What is your diagnosis? Segmental dilatation of the small intestine with intra-intestinal fluid and air indicative of small-intestinal obstruction.
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Animals↗
Biomedical subjects
P R Young
Publications and source records attributed to P R Young.
Renal metastases from thyroid papillary carcinoma: study of sodium iodide symporter expression.
Kidney metastases from thyroid cancer are rare. We report two such patients and demonstrate that the in vivo 131I uptake by the kidney metastasis is associated with high levels of sodium iodide (Na+/I-) symporter (NIS) expression in the first case. Case 1: A 61-year-old woman with papillary thyroid carcinoma-follicular variant (PTC-FV) presented with scapular metastasis. After thyroidectomy and scapulectomy, a 131I posttherapy scan showed left upper quadrant uptake. A 3.0-cm metastatic PTC-FV deposit was removed by partial nephrectomy. Case 2: A 53-year-old woman presented with back pain. A computed tomography (CT) scan showed a 3.5-cm renal mass, a multinodular goiter, and lung metastases thought secondary to a renal cell carcinoma. A unilateral nephrectomy revealed metastatic PTC-FV. After thyroidectomy, a 131I posttherapy scan showed lung and skeletal metastases. NIS immunoreactivity in tumoral tissue was strongly positive in the primary tumor, shoulder, and kidney metastasis in case 1, as well as in the primary tumor in case 2. Spotty, low-level NIS expression was observed in the kidney metastasis in case 2. In conclusion, kidney metastases of PTC-FV may occasionally retain adequate levels of NIS expression, enabling their detection during life. Thus, intense uptake in the abdomen during 131I imaging should not be assumed to be physiological gastrointestinal tract residual radionuclide activity.
Carcinoma, Papillary↗
Systematic transperineal ultrasound guided template biopsy of the prostate in patients at high risk.
PURPOSE: A negative biopsy result does not necessarily equate with cancer in specific high risk groups. We describe an alternative systematic biopsy technique for evaluating this subgroup of patients. MATERIALS AND METHODS: From March 1997 to May 1999 a total of 88 men underwent systematic ultrasound guided biopsy using the transperineal template technique. All patients had undergone at least 1 and 75 (85%) had undergone 2 or more previous sets of biopsies. In addition, study inclusion required high risk parameters, including prostate specific antigen (PSA) velocity greater than 0.75 ng./ml., PSA greater than 10 ng./ml. or previous prostatic intraepithelial neoplasia on biopsy, and/or atypical small cell acinar proliferation. RESULTS: Cancer was identified in 38 of the 88 men (43%) in this high risk subgroup undergoing repeat biopsy. A mean of 15.1 previous biopsy cores had been obtained. The most common biopsy grade was 6 (range 4 to 9). Adenocarcinoma was identified in the transition zone area in 29 of 38 cases (76%), including 15 (39%) in which disease was detected in the transition zone only. Persistent PSA acceleration greater than 0.75 ng./ml. was the major indicator for transperineal template biopsy in 83 of the 88 patients (94%). The only significant independent variable predictive of positive biopsy was prostate volume. Mean prostate volume in the positive and negative biopsy groups was 48 and 73 gm., respectively (p <0.001). Complications were rare and self-limiting, consisting primarily of hematuria and urinary retention requiring overnight catheterization in 2 patients. CONCLUSIONS: Systematic transperineal template biopsy of the prostate is a safe and precise repeat biopsy technique in patients who remain at high risk for adenocarcinoma.
Adenocarcinoma↗
Radiographic imaging of the artificial urinary sphincter pressure regulating balloon.
PURPOSE: Radiography of the artificial urinary sphincter is done for the postoperative evaluation of recurrent incontinence. We investigated the ability of urologists and radiologists to detect changes in the radiographic appearance of the pressure regulating balloon at various volumes of contrast solution. MATERIALS AND METHODS: We obtained 20 sequential radiographs of a pressure regulating balloon lying atop the pelvic region of a body phantom. The volume of contrast solution within the balloon was decreased by 1 cc in each radiograph from 20 to 1 cc. Urologists and radiologists examined the radiographs for changes in balloon size, density and circularity. Radiographs were reviewed in side-by-side comparison with a baseline radiograph and also independently without reference to baseline study. RESULTS: On side-by-side comparison changes in balloon size, density and circularity were first seen at 17, 13 and 8 cc of contrast solution, respectively. On independent review changes in size, density and circularity were first seen at 10, 8 and 6 cc, respectively. CONCLUSIONS: If there are no contraindications, contrast solution should be used to fill the balloon component of the artificial urinary sphincter system. Immediately after implantation a baseline radiograph should be obtained. Without a baseline film for comparison radiographic imaging of the balloon does not detect changes until at least 50% of its volume has been lost. Because comparison imaging is invaluable for detecting volume loss, a radiograph should be obtained immediately after initial placement of the artificial urinary sphincter.
Contrast Media↗
Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain.
We have identified a type I cytokine receptor, which we have termed novel interleukin receptor (NILR), that is most related to the IL-2 receptor beta chain (IL-2Rbeta) and physically adjacent to the IL-4 receptor alpha chain gene on chromosome 16. NILR mRNA is most highly expressed in thymus and spleen, and is induced by phytohemagglutinin in human peripheral blood mononuclear cells. NILR protein was detected on human T cell lymphotropic virus type I-transformed T cell lines, Raji B cells, and YT natural killer-like cells. Artificial homodimerization of the NILR cytoplasmic domain confers proliferation to Ba/F3 murine pro-B cells but not to 32D myeloid progenitor cells or CTLL-2 murine helper T cells. In these latter cells, heterodimerization of IL-2Rbeta and the common cytokine receptor gamma chain (gamma(c)) cytoplasmic domains allows potent proliferation, whereas such heterodimerization of NILR with gamma(c) does not. This finding suggests that NILR has signaling potential but that a full understanding of its signaling partner(s) is not yet clear. Like IL-2Rbeta, NILR associates with Jak1 and mediates Stat5 activation.
Amino Acid Sequence↗
The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins.
The p38 mitogen-activated protein (MAP) kinase is activated during engagement of the type I interferon (IFN) receptor and mediates signals essential for IFNalpha-dependent transcriptional activation via interferon-stimulated response elements without affecting formation of the ISGF3 complex. In the present study, we provide evidence that the small GTPase Rac1 is activated in a type I IFN-dependent manner and that its function is required for downstream engagement of the p38 MAP kinase pathway. We also demonstrate that p38 is required for IFNalpha-dependent gene transcription via GAS elements and regulates activation of the promoter of the PML gene that mediates growth inhibitory responses. In studies to determine whether the regulatory effects of p38 are mediated by serine phosphorylation of Stat1 or Stat3, we found that the p38 kinase inhibitors SB203580 or SB202190 or overexpression of a dominant negative p38 mutant do not inhibit phosphorylation of Stat1 or Stat3 on Ser-727 in several IFNalpha-sensitive cell lines. Altogether these data demonstrate that the Rac1/p38 MAP kinase signaling cascade plays a critical role in type I IFN signaling, functioning in cooperation with the Stat-pathway, to regulate transcriptional regulation of IFNalpha-sensitive genes and generation of growth inhibitory responses.
DNA-Binding Proteins↗
Identification and initial characterization of four novel members of the interleukin-1 family.
Interleukin-1 (IL-1), fibroblast growth factors (FGFs), and their homologues are secreted factors that share a common beta-barrel structure and act on target cells by binding to cell surface receptors with immunoglobulin-like folds in their extracellular domain. While numerous members of the FGF family have been discovered, the IL-1 family has remained small and outnumbered by IL-1 receptor homologues. From expressed sequence tag data base searches, we have now identified four additional IL-1 homologues, IL-1H1, IL-1H2, IL-1H3, and IL-1H4. Like most other IL-1/FGFs, these proteins do not contain a hydrophobic leader sequence. IL-1H4 has a propeptide sequence, while IL-1H1, IL-1H2, and IL-1H3 encode only the mature protein. Circular dichroism spectra and thermal stability analysis suggest that IL-1H1 folds similarly to IL-1ra. The novel homologues are not widely expressed in mammals. IL-1H1 is constitutively expressed only in placenta and the squamous epithelium of the esophagus. However, IL-1H1 could be induced in vitro in keratinocytes by interferon-gamma and tumor necrosis factor-alpha and in vivo via a contact hypersensitivity reaction or herpes simplex virus infection. This suggests that IL-1H1 may be involved in pathogenesis of immune mediated disease processes. The addition of four novel IL-1 homologues suggests that the IL-1 family is significantly larger than previously thought.
Amino Acid Sequence↗
Monodon baculovirus from Australia: ultrastructural observations.
The cytopathology, virogenesis and replication of monodon baculovirus (MBV) in Penaeus monodon from Australia are described. Electron-dense unenveloped nucleocapsids, not previously described for MBV, are shown in the cytoplasm and attached to the nuclear envelope of infected hepatopancreatocytes. These nucleocapsids comprise a missing link in the published literature on the replication cycle of MBV by providing evidence for the means by which the viral genome travels from the plasma membrane of the hepatopancreatocyte to the nucleus. Features similar to those of MBV from other areas, but not previously reported for MBV from Australia include empty capsids attached to the nuclear pore, central filaments in developing capsids, capsids partly filled with nucleic acid, and filaments in subapical envelope expansions. A model for virogenesis and replication is illustrated which takes into account the new observations as well as previously described ultrastructural characteristics of the developing viral particle.
Animals↗
Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways.
Apoptosis is a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and a unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines (FAS/TNF alpha-receptor signaling), stress conditions (chemical or physical, e.g., radiation), sphingolipid metabolites (ceramide) and autocoids, e.g., angiotensin II. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of numerous molecular targets associated with cardiomyocyte apoptosis may provide novel therapeutic strategies for diverse cardiac ailments, as recently suggested by pharmacologic studies in experimental animals. This review paper is aimed to highlight the role of protein kinase signaling pathways in apoptosis with special attention to the stress-activated protein kinases (SAPK) and mitogen-activated protein kinases (MAPK) systems.
Adrenergic alpha-Antagonists↗
Evaluating energetics of erythropoietin ligand binding to homodimerized receptor extracellular domains.
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Animals↗
Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction.
Dengue virus nonstructural protein 1 (NS1) is expressed on the surface of infected cells and is a target of human antibody responses to dengue virus infection. We show here that dengue virus uses the cellular glycosyl-phosphatidylinositol (GPI) linkage pathway to express a GPI-anchored form of NS1 and that GPI anchoring imparts a capacity for signal transduction in response to binding of NS1-specific antibody. This study is the first to identify GPI linkage of a virus-encoded protein. The GPI anchor addition signal for NS1 was identified, by transfection of HeLa cells with dengue cDNA constructs, as a downstream hydrophobic domain in NS2A. GPI linkage of NS1 in both transfected and infected cells was demonstrated by cleavage of NS1 from the surface by PI-specific phospholipase C and by metabolic incorporation of the GPI-specific components ethanolamine and inositol. In common with other GPI-anchored proteins, addition of specific antibody resulted in signal transduction, as evidenced by tyrosine phosphorylation of cellular proteins. Antibody-induced signal transduction by GPI-linked NS1 suggests a mechanism of cellular activation that may contribute to the pathogenesis of human dengue disease. Signal transduction by a GPI-anchored viral antigen interacting with a specific antibody that it induces is a new concept in the pathogenesis of viral disease.
Amino Acid Sequence↗
Non-protein thiols flux to S-nitrosothiols in endothelial cells: an LPS redox signal.
Lipopolysaccharide (LPS) injures blood vessels by activating pathways in the endothelium that lead either to cell survival and proliferation or apoptosis. It has been suggested that these outcomes are determined when reactive oxygen and nitrogen intermediates oxidize low molecular weight non-protein thiols (NPSHs) such as glutathione (GSH) and cysteine (Cys), which serve as major intracellular reducing agents. The oxidoreduction of NPSHs could be an important redox signal if it were shown to occur rapidly following injury. Towards that end, cultured bovine aortic endothelial cells were stained with the thiol fluorescent probe, monobromobimane (MBB). Most of the acid extractable MBB-reactive adducts are GSH (approximately 90%) and Cys (approximately 90%). Within 1 min of LPS exposure, 50-70% of the MBB-reactive NPSHs are consumed without evidence for concomitant net generation of superoxide, hydrogen peroxide, singlet oxygen, or glutathione disulfide (GSSG). Although LPS induces an increased rate of thiol-disulfide exchange, the slight increase does not explain the magnitude of NPSH consumption. Within the first 10 min of recovery from LPS exposure, the MBB-reactive NPSH fluorescence returns at or slightly above baseline values. When HgCl2 was added to the acid extract, one mole of S-nitrosothiol oxidizing equivalent was found for every mole of MBB-reactive NPSH consumed. It is suspected that the rapid flux of MBB-reactive NPSHs and Hg2+-inducible oxidants reflects transition of GSH to GSNO (S-nitrosoglutathione) and could be an important redox signal in endothelial cells exposed to LPS.
Animals↗
An antigen capture enzyme-linked immunosorbent assay reveals high levels of the dengue virus protein NS1 in the sera of infected patients.
We describe the development of a capture enzyme-linked immunosorbent assay for the detection of the dengue virus nonstructural protein NS1. The assay employs rabbit polyclonal and monoclonal antibodies as the capture and detection antibodies, respectively. Immunoaffinity-purified NS1 derived from dengue 2 virus-infected cells was used as a standard to establish a detection sensitivity of approximately 4 ng/ml for an assay employing monoclonal antibodies recognizing a dengue 2 serotype-specific epitope. A number of serotype cross-reactive monoclonal antibodies were also shown to be suitable probes for the detection of NS1 expressed by the remaining three dengue virus serotypes. Examination of clinical samples demonstrated that the assay was able to detect NS1 with minimal interference from serum components at the test dilutions routinely used, suggesting that it could form the basis of a useful additional diagnostic test for dengue virus infection. Furthermore, quantitation of NS1 levels in patient sera may prove to be a valuable surrogate marker for viremia. Surprisingly high levels of NS1, as much as 15 microg/ml, were found in acute-phase sera taken from some of the patients experiencing serologically confirmed dengue 2 virus secondary infections but was not detected in the convalescent sera of these patients. In contrast, NS1 could not be detected in either acute-phase or convalescent serum samples taken from patients with serologically confirmed primary infection. The presence of high levels of secreted NS1 in the sera of patients experiencing secondary dengue virus infections, and in the context of an anamnestic antibody response, suggests that NS1 may contribute significantly to the formation of the circulating immune complexes that are suspected to play an important role in the pathogenesis of severe dengue disease.
Acute Disease↗
Stable high-level expression of heterologous genes in vitro and in vivo by noncytopathic DNA-based Kunjin virus replicon vectors.
Primary features of the flavivirus Kunjin (KUN) subgenomic replicons include continuous noncytopathic replication in host cell cytoplasm and the ability to be encapsidated into secreted virus-like particles (VLPs). Previously we reported preparation of RNA-based KUN replicon vectors and expression of heterologous genes (HG) in cell culture after RNA transfection or after infection with recombinant KUN VLPs (A. N. Varnavski and A. A. Khromykh, Virology 255:366-375, 1999). In this study we describe the development of the next generation of KUN replicon vectors, which allow synthesis of replicon RNA in vivo from corresponding plasmid DNAs. These DNA-based vectors were able to direct stable expression of beta-galactosidase (beta-Gal) in several mammalian cell lines, and expression remained high ( approximately 150 pg per cell) throughout cell passaging. The applicability of these vectors in vivo was demonstrated by beta-Gal expression in the mouse lung epithelium for at least 8 weeks after intranasal inoculation and induction of anti-beta-Gal antibody response after intramuscular inoculation of the beta-Gal-encoding KUN replicon DNA. The noncytopathic nature of DNA-based KUN replicon vectors combined with high-level and stability of HG expression in a broad range of host cells should prove them to be useful in a variety of applications in vitro and in vivo.
Animals↗
Identification of two distinct regions of p38 MAPK required for substrate binding and phosphorylation.
The mechanism by which different mitogen activated protein kinases (MAPKs) distinguish between different substrates is poorly understood. For example, p38 and SAPK4 are two closely related p38 MAPKs that both phosphorylate ATF2 and MBP. However, p38 phosphorylates MAPKAPK-2 and -3, whereas SAPK4 does not. In this study, we have used mutagenesis to determine the regions of p38 required for substrate selection. Alanine scanning mutagenesis identified one region of p38 that was required for its ability to phosphorylate MAPKAPK-2 and -3, but that did not significantly affect its binding to these substrates. Chimeras of p38 and SAPK4 identified a second region of p38 that affected the ability of p38 to both bind and phosphorylate MAPKAPK-2 and -3. Hence, we show for the first time that MAPKs contain two distinct regions for recognizing and phosphorylating protein substrates.
Activating Transcription Factor 2↗
Activation of the p38 mitogen-activated protein kinase by type I interferons.
The p38 mitogen-activated protein (Map) kinase plays a critical role in the generation of signals in response to stress stimuli, but its role in interferon (IFN) signaling and its potential regulatory role in the activation of Jak-signal transducer and activator of transcription (Stat) pathway are not known. In the present study, we provide evidence that the p38 Map kinase is rapidly phosphorylated and activated during treatment of cells with Type I interferons (IFNalpha and IFNbeta). Furthermore, the Type I IFN-dependent activation of p38 regulates induction of the catalytic domains of MapKap kinase-2 and MapKap kinase-3, strongly suggesting the existence of an IFNalpha signaling cascade activated downstream of the p38 kinase. The engagement of this pathway in interferon signaling plays a critical role in interferon-dependent transcriptional regulation, as evidenced by the fact that inhibition of p38 activation results in abrogation of interferon-dependent gene transcription via interferon-stimulated response elements. Interestingly, inhibition of the kinase activity of the p38 blocks IFNalpha-induced gene transcription without inhibiting DNA binding or tyrosine phosphorylation of Stat proteins, suggesting that the p38 pathway acts in cooperation with the Stat pathway. Thus, the p38 kinase signaling cascade is activated by the Type I interferon receptor and plays a critical role in interferon signaling and interferon-dependent transcriptional regulation.
Base Sequence↗
Ceramide and cyclic adenosine monophosphate (cAMP) induce cAMP response element binding protein phosphorylation via distinct signaling pathways while having opposite effects on myeloid cell survival.
The role of ceramide as a second messenger is a subject of great interest, particularly since it is implicated in signaling in response to inflammatory cytokines. Ceramide induces apoptosis in both cytokine-dependent MC/9 cells and factor-independent U937 cells. Elevation of cyclic adenosine monophosphate (cAMP) levels inhibits apoptosis induced by ceramide and several other treatments. One target of cAMP-mediated signaling is the transcription factor CREB (cAMP response element binding protein), and recently CREB phosphorylation at an activating site has been shown to also be mediated by a cascade involving p38 mitogen-activated protein kinase (MAPK), one of the stress-activated MAP kinases. Because no role for p38 MAPK in apoptosis has been firmly established, we examined the relationship between p38 MAPK and CREB phosphorylation under various conditions. Ceramide, or sphingomyelinase, like tumor necrosis factor- (TNF-) or the hematopoietic growth factor, interleukin-3 (IL-3), was shown to activate p38 MAPK, which in turn activated MAPKAP kinase-2. Each of these treatments led to phosphorylation of CREB (and the related factor ATF-1). A selective p38 MAPK inhibitor, SB203580, blocked TNF-- or ceramide-induced CREB phosphorylation, but had no effect on the induction of apoptosis mediated by these agents. The protective agents cAMP and IL-3 also led to CREB phosphorylation, but this effect was independent of p38 MAPK, even though IL-3 was shown to activate both p38 MAPK and MAPKAP kinase-2. Therefore, the opposing effects on apoptosis observed with cAMP and IL-3, compared with ceramide and TNF-, could not be explained on the basis of phosphorylation of CREB. In addition, because SB203580 had no effect of TNF- or ceramide-induced apoptosis, our results strongly argue against a role for p38 MAPK in the induction of TNF-- or ceramide-induced apoptosis.
Animals↗
Patients don't present with five choices: an alternative to multiple-choice tests in assessing physicians' competence.
PURPOSE: To evaluate an open-ended, computer-scored testing format designed to overcome certain limitations of multiple-choice questions. METHOD: Test items covering content in family medicine were administered in two different formats to 7,036 resident physicians in 380 training programs, and to 35 experienced, board-certified physicians in conjunction with the In-training Examination of the American Board of Family Practice. Examinees completed a booklet of 40 open-ended, uncued (UnQ) test items by selecting the answer to each item from a list of over 500 responses. Similar items were administered using the standard multiple-choice question (MCQ) format. One year later, another test of 40 UnQ test items dealing with core content in family medicine was administered to 7,138 residents. RESULTS: Examinees completed over 560,000 UnQ responses with high compliance and few errors. Both reliability and validity for the UnQ format were higher than for the MCQ format, and the UnQ items discriminated more accurately among levels of physicians' experience. The UnQ format almost eliminated the possibility that the physicians could answer questions by sight recognition or random guessing, and it was particularly effective in measuring knowledge of core content. CONCLUSIONS: This study supports the feasibility of administering open-ended test items to enhance tests of physicians' competence.
Clinical Competence↗