Biomedical subjects
Publications and source records attributed to G Joseph.
Transjugular balloon pulmonary valvuloplasty was safely and successfully performed in five patients, two of whom had severe right heart failure. Crossing the stenotic pulmonary valve from the right internal jugular vein was consistently easy and quick. This approach should be considered whenever difficulties are experienced or anticipated in the femoral approach.
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Definitive percutaneous treatment of a patient with Lutembacher's syndrome was successfully accomplished using the Amplatzer septal occluder to close a secundum atrial septal defect and the Joseph mitral balloon catheter to dilate rheumatic mitral valve stenosis. Transcatheter therapy is an effective alternative to surgery in selected patients with Lutembacher's syndrome. Cathet. Cardiovasc. Intervent. 48:199-204, 1999.
BACKGROUND: Since postoperative hypotony has been a frequent complication of glaucomatous filtration surgery with adjunctive use of mitomycin C (MMC), the question arises of whether there may be another application method which can minimize this side effect. The purpose of this study was to establish the morphologic side effects of different application methods. METHODS: MMC 0.2 mg/ml was applied to the episclera of nine eyes of six pigmental rabbits at random via collagen shield (CS), soft contact lens (CL), or lyophilisate (20 microg; LY) for 5 min. Two eyes (controls) had a subconjunctival injection of BSS only. Another control eye was left untreated (no injection). No trabeculectomy was performed. One hour later the amounts of MMC in the conjunctiva and aqueous were analyzed by reverse-phase high-pressure liquid chromatography. Ciliary bodies were dissected from the enucleated eyes, embedded and investigated by transmission electron microscopy (TEM). Cell height of the nonpigmented ciliary epithelium was morphometrically assessed by means of computer-assisted image analysis. RESULTS: The light-microscopic analysis of the sectioned cell area revealed reduction of the cell height of the non-pigmented ciliary epithelium (NPCE) after application with soft contact lens (fourfold) and collagen shield (2.5-fold) but not with lyophilisate compared to the untreated eye. The following ultrastructural changes were seen: loss of apical microvilli (CS, CL, LY), disintegrating melanin granules within NPCE (CS), lysis of entire areas with NPCE cells (CS), myelin figures within mitochondria (LY), intracellular vacuoles (CS, CL), lysis of myelinated nerves (CS), myelin figures in mitochondria of endothelial cells (LY), and lysis of stromal fibrocytes (CS). In the control eyes (injection of BSS) none of these ultrastructural changes were detected in the cylindrical NPCE cells. The concentration of mitomycin in the aqueous humor after topical application of MMC on the episclera for 5 min were all below the detection limit (<10 ng/ml). The concentration of MMC in the conjunctiva ranged from 2.1 to 3.7 microg/g. CONCLUSION: Severe morphologic alterations were seen at the electron-microscopic level after application of MMC 0.2 mg/ml with a collagen shield and with a soft contact lens. They were mildest with lyophilisate and absent in the BSS controls. A new administration device is needed if trabeculectomy is to be performed successfully using MMC in human glaucomatous eyes.
OBJECTIVE AND IMPORTANCE: Spinal dural arteriovenous fistulae (Type I spinal arteriovenous malformations [AVMs]) have been recognized as a treatable cause of progressive myelopathy. The diagnosis and characterization of these lesions rest heavily on spinal angiography. CLINICAL PRESENTATION: We present three patients whose clinical presentations were consistent with a spinal dural AVM but whose spinal angiographic results were negative. INTERVENTION: The surgical treatment of these angiographically occult spinal AVMs is described. In retrospect, in each case, the feeding vessel to the AVM was injected but not seen. CONCLUSION: Some spinal dural arteriovenous fistulae will be angiographically occult. If the clinical and radiographic presentations strongly suggest the presence of an arteriovenous fistula, surgical exploration should be considered.
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The superoxide generating NADPH oxidase of phagocytes consists, in resting cells, of a membrane-associated electron transporting flavocytochrome (cytochrome b559) and four cytosolic proteins as follows: p47(phox), p67(phox), p40(phox), and the small GTPase, Rac(1 or 2). Activation of the oxidase is consequent to the assembly of a membrane-localized multimolecular complex consisting of cytochrome b559 and the cytosolic components. We used "peptide walking" (Joseph, G., and Pick, E. (1995) J. Biol. Chem. 270, 29079-29082) for mapping domains in the amino acid sequence of p47(phox) participating in the molecular events leading to the activation of NADPH oxidase. Ninety-five overlapping pentadecapeptides, with a four-residue offset between neighboring peptides, spanning the complete p47(phox) sequence, were tested for the ability to inhibit NADPH oxidase activation in a cell-free system. This consisted of solubilized macrophage membranes, recombinant p47(phox), p67(phox), and Rac1, and lithium dodecyl sulfate, as the activator. Eight functional domains were identified and labeled a-h. These were (N- and C-terminal residue numbers are given for each domain) as follows: a (21-35); b (105-119); c (149-159); d (193-207); e (253-267); f (305-319); g (325-339), and h (373-387). Four of these domains (c, d, e, and g) correspond to or form parts of regions shown before to participate in NADPH oxidase assembly. Thus, domain c corresponds to a region on the N-terminal boundary of the first src homology 3 (SH3) domain, whereas domains d and e represent more precisely defined sites within the full-length first and second SH3 domains, respectively. Domain g overlaps an extensively investigated arginine-rich region. Domains a and b, in the N-terminal half of p47(phox), and domains f and h, in the C-terminal half, represent newly identified entities, for which there is no earlier experimental evidence of involvement in NADPH oxidase activation. "Peptide walking" was also applied to the identification of domains in p47(phox) mediating binding to p67(phox). This was done by quantifying, by enzyme-linked immunosorbent assay, the binding of p67(phox), in solution, to a series of 95 overlapping biotinylated p47(phox) peptides, attached to streptavidin-coated 96-well plates. A single proline-rich domain (residues 357-371) was found to bind p67(phox) in the absence and presence of lithium dodecyl sulfate.
We studied the effects of glucosylation of RhoA, Rac1, and Cdc42 at threonine-35 and -37 by Clostridium difficile toxin B on nucleotide binding, GTPase activity, and effector coupling and compared these results with the ADP ribosylation of RhoA at asparagine-41 catalyzed by Clostridium botulinum C3 transferase. Whereas glucosylation and ADP ribosylation had no major effects on GDP release from RhoA, Rac1, and Cdc42, the rate of GTPgammaS release from Rho proteins was increased 3-6-fold by glucosylation. ADP ribosylation decreased the rate of GTPgammaS release by about 50%. Glucosylation reduced the intrinsic activities of the GTPases by 3-7-fold and completely blocked GTPase stimulation by Rho-GAP. In contrast, ADP ribosylation slightly increased GTPase activity ( approximately 2-fold) and had no major effect on GAP stimulation of GTPase. Whereas ADP ribosylation did not affect the interaction of RhoA with the binding domain of protein kinase N, glucosylation inhibited this interaction. Glucosylation of Rac1 markedly diminished its ability to support the activation of the superoxide-generating NADPH oxidase of phagocytes. Glucosylated Rac1 did not interfere with NADPH oxidase activation by unmodified Rac1, even when present in marked molar excess, indicating that it was incapable of competing for a common effector. The data indicate that the functional inactivation of small GTPases by glucosylation is mainly caused by inhibition of GTPase-effector protein interaction.
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In 2340 adult patients above the age of 26 years with rheumatic valvular disease (RHD) seen since 1987, injection benzathine penicillin (once in 3 weeks) was discontinued and the patients were followed for evidence of rheumatic fever for a period of one to nine years (mean of 3 years). Recurrence of rheumatic fever was seen in 5 patients (0.21%). This study confirms that recurrence of rheumatic fever in patients with RHD above 26 years of age is very low and hence we recommend long term chemoprophylaxis to the patients above the age of 26 on an individual basis.
An improved high-performance liquid chromatographic assay for the cytostatic drug mitomycin C in plasma is presented. The principal steps are precipitation of plasma proteins with acetonitrile, lyophilization of the supernatant and reversed-phase chromatography on a Hypersil ODS 5 microm column with 0.01 M NaH2PO4 buffer (pH 6.5)-methanol (70:30, v/v) in isocratic mode. At a flow-rate of 1.3 ml/min a column pressure of 180-220 bar resulted. Porfiromycin served as internal standard. UV detection was performed at 365 nm. Quantitation limit based on a coefficient of variation <10% in intra- and inter-day assay was 5 microg/l mitomycin C, detection limit based on a signal-to-noise ratio of 3 was 1 microg/l. Recovery was 100% and linearity was shown for the whole range of concentration (1-500 microg/l). None of the five drugs used during chemoembolisation interfered with the assay in vitro. The assay meets the requirements for pharmacokinetic studies of mitomycin C in patients as regards sensitivity and ease of use.
Nucleolin is an abundant nucleolar RNA-binding protein that seems to be involved in many aspects of ribosome biogenesis. Nucleolin contains four copies of a consensus RNA-binding domain (CS-RBD) found in several other proteins. In vitro RNA-binding studies previously determined that nucleolin interacts specifically with a short RNA stem-loop structure. Taken individually, none of the four CS-RBDs interacts significantly with the RNA target, but a peptide that contains the first two adjacent CS-RBDs (R12) is sufficient to account for nucleolin RNA-binding specificity and affinity. The full integrity of these two domains is required, since N- or C-terminal deletion abolishes the specific interaction with the RNA. Mutation of conserved amino acids within the RNP-1 sequence of CS-RBD 1 or 2 drastically reduces the interaction with the RNA, whereas mutation of the analogous residues in CS-RBDs 3 and 4 has no effect in the context of the R1234G protein (which corresponds to the C-terminal end of nucleolin). Our results demonstrate that nucleolin RNA-binding specificity is the result of a cooperation between two CS-RBDs (RBDs 1 and 2) and also suggests a direct or indirect involvement of the RNP-1 consensus sequence of both CS-RBDs in the recognition of the RNA target.
We report on a patient with pulseless disease (Takayasu's arteritis) in whom access to the central circulation by extremity arterial cannulation was not possible due to absent pulses in all four limbs. The transseptal approach was used for aortography, bilateral selective carotid angiography, and successful elective stent deployment in the right common carotid artery.
Mechanisms of cardiac perforation in 10 cases of cardiac tamponade encountered in a single-center series of 903 balloon mitral valvuloplasty procedures were elucidated by precise localization of the site of perforation at subsequent surgery. These mechanisms were perforation of the aortic root and adjacent right atrium by sliding up of the transseptal set (2), apical tears by straight-tip balloon catheters driven distally during mitral valve dilatation (3), apical perforations by guidewires introduced through catheters wedged in the apex (2), tear of the posterior right atrial wall by dilatation of the track produced by very low septal punctures (2), and right ventricular perforation by a pacing catheter (1). Multivariate analysis showed cardiac perforation to be significantly related to the total experience at the center (inversely) and to patient age (directly). Left ventricular perforation occurred exclusively in patients > 40 yr of age. Understanding these mechanisms has enabled formulation of effective strategies to prevent cardiac perforation.
Transfemoral balloon angioplasty of native aortic coarctation was initially not feasible in two patients, because of inability to cannulate the femoral artery percutaneously in one, and to cross the coarctation in the other. The percutaneous brachial approach helped overcome both these problems, after which utilization of intravascular snares allowed successful transfemoral completion of angioplasty.
The feasibility of a transjugular approach to septal puncture and Inoue-balloon mitral valvuloplasty (BMV) was studied in 20 patients with severe mitral stenosis and varying degrees of anatomic atrial distortion. Left atrial entry by transjugular septal puncture was achieved without difficulty and BMV completed in all patients. In all of 16 patients who had high septal punctures, crossing the mitral valve with the Inoue-balloon was consistently simple and quick. In one patient, septal dilation after very high septal puncture led to a tear extending to the atrial free wall, resulting in cardiac tamponade requiring surgery. Another patient developed severe mitral regurgitation after BMV and required mitral valve replacement. Excellent results were obtained in 16 patients. The transjugular approach simplifies BMV procedure significantly in patients with distorted atrial anatomy and allows rapid patient mobilization. Its safety and efficacy need to be established in larger studies.
The clinical value of coronary vasodilators in antianginal therapy depends on the ratio of their epicardial versus resistance coronary vessel actions. The coronary flow measured in standard isolated heart preparations, however, does not allow any conclusion about the function of epicardial vessels. Thus, we established a new technique assessing the epicardial coronary diameter directly by video angiometry. Pictures from the cardiac surface were taken by a videocamera mounted on a long-distance microscope. The video signal was digitized for computer-aided evaluation. An area of interest (AOI) was laid over the vascular section to be measured. The gray values of the pixels across the epicardial vessel were registered, and a mean curve of distribution was obtained by averaging the gray values from all video lines within the AOI. The inner epicardial coronary diameter resulted from the distance between the points of inflection of this mean curve of distribution. Experiments with NO-vasodilators and adenosine showed that epicardial coronary arteries of isolated perfused rabbit hearts have no appreciable tone. Pretreatment of the hearts with a combination of histamine (10[-6] mol/l), cimetidine (10[-5] mol/l), and adenosine (10[-7] mol/1), however, caused a marked contraction of the conductive vessels. NO-donors selectively dilated epicardial vessels in such pretreated hearts whereas adenosine increased both epicardial coronary diameter and coronary flow, with only a slight tendency toward preferential action on resistance vessels in low concentrations. Simultaneous registration of coronary flow and epicardial coronary diameter in isolated rabbit hearts pretreated with a spasmogenic drug combination (histamine, cimetidine, and adenosine) may be a feasible method assessing epicardial selectivity of coronary vasodilators.
The influence of collection time on the correlation of caffeine concentrations in saliva and serum was examined in six healthy adults after peroral administration of 5 mg/kg caffeine citrate. Saliva was obtained from three different salivary glands (sublingual, right parotid, and left parotid) and evaluated separately. Caffeine concentrations in saliva and serum samples were determined by high-performance liquid chromatography. There were no differences in the caffeine concentrations in saliva from the three investigated glands (alpha = 0.05). Saliva samples collected earlier than 2 hours after caffeine intake showed higher caffeine concentrations than could be expected from the corresponding serum samples. Gingiva contamination was shown to be responsible for the higher caffeine concentrations in saliva, and it was concluded that saliva is a feasible matrix for therapeutic drug monitoring of caffeine. If caffeine is administered orally, saliva samples should be taken at least 2 hours after caffeine intake. If caffeine-containing beverages are used as the source of caffeine or if subjects do not cooperate by rinsing the mouth of caffeine contamination, an additional 60 minutes should be added before saliva sampling.