Biomedical subjects
Publications and source records attributed to Jennifer A Williams.
We report a novel series of noncovalent inhibitors of cathepsin S. The synthesis of the peptidomimetic scaffold is described and structure-activity relationships of P3, P1, and P1' subunits are discussed. Lead optimization to a non-peptidic scaffold has resulted in a new class of potent, highly selective, and orally bioavailable cathepsin S inhibitors.
The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.
OBJECTIVE: To describe the occurrence of intrauterine adhesions after manual vacuum aspiration for early pregnancy failure. DESIGN: Case series. SETTING: Tertiary care center. PATIENT(S): Three women with intrauterine adhesions after manual vacuum aspiration for the treatment of early pregnancy failure. INTERVENTION(S): Chart review. MAIN OUTCOME MEASURE(S): Hysteroscopic diagnosis of intrauterine adhesions after manual vacuum aspiration. RESULT(S): Three cases of symptomatic intrauterine adhesions after manual vacuum aspiration. CONCLUSION(S): Intrauterine adhesion formation may follow manual vacuum aspiration for early pregnancy loss.
A series of N(alpha)-2-benzoxazolyl-alpha-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported.
Nurses'perceptions of effective use of their time are critical to the successful implementation of information system changes. We examined the effects of implementing computerized practitioner order entry and nursing documentation in our emergency department with an anonymous survey of nurses and repeated time-motion studies. Emergency care nurses were positive about effects of CPOE, reporting needing less time to complete medication, laboratory, and radiology orders and less time spent clarifying orders. Their perceptions of time spent were congruent with observations from time-motion studies where combined computer-and-paper time and direct-patient-care time did not change significantly. Nurses also reported supplementing template options with free text, and those who were more comfortable using computers reported supplementing template options more often than their counterparts, suggesting that assessments of users' expertise in computer use may influence their ability to maximize their use of the functionality of emergency department information systems.
A series of Nalpha-acyl-alpha-amino acid-(arylaminoethyl)amides were found to be potent and noncovalent cathepsin S inhibitors. Compound 20 possessed high cathepsin S affinity (Ki=3.3 nM) and showed excellent selectivity over cathepsin K, L, F, and V. Molecular modeling, design, synthesis, and in vitro activity are described.
High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solid-phase chemistry resulted in the identification of compounds with high-affinity for the 5-ht5A receptor. The structure-activity relationship within this series and further array synthesis led to the identification of the biphenylmethylamine derivative 11, a potent and selective 5-ht5A receptor antagonist.
A strategy was developed to determine the prime and non-prime substrate specificity of serine, threonine and cysteine proteases. ACC positional scanning technology was employed to determine the P4-P1 non-prime site substrate specificity. The data was used to synthesize biased donor-quencher positional scanning libraries to profile the P1'-P4' prime site substrate specificity. Directed sorting using the Irori Nanokan system allowed for the archiving of multiple P1'-P4' positional scanning libraries. From these libraries focused donor-quencher libraries incorporating P4-P1 data for each protease under study could be rapidly prepared. The profiling of thrombin and caspase-3 P4-P4' substrate specificity, comparison of the library specificity data to single substrates, and the analysis of physiological cleavage sites are described.
Regulated proteolysis by the two-component NS2B/NS3 protease of dengue virus is essential for virus replication and the maturation of infectious virions. The functional similarity between the NS2B/NS3 proteases from the four genetically and antigenically distinct serotypes was addressed by characterizing the differences in their substrate specificity using tetrapeptide and octapeptide libraries in a positional scanning format, each containing 130,321 substrates. The proteases from different serotypes were shown to be functionally homologous based on the similarity of their substrate cleavage preferences. A strong preference for basic amino acid residues (Arg/Lys) at the P1 positions was observed, whereas the preferences for the P2-4 sites were in the order of Arg > Thr > Gln/Asn/Lys for P2, Lys > Arg > Asn for P3, and Nle > Leu > Lys > Xaa for P4. The prime site substrate specificity was for small and polar amino acids in P1' and P3'. In contrast, the P2' and P4' substrate positions showed minimal activity. The influence of the P2 and P3 amino acids on ground state binding and the P4 position for transition state stabilization was identified through single substrate kinetics with optimal and suboptimal substrate sequences. The specificities observed for dengue NS2B/NS3 have features in common with the physiological cleavage sites in the dengue polyprotein; however, all sites reveal previously unrecognized suboptimal sequences.
OBJECTIVE: To determine the effect of different doses of Salacia oblonga extract, an herbal alpha-glucosidase inhibitor, on postprandial glycemic, insulinemic, and breath hydrogen responses in healthy adults. DESIGN: Double-masked, randomized crossover design. INTERVENTION: Subjects, after fasting for 12 hours, consumed four test meals consisting of 480 mL of study beverage (14 g fat, 82 g carbohydrate, and 20 g protein) with 0, 500, 700, or 1,000 mg of S oblonga extract on four separate occasions. Capillary finger-prick plasma glucose and venous serum insulin concentrations were measured at baseline and for 2 hours postprandially. Breath hydrogen excretion was measured at baseline and hourly for 8 hours postprandially. SUBJECTS/SETTING: Thirty-nine healthy, nondiabetic adults (body mass index=23.7+/-0.4, age=25.7+/-0.9 years. STATISTICAL ANALYSES PERFORMED: Repeated-measures analysis of variance was applied to the raw data or data that had been transformed (log, rank) when necessary due to nonnormality. The Tukey-Kramer post hoc test was used for pairwise comparisons. RESULTS: Compared with the control, the 1,000-mg S oblonga extract dose reduced the plasma glucose and serum insulin incremental areas under the curve (0 to 120 minutes postprandial) by 23% ( P =.32) and 29% ( P =.01), respectively. The other doses of S oblonga extract did not impact glycemia or insulinemia. Breath hydrogen excretion increased linearly as the dose of S oblonga extract was advanced. CONCLUSIONS: The presence of S oblonga extract tended to lower postprandial glycemia and significantly reduced the postprandial insulin response. The increase in breath hydrogen excretion suggests a mechanism similar to prescription alpha-glucosidase inhibitors. Future studies of S oblonga extract in patients with diabetes are needed.
Human prostasin was recently identified as a potential regulator of epithelial sodium channel (ENaC) function. Through the use of positional scanning combinatorial substrate libraries, prostasin was shown to have a preference for poly-basic substrates: in position P4 preference was for arginine or lysine; in P3 preference was for histidine, lysine or arginine; in P2 preference was for basic or large hydrophobic amino acids; and in P1 preference was for arginine and lysine. P1', P2', and P3' displayed broad selectivity with the exception of a lack of activity for isoleucine, and P4' had a preference for small, unbranched, amino acids such as alanine and serine. A prostasin-preferred poly-basic cleavage site was found in the extracellular domains of the ENaC alpha- and beta-subunits, and may present a mechanism for prostasin activation. The absence of activity seen with substrates containing isoleucine in position P1' explains the inability of prostasin to autoactivate and suggests that prostasin proteolytic activity is regulated by an upstream protease. Prostasin activity was highly influenced by mono- and divalent metal ions which were potent inhibitors and substrate specific modulators of enzymatic activity. In the presence of sub-inhibitory concentrations of zinc, the activity of prostasin increased several-fold and its substrate specificity was significantly altered in favor of a strong preference for histidine in positions P3 or P4 of the substrate.
OBJECTIVE: The study was undertaken to identify factors contributing to the poor student perception of the obstetrics and gynecology clerkship. STUDY DESIGN: Third-year medical students at the University of Michigan complete an annual questionnaire about the overall quality of their clinical experiences. In addition, at the end of each rotation, the students complete an evaluation form assessing various aspects of their learning experience. We reviewed data collected from 2000 to 2002. We calculated effect sizes using mean scores and SDs to compare individual aspects of the learning environment across the clerkships. RESULTS: Twenty-six percent of the third-year medical students at the University of Michigan rated the strength of their obstetrics and gynecology experience as very or exceptionally strong. Compared with the other 6 clerkships, the rotation had one of the lowest ratings for overall quality. Aspects of the clerkship experience we identified as potentially explaining this overall poor rating include the clarity of the clerkship goals and objectives, clarity of expectations for student performance, accessibility of faculty, experiences in learning history-taking skills, experiences in learning physical examination skills, and student perception that they were treated in a respectful/professional manner. CONCLUSION: Aspects of the clerkship experience identified by this study as potentially explaining the low ratings of the obstetrics and gynecology rotation should be studied in greater detail. Addressing these factors will be critical for improving the overall student perception of the obstetrics and gynecology clerkship.
A novel induced viscosity fiber (IVF) crispy bar was formulated with the viscous dietary fibers alginate and guar gum. To evaluate the glycemic response and gastrointestinal tolerance to IVF crispy bars, nondiabetic healthy adult subjects (n = 48) were studied in a randomized, double-masked, crossover design. The control crispy bars and IVF crispy bars were identical except for the 2 dietary fibers contained in the experimental (IVF) bars. After an overnight fast, subjects consumed test bars containing 50 g carbohydrate. Their capillary blood glucose response was determined for 180 min postprandially. When subjects consumed IVF, the incremental blood glucose excursions were reduced (P < 0.05) at 15, 30, 45, and 120 min. At 180 min, the subjects' blood glucose concentration was maintained above the basal blood glucose concentration for both bars. Compared with controls, the incremental peak blood glucose concentration was reduced (P < 0.001) 30% when subjects consumed IVF. When subjects consumed IVF, the positive incremental area under the curve for glucose was reduced (P < 0.01) by 33% compared with controls. In the 24-h postprandial period after each treatment, the frequency and intensity of gastrointestinal tolerance symptoms did not differ. In conclusion, compared with a control crispy bar, the IVF crispy bar attenuated the postprandial glycemic excursion without gastrointestinal intolerance in healthy adult subjects.
The objective of this experiment was to determine whether supplementation with fructooligosaccharides (FOS) and (or) Lactobacillus acidophilus (LAC) affected bowel function and fermentative end-product concentrations in feces of healthy humans. Subjects (n = 68) were enrolled in a randomized, double-blind, placebo-controlled, parallel study design. After a 4-wk baseline period, subjects consumed one of the following treatments twice daily for 4 wk: 1) 3 g sucrose + 80 mg cornstarch; 2) 3 g FOS + 80 mg cornstarch; 3) 3 g sucrose + 1 x 10(9) colony-forming units (cfu) LAC; or 4) 3 g FOS + 1 x 10(9) cfu LAC. Subjects completed 7-d bowel function forms and 3-d dietary records before collection of fresh stool samples at wk 4, 6 and 8. Statistical analyses were performed on differences from baseline using the General Linear Models procedure of SAS. Fructooligosaccharides decreased fecal ammonia (P = 0.07) and isovalerate (P = 0.12) concentrations at wk 6. At wk 8, FOS tended (P = 0.11) to increase fecal putrescine concentrations. Lactobacillus decreased fecal organic matter percentage at wk 6 (P < 0.05) and 8 (P = 0.07). At wk 6 and 8, LAC increased (P < 0.05) fecal 2-methylindole, total indole, and total indole and phenol concentrations. At wk 8, LAC decreased fecal agmatine (P = 0.08) and phenylethylamine (P < 0.05) concentrations. In conclusion, FOS and LAC modified several metabolites associated with gut health, with FOS tending to be beneficial (decreased fecal protein catabolites) and LAC being negative (increased fecal protein catabolites).
OBJECTIVE: This study evaluated the postprandial glycemic, insulinemic, and breath hydrogen responses to a liquid nutritional product containing Salacia oblonga extract, an herbal alpha-glucosidase inhibitor, and two insulinogenic amino acids. METHODS: In a randomized, double-masked, crossover design, 43 healthy subjects were fed the following meals on separate days after overnight fasting: control (C; 480 mL of a study beverage containing 82 g of carbohydrate, 20 g of protein, and 14 g of fat), control plus 3.5 g each of phenylalanine and leucine (AA), control plus 1000 mg of S. oblonga extract (S), and control plus S and AA (SAA). Postprandially, fingerstick capillary plasma glucose and venous serum insulin levels were measured for 180 min, and breath hydrogen excretion was measured for 480 min. RESULTS: The baseline-adjusted peak glucose response was not different across meals. However, changes in plasma glucose areas under the curve (0 to 120 min and 0 to 180 min, respectively) compared with C were -9% and -11% for AA (P>0.05 each), -27% and -24% for S (P=0.035 and 0.137), and -27% and -29% for SAA (P<0.05 each). Changes in insulin areas under the curve were +5% and +5% for AA (P>0.05 each), -35% and -36% for S (P<0.001 each), and -6% and -7% for SAA (P>0.05 each). Breath hydrogen excretion was 60% greater (P<0.001) in the S-containing meals than in the C- and AA-containing meals and was associated with mild flatulence. CONCLUSIONS: Salacia oblonga extract is a promising nutraceutical ingredient that decreased glycemia in this study. Supplementation with amino acids had no significant additional effect on glycemia.