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J L Smith

Publications and source records attributed to J L Smith.

At least 55 records · Page 3Linked to original sources
PubMed2001

Cancer education for the generalist physician.

BACKGROUND AND OBJECTIVES: The care of cancer patients has become increasingly complex and multidisciplinary while more responsibility for cancer care has been shifted to primary care physicians. We developed a medical student educational program to teachfuture primary care physicians about care of cancer patients. METHODS: The Multidisciplinary Oncology Clerkship was designed for fourth-year medical students planning to enter primary care residencies. The clerkship hasfive major components: ambulatory patient care, multidisciplinary conferences, skill stations, problem-based learning in small groups, and supervised objective structured clinical examinations. Learning during the clerkship was evaluated with knowledge tests before, immediately after, and 6 months after the clerkship. RESULTS: Twenty-four students participated in the first year of the clerkship. Program evaluation revealed that the students' scores on the knowledge test rose 40% between the pre-clerkship and post-clerkship tests. Retesting at 6 months demonstrated knowledge retention of 90%. CONCLUSIONS: Multidisciplinary cancer education, using the combination of problem-based learning, skill stations, clinical exposure, and standardized patients, increases the cancer-care knowledge of medical students dedicated to a career in primary care.

Clinical Clerkship↗
PubMed2001

Granular cell tumor of the parotid: a case report and literature review.

Granular cell tumors are relatively uncommon soft tissue lesions that originate in Schwann's cells. Although these tumors can occur at any site, their presence in the parotid gland is very unusual. This article describes one such case in a 48-year-old woman, followed by a brief review of the literature on this subject.

Diagnosis, Differential↗
PubMed2001

Determining explosivity part II: comparison of small-scale cartridge tests to actual pipe bombs.

The small-scale explosivity device (SSED) has been used to assess the explosive power of a number of low explosives-smokeless powders (WC-870, Red Dot, Bullseye, Winchester Action Pistol, and IMR-PB), Pyrodex, black powder, and an improvised explosive (TATP). The device requires 2 g of energetic material, a heavy-walled containment vessel, and a standard blast shield to permit use in most laboratories. The data from the SSED are compared with the fragmentation of pipe bombs which contained 300 to 700 g of powder. The SSED provided the same relative ordering of explosivity as suggested by the fragmentation of the real devices. In addition, the SSED was used to evaluate the chemical residue remaining after an explosion. Issues in using the device such as optimal detonators and restricted reaction volume were probed using three high explosives--TNT, Tetryl, and RDX.

Journal Article↗
PubMed2001

Crystal structure of imidazole glycerol phosphate synthase: a tunnel through a (beta/alpha)8 barrel joins two active sites.

BACKGROUND: Imidazole glycerol phosphate synthase catalyzes a two-step reaction of histidine biosynthesis at the bifurcation point with the purine de novo pathway. The enzyme is a new example of intermediate channeling by glutamine amidotransferases in which ammonia generated by hydrolysis of glutamine is channeled to a second active site where it acts as a nucleophile. In this case, ammonia reacts in a cyclase domain to produce imidazole glycerol phosphate and an intermediate of purine biosynthesis. The enzyme is also a potential target for drug and herbicide development since the histidine pathway does not occur in mammals. RESULTS: The 2.1 A crystal structure of imidazole glycerol phosphate synthase from yeast reveals extensive interaction of the glutaminase and cyclase catalytic domains. At the domain interface, the glutaminase active site points into the bottom of the (beta/alpha)(8) barrel of the cyclase domain. An ammonia tunnel through the (beta/alpha)(8) barrel connects the glutaminase docking site at the bottom to the cyclase active site at the top. A conserved "gate" of four charged residues controls access to the tunnel. CONCLUSIONS: This is the first structure in which all the components of the ubiquitous (beta/alpha)(8) barrel fold, top, bottom, and interior, take part in enzymatic function. Intimate contacts between the barrel domain and the glutaminase active site appear to be poised for crosstalk between catalytic centers in response to substrate binding at the cyclase active site. The structure provides a number of potential sites for inhibitor development in the active sites and in a conserved interdomain cavity.

Aminohydrolases↗
PubMed2000

Generation of murine dendritic cells from flt3-ligand-supplemented bone marrow cultures.

Murine dendritic cells (DCs) can be classified into at least 2 subsets, "myeloid-related" (CD11b(bright), CD8alpha(-)) and "lymphoid-related" (CD11b(dull), CD8alpha(+)), but the absolute relationship between the 2 remains unclear. Methods of generating DCs from bone marrow (BM) precursors in vitro typically employ granulocyte-macrophage colony-stimulating factor (GM-CSF) as the principal growth factor, and the resultant DCs exhibit a myeloidlike phenotype. Here we describe a flt3-ligand (FL)-dependent BM culture system that generated DCs with more diverse phenotypic characteristics. Murine BM cells cultured at high density in recombinant human FL for 9 days developed into small lymphoid-sized cells, most of which expressed CD11c, CD86, and major histocompatibility complex (MHC) class II. The CD11c(+) population could be divided into 2 populations on the basis of the level of expression of CD11b, which may represent the putative myeloid- and lymphoid-related subsets. The FL in vitro-derived DCs, when treated with interferon-alpha or lipopolysaccharide during the final 24 hours of culture, expressed an activated phenotype that included up-regulation of MHC class II, CD1d, CD8alpha, CD80, CD86, and CD40. The FL-derived DCs also exhibited potent antigen-processing and antigen-presenting capacity. Neutralizing anti-interleukin-6 (IL-6) antibody, but not anti-GM-CSF, significantly reduced the number of DCs generated in vitro with FL, suggesting that IL-6 has a role in the development of DCs from BM precursors. Stem cell factor, which exhibits some of the same bioactivities as FL, was unable to replace FL to promote DC development in vitro. This culture system will facilitate detailed analysis of murine DC development.

Animals↗
PubMed2000

Effects of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae in children with acute otitis media.

The effect of antibiotic therapy on nasopharyngeal colonization by Streptococcus pneumoniae and Haemophilus influenzae was evaluated in children diagnosed with acute otitis media. Children were randomly assigned to receive either amoxicillin/clavulanate or azithromycin therapy, and nasopharyngeal swabs were obtained for culture before and after starting therapy. Amoxicillin/clavulanate therapy eradicated or suppressed all strains of S. pneumoniae susceptible to penicillin, 75% of strains with intermediate resistance, and 40% of strains resistant to penicillin. Azithromycin therapy cleared two-thirds of azithromycin-susceptible strains of S. pneumoniae but none of azithromycin-nonsusceptible strains. Selection for antibiotic-resistant strains in individual children was not observed in children who received amoxicillin/clavulanate therapy but was observed in 2 children who received azithromycin therapy. Carriage of H. influenzae was also reduced by antimicrobial therapy but more so by amoxicillin/clavulanate. Antibiotic therapy does not directly increase the number of resistant strains in the population but, by eradicating susceptible strains, allows greater opportunity for carriage and spread of resistant strains.

Acute Disease↗
PubMed2000

Interruption of the internal water chain of cytochrome f impairs photosynthetic function.

The structure of cytochrome f includes an internal chain of five water molecules and six hydrogen-bonding side chains, which are conserved throughout the phylogenetic range of photosynthetic organisms from higher plants, algae, and cyanobacteria. The in vivo electron transfer capability of Chlamydomonas reinhardtii cytochrome f was impaired in site-directed mutants of the conserved Asn and Gln residues that form hydrogen bonds with water molecules of the internal chain [Ponamarev, M. V., and Cramer, W. A. (1998) Biochemistry 37, 17199-17208]. The 251-residue extrinsic functional domain of C. reinhardtii cytochrome f was expressed in Escherichia coli without the 35 C-terminal residues of the intact cytochrome that contain the membrane anchor. Crystal structures were determined for the wild type and three "water chain" mutants (N168F, Q158L, and N153Q) having impaired photosynthetic and electron transfer function. The mutant cytochromes were produced, folded, and assembled heme at levels identical to that of the wild type in the E. coli expression system. N168F, which had a non-photosynthetic phenotype and was thus most affected by mutational substitution, also had the greatest structural perturbation with two water molecules (W4 and W5) displaced from the internal chain. Q158L, the photosynthetic mutant with the largest impairment of in vivo electron transfer, had a more weakly bound water at one position (W1). N153Q, a less impaired photosynthetic mutant, had an internal water chain with positions and hydrogen bonds identical to those of the wild type. The structure data imply that the waters of the internal chain, in addition to the surrounding protein, have a significant role in cytochrome f function.

Animals↗
PubMed2000

Microbial risk assessment: dose-response relations and risk characterization.

Characterizations of the risks associated with foodborne pathogens are dependent on the availability of information on the population's exposure to the biological agents. However, by itself, exposure data are insufficient to assess the public health impact of pathogenic microorganisms. This requires the availability of effective dose-response models. Successful development of models that describe dose-response relations for enteric pathogens is dependent on a sound understanding of the mechanisms of pathogenicity associated with individual pathogens. This includes knowledge of how the various pathogen, host, and food matrix factors influence pathogenicity. Currently, a group of sigmoidal mathematical equations are used to empirically describe dose-response relations. While these have proven to be highly useful, advances in microbial food safety risk assessment will likely require the development of mechanistic models that more effectively consider the range of factors that influence the frequency and severity of foodborne infections in a population.

Animals↗
PubMed2000

The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells.

FcgammaR clustering in monocytes initiates a cascade of signaling events that culminate in biological responses such as phagocytosis, production of inflammatory cytokines, and generation of reactive oxygen species. We have identified and determined the function of the adapter protein linker of activation of T cell (LAT) in FcgammaR-mediated signaling and function. Clustering of FcgammaRs on the human monocytic cell line, THP-1, induces phosphorylation of a major 36-kDa protein which immunoreacts with anti-LAT antisera. Our data indicate that although both the 36-kDa and 38-kDa isoforms of LAT are expressed in THP-1 and U937 human monocytic cells, FcgammaR clustering induces phosphorylation of the 36-kDa isoform only. Co-immunoprecipitation experiments revealed a constitutive association of p36 LAT with both FcgammaRI and FcgammaRIIa immunoprecipitates, and an activation-induced association of LAT with PLCgamma1, Grb2, and the p85 subunit of phosphatidylinositol 3-kinase. Transient transfection experiments in COS-7 cells indicated that overexpression of a wild type but not a dominant-negative LAT, that is incapable of binding to p85, enhances phagocytosis by FcgammaRI. Furthermore, bone marrow-derived macrophages from LAT-deficient mice displayed reduced phagocytic efficiency in comparison to the macrophages from wild-type mice. Thus, we conclude that p36 LAT serves to enhance FcgammaR-induced signal transduction in myeloid cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Tryptophan-heme pi-electrostatic interactions in cytochrome f of oxygenic photosynthesis.

Cytochrome f of oxygenic photosynthesis has an unprecedented structure, including the N-terminus being a heme ligand. The adjacent N-terminal heme-shielding domain is enriched in aromatic amino acids. The atomic structures of the chloroplast and cyanobacterial cytochromes f were compared to explain spectral and redox differences between them. The conserved aromatic side chain in the N-terminal heme-shielding peptide at position 4, Phe and Tyr in plants and algae, respectively, and Trp in cyanobacteria, is in contact with the heme. Mutagenesis of cytochrome f from the eukaryotic green alga Chlamydomonas reinhardtii showed that a Phe4 --> Trp substitution in the N-terminal domain was unique in causing a red shift of 1 and 2 nm in the cytochrome Soret (gamma) and Q (alpha) visible absorption bands, respectively. The resulting alpha band peak at 556 nm is characteristic of the cyanobacterial cytochrome. Conversely, a Trp4 --> Phe mutation in the expressed cytochrome from the cyanobacterium Phormidium laminosum caused a blue shift to the 554 nm alpha band peak diagnostic of the chloroplast cytochrome. Residue 4 was found to be the sole determinant of this 60 cm(-)(1) spectral shift, and of approximately one-half of the 70 mV redox potential difference between cytochrome f of P. laminosum and C. reinhardtii (E(m7) = 297 and 370 mV, respectively). The proximity of Trp-4 to the heme implies that the spectral and redox potential shifts arise through differential interaction of its sigma- or pi-electrostatic potential with the heme ring and of the pi-potential with the heme Fe orbitals, respectively. The dependence of the visible spectrum and redox potential of cytochrome f on the identity of aromatic residue 4 provides an example of the use of the relatively sharp cytochrome spectrum as a "spectral fingerprint", and of the novel structural connection between the heme and a single nonliganding residue.

Amino Acid Sequence↗
PubMed2000

Dual role for the glutamine phosphoribosylpyrophosphate amidotransferase ammonia channel. Interdomain signaling and intermediate channeling.

Glutamine phosphoribosylpyrophosphate (PRPP) amidotransferase catalyzes the first reaction of de novo purine nucleotide synthesis in two steps at two sites. Glutamine is hydrolyzed to glutamate plus NH(3) at an N-terminal glutaminase site, and NH(3) is transferred through a 20-A hydrophobic channel to a distal PRPP site for synthesis of phosphoribosylamine. Binding of PRPP is required to activate the glutaminase site (termed interdomain signaling) to prevent the wasteful hydrolysis of glutamine in the absence of phosphoribosylamine synthesis. Mutations were constructed to analyze the function of the NH(3) channel. In the wild type enzyme, NH(3) derived from glutamine hydrolysis was transferred to the PRPP site, and little or none was released. Replacement of Leu-415 at the PRPP end of the channel with an alanine resulted in a leaky channel and release of NH(3) to the solvent. Mutations in five amino acids that line the channel and two other residues required for the reorganization of phosphoribosyltransferase domain "flexible loop" that leads to formation of the channel perturbed channel function as well as interdomain signaling. The data emphasize the role of the NH(3) channel in coupling interdomain signaling and NH(3) transfer.

Amidophosphoribosyltransferase↗
PubMed2000

Adenocarcinoma of the esophagus with and without Barrett mucosa.

HYPOTHESIS: Previous studies have demonstrated an improved prognosis in patients with Barrett adenocarcinoma as compared with esophageal adenocarcinoma without Barrett. It has been suggested that an earlier presentation due to gastroesophageal reflux disease (GERD) may lead to detection of adenocarcinoma at an earlier stage. DESIGN: The records of 178 patients with esophageal adenocarcinoma presenting to Roswell Park Cancer Institute (Buffalo, NY) between 1991 and 1996 were reviewed. MAIN OUTCOME MEASURES: The clinical presentation, work-up, therapy, and outcome were compared between patients with Barrett esophagus (n = 66) and those without endoscopic or pathologic evidence of Barrett esophagus (n = 112). RESULTS: There were several favorable prognostic signs in the Barrett group, including smaller tumors, lower grade, and earlier stage. More patients in the Barrett group had surgically resectable tumors, resulting in an improved overall survival. However, there were no differences in the type or duration of symptoms. Overall, very few patients presented because of GERD, and only slightly more in the Barrett group (14% vs 4%). While survival greatly improved in patients diagnosed with Barrett due to GERD, this did not account for the difference in prognosis. CONCLUSIONS: Improved prognosis and survival for the Barrett group is not due to earlier presentation due to symptoms of GERD. It is more likely that all esophageal adenocarcinoma arises from Barrett esophagus, and that it is obscured by larger tumors. Reviews limited to resected patients greatly overestimate the number of adenocarcinoma cases diagnosed due to GERD. Increased efforts to identify high-risk patients and initiate screening are necessary to diagnose adenocarcinoma at an earlier stage.

Adenocarcinoma↗
PubMed2000

Molecular analysis reveals somatically mutated and unmutated clonal and oligoclonal B cells in T-cell-rich B-cell lymphoma.

This paper describes the immunohistology and molecular genetics of 18 cases of T-cell-rich B-cell lymphoma (TCRBL). In all cases, the large B cells stained strongly for CD20, with more variable expression of CD79a, and were negative for CD30 and CD15. The majority of T cells were predominantly positive for TIA-1 and negative for CD57; a large population of histiocytes was present in all cases. Epstein-Barr virus (EBV)-coded RNA (EBER) was found in B blasts from four cases and in one case was present among the background lymphoid cells. IgH PCR products were generated in 16/18 cases and revealed clonal, oligoclonal and polyclonal PCR products in 12, two and two cases, respectively. In addition, TCRG clonal gene rearrangements were identified in two cases. TCRB gene rearrangements were polyclonal. Sequence analysis of seven cases with clonal/oligoclonal IgH gene rearrangements revealed functional sequences with predominant V(H)3 gene usage associated with various D genes and J(H)4 or J(H)6 gene segments. Four cases displayed varying degrees of replacement and silent mutations (1.8-21%), with one case exhibiting intraclonal heterogeneity; the distribution of mutations was indicative of antigen selection in three cases. The remaining three cases, including two cases with functional oligoclonal IgH rearrangements, harboured unmutated V region genes. The EBV-positive cases were associated with clonal, oligoclonal and polyclonal PCR products and with mutated and germline clonal sequences. These data indicate that TCRBL may be a heterogeneous entity associated with clonal and oligoclonal B cells derived from both germinal centre and naïve B cells.

Adult↗
PubMed2000

Frequent T and B cell oligoclones in histologically and immunophenotypically characterized angioimmunoblastic lymphadenopathy.

The identification of clonal rearrangements of T cell receptor (TCR) genes is central to the diagnosis of T cell lymphomas. However, in angioimmunoblastic lymphadenopathy (AILD), first described as a nonneoplastic proliferation associated with immunodeficiency, the heterogeneity of TCR and IgH gene rearrangements suggest that some cases may harbor multiple lymphoid clones. In this study we have isolated DNA from archival paraffin biopsy material from 22 cases of AILD identified on the basis of classical histological and immunohistochemical features with the aim of establishing the occurrence of clones and oligoclones, the frequency of TCR and immunoglobulin heavy chain (IgH) variable (v) gene use, and the relationship of these findings to the presence of Epstein-Barr virus. DNA extracted from the biopsies was amplified using the polymerase chain reaction (PCR) and sequenced to detect functional and nonfunctional gene rearrangements. Epstein-Barr virus-encoded short RNA species (EBERs) were detected using in situ hybridization combined with immunochemistry to identify the phenotype of the Epstein-Barr virus-infected cells. Fifty-seven clonal products were found in 20/22 patients: TCRgamma clonal products were identified in 16/22, TCRbeta clonal products in 16/22 and IgH clonal products in 6/22 cases. Oligoclonal PCR products were seen for TCR in 3/22 and for IgH in 3/22 cases. In one biopsy PCR products from all reactions were polyclonal. Sequence analysis revealed functional TCRgamma, TCRbeta, and IgH sequences in 6/12, 9/11, and 8/8 cases, respectively. Functional TCR and/or IgH oligoclones were detected in 6/20 (30%) cases. In addition, nonfunctional TCR and IgH sequences were found in 11 cases. EBERs were identified in 18/20 cases varying from occasional to 25 to 30% nuclei staining and were associated with both T and B cells, although the majority were of indeterminate phenotype. The presence of EBERs was not associated with all clonal IgH gene rearrangements but was associated with B cell oligoclones. Patterns of gene recombinations indicated that the majority of TCRgamma recombinations used GV1 and GJ1S3/2S3 genes. Six out of eleven cases used TCR BV4S1 or BV2S1 genes associated with various BJ and BD1/2 genes. No common IgH gene usage was identified, but 8 clones had varying degrees of replacement and silent mutations (0.6-10.1%), consistent with B cell clones having undergone somatic mutation in the germinal center, and 3 clones harbored unmutated V genes, consistent with naive B cells. Our data do not support the concept of AILD as a clearly defined peripheral T cell lymphoma (PTCL). Rather, they suggest that AILD as defined by histology and immunohistochemistry is either a heterogeneous entity or represents a lymphoproliferation associated with immunodeficiency in which clonal T cell or B cell proliferation may occur.

Aged↗
PubMed2000

Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones.

BACKGROUND AND AIMS: There is limited information available on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on hepatic and biliary cholesterol metabolism in patients with gallstones. The aims of this study were to determine the effect of simvastatin on the regulatory elements of cholesterol metabolism that determine the concentrations of cholesterol in plasma and bile. METHODS: Thirty-one gallstone patients were enrolled in the study; 17 were treated with 20 mg simvastatin daily for 3 weeks prior to cholecystectomy and 14 served as controls. Samples of blood, liver, gall-bladder bile and bile from the common bile duct (CBD) were collected and analysed. RESULTS: The plasma cholesterol (-30%), triacylglycerol (-23%) and low-density lipoprotein (LDL) cholesterol (-42%) concentrations were significantly lowered by simvastatin treatment, as was the plasma lathosterol: cholesterol (-70%), which reflects whole-body cholesterol synthesis. Despite these changes, the hepatic LDL receptor protein and LDL receptor activity in circulating mononuclear cells were similar in both groups. There were no differences in the plasma phytosterol: cholesterol, which reflects the intestinal cholesterol absorption capacity or in the activity of hepatic acyl-coenzyme A: cholesterol acyltransferase. There were however, lower cholesterol concentrations in CBD (-68%) and gall bladder (-41%) bile, and decreased lithogenic (-47%) and bile acid hydrophobicity (-22%) indices of CBD bile in the simvastatin group. CONCLUSIONS: These data indicate that simvastatin reduced plasma and biliary cholesterol levels primarily by reducing cholesterol synthesis. The reduction in CBD bile lithogenicity and bile acid hydrophobicity by simvastatin suggests that this agent may be useful for people who have early stages of cholesterol gallstone development and in whom a choleretic effect is required.

Adult↗
PubMed2000

Rheumatoid arthritis T cells produce Th1 cytokines in response to stimulation with a novel trispecific antibody directed against CD2, CD3, and CD28.

Rheumatoid arthritis (RA) T cells respond poorly to conventional mitogens. We have examined the proliferative and cytokine responses of T cells to a synthetic trispecific antibody (Tsab) directed against CD2, CD3, and CD28. In 11 subjects RA T cells proliferated more, and secreted significantly more IL-2, in response to Tsab than did control peripheral blood (PB) cells. Very high levels of IL-2 were produced by 2 patients with aggressive disease. Measurement of intracellular IL-2, IFN-gamma, IL-4, and IL-5 by flow cytometry showed a Th1 pattern of cytokine production in 13 RA and 9 control subjects. We conclude that RA T cells are not irreversibly inactivated, and that spatial arrangement of stimulating molecules may be important in eliciting maximal responses.

Antibodies, Monoclonal↗
PubMed2000

A primary care intervention for depression.

To assess a guideline-based intervention's impact on depression care provided in rural vs. urban primary care settings, 12 community primary care practices (four rural, eight urban) were randomized to enhanced (i.e., intervention) and usual care study conditions. The study enrolled 479 depressed patients, with 432 (90.2 percent) completing telephone follow-up at six months. Multilevel analytic models revealed that rural enhanced care patients had 2.70 times the odds (P = 0.02) of rural usual care patients of taking a three-month course of antidepressant medication at recommended dosages in the six months following baseline; urban enhanced care patients had 2.43 times the odds compared with their urban usual care counterparts (P = 0.007). Rural enhanced care patients had 3.00 times the odds of rural usual care patients of making eight or more visits to a mental health specialist for counseling in the six months following baseline (P = 0.03). Comparisons of patients in enhanced care practices showed that rural enhanced care patients had 2.00 times the odds (P = 0.12) of urban enhanced care patients of making at least one visit to a mental health specialist for counseling in the six months following baseline and had comparable odds to urban enhanced care patients (odds ratio [OR] = 1.06, P = 0.77) of making eight or more visits to such specialists during that interval. The study's intervention improved the care received by both rural and urban depressed primary care patients. Moreover, the intervention's effect appears to have been greater in rural settings, particularly in terms of increasing depressed rural patients' use of mental health specialists for counseling.

Adult↗