[A qualitative study of Falls Efficacy Scale-International/Hips. What do we measure?]. / Een kwalitatieve studie naar de Falls Efficacy Scale-International/Hips. Is meten weten?

OBJECTIVE: Pilot-testing a new instrument: the Falls Efficacy Scale-International/Hips (FES-I/Hips). This instrument is intended to measure 'Fear of Falling' (FoF). To the current instrument, the Falls Efficacy Scale-International, are four questions added for patients who are rehabilitating in a nursing home. It is pretested and used in the HIPS-study. METHODS: Qualitative exploratory study with interviews in a Three Step Test Interview (TSTI) protocol. Respondents (N = 12) were asked to think aloud while completing the questionnaire. RESULTS: The instruction how to complete the questionnaire is well understood by patients but was not properly used by them. The questionnaire contains questions with difficult words and questions which are no longer relevant. There are six "two-in-one questions" that cause confusion. CONCLUSION: Use of the standard instruction when completing the FES-I/Hips can lead to underreporting of FoF. Adaptation of certain items may improve content validity. Further psychometric studies are recommended to determine whether the proposed adjustments are appropriate.

Rationale and design of CAPITA: a RCT of 13-valent conjugated pneumococcal vaccine efficacy among older adults.

The burden of community-acquired pneumonia (CAP) among the elderly is high and has increased over the last decades. Streptococcus pneumoniae is the most common cause of CAP and in 10% the infection may be fatal. Although the 23-valent polysaccharide pneumococcal vaccine (23vPS) is considered effective in the prevention of invasive pneumococcal disease in the elderly population, the evidence is mainly from nonrandomised observational studies and effects on the occurrence of pneumonia have not been demonstrated. Conjugated pneumococcal vaccines which also stimulate T-cell dependent immune responses induced antibody responses in elderly persons which are similar to those induced by a primary series of 7-valent conjugated pneumococcal vaccine (7vPnC) in infants, and the response appeared similar or superior for all vaccine serotypes to that induced by 23vPS. The primary objective of the planned trial entitled CAPITA (Community Acquired Pneumonia Immunization Trial in Adults) is to establish the efficacy of a 13-valent PnC vaccine in the prevention of a first episode of vaccine-serotype specific pneumococcal CAP in 85,000 community-dwelling adult persons aged 65 years and older. This is a parallel group, randomised, placebo-controlled trial, with a 1:1 random allocation to vaccine or placebo vaccine. The occurrence of the primary outcome of vaccine-serotype specific (VT)-CAP will be established in hospitals on the basis of three sets of criteria: (1) a clinical definition of CAP; (2) independent interpretation of chest radiograph consistent with pneumonia: and (3) determination of S. pneumonia serotype. the trial will be critical to determine the position of conjugate pneumococcal vaccines in the prevention of pneumococcal disease.

On the design of national vaccination programmes.

The decision to include a vaccine in a national vaccination programme (or not) is usually evidence-based. Thereby, it is essential that the target disease causes a high burden of disease and that vaccination reduces this burden considerably. Furthermore, vaccination should be considered to be cost-effective by a government. Vaccines are usually administered according to standard vaccination schedules, which have been established on historical grounds. We argue and demonstrate with examples (meningococci C, Haemophilus influenzae, pneumococci and Bordetella pertussis) that adaptation of these standard vaccination schedules can be cost-saving and lead to better protection. To facilitate the improvement of vaccination programmes, a better understanding of protective immune responses (correlates of protection) and immunologic memory are required.

Oculomotor plasticity during vestibular compensation does not depend on cerebellar LTD.

Vestibular paradigms are widely used for investigating mechanisms underlying cerebellar motor learning. These include adaptation of the vestibuloocular reflex (VOR) after visual-vestibular mismatch training and vestibular compensation after unilateral damage to the vestibular apparatus. To date, various studies have shown that VOR adaptation may be supported by long-term depression (LTD) at the parallel fiber to Purkinje cell synapse. Yet it is unknown to what extent vestibular compensation may depend on this cellular process. Here we investigated adaptive gain changes in the VOR and optokinetic reflex during vestibular compensation in transgenic mice in which LTD is specifically blocked in Purkinje cells via expression of a peptide inhibitor of protein kinase C (L7-PKCi mutants). The results demonstrate that neither the strength nor the time course of vestibular compensation are affected by the absence of LTD. In contrast, analysis of vestibular compensation in spontaneous mutants that lack a functional olivo-cerebellar circuit (lurchers) shows that this form of motor learning is severely impaired. We conclude that oculomotor plasticity during vestibular compensation depends critically on intact cerebellar circuitry but not on the occurrence of cerebellar LTD.

Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control.

While firing rate is well established as a relevant parameter for encoding information exchanged between neurons, the significance of other parameters is more conjectural. Here, we show that regularity of neuronal spike activities affects sensorimotor processing in tottering mutants, which suffer from a mutation in P/Q-type voltage-gated calcium channels. While the modulation amplitude of the simple spike firing rate of their floccular Purkinje cells during optokinetic stimulation is indistinguishable from that of wild-types, the regularity of their firing is markedly disrupted. The gain and phase values of tottering's compensatory eye movements are indistinguishable from those of flocculectomized wild-types or from totterings with the flocculus treated with P/Q-type calcium channel blockers. Moreover, normal eye movements can be evoked in tottering when the flocculus is electrically stimulated with regular spike trains mimicking the firing pattern of normal simple spikes. This study demonstrates the importance of regularity of firing in Purkinje cells for neuronal information processing.

Simple spike and complex spike activity of floccular Purkinje cells during the optokinetic reflex in mice lacking cerebellar long-term depression.

Cerebellar long-term depression (LTD) at parallel fibre-Purkinje cell (P-cell) synapses is thought to embody neuronal information storage for motor learning. Transgenic L7-protein kinase C inhibitor (PKCI) mice in which cerebellar LTD is selectively blocked do indeed exhibit impaired adaptation in the vestibulo-ocular reflex (VOR) while their default oculomotor performance is unaffected. Although supportive, these data do not definitively establish a causal link between memory storage required for motor learning and cerebellar LTD. As the L7-PKCI transgene is probably activated from the early stages of P-cell development, an alternative could be that P-cells develop abnormal signals in L7-PKCI mutants, disturbing mechanisms of motor learning that rely on proper P-cell outputs. To test this alternative hypothesis, we studied simple spike (SS) and complex spike (CS) activity of vertical axis P-cells in the flocculus of L7-PKCI mice and their wild-type littermates during sinusoidal optokinetic stimulation. Both SS and CS discharge dynamics appeared to be very similar in wild-type and transgenic P-cells at all stimulus frequencies (0.05-0.8 Hz). The CS activity of all vertical axis cells increased with contralateral stimulus rotation and lagged ipsiversive eye velocity by 165-180 degrees. The SS modulation was roughly reciprocal to the CS modulation and lagged ipsiversive eye velocity by approximately 15 degrees. The baseline SS and CS discharge characteristics were indistinguishable between the two genotypes. We conclude that the impaired VOR learning in L7-PKCI mutants does not reflect fundamental aberrations of the cerebellar circuitry. The data thus strengthen the evidence that cerebellar LTD is implicated in rapid VOR learning but not in the development of normal default response patterns.

Cerebellar LTD facilitates but is not essential for long-term adaptation of the vestibulo-ocular reflex.

The induction of cerebellar long-term depression (LTD) at the parallel fibre-Purkinje cell synapse is selectively blocked in L7-PKCi transgenic mice, rendering these mice unable to adaptively modify their vestibulo-ocular reflex (VOR) during visuo-vestibular training for a few hours. Despite this deficit, their eye movement performance as well as their general motor behaviour appears unaffected. This combination suggests that, in the long term, residual forms of plasticity in the vestibulo-cerebellar circuitry can compensate for the absence of cerebellar LTD. To investigate whether LTD-deficient mice exhibit motor learning in the long run, we subjected L7-PKCi transgenic mice to visuo-vestibular training paradigms that were aimed at either increasing or decreasing the VOR response in the course of eight consecutive days. During the increasing paradigm, the VOR gain of transgenic mice increased significantly, while VOR gain decreased and VOR phase-lead increased during the decreasing paradigm. The impact of these long training periods on the VOR was significantly smaller in LTD-deficient mice than in wild type littermates. Thus, while LTD may be necessary for short-term VOR adaptation, it facilitates but is not required for long-term adaptation of the VOR.

Motor performance and motor learning in Lurcher mice.

In adult Lurcher mice virtually all cerebellar Purkinje cells have degenerated as a direct consequence of mutant gene action, providing a natural model for studying the effect of cerebellar cortical lesions on the generation of compensatory eye movements. Lurcher mice possess both optokinetic (OKR) and vestibular (VOR) compensatory reflexes. However, clear differences were observed in control of the OKR consisting of a large reduction in gain and a moderate increase in phase lag. Minor differences were also observed in the VOR in that gain and phase lead of the reflex were both increased in Lurcher animals. Subjecting Lurcher animals to eight days of visuovestibular training tested the assumption that increased VOR gain reflected an adaptive mechanism within remaining brainstem oculomotor pathways to compensate for the reduced OKR. Contrary to control animals, Lurcher animals were unable to modify either VOR or OKR in the course of training and therefore confirmed that an intact cerebellum is indispensable for the implementation of adaptive modifications to the oculomotor system.

Hereditary familial vestibular degenerative diseases.

Identification of genes involved in hereditary vestibular disease is growing at a remarkable pace. Mutant mouse technology can be an important tool for understanding the biological mechanism of human vestibular diseases.

The dynamic characteristics of the mouse horizontal vestibulo-ocular and optokinetic response.

In the present study the optokinetic reflex, vestibulo-ocular reflex and their interaction were investigated in the mouse, using a modified subconjunctival search coil technique. Gain of the ocular response to sinusoidal optokinetic stimulation was relatively constant for peak velocities lower than 8 degrees /s, ranging from 0.7 to 0.8. Gain decreased proportionally to velocity for faster stimuli. The vestibulo-ocular reflex acted to produce a sinusoidal compensatory eye movement in response to sinusoidal stimuli. The phase of the eye movement with respect to head movement advanced as stimulus frequency decreased, the familiar signature of the torsion pendulum behavior of the semicircular canals. The first-order time constant of the vestibulo-ocular reflex, as measured from the eye velocity decay after a vestibular velocity step, was 660 ms. The response of the vestibulo-ocular reflex changed with stimulus amplitude, having a higher gain and smaller phase lead when stimulus amplitude was increased. As a result of this nonlinear behavior, reflex gain correlated strongly with stimulus acceleration over the 0.1-1.6 Hz frequency range. When whole body rotation was performed in the light the optokinetic and vestibular system combined to generate nearly constant response gain (approximately 0.8) and phase (approximately 0 degrees ) over the tested frequency range of 0.1-1.6 Hz. We conclude that the compensatory eye movements of the mouse are similar to those found in other afoveate mammals, but there are also significant differences, namely shorter apparent time constants of the angular VOR and stronger nonlinearities.

Origin of vestibular dysfunction in Usher syndrome type 1B.

It is still debated to what extent the vestibular deficits in Usher patients are due to either central vestibulocerebellar or peripheral vestibular problems. Here, we determined the origin of the vestibular symptoms in Usher 1B patients by subjecting them to compensatory eye movement tests and by investigating the shaker-1 mouse model, which is known to have the same mutation in the myosin-VIIa gene as Usher 1B patients. We show that myosin-VIIa is not expressed in the human or mouse cerebellum and that the vestibulocerebellum of both Usher 1B patients and shaker-1 mice is functionally intact in that the gain and phase values of their optokinetic reflex are normal. In addition, Usher 1B patients and shaker-1 mice do not show an angular vestibuloocular reflex even though eye movement responses evoked by electrical stimulation of the vestibular nerve appear intact. Finally, we show histological abnormalities in the vestibular hair cells of shaker-1 mice at the ultrastructural level, while the distribution of the primary vestibular afferents and the vestibular brainstem circuitries are unaffected. We conclude that the vestibular dysfunction of Usher 1B patients and shaker-1 mice is peripheral in origin.

A comparison of video and magnetic search coil recordings of mouse eye movements.

Interest in connecting molecular biology and behavior is motivating research into the eye movements of mice. Unfortunately, recording eye movements in this diminutive animal is technically difficult. We present the first method for obtaining calibrated video oculography, and contrast the results with simultaneously obtained scleral search coil recordings in C57BL/6 pigmented mice. We determined the distance of the pupil from the center of corneal curvature, based upon relative motions of the pupil and corneal reflections during camera movements, and used the distance to convert subsequent video measurements of pupil motion to eye rotation. We recorded responses during sinusoidal rotation (0.1-1.6 Hz) in the light, by video prior to search coil implantation, and by video and search coil simultaneously following implantation. Pre-implantation, video-derived gains ranged from 0.86+/-0.03 (mean+/-SD) at 0.1 Hz to 0.95+/-0.03 at 0.8 Hz. Phase progressed monotonically from -3.1+/-2. 6 degrees (eye leads head) at 0.1 Hz to +5.9+/-1.1 degrees at 1.6 Hz. Coil implantation reduced the range of video-derived gains to 0. 64-0.79. This reduction reflects disruption of normal behavior by the coil. Coil data confirmed the video results. Video and search coil techniques each have advantages. Specific precautions are required when designing and interpreting experiments using the coil technique.

The effect of item observability, clarity and wording on patient/nurse ratings when using the ASA scale.

Many studies show discrepancies between patients' and professionals' ratings on the same questionnaire regarding the patient's health. A relevant question is whether the differences in ratings reflect real differences between patients and professionals or whether they are caused by characteristics of the instrument. In this study, we address the latter option by examining the effects of 3 item characteristics (item wording, observability and clarity) on the degree of patient/nurse discrepancies in ratings of the items of the Appraisal of Self-care Agency (ASA) scale. Secondary analysis on 252 patient/nurse ratings showed that item wording (positively and negatively formulated items), and the observability of the items have a significant effect on the mean absolute difference score. No effect was found for clarity. These results were generally confirmed by subgroup analyses.

Recording eye movements in mice: a new approach to investigate the molecular basis of cerebellar control of motor learning and motor timing.

The vestibulocerebellum is involved in the control of compensatory eye movements. To investigate its role in learning and timing of motor behavior, we investigated compensatory eye movements in mice with the use of search coils. Wild-type mice showed the ability to increase the gain of their vestibulo-ocular reflex by visuovestibular training. This adaptation did not occur in lurcher mice, a natural mouse mutant that completely lacks Purkinje cells. During the optokinetic reflex the phase of the eye movements of lurcher mice in reference to the stimulus lagged behind that of wild-type littermates, whereas during the vestibulo-ocular reflex it led that of the wild-type mice. During combined optokinetic and vestibular stimulation, the phase of the lurcher mice lagged behind that of the wild-type mice at the low stimulus frequencies, whereas it led the phase of the wild-type mice at the high frequencies. In addition, the optokinetic response of the lurcher mice showed a significantly longer latency during constant-velocity step stimulation than that of the wild-type mice. We conclude that Purkinje cells are necessary for both learning and timing of compensatory eye movements in mice. The present description of gain adaptation and phase dynamics provides the basis for studies in which the molecular mechanisms of cerebellar control of compensatory eye movements are investigated with the use of genetically manipulated mice.

Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex.

Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluRdelta2, glial fibrillary acidic protein) have supported this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that functional compensation can occur via similar gene family members. To overcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC[19-31], was selectively expressed in Purkinje cells under the control of the pcp-2(L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induction. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolute gain, phase, and latency values of the vestibulo-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to adapt their vestibulo-ocular reflex gain during visuo-vestibular training was absent. These data strongly support the hypothesis that activation of PKC in the Purkinje cell is necessary for cerebellar LTD induction, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibulo-ocular reflex.

Climbing fibre collaterals contact neurons in the cerebellar nuclei that provide a GABAergic feedback to the inferior olive.

The inferior olive provides climbing fibres to Purkinje cells in the cerebellar cortex and gives off axon collaterals to the cerebellar nuclei. The cerebellar nuclei contain GABAergic neurons that provide an inhibitory projection to the inferior olive and excitatory neurons that influence behaviour through various other premotor nuclei in the brainstem and diencephalon. Whether the olivary axon collaterals innervate the GABAergic neurons in the cerebellar nuclei is unknown. In the present study we investigated this projection in mice at the ultrastructural level using post-embedding GABA immunocytochemistry and anterograde and retrograde tracing of biotinylated dextrane amine and gold-lectin. It is demonstrated that the olivary axon collaterals do not only innervate non-GABAergic neurons in the cerebellar nuclei, but also GABAergic nucleo-olivary cells, thus establishing a direct feedback loop to the inferior olive.

A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844.

PURPOSE: Cerebral low-grade gliomas (LGG) in adults are mostly composed of astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. There is at present no consensus in the policy of treatment of these tumors. We sought to determine the efficacy of radiotherapy and the presence of a dose-response relationship for these tumors in two multicentric randomized trials conducted by the European Organization for Research and Treatment of Cancer (EORTC). The dose-response study is the subject of this article. METHODS AND MATERIALS: For the dose-response trial, 379 adult patients with cerebral LGGs were randomized centrally at the EORTC Data Center to receive irradiation postoperatively (or postbiopsy) with either 45 Gy in 5 weeks or 59.4 Gy in 6.6 weeks with quality-controlled radiation therapy. All known parameters with possible influences on prognosis were prospectively recorded. Conventional treatment techniques were recommended. RESULTS: With 343 (91%) eligible and evaluable patients followed up for at least 50 months with a median of 74 months, there is no significant difference in terms of survival (58% for the low-dose arm and 59% for the high-dose arm) or the progression free survival (47% and 50%) between the two arms of the trial. However, this prospective trial has revealed some important facets about the prognostic parameters: The T of the TNM classifications as proposed in the protocol appears to be one of the most important prognostic factors (p < 0.0001) on multivariate analysis. Other prognostic factors, most of which are known, have now been quantified and confirmed in this prospective study. CONCLUSION: The EORTC trial 22844 has not revealed the presence of radiotherapeutic dose-response for patients with LGG for the two dose levels investigated with this conventional setup, but objective prognostic parameters are recognized. The tumor size or T parameter as used in this study appears to be a very important factor.

Likert or Rasch? Nothing is more applicable than good theory.

In nursing research many concepts are measured by questionnaires. Respondents are asked to respond to a set of related statements or questions. In unidimensional scaling these statements or questions are indicants of the same concept. Scaling means to assign numbers to respondents, according to their position on the continuum underlying the concept. It is very common to use the summative Likert scaling procedure. The sumscore of the responses to the items is the estimator of the position of the patient on the continuum. The rationale behind this procedure is classical test theory. The main assumption in this theory is that all items are parallel instruments. The Rasch model offers an alternative scaling procedure. With Rasch both respondents and items are scaled on the same continuum. Whereas in Likert scaling all items have the same weight in the summating procedure, in the Rasch model items are differentiated from each other by 'difficulty'. The model holds that the probability of a positive response to an item is dependent on the difference between the difficulty of the item and the value of the person on the latent trait. The rationale behind this procedure is item response theory. In this paper both scaling procedures and their rationales are discussed.

Antibodies against cell envelope antigens of Yersinia enterocolitica in reactive arthritis and ankylosing spondylitis.

Yersinia enterocolitica is suspected of involvement in the aetiology of reactive arthritis and ankylosing spondylitis. Its two major outer membrane proteins are important targets for IgA and other protein A reactive immunoglobulins in the sera of some patients with these diseases.