Medical student clerkship performance and career selection after a junior medical student surgical mentorship program.

BACKGROUND: The impact of early medical school mentorship in students' clerkships performance and career selection is unknown. METHODS: We administered Introduction to Surgery, a resident-directed, semester-long, preclinical elective to junior medical students who answered a Likert-type survey after residency application. Elective participants (EPs) were compared with nonparticipant applicants (EAs), medical school class (MS), and national match outcomes (USA). RESULTS: All 18 EPs (7 M1's, 11 M2's) completed the elective and survey. EP reported more confidence and improved surgical skills, especially attributed to resident mentorship (F(13,237) = 2.3, P = 8*10(-3)). EP "honored" the clerkship more than MS (P = .05); 55.6% of EP, 37.5% of EA, and 27.7% of MS chose surgical fields, yielding a relative risk of 2.0 for EP vs MS (95% confidence interval: 1.3 to 3.2, P = 4*10(-3)). EP "strongly agree" with future mentorship programs (4.6/5), and 1 EP reported the course to be the "main reason" for applying to general surgery. CONCLUSIONS: Introduction to Surgery provides a model for a multifaceted junior medical student mentorship program, which has the potential to retain interested students for surgical career selection.

Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.

Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.

PNU-107484A with alpha isoform-dependent functional changes in alpha(x)beta2gamma2 subtypes of rat recombinant GABA(A) receptors.

1. We discovered a novel gamma-aminobutyric acidA (GABA(A)) receptor ligand displaying seemingly opposite functionalities, depending on the alpha isoform of the alpha(x)beta2gamma2 subtypes. PNU-107484A enhanced GABA-induced Cl- currents in the alpha1beta2gamma2 subtype, but inhibited the currents in the alpha3beta2gamma2 and alpha6beta2gamma2 subtypes, and its half-maximal concentrations in the subtypes were 3.1 +/- 0.5, 4.2 +/- 1, and 3.5 +/- 0.2 microM, respectively, without showing much dependency on alpha isoforms. 2. In the alpha1beta2 subtype, the drug at concentrations up to 40 microM showed no effect on GABA-induced Cl- currents, suggesting the requirement of the gamma subunit for its action. 3. PNU-107484A behaved like a positive allosteric modulator of the alpha1beta2gamma2 subtype with its binding site distinct from those for benzodiazepines, barbiturates and neurosteroids. With the alpha3beta2gamma2 subtype, the drug behaved like a non-competitive inhibitor of GABA, thus blocking Cl- currents by GABA alone or in the presence of pentobarbitone and neurosteroids. 4. It appears that PNU-107484A is a unique GABA(A) receptor ligand with alpha isoform-dependent functionalities, which may provide a basis for development of alpha isoform-selective ligands, and it could be useful as a probe to investigate the physiological roles of the various alpha isoform subtypes.

Thyrotropin-releasing hormone (TRH) degradation in NIH:N mouse cerebral cortex and spinal cord.

Thyrotropin-releasing hormone (TRH) metabolism in NIH:N mouse cerebral cortex and spinal cord was studied with high pressure liquid chromatography. Degradation of added TRH was significantly (P less than 0.001) slower in the spinal cord (2.19 +/- 0.46%/min) than in the cerebral cortex (7.54 +/- 0.31%/min). Bacitracin, a non-competitive inhibitor of TRH deamidase, inhibited TRH degradation by 61.3 +/- 3.7% in the spinal cord but only by 35.9 +/- 1.0% in the cerebral cortex (P less than 0.001). Catabolism of TRH in the mouse spinal cord proceeds at a slower rate and predominantly via the TRH deamidase pathway.

Characterization of antigenic variation among mink enteritis virus isolates.

Three antigenic forms of natural field isolates of mink enteritis virus were revealed with a panel of monoclonal antibodies generated against the closely studied feline panleukopenia virus and canine parvovirus-2 virus. Two types (types 2 and 3) were shown to be closely related by agar-gel precipitin tests and by restriction enzyme mapping. However, types 2 and 3 differed from the type 1 isolates in the same tests. In cross-protection studies, inactivated viral vaccines made from any one of the 3 variant types of mink enteritis virus protected mink against challenge exposure by the homologous, as well as the heterologous, antigenic types.

Rapid separation of tritiated thyrotropin-releasing hormone and its catabolic products from mouse and human central nervous system tissues by high-performance liquid chromatography with radioactive flow detection.

Reversed-phase high-performance liquid chromatography with radioactive flow detection was utilized to investigate the catabolism of thyrotropin-releasing hormone (TRH) in central nervous system (CNS) tissues. Two different column/gradient solvent systems were tested: (1) octadecylsilane (ODS) with an acetic acid-acetonitrile gradient and (2) poly(styrenedivinylbenzene) (PRP-1) with a trifluoroacetic acid-acetonitrile gradient. Both systems used 1-hexanesulfonic acid as the second ion-pairing reagent and yielded excellent separation of TRH and its catabolic products, TRH acid, cyclo(histidyl-proline), histidyl-proline, proline, and prolinamide, produced in CNS tissue homogenates. The PRP-1 column with a trifluoroacetic acid-acetonitrile solvent system produced a better and more reproducible separation of TRH catabolic products than the ODS column with the acetic acid-acetonitrile solvent system. This PRP-1 technique was utilized to demonstrate different rates and products of TRH catabolism in mouse and human spinal cord compared with cerebral cortex.

Bioactivation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) to reactive intermediates that bind covalently to macromolecules and produce genotoxicity.

U-89843 is a novel pyrrolo[2,3-d]pyrimidine antioxidant with prophylactic activity in animal models of lung inflammation. During preclinical safety evaluation, U-89843 was found to give a positive response in the in vitro unscheduled DNA synthesis (UDS) assay, an assay which measures DNA repair following chemically-induced DNA damage in metabolically competent rat hepatocytes. Incubation of [14C]U-89843 with liver microsomes resulted in covalent binding of radioactive material to macromolecules by a process that was NADPH-dependent. U-89843 has been shown to undergo C-6 methylhydroxylation to give U-97924, in rat both in vivo and in vitro, in a reaction catalyzed by cytochrome P450 2C11. Synthetical U-97924 is chemically reactive and undergoes dimerization in aqueous solution. The dimerization of U-97924 was significantly inhibited by addition of nucleophiles such as methanol, glutathione, and N-acetylcysteine. Characterization of the corresponding methanol, glutathione, and N-acetylcysteine adducts of U-97924 supported the hypothesis of a reaction pathway involving reactive iminium species formed via dehydration of U-97924. The metabolism-dependent irreversible covalent binding of radioactive material to liver microsomal protein and DNA also is dramatically reduced in the presence of reduced glutathione (GSH). A trifluoromethyl analog of U-89843 was prepared in an effort to block the corresponding metabolic hydroxylation pathway. This new compound (U-107634) was found to be negative in the in vitro UDS assay, and its metabolic susceptibility toward hydroxylation at the C-6 methyl group was eliminated. These observations suggest that the positive in vitro UDS results of U-89843 are mediated by the bioactivation of U-89843, leading to reactive electrophilic intermediates derived from the (hydroxymethyl)pyrrole metabolite U-97924.