A Revised Occupational Stress Measure for Popular Musicians: Pilot Test of Validity and Reliability.

OBJECTIVE: Popular (i.e., nonclassical) musicians have higher rates of depression, anxiety, and suicide than the general population. Occupational and financial stress have been suggested to be social determinants of musician mental health burden. A pilot study was conducted to assess the internal consistency and test-retest reliability of a revised measure of popular musician occupational stress and compare the results to those of other, previously validated instruments used in the same survey. METHODS: An online survey was emailed to a convenience sample of 150 musicians who had formerly accessed mental health services through a non-profit organization in Austin, Texas. The survey included a revised Musician Occupational Stress Scale (MOSS), a measure of financial stress, and instruments to screen for clinically significant depression, anxiety, and alcohol misuse. RESULTS: Forty musicians (26.7%) completed the initial survey and 19 completed a repeat survey 2 weeks later for the test-retest comparison. Internal consistency coefficients for individual instruments ranged from 0.86-0.92. The piloted MOSS demonstrated good internal consistency (Cronbach's α=0.91; one-sided 95% CI ≥0.88) and test-retest reliability (r=0.86; p<0.0001). The MOSS also showed reasonable construct validity, correlating well with a single question of perceived occupational stress (ρ=0.46; p<0.001) over career satisfaction (ρ=-0.09; p>0.05). CONCLUSION: The individual, construct-specific measures included in this survey all demonstrated good internal consistency and test-retest reliability on examination. While the results are preliminary due to the small sample size, the MOSS psychometrically performed at a level equal to or better than other widely used and well-validated measures included in this survey.

Strength limits in mesoscaled 3Y-TZP ceramics for micro-surgical instruments.

Micro-surgical instruments are a new application for mesoscale ceramics formed using the lost mold-rapid infiltration forming (LM-RIF) process. Instrument strength and reliability are the foremost concerns for this sensitive application. It is hypothesized that increasing grain size can improve the damage tolerance of the parts associated with the transformation toughening in the 3Y-TZP material, while retaining high strength. In this work, mesoscale bend bars (314 × 22 × 18 µm) of 3Y-TZP fabricated using the LM-RIF process were heat treated at 1400 °C for 1 h, 8 h, or 16 h, respectively, to obtain samples with different grain sizes. Strength tests were performed under three-point bending and results were evaluated using Weibull statistics. Fractographic and confocal Raman spectroscopic analyses were carried out to interpret the data. Experimental findings showed that the characteristic strength decreased with increasing grain size contrary to the damage tolerance hypothesis. An Orowan-Petch model was recalled to correlate the strength with the flaw size to grain size ratio. At fine grain sizes the strength was controlled by the flaws introduced by the LM-RIF process, whereas at large grain sizes the strength become more grain size controlled. Although larger-grained samples did have a higher propensity to transform, and thus increase toughening, exaggerated grain growth in some of the specimens tested caused an additional flaw population which led to an overall lower strength. Finally, based on the experimental observations and fracture mechanics considerations, we believe that an upper bound of ∼2.5 GPa exists for the strength of mesoscale as-fabricated 3Y-TZP ceramic parts.

A synergistic combination of local tight binding theory and second harmonic generation elucidating surface properties of ZnO nanoparticles.

Zinc oxide (ZnO) in the form of nanoparticles (NPs) is an important nanomaterial due to its catalytic and optoelectronic properties. An interesting aspect of ZnO is that its crystal structure is anisotropic, which leads to a strong 2nd order nonlinear response, such as frequency doubling or second harmonic generation (SHG). In this article we show that not only the bulk but the surface of ZnO NPs in contact with a liquid medium can contribute to the overall SHG. We have developed and applied a synergistic combination of tight binding (TB) theory and optical SHG spectroscopy to determine the surface second order susceptibilities of nearly spherical 33 ± 13 nm crystalline ZnO NPs dispersed in acetonitrile. The corresponding χ and χ were determined to be 0.86 × 10-8 esu and 1.72 × 10-8 esu for the O-terminated surface and 3.28 × 10-8 esu and 6.64 × 10-8 esu for the Zn-terminated surface. A further application of the TB-SHG approach revealed that adsorption of coumarin based dye, which forms a bidentate attachment between the carboxyl and Zn-terminated surface, does not restructure the NP surface significantly to manifest a change in the SHG polarization profile. However, if the dye acts as an independent source of SHG, its orientation on the surface dictates the overall change in the observed SHG. The results highlighted here bear a strong potential to further our knowledge of molecular interactions at the solid-liquid interface of crystalline nanostructures.

Brain structure and verbal function across adulthood while controlling for cerebrovascular risks.

The development and decline of brain structure and function throughout adulthood is a complex issue, with cognitive aging trajectories influenced by a host of factors including cerebrovascular risk. Neuroimaging studies of age-related cognitive decline typically reveal a linear decrease in gray matter (GM) volume/density in frontal regions across adulthood. However, white matter (WM) tracts mature later than GM, particularly in regions necessary for executive functions and memory. Therefore, it was predicted that a middle-aged group (MC: 35-45 years) would perform best on a verbal working memory task and reveal greater regional WM integrity, compared with both young (YC: 18-25 years) and elder groups (EC: 60+ years). Diffusion tensor imaging (DTI) and magnetoencephalography (MEG) were obtained from 80 healthy participants. Objective measures of cerebrovascular risk and cognition were also obtained. As predicted, MC revealed best verbal working memory accuracy overall indicating some maturation of brain function between YC and MC. However, contrary to the prediction fractional anisotropy values (FA), a measure of WM integrity, were not greater in MC (i.e., there were no significant differences in FA between YC and MC but both groups showed greater FA than EC). An overall multivariate model for MEG ROIs showed greater peak amplitudes for MC and YC, compared with EC. Subclinical cerebrovascular risk factors (systolic blood pressure and blood glucose) were negatively associated with FA in frontal callosal, limbic, and thalamic radiation regions which correlated with executive dysfunction and slower processing speed, suggesting their contribution to age-related cognitive decline. Hum Brain Mapp 38:3472-3490, 2017. © 2017 Wiley Periodicals, Inc.

Foamy viral vector integration sites in SCID-repopulating cells after MGMTP140K-mediated in vivo selection.

Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector-transduced human repopulating cells is needed. Human CD34(+) human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT)P140K transgene, transplanted into immunodeficient NOD/SCID IL2Rγ(null) mice, and selected in vivo for gene-modified cells. The retroviral insertion site profile of repopulating clones was examined using modified genomic sequencing PCR. We observed polyclonal repopulation with no evidence of clonal dominance even with the use of a strong internal spleen focus forming virus promoter known to be genotoxic. Our data supports the use of FV vectors with MGMTP140K for HSC gene therapy but also suggests additional safety features should be developed and evaluated.

Characterization of a normal control group: are they healthy?

We examined the health of a control group (18-81years) in our aging study, which is similar to control groups used in other neuroimaging studies. The current study was motivated by our previous results showing that one third of the elder control group had moderate to severe white matter hyperintensities and/or cortical volume loss which correlated with poor performance on memory tasks. Therefore, we predicted that cardiovascular risk factors (e.g., hypertension, high cholesterol) within the control group would account for significant variance on working memory task performance. Fifty-five participants completed 4 verbal and spatial working memory tasks, neuropsychological exams, diffusion tensor imaging (DTI), and blood tests to assess vascular risk. In addition to using a repeated measures ANOVA design, a cluster analysis was applied to the vascular risk measures as a data reduction step to characterize relationships between conjoint risk factors. The cluster groupings were used to predict working memory performance. The results show that higher levels of systolic blood pressure were associated with: 1) poor spatial working memory accuracy; and 2) lower fractional anisotropy (FA) values in multiple brain regions. In contrast, higher levels of total cholesterol corresponded with increased accuracy in verbal working memory. An association between lower FA values and higher cholesterol levels were identified in different brain regions from those associated with systolic blood pressure. The conjoint risk analysis revealed that Risk Cluster Group 3 (the group with the greatest number of risk factors) displayed: 1) the poorest performance on the spatial working memory tasks; 2) the longest reaction times across both spatial and verbal memory tasks; and 3) the lowest FA values across widespread brain regions. Our results confirm that a considerable range of vascular risk factors are present in a typical control group, even in younger individuals, which have robust effects on brain anatomy and function. These results present a new challenge to neuroimaging studies both for defining a cohort from which to characterize 'normative' brain circuitry and for establishing a control group to compare with other clinical populations.

Development and decline of memory functions in normal, pathological and healthy successful aging.

Many neuroimaging studies of age-related memory decline interpret resultant differences in brain activation patterns in the elderly as reflecting a type of compensatory response or regression to a simpler state of brain organization. Here we review a series of our own studies which lead us to an alternative interpretation, and highlights a couple of potential confounds in the aging literature that may act to increase the variability of results within age groups and across laboratories. From our perspective, level of cognitive functioning achieved by a group of elderly is largely determined by the health of individuals within this group. Individuals with a history of hypertension, for example, are likely to have multiple white matter insults which compromise cognitive functioning, independent of aging processes. The health of the elderly group has not been well-documented in most previous studies and elderly participants are rarely excluded, or placed into a separate group, due to health-related problems. In addition, recent results show that white matter tracts within the frontal and temporal lobes, regions critical for higher cognitive functions, continue to mature well into the 4th decade of life. This suggests that a young age group may not be the best control group for understanding aging effects on the brain since development is ongoing within this age range. Therefore, we have added a middle-age group to our studies in order to better understand normal development across the lifespan as well as effects of pathology on cognitive functioning in the aging brain.

Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice.

BACKGROUND: Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma. METHODS: We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo. RESULTS: Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53%; HLA: 89%; VHLA: 100%; P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM-2MD3 cells in the mouse model. CONCLUSION: Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention.

Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector.

One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P<0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P<0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA.

Different strategies for auditory word recognition in healthy versus normal aging.

To explore the effects of commonly encountered pathology on auditory recognition strategies in elderly participants, magnetoencephalographic (MEG) brain activation patterns and performance were examined in 30 elderly [18 controls and 12 elderly with mild cognitive impairment (MCI) or probable Alzheimer's disease (AD)]. It was predicted that participants with known pathology would reveal different networks of brain activation, compared to healthy elderly, which should correlate with poorer performance. Participants heard a list of words representing common objects, twice. After 20 minutes a list of new and old words was presented and participants judged whether each word was heard earlier. MEG responses were analyzed using a semiautomated source modeling procedure. A cluster analysis using all subjects' MEG sources revealed three dominant patterns of activity which correlated with IQ and task performance. The highest performing group revealed activity in premotor, anterior temporal, and superior parietal lobes with little contribution from prefrontal cortex. Performance and brain activation patterns were also compared for individuals with or without abnormalities such as white matter hyperintensities and/or volume reduction evidenced on their MRIs. Memory performance and activation patterns for individuals with white matter hyperintensities resembled the group of MCI/AD patients. These results emphasize the following: (1) general pathology correlates with cognitive decline and (2) full characterization of the health of elderly participants is important in studies of normal aging since random samples from the elderly population are apt to include individuals with subclinical pathology that can affect cognitive performance.

Measuring the fluorescent quantum efficiency of indocyanine green encapsulated in nanocomposite particulates.

We present results of a fluorescent quantum efficiency (Φ(F)) study on the encapsulation of the near-infrared dye indocyanine green (ICG) in bioresorbable calcium phosphate nanoparticles (CPNPs). The Φ(F) (described as the ratio of photons emitted to photons absorbed) provides a quantitative means of describing the fluorescence of an arbitrary molecule. However, standard quantum efficiency measurement techniques provide only the Φ(F) of the smallest fluorescing unit-in the case of a nanoparticle suspension, the nanoparticle itself. This presents a problem in accurately describing the Φ(F) of fluorophores embedded in an inorganic nanoparticle. Combining the incidence of scattering with an evaluation of the differences in local electric field and photochemical environment, we have developed a method to determine the Φ(F) of the constituent fluorescent molecules embedded in such a nanoparticle, which provides a more meaningful comparison with the unencapsulated fluorophore. While applicable to generic systems, we present results obtained by our method for the ICG-CPNP in a phosphate buffered 0.15 M saline solution (PBS, pH 7.4)--specifically, Φ(F, free dye) = 0.027 ± 0.001, Φ(F, particle) = 0.053 ± 0.003, and for the individual encapsulated molecules, Φ(F, molecule) = 0.066 ± 0.004. The method developed also provides insight into the influences of encapsulation and key parameters to engineer resonant enhancement effects from the emission of the encapsulated fluorophores corresponding to an eigenmode of the embedding particle for tailored optical properties.

Temozolomide: Expanding its role in brain cancer.

Management of central nervous system (CNS) malignancies continues to be a therapeutic challenge. Both primary and secondary (metastatic) CNS tumors are frequently resistant to commonly used chemotherapeutic agents. Surgery and radiotherapy provide palliation of symptoms but usually do not lead to curative outcomes. Alkylating agents have been used in the therapy of primary brain cancer for several decades. This group of medications has the ability to penetrate blood-brain barrier, achieving cytotoxic concentrations in cerebrospinal fluid and brain parenchyma. Temozolomide is a second-generation alkylating chemotherapeutic agent, introduced to therapy of primary brain tumors in the 1990s. It has since been approved for the therapy of recurrent and newly diagnosed malignant glioma. Temozolomide offers improved outcomes when used alone or in combination with irradiation. Its role in the therapy of other types of brain cancer, and specifically primary CNS lymphoma, continues to develop. This review will discuss the early stages of development of temozolomide, its introduction into the therapy of glioma, its role in the therapy of elderly patients, mechanisms of resistance and the evolution of its current and future applications.

Education research: neurology residency training in the new millennium.

OBJECTIVE: To survey adult neurology program directors (ANPD) to identify their most pressing needs at a time of dramatic change in neurology resident education. METHODS: All US ANPD were surveyed in 2007 using an instrument adjusted from a 1999 survey instrument. The goal was to characterize current program content, the institution and evaluation of the core competencies, program director characteristics, program director support, the institution of work duty hour requirements, resident support, and the curriculum needs of program directors and programs. RESULTS: A response rate of 82.9% was obtained. There is a significant disconnect between administration time spent by ANPD and departmental/institutional support of this, with ANPD spending approximately 35% of a 50-hour week on administration with only 16.7% salary support. Rearrangement of rotations or services has been the most common mode for ANPD to deal with work duty hour requirements, with few programs employing mid level providers. Most ANPD do not feel work duty hour reform has improved resident education. More residents are entering fellowships following graduation than documented in the past. Curriculum deficiencies still exist for ANPD to meet all Neurology Program Requirements, especially for nontraditional neurology topics outside the conventional bounds of clinical neurology (e.g., practice management). Nearly one quarter of neurology residency programs do not have a meeting or book fund for every resident in the program. CONCLUSIONS: Adult neurology program directors (ANPDs) face multiple important financial and organizational hurdles. At a time of increasing complexity in medical education, ANPDs need more institutional support.

Dominant limb motor impersistence associated with callosal disconnection.

Motor impersistence occurs more frequently after right than left hemispheric lesions. Following a callosal lesion, motor impersistence may thus occur more frequently in the right (dominant) than left limb. After an infarction involving the right medial frontal lobe and corpus callosum, a 66-year-old right-handed man demonstrated right limb motor impersistence on bedside evaluation, which was substantiated experimentally. Results demonstrated hemispatial effects with greater impersistence in the neglected (right) space.

Survey of training programs' means for promoting neurology and attracting trainees.

OBJECTIVE: To determine neurology training opportunities available to medical students and to define factors that influence program choice. METHODS: All neurology residency program directors and a random sample of residents were surveyed. Resident questions related to application, interview, and training experience. Directors' questions focused on ways their department generated interest in clinical neurosciences. RESULTS: Medical schools introduce students to clinical neurology primarily through required clerkships. Contact time averages less than 4 weeks and emphasizes inpatient encounters. Preceptorships with neurology faculty do not exist at almost 40% of schools and only 14% have neuroscience tracks. Nearly all residency applicants matched their first or second choice. The majority declined at least one interview and 39% failed to rank at least one site they visited. When choosing where to apply, the programs' reputation and geographic considerations were paramount. When making a rank list, interactions with faculty and residents at interview were most important. Residents generally reported satisfaction with their programs and attribute morale to supportive relationships with faculty and residents. CONCLUSIONS: Neurology programs may be able to enhance students' impression of neurology through changes in their clinical experience and development of venues for more meaningful relationships with faculty. Attention to the residents' personal needs may increase the likelihood of matching the best available candidates and ensuring their satisfaction.

The Character-line Bisection Task: a new test for hemispatial neglect.

A failure to report or respond to stimuli presented in a portion of space is termed hemispatial neglect. Line bisection and line cancellation are two of the tests used most commonly to assess for neglect. Perhaps, because neglect can be induced by a variety of deficits, neither of these tests used alone is as sensitive as both used together. Hence, the primary purpose of this study was to assess the sensitivity, reliability and validity of a new test called the Character-line Bisection Task (CLBT) that combines features of both the bisection and cancellation tests. Since local attention and language are primarily mediated by and activate the left hemisphere, our second goal was to learn if the CLBT and especially the letter version induce a greater rightward bias than the solid-line bisection task. Eighty patients with acute right hemisphere stroke and 81 controls performed the CLBT that consists of two subtests, the Letter-line and Star-line Bisection tasks. All subjects also completed four conventional tests for neglect (Standard solid-line bisection, line cancellation, Star Cancellation, and figure copying). In the bisection tasks both patients and controls bisected to the right with the CLBT than with the solid-line bisection task, suggesting the CLBT induces asymmetrical hemispheric activation. This enhanced rightward deviation with the CLBT was the same for the Letter-line and Star-line Bisection tasks. In regard to sensitivity, we defined the presence of neglect syndrome based on a total score derived from performance of controls on all six tests. This total score detected 55 (68.8%) patients with neglect. Within this group, the Letter-line and Star-line tasks diagnosed neglect in 50 and 48 patients, respectively, resulting in the highest sensitivities (90.9, 87.3%) of the six tests. Thus, the CLBTs demonstrated higher sensitivities than the other commonly used neglect tests and these new tests can be useful for the detection and quantification of unilateral neglect.

Ideomotor limb apraxia in Huntington's disease: implications for corticostriate involvement.

Ideomotor limb apraxia, a disorder of goal-directed movement, has been attributed to lesions in the frontal and parietal lobes, but the role of subcortical structures is less certain. In order to determine its prevalence in a disorder affecting the basal ganglia and corticostriatal connections, we examined imitation of hand gestures in Huntington's disease (HD) patients. We also assessed the relationship between apraxia and cognitive and motor dysfunction in an effort to better understand the neural underpinnings of apraxia in HD. If damage restricted to the basal ganglia produces ideomotor limb apraxia, then we would expect to find evidence of apraxia in patients who were early in the disease course when selective striatal damage is most common. Such a pattern, however, was not found in our sample. Instead, patients with greater neurological impairment and with a longer duration of disease were more likely than less affected patients to demonstrate apraxia. Apraxia was not related to severity of chorea, but was associated with greater impairment in eye movements, voluntary movements, and verbal fluency. These findings suggest that apraxia in HD results from damage to the corticostriate pathways and the basal ganglia rather than from damage restricted to the basal ganglia.

Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease.

The antioxidant N-acetylcysteine (NAC) or placebo was administered in a double-blind fashion to patients who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD. Testing for efficacy occurred after 3 and 6 months of treatment. Comparison of interval change favored NAC treatment on nearly every outcome measure, although significant differences were obtained only for a subset of cognitive tasks.

Sneddon's syndrome: a cause of cognitive decline in young adults.

OBJECTIVE: To review the clinical, psychometric, laboratory, and radiologic findings of 6 patients with Sneddon's syndrome (SS) who presented with cognitive dysfunction rather than stroke. DESIGN AND METHODS: Case series. All patients fulfilled were diagnosed as SS based on the co-occurrence of livedo racemosa and neurologic disease. Patients presenting with clinical stroke were excluded. RESULTS: Patients presented with cognitive complaints at an early age and all noted skin lesions from 6 months to 10 years before onset of cognitive symptoms. Associated systemic disorders included hypertension and seizures. Laboratory evidence of a hypercoagulable condition was identified in 4 of 6 cases. Brain MRI scans demonstrated atrophy, especially in parieto-occipital regions and cerebral blood flow on brain SPECT scan was reduced in a similar distribution. CONCLUSION: Patients with SS can develop dementia without antecedent clinical stroke. While the specific pathogenic mechanism of dementia in SS remains speculative, the disease predominantly injures brain tissue in vascular "watershed" territories.