The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics.

UNLABELLED: Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as 'GB multiforme'). GB is the most common and aggressive primary malignant brain tumor and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but is upregulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype; (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue; and (iii) TWEAK: Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.

Genetic-environmental interaction in the genesis of aggressivity and conduct disorders.

BACKGROUND: The purpose of this study was to determine the effect of an adverse adoptive home environment on adoptee conduct disorder, adult antisocial behavior, and two measures of aggressivity, all of which are behaviors that contribute to adult antisocial personality disorder and that also are associated with increased vulnerability to drug abuse and/or dependence. METHODS: The study used an adoption paradigm in which adopted offspring who were separated at birth from biologic parents with documented (by prison and hospital records) antisocial personality disorder and/or alcohol abuse or dependence were followed up as adults. They and their adoptive parents were interviewed in person. These adoptees were compared with controls whose biologic background was negative for documented psychopathologic behavior. Subjects were 95 male and 102 female adoptees and their adoptive parents. RESULTS: Multiple regression analysis was used to measure separately genetic and environmental effects. It showed that (1) a biologic background of antisocial personality disorder predicted increased adolescent aggressivity, conduct disorder, and adult antisocial behaviors, and (2) adverse adoptive home environment (defined as adoptive parents who had marital problems, were divorced, were separated, or had anxiety conditions, depression, substance abuse and/or dependence, or legal problems) independently predicted increased adult antisocial behaviors. Adverse adoptive home environment interacted with biologic background of antisocial personality disorder to result in significantly increased aggressivity and conduct disorder in adoptees in the presence of but not in the absence of a biologic background of antisocial personality disorder. CONCLUSIONS: Environmental effects and genetic-environmental interaction account for significant variability in adoptee aggressivity, conduct disorder, and adult antisocial behavior and have important implications for the prevention and intervention of conduct disorder and associated conditions such as substance abuse and aggressivity.

Adoption study demonstrating two genetic pathways to drug abuse.

BACKGROUND: Studies of adoptees have demonstrated that there are two genetic factors leading to alcohol abuse and/or dependence (abuse/dependence). In addition, environmental factors found in the adoptive family also predict alcohol abuse/dependency independently. One study has found evidence that a similar model of two genetic factors and independent adoptive family factors were involved in drug abuse. Our study was designed to test the hypothesis that genetic factors defined by alcohol abuse/dependency and anti-social personality disorder in biologic parents were etiologic in drug abuse/dependency and that psychiatric problems in adoptive parents were an additional factor associated with drug abuse/dependence. METHODS: A sample of 95 male adoptees, separated at birth from their biologic parents, were followed up as adults to determine their psychiatric diagnosis and their substance use/abuse in a structured interview administered blind to biologic parent diagnoses. A high-risk, case-control design was used wherein half of the adoptees came from biologic parents known to be alcohol abuser/dependent and/or have antisocial personalities (diagnoses from hospital or prison records). These adoptees were matched for age, sex, and adoption agency to a control group of adoptees whose biologic parents were not found in the hospital and prison record search. Adoptive home environment was assessed by structured interviews, including psychiatric assessment of both adoptive parents. RESULTS: Data were analyzed by log-linear modeling, which showed evidence of two genetic pathways to drug abuse/dependency. One pathway went directly from a biologic parent's alcoholism to drug abuse/dependency. The second pathway was more circuitous, and started with anti-social personality disorder in the biologic parent and proceeded through intervening variables of adoptee aggressivity, conduct disorder, antisocial personality disorder, and, eventually, ended in drug abuse/dependency. Environmental factors defined by psychiatric conditions in adoptive families independently predicted increased antisocial personality disorder in the adoptee. Adoptees born of alcohol-abusing mothers showed evidence of fetal alcohol syndrome, but controlling for this did not diminish the evidence for the direct genetic effect between an alcohol-abusing biologic parent and drug abuse/dependency in offspring. CONCLUSIONS: This study confirms the model of two independent genetic factors involved in drug abuse/dependence and previous findings that disturbed adoptive parents are associated with adoptee drug abuse/dependency.

Iowa FICSIT trial: the feasibility of elderly wearing a hip joint protective garment to reduce hip fractures.

Hip fractures exact a heavy toll in the elderly population. While intervention strategies are being investigated to reduce the numbers of geriatric falls and to improve the body's resiliency, the geriatric population remains at risk for the mortality and morbidity associated with fractures. The Iowa FICSIT site is investigating the feasibility of passive protection of the proximal femur through the use of hip pads. The pad is designed to disperse throughout the pad the energy created in a fall. The focus of the Iowa trial is to determine if elderly will wear hip pads for the majority of their waking hours. Thirty subjects are being recruited from each of six elderly populations who are at high risk to fall and at increased risk of injury. To facilitate compliance, the following strategies are utilized: run-in period, graduated implementation, tailoring of wearing times, and self-report of compliance. Outcome measures include compliance rates and injuries sustained during falls.

Evidence of heterogeneity of genetic effect in Iowa adoption studies.

This paper describes male adoption studies at the University of Iowa using private and public adoption agencies within the state of Iowa from 1974 to the present time. This research involves four large studies, the first two of which demonstrated significant genetic as well as environmental effects in the etiology of alcoholism as well as significant correlations between adoptee conditions of antisocial personality and alcohol abuse. Findings in the first two studies were similar. However, the third study, using a sample from Catholic-sponsored adoption agencies across the state, failed to show a genetic effect. The final and fourth study was designed in part to look for heterogeneity in the manifestation of a genetic factor from one sample to another in the Iowa studies. This was done by sampling from two agencies, one of which had shown a genetic effect and the other that had not. In this fourth study, the agency that had not shown a genetic effect in the previous study also failed to show an effect, but the agency that had shown a significant genetic effect in the past did demonstrate a significant genetic effect. There were two remaining agencies in the fourth study for which no comparison with past samples could be made. One of these agencies showed a marginally significant genetic effect and the other showed no effect. Statistical analysis of this last study suggested that observed variability in the odds ratio from sample to sample was due to differences in manifestation of the genetic effect.

Driving simulation study: bilateral array multifocal versus bilateral AMO monofocal intraocular lenses.

PURPOSE: To determine whether differences exist in the driving performance of patients with bilateral Array multifocal intraocular lenses (IOLs) and those with bilateral AMO monofocal IOLs under low-contrast environmental conditions. SETTING: The Iowa Driving Simulator at the Center for Computer Aided Design, the University of Iowa, Iowa City, Iowa, USA. METHODS: This prospective study was a test-operator-masked, parallel-group comparison of the driving performance of 33 bilateral multifocal IOL patients and 33 bilateral monofocal IOL patients from the U.S. Array Multifocal study. Driving performance was evaluated under 3 poor visibility conditions (clear weather at night, clear weather at night in the presence of a glare source, and fog). Measures of performance included recognition rates and distances for signs, as well as detection rates, distances, and avoidance behaviors for hazards. Contrast acuity and sensitivity were also measured to evaluate possible correlations with driving performance. RESULTS: No statistically significant differences between the IOL groups were found in 26 of 30 comparisons (86.7%). The monofocal group performed better than the multifocal group in comparisons in which there were statistically significant differences: the percentage of correctly recognized warning signs at night in clear weather (P = .028), sign recognition distances for guide (P = .030) and warning (P = .036) signs in fog, and the detection distance for 1 of 4 hazards (suitcase; P = .026). Correlation coefficients between driving performance and low-contrast acuity and sensitivity were statistically significant; however, they were low and not likely predictive of driving performance. CONCLUSION: Differences between patients with bilateral multifocal IOLs and those with bilateral monofocal IOLs were detected; however, the results indicate no consistent difference in driving performance and safety.

Electrically evoked compound action potentials of guinea pig and cat: responses to monopolar, monophasic stimulation.

We recorded electrically evoked compound action potentials (EAPs) from guinea pigs and cats using monophasic current pulses delivered by a monopolar intracochlear electrode. By using simple stimuli, we sought results that could shed light on basic excitation properties of the auditory nerve. In these acute experiments, the recording electrode was placed directly on the auditory nerve. Responses to anodic and cathodic stimulus pulses were recorded separately to evaluate stimulus polarity effects. Several polarity-dependent properties were observed. Both EAP morphology and latency were polarity-dependent, with greater latencies for cathodic stimulation. Threshold stimulus level was also polarity-dependent, but in different directions in the two species: cats had lower cathodic thresholds while guinea pigs had lower anodic thresholds. We also observed that the slopes of the EAP amplitude-level functions depended upon stimulus polarity. In most cases where EAP saturation amplitude could be measured, that amplitude was similar for anodic and cathodic stimuli, suggesting that either stimulus polarity can recruit all fibers, or at least a comparable numbers of fibers. The common findings (e.g., EAP morphology and polarity-dependent latency) observed in these two species suggest results that can be extrapolated to responses obtained in humans, while the species-specific findings (e.g., dependence of threshold on polarity) may point to underlying anatomical differences that caution against overgeneralization across species. Some of our observations also bear upon hypotheses of how electrical stimuli may excite different sites on auditory nerve fibers.

Factors influencing the angular velocity of a human limb segment.

The angular velocity of a knee extension performed after flexion with different range and velocity, i.e. the kicking movement with stabilized thigh, was investigated and described. In addition, the maximum velocity of extension reached after prestretch was compared to that obtained in trials without prestretch. The maximum velocity of extension varied from 213 to 1087 degrees s-1 depending on the range and velocity of prestretch. In trials without prestretch the velocity of extension was worse up to 43% when small range of movement was involved. In trials with full range of movement the velocity of extension was similar in the tasks with and without prestretch. In this context the possible role of elastic energy is discussed. The method used was electrogoniometry.

Surgical management of Bell's palsy.

OBJECTIVES: Incomplete return of facial motor function and synkinesis continue to be long-term sequelae in some patients with Bell's palsy. The aim of this report is to describe a prospective study in which a well-defined surgical decompression of the facial nerve was performed in a population of patients with Bell's palsy who exhibit the electrophysiologic features associated with poor outcomes. In addition, management issues related to Bell's palsy including herpes simplex virus typel etiology, the natural history, electrodiagnostic testing, and efficacy of surgical strategies are reviewed. STUDY DESIGN AND METHODS: A multicenter prospective clinical trial was designed utilizing electroneurography (ENOG) and voluntary electromyography (EMG) to identify patients with Bell's palsy who would most likely develop poor return of facial function, as suggested by Fisch and Esslen. Patients who displayed electrodiagnostic features of poor outcome, >90% degeneration on ENOG testing and no voluntary motor unit EMG potentials within 14 days of onset of total paralysis, were offered a surgical decompression of the facial nerve through a middle cranial fossa surgical exposure, including the tympanic segment, geniculate ganglion, labyrinthine segment, and meatal foramen. Control subjects were those who displayed similar electrodiagnostic features and time course. RESULTS: Subjects who did not reach 90% degeneration on ENOG within 14 days of paralysis all returned to House-Brackmann grade I (n = 48) or II (n = 6) at 7 months after onset of the paralysis. Control subjects self-selecting not to undergo surgical decompression when >90% degeneration on ENOG and no motor unit potentials on EMG were identified had a 58% chance of developing a poor outcome at 7 months after onset of paralysis (House-Brackmann grade III or IV [n = 19]). A group with similar ENOG and EMG findings undergoing middle fossa facial nerve decompression exhibited House-Brackmann grade I (n = 14) or II (n = 17) in 91% of the cases. An exact permutation test confirmed that the surgical group had a significantly higher proportion of patients with a good outcome (House-Brackmann grade I or II) (P = .0002). CONCLUSION: Electroneurography in combination with voluntary EMG successfully identified patients who will most likely return to normal from those who had a greater chance of long-term sequelae from Bell's palsy. Surgical decompression medial to the geniculate ganglion significantly improves the chances of normal or near-normal return of facial function in the group that has a high probability of a poor result. Surgical decompression must be performed within 2 weeks of onset of total paralysis for it to be effective.

Evaluation of five different cochlear implant designs: audiologic assessment and predictors of performance.

The audiologic performance of 54 postlingually deafened adults wearing cochlear implants was uniformly evaluated. The participants had 9 months' or more experience with one of five different cochlear prostheses (Los Angeles Single Channel (N = 11), Vienna Single Channel (N = 4), Melbourne Multichannel (N = 18), Utah Multichannel (N = 19), San Francisco Multichannel (N = 2). The multichannel designs enabled participants to recognize more environmental sounds, provided more speech reading enhancement, and enabled most users to understand limited speech in the sound-only condition, compared to the single-channel implant group.

Speech perception by prelingually deaf children using cochlear implants.

In this investigation we measured the performance of 50 prelingually deaf children on several speech perception tests. Children were from 2 to 15 years of age, and some children were tested with as much as 5 years of cochlear implant use. Speech perception tests included the recognition of stress pattern, consonants, vowels, words, and sentences. The audiovisual perception of consonants was also measured. Average results indicated that gains were being made in the perception of stress and words in a closed-set context within 1 year from implantation. The perception of words in an open-set context demonstrated much slower increases over time. Large individual differences were observed. Some preliminary data suggest that children who receive implants before the age of 4 years obtain higher scores, on average, than children who receive implants after the age of 5 years. Some children become part-time users or nonusers of their cochlear implants. The average results from 18 congenitally deaf children were significantly higher than the average results from 12 children with prelingually acquired deafness after 3 years of implant use. Information on vowel and consonant features shows increases in performance after 2 years of cochlear implant use, with the exception of the place feature. For this feature, no changes were observed. Vision-alone testing indicated that lipreading performance increased over time. An audiovisual enhancement provided by the cochlear implant was observed for all features.

Multivariate predictors of audiological success with multichannel cochlear implants.

To predict the audiological outcomes of 2 multichannel cochlear implants, a preoperative battery of historical, audiological, electrophysiologic, and psychologic variables from 48 postlingually deafened adults was tested in a prospective randomized clinical trial. Multivariate analyses were used to select and combine these preoperative variables in a predictive index that was significantly related to audiological outcome at 9 months. The preoperative variables included in the predictive index were duration of profound deafness, speech reading ability, residual hearing, cognitive ability, measures of compliance and engagement with treatment, and use of nonverbal communication strategies. The preoperative predictive index had correlations of .81 with the Iowa Sentences Test, and .78 with the NU-6 word understanding scores, both obtained in a sound-only test. Probability and percentile curves generated from these data offer considerable optimism in forecasting the range of likely audiological outcomes that would be realized by postlingually deafened adult candidates for multichannel cochlear implants.

Psychological predictors of audiological outcomes of multichannel cochlear implants: preliminary findings.

The purpose of this research was to determine whether psychological variables were associated with the variability that characterizes the audiological performance of recipients of multichannel cochlear implants. Twenty-nine consecutive recipients of multichannel implants participated in a preoperative psychological assessment and audiological follow-up assessments after 18 months of implant use. Experimental cognitive measures that assess an ability to rapidly detect and respond to features imbedded in sequentially arrayed information accounted for up to 30% of the variance in implant outcome, suggesting the importance of cognitive abilities in implant outcome. Standardized measures of intellectual ability, however, were not predictive of outcome. The Health Opinion Survey, a measure of participatory engagement, was also a significant predictor of audiological outcome. Overall, the results implicated the importance of several specific psychological factors in the audiological outcome of cochlear implants in postlingually deafened adult recipients.

Psychological change following 18 months of cochlear implant use.

Consecutive recipients of multichannel cochlear implants participated in preimplant as well as 9-month and 18-month psychological evaluations. Before receiving a cochlear implant, psychological tests indicated that the implant recipients were more depressed, suspicious, socially isolated, lonely, and socially anxious than was the general population. After 18 months of implant use, there was a significant reduction in depression, loneliness, social anxiety, social isolation, and suspiciousness. These changes in psychological state did not correlate with improved performance on audiological measures. The data suggest that although cochlear implants can have a positive effect on the emotional and behavioral status of persons with acquired postlingual profound deafness, the psychological outcome of implants is not simply a function of the audiological benefit assessed with standardized speech-based audiological tests.

Age-related changes in motor control during articulator visuomotor tracking.

The present study provides normative data on changes in visuomotor control of the oral-facial system across the lifespan. Control of the lower lip, jaw, and larynx (i.e., fundamental frequency) was examined using a nonspeech visuomotor tracking (VMT) task, where subjects move the articulator of interest to track a moving target on an oscilloscope screen. This task examines articulator motor control during movements that are similar to speech but that do not impose linguistic units or the demands of coordinating multiple structures. Accuracy and within- and between-subject variability in tracking performance were measured by cross correlation, gain ratio, phase shift, and target-tracker amplitude difference. Cross-correlation analyses indicated that performance of children (aged 8;2 to 17;0 [years;months]) and older adults (aged 45;1 to 84;3) is poorer than that of younger adults (aged 17;1 to 45;0). Accuracy of movement amplitude tended to increase during development and decline with aging, whereas age did not appear to influence accuracy of temporal parameters in lip and jaw tracking. In contrast, age tended to influence individual variability in temporal but not amplitude parameters. Differences were noted between articulators. The data complement previous studies that considered accuracy and variability of articulator movement during speech. The VMT method and the data provided may be applied to assessment of impairments in the motor speech system and to differential diagnosis of motor speech versus linguistically based disorders.

Cochlear implant use by prelingually deafened children: the influences of age at implant and length of device use.

This study focused on long-term speech perception performances of 34 prelingually deafened children who received multichannel cochlear implants manufactured by Cochlear Corporation. The children were grouped by the age at which they received cochlear implants and were characterized by the amount of time they used their device per day. A variety of speech perception tests were administered to the children at annual intervals following the connection of the external implant hardware. No significant differences in performance are evident for children implanted before age 5 compared to children implanted after age 5 on closed-set tests of speech perception ability. All children demonstrated an improvement in performance compared to the pre-operative condition. Open-set word recognition performance is significantly better for children implanted before age 5 compared to children implanted after age 5 at the 36-month test interval and the 48-month test interval. User status, defined by the amount of daily use of the implant, significantly affects all measures of speech perception performance except pattern perception.

Preliminary results with the Clarion cochlear implant in postlingually deaf adults.

A clinical trial of three different multichannel cochlear implants is in progress at The University of Iowa. Fifty postlingually deaf adults participated in a prospective randomized study of the Nucleus implant and the Ineraid device. Subsequently, 23 consecutive postlingually deaf adults have been implanted with the Clarion system. The speech perception performance obtained after 9 months of implant use with all devices was compared. In addition, Clarion patient results at 9 months were compared with long-term (36 months) results from subjects using the other two multichannel implants. Preliminary speech perception scores on the Iowa sentence test (sound-only) and NU-6 words (sound-only) demonstrate that the Clarion subjects, as a group, perform at higher levels than subjects using the other two systems. A wide range of performance is observed with all devices. The continuous interleaved pulsatile strategy of the Clarion device appears to be advantageous for this group of subjects.

Timbral recognition and appraisal by adult cochlear implant users and normal-hearing adults.

The purpose of this study was to examine the appraisal and recognition of timbre (four different musical instruments) by recipients of Clarion cochlear implants (CIS strategy, 75- or 150-microsec pulse widths) and to compare their performance with that of normal-hearing listeners. Twenty-eight Clarion cochlear implant users and 41 normal-hearing listeners were asked to give a subjective assessment of the pleasantness of each instrument using a visual analog scale with anchors of "like very much" to "dislike very much," and to match each sound with a picture of the instrument they believed had produced it. No significant differences were found between the two different pulse widths for either appreciation or recognition; thus, data from the two pulse widths following 12 months of Clarion implant use were collapsed for further analyses. Significant differences in appraisal were found between normal-hearing listeners and implant recipients for two of the four instruments sampled. Normal-hearing adults were able to recognize all of the instruments with significantly greater accuracy than implant recipients. Performance on timbre perception tasks was correlated with speech perception and cognitive tasks.

Deriving passage difficulties for a tracking study via the Cloze technique.

The current report demonstrates the importance of formally accounting for passage difficulty when using the tracking procedure. Cloze responses to 82 encyclopedia excerpts (343-349 words each) were obtained from a large pool of normal-hearing adults and scored verbatim. Passage difficulty, derived via ANOVA, was then defined as the deviation of a passage's mean Cloze score from the score for all passages, corrected for differences among respondents. The passage difficulties were applied in an alternating conditions tracking experiment with one adult cochlear implant user. Conditions included conventional auditory-visual and auditory-only tracking and experimental mode-switching techniques in which the talker changed modalities during the correction phase. An ANCOVA of the word-per-minute scores was conducted, with passage difficulty as a covariate and passage adjustment values as the output. Tracking rates and percentage of words correct from the beginning and end of training were examined. Use of adjusted data reversed the interpretation of performance change, demonstrating the need for determining passage difficulties a priori.