Activated human platelet products induce proarrhythmic effects in ventricular myocytes

Sudden cardiac death remains one of the most prevalent modes of death and is mainly caused by ventricular fibrillation (VF) in the setting of acute ischemia resulting from coronary thrombi. Animal experiments have shown that platelet activation may increase susceptibility of ischemic myocardium to VF, but the mechanism is unknown. In the present study, we evaluated the effects of activated blood platelet products (ABPPs) on electrophysiological properties and intracellular Ca²⁺ (Ca²⁺_i) homeostasis. Platelets were collected from healthy volunteers. After activation, their secreted ABPPs were added to superfusion solutions. Rabbit ventricular myocytes were freshly isolated, and membrane potentials and Ca²⁺_i were recorded using patch-clamp methodology and indo-1 fluorescence measurements, respectively. ABPPs prolonged action potential duration and induced early and delayed afterdepolarizations. ABPPs increased L-type Ca²⁺ current (I_Ca,L) density, but left densities of sodium current, inward rectifier K⁺ current, transient outward K⁺ current, and rapid component of the delayed rectifier K⁺ current unchanged. ABPPs did not affect kinetics or (in)activation properties of membrane currents. ABPPs increased systolic Ca²⁺_i, Ca²⁺_i transient amplitude, and sarcoplasmic reticulum Ca²⁺ content. ABPPs did not affect the Na⁺− Ca²⁺ exchange current (I_NCX) in Ca²⁺-buffered conditions. Products secreted from activated human platelets induce changes in I_Ca,L and Ca²⁺_i, which result in action potential prolongation and the occurrence of early and delayed afterdepolarizations in rabbit myocytes. These changes may trigger and support reentrant arrhythmias in ischemia models of coronary thrombosis.     

Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice

Background and purpose:

Histamine H₃ receptor antagonists are currently being evaluated for their potential use in a number of central nervous system disorders including Alzheimer''s Disease (AD). To date, little is known about the state of H₃ receptors in AD.

Experimental approach:

In the present study we used the radiolabelled H₃ receptor antagonist [³H]GSK189254 to investigate H₃ receptor binding in the amyloid over-expressing double mutant APPswe × PSI.MI46V (TASTPM) transgenic mouse model of AD and in post-mortem human AD brain samples.

Key results:

No significant differences in specific H₃ receptor binding were observed between wild type and TASTPM mice in the cortex, hippocampus or hypothalamus. Specific [³H]GSK189254 binding was detected in sections of human medial frontal cortex from AD brains of varying disease severity (Braak stages I–VI). With more quantitative analysis in a larger cohort, we observed that H₃ receptor densities were not significantly different between AD and age-matched control brains in both frontal and temporal cortical regions. However, within the AD group, [³H]GSK189254 binding density in frontal cortex was higher in individuals with more severe dementia prior to death.

Conclusions and implications:

The maintenance of H₃ receptor integrity observed in the various stages of AD in this study is important, given the potential use of H₃ antagonists as a novel therapeutic approach for the symptomatic treatment of AD.     

Reintoxication: the release of fat-stored Δ9-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure

Background and purpose:

Δ⁹-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in adipose tissue where it is stored for long periods of time. Here we investigated whether conditions that promote lipolysis can liberate THC from adipocytes to yield increased blood levels of THC.

Experimental approach:

In vitro studies involved freshly isolated rat adipocytes that were incubated with THC before exposure to the lipolytic agent adrenocorticotrophic hormone (ACTH). A complementary in vivo approach examined the effects of both food deprivation and ACTH on blood levels of THC in rats that had been repeatedly injected with THC (10 mg·kg⁻¹) for 10 consecutive days. Lipolysis promoted by ACTH or food deprivation was indexed by measurement of glycerol levels.

Key results:

ACTH increased THC levels in the medium of THC-pretreated adipocytes in vitro. ACTH also enhanced THC release from adipocytes in vitro when taken from rats repeatedly pretreated with THC in vivo. Finally, in vivo ACTH exposure and 24 h food deprivation both enhanced the levels of THC and its metabolite, (-)-11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THC-COOH) in the blood of rats that had been pre-exposed to repeated THC injections.

Conclusions and implications:

The present study shows that lipolysis enhances the release of THC from fat stores back into blood. This suggests the likelihood of ‘reintoxication’ whereby food deprivation or stress may raise blood THC levels in animals chronically exposed to the drug. Further research will need to confirm whether this can lead to functional effects, such as impaired cognitive function or ‘flashbacks’.     

Editorial

A themed section in this issue of Br J Pharmacol, on ‘Advances in Nutritional Pharmacology’, provides a valuable and timely update on progress in this area.The value of dietary components to improvement in health and, particularly, to prevention of cardiovascular disease and cancer, is frequently reported in the media and therefore often captures the attention of the wider public. Understanding the pharmacological mechanisms by which nutritional elements confer their health benefits enables us to keep the public informed, but also aids in the identification of new targets for drug development. In recent years there has been significant progress in this field.Four rapidly developing areas are reviewed. Vosper (2009) covers the identification of a receptor for niacin and the subsequent development of selective agonists as lipid lowering agents. Wu-Wong (2009) describes the development of new Vitamin D analogues for the treatment of cardiovascular disease. de Roos et al. (2009) provide detailed insight into how omega-3 fatty acids, also known as longchain n-3 polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease. Zhou et al. (2009) cover the mechanisms underlying the beneficial effects of resveretrol in protection against cancer.These reviews are complimented by three key original articles focusing on endogenous mechanisms of weight control involving endocannabinoids (Izzo et al., 2009), a circulating protein, the soluble leptin receptor (Zhang & Scarpace, 2009) and a treatment, zinc plus cyclo-(His-Pro) (CHP), known to increase insulin metabolism (Song et al., 2009).The value of dietary components to improvement in health and, particularly, to prevention of cardiovascular disease and cancer, is frequently reported in the media and therefore often captures the attention of the wider public. Understanding the pharmacological mechanisms by which nutritional elements confer their health benefits enables us to keep the public informed, but also aids in the identification of new targets for drug development. In recent years there has been significant progress in this field.A themed section in this issue of Br J Pharmacol, on ‘Advances in Nutritional Pharmacology’, edited by Cherry Wainwright, aims to provide a valuable and timely update on progress in this area.This issue includes several reviews that provide an update in four rapidly developing areas. Vosper (2009) has written a narrative tracking the research that led to the identification of a receptor for niacin and the subsequent development of selective agonists as lipid lowering agents. Within this review, the benefits and pitfalls of niacin receptor agonists are discussed, alongside a consideration of the impact of blocking their undesirable effects, such as skin flushing. Two further reviews describe the development of new Vitamin D analogues for the treatment of cardiovascular disease(Wu-Wong, 2009) and provide detailed insight into how omega-3 fatty acids, also known as longchain n-3 polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease (de Roos et al., 2009). The fourth review provides greater understanding of the mechanisms underlying the beneficial effects of resveretrol in protection against cancer (Zhou, 2009).These reviews are complimented by three key original articles focusing on endogenous mechanisms of weight control. In an elegant study in lean and fatty mice with diet induced obesity, Izzo et al. (2009) have provided evidence to support the idea that dysregulation of peripheral endocannabinoids can contribute to obesity. In a further in vivo study, direct evidence is provided that a circulating protein, the soluble leptin receptor, may play a regulatory role in energy homeostasis and weight gain by neutralizing leptin (Zhang & Scarpace, 2009). Finally Song et al. (2009) have demonstrated in both diabetic and non-diabetic overweight aged rats that zinc plus cyclo-(His-Pro) (CHP), a treatment known to increase insulin metabolism, improves weight control through reducing food intake and altering the balance between plasma leptin and adiponectin levels, suggesting this may be a possible treatment for overweight and obese patients.     

α1A/B-Knockout mice explain the native α1D-adrenoceptor's role in vasoconstriction and show that its location is independent of the other α1-subtypes

Background and purpose:

Theoretically, three α₁-adrenoceptor subtypes can interact at the signalling level to alter vascular contraction or at the molecular level to alter each other''s cellular location. The α_1A/B-adrenoceptor knockout mouse (α_1A/B-KO) was used to study the isolated α_1D-adrenoceptor to consider these potential interactions in native tissue.

Experimental approach:

Pharmacological analysis of carotid and mesenteric arteries employed wire myography and fluorescent ligand binding (α₁-adrenoceptor ligand BODIPY FL-prazosin, QAPB).

Key results:

α_1A/B-KO carotid had clear α_1D-adrenoceptor-induced contractions. In WT carotid α_1D-adrenoceptor dominated but all three α₁-subtypes participated. α_1A/B-KO mesenteric had α_1D-adrenoceptor responses with high sensitivity and small maximum, explaining how α_1D-adrenoceptor could determine agonist sensitivity in WT. In both arteries α_1A/B-KO fluorescence levels were reduced but pharmacologically more consistent with ‘pure’α_1D-adrenoceptors. α_1D-Adrenoceptor binding in α_1A/B-KO was observed on the cell surface and intracellularly and was present in a high proportion of smooth-muscle cells in both strains, regardless of artery type.

Conclusions and implications:

‘Pure’α_1D-adrenoceptor pharmacology in α_1A/B-KO provides a quantitative standard. Functionally, the α_1D- and α_1A-adrenoceptors produce additive responses and do not significantly compensate for each other. α_1D-Adrenoceptor contributes to sensitivity even in resistance arteries. In α_1A/B-KO, the loss of α_1A- and α_1B-adrenoceptors is reflected by a general decrease in fluorescence, but similar binding distribution to WT indicates that the α_1D-adrenoceptor location in native smooth-muscle cells is not influenced by other α₁-adrenoceptors. Equivalent levels of receptors did not correspond to equivalent responses. In conclusion, α₁-subtypes do not interact but provide independent alternative signals for vascular regulation.     

Effects of 1,8-cineole on electrophysiological parameters of neurons of the rat superior cervical ganglion

• 1 1,8‐Cineole is a non‐toxic small terpenoid oxide believed to have medicinal properties in folk medicine. It has been shown to have various pharmacological effects, including blockade of the compound action potential (AP). In the present study, using intracellular recording techniques, we investigated the effects of 1,8‐cineole on the electrophysiological parameters of neurons of the superior cervical ganglion (SCG) in rats.
• 2 1,8‐Cineole (0.1–6 mmol/L) showed reversible and concentration‐dependent effects on various electrophysiological parameters. At 3 and 6 mmol/L, but not at 0.1 and 1 mmol/L, 1,8‐cineole significantly diminished the input resistance (R_i) and altered the resting potential (E_m) to more positive values. At 6 mmol/L, 1,8‐cineole completely blocked all APs within 2.7 ± 0.6 min (n = 12). In neurons exposed to 3 and 1 mmol/L 1,8‐cineole, the effects regarding excitability varied from complete AP blockade to minor inhibition of AP parameters. The depolarization of E_m and the decrease in R_i induced by 6 mmol/L 1,8‐cineole were unaltered by 200 µmol/L niflumic acid, a well known blocker of Ca²⁺‐activated Cl^? currents.
• 3 Significant correlations (Pearson correlation test) were found between changes in E_m and decreases in AP amplitude (r = –0.893; P < 0.00282) and maximum ascendant inclination (r = –0.799; P < 0.0173), but not for maximum descendant inclination (r = 0.598; P < 0.117). Application of current to restore the transmembrane potential equal to control E_m values in the presence of 6 mmol/L 1,8‐cineole resulted in the partial recovery of AP.
• 4 The present study shows that 1,8‐cineole effectively blocks the excitability of SCG neurons, probably through various mechanisms, one of which acts indirectly via depolarization of the neuronal cytoplasmatic membrane.

     

Malnutrition prevalence in The Netherlands: results of the annual dutch national prevalence measurement of care problems

The objective of this study was to provide data on malnutrition prevalence in hospitals, nursing homes and home-care organisations in The Netherlands in a nationally representative sample, and to assess the factors such as age, sex, time since admission, ward type and disease for identifying patients at high risk of malnutrition. A cross-sectional, multi-centre design with a standardised questionnaire was used to measure the prevalence of malnutrition. Nutritional status was assessed by BMI, undesired weight loss and nutritional intake. In this study, 12 883 patients were included. The prevalence of malnutrition was the highest in hospitals (23.8 %), followed by home-care organisations (21.7 %) and nursing homes (19.2 %). Logistic regression analysis revealed no association with age, time since admission and ward type. Being female was associated with malnutrition only in nursing homes. Blood diseases, gastrointestinal tract diseases, infection, chronic obstructive pulmonary disease, dementia and cancer were the factors associated with malnutrition in hospitals. Dementia was associated with malnutrition in nursing homes, while gastrointestinal tract diseases, diabetes mellitus and cancer were the associated factors in home care. This study shows that malnutrition is still a substantial problem in hospitals, nursing homes and home care in The Netherlands. Malnutrition is a problem for more than one in five patients. Despite growing attention to the problem, more continued alertness is required.     

Laparoscopic extended right hepatectomy for posterior and completely caudate massive liver tumor (with videos)

<正>To the Editor: Liver tumor may occur in any hepatic segment or lobe, and thus the liver resection is individualized as per the location and size of the tumor. In addition, the resection of the posterior and caudate lobes of the liver is especially difficult amongst all types of hepatectomy. Kawaguchi et al. believed that the laparoscopic resection of right posterior liver lobe was a difficult surgical procedure [1].