Association of tumor necrosis factor-2 allele with plasma tumor necrosis factor-alpha levels and mortality from septic shock.
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APACHE↗
Biomedical subjects
E Dupont
Publications and source records attributed to E Dupont.
The gap-junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation.
BACKGROUND: Atrial fibrillation (AF), a cardiac arrhythmia arising from atrial re-entrant circuits, is a common complication after cardiac surgery, but the proarrhythmic substrate underlying the development of postoperative AF remains unclear. This study investigated the hypothesis that altered expression of connexins, the component proteins of gap junctions, is a determinant of a predisposition to AF. METHODS AND RESULTS: The expression of the 3 atrial connexins-connexins 43, 40, and 45-was analyzed at the mRNA and protein levels by Northern and Western blotting techniques and immunoconfocal microscopy in right atrial appendages from patients with ischemic heart disease who were undergoing coronary artery bypass surgery. Twenty percent of the patients subsequently developed AF, which allowed retrospective division of the samples into 2 groups, non-AF and AF. Connexin43 and connexin45 transcript and protein levels did not differ between the groups. However, connexin40 transcript and protein were expressed at significantly higher levels in the AF group. Connexin40 protein was markedly heterogeneous in distribution. CONCLUSIONS: Atrial myocardium susceptible to AF is distinguished from its nonsusceptible counterpart by elevated connexin40 expression. The heterogeneity of connexin distribution could give rise to different resistive properties and conduction velocities in spatially adjacent regions of tissue, which become enhanced and, hence, proarrhythmic the higher the overall level of connexin40.
Aged↗
Immunocytochemical analysis of connexin expression in the healthy and diseased cardiovascular system.
Gap junctions play essential roles in the normal function of the heart and arteries, mediating the spread of the electrical impulse that stimulates synchronized contraction of the cardiac chambers, and contributing to co-ordination of activities between cells of the arterial wall. In common with other multicellular systems, cardiovascular tissues express multiple connexin isotypes that confer distinctive channel properties. This review highlights how state-of-the-art immunocytochemical and cellular imaging techniques, as part of a multidisciplinary approach in gap junction research, have advanced our understanding of connexin diversity in cardiovascular cell function in health and disease. In the heart, spatially defined patterns of expression of three connexin isotypes-connexin43, connexin40, and connexin45-underlie the precisely orchestrated patterns of current flow governing the normal cardiac rhythm. Derangement of gap junction organization and/or reduced expression of connexin43 are associated with arrhythmic tendency in the diseased human ventricle, and high levels of connexin40 in the atrium are associated with increased risk of developing atrial fibrillation after coronary by-pass surgery. In the major arteries, endothelial gap junctions may simultaneously express three connexin isotypes, connexin40, connexin37, and connexin43; underlying medial smooth muscle, by contrast, predominantly expresses connexin43, with connexin45 additionally expressed at restricted sites. In normal arterial smooth muscle, the abundance of connexin43 gap junctions varies according to vascular site, and shows an inverse relationship with desmin expression and positive correlation with the quantity of extracellular matrix. Increased connexin43 expression between smooth muscle cells is closely linked to phenotypic transformation in early human coronary atherosclerosis and in the response of the arterial wall to injury. Current evidence thus suggests that gap junctions in both their guises, as pathways for cell-to-cell signaling in the vessel wall and as pathways for impulse conduction in the heart, contribute to the initial pathogenesis and eventual clinical manifestation of human cardiovascular disease.
Cardiovascular Diseases↗
Altered connexin expression in human congestive heart failure.
Congestive heart failure is associated with a high risk of life-threatening ventricular re-entrant arrhythmias. Down-regulation of the principal gap-junctional protein of the ventricular myocytes, connexin43, has previously been implicated in arrhythmia in ischaemic heart disease, but it is not known whether connexin43 is similarly reduced in heart failure due to idiopathic dilated cardiomyopathy, whether disease-related connexin43 down-regulation occurs at the level of transcription or translation, or whether the expression of other connexin isotypes is altered in congestive heart failure. We therefore investigated the expression of the four connexins expressed in the heart-connexins 43, 40, 45 and 37-at the mRNA and protein levels in explanted hearts from transplant patients with end-stage heart failure (NYHA class 4) by immunoconfocal analysis, and northern and western blotting. Connexin43 mRNA and protein were markedly downregulated in the left ventricle in end-stage heart failure due both to ischaemic cardiomyopathy and idiopathic dilated cardiomyopathy. Connexin43 content was spatially heterogeneous in the diseased ventricle. Connexin40 mRNA was increased in the ischaemic group, more so in the left ventricle than the right. This correlated with an increased depth of connexin40 protein expression in myocytes at the endocardial surface. Connexin45 mRNA and protein, present only in very low quantities, followed a similar trend to connexin43, while connexin37 (exclusively expressed in endothelium) showed no change. Our findings show that congestive heart failure is associated with significantly reduced levels of the principal gap junction protein, connexin43, in the left ventricle, potentially contributing to enhanced arrhythmogenicity and contractile dysfunction. This down-regulation is due predominantly to a reduced transcript steady-state level. Elevated connexin40 may represent a compensatory response that improves the spread of depolarization in the otherwise compromised ischaemic ventricle.
Adult↗
Utility of internal mammary lymph node removal when noted by intraoperative gamma probe detection.
BACKGROUND: Lymphatic mapping (LM) for breast cancer has made internal mammary node (IMN) detection practical and dependable. This study demonstrates the necessity of IMN removal when suggested by intraoperative radioguided surgery detection. METHODS: From April 1998 to July 2000, 1273 patients underwent LM for breast cancer. LM was performed using the combined dye and radiocolloid technique. Patients were scanned operatively with a gamma probe over the IMN area, and most underwent preoperative lymphoscintigraphy. Nodes were removed from patients in whom radioactivity was detected in the internal mammary area. RESULTS: Thirty of the 1273 (2.4%) patients mapped had at least one IMN removed. Twenty-two of 30 (73.3%) had inner quadrant lesions. Five of 30 (16.7%) patients had IMNs that were positive for metastatic disease. Three of these five had no metastatic spread to the axillary sentinel lymph node (SLN). One of thirty (3.3%) patients with IMN localization had neither hot nor blue nodes detected in an SLN procedure. CONCLUSIONS: Radioguided SLN detection should be attempted in the IMN basin with all tumors. If an IMN is identified, it should be removed. IMN biopsy is a feasible, low-risk procedure when directed by radioguided LM and provides a guide for radiotherapy for patients with positive IMNs.
Breast Neoplasms↗
Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.
Recent studies have indicated that bone marrow angiogenesis is increased in multiple myeloma, suggesting that treatment with an antiangiogenic agent might be useful. Among the new antiangiogenic drugs in development, Neovastat (AE-941; Aeterna Laboratories, Quebec City, Canada) can be classified as a naturally occurring multifunctional antiangiogenic agent. It has a marked inhibitory effect on the formation of blood vessels in the chicken embryo vascularization assay (EVT) and endothelial cell proliferation. Furthermore, in vivo experiments showed that oral administration of Neovastat blocks the formation of blood vessels in Matrigel implants containing basic fibroblast growth factor (bFGF). The antiangiogenic activity of Neovastat was found to be associated with two mechanisms of action. In addition to the inhibition of the matrix metalloproteinase activities (MMP-2, MMP-9, and MMP-12), Neovastat inhibits vascular endothelial growth factor (VEGF) binding to endothelial cells, VEGF-dependent tyrosine phosphorylation, and VEGF-induced vascular permeability in mice. Neovastat was also found to have a significant antitumor activity. Oral administration of Neovastat in mice with subcutaneous grafted breast cancer (DA3) cells showed a significant reduction in tumor volume. Neovastat also decreased the number of lung metastases in the Lewis lung carcinoma model. Interestingly, the effect of Neovastat was additive to cisplatin in this model. Furthermore, no treatment-related mortality or loss of body weight was observed. Also, toxicology studies in rats and monkeys demonstrate no dose-limiting toxicity or target organ damage after 1 year of chronic exposure, thus suggesting that Neovastat could be safely administered in humans. Four clinical studies have been conducted to establish the dosing, safety, and early efficacy of Neovastat administered orally. In the oncology field, 482 patients have received Neovastat, of which 146 with solid tumors were exposed to the drug for more than 6 months. Two phase III clinical trials are currently underway. A phase III double-blind placebo-controlled study is being conducted to evaluate the efficacy of Neovastat in addition to induction chemotherapy/radiotherapy combined modality treatment in patients with unresectable non-small cell lung cancer stage IIIA and IIIB. A second phase III randomized, double-blind placebo-controlled study evaluates the efficacy of Neovastat as a monotherapy in metastatic renal cell carcinoma patients who have progressed following a first-line immunotherapy. Neovastat efficacy is also being evaluated in a registration phase II trial in patients with early relapse or refractory multiple myeloma.
Angiogenesis Inhibitors↗
The effects of postinjection massage on the sensitivity of lymphatic mapping in breast cancer.
BACKGROUND: The technique of lymphatic mapping and sentinel lymph node (SLN) biopsy is rapidly becoming the preferred method of staging the axilla of the breast cancer patient. This report describes the impact of postinjection massage on the sensitivity of this surgical technique. STUDY DESIGN: Lymphatic mapping at the H Lee Moffitt Cancer Center is performed using a combination of isosulfan blue dye and Tc99m labeled sulfur colloid. Data describing the rate of SLN identification and the node characteristics from 594 consecutive patients were calculated. Patients who received a 5-minute massage after injection of blue dye and radiocolloid were compared with a control group in which the patients did not receive a postinjection massage. RESULTS: When compared with controls, the proportion of patients who had their SLN identified using blue dye after massage increased from 73.0% to 88.3%, and the proportion of patients who had their SLN identified using radiocolloid after massage increased from 81.7% to 91.3%. The overall rate of SLN identification increased from 93.5% to 97.8%. The proportion of nodes that were stained blue among those removed increased from 73.4% to 79.7% after massage. CONCLUSIONS: As experience increases with this new procedure, the surgical technique of lymphatic mapping continues to evolve. The addition of a postinjection massage significantly improves the uptake of blue dye by SLNs and may also aid in the accumulation of radioactivity in the SLNs, further increasing the sensitivity of this procedure.
Breast Neoplasms↗
Regional differentiation of desmin, connexin43, and connexin45 expression patterns in rat aortic smooth muscle.
The gap-junctional protein, connexin43, is differentially expressed in vascular smooth muscle cells (SMCs) according to phenotype. Previous studies suggest that desmin-negative SMCs are characterized by high levels of connexin43, whereas desmin-positive SMCs (of a more contractile phenotype) typically have low connexin43 levels. In this study, we examine systematically the inverse relationship between connexin43 and desmin in SMCs of defined regions of the rat aortic media and determine whether additional connexin isotypes are expressed and contribute to this relationship. Immunoconfocal microscopy demonstrated that (1) the inverse relationship between connexin43 and desmin expression holds true for the media of sequential aortic zones, with 1 exception, the ascending aorta, and (2) an additional vascular connexin, connexin45, is expressed by aortic SMCs. Examination of connexin43, connexin45, and desmin expression in sequential aortic zones reveals 3 SMC subpopulations. The first, predominating in the aortic arch and thoracic aorta, is desmin negative and contains high connexin43 levels; the second, predominating in the abdominal aorta and iliac artery, is desmin positive and contains low connexin43 levels; and the third, which is restricted to the ascending aorta, is desmin positive and expresses high connexin43 levels. Connexin45 levels are high in the ascending aorta but low in the other aortic segments. In para-aortic veins, a fourth SMC subpopulation appears, one that is desmin positive and contains connexin45 but not connexin43. These results demonstrate that a diversity of connexin expression patterns characterizes distinctive subpopulations of medial SMCs in situ with a potential to contribute to regional differentiation of vascular function.
Animals↗
Comparison of connexin 43, 40 and 45 expression patterns in the developing human and mouse hearts.
The mouse is currently widely used as a model organism in the analysis of gene function but how developmentally regulated patterns of connexin gene expression in the mouse compare with those in the human is unclear. Here we compare the patterns of connexin expression in the heart during the development of the mouse (from embryonic day 12.5 to 6 weeks postpartum) and the human (at 9 weeks gestation and adult stage). The extent of connexin43 expression in the ventricles progressively increased during development of the mouse heart. The developmental pattern of expression for connexins 40 and 45 in the mouse heart was similar, but not identical, and in the ventricles showed a progressive and preferential expression in the conduction system. In general, these dynamic changes of connexins 43, 40 and 45 during mouse cardiac development appear to be mirrored in the human.
Adult↗
Importance of lymphatic mapping in ductal carcinoma in situ (DCIS): why map DCIS?
The appropriateness of sentinel lymph node biopsy in the management of patients with biopsy diagnoses of ductal carcinoma in situ (DCIS) or DCIS with microinvasion (DCISM) has not been established. Three hundred forty-one patients presented with a biopsy diagnosis of DCIS or DCISM. Two hundred forty (70%) underwent sentinel node biopsy at their definitive procedure. All clinical and pathologic data were collected prospectively. Of 224 patients with a biopsy diagnosis of DCIS 23 (10%) were upstaged to infiltrating ductal carcinoma (IDC) at their definitive therapy and of 16 patients with a biopsy diagnosis of DCISM seven (44%) were upstaged to IDC. Excisional biopsies were no more sensitive for detecting IDC than was core biopsy. Lymph node metastases were detected in 26 of 195 (13%) patients with a definitive diagnosis of DCIS, in three of 15 (20%) with a definitive diagnosis of DCISM, and in eight of 30 (27%) with a definitive diagnosis of IDC. Sentinel lymph node biopsy is a valuable tool in the treatment of patients with DCIS and DCISM and is particularly needed in those undergoing mastectomy. No "high-risk" group of patients can be identified for selective sentinel lymph node biopsy.
Breast Neoplasms↗
NPDC-1, a regulator of neural cell proliferation and differentiation, interacts with E2F-1, reduces its binding to DNA and modulates its transcriptional activity.
We have previously identified NPDC-1, a neural factor involved in the control of proliferation and differentiation, and we have shown that the stable introduction of NPDC-1 into transformed cells down-regulates cell proliferation both by increasing the generation time and by suppressing transformed properties. The data presented here indicate that, in vitro, NPDC-1 is able to interact with the transcription factor E2F-1 and some cell cycle proteins, such as D-cyclins and cdk2. In addition, two-hybrid experiments in mammalian cells show that the interaction between NPDC-1 and E2F-1 can also occur in vivo. This interaction reduces the binding of E2F-1 to DNA and its transcriptional activity. Taken together, the data suggest that NPDC-1 could influence cell cycle progression and neural differentiation through its association with E2F-1.
Animals↗
[Basal ganglia disease. Functional neuroanatomy and therapeutic perspectives].
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Animals↗
[Surgical treatment of Parkinson disease and essential tremor].
Recognition of the often failing effect of levodopa treatment as Parkinson's disease (PD) progresses has led to the resumption of surgical treatment. In the 1950'ies and 1960'ies pallidotomy and thalamotomy were commonly performed to reduce parkinsonian symptoms, whilst today these permanent lesions are replaced by Deep Brain Stimulation (DBS) of implanted leads. The advantages of DBS in either the subthalamic nuclei (STN) or the internal part of the globus pallidus are that implantation of leads into these nuclei can be performed bilaterally, and that DBS is a reversible treatment. Pallidotomy and thalamotomy are permanent lesions and if performed bilaterally these lesions often cause unacceptable complications. Bilateral stimulation of the STN is often preferred due to the reduction of rigidity, hypokinesia and tremor as well as the significant reduction of dyskinesias and off-periods. The motor functions are significantly improved and stabilized.
Brain↗
[Treatment of severe Parkinson disease with electric stimulation of the subthalamic nuclei].
INTRODUCTION: Patients with Parkinson's disease suffering from severe fluctuations, i.e. dyskinesias and on-off periods and/or severe tremor, who cannot be improved by adjustment of the medical treatment, can be treated with deep brain stimulation via leads implanted bilaterally into the subthalamic nuclei. METHODS: Nine patients with advanced idiopathic Parkinson's disease were treated with stereotactic and bilateral implantation of leads into the subthalamic nuclei. All patients had levodopa responsive Parkinson's disease and levodopa induced fluctuations in the form of on-off periods and dyskinesias. The mean age was 61 years and the mean duration of disease 15 years. The patients were followed for 12 months and evaluated with the Unified Parkinson's Disease Rating Scale off and on medications before and after lead implantation. RESULTS: The Hoehn & Yahr stage fell from 3.9/2.8 before lead implantation and off/on medication to 3.0/2.3 with lead stimulation turned on and off/on medication. The activity of daily living (ADL) index was significantly improved and reduced from 27/13 before lead implantation and off/on medication to 12/7 with the stimulation turned on and off/on medication i.e. with 55%/46% on stimulation. The motor score was likewise significantly improved and reduced from 55/28 to 24/17 i.e. with 56%/39% on stimulation. The most important results of deep brain stimulation in the subthalamic nuclei is the significant reduction of the motor fluctuations. On stimulation off periods were reduced from 30% to 6% and the dyskinesias were significantly reduced from 47% to 14% of the daytime. The mean dose of levodopa equivalent medication was reduced with 26%. DISCUSSION: In conclusion, patients with advanced Parkinson's disease and levodopa induced fluctuations can be successfully treated with bilateral high frequency electric stimulation of leads implanted into the subthalamic nuclei.
Adult↗
Do cytokeratin-positive-only sentinel lymph nodes warrant complete axillary lymph node dissection in patients with invasive breast cancer?
The small number of nodes harvested with lymphatic mapping and sentinel lymph node (SLN) biopsy has allowed a more detailed pathologic examination of those nodes. Immunohistochemical stains for cytokeratin (CK-IHC) have been used in an attempt to minimize the false negative rate for SLN mapping. This study examines the value of CK-IHC positivity in predicting further lymph node involvement in the axillary basin. From April 1998 through May 1999, 519 lymphatic mappings and SLN biopsies were performed for invasive breast cancer. SLNs were examined by imprint cytology, hematoxylin and eosin (H&E), and CK-IHC. Patients with evidence of metastatic disease by any of the above techniques were eligible for complete axillary node dissection (CAND). The frequency with which these modalities predicted further lymph node involvement in the axillary basin was compared. Of the 519 lymphatic mappings, 39 patients (7.5%) had a CK-IHC-positive-only SLN. Five (12.8%) of these 39 patients had at least 2 SLNs positive by CK-IHC. Twenty-six of the CK-IHC-positive-only patients underwent CAND. Three of these 26 patients (11.5%) had additional metastases identified after CAND. The sensitivity levels with which each modality detected further axillary lymph node involvement were as follows: CK-IHC, 98 per cent; H&E, 94 per cent; and imprint cytology, 87 per cent. A logistic regression to compare the prognostic value of the three modalities was performed. All were significant, with odds ratios of 19.1 for CK-IHC (P = 0.015), 5.3 for H&E (P = 0.033), and 3.86 for imprint cytology (P = 0.0059). These data validate the enhanced detection of CK-IHC for the evaluation of SLNs. Detection of CK-IHC-positive SLNs appears to warrant CAND in patients with invasive breast cancer. However, the therapeutic value of CAND or adjuvant therapies based on CK-IHC-positive SLNs would be best answered by prospective randomized trials.
Breast Neoplasms↗
[Albert Hustin (1882-1967) and the first blood transfusion].
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Belgium↗
Dephosphorylation agents depress gap junctional communication between rat cardiac cells without modifying the Connexin43 phosphorylation degree.
The functional state of gap junctional channels and the phosphorylation status of Connexine43 (Cx43), the major gap junctional protein in rat heart, were evaluated in primary cultures of neonatal rat cardiomyocytes. H7, able to inhibit a range of serine/threonine protein kinases, progressively reduced gap junctional conductance to approximately 13% of its initial value within 10 min except when protein phosphatase inhibitors were also present. The dephosphorylating agent 2,3-Butanedione monoxime (BDM) produced both a quick and reversible interruption of cell-to-cell communication as well as a parallel slow inhibition of junctional currents. The introduction of a non-hydrolysable ATP analogue (ATPgammaS) in the cytosol delayed the second component, suggesting that it was the consequence of protein dephosphorylation. Western blot analysis reveals 2 forms of Cx43 with different electrophoretic mobilities which correspond to its known phosphorylated and dephosphorylated forms. After exposure of the cells to H7 (1 mmol/l, 1h) or BDM (15 mmol/l, 15 min), no modification in the level of Cx43 phosphorylation was observed. The lack of direct correlation between the inhibition of cell-to-cell communication and changes in the phosphorylation status of Cx43 suggest that the functional state of junctional channels might rather be determined by regulatory proteins associated to Cx43.
Animals↗
Chamber-related differences in connexin expression in the human heart.
Electrical coupling in the heart is mediated by gap junctions, aggregates of cell-to-cell channels composed of connexins. The principal cardiac gap-junctional connexin, connexin43 (Cx43), is reduced in diseased human myocardium that is prone to arrhythmia. Three additional connexin isoforms, Cx40, Cx45 and Cx37, of distinctive functional capacities in vitro, are expressed in cardiovascular cells, but our knowledge of their expression patterns in the human heart is fragmentary. In the present study, we therefore applied Northern blotting, Western blotting and immunoconfocal microscopy to analyse and compare the expression of Cx43, Cx40, Cx37 and Cx45 mRNA and protein in the human left ventricle, right ventricle, left atrium and right atrium of the human heart. Cx43 was confirmed to be abundantly expressed at similar levels by myocytes in all four chambers. Cx40 levels varied between chambers in the order right atrium >left atrium >/= right ventricle approximately left ventricle. Cx37 (exclusively expressed in the endothelium) was expressed at similar overall levels in all chambers (as judged from Northern blots). Cx45 was detectable only at very low levels, with a trend toward higher levels in the atria than the ventricles in a pattern similar to Cx40. The results indicate that in humans, the ventricles and atria have distinctive connexin expression profiles, and that the atrial-type connexin profile is more pronounced in the right atrium than the left atrium. While the ventricular connexin expression pattern resembles that of other mammalian species, atrial connexin expression shows greater species variation. These differences contribute to the interpretative framework for examining the potential role of altered connexin expression in ventricular and atrial arrhythmia in the human heart.
Blotting, Northern↗