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Biomedical subjects

D Meaney

Publications and source records attributed to D Meaney.

5 recordsLinked to original sources
PubMed2001

Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels.

Diffuse axonal injury (DAI) is one of the most common and important pathologies resulting from the mechanical deformation of the brain during trauma. It has been hypothesized that calcium influx into axons plays a major role in the pathophysiology of DAI. However, there is little direct evidence to support this hypothesis, and mechanisms of potential calcium entry have not been explored. In the present study, we used an in vitro model of axonal stretch injury to evaluate the extent and modulation of calcium entry after trauma. Using a calcium-sensitive dye, we observed a dramatic increase in intra-axonal calcium levels immediately after injury. Axonal injury in a calcium-free extracellular solution resulted in no change in calcium concentration, suggesting an extracellular source for the increased post-traumatic calcium levels. We also found that the post-traumatic change in intra-axonal calcium was completely abolished by the application of the sodium channel blocker tetrodotoxin or by replacement of sodium with N-methyl-d-glucamine. In addition, application of the voltage-gated calcium channel (VGCC) blocker omega-conotoxin MVIIC attenuated the post-traumatic increase in calcium. Furthermore, blockade of the Na(+)-Ca(2+) exchanger with bepridil modestly reduced the calcium influx after injury. In contrast to previously proposed mechanisms of calcium entry after axonal trauma, we found no evidence of calcium entry through mechanically produced pores (mechanoporation). Rather, our results suggest that traumatic deformation of axons induces abnormal sodium influx through mechanically sensitive Na(+) channels, which subsequently triggers an increase in intra-axonal calcium via the opening of VGCCs and reversal of the Na(+)-Ca(2+) exchanger.

Axons↗
PubMed2000

Tissue tears in the white matter after lateral fluid percussion brain injury in the rat: relevance to human brain injury.

A characteristic feature of severe diffuse axonal injury in man is radiological evidence of the "shearing injury triad" represented by lesions, sometimes haemorrhagic, in the corpus callosum, deep white matter and the rostral brain stem. With the exception of studies carried out on the non-human primate, such lesions have not been replicated to date in the multiple and diverse rodent laboratory models of traumatic brain injury. The present report describes tissue tears in the white matter, particularly in the fimbria of Sprague-Dawley rats killed 12, 24, and 48 h and 7 days after lateral fluid percussion brain injury of moderate severity (2.1-2.4 atm). The lesions were most easily seen at 24 h when they appeared as foci of tissue rarefaction in which there were a few polymorphonuclear leucocytes. At the margins of these lesions, large amounts of accumulated amyloid precursor protein (APP) were found in axonal swellings and bulbs. By 1 week post-injury, there was macrophage infiltration with marked astrocytosis and early scar formation. This lesion is considered to be due to severe deformation of white matter and this is the first time that it has been identified reproducibly in a rodent model of head injury under controlled conditions.

Amyloid beta-Protein Precursor↗
PubMed1996

Uterine papillary serous carcinoma evolves via a p53-driven pathway.

Uterine papillary serous carcinoma (UPSC) is a highly aggressive type of endometrial cancer that occurs in the absence of hyperestrogenism and endometrial hyperplasia. Biologically, UPSC belongs to a distinct group of aggressive neoplasms of the extended Müllerian epithelium that are characterized by hypoestrogenism, advanced disease at diagnosis, a serous papillary histotype, and a dismal prognosis. There is mounting evidence that loss of p53 function is critical for the molecular genetic cause of all tumors in this group. To further assess the role of p53 alterations in UPSC, we studied 40 patients using immunohistochemical expression analysis. Thirty-four tumors (85%) showed intense nuclear overexpression of p53, whereas six tumors (15%) were p53 negative. Thirteen p53-positive tumors had multiple samplings from distinct anatomic sites, and all showed complete concordance in p53 staining, suggesting that p53 alterations occur early in UPSC carcinogenesis. p53 positivity was associated with loss of hormone receptors. Thirty-nine cases were concomitantly analyzed for estrogen or progesterone receptor expression. Among those, 31 tumors were p53 positive but hormone receptor negative throughout, in contrast to only two tumors that were diffusely p53 positive and focally hormone receptor positive. Patients whose tumors overexpressed p53 had a statistically significant shorter survival than those whose tumors did not at 24 and 48 months (P = .03). This study represents one of the two largest analyses published to date that confirm the strong association between UPSC and p53 overexpression. Furthermore, we suggest that the concept of UPSC be broadened: UPSC is a p53-driven neoplasm that biologically is a kin to other serous papillary malignancies of the ovaries and peritoneum. This group of tumors bypasses the slow hormone-dependent pathway of tumorigenesis but instead undergoes early p53 alterations that lead to rapid tumor development.

Aged↗
PubMed1994

Bovine bladder compliance increases with normal fetal development.

In this study we characterized the elastic properties of the normal bovine bladder throughout fetal life, the newborn period and into adulthood. The elasticity of the bladder was measured with a novel circularly clamped bladder testing system. Pressurization of a circularly clamped bladder tissue sample caused the tissue to deflect upward repetitively in the shape of a spherical cap. If the centerline deflection is much larger than the tissue thickness, the elastic modulus, considered the inverse of compliance, can be determined using linear regression techniques. The results of our analyses showed that the elastic modulus decreases in direct proportion with increasing gestational age. These data suggest that during normal development of the bovine fetal bladder there is a progressive change from a rather stiff noncompliant bladder characterized by a high elastic modulus to a compliant bladder with a lower elastic modulus. Moreover, the increase in compliance appears in the developmental period when urine production first occurs. These observations suggest that volume work may be a significant event in the normal development process of the bovine bladder and results in an increase in bladder compliance. Conversely, the poorly compliant fetal bladder may explain some of the transient dilatations of the upper urinary tract which have been documented in utero. Finally, from the newborn period to the mature adult bovine we documented a relatively modest increase in the elastic modulus or decrease in bladder compliance which may reflect the normal aging process.

Animals↗