bluuebunny/crossref_metadata_2025 huggingface dataset:
High prevalence of foot diseases in Europe: results of the Achilles Project
Authors: Burzykowski T. , Molenberghs G. , Abeck D. , Haneke E. , Hay R. , Katsambas A. , Roseeuw D. , Van De Kerkhof P. , Van Aelst R. , Marynissen G.
Published: November 2003

Objective. To provide an insight into the prevalence of foot disease in Europe, and to include an assessment of the prevalence of predisposing factors and their correlation with foot disease.

Design. Large population‐based survey conducted in 16 European countries.

Setting. The project consisted of two parts (study I and study II), in which all patients presenting to general practitioners and dermatologists over a defined time period were invited to participate.

Patients. In study I, 70 497 patients presenting to dermatologists or general practitioners were recruited, and in study II 19 588 patients presenting to dermatologists were recruited.

Main outcome measure. The feet of all participants were examined for signs of foot disease. The assessors also recorded relevant details such as the age and sex of patients, and the presence of predisposing factors for foot disease. In addition, patients in study II were offered a free mycological examination of the toenails and skin on the feet.

Results. In study I, 57.0% of patients had at least one foot disease. In study II, 61.3% had at least one foot disease. The proportions of patients with fungal foot disease and non‐fungal foot disease in study I were 34.9% and 38.4%, respectively, and in study II were 40.6% and 41.7%, respectively. Orthopedic conditions and metatarsal corns were the most frequently reported non‐fungal foot diseases, and onychomycosis and tinea pedis were the most frequently observed fungal infections.

Conclusions. This large‐scale survey suggests that the prevalence of fungal and non‐fungal foot disease is higher than previously estimated.
Cutaneous sporotrichosis: an unusual clinico‐pathologic and therapeutic presentation
Authors: Sharma N. L. , Mahajan V. K. , Verma N. , Thakur S.
Published: November 2003

This report presents a number of unusual clinico‐histopathologic and therapeutic features in a culture proven case of cutaneous sporotrichosis. These include lymphocutaneous sporotrichosis involving face; its dissemination in an otherwise healthy patient; its histology mimicking cutaneous cryptococcosis; two episodes of severe purulent inflammatory reaction bordering the lesion during therapy with saturated solution of potassium iodide; no therapeutic response to potassium iodide therapy and rapid healing of lesion with high‐dose of fluconazole.
Development and evaluation of a one‐tube seminested PCR assay for the detection and identification of Penicillium marneffei
Authors: Prariyachatigul C. , Chaiprasert A. , Geenkajorn K. , Kappe R. , Chuchottaworn C. , Termsetjaroen S. , Srimuang S.
Published: November 2003

A one‐tube seminested polymerase chain reaction (PCR) assay was developed to detect and identify Penicillium marneffei DNA coding for 18S rRNA both from purified DNA and from clinical samples. DNA from 120 strains of organisms and 19 blood samples from AIDS patients was amplified with F3, CPL1 and PM primers. Under optimized conditions, these primers detected 100% specifically amplified products of 251 and 331 bp from all P. marneffei DNA preparations (47 strains) and from two blood samples of AIDS patients suspected to suffer from penicilliosis marneffei. The assay was sensitive to detect as little as 10 pg purified DNA, which is equivalent to 250 cells. This PCR assay might be useful as an alternative test, if a rapid diagnosis of penicilliosis marneffei is needed.
The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates
Authors: Saito Y. A. , Talley N. J. , J. Melton L. , Fett S. , Zinsmeister A. R. , Locke G. R.
Published: December 2003

Abstract  The ‘Rome’ criteria for irritable bowel syndrome (IBS) have evolved over 15 years with four published versions. The impact of these changes on community prevalence rates is not known. Study aims were to estimate the prevalence of IBS using the four Rome criteria and agreement between Rome II and previous criteria. Questionnaires were mailed to a random sample of Olmsted County, Minnesota residents in 1992. Age‐ and gender‐adjusted prevalence estimates were calculated for Rome II (1999), Rome I (1992), Rome (1990), and Rome (1989) criteria. Per cent agreement and kappa values were calculated to assess agreement. Of 892 eligible subjects, 643 (72%) responded. The age‐ and gender‐adjusted prevalence of IBS was 5.1% [95% confidence interval (CI): 3.1, 7.0], 6.8% (95% CI: 4.7, 8.9), 5.1% (95% CI: 3.2, 7.1) and 27.6% (95% CI: 23.6, 31.5), respectively. In comparison with Rome II criteria, per cent agreement and κ values were 97.2% and 0.78 (95% CI: 0.69, 0.88), 96.4% and 0.68 (95% CI: 0.55, 0.80), and 79.0% and 0.29 (95% CI: 0.19, 0.40), respectively. Thus, although differences were seen with the older criteria, compared with the Rome I criteria, good agreement was seen and community prevalence estimates were similar with the Rome II criteria.
Neurochemical coding of myenteric neurones in the human gastric fundus
Authors: Pimont S. , Bruley des Varannes S. , Le Neel J. C. , Aubert P. , Galmiche J. P. , Neunlist M.
Published: December 2003

Abstract  The major functions of the stomach are under the control of the enteric nervous system (ENS), but the neuronal circuits involved in this control are largely unknown in humans. Enteric neurones can be characterized by their neuromediator or marker content, i.e. by neurochemical coding. The purpose of this study was to characterize the presence and co‐localization of neurotransmitters in myenteric neurones of the human gastric fundus. Choline acetyltransferase (ChAT), neurone‐specific enolase (NSE), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), substance P (SP) were detected by immunohistochemical methods in whole mounts of gastric fundus myenteric plexus (seven patients). Antibodies against ChAT and NOS labelled the majority of myenteric neurones identified by NSE (57.2 ± 5.6% and 40.8 ± 4.5%, respectively; mean ± SD). The proportions of VIP‐ and SP‐immunoreactive neurones were significantly smaller, constituting 19.6 ± 6.9% and 16.0 ± 3.7%, respectively. Co‐localization studies revealed five major populations representing over 75% of the myenteric neurones: ChAT/‐, 30.1 ± 6.1%; NOS/‐, 24.2 ± 4.4%; ChAT/SP/‐, 8.3 ± 3.1%; NOS/VIP/‐, 7.2 ± 6.0%; ChAT/VIP/‐, 4.9 ± 2.6. Some similarities are apparent in the neurochemical coding of myenteric neurones in the stomach and intestine of humans, and between the stomach of humans and animals, but striking differences exist. The precise functional role of the neurochemically identified classes of neurones remains to be determined.
Cholinergic transmission to colonic circular muscle of children with slow‐transit constipation is unimpaired, but transmission via NK2 receptors is lacking
Authors: Stanton M. P. , Hengel P. T. , Southwell B. R. , Chow C. W. , Keck J. , Hutson J. M. , Bornstein J. C.
Published: December 2003

Abstract  Tachykinins (TKs) colocalize with acetylcholine in excitatory motor neurones supplying human colonic circular muscle (CCM). Some children with slow‐transit constipation (STC) have reduced TK‐immunoreactivity in nerve terminals in CCM suggesting a deficit in neuromuscular transmission. This study aimed to test this possibility. Seromuscular biopsies of transverse colon were obtained laparoscopically from STC children (37, 17 with low density of TK‐immunoreactivity). Specimens of transverse (17) and sigmoid colon (20) were obtained from adults undergoing colonic resection for cancer. CCM contractions were measured isotonically and responses to carbachol, neurokinin A (NKA) and electrical field stimulation (EFS) recorded. Carbachol and NKA‐evoked contractions in adult and STC colon. Hyoscine (2 μmol L−1) significantly depressed responses to EFS in all preparations. Blockade of NK2 receptors (SR 48968, 2 μmol L−1) significantly depressed EFS‐evoked contractions of adult transverse CCM, but had no effect on STC preparations. Thus, neuromuscular transmission in both adults and STC children is predominantly cholinergic and this component is unimpaired in the latter, indicating that reduced TK‐immunoreactivity is not a marker for depressed cholinergic responses. Although pharmacologically responsive TK receptors are present in STC colon, we did not detect neuromuscular transmission mediated by release of TKs in these preparations.
Effects of phosphodiesterase inhibitors on oesophageal neuromuscular functions
Authors: Park H. , Clark E. , Conklin J. L.
Published: December 2003

Abstract  The cyclic nucleotides adenosine 3′,5′‐cyclic monophosphate (cAMP) and guanosine 3′,5′‐cyclic monophosphate (cGMP) mediate the inhibitory effects of vasoactive intestinal polypeptide and nitric oxide on oesophageal smooth muscle. Phosphodiesterases (PDE) terminate their actions. We hypothesized that PDE inhibitors alter nerve‐induced responses of oesophageal and lower oesophageal sphincter (LES) smooth muscle. An electrical field known to activate intrinsic oesophageal nerves was used to stimulate transverse muscle strips from the opossum oesophagus. This produced a contractile off‐response from circular oesophageal muscle and a biphasic relaxation of the LES – an initial rapid relaxation (R1) and a slower sustained relaxation (R2). The effects on LES and oesophageal muscle of zaprinast (type V), zardaverine (type III/IV) and theophylline (non‐specific) PDE inhibitors were explored. All three PDE inhibitors decreased LES tone and attenuated the off‐response. Zaprinast and theophylline increased the latency of the off‐response. Zaprinast prolonged R1, and slowed its recovery. It also increased the percentage relaxation of the second R2. Zardaverine increased the percentage relaxation of R2. Theophylline slowed the recovery of R2. PDEs play a role in maintaining LES tone and its recovery after LES relaxation. They may also modulate oesophageal motor activity.
Interleukin‐1β selectively increases substance P release and augments the ascending phase of the peristaltic reflex
Authors: Grider J. R.
Published: December 2003

Abstract  Exposure of muscle strips to interleukin (IL)‐1β stimulates substance P (SP) expression, suggesting a link between IL‐1β and the increase in SP expression during intestinal inflammation. The present study examined whether the SP expression induced by IL‐1β is reflected by enhanced SP release and SP‐mediated reflex activity. Exposure of innervated longitudinal colonic muscle strips to IL‐1β for 8 h increased SP synthesis in, and greater SP release from excitatory motor neurones in response to KCl or electrical field stimulation (EFS), and enhanced longitudinal muscle contraction in response to EFS. IL‐1 Ra and IL‐1β antibody blocked IL‐1β‐induced increase in SP release and muscle contraction. Neither vasoactive intestinal peptide (VIP) nor somatostatin release was increased. The increase in SP release was reflected in enhanced circular muscle contraction in response to stretch. VIP‐mediated descending relaxation of circular muscle was not affected. The selective increase in ascending contraction induced by exposure to IL‐1β was blocked by IL‐1 Ra or IL‐1β antibody. We conclude that the selective increase in SP expression induced by IL‐1β in excitatory motor neurones is reflected by enhanced SP release and longitudinal muscle contraction in response to EFS, and enhanced SP release and circular muscle contraction during the ascending phase of the peristaltic reflex.
Is there a role for the IHH gene in Hirschsprung's disease?
Authors: Garcia‐Barceló M.‐M. , Lee W.‐S. , Sham M.‐H. , Lui V. C.‐H. , Tam P. K.‐H.
Published: December 2003

Abstract  Hirschsprung disease (HSCR) is characterized by the absence of ganglion cells along a variable length of the intestine. HSCR has a complex genetic aetiology with 50% of the patients unexplained by mutations in the major HSCR genes. The Ihh gene is involved in the development of the enteric nervous system (ENS) and Ihh mutant mice present with a phenotype reminiscent of HSCR. The requirement of Ihh signalling for the proper development of the ENS, together with the evidence presented by the Ihh murine model, prompted us to investigate the involvement of the human IHH gene in HSCR. Sequence analysis revealed seven single nucleotide polymorphisms, six of which were new. Allele and haplotype frequencies were compared between cases and controls, and, among the cases, between genders, between different phenotypes, and between patients with different mutation status in the main HSCR genes. Despite the involvement of IHH in the development of the ENS, IHH is not a major gene in HSCR. Nevertheless, as the manifestation of the HSCR phenotype is genetic background dependent, polymorphic loci should be tested simultaneously to characterize gene–gene interaction. The involvement of IHH in other intestinal anomalies should be investigated.
Kit/stem cell factor receptor‐induced phosphatidylinositol 3′‐kinase signalling is not required for normal development and function of interstitial cells of Cajal in mouse gastrointestinal tract
Authors: Gibbons S. J. , Rich A. , Distad M. A. , Miller S. M. , Schmalz P. F. , Szurszewski J. H. , Sha L. , Blume‐Jensen P. , Farrugia G.
Published: December 2003

Abstract  Signalling mediated by the receptor tyrosine kinase c‐Kit is required for normal development of interstitial cells of Cajal (ICC). c‐Kit activates several signalling pathways, including the phosphatidylinositol 3′‐kinase (PI3′‐kinase) pathway. The signals required for ICC development and maintenance are not well understood. Studies indicate a role for PI3′‐kinase. We studied ICC function and morphology in mice homozygous for the tyrosine 719 to phenylalanine c‐Kit mutation, which disrupts all PI3′‐kinase binding to c‐Kit. Functionally, the electrical slow waves in the jejunum and inhibitory junction potentials were normal in adult mutants. Morphologically, the distribution of ICC was not altered in mutants. There was no difference in the density of ICC in the jejunum of adults or newborns from quantitative analysis of c‐Kit immunoreactivity. The number of ICC obtained in culture was the same using mutants or wild‐type littermates. The density and organization of nerves in the jejunum of mutants was not affected. Deletion of c‐Kit‐induced PI3′‐kinase signalling does not affect the function or development of ICC in the mouse. This is an important and counterintuitive result, given the role of PI3′‐kinase signalling downstream of c‐Kit and the role of both c‐Kit and PI3′‐kinase individually in ICC development.
Coupling and innervation patterns of interstitial cells of Cajal in the deep muscular plexus of the guinea‐pig
Authors: Kobilo T. , Szurszewski J. H. , Farrugia G. , Hanani M.
Published: December 2003

Abstract  Interstitial cells in the deep muscular plexus (ICC‐DMP) are thought to be essential for neurotransmission in the circular muscle. There is evidence for gap junctions within the ICC‐DMP network and between ICC‐DMP and muscle cells; however, there is no evidence for functional coupling via these gap junctions. In addition, the innervation of individual ICC‐DMP has not been studied. We investigated these questions by injecting the dye Lucifer yellow into ICC‐DMP of guinea‐pig ileum. Nerves were labelled immunohistochemically for protein gene product 9.5. Cells were imaged by confocal microscopy. Most (79%) of the dye‐injected ICC‐DMP were coupled to one to five other ICC‐DMP, and 86% of them were coupled to one to five circular muscle cells. Octanol effectively blocked all coupling. Incubation in pH 6.8–7.0 reduced ICC–ICC coupling to 49% and ICC–muscle coupling to 32%. In contrast, pH 7.8–7.9 increased ICC–ICC and ICC–muscle coupling to 100%. Most ICC somata (95%) and processes (60%) were in close proximity with both nerve fibres and smooth muscle cells. These results provide direct evidence for functional coupling within the ICC‐DMP network, and between this network and cells of the outer circular muscle layer and showed that coupling can be affected by pH.
The effect of sildenafil on oesophageal motor function in healthy subjects and patients with nutcracker oesophagus
Authors: Lee J. I. , Park H. , Kim J. H. , Lee S. I. , Conklin J. L.
Published: December 2003

Abstract  Type 5 phosphodiesterase terminates the action of nitric oxide (NO) induced 3′,5′‐cyclic monophosphate (cGMP). Sildenafil inhibits this phosphodiesterase, increases cellular cGMP concentrations and enhances NO‐induced smooth muscle relaxation. We investigated the effect of sildenafil on the oesophageal motor function of healthy subjects and patients with nutcracker oesophagus. Eight healthy volunteers and nine patients with nutcracker oesophagus participated in this study. The participants underwent oesophageal manometries on two separate days after either 20 mL of distilled water or 0.8 mg kg−1 sildenafil dissolved in 20 mL of water was infused into the stomach. Lower oesophageal sphincter (LOS) resting pressure, the duration of LOS relaxation and the amplitudes of oesophageal pressure waves were examined before, and 7.5, 15, 30 and 60 min after either placebo or sildenafil. In both healthy subjects and patients with nutcracker oesophagus, sildenafil decreased resting LOS pressure and the amplitude of peristaltic pressure waves at 3, 8 and 13 cm above LOS. Sildenafil also prolonged the duration of LOS relaxation. It had no effect on the velocity of peristalsis or the amplitude of peristaltic pressure waves 18 cm above LOS. Sildenafil may be considered as an alternative treatment in nutcracker oesophagus although there are several limitations to be overcome.
Influence of sex and experimental protocol on the effect of maternal deprivation on rectal sensitivity to distension in the adult rat
Authors: Rosztóczy A. , Fioramonti J. , Jármay K. , Barreau F. , Wittmann T. , Buéno L.
Published: December 2003

Abstract  Neonatal maternal separation induces visceral hyperalgesia before and after stress in male rats. This study compares the effects on sensitivity to rectal distension in adult male and female rats, using two protocols of deprivation. Between postnatal days 1 and 14, maternal deprivation was performed for 2 h per day according to a protocol of type M (removal of all pups from home cage) or type P (separation of half of littermates). Visceral sensitivity was assessed at 12 weeks of age by the number of abdominal contractions induced by rectal distension before and after restraint stress. Calcitonin gene‐related peptide (CGRP) was identified in the rectal wall by immunohistochemistry. In basal conditions, both separation protocols induced hyperalgesia, that was greater after type M than type P, and in females than in males for type P separation. Acute restraint stress induced hyperalgesia in control females only, and this effect was similarly enhanced by both type P and M separation. No difference was found between controls and deprived rats in rectal CGRP immunoreactivity which was greater in females and increased after rectal distension. These results indicate that long‐term visceral hyperalgesia depends upon the type of maternal deprivation and that females are more sensitive than males.
Perchlorate differentially potentiates excitation–contraction coupling of diaphragm muscle from mdx and control mice
Authors: PÉRÉON Y. , KHAMMARI A. , NOIREAUD J.
Published: November 2003

The effects of perchlorate (6–40 mm) on contractile properties and depolarization–contraction coupling of diaphragm have been tested in muscle fibre bundles from 8 to 12‐week‐old mdx and control mice. Twitch contractile properties were affected by perchlorate to a similar extent in mdx and control muscles. In the absence of perchlorate, voltage‐dependent parameters of both activation and inactivation were similar in mdx and control muscles. In both mdx and control muscles, perchlorate induced a shift of activation and inactivation curves toward more negative potentials. However, mdx diaphragm fibres were less sensitive to perchlorate in the low range of concentrations (6–12 mm). These results are unlikely to be due to a possible effect of the lack of dystrophin on the excitation–contraction coupling voltage sensor or ryanodine receptor. However, necrosis and regeneration occur in mdx mouse diaphragm and it is postulated that the presence of a high proportion of not fully mature fibres could contribute to the reduced sensitivity of mdx diaphragm fibres to perchlorate.
Acute growth hormone injection reduced gastrointestinal and increased hepatic oleic acid oxidation in swine
Authors: UNNEBERG K. , STEIGEN T. , REVHAUG A. , LARSEN T. , MJAALAN M.
Published: November 2003

Gastrointestinal, hepatic, and hindleg oxidation of 3H‐labelled oleic acid and 14C‐labelled glucose based on arterial‐venous differences in 3H2O and 14CO2 were studied before and after an intravenous injection of 24 IU of growth hormone in 10 piglets. Hepatic oleic acid oxidation increased transiently while gastrointestinal oleic acid oxidation decreased correspondingly, maintaining a constant splanchnic oleic acid oxidation. Administration of a growth hormone led to a transient, parallel decrease in both hepatic and gastrointestinal glucose oxidation. We conclude that, in contrast to the growth hormone effect on splanchnic glucose oxidation, growth hormone effect on splanchnic fat oxidation appears to be organ specific.
Characteristics of the glomerular capillary membrane of the rat kidney as a hydrated gel. I. Hypothetical structure
Authors: WOLGAST M. , ÖKÄLLSKOG  , WAHLSTRÖM H.
Published: November 2003

It is suggested that the glomerular capillary membrane constitutes a flexible gel, where negative charges fixed to the matrix of the membrane account for the maintenance of its integrity. In this model, the hydrostatic pressure throughout the membrane is assumed to equal the glomerular capillary pressure, Pglom, of 56.7 mmHg. On the plasma side of the membrane, the charge‐induced electro‐osmotic pressure therefore has to balance the colloid osmotic pressure of glomerular plasma, and on its Bowman's space side, it has to balance the pressure drop, Pglom‐PBow, across this interphase. Using micropuncture technique, the glomerular plasma colloid osmotic pressure of 20.6 mmHg was found to require a charge density of 24.8 mEq L‐1 and the pressure drop at the Bowman's space side of 56.7‐12.2=44.5 mmHg a density of 36.6 mEq L‐1. The transmembranous electric potential difference was estimated at ‐1.1 mV, a potential which, in a negatively charge membrane, will also constitute the net driving force for the fluid transfer; this force will be close to, but not identical with, that calculated as conventional from the Starling forces of, in the present case, 23.9 mmHg. In the present analysis the distribution of charges in the fluid of the pore resulting from charged groups fixed to the rim of the pore is also considered.
Characteristics of the glomerular capillary membrane of the rat kidney as a hydrated gel. II. On the validity of the model
Authors: WOLGAST M. , KÄLLSKOG Ö. , WAHLSTRÖM H.
Published: November 2003

In our gel model applied to the glomerulus, maintenance of membrane integrity is assumed to be preserved not by rigid elements but by the electro‐osmotic and balancing hydrostatic pressure offered by negative, fixed charges such that the membrane is able to withstand the external colloid osmotic and hydrostatic forces. In a previous study we used micropuncture data to estimate the charge densities required to fulfil this assumption. In the present study the validity of the model was examined from the transport of neutral and negative charged myoglobin as derived from their concentrations in renal venous blood. In order to determine the size of the pores, or rather meshes in the network, the venous concentration of [51Cr]EDTA was also analysed. Based on the ratio between EDTA and neutral myoglobin of 1.08±0.010 (mean±SE, n=9), the equivalent pore radius was calculated to be ∼40 Å. The ratio of neutral to negative myoglobin in the two series performed was found to be 0.96±0.018 (n=8) and 0.97±0.05 (n=7), figures which were the same as ratio of 0.97 predicted on theoretical grounds. It is concluded that the experimental data support the hypotheses, although they may also be adapted to the transport in a homogeneously charged membrane; the charge density in this case was estimated at 2.3 mEq L‐1. Assuming that the membrane constitutes a network with quadratic meshes, each fibre would seem to carry binding sites ∼80 Å apart and where, in between these binding sites, each fibre was calculated to carry three charges such that the mesh will thus be surrounded by 12 charges.
Intrarenal administration of angiotensin II does not moderate afferent renal nerve mediated cardiovascular reflexes in the anaesthetized rabbit
Authors: ASHTON N. , F. V.
Published: November 2003

Stimulation of the afferent renal nerves in the anaesthetized rabbit by acute reduction in renal perfusion pressure results in a neurally mediated, reflex increase in hindlimb vascular resistance. To determine whether exogenous angiotensin II moderates the reflex, the kidneys of anaesthetized rabbits were vascularly isolated and renal blood flow was occluded acutely, following intrarenal administration of vehicle (0.9% saline) or angiotensin II (0.5 ng), and the hindlimb vascular response was measured. Occlusion of renal blood flow resulted in similar, significant increases in femoral perfusion pressure of 39.7±7.1 mmHg after vehicle and 21.3±8.9 mmHg (P<0.05, n=6) after angiotensin II. The viability of the preparation following repeated episodes of renal blood flow occlusion was tested by a series of three rapid (2–3 min delay) occlusions and three delayed (30 min delay) occlusions. Femoral perfusion pressure rose by 43.1±10.7 mmHg (rapid, P<0.05, n=11) and 64.4±12.3 mmHg (delayed, P<0.05, n = 5) on the first occasion. On the second occasion, the rapid occlusion did not result in a significant increase in femoral perfusion pressure (29.1±8.1 mmHg), but the delayed group did (54.6±22.4 mmHg, P<0.05). On the third occasion, neither group showed a significant change (20.9±16.3 and 30.8±13.5 mmHg). These data suggest that exogenous angiotensin II does not moderate the afferent renal nerve reflex. The decline in hindlimb response following rapid serial occlusion may be attributed to a diminution of an intermediary substance(s) at the nerve receptor site.
Acoustically induced vibrations of the Reissner's membrane in the guinea‐pig inner ear
Authors: ULFENDAHL M. , KHANNA S. M. , DECRAEMER W. F.
Published: November 2003

In the inner ear, the Reissner's membrane separates the scala vestibuli from the scala media and is thus of importance for maintaining a positive endocochlear potential. The motion of the membrane is thought to be driven by the vibrations of the underlying hearing organ caused by a hydromechanical coupling between the structures. Since the Reissner's membrane is relatively easily accessible in the cochlea its vibratory response has been used as a measure of the micromechanical behaviour of the hearing organ. To determine whether this indirect measure revealed the true characteristics of the hearing organ, experiments were performed using laser heterodyne interferometry in an in vitro preparation of the guinea‐pig temporal bone. Interferometric measurements at the Reissner's membrane and at the surface of the hearing organ directly beneath made it possible to compare the mechanical tuning characteristics of both structures. It was found that the mechanical response characteristics of the Reissner's membrane differed considerably from the hearing organ. The tuning frequency was different and only minor changes in the maximal vibration amplitude were seen when measuring at different radial locations. However, the shape of the response curve changed with location. The Reissner's membrane response appeared to be affected by the mechanical vibrations originating both at the middle ear ossicles and at the hearing organ. It is concluded that the Reissner's membrane response is a poor indicator of cochlear mechanics and that investigations of cochlear micromechanics should be performed directly at the level of the hearing organ.
Pharmacological evidence that different a1 adrenoceptor subtypes mediate contraction in rabbit prostate and hypogastric artery
Authors: DELAFLOTTE S. , AUGUET M. , CHABRIER P. E
Published: November 2003

The α1‐adrenoceptor subtypes mediating contraction of rabbit prostate and hypogastric artery were pharmacologically characterized using an isolated organ bath technique. The prostate had the same sensitivity to the contractile action of methoxamine and phenylephrine, whereas the hypogastric artery was five times less sensitive to the action of methoxamine in comparison with phenylephrine. Clonidine elicited contraction in the hypogastric artery but not in the prostate. BMY7378 was about 70‐fold more potent to antagonize the phenylephrine‐induced contraction in the hypogastric artery (pA2 8.14) than in the prostate (pA2 6.28), and 5‐methyl‐urapidil was about three‐fold more potent on prostrate than on hypogastric artery. The potency of different α1‐adrenoceptor antagonists tested in the rabbit prostate was significantly correlated with their binding affinity for the expressed recombinant α1A‐, but not α1B‐ or α1D‐, adrenoceptor subtype, whereas, the potency of the α1‐adrenoceptor antagonists tested in the rabbit hypogastric artery was better correlated with the defined α1D‐adrenoceptor. Chloroethylclonidine produced a 10‐fold rightward shift in the phenylephrine concentration–response curve in the hypogastric artery but only had a weak effect in the prostate. The results indicate that significant heterogeneity exists among α1‐adrenoceptor in the rabbit hypogastric artery (α1D‐adrenoceptor) and the prostate (α1A‐adrenoceptor).
N‐methyl‐d‐aspartate receptor antagonists potentiate morphine's antinociceptive effect in the rat
Authors: GRASS S. , HOFFMANN O , XU X.‐J. , WIESENFELD‐HALLIN Z.
Published: November 2003

The interaction between morphine and three antagonists of the N‐methyl‐d‐aspartate (NMDA) receptor, MK‐801 (non‐competitive channel blocker), dextromethorphan (clinically available non‐competitive antagonist) and CGS19755 (competitive receptor antagonist), was examined in rats with the hot plate test. The NMDA antagonists were administered intraperitoneally and none of them caused antinociception at doses that did not produce motor deficits (0.1 mg kg‐1 MK‐801, 30 mg kg‐1 dextromethorphan and 5 mg kg‐1 CGS19755). However, pretreatment with the NMDA antagonists at these doses 30 min prior to subcutaneous injection of 5 mg kg‐1 morphine significantly potentiated the antinociceptive effect of morphine, with strongest effect observed with dextromethorphan. It is suggested that blockade of NMDA receptors enhances the antinociceptive effect of morphine and NMDA antagonists may improve the analgesic efficacy of morphine in the clinic.
Acute and long‐term effects of 17b‐oestradiol on agonist‐stimulated force in rat tail artery
Authors: LYDRUP M.‐L. , NILSSON B. O.
Published: November 2003

The effects of 17β‐oestradiol on the force responses to KCl and noradrenaline were investigated in rings of the rat tail artery. Incubation with 10 μm 17β‐oestradiol for 100–295 min reduced the force amplitude after 5 min in high‐K+ (140 mm ) to 10% of the control value. The inhibitory effect of the steroid was unaffected by the NO‐synthase inhibitor l‐NAME. Rings activated by an intermediate degree of depolarization (60 mm K+) were less affected by the steroid (58% of control force). The sustained force response to 1 μm noradrenaline was reduced in the presence of 17β‐oestradiol to 60% of control value. Lower concentrations of 17β‐oestradiol (0.1 and 1 μm) were without acute effects on force development. However, long‐term effects of 17β‐oestradiol on vessel reactivity were found at these low concentrations. Rings were cultured for 3–7 days in the absence or in the presence of the steroid before they were stimulated with agonists. Cultured rings developed an increased sensitivity to noradrenaline compared with freshly prepared ones. Cocaine (30 μm) shifted the noradrenaline concentration–response curve to the left in freshly prepared rings while it had no effect in cultured ones, indicating that the increased sensitivity to noradrenaline in cultured rings depends on loss of noradrenaline uptake. Rings cultured for 7 days in the presence of 0.1 μm 17β‐oestradiol developed a more pronounced supersensitivity to noradrenaline (EC50 for noradrenaline was 0.13±0.03 μm in steroid exposed rings vs. 0.38±0.09 μm in control rings). Thus, prolonged treatment with 17β‐oestradiol results in a potentiation of noradrenaline evoked force, in contrast to the acute effect of the steroid.
Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria
Authors: BARENNES H. , PUSSARD E. , MAHAMAN SANI A. , CLAVIER F. , KAHIATANI F. , GRANIC G. , HENZEL D. , RAVINET L. , VERDIER F.
Published: November 2003

1Three groups of seven children aged 2–14 years with acute uncomplicated Plasmodium falciparum malaria received 12.8 mg kg−1 quinine gluconate by the intrarectal route (new cream formulation) or 8 mg kg−1 Quinimax (a Cinchona alkaloid combination) by the intramuscular or intravenous (4 h infusion) route every 8 h for 3 days. Clinical and parasitological status was similar in the three groups at enrolment.

2At 36 h, body temperature of all children of the three groups was returned to normal and remained so until day 7.

3The decrease in parasitaemia did not differ between the three groups and the time required for a 50% fall in parasitaemia relative to baseline was 12.3±5.4, 18.2±6.1 and 14.5±4.2 h in the intrarectal, intramuscular and intravenous treatment groups, respectively. Parasitaemia expressed as a percentage of initial values was not significantly different in the three groups after 48 h of treatment (7.4±16.0, 4.1±4.2 and 2.2±3.8% in the intrarectal, intramuscular and intravenous treatment groups, respectively). All the patients were aparasitaemic by day 7.

4The tolerability of the three treatments was good; in particular, no rectal irritation was reported with the cream formulation.

5The tmax occurred later after intrarectal (4.1±2.4 h) and intravenous infusion (3.8±0.5 h) than after intramuscular injection (1.6±1.3 h) (P=0.02). Cmax was lower with the intrarectal (3.0±1.0 mg l−1) and intramuscular routes (3.2±0.7 mg l−1) than with the intravenous route (5.1±1.4 mg l−1) (P=0.003). Areas under the curve (AUC(0, 8 h)) were smaller with the intrarectal (17.0±7 mg l−1 h) and intramuscular routes (19.4±4.8 mg l−1 h) than with the intravenous route (27.8±8.2 mg l−1 h) (P=0.02). The approximate bioavailability of intrarectal quinine from 0 to 8 h was 36%vs intravenous quinine and 51%vs intramuscular quinine.

6The good tolerability and efficacy of this new intrarectal quinine formulation outweigh its low approximate bioavailability. This new approach might thus be a safe and effective alternative to intramuscular quinine injection for the treatment of children with acute uncomplicated Plasmodium falciparum malaria in the field.
The antiemetic efficacy of tropisetron plus dexamethasone as compared with conventional metoclopramide‐dexamethasone combination in Orientals receiving cisplatin chemotherapy: a randomized crossover trial
Authors: CHUA D. T. T. , SHAM J. S. T. , AU G. K. H. , CHOY D. , KWONG D. L. W. , YAU C. C. , CHENG A. C. K.
Published: November 2003

1We report a single‐blind randomized crossover trial comparing the efficacy of tropisetron plus dexamethasone (TROPDEX) vs conventional combination of metoclopramide, dexamethasone and diphenhydramine (METDEX) in prevention of acute and delayed vomiting in Chinese patients receiving high dose cisplatin.

2Thirty‐six consecutive patients with nasopharyngeal carcinoma were entered into the study, all received cisplatin at a dose range of 60–100 mg/m2. Patients were randomized in the sequence of antiemetic regimens used in two consecutive cycles.

3The TROPDEX regimen consisting of tropisetron 5 mg i.v. and dexamethasone 20 mg i.v. given on day 1 of chemotherapy, followed by oral maintenance with tropisetron 5 mg daily and dexamethasone 4 mg twice daily from day 2 to 6. The METDEX regimen consisting of metoclopramide 1 mg kg−1 i.v., dexamethasone 20 mg i.v. and diphenhydramine 25 mg i.v. given before chemotherapy and then 2 hourly for two more doses on day 1, followed by oral metoclopramide 20 mg 6 hourly from day 2 to 6.

4Complete control of acute vomiting was observed in 64% of patients with TROPDEX as compared with 14% with METDEX (P<0.01). While complete plus major control of acute vomiting was observed in 84% with TROPDEX as compared with 58% with METDEX. The mean vomiting episodes on day 1 were 1.4 with TROPDEX as compared with 3.5 with METDEX (P<0.01). There was, however, no significant difference between the two regimens in the control of delayed vomiting.

5When patients randomized to TROPDEX in the second cycle were compared with those with TROPDEX in the first cycle, the antiemetic efficacy was reduced, with mean acute vomiting episodes of 2 in the former compared with 0.8 in the latter (P<0.01).

6The most common adverse effect observed was headache in TROPDEX (27%) and dizziness in METDEX (40%).

7In conclusion, the antiemetic regimen TROPDEX is effective in Chinese patients receiving high dose cisplatin chemotherapy and is well tolerated. It is better than conventional METDEX regimen in the control of acute vomiting, but not in the control of delayed vomiting.
Haemodynamic effects of molsidomine and propranolol in patients with cirrhosis
Authors: COMBIS JEAN‐MARC , VINEL JEAN‐PIERRE , BADIA PHILIPPE , BARANGE KARL , PAYEN JEAN‐LOUIS , COMBIS FLORENCE , DESMORAT HERVÉ , PASCAL JEAN‐PIERRE
Published: November 2003

Propranolol and molsidomine have both been shown to decrease the hepatic venous pressure gradient in patients with cirrhosis. The present study aimed at assessing the effects of the combination of these two drugs on splanchnic and systemic haemodynamics of cirrhotic patients. Fifteen patients with biopsy proven alcoholic cirrhosis had haemodynamic measurements under basal conditions, 60 min after oral administration of 4 mg molsidomine then 15 min after intravenous administration of 15 mg propranolol. As compared with baseline values, molsidomine was found to decrease mean arterial pressure (−7.9%, P<0.01), cardiac output (−7.3%, P<0.01), pulmonary wedged pressure (−45.8%, P<0.05) and hepatic venous pressure gradient (−11.7%, P<0.01). Propranolol decreased heart rate (−21%, P<0.01), further decreased cardiac output (−20.6%, P<0.01) and hepatic venous pressure gradient (−10.5%, P<0.01). As a whole, molsidomine plus propranolol decreased mean arterial pressure (−8%, P<0.01), heart rate (−19%, P<0.01), cardiac output (−26.5%, P<0.01) and hepatic venous pressure gradient (−21%, P<0.01). Pulmonary wedged pressure, liver blood flow and hepatic intrinsic clearance of indocyanine green were not significantly changed by the association of molsidomine and propranolol. We conclude that in patients with cirrhosis, molsidomine and propranolol potentiate their effects on hepatic venous pressure gradient. Such a combination could therefore prove useful in the treatment of portal hypertension.
Pharmacokinetics of butorphanol nasal spray in patients with renal impairment
Authors: SHYU W. C. , MORGENTHIEN E. A. , BARBHAIYA R. H.
Published: November 2003

1The pharmacokinetics of butorphanol were evaluated in 18 female volunteers with varying degrees of renal function following a single, 1 mg transnasal dose of butorphanol tartrate. The creatinine clearance (CLCR) values for subjects in the normal (NOR), moderately impaired (MI), and severely impaired (SI) groups were ≥70 ml min−1, 30–60 ml min−1, and ≤30 ml min−1, respectively.

2Serial blood and urine samples were collected immediately after dosing for 48 h. Plasma concentrations of butorphanol were determined using a specific radioimmunoassay. Urine concentrations of butorphanol and its metabolites (hydroxy‐butorphanol, norbutorphanol and their glucuronide conjugates) were determined using h.p.l.c. with fluorescence detection.

3There was no significant difference between the three treatments for peak plasma concentration of butorphanol and time to peak. Statistically significant differences were detected among the study groups for AUC, t1/2, MRT, and CLR with the mean values for severely impaired subjects significantly different from those of normal renal subjects; mean values for moderately impaired subjects were not significantly different from either the normal or severely impaired groups for all respective parameters.

4The elimination half‐life of butorphanol increased from 5.75 h in NOR to 10.48 h in SI. A similar trend was observed for MRT. Creatinine clearance (CLCR) significantly correlated with CLR (r=0.563, P=0.019), CLT/F (r=0.505, P=0.033), t1/2 (r=−0.554, P=0.017) and λ (r=0.606, P=0.008).

5Although the exposure of butorphanol was greater in subjects with renal impairment, there was no trend for an increase in the number of adverse experiences reported by subjects with renal dysfunction.

6Patients with less than 30 ml min−1 creatinine clearance may require less frequent administration of transnasal butorphanol as compared with subjects with normal or moderately impaired renal function.
Warfarin and aspirin as thromboprophylaxis in atrial fibrillation
Authors: LIP G. Y. H. , LOWE G. D. O.
Published: November 2003

1Anticoagulant therapy with warfarin is now established as effective thromboprophylaxis against stroke in atrial fibrillation, in high‐risk persons. Aspirin is indicated in moderate‐risk persons or if warfarin is contraindicated.

2Risk stratification is suggested, using clinical factors supplemented by echocardiography, to aid choice of prophylaxis.

3Further studies are required to establish how best to identify undiagnosed patients who have atrial fibrillation; to develop new therapeutic strategies; and to refine risk stratification to define which patients with atrial fibrillation are at the highest risk of stroke.
A comparison of the effects of fluvastatin and bezafibrate on exercise metabolism: a placebo‐controlled study in healthy normolipidaemic subjects
Authors: EAGLES C. J. , KENDALL M. J. , MAXWELL S.
Published: November 2003

1We have examined the interaction between aerobic exercise and lipid‐lowering drugs in a crossover study of 16 healthy normolipidaemic volunteers who each received 21 days' treatment with bezafibrate (400 mg), fluvastatin (40 mg), and placebo, in random order.

2Fluvastatin treatment reduced pre‐exercise total cholesterol (TC) by 23% (P <0.0001), low‐density lipoprotein cholesterol (LDL‐C) by 33% (P<0.0001), and plasma triglycerides by 11%, compared with pre‐treatment values. Bezafibrate reduced TC by 11% (P<0.01); LDL‐C by 9%; and plasma triglycerides by 40% (P<0.01), compared with pre‐treatment values.

3During exercise, in comparison with placebo, and fluvastatin treatment, respectively, bezafibrate significantly reduced mean fat oxidation: 31%vs 39%, P=0.035, 31%vs 39%, P=0.002, plasma free fatty acid (FFA) availability, e.g. after 90 min of exercise: (t90) 520 vs 662 μmol l−1, P=0.054, 520 vs 725 μmol l−1, P=0.016, and plasma levels of glycerol (t90): 59 vs 74 μmol l−1, P=0.037, 59 vs 73 μmol l−1, P=0.016. Fluvastatin had no impact on fat metabolism in comparison with placebo.

4Reduced plasma FFA concentration and lower fat oxidation during prolonged exercise on bezafibrate treatment may be due to an inhibition of hepatic acetyl coenzyme A carboxylase, resulting in reduced FFA release from adipose tissue.

5The possibility that impaired fat metabolism on fibrates could induce premature fatigue during exercise of moderate duration and intensity should be examined in hyperlipidaemic patients.
Rebuilding confidence in oral contraceptives: a new imperative in family planning
Authors: SPITZER WALTER O.
Published: November 2003

On December 14, 1995, the first public presentation of results of the Transnational Case‐Control Study of Oral Contraceptives and the Health of Young Women was made at the winter meeting of the British Pharmacological Society at Brighton. Four weeks later, those results and further analyses were published in the British Medical Journal. There has been much debate about them in Europe and elsewhere. I feel privileged to have been invited to write a Leading Article about the safety of combined oral contraceptives in the British Journal of Clinical Pharmacology. These are personal opinions about the meaning of all the recent pharmacoepidemiological findings. With an historical context as the background I have added my personal reflections as a scientist and a public health doctor. These views do not necessarily reflect the views of my co‐investigators.
Effect of food on the comparative pharmacokinetics of modified‐release morphine tablet formulations: Oramorph SR and MST Continus
Authors: DRAKE J. , KIRKPATRICK C. T. , ALIYAR C. A. , CRAWFORD F. E. , GIBSON P. , HORTH C. E.
Published: November 2003

The relative bioavailability and pharmacokinetic profiles of Oramorph SR (OSR) and MST Continus (MST), were evaluated by a randomized, four‐way cross‐over study in 24 healthy, male volunteers given single oral (30 mg) doses whilst fasting or after a high‐fat breakfast. Mean Cmax, tmax, AUC(0,24h), AUC and tlag were significantly greater in fed compared with fasting subjects. Overall relative bioavailability of the two formulations (log AUC), was within the acceptable 80–125% limits for bioequivalence both fed and fasting. Mean fasting Cmax for OSR was greater than MST (P<0.05) but there was no difference between formulations in mean fed Cmax. No statistically significant difference between OSR and MST was found for other parameters nor in the incidence of adverse events. These results suggest that OSR and MST are bioequivalent and that if patients were to transfer between formulations, dosage adjustment would be unnecessary, irrespective of their meal schedules or food intake.
Effects of exogenous female sex‐steroid hormones on lymphocyte β2‐adrenoceptors in normal females
Authors: TAN K. S. , McFARLANE L. C. , COUTIE W. J. , LIPWORTH B. J.
Published: November 2003

We have previously shown that lymphocyte β2‐adrenoceptors (AR) are under cyclical control of sex‐steroid hormones with greater receptor density during the luteal phase of the menstrual cycle. It has also been postulated that abnormal cyclical regulation of β2‐AR might be a possible mechanism for premenstrual asthma. The effects of exogenous female sex‐steroid hormones on lymphocyte β2‐AR function were studied in eight normal healthy females. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1–6). They were randomized to receive single oral doses of either ethinyloestradiol 50 μg or medroxyprogesterone 10 mg in a cross‐over study. Lymphocyte β2‐AR parameters were evaluated at baseline (t0), 24 h (t24) and 72 h (t72) after ingestion. Baseline levels of progesterone and oestradiol were comparable on both cycles. Receptor density (Bmax) increased significantly (P<0.01) from t0 after progesterone but not oestradiol at t24: a 1.39‐fold geometric mean difference (95% CI 0.96–2.00) between t24vs t0. Receptor affinity (Kd) and maximal cAMP response to isoprenaline (Emax) were not altered by either treatment. These results show that exogenous progesterone but not oestradiol, given during the follicular phase, significantly increased β2‐AR. This, therefore, suggests that endogenous progesterone is probably responsible for previously observed increase in Bmax during the luteal phase of the female menstrual cycle. These findings may suggest possible therapeutic strategies for modulation of β2‐AR in premenstrual asthma.