Differential sensitivity of sodium channel isoforms and sequence variants to pyrethroid insecticides

Pyrethroids are commonly regarded as safe insecticides. However, some widely used pyrethroids, particularly single neurotoxic isomers of potent Type II compounds, have acute oral toxicities comparable to many organophosphorus insecticides. The majority of studies of the action of pyrethroids on voltage-sensitive sodium channels, the principal target sites for these compounds, have not considered differences in sodium channel structure as determinants of sensitivity. In mammals, voltage-sensitive sodium channels are encoded by a multi-gene family and exhibit both anatomical and developmental regulation of expression. Studies in this laboratory using cloned rat sodium channel isoforms expressed in Xenopus oocytes have documented profound differences in pyrethroid sensitivity between isoforms. Although the role of sodium channel gene mutations in altering pyethroid sensitivity has not been addressed in the case of the mammalian sodium channel gene family, the potential significance of allelic variation is illustrated in studies of point mutations in a sodium channel gene of the house fly that confer resistance to the lethal actions of pyrethroids and modify the sensitivity of house fly sodium channels expressed in Xenopus oocytes to these compounds. It is of particular interest that some of these resistance-associated mutations in the fly sodium channel occur at amino acid residues that are also the sites of mutations in human skeletal muscle sodium channels that are associated with inherited paralytic disorders. These findings document the pharmacological significance of structural differences between sodium channel isoforms and between genetic variants of an individual isoform as determinants of pyrethroid sensitivity.     

踏车运动较潘生丁负荷13^N-氨PET检查可引起更严重的心肌灌注缺损

目的:本研究旨在比较踏车运动(TEX)与潘生丁负荷对心肌摄取及潴留13N-氨的影响。背景:负荷诱发心肌灌注缺损的大小和严重程度具有重要的临床意义。由于心肌对氨的摄取和潴留似乎与心肌血流灌注、心肌存活和代谢有关,因此运动负荷将比潘生丁负荷诱发出更大范围的心肌灌注缺损。方法:26例患者接受TEX和潘生丁负荷13N-氨正电子发射断层扫描(PET)检查。用17节段模型及5分评分法对图像进行分析。计算负荷状态总评分(SSS)、静息状态总评分(SRS)和差值总评分(SDS)。根据异常灌注阈值的70%定量测定左室(LV)缺损的大小。结果:与潘生丁负荷相…     

MRI techniques: bilateral findings and "normal findings"

Magnetic resonance imaging (MRI) techniques allow for significantly better imaging of the temporal lobe compared to computed tomography (CT) or other non-invasive modalities. For detection of foreign tissue lesions, MRI surpasses CT. For the highest non-invasive yield for detection of mesial temporal sclerosis, optimal sequences that should be employed are a heavily T1-weighted volumetric acquisition (to enable both volumetric calculation of hippocampal volume, and, if needed, intracranial volume), T2-weighted coronal sequences, with or without T2-mapping, fluid-attenuated inversion recovery (FLAIR) and, to exclude subtle susceptibility effects from hematoma or cavernoma, gradient echo scans. Magnetic resonance spectroscopy (MRS) may show a decrease in N-acetyl aspartate (NAA) concentration, or NAA: Choline + creatine ratio. Functional MRI is a new and exciting tool that offers the promise of accurately localizing hemispheric functions; its role in the preoperative evaluation of temporal lobe seizures remains uncertain at present.     

Attempted suicide and polymorphism of the serotonin transporter gene in Chinese patients with schizophrenia

Abnormalities of serotonin synthesis and metabolism may be associated with suicidality. The serotonin transporter gene (5-HTT) is one of the important genes involved in the regulation of serotonin neurotransmission. We examined the association of suicidal behavior in Chinese schizophrenic patients with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). The 5-HTTLPR genotype was determined by polymerase chain reaction for 76 suicidal and 262 non-suicidal patients with a diagnosis of schizophrenia (DSM-IV criteria). All subjects were unrelated to each other, and all were Chinese. There was no significant genotypic or allelic association of the 5-HTTLPR polymorphism with history of attempted suicide. From our results, this 5-HTTLPR polymorphism is unlikely to have a major effect on suicidal behavior in Chinese patients with schizophrenia.     

Unbalanced atrioventricular septal defect with parachute valve

A 5-month-old male patient presented with right-dominant unbalanced atrioventricular septal defect and left-sided parachute valve, and underwent successful biventricular repair. Because of the presence of a small left ventricle, left atrium, and a single left papillary muscle, an additional orifice was created in the left-sided atrioventricular valve with artificial partitioning of the right-sided atrioventricular valve. There was no evidence of mitral stenosis or regurgitation on follow-up echocardiography.     

Time-dependent inhibition and tetrahydrobiopterin depletion of endothelial nitric-oxide synthase caused by cigarettes.

Smoking causes a dysfunction in endothelial nitric-oxide synthase (eNOS), which is ameliorated, in part, by administration of tetrahydrobiopterin (BH(4)). The exact mechanism by which the nitric oxide deficit occurs is unknown. We have previously shown that aqueous extracts of chemicals in cigarettes (CE) cause the suicide inactivation of neuronal NO synthase (nNOS) by interacting at the substrate-binding site. In the current study, we have found that CE directly inactivates eNOS by a process that is not affected by the natural substrate l-arginine and is distinct from the mechanism of inactivation of nNOS. We discovered that CE causes a time-, concentration-, and NADPH-dependent inactivation of eNOS in an in vitro system containing the purified enzyme, indicating a metabolic component to the inactivation. The CE-treated eNOS but not nNOS was nearly fully reactivated upon incubation with excess BH(4), suggesting that BH(4) depletion is a potential mechanism of inactivation. Moreover, in the presence of CE, eNOS catalyzed the oxidation of BH(4) to dihydrobiopterin and biopterin by a process attenuated by high concentrations of superoxide dismutase but not catalase. We speculate that a redox active component in CE, perhaps a quinone compound, causes oxidative uncoupling of eNOS to form superoxide, which in turn oxidizes BH(4). The discovery of a direct inactivation of eNOS by a compound(s) present in tobacco provides a basis not only for further study of the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of eNOS.     

Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor.

Targeted therapies that inhibit the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) have shown activity against solid malignancies when used as single agents or in combination with chemotherapy. Although anti-EGFR therapies are active in some patients, eventually disease in nearly all patients will become refractory to therapy. Therefore, a better understanding of the mechanisms of resistance to anti-EGFR therapies is critical to further improve the efficacy of this class of agents. Mechanisms that mediate resistance to anti-EGFR therapies include the presence of redundant tyrosine kinase receptors, increased angiogenesis, and the constitutive activation of downstream mediators. Two recent landmark publications have also shown that specific mutations in the kinase domain of EGFR in some lung carcinomas are associated with markedly improved response rates to an EGFR tyrosine kinase inhibitor. Mutations in the EGFR receptor seem to play a significant role in determining the sensitivity of tumor cells to EGFR inhibitor therapy by altering the conformation and activity of the receptor. As the field of molecular therapeutics continues to evolve, a comprehensive understanding of resistance mechanisms will ultimately lead to refinements in our regimens to provide better care for patients with cancer.