Value of the real-time myocardial contrast echocardiography for risk stratification and for the detection of significant coronary stenosis in patients with end-stage renal disease.

Sir, Coronary artery disease (CAD) is common in patients with end-stagerenal disease (ESRD), and is associated with poor clinical outcome.However, routine screening for CAD in asymptomatic ESRD patientsis usually not required, except for renal transplant candidates[1]. Myocardial contrast echocardiography (MCE) is a new bedsidetechnique providing information regarding myocardial tissueperfusion. The assumption that MCE might be useful in patientswith ESRD has not been previously investigated. Moreover, thereare no published data concerning prognostic utility of MCE inpatients with ESRD. The aim of the study was to assess the prognostic significanceof MCE in patients with ESRD, and to     

The effect of loperamide on anorectal function in normal healthy men.

Loperamide improves anorectal functioning in patients with diarrhea and incontinence. Loperamide reduces sensitivity of the recto-anal inhibitory reflex and increases internal anal sphincter tone. Additionally, it has an effect on rectal compliance in incontinent patients with diarrhea. We studied the effect of loperamide versus placebo at different distances from the anal verge in 18 healthy male volunteers, using standard anorectal manometry was a double-blind, two-factorial design. We found that the recto-anal inhibitory reflex is most pronounced when stimulated in regions close to the anal canal and that distention stimuli are also perceived best in that region. Both effects are counteracted by loperamide. We found no effect on internal sphincter tone or rectal compliance. These results imply a gradient of sensitivity for rectal perception and the recto-anal inhibitory reflex in healthy volunteers. Loperamide action on both mechanisms suggests a common mediator for both effects.     

Phosphoinositide 3-kinase is involved in the induction of the human sperm acrosome reaction downstream of tyrosine phosphorylation

In somatic cells phosphoinositide 3-kinase (PI 3-kinase) is activated upon interaction with both receptor tyrosine kinases (RTK) and G- proteins resulting in the production of moieties involved in the inositol phospholipid signalling pathway. As G proteins, RTK and the inositol phospholipids have all been implicated in the human sperm acrosome reaction, experiments were carried out to determine whether PI 3-kinase was also involved in this phenomenon. Wortmannin is a selective inhibitor of PI 3-kinase and was shown to significantly inhibit the acrosome reaction induced by both mannose-bovine serum albumin (mannose-BSA) (10, 50 and 100 nM) and a polyclonal antibody raised against an extracellular region of the sperm zona receptor kinase (ZRK, at 100 nM only). Wortmannin did not inhibit the A23187- or progesterone-induced acrosome reaction. These results suggest that PI 3- kinase is involved in the human sperm acrosome reaction. The levels of tyrosine phosphorylation of sperm proteins as detected by Western blotting using antiphosphotyrosine antibodies was not affected by wortmannin in agonist (A23187 and mannose-BSA)-stimulated spermatozoa. This indicated that PI 3-kinase operates downstream of tyrosine phosphorylation in the signal transduction cascade which leads to the human sperm acrosome reaction.      

Likelihood ratios in the diagnosis of renal artery stenosis by magnetic resonance angiography compared with renal angiography

BACKGROUND: Renal angiography (RA) is considered to be the gold standard for the diagnosis of renal artery stenosis (RAS). However, it is invasive and potentially harmful; hence there is a need for an optimal noninvasive test. Magnetic resonance angiography (MRA) is currently accepted as the optimal noninvasive test by many. However, its major drawback is its inability to grade quantitatively the degree of stenosis. In this study, likelihood ratios (LR) were used to compare the diagnostic accuracy of MRA with that of RA. METHODS: To test the hypothesis that semiquantitatively graded MRA would correlate with RA, a retrospective analysis was performed to determine the LR of MRA to diagnose RAS compared with RA. It was believed that LR > or = 10.0 or < or =0.1 might generate conclusive changes from pretest to post-test probabilities. In this study a total of 94 renal arteries from 48 patients were analyzed for RAS by MRA and RA. Stenoses were graded by MRA as mild (<50%), moderate (50% to 75%), or severe (>75%); and by RA as <75% or > or =75% stenosis. RESULTS: The LR was 0.13 (95% CI = 0.09 to 0.19) for mild stenosis, 0.11 (95% CI = 0.08 to 0.15) for moderate stenosis, and 2.2 (95% CI = 1.9 to 3.1) for severe stenosis by MRA. CONCLUSIONS: Nonsevere stenosis can be sufficiently diagnosed by MRA and may not warrant RA. However, it may be insufficiently precise to establish severe RAS based on LR results. Therefore, for severe RAS by MRA, the decision to obtain RA can be made with the help of post-test probability, which is determined using pretest probability and LR.     

Esperamicins, a class of potent antitumor antibiotics: mechanism of action

The esperamicins represent a class of antitumor antibiotics characterized by an unusual chemical core structure and extremely potent cytotoxicity. The mechanism by which these drugs produce cytotoxicity was investigated and found to be related to the formation of single- and double-strand DNA breaks. Using five structurally related analogs, we defined a structure-activity relationship for cytotoxicity in various eukaryotic and DNA-repair-deficient prokaryotic cell lines, for DNA breakage in a human colon carcinoma cell line, and for DNA breakage in vitro in pBR322 DNA. Mild reducing agents such as dithiothreitol greatly increased the DNA breakage potency of these analogs in vitro. Results suggest that the pendant aromatic chromophore of esperamicin A1 may contribute to the uptake of the drug into cells but may also hinder double-strand DNA break formation. Little DNA breakage specificity was observed for the drug in a 139-base-pair fragment of pBR322 DNA. Evidence supports a previously proposed mechanism whereby esperamicins may produce the observed DNA breaks through reduction of the methyl trisulfide group to a thiolate anion followed by a Michael addition of the anion across the alpha,beta-unsaturated ketone. This addition may result in the saturation of the bridgehead double bond, thus allowing the two triple bonds to approach each other, causing cyclization of the diyn-ene to form a phenylene diradical. It is likely that this diradical is the active form of the drug responsible for single- and double-strand DNA breakage produced by this class of antitumor agents.     

A monoclonal antibody-defined membrane antigen complex is required for neutrophil-neutrophil aggregation

We examined the aggregation responses of normal neutrophils treated with the murine monoclonal antibody (MoAb) 60.3. Addition of MoAb 60.3 to normal neutrophils produced dose-dependent inhibition of neutrophil aggregation in response to phorbol myristate acetate, zymosan-activated plasma, and N-formyl-methionylleucylphenylalanine. We conclude that the membrane glycoprotein complex recognized by MoAb 60.3--designated CDw18- -is required for neutrophil-neutrophil aggregation in vitro.