Would Socrates Have Actually Used the "Socratic Method" for Clinical Teaching?

Medical students and residents are familiar with clinical teaching methods in which a faculty member poses a series of questions to them. This technique is often called the "Socratic method," but it is frequently perceived by learners as an attempt to demean them, a practice that is colloquially known as "pimping." The distinction between Socratic teaching and pimping lies in the perception of "psychological safety." Psychological safety allows learners to answer questions or ask for help without threats to their dignity or worthiness. In a psychologically safe clinical teaching context, learners recognize that questions posed by attending physicians probe their current understanding and guide them to expand their knowledge. In pimping, questions are posed to embarrass the learner and to reinforce the teacher's position of power over them. Absent a threat of disparagement or condemnation, learners are able to focus on building schema for knowledge, skills, and attitudes, rather than worrying about shielding their self-worth. This article presents the proper Socratic method, as intended by Socrates, and contrasts it with pimping. This perspective defines psychological safety as the pivotal factor distinguishing Socratic teaching from pimping, and establishes the foundation for empirical studies of these common practices in medical education.

The accuracy of computed tomography to predict completeness of pulmonary fissures. A prospective study.

RATIONALE: Endobronchial valves are a potential alternative to lung volume reduction surgery for advanced emphysema. The greatest improvements in pulmonary function are seen in patients with complete pulmonary fissures, as determined by computed tomography (CT). However, the accuracy of CT to predict completeness of pulmonary fissures has not been compared with the reference standard of direct observation during thoracic surgery. OBJECTIVES: To determine the accuracy of CT scans to predict completeness of pulmonary fissures. METHODS: We conducted a double-blind, prospective trial in which completeness of pulmonary fissures was evaluated by direct observation during thoracic surgery. Preoperative CT scans were independently reviewed by two dedicated thoracic radiologists and completeness of the fissures was recorded and compared with intraoperative findings. MEASUREMENTS AND MAIN RESULTS: The fissures of 46 patients were evaluated. The positive predictive value of CT scan to detect a complete fissure was 100% for the right major fissure and 75% for the left fissure, but only 33% for the right minor fissure. CT scans had a negative predictive value of 29% in evaluation of the right major fissure. CONCLUSIONS: CT scans overestimate completeness of the right minor fissure and underestimate completeness of the right major fissure. These findings may have implications for the use of CT scans to select patients for endobronchial valve insertion.

Oleoyl serine, an endogenous N-acyl amide, modulates bone remodeling and mass.

Bone mass is determined by a continuous remodeling process, whereby the mineralized matrix is being removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. Here we report the presence of endogenous amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) in mouse bone. Of these compounds, N-oleoyl-l-serine (OS) had the highest activity in an osteoblast proliferation assay. In these cells, OS triggers a Gi-protein-coupled receptor and Erk1/2. It also mitigates osteoclast number by promoting osteoclast apoptosis through the inhibition of Erk1/2 phosphorylation and receptor activator of nuclear-κB ligand (RANKL) expression in bone marrow stromal cells and osteoblasts. In intact mice, OS moderately increases bone volume density mainly by inhibiting bone resorption. However, in a mouse ovariectomy (OVX) model for osteoporosis, OS effectively rescues bone loss by increasing bone formation and markedly restraining bone resorption. The differential effect of exogenous OS in the OVX vs. intact animals is apparently a result of an OVX-induced decrease in skeletal OS levels. These data show that OS is a previously unexplored lipid regulator of bone remodeling. It represents a lead to antiosteoporotic drug discovery, advantageous to currently available therapies, which are essentially either proformative or antiresorptive.

Identification of endogenous acyl amino acids based on a targeted lipidomics approach.

Using a partially purified bovine brain extract, our lab identified three novel endogenous acyl amino acids in mammalian tissues. The presence of numerous amino acids in the body and their ability to form amides with several saturated and unsaturated fatty acids indicated the potential existence of a large number of heretofore unidentified acyl amino acids. Reports of several additional acyl amino acids that activate G-protein coupled receptors (e.g., N-arachidonoyl glycine, N-arachidonoyl serine) and transient receptor potential channels (e.g., N-arachidonoyl dopamine, N-acyl taurines) suggested that some or many novel acyl amino acids could serve as signaling molecules. Here, we used a targeted lipidomics approach including specific enrichment steps, nano-LC/MS/MS, high-throughput screening of the datasets with a potent search algorithm based on fragment ion analysis, and quantification using the multiple reaction monitoring mode in Analyst software to measure the biological levels of acyl amino acids in rat brain. We successfully identified 50 novel endogenous acyl amino acids present at 0.2 to 69 pmol g(-1) wet rat brain.

The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways.

BACKGROUND: N-arachidonoyl glycine (NAGly) is an endogenous signaling lipid with a wide variety of biological activity whose biosynthesis is poorly understood. Two primary biosynthetic pathways have been proposed. One suggests that NAGly is formed via an enzymatically regulated conjugation of arachidonic acid (AA) and glycine. The other suggests that NAGly is an oxidative metabolite of the endogenous cannabinoid, anandamide (AEA), through an alcohol dehydrogenase. Here using both in vitro and in vivo assays measuring metabolites with LC/MS/MS we test the hypothesis that both pathways are present in mammalian cells. RESULTS: The metabolic products of deuterium-labeled AEA, D4AEA (deuterium on ethanolamine), indicated that NAGly is formed by the oxidation of the ethanolamine creating a D2NAGly product in both RAW 264.7 and C6 glioma cells. Significantly, D4AEA produced a D0NAGly product only in C6 glioma cells suggesting that the hydrolysis of AEA yielded AA that was used preferentially in a conjugation reaction. Addition of the fatty acid amide (FAAH) inhibitor URB 597 blocked the production of D0NAGly in these cells. Incubation with D8AA in C6 glioma cells likewise produced D8NAGly; however, with significantly less efficacy leading to the hypothesis that FAAH-initiated AEA-released AA conjugation with glycine predominates in these cells. Furthermore, the levels of AEA in the brain were significantly increased, whereas those of NAGly were significantly decreased after systemic injection of URB 597 in rats and in FAAH KO mice further supporting a role for FAAH in endogenous NAGly biosynthesis. Incubations of NAGly and recombinant FAAH demonstrated that NAGly is a significantly less efficacious substrate for FAAH with only ~50% hydrolysis at 30 minutes compared to 100% hydrolysis of AEA. Co-incubations of AEA and glycine with recombinant FAAH did not, however, produce NAGly. CONCLUSION: These data support the hypothesis that the signaling lipid NAGly is a metabolic product of AEA by both oxidative metabolism of the AEA ethanolamine moiety and through the conjugation of glycine to AA that is released during AEA hydrolysis by FAAH.

Targeted lipidomics approach for endogenous N-acyl amino acids in rat brain tissue.

Great effort has been devoted to characterize signaling lipids in central nervous system. This has led to a search for novel strategies to characterize hitherto unknown lipid compositions. Here we developed two methods, one for identification and one for quantification, for N-acyl amino acids, a novel lipid family. The identification method contains a series of purification steps followed by nano-LC/MS/MS and high-throughput screening of the datasets with a potent search algorithm based on fragment ion analysis. MS/MS spectra with good quality can be obtained with 150 fmol of targeted lipids on column with our nano-LC/MS/MS. More than one thousand mass spectra generated using the information dependent acquisition mode of Analyst QS software can be analyzed in 1 min using our home built software. The quantification method utilized the multiple reaction monitoring mode in Analyst software to measure the endogenous levels of N-acyl amino acids in rat brain. Using these two methods we were able to identify and quantify 11 previously reported N-acyl amino acids with endogenous levels ranging from 0.26 to 333 pmol g(-1) wet rat brain.

Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: synthesis of N-acyl glycinals.

N-Arachidonoyl ethanolamide or anandamide is an endocannabinoid found in most tissues where it acts as an important signaling mediator in a number of physiological and pathophysiological processes. Consequently, intense effort has been focused on understanding all its biosynthetic and metabolic pathways. Herein we report human alcohol dehydrogenase-catalyzed sequential oxidation of anandamide to N-arachidonoyl glycine, a prototypical member of the class of long chain fatty acyl glycines, a new group of lipid mediators with a wide array of physiological effects. We also present a straightforward synthesis for a series of N-acyl glycinals including N-arachidonoyl glycinal, an intermediate in the alcohol dehydrogenase-catalyzed oxidation of anandamide.

Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92.

A series of small compounds acting at the orphan G protein-coupled receptor GPR92 were screened using a signaling pathway-specific reporter assay system. Lipid-derived molecules including farnesyl pyrophosphate (FPP), N-arachidonylglycine (NAG), and lysophosphatidic acid were found to activate GPR92. FPP and lysophosphatidic acid were able to activate both G(q/11)- and G(s)-mediated signaling pathways, whereas NAG activated only the G(q/11)-mediated signaling pathway. Computer-simulated modeling combined with site-directed mutagenesis of GPR92 indicated that Thr(97), Gly(98), Phe(101), and Arg(267) of GPR92 are responsible for the interaction of GPR92 with FPP and NAG. Reverse transcription-PCR analysis revealed that GPR92 mRNA is highly expressed in the dorsal root ganglia (DRG) but faint in other brain regions. Peripheral tissues including, spleen, stomach, small intestine, and kidney also expressed GPR92 mRNA. Immunohistochemical analysis revealed that GPR92 is largely co-localized with TRPV1, a nonspecific cation channel that responds to noxious heat, in mouse and human DRG. FPP and NAG increased intracellular Ca(2+) levels in cultured DRG neurons. These results suggest that FPP and NAG play a role in the sensory nervous system through activation of GPR92.

N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons.

N-arachidonoyl glycine is an endogenous arachidonoyl amide that activates the orphan G protein-coupled receptor (GPCR) GPR18 in a pertussis toxin (PTX)-sensitive manner and produces antinociceptive and antiinflammatory effects. It is produced by direct conjugation of arachidonic acid to glycine and by oxidative metabolism of the endocannabinoid anandamide. Based on the presence of enzymes that conjugate fatty acids with glycine and the high abundance of palmitic acid in the brain, we hypothesized the endogenous formation of the saturated N-acyl amide N-palmitoyl glycine (PalGly). PalGly was partially purified from rat lipid extracts and identified using nano-high-performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry. Here, we show that PalGly is produced after cellular stimulation and that it occurs in high levels in rat skin and spinal cord. PalGly was up-regulated in fatty acid amide hydrolase knockout mice, suggesting a pathway for enzymatic regulation. PalGly potently inhibited heat-evoked firing of nociceptive neurons in rat dorsal horn. In addition, PalGly induced transient calcium influx in native adult dorsal root ganglion (DRG) cells and a DRG-like cell line (F-11). The effect of PalGly on the latter cells was characterized by strict structural requirements, PTX sensitivity, and dependence on the presence of extracellular calcium. PalGly-induced calcium influx was blocked by the nonselective calcium channel blockers ruthenium red, 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole (SK&F96365), and La3+. Furthermore, PalGly contributed to the production of NO through calcium-sensitive nitric-oxide synthase enzymes present in F-11 cells and was inhibited by the nitric-oxide synthase inhibitor 7-nitroindazole.

Structural analysis of leukotriene C4 isomers using collisional activation and 157 nm photodissociation.

The fragmentation of 5-hydroxy-6-glutathionyl-7,9,11,14-eicosatetraenoic acid [leukotriene C4 or LTC4 (5, 6)] and its isomeric counterpart LTC4 (14, 15) were studied by low and high-energy collisional induced dissociation (CID) and 157 nm photofragmentation. For singly charged protonated LTC4 precursors, photodissociation significantly enhances the signal intensities of informative fragment ions that are very important to distinguish the two LTC4 isomers and generates a few additional fragment ions that are not usually observed in CID experiments. The ion trap enables MSn experiments on the fragment ions generated by photodissociation. Photofragmentation is found to be suitable for the structural identification and isomeric differentiation of cysteinyl leukotrienes and is more informative than low or high-energy CID. We describe for the first time the structural characterization of the LTC4 (14, 15) isomer by mass spectrometry using CID and 157 nm light activation methods.

Fatty acyl amides of endogenous tetrahydroisoquinolines are active at the recombinant human TRPV1 receptor.

The SAR of capsazepine revealed that tetrahydroisoquinoline (TIQ) moiety is a core pharmacophore of TRPV1 activity. This implied that conjugates of endogenous TIQs with fatty acids would be active at TRPV1 receptors. Six such compounds were synthesized and tested for calcium mobilization at recombinant TRPV1 receptors overexpressed in HEK293 cells. Three compounds showed partial TRPV1 agonism with EC(50) values in the low micromolar range and maximal efficacies between 25% and 55% of capsaicin.

Evidence-based and population-based medicine: national implementation under the UME-21 project.

BACKGROUND AND OBJECTIVES: The Undergraduate Medical Education for the 21st Century (UME-21) project developed and implemented innovations to medical school curricula at medical schools across the country. This report describes the development and implementation of innovative approaches to improving instruction in evidence-based medicine with a population-based perspective. METHODS: Each school participating in the UME-21 project designed, implemented, and evaluated its own unique curriculum initiatives. We examined these initiatives using data abstracted from written reports submitted to the project Executive Committee. Additional data were obtained by personal communication with project directors and evaluators at the various schools, student and preceptor comments, internal program evaluation at each school, and external evaluation by the UME-21 project leadership. The Association of American Medical Colleges Graduation Questionnaire was also used. RESULTS: Fourteen of 18 participating schools implemented a broad range of curricula to facilitate teaching and learning about evidence-based and population-based medicine. Common themes included the application of evidence to patient care, use of clinical practice guidelines and pathways, and the general incorporation of evidence-based techniques (literature searching, critical appraisal, etc) into the teaching of other content, such as clinical science and managed care. Teaching approaches included Web-based and other computer-based education, an emphasis on active and self-directed learning, use of small groups and workshops, and distribution of this content over multiple years. As an alternative to full-length evidence-based medicine courses, many schools incorporated an evidence-based approach into existing courses and clerkships. Data demonstrated an upward trend in student satisfaction with how topics were presented at UME-21 schools. CONCLUSIONS: These innovations successfully demonstrated that evidence-based and population-based medicine content can be introduced into medical school curricula. Introducing these constructs in ways that demonstrate their relevance to patient care facilitates student learning.

Teaching the basics of clinical pharmaceutical care: innovative pharmacy workshops at the University of Wisconsin and the University of Nebraska.

BACKGROUND: Safe and effective prescription writing, using drug formularies, and managing pharmaceutical care are skills medical students need to acquire. Spurred by the Undergraduate Medical Education for the 21st Century (UME-21) grants, the University of Wisconsin and the University of Nebraska independently developed educational workshops to address these competencies. METHODS: The University of Wisconsin's workshop is presented to medical students at the start of their third year. They receive information from pharmacists on medication errors, prescription writing, and drug formularies. A "learners guide" summary is discussed by a physician, which brings into focus the clinical application of the didactic session. A small-group session follows with hands-on experience in writing prescriptions and using formularies for three patient case scenarios. The workshop at the University of Nebraska consists of three sessions during the third-year internal medicine clerkship. In the first session, pharmacists discuss formularies, the Pharmacy and Therapeutics (PT) committee, and the preparation of a drug monograph. During the second session, students develop an evidence-based drug monograph on a product or herbal. In the final session, the class functions as a mock PT committee, and after listening to the drug monographs, determines whether the product should be added to the formulary. We evaluated students' satisfaction with the workshops using Likert scales and assessed students' ability to correctly fill out a prescription form. RESULTS: Both workshops were well received. The mean rating at University of Wisconsin was 1.7 on a scale of 1 (satisfied) to 7 (dissatisfied), and at University of Nebraska it was 3.8 with 5 (outstanding) to 1 (unacceptable). At the University of Wisconsin, on a year-end skills assessment involving 148 students, 100% of the students properly filled out a prescription. Ninety-four percent received an excellent grade, 6% a pass, and no marginal or failing grades were given out. CONCLUSIONS: The workshop on pharmaceutical prescribing was rated favorably by students. After participating in the workshop, students acquired skills in prescription writing.

From library to discharge: a managing care student project.

BACKGROUND AND OBJECTIVES: The Patient Care Project (PCP) was a central component of the Undergraduate Medical Education for the 21st Century (UME-21) grant project at the University of Nebraska. With the primary goal of improving students' critical thinking skills, the PCP was directed more toward an understanding of managing care than the business aspects of managed care and emphasized written communication skills, clinical hypothesis testing, and exploring ways to solve medical and ethical questions. METHODS: All 239 students graduating in 2000 and 2001 were required to analyze the medical care received by one of their hospitalized patients. Using a criterion-based evaluation tool, students' written critiques were assessed in five specific areas, all of which required critical thinking skills. Students also received an overall grade for the project. The UME-21 Graduation Survey was used to assess changes in attitudes and behavior. Students graduating in 1999, prior to the institution of the PCP graduation requirement, served as a control group. RESULTS: The most frequently discussed topic of the PCPs was cardiovascular disease. The mean overall rating by the faculty for the PCPs was 3.7 and 3.8 in academic years 2000 and 2001, respectively (maximum=5). In a qualitative analysis of the PCPs, students demonstrated insight into their patients' overall medical care, including the use of evidence-based medicine (EBM), quality improvement, and cost containment. There were no statistically significant differences, however, between the PCP and control groups on the UME-21 Graduation Survey. Nonetheless, more students who had completed the PCP reported that they had identified the total cost of a patient's stay, designed a quality improvement loop, and obtained clinical evidence from an EBM computer database. On this same survey, all students agreed with the use of clinical practice guidelines and cost containment. CONCLUSIONS: The PCP appeared to be relevant to the students' learning needs, and they provided cogent critiques of the medical care they had rendered as well as critical analyses of their patients' discharge summaries and the cost of care including ways to reduce cost. On the other hand, we were unable to demonstrate any substantial differences in the results of the UME-21 Graduation Survey given to both the PCP and control groups. In spite of this lack of effect on students' attitudes, the PCP was perceived by the faculty to be valuable and has been incorporated into the required third-year family medicine clerkship at the University of Nebraska.

Synthesis of 3-substituted quinolines via transition-metal-catalyzed reductive cyclization of o-nitro Baylis-Hillman acetates.

Reductive cyclization of o-nitro-substituted Baylis-Hillman acetates by carbon monoxide, catalyzed by [CpFe(CO)(2)](2), gives moderate to good yields of 3-substituted quinolines.