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Biomedical subjects

S E Hartman

Publications and source records attributed to S E Hartman.

At least 19 recordsLinked to original sources
PubMed2001

Correlation of scores for the Comprehensive Osteopathic Medical Licensing Examination with osteopathic medical school grades.

The authors evaluated construct validity of scores for the Comprehensive Osteopathic Medical Licensing Examination (COMLEX-USA), the examination used to evaluate osteopathic physicians for licensure. They computed correlations between students' grades in the first 2 years of osteopathic medical school and their scores on the COMPLEX-USA Level 1 (N = 187) and Level 2 (N = 86), as well as correlations between third- and fourth-year clerkship grades and the COMLEX-USA Level 2. Correlations of Level 1 scores with grades for years one, two, and the first 2 years combined were .74, .80, and .81, respectively; for Level 2, correlations were .59, .70, and .71. Correlation between clerkship grades and scores for the COMLEX-USA Level 2 was .26. The strong correlation between COMLEX-USA results and grades for the didactic curriculum in the first 2 years of medical school provides evidence for the construct validity of scores for the COMLEX-USA Levels 1 and 2.

Adult↗
PubMed2000

Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation.

Protein-tyrosine kinases play crucial roles in mast cell activation through the high-affinity IgE receptor (FcepsilonRI). In this study, we have made the following observations on growth properties and FcepsilonRI-mediated signal transduction of primary cultured mast cells from Btk-, Lyn-, and Btk/Lyn-deficient mice. First, Lyn deficiency partially reversed the survival effect of Btk deficiency. Second, FcepsilonRI-induced degranulation and leukotriene release were almost abrogated in Btk/Lyn doubly deficient mast cells while singly deficient cells exhibited normal responses. Tyrosine phosphorylation of cellular proteins including phospholipases C-gamma1 and C-gamma2 was reduced in Btk/Lyn-deficient mast cells. Accordingly, FcepsilonRI-induced elevation of intracellular Ca2+ concentrations and activation of protein kinase Cs were blunted in the doubly deficient cells. Third, in contrast, Btk and Lyn demonstrated opposing roles in cytokine secretion and mitogen-activated protein kinase activation. Lyn-deficient cells exhibited enhanced secretion of TNF-alpha and IL-2 apparently through the prolonged activation of extracellular signal-related kinases and c-Jun N-terminal kinase. Potentially accounting for this phenomenon and robust degranulation in Lyn-deficient cells, the activities of protein kinase Calpha and protein kinase CbetaII, low at basal levels, were enhanced in these cells. Fourth, cytokine secretion was severely reduced and c-Jun N-terminal kinase activation was completely abrogated in Btk/Lyn-deficient mast cells. The data together demonstrate that Btk and Lyn are involved in mast cell signaling pathways in distinctly different ways, emphasizing that multiple signal outcomes must be evaluated to fully understand the functional interactions of individual signaling components.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2000

Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk.

Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and members of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B lymphocytes and high-affinity IgE receptors (FcepsilonRI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on FcepsilonRI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKCbetaI among the conventional PKC isoforms (alpha, betaI, and betaII) expressed in mast cells. Syk/Btk-mediated PKCbetaI regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor alpha genes through the JNK pathway induced by FcepsilonRI stimulation. Accordingly, FcepsilonRI-induced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selective inhibitor of PKCbeta. Specific regulation of PKCbetaI by Btk is consistent with the selective association of Btk with PKCbetaI. Components of this signaling pathway may represent an attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immunologic diseases.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Terreic acid, a quinone epoxide inhibitor of Bruton's tyrosine kinase.

Bruton's tyrosine kinase (Btk) plays pivotal roles in mast cell activation as well as in B cell development. Btk mutations lead to severe impairments in proinflammatory cytokine production induced by cross-linking of high-affinity IgE receptor on mast cells. By using an in vitro assay to measure the activity that blocks the interaction between protein kinase C and the pleckstrin homology domain of Btk, terreic acid (TA) was identified and characterized in this study. This quinone epoxide specifically inhibited the enzymatic activity of Btk in mast cells and cell-free assays. TA faithfully recapitulated the phenotypic defects of btk mutant mast cells in high-affinity IgE receptor-stimulated wild-type mast cells without affecting the enzymatic activities and expressions of many other signaling molecules, including those of protein kinase C. Therefore, this study confirmed the important roles of Btk in mast cell functions and showed the usefulness of TA in probing into the functions of Btk in mast cells and other immune cell systems. Another insight obtained from this study is that the screening method used to identify TA is a useful approach to finding more efficacious Btk inhibitors.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Multiple signaling pathways for the activation of JNK in mast cells: involvement of Bruton's tyrosine kinase, protein kinase C, and JNK kinases, SEK1 and MKK7.

Stimulation of the high affinity IgE receptor (FC epsilonRI) as well as a variety of stresses induce activation of c-Jun N-terminal protein kinases (JNKs) stress-activated protein kinases in mast cells. At least three distinct signaling pathways leading to JNK activation have been delineated based on the involvements of Bruton's tyrosine kinase (Btk), protein kinase C (PKC), and the JNK-activating cascades composed of multiple protein kinases. The PKC-dependent pathway, which is inhibited by a PKC inhibitor Ro31-8425 and can be activated by PMA, functions as a major route in FC epsilon RI-stimulated mast cells derived from btk gene knockout mice. On the other hand, wild-type mouse-derived mast cells use both PKC-dependent and PKC-independent pathways for JNK activation. A PKC-independent pathway is regulated by Btk and SEK1 via the PAK-->MEKK1-->SEK1-->JNK cascade, and is sensitive to phosphatidylinositol 3-kinase inhibitors, wortmannin and LY-294002, while the PKC-dependent pathway is affected to a lesser extent by both wortmannin treatment and overexpression of wild-type and dominant negative mutant SEK1 proteins. Another PKC-independent pathway involves Btk and MKK7, a recently cloned direct activator of JNK. Among the stresses tested, UV irradiation seems to activate Btk and JNK via the PKC-independent pathways.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Involvement of Ras in Bruton's tyrosine kinase-mediated JNK activation.

Defects in Bruton's tyrosine kinase (Btk) result in B cell immunodeficiencies in humans and mice. Recent studies showed that Btk is required for maximal activation of JNK, a family of stress-activated protein kinases, induced by several extracellular stimuli including interleukin (IL)-3. On the other hand, IL-3-induced JNK activation is dependent on Ras. In the present study we have investigated whether Ras is involved in Btk-mediated JNK activation in BaF3 mouse pro-B cells. Overexpression of wild-type Btk protein in these cells enhanced JNK activation upon IL-3 stimulation, whereas expression of kinase-dead Btk partially suppressed JNK activation. Induced expression of the dominant negative Ras(N17) in the cells overexpressing wild-type Btk suppressed JNK activation. Importantly, overexpression of Btk enhanced the level of the GTP-bound, active form of Ras in response to IL-3 stimulation. Btk overexpression also increased the Shc-Grb2 association induced by IL-3 stimulation. Expression of either N17Ras or V12Ras did not impose any effects on Btk kinase activity. These data collectively indicate that Ras plays a role of an intermediary signaling protein in Btk-mediated JNK activation induced by the IL-3 signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Bruton's tyrosine kinase-mediated interleukin-2 gene activation in mast cells. Dependence on the c-Jun N-terminal kinase activation pathway.

Cross-linking of the high affinity IgE receptor (FcepsilonRI) on mast cells induces secretion of cytokines, including interleukin (IL)-2, through transcriptional activation of cytokine genes. Previously, defects in the gene coding for Bruton's tyrosine kinase (Btk) were shown to result in defective cytokine production in mast cells, and thereby mice carrying btk mutations exhibited diminished anaphylactic reactions in response to IgE and antigen. In this study, we provide evidence that the transcription factors involved in the IL-2 gene expression in T cells are also required for maximal activation of the IL-2 gene in FcepsilonRI-stimulated mast cells. Among them, AP-1 (Jun/Fos) and NF-AT were identified as candidate transcription factors that are regulated by Btk. Consistent with our previous data indicating that Btk regulates stress-activated protein kinases, c-Jun N-terminal kinase (JNK), c-Jun and other JNK-regulatable transcription factors are activated by FcepsilonRI cross-linking in a Btk-dependent manner. Further, FcepsilonRI-induced IL-2 gene activation is dependent on c-Jun and a component, SEK1, of its upstream activation pathway. Collectively, these data demonstrate that Btk regulates the transcription of the IL-2 gene through the JNK-regulatable transcription factors in FcepsilonRI-stimulated mast cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production.

We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1997

Bruton's tyrosine kinase regulates apoptosis and JNK/SAPK kinase activity.

Mast cells derived from Bruton's tyrosine kinase (Btk)-defective xid or btk null mice showed greater expansion in culture containing interleukin-3 (IL-3) than those from wild-type (wt) mice. Although the proliferative response to IL-3 was not significantly different between the wt and xid mast cells, xid and btk null mast cells died by apoptosis more slowly than their wt counterparts upon IL-3 deprivation. Consistent with these findings, the apoptosis-linked c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity was compromised in these btk-mutated cells upon Fc(epsilon)RI crosslinking or upon stimulation with IL-3 or with stem cell factor. p38 activity was less severely, but significantly, affected by btk mutation, whereas extracellular signal-regulated kinases were not affected by the same mutation. Btk-mediated regulation of apoptosis and JNK activity was confirmed by reconstitution of btk null mutant mast cells with the wt btk cDNA. Furthermore, growth factor withdrawal induced the activation and sustained activity of JNK in wt mast cells, while JNK activity was consistently lower in btk-mutated mast cells. These results support the notion that Btk regulates apoptosis through the JNK activation.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1997

Estimates of validity and reliability for the hemispheric mode indicator.

Concurrent validity of scores of the Hemispheric Mode Indicator (a measure of cognitive hemispheric dominance) was assessed by product-moment correlation with scores for the Human Information Processing Survey (a more-studied measure of hemispheric dominance) for 27 nurse-anesthetist students and 94 medical students (r = .61 and .69, respectively). For 70 of the medical students, test-retest stability was only fair (r = .74). For 525 undergraduates and 156 medical students, although alpha coefficients were .78 and .84, respectively, consideration of interitem correlations and principal components analyses indicated that some of the Hemispheric Mode Indicator's items are unsuitable as worded and that the 32 items probably represent more than one underlying latent variable.

Adult↗
PubMed1993

Ratios as a size adjustment in morphometrics.

Simple ratios in which a measurement variable is divided by a size variable are commonly used but known to be inadequate for eliminating size correlations from morphometric data. Deficiencies in the simple ratio can be alleviated by incorporating regression coefficients describing the bivariate relationship between the measurement and size variables. Recommendations have included: 1) subtracting the regression intercept to force the bivariate relationship through the origin (intercept-adjusted ratios); 2) exponentiating either the measurement or the size variable using an allometry coefficient to achieve linearity (allometrically adjusted ratios); or 3) both subtracting the intercept and exponentiating (fully adjusted ratios). These three strategies for deriving size-adjusted ratios imply different data models for describing the bivariate relationship between the measurement and size variables (i.e., the linear, simple allometric, and full allometric models, respectively). Algebraic rearrangement of the equation associated with each data model leads to a correctly formulated adjusted ratio whose expected value is constant (i.e., size correlation is eliminated). Alternatively, simple algebra can be used to derive an expected value function for assessing whether any proposed ratio formula is effective in eliminating size correlations. Some published ratio adjustments were incorrectly formulated as indicated by expected values that remain a function of size after ratio transformation. Regression coefficients incorporated into adjusted ratios must be estimated using least-squares regression of the measurement variable on the size variable. Use of parameters estimated by any other regression technique (e.g., major axis or reduced major axis) results in residual correlations between size and the adjusted measurement variable. Correctly formulated adjusted ratios, whose parameters are estimated by least-squares methods, do control for size correlations. The size-adjusted results are similar to those based on analysis of least-squares residuals from the regression of the measurement on the size variable. However, adjusted ratios introduce size-related changes in distributional characteristics (variances) that differentially alter relationships among animals in different size classes.

Animals↗
PubMed1990

A hospital payment system with incentives for improvement in quality of care: first lessons.

A demonstration program of five member hospitals of the Rochester Area Hospitals Corporation in Rochester, New York, is introducing two major changes into traditional quality assurance programs in hospitals: (1) a shift of focus from structure and process to outcomes and (2) replacement of punitive approaches with a positive, reward-oriented approach. Relying on the MedisGroups information system to measure outcomes and on statistical techniques to identify variations in hospitals' performance, the demonstration offers financial awards in the form of a payment adjustment incorporated into the hospital reimbursement system, based on each hospital's outcomes compared to both an external and a local standard. The authors report the first experiences with the demonstration and the prospects for continuous improvement of quality of care.

Databases, Bibliographic↗
PubMed1989

Stereophotogrammetric analysis of occlusal morphology of extant hominoid molars: phenetics and function.

Because teeth are commonly preserved in the fossil record, dental remains have often been employed in estimating evolutionary relationships among fossil hominoids. This is appropriate, however, only to the extent that dental morphology is phylogenetically informative. I have used phenetic analytic techniques to assess whether hominoid molars are likely to be useful for phylogenetic inference. Thirty-four occlusal landmarks for first and second molars were chosen; seven on each maxillary and ten on each mandibular tooth. Three-dimensional locations of these points were determined from stereophotographs of dental arcades of more than 260 specimens from six taxa (gorilla, chimpanzee, human, orangutan, siamang, and gibbon). Analytic emphasis was on canonical variates analyses of landmark coordinates for mandibular and maxillary second molars, adjusted for intergroup size differences. There is little correspondence between the systematic implications of hominoid molar morphometrics and reliable estimates of evolutionary propinquity based on interhominoid biomolecular similarities. The former seem to have been determined largely by dietary constraints. Although this suggests the possibility of using the protocol employed here to infer diets of fossil hominoids, molar crown measurements seem unlikely to serve well as phylogenetic indicators in the Hominoidea.

Animals↗
PubMed1989

"How might a low-cost hospital system look?" Lessons from the Rochester experience.

An innovative, collaborative approach to promoting the effective and efficient delivery of hospital services and to maintaining the solvency of the nine participating hospitals in the greater Rochester, New York area has been successful. An evaluation of the early years (1980-1984) of the Hospital Experimental Payments Program (HEP) shows: 1) per capita hospital costs in Rochester increased at half the rate of increase of the national average; 2) by 1984, per capita hospital expenditures were at $446 compared with $521 nationally; 3) cost containment was achieved through a wide array of strategies such as changes in hospital resource allocation and physician practice patterns; and 4) during the same period, quality and access remained stable or improved. This project demonstrates that through self-control, hospitals can become efficient providers of health care.

Cost Control↗