[BEST disease. Ophthalmoscopic and OCT views].
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Humans↗
Biomedical subjects
M Dominguez
Publications and source records attributed to M Dominguez.
Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.
BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED; OMIM 240300) is a rare autosomal recessive disorder defined by a variable combination of endocrine failure, chronic mucocutaneous candidiasis (CMC), and dystrophy of the dental enamel and nails. APECED is caused by mutations in the autoimmune regulator gene (AIRE). Alopecia areata (AA) and vitiligo are diseases with autoimmune pathogeneses, and have been recognized as part of the APECED complex. There are rare reports of other cutaneous manifestations. OBJECTIVES: We sought to delineate the dermatological features of APECED in an Irish case series with emphasis on timing of their appearance and association with disease severity. Furthermore, we looked for evidence of genotype: phenotype correlation. Finally, we wanted to determine if the ectodermal changes described represent a primary ectodermal dysplasia or whether the ectodermal manifestations are secondary phenomena. METHODS: Irish patients with APECED were invited to attend a multidisciplinary clinic (Dermatology, Endocrinology, Dentistry and Ophthalmology) held in Our Lady's Hospital for Sick Children, Dublin. Clinical data were compiled from case notes and questionnaires. All patients had a detailed cutaneous examination. Blood samples were obtained for mutational analysis. RESULTS: Eighteen patients (seven males and 11 females) from 15 families were interviewed and examined. The mean age at diagnosis was 6 years (range 8 months-18 years). All patients had evidence of CMC, 13 (72%) had candidal onychomycosis or paronychia, six (33%) had AA and two had vitiligo. In the case of two patients the diagnosis was made on recognition of dermatological manifestations and confirmed by mutational analysis. Both patients developed Addison's disease on follow-up. CMC was an early feature, often predating diagnosis (10 of 18). AA and vitiligo presented later, and may reflect more severe disease in these cases. There was no correlation between the AIRE mutations identified on mutational analysis and the clinical presentation. We found no evidence of an isolated nail dystrophy or features consistent with a primary ectodermal dysplasia. CONCLUSIONS: APECED is a rare but complex and potentially life-threatening autoimmune disease. CMC is a common and early feature; diagnosis at this stage may pre-empt life-threatening endocrinological crises. It is important for dermatologists to be aware of this association as they are likely to be the earliest clinicians who encounter these children. AA and vitiligo in our series occurred in the setting of established disease. The term "ectodermal dystrophy" is misleading as the ectodermal features described in our series and in the literature are most likely to be secondary phenomena.
Adolescent↗
Outbreak of Salmonella enterica serotype Manhattan infection associated with meat products, France, 2005.
Between August 2005 and March 2006 in France, 69 cases of Salmonella enterica serotype Manhattan (Salmonella Manhattan) were reported, 51 (74%) of them from southeastern France. At the time of the alert (November 2005), 13 cases and 33 controls were interviewed. Cases were more likely than controls to have eaten pork sausages (OR=5.9, confidence interval CI [1.3; 26.9]) and beef (OR=9.3, CI [1.3; 68.6]). At the same time, 19 strains of Salmonella Manhattan isolated from meat products in southeastern France, reported to the French food safety agency (Afssa, Agence francaise de securite sanitaire des aliments) in September and November 2005, had an indistinguishable PFGE profile to the 7 human isolates of Salmonella Manhattan from the outbreak in southeastern France. Trace-back investigations revealed that pork samples came from one wholesaler whose pork products had tested positive for S. Manhattan during routine food testing in August 2005. This wholesaler supplied retail outlets in southeastern France. Additionally, a slaughterhouse supplying the wholesaler was inspected and widespread contamination with Salmonella spp. and S. Manhattan was found. Cooperation between the national agencies in charge of human health (Institut de veille sanitaire, InVS) and food safety (Afssa) allowed us to determine the most probable source of contamination and to take appropriate control measures.
Adult↗
Regulation of membrane trafficking by a novel Cdc42-related protein in Caenorhabditis elegans epithelial cells.
Rho GTPases are mainly known for their implication in cytoskeleton remodeling. They have also been recently shown to regulate various aspects of membrane trafficking. Here, we report the identification and the characterization of a novel Caenorhabditis elegans Cdc42-related protein, CRP-1, that shows atypical enzymatic characteristics in vitro. Expression in mouse fibroblasts revealed that, in contrast with CDC-42, CRP-1 was unable to reorganize the actin cytoskeleton and mainly localized to trans-Golgi network and recycling endosomes. This subcellular localization, as well as its expression profile restricted to a subset of epithelial-like cells in C. elegans, suggested a potential function for this protein in polarized membrane trafficking. Consistent with this hypothesis, alteration of CRP-1 expression affected the apical trafficking of CHE-14 in vulval and rectal epithelial cells and sphingolipids (C(6)-NBD-ceramide) uptake and/or trafficking in intestinal cells. However, it did not affect basolateral trafficking of myotactin in the pharynx and the targeting of IFB-2 and AJM-1, two cytosolic apical markers of intestine epithelial cells. Hence, our data demonstrate a function for CRP-1 in the regulation of membrane trafficking in a subset of cells with epithelial characteristics.
Actins↗
[Spontaneous retrohyaloid hemorrhage treated with YAG laser].
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Adult↗
Detection of extended-spectrum beta-lactamases produced by Chilean isolates of Klebsiella pneumoniae by two synergy methods.
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Cephalosporins↗
Babesia bovis merozoite surface protein-2c (MSA-2c) contains highly immunogenic, conserved B-cell epitopes that elicit neutralization-sensitive antibodies in cattle.
The search for vaccine candidates against bovine babesiosis caused by Babesia bovis is greatly focused on the identification of merozoite surface-exposed antigens that are widely conserved, functionally relevant and immunodominant in cattle protected against B. bovis infections. We have recently identified msa-2c, a member of the B. bovis variable merozoite surface antigen (VMSA) gene family, which in contrast to other members, appears to be highly conserved among geographically distant B. bovis strains. In this study, we further investigated the potential of the msa-2c gene product as diagnostic and vaccine candidate for bovine babesiosis. RT-PCR studies demonstrated that MSA-2c is transcribed in merozoites of the Argentine R1A strain. In addition, antibodies against R1A recombinant MSA-2c reacted in immunoblots with a single protein of approximately 30kDa in B. bovis merozoite extracts from both R1A and Australian "S" strains, demonstrating translation of this protein in these two strains and conservation of B-cell epitopes between them. These antibodies reacted with the cell surface of R1A merozoites in fixed immunofluorescence assays, indicating the surface localization of MSA-2c. This localization was confirmed by live immunofluorescence studies in two different strains, R1A and S2P. These results also demonstrate the conservation of MSA-2c surface-exposed B-cell epitopes between these two strains. Sera from cattle either naturally or experimentally infected with Argentine strains of B. bovis specifically recognized rMSA-2c in immunoblots, reinforcing the idea that B-cell epitopes in rMSA-2c are widely conserved among field strains of B. bovis. Furthermore, our results show that these B-cell epitopes are highly immunogenic, suggesting that MSA-2c may be a useful diagnostic tool for the detection of bovine babesiosis by B. bovis. Experimental vaccination of five bovines with rMSA-2c resulted in elicitation of high specific anti-rMSA-2c IgG titers, with similar amounts of IgG(1) and IgG(2) produced. Importantly, bovine anti-rMSA-2c antibodies were able to neutralize in vitro bovine erythrocyte invasion by R1A merozoites suggesting a significant functional role for MSA-2c. Taken together these results postulate MSA-2c as a candidate for the development of novel tools for improved control of bovine babesiosis.
Animals↗
Two-step process for photoreceptor formation in Drosophila.
The formation of photoreceptor cells (PRCs) in Drosophila serves as a paradigm for understanding neuronal determination and differentiation. During larval stages, a precise series of sequential inductive processes leads to the recruitment of eight distinct PRCs (R1-R8). But, final photoreceptor differentiation, including rhabdomere morphogenesis and opsin expression, is completed four days later, during pupal development. It is thought that photoreceptor cell fate is irreversibly established during larval development, when each photoreceptor expresses a particular set of transcriptional regulators and sends its projection to different layers of the optic lobes. Here, we show that the spalt (sal) gene complex encodes two transcription factors that are required late in pupation for photoreceptor differentiation. In the absence of the sal complex, rhabdomere morphology and expression of opsin genes in the inner PRCs R7 and R8 are changed to become identical to those of outer R1-R6 PRCs. However, these cells maintain their normal projections to the medulla part of the optic lobe, and not to the lamina where outer PRCs project. These data indicate that photoreceptor differentiation occurs as a two-step process. First, during larval development, the photoreceptor neurons become committed and send their axonal projections to their targets in the brain. Second, terminal differentiation is executed during pupal development and the photoreceptors adopt their final cellular properties.
Animals↗
Clathrin-dependent and -independent internalization of plasma membrane sphingolipids initiates two Golgi targeting pathways.
Sphingolipids (SLs) are plasma membrane constituents in eukaryotic cells which play important roles in a wide variety of cellular functions. However, little is known about the mechanisms of their internalization from the plasma membrane or subsequent intracellular targeting. We have begun to study these issues in human skin fibroblasts using fluorescent SL analogues. Using selective endocytic inhibitors and dominant negative constructs of dynamin and epidermal growth factor receptor pathway substrate clone 15, we found that analogues of lactosylceramide and globoside were internalized almost exclusively by a clathrin-independent ("caveolar-like") mechanism, whereas an analogue of sphingomyelin was taken up approximately equally by clathrin-dependent and -independent pathways. We also showed that the Golgi targeting of SL analogues internalized via the caveolar-like pathway was selectively perturbed by elevated intracellular cholesterol, demonstrating the existence of two discrete Golgi targeting pathways. Studies using SL-binding toxins internalized via clathrin-dependent or -independent mechanisms confirmed that endogenous SLs follow the same two pathways. These findings (a) provide a direct demonstration of differential SLs sorting into early endosomes in living cells, (b) provide a "vital marker" for endosomes derived from caveolar-like endocytosis, and (c) identify two independent pathways for lipid transport from the plasma membrane to the Golgi apparatus in human skin fibroblasts.
Adaptor Proteins, Signal Transducing↗
Kringles of the plasminogen--prothrombin gene family share conformational epitopes with recombinant apolipoprotein (a): specificity of the fibrin-binding site.
Monoclonal antibodies directed against recombinant apolipoprotein (a) (r-apo(a)) lacking plasminogen-like KIV-2 repeats were used to identify structurally related conformational epitopes in various members of the plasminogen-prothrombin gene family. A number of procedures including a fibrin-binding inhibition immunoassay and surface plasmon resonance studies were used. Two antibodies (A10.1 and A10.4) recognised common conformational structures in r-apo(a), prothrombin, factor XII, plasminogen and its tissue-type and urokinase-type activators. In contrast, two other antibodies recognised specifically an epitope comprising residues of the lysine-binding site (A10.2) or close to it (A10.5) and inhibited the fibrin-binding function of r-apo(a) (IC(50)=36 pmol/l and 9.76 nmol/l, respectively). Interestingly, these antibodies distinctly recognised the elastase-derived fragments of plasminogen K4 (A10.2) and K1+2+3 (A10.5) without affecting plasminogen binding to fibrin. These results suggest that highly conserved conformational regions are common to various proteins of the plasminogen-prothrombin gene family and are in agreement with the concept that these proteins constitute a monophyletic group derived from an ancestral gene.
Antibodies, Monoclonal↗
Elevated plasma tissue plasminogen activator and anti-THP-1 antibodies are independently associated with decreased graft survival in cardiac transplant recipients.
Hemostatic and immunologic factors have been implicated in future cardiac events in patients with coronary artery disease. The role of these factors and their interaction is less established in cardiac transplant recipients. We sought to characterize the role of these factors in these patients. Cardiac transplant patients who presented for surveillance coronary angiography and/or endomyocardial biopsy were eligible for enrollment. Ninety-nine consecutive patients were enrolled. Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1, von Willebrand factor, fibrin D-dimer, and anti-t-PA antibody were determined by enzyme-linked immunosorbent assays. Anti-THP-1 cell antibodies directed against a monocytic leukemia cell line were detected by incubating patient plasma with THP-1 cells. Bound antibody was detected using goat peroxidase-labeled immunoglobulin G directed against human immunoglobulins. Lipids were measured by enzymatic methods. Multivariate analysis identified the presence of anti-THP-1 cell antibodies (risk ratio 4.41, p = 0.002), t-PA antigen (risk ratio 1.10, p = 0.033), donor age 20 to 26 years (risk ratio 8.83, p = 0.042), and donor age >36 years (risk ratio 15.53, p = 0.009) as predictors of allograft failure. Altered hemostatic function, as demonstrated by elevated plasma t-PA antigen levels, is predictive of subsequent allograft failure in cardiac transplant recipients. In addition, the presence of anti-THP-1 cell antibodies in these patients is predictive of allograft failure.
Chi-Square Distribution↗
Identification of active site residues in glucosylceramide synthase. A nucleotide-binding catalytic motif conserved with processive beta-glycosyltransferases.
Glucosylceramide synthase (GCS) transfers glucose from UDP-Glc to ceramide, catalyzing the first glycosylation step in the formation of higher order glycosphingolipids. The amino acid sequence of GCS was reported to be dissimilar from other proteins, with no identifiable functional domains. We previously identified His-193 of rat GCS as an important residue in UDP-Glc and GCS inhibitor binding; however, little else is known about the GCS active site. Here, we identify key residues of the GCS active site by performing biochemical and site-directed mutagenesis studies of rat GCS expressed in bacteria. First, we found that Cys-207 was the primary residue involved in GCS N-ethylmaleimide sensitivity. Next, we showed by multiple alignment that the region of GCS flanking His-193 and Cys-207 (amino acids 89-278) contains a D1,D2,D3,(Q/R)XXRW motif found in the putative active site of processive beta-glycosyltransferases (e.g. cellulose, chitin, and hyaluronan synthases). Site-directed mutagenesis studies demonstrated that most of the highly conserved residues were essential for GCS activity. We also note that GCS and processive beta-glycosyltransferases are topologically similar, possessing cytosolic active sites, with putative transmembrane domains immediately N-terminal to the conserved domain. These results provide the first extensive information on the GCS active site and show that GCS and processive beta-glycosyltransferases possess a conserved substrate-binding/catalytic domain.
Amino Acid Sequence↗
Atrioventricular interval optimization and exercise tolerance.
Modern pacemakers offer many programming options regarding the AV interval including the ability to vary AV intervals depending on whether atrial activity is paced or spontaneous and to shorten AV intervals with increasing rates. To determine if optimization of these features improves exercise tolerance, 14 patients with intact sinus node function and AV block treated with dual chamber pacemakers were enrolled in a randomized double-blind crossover trial. Doppler echocardiographic measurements of cardiac index and mitral flow were assessed over a range of programmable AV intervals at rest to determine each patient's optimal AV interval. Eleven patients completed serial graded exercise tests with spiroergometry after randomly programming the AV interval three ways in a crossover manner: fixed AV interval = 150 ms without rate adaptation (150/Fixed), fixed AVinterval = 150 ms with rate adaptation (150/R), or optimized AV interval with rate adaptive AV interval shortening (optimized/R). Exercise capacity was determined by maximum oxygen uptake. Ten men and four women, age 64 +/- 8 years, were enrolled. At rest, optimization of the AVintervalimproved the cardiac index by 21% (P < 0.001) and mitral flow by 13.4% (P < 0.001) when compared to least-favorable AV intervals. During exercise, no differences in maximum heart rates were noted. Maximum oxygen uptake was increased in both groups with rate adaptive AVinterval shortening when compared tofixed AVinterval without rate adaptation: 13.9% (adjusted P < 0.04) and 14.6% (adjusted P < 0.02) in optimized/R and 150/R, respectively. No differences were noted between optimized/R and 150/R. In conclusion, rate adaptive AV interval shortening improved exercise tolerance independent of changes in heart rate. However, optimization of the AV interval with Doppler echocardiography at rest did not further improve exercise capacity.
Atrial Function↗
Autoantibodies to receptor induced neoepitopes of fibrinolytic proteins in rheumatic and vascular diseases.
OBJECTIVE: Abnormal plasminogen activation has been implicated in vascular and rheumatic diseases. The development of an autoimmune response to neoepitopes of plasminogen and its activator (tissue-type plasminogen activator, t-PA) was explored in sera from patients with rheumatoid arthritis (RA, n = 30), Behcet's disease (n = 20), primary antiphospholipid syndrome (APS, n = 23), and idiopathic arterial (n = 33) or venous thrombosis (n = 16). METHODS: Sera diluted 1/50 were incubated with either plasminogen or t-PA bound to their natural receptors (immobilized fibrin or monocytic cells), and bound immunoglobulins were detected using a sheep peroxidase labeled anti-human Fab IgG. Controls included plates coated with fibrin or cells alone or plasminogen passively adsorbed to the plastic. Sera were considered positive when the absorbance at 405/490 nm was above the mean + 2 SD of normal sera. RESULTS: Reactivity of sera against plasminogen bound to cells (28%) or to fibrin (22%) was a predominant feature in patients with RA compared with other patient groups and controls. However, some patients with primary APS had reactivity against cell and fibrin bound plasminogen (9 and 13%, respectively). Autoantibodies against fibrin bound t-PA were detected in only 8% of patients with arterial or venous thrombosis. CONCLUSION: Conformational changes induced by molecular assembly of plasminogen on cell or fibrin surfaces result in the expression of neoepitopes recognized by autoantibodies. These autoantibodies could be markers of the proteolytic events associated with plasminogen activation in autoimmune diseases.
Adult↗
[Cloxacilin and vancomycin bacterial action against oxalicin-susceptible Staphylococcus aureus].
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Anti-Bacterial Agents↗
Applications of BODIPY-sphingolipid analogs to study lipid traffic and metabolism in cells.
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Animals↗
Membrane traffic in sphingolipid storage diseases.
In this review, we summarize our studies of membrane lipid transport in sphingolipid storage disease (SLSD) fibroblasts. We recently showed that several fluorescent SL analogs were internalized from the plasma membrane predominantly to the Golgi complex of normal cells, while in ten different SLSD cell types, these lipids accumulated in endosomes and lysosomes (The Lancet 1999;354: 901-905). Additional studies showed that cholesterol homeostasis is perturbed in multiple SLSDs secondary to SL accumulation and that mistargeting of SL analogs was regulated by cholesterol (Nature Cell Biol 1999;1: 386-388). Based on these findings, we hypothesize that endogenous sphingolipids, which accumulate in SLSD cells due to primary defects in lipid catabolism, result in an altered intracellular distribution of cholesterol, and that this alteration in membrane composition then results in defective sorting and transport of SLs. The importance of SL/cholesterol interactions and potential mechanisms underlying the regulation of lipid transport and targeting are also discussed. These studies suggest a new paradigm for regulation of membrane lipid traffic along the endocytic pathway and could have important implications for future studies of protein trafficking as well as lipid transport. This work may also lead to important future clinical developments (e.g. screening tests for SLSD, new methodology for screening drugs which abrogate lipid storage, and possible therapeutic approaches to SLSD).
Biological Transport, Active↗
Antibodies to tissue-type plasminogen activator in plasma from patients with primary antiphospholipid syndrome.
A reduction in fibrinolysis has been described in association with thrombosis in the primary antiphospholipid syndrome (PAPS). In this study, we measured anti-tissue-type plasminogen activator (t-PA) antibodies and anti-fibrin-bound t-PA antibodies as possible causes of hypofibrinolysis in 39 patients with PAPS. We also evaluated the differences in anti t-PA antibodies between patients without previous thrombosis (20 patients) and patients with previous episodes of thrombosis (19 patients: deep vein thrombosis in nine, ischaemic stroke in six, arterial leg thrombosis in one, hepatic vein thrombosis in one, thrombophlebitis in one and cerebral venous thrombosis in one). Anti-t-PA antibodies were measured by an enzyme-linked immunosorbent assay (ELISA), and anti-t-PA fibrin-bound antibodies were measured by a solid-phase fibrin immunoassay (SOFIA) in 39 patients with PAPS and in 39 controls matched for gender and age. High levels of IgG anti-t-PA were found in three out of 39 patients with PAPS, and all three patients had a history of thrombosis; four other patients, one of whom had a history of thrombotic events, had high titres of antibodies directed against fibrin-bound t-PA. In addition, patients with ischaemic stroke had significantly higher levels of IgG anti-t-PA than patients without thrombosis (P = 0.029). In conclusion, our data showed that, in patients with PAPS, the highest levels of anti-t-PA antibodies were present in subjects with previous thrombotic events. The discrepancy in the results obtained with two methods of detection of anti-t-PA antibodies, ELISA and SOFIA, indicates a different interaction of the antibodies with the t-PA molecules, which are directly bound to polystyrene plates in ELISA and bound to fibrin as a bridging molecule in SOFIA.
Adult↗