Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Virtual reality as a countermeasure for astronaut motion sickness during simulated post-flight water landings.

Entry motion sickness (EMS) affects crewmembers upon return to Earth following extended adaptation to microgravity. Anticholinergic pharmaceuticals (e.g., Meclizine) are often taken prior to landing; however, they have operationally adverse side effects (e.g., drowsiness). There is a need to develop non-pharmaceutical countermeasures to EMS. We assessed the efficacy of a technological countermeasure providing external visual cues following splashdown, where otherwise only nauseogenic internal cabin visual references are available. Our countermeasure provided motion-congruent visual cues of an Earth-fixed scene in virtual reality, which was compared to a control condition with a head-fixed fixation point in virtual reality in a between-subject design with 15 subjects in each group. We tested the countermeasure's effectiveness at mitigating motion sickness symptoms at the end of a ground-based reentry analog: approximately 1 h of 2Gx centrifugation followed by up to 1 h of wave-like motion. Secondarily, we explored differences in vestibular-mediated balance performance between the two conditions. While Motion Sickness Questionnaire outcomes did not differ detectably between groups, we found significantly better survival rates (with dropout dictated by reporting moderate nausea consecutively over 2 min) in the visual countermeasure group than the control group (79% survival vs. 33%, t(14) = 2.50, p = 0.027). Following the reentry analogs, subjects demonstrated significantly higher sway prior to recovery (p = 0.0004), which did not differ between control and countermeasure groups. These results imply that providing motion-congruent visual cues may be an effective mean for curbing the development of moderate nausea and increasing comfort following future space missions.

Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections. The long-term safety effects of this procedure, however, have not yet been investigated in detail. We here present case reports of three children with SMA in which routine laboratory investigation revealed increased leukocyte counts in cerebrospinal fluid (CSF) collected during the course of nusinersen treatment. To further characterize this observation, we used a multiplex method to analyse a broad spectrum of inflammatory markers in the CSF of these patients. We found that interleukin-10 (IL10) was consistently elevated in CSF with increased leukocyte counts, but other inflammatory markers were not. Based on this analysis we selected 7 markers for further analysis in a cohort of 38 children with SMA and determined their expression during the course of nusinersen therapy. No consistent association was found between levels of inflammatory markers and the duration of nusinersen therapy in individual patients. However, monocyte chemoactive protein 1 (MCP1/CCL2) -a neuroprotective protein secreted by astrocytes and previously associated with SMA- levels increased over the course of nusinersen treatment, indicating a possible neuroprotective mechanism associated with nusinersen therapy. In summary, our findings confirm that repeated intrathecal injections are safe and do not trigger unwanted immune responses.

Toward omitting sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with clinically node-negative breast cancer.

BACKGROUND: The nodal positivity rate after neoadjuvant chemotherapy (ypN+) in patients with clinically node-negative (cN0) breast cancer is low, especially in those with a pathological complete response of the breast. The aim of this study was to identify characteristics known before surgery that are associated with achieving ypN0 in patients with cN0 disease. These characteristics could be used to select patients in whom sentinel lymph node biopsy may be omitted after neoadjuvant chemotherapy. METHODS: This cohort study included patients with cT1-3 cN0 breast cancer treated with neoadjuvant chemotherapy followed by breast surgery and sentinel node biopsy between 2013 and 2018. cN0 was defined by the absence of suspicious nodes on ultrasound imaging and PET/CT, or absence of tumour cells at fine-needle aspiration. Univariable and multivariable logistic regression analyses were performed to determine predictors of ypN0. RESULTS: Overall, 259 of 303 patients (85.5 per cent) achieved ypN0, with high rates among those with a radiological complete response (rCR) on breast MRI (95·5 per cent). Some 82 per cent of patients with hormone receptor-positive disease, 98 per cent of those with triple-negative breast cancer (TNBC) and all patients with human epidermal growth factor receptor 2 (HER2)-positive disease who had a rCR achieved ypN0. Multivariable regression analysis showed that HER2-positive (odds ratio (OR) 5·77, 95 per cent c.i. 1·91 to 23·13) and TNBC subtype (OR 11·65, 2·86 to 106·89) were associated with ypN0 status. In addition, there was a trend toward ypN0 in patients with a breast rCR (OR 2·39, 0·95 to 6·77). CONCLUSION: The probability of nodal positivity after neoadjuvant chemotherapy was less than 3 per cent in patients with TNBC or HER2-positive disease who achieved a breast rCR on MRI. These patients could be included in trials investigating the omission of sentinel node biopsy after neoadjuvant chemotherapy.

Impact of Second Opinions in Breast Cancer Diagnostics and Treatment: A Retrospective Analysis.

BACKGROUND: Breast cancer care is becoming increasingly complex, and patients with breast cancer are increasingly aware of the different treatment options, resulting in requests for second opinions (SOs). The current study investigates the impact of breast cancer SOs on final diagnosis and treatment in the Netherlands Cancer Institute (NCI) using a newly designed Breast Cancer Second Opinion (BCSO) classification system. METHODS: Patients who visited the NCI for an SO between October 2015 and September 2016 were included. Demographics, diagnostics, and treatment proposals were compared between first and SO. Discrepancy was categorized using our BCSO classification system, categorizing SOs into (1) noncomparable, (2) identical, and (3) minor or (4) major discrepancy. RESULTS: The majority of SOs (n = 591) were patient initiated (90.7%). A total of 121 patients underwent treatment prior to their SO, leaving 470 patients for assessment of discrepancies according to our BCSO classification system. More than 45% of these SOs resulted in at least one discrepancy, with comparable rates for physician- and patient-initiated SOs (42.5% vs. 45.6%, p = 0.708). Significantly more discrepancies were observed in patients with additional imaging (51.3% vs. 37.2%, p = 0.002) and biopsies (53.7% vs. 40.3%, p = 0.005). Almost 60% of all discrepancies were categorized as major (neoadjuvant systemic treatment instead of primary surgery, breast-conserving surgery instead of mastectomy, and proposing postmastectomy immediate breast reconstruction). CONCLUSIONS: Our findings show substantial differences in diagnostic and treatment options in breast cancer patients visiting the Netherlands Cancer Institute for an SO, thereby emphasizing more consensus for the indications of these treatment modalities.

Major Reduction in Axillary Lymph Node Dissections After Neoadjuvant Systemic Therapy for Node-Positive Breast Cancer by combining PET/CT and the MARI Procedure.

BACKGROUND: Axillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positron emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy. METHODS: All breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor-positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node. RESULTS: The data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG-avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment. CONCLUSION: Combining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cN + breast cancer patients.

Breast conserving surgery for extensive DCIS using multiple radioactive seeds.

BACKGROUND AND OBJECTIVES: Breast conserving surgery (BCS) can be challenging for large regions of ductal carcinoma in situ (DCIS), resulting in high rates of positive resection margins. Radioactive seed localization (RSL) using multiple radioactive iodine (125I) seeds can be used to bracket extensive DCIS (eDCIS). The goal of this study was to retrospectively compare the use of a single or multiple 125I seeds in RSL to enable BCS in patients with eDCIS. METHODS: All patients with eDCIS (area of ≥3.0 cm) who underwent either single or multiple-seed RSL between January 2008 and December 2016 were included. Patient, tumor and surgery characteristics were compared between both groups. Primary outcome measures were positive resection margin and re-operation rates. RESULTS: Respectively 48 and 58 patients with eDCIS underwent single- and multiple-seed RSL and subsequent BCS. The rate of positive resection margin (focal and more than focal) with single-seed RSL was 47.9%, compared to 29.3% with multiple-seed RSL (p = 0.06). The re-operation rate was 39.6% with single-seed RSL and 20.7% in the multiple-seed RSL group (p = 0.05). CONCLUSION: Multiple-seed RSL enables bracketing of large areas of DCIS, with the potential to decrease the high rate of positive resection margins in this patient group.

Design of a controlled trial to evaluate the effectiveness of Supportive Parenting ('Stevig Ouderschap'): an intervention to empower parents at increased risk of parenting problems by providing early home visits.

BACKGROUND: In the Netherlands, 15% of all families with children under the age of 13 years deal with significant parenting problems. Severe parenting problems may lead to adverse physical, cognitive, and psychosocial outcomes for children, both in the short and long run. The intervention Supportive Parenting (in Dutch: "Stevig Ouderschap") is a preventive program, which aims to reduce the risk of (developing) parenting problems among parents at risk of these problems. The intervention consists of six additional home visits by a Youth Health Care nurse during the first 18 months after childbirth and is focusing on the following elements of parental empowerment: activating social networks, increasing parenting skills and supporting parent(s)/caregiver(s) in getting grip on their own life. METHODS AND DESIGN: A controlled trial is performed in two regions in the Netherlands. An intervention group receives the intervention Supportive Parenting, and a control group receives 'care-as-usual'. Parents in both the intervention and control group fill out three questionnaires focusing on various elements of empowerment (social support, parenting skills, self-sufficiency and resilience), behavioral and emotional problems of the child. The effects of the intervention will be evaluated at child age 1-3 months (baseline) and child age 18 months by comparing the outcomes between the intervention group and the control group on the primary outcomes. Additionally, interviews and focus group interviews will be held to identify factors, which hinder or stimulate a wider implementation of the intervention Supportive Parenting. DISCUSSION: It is hypothesized that parents at increased risk of parenting problems who receive the intervention Supportive Parenting during the first 18 months after childbirth, will have enhanced their social support networks and parenting skills, increased their self-sufficiency and strengthened resilience compared to at risk parents receiving care-as-usual. Additionally children of parents from the intervention group will display less parent-reported behavioral and emotional problems. TRIAL REGISTRATION: Netherlands Trial Register NTR5307. Registered 16 July 2015.

The use of radioactive iodine-125 seed localization in patients with non-palpable breast cancer: a comparison with the radioguided occult lesion localization with 99m technetium.

BACKGROUND: Radioactive Seed Localization with a radioactive iodine-125 seed (RSL) and Radioguided Occult Lesion Localization with 99mTechnetium colloid (ROLL) are both attractive alternatives to wire localization for guiding breast conserving surgery (BCS) of non-palpable breast cancer. The aim of this study was to evaluate and compare the efficacy of RSL and ROLL. METHODS: We retrospectively analyzed 387 patients with unifocal non-palpable ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCS at the Netherlands Cancer Institute. In total 403 non-palpable lesions were localized either by RSL (N = 128) or by ROLL (N = 275). Primary outcome measures were positive margins and re-excision rates; the secondary outcome measure was weight of the specimen. RESULTS: Pre-operative mammography or ultrasound showed similar sizes of DCIS and invasive tumours in both RSL and ROLL groups. In the RSL group, more lesions were DCIS (58%) than in the ROLL group, where 32% of the lesions were pure DCIS. The proportions of focally positive margins (11% vs. 10%) and more than focally positive margins (9% vs. 9%) were comparable between the RSL and the ROLL group, resulting in the same re-excision rate in both RSL and ROLL groups (9% vs. 10%). For DCIS lesions, the specimen weight was significantly lower in the RSL group than in the ROLL group after adjusting for tumour size on mammography (12 g; 95% CI 2.6-21). CONCLUSION: Margin status and re-excision rates were comparable for RSL and ROLL in patients with non-palpable breast lesions. Because of the significant lower weight of the resected specimen in DCIS, the feasibility of position verification of the I-125 seed and more convenient logistics, we favour RSL over ROLL to guide breast-conserving therapy.

Integration of visual and inertial cues in the perception of angular self-motion.

The brain is able to determine angular self-motion from visual, vestibular, and kinesthetic information. There is compelling evidence that both humans and non-human primates integrate visual and inertial (i.e., vestibular and kinesthetic) information in a statistically optimal fashion when discriminating heading direction. In the present study, we investigated whether the brain also integrates information about angular self-motion in a similar manner. Eight participants performed a 2IFC task in which they discriminated yaw-rotations (2-s sinusoidal acceleration) on peak velocity. Just-noticeable differences (JNDs) were determined as a measure of precision in unimodal inertial-only and visual-only trials, as well as in bimodal visual-inertial trials. The visual stimulus was a moving stripe pattern, synchronized with the inertial motion. Peak velocity of comparison stimuli was varied relative to the standard stimulus. Individual analyses showed that data of three participants showed an increase in bimodal precision, consistent with the optimal integration model; while data from the other participants did not conform to maximum-likelihood integration schemes. We suggest that either the sensory cues were not perceived as congruent, that integration might be achieved with fixed weights, or that estimates of visual precision obtained from non-moving observers do not accurately reflect visual precision during self-motion.

Neonatal folate, homocysteine, vitamin B12 levels and methylenetetrahydrofolate reductase variants in childhood asthma and eczema.

OBJECTIVES: To assess the associations of folate, homocysteine and vitamin B12 levels of children at birth and their methylenetetrahydrofolate reductase (MTHFR) variants with asthma and eczema in childhood. METHODS: This study was embedded in a population-based prospective cohort study (n = 2,001). Neonatal cord blood folate, homocysteine and vitamin B12 levels were measured, and MTHFR C677T and A1298C genotyped. Wheezing and physician-diagnosed eczema were annually obtained by questionnaire until 4 years. At 6 years, we collected information on physician-diagnosed asthma ever and self-reported eczema ever, measured fractional exhaled nitric oxide (FeNO), and interrupter resistance (Rint). Data were analysed with generalized estimating equations or logistic regression: continuous outcomes with linear regression models. RESULTS: Folate, homocysteine and vitamin B12 levels of children at birth were not associated with wheezing or eczema until 4 years, asthma and eczema ever, or FeNO or Rint at 6 years. In children carrying C677T mutations in MTHFR, higher folate levels were associated with an increased risk of eczema (repeated eczema until 4 years: OR 1.40 (95% CI 1.09-1.80) (SD change) P-interaction = 0.003, eczema ever at 6 years: OR 1.41 (0.97-2.03) P-interaction = 0.011). No interactions between MTHFR and child folate and homocysteine levels were observed for wheezing and asthma. CONCLUSIONS: Folate, homocysteine and vitamin B12 levels of children at birth did not affect asthma- and eczema-related outcomes up to the age of 6 years. Further studies are warranted to establish the role of MTHFR variants in these associations.

The time constant of the somatogravic illusion.

Without visual feedback, humans perceive tilt when experiencing a sustained linear acceleration. This tilt illusion is commonly referred to as the somatogravic illusion. Although the physiological basis of the illusion seems to be well understood, the dynamic behavior is still subject to discussion. In this study, the dynamic behavior of the illusion was measured experimentally for three motion profiles with different frequency content. Subjects were exposed to pure centripetal accelerations in the lateral direction and were asked to indicate their tilt percept by means of a joystick. Variable-radius centrifugation during constant angular rotation was used to generate these motion profiles. Two self-motion perception models were fitted to the experimental data and were used to obtain the time constant of the somatogravic illusion. Results showed that the time constant of the somatogravic illusion was on the order of two seconds, in contrast to the higher time constant found in fixed-radius centrifugation studies. Furthermore, the time constant was significantly affected by the frequency content of the motion profiles. Motion profiles with higher frequency content revealed shorter time constants which cannot be explained by self-motion perception models that assume a fixed time constant. Therefore, these models need to be improved with a mechanism that deals with this variable time constant. Apart from the fundamental importance, these results also have practical consequences for the simulation of sustained accelerations in motion simulators.

Decontamination of the digestive tract and oropharynx in ICU patients.

BACKGROUND: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting. METHODS: We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in The Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance. RESULTS: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. CONCLUSIONS: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.)

How to use body tilt for the simulation of linear self motion.

We examined to what extent body tilt may augment the perception of visually simulated linear self acceleration. Fourteen subjects judged visual motion profiles of fore-aft motion at four different frequencies between 0.04-0.33 Hz, and at three different acceleration amplitudes (0.44, 0.88 and 1.76 m/s(2)). Simultaneously, subjects were tilted backward and forward about their pitch axis. The amplitude of pitch tilt was systematically varied. Using a two-alternative-forced-choice paradigm, psychometric curves were calculated in order to determine: 1) the minimum tilt amplitude required to generate a linear self-motion percept in more than 50% of the cases, and 2) the maximum tilt amplitude at which rotation remains sub-threshold in more than 50% of the cases. The results showed that the simulation of linear self motion became more realistic with the application of whole body tilt, as long as the tilt rate remained under the detection threshold of about 3 deg/s. This value is in close agreement with the empirical rate limit commonly used in flight simulation. The minimum required motion cue was inversely proportional to stimulus frequency, and increased with the amplitude of the visual displacement (rather than acceleration). As a consequence, the range of useful tilt stimuli became more critical with increasing stimulus frequency. We conclude that this psychophysical approach reveals valid parameters for motion driving algorithms used in motion base simulators.

Bronchoalveolar lavage fluid cytology in patients with Pneumocystis carinii pneumonia.

OBJECTIVE: To evaluate bronchoalveolar lavage (BAL) cytology and organism burden in patients with Pneumocystis carinii pneumonia (PCP) who were infected with the human immunodeficiency virus (HIV) and in those with other immunodeficiencies. STUDY DESIGN: BAL fluid samples from patients with PCP were selected (HIV-infected patients, n = 15; patients with other immunodeficiencies, n = 11). May-Grünwald-Giemsa-stained cytocentrifuge preparations were evaluated. Foamy alveolar casts (FACs) and P carinii clusters were counted. RESULTS: The numbers of FACs and P carinii clusters in BAL fluid samples of HIV-infected patients were significantly higher as compared to those in samples from patients with other immunodeficiencies. Striking cytologic findings observed in half the samples from both patient groups included the presence of foamy alveolar macrophages, activated lymphocytes, plasma cells and reactive type II pneumocytes. Furthermore, a peculiar cell type, "nonidentified cell" (NIC), was observed almost exclusively in BAL fluid samples from HIV-infected patients. CONCLUSION: BAL fluid samples from HIV-infected patients with PCP displayed higher organism burdens as compared to those from patients with other immunodeficiencies. Moreover, cytologic findings suggestive of noninfectious lung conditions were common in BAL fluid samples obtained from patients with PCP. Further study is required to elucidate the identity of the NIC cell type.

Contribution of the otoliths to the human torsional vestibulo-ocular reflex.

The dynamic contribution of the otolith organs to the human ocular torsion response was examined during passive sinusoidal body roll about an earth-horizontal axis (varying otolith inputs) and about an earth-vertical axis (invariant otolith inputs). Torsional eye movements were registered in 5 subjects by means of video-oculography. At a fixed amplitude of 25 degrees, the stimulus frequency was varied from 0.05 to 0.4 Hz. Additionally, at a fixed frequency of 0.2 Hz, the response was also measured at the amplitudes to 12.5 degrees and 50 degrees. The results showed that the gain and phase of the torsional slow component velocity (SCV) did not depend on stimulus amplitude, indicating a linear response. Contribution of the otoliths affected the ocular torsion response in three different ways. First, the gain of the SCV was slightly, but consistently, higher during rotation about an earth-horizontal axis than during rotation about an earth-vertical axis. With invariant otolith inputs the average gain increased from 0.10 at 0.05 Hz to 0.26 at 0.25 Hz. With varying otolith inputs, the average gain increased from 0.14 to 0.37. Second and more substantially, contribution of the otoliths improved the response dynamics by reducing the phase lead at frequencies up to 0.02 Hz. Third, the nystagmus showed considerably less anticompensatory saccades in upright conditions than in supine conditions, even though the SCV gain was lower in the latter. As a consequence, the average excursion of torsional eye position was highest during earth-horizontal rotation. This effect was observed in the entire frequency range. Thus, the otoliths controlled the human torsional VOR not only at low stimulus frequencies by keeping the slow component in phase with head motion, but also in a wider frequency range by modulating the saccadic behavior as to increase the amplitude of ocular torsion. We conclude that the primary concern of the otolith-oculomotor system during head tilt is to stabilize eye position in space, rather than to prevent retinal blur.

A comparison of the pharmacokinetics and tolerability of riluzole after repeat dose administration in healthy elderly and young volunteers.

The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender- and weight-matched young volunteers. All participants received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half-life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.