Enhancement of awareness through feedback does not lead to interlimb transfer of obstacle crossing in virtual reality.

Locomotor skill transfer is an essential feature of motor adaptation and represents the generalization of learned skills. We previously showed that gait adaptation after crossing virtual obstacles did not transfer to the untrained limb and suggested it may be due to missing feedback of performance. This study investigated whether providing feedback and an explicit goal during training would lead to transfer of adaptive skills to the untrained limb. Thirteen young adults crossed 50 virtual obstacles with one (trained) leg. Subsequently, they performed 50 trials with their other (transfer) leg upon notice about the side change. Visual feedback about crossing performance (toe clearance) was provided using a color scale. In addition, joint angles of the ankle, knee, and hip were calculated for the crossing legs. Toe clearance decreased with repeated obstacle crossing from 7.8 ± 2.7 cm to 4.6 ± 1.7 cm for the trained leg and from 6.8 ± 3.0 cm to 4.4 ± 2.0 cm (p < 0.05) for the transfer leg with similar adaptation rates between limbs. Toe clearance was significantly higher for the first trials of the transfer leg compared to the last trials of the training leg (p < 0.05). Furthermore, statistical parametric mapping revealed similar joint kinematics for trained and transfer legs in the initial training trials but differed in knee and hip joints when comparing the last trials of the trained leg with the first trials of the transfer leg. We concluded that locomotor skills acquired during a virtual obstacle crossing task are limb-specific and that enhanced awareness does not seem to improve interlimb transfer.

Differences in motor response to stability perturbations limit fall-resisting skill transfer.

This study investigated transfer of improvements in stability recovery performance to novel perturbations. Thirty adults (20-53 yr) were assigned equally to three treadmill walking groups: groups exposed to eight trip perturbations of either low or high magnitude and a third control group that walked unperturbed. Following treadmill walking, participants were exposed to stability loss from a forward-inclined position (lean-and-release) and an overground trip. Lower limb joint kinematics for the swing phase of recovery steps was compared for the three tasks using statistical parametric mapping and recovery performance was analysed by margin of stability and base of support. The perturbation groups improved stability (greater margin of stability) over the eight gait perturbations. There was no group effect for stability recovery in lean-and-release. For the overground trip, both perturbation groups showed similar enhanced stability recovery (margin of stability and base of support) compared to controls. Differences in joint angle kinematics between treadmill-perturbation and lean-and-release were more prolonged and greater than between the two gait perturbation tasks. This study indicates that: (i) practising stability control enhances human resilience to novel perturbations; (ii) enhancement is not necessarily dependent on perturbation magnitude; (iii) differences in motor response patterns between tasks may limit transfer.

Stability recovery performance in adults over a wide age range: A multicentre reliability analysis using different lean-and-release test protocols.

The ability to effectively increase the base of support is crucial to prevent from falling due to stability disturbances and has been commonly assessed using the forward-directed lean-and-release test. With this multicentre study we examined whether the assessment of stability recovery performance using two different forward lean-and-release test protocols is reliable in adults over a wide age range. Ninety-seven healthy adults (age from 21 to 80 years) were randomly assigned to one out of two lean angle protocols: gradual increase to maximal forward-lean angle (maximal lean angle; n = 43; seven participants were excluded due to marker artefacts) or predefined lean angle (single lean angle; n = 26; 21 participants needed to be excluded due to multiple stepping after release or marker artefacts). Both protocols were repeated after 0.5 h and 48 h to investigate intra- and inter-session reliability. Stability recovery performance was examined using the margin of stability at release (MoSRL) and touchdown (MoSTD) and increase in base of support (BoSTD). Intraclass correlation coefficients (confidence intervals at 95%) for the maximal lean angle and for the single lean angle were respectively 0.93 (0.89-0.96) and 0.94 (0.89-0.97) in MoSRL, 0.85 (0.77-0.91) and 0.67 (0.48-0.82) in MoSTD and 0.88 (0.81-0.93) and 0.80 (0.66-0.90) in BoSTD, with equivalence being revealed for each parameter between all three measurements (p < 0.01). We concluded that the assessment of stability recovery performance parameters in adults over a wide age range with the means of the forward lean-and-release test is reliable, independent of the used lean angle protocol.

Obstacle avoidance training in virtual environments leads to limb-specific locomotor adaptations but not to interlimb transfer in healthy young adults.

Obstacle avoidance is one of the skills required in coping with challenging situations encountered during walking. This study examined adaptation in gait stability and its interlimb transfer in a virtual obstacle avoidance task. Twelve young adults walked on a treadmill while wearing a virtual reality headset with their body state represented in the virtual environment. At random times, but always at foot touchdown, 50 virtual obstacles of constant size appeared 0.8 m in front of the participant requiring a step over with the right leg. Early, mid and late adaptation phases were investigated by pooling data from trials 1-3, 24-26 and 48-50. One left-leg obstacle appearing after 50 right-leg trials was used to investigate interlimb transfer. Toe clearance and the anteroposterior margin of stability (MoS) at foot touchdown were calculated for the stepping leg. Toe clearance decreased over repeated practice between early and late phases from 0.13 ± 0.05 m to 0.09 ± 0.04 m (mean ± SD, p < 0.05). MoS increased from 0.05 ± 0.02 m to 0.08 ± 0.02 m (p < 0.05) between early and late phases, with no significant differences between mid and late phases. No differences were found in toe clearance and MoS between the practiced right leg for early phase and the single trial of the left leg. Obstacle avoidance during walking in a virtual environment stimulated adaptive gait improvements that were related in a nonlinear manner to practice dose, though such gait adaptations seemed to be limited in their transferability between limbs.

Evidence that ageing does not influence the uniformity of the muscle-tendon unit adaptation in master sprinters.

Differences in the adaptation processes between muscle and tendon in response to mechanical loading can lead to non-uniform mechanical properties within the muscle-tendon unit (MTU), potentially increasing injury risk. The current study analysed the mechanical properties of the triceps surae (TS) MTU in 10 young (YS; 22 ± 3 yrs) and 10 older (OS; age 65 ± 8 yrs; i.e. master) (inter)national level sprinters and 11 young recreationally active adults (YC; 23 ± 3 yrs) to detect possible non-uniformities in muscle and tendon adaptation due to habitual mechanical loading and ageing. Triceps surae muscle strength, tendon stiffness and maximal tendon strain were assessed in both legs during maximal voluntary isometric plantarflexion contractions via dynamometry and ultrasonography. Irrespective of the leg, OS and YC in comparison to YS demonstrated significantly (P < 0.05) lower TS muscle strength and tendon stiffness, with no differences between OS and YC. Furthermore, no group differences were detected in the maximal tendon strain (average of both legs: OS 3.7 ± 0.8%, YC 4.4 ± 0.8% and YS 4.3 ± 0.9%) as well as in the inter-limb symmetry indexes in muscle strength, tendon stiffness and maximal tendon strain (range across groups: -5.8 to 4.9%; negative value reflects higher value for the non-preferred leg). Thus, the findings provide no clear evidence for a disruption in the TS MTU uniformity in master sprinters, demonstrating that ageing tendons can maintain their integrity to meet the increased functional demand due to elite sports.

A Randomized, Double-Blind, Phase 2 Study of the Effects of the Vaccine Vanutide Cridificar with QS-21 Adjuvant on Immunogenicity, Safety and Amyloid Imaging in Patients with Mild to Moderate Alzheimer's Disease.

BACKGROUND: Vanutide Cridificar (ACC-001), a novel investigational immunotherapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease (AD). OBJECTIVES: To evaluate the immunogenicity, safety and impact of ACC-001 with Quillaja saponaria (QS-21) adjuvant on the reduction of brain fibrillar amyloid burden, assayed by positron emission tomography (PET) imaging, in patients with mild to moderate AD. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01284387. PARTICIPANTS: Individuals with mild to moderate Alzheimer's disease (Mini-Mental State Examination scores 18-26; measurable amyloid burden in the expected range, on the screening 18F-florbetapir PET scan; and a Rosen modified Hachinski ischemic score ≤4). INTERVENTION: Participants were randomized to 3 µg or 10 µg ACC-001 (each in combination with 50 µg QS-21) or placebo (without QS-21). MEASUREMENTS: Primary endpoint was the change from baseline to week 104 in cerebral amyloid burden as measured by the global cortical average (GCA) standard value uptake ratio (SUVR) based on the brain 18F-florbetapir PET composite cortical SUVR between each ACC-001+QS-21 dose compared with placebo. Secondary endpoints included safety, immunogenicity and pharmacodynamics. Exploratory endpoints included cognitive and functional efficacy, and health outcome measures. RESULTS: Of 126 randomized patients (placebo: 40; ACC-001 3 µg+QS-21: 43; and ACC-001 10 µg+QS-21: 43), 125 received study treatment; 92 (73%) completed the study. Change in 18F-florbetapir PET GCA SUVR, was not significantly different between either of the two ACC-001+QS-21 treatment groups and placebo (3 µg +QS-21 vs. placebo diff=-0.03, p=0.54; 10 µg +QS-21 vs. placebo diff=-0.08, p=0.07), but the trend was numerically consistent with a dose response. The geometric mean peak anti-Aß IgG titers were slightly higher in the 10 µg than the 3 µg group. The proportion of responders was similar in both dose groups of ACC-001+QS-21. The cerebrospinal fluid (CSF) p-tau changes from baseline in both active treatment groups were not statistically different from placebo, but were numerically consistent with a dose response (3 µg +QS-21 vs. placebo diff=-3.2, p=0.57; 10 µg +QS-21 vs. placebo diff=-7.0, p=0.19). The vMRI showed statistically significant faster treatment-related decrease in brain volume in the 10 µg group but was not significant in the 3 µg group, compared with placebo (3 µg diff =-1.3 mL/year, p=0.50; 10 µg diff=-4.2 mL/year, p=0.02). Measured plasma Aß levels increased in parallel with peak anti-Aß titers after each injection. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) were more frequent in patients who received ACC-001+QS-21 than placebo (6% vs. 0%) but none were symptomatic. The most common treatment-emergent adverse events in the active groups were injection reactions, and occurred more frequently in the ACC-001+QS-21 groups than the placebo (48% vs 8%), the majority of which were mild and transient. CONCLUSIONS: Primary biomarker efficacy endpoints were not statistically significant in either dose group. The numerical decreases in 18F-florbetapir PET GCA SUVR suggests a dose-related trend for greater reductions in fibrillar amyloid burden in the ACC-001+QS-21 10 µg group compared with placebo. Likewise, while not significant, there was a numerical trend of decreased CSF p-tau levels with ACC-001, possibly consistent with a downstream effect in the ACC-001+QS-21 group. Insufficient antibody titers or quality, insufficient power to detect a difference, or too short duration of follow up may be reasons why a statistically significant response was not observed. Brain volume measures showed faster volume loss in the 10 µg treatment group, similar to the effect seen in few earlier AD immunotherapy trials which may suggest removal of amyloid and resultant decrease in inflammation. No new, unexpected safety signals were detected.

[Diverse effectiveness of the trabectome for different types of glaucoma]. / Unterschiedliche Effekte der Trabektomoperation auf unterschiedliche Glaukomformen.

PURPOSE: Ab interno trabeculotomy using the trabectome device is a intraocular pressure (IOP) decreasing operation by ablation of the trabecular meshwork and the inner wall of Schlemm's channel. This prospective study analyses the effectiveness of the trabectome operation in 122 patients. PATIENTS AND METHODS: The operation was conducted when topical medication was maxed out with the intraocular pressure (IOP) remaining above the desired target range. In addition to the evaluation of the whole study group further analysis concerned the effectiveness of the trabectome in different subclassifications of glaucoma. In some cases the procedure was combined with cataract surgery and subsequently the results were compared to the plain trabectome OP. The results were split into two groups: "complete success" (without postoperative medication) and "qualified success" (with medication). The evaluation was processed for the IOP levels ≤ 21 mmHg, ≤ 18 mmHg, ≤ 15 mmHg und ≤ 12 mmHg. Follow-up dates were 6 and 12 months after surgery. RESULTS: Baseline IOP was 20.15 ± 7.1 mmHg. After 6 months the average IOP of all patients was 16.53 ± 5.89 mmHg, after 12 months the IOP amounted to 15.6 ± 4.45 mmHg. At both follow-ups approximately 90 % of the "complete success" group exhibited an IOP ≤ 18 mmHg. Also at both follow-ups 75 % of the "qualified success" group achieved a range ≤ 18 mmHg - whereas 50 % gained an IOP ≤ 15 mmHg. In secondary glaucoma an IOP decrease of 36 % was achieved. In open-angle glaucomas and those with dysgenetic altered angles the operation evoked a pressure loss of ca. 20 %. The trabectome-only group as well as the group of combined surgery exhibited a significant lowering of IOP. This was accomplished by a significant reduction of eye drops. After surgery nearly half of all patients required none or 1 eye drop at most. CONCLUSION: The trabectome offers a safe and significant lowering of IOP for around 36 % and seems to be very effective in secondary glaucomas. In dysgenetic alterations and open-angle glaucoma a moderate lowering of IOP (ca. 20 %) may be expected. The amount of eye drops can be reduced for about 42 %. After surgery every second patient requires at most 1 eye drop. The technique can be combined with cataract surgery and permits a penetrating operation at a later date.

The use of a clinical utility index to compare insomnia compounds: a quantitative basis for benefit-risk assessment.

The use of a clinical utility index (CUI) was proposed in order to compare two calcium channel alpha2delta ligands that were in development for the treatment of insomnia. The important attributes included in the CUI were two measures of residual sedation and five measures of efficacy (wake after sleep onset, sleep quality, sleep latency, and sleep stages (stage 1 and stages 3-4)). Dose-response analyses were conducted on each end point, and a sensitivity analysis was conducted to determine a clinically meaningful difference in CUI. Nonparametric bootstrap parameters were used to build confidence intervals (CIs). Peak CUI (80% CI) was 0.345 (0.25-0.43), observed at a dose of approximately 30 mg with the lead compound and 0.436 (0.35-0.52) observed at >600-mg dose for the backup. Although CUI was slightly greater for the backup, peak CUI values were observed at doses that were not considered viable, and therefore development of the ligand was discontinued. The use of the CUI allowed an efficient, quantitative, and transparent decision.

Failure and success of hydrodynamic interaction models.

In suspensions with charged particles, electrostatic forces and hydrodynamic interactions are both important to describe the system. We study different models of hydrodynamic interaction for monopolarly charged particles in a non-polar liquid. In this case, there is no screening of the Coulomb repulsion, so the repulsion between all pairs must be taken into account. The particles are expected to drift away from each other, however at a lower rate when hydrodynamic interaction between the particles is taken into account. Existing, frequently used models of hydrodynamic interactions tend to overestimate the slowing down of the charged particles, even to the extent that the particles effectively attract each other. This is demonstrated for some selected particle setups. We find that these anomalies even occur in dilute systems, if they contain sufficiently many particles. We explain why these anomalies can be avoided by an approach, in which the superposition of interactions is done in the friction tensor instead of the mobility tensor.

Psychosocial issues near the end of life.

End-of-life care has received increasing attention in the last decade; however, the focus continues to be on the physical aspects of suffering and care to the virtual exclusion of psychosocial areas. This paper provides an overview of the literature on the intra- and interpersonal aspects of dying, including the effects that psychosocial variables have on end-of-life decision-making; common diagnosable mental disorders (e.g., clinical depression, delirium); other types of personal considerations (e.g., autonomy/control, grief); and interpersonal/environmental issues (e.g., cultural factors, financial variables). Six roles that qualified mental health professionals can play (i.e., advocate, counselor, educator, evaluator, multidisciplinary team member, and researcher) are also outlined. Because psychosocial issues are ubiquitous and can have enormous impact near the end of life, properly trained mental health professionals can play vital roles in alleviating suffering and improving the quality of life of people who are dying.

Using the Youk-Kevorkian case to teach about euthanasia and other end-of-life issues.

Dr. Jack Kevorkian's actions have generated much controversy and press coverage during the past decade. His appearance on a nationally televised newsprogram with a videotape showing him deliberately causing the death of a man led to his imprisonment. This article discusses how Kevorkian's euthanasia case can be used to teach undergraduate students about end-of-life issues, especially psychosocial aspects of the debate over hastened death.

U.S. involuntary mental health commitment statutes: requirements for persons perceived to be a potential harm to self.

The civil commitment statutes of all 50 states and the District of Columbia were reviewed to determine: (1) What is required for a person who is believed to be at serious and imminent risk of self-harm to be eligible for involuntary hospitalization; and (2) Whether an attempt to involuntarily hospitalize was required or was merely an option when the requirements found in number 1 were met. The analysis revealed that nearly 85% of the jurisdictions require dangerousness to self to be the result of a mental illness, and only two jurisdictions mandate attempts at involuntary commitment if a person is deemed to be an imminent harm to self. These results have implications for practice with individuals who are suicidal.

Morbidity in patients with hidradenitis suppurativa.

BACKGROUND: Although skin diseases are often immediately visible to both patients and society, the morbidity they cause is only poorly defined. It has been suggested that quality-of-life measures may be a relevant surrogate measure of skin disease. Hidradenitis suppurativa (HS) leads to painful eruptions and malodorous discharge and is assumed to cause a significant degree of morbidity. The resulting impairment of life quality has not previously been quantitatively assessed, although such an assessment may form a pertinent measure of disease severity in HS. OBJECTIVES: To measure the impairment of life quality in patients with HS. METHODS: In total, 160 patients suffering from HS were approached. The following data were gathered: quality-of-life data (Dermatology Life Quality Index, DLQI questionnaire), basic demographic data, age at onset of the condition and the average number of painful lesions per month. RESULTS: One hundred and fourteen patients participated in the study. The mean +/- SD age of the patients was 40.9 +/- 11.7 years, the mean +/- SD age at onset 21.8 +/- 9.9 years and the mean +/- SD duration of the disease 18.8 +/- 11.4 years. Patients had a mean +/- SD DLQI score of 8.9 +/- 8.3 points. The highest mean score out of the 10 DLQI questions was recorded for question 1, which measures the level of pain, soreness, stinging or itching (mean 1.55 points, median 2 points). Patients experienced a mean of 5.1 lesions per month. CONCLUSIONS: HS causes a high degree of morbidity, with the highest scores obtained for the level of pain caused by the disease. The mean DLQI score for HS was higher than for previously studied skin diseases, and correlated with disease intensity as expressed by lesions per month. This suggests that the DLQI may be a relevant outcome measure in future therapeutic trials in HS.

Policy and psychosocial considerations associated with non-physician assisted suicide: a commentary on Ogden.

The report by Russel Ogden (2001) on a conference where devices designed to facilitate death were displayed and discussed highlights how far some individuals will go if they are committed to helping suffering people die. In this commentary, the author discusses the federal policy developments that have contributed to this movement and then expresses his concerns about using lay people to provide assistance with hastening death.

The clinical genetics of hidradenitis suppurativa revisited.

A familial form of hidradenitis suppurativa (HS) with autosomal dominant inheritance was described in a study conducted 15 years ago in Nottingham but has not been systematically confirmed elsewhere. Prior to commencing molecular genetic studies, we wanted to test the validity of the previous study by assessing its reproducibility on the basis of a strict, newly devised disease definition for HS. We were also interested whether new cases of the disease had arisen meantime in the study group as should be expected for an autosomal dominant disease. We reviewed 14 surviving probands and their families. Seven of these probands had previously been noted to have a positive family history whereas the others had been classified as having a negative or possible family history. One hundred and thirty-two family members were assessed for their respective disease status. Participants were initially contacted by telephone or letter, and those who acknowledged a history of at least one previous boil were invited for a personal examination and interview. Only personally examined individuals were classified as a case. Twenty-eight relatives with HS were detected in total, and 27 of these were in the group previously labelled family history positive. Nine of these cases had not been detected in the previous study and in at least seven of these the disease had developed after the previous study had been conducted. Only twice did our criteria fail to confirm cases that had been labelled as HS in the previous study. Both times we classified the patients as 'possibly affected'. A further 16 relatives were judged to be possibly affected. In the group with positive family history we found 10 affected and nine possibly affected individuals among 37 surviving first-degree relatives of HS sufferers. Our findings support the concept of a familial form of HS with autosomal dominant inheritance. An insufficiently sensitive disease definition, a variable degree of gene penetrance and possibly a hormonal influence on gene expression may explain the reduced risk to first-degree relatives, which falls short of the expected 50% mark. Molecular genetic studies to clarify whether one or more gene(s) are involved in HS are now necessary and have been commenced.

Reversible physiological alterations in sympathetic neurons deprived of NGF but protected from apoptosis by caspase inhibition or Bax deletion.

Cell death in nervous system development and in many neurodegenerative diseases appears to be apoptotic or programmed. Withdrawal of nerve growth factor (NGF) from cultures of superior cervical ganglia neurons (SCG) is an excellent model of programmed cell death (PCD), producing apoptosis within 24-48 h. This death can be prevented by treatment with caspase inhibitors or deletion of the proapoptotic Bax gene. Since inhibition of apoptosis is an attractive strategy for the therapy of many neurological diseases and little is known about the function of neurons when apoptosis has been aborted, we examined the electrophysiological properties of NGF-deprived SCG neurons from rats and mice, saved by the caspase inhibitor boc-aspartyl(OMe)fluoromethyl ketone (BAF) or by Bax deletion. Compared to NGF-maintained controls, the resting membrane potentials of BAF-saved neurons were depolarized by 9 mV and the action potentials were prolonged by over 50%. Nicotinic cholinergic current density was depressed by about 50%. Electrophysiological parameters returned to normal within 4 days after NGF restoration. Neurons from Bax-deficient mice were altered differently by NGF withdrawal. There were no detectable changes in resting or action potentials. However, nicotinic current density was reduced just as in BAF-saved rat neurons. There were no observable changes in the processes of individual neurons after 6 days of NGF deprivation in the presence of BAF. Our results indicate that neurons are physiologically altered during pharmacological inhibition of PCD, but fully recover after trophic support is returned.

Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group.

OBJECTIVES: [corrected] To assess efficacy and safety of gabapentin in the treatment of bipolar disorder. METHODS: This was a double-blind, placebo-controlled trial of adjunctive gabapentin (dosed flexibly between 900 and 3,600 mg/day). Patients with a lifetime diagnosis of bipolar disorder (type I), and who were currently suffering from symptoms of either mania, hypomania or a mixed state despite ongoing therapy with lithium, valproate, or lithium and valproate in combination were eligible for inclusion. The primary efficacy measures were the baseline to endpoint change in total score on the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HAM-D). RESULTS: Both treatment groups had a decrease in total YMRS from baseline to endpoint, but this decrease was significantly greater in the placebo group (-9) than the gabapentin group (-6) (p < 0.05). No difference between treatments was found for the total score on the HAM-D. Secondary efficacy measures were not different between treatment groups. More patients in the placebo group had changes made to their ongoing lithium therapy (n = 12) compared to the gabapentin group (n = 4). When these patients are removed from the efficacy analysis, the YMRS treatment difference still favors placebo, but is no longer statistically significant. Based on gabapentin plasma levels at termination, some patients did not take the study drug as prescribed. CONCLUSIONS: The findings of this study did not demonstrate that gabapentin is an effective adjunctive treatment when administered to outpatients with bipolar disorder.

Observations on the first year of Oregon's Death with Dignity Act.

Using data from the files of Compassion in Dying, we describe 34 individuals who approached Compassion wanting to use the Death with Dignity Act and who died during the first year of the Act's implementation. Of these 34, 10 died using medication prescribed under the Act. Using first-hand data from the dying individuals, their families, and their health care teams, we provide comparisons between predicted outcomes and actual experiences, discuss important elements of the physician-patient relationship, and describe several averted suicides and homicides. We also review changes in end-of-life care in Oregon and provide recommendations about issues in need of further research.