Modulation of 5-HT3 receptor desensitization by the light chain of microtubule-associated protein 1B expressed in HEK 293 cells

Regulation of ligand-gated ion channel (LGIC) function and trafficking by cytoskeleton proteins has been the topic of recent research. Here, we report that the light chain (LC1) of microtubule-associated protein 1B (MAP1B) specifically interacted with the 5-HT_3A receptor, a predominant serotonin-gated ion channel in the brain. LC1 and 5-HT_3A receptors were colocalized in central neurons and in HEK 293 cells expressing 5-HT_3A receptors. LC1 reduced the steady-state density of 5-HT_3A receptors at the membrane surface of HEK 293 cells and significantly accelerated receptor desensitization time constants from 3.8 ± 0.3 s to 0.8 ± 0.1 s. However, LC1 did not significantly alter agonist binding affinity and single-channel conductance of 5-HT_3A receptors. On the other hand, application of specific LC1 antisense oligonucleotides and nocodazole, a microtubule disruptor, significantly prolonged the desensitization time of the recombinant and native neuronal 5-HT₃ receptors by 3- to 6-fold. This kinetic change induced by nocodazole was completely rescued by addition of LC1 but not GABA_A receptor-associated protein (GABARAP), suggesting that LC1 can specifically interact with 5-HT_3A receptors. These observations suggest that the LC1–5-HT_3A receptor interaction contributes to a mechanism that regulates receptor desensitization kinetics. Such dynamic regulation may play a role in reshaping the efficacy of 5-HT₃ receptor-mediated synaptic transmission.     

Investigations into Pulsed High-Intensity Focused Ultrasound–Enhanced Delivery: Preliminary Evidence for a Novel Mechanism

Pulsed high-intensity focused ultrasound (HIFU) exposures without ultrasound contrast agents have been used for noninvasively enhancing the delivery of various agents to improve their therapeutic efficacy in a variety of tissue models in a nondestructive manner. Despite the versatility of these exposures, little is known about the mechanisms by which their effects are produced. In this study, pulsed-HIFU exposures were given in the calf muscle of mice, followed by the administration of a variety of fluorophores, both soluble and particulate, by local or systemic injection. In vivo imaging (whole animal and microscopic) was used to quantify observations of increased extravasation and interstitial transport of the fluorophores as a result of the exposures. Histological analysis indicated that the exposures caused some structural alterations such as enlarged gaps between muscle fiber bundles. These effects were consistent with increasing the permeability of the tissues; however, they were found to be transient and reversed themselves gradually within 72 h. Simulations of radiation force–induced displacements and the resulting local shear strain they produced were carried out to potentially explain the manner by which these effects occurred. A better understanding of the mechanisms involved with pulsed HIFU exposures for noninvasively enhancing delivery will facilitate the process for optimizing their use. (E-mail: vfrenkel@cc.nih.gov)     

26万女性队列人群中乳腺癌与人工流产关系的研究（上海）

目的：评估人工流产（指手术流产）对乳腺癌危险性的可能影响。方法：研究在上海267040例妇女的一项乳房自我检查随机试验的队列人群中进行，由队列研究和巢式病例对照研究两部分组成。结果：依据基线调查表采集的资料分析，人工流产不增加乳腺癌危险性。调整潜在的混淆因素后，OR=1．06（95％CI：0．91～1．25）。人工流产次数增加无危险性趋势增加。从更详细的652例乳腺癌病例和694例对照资料分析，得出相似的结果。人工流产发生在首次生育后不增加危险性；少数妇女在首次生育前人工流产以及妊娠13周后人工流产，虽然被观察到危险性有增加，但无显著性统计学意义。结论：在中国，人工流产不是乳腺癌发生的重要原因。     

Airway reactivity response to aged carbon-graphite/epoxy composite material smoke

Exposure of na&ıuml;ve guinea pigs for a total of 30 min to aged smoke from pyrolysis of 5, 10 and 100 g of carbon–graphite/epoxy‐advanced composite material (cgeCM) elicited changes in the ventilation and breathing pattern reminiscent of an acute, asthmatic episode. The severity of these responses was dose related. Although breathing pattern changes were not definitive of stimulation by a single type of respiratory irritant, non‐dimensional indices derived from breath structure appeared to be characteristic of bronchoconstriction possibly complicated by CO₂‐stimulated ventilation. The highest exposure concentration also elicited convulsions in the animals, which may or may not be related to the airway reactivity (AR) response. Upon treatment with fresh air, breathing returned to normal. However, this recovery was transient with some respiratory parameters returning to abnormal levels, possibly indicating a rebound or delayed component of the response. Filtration of particulate material from the smoke moderated but did not eliminate the AR response. Animals exposed to diluted smoke from the pyrolysis of 2 g of cgeCM showed no remarkable changes in breathing or ventilation, suggesting that there may be a threshold for aged cgeCM smoke‐elicited AR response. Published in 2002 by John Wiley & Sons, Ltd.     

CT screening for lung cancer: the first ten years

This article reviews the current state of knowledge regarding computed tomography (CT) screening for lung cancer. The initial 3 studies have demonstrated the superiority of CT-based screening for lung cancer over traditional radiography. Furthermore, false-positive tests common on baseline screening were manageable without notable excess of biopsies or thoracotomies. Differences and similarities of various screening regimens are discussed in relation to reported study results. When comparing the various studies, the focus should be placed on the diagnostic distribution achieved under annual repeat screening, as it is this distribution which is obtained year after year of repeat screening and this distribution and the curability of these repeat screen-diagnosed lung cancer which determine the usefulness of the screening regimen. To date, these studies demonstrate a consistent shift to over 80% of the cancer being diagnosed in Stage IA. This marked shift suggest that the curability of screen-detected lung cancers will be markedly improved.     

Ethical issues in aging and renal disease

The incidence of elderly patients reaching end-stage renal disease (ESRD) and requiring renal replacement is increasing. Better medical care is helping patients live longer but, at the same time, is raising ethical questions. Treatment decisions for ESRD patients present a forum for the consideration of ethical questions surrounding the issues of scarce health care resource allocation and the withholding or withdrawal of life-sustaining treatment. As background for the consideration of ethical issues in ESRD patients, the quality of life they experience and what they may expect as death approaches also are discussed.     

Risk of cancer among relatives of patients with glioma.

We report a population-based, retrospective study of 396 Icelandic people diagnosed with glioma in the years 1940-1995. The purpose of this study was to test whether astrocytomas, other glial tumors, other central nervous system tumors, or other cancers aggregate in families identified through glioma probands who were of Icelandic origin. Pedigrees of the 396 cases were traced by the Genetical Committee of the University of Iceland and linked to the Icelandic Cancer Registry. A total of 25,546 relatives, including 2,080 individuals with cancer were identified within these pedigrees. There was no statistically significant increase of glioma in relatives of glioma patients, nor was there any statistically significant increase in risk for other central nervous system tumors. There was no overall increase in incidence of all cancer combined, nor of specific common cancers (lung, prostate, breast, stomach, and colorectal) and uncommon cancers (melanoma and pancreas) in the relatives of glioma patients. Our results do not support the hypothesis of a familial aggregation of glioma indicative of a glioma susceptibility gene.     

Chemokine receptor CCR5 and CXCR4 expression in HIV-associated kidney disease

The chemokine receptors CCR5 and CXCR4 have been identified as essential coreceptors for entry of HIV-1 strains into susceptible cells. Direct infection of renal parenchymal cells has been implicated in the pathogenesis of HIV-associated renal disease, although data are conflicting. The localization of CCR5 and CXCR4 in kidneys with HIV-associated renal disease is unknown. Formalin-fixed, paraffin-embedded renal biopsies from patients with HIV-associated nephropathy (HIVAN) (n = 13), HIV-associated immune complex glomerulonephritis (n = 3), HIV-associated thrombotic microangiopathy (n = 1), and HIV-negative patients with collapsing glomerulopathy (n = 8) were analyzed in this study. Cellular sites of expression of CCR5 and CXCR4 were identified by immunohistochemistry and by in situ hybridization. The presence of HIV-1 was detected by immunohistochemistry and by in situ hybridization. Expression of both chemokine receptors CCR5 and CXCR4 was undetectable in intrinsic glomerular, tubular, and renovascular cells in all analyzed cases. In the presence of tubulointerstitial inflammation, CCR5 and CXCR4 expression was localized to infiltrating mononuclear leukocytes. HIV-1 protein was undetectable by immunohistochemistry in all cases of HIV-associated renal disease. HIV-1 RNA was identified in one case of HIVAN but was restricted to infiltrating leukocytes. HIV-1 RNA was not detected in intrinsic renal cells in all analyzed cases. Identifying the cellular expression of HIV-coreceptors CCR5 and CXCR4 may help to clarify which tissues are permissive for direct HIV infection. These data do not support a role of productive HIV-1 infection of renal parenchymal cells in the pathogenesis of HIV-associated renal disease.