Practical Strategies and Tools for Use by Occupational and Environmental Medicine Departments During COVID-19 Pandemic Surges.

OBJECTIVES: Occupational and environmental medicine (OEM) departments in healthcare institutions can be quickly overwhelmed when COVID-19 infection rates rapidly and simultaneously increase in the workforce and the patients served. Our goal is to present a detailed toolkit of practical approaches for use by front-line OEM specialists to address workforce management tasks during pandemic surges. METHODS: Specific focus is on tasks related to employee symptom triage, exposure risk assessment, workplace contact tracing, and work restrictions. RESULTS: Tools include strategies used by customer call centers, two decision support algorithms (exposure due to cohabitation or non-cohabitation), a color-coded employee case tracking tool, a contact tracing protocol, and documentation templates that serve as memory aids for encounters. CONCLUSIONS: These tools are created with commonly used software. Implementation is feasible in most front-line OEM settings, including those with limited resources.

Non-invasive approaches to functional recovery after spinal cord injury: Therapeutic targets and multimodal device interventions.

This paper is an interdisciplinary narrative review of efficacious non-invasive therapies that are increasingly used to restore function in people with chronic spinal cord injuries (SCI). First presented are the secondary injury cascade set in motion by the primary lesion and highlights in therapeutic development for mitigating the acute pathophysiologic process. Then summarized are current pharmacological strategies for modulation of noradrenergic, serotonergic, and dopaminergic neurotransmission to enhance recovery in bench and clinical studies of subacute and chronic SCI. Last examined is how neuromechanical devices (i.e., electrical stimulation, robotic assistance, brain-computer interface, and augmented sensory feedback) could be comprehensively engineered to engage efferent and afferent motosensory pathways to induce neuroplasticity-based neural pattern generation. Emerging evidence shows that computational models of the human neuromusculoskeletal system (i.e., human digital twins) can serve as functionalized anchors to integrate different neuromechanical and pharmacological interventions into a single multimodal prothesis. The system, if appropriately built, may cybernetically optimize treatment outcomes via coordination of heterogeneous biosensory, system output, and control signals. Overall, these rehabilitation protocols involved neuromodulation to evoke beneficial adaptive changes within spared supraspinal, intracord, and peripheral neuromuscular circuits to elicit neurological improvement. Therefore, qualitatively advancing the theoretical understanding of spinal cord neurobiology and neuromechanics is pivotal to designing new ways to reinstate locomotion after SCI. Future research efforts should concentrate on personalizing combination therapies consisting of pharmacological adjuncts, targeted neurobiological and neuromuscular repairs, and brain-computer interfaces, which follow multimodal neuromechanical principles.

Beyond pros and cons - developing a patient decision aid to cultivate dialog to build relationships: insights from a qualitative study and decision aid development.

BACKGROUND: An individualized approach using shared decision-making (SDM) and goal setting is a person-centred strategy that may facilitate prioritization of treatment options. SDM has not been adopted extensively in clinical practice. An interprofessional approach to SDM with tools to facilitate patient participation may overcome barriers to SDM use. The aim was to explore decision-making experiences of health professionals and people with diabetes (PwD), then develop an intervention to facilitate interprofessional shared decision-making (IP-SDM) and goal-setting. METHODS: This was a multi-phased study. 1) Feasibility: Using a descriptive qualitative study, individual interviews with primary care physicians, nurses, dietitians, pharmacists, and PwD were conducted. The interviews explored their experiences with SDM and priority-setting, including facilitators and barriers, relevance of a decision aid for priority-setting, and integration of SDM and a decision aid into practice. 2) Development: An evidence-based SDM toolkit was developed, consisting of an online decision aid, MyDiabetesPlan, and implementation tools. MyDiabetesPlan was reviewed by content experts for accuracy and comprehensiveness. Usability assessment was done with 3) heuristic evaluation and 4) user testing, followed by 5) refinement. RESULTS: Seven PwD and 10 clinicians participated in the interviews. From interviews with PwD, we identified that: (1) approaches to decision-making were diverse and dynamic; (2) a trusting relationship with the clinician and dialog were critical precursors to SDM; and, (3) goal-setting was a dynamic process. From clinicians, we found: (1) complementary (holistic and disease specific) approaches to the complex patient were used; (2) patient-provider agendas for goal-setting were often conflicting; (3) a flexible approach to decision-making was needed; and, (4) conflict could be resolved through SDM. Following usability assessment, we redesigned MyDiabetesPlan to consist of data collection and recommendation stages. Findings were used to finalize a multi-component toolkit and implementation strategy, consisting of MyDiabetesPlan, instructional card and videos, and orientation meetings with participating patients and clinicians. CONCLUSIONS: A decision aid can provide information, facilitate clinician-patient dialog and strengthen the therapeutic relationship. Implementation of the decision aid can fit into a model of team care that respects and exemplifies professional identity, and can facilitate intra-team communication. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02379078. Date of Registration: 11 February 2015.

Caffeine content of Nespresso® pod coffee.

BACKGROUND:: Little independent information on the caffeine content of the popular Nespresso® coffee pod range exists. AIM:: To quantify the caffeine content of Nespresso® pod coffees. METHODS:: Initially, three serves (ristretto (S), espresso (M), lungo (L)) of two pod varieties (Livanto and Roma) were prepared on three different Nespresso® machines (2 × U-Delonghi (1 × 5 years since purchase (old), 1 × recently purchased (new)), 1 × new Lattissima Pro (alternate)) using two different batches (sleeves). Caffeine content was then determined via triplicate samples using high-performance liquid chromatography. Differences in content (i.e. serve size, machine or sleeve) were determined via an analysis of variance or paired sample t-tests. RESULTS:: Coffees prepared on different machines or pods from different sleeves did not influence the caffeine content (old = 63 ± 13, new = 60 ± 8, alternate = 60 ± 10 mg·serve-1; p = 0.537, sleeveA = 63 ± 11, sleeveB = 59 ± 9 mg·serve-1; p = 0.134). Less caffeine was delivered in S (51 ± 7 mg·serve-1) compared to larger sizes (M = 66 ± 7 and L = 66 ± 10 mg·serve-1). Subsequently, the caffeine content from two serve sizes (S and L) from 17 other varieties within the Nespresso® range was determined and compared to the manufacturer's values. Caffeine content (all pods) ranged from 19 to 147 mg·serve-1, and represented 51-162% of manufacturer's values. CONCLUSION:: Nespresso® consumers are exposed to variable amounts of caffeine, which often differ from the manufacturer's reports.

Caffeine content of pre-workout supplements commonly used by Australian consumers.

The stimulant properties of caffeine are often promoted in pre-workout supplements (PWS) to assist with training, reduce the perception of fatigue, and for some brands, assist body fat loss. While manufacturers of PWS often indicate the inclusion of significant amounts of caffeine, no independent verification of the caffeine content of these products exists. The aim of this investigation was to independently assess the caffeine content of popular PWS in Australia and compare these values to nutrition information panel data. Fifteen PWS were tested for their caffeine content (both within and between batches of the same product). The caffeine content of selected PWS ranged from 91 to 387 mg·serve-1 . Only 6 of the 15 PWS nutrition information panels included details on caffeine content. The percent of caffeine present ranged from 59% to 176% of packaging claims. All but one PWS contained a variation of caffeine within and between batches that was considered "practically" significant (ie, ≥40 mg·serve-1 variation). Consumers are likely to be exposed to large and variable caffeine doses if ingesting PWS. Product information panels do little to improve consumer awareness of likely caffeine intakes.

Cumulative Burden of Glucocorticoid-related Adverse Events in Patients with Systemic Lupus Erythematosus: Findings from a 12-year Longitudinal Study.

OBJECTIVE: The aim of this population-based study is to examine the adverse events (AE) associated with longitudinal systemic glucocorticoid (GC) use among an ethnic Chinese systemic lupus erythematosus (SLE) cohort. METHODS: Our study subjects were patients with newly diagnosed SLE aged 18 and older who received at least 1 prescription of systemic GC between 2001 and 2012 from Taiwan's National Health Insurance Research Database (NHIRD). The earliest prescription date of systemic GC for each subject was defined as the index date. For each subject, we calculated the average prednisolone-equivalent dose and the medication possession ratio (MPR) of GC use every 90 days for each patient after the index date. Patients with a diagnosis of AE (defined by the International Classification of Diseases-9-Clinical Modification diagnosis code) during the followup were also identified from the NHIRD. Generalized estimating equations adjusted for propensity score were applied to examine the association between longitudinal GC use and risks of prespecified AE (musculoskeletal, gastrointestinal, ophthalmologic, infectious, cardiovascular, neuropsychiatric, metabolic, and dermatologic diseases). RESULTS: We identified 11,288 patients with SLE (mean followup: 6.28 yrs). Higher doses and higher MPR of GC were associated with increased risk of osteonecrosis [adjusted OR (aOR) 2.87-9.09]. Similar results were found regarding the risk of osteoporosis (aOR 1.71-3.67), bacterial infection (aOR 2.12-3.89), Cushingoid syndrome (aOR 6.51-62.03), and sleep disorder (aOR 1.42-3.59). CONCLUSION: To our knowledge, this is the first study to show that the dose and intensity of longitudinal use of GC were both associated with risk of AE among a nationwide Asian SLE cohort.

Identification of sperm mRNA biomarkers associated with testis injury during preclinical testing of pharmaceutical compounds.

The human testis is sensitive to toxicant-induced injury but current methods for detecting adverse effects are limited, insensitive and unreliable. Animal studies use sensitive histopathological endpoints to assess toxicity, but require testicular tissue that is not available during human clinical trials. More sensitive and reliable molecular biomarkers of testicular injury are needed to better monitor testicular toxicity in both clinical and preclinical. Adult male Wistar Han rats were exposed for 4weeks to compounds previously associated with testicular injury, including cisplatin (0, 0.2, 0.3, or 0.4mg/kg/day), BI665915 (0, 20, 70, 100mg/kg/d), BI665636 (0, 20, 100mg/kg/d) or BI163538 (0, 70, 150, 300mg/kg/d) to evaluate reproductive toxicity and assess changes in sperm mRNA levels. None of the compounds resulted in any significant changes in body, testis or epididymis weights, nor were there decreases in testicular homogenization resistant spermatid head counts. Histopathological evaluation found that only BI665915 treatment caused any testicular effects, including minor germ cell loss and disorganization of the seminiferous tubule epithelium, and an increase in the number of retained spermatid heads. A custom PCR-array panel was used to assess induced changes in sperm mRNA. BI665915 treatment resulted in a significant increase in clusterin (Clu) levels and decreases in GTPase, IMAP family member 4 (Gimap4), prostaglandin D2 synthase (Ptgds) and transmembrane protein with EGF like and two follistatin like domains 1 (Tmeff1) levels. Correlation analysis between transcript levels and quantitative histopathological endpoints found a modest association between Clu with retained spermatid heads. These results demonstrate that sperm mRNA levels are sensitive molecular indicators of testicular injury that can potentially be translated into a clinical setting.

Effect of Coffee in Lipopolysaccharide-Induced Indoleamine 2,3-Dioxygenase Activation and Depressive-like Behavior in Mice.

Research has identified a potential inverse correlation between coffee consumption and the risk of depression. The aim of this study was to investigate the effects of caffeinated coffee on lipopolysaccharide-induced depressive-like behaviors and inflammatory biomarkers in an in vivo model of depression in a C57BL/6J mouse model. The behavioral studies showed that caffeinated coffee decreased immobility time in both the tail suspension test (caffeinated coffee 56.60 ± 9.17; p < 0.0001) and the forced swimming test (caffeinated coffee 28.80 ± 5.93; p < 0.0001), suggesting antidepressant-like activity. The effects of caffeinated coffee on the inflammatory biomarkers associated with depression supported the results observed in the behavioral studies. Statistically significant decreases in indoleamine 2,3-dioxygenase activity (p < 0.001) and the neopterin/biopterin ratio (p < 0.001) were observed in animals pretreated with caffeinated coffee 24 h post-lipopolysaccharide exposure in comparison to the lipopolysaccharide control group. In conclusion, this study has provided evidence to suggest that caffeinated coffee has antidepressant-like activities; however, further studies are required to fully investigate these effects.

Evaluation of correlations between frequencies of complete denture relines and serum levels of 3 bone metabolic markers: A cross-sectional pilot study.

STATEMENT OF PROBLEM: Continuous bone resorption is the primary reason for complete denture relines. Because resorption rates vary, the frequency at which individuals require relines also varies. Currently, there are no predictors to identify individuals at risk of frequent relines or to guide clinicians in decisions related to relines. PURPOSE: The purpose of this cross-sectional pilot study was to determine the utility of measuring bone metabolic markers (C-terminal telopeptide, osteocalcin, 25-OH hydroxy vitamin D) to predict the frequency of complete denture relines. MATERIAL AND METHODS: One hundred adult participants with complete dentures (either maxillary, mandibular, or both) participated in 1 dental clinic visit involving a dental examination and brief interview to obtain relevant medical and dental history, information on medication/supplement use, and 1 laboratory blood draw for the measurement of bone metabolic markers. Data were analyzed by using the Pearson correlation, independent Student t test, or analysis of variance (α=.05). RESULTS: Significant correlations were found between the frequency of relines and C-telopeptide and osteocalcin levels but not with vitamin D or age. No significant associations with reline frequency and other factors (sex, ethnicity, presence or absence of diabetes, use of calcium and vitamin D supplements) were observed. CONCLUSIONS: Elevated levels of bone turnover markers in individuals with edentulism were associated with increased frequency of denture relines.

Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network.

PURPOSE: To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients. METHODS: A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists. RESULTS: In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib. CONCLUSIONS: Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.

Ghrelin ameliorates adhesions in a postsurgical mouse model.

BACKGROUND: Peritoneal adhesion formation is a well-recognized consequence of abdominal and pelvic surgery, causing infertility, chronic pelvic pain, and intestinal obstruction. We hypothesized that ghrelin, a 28-amino acid peptide predominantly found in the stomach, plays an important role in preventing postoperative surgical adhesions. The purpose of this study was to develop a new surgical peritoneal adhesion model to define the role that ghrelin plays in wound healing and adhesion formation. MATERIALS AND METHODS: C57BL/6 wild-type mice (n = 40) and growth hormone secretagogue receptor-knockout (GHSR KO) mice (n = 20) underwent a midline laparotomy to establish a peritoneal adhesion model characterized by the combination of two different techniques: ischemic peritoneal buttons and cecal multiple abrasion. All mice received intraperitoneal injections with ghrelin (0.16 mg/kg) or saline twice daily for 20 d after surgery. Peritoneal ischemic buttons were harvested to determine protein expression of collagen (Masson trichrome, picrosirius red stain, and Western blot). RESULTS: The novel mouse model demonstrated consistent and easily reproducible formation of intra-abdominal adhesions. Ghrelin administration significantly reduced postoperative adhesion formation (P < 0.001) in wild-type mice. The antifibrotic effect of ghrelin in wild-type mice was confirmed by measuring collagen I protein levels via Western blot analysis. The anti-adhesion effect of ghrelin seen in wild-type mice was not detected in GHSR KO mice demonstrating that this effect is mediated by the GHSR-1a receptor. CONCLUSIONS: Ghrelin administration may improve surgical outcome by reducing peritoneal adhesion formation and fibrotic response in a mouse model.

Using technology to deliver cancer follow-up: a systematic review.

BACKGROUND: People with cancer receive regular structured follow up after initial treatment, usually by a specialist in a cancer centre. Increasing numbers of cancer survivors prompts interest in alternative structured follow-up models. There is worldwide evidence of increasing interest in delivering cancer follow-up using technology. This review sough evidence supporting the use of technology in cancer follow-up from good quality randomised controlled trials. METHOD: A search strategy was developed to identify randomised controlled trials and reviews of randomised trials of interventions delivering some aspect of structured cancer follow-up using new technologies. Databases searched were: All EBM Reviews; Embase; Medline (No Revisions); Medline (Non-Indexed Citations), and CAB Abstracts. Included articles were published in English between 2000 and 2014. Key words were generated by the research question. Papers were read independently and appraised using a standardised checklist by two researchers, with differences being resolved by consensus [J Epidemiol Community Health, 52:377-384, 1998]. Information was collected on the purpose, process, results and limitations of each study. All outcomes were considered, but particular attention paid to areas under consideration in the review question. RESULTS: The search strategy generated 22879 titles. Following removal of duplicates and abstract review 17 full papers pertaining to 13 randomised controlled studies were reviewed. Studies varied in technologies used and the elements of follow-up delivered, length of follow-up, tumour type and numbers participating. Most studies employed only standard telephone follow-up. Most studies involved women with breast cancer and included telephone follow-up. Together the results suggest that interventions comprising technology had not compromised patient satisfaction or safety, as measured by symptoms, health related quality of life or psychological distress. There was insufficient evidence to comment on the cost effectiveness of technological cancer follow-up interventions. CONCLUSIONS: Modern technology could deliver cancer follow-up that is acceptable and safe. More research is required to develop cancer follow-up systems which exploit modern technology, which should be assessed using randomised trials, with consistent outcomes, so that evidence on the acceptability, safety, cost effectiveness and impact in quality of life of technological follow-up can accumulate and be made available to patients, professionals and policy makers.

The three-channel model of sound localization mechanisms: interaural time differences.

Previous psychophysical work on sound localization in humans has proposed that a midline channel be added to the current two-channel model of mammalian sound localization mechanisms. Evidence for this third channel has been found in interaural time difference (ITD) studies with low-frequency tones, and interaural level difference (ILD) studies with both high- and low-frequency tones. The latter is interesting because it suggests that, despite the fact that low frequencies do not generate significant ILDs for humans in natural settings, there is a constancy of ILD coding mechanisms across the frequency domain. To complement this finding, the present study sought to determine whether the three-channel model holds for ITDs at high frequencies. In three experiments, a selective adaptation paradigm was used in combination with transposed tones to probe for the existence of three (left, right, and midline) perceptual channels for sound source azimuth. The experiments provided evidence for lateral hemifield ITD channels but little evidence for a midline ITD channel at high frequencies.

Low dietary or supplemental zinc is associated with depression symptoms among women, but not men, in a population-based epidemiological survey.

BACKGROUND: Prior studies indicate that the biochemical alterations of depressive episodes result in decreased serum zinc concentrations. Given these findings, it is plausible that consistently low dietary zinc intakes contribute to depressive symptoms, yet epidemiological data are lacking. The authors tested the hypothesis that low zinc intake is associated with depressive symptoms using cross-sectional data from the population-based Boston Area Community Health survey (2002-2005). METHODS: Dietary and supplement use data were collected by validated food frequency questionnaire. Current depressive symptoms were assessed by the abridged validated Center for Epidemiologic Studies Depression scale and analyzed using multivariate logistic regression, adjusting for sociodemographic, health and lifestyle characteristics. RESULTS: Results showed an interaction (P=0.03) with gender, whereby zinc was associated with depressive symptoms in women (N=2163), but not men (N=1545). Women with low dietary or supplemental zinc intake were more likely to have depressive symptoms (e.g., dietary zinc quartile 1 vs. 4, OR=1.76, 95% CI: 1.26, 2.45; P-trend=0.004; supplemental zinc P-trend=0.03). Associations were stronger among women using antidepressant medications (e.g., total zinc OR=4.75, 95% CI: 1.98, 11.4; P-trend=0.0005). LIMITATIONS: The cross-sectional, observational nature of the study leaves uncertain whether the observed associations represent actual causal relationships between zinc intake and depressive symptoms. CONCLUSIONS: These findings suggest: (1) gender-specific pathophysiological mechanisms of depression, (2) inadequate dietary zinc intake contributes to depressive symptoms in women, and (3) supplemental zinc is a beneficial adjunct to antidepressant therapy in women. Additional research on both men and women is needed to verify these novel findings. If confirmed by other studies, the potential importance of adequate zinc intake is underscored by the recognized limitations of pharmacotherapy for depression.

Is non-therapeutic aspirin use in children a problem in South Africa?

BACKGROUND: Aspirin should not be used in children except for specific therapeutic reasons. We report on a severely ill infant who had ingested aspirin contained in a traditional medicine and review 21 other patients with pre-admission non-therapeutic salicylate exposure. OBJECTIVES AND METHODS: We reviewed laboratory, clinical and poisons unit records to determine how many children were admitted to our hospital over an 18-month period with evidence of salicylate ingestion not prescribed for therapeutic reasons. We determined the source of the salicylate, elapsed time between ingestion and laboratory assay, morbidity and mortality and final diagnosis. RESULTS: Twenty-one children meeting our criteria, including 9 under 6 months of age, were admitted during this period. The most prevalent source of salicylate was over-the-counter (OTC) aspirin, but some had reportedly only been given traditional medicines. Nineteen were seriously ill, 4 died and 3 had severe brain injury. Two, initially diagnosed with Reye's syndrome, probably had inherited metabolic disorders. Only 2 patients had salicylate levels that at the time of measurement are normally considered toxic; however, the literature suggests that lower levels may exacerbate illness severity in young children. CONCLUSIONS: We found inappropriate use of OTC aspirin in children that requires explanation. There may be policy implications for the content and presentation of patient information; the incorporation of pharmaceuticals in traditional medicines merits further study. Salicylate toxicity should be considered in children with unexplained metabolic acidosis out of keeping with the severity of their acute illness.

A midline azimuthal channel in human spatial hearing.

Neurophysiological and psychophysical evidence has driven the formulation of a hemifield model of mammalian sound localization in which the perceived location of a stimulus is based on the relative activity of two hemifield-tuned azimuthal channels that are broadly responsive to contralateral auditory space and have overlapping medial borders. However, neurophysiological work in mammals has consistently found neurons selective for sound sources at the midline, which may indicate the existence of a third, 'midline', perceptual channel. In three experiments, the existence of three (left, right, midline) perceptual channels for azimuth in man was examined using auditory selective adaptation paradigms. If no midline channel exists, exposure to highly lateralized, symmetrical adaptor frequencies should not result in a shift in the perceived intracranial location of subsequent test tones away from the adaptors because the relative activation of the two hemifield channels will remain the same. Rather, our results indicate a shift in perceived test tones towards the azimuthal midline. This result can best be explained by a perceptual/neural channel tuned to sounds located along the midline. The present study gives the first psychophysical evidence of a midline channel serving human auditory localization, adding to the earlier evidence on the same point from animal neurophysiological studies.

Adaptation of central pitch-specific mechanisms.

Three previous psychophysical studies have demonstrated that interaural time difference (ITD) coding mechanisms can undergo frequency-specific, selective adaptation. We sought to determine whether this phenomenon extends to the pitch domain, by employing the same psycho-physical paradigm as one used previously, but with harmonic tone complexes lacking energy at the fundamental frequency. Ten normal listeners participated in experiment 1. Psychometric functions for ITDs were obtained for harmonic tone complexes with fundamental frequencies of 110 Hz and 185 Hz, before and after selective adaptation with complexes of the same fundamental frequencies lateralised to opposite sides. In experiment 1, each subject was tested twice. On separate days, subjects were tested with 110 Hz and 185 Hz stimuli that were either partially resolvable complexes or unresolvable ones. Both partially resolved and unresolved stimuli supported adaptation, and at both fundamental frequencies. In experiment 2, which employed nine listeners, the adaptor tone complexes were presented in conjunction with a diotic noise background designed to mask difference tones generated by the adaptor stimuli. The use of the masker had little effect on the mean strength of the adaptation effected by the unresolved adaptor stimuli, and only slightly weakened the adaptation effect found with the partially resolved adaptor stimuli. Taken together, these data constitute the first demonstration of selective adaptation exerted on a central mechanism in the pitch domain.

The effects of lateralized adaptors on lateral position judgements of tones within and across frequency channels.

Two experiments examined the effect of highly lateralized adaptor tone pulses on the perceived intracranial location of subsequent test tones. In Experiment 1, adaptor tones of each of two frequencies, highly lateralized to opposite sides by a quarter-period interaural time difference (ITD), were found to shift the perceived intracranial location of test tones of each adaptor frequency away from the side of the adaptor. The shift in perceived location was seen for all test tone ITDs with the same sign as the adaptor tone, and sometimes extended to include test tones with small ITDs favoring the opposite ear. The generality of the effect across test tone ITDs of the same sign as the adaptor suggests that the human auditory lateralization system is built of two (left, right) hemifield-tuned azimuthal channels, and that perceived lateral location depends on the relative outputs of those two channels. In Experiment 2, the perceived location of test tones lateralized by ITD was studied in the same listeners at each of the same two frequencies, but after selective adaptation with tone pulses of only one frequency and laterality. The perceived lateral position of test tones with the same frequency as that of the adaptor underwent the same changes as seen in Experiment 1. The perceived lateral position of test tones of the nonadapted frequency usually shifted weakly in the opposite direction, i.e., in the direction expected if the second adaptor from Experiment 1 had actually been present. These data have implications both for the processes mediating selective adaptation using contingent stimuli, and for the azimuthal tuning of auditory spatial channels in man.

Cytoplasmic YY1 is associated with increased smooth muscle-specific gene expression: implications for neonatal pulmonary hypertension.

Immediately after birth the adluminal vascular SMCs of the pulmonary elastic arteries undergo transient actin cytoskeletal remodeling as well as cellular de-differentiation and proliferation. Vascular smooth muscle phenotype is regulated by serum response factor, which is itself regulated in part by the negative regulator YY1. We therefore studied the subcellular localization of YY1 in arteries of normal newborn piglets and piglets affected by neonatal pulmonary hypertension. We found that YY1 localization changed during development and that expression of gamma-smooth muscle actin correlated with expression of cytoplasmic rather than nuclear YY1. Analysis of the regulation of YY1 localization in vitro demonstrated that polymerized gamma-actin sequestered EGFP-YY1 in the cytoplasm and that YY1 activation of c-myc promoter activity was inhibited by LIM kinase, which increases actin polymerization. Consistent with these data siRNA-mediated down-regulation of YY1 in C2C12 cells increased SM22-alpha expression and inhibited cell proliferation. Thus, actin polymerization controls subcellular YY1 localization, which contributes to vascular SMC proliferation and differentiation in normal pulmonary artery development. In the absence of actin depolymerization, YY1 does not relocate to the nucleus, and this lack of relocation may contribute to the pathobiology of pulmonary hypertension.