bluuebunny/crossref_metadata_2025 huggingface dataset:
Echo-morphological correlates concerning the functionally univentricular heart in the setting of isomeric atrial appendages
Authors: Mahle William T. , Silverman Norman H. , Marx Gerald R. , Anderson Robert H.
Published: January 2006

It has long been known that the most complex combinations of cardiac malformations are those found in the setting of the so-called “splenic syndromes”.1 Many aspects of these syndromes have been controversial over recent years, not least the presence or absence of features of isomerism within the heart.2,3 Recent experience with genetic manipulation of mice, nonetheless, has now shown that it is possible to generate unequivocal evidence of cardiac isomerism, particularly in those animals which show features of right isomerism when the genes responsible for morphologically leftness are knocked out.4 Furthermore, when the crucial philosophical principle known as the “morphological method”5 is applied to the hearts of patients known to have visceral heterotaxy, it is equally clear that patients falling within these groups, when judged on the extent of the pectinate muscles relative to the atrioventricular junctions, exhibit isomerism of either the morphologically right or left atrial appendages.3
Perioperative management of patients with poorly functioning ventricles in the setting of the functionally univentricular heart
Authors: Rossano Joseph W. , Chang Anthony C.
Published: January 2006

The patient with a functionally univentricular heart is at increased risk for ventricular dysfunction for a variety of reasons. At birth, the pulmonary and systemic circulations are in parallel, leading to pulmonary overcirculation and a volume-loaded functional ventricle. Significant atrioventricular valvar regurgitation, abnormal ventriculoarterial coupling, diastolic dysfunction, and altered ventricular geometry can also contribute to long-term ventricular dysfunction. These collected circumstances place the patient at increased risk for perioperative morbidity and mortality. We will discuss in this review the pathophysiology that leads to ventricular dysfunction at each stage of surgical palliation, as well as the strategies for perioperative management. In addition, we will highlight novel strategies for management of ventricular dysfunction.
Mechanical support of the functionally single ventricle
Authors: Ravishankar Chitra , Gaynor J. William
Published: January 2006

Children with a functionally single ventricle constitute just over 1% of congenital cardiac defects.1A majority of children with the functionally univentricular circulation undergo a three-staged reconstruction to achieve completion of the Fontan circulation. The first stage is usually performed in the neonatal period, and is either banding of the pulmonary trunk, an aorto-pulmonary shunt alone, or the shunt included as part of the first stage of reconstruction. In recent years, a conduit placed from the right ventricle to the pulmonary arteries is being used as an alternate source of flow of blood to the lungs. The second stage is the bidirectional cavopulmonary anastomosis, the two surgical variations being the so-called “hemifontan”, and “bidirectional Glenn” procedures, while the third stage is the completion of the Fontan circulation, the two surgical variations being either construction of a lateral tunnel, or placement of an extra-cardiac conduit, each being possible with or without a fenestration. In many centres, patients with the functionally univentricular circulation make up one-fifth of the total surgical volume. The syndrome of low cardiac output is quite common in this population through all three stages of reconstruction, and some of these patients will eventually require cardiac transplantation. While conventional therapy, with inotropic support and afterload reduction, remains the mainstay of therapy for the failing heart in children, mechanical support is being increasingly used.3Most of this experience is limited to extracorporeal membrane oxygenation.2–5In this review, we discuss the current experiences with extracorporeal membrane oxygenation in patients with a functionally univentricular circulation, and describes some of their unique features. We also focus on the pulsatile ventricular assist devices capable of providing support over the longer term, and other new devices that may have a role in the future in these patients.6
Optimal timing of the second stage of palliation for hypoplastic left heart syndrome facilitated through home monitoring, and the results of early cavopulmonary anastomosis
Authors: Ghanayem Nancy S. , Tweddell James S. , Hoffman George M. , Mussatto Kathleen , Jaquiss Robert D. B.
Published: January 2006

For children with hypoplastic left heart syndrome, contemporary management over three stages includes a window of high risk for sudden death between the initial stage of palliation, the Norwood operation itself, and the second stage, creation of the bidirectional superior cavopulmonary connection. The risk is highest at a time when patients have been discharged from the hospital to grow and prepare for the second stage,1–4and has persisted despite the remarkable improvements in immediate postoperative and hospital survival after the initial surgery.5,6Potential contributing factors to the increased vulnerability to sudden death between the stages include the limited circulatory reserve inherent in the parallel circulations supported by a functionally univentricular heart, the reliance on a prosthetic shunt which is susceptible to thrombosis, and congenital or acquired anatomical cardiovascular abnormalities such as aortic atresia, residual obstruction in the aortic arch, tricuspid valvar insufficiency, or right ventricular dysfunction.7–12
Fontan's operation: evolution from a procedure to a process
Authors: Giroud Jorge M. , Jacobs Jeffrey P.
Published: January 2006

It was in 1971, Fontan and Baudet1published their experience using a surgical procedure to restore a physiologic circulation in three patients with tricuspid atresia. Of the three patients, two survived, thus ushering a new era in the treatment of children with complex forms of congenital cardiac disease. This operation itself, however, was the culmination of a series of experimental and clinical observations that underlined the clinical possibility totally to bypass the right side of the heart.
Surgery for the functionally univentricular heart in patients with visceral heterotaxy
Authors: Tchervenkov Christo I. , Jacobs Marshall L. , Duca Danny Del
Published: January 2006

The heterotaxy syndromes are characterized by a high incidence of cardiac anomalies of extreme heterogeneity. Due to this, the surgical management is varied and challenging. Although a minority of patients can undergo biventricular repair, the complexity of the cardiac defects, and the high incidence of ventricular hypoplasia, mandate a surgical approach in the majority of patients depending on the creation of a functionally univentricular heart. Traditionally, the functionally univentricular approach was associated with a high mortality. More recently, the results have been improving as a result of better understanding of these malformations, and logical improvements in surgical technique. In this review, we will make brief comments on the nomenclature and classification of the heterotaxy syndromes, and the range of cardiac anomalies, before concentrating on the surgical treatment for those patients having functionally univentricular hearts in the setting of heterotaxy. More specifically, we will review initial palliation in early life, creation of the cavopulmonary anastomoses, including the Kawashima procedure and the Fontan circulation, and the role of transplantation.
Late complications associated with the Fontan circulation
Authors: Jacobs Marshall L. , Pelletier Glenn
Published: January 2006

The recent significant reduction in operative mortality associated with surgical completion of the Fontan circulation is clearly multi-factorial. Better understanding of the fundamental physiological and anatomical issues have led to refinements in operative technique, early neutralization of potential risk factors, widespread use of a staged approach, and selective application of the concept of fenestration or incomplete partitioning. While further reduction of operative mortality is important, and may be anticipated in the future, major emphasis now must be placed on optimizing functional outcome, and understanding and managing the late complications associated with the unique physiology produced by the Fontan circulation.
Scale separation for moisture‐laden regions in the tropical atmosphere
Authors: Bellon G. , Ghil M. , Le Treut H.
Published: January 2006

The size distribution of moist regions in the tropical atmosphere exhibits two modes of organization, one at synoptic scales and the other at planetary scales. We show the existence of these two modes in two data sets: column‐integrated precipitable water and outgoing long‐wave radiation. A simple two‐column model of radiation and convection in the Tropics helps interpret the presence of these two modes. The coupling between radiative effects and low‐level atmospheric dynamics provides a plausible mechanism for scale selection.
More frequent cloud‐free sky and less surface solar radiation in China from 1955 to 2000
Authors: Qian Yun , Kaiser Dale P. , Leung L. Ruby , Xu Ming
Published: January 2006

Newly available data from extended weather stations and time period reveal that much of China has experienced significant decreases in cloud cover over the last half of the Twentieth century. This conclusion is supported by the analysis of the more reliably observed frequency of cloud‐free sky and overcast sky. The total cloud cover and low cloud cover have decreased 0.88% and 0.33% per decade, respectively, and cloud‐free days have increased 0.60% and overcast days decreased 0.78% per decade in China from 1954–2001. Meanwhile, both solar radiation and pan evaporation have decreased in China, with solar radiation decreasing 3.1 W/m2 and pan evaporation decreasing 39 mm per decade. Combining these results with findings of previous studies, we speculated that increased air pollution may have produced a fog‐like haze that reflected/absorbed radiation from the sun and resulted in less solar radiation reaching the surface, despite concurrent increasing trends in cloud‐free sky over China.
Filtering of GCM simulated Sahel precipitation
Authors: Tippett Michael K.
Published: January 2006

Atmospheric general circulation models (GCMs) forced with observed sea surface temperature (SST) reproduce some aspects of observed Sahel rainfall variability, particularly decadal variability. Here a filter based on signal‐to‐noise (S/N) EOFs is applied to seven GCM simulations of Sahel precipitation to extract SST‐forced variability. Using filter coefficients based on GCM estimates of internal variability has limited, though positive, impact on simulation skill. Additional removal of empirically identified model error improves the representation of both decadal and interannual variability. The model error shows some coherence across the seven GCMs and correlates with local Atlantic SST. We hypothesize that the model error is related to the representation of ocean‐atmosphere interactions in the SST‐forced GCM simulations.
A potential climatic index for total Saharan dust: the Sun insolation
Authors: Alpert P. , Barkan J. , Kishcha P.
Published: January 2006

It is shown that the daily course of the total amount of dust in the atmosphere, based on the TOMS aerosol index (AI), is highly correlated (0.98) with the integrated daily solar insolation over the Sahara region for spatially and temporally averaged data. Moreover, the annual maximum is even reached nearly at the same day, i.e., the 17th (18th) June for the surface (top of the atmosphere) solar insolation, as compared to 21st June for the date of maximum atmospheric dust loading. Other factors like cloudiness, rainfall soil moisture, and wind probably play a more dominant role in smaller areas. The fact that on a very large scale, like the whole of the Sahara, the solar insolation becomes the one single forcing directly correlated with the total amount of dust in the atmosphere is suggesting a simple climatic index for the total dust loading in the atmosphere. This index is shown for the Saharan region only, while more studies are needed for other regions. The 3–4 day time‐lag between the maximum insolation and the maximum dust loading in the atmosphere is compared to about a one‐month delay with the maximum ground or air temperatures and may serve as an estimate to the surface response to the major forcing of the Sun. The maximum ground temperature, delayed to the 17th July, can be explained by the delay in the lagged‐heating of the deeper soil layers. The 3–4 day delay only with the Sun insolation is probably linked to the period in which the dust is maintained in the atmosphere until it is deposited. One application to the present finding may be for climate models, since such a high correlation for spatially and temporarily averaged data may be used as an integrated index for the total amount of Saharan dust and for potentially validating the complex model parameterizations in climate models.
The role of inflammation in CNS injury and disease
Authors: Lucas Sian‐Marie , Rothwell Nancy J , Gibson Rosemary M
Published: January 2006

For many years, the central nervous system (CNS) was considered to be ‘immune privileged’, neither susceptible to nor contributing to inflammation. It is now appreciated that the CNS does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Much of the key evidence demonstrating that inflammation and inflammatory mediators contribute to acute, chronic and psychiatric CNS disorders is summarised in this review. However, inflammatory mediators may have dual roles, with detrimental acute effects but beneficial effects in long‐term repair and recovery, leading to complications in their application as novel therapies. These may be avoided in acute diseases in which treatment administration might be relatively short‐term. Targeting interleukin (IL)‐1 is a promising novel therapy for stroke and traumatic brain injury, the naturally occurring antagonist (IL‐1ra) being well tolerated by rheumatoid arthritis patients. Chronic disorders represent a greater therapeutic challenge, a problem highlighted in Alzheimer's disease (AD); significant data suggested that anti‐inflammatory agents might reduce the probability of developing AD, or slow its progression, but prospective clinical trials of nonsteroidal anti‐inflammatory drugs or cyclooxygenase inhibitors have been disappointing. The complex interplay between inflammatory mediators, ageing, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration, and be critical for development of effective therapies for CNS diseases.

British Journal of Pharmacology (2006) 147, S232–S240. doi:10.1038/sj.bjp.0706400
Antiplatelet drugs
Authors: Born Gustav , Patrono Carlo
Published: January 2006

British Journal of Pharmacology (2006) 147, S241–S251. doi:10.1038/sj.bjp.0706401
Cannabinoid pharmacology: the first 66 years
Authors: Pertwee Roger G
Published: January 2006

Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1‐ and CB2‐selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified.

British Journal of Pharmacology (2006) 147, S163–S171. doi:10.1038/sj.bjp.0706406
Neuropharmacology of 5‐hydroxytryptamine
Authors: Richard Green A
Published: January 2006

This review outlines the history of our knowledge of the neuropharmacology of 5‐hydroxytryptamine (5‐HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5‐HT in 1949. The presence of 5‐HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5‐HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5‐HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5‐HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5‐HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5‐HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor‐specific drugs and use the information gained to better treat central nervous system disorders.

British Journal of Pharmacology (2006) 147, S145–S152. doi:10.1038/sj.bjp.0706427
Neurotransmitter transporters and their impact on the development of psychopharmacology
Authors: Iversen Leslie
Published: January 2006

The synaptic actions of most neurotransmitters are inactivated by reuptake into the nerve terminals from which they are released, or by uptake into adjacent cells. A family of more than 20 transporter proteins is involved. In addition to the plasma membrane transporters, vesicular transporters in the membranes of neurotransmitter storage vesicles are responsible for maintaining vesicle stores and facilitating exocytotic neurotransmitter release. The cell membrane monoamine transporters are important targets for CNS drugs. The transporters for noradrenaline and serotonin are key targets for antidepressant drugs. Both noradrenaline‐selective and serotonin‐selective reuptake inhibitors are effective against major depression and a range of other psychiatric illnesses. As the newer drugs are safer in overdose than the first‐generation tricyclic antidepressants, their use has greatly expanded. The dopamine transporter (DAT) is a key target for amphetamine and methylphenidate, used in the treatment of attention deficit hyperactivity disorder. Psychostimulant drugs of abuse (amphetamines and cocaine) also target DAT. The amino‐acid neurotransmitters are inactivated by other families of neurotransmitter transporters, mainly located on astrocytes and other non‐neural cells. Although there are many different transporters involved (four for GABA; two for glycine/D‐serine; five forL‐glutamate), pharmacology is less well developed in this area. So far, only one new amino‐acid transporter‐related drug has become available: the GABA uptake inhibitor tiagabine as a novel antiepileptic agent.

British Journal of Pharmacology(2006)147, S82–S88. doi:10.1038/sj.bjp.0706428
Purinergic signalling
Authors: Burnstock Geoffrey
Published: January 2006

While there were early papers about the extracellular actions of purines, the role of ATP as a purinergic neurotransmitter in nonadrenergic, noncholinergic nerves in the gut and bladder in 1972 was a landmark discovery, although it met considerable resistance for the next 20 years. In the early 1990s, receptors for purines were cloned: four P1 receptor subtypes and seven P2X ionotropic and eight P2Y metabotropic receptor subtypes are currently recognized and characterized. The mechanisms underlying ATP release and breakdown are discussed. Purines and pyrimidines have major roles in the activities of non‐neuronal cells as well as neurons. This includes fast signalling roles in exocrine and endocrine secretion, platelet aggregation, vascular endothelial cell‐mediated vasodilation and nociceptive mechanosensory transduction, as well as acting as a cotransmitter and neuromodulator in most, if not all, nerve types in the peripheral and central nervous systems. More recently, slow (trophic) purinergic signalling has been implicated in cell proliferation, migration, differentiation and death in embryological development, wound healing, restenosis, atherosclerosis, ischaemia, cell turnover of epithelial cells in skin and visceral organs, inflammation, neuroprotection and cancer.

British Journal of Pharmacology(2006)147, S172–S187. doi:10.1038/sj.bjp.0706429
75 years of opioid research: the exciting but vain quest for the Holy Grail
Authors: Corbett Alistair D , Henderson Graeme , McKnight Alexander T , Paterson Stewart J
Published: January 2006

Over the 75‐year lifetime of the British Pharmacological Society there has been an enormous expansion in our understanding of how opioid drugs act on the nervous system, with much of this effort aimed at developing powerful analgesic drugs devoid of the side effects associated with morphine – the Holy Grail of opioid research. At the molecular and cellular level multiple opioid receptors have been cloned and characterised, their potential for oligomerisation determined, a large family of endogenous opioid agonists has been discovered, multiple second messengers identified and our understanding of the adaptive changes to prolonged exposure to opioid drugs (tolerance and physical dependence) enhanced. In addition, we now have greater understanding of the processes by which opioids produce the euphoria that gives rise to the intense craving for these drugs in opioid addicts. In this article, we review the historical pathway of opioid research that has led to our current state of knowledge.

British Journal of Pharmacology(2006)147, S153–S162. doi:10.1038/sj.bjp.0706435
Drugs for asthma
Authors: Barnes Peter J
Published: January 2006

Current drug therapy for asthma is highly effective and has evolved from naturally occurring substances through logical pharmaceutical developments. Pharmacology has played a critical role in asthma drug development and several key experimental observations have been published in this journal. Understanding the pharmacology of effective drug therapies has also taught us much about the underlying mechanisms of asthma.β2‐Adrenoceptor agonists are the most effective bronchodilators and evolved from catecholamines from the adrenal medulla, whereas corticosteroids, from the adrenal cortex, are by far the most effective controllers of the underlying inflammatory process in the airways. The current ‘gold standard’ of asthma therapy is a combination inhaler containing a long‐actingβ2‐agonist with a corticosteroid – an improved form of adrenal gland extract. Cromoglycate, derived from a plant product and theophylline, a dietary methyl xanthine, have also been extensively used in the therapy of asthma, but we still do not understand their molecular mechanisms. Pharmacology has played an important role in improving natural products to make effective long lasting and safe asthma therapies, but has so far been challenged to produce new classes of antiasthma therapy. The only novel class of antiasthma therapy introduced in the last 30 years are leukotriene antagonists, which are less effective than existing treatments. New, more specific, therapies targeted at specific cytokines are less effective than corticosteroids, whereas more effective therapies carry a risk of side effects that may not be acceptable. It seems likely that pharmacology, rather than molecular genetics, will remain the main approach to the further improvement of treatment for asthma.

British Journal of Pharmacology(2006)147, S297–S303. doi:10.1038/sj.bjp.0706437
A short history of voltage‐gated calcium channels
Authors: Dolphin Annette C
Published: January 2006

British Journal of Pharmacology (2006) 147, S56–S62. doi:10.1038/sj.bjp.0706442
The glutamate story
Authors: Watkins Jeffrey C , Jane David E
Published: January 2006

Glutamatergic synaptic transmission in the mammalian central nervous system was slowly established over a period of some 20 years, dating from the 1950s. Realisation that glutamate and like amino acids (collectively known as excitatory amino acids (EAA)) mediated their excitatory actionsviamultiple receptors preceded establishment of these receptors as synaptic transmitter receptors. EAA receptors were initially classified asN‐methyl‐D‐aspartate (NMDA) and non‐NMDA receptors, the latter subdivided into quisqualate (later AMPA) and kainate receptors after agonists that appeared to activate these receptors preferentially, and by their sensitivity to a range of differentially acting antagonists developed progressively during the 1970s. NMDA receptors were definitively shown to be synaptic receptors on spinal neurones by the sensitivity of certain excitatory pathways in the spinal cord to a range of specific NMDA receptor antagonists. Importantly, specific NMDA receptor antagonists appeared to be less effective at synapses in higher centres. In contrast, antagonists that also blocked non‐NMDA as well as NMDA receptors were almost universally effective at blocking synaptic excitation within the brain and spinal cord, establishing both the existence and ubiquity of non‐NMDA synaptic receptor systems throughout the CNS. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways, acting in concert with non‐NMDA receptors under conditions where a protracted excitatory postsynaptic potential was effected in response to intense stimulation of presynaptic fibres. Such activation of NMDA receptors together with non‐NMDA receptors led to the phenomenon of long‐term potentiation (LTP), associated with lasting changes in synaptic efficacy (synaptic plasticity) and considered to be an important process in memory and learning. During the 1980s, it was shown that certain glutamate receptors in the brain mediated biochemical changes that were not susceptible to NMDA or non‐NMDA receptor antagonists. This dichotomy was resolved in the early 1990s by the techniques of molecular biology, which identified two families of glutamate‐binding receptor proteins (ionotropic (iGlu) and metabotropic (mGlu) receptors). Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.

British Journal of Pharmacology(2006)147, S100–S108. doi:10.1038/sj.bjp.0706444
The future of pharmacology
Authors: Vallance Patrick , Smart Trevor G
Published: January 2006

British Journal of Pharmacology (2006) 147, S304–S307. doi:10.1038/sj.bjp.0706454
Glucocorticoids: exemplars of multi‐tasking
Authors: Buckingham Julia C
Published: January 2006

Well over 80 years ago Philip Smith described the beneficial clinical effects of adrenocortical extracts in animal models of adrenal insufficiency. In the ensuing years, scientists across the globe have sought to understand the mechanisms by which adrenal hormones and their synthetic analogues produce their complex and varied actions. Particular attention has focused on the glucocorticoids, partly because they have a vital place in the treatment of inflammatory and autoimmune disorders but also because dysregulation of the secretion and/or activity of endogenous glucocorticoids is increasingly implicated in a number of common disorders that pose a growing clinical burden, such as obesity, type II diabetes, the metabolic syndrome, hypertension and depression. This review considers some of the key advances that have been made in our understanding of the physiology, pathology and pharmacology of the glucocorticoids. Emphasis is placed on the molecular mechanisms of glucocorticoid signalling and the complex mechanisms that regulate the access of steroids in the systemic circulation to their receptors in their various target cells and tissues. In addition, consideration is given to the irreversible ‘organisational’ actions of glucocorticoids in perinatal life and to the potential role of the steroids in the aetiology of disease.

British Journal of Pharmacology (2006) 147, S258–S268. doi:10.1038/sj.bjp.0706456
Neuropeptides and their receptors: innovative science providing novel therapeutic targets
Authors: Brain Susan D , Cox Helen M
Published: January 2006

This review examines our current understanding of the roles of some of the best known neuropeptides that have played major roles in our combined research programmes. Evidence obtained from over 75 years of research shows involvement of these transmitters in a wide range of organs relevant to cardiovascular, respiratory, cutaneous, neuronal and intestinal systems. There is an increasing understanding of the mechanisms involved in the release of the peptides (substance P and calcitonin gene‐related peptide (CGRP)) from sensory nerves or, neuropeptide Y (NPY) from sympathetic, parasympathetic and nonadrenergic, noncholinergic (NANC) neurons. Responses in target tissues result from interactions of the neuropeptides, or related forms, with specific G‐protein coupled receptors (GPCRs or 7 transmembrane‐spanning, 7TM proteins) that belong to either rhodopsin‐like, class 1 (neurokinin (NK) and NPY Y receptors) or secretin‐like, class 2 GPCRs (CGRP receptors). The majority of receptors activated by our chosen neuropeptides are now cloned, with knowledge of preferred agonists and selective antagonists for many receptor subtypes within these families. The study of neuropeptides in animal models has additionally revealed physiological and pathophysiological roles that in turn have led to the ongoing development of new drugs, through utilization predominantly of antagonist activities.

British Journal of Pharmacology(2006)147, S202–S211. doi:10.1038/sj.bjp.0706461
Drug metabolism and pharmacogenetics: the British contribution to fields of international significance
Authors: Caldwell John
Published: January 2006

The branch of pharmacology we now call ‘drug metabolism’, the consideration of the enzymes and procesess determining the disposition of drugs in the body, emerged in the 1840s on the continent of Europe, but British science made little or no contribution until the 1920s. From this point on, the development of the field through the 20th century was shaped to a very significant extent by a series of influential British workers, whose contributions were of global significance and who can now be seen as fathers of the subject. Since the 1950s, and gaining pace inexorably from the 1970s, the significance of drug metabolism to human therapeutics has been greatly added to by the emergence of pharmacogenetics, clinically important hereditary variation in response to drugs, which underpins the current emphasis on personalised medicine. This review examines the British contributions to both these fields through the lives of seven key contributors and attempts to place their work both in the context of its time and its lasting influence.

British Journal of Pharmacology (2006) 147, S89–S99. doi:10.1038/sj.bjp.0706466
Acetylcholine
Authors: Brown David A
Published: January 2006

This article traces the development of knowledge about the physiology and pharmacology of acetylcholine and its receptors between 1930 and 2005, with emphasis on contributions by members of the British Pharmacological Society, and by other British pharmacologists and physiologists.

British Journal of Pharmacology(2006)147, S120–S126. doi:10.1038/sj.bjp.0706474
The attraction of chemokines as a target for specific anti‐inflammatory therapy
Authors: Pease James E , Williams Timothy J
Published: January 2006

Since the identification of the first chemotactic cytokines 20 years ago, the field has mushroomed, with the discovery of approximately 40 ligands, which interact with 20 different cell surface receptors. At the time of writing this review, a PubMed trawl using the word ‘chemokine’ will recover over 28,000 manuscripts. In this article, we will give a short history of the discovery of chemokines and provide examples of the potential for therapeutic targeting of the chemokine network in inflammatory disease.

British Journal of Pharmacology (2006) 147, S212–S221. doi:10.1038/sj.bjp.0706475
Antiarrhythmic drug research
Authors: Walker M J A
Published: January 2006

This article was written as part of the 75th anniversary celebration of the British Pharmacological Society (BPS). It discusses antiarrhythmic drug research conducted by members of BPS, and as published in the British Journal of Pharmacology (BJP). BPS members, past and present, as well as antiarrhythmic manuscripts published in the BJP have been identified. From these data, the article attempts to semiquantitatively summarize results published in the journal, but only quotes selected manuscripts and individuals. Apologies are offered for omissions and errors, but as in any history, a writer's biases and opinions are unavoidable.

British Journal of Pharmacology (2006) 147, S222–S231. doi:10.1038/sj.bjp.0706500
Agonist‐activated ion channels
Authors: Colquhoun David
Published: January 2006

This paper looks at ion channels as an example of the pharmacologist's stock in trade, the action of an agonist on a receptor to produce a response. Looked at in this way, ion channels have been helpful because they are still the only system which is simple enough for quantitative investigation of transduction mechanisms. A short history is given of attempts to elucidate what happens between the time when agonist first binds, and the time when the channel opens.

British Journal of Pharmacology (2006) 147, S17–S26. doi:10.1038/sj.bjp.0706502
Prostaglandins, bioassay and inflammation
Authors: Flower R J
Published: January 2006

The formation of the British Pharmacological Society coincided almost exactly with a series of ground‐breaking studies that ushered in an entirely new field of research – that of lipid mediator pharmacology. For many years following their chemical characterisation, lipids were considered only to be of dietary or structural importance. From the 1930s, all this changed – slowly at first and then more dramatically in the 1970s and 1980s with the emergence of the prostaglandins (PGs), the first intercellular mediators to be clearly derived from lipids, in a dynamic on‐demand system. The PGs exhibit a wide range of biological activities that are still being evaluated and their properties underlie the action of one of the world's all‐time favourite medicines, aspirin, as well as its more modern congeners. This paper traces the development of the PG field, with particular emphasis on the skilful utilisation of the twin techniques of bioassay and analytical chemistry by U.K. and Swedish scientists, and the intellectual interplay between them that led to the award of a joint Nobel Prize to the principal researchers in the PG field, half a century after the first discovery of these astonishingly versatile mediators.

British Journal of Pharmacology (2006) 147, S182–S192. doi:10.1038/sj.bjp.0706506
Error criteria for cross validation in the context of chaotic time series prediction
Authors: Lim Teck Por , Puthusserypady Sadasivan
Published: January 2006

The prediction of a chaotic time series over a long horizon is commonly done by iterating one-step-ahead prediction. Prediction can be implemented using machine learning methods, such as radial basis function networks. Typically, cross validation is used to select prediction models based on mean squared error. The bias-variance dilemma dictates that there is an inevitable tradeoff between bias and variance. However, invariants of chaotic systems are unchanged by linear transformations; thus, the bias component may be irrelevant to model selection in the context of chaotic time series prediction. Hence, the use of error variance for model selection, instead of mean squared error, is examined. Clipping is introduced, as a simple way to stabilize iterated predictions. It is shown that using the error variance for model selection, in combination with clipping, may result in better models.
Evaluating the conformational entropy of macromolecules using an energy decomposition approach
Authors: Ohkubo Y. Zenmei , Thorpe Ian F.
Published: January 2006

We have developed a novel method to compute the conformational entropy of any molecular system via conventional simulation techniques. This method only requires that the total energy of the system is available and that the Hamiltonian is separable, with individual energy terms for the various degrees of freedom. Consequently the method, which we call the energy decomposition (Edcp) approach, is general and applicable to any large polymer in implicit solvent. Edcp is applied to estimate the entropy differences due to the peptide and ester groups in polyalanine and polyalanil ester. Ensembles over a wide range of temperatures were generated by replica exchange molecular dynamics, and densities of states were estimated using the weighted histogram analysis method. The results are compared with those obtained via evaluating the PlnP integral or employing the quasiharmonic approximation, other approaches widely employed to evaluate the entropy of molecular systems. Unlike the former method, Edcp can accommodate the correlations present between separate degrees of freedom. In addition, the Edcp model assumes no specific form for the underlying fluctuations present in the system, in contrast to the quasiharmonic approximation. For the molecules studied, the quasiharmonic approximation is observed to produce a good estimate of the vibrational entropy, but not of the conformational entropy. In contrast, our energy decomposition approach generates reasonable estimates for both of these entropy terms. We suggest that this approach embodies a simple yet effective solution to the problem of evaluating the conformational entropy of large macromolecules in implicit solvent.
Simultaneous estimation of phase behavior and second-derivative properties using the statistical associating fluid theory with variable range approach
Authors: Lafitte Thomas , Bessieres David , Piñeiro Manuel M. , Daridon Jean-Luc
Published: January 2006

A modified statistical associating fluid theory (SAFT) with variable range version is presented using the family of m-n Mie potentials. The use of this intermolecular potential for modeling repulsion-dispersion interactions between the monomer segments, together with a new method for optimizing the molecular parameters of the equation of state, is found to give a very accurate description of both vapor-liquid equilibria and compressed liquid bulk properties (volumetric and derivative properties) for long-chain n-alkanes. This new equation improves other SAFT-like equations of state which fail to describe derivative properties such as the isothermal compressibility and the speed of sound in the condensed liquid phase. Emphasis is placed on pointing out that the key for modeling the latter properties is the use of a variable repulsive term in the intermolecular potential. In the case of the n-alkanes series, a clear dependence of the characteristic molecular parameters on increasing chain length is obtained, demonstrating their sound physical meaning and the consistency of the new fitting procedure proposed. This systematic method for optimizing the model parameters includes data on the saturation line as well as densities and speed of sound data in the condensed liquid phase, and the results show undoubtedly that the model performance is enhanced and its range of applicability is now widened, keeping in any case a good balance between the accuracy of the different estimated properties.
Shape versus inverse-shape selective adsorption of alkane isomers in carbon nanotubes
Authors: Jiang Jianwen , Sandler Stanley I.
Published: January 2006

Simulation results are reported for the adsorption of pure pentane (C5) isomers and their ternary mixture in a series of open-ended armchair-type (m,m) single-walled carbon nanotubes (SWNTs). Inverse-shape selective adsorption occurs in the order of nC5<iC5neoC5 as a result of the configurational entropy effect. In smaller SWNTs, depending on the diameter, only nC5 adsorbs, or no adsorption at all occurs. The entropy effects are found to lead to a large adsorptive separation among the C5 isomers from their mixture. Using the ideal-adsorbed-solution theory with data on the adsorption of only the pure isomers, we predict mixture adsorption. The agreement between predictions and simulations deteriorates with decreasing diameter of the SWNT.
Experimental and theoretical elastic cross sections for electron collisions with the C3H6 isomers
Authors: Makochekanwa C. , Kato H. , Hoshino M. , Tanaka H. , Kubo H. , Bettega M. H. F. , Lopes A. R. , Lima M. A. P. , Ferreira L. G.
Published: January 2006

In the present work we report cross sections for electron collisions with the isomers propene (C3H6) and cyclopropane (c-C3H6). Electron-scattering differential cross sections (DCS) are reported for measurements carried out for energies 1.5–100 eV and the angular range of 20°–120°. Elastic integral cross sections (ECS), DCS, and momentum-transfer cross sections (MTCS) are reported for calculations carried out using the Schwinger multichannel method with pseudopotentials for the energy range of 2.0–40 eV and angular range of 0°–180°. The resemblance of the π* shape resonance in the cross sections, observed at 1.5–2.0 eV for propene, to those in C2H4 and C2F4 clearly points to the effect of the double bond in the molecular structures for these molecules. Below 60 eV, we observed clear differences in peak positions and magnitudes between the DCS, ECS, and MTCS for C3H6 and c-C3H6, which we view as the isomer effect.
Organometallic molecular rectification
Authors: Liu Rui , Ke San-Huang , Yang Weitao , Baranger Harold U.
Published: January 2006

We study the rectification of current through a single molecule with an intrinsic spatial asymmetry. The molecule contains a cobaltocene moiety in order to take advantage of its relatively localized and high-energy d states. A rectifier with large voltage range, high current, and low threshold can be realized. The evolution of molecular orbitals under both forward and reverse biases is captured in a self-consistent nonequilibrium Green function plus density functional theory description. Our calculations demonstrate the plausibility of making excellent molecular diodes by using metallocenes, pointing to a fruitful class of molecules.
Analysis of adiabatic passage by light-induced potentials with chirped laser pulses in three- and four-level diatomic systems
Authors: Heesel E. , Garraway B. M. , Marangos J. P.
Published: January 2006

This paper describes an investigation into the process of adiabatic passage by light-induced potentials (APLIP), which was previously suggested as a method for employing two strong picosecond laser pulses to transfer the population between two electronic states. We have extended earlier numerical studies in order to assess the feasibility of an experimental implementation of the APLIP concept. APLIP has been modeled in a three-level model system based on Na2 with chirped pulses, using laser parameters available from a typical chirped pulse amplified Ti:sapphire laser. The model showed that the APLIP process remains essentially unchanged for chirped pulses of equal magnitude and the opposite, or equal and positive sign of chirp as compared to the transform-limited case. We also examined the case of additional electronic states by introduction of a fourth state that lies close to the “target,” i.e., final, state. The investigation showed that there are circumstances in which a significant fraction of the population gets transferred to this state which will disrupt the APLIP process. However, by switching to this fourth state as the target state in an experiment, good transfer efficiency is recovered. The results of the extension of the original APLIP modeling to chirped pulses and additional electronic states indicate that an APLIP experimental realization should be feasible in Na2.
Distributed polarizabilities obtained using a constrained density-fitting algorithm
Authors: Misquitta Alston J. , Stone Anthony J.
Published: January 2006

A computationally efficient method for obtaining distributed polarizabilities of arbitrary rank using a constrained density-fitting algorithm is demonstrated on the hydrogen, carbon dioxide, formamide, and N-methylpropanamide molecules. A description of the molecular polarization in terms of local polarizabilities without charge-flow terms is obtained when the nonlocal components of the polarizability tensor are transformed away using the localization method of Le Sueur and Stone [Mol. Phys. 83, 293 (1994)]. The resulting local polarizabilities are shown to be stable with respect to basis set used, exhibiting none of the artifacts of earlier basis-space partitioning methods. We also investigate the transferability of the resulting local polarizability models.
A comparative ab initio study of Br2•− and Br2 water clusters
Authors: Pathak A. K. , Mukherjee T. , Maity D. K.
Published: January 2006

The work presents ab initio results on structure and electronic properties of Br2•−.nH2O(n=1–10) and Br2.nH2O(n=1–8) hydrated clusters to study the effects of an excess electron on the microhydration of the halide dimer. A nonlocal density functional, namely, Becke’s half-and-half hybrid exchange-correlation functional is found to perform well on the present systems with a split valence 6-31++G(d,p) basis function. Geometry optimizations for all the clusters are carried out with several initial guess structures and without imposing any symmetry restriction. Br2•−.nH2O clusters prefer to have symmetrical double hydrogen-bonding structures. Results on Br2.nH2O(n⩾2) cluster show that the O atom of one H2O is oriented towards one Br atom and the H atom of another H2O is directed to other Br atom making Br2 to exist as Br+–Br− entity in the cluster. The binding and solvation energies are calculated for the Br2•−.nH2O and Br2.nH2O clusters. Calculations of the vibrational frequencies show that the formation of Br2•− and Br2 water clusters induces significant shifts from the normal modes of isolated water. Excited-state calculations are carried out on Br2•−.nH2O clusters following configuration interaction with single electron excitation procedure and UV-VIS absorption profiles are simulated. There is an excellent agreement between the present theoretical UV-VIS spectra of Br2•−.10H2O cluster and the reported transient optical spectra for Br2•− in aqueous solution.
Mimicking solvent shells in the gas phase. II. Solvation of K+
Authors: Miller Dorothy J. , Lisy James M.
Published: January 2006

The observed gas-phase coordination number of K+ in K+(H2O)m clusters is smaller than that observed in bulk solution, where the coordination number has been reported to be between 6 and 8. Both theoretical and gas-phase studies of K+(H2O)m cluster ions point to a coordination number closer to 4. In the gas phase, the coordination number is determined by a variety of factors—the most critical being the magnitude of the K+⋯ligand pairwise interaction. Decreasing the magnitude of the ion⋯ligand interaction allows more ligands to directly interact with the cation. One method for decreasing the ion⋯ligand interaction in K+(H2O)m clusters is to systematically substitute weakly bound ligands for the more strongly bound water molecules. The systematic introduction of para-difluorobenzene (DFB) to K+(H2O)m clusters was monitored using infrared photodissociation spectroscopy in the OH stretching region. By varying the ratio of DFB molecules to water molecules present in K+(H2O)m(DFB)n clusters, the observed coordination number of gas-phase K+ was increased to 8, similar to that reported for bulk solution.