Molecular determinants of state-dependent block of voltage-gated sodium channels by pilsicainide

Background and purpose:

Pilsicainide, an anti-arrhythmic drug used in Japan, is described as a pure sodium channel blocker. We examined the mechanisms by which it is able to block open channels, because these properties may be especially useful to reduce hyperexcitability in pathologies characterized by abnormal sodium channel opening.

Experimental approach:

The effects of pilsicainide on various heterologously expressed human sodium channel subtypes and mutants were investigated using the patch clamp technique.

Key results:

Pilsicainide exhibited tonic and use-dependent effects comparable to those of mexiletine and flecainide on hNav1.4 channels. These use-dependent effects were abolished in the mutations F1586C and Y1593C within segment 6 of domain IV, suggesting that the interaction of pilsicainide with these residues is critical for its local anaesthetic action. Its affinity constants for closed channels (K_R) and channels inactivated from the closed state (K_I) were high, suggesting that its use-dependent block (UDB) requires the channel to be open for it to reach a high-affinity blocking site. Accordingly, basic pH, which slightly increased the proportion of neutral drug, dramatically decreased K_R and K_I values. Effects of pilsicainide were similar on skeletal muscle hNav1.4, brain hNav1.1 and heart hNav1.5 channels. The myotonic R1448C and G1306E hNav1.4 mutants were more and less sensitive to pilsicainide, respectively, due to mutation-induced gating modifications.

Conclusions and implications:

Although therapeutic concentrations of pilsicainide may have little effect on resting and closed-state inactivated channels, it induces a strong UDB due to channel opening, rendering the drug ideally suited for inhibition of high-frequency action potential firing.     

Trolox ameliorates 3-nitropropionic acid-induced neurotoxicity in rats

3-nitropropionic acid (3-NPA) is a naturally occurring neurotoxin produced by legumes of the genus Astragalus and Arthrium fungi. Acute exposure to 3-NPA results in striatal astrocytic death and variety of behavior dysfunction in rats. Oxidative stress has been reported to play an important role in 3-NPA-induced neurotoxicity. Trolox is a potent free radical chain breaking antioxidant which has been shown to restore structure and function of the nervous system following oxidative stress. This rapid and efficient antioxidant property of trolox was attributed to its enhanced water solubility as compared with alpha-tocopherol. This investigation was aimed to study the effect of trolox against 3-NPA-induced neurotoxicity in female Wistar rats. The animals received trolox (0, 40 mg, 80 mg and 160 mg/kg, orally) daily for 7 days. 3-NPA (25 mg/kg, i.p.) was administered daily 30 min after trolox for the same duration. One additional group of rats served as control (vehicle only). On day 8, the animals were observed for neurobehavioral performance. Immediately after behavioral studies, the animal's brains were dissected out for histological studies. Lesions in the striatal dopaminergic neurons were assessed by immunohistochemical method using tyrosine hydroxylase immunostaining. Administration of 3-NPA alone caused significant depletion of striatal dopamine and glutathione, whereas, the levels of thiobarbituric acid reactive substance (TBARS) and nitric oxide (NO) were significantly increased suggesting an elevated level of oxidative stress. Trolox significantly and dose-dependently protected animals against 3-NPA-induced neurobehavioral, neurochemical and structural abnormalities. These results clearly suggest that protective effect of trolox against 3-NPA-induced neurotoxicity is mediated through its free radical scavenging activity.     

Postchemotherapy retroperitoneal surgery remains necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses.

PURPOSE: To determine preoperative parameters that predict the histology of specimens obtained by retroperitoneal lymph node dissection (RPLND) in patients with nonseminomatous germ cell cancer (NSGCT) whose residual mass was 相似文献   

Spättoxizität nach Hodentumortherapie unter besonderer Berücksichtigung sexueller Störungen

Due to cisplatin-based chemotherapy, the survival rate of testicular cancer patients approaches 90%. Chemo- or radiotherapy may cause long-term complications, e.g. cardiovascular disease, secondary cancers and reduced fertility. Sperm cryopreservation is recommended depending on the extent of therapy and should be performed before orchiectomy. Furthermore, patients should be informed about long-term complications and their possible reduction by optimizing the risk factor profile.     

The association between socioeconomic status and osteoporotic fracture in population-based adults: a systematic review

Summary  Although socioeconomic status (SES) is inversely related to most diseases, this systematic review showed a paucity of good quality data examining influences of SES on osteoporotic fracture to confirm this relationship. Further research is required to elucidate the issue and any underlying mechanisms as a necessary precursor to considering intervention implications. Introduction  The association between socioeconomic status (SES) and musculoskeletal disease is little understood, despite there being an inverse relationship between SES and most causes of morbidity. We evaluated evidence of SES as a risk factor for osteoporotic fracture in population-based adults. Methods  Computer-aided search of Medline, EMBASE, CINAHL, and PsychINFO from January 1966 until November 2007 was conducted. Identified studies investigated the relationship between SES parameters of income, education, occupation, type of residence and marital status, and occurrence of osteoporotic fracture. A best-evidence synthesis was used to summarize the results. Results  Eleven studies were identified for inclusion, which suggested a lack of literature in the field. Best evidence analysis identified strong evidence for an association between being married/living with someone and reduced risk of osteoporotic fracture. Limited evidence exists of the relationship between occupation type or employment status and fracture, or for type of residence and fracture. Conflicting evidence exists for the relationship between osteoporotic fracture and level of income and education. Conclusion  Limited good quality evidence exists of the role SES might play in osteoporotic fracture. Further research is required to identify whether a relationship exists, and to elucidate underlying mechanisms, as a necessary precursor to considering intervention implications.     

Are Retinal Microvascular Caliber Changes Associated with Severity of Coronary Artery Disease in Symptomatic Cardiac Patients?

Objectives: Recent population‐based studies have shown that retinal vascular caliber may predict the risk of clinical coronary artery disease (CAD) events. Whether this association is related to macro‐ or microvascular mechanisms remains unknown. We investigated the relationship of retinal vascular caliber with severity and extent of CAD in symptomatic cardiac patients. Materials and Methods: Overall, 98 patients attending diagnostic coronary angiography were recruited. Coronary angiography was used to assess for the severity and extent of CAD. Digital retinal photography was performed immediately prior to cardiac catheterization, and retinal vascular caliber was measured from these photographs by using a computer program and summarized as central retinal arteriolar (CRAE) and venular (CRVE) equivalents. Results: Retinal arteriolar and venular calibers were not associated with increasing severity of CAD, as assessed by Leaman scores (CRAE/CRVE: P for trend=0.17/0.57), presence of clinically significant CAD (CRAE/CRVE: P=0.35/0.32), or number of diseased vessels (CRAE/CRVE: P for trend=0.18/0.69). Conclusions: Retinal vascular caliber changes are not associated with the severity of obstructive CAD in symptomatic patients. These data suggest that the association of retinal vascular caliber with clinical CAD seen in epidemiological studies may not be applicable to clinical symptomatic patients and may be related to microvascular, rather than macrovascular, mechanisms.     

Hepatic Transit Time Analysis Using Contrast-Enhanced Ultrasound with BR1: A Prospective Study Comparing Patients with Liver Metastases from Colorectal Cancer with Healthy Volunteers

We prospectively compared hepatic transit time (HTT) measurements in subjects with liver metastases from colorectal cancer (group a) and healthy volunteers (group b) using contrast-enhanced ultrasound with BR1. The purpose of this study was to verify our hypothesis that the hemodynamic changes of the liver, which occur during metastasis seeding, would shorten the HTT, and we expect that such changes could be used for the detection of occult liver metastases from colorectal cancer in the future. The study had institutional review board approval and all subjects gave informed written consent. Group a and group b consisted of 22 subjects each. Baseline and post contrast images were acquired starting 10 s before and ending 40 s after administration of BR1, using nonlinear imaging at a frame rate of 5/s. The baseline images were used to determine the signal intensity without contrast enhancement as the reference signal. Arrival times (AT) of the contrast agent for the hepatic artery, the portal vein and one hepatic vein were determined using (i) quantitative analysis and (ii) subjective analysis by two blinded readers. HTT was calculated based on arrival time measurements. Quantitative and subjective analysis showed significantly shorter arterial to venous and portal to venous HTT in group a compared with group b (p < 0.001). Arterial to venous HTT (quantitative analysis) was ≤9 s in 19 of 22 subjects of group a and >9 s in 18 of 22 subjects of group b (sensitivity 86%, specificity 82%, positive predictive value 83%, negative predictive value 86%, area under the curve [AUC] 0.87). Portal to venous HTT (quantitative analysis) was < 7 s in 21 of 22 subjects of group a and > 7s in 15 of 22 subjects of group b (sensitivity 95%, specificity 68%, PPV 75%, NPV 94%, AUC 0.85). There was an inverse relation with number of liver segments involved for arterial to venous and portal to venous HTT in group a (p < 0.05), but no correlation between HTT and overall volume of metastases (group a) or subject age (group b). From the results of our study, we conclude that HTT measurements using contrast-enhanced ultrasound with BR1 can detect hemodynamic changes caused by metastatic liver disease from colorectal cancer. However, comparison with the literature suggests that the use of other contrast agents might provide better results. Comparison of different contrast agents for the purpose of transit time analysis would therefore be useful before embarking on a prospective trial looking at the detection of occult liver metastases in patients with colorectal cancer. (E-mail: jhohmann@uhbs.ch)     

Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus

Cluster headache (CH) is a debilitating neurovascular condition characterized by severe unilateral periorbital head pain. Deep brain stimulation of the posterior hypothalamus has shown potential in alleviating CH in its most severe, chronic form. During surgical implantation of stimulating macroelectrodes for cluster head pain, one of our patients suffered a CH attack. During the attack local field potentials displayed a significant increase in power of approximately 20 Hz. To the authors' knowledge, this is the first recorded account of neuronal activity observed during a cluster attack. Our results both support and extend the current literature, which has long implicated hypothalamic activation as key to CH generation, predominantly through indirect haemodynamic neuroimaging techniques. Our findings reveal a potential locus in CH neurogenesis and a potential rationale for efficacious stimulator titration.     

Effect of nickel on the mineralization of hydrocarbons by indigenous microbiota in Kuwait soils

Assessment of nickel contents in soil samples in Kuwait indicated only a minor difference in concentration in hydrocarbon‐contaminated (86 mg kg^–1 soil) and non‐contaminated soils (84 mg kg^–1 soil). The potential inhibitory effects of nickel on the number of hydrocarbon degraders, and hydrocarbon utilization were investigated over a wide range of nickel concentrations to span concentrations observed in the soil. Nickel addition, as nickel sulphate, to soil samples reduced the number of hydrocarbon degraders in all samples by a wide range (15–96%) depending on concentration and the hydrocarbon substrate utilized. Similarly, the metabolic activities were affected as observed in mineralization (3–60%) of soils amended with various concentrations of nickel. The inhibitive effects of nickel on hexadecane and crude oil utilization were minimal but were significantly higher with naphthalene (P < 0.05) in both hydrocarbon‐contaminated and non‐contaminated soils. Polarographic determination of hydrocarbons induced oxygen uptake rate demonstrated the tendency of nickel to significantly inhibit (P < 0.05) the oxidation of polyaromatic hydrocarbons compared to aliphatic hydrocarbons. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)