bluuebunny/crossref_metadata_2025 huggingface dataset:
An analysis of inter‐ and intraspecific genetic variabilities in the Kluyveromyces marxianus group of yeast species for the reconsideration of the K. lactis taxon
Authors: Belloch Carmela , Fernández‐Espinar Teresa , Querol Amparo , Dolores García M. , Barrio Eladio
Published: January 2005

In the present work, we analyse the sequences of the 5.8S rRNA gene and the two internal transcribed spacers 1 and 2 (5.8S‐ITS region), obtained from 39 strains belonging to the species Kluyveromyces aestuarii, K. dobzhanskii, K. lactis and K. marxianus, K. nonfermentans and K. wickerhamii, to solve the phylogenetic relationships among these species and also to determine the possible genetic basis for the delimitation of the two currently accepted K. lactis varieties: lactis, including lactose‐positive strains isolated from dairy products, and drosophilarum, comprising lactose‐negative strains isolated from insects and plant exudates. The determination of the phylogenetic relationships within the species K. lactis, together with the examination of the electrophoretic karyotypes and phenotypic characterization of strains representatives of K. lactis var. lactis and var. drosophilarum, allowed differentiation of two groups of strains. The first, and ancestral, group comprises lactose‐negative strains isolated from natural habitats in North America. The second, and derived, group includes both lactose‐negative strains isolated from natural habitats in Europe and wine fermentation in South Africa, and lactose‐positive strains associated with dairy products. These results suggest that the present taxon K. lactis is a complex of different species, subspecies or, at least, genetically structured populations. Copyright © 2002 John Wiley & Sons, Ltd.
Simple Truths, Hard Problems: Some thoughts on terror, justice, and self-defence
Authors: Chomsky Noam
Published: January 2005

Among the most elementary of moral truisms is the principle of universality: we apply to ourselves the same standards we do to others, more stringent ones if we are serious. A near-universal principle of intellectual culture is the rejection of this truism, sometimes explicitly. Rejection of this and similar moral truisms has severe human consequences, and yields what are regarded as “hard problems”—hard in no small measure because truisms are rejected. Illustrations range from establishment of “norms” for international behavior to practice and doctrine with regard.
If the past is a different country, are different countries in the past?
Authors: Goto-Jones C. S.
Published: January 2005

It is often asserted that even our own past is a foreign country: the ideas of past thinkers are, in some ways, alien to us today. For the European historian of non-European philosophy, not only is the past held to be a different country, but it is also the past of a different country. This is both convenient and problematic all at once. The ‘Western’ historian of non-European philosophy faces a double separation from his/her subject matter; she is both a foreigner and an alien. In this paper, I approach questions of how this historian should orientate herself towards her subject, and why she (and we) should care about it at all.
Pulmonary atresia with intact ventricular septum: management of, and outcomes for, a cohort of 210 consecutive patients
Authors: Dyamenahalli Umesh , McCrindle Brian W. , McDonald Cathy , Trivedi Kalyani R. , Smallhorn Jeffrey F. , Benson Lee N. , Coles John , Williams William G. , Freedom Robert M.
Published: January 2005

Objectives:We sought to determine trends, and outcomes, for a cohort of patients with pulmonary atresia with intact ventricular septum born between 1965 and 1998.Background:Pulmonary atresia with intact ventricular septum is a complex lesion that remains a therapeutic challenge, particularly regarding the suitability for biventricular repair.Methods:We identified 210 consecutive patients, and reviewed their medical records, initial angiograms, and echocardiograms, along with the relevant surgical and pathology reports.Results:The mean initial Z-score for the diameter of the tricuspid valve was −0.99 ± 1.95, with Ebstein's malformation in 8%. A right ventricular dependent coronary arterial circulation was found in 23%. The proportion of patients who received treatment increased over time, although placement of an arterial shunt was the predominant initial procedure throughout the experience. At the last follow-up, 107 patients had not reached the planned final stage of their repair, and 79% of these had died. Of the 103 reaching the final stage of planned repair, 58 had undergone attempted biventricular repair, with 34% dying; 14 had undergone attempted one and a half ventricular repair, with 7% dying, and 31 had undergone attempted functionally univentricular repair, with 10% dying. Overall, survival was 57% at the age of 1 year, 48% at 5 years, and 43% at 10 years. Survival improved over time, with survival of 75% at 1 year, and 67% at 5 years, for patients born between 1992 and 1998. An earlier date of birth, the presence of Ebstein's malformation, and prematurity were all significant independent factors associated with decreased survival. A greater severity of coronary arterial abnormalities was significantly associated with a greater likelihood of left ventricular dysfunction during follow-up.Conclusions:The outcomes for patients born with pulmonary atresia with intact ventricular septum have improved over time, albeit that careful initial management, and better selection, is still indicated for those planned to undergo biventricular repair.
Parental decision-making in congenital heart disease
Authors: Hoehn K. Sarah , Wernovsky Gil , Rychik Jack , Tian Zhi-yun , Donaghue Denise , Alderfer Melissa A. , Gaynor J. William , Kazak Anne E. , Spray Thomas L. , Nelson Robert M.
Published: January 2005

Objective:To explore whether prenatal diagnosis of congenital heart disease is associated with lower levels of parental distress and greater satisfaction with decisions about cardiothoracic surgery when compared to postnatal diagnosis.Methodology:A combined quantitative–qualitative design was used. Participants included the parents of 31 neonates (30 mothers and 22 fathers) admitted to the cardiac intensive care unit between 1 November 2001 and 1 May 2002 for repair of congenital cardiac malformations. Participants completed self-report measures of anxiety, optimism, and life events pre-operatively, and semi-structured qualitative interviews assessing satisfaction with decision-making within 1 week of the operation.Results:At the time of surgery, mothers of neonates receiving the diagnosis prenatally did not differ from mothers of neonates receiving the diagnosis postnatally on measures of anxiety, optimism, and life events. Fathers of neonates receiving the diagnosis prenatally, however, reported more optimism, lower state and trait anxiety, and fewer negative life events than fathers of neonates receiving the diagnosis postnatally. When we analyzed the interviews, we found that, regardless of the timing of the diagnosis, parents felt as though they made a genuine choice for their baby to have surgery.Conclusions:In this pilot study, fathers who learned prenatally that their child had a congenital cardiac malformation were less distressed than those who discovered this fact only postnatally. From the parental perspective, nonetheless, distress and urgency do not impair their ability to make decisions about neonatal cardiac surgery.
Use of a saphenous venous homograft for constructing a conduit from the right ventricle to the pulmonary arteries in the Norwood procedure
Authors: Vricella Luca A. , Crosson Jane E. , Cameron Duke E.
Published: January 2005

The use of a conduit of polytetrafluoroethylene placed between the right ventricle and the pulmonary arteries as source of pulmonary arterial supply during the first stage of palliation for the hypoplastic left heart syndrome has facilitated post-operative management and resulted in decreased mortality. We describe here the use of a cryopreserved saphenous vein inserted in reversed direction to create the connection between the right ventricle and the pulmonary arteries in a neonate with low birth weight undergoing the modified Norwood procedure.
Emergency trans-oesophageal ventricular pacing in a child
Authors: Villain Elisabeth , Boudjemline Younes , Bonnet Damien
Published: January 2005

We report our experience with an 8-year-old boy with complete atrioventricular block and syncopal bradycardia who required urgent pacing. Each attempt to cross the tricuspid valve with a femoral lead triggered ventricular standstill, followed by fibrillation, and pacing through the coronary sinus failed. Successful ventricular pacing was finally achieved through the oesophagus, allowing subsequent implantation of a transvenous pacemaker.
Is routine echocardiography valuable after uncomplicated catheter ablation in children?
Authors: Kammeraad Janneke A. E. , Sreeram Narayanswami , van Driel Vincent , Oliver Ron , Balaji Seshadri
Published: January 2005

We determined the clinical value of routine transthoracic echocardiography performed after catheter ablation of supraventricular tachyarrhythmias in children. Between April 1996 and December 2003, 253 children, of whom 135 male, with the overall group having a median age of 9, ranging from 0.1 to 19 years, underwent 280 uncomplicated radiofrequency catheter ablation procedures for supraventricular tachyarrhythmias at three institutions. In every child, transthoracic Doppler echocardiography was performed before and after the procedure. The pre-ablation transthoracic echocardiograms were normal in all, and this was one of the criterions for inclusion. The post-ablation echocardiogram showed a disorder in four asymptomatic patients. In one patient, with focal atrial tachycardia, ablated via a retrograde aortic approach, there was mild aortic valvar insufficiency. This had resolved 6 months later. Pericardial effusions developed in 3 other children. In 2 the effusions resolved spontaneously but 1 patient required pericardial drainage. This same patient also developed clinically asymptomatic mild aortic insufficiency, which resolved spontaneously within 6 months. Routine echocardiography after uncomplicated catheter ablation procedures is of clinical value, and is especially indicated when a retrograde aortic approach has been used.
Perioperative predictors of developmental outcome following cardiac surgery in infancy
Authors: Robertson Daphene R. , Justo Robert N. , Burke Chris J. , Pohlner Peter G. , Graham Petra L. , Colditz Paul B.
Published: January 2005

At 1 year we assessed the neurodevelopmental outcomes in infants undergoing cardiac surgery, seeking to explore the predictive value of perioperative markers of cerebral injury. We prospectively enroled 47 neurodevelopmentally normal infants prior to planned cardiac surgery. Postoperative monitoring consisted of 10-channel video synchronised, continuous electroencephalography from 6 to 30 h, Doppler assessment of cerebral blood flow in the anterior cerebral artery at 1, 2, 3 and 5 h, and measurement of serum S-100B at 0 and 24 h. Neurodevelopmental assessments were performed using the second edition of the Bayley Scale of Infant Development. Follow-up at 1 year was available on 35 infants. The mean age of these patients at surgery had been 57 ± 15 days. We observed clinical seizures in 1 patient, with 3 other patients having electroencephalographic abnormalities. At follow-up of 1 year, neurodevelopmental scores were lower than preoperative scores, with mean mental scores changing from 103 ± 5 to 94 ± 13 (p = 0.001), and mean motor scores changing from 99 ± 8 to 89 ± 20 (p = 0.004). No association was found between electroencephalographic abnormalities, reduced cerebral blood flow, or elevation of serum S-100B levels and impaired neurodevelopmental outcome at 1 year. Infants with electroencephalographic abnormalities had elevation of the levels of S-100B in the serum (p = 0.02). At 1 year of follow-up, infants undergoing cardiac surgery demonstrated a reduction in the scores achieved using the second edition of the Bayley Scale of Infant Development. They require ongoing assessment of their progress. Electroencephalographic abnormalities, cerebral blood flow, or levels of S-100B in the serum were not useful perioperative markers for predicting a poor neurodevelopmental outcome in the clinical setting.
Clinical presentation, natural history, and outcome of patients with the absent pulmonary valve syndrome
Authors: Zucker Nili , Rozin Ilya , Levitas Aviva , Zalzstein Eli
Published: January 2005

So-called ‘absent pulmonary valve syndrome’ is a rare cardiac malformation, usually associated with tetralogy of Fallot. Congenital absence of the leaflets of the pulmonary valve is less common when the ventricular septum is intact. Characteristic features of the syndrome include dysplasia or absence of the pulmonary valvar leaflets, permitting severe pulmonary regurgitation, and aneurysmal dilation of the pulmonary arteries. The purpose of our study was to review our experience with patients diagnosed as having the absent pulmonary valve syndrome, and to describe their clinical presentation, natural history, and outcome. We reviewed retrospectively data from 18 patients with absent pulmonary valve syndrome, 10 boys and eight girls, treated between March 1983 and May 2003. We identified two groups of patients, one made up of 11 patients with a ventricular septal defect, in whom the morphology of the subpulmonary outflow tract was phenotypic for tetralogy of Fallot, and another group, with seven patients, having an intact ventricular septum. Family history of congenital heart disease was common only in patients with ventricular septal defect, being found in 73%, all of whom were diagnosed during infancy with variable respiratory distress. Diagnosis was delayed in 43% of the patients with an intact ventricular septum. Cardiac surgery was performed in eight patients with ventricular septal defect (73%), compared to only two patients (28%) with an intact ventricular septum. Overall mortality was 28%, with five patients dying. Although our sample was small, two clinical patterns emerged depending on the presence or absence of a ventricular septal defect. Patients with a ventricular septal defect and phenotypic features of tetralogy of Fallot have a strong family history of congenital cardiac disease, develop respiratory symptoms during infancy and exhibit a variable prognosis, despite cardiac surgery. Patients with an intact ventricular septum are usually asymptomatic, present later in life, and show a relatively benign prognosis.
Bilateral scimitar syndrome
Authors: Kabbani Mohamed , Haider Naser , Abu-Sulaiman Riyadh
Published: January 2005

Scimitar syndrome is a rare congenital anomaly that affects classically the right lung and the heart. We present a rare variant that involves both lungs in association with totally anomalous pulmonary venous connection, horseshoe lung, and right pulmonary cyst.
Outcomes for patients with an aortopulmonary window, and the impact of associated cardiovascular lesions
Authors: Bagtharia Rajesh , Trivedi Kalyani R. , Burkhart Harold M. , Williams William G. , Freedom Robert M. , Van Arsdell Glen S. , McCrindle Brian W.
Published: January 2005

An aortopulmonary window is a communication between the ascending aorta and pulmonary trunk in the presence of two separate arterial valves, and is often complicated by other associated defects. We sought to determine management and related outcomes in patients with this malformation.

We identified those patients presenting between 1969 and 1999 from the databases held in our Departments of Cardiology, Pathology and Cardiovascular Surgery. We obtained data relating to issues concerning demography, clinical findings, imaging, management and outcome.

The median age at presentation for the 42 patients identified, of whom 23 were female, was 62 days, with a range from birth to 6 years. Associated cardiac defects were present in 34 patients, including interruption of the aortic arch in 6 patients. The correct diagnosis was initially missed in 13 patients. Of the patients, six died without surgical repair, and 1 patient was lost-to-follow-up. Repair was performed in 35 patients, subsequent to repair of other defects in 4, in association with repair of other defects in 17, of whom 3 died, and as an isolated procedure in 14 patients, one of the latter being treated by transcatheter closure. Overall, there were 9 deaths, all in patients with complex associated defects, except 1 patient with a missed aortopulmonary window after repair of aortic coarctation. Kaplan-Meier estimates of survival were 81% at 3 months until 11.5 years, and 69% up to 21 years. Only the presence of interrupted aortic arch was independently associated with increased time-related mortality, the hazard ratio being 5.87 (p = 0.009).

The outcome for an isolated lesion is excellent. Mortality occurs mainly before repair, mostly with complex associated lesions, particularly interruption of the aortic arch.
Mechanisms of mitral valvar insufficiency in children and adolescents with severe rheumatic heart disease: an echocardiographic study with clinical and epidemiological correlations
Authors: Nassri Câmara Edmundo J. , Neubauer Christiane , Câmara Gabriel Ferreira , Lopes Antonio Alberto
Published: January 2005

We carried out a detailed clinical, epidemiological, and echocardiographic study in 41 patients ≤14 years of age who were admitted in a public hospital in Salvador, Brazil, with severe rheumatic heart disease.

Mitral insufficiency was severe in 90%, and moderate in 10%, of the patients. A posteriorly directed jet was seen in 93% of the patients. We identified three mechanisms producing the regurgitation: prolapse of the aortic leaflet of the mitral valve in 13 (32%) patients, rupture of tendinous cords in 14 (34%), and a retracted, non-coapting mural leaflet in 14 (34%). The mean ages, with standard deviations, for these three groups were 7.0 (1.6) years, 7.9 (2.2) years, and 10.5 (2.4) years, respectively (p < 0.001). Rheumatic activity was diagnosed in 58.5% of them. Evidence of previous rheumatic fever was present in 54% of patients with prolapse, in all patients with rupture, and in 93% of those with non-coapting leaflets (p = 0.002).

Prolapse of the aortic leaflet, rupture of tendinous cords, and a retracted, non-coapting mural leaflet are the mechanisms responsible for mitral valvar insufficiency in children and adolescents with severe rheumatic heart disease. Prolapse seems to be an early phenomenon in the natural history of rheumatic heart disease, while rupture and non-coaption of the leaflets were associated with older age and signs of chronic rheumatic disease.
Cleft mitral valve in transposition with intact ventricular septum
Authors: Menahem Samuel , Anderson Robert H.
Published: January 2005

We describe two cases of an isolated cleft of the mitral valve in transposition with intact ventricular septum. The cleft is positioned leftward in the pulmonary leaflet, at about 2 o’clock, when viewed from below looking at the cardiac short axis with the right ventricle to one’s left hand. Such clefts, when seen in the Taussig-Bing malformation are also positioned leftward.

In keeping with our current knowledge of cardiac development, our cases provide further evidence that transposition with an intact ventricular septum is the end-point of the Taussig-Bing spectrum.
QT prolongation in the newborn and maternal alcoholism
Authors: Krasemann Thomas
Published: January 2005

I discuss a newborn whose mother is addicted to alcohol. On the third day of life, the newborn was found to have ventricular tachycardia. After spontaneous termination of the abnormal rhythm, the duration of the corrected QT interval was 0.48 s. During the next days, the duration of the interval normalized, and has now remained stable for 5 years. I conclude that the so-called “alcohol withdrawal syndrome of the newborn” might cause postnatal prolongation of the QT interval.
Designing therapeutic strategies for patients with a dominant left ventricle, discordant ventriculo-arterial connections, and unobstructed flow of blood to the lungs
Authors: Freedom Robert M. , Yoo Shi-Joon , Russell Jennifer , Perrin Donald , Williams William G.
Published: January 2005

The palliation of the cyanotic child with a dominant morphologically left ventricle, discordant ventriculo-arterial connections, and obstruction to the pulmonary outflow tract has continued to evolve and mature. The evolution began in the early days of surgical palliation with the Blalock–Taussig shunt, extended to construction of cavopulmonary shunts, if required, and then to the Fontan procedure and its subsequent modifications. This journey took nearly 30 years to complete. There is increasing clinical data to document the beneficial effects of this approach, with ever-improving outcomes. Some aspects of the history of the cavopulmonary shunt have been previously reviewed in this journal and elsewhere,1–5as have analysis of outcomes for some groups of patients considered for surgical completion of the Fontan circulation.6–12While there has been some ongoing interest in ventricular septation since the early success of Sakakibara et al.,13this approach has largely been abandoned. Considerably more challenges and debate resonate in the surgical algorithms defined for patients whose hearts are characterized by a dominant left ventricle, discordant ventriculo-arterial connections, and unobstructed flow of blood to the lungs. This latter group will be the focus of this review, as will the aetiology of the myocardial hypertrophy that is particularly frequent in this group of patients, its clinical recognition, indeed its anticipation, and the multiple surgical strategies designed to prevent or treat it. All these manoeuvres are considered to optimise suitability for, and outcome from, creation of the Fontan circulation.
Myocardial infarction in infancy caused by compression of an anomalous left coronary artery arising from the right coronary artery
Authors: Duke Christopher , Rosenthal Eric , Simpson John M.
Published: January 2005

A 5-week-old child presented with a cardiac arrest secondary to myocardial ischaemia. Echocardiography demonstrated a single coronary artery arising from the right sinus of Valsalva. The coronary artery branched into left and right arteries, with the left artery then coursing anomalously in the tissue plane between the aortic root and the subpulmonary infundibulum. Compression of the left coronary artery caused severe myocardial ischaemia that resolved following construction of a bypass graft using the left internal thoracic artery. Stenosis at the anastomosis between the graft and the coronary artery was successfully treated by coronary angioplasty 2 years later.
Acute myocardial infarction in a 15-year old secondary to myxomatous embolisation
Authors: van Gelder Hugh M. , Jacobs Jeffrey P. , McCormack Jorge
Published: January 2005

We present a 15-year-old white male who presented with an acute myocardial infarction secondary to embolisation of tissue from a left atrial myxoma. He successfully underwent resection of the myxoma, and embolectomy of the fragments of tumour lodged in the coronary artery.
Double switch operation in a young infant
Authors: Ishibashi Nobuyuki , Aoki Mitsuru , Fujiwara Tadashi
Published: January 2005

We performed a combined Senning and arterial switch operation on a 2-month-old patient with congenitally corrected transposition, Ebstein's malformation producing severe tricuspid regurgitation, ventricular septal defect, pulmonary hypertension, and congestive heart failure. The tricuspid regurgitation was improved. The double switch operation has the advantage of improving the function of the systemic atrioventricular valve, especially in newborns or young infants in whom the outcome of the valvar repair is poor.
Longevity in the setting of tetralogy of Fallot: survival to the 84th year
Authors: Gerlis Leon M. , Ho Siew Yen , Sheppard Mary N.
Published: January 2005

A patient with tetralogy of Fallot suffered minimal disability until the age of 45 years, when she developed bacterial endocarditis complicated by hemiplegia. She remained well, but became markedly polycythaemic and, at the age of 50 years, underwent surgical correction to reduce the risk of further thromboembolic incidents. She continued in remarkably good health until her death from lobar pneumonia in her 84th year. We present the post-mortem findings, since as far as we are aware this is the longest recorded survivorship of a patient with tetralogy of Fallot.
Cardiac effects of quinidine on guinea‐pig isolated perfused hearts after in vivo quinidine pretreatment
Authors: Yang Quan , Padrini Roberto , Piovan Donatella , Ferrari Mariano
Published: January 2005

Experimental and clinical studies suggest that class I and class III antiarrhythmic drugs may be subject to pharmacological tolerance during long term treatment, leading to loss of therapeutic effectiveness.

The aim of this study was to ascertain whether prolonged in vivo treatment with the Class Ia agent quinidine can modify cardiac (electrical and mechanical) responses to the drug.

A group of guinea‐pigs (n=7) were treated intraperitoneally (q.d.) for 6 days with 75 mg kg−1 quinidine sulphate. Preliminary pharmacokinetic experiments indicated that this dose could attain plasma concentrations similar to those that are therapeutic in man (2–5 mg l−1). A control group (n=7) received a saline solution for the same period.

Twenty‐four hours after the last administration hearts were removed and retrogradely perfused at constant flow (stimulation frequency: 2.5 Hz). The following parameters were measured: maximal derivative of intraventricular pressure (dP/dtmax); coronary perfusion pressure (Cp); PR, QRS and JT intervals, on surface ECG. The effects of quinidine on these parameters were measured at different concentrations (2, 4, 8, 12, 16, 20 μM) and compared in the two experimental groups.

In the control group quinidine decreased in a dose‐dependent manner dP/dt and increased PR and QRS intervals. JT interval was increased at the lowest concentrations and decreased at the highest (biphasic effect). Cp did not change significantly.

In the pretreated group quinidine qualitatively produced the same effects on dP/dt and ECG intervals as in control group. Also the magnitude of these effects was not significantly different between the two groups. In contrast with findings in control experiments, Cp was significantly decreased by increasing quinidine concentration. Mean baseline Cp was higher in pretreated than in the control group (though not significantly, P=0.072) and quinidine addition abolished this difference. Thus, it is suggested that quinidine withdrawal induced a rebound increase in coronary tone, due to the unmasking of vasoconstrictor homeostatic mechanisms elicited by the in vivo vasodilating effect of the drug.

In conclusion, our data do not support the possibility that tolerance ensues during long term quinidine treatment, at least as far as electrophysiological and contractility effects are concerned. Further experimental work is needed to explain the appearance of a coronary vasodilating effect in pretreated hearts.

British Journal of Pharmacology (1997) 122, 7–12; doi:10.1038/sj.bjp.0701318
The regulation by phosphorylation of ‘priming’ of phospholipase A2 activity in the neutrophil model system, differentiated HL60 cells
Authors: Stewart Allison , Jackson Clive G. , Wakelam Michael J. O.
Published: January 2005

Differentiated HL60 cells have been utilized as a model system to examine the ‘priming’ of neutrophil phospholipase A2 activity. In control cells activation of phospholipase A2 by a 5 min stimulation with the chemotactic peptide formyl‐methionyl‐leucyl‐phenylalanine (100 nM) was essentially undetectable. When cells were primed by preincubation with 5 μM cytochalasin B for 5 min arachidonate release, a measure of phospholipase A2 activation, was observed within 20 s.

Priming by cytochalasin B did not involve or require a change in intracellular free calcium concentration.

Priming was associated with an increase in general protein tyrosine phosphorylation and could also be induced by the receptor tyrosine kinase agonist granulocyte macrophage colony‐stimulating factor (GM‐CSF, 20 ng ml−1) and be mimicked by treatment with the phosphotyrosine phosphatase inhibitor perhydrovanadate (0.5 mM). However, an increase in MAP kinase activity was not involved in the priming process.

Western blot analysis demonstrated that phospholipase A2 was phosphorylated in both control and primed cells, but that an increase in the amount of membrane associated enzyme was found in the primed cells.

Thus priming appears to be due to membrane association of the phospholipase and this may be regulated by tyrosine kinase activities.

British Journal of Pharmacology (1997) 122, 13–20; doi:10.1038/sj.bjp.0701323
D2 dopamine receptors and modulation of spontaneous acetylcholine (ACh) release from rat striatal synaptosomes
Authors: Clos M. V. , García‐Sanz A. , Vivas N. M. , Badia A.
Published: January 2005

The effect of two D3/2 dopamine receptor agonists, LY‐171555 (quinpirole) and 7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin (7‐OH‐DPAT) on spontaneous [3H]‐acetylcholine ([3H]‐ACh) release were investigated in rat striatal synaptosomes.

Quinpirole and 7‐OH‐DPAT inhibited in a concentration‐dependent manner the basal efflux of [3H]‐ACh with similar Emax (maximal inhibitory effect) values (29.95±2.91% and 33.19±1.21%, respectively). Significant differences were obtained between the pEC50 (−log of molar concentration) of quinpirole (7.87±0.12) and 7‐OH‐DPAT (7.21±0.17; P<0.01).

Different concentrations (0.3–10 nM) of haloperidol (D2/3 dopamine receptor antagonist) shifted to the right the concentration‐response curves elicited by quinpirole and 7‐OH‐DPAT, without modifications in the Emax.

Slopes of a Schild plot obtained with haloperidol in the presence of quinpirole and 7‐OH‐DPAT were not signficantly different from unity (0.85±0.05 and 1.17±0.11, respectively) and consequently haloperidol interacted with a homogeneous receptor population. The pKB values of haloperidol obtained from Schild regression were 9.96±0.15 (in presence of quinpirole) and 9.90±0.09 (in presence of 7‐OH‐DPAT).

Specific binding of [3H]‐YM‐09151‐2 to membranes of striatal synaptosomes and cells expressing D2 and D3 dopamine receptors was inhibited by haloperidol. Analysis of competition curves revealed the existence of a single population of receptors. There were no differences between the estimated pKi (−log of molar concentration) values for synaptosomes (8.96±0.02) and cells expressing D2 receptors (8.81±0.05), but the pKi value from cells expressing D3 dopamine receptors differed significantly (8.48±0.06; P<0.01).

In conclusion, the data obtained in the present study indicate that quinpirole and 7‐OH‐DPAT, two D3/2 dopamine receptor agonists, inhibit the spontaneous [3H]‐ACh efflux and this effect is competitively antagonized by haloperidol and probably mediated through dopamine D2 receptors.

British Journal of Pharmacology (1997) 122, 286–290; doi:10.1038/sj.bjp.0701327
Cloning, expression and pharmacology of a truncated splice variant of the human 5‐HT7 receptor (h5‐HT7(b))
Authors: Jasper J. R. , Kosaka A. , To Z. P. , Chang D. J. , Eglen R. M.
Published: January 2005

The rat 5‐hydroxytryptamine (5‐HT)7 receptor displays two splice variations, a long form, and a truncated splice isoform, arising from the introduction of a stop codon near the carboxy‐terminus. The human 5‐HT7 receptor gene contains at least two introns and encodes a 445 amino acid 5‐HT receptor.

A truncated splice variation in the human 5‐HT7 receptor was isolated from a human placental cDNA library. In accordance with current NC‐IUPHAR nomenclature guidelines, it is suggested that this receptor be denoted as the h5‐HT7(b) receptor and the long form of the receptor as h5‐HT7(a).

The h5‐HT7(b) receptor was stably expressed in HEK 293 cells and ligand affinities were determined by displacement of [3H]‐5‐carboxyamidotryptamine (5‐CT; Kd=0.28±0.06 nM, Bmax=7.3±1.7 pmol mg−1 protein). The rank order of affinities (pKi) for a series of ligands was: 5‐carboxamidotryptamine (5‐CT, 9.65)>5‐hydroxytryptamine (5‐HT, 9.41)>methiothepin (8.87)>mesulergine (7.87)>8‐hydroxy‐2(di‐n‐propylamino)tetralin (8‐OH‐DPAT, 6.85)>ketanserin (6.44).

The h5‐HT7(b) receptor coupled positively to adenylyl cyclase in HEK 293 cells. This response was elicited by a number of agonists with the following order of potency (pEC50): 5‐CT (8.7±0.11)>5‐MeOT (5‐methoxytryptamine; 8.1±0.20)>5‐HT (7.5±0.13)>tryptamine (5.6±0.36)>8‐OH‐DPAT (5.3±0.28)>5‐methoxytryptamine (5.0±0.06). This rank order was comparable to that observed in the radioligand binding studies.

In a similar fashion to that described for the 5‐HT7(a) receptor, PCR studies suggested that the 5‐HT7(b) receptor mRNA is found in great abundance throughout the brain, in the small intestine and aorta.

It is concluded that the h5‐HT7 receptor, like the rat receptor, exists as splice variants exhibiting similar pharmacology, signal transduction and distribution. It is thus likely that there exists a complex physiological role for alternate splicing products of the 5‐HT7 receptor gene.

British Journal of Pharmacology (1997) 122, 126–132; doi:10.1038/sj.bjp.0701336
Effect of endogenous nitric oxide on tumour necrosis factor‐α‐induced leukosequestration and IL‐8 release in guinea‐pigs airways in vivo
Authors: Kuo H.‐P. , Hwang K.‐H. , Lin H.‐C. , Wang C.‐H. , Lu L.‐C.
Published: January 2005

Tumour necrosis factor‐α (TNF‐α) is implicated in the pathogenesis of many pulmonary and airway diseases. TNF‐α stimulation may release interleukin‐8 (IL‐8) in airways mediated via an increase in intracellular oxidant stress. In the present study, we have assessed leukosequestration and IL‐8 release in the airways in response to intratracheal administration of human recombinant TNF‐α, and examined the modulatory role of endogenous NO by pretreatment with a NO synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME).

TNF‐α (102–104 u) was administered intratracheally in male guinea‐pigs which were anaesthetized with urethane and were ventilated artificially. TNF‐α induced a time‐ and dose‐related increase in neutrophil numbers and a concomitant increase in human IL‐8 equivalent level retrieved from bronchoalveolar lavage (BAL) with the peak effect at 103 u at 6 h of TNF‐α injection (late phase). Intratracheal administration of recombinant human (rh)IL‐8 (0.025, 0.25, 2.5 ng) producing a similar range of human IL‐8 equivalent levels in BAL as measured in our results induced neutrophil recovery in BAL fluid to a similar extent. Administration of anti‐IL‐8 antibody prevented the late phase of neutrophil recruitment induced by TNF‐α or rhIL‐8.

Pretreatment with L‐NAME significantly enhanced the TNF‐α (103 u)‐induced neutrophil recruitment and human IL‐8 equivalents production at 6 h, but not at 1 h of TNF‐α administration (early phase). L‐Arginine reversed the responses to L‐NAME. Pretreatment with 0.2% DMSO (i.v.) significantly inhibited TNF‐α‐induced neutrophil recruitment and human IL‐8 equivalents release both in the early and late phase of the responses. Pretreatment with DMSO also inhibited the enhancement effect of L‐NAME on the late phase of TNF‐α‐induced responses. DMSO failed to modify exogenous rhIL‐8‐induced neutrophil recruitment. Neither L‐NAME nor DMSO alone induced any significant change in neutrophil numbers or human IL‐8 equivalent level in BAL fluid.

Neutrophil depletion by cyclophosphamide pretreatment failed to modify TNF‐α‐induced human IL‐8 equivalent release.

The expression of β2‐integrin, CD11b/CD18 on neutrophils was increased only in the late but not early phase of TNF‐α stimulation. L‐NAME failed to modify these responses.

In conclusion, we demonstrated that NO may be an important endogenous inhibitor of TNF‐α‐induced leukocyte chemotaxis via inhibition of IL‐8 production. Thus, the production of NO in airway inflammatory diseases may play a negative feedback role in self‐limiting the magnitude of inflammatory responses.

British Journal of Pharmacology (1997) 122, 103–111; doi:10.1038/sj.bjp.0701338
G protein‐independent stimulation of human myocardial phospholipase C by mastoparan
Authors: Schnabel Petra , Gäs Heidi , Nohr Theo , Böhm Michael
Published: January 2005

Phosphoinositide‐specific phospholipase C (PLC) is involved in the regulation of many cellular functions. In the myocardium, PLC‐generated second messengers play a role in the regulation of contractile function and in the pathophysiology of myocardial hypertrophy.

In the present study, the effect of mastoparan, a tetradecapeptide which is capable of activating heterotrimeric G proteins by mimicking the action of an activated receptor, on membrane‐bound human myocardial PLC, was investigated in a cell‐free assay with exogenous phospholipids as a substrate.

Mastoparan stimulated human myocardial PLC approximately two fold with a half‐maximal effect at approximately 2 μM and a maximal effect at 10 μM. The peptide did not alter the dependence of PLC on free calcium ions. In order to exclude non‐specific effects of mastoparan due to its amphiphilic properties, different mastoparan derivatives were used as positive and negative controls. Mas17, an inactive mastoparan analogue with phsyical properties very similar to mastoparan, did not induce substantial PLC stimulation in human myocardial membranes. In contrast, Mas7, the most active mastoparan derivative known, caused a more pronounced PLC activation compared with the mother compound indicating that the effect was sequence‐specific. Human myocardial PLC stimulation was pertussis toxin‐insensitive and could not be abolished by addition of excess α‐subunits from purified retinal transducin or by excess GDP or GDPβS. In order to investigate whether mastoparan stimulated PLC via pertussis toxin‐insensitive αq, a deletion mutant of PLCβ2 deficient of the site of interaction with αq‐subunits was expressed in COS‐1 cells. Both wild‐type and mutant PLCβ2 were similarly sensitive to stimulation by mastoparan.

It is concluded that mastoparan stimulates human myocardial PLC by a mechanism distinct from heterotrimeric G proteins.

British Journal of Pharmacology (1997) 122, 31–36; doi:10.1038/sj.bjp.0701341
Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats
Authors: Matsuura Takeshi , Miura Katsuyuki , Ebara Tsuneyuki , Yukimura Tokihito , Yamanaka Shinya , Kim Shokei , Iwao Hiroshi
Published: January 2005

Endothelin (ET) is a potent vasoconstrictor peptide which has been shown to have an important role in the regulation of systemic and renal haemodynamics. In order to elucidate the role of endogenous ET in the kidney, we examined the effects of ET receptor antagonists on systemic and renal vasculature in normotensive anaesthetized rats.

Intravenous injection of a selective ETA receptor antagonist, FR139317 (0.5 μmol kg−1, for 20 min) induced a very small fall in blood pressure. Similarly, a non‐selective ETA/ETB receptor antagonist, TAK‐044 (12.5 μmol kg−1, for 20 min) slightly decreased blood pressure. A selective ETB receptor antagonist, BQ‐788 (0.5 μmol kg−1, for 20 min) had no effect on blood pressure.

FR139317 and TAK‐044 did not affect renal blood flow or calculated renal vascular resistance. In contrast, BQ‐788 significantly reduced renal blood flow by 18.2±2.4% and increased renal vascular resistance. Furthermore, the renal vascular action of BQ‐788 was not observed when combined with FR139317.

Pretreatment with a nitric oxide (NO) synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 37 μmol kg−1, i.v.) and a cyclo‐oxygenase inhibitor ibuprofen (44 μmol kg−1, i.v.) completely abolished the BQ‐788‐mediated renal vasoconstriction.

These results indicate that activation of ETB receptors by endogenous ET acts as a physiological brake for the ETA‐mediated renal vasoconstriction; this effect appears to be mediated by stimulation of NO and/or vasodilator prostaglandin(s) release.

British Journal of Pharmacology (1997) 122, 81–86; doi:10.1038/sj.bjp.0701349
Role of Na+‐K+ ATPase in cyclic GMP‐mediated relaxation of canine pulmonary artery smooth muscle cells
Authors: Tamaoki J. , Tagaya E. , Nishimura K. , Isono K. , Nagai A.
Published: January 2005

Sodium‐potassium adenosine triphosphatase (Na+‐K+ ATPase) plays a role in the regulation of vascular tone, but contribution of this enzyme to nitrovasodilator‐induced pulmonary vasodilatation remains uncertain. We thus studied the interaction between guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) and Na+‐K+ ATPase in smooth muscle cells isolated from canine pulmonary artery.

To assess the contractile properties, changes in smooth muscle cell length were determined microscopically. Application of potassium chloride (KCl) shortened the cell length, an effect which was reduced by sodium nitroprusside and 8‐bromo‐cyclic GMP in a concentration‐dependent manner. Pretreatment of cells with the cyclic GMP‐dependent kinase inhibitor KT 5823 (2 μM) abolished the effects of sodium nitroprusside and 8‐bromo‐cyclic GMP.

Ouabain (0.3 μM) did not alter the KCl‐induced muscle shortening, but inhibited the relaxant responses to sodium nitroprusside and 8‐bromo‐cyclic GMP.

Incubation of smooth muscle cells with sodium nitroprusside concentration‐dependently increased intracellular cyclic GMP levels and ouabain‐sensitive 86Rb uptake, and these values were significantly correlated. In the presence of KT 5823, sodium nitroprusside increased cyclic GMP levels but did not alter ouabain‐sensitive 86Rb uptake.

These results suggest that there is a link between accumulation of intracellular cyclic GMP and activation of sarcolemmal Na+‐K+ ATPase in pulmonary artery smooth muscle cells and that this link may be involved in the sodium nitroprusside‐induced pulmonary vasodilatation.

British Journal of Pharmacology (1997) 122, 112–116; doi:10.1038/sj.bjp.0701351
Regulation of apical and basolateral K+ conductances in the rat colon
Authors: Schultheiß G. , Diener M.
Published: January 2005

Apical administration of an ionophore, nystatin, and basolateral depolarization by K+ were used to investigate the regulation of apical and basolateral electrogenic transport pathways for K+ in the rat proximal and distal colon.

Administration of nystatin (100 μg ml−1 at the mucosal side), in the presence of Na+ and in the presence of a serosally directed K+ gradient, stimulate a large increase in short‐circuit current (ISC) and tissue conductance in both colonic segments. This response was composed of a pump current generated by the Na+‐K+‐ATPase and of a current across a quinine‐sensitive basolateral K+ conductance.

The pump current, measured as Na+‐dependent or scilliroside‐sensitive current in the absence of a K+ gradient, was significantly greater in the distal than in the proximal colon. The pump current was unaltered by pretreatment of the tissue with forskolin (5×10−6 mol l−1).

The current across the basolateral K+ conductance, measured as current in the presence of a serosally directed K+ gradient either in the absence of Na+ or in the presence of scilliroside, was increased by the cholinoreceptor agonist, carbachol (5×10−5 mol l−1), but inhibited by forskolin (5×10−6 mol l−1).

Basolateral K+ depolarization induced a negative ISC in both colonic segments, which was inhibited by the K+ channel blocker quinine (10−3 mol l−1 at the mucosal side), but was resistant to tetraethylammonium (5×10−3 mol l−1 at the mucosal side). This K+ current across an apical K+ conductance was stimulated in both colonic segments by carbachol, whereas forskolin had no effect, although control experiments revealed that forskolin was still able to open an apical Cl− conductance under these conditions.

These results demonstrate that an increase in intracellular Ca2+ concentration induced by carbachol causes an increase in the basolateral and the apical K+ conductance, thereby inducing K+ secretion in parallel with an indirect support for Cl− secretion due to the hyperpolarization of the cell membrane. In contrast, the dominating effect of an increase in the intracellular cyclic AMP concentration is inhibition of a basolateral K+ conductance; a mechanism which might contribute to the inhibition of K+ absorption.

British Journal of Pharmacology (1997) 122, 87–94; doi:10.1038/sj.bjp.0701353
Response of normoxic pulmonary arteries of the rat in the resting and contracted state to NO synthase blockade
Authors: Steeds R. P. , Thompson J. S. , Channer K. S. , Morice A. H.
Published: January 2005

The pulmonary vasculature is normally in a low resting state of tone. It has been hypothesized that this basal tone is actively maintained by the continuous release of a vasodilator in the resting state. However, evidence for basal release of nitric oxide (NO) is inconclusive.

We studied the release of NO in arteries from the pulmonary circulation of male Wistar‐Kyoto rats by examining the effects of the L‐arginine analogue NG‐nitro‐L‐arginine methyl ester (L‐NAME) on resting pulmonary arteries and on vessels pre‐contracted with prostaglandin F2α (PGF2α).

Rats (n=21) were killed by an overdose with pentobarbitone. Pulmonary arteries were dissected (mean internal diameter 459±11 μm) and mounted in a small vessel wire myograph. Resting tensions were set to simulate transmural pressures of 17.5 mmHg.

L‐NAME (100 μM) was found to produce a contraction of 0.64±0.09 mN mm−1 in resting pulmonary arteries when added alone to the myograph bath. This contraction was not produced following removal of the endothelium. Vessel contraction to PGF2α (100 μM) was found to be significantly greater when carried out in the presence of L‐NAME (100 μM)–1.37±0.15 mN mm−1 compared with 1.96±0.17 mN mm−1. Dilatation following acetylcholine (ACh) (1 μM) was abolished in the presence of L‐NAME (100 μM).

Rat pulmonary artery contraction in response to the addition of L‐NAME and the absence of contraction upon removal of the endothelium provides supportive evidence of the active release of nitric oxide for the maintenance of resting tone.

British Journal of Pharmacology (1997) 122, 99–102; doi:10.1038/sj.bjp.0701356