Showing papers by "Radboud University Nijmegen published in 1997"

The stress response in fish

Abstract: The stress response in teleost fish shows many similarities to that of the terrestrial vertebrates These concern the principal messengers of the brain-sympathetic-chromaffin cell axis (equivalent of the brain-sympathetic-adrenal medulla axis) and the brain-pituitary-interrenal axis (equivalent of the brain-pituitary-adrenal axis), as well as their functions, involving stimulation of oxygen uptake and transfer, mobilization of energy substrates, reallocation of energy away from growth and reproduction, and mainly suppressive effects on immune functions There is also growing evidence for intensive interaction between the neuroendocrine system and the immune system in fish Conspicuous differences, however, are present, and these are primarily related to the aquatic environment of fishes For example, stressors increase the permeability of the surface epithelia, including the gills, to water and ions, and thus induce systemic hydromineral disturbances High circulating catecholamine levels as well as structural damage to the gills and perhaps the skin are prime causal factors This is associated with increased cellular turnover in these organs In fish, cortisol combines glucocorticoid and mineralocorticoid actions, with the latter being essential for the restoration of hydromineral homeostasis, in concert with hormones such as prolactin (in freshwater) and growth hormone (in seawater) Toxic stressors are part of the stress literature in fish more so than in mammals This is mainly related to the fact that fish are exposed to aquatic pollutants via the extensive and delicate respiratory surface of the gills and, in seawater, also via drinking The high bioavailability of many chemicals in water is an additional factor Together with the variety of highly sensitive perceptive mechanisms in the integument, this may explain why so many pollutants evoke an integrated stress response in fish in addition to their toxic effects at the cell and tissue levels Exposure to chemicals may also directly compromise the stress response by interfering with specific neuroendocrine control mechanisms Because hydromineral disturbance is inherent to stress in fish, external factors such as water pH, mineral composition, and ionic calcium levels have a significant impact on stressor intensity Although the species studied comprise a small and nonrepresentative sample of the almost 20,000 known teleost species, there are many indications that the stress response is variable and flexible in fish, in line with the great diversity of adaptations that enable these animals to live in a large variety of aquatic habitats

Subtilases: the superfamily of subtilisin-like serine proteases.

Abstract: Subtilases are members of the clan (or superfamily) of subtilisin-like serine proteases. Over 200 subtilases are presently known, more than 170 of which with their complete amino acid sequence. In this update of our previous overview (Siezen RJ, de Vos WM, Leunissen JAM, Dijkstra BW, 1991, Protein Eng 4:719-731), details of more than 100 new subtilases discovered in the past five years are summarized, and amino acid sequences of their catalytic domains are compared in a multiple sequence alignment. Based on sequence homology, a subdivision into six families is proposed. Highly conserved residues of the catalytic domain are identified, as are large or unusual deletions and insertions. Predictions have been updated for Ca(2+)-binding sites, disulfide bonds, and substrate specificity, based on both sequence alignment and three-dimensional homology modeling.

Habit, information acquisition, and the process of making travel mode choices

Abstract: Three studies examined the role of habit on information acquisition concerning travel mode choices. On the basis of Triandis’ (1980) model of attitude‐behaviour relations it was expected that habit strength attenuates the elaborateness of choice processes. The studies focused on different phases in the choice process, namely the appreciation of situational cues and appreciation of choice option information. In line with expectations, it was found that, compared to weak habit participants, those who had a strong habit towards choosing a particular travel mode acquired less information and gave evidence of less elaborate choice strategies. It was attempted to break effects of habit by manipulating either accountability demands or level of attention. Although accountability demands raised the level of information acquisition, no interactions with habit were found. Enhanced attention to the choice process initially did override habit effects in a series of choice trials. However, in spite of this manipulation, chronic habit effects emerged during later trials. The results demonstrate the profound effects that habit may have on the appreciation of information about choice situations and choice options. #1997 John Wiley & Sons, Ltd.

Personal paper: Beliefs and evidence in changing clinical practice

Abstract: That improvements are possible in many areas of clinical care has become increasingly clear. The different players within health care, however—clinicians, epidemiologists, health services researchers, educationalists, social scientists, economists, health authorities—often have different ideas on the best strategies to improve practice and the best way of making changes. Let us assume that aggregated data, collected by health authorities, disclose that the rate of caesarean section in a specific district is exceptionally high. A committee is formed with experts and representatives of various interests to develop plans for improving obstetric care. Hearing the problem, all are worried. The clinician either denies there is a problem or proposes setting up a well designed course to increase clinicians' knowledge and skills. “OK,” says the clinical epidemiologist, “but we first need to know what the evidence is on the indications for a caesarean section. We should perform a meta-analysis and come up with evidence based guidelines to disseminate among the obstetricians.” “No,” says the educational expert: “that is a top down approach and such strategies will usually fail. Form small groups of doctors and let them discuss the problem, using cases and experiences from their own practices as the basis for local arrangements on new routines.” “We should take a look at the facts first,” says the health services researcher. “Let us set up a multicentre audit first and collect data on actual variation between hospitals and include data on casemix. Feeding this information back to the hospitals will probably stimulate improvement.” “You are all focusing too much on the individual doctor,” says the management expert. “The problem is not the doctor, but the system. We should analyse the process of decision making and performing the caesarean sections and see what structures determine the process. Next we need a quality improvement team.” “This is …

Germline Mutations in the PTEN/MMAC1 Gene in Patients With Cowden Disease

Abstract: Cowden disease, also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome with a high risk of breast and thyroid cancer. The gene involved has been localized to chromosome 10q22-23. Recently, the tumour suppressor gene PTEN/MMAC1, encoding a putative protein tyrosine or dual-specificity phosphatase, was cloned from that region and three mutations were detected in patients with Cowden disease. We confirmed that the PTEN/MMAC1 gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN/MMAC1 gene and, by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various regions of the PTEN/MMAC1 gene. One mutation was detected twice. All detected changes in the gene can be predicted to have a very deleterious effect on the putative protein. Five of the nine patients have a mutation in exon 5 coding for the putative active site and flanking amino acids. Evaluation of the clinical data of the patients in which a mutation could be detected gives no clear indications for a correlation between the genotype and phenotype. In 10 patients no mutation could be detected so far. In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogeneity.

The prevalence of mental retardation: a critical review of recent literature.

Abstract: Mental retardation (AIR) is a serious and lifelong disability that places heavy demands on society and the health system. Since the first publication on this topic',theprevalenceofMR has been thoroughly studied for different purposes. Most prevalence studies are designed for the planning of services and establish an 'ascertained' prevalence rate, which is the number of cases officially recorded by the authorities'.The 'true'prevalence rate is the total number of mentally retarded people in a population, whether or not they require services,and is defined by the prevalence of MR a t birth and the mortality rate.For mild mental retardation (MWR, I& 50-70) ' the true prevalence rate is more difficult to estimate than for severe mental retardation (SMR, IQ <50).Very often ascertained prevalence rates are mistaken for true prevalence rates. Moreover, the estimates of both rates are influenced by the design of the study, the assessment criteria used, and the method applied for the identification of case^^-^. As a result, differences in prevalence rates might partly reflect the true variation over populations and partly reveal discrepancies between studies and in the interpretation of the prevalence measure used. For instance, different frequencies are yielded by uses of the organic, psychological and social WHO criteria, which are reflected in impairment, disability and handicaps. The prevalence rates observed range from two to 85 per 1000. According to the WHO, the true prevalence rate of total MR in industrialised countries comes close to 3%\".O, but in the United States controversy exists over whether the rate is 1% versus 3%5.7.'0.1', whereas the Scandinavian countries claim that the 1 % figure is their true pre~alence~. '~ . '~ . ' The aim ofthis annotation is to establish valid estimates of the true prevalence rates for SMR and AIMR in children of school age and to elucidate the variation in prevalence rates. Therefore the methodology of prevalence studies performed since 1960 was critically evaluated and a distinction was made between ascertained and true prevalence estimates.

Of flying frogs and levitrons

Abstract: Diamagnetic objects are repelled by magnetic fields. If the fields are strong enough, this repulsion can balance gravity, and objects levitated in this way can be held in stable equilibrium, apparently violating Earnshaw's theorem. In fact Earnshaw's theorem does not apply to induced magnetism, and it is possible for the total energy (gravitational+magnetic) to possess a minimum. General stability conditions are derived, and it is shown that stable zones always exist on the axis of a field with rotational symmetry, and include the inflection point of the magnitude of the field. For the field inside a solenoid, the zone is calculated in detail; if the solenoid is long, the zone is centred on the top end, and its vertical extent is about half the radius of the solenoid. The theory explains recent experiments by Geimet al, in which a variety of objects (one of which was a living frog) was levitated in a field of about 16 T. Similar ideas explain the stability of a spinning magnet (Levitron TM ) above a magnetized base plate. Stable levitation

Age and ultimate attainment in the pronunciation of a foreign language

Abstract: This paper reports on two studies that addressed the issue of ultimate attainment by late second language learners. The aim of the studies, which included a carefully screened group of highly successful Dutch learners of English in their designs, was to determine whether or not late second language learners who had achieved a nativelike performance in the pronunciation of a second language could be identified. Speech samples provided by two groups of learners, one of which consisted of highly successful learners only, and a native speaker control group were rated for accent by native speakers of English. The ratings obtained by some learners were within the range of the ratings assigned to the native speaker controls. Such results suggest that it is not impossible to achieve an authentic, nativelike pronunciation of a second language after a specified biological period of time. Examination of the learning histories of the highly successful learners lead the authors to argue that certain learner characteristics and learning contexts may work together to override the disadvantages of a late start.

BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients

Abstract: To date, more than 300 distinct small deletions, insertions and point mutations, mostly leading to premature termination of translation, have been reported in the breast/ovarian-cancer susceptibility gene BRCA1. The elevated frequencies of some mutations in certain ethnic subpopulations are caused by founder effects, rather than by mutation hotspots. Here we report that the currently available mutation spectrum of BRCA1 has been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PTT) and direct sequencing, using genomic DNA as template. Three large genomic deletions that are not detected by these approaches comprise 36% of all BRCA1 mutations found in Dutch breast-cancer families to date. A 510-bp Alu- mediated deletion comprising exon 22 was found in 8 of 170 breast-cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counselling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 6 of the 170 research families, while an deletion of approximately 14 kb was detected in a single family. Haplotype analyses indicated that each recurrent deletion had a single common ancestor.

A Critical Examination of the Demand-Control-Support Model from a Work Psychological Perspective

Abstract: The most striking development in modern work organizations is the changing nature of work itself and its increased mental and emotional workload. Since the early sixties, many attempts have been made to gain more insight into the particular relationship between work-related psychosocial risks and employee health by means of theoretical models. One of these models is the Demand-Control-Support (DCS) Model. The DCS Model distinguishes itself from other work stress models by its simplicity and the extent to which it has gained a paradigmatic function in research in the field of work and health. The aim of the current paper is to examine its theoretical and empirical status from a work psychological perspective. Studies into the DCS Model can roughly be divided into (1) epidemiological studies, (2) cross-sectional, homogenous, or heterogenous studies, (3) psychophysiological studies, and (4) intervention studies. It is concluded that (1) epidemiological studies offer the most support for the DCS Model, (2) its interaction hypothesis is not often supported, and (3) examples of carefully examined evaluations of interventions are rather scarce. Furthermore, nine critical comments on the model are discussed. In conclusion, although there are various relevant comments on the model, the core structure of the model still holds. Directions for future research are depicted.

Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22

Abstract: Opitz syndrome (OS) is an inherited disorder characterized by midline defects including hypertelorism, hypospadias, lip-palate-laryngotracheal clefts and imperforate anus. We have identified a new gene on Xp22f MIDI (Midline 1), which is disrupted in an OS patient carrying an X-chromosome inversion and is also mutated in several OS families. MID1 encodes a member of the B-box family of proteins, which contain protein–protein interaction domains, including a RING finger, and are implicated in fundamental processes such as body axis patterning and control of cell proliferation. The association of MID1 with OS suggests an important role for this gene in midline development.

Interplay between the magnetic and transport properties in the III-V diluted magnetic semiconductor Ga1-xMnxAs

Abstract: Using a low-temperature molecular-beam epitaxy growth procedure, ${\mathrm{Ga}}_{1\ensuremath{-}x}{\mathrm{Mn}}_{x}\mathrm{As}$ --- a III-V diluted magnetic semiconductor --- is obtained with Mn concentrations up to $x\ensuremath{\sim}9%.$ At a critical temperature ${T}_{c}$ (${T}_{c}\ensuremath{\approx}50\mathrm{K}$ for $x=0.03--0.05$), a paramagnetic to ferromagnetic phase transition occurs as the result of the interaction between $\mathrm{M}\mathrm{n}\ensuremath{-}h$ complexes. Hole transport in these compounds is strongly affected by the antiferromagnetic exchange interaction between holes and Mn $3d$ spins. A model for the transport behavior both above and below ${T}_{c}$ is given. Above ${T}_{c},$ all materials exhibit transport behavior which is characteristic for systems near the metal-insulator transition. Below ${T}_{c},$ due to the rising spontaneous magnetization, spin-disorder scattering decreases and the relative position of the Fermi level towards the mobility edge changes. When the magnetization has reached its saturation value (below $\ensuremath{\sim}10\mathrm{K}$) variable-range hopping is the main conduction mechanism. The negative magnetoresistance is the result of the expansion of the hole wave functions in an applied magnetic field.

From Complex Organizations with Simple Jobs to Simple Organizations with Complex Jobs

Abstract: Organization redesign has become widely acceptedas a regular task for management, recently invigoratedby the interest in Business Process Reengineering. Inspite of that, it is still a neglected area in organization science. This paper emphasizesthe importance of design theory and design-orientedresearch. The potential role of design theory isexemplified by the description of IntegralOrganizational Renewal (IOR), a design theory grounded inpractical experience in the Netherlands. This approachcan be viewed as a Dutch variant of SociotechnicalSystems Design. The essence of this approach lies in the transformation of complex organizationsoffering simple jobs into simple organizations offeringcomplex jobs. IOR can both be regarded as an expertapproach and as a route for self-design. The approach enables the members of the organization todevelop and use their own design expertise. IOR istherefore not only a strategy for organization design,but for organization development as well. The paperpoints to opportunities to make organization researchmore relevant to organization practice.

Phase transitions in individual sub-micrometre superconductors

Abstract: The properties of a superconductor are expected to change radically when its size becomes comparable to that of the Cooper pairs, the quasiparticles responsible for superconductivity. The effect of such confinement is well understood for the case of thesuppression of superconductivity by magnetic fields (which gives rise to so-called Little–Parks oscillations of the phase boundary)1,2,3,4. But little is known about what happens in small superconductors in the zero-resistance state, which cannot be probed by resistance measurements. Here we apply a new technique of ballistic Hall magnetometry5 to study the magnetization of individual superconducting discs of diameters down to 100 nm. The superconducting state of these discs is found to be qualitatively different from both macroscopic and microscopic6 superconductors, with numerous phase transitions whose character changes rapidly with size and temperature. This exotic behaviour is due to size quantization of the Cooper-pair motion and resulting transitions between discrete states of the superconducting Bose condensate in a magnetic field.

Endemic African mammals shake the phylogenetic tree

Abstract: The order Insectivora, including living taxa (lipotyphlans) and archaic fossil forms, is central to the question of higher-level relationships among placental mammals1. Beginning with Huxley2, it has been argued that insectivores retain many primitive features and are closer to the ancestral stock of mammals than are other living groups3. Nevertheless, cladistic analysis suggests that living insectivores, at least, are united by derived anatomical features4. Here we analyse DNA sequences from three mitochondrial genes and two nuclear genes to examine relationships of insectivores to other mammals. The representative insectivores are not monophyletic in any of our analyses. Rather, golden moles are included in a clade that contains hyraxes, manatees, elephants, elephant shrews and aardvarks. Members of this group are of presumed African origin5,6. This implies that there was an extensive African radiation from a single common ancestor that gave rise to ecologically divergent adaptive types. 12S ribosomal RNA transversions suggest that the base of this radiation occurred during Africa's window of isolation in the Cretaceous period before land connections were developed with Europe in the early Cenozoic era.

Meta-Analytic Study on Treatment Effectiveness for Problem Behaviors with Individuals Who Have Mental Retardation.

Abstract: Meta-analysis of 482 empirical studies on treatment of problem behaviors of individuals with mental retardation was conducted. A metric of treatment effectiveness was computed for 1,451 comparisons between baselines and treatments, 34 topographies of problem behavior, and 64 treatment procedures. Analysis of variance with percentage of nonoverlapping data as the dependent variable and comparison as the basic unit of analysis revealed that treatment of externally destructive behaviors had significantly lower mean percentage of nonoverlapping data scores than did treatment of socially disruptive and internally maladaptive behaviors. Response contingent procedures were significantly more effective than were other procedures. No significant interactions were found. Results of a stepwise regression showed that only performing a functional analysis made a significant contribution. These results may lead to more objective assignment of treatment procedures to problem behaviors.

National context, parental socialization, and religious belief: results from 15 nations

Abstract: ear regression to control for a nation's level of economic development and exposure to Communism, andfor the individual's denomination, age, gender, and education. We find that (1) people living in religious nations will, in proportion to the religiosity of their fellow-citizens, acquire more orthodox beliefs than otherwise similar people living in secular nations; (2) in relatively secular nations, family religiosity strongly shapes children's religious beliefs, while the influence of national religious context is small; (3) in relatively religious nations family religiosity, although important, has less effect on children's beliefs than does national context. These three patterns hold in rich nations and in poor nations, in formerly Communist nations and in established democracies, and among old and young, men and women, the welleducated and the poorly educated, andfor Catholics and Protestants. Findings on the link between belief and church attendance are inconsistent with the influential "supply-side" analysis of differences between nations. R eligion remains a central element of modern life, shaping people's worldviews, moral standards, family lives, and in many nations, their politics. But in many Western nations, modernization and secularization may be eroding Christian beliefs, with profound consequences that have intrigued sociologists since Durkheim. Yet this much touted secularization may be overstated-certainly it varies widely among nations and is absent in the United States

Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia

Abstract: In this study, Fos immunohistochemistry was used to map brainstem neuronal pathways activated during hypercapnia and hypoxia. Conscious rats were exposed to six different gas mixtures: (a) air ; (b) 8% CO2 in air; (c) 10% CO2 in air; (d) 15% CO2 in air; (e) 15% CO2 + 60% O2, balance N2; (f) 9% O2, balance N2. Double-staining was performed to show the presence of tyrosine hydroxylase. Hypercapnia, in a dose-dependent way, caused Fos expression in the following areas: caudal nucleus tractus solitarius (NTS), with few labeled A2 noradrenergic neurons; noradrenergic A1 cells and noncatecholaminergic neurons in the caudal ventrolateral medulla; raphe magnus and gigantocellular nucleus pars α (GiA); many noncatecholaminergic (and relatively few C1) neurons in the lateral paragigantocellular nucleus (PGCl), and in the retrotrapezoid nucleus (RTN); locus coeruleus (LC), external lateral parabrachial and Kolliker-Fuse nuclei, and A5 noradrenergic neurons at pontine level; and in caudal mesencephalon, the ventrolateral column of the periaqueductal gray (vlPAG). In most of these nuclei, hypoxia also induced Fos expression, albeit generally less than after hypercapnia. However, hypoxia did not cause labeling in RTN, juxtafacial PGCl, GiA, LC, or vlPAG. After normoxic hypercapnia, more labeled cells were present in NTS and PGCl than after hyperoxic hypercapnia. Part of the observed labeling could be caused by stress- or cardiovascular-related sequelae of hypoxia and hypercapnia. Possible implications for the neural control of breathing are also discussed, particularly with regard to the finding that several nuclei, not belonging to the classical brainstem respiratory centres, contained labeled cells. J. Comp. Neurol. 388:169–190, 1997. © 1997 Wiley-Liss, Inc.

Coxsackievirus protein 2B modifies endoplasmic reticulum membrane and plasma membrane permeability and facilitates virus release

Abstract: Digital-imaging microscopy was performed to study the effect of Coxsackie B3 virus infection on the cytosolic free Ca2+ concentration and the Ca2+ content of the endoplasmic reticulum (ER). During the course of infection a gradual increase in the cytosolic free Ca2+ concentration was observed, due to the influx of extracellular Ca2+. The Ca2+ content of the ER decreased in time with kinetics inversely proportional to those of viral protein synthesis. Individual expression of protein 2B was sufficient to induce the influx of extracellular Ca2+ and to release Ca2+ from ER stores. Analysis of mutant 2B proteins showed that both a cationic amphipathic alpha-helix and a second hydrophobic domain in 2B were required for these activities. Consistent with a presumed ability of protein 2B to increase membrane permeability, viruses carrying a mutant 2B protein exhibited a defect in virus release. We propose that 2B gradually enhances membrane permeability, thereby disrupting the intracellular Ca2+ homeostasis and ultimately causing the membrane lesions that allow release of virus progeny.

Is the common 677C→T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis

Abstract: The common 677C-->T mutation (+) in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme, has been associated with spina bifida neural tube defects (NTD). We combined all known Dutch control groups, a total of 1273 individuals, and found a prevalence of the 677C-->T mutation of 8.4%. When compared with the frequencies in 55 SB patients and to mothers with a child with SB their parents, this gave an OR of 1.9 [95% CI 1.1-3.3] for mothers and an OR of 1.5 [95% CI 0.74-3.1] for patients. The frequency of this mutation and its associated risk for NTD may be population-dependent. However, the frequencies of the 677C-->T mutation in different national and international control groups are almost all in the same range. We therefore combined the observed frequencies of the 677C-->T mutation in all reported studies. The mutation was present in 9.2% of controls, resulting in ORs for all reported NTD patients and their parents of: 1.7 [95% CI: 1.1-2.6]; 1.8 [95% CI: 1.1-3.1] and 1.9 [95% CI: 1.3-2.8] for mothers (combined prevalence 14.5%), fathers (combined prevalence 15.5%) and NTD patients (combined prevalence 16.4%), respectively, vs. all international controls. This meta-analysis confirms that the 677C-->T mutation is a genetic risk factor for NTD.

Ammonium toxicity in eelgrass Zostera marina

Abstract: Seagrasses are declining all over the world, resulting in a substantial loss of biodiversity, coastal sediment stabilization and nursery areas of economically important fish. The seagrass decline has often been associated with increasing eutrophication of coastal areas. We tested possible toxic effects of high nitrogen concentrations in the water layer on the seagrass Zostera marina L., which is often the sole higher plant inhabiting coastal zones in the northern hemisphere. Plants grown in either mud or sand were subjected to various water ammonium and nitrate concentrations, whereby ammonium and nitrate supply were balanced (both 25 pM or 75 PM), or unbalanced (ammonium 125 pM and nitrate 25 pM, and vice versa). We used 2 temperatures, 15 and 20°C. Analyses were made after 2 and 5 wk of exposure. In an additional experiment, 9 pM ammonium and 3 yM nitrate were supplied. An ammonium concentration of 125 pM in the water layer was toxic for 2. marina: the plants became necrotic within 2 wk. After 5 wk, plants in all treatments except for the 9 pM treatment were either necrotic or had died. This suggests that toxicity occurs at ammonium concentrations as low as 25 pM. Nitrate treatment had no effect. Ammonium toxicity effects were more pronounced in plants grown on sand and at the higher temperature. It is argued that the ammonium toxicity effects on Z. marina are expected to be strongest in autumn when irradiance decreases, temperature is still high, and ambient ammonium concentrations rise.

Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial.

Abstract: To compare the efficacy of sulphasalazine, methotrexate, and the combination of both in patients with early rheumatoid arthritis (RA), not treated with disease-modifying anti-rheumatic drugs previously, we conducted a double-blind, double-dummy, controlled, clinical trial. One hundred and five patients with active, early RA, rheumatoid factor and/or HLA DR1/4 positive were randomized between sulphasalazine (SSZ) 2000 (maximum 3000) mg daily, or methotrexate (MTX) 7.5 (maximum 15) mg weekly, or the combination (COMBI) of both, and were followed up by a single observer for 52 weeks. The mean change over time per patient, including all visits, in Disease Activity Score (DAS) was: SSZ: -1.6 (95% CI -2.0 to -1.2); MTX: -1.7 (-2.0 to -1.4); COMBI: -1.9 (-2.2 to -1.6); the difference week 0-week 52 (SSZ, MTX, COMBI respectively); DAS: -1.8, -2.0, -2.3, Ritchie articular index: -9.2, -9.5, -10.6, swollen joints: -9.2, -12.4, -14.3, erythrocyte sedimentation rate: -17, -21, -28. Nausea occurred significantly more in the COMBI group. The numbers of drop-outs due to toxicity were SSZ 9, MTX 2, COMBI 5. In conclusion, there were no significant differences in efficacy between combination and single therapy, only a modest trend favouring COMBI. The results of MTX and SSZ were very comparable. Nausea occurred more often in the COMBI group: the number of withdrawals due to adverse events did not differ significantly.

Human eye-head coordination in two dimensions under different sensorimotor conditions.

Abstract: The coordination between eye and head movements during a rapid orienting gaze shift has been investigated mainly when subjects made horizontal movements towards visual targets with the eyes starting at the centre of the orbit. Under these conditions, it is difficult to identify the signals driving the two motor systems, because their initial motor errors are identical and equal to the coordinates of the sensory stimulus (i.e. retinal error). In this paper, we investigate head-free gaze saccades of human subjects towards visual as well as auditory stimuli presented in the two-dimensional frontal plane, under both aligned and unaligned initial fixation conditions. Although the basic patterns for eye and head movements were qualitatively comparable for both stimulus modalities, systematic differences were also obtained under aligned conditions, suggesting a task-dependent movement strategy. Auditory-evoked gaze shifts were endowed with smaller eye-head latency differences, consistently larger head movements and smaller concomitant ocular saccades than visually triggered movements. By testing gaze control for eccentric initial eye positions, we found that the head displacement vector was best related to the initial head motor-error (target-re-head), rather than to the initial gaze error (target-re-eye), regardless of target modality. These findings suggest an independent control of the eye and head motor systems by commands in different frames of reference. However, we also observed a systematic influence of the oculomotor response on the properties of the evoked head movements, indicating a subtle coupling between the two systems. The results are discussed in view of current eye-head coordination models.