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Biomedical subjects

M Wachtel

Publications and source records attributed to M Wachtel.

6 recordsLinked to original sources
PubMed2001

Molecular and cellular permeability control at the blood-brain barrier.

The blood-brain barrier (BBB) is formed by brain capillary endothelial cells. These cells have at least three properties which distinguish them from their peripheral counterparts: (1) tight junctions (TJs) of extremely low permeability; (2) low rates of fluid-phase endocytosis; (3) specific transport and carrier molecules. In combination, these features restrict the nonspecific flux of ions, proteins, and other substances into the central nervous system (CNS) environment. The restriction protects neurons from harmful compositional fluctuations occurring in the blood and allows uptake of essential molecules. Breakdown of the BBB is associated with a variety of CNS disorders and results in aggravation of the condition. Restoration of the BBB is thus one strategy during therapy of CNS diseases. Its success depends on a precise knowledge of the structural and functional principles underlying BBB functionality. In this review we have tried to summarise the current knowledge of TJs, including information gained from non-neuronal systems, and describe selected mechanisms involved in permeability regulation.

Animals↗
PubMed2001

Down-regulation of occludin expression in astrocytes by tumour necrosis factor (TNF) is mediated via TNF type-1 receptor and nuclear factor-kappaB activation.

Tight junctions form the diffusion barrier of brain microcapillary endothelial cells and support cell polarity. Also astrocytes express tight junction components such as occludin, claudin-1, ZO-1 and ZO-2, but do not establish a permeability barrier. However, little is known about the function and regulation of these molecules in astrocytes. We studied the impact of tumour necrosis factor (TNF) on occludin and ZO-1 expression in astrocytes. TNF decreased occludin, but not ZO-1 expression. In brain microcapillary endothelial cells, as well as in epithelial cells, occludin expression was not influenced by TNF. Removal of TNF from astrocytes restored the basal level of occludin. Down-regulation was inhibited by caffeic acid phenethyl ester, a specific inhibitor of nuclear factor-kappaB (NF-kappaB) activation. Exposure of astrocytes isolated from mice deficient in either TNF type-1 receptor (TNFR1), TNF type-2 receptor (TNFR2), or both, respectively, revealed that down-regulation was mediated entirely by TNFR1. ZO-1, which can interact with occludin, was found to co-precipitate connexin43, but not occludin. These findings demonstrate that TNF selectively down-regulates occludin in astrocytes, but not in cells forming established tight junctions, through TNFR1 and suggest that NF-kappaB is involved as a negative regulator.

Animals↗
PubMed1999

Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition.

Regulation of epithelial and endothelial permeability is essential for proper function of compartmentalized organisms, and tyrosine phosphorylation plays an important role in this process. We analyzed the impact of protein tyrosine phosphatase (PTP) inhibition on the structure of endothelial junctional proteins. In human umbilical vein endothelial cells (HUVECs) the PTP inhibitors phenylarsine oxide (PAO) and pervanadate induced proteolysis of the tight junction protein occludin. Occludin proteolysis was inhibited by the metalloproteinase inhibitor 1,10-phenanthroline (PHEN), but not by inhibitors against other types of proteases. The junctional proteins ZO-1, cadherin and beta-catenin were not cleaved. Under conditions of occludin proteolysis, PAO treatment elevated permeability for FITC-dextran. Simultaneous incubation of HUVECs with PAO and PHEN inhibited the rise in permeability by more than 60%. PAO treatment lead to progressive disappearance of occludin from the cell periphery. In contrast, ZO-1, cadherin and beta-catenin retained their positions at the sites of intercellular contact. Simultaneous administration of PAO and PHEN greatly prevented the redistribution of occludin. These results demonstrate a selective cleavage of occludin by a metalloproteinase and suggest that this process can contribute to the control of paracellular permeability in endothelial cells.

Arsenicals↗
PubMed1995

Use of the "triple test" for palpable breast lesions yields high diagnostic accuracy and cost savings.

BACKGROUND: The "triple test" for palpable breast lesions consists of physical examination, mammography, and fine-needle aspiration. METHODS: Forty-six lesions in 43 patients were subjected to all three components of the triple test, followed by confirmatory open biopsy. RESULTS: In all 21 cases where the triple test was concordant (elements had either all malignant or all benign results), pathologic analysis of open biopsy samples was confirmatory (predictive value and sensitivity 100%). Fine-needle aspiration was the most reliable element of the triple test in cases where the elements of the test were nonconcordant (negative predictive value and sensitivity of 95% and 96%, respectively). CONCLUSIONS: The triple test was 100% accurate in the diagnosis of palpable breast lesions when all three elements were concordant. Cost analysis revealed that elimination of confirmatory open biopsy in such cases and also in cases in which the fine-needle aspiration and one other element of the test had a suspicious or malignant result, could yield an average per-case cost savings of up to $1,412 compared to triple test followed by routine confirmatory open biopsy.

Adult↗
PubMed1993

Clusters of chromosome 9 aberrations are associated with clinico-pathologic subsets of non-Hodgkin's lymphoma.

In this study we analyzed nonrandom aberrations affecting chromosome 9 in a series of 426 consecutively ascertained, karyotypically abnormal non-Hodgkin's lymphoma (NHL) tumors derived from 407 patients. Cytogenetic abnormalities were correlated with clinical, histologic, and immunologic features. Structural abnormalities of chromosome 9 were identified in 60 specimens derived from 59 patients. The recurring abnormalities among these were associated with 4 clinico-pathologic subsets. The first comprised 7 cases of t(9;14)(p13;q32), 6 of which had small lymphocytic lymphoma, plasmacytoid subtype, and an indolent clinical course. The second group included 12 cases with breaks at 9q11-13 and diffuse lymphomas with a large-cell component and a typical response to combination chemotherapy. The third group was comprised of 7 cases with 9q deletions, with a common deleted region encompassing 9q31-32. These cases were characterized by diffuse B-cell histology, young age, and poor clinical outcome. The fourth subset included 5 intermediate- to high-grade T-cell tumors with breaks at 9q34. This analysis of chromosome 9 aberrations in NHL comprises the first such effort based on a large series of tumors. We identify and report here new clinico-pathologic subsets with shared abnormalities of chromosome 9, which should facilitate new approaches to the analysis of the etiology and clinical behavior of NHL.

Biopsy↗