts of interest are common for authors of American Academy of Neurology clinical practice guidelines across many domains of personal and professional interests. More research is needed to improve the methods to identify and quantify the types of conflicts and their potential biasing effects on selecting guideline topics, grading research evidence, and formulating practice recommendations.

Thrombin inhibitors based on [5,5] trans-fused indane lactams.

A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.

Synthetic [5,5] trans-fused indane lactones as inhibitors of thrombin.

Synthesis of trans-fused lactones containing the indane nucleus has resulted in a series of potent acylating inhibitors of thrombin. As an example compound 11e has an apparent second order rate constant of 11 x 10(6) M(-1)sec(-1) for the inhibition of thrombin. The anticoagulant activity of these compounds is discussed.

Diagnosis and management of hypothyroidism in pregnancy.

Hypothyroidism is not a common occurrence in pregnancy, but it is important that nurse practitioners recognize it early. Complications of hypothyroidism in pregnancy are pregnancy-induced hypertension, preeclampsia, abruptio placentae, low birth weight and stillbirth, and fetal distress in labor. Careful monitoring of pregnant women for hypothyroidism and correction with levothyroxine therapy can prevent these complications. During pregnancy, the thyroxine needs of women with hypothyroidism are increased, and their dosage of levothyroxine should be individualized. Nurse practitioners can provide holistic care to the woman with hypothyroidism to ensure optimal maternal and fetal health.

Novel natural product 5,5-trans-lactone inhibitors of human alpha-thrombin: mechanism of action and structural studies.

High-throughput screening of methanolic extracts from the leaves of the plant Lantana camara identified potent inhibitors of human alpha-thrombin, which were shown to be 5,5-trans-fused cyclic lactone euphane triterpenes [O'Neill et al. (1998) J. Nat. Prod. (submitted for publication)]. Proflavin displacement studies showed the inhibitors to bind at the active site of alpha-thrombin and alpha-chymotrypsin. Kinetic analysis of alpha-thrombin showed tight-binding reversible competitive inhibition by both compounds, named GR133487 and GR133686, with respective kon values at pH 8.4 of 1.7 x 10(6) s-1 M-1 and 4.6 x 10(6) s-1 M-1. Electrospray ionization mass spectrometry of thrombin/inhibitor complexes showed the tight-bound species to be covalently attached, suggesting acyl-enzyme formation by reaction of the active-site Ser195 with the trans-lactone carbonyl. X-ray crystal structures of alpha-thrombin/GR133686 (3.0 A resolution) and alpha-thrombin/GR133487 (2.2 A resolution) complexes showed continuous electron density between Ser195 and the ring-opened lactone carbonyl, demonstrating acyl-enzyme formation. Turnover of inhibitor by alpha-thrombin was negligible and mass spectrometry of isolated complexes showed that reversal of inhibition occurs by reformation of the trans-lactone from the acyl-enzyme. The catalytic triad appears undisrupted and the inhibitor carbonyl occupies the oxyanion hole, suggesting the observed lack of turnover is due to exclusion of water for deacylation. The acyl-enzyme inhibitor hydroxyl is properly positioned for nucleophilic attack on the ester carbonyl and therefore relactonization; furthermore, the higher resolution structure of alpha-thrombin/GR133487 shows this hydroxyl to be effectively superimposable with the recently proposed deacylating water for peptide substrate hydrolysis [Wilmouth, R. C., et al. (1997) Nat. Struct.Biol. 4, 456-462], suggesting the alpha-thrombin/GR133487 complex may be a good model for this reaction.

The rapid purification and partial characterization of human serum angiotensinogen.

Human angiotensinogen has been purified 390-fold from serum by a rapid high-yielding procedure that involved chromatography on Blue Sepharose, phenyl-Sepharose, hydroxyapatite and immobilized 5-hydroxytryptamine (5-HT). Angiotensinogen was specifically bound to immobilized 5-HT, which effected a partial resolution into multiple forms, which were also evident when analysed by SDS/polyacrylamide-gel electrophoresis (Mr 59,400, 60,600, 62,600 and 63,800). This heterogeneity was confirmed by resolution into six main bands on isoelectric focusing, ranging from pI 4.40 to 4.82. N-terminal analysis, digestion with human renal renin and deglycosylation studies implied that the preparation comprised several forms of angiotensinogen, varying in their degree of glycosylation. The presence of sialic acid was shown to be a major factor in determining the heterogeneity.