Regulation of antigen receptor signal transduction by protein tyrosine kinases

The purpose of this study was to assess the value of electron beam computed tomography in the detection of cardiac calcifications in coronaries and valves of dialysis patients and to determine the rate at which calcification progresses. Forty-nine chronic hemodialysis patients aged 28 to 74 years were compared with 102 non-dialysis patients aged 32 to 73 years with documented or suspected coronary artery disease, all of whom underwent coronary angiography. We used high-resolution electron beam computed tomography scanning to make 30 axial slices with a distance of 3 mm between each slice. The number of calcifications, the surface area, and the average and highest density values were measured. We calculated a quantitative coronary artery calcium score and assessed calcification of mitral and aortic valves. In dialysis patients, the measurements were repeated after 12 months. The coronary artery calcium score was from 2.5-fold to fivefold higher in the dialysis patients than in the non-dialysis patients. Hypertensive dialysis patients had higher calcium scores than non-hypertensive dialysis patients (P < 0.05). A stepwise, multiple regression analysis confirmed the importance of age and hypertension. No correlation between calcium, phosphate, or parathyroid hormone values and the coronary calcium score was identified; however, the calcium score was inversely correlated with bone mass in the dialysis patients (r = 0.47, P < 0.05). The mitral valve was calcified in 59% of dialysis patients, while the aortic valve was calcified in 55%. The coronary artery calcium score was correlated with aortic valvular, but not mitral valvular calcification. A repeat examination of the dialysis patients at an interval of 1 year showed a disturbing tendency for progression. Our data under-score the frequency and severity of coronary and valvular calcifications in dialysis patients, and illustrate the rapid progression of this calcification. Finally, they draw attention to hypertension as an important risk factor in this process.     

Incremental value of myocardial perfusion scintigraphy in prognosis and outcomes of patients with coronary artery disease

The concept of incremental value in prognosis and outcome of patients with coronary artery disease is important to the field of noninvasive imaging. Because these tests are expensive, they should be held to the standard of demonstrating a statistical improvement over the information provided by clinical assessment and treadmill testing. Responding to the demand for cost-effective applications of myocardial perfusion scintigraphy, a large amount of research has recently been devoted to defining specific patient subsets in which incremental value exists for scintigraphy. Subsets thus far demonstrated to benefit incrementally include those men and women referred for possible coronary artery disease, with known coronary artery disease, and after percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, unstable angina, or recent infarction. Incremental cost savings also apply to these subsets except for patients with normal ECGs at rest and less than 15% likelihood for significant coronary artery disease.     

Kinematic analysis of patients with spinal muscular atrophy during spontaneous breathing and mechanical ventilation

Dinoseb is a herbicide known to inhibit photosystem II electron transfer like DCMU, triazine and phenolic-type herbicides. The mutant Din7 of the cyanobacterium Synechocystis sp. PCC 6803, selected for resistance to dinoseb, and the mutant Ins2, constructed by the insertion of the kanamycin resistance cassette into the drgA gene, were cross-resistant to other nitrophenolic herbicides (DNOC, 2,4-dinitrophenol) and to the cell inhibitor metronidazole but not to the photosystem II inhibitors DCMU or ioxynil. The Din7 mutant had the same characteristics of photosystem II inhibition by dinoseb as the wild type. This result suggested the existence of another site for dinoseb inhibition. The wild type cells modified dinoseb to a non-toxic product that gave an absorption spectrum similar to that of dithionite treated dinoseb containing reduced nitro groups. In contrast, the Din7 mutant did not modify dinoseb. These phenomena were controlled by the drgA gene encoding a protein which showed similarity to several enzymes having nitroreductase activity. The addition of superoxide dismutase to the medium relieved the toxic effect of dinoseb in wild type cells but not in Din7. It is proposed that in wild type cells of Synechocystis sp. PCC 6803 the DrgA protein is involved in detoxification of dinoseb via the reduction of the nitro group(s) and this process is accompanied by the formation of toxic superoxide anions. Mutations blocking the activity of the DrgA protein lead to the development of resistance to nitrophenolic herbicides and metronidazole.     

Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox

The agr P2 operon in Staphylococcus aureus codes for the elements of a density-sensing cassette made up of a typical two-component signalling system and its corresponding inducer. It is postulated that the autoinducer, a post-translationally modified octapeptide generated from the AgrD peptide, interacts with a receptor protein, coded by agrC, to transmit a signal via AgrA regulating expression of staphylococcal virulence genes through expression of agr RNA III. We show by analysis of PhoA fusions that AgrC is a transmembrane protein, and confirm using Western blotting that a 46 kDa protein corresponding to AgrC is present in the bacterial membrane. This protein is autophosphorylated on a histidine residue only in response to supernatants from an agr+ strain, and can also respond to the purified native octapeptide. A recombinant fusion protein where most of the N-terminal region of AgrC is replaced by the Escherichia coli maltose-binding protein is also autophosphorylated in response to stimulation by agr+ supernatants or purified octapeptide. We conclude that AgrC is the sensor molecule of a typical two-component signal system in S. aureus, and that the ligand-binding site of AgrC is probably located in the third extracellular loop of the protein.     

Manifestations of scleroderma pulmonary disease

Scleroderma is a multisystem disease of unknown cause characterized by synthesis and deposition of excessive extracellular matrix and vascular anti-GBM antibodies, leading to pulmonary hemorrhage and glomerulonephritis with rapidly progressive renal insufficiency. Recent advances in the understanding of disease pathogenesis and diagnosis and treatment have significantly improved our ability to recognize the syndrome, distinguish it from other similar disorders, and offer successful treatment. This article focuses on the pathogenetic features, clinical manifestations, diagnostic strategies, and therapeutic principles of anti-GBM disease.     

Characterization of CD34+ thymic stromal cells located in the subcapsular cortex of the human thymus

In this paper we report that suspensions of human fetal thymocytes contain cells that express high levels of CD34 and Thy-1. These cells were characterized with regard to location within the thymus, phenotype, and function. Confocal laser scan analysis of frozen sections of fetal thymus with anti-CD34 and Thy-1 antibodies revealed that the double-labeled cells were located in the pericortical area. In addition, it was found that the CD34+Thy-1+ cells lacked CD45 and CD50, indicating that these cells are not of hematopoietic origin; this was confirmed by the finding that these cells could be cultured as adherent cells in a medium with cholera toxin and dexamethasone, but failed to grow in mixtures of hematopoietic growth factors. Further analysis indicated that most cultured CD34+Thy-1+ cells expressed cytokeratin (CK) 14 but lacked CK 13, suggesting that these cells are immature epithelial cells. Cultured CD34+Thy-1+ cells were able to induce differentiation of CD1-CD34+CD3-CD4-CD8- thymic precursors into CD4+CD8+ cells in a reaggregate culture in the absence of exogenous cytokines. The CD4+CD8+ cells that developed in these cultures did not express CD3, indicating that CD34+Thy-1+ thymic stromal cells are not capable of completing full T cell differentiation of thymic hematopoietic progenitor cells.     

Hydrogen peroxide induces protection against lethal effects of cumene hydroperoxide in Escherichia coli cells: an Ahp dependent and OxyR independent system?

Despite a large body of evidence showing the beneficial effects of successful treatment of anemia with recombinant human erythropoietin (EPO) in patients with end-stage renal disease, controversy remains as to whether EPO treatment of anemia can improve the nutritional status in patients on maintenance hemodialysis. This prompted us to conduct a prospective study in 41 hemodialysis patients with basal hemoglobin less than 9 g/dl. The dose of EPO was increased for 12 weeks to achieve the target hemoglobin concentration of 10 g/dl and then titrated in the following 12 weeks to maintain the target value. Nutritional status was assessed at baseline and after 6 months of follow-up, using the global protein-calorie malnutrition (PCM) index proposed by Bilbrey and Cohen. A low global PCM score indicates better nutrition. The results showed that hemoglobin values significantly increased from 8.7 +/- 0.8 g/dl at baseline to 10.7 +/- 0.5 g/dl in the 6th month (p < 0.001). No significant changes were observed in the normalized protein catabolic rate and Kt/V during the study period. Global PCM scores improved from 30.0 +/- 7.5 to 23.6 +/- 3.1 (p < 0.001) and paralleled the correction of anemia by EPO treatment. The data were consistent with a major improvement in the nutritional markers of relative body weight, triceps skinfold, midarm circumference, midarm muscle circumference, serum albumin, serum transferrin and total lymphocyte count in the 6th month as compared to baseline. The percentages of mild and moderate-severe PCM at baseline were 32 and 58%, respectively. These percentages were significantly reduced during the 6th month to 20 and 30%, respectively (p = 0.0004). In summary, correction of renal anemia with EPO improves the nutritional status in hemodialysis patients. A postulated mechanism is that EPO may exhibit anabolic effects, with a better utilization of ingested protein.