Diagnostic dilemma. Gangrenous cholecystitis.
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Abscess↗
Biomedical subjects
J Yee
Publications and source records attributed to J Yee.
Transcriptional analysis of the glutamate dehydrogenase gene in the primitive eukaryote, Giardia lamblia. Identification of a primordial gene promoter.
We studied gene expression in the ancient eukaryote, Giardia lamblia, by taking advantage of assays developed recently in our laboratory, which allow new genetic analyses of this organism. We examined the transcription of a 2.2-kilobase segment of the Giardia genome that contains the glutamate dehydrogenase (GDH) gene and a portion of a second open reading frame encoding an uncharacterized gene. Nuclear run-on analyses showed that the genes are transcribed as two separate units spaced less than 200 base pairs apart, and transcription of the GDH gene initiates just 3-6 nucleotides upstream of its translation start codon. We characterized the GDH promoter by transfecting Giardia with DNA constructs that used the GDH upstream sequence to drive the expression of a luciferase reporter gene. By deletion and mutational analyses, we localized promoter function to three motifs within a 50-base pair region of the GDH upstream sequence. Using band shift assays and UV cross-linking, we demonstrated specific binding of a 68-kDa protein from Giardia nuclear extracts to short poly(T) tracts contained within two of the sequence motifs on single-stranded DNA from the promoter region. This report describes one of the first functional gene promoter and its cognate DNA-binding protein in this primitive eukaryote.
Animals↗
Balance of mass, momentum, and energy in splintering central collisions for 40Ar up to 115 MeV /Nucleon
For central collisions of (17-115)A MeV 40Ar+Cu, Ag, Au, an overall balance is determined for the average mass, energy, and longitudinal momentum. Light charged particles and fragments are separated into forward-focused and isotropic components in the frame of the heaviest fragment. Energy removal by the isotropic component reaches 1-2 GeV. For such high deposition energies, statistical multifragmentation models predict much more extensive nuclear disassembly than is observed.
Journal Article↗
Thyroid hormone receptor, v-ErbA, and chromatin.
The thyroid hormone receptor and the highly related viral oncoprotein v-erbA are found exclusively in the nucleus as stable constituents of chromatin. Unlike most transcriptional regulators, the thyroid hormone receptor binds with comparable affinity to naked and nucleosomal DNA. In vitro reconstitution experiments and in vivo genomic footprinting have delineated the chromatin structural features that facilitate association with the receptor. Chromatin bound thyroid hormone receptor and v-erbA generate Dnase I hypersensitive sites independent of ligand. The unliganded thyroid hormone receptor and v-erbA associate with a corepressor complex containing NCoR, SIN3, and histone deacetylase. The enzymatic activity of the deacetylase and a chromatin environment are essential for the dominant repression of transcription by both the unliganded thyroid hormone receptor and v-erbA. In the presence of ligand, the thyroid hormone receptor undergoes a conformational change that weakens interactions with the corepressor complex while facilitating the recruitment of transcriptional coactivators such as p300 and PCAF possessing histone acetyltransferase activity. The ligand-bound thyroid hormone receptor directs chromatin disruption events in addition to histone acetylation. Thus, the thyroid hormone receptor and v-erbA make very effective use of their stable association with chromatin and their capacity to alter the chromatin environment as a major component of the transcription regulation process. This system provides an exceptionally useful paradigm for investigating the structural and functional consequences of targeted chromatin modification.
Animals↗
Risks associated with renal dysfunction in patients in the coronary care unit.
OBJECTIVES: The purpose of this study was to quantify the impact of baseline renal dysfunction on morbidity and mortality in patients in the coronary care unit (CCU). BACKGROUND: The presence of renal dysfunction is an established independent predictor of survival after acute myocardial infarction and revascularization procedures. METHODS: We analyzed a prospective CCU registry of 12,648 admissions by 9,557 patients over eight years at a single, tertiary center. Admission serum creatinine was available in 9,544 patients. Those not on long-term dialysis were classified into quartiles of corrected creatinine clearance, with cut-points of 46.2, 63.1 and 81.5 ml/min per 72 kg. Dialysis patients (n = 527) were considered as a fifth comparison group. RESULTS: Baseline characteristics, including older age, African-American race, diabetes, hypertension, previous coronary disease and heart failure, were incrementally more common across increasing renal dysfunction strata. There were graded increases in the relative risk for atrial and ventricular arrhythmias, heart block, asystole, development of pulmonary congestion, acute mitral regurgitation and cardiogenic shock across the risk strata. Survival analysis demonstrated an early mortality hazard for those with renal dysfunction, but not on dialysis, for the first 60 months, followed by graded decrements in survival across increasing renal dysfunction strata. CONCLUSIONS: Baseline renal function is a powerful predictor of short- and long-term events in the CCU population. There is an early hazard for in-hospital and postdischarge mortality for those with a corrected creatinine clearance <46.2 ml/min per kg, but not on dialysis.
Aged↗
A novel HLA-B*40 allele and novel exon 1 sequences of two B*40 alleles identified in potential marrow donors.
Sequence-specific oligonucleotide probe hybridization and sequence-specific primer polymerase chain reaction (PCR) typing suggested the presence of variants of HLA-B*40 in three individuals. Two were part of 3,500 potential marrow donors being screened for the National Marrow Donor Program, while the third was a clinical specimen. PCR products encompassing HLA-B locus exons 1 through 3 were prepared and subcloned. In one individual, a native of the Pacific Islands, sequencing revealed a novel HLA-B*40 allele (B*4023). In two other individuals, a previously unknown exon 1 sequence was determined for HLA-B*4016 (ethnicity unknown) and B*4020 (Hispanic). These findings further illustrate the substantial genetic variation present at the HLA-B locus within human populations.
Alleles↗
Novel HLA-B*15 alleles identified in potential marrow donors.
Several methods for low-resolution class I typing of potential bone marrow donors are available. The National Marrow Donor Program (NMDP) has initiated pilot projects for large-scale DNA-based class I typing to initially characterize donors. Sequence-specific oligonucleotide probe hybridization and sequence-specific primer polymerase chain reaction (PCR) screening of 3,500 NMDP potential donors suggested the presence of variants of known HLA-B*15 variants in 3 donors. PCR products encompassing HLA-B locus exons 1 through 3 were prepared and subcloned. Sequencing revealed 3 alleles differing from known HLA-B*15 alleles by nucleotide substitutions resulting in predicted novel HLA-B antigens. The new alleles occur in distinct ethnic groups. These findings further illustrate the substantial genetic variation present at the HLA-B locus within human populations.
Alleles↗
F-actin fiber distribution in glomerular cells: structural and functional implications.
BACKGROUND: Glomerular distention is associated with cellular mechanical strain. In addition, glomerular distention/contraction is assumed to influence the filtration rate through changes in filtration surface area. A contractile cytoskeleton in podocytes and mesangial cells, formed by F-actin-containing stress fibers, maintains structural integrity and modulates glomerular expansion. In this study, the glomerular cell distribution of F-actin and vimentin filaments was studied in normal control and nine-month streptozotocin-diabetic rats. Results in situ were compared with observations in tissue culture. METHODS: Microdissected rat glomeruli were perfused to obtain a physiological 25% glomerular expansion over the basal value. Fixation was done without change in glomerular volume. Dual fluorescent labeling of F-actin and vimentin was carried out, and samples were examined by confocal laser scanning microscopy. RESULTS: The podocyte cell bodies and their cytoplasmic projections, including the foot processes, contained bundles of vimentin-containing fibers. Except for a thin layer at the base of foot processes, they did not demonstrate F-actin. While mesangial cells in culture had F-actin as long stress fibers resembling tense cables, mesangial cells stretched in situ contained a maze of short tortuous F-actin fibers organized in bundles that often encircled vascular spaces. This fibrillar organization was disrupted in diabetic glomeruli. CONCLUSION: Mesangial cells, but not podocytes, contain a cytoskeleton capable of contraction that is disorganized in long-term diabetes. Together with previous observations, the distribution of this cytoskeleton suggests that mesangial cell contraction may be involved in the redistribution of glomerular capillary blood flow, but not substantially in the modulation of glomerular distention. Disorganization of stress fibers may be a cause of hyperfiltration in diabetes.
Actins↗
Modelling the effects of vascular stress in mesangial cells.
It has recently been shown that mesangial cells are subjected to multiple forms of mechanical strain (fluid shear, hydrostatic pressure, and triaxial stretch) as a result of forces exerted by the vasculature. Nevertheless, the exact nature and the relative response to these stimuli have not been clarified. Although it is now well established that cyclic stretching of mesangial cells in culture results in the overproduction of extracellular matrix, indicating how intraglomerular hypertension may lead to glomerular scar formation, the contribution of different intracellular signalling mechanisms and extracellular mediators of the response are only now being identified. Recent studies point to a role for high glucose concentrations, transforming growth factor beta and its receptors, vascular endothelial growth factor, and connective tissue growth factor as important mediators, or modifiers of the response to mechanical strain. Although evidence exists for a role for protein kinase C, recent studies also implicate the mitogen-activated protein kinases along with enhanced DNA-binding activity of AP-1 as part of the signalling cascade altering matrix synthesis and cell proliferation in response to stretch. Finally, recent studies examining the effects of oscillating hyperbaric pressure demonstrate similarities, as well as differences, in comparison to those of cyclic stretch.
Animals↗
Simian immunodeficiency viruses of diverse origin can use CXCR4 as a coreceptor for entry into human cells.
Primary simian immunodeficiency virus (SIV) isolated from sooty mangabey (SIVsm [n = 6]), stumptail (SIVstm [n = 1]), mandrill (SIVmnd [n = 1]), and African green (SIVagm [n = 1]) primates were examined for their ability to infect human cells and for their coreceptor requirements. All isolates infected human peripheral blood mononuclear cells (PBMCs) from a CCR5(+/+) donor, and seven of eight isolates tested also infected CCR5(-/-) PBMCs. Analysis of coreceptor utilization using GHOST and U87 cell lines revealed that all of the isolates tested used CCR5 and the orphan receptors STRL33 and GPR15. Coreceptors such as CCR2b, CCR3, CCR8, and CX3CR1 were also utilized by some primary SIV isolates. More importantly, we found that CXCR4 was used as a coreceptor by the SIVstm, the SIVagm, and four of the SIVsm isolates in GHOST and U87 cells. These data suggest that primary SIV isolates from diverse primate species can utilize CXCR4 for viral entry, similar to what has been described for human immunodeficiency viruses.
Animals↗
Sublingual capnometry : in search of its holy grail.
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Capnography↗
Littoral cell angioma of the spleen: imaging features.
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Hemangioma↗
Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis.
BACKGROUND: Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate. METHODS: Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group). RESULTS: Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups. CONCLUSIONS: Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients.
Adult↗
Characterization of the rat mesangial cell type 2 sulfonylurea receptor.
BACKGROUND: Sulfonylurea receptors are classified as either high-affinity type 1 (SUR1) or low-affinity type 2 receptors (SUR2), and the gene expression of SURs has recently been demonstrated in kidney. However, functional data regarding a renal SUR are lacking. We previously demonstrated that mesangial cell (MC) gene and protein expression of extracellular matrix components were up-regulated by the sulfonylurea, tolazamide. After noting this biological response, we next sought to investigate the presence of a sulfonylurea receptor in rat MCs. METHODS: Equilibrium binding studies employing [3H]glibenclamide as a ligand were performed on crude MC membrane preparations. Gene expression for SUR was explored by Northern analysis of cultured MCs and whole kidney tissue. The effect of sulfonylurea on intracellular Ca2+ in MCs was assayed by spectrofluorometry, and glibenclamide-induced changes in the contractility of MCs were assessed. RESULTS: MCs bound [3H]glibenclamide with a KD of 2.6 microM and a Bmax of 30.4 pmol/mg protein as determined by Scatchard analysis. Three SUR2 transcripts were detected in MCs. A major transcript was detected at 5.5 kb and minor transcripts at 7.5 and 8.6 kb. Following sulfonylurea treatment of MCs, real-time videomicroscopy revealed intense MC contraction, coinciding with oscillatory increments of intracellular Ca2+ concentration. Further evidence of sulfonylurea-induced MC contraction was demonstrated by glibenclamide-induced deformation of a silicone rubber substrate. CONCLUSIONS: These results demonstrate that SUR2 resides on MCs. Functional activation of this receptor by sulfonylurea induces Ca2+ transients that result in MC contraction.
ATP-Binding Cassette Transporters↗
TGF-beta receptor expression and binding in rat mesangial cells: modulation by glucose and cyclic mechanical strain.
BACKGROUND: Transforming growth factor-beta (TGF-beta) is a causal factor in experimental glomerulosclerosis, and it mediates the increased extracellular matrix (ECM) accumulation that occurs in cultured mesangial cells (MCs) exposed to high glucose concentrations and cyclic mechanical strain. This change is associated with increased levels of TGF-beta, but may also involve alterations in receptor expression and binding. METHODS: Rat MCs cultured in media containing either 8 or 35 mM glucose were seeded into culture plates with elastin-coated flexible bottoms. Thereafter, they were subjected to cyclic stretch or static conditions and then examined for 125I-TGF-beta1 binding and expression of TGF-beta receptors at the gene and protein levels. RESULTS: Kinetic studies showed that MCs bound TGF-beta1 in a time- and concentration-dependent manner, expressing 6800 high-affinity receptors per cell, with an apparent dissociation constant (Kd) of 15.4 pM, while cross-linking analysis identified three TGF-beta receptors (betaR) corresponding to betaRI, betaRII, and betaRIII of 54, 73, and 200 kDa, respectively. Immunocytochemical studies of betaRI and betaRII protein revealed MC expression in a homogeneous, punctate distribution, whereas Northern analysis demonstrated the presence of the corresponding mRNAs. Exposure to cyclic stretching significantly increased (10%) the overall number of TGF-beta receptors, whereas ligands associated with betaRs I, II, and III also increased (25 to 50%). The finding of increased (30 to 40%) betaRI and betaRII transcript levels and immunoreactive protein (163 and 59%, respectively) in the absence of significant changes in the apparent Kd indicated that stretch-induced binding was the result of increased receptor synthesis and expression and not due to a change in binding affinity. In a similar, but more dramatic fashion, exposure to high glucose also elevated (50%) the receptor number, as well as the amount of ligands associated with betaRs I, II, and III (100 to 250%). This same treatment also increased the levels of betaRI and betaRII mRNA (30 to 40%) and the immunoreactive protein (82 and 82%, respectively), without significantly altering the binding affinity of the receptor. A concerted or synergistic effect of both stimuli was not evidenced. CONCLUSION: These results suggest that the modulation of TGF-beta receptors may be an additional control point in mediating the glucose- and mechanical force-induced increase in ECM deposition by MCs.
Activin Receptors, Type I↗
Mechanical strain of glomerular mesangial cells in the pathogenesis of glomerulosclerosis: clinical implications.
Due to their elasticity, glomeruli will undergo excessive expansion and repetitive cycles of distension contraction under conditions of impaired glomerular pressure autoregulation and systemic arterial hypertension. These alterations in glomerular volume are associated with mesangial cell stretch which in turn stimulates the synthesis and deposition of ECM with eventual mesangial expansion and glomerulosclerosis. Hyperactivity of growth factors with prosclerotic activity is an important component in the translation of cellular mechanical strain into the abnormal metabolism of ECM components. Although mesangial cell mechanical strain is expected to occur in both remnant glomeruli and in glomeruli of diabetic kidneys, quantitatively different factors will determine the resultant metabolic consequences. In remnant glomeruli, the mechanical stretch is intense, being accounted for largely by the marked glomerular hypertrophy and increased glomerular compliance. In diabetic glomeruli, however, the mechanical stretch is less prominent but its effect on ECM synthesis is markedly aggravated by the presence of hyperglycaemia. There are presently no methods clinically available to diminish the prosclerotic action of growth factors at the glomerular level. In addition, there are no effective means to specifically improve glomerular pressure autoregulation. Therefore, current therapies must be aimed at decreasing systemic arterial pressure, blocking angiotensin II action and reducing glomerular hypertrophy. While there are effective drugs for the treatment of hypertension and for angiotensin II inhibition, protein restriction is the only measure available to diminish glomerular hypertrophy. Finally, in diabetes correction of systemic and glomerular hypertension should be coupled with strict glycaemic control to correct both glomerular autoregulation and increased ECM deposition.
Biomechanical Phenomena↗
Mechanisms for the diminished neutrophil exudation to secondary inflammatory sites in infected patients with a systemic inflammatory response (sepsis).
OBJECTIVE: To determine the mechanism for the reduced polymorphonuclear neutrophil exudation to secondary inflammatory sites in critically ill patients with infection and systemic inflammatory response (sepsis). DESIGN: Prospective cohort study. SETTING: Research laboratory and integrated intensive care unit of a tertiary care university-affiliated teaching hospital. PATIENTS: Healthy subjects or critically ill patients with confirmed infection and a systemic inflammatory response (septic patients). MEASUREMENTS AND MAIN RESULTS: We found that polymorphonuclear neutrophil delivery to a secondary inflammatory site (skin window blisters) is reduced by >70% in humans with sepsis, defined as serious infection and a systemic inflammatory response compared with healthy controls. The expression of the endothelial adhesion molecules intercellular adhesion molecule-1, E-selectin and P-selectin in microvessels from skin biopsies was comparable in the two study groups. Also, CD11a and CD11b levels were equal in circulating polymorphonuclear neutrophils (PMNs) from both study groups. Both adhesion molecules were markedly and equally up-regulated during exudation. Circulating PMNs from septic patients showed marked shedding of L-selectin compared to those of healthy controls, with a corresponding increase in their plasma L-selectin levels. An increased concentration gradient between plasma and exudate fluid was found for tumor necrosis factor-alpha and interleukin-8 in septic patients, but not for C5a. The phagocytic and bactericidal capacity of septic patient circulating PMNs was higher then in healthy control patients, but these differences were lost after exudation. There were no major differences in oxidative burst or intracellular calcium flux of circulating PMNs from the two study groups. Polymorphonuclear neutrophil exudation primed both responses to different extents. CONCLUSIONS: Septic patients deliver fewer PMNs to secondary inflammatory sites. In addition, neutrophil exudation results in loss of the small priming effect for phagocytosis and bactericidal function induced by sepsis. Failure to produce a gradient to C5a and intravascular shedding of L-selectin may be responsible for this sepsis-induced reduction in neutrophil exudation to secondary inflammatory sites.
Biomarkers↗
Selective review of key perioperative renal-electrolyte disturbances in chronic renal failure patients.
The medical care of chronic renal failure patients is often complicated by the comorbid conditions of hypertension and coronary artery disease in the perioperative period. The limitations on solute and water excretion imposed by renal dysfunction increase the susceptibility of this population to both salt deficit and surfeit, as well as hyponatremia and hypernatremia perioperatively. Accurate assessment and successful treatment of these complications in renal failure patients require understanding of the concept of electrolyte-free water, proper utilization of diuretics, and calculated prescription of fluid therapy. The presence of hyperkalemia in the adapted renal failure patient generally indicates a severe reduction in glomerular filtration, such that nonrenal hypokalemic treatments are imperative. IV calcium-based therapy and infusion of insulin with glucose represent the mainstays of immediate therapy, and sodium bicarbonate therapy should be given only when severe acidemia is present. Perioperative aggravation of preexistent hypertension is common. Rebound hypertension attributable to injudicious adjustment of the medical regimen should be diligently searched for first, before any new therapies are recommended. Relief of pain or anxiety may be all that is necessary. Briefly acting calcium channel blocker therapy should not be employed in these cases, and smooth IV control by a variety of agents is preferable, the choice of the agent contingent on the clinical scenario.
Antihypertensive Agents↗