Endothelium in pharmacology: 30 years on

In this issue, BJP is proud to publish an Endothelium Themed Section to celebrate the life of Robert F. Furchgott, who died on May 19th 2009. It is 30 years since he discovered endothelium-derived relaxant factor and a decade since he was awarded the Nobel Prize for this work. His discovery has led to an array of new therapeutic targets. The themed section includes three reviews on the pathophysiology of the endothelium and the drug targets that this presents, four research papers and three commentaries on research.This themed section also forms the nucleus of an online Virtual Issue that collects in one place further reviews and research papers on the topic of the ‘Endothelium’ that BJP and our sister journal BJCP have published in the past year, and that should help researchers and students to find the latest work in this field.To view the entire Endothelium Themed Section and the Endothelium Virtual Issue, please visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009British Journal of Pharmacology (2009) 157, 491–493; doi:10.1111/j.1476-5381.2009.00366.xThis article is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009Thirty years ago Robert F Furchgott found that a substance was released from vascular endothelium that caused relaxation of the smooth muscle in the vascular wall (Furchgott and Zawadzki, 1980), a discovery for which, a decade ago, he was awarded the Nobel Prize (Furchgott, 1999). This remarkable finding was, from my recollection anyway, the most exciting aspect of the second Symposium on Mechanisms of Vasodilatation, held at Wilrijk, Belgium in July 1980 (Vanhoutte and Leusen, 1981) and has been, one suspects, a major part of the reason that this series is now celebrating its 10th occurrence at Matsushima, Miyagi, Japan, in June 2009 (it is planned to publish work arising from this event in Circulation Journal).Thirty years on, the endothelium continues to yield information on pathophysiological mechanisms that provides many therapeutic targets for drug discovery and new explanations for drug action. A special Endothelium Themed Section in this issue of BJP collates three new reviews on the pathophysiology of the endothelium and the drug targets that this presents (Esposito and Cuzzocrea, 2009; Grgic et al., 2009; Versari et al., 2009), four research papers (de Andrade et al., 2009; Andrews et al., 2009; McKenzie et al., 2009; Orie et al., 2009) and three commentaries on research papers that discuss the significance and draw out controversies from their new findings (Martin, 2009, commenting on Andrews et al., 2009; Tammaro, 2009, commenting on Orie et al., 2009; Miller and Wadsworth, 2009, commenting on Wenzl et al., 2009 that was published in an earlier issue).These Endothelium reviews and two others already published (Félétou, 2009; Félétou et al., 2009) follow up symposia held at the Meeting of the Federation of European Pharmacological Societies (EPHAR) in Manchester, UK, in July 2008, and show the continuing importance of this field. To reflect this and provide access to our extensive portfolio of endothelial papers, we have collated this section with other recent reviews, commentaries and original articles from BJP and from our sister journal BJCP, in a Virtual Issue on Endothelium, available at: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 (see http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009)

Irbesartan-mediated reduction of renal and cardiac damage in insulin resistant JCR : LA-cp rats

Background and purpose:

Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro- and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin-resistant JCR : LA-cp rat that exhibits micro- and macrovascular disease with ischaemic myocardial lesions and renal disease.

Experimental approach:

Obese male rats were treated with irbesartan (30 mg·kg⁻¹·day⁻¹, incorporated into chow) from 12 to 25 weeks of age.

Key results:

Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA-cp rats was marginally improved, at the expense of increased plasma insulin levels (∼50%). Fasting plasma triglycerides were marginally reduced (∼25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium-dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%).

Conclusions and implications:

Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end-stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.     

Identification of malaria hot spots for focused intervention in tribal state of India: a GIS based approach

Background  

In India, presently malaria shows a declining trend whereas Plasmodium falciparum (Pf) cases show an up trend. In central India, specifically, Madhya Pradesh (M.P.) a forested and tribal area, control of malaria is logistically difficult and outbreaks are frequently recorded, reasons for this being inadequate surveillance, poor reporting, a time lag in reporting to decision makers and a lack of geo referenced information to pin point the trouble spots for a timely preventive action.     

Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital

Introduction

Major blood loss can often be life-threatening and is most commonly encountered in the settings of surgery and trauma. Patients receiving anticoagulant therapy are also at increased risk of bleeding. We investigated the use of a prothrombin complex concentrate (PCC; Beriplex P/N, CSL Behring, Marburg, Germany) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy and other surgery.

Methods

Thirty consecutive patients who had received PCC were identified from blood transfusion records. For cardiac surgery and warfarin reversal, PCC was administered in accordance with hospital protocols. PCC was administered to cardiac and other surgical patients responding poorly to recognized blood products, whereas it was administered first-line to patients with life-threatening bleeds and requiring warfarin reversal, in accordance with British Committee for Standards in Haematology guidelines. We conducted a retrospective analysis of patient records in order to ascertain PCC dose, use of other blood products and response to PCC (clotting screen results before and after PCC administration, haemostasis achievement, and survival).

Results

Six patients (20%) were excluded because of inadequate documentation (n = 5) or acquired haemophilia (n = 1). Therefore, 24 patients were included in the analysis: coronary artery bypass graft (n = 5), mitral/aortic valve replacement (n = 2), other surgery (n = 9) and warfarin reversal (n = 8). Most patients (83.3%) received no more than 1500 IU of Beriplex P/N 500. Considerable reduction in administration of other blood products was seen during the 24 hours after PCC administration. Partial or complete haemostasis was achieved in 14 out of 18 cases (77.8%). In total, 12 out of 24 patients (50%) died during the study; two-thirds of the deaths were considered unrelated to bleeding. No thrombotic complications or adverse drug reactions were observed.

Conclusion

This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.     

Les mouvements anormaux psychogènes

Psychogenic Movement Disorders (PMDs) are a subtype of conversion disorder, classified under somatoform disorders in the DSM. Diagnosis and treatment of PMDs are challenging for both neurologists and psychiatrists. Typical clinical characteristics of these disorders are acute onset, fast progression, movement patterns incongruent with organic movement disorders, distractibility, variability and simultaneous occurrence of various abnormal movements and dysfunctions. The diagnosis of PMDs should not be regarded as a diagnosis of exclusion and electrophysiology is not always helpful. The cause of PMDs is unknown and the underlying brain mechanisms remain uncertain. However, recent functional magnetic resonance imaging studies have demonstrated altered blood flow in conversion disorders that may reflect changes in synaptic activity. Involvement of allied health professionals and psychotherapy continue to be the mainstay of treatment.     

清除骨髓中癌细胞的磁性微球研究 II.聚苯乙烯磁性微球的研制

为制备能用于清除骨髓中癌细胞的磁性微球,首先合成了单分散、大粒径的多孔聚苯乙烯交联微球,借助微球多孔结构对其进行磁化。探讨了影响磁化效果的主要因素。为使其与单抗连接紧密,在微球表面聚合了一层聚丙烯醛膜,使其表面带上易与单抗反应的醛基。同时测定了所制微球的磁响应性。X-射线衍射证明磁性物质为γ-Fe₂O₃。     

PATIENT ACCIDENTS IN HOSPITAL: INCIDENCE,DOCUMENTATION AND SIGNIFICANCE

SUMMARY Many previous studies of reported patient accidents in hospital used the accident report forms as the only data source, without questioning their reliability and despite 80% of the accidents being unwitnessed. This paper reports on three studies using data from patient interviews, staff questionnaires, medical and nursing notes and the accident report forms. The studies confirm that falls amongst elderly patients are the most common type of patient accident. However, patients' and staff's versions of the event often differed widely. Accident reports are stated to be required for legal purposes, but they were often incomplete and unreliable. Patient accidents and safety are too important to remain marginalised to mere compliance with out-of-date regulations. A new, ‘slim-line‘, more accurate but less time-consuming patient accident reporting system should be developed, for which improvement in patient safety is the main aim and legal considerations the secondary aim.