Avenues for professional development: faculty perspectives from an Indian medical school.

BACKGROUND: Medical school faculty in India are challenged to balance teaching and professional development. Melaka Manipal Medical College (MMMC), Manipal Campus, Manipal University, India offers the Bachelor of Medicine and Bachelor of Surgery (MBBS) program. The institution incorporates certain effective practices based on adult learning principles which are aimed at fostering the professional development of faculty members. OBJECTIVES: The present study was undertaken to explore the perceptions of faculty members regarding the scope for professional development at Melaka Manipal Medical College, Manipal Campus. METHODS: In September 2009, a questionnaire comprising items (23) focusing on five adult learning principles (active participation, relevant learning, constructive feedback, safe, non-threatening environment and previous experiences) was designed and faculty members (n=23) were asked to respond to it on a 5-point Likert scale. Additionally, a force field analysis was conducted by asking the faculty to identify three factors which facilitated them to consciously get involved in professional development activities. They were also asked to identify three unfavorable factors that hindered their professional development. RESULTS: Among the five characteristics, relevant learning was found to have a high mean score. Frequency analysis of responses revealed that at Melaka Manipal Medical College, there was ample scope for relevant self-learning that fosters professional development (91.3%). Force field response analysis revealed Melaka Manipal Medical College offered considerable flexibility and opportunities for continuing professional development along with faculty members' prevailing role as teachers. Nevertheless, the need for more research facilities and funds was highlighted. CONCLUSIONS: Adherence to adult learning principles may provide avenues for professional development in medical schools. An organized attempt to make the medical school faculty aware of the scope of these practices appears to be necessary to nurture professional development in settings where there are resource constraints.

Effect of imatinib on the biochemical parameters of the reproductive function in male Swiss albino mice.

BACKGROUND: Treatment of cancers with cytotoxic agents such as tyrosine kinase inhibiting drugs often, but not always, result in transient to permanent testicular dysfunction. Germ cells are important targets of many chemicals. Most of the drugs are genotoxins and induce irreversible effect on genetic makeup. These mutagenic changes are proportionally related to carcinogenesis. This is alarmingly dangerous in youth and children, since these effects last longer, affecting fertility or forming basis for carcinogenesis. There is paucity of reports on planned studies of imatinib on the testicular function. Hence, the study was planned to assess the effects of imatinib on biochemical markers of testicular functions in male Swiss albino mice. MATERIALS AND METHODS: Male Swiss albino mice were treated with imatinib and sacrificed at the end of first, second, fourth, fifth, seventh, and tenth week after the last exposure to imatinib. The testis were removed, weighed, and processed for biochemical analysis. RESULTS: The intratesticular testosterone level was significantly (P<0.001) reduced in treated groups and severe effect was observed on week 4 and 5. The intratesticular lactate dehydrogenase (LDH) level was significantly increased by imatinib in all treated groups up to week 5. CONCLUSION: Imatinib does affect testosterone and LDH level significantly, but this effect is reversible once the drug is withdrawn. This finding may help the clinicians to plan and address the fertility-related issues in young patients of reproductive age who are being treated with imatinib for gastrointestinal tumors and chronic myeloid leukemia.

Fostering research skills in undergraduate medical students through mentored students projects: example from an Indian medical school.

BACKGROUND: Healthcare decision-making is largely reliant on evidence-based medicine; building skills in scientific reasoning and thinking among medical students becomes an important part of medical education. Medical students in India have no formal path to becoming physicians, scientists or academicians. OBJECTIVES: This study examines students' perceptions regarding research skills improvement after participating in the Mentored Student Project programme at Melaka Manipal Medical College, Manipal Campus, India. Additionally, this paper describes the initiatives taken for the continual improvement of the Mentored Student Project programme based on faculty and student perspectives. METHODS: At Melaka Manipal Medical College, Mentored Student Project was implemented in the curriculum during second year of Bachelor of Medicine and Bachelor of Surgery programme with the intention of developing research skills essential to the career development of medical students. The study design was cross-sectional. To inculcate the spirit of team work students were grouped (n=3 to 5) and each group was asked to select a research project. The students' research projects were guided by their mentors. A questionnaire (Likert's five point scale) on students' perceptions regarding improvement in research skills after undertaking projects and guidance received from the mentor was administered to medical students after they had completed their Mentored Student Project. The responses of students were summarised using percentages. The median grade with inter-quartile range was reported for each item in the questionnaire. The median grade for all the items related to perceptions regarding improvement in research skills was 4 which reflected that the majority of the students felt that Mentored Student Project had improved their research skills. The problems encountered by the students during Mentored Student Project were related to time management for the Mentored Student Project and mentors. RESULTS: This study shows that students acknowledged that their research skills were improved after participating in the Mentored Student Project programme. CONCLUSIONS: The Mentored Student Project programme was successful in fostering positive attitudes among medical students towards scientific research. The present study also provides scope for further improvement of the Mentored Student Project programme based on students' and faculty perspectives.

Learning approaches of undergraduate medical students to physiology in a non-PBL- and partially PBL-oriented curriculum.

Melaka Manipal Medical College (Manipal Campus; Manipal, Karnataka, India) conducts the Bachelor of Medicine and Bachelor of Surgery program, for which the admission intakes are during the months of March and September. The present study was undertaken to study the differences in learning approaches to physiology of undergraduate medical students in a partially problem-based learning (PBL)- and non-PBL-oriented curriculum. PBL was introduced as a curricular reform for the September 2006 batch of students (partially PBL group), whereas it was not incorporated for the March 2006 batch of students (non-PBL group). Learning approaches to physiology of both groups of students were compared using the short inventory of approaches to learning. Mean scores for deep and strategic approaches were found to be significantly higher for the partially PBL group compared with the non-PBL group. The results of the present study support the earlier observation that PBL promotes a deep approach to learning.

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha.

The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.

Sequencing and model structure of a Naja naja atra protein fragment.

We report the amino acid sequence of a basic protein isolated from the snake venom of Naja naja atra. An automated Edman sequencer was used to determine the 65-residue sequence, aided by electrospray ionization/mass spectrometry. Online reduction and pyridylethylation of the peptide was performed to identify the cysteine residues. Trypsin, chymotrypsin and aspartic digestions were carried out to derive peptide fragments for further sequencing. Fragmented peptides were overlapped to obtain the complete sequence. Molecular mass measurements of the whole protein and its fragments were used as a countercheck for sequence assignment. Further confirmation of the sequence was indicated by sequence homology to other snake venom neurotoxins. A molecular model of the tertiary structure was constructed based on sequence homology, and was refined by global minimization and extensive quality control algorithms. Electrostatic and hydrophobic surface calculations and molecular dynamics simulations were carried out to determine the functional properties of the molecule.

The bone marrow in Hodgkin's disease--a two year study.

A total of forty bone marrow trephine biopsies and aspirates were studied from thirty five patients suffering from Hodgkin's disease during the two year period 1994 and 1995. Of these twenty five were at the time of diagnosis of the disease and fifteen after treatment. The biopsies were studied for incidence of involvement as well as associated findings in both the positive and negative biopsies. A comparison of the trephine biopsy with marrow aspirate with respect to yield of positivity was made. Five patients (20%) at the time of diagnosis and two (13.33%) after treatment showed involvement of the marrow. None of the seven corresponding aspirates were positive for involvement showing that biopsies were superior to aspirates in detecting marrow infiltration in Hodgkin's disease. Suppression of the marrow, fibrosis and lymphocytic aggregates were the other findings in positive biopsies. Eosinophilia and myelosuppression were notable changes in the negative biopsies. One biopsy also showed granulomas. The probable significance of these findings are also discussed.

Toward designing drug-like libraries: a novel computational approach for prediction of drug feasibility of compounds.

Prediction of the degree of drug-like character in small molecules is of great industrial interest. The major barrier, however, is the lack of a definition for drug-like character. We used the concept of the multilevel chemical compatibility (MLCC) between a compound and a drug library as a measure of the drug-like character of a compound. The rationale is that the local chemical environment of each atom or group of atoms in a compound largely contributes to the stability, toxicity, and metabolism in vivo. A systematic comparison of the local environments within a compound and those within the existing drugs provides a basis for determining whether and how much a compound is drug-like. We applied the MLCC calculations to four test sets: top selling drugs, compounds under biological testing prior to the preclinical test, anticancer drugs, and compounds known to have poor drug-like character. The following conclusions were obtained: (1) A convergent number of unique local structure types were found in the analysis of the library of the existing drugs. It suggests that the current drug library contains about 80% of all the viable types; therefore, discovery of a drug with new local structures is only an event of relatively small probability. (2) The method is highly selective in discerning drug-like compounds: most of the top drugs are predicted to be drug-like, about one-quarter of the biological testing compounds are drug-like, and about one-fifth of the anticancer drugs are drug-like. (3) The method also correctly predicted that none of the known problematic compounds are drug-like. (4) The method is fast enough for computational screening of virtual combinatorial chemistry libraries and databases of available compounds.

Analysis of high-affinity binding determinants in the receptor binding epitope of basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) is implicated in the pathogenesis of several vascular and connective diseases. A key step in the discovery of bFGF receptor antagonists to mitigate these actions is to define the functional epitope required for receptor binding of the growth factor. In previous studies, we identified Glu96 as an essential residue in this epitope using site-directed mutagenesis. Here we examined the role of solvent accessible neighboring residues of Glu96 of bFGF on receptor binding affinity. Wild-type bFGF and its muteins were cloned and expressed in Escherichia coli and evaluated for FGF receptor binding affinity. Replacement of Asn104 of bFGF by alanine reduced receptor binding affinity over 400-fold compared with wild-type bFGF. We next explored the effect of neighboring residues of Asn104 on receptor binding affinity-Muteins in which Arg97, Leu98, Glu99, Asn101, Asn102, Thr105 and Pro141 were individually replaced by alanine exhibited receptor binding similar to wild-type bFGF. By contrast, substitution of Tyr103 or Leu140 by alanine reduced receptor binding affinity about 400- and 150-fold, respectively, in accord with a previous report. We conclude that at least six solvent-accessible residues in bFGF are crucial for high-affinity receptor binding, as evidenced by at least a 10-fold diminution in the affinity of the corresponding alanine muteins. The polar residues Glu96 and Asn104 appear to form an area important for facilitating the initial contact between ligand and receptor, whereas Tyr24, Tyr103, Leu140 and Met142 form a hydrophobic patch that may stabilize the complex. The detailed structure of this functional epitope can be employed in the discovery and design of bFGF antagonists using computational methods.

Conformational studies on model peptides with 1-aminocyclobutane 1-carboxylic acid residues.

Conformationally constrained peptidomimetics are being increasingly used in the development of 3-D pharmacophores of peptide-based drug candidates and to alter their metabolic stability towards achievements of oral bioavailability. Here we present conformational energy calculations on model compounds containing 1-aminocyclobutane carboxylic acid (ACBC) and its derivatives using molecular mechanics methods. The low-energy models adopt conformations characteristic of a variety of regular structures such as the alpha-helix, 3(10)-helix, gamma-turn and polyproline-II-type three- and fourfold helices. The energetically most favored models adopt the gamma-turn (2.2(7) helix) conformation or alpha-/3(10)-helical conformation, both of either handedness, depending on the substituents on the cyclobutane. These results are qualitatively consistent with the crystal structures of peptide analogs containing ACBC and have implications for the design of peptidomimetics.

Conformational studies on model peptides with 1-aminocyclopropane 1-carboxylic acid residues.

The design of metabolically stable, conformationally constrained peptidomimetics is an increasingly used approach in developing orally active drug candidates in pharmaceutical research. In this paper we present conformational energy calculations on model compounds containing 1-aminocyclopropane carboxylic acid (ACC) and its derivatives using molecular mechanics methods. The low energy models adopt conformations characteristic of a variety of regular structures such as the alpha-helix, gamma-turn and three- and fourfold helices. The energetically most favored models adopt either the left- or right-handed 2.2(7) helical conformation or the gamma-turn. These results are qualitatively consistent with the crystal structures of peptide analogs containing ACC and have potential implications for the design of peptidomimetics where the conformational features characteristic of a specific type of gamma-turn are desired.

Pilomatricoma: report of two cases in children.

Two children with pilomatricoma are reported. The characteristics of this benign tumor and general principles of treatment (surgical excision) are described.

Conformational studies on beta-amino acid-containing peptides. I.

Modified amino acids (such as beta-amino acids) are becoming increasingly popular research tools in the development of orally active and metabolically stable peptidomimetics. We present conformational energy calculations using molecular mechanics (MM2) on two model compounds containing beta-amino acids. The low-energy models are characterized by a lack of intramolecular hydrogen-bonding interactions, qualitatively consistent with the results of the IR studies. The structures obtained from the limited amount of x-ray crystal data on compounds with beta-amino acid incorporated lie within 3 kcal/mol of the global minimum obtained from the present calculations. Preliminary stereochemical guidelines for the incorporation of beta-amino acid residues have been proposed.

Identification of an extracytoplasmic region of H+,K(+)-ATPase labeled by a K(+)-competitive photoaffinity inhibitor.

The photoaffinity reagent 8-[(4-azidophenyl)-methoxy]-1-tritiomethyl-2, 3-dimethylimidazo-[1,2-alpha]pyridinium iodide ([3H]mDAZIP) has been synthesized and used to photoinactivate and label purified hog gastric H+,K(+)-ATPase. The specific (K(+)-sensitive) components of both photoinactivation and labeling showed dependences on inhibitor concentration consistent with covalent modification at an extracytoplasmic site of reversible K(+)-competitive binding in the dark. The maximum amount of specific labeling (1.2 nmol/mg) was similar to the number of phosphorylation sites measured (1.0 +/- 0.14 nmol/mg). Specific labeling was distributed 76% on the alpha chain, 18% on the beta chain, and 6% on undefined peptides. Various digestions with trypsin, protease V8, and thermolysin were employed to fragment the labeled enzyme. Gasphase sequencing of the radioactive peptides identified the major site of specific labeling to be within a region where only two stretches of amino acids (Leu105 to Ile126 and Leu139 to Phe155, designated H1 and H2, respectively) are predicted to span the membrane. This in turn suggested that the labeling site was located within or close to the proposed loop between them (Gln127 to Asn138). A computer-driven energy minimization protocol yielded a loop structure to which SCH 28080 (the parent structure of [3H]mDAZIP) could be docked. Conversely, modeling of the corresponding region of Na+,K(+)-ATPase (a homologous enzyme with much lower affinity for SCH 28080) yielded no apparent binding site. Similarities in the inhibition of H+,K(+)-ATPase by SCH 28080 and of Na+,K(+)-ATPase by ouabain lead to the hypothesis that, in each case, inhibitor binding to E2-P is associated with an increase in the hydrophobicity of the environment of the loop between H1 and H2.

Peripheral ameloblastoma.

The clinical presentation and histological features of peripheral ameloblastoma, occurring on the floor of the mouth in a 65-year-old male, are described. The lesion was surgically excised. All the classical features of peripheral ameloblastoma were seen in this patient.