Learning Activities and Third-Year Medical Student Ratings of High Quality Teaching Across Different Clerkships.

OBJECTIVE: To identify and compare learning activities that students associate with high quality teaching across clerkships. METHODS: For six months, 110 third year medical students recorded data on learning activities and teaching quality using personal digital assistants (PDAs) during five different required clinical clerkships. Univariate and multivariate analyses were performed to assess the association between learning activities and student ratings of high teaching quality. RESULTS: 11,450 teaching interactions were recorded. Univariate analysis revealed that feedback was associated with perceptions of high quality teaching in all clerkships. Proposing a plan, formulating an assessment and giving an oral case presentation were associated with high quality teaching in 80% of the clerkships (p < 0.01). Multivariate analysis demonstrated that receiving high quality feedback was an independent predictor of student ratings of high quality teaching for all clerkships. CONCLUSION: Receiving high quality feedback is the learning activity most strongly associated with students' ratings of high quality teaching across four different clerkships.

Mapping of IFN-beta epitopes important for receptor binding and biologic activation: comparison of results achieved using antibody-based methods and alanine substitution mutagenesis.

The epitopes important for receptor binding and activation of human interferon-beta1a (IFN-beta1a) were mapped with monoclonal antibodies (mAb), grouped on the basis of their specificity and ability to neutralize biologic activity, and alanine scanning mutagenesis (ASM). The binding properties of nine mAb were defined, using ASM-IFN-beta mutants having alanine substituted at targeted, surface-exposed residues. The results were correlated with the mAb neutralizing potency. Of six mAb that bound either at or adjacent to the IFNAR-2 receptor chain binding site defined by the ASM epitopes, only three had measurable neutralizing activity. Two of these inhibited IFN-beta/IFNAR-2 complex formation, suggesting that steric hindrance of receptor binding constitutes their mechanism of neutralization. However, two mAb that bound to sites remote from the IFNAR-2 binding site on IFN-beta also inhibited IFN-beta/IFNAR-2 complex formation and demonstrated potent neutralizing activity. Thus, neutralizing mAb may employ mechanisms other than steric blockade to inhibit directly the binding of receptor by cytokine, limiting their usefulness as tools to define precise receptor-ligand interaction sites.

Selective specimen preparation for TEM observation of the cross-section of individual carbon nanotube/metal junctions

We present here an efficient method to prepare a transmission electron microscopy (TEM) specimen for selective observation of the cross-section of individual nanoscale structures. As a typical example, the cross-sectional TEM observation of a quasi-one-dimensional material - a nano-electronic component based on an individual carbon nanotube - is presented.

Quantitative liquid-phase chemiluminescence ELISA: detection of subtle epitope differences in HuIFN-beta.

We have developed a new liquid-phase, chemiluminescence-enhanced, inhibition ELISA (LP-CEI-ELISA) to explore the binding sites recognized by two neutralizing monoclonal antibodies (mAb) against recombinant human IFN-(beta)ser (rHuIFN-(beta)ser). In this assay, the initial antigen-antibody reaction occurs in solution under more physiologic conditions than in a standard solid-phase ELISA. Subsequently, the reaction mixture is applied to a membrane that is exposed to a second, peroxidase-labeled mAb, chemiluminescent reagents are added, and the membrane is photographically recorded. Competitive inhibition of binding of a second, labeled mAb by the first mAb decreases the signal detected. Two well-characterized mAb A1 and A7, have been shown to recognize distinct epitopes on rHuIFN-(beta)ser and to neutralize its antiviral and antiproliferative activity (Proc. Natl. Acad. Sci. USA 88, 4040-4044, 1991). In conventional solid-phase ELISA, mAb A1 does not inhibit the binding of A7 to rHuIFN-(beta)ser, but we observed partial inhibition in the new liquid-phase assay. In contrast, A7 did not inhibit the binding of A1, consistent with the solid-phase ELISA results. This observation suggests that in the LP-CEI-ELISA, A1 and A7 may recognize epitopes differently than in solid-phase assays. Thus, the LP-CEI-ELISA, which is simple, sensitive, and quantifiable, appears also to be able to detect subtle, conformational differences of epitopes not evident in a standard solid-phase ELISA.

Acquisition of surgical skills: a randomized trial of didactic, videotape, and computer-based training.

BACKGROUND: Although computer-based training (CBT) can enhance didactic instruction, few studies have assessed the efficacy of CBT for basic surgical skills training. This study compares CBT with traditional methods of basic surgical skills training. METHODS: Sixty-nine naive medical students were randomized into 3 treatment groups for basic surgical skills instruction: didactic, videotape, or CBT. All instructional material contained the same pictures, text, and audio. With use of a multiple-choice question examination and a series of performance stations, students were objectively assessed before, immediately after, and 1 month after skills instruction. Raters were blinded to treatment modality during the follow-up evaluation. RESULTS: There were no significant differences among the groups before treatment. After treatment, the didactic group scored higher on the multiple-choice question examination. In contrast, the videotape and CBT groups demonstrated statistically significant (P < .01) enhancement of technical skills compared with the didactic group. After 1 month, a calculated performance quotient revealed statistically significant (P < .01) improvement only in the CBT group. The amount of time students spent practicing their skills was not significantly different among the groups. CONCLUSIONS: CBT is as effective as, and possibly more efficient, than traditional methods of basic surgical skills training for medical students.

Molecular metastases in stage I pancreatic cancer: improved survival with adjuvant chemoradiation.

BACKGROUND: Reports of improved survival rates for patients with resected adenocarcinoma of the pancreas coincide with the adoption of adjuvant chemoradiation protocols. The impact of nodal micrometastases demonstrated by molecular assays and adjuvant therapy on survival of patients with stage I pancreatic cancer has not been adequately assessed. METHODS: A retrospective analysis of postoperative chemoradiation on survival in 61 patients undergoing resection of pancreatic adenocarcinomas from 1984 to 1997 was performed. Archival tumors and regional nodes from 25 patients with stage I cancers were tested for a Kiras oncogene mutation using polymerase chain reaction and analysis for restriction fragment length polymorphisms (PCR/RFLP). RESULTS: Adjuvant chemoradiation was associated with improved survival for stage I (P < .01), but not stage III, disease. Seventeen (68%) of 25 patients with stage I disease tested had evidence of mutant Kiras in one or more regional nodes. Survival did not differ for patients with molecular micrometastases. Six of 17 (35%) patients with micrometastases received adjuvant chemoradiation and had improved survival (P < .05). CONCLUSIONS: The majority of patients with stage I pancreatic cancer have PCR/RFLP evidence of lymph node micrometastases. Adjuvant chemoradiation improves survival in these patients by treating micrometastases not detected by histology. Adjuvant chemoradiation should be used for patients with stage I pancreatic cancers.

Carcinoma of the breast in males: a multiinstitutional survey.

BACKGROUND: Breast carcinoma in males is infrequent, and information regarding the results of modern treatment is limited. Cases of breast carcinoma in males were accrued from multiple hospitals in one region to determine treatment, survival, and prognostic factors. METHODS: A retrospective review was performed of 217 cases of breast carcinoma in males accessioned at tumor registries of 18 health care institutions in eastern Wisconsin between 1953 and 1995. RESULTS: Of the 217 cases, 215 (99.1%) were carcinomas. The majority of carcinomas were of invasive ductal type and presented as masses. Carcinoma in situ accounted for 5.5% of cases. The 5- and 10-year observed survivals for men were 50.6% and 23.7%, respectively. A high rate of post-treatment mortality from comorbid disease was found. Stage, axillary lymph node status, number of lymph nodes with metastases, and tumor hormone receptors were significant indicators of prognosis. Adjuvant systemic chemotherapy and hormone therapy improved the prognosis of patients with axillary lymph node metastases and hormone receptor positive tumors. Earlier stage at presentation and improved 5-year survival were found in cases occurring between 1986-1995 compared with those occurring in earlier years. Use of modified radical mastectomy and systemic adjuvant therapy also increased since 1986. CONCLUSIONS: The clinical, pathologic, and prognostic features of breast carcinoma in men are similar to those reported for women. The poorer prognosis of men is related to older age at diagnosis, more advanced stage of disease at presentation, and high mortality from comorbid disease. Earlier diagnosis, less radical surgery, and use of systemic adjuvant therapy are coincident with an improved prognosis for men.

Surgical management of colorectal metastases to the liver: role of resection and cryosurgery.

Long-term results of 41 patients who underwent hepatic resection and early experience with 21 patients treated by hepatic cryosurgery alone or combined with resection for colorectal metastases are presented. Patients treated by resection had three or fewer metastases, no perioperative mortality, and a mean follow-up of 43.5 months. The five-year overall survival is 34% with a median survival of 48 months. By multivariate analysis, only transfusions correlated significantly with survival, but in a negative manner (p = 0.05). A mean of 4.3 units were transfused per patient, though only 25 patients actually received transfusions.

Breast cancer in men.

Aside from its much lower frequency, breast cancer in men is remarkably similar to the disease in women. The cause remains equally obscure; the clinical presentation, pathology, and natural history are similar; and men are probably as curable in similar circumstances. Men are generally older and in more advanced stages than women when diagnosed, the tumors are located more often beneath the nipple and are more often responsive to hormonal therapy, but otherwise differences are negligible. Stage and axillary node status are strong prognostic indicators. Modified radical mastectomy has replaced radical mastectomy for surgical treatment of early states, and systemic adjuvant therapy appears to improve the prognosis for cases with involvement of lymph nodes.

Primary squamous cell carcinoma of the breast: sensitivity to cisplatinum-based chemotherapy.

Primary squamous cell carcinoma (SCC) of the breast is a rare malignancy whose optimal treatment and prognosis are unknown. A patient with SCC whose tumor responded dramatically to chemotherapy as part of multimodal treatment is presented. A 61-year-old woman had a palpable 5.5-cm tender left breast mass with overlying skin edema and erythema and irregular margins by mammography. Fine needle aspiration revealed malignant squamous cells with keratinization; incisional biopsy confirmed SCC. Extensive evaluation for an extramammary primary site of disease was negative. Neoadjuvant cisplatinum and 5-fluorouracil (5-FU) led to tumor shrinkage and complete resolution of pain and erythema. Modified radical mastectomy with post-operative chest wall radiation were performed. Neither residual invasive carcinoma nor metastatic nodal disease was found, though intraductal carcinoma with marked squamous features was identified. The patient remains disease-free 2.5 years after diagnosis. Cisplatinum-based chemotherapy should be considered in the treatment regimen of this disease.

Doping graphitic and carbon nanotube structures with boron and nitrogen.

Composite sheets and nanotubes of different morphologies containing carbon, boron, and nitrogen were grown in the electric arc discharge between graphite cathodes and amorphous boron-filled graphite anodes in a nitrogen atmosphere. Concentration profiles derived from electron energy-loss line spectra show that boron and nitrogen are correlated in a one-to-one ratio; core energy-loss fine structures reveal small differences compared to pure hexagonal boron nitride. Boron and carbon are anticorrelated, suggesting the substitution of boron and nitrogen into the carbon network. Results indicate that singlephaase CyBxNx as well as separated domains (nanosize) of boron nitride in carbon networks may exist.

Clostridium difficile toxin A therapy for HCT 116 human colon cancer in nude mice.

Clostridium difficile toxin A was evaluated for an antitumor effect in vivo on HCT 116 human colon carcinoma cells growing subcutaneously in nude mice. A mean reduction in tumor volume of at least 65%, by measurement in three dimensions, was observed in mice who received two 9- to 13-day courses of daily intraperitoneal injections of toxin A as compared to mice receiving diluent alone. Reversible adverse effects of toxin A were noted in some animals, consisting primarily of liver toxicity and skin rash. HCT 116 cells in toxin A-treated mice grew as flattened tumors with ulcerated centers compared to rounded tumors without ulceration in controls. Histologic examination of tumors from representative mice revealed that two thirds of the tumor in a treated mouse was necrotic compared to only one third in a control, suggesting greater antitumor efficacy of toxin A than estimated by tumor measurements alone.

Trends in the stage of cancer at the time of diagnosis.

The stage of cancers at the time of diagnosis for 10 major sites of disease from patients treated at two Medical College of Wisconsin teaching hospitals was analyzed from tumor registry data and compared from the years 1983, 1987, and 1991. A trend toward earlier stages of cancer of major sites was noted, with patients having in situ or localized disease increasing from 35% in 1983 to 48% in 1991. Patients with breast cancer demonstrated the strongest trend, with 44% of the cases representing in situ or localized disease in 1983 compared to 61% in 1991 (p = 0.03). A shift toward earlier stage of cancer at diagnosis was also noted for other major sites including: lung, trachea and bronchus; colon and rectum; and prostate cancers. Trends toward an earlier stage of cancer may result from patient and physician education, local practice patterns, as well as proper use of screening programs. Information on such trends from hospital tumor registries may be helpful in the appropriate and efficient allocation of local health care resources.

Cytotoxicity of Clostridium difficile toxin A for human colonic and pancreatic carcinoma cell lines.

The use of bacterial exotoxins may constitute novel adjuncts to treatment of gastrointestinal tract malignancies. Clostridium difficile toxin A was evaluated for its cytotoxic effect in vitro on 24 human cell lines and strains including carcinomas of the colon, pancreas, prostate, lung, breast, and lymphoid malignancies, as well as nonmalignant tissues. All nine colon and five pancreas cell lines were extraordinarily sensitive to the cytotoxic effect of Clostridium difficile toxin A at very low concentrations. This effect, which occurred rapidly and was dose dependent, was observed in all cells of seven colon and two pancreas cell lines at concentrations as low as 1-5 ng/ml (10(-12) to 10(-11) M), whereas cells derived from other sites required 60 to greater than 500 ng/ml to achieve an equivalent effect. The data suggest that Clostridium difficile toxin A may have potential therapeutic value in the treatment of some gastrointestinal tract cancers.

Antibodies that neutralize human beta interferon biologic activity recognize a linear epitope: analysis by synthetic peptide mapping.

The location of biologically relevant epitopes on recombinant human beta interferon in which Ser-17 replaces Cys-17 (rh[Ser17]IFN-beta) was evaluated by testing the immunoreactivity of antibodies against 159 sequential, overlapping octamer peptides. Three monoclonal antibodies (mAbs) that neutralize rh[Ser17]IFN-beta biologic activity, designated A1, A5, and A7, bound to peptides spanning only residues 39-48, whereas nonneutralizing mAb bound less specifically at multiple sites near the amino terminus. The immunoreactivity of peptides spanning residues 40-47 that contained a series of single amino acid substitutions suggested that residues 41-43 (Pro-Glu-Glu) and 46 (Gln) are important for the binding of neutralizing mAbs. The reactivity of mAbs to larger synthetic peptides containing rh[Ser17]IFN-beta sequences from residue 32 through residue 56 was evaluated. All mAbs except A7 reacted with synthetic peptides representing rh[Ser17]IFN-beta residues 32-47, 40-56, and 32-56, but only mAbs A1 and A5 bound to the core peptide composed of residues 40-47. Peptide 32-56 effectively blocked the binding of mAbs A1 and A5 to rh[Ser17]IFN-beta and markedly inhibited their neutralizing activity. Biologic activity of the peptides was undetectable. Rabbit antisera raised against peptides 32-47 and 40-56 recognized rh[Ser17]IFN-beta but did not neutralize its antiviral activity. Thus, structure-function analysis by peptide mapping has permitted the identification of a linear epitope recognized by neutralizing antibody on a biologically active cytokine. We conclude that the region spanning residues 32-56 is of major importance in the expression of the biologic activity of human IFN-beta.

Immunochemical characterization of antigenic domains on human interferon-beta: spatially distinct epitopes are associated with both antiviral and antiproliferative activities.

The use of a panel of monoclonal antibodies (mAb) raised against recombinant (serine-17) human interferon-beta (rHuIFN-beta ser) has permitted the identification of three epitopes on HuIFN-beta, designated as sites I, II and III, based solely on functional differences, i.e., the neutralization of antiviral and antiproliferative activities of natural and recombinant HuIFN-beta (Redlich, P.N. and Grossberg, S. E., J. Immunol. 1989. 143: 1887). Site I- and II-directed mAb possessed neutralizing activity whereas none was noted by mAb recognizing site III. To characterize further these epitopes by immunochemical means, we studied their (a) spatial relationship by competitive binding assays, (b) antigenic structure by Western blotting, and (c) sensitivity to chemical modification by the measurement of mAb reactivity after radioiodination. Competitive antibody binding studies revealed site II to be spatially distinct from sites I and III. Furthermore, site I- and II-directed mAb could easily recognize rHuIFN-beta ser on a Western blot, suggesting that both these epitopes are primarily sequential in structure or denaturation resistant. Chemical modification by radioiodination, which did not alter the biologic activity of rHuIFN-beta ser, had likewise little effect on mAb reactivity to site I; however, reactivity to site II was diminished and reactivity to site III was minimal following the radioiodination process. Both site I- and II-directed mAb inhibited the binding of 125I-rHuIFN-beta ser to intact Daudi cells, suggesting that inhibition of receptor binding is their mechanism of neutralization. Thus, we conclude that epitopes I and II, which are associated with both antiviral and antiproliferative activities of rHuIFN-beta, are spatially and immunochemically distinct.

Analysis of antigenic domains on natural and recombinant human IFN-beta by the inhibition of biologic activities with monoclonal antibodies.

Human IFN-beta (HuIFN-beta) is a biologically potent protein with both antiviral and antiproliferative activities. To understand better its mode of action, a number of murine mAb were developed against a recombinant (serine-17) HuIFN-beta (rHuIFN-beta ser) and screened by ELISA and neutralization of antiviral activity. The panel of antibodies, composed of both IgA and IgG immunoglobulins, were specific for HuIFN-beta and did not crossreact with HuIFN-alpha or gamma. Furthermore, three functionally distinct epitopes (designated as sites I, II, and III) were identified based on mAb neutralization of antiviral and antiproliferative activities of recombinant and natural HuIFN-beta. Antibodies directed to sites I and II neutralized the antiviral and antiproliferative activities of rHuIFN-beta ser, though the antiviral neutralization potency of the mAb to site II was approximately 10-fold less than mAb to site I. Antibodies directed to site I neutralized both recombinant and natural HuIFN-beta, although the antiviral neutralization potency was approximately 10-fold higher against rHuIFN-beta ser than the native protein. The mAb directed to site II did not demonstrate any significant neutralization of the antiviral or antiproliferative activity of natural HuIFN-beta but neutralized a recombinant HuIFN-beta containing the native sequence. Antibodies recognizing site III did not neutralize the biologic activity of either recombinant or natural HuIFN-beta. Thus, three epitopes on HuIFN-beta have been identified, two of which are associated with both antiviral and antiproliferative activities.

Impaired immune function in obstructive jaundice.

Sepsis is a common and occasionally lethal complication of obstructive jaundice. The reasons for this increased susceptibility to infection are unknown. This study examines lymphocyte and reticuloendothelial (RES) function in animals with obstructive jaundice. Twelve New Zealand white rabbits (3-4 kg) were studied. Lymphocyte function was evaluated in six rabbits by phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) stimulation. In six animals, hepatic RES function was assessed by calculating the phagocytic index (PI) using the disappearance of 99Tc sulfacolloid (5 mg/kg) iv. After baseline studies, the common bile duct was divided and ligated. The above studies and serum bilirubin were repeated at 3 weeks. Obstruction was then relieved by cholecystojejunostomy (CJ) and RES studies repeated monthly x 6. Preobstructive lymphocyte function showed a stimulation index ratio (log) of 0.85 +/- 0.25 for PHA, 0.75 +/- 0.3 for Con A, and 0.71 +/- 0.25 for PWM. With biliary obstruction, the values fell to -0.23 +/- 15 (P less than 0.006), -0.31 +/- 0.12 (P less than 0.006), and -0.29 (P less than 0.006), demonstrating impaired lymphocyte function. When tested lymphocytes were mixed with control pooled rabbit serum, however, no lymphocyte impairment was noted. Baseline hepatic PI was 6.02 +/- 0.18 and fell to 3.79 +/- 0.33 with obstruction (P less than .01) and remained low at (3.20 +/- 0.14) 1 month (P less than 0.01) and (3.33 +/- 0.23) at 3 months (P less than .01), after CJ but returned to normal (8.04 +/- 0.97) at 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)