bluuebunny/crossref_metadata_2025 huggingface dataset:
An efficacy and safety analysis of Exelon® in Alzheimer’s disease patients with concurrent vascular risk factors
Authors: Kumar V. , Anand R. , Messina J. , Hartman R. , Veach J.
Published: March 2003

We evaluated the efficacy and safety of the centrally acting cholinesterase inhibitor, rivastigmine tartrate, for patients with mild to moderately severe Alzheimer’s disease (AD) with or without concurrent vascular risk factors (VRF). Patients (45–90 years of age) were randomized to placebo (n = 235), low‐dose rivastigmine (1–4 mg/day, n = 233), or high‐dose rivastigmine (6–12 mg/day, n = 231) for 26 weeks. Efficacy measures included the Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog), the Clinician’s Interview Based Impression of Change (CIBIC‐Plus), the Progressive Deterioration Scale (PDS), the Global Deterioration Scale (GDS), and the Mini‐Mental State Examination (MMSE). For efficacy and safety analysis, patients were categorized by baseline Modified Hachinski Ischemic Score (MHIS) for the determination of VRF (MHIS > 0: presence of VRF; MHIS = 0: absence of VRF). As early as 12 weeks, the mean change from the baseline ADAS‐Cog score was significantly different for those patients treated with high‐dose rivastigmine compared with placebo controls in both MHIS categories. However, the treatment difference between high‐dose rivastigmine and placebo at each time‐point was larger for patients with MHIS > 0. The proportion of responders was significantly greater in the high‐dose rivastigmine group for each level of improvement. No differences were noted between treatment groups regarding safety evaluations. Rivastigmine is effective in both categories of patients, and those with VRF experience greater clinical benefit (cognition, activities of daily living, and disease severity).
Paroxysmal dystonia induced by exercise and acetazolamide
Authors: Guimarães J. , Vale Santos J.
Published: March 2003

We report a case of a 40‐year‐old woman with dystonic attacks precipitated by slight exercise. Episodes lasted 2–5 min and were not precipitated by sudden movements or by being startled, drinking alcohol, coffee or tea, or by stress. Secondary dystonia was ruled out and brain magnetic resonance imaging (MRI) was unremarkable. Routine and video electroencephalogram (EEG) during and between attacks were normal. Acetazolamide greatly worsened her condition, whereas gabapentin [1‐(aminomethyl) cyclohexaneacetic acid] treatment markedly reduced the frequency and severity of the episodes.
Are periodic leg movements during sleep (PLMS) responsible for sleep disruption in insomnia patients?
Authors: Karadeniz D. , Ondze B. , Besset A. , Billiard M.
Published: March 2003

On the basis of polygraphic findings, it has been suggested that periodic leg movements during sleep are not responsible for sleep impairment (Lugaresi et al., 1972). However, for some authors it is an important cause of insomnia (Guilleminault et al., 1975; Coleman, 1982). Thus, the relationship between periodic leg movements during sleep, sleep disruption and the complaint of patients is particularly complex. We investigated the macro‐ and micro‐structure of sleep with and without leg movements in 10 PLMS patients complaining of insomnia to clarify whether periodic leg movements are responsible for sleep disruption. The total sleep time without periodic leg movements was significantly longer than sleep time with leg movements. Sleep time without leg movements was longer than sleep time with leg movements in stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Short lasting awakenings were significantly more frequent during periodic leg movements associated sleep whilst long lasting awakenings were equally frequent during sleep with and without periodic leg movements. The percentage of the four electroencephalogram (EEG) activities (delta, theta, alpha and spindles) did not show any significant difference between periodic leg movements associated and not associated with sleep stages and total sleep time. The lack of significant differences in both the macro‐ and micro‐structure of sleep and EEG activity content regarding the association with movements confirm the hypothesis that periodic leg movements did not primarily cause sleep disturbance.
Weekday distribution of alcohol consumption in Norway: influence on the occurrence of epileptic seizures and stroke?
Authors: Bråthen G. , Brodtkorb E. , Sand T. , Helde G. , Bovim G.
Published: March 2003

Binge drinking at weekends is considered to be a predominant feature of alcohol consumption in the Nordic countries. Neurological diseases, such as seizures and stroke, have been reported to occur in temporal relation to alcohol intoxication and withdrawal. We wanted to investigate weekday variances in alcohol consumption in relation to the onset of neurological symptoms in these disorders.

Consecutive patients admitted for epileptic seizures (n = 142) and ischemic strokes (n = 91) were included in the study. Control groups were consecutively hospitalized sciatica patients (n = 181), outpatients with epilepsy (n = 91), and healthy subjects (n = 254). The day‐by‐day alcohol intake during the 8 days prior to hospital admission was recorded. Seizures occurring in subjects with hazardous alcohol consumption, operationally defined by a score ≥8 in the Alcohol Use Disorders Identification Test (AUDIT‐positive) were considered to be related to alcohol use. Binge drinkers were identified by an alcohol intake, on at least 1 of the last 3 days, of ≥6 standard units in men, or ≥4 standard units in women.

Thirty‐five percent of seizure patients were AUDIT‐positive, in contrast to 18% and 16% of stroke and sciatica patients, and 12% and 13% of epilepsy outpatients and healthy controls. Twenty‐three percent of seizure patients were binge drinkers whereas in the other groups, this proportion did not exceed 10%. In all groups, alcohol consumption peaked on Saturdays. More seizures occurred on Mondays compared to Saturdays, with a diminishing trend through the week. However, AUDIT‐negative seizure patients, of which binge drinking occurred in only 5%, caused this difference. AUDIT‐positive seizure patients had a higher and more evenly distributed alcohol intake through the week, and the occurrence of seizures in this group did not differ significantly between days of the week. Alcohol consumption peaked 2 days prior to the onset of withdrawal seizures.

The weekend drinking pattern was confirmed for all the study groups. Hazardous alcohol consumption preceded every third acute seizure, but was found in only one of eight outpatients with epilepsy. AUDIT‐negative patients caused a peak of seizure admissions on Mondays, compared to Saturdays, with a diminishing trend through the week.
Single event multilevel botulinum toxin type A treatment and surgery: similarities and differences
Authors: Molenaers G. , Desloovere K. , De Cat J. , Jonkers I. , De Borre L. , Pauwels P. , Nijs J. , Fabry G. , De Cock P.
Published: March 2003

The present study attempts to provide objective evidence of two treatment options for children with cerebral palsy (CP): multilevel botulinum toxin type A (BTX‐A) injections and multilevel surgery. The purpose of the study was to clarify the differences and the similarities, and common treatment principles of both treatment strategies. Objective three dimensional gait analysis data were studied retrospectively in two patient groups pre‐ and post‐treatment (randomly selected from a group of children that were treated between 1998 and 1999). In the first group, 29 children with CP were managed with BTX‐A injections according to an integrated multilevel approach (Molenaers et al., 1999a). A second group of 23 children with CP were managed by a more traditional single event multilevel surgery, also according to an integrated approach. Our aim was to evaluate the differences as well as the similarities between both patient groups, using a set of 56 parameters selected from three‐dimensional gait analysis. The unifying concept between management with BTX‐A injections and orthopaedic surgery was the adoption of a multilevel approach at one session. The groups demonstrated considerable differences with respect to age, pretreatment condition and amount and level of improvement after treatment. The children who received BTX‐A were typically younger, and showed primary gait problems in the distal joints, whereas the children who underwent surgery demonstrated a higher frequency of gait deviations in the transverse plane and had more complications. Although the benefit of both treatments was confirmed by the present study, a difference in the amount and level of improvement was also demonstrated. In conclusion, these treatment modalities should be regarded as complementary rather than mutually exclusive treatments, with both calling for an integrated approach.
Atypical neurological involvement associated with celiac disease
Authors: Hanagasi H. A. , Gürol E. , Sahin H. A. , Emre M.
Published: March 2003

We report an unusual case of celiac disease in a 31‐year‐old woman with gait disorder, stimulus‐induced myoclonus and abnormalities of eye movement. We suggest that celiac disease can present with a variety of unusual neurological manifestations.
Marchiafava–Bignami disease: two cases with favourable outcome
Authors: Helenius J. , Tatlisumak T. , Soinne L. , Valanne L. , Kaste M.
Published: March 2003

Marchiafava–Bignami disease (MBD) is a rare disorder of an unknown aetiology but strongly associated with alcoholism. MBD primarily affects the corpus callosum leading to confusion, dysarthria, seizures and frequently to death. Over 250 cases from all races and from almost all nationalities have been reported, most cases being alcoholics. We report two cases with a favourable outcome. Magnetic resonance imaging (MRI) demonstrated a typical lesion of the corpus callosum, in both patients. The patients, a 44‐year‐old male and a 40‐year‐old female, presented with depressed consciousness and a variety of other symptoms, but finally made a reasonably good recovery leading to home discharge. To the best of our knowledge, only one additional case of MBD from Scandinavia has been published. As alcoholism is a major public health problem in Scandinavia, we assume that MBD is underdiagnosed and/or under‐reported. Non‐specific general symptoms and encephalopathy in an alcoholic may harbour undiagnosed MBD. We suggest that the incidence of MBD may be higher and its prognosis may be milder than generally believed.
Idiopathic normal‐pressure hydrocephalus: evaluation and findings in a multidisciplinary memory clinic
Authors: Bech‐Azeddine R. , Waldemar G. , Knudsen G. M. , Høgh P. , Bruhn P. , Wildschiødtz G. , Gjerris F. , Paulson O. B. , Juhler M.
Published: March 2003

The diagnostic evaluation of patients with possible idiopathic normal‐pressure hydrocephalus (INPH) is traditionally performed in the settings of either neurological, neurosurgical or psychiatric departments. The diagnostic procedure and findings in 71 consecutive patients referred with a clinical and radiological suspicion of INPH to our out‐patient multidisciplinary memory clinic are evaluated. Primary diagnoses and potential concomitant disorders considered of secondary importance for the symptomatologies were established. Abnormal hydrodynamics, demonstrated by intraventricular pressure monitoring and infusion test were mandatory for the diagnosis of INPH. Mean age was 68 years and mean Mini‐Mental State Examination (MMSE) score was 22. DSM IV criteria of dementia were fulfilled in 42%. In half of the referred patients (n=36), the suspicion of INPH was already disproved subsequently to the evaluation programme performed in the outpatient clinic. The main primary diagnosis was cerebrovascular disease (CVD) comprising 27% (n=19) of the referrals, whereas INPH was diagnosed in only 20% (n=14). Shunt improvement rate was 72%. The remaining patients were diagnosed as having one of 26 different conditions. A multiplicity of disorders mimics the INPH syndrome, with CVD being the primary differential diagnosis. Evaluating patients with possible INPH in an outpatient multidisciplinary memory clinic is an effective and rational diagnostic approach.
EFNS Task Force on Teaching of Neuroimaging in Neurology Curricula in Europe: present status and recommendations for the future
Authors: Pantano P. , Chollet F. , Paulson O. , Von Kummer R. , Laihinen A. , Leenders K. , Yancheva S.
Published: March 2003

A Task Force on ‘Teaching of Neuroimaging in Neurology Curricula in Europe’ was appointed in September 1998 by the education committee of the European Federation of Neurological Societies (EFNS) in order to: (1) examine the present status of teaching of neuroimaging in the training of neurology in European countries, and, in particular, to assess the strengths and weaknesses of the various countries; (2) give recommendations for global improvement and harmonization of such training.

A questionnaire was completed in February 1999 and sent to 35 delegates of national neurological societies. Completed questionnaires were received from 21 countries: Albania, Austria, Croatia, Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Hungary, Israel, Italy, Netherlands, Norway, Poland, Portugal, Slovakia, Spain, Switzerland, Turkey and UK.

The questionnaire revealed that the situation in Europe is highly heterogeneous, both as regards the training in neurology in general and, more specifically, the teaching of neuroimaging during the training.

Some recommendations to make the teaching of neuroimaging more homogeneous across European countries and to improve it are provided.
Cerebral vasculitis and ischaemic stroke in Behçet’s disease: report of one case and review of the literature
Authors: Krespi Y. , Akman‐Demir G. , Poyraz M. , Tugcu B. , Coban O. , Tuncay R. , Serdaroglu P. , Bahar S.
Published: March 2003

Introduction. Behçet’s disease (BD) is a multisystemic, recurrent, inflammatory disorder. Neurological involvement is well‐known but cerebral vasculitis and ischaemic stroke are unusual.

Case description. A 43‐year‐old male patient presented with acute left hemiparesis, he had recurrent oral aphthae and scrotal ulcerations. Two episodes of transient brainstem ischaemia and an episode of right hemiparesis were reported in the past 2 years. Cranial magnetic resonance (MR) imaging showed a right striatocapsular infarction and multiple segmental stenosis, fusiform enlargement and beading of the arteries of the polygone of Willis were seen on angiography. Cerebro‐spinal fluid (CSF) examination disclosed lymphocytic pleocytosis. Skin pathergy test was positive. A diagnosis of BD with cerebral vasculitis was made and immunosuppressive therapy was started. Some improvement of the arterial lesions on MR angiography and normalization of CSF were observed after 1 year of treatment.

Discussion. Low grade chronic meningo‐encephalitis is the core neuropathological process in neuro‐Behçet’s disease. Nevertheless BD is a systemic disease known to cause vasculitis and can exceptionally lead to cerebral vasculitis and brain infarction. While BD is usually not part of the differential diagnosis of cerebral vasculitis, it should be borne in mind especially in endemic areas of the disease and in patients from these areas.
Lower limb nerve impairment in diabetic patients: multiperspective assessment
Authors: Padua L. , Saponara C. , Ghirlanda G. , Padua R. , Aprile I. , Caliandro P. , Tonali P.
Published: March 2003

To assess the relationship between patient’s perception of his own inferior limbs symptom and function and the clinical‐neurophysiological assessment in patients affected by insulin‐dependent diabetes mellitus (IDDM).

We studied 50 consecutive outpatients affected by IDDM (23 men, 27 women). We used validated measurements clinical [Semmes–Weinstein (SW), vibration perception threshold (VPT), muscle strength, osteotendineous reflexes, etc.], neurophysiological (sural, peroneal nerves), metabolic and patient‐oriented [North American Spine Society (NASS) questionnaire].

Patient‐oriented scores were significantly related with neurophysiological findings of the inferior limbs.

Our data suggest that electrodiagnostic tests are useful to assess the severity of the diabetic polyneuropathy not only because they provide a biological measurement of the nerve function but also because they appeared related to the patient’s quality of life related to the peripheral nerve involvement.
Decrease in heart ventricular ejection fraction during multiple sclerosis
Authors: Olindo S. , Guillon B. , Helias J. , Phillibert B. , Magne C. , Fève J. R.
Published: March 2003

Recent studies have shown that mitoxantrone is effective in patients with active multiple sclerosis (MS) and that cardiac monitoring is usually required. However, right and left ventricular ejection fractions (VEFs) have never been studied in MS patients as compared with control subjects. Radionuclide angiocardiography (RA) was performed to assess right and left VEFs at rest in 40 consecutive patients with active definite MS [15 men and 25 women; mean age 33.9 ± 10 years; mean disease duration 8 ± 6.5 years; 18 had relapsing–remitting and 22 had secondary progressive forms of the disease; mean Expanded Disability Status Scale (EDSS) score 4.8 ± 1.9]. The control group consisted of 40 subjects free of neurological or cardiovascular disease (17 men and 23 women; 44.6 ± 13.4 years of age). The VEF values obtained in the control group defined the normal limits (right VEF 32–54%; left VEF 50–74%). A statistically significant decrease of right (P=0.02) and left (P < 0.0001) VEFs was found in MS patients as compared with control subjects. RA showed pathological results for right (7.5%), left (10%) and both (7.5%) VEFs in 25% of MS patients. No correlation was found between VEF and sex, age, disease duration, disease course, EDSS score or previous treatment. Autonomic impairment, which frequently occurs in MS patients, may have accounted for the decrease in VEFs. Further physiological studies are required to determine factor responsible for the decrease of VEFs in MS.
EFNS Guidelines on cognitive rehabilitation: report of an EFNS Task Force
Authors: Cappa S. F. , Benke T. , Clarke S. , Rossi B. , Stemmer B. , Van Heugten C. M.
Published: March 2003

In 1999, a Task Force was set up under the auspices of the European Federation of Neurological Societies with the aim to evaluate the existing evidence for the clinical effectiveness of cognitive rehabilitation. This review led to the development of a set of guidelines to be used in the management of adult patients with cognitive disorders due to acquired focal neurological damage.
Towards the creative management of risk: perceptions, practices and policies
Authors: Alaszewski Andy , Alaszewski Helen
Published: March 2003

The present paper examines the importance of risk when supporting individuals with learning disabilities. It uses data from a small research project designed to examine the perceptions of risk held by users, carers and professionals, as well as the risk policies of agencies. Risk is an important issue in the provision of support. The service users in the present study saw risk primarily in terms of hazards. The carers were concerned about hazards and harm, but recognized the need for risk‐taking. The professionals emphasized the importance of reasonable risk‐taking. Agencies also recognized the importance of risk management, and most had or were developing risk policies. However, most of these policies are based on a restricted approach to risk which emphasizes hazard assessment, and health and safety issues. There was limited evidence of broader integrated approaches to risk management which had the capacity to link and balance safety and empowerment.
Fluid trapping at the brittle–ductile transition re‐examined
Authors: Simpson F.
Published: March 2003

The brittle–ductile transition has been suggested to provide a mechanical trap to deep crustal fluids. The mechanism was advanced as a way of reconciling the geophysical case for a wet lower crust, founded on the revelation of deep crustal electrical conductors and seismic reflectors, with the problem of maintaining interconnected, low‐density fluids in stable crust for geologically significant timescales. Although some deep crustal conductors are now attributed to graphite, the hypothesis of fluid trapping at the brittle–ductile transition has been widely adopted in electromagnetic literature, with no regard to tectonic regime, and in association with standardized temperatures of 300–450°C. Meanwhile, petrologists continue to argue that the lower crust is dry.

This paper re‐examines the arguments on which the hypothesis of fluid trapping at the brittle–ductile transition has been founded, and concludes that there is a geophysical case for a dry lower crust based on electromagnetic studies. The magnetotelluric (MT) technique yields electrical conductances (conductivity–thickness products) that are direction dependent (or anisotropic). The necessity of considering direction‐dependent conductances, rather than a bulk conductance, is demonstrated using data from Saxothuringia, Germany. A quantitative model is developed to facilitate joint interpretation of the maximum conductance and the anisotropy of conductance (ratio of maximum to minimum conductance). The model yields quantitative arguments against fluids being the principal cause of deep crustal electrical conductivity, because unreasonably thick layers and unreasonably high porosities are required.
Cookbooks as a social and historical document. A Scottish case study
Authors: Mitchell Janet
Published: March 2003

Cookbooks are not only instructional manuals for the culinary arts and repositories for traditional dishes, they also reflect food habits of a population, act as historical markers of major events, and record technological advances in a society. Evidence of this was gathered from Scottish cookbooks, published between 1890 and 1990, listed in the catalogue of printed books in the National Library of Scotland. Textual analysis of the cookbooks included an examination of their authors, audience, and contents. The results validated the claim that a cookbook can be regarded as a socio‐historic and cultural document.
Food services trends in New South Wales hospitals, 1993–2001
Authors: Mibey Redemptor , Williams Peter
Published: March 2003

A survey of the food service departments in 93 hospitals throughout NSW Australia (covering 51% of hospital beds in the state) was conducted using a mailed questionnaire and the results compared with those from similar surveys conducted in 1986 and 1993. Over the past eight years there has been a significant increase in the proportion of hospitals using cook‐chill food service production systems, from 18% in 1993 to 42% in 2001 (P < 0.001). Hospitals with cook‐chill systems had better staff ratios than those with cook‐fresh systems (8.3 vs. 6.4 beds/full time equivalent staff; p < 0.05), but there was no significant difference in the ratio of meals served per FTE. There was no difference between public and private hospitals in terms of ratios of beds or meals to food service staff. Managers using cook‐chill systems reported significantly lower levels of satisfaction with the food service system compared to those using cook‐fresh. Two aspects of the services have not changed since the last survey: approximately a quarter of food service departments are still managed by staff without formal qualifications and meal times remain the same, with more than 90% of hospitals serving the evening meal before 5.30 p.m. and a median of 14.25 h gap between the evening meal and breakfast.
Distribution patterns of biodiversity and the design of a representative reserve network in Portugal
Authors: Araújo Miguel B.
Published: March 2003

Representativeness is a desirable property of conservation networks. In this paper an attempt is made to assess the efficiency of current conservation networks in Portugal in representing vertebrates (reptiles and amphibians) and plants (gymnosperms, pteridophytes and bryophytes). It was found that whilst the protected areas do not sample all species in the database they provide a better result than choosing areas at random. For the goal of maximizing representation of taxa per unit area hotspots and complementarity performed better. A pattern of over‐representation of vertebrates in relation to lower plants was discovered among selected conservation areas in Portugal suggesting that charismatic organisms with large home ranges may not always be the most appropriate surrogates for biodiversity when representativeness is sought. When trying to fill the gaps in current protected areas with additional areas only complementarity performed better than choosing areas at random. Both rarity and richness hotspots gave worse results. Opportunistic administrative criteria such as supplementing the PAS with other conservation areas (CORINE Biotopes) without taking into account their contribution to a representation goal was nearly half as good as choosing areas at random. The results recall for the need of explicit goals and accountable methods in area selection for conservation and reinforce the role of complementarity for finding additional areas to protected areas when limited resources are available for ‘in situ’ conservation.
Monitoring temporal changes in the spatial patterns of a Mediterranean shrubland using Landsat™ images
Authors: Viedma O. , Meliá J.
Published: March 2003

The overall goal of this study is to understand the structure and function of a Mediterranean shrubland at landscape scale by means of satellite images and GIS. Specifically, to assess the sensitivity of several spatial statistics to characterise landscape pattern, measure fragmentation and quantify the change through time. We study the landscape structure of a Mediterranean shrubland located in the east part of Spain (Valencia) and the change in spatial patterns of different shrubs types from 1984 to 1994. To accomplish these objectives, we used 10 Landsat™ images from 1984 to 1994 (except 1988) to which a geometric correction and an atmospheric normalization was applied. In addition, a Digital Terrain Model (DTM) of 10×10 m resolution, which was resampled to 30×30 m to make possible the comparison with the satellite images, was used to extract the topographic information. Firstly, the landscape was divided into a set of units based on their different spatial patterns of shrub‐type distribution on topography. The elaboration of ‘landscape units’ involved a quantitative description of each topographic gradient derived from a D™ as a function of their vegetation composition. The results obtained differentiated clearly among areas showing different vegetation developments under diverse environmental conditions in which differences in solar radiation (aspect), availability of soil nutrients (slope) and humidity (elevation) were very important. These environmental constraints exert a strong and persistent effect on vegetation composition and strengthen the association between current vegetation and site variables. Finally, we analysed the multitemporal behaviour of those landscape units in which the species and communities were adapted to biotic and abiotic environmental changes (rainfalls and phenological dates).
Compost heaps — refuges and stepping‐stones for alien arthropod species in northern Europe
Authors: Ødegaard Frode , Tømmerås Bjørn Åge
Published: March 2003

Abstract.  Compost heaps house a species‐rich fauna of arthropods. This survey reviews changes in the composition of the beetle fauna in compost heaps in the Nordic countries during the 20th century. A total of 34 alien beetle species have established in compost heaps; 12 of these are also established in natural habitats. A combination of long‐distance human transport and short‐distance natural spread are proposed as dominant factors, explaining the dispersal of the species. An eastern route of immigration is proposed for Baeocrara japonica, Lithocharis nigriceps, Bohemiella paradoxa, Acrotona pseudotenera and Oxytelus migrator, while a southern route of immigration is proposed for Perigona nigriceps, Acrotona parens, Falagrioma concinna, Trichiusa immigrata, Cartodere nodifer, Ahasverus advena, Oryctes nasicornis and Atheta triangulum. There is no relationship between the types of compost preferred by the different species and the dominant way of dispersal. Among the trophic guilds that species belong to, the predators are more dependent on human transport than natural dispersal. The trophic guild to which a species belongs has no effect on whether or not the species is established away from compost heaps. The generalized compost fauna and species associated with bark compost naturalize away from compost heaps more successfully than expected. It is hypothesized that the successful establishment of alien species in compost habitats results from increased frequency of introductions and warm, thermal stability in large compost heaps during the Nordic winter. The establishment of new species in compost habitats probably has a minor impact on native inhabitants.
Diazepam enhances etoposide‐induced cytotoxicity in U‐87 MG human glioma cell line
Authors: Lavička Juraj , Šarišský Marek , Miroššay Andrej , Šulla Igor , Mojziš Ján , Mirossay Ladislav
Published: March 2003

Various approaches might be employed in an effort to increase efficacy of the chemotherapeutic treatment of cancer. Recently, various modulators of anticancer therapy effectiveness have been studied. Antiproliferative effects of peripheral benzodiazepine receptor (PBR) ligands might be exploited to enhance cytotoxic effect of a chemotherapeutic drug towards cancer cells.

In this work, we sought to enhance cytotoxic effect of etoposide (VP‐16) by a PBR ligand, diazepam (DZ) in U‐87 MG human glioma cells. Cytotoxicity of VP‐16, DZ and their combinations was assessed by using the microculture MTT assay. Cell survival, effective concentrations (EC) and the onset of cytotoxic effect were determined.

After 72 h of cultivation, survival of U‐87 MG cells was reduced to 57 ± 7% in the presence of VP‐16 at 12.5 μg/mL alone, whereas DZ at 10–4 mol/L alone caused 28 ± 6% reduction in cell survival. Coincubation of VP‐16 at 12.5 μg/mL with DZ at 10–4 mol/L led to a further decrease in cell survival to 45 ± 6%. Furthermore, DZ at 10–4 mol/L significantly decreased effective concentrations, EC10, EC30 and EC50, of VP‐16 and the dose–response curves were shifted to the left. Addition of DZ at 10–4 mol/L to VP‐16 also facilitated the onset of its cytotoxic effect. The same decrease in survival was thus achieved approximately 30 h earlier in comparison with VP‐16 alone. However, DZ at 10–9 mol/L failed both to exert any effect on glioma cells survival and enhance cytotoxic effect of VP‐16.

DZ at 10–4 mol/L was capable of both reducing U‐87 MG glioma cells survival when applied alone and also enhancing the cytotoxic effect of VP‐16. No such observation was made for the lower concentrations of DZ. Potential implementation of diazepam in the antiglioma/anticancer armamentarium awaits further experimentation but phase I and phase II clinical trials could be suggested.
Deleterious effects of nifedipine on smooth muscle cells implies alterations of intracellular calcium signaling
Authors: Raicu Monica , Florea Stela
Published: March 2003

Nifedipine (NIF), a calcium channel blocker (CCB) from the first generation of dihydropyridines, induces detrimental effects on patients with cardiovascular diseases. We designed experiments to study, at cellular and molecular level, the mechanisms involved in the induction of deleterious effects by this drug. To this purpose, cultured human smooth muscle cells (HSMC) were used. The effect of NIF and two other CCB (FEL, AML) and inhibitors of intracellular signaling pathways (RR, TG, CAF and GEN) on intracellular calcium [Ca2+]I was determined by spectrofluorimetry using Fura 2 AM assay. The results showed that: (i) 10 μM NIF induced the increase of [Ca2+]I above the basal values (202.77 ± 23.98 nM vs. 48.68 ± 6.45 nM), an effect that was prevented by RR (50.45 ± 13.9 nM) and was not induced by the two other CCB; (ii) NIF had a thapsigargin‐like effect, because it induced the same release of intracellular calcium as TG (212.1 ± 25.62 nM); (iii) The response to NIF was reduced by 40% after the inhibition of IP3 receptor (121.21 ± 26.01 nM) and by 50% after the inhibition of tyrosine kinase (101.91 ± 7.76 nM). Together, these data demonstrate that NIF produces a deregulation of intracellular calcium homeostasis. The abnormal increase of [Ca2+]I is due to the activation of store operated channels from the plasma membrane responsible for capacitative calcium entry, a process modulated by the activity of tyrosine kinase and the Ca2+‐ATPase pump from the sarcoplasmic reticulum.
5‐fluorocytosine‐related bone‐marrow depression and conversion to fluorouracil: a pilot study
Authors: Vermes András , Guchelaar Henk‐Jan , Van Kuilenburg Andre B.P. , Dankert Jacob
Published: March 2003

The aim of this study is to investigate whether fluorouracil (5‐FU) could be responsible for bone‐marrow depression occurring in fluorocytosine (5‐FC) treated patients. Six 5‐FC treated patients were included in this pilot study. Toxicity was monitored by means of thrombocyte and leucocyte counts. 5‐FC and 5‐FU serum levels were measured using a high‐performance liquid chromatography (HPLC) assay that allows simultaneous determination of both compounds.

The amounts of 5‐FU in the 34 available serum samples remained below the limit of quantitation (< 0.05 mg/L), whereas 5‐FC levels could be detected in all samples. Instead, low levels of the 5‐FU catabolite α‐fluoro‐β‐alanine (FBAL) were detected in several of the investigated serum samples. In case of three patients thrombocyte counts remained within the normal range during 5‐FC treatment, whereas one patient developed thrombocytopenia (50 × 109 thrombocytes/L) during therapy. Furthermore, one patient developed leucocytopenia (2.6 × 109 leucocytes/L) during 5‐FC therapy, whereas the remaining five patients were suffering from leucocytosis prior to 5‐FC therapy.

In conclusion, we found nondetectable 5‐FU serum concentrations (< 0.05 mg/L) in ICU patients treated with intravenous 5‐FC, making it unlikely that 5‐FC‐associated toxicity results from 5‐FU exposure in patients receiving intravenous 5‐FC therapy. These findings may be explained by the fact that our patients received 5‐FC intravenously instead of orally, therefore not allowing active conversion of 5‐FC to 5‐FU by the human intestinal microflora.
Interaction of chelerythrine with inositol phosphate metabolism
Authors: Le Corvoisier Philippe , Lacotte Jérôme , Laplace Monique , Crozatier Bertrand
Published: March 2003

Chelerythrine, a potent inhibitor of protein kinase C (PKC), was evaluated for its effect on inositol phosphate (IP) metabolism in newborn rat cardiomyocytes in culture. In a first step, we evaluated the effect of chelerythrine on IP accumulation in basal conditions. For a 10–4 M dose, 5‐phosphatase activity (which dephosphorylates IP3 into IP2) was completely blocked and we observed a large increase in IP accumulation limited to IP2 without any increase in IP3, strongly suggesting that chelerythrine at this dose modifies IP metabolism. At a lower dose (10–5 M) of chelerythrine, which did not modify IP accumulation and 5‐phosphatase activity in basal conditions, the response to angiotensin II stimulation was completely abolished by the addition of chelerythrine. We conclude thus that chelerythrine, even at 10–5 M, interacts markedly with IP metabolism, and caution should be exerted when interpreting the results obtained with this drug, which is still currently used at this dose.
Enhanced efficacy of porcine lung surfactant extract by utilization of its aqueous swelling dynamics
Authors: Larsson Marcus , Haitsma Jack J. , Lachmann Burkhard , Larsson Kåre , Nylander Tommy , Wollmer Per
Published: March 2003

This study investigates the interactions between a porcine lung surfactant (PLS) extract and distilled water, saline solution or Ringer solution. The phases which coexist in equilibrium with water or electrolyte solutions were analysed by X‐ray diffraction and cryo transmission electron microscopy (cryo‐TEM). A lamellar phase with a structure unit consisting of double bilayers was observed in water, whereas lamellar phases with the usual bilayer structure unit were formed in saline and in Ringer solutions. At 25°C the presence of a 4·2‐A˚ peak in the X‐ray diffraction wide‐angle region of these three maximally swollen phases showed that most of the hydrocarbon chains were organized in a crystalline packing. At 42°C the chains in all three phases were melted which, in combination with the low‐angle diffraction, shows that they were liquid‐crystalline. Polyhedral‐like vesicles and spherically shaped multilamellar vesicles were observed in cryo‐TEM. The bilayer unit structures were consistent with the periodicity seen by X‐ray diffraction. The dynamic swelling behaviour was followed in the polarizing microscope. A remarkable growth of birefringent networks was seen at the air interface of samples swollen in Ringer solution and saline solution. No such interfacial growth phenomena were observed during swelling in water without electrolytes. Then, these dynamics were analysed in relation to time‐dependent pulmonary administration of the surfactant extract in rats. Variation in the time of administration (20 and 60 min) after mixing the extract with saline or Ringer solution showed clear differences in physiological effects. At pulmonary administration when the swelling behaviour in vitro showed a maximum in dynamics, the arterial oxygenation was superior to that of administration at a time after a steady‐state had been reached. This means that the clinical performance of mammalian lung surfactant extracts can be significantly improved by taking the time‐dependent aqueous swelling of the extract into account.
Absorption across the nasal airway mucosa in house dust mite perennial allergic rhinitis
Authors: Greiff Lennart , Andersson Morgan , Svensson Jenny , Wollmer Per , Lundin Stefan , Persson Carl G. A.
Published: March 2003

House dust mite allergens express protease activity and it has been suggested that this property has pathogenic effects by increasing airway absorption. In accordance, house dust mite allergens may increase mucosal permeability in vitro. The objective of the present study was to examine nasal absorption of desmopressin (1‐deamino‐8‐D‐arginine vasopressin) in patients with perennial house dust mite allergic rhinitis and in healthy subjects in vivo. Patients with perennial allergic rhinitis were examined after a 4‐week treatment withdrawal period, when symptoms of allergic rhinitis occurred, and healthy subjects were examined together with the patients. Desmopressin (20 μg ml–1) was moved into the nasal cavity using a nasal pool‐device that contained 15 ml fluid. The fluid was kept in the nasal cavity for 15 min and then recovered. Urine was collected for 24 h after the nasal administration and the urinary excretion of desmopressin was determined as an index of nasal absorption. The urinary excretion of desmopressin was 1148 ± 535 pmol 24 h–1 in patients with perennial house dust mite allergic rhinitis and 1012 ± 291 pmol 24 h–1 in healthy subjects. We conclude that nasal airway absorption of the 1067 Da peptide desmopressin is unaffected in perennial house dust mite allergic rhinitis compared with healthy subjects.
Pulse pressure in tests improves the prediction of left ventricular mass: 10 years of follow‐up
Authors: Jokiniitty J. , Majahalme S. , Kähönen M. , Tuomisto M. T. , Turjanmaa V.
Published: March 2003

Literature does not agree with the usefulness of exercise blood pressure (BP) in predicting hypertension or target organ damage. In this prospective 10 years of follow‐up, we evaluated if exaggerated BP responses to tests may improve the prediction of left ventricular mass index (LVMI). At baseline, BP was recorded by casual measurements, and during tests using intra‐arterial monitoring. The subjects were 97 healthy, untreated 35‐ to 45‐year‐old‐men (34 normotensive, 29 borderline hypertensive, and 34 mild hypertensive). At 10‐year follow‐up, echocardiography was performed to 86 (89%) of them. Subjects not taking antihypertensive medication (n = 66) were included in the prediction of LVMI(g m–2). Echocardiography data at baseline was available from 70 (72%) of the subjects, of whom 52 did not use antihypertensive medication at follow‐up. Pulse pressure (PP) at supine test (r = 0·337, P = 0·006), PP at dynamic exercise last work load (r = 0·332, P = 0·006), and PP after dynamic exercise (r = 0·316, P = 0·010) were the best BP variables achieved in tests in predicting future LVMI of the 66 subjects. Casual BP did not significantly correlate with future LVMI. The best model in predicting LVMI included PP achieved after dynamic exercise, family history of hypertension, and body mass index (BMI) (adj.R2 = 0·207). Baseline LVMI correlated significantly with future LVMI only among the 52 unmedicated subjects (r = 0·508, P<0·0001). The predictive value of baseline LVMI on future LVMI among them (adj.R2 = 0·243) was best improved by PP achieved in supine test and age (adj.R2 = 0·350). In conclusion, BP measurements during tests improved the prediction of LVMI compared with casual BP. For the first time, the pulsatile component of BP in tests was found to be the most significant BP parameter in predicting future LVMI.
A single‐blind placebo‐controlled investigation into the analgesic effects of interferential currents on experimentally induced ischaemic pain in healthy subjects
Authors: Johnson Mark I. , Tabasam Ghazala
Published: March 2003

The aim of this single‐blind placebo‐controlled study was to examine the analgesic effects of interferential currents (IFC) on experimentally induced ischaemic pain. Ischaemic pain was induced using the submaximal effort tourniquet technique (SETT) and pain intensity was recorded using a visual analogue scale at 1‐min intervals was used as the primary outcome measure. Following baseline recordings 30 healthy volunteers received either active IFC, sham IFC, or no treatment (10 subjects per group). Data were analysed by calculating the mean change in pain intensity at each 1‐min interval by subtracting data during treatment from the baseline data. IFC was administered throughout the duration of the ischaemic pain test via four electrodes (quadripolar application) on the forearm. Active IFC delivered electrical currents at a `strong but comfortable' intensity. A `dummy' stimulator that delivered no current was used as sham IFC. Subjects in the no treatment control group were informed that the IFC device was not switched on. There were significant effects for Groups (P=0·04) which were attributed to a significant reduction in pain intensity for the IFC group when compared with sham and no‐treatment control (P≤0·05). There were no significant effects for Time (P=0·69) or Group–Time interaction (P=0·45). In conclusion, IFC produced significantly greater analgesia than sham and no‐treatment control groups under the present experimental conditions.
Intracellular free calcium in the neutrophils of maintenance haemodialysis patients
Authors: Koorts A. M. , Kruger M. C. , Potgieter C. D. , Viljoen M.
Published: March 2003

Chronic renal failure has on occasion been referred to as a state of calcium toxicity. The aim of this study was to investigate the status of intracellular free Ca2+ in the neutrophils of chronic renal failure patients on maintenance haemodialysis treatment. Factors previously suggested to influence intracellular free Ca2+ were investigated including PTH levels, oxidative stress and recombinant human erythropoietin administration. The study involved 14 chronic renal failure patients on the haemodialysis programme of the Pretoria Academic hospital. Intracellular free Ca2+ and transmembrane Ca2+ fluxes were investigated by fluorescence spectrophotometry. Increases above control values were found in intracellular free Ca2+ (P‐value 0·0242) and in the transmembrane Ca2+ flux upon fMLP stimulation (P‐value 0·0002). The results showed significant differences in intracellular free Ca2+ between patients on rHuEPO and patients not on rHuEPO. The apparently rHuEPO‐induced increase in intracellular free Ca2+ persisted in the presence of calcium channel blockers. No overt indications of oxidative stress could be detected by the antioxidant vitamin levels. It is concluded that factors other than those associated with uraemia, such as rHuEPO administration, might contribute to the often reported increase in intracellular free Ca2+ in these patients. Further studies to investigate the relationship between intracellular free Ca2+, rHuEPO and calcium channel blockers are suggested.
Reproducibility of air plethysmography for the evaluation of arterial and venous function of the lower leg
Authors: Yang Danian , Sacco Paul
Published: March 2003

This study assessed the test–retest reliability of air plethysmographic parameters for the evaluation of arterial and venous function of the lower extremity in normal, healthy adults. Fourteen voluntary subjects underwent air plethysmographic tests on two occasions, 1–2 weeks apart, with three tests being performed at each visit. Test–retest reliability was assessed via correlation coefficients and the intraclass correlations. Differences in the parameters of arterial inflow (AI), venous volume (VV), venous refilling time (VFT), venous refilling index (VFI), ejection volume (EV) and residual fraction (EF) obtained on the two separate occasions were small (r = 0·81 ∼ 0·95; ICC = 0·94 ∼ 0·99), whereas differences in ejection fraction (EF), residual volume (RV) and venous outflow (OF) measurements were much larger (r = 0·50 ∼ 0·61; ICC = 0·58 ∼ 0·95). The findings demonstrate that evaluation of blood flow in the lower limbs of healthy individuals using air plethysmography is reliable in test–retest measures, suggesting that this technique represents a sensitive method for quantifying changes in parameters of arterial and venous functions of the lower extremity.
Analysis of endothelium‐dependent vasodilation by use of the radial artery pulse wave obtained by applanation tonometry
Authors: Lind Lars , Pettersson Knut , Johansson Kristina
Published: March 2003

Objectives: To evaluate applanation tonometry as a method to obtain arterial pulse waves suitable for pulse wave analysis of the height of the diastolic inflection point (IP), and to use this technique to study endothelium‐mediated vasodilation by evaluation of the contribution of nitric oxide (NO) to the reduction in the height of the IP induced by β2‐adrenergic stimulation.

Methods: The radial artery pulse waveform was recorded by applanation tonometry in young healthy subjects before and after interventions both locally in the forearm and systemically by different vasodilators and vasoconstrictors, and vasodilatation was analysed as a change in the height of the IP. The mechanism behind the reduction in the height of the IP induced by terbutaline was investigated by systemic interventions with both N(G)‐monomethyl‐l‐arginine (l‐NMMA) and noradrenaline (NA).

Results: Applanation tonometry was a convenient method to obtain radial artery pulse waves of good quality. The reduction in IP was substantially more pronounced when vasodilators were given systemically than when given locally in the forearm, indicating that the effect was obtained through an effect on peripheral pulse wave reflection. Systemically given l‐NMMA, but not NA, increased the IP (P<0·05). Systemically given l‐NMMA also caused a more pronounced attenuation than NA of the reduction in IP following terbutaline injection (P<0·05).

Conclusion: Changes in IP following β2‐adrenergic stimulation appears to be a measurement of pulse wave reflection mainly governed by NO. Applanation tonometry and pulse wave analysis is a minimally invasive method suitable to assess endothelium‐dependent vasodilation in large‐scale studies.