The Impact on Environmental Health from Cemetery Waste in Middle Tennessee.

The burial of caskets with arsenic-treated wood and formaldehyde-based embalming fluids can harm the environment and health. Arsenic (As) can leach into water, affecting aquatic life and the food chain. Formaldehyde can contaminate groundwater, risking drinking water and causing health problems. The purpose of this study was to investigate the prevalence of As and formaldehyde in cemetery plots of different ages. For this, we evaluated whether there is a potential for formaldehyde and As from cemetery caskets to contaminate waterways, which could impact livestock and allow transmission to individuals. There were six soil samples (n = 6), collected at 2 m depth, close to the buried caskets, as well as two (n = 2) groundwater samples (soil + groundwater) collected from a cemetery in Middle Tennessee. The soil was analyzed by an environmental lab using EPA 8315A for formaldehyde and EPA 3050B for As. All samples were below the limit of detection (

A Cross-Sectional Study of Myopia and Morning Melatonin Status in Northern Irish Adolescent Children.

Purpose: Previous studies have demonstrated an association between melatonin status and both refractive error and axial length in young adult myopes. This study aimed to determine if this relationship extends to a younger adolescent cohort. Methods: Healthy children aged 12-15 years provided morning saliva samples before attending Ulster University (55°N) for cycloplegic autorefraction and axial length measures. Participants completed questionnaires describing recent sleep habits and physical activity. Salivary melatonin was quantified using high-performance liquid chromatography-tandem mass spectrometry. Data collection for all participants occurred over a 1-week period (April 2021). Results: Seventy participants aged 14.3 (95% CI: 14.2-14.5) years were categorised by spherical equivalent refraction [SER] (range: -5.38DS to +1.88DS) into two groups; myopic SER ≤ -0.50DS (n = 22) or nonmyopic -0.50DS < SER ≤ +2.00DS (n = 48). Median morning salivary melatonin levels were 4.52 pg/ml (95% CI: 2.60-6.02) and 4.89 pg/ml (95% CI: 3.18-5.66) for myopic and nonmyopic subjects, respectively, and did not differ significantly between refractive groups (P = 0.91). Melatonin levels were not significantly correlated with SER, axial length, sleep, or activity scores (Spearman's rank, all P > 0.39). Higher levels of physical activity were associated with higher sleep quality (Spearman's rank, ρ = -0.28, P = 0.02). Conclusion: The present study found no significant relationship between morning salivary melatonin levels and refractive error or axial length in young adolescents. This contrasts with outcomes from a previous study of adults with comparable methodology, season of data collection, and geographical location. Prospective studies are needed to understand the discrepancies between adult and childhood findings and evaluate whether melatonin levels in childhood are indicative of an increased risk for future onset of myopia and/or faster axial growth trajectories and myopia progression in established myopes. Future work should opt for a comprehensive dim-light melatonin onset protocol to determine circadian phase.

Relative peripheral hyperopia leads to greater short-term axial length growth in White children with myopia.

PURPOSE: Controversy exists regarding the influence of peripheral visual experience on the onset and progression of childhood myopia. This longitudinal, observational study evaluated the relationship between relative peripheral refraction (RPR) and changes in refractive error and axial length (AL) over 12 months in White children aged 6-7 and 12-13 years with a range of baseline refractive errors. METHODS: Cycloplegic baseline autorefraction at horizontal retinal eccentricities of 0° and ±30° were recorded with the Shin-Nippon NVision-K 5001 while AL was measured using the Zeiss IOLMaster 700. Measurements were repeated after 12 months on a subgroup. Refractive data were transposed into power vectors as mean spherical equivalent (M), J0 and J45 . RPR was calculated by subtracting central from peripheral measurements. Participants were defined as myopic (M ≤ -0.50 D), premyopic (-0.50 D < M ≤ +0.75 D), emmetropic (+0.75 D < M < +2.00 D) or hyperopic (M ≥ +2.00 D). RESULTS: Data were collected from 222 and 245 participants aged 6-7 and 12-13 years, respectively. Myopic eyes demonstrated, on average, more hyperopic RPR. Emmetropes and premyopes displayed emmetropic RPR, and hyperopes showed a myopic RPR. Fifty-six 6- to 7-year-olds and seventy 12- to 13-year-olds contributed 12-month repeated measures. Longitudinal data demonstrated a significant relationship between a more hyperopic RPR in the nasal retina and greater short-term axial elongation in teens with myopia at baseline (ß = 0.69; p = 0.04). Each dioptre of relative peripheral hyperopia in the nasal retina was associated with an additional 0.10 mm (95% CI: 0.02-0.18 mm) annual increase in AL. CONCLUSIONS: Hyperopic RPR in the nasal retina of myopic children is indicative of increased risk for rapid axial elongation and may be a useful metric to support decision-making in myopia management.

Elevated Melatonin Levels Found in Young Myopic Adults Are Not Attributable to a Shift in Circadian Phase.

Purpose: To evaluate the relationship between refractive error, circadian phase, and melatonin with consideration of prior light exposure, physical activity, and sleep. Methods: Healthy young myopic (spherical equivalent refraction [SER] ≤-0.50DS) and emmetropic adults underwent noncycloplegic autorefraction and axial length (AL) measures. Objective measurements of light exposure, physical activity, and sleep were captured across 7 days by wrist-worn Actiwatch-2 devices. Questionnaires assessed sleep quality and chronotype. Hourly evening saliva sampling during a dim-light melatonin onset (DLMO) protocol evaluated circadian phase, and both morning serum and saliva samples were collected. Liquid chromatography/mass spectrometry quantified melatonin. Results: Subjects (n = 51) were aged 21.4 (interquartile range, 20.1-24.0) years. Melatonin was significantly higher in the myopic group at every evening time point and with both morning serum and saliva sampling (P ≤ 0.001 for all). DLMO-derived circadian phase did not differ between groups (P = 0.98). Multiple linear regression analysis demonstrated significant associations between serum melatonin and SER (B = -.34, ß = -.42, P = 0.001), moderate activity (B = .009, ß = .32, P = 0.01), and mesopic illumination (B = -.007, ß = -.29, P = 0.02), F(3, 46) = 7.23, P < 0.001, R2 = 0.32, R2adjusted = .28. Myopes spent significantly more time exposed to "indoor" photopic illumination (3 to ≤1000 lux; P = 0.05), but "indoor" photopic illumination was not associated with SER, AL, or melatonin, and neither sleep, physical activity, nor any other light exposure metric differed significantly between groups (P > 0.05 for all). Conclusions: While circadian phase is aligned in adult myopes and emmetropes, myopia is associated with both elevated serum and salivary melatonin levels. Prospective studies are required to ascertain whether elevated melatonin levels occur before, during, or after myopia development.

In-vivo anterior segment OCT imaging provides unique insight into cerulean blue-dot opacities and cataracts in Down syndrome.

Down syndrome (DS) is frequently associated with cataract, but there remains scant information about DS cataract morphology. Supra-nuclear cataracts in DS have been proposed as indicative of beta-amyloid (Aß) aggregation and thus potential biomarkers for Alzheimer's (AD). This study employed anterior segment OCT (AS-OCT) and slit-lamp (SL) photography to image the crystalline lens in DS, compared with adult controls. Lens images were obtained post-dilation. Using MATLAB, AS-OCT images were analysed and lens opacities calculated as pixel intensity and area ratios. SL images were classified using LOCS III. Subjects were n = 28 DS (mean ± SD 24.1 ± 14.3years), and n = 36 controls (54.0 ± 3.4years). For the DS group, AS-OCT imaging revealed the frequent presence of small dot opacities (27 eyes, 50%) in the cortex and nucleus of the lens, covering an area ranging from 0.2-14%. There was no relation with age or visual acuity and these dot opacities (p > 0.5) and they were not present in any control lenses. However, their location and morphology does not coincide with previous reports linking these opacities with Aß accumulation and AD. Four participants (14%) in the DS group had clinically significant age-related cataracts, but there was no evidence of early onset of age-related cataracts in DS.

Effects of Mydriatics on Rod/Cone- and Melanopsin-driven Pupil Responses.

SIGNIFICANCE: Pupillometry protocols evaluating rod/cone- and melanopsin-driven responses often use mydriatics to ensure maximal stimulus exposure; however, retinal effects of mydriatics are not fully understood. We demonstrate that dilation with either atropine or phenylephrine results in similar enhancements of rod/cone- and melanopsin-driven pupil responses. PURPOSE: The purposes of this study were to compare the effects of atropine, a muscarinic antagonist, and phenylephrine, an adrenergic agonist, on consensual pupil responses and to assess the repeatability of pupil metrics without mydriasis. METHODS: Right eye pupil responses of 20 adults aged 21 to 42 years were recorded before and 45 minutes after instillation of 0.5% atropine or 2.5% phenylephrine in the left eye. Stimuli were presented to the left eye and included six alternating 1-second 651-nm "red" and 456-nm "blue" flashes. Metrics included baseline pupil diameter, maximal constriction, 6- and 30-second post-illumination pupil responses, and early (0 to 10 seconds) and late (10 to 30 seconds) areas under the curve. RESULTS: Dilation of the stimulated eye with either mydriatic significantly increased the 6-second post-illumination pupil response and early and late areas under the curve for blue stimuli, and early area under the curve for red stimuli (P < .05 for all). Melanopsin-driven post-illumination pupil responses, achieved with either phenylephrine or atropine, did not significantly differ from each other (P > .05 for all). Without mydriasis, intersession intraclass correlation coefficients for pupil metrics were 0.63 and 0.50 (6- and 30-second post-illumination pupil responses, respectively) and 0.78 and 0.44 (early and late areas under the curve, respectively) for blue stimuli, with no significant difference between sessions (P > .05 for all). CONCLUSIONS: Dilation with phenylephrine or atropine resulted in similar enhancements of the rod/cone- and melanopsin-driven pupil responses, despite differing mechanisms. Early pupil metrics without mydriasis demonstrated moderate to good intersession repeatability.

Endocannabinoids in aqueous humour of patients with or without diabetes.

OBJECTIVE: The primary aim was to determine endocannabinoid (EC) concentrations of 2-arachidonoylglycerol (2-AG), oleoylethanolamine (OEA), palmitoylethanolamine (PEA) and anandamide (AEA) in the aqueous humour of patients, and to investigate any differences in gender and diabetic or ocular disease status. METHODS AND ANALYSIS: Adult participants (age >18 years) listed for a routine cataract surgery were recruited. For patients with diabetes, results from their most recent retinopathy grading were recorded. A sample of aqueous humour was removed from the anterior chamber of the patients and snap-frozen in liquid nitrogen. Levels of 2-AG, PEA, OEA and AEA were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Aqueous humour samples were taken from 93 patients (female:male=58:35), with a mean age±SD of 72.7±9.5 years. Following gender-specific analysis, the mean aqueous concentration of AEA in female patients without diabetes was significantly higher than in female patients with diabetes (0.20±0.03 nM vs 0.07±0.02 nM, p=0.001). Among female patients with diabetes, the aqueous concentration of 2-AG was higher in those with diabetic retinopathy compared with those with no retinopathy (0.30+0.16 nM vs 0.04±0.01 nM, p=0.0025). The aqueous level of the sum of EC was higher in those with ocular comorbidity (2.49±0.73 vs 1.44±0.17, p=0.0002). CONCLUSION: There were gender, diabetes status and comorbidity differences in aqueous humour EC levels. Since EC receptors are present in ocular tissues, including the retina (neurons, glia and endothelial cells), differential levels of ECs in the aqueous humour of patients with and without diabetes may provide a novel therapeutic target for diabetic retinopathy.

Conjunctival ultraviolet autofluorescence area, but not intensity, is associated with myopia.

BACKGROUND: Conjunctival ultraviolet autofluorescence (CUVAF) has been used as a biomarker of time spent outdoors. Smaller CUVAF area is associated with myopia in southern hemisphere cohorts. Further research is required to determine if this association is replicated in northern latitudes and whether average CUVAF intensity is a valuable metric. This prospective study explored the association between myopia, CUVAF (area and intensity) and additional indicators of sun exposure (vitamin D3 and self-reported sun exposure preferences) across seasons at a location of 55° north. METHODS: Young adults (age 18-20) provided blood samples biannually (March/April and September/October) over an 18-month period (four phases) for the assessment of 25-hydroxyvitamin D (25(OH)D3 ) concentrations (liquid chromatography-tandem mass spectrometry). CUVAF (total area, average intensity) and self-reported sun exposure preferences were recorded at each phase. Axial length and corneal radius were measured. Refractive error was measured by autorefractor and spherical equivalent refraction used to classify participants into refractive groups: myopic (spherical equivalent refraction ≤ -0.50 DS) or non-myopic. RESULTS: Fifty-four participants (24 myopes, 30 non-myopes) participated. CUVAF area was negatively associated with the presence of myopia (odds ratio = 0.94, 95 per cent confidence interval = 0.90-0.98, p = 0.002). Myopes = 4.5 mm2 (interquartile range [IQR] 0.95-6.4 mm2 ), non-myopes = 7.0 mm2 (IQR = 2.0-10.7 mm2 ). No significant association was found between CUVAF intensity and refractive group (p = 0.17). There was no significant association between sun exposure preferences or serum concentration of 25(OH)D3 and refractive status (all p ≥ 0.21). CUVAF measures were not associated with ocular biometry measures (all p ≥ 0.084). CUVAF area was unaffected by season (all p ≥ 0.45) and variations in CUVAF area over the study period did not exceed the repeatability of the measurement technique. CONCLUSION: Myopia was associated with smaller areas of CUVAF indicative of less cumulative ultraviolet-B exposure. These findings suggest that CUVAF measures are a useful, non-invasive biomarker of the time spent outdoors in adults in northern hemisphere populations.

Short-Term Impact of Bariatric Surgery on Best-Corrected Distance Visual Acuity and Diabetic Retinopathy Progression.

The immediate impact of rapid glucose lowering induced by bariatric surgery on diabetic retinopathy (DR) progression remains unclear. We present 3-year changes in the best-corrected visual acuity and DR grade in a retrospective observational study of 32 morbidly obese patients (64 eyes) who underwent Roux-en-Y-gastric bypass surgery. We found that despite overall benefits in vision, there was an initial progression from no retinopathy to background retinopathy in 18.9% and 21.7% at years 1 and 2 respectively. Patients with pre-proliferative DR at baseline were at increased risk of developing sight-threatening DR. We recommend that patients with diabetes undergoing bariatric surgery have a baseline visual acuity, macular optical coherent tomography and diabetic retinopathy grading from wide-field digital imaging to identify those at risk of sight-threatening diabetic retinopathy.

The use of conjunctival ultraviolet autofluorescence (CUVAF) as a biomarker of time spent outdoors.

PURPOSE: Conjunctival ultraviolet autofluorescence (CUVAF) has been used in previous Southern Hemisphere myopia research as a marker for time spent outdoors. The validity of CUVAF as an indicator of time spent outdoors is yet to be explored in the Northern Hemisphere. It is unclear if CUVAF represents damage attributed to UV exposure or dry eye. This cross-sectional study investigated the association between CUVAF measures, self-reported time spent outdoors and measures of dry eye. METHODS: Participants were recruited from University staff and students (n = 50, 19-64 years; mean 41). None were using topical ocular medications (with the exception of dry eye treatments). Sun exposure and dry eye questionnaires (Ocular Surface Disease Index and McMonnies) were completed by the participant. Dryness was also assessed using slit lamp biomicroscopy and invasive tear break up time. Images of the temporal and nasal conjunctiva from the right and left eye were captured using a bespoke photography system. The total CUVAF area, average CUVAF pixel intensity per mm(2) and total CUVAF pixel intensity were analysed using MATLAB R2013a (The MathWorks Inc). RESULTS: Of the 50 participants, 42% were classified as having dry eye. Self-reported sunglasses use was negatively associated with all CUVAF measures (Kruskal Wallis total CUVAF area, p = 0.04, ptrend  = 0.03, average CUVAF pixel intensity p = 0.02, ptrend  = 0.02, total CUVAF pixel intensity: p = 0.04, ptrend  = 0.02). Time spent outdoors was positively associated with all CUVAF measures (Spearman's correlation coefficients, total CUVAF area: r = 0.37, p = 0.01, average CUVAF pixel intensity: r = 0.36, p = 0.01, total CUVAF pixel intensity: r = 0.37, p = 0.01) and remained significant when sunglasses use was controlled for (partial correlation, total CUVAF area: r = 0.32, p = 0.03, average CUVAF pixel intensity: r = 0.39, p = 0.01, total CUVAF pixel intensity: r = 0.39, p = 0.03). Neither CUVAF area nor intensity measures were associated with any dry eye measure (Ocular Surface Disease Index: all p ≥ 0.41, corneal staining: all p ≥ 0.38, McMonnies: all r ≤ 0.09 all p ≥ 0.52, slit lamp biomicroscopy: all r ≤ 0.20 all p ≥ 0.17, invasive tear break up time: all r ≤ -0.07 all p ≥ 0.31). CONCLUSIONS: CUVAF area and intensity were not associated with clinical measures of dry eye. Greater CUVAF area and intensity were associated with wearing sunglasses less frequently and spending more time outdoors. If sunglass wear is accounted for, CUVAF may be a useful biomarker of time spent outdoors in future myopia studies.

Outdoor tobacco smoke exposure at the perimeter of a tobacco-free university.

There are few studies measuring exposure to outdoor tobacco smoke (OTS). Tobacco users often gather at the boundaries of tobacco-free campuses, resulting in unintended consequences. The objective of this study was to measure exposure levels from OTS on sidewalks bordering a tobacco-free university campus. Data were collected while walking along a sidewalk adjacent to a medium traffic road between May and August 2011. Monitoring occurred during "background," "stop," and "walk-through" conditions at and near hot spot area to measure fine particulate matter (< 2.5 microm; PM2.5) from OTS using a portable aerosol monitor The average PM2.5 levels during stop and walk-through conditions were significantly higher than during background conditions. PM2.5 peak occurrence rate and magnitude of peak concentration were significantly different depending on smoking occurrence. The peak occurrence rate during the stop condition was 10.4 times higher than during the background condition, and 3.1 times higher than during the walk-through condition. Average peak PM2.5 concentrations during the stop condition were 48.7% higher than during the background condition. In conclusion, individuals could be exposed to high levels of PM2.5 when stopping or even passing by smokers outdoors at the perimeter of tobacco-free campuses. The design and implementation of tobacco-free campus policies need to take into account the unintended consequences of OTS exposure at the boundaries. Implications: In this study, outdoor tobacco smoke (OTS) exposure was measured at the perimeter of tobacco-free campus. OTS exposure could be determined by peak analysis. Peak occurrence rate and peak concentration for OTS exposure were identified by using peak analysis. People could be exposed to high levels of PM2.5 when standing or even passing by smokers at the perimeter of tobacco-free campus. OTS exposure measurement in other outdoor locations with smokers is needed to support outdoor smoking regulation.

Using a rhabdomyosarcoma patient-derived xenograft to examine precision medicine approaches and model acquired resistance.

BACKGROUND: Precision (Personalized) medicine has the potential to revolutionize patient health care especially for many cancers where the fundamental disease etiology remains either elusive or has no available therapy. Here we outline a study in alveolar rhabdomyosarcoma, in which we use gene expression profiling and a series of drug prediction algorithms combined with a matched patient-derived xenograft (PDX) model to test bioinformatically predicted therapies. PROCEDURE: A PDX model was developed from a patient biopsy and a number of drugs identified using gene expression analysis in combination with drug prediction algorithms. Drugs chosen from each of the predictive methodologies, along with the patient's standard-of-care therapy (ICE-T), were tested in vivo in the PDX tumor. A second study was initiated using the tumors that re-grew following the ICE-T treatment. Further expression analysis identified additional therapies with potential anti-tumor efficacy. RESULTS: A number of the predicted therapies were found to be active against the tumors in particular BGJ398 (FGFR2) and ICE-T. Re-transplanted ICE-T treated tumorgrafts demonstrated a decreased response to ICE-T recapitulating the patient's refractory disease. Gene expression profiling of the ICE-T treated tumorgrafts identified cytarabine (SLC29A1) as a potential therapy, which was shown, along with BGJ398, to be highly active in vivo. CONCLUSIONS: This study illustrates that PDX models are suitable surrogates for testing potential therapeutic strategies based on gene expression analysis, modeling clinical drug resistance and hold the potential to assist in guiding prospective patient care.

Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue.

BACKGROUND: There is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status. METHODS: Fresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune-compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serial in vivo generations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection. RESULTS: Fresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity. CONCLUSIONS: The preservation of the patient's tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology.

Phase II trial to evaluate gemcitabine and etoposide for locally advanced or metastatic pancreatic cancer.

Prior studies suggest that tumor cell lines harboring RAS mutations display remarkable sensitivity to gemcitabine and etoposide. In a phase II clinical trial of patients with locally advanced or metastatic pancreatic cancer, we evaluated the response rate to a combination of these drugs. Forty chemo-naïve patients with nonresectable and histologically confirmed pancreatic cancer were accrued. Patients received gemcitabine 1,000 mg/m(2) (days 1 and 8) and etoposide 80 mg/m(2) (days 8, 9, and 10; 21-day cycle). The primary end point was radiological response rate. Secondary objectives were determination of overall survival, response duration (time to progression), quality of life, toxicity, and CA 19-9 biomarker response. In 35 evaluable patients, 10 exhibited a radiological partial response and 12 had stable disease in response to treatment. Twenty patients exhibited a >20% decrease in CA 19-9 biomarker levels. Median overall survival was 6.7 months for all patients (40) and 7.2 months for evaluable patients (35). Notably, four patients survived for longer than 1 year, with two patients surviving for more than 2 years. Median time to progression for evaluable patients was 3.1 months. The median overall survival for locally advanced patients was 8.8 months and 6.75 months for metastatic patients. One-year survival was 10% for all patients and 11.4% for evaluable patients. Quality of life improved in 12 patients and remained stable in 3 of the evaluable patients. The primary dose-limiting toxicities were hematologic toxicity and fatigue. These results show that the gemcitabine and etoposide combination is generally well-tolerated and exhibits a response rate similar to other published studies.

MicroRNA 92a-2*: a biomarker predictive for chemoresistance and prognostic for survival in patients with small cell lung cancer.

PURPOSE: Although the majority of patients with small cell lung cancer (SCLC) respond to initial chemotherapy, those with disease progression at first response assessment (chemoresistance) have inferior outcomes. There is a need for predictive biomarkers to aid investigators in designing future clinical trials that better stratify patients beyond standard clinical and laboratory parameters and to identify new treatments for this patient subpopulation. We hypothesized that tumor microRNAs (miRNAs) could serve as predictive biomarkers for chemoresistance and prognostic biomarkers for survival of patients with SCLC treated with systemic chemotherapy. PATIENTS AND METHODS: SCLC samples annotated with clinical characteristics and baseline comorbidities were available. miRNA microarray profiling was performed on diagnostic SCLC tumor samples, and analysis was performed using XenoBase, a data integration and discovery tool. Confirmation of the top 16 miRNA candidates was performed using quantitative real-time polymerase chain reaction followed by analyses to determine clinical and miRNA biomarkers associated with chemoresistance and survival. RESULTS: miRNAs significantly associated with chemoresistance were miR-92a-2* (p = 0.010), miR-147 (p = 0.018), and miR-574-5p (p = 0.039). By stepwise multivariate analysis, only gender and miR-92a-2* contributed significantly to survival (p = 0.023) and (p = 0.015), respectively. Baseline comorbidities were not associated with chemoresistance or survival. CONCLUSIONS: Higher tumor miR-92a-2* levels are associated with chemoresistance and with decreased survival in patients with SCLC. Tumor miR-92a-2* may have application in screening patients with SCLC at risk for de novo chemoresistance in an effort to design more tailored clinical trials for this subpopulation. Further validation in independent sample sets is warranted.

Tonically discharging genioglossus motor units show no evidence of rate coding with hypercapnia.

The genioglossus (GG) is considered the principle protrudor muscle of the human tongue. Unlike most skeletal muscles, GG electromyographic (EMG) activities are robustly preserved in sleep and thus may fulfill a critical role in preserving airway patency. Previous studies in human subjects also confirm that the GG EMG increases in response to chemoreceptor and mechanoreceptor stimulation. This increase occurs secondary to the recruitment of previously inactive motor units (MUs) and/or an increase in firing rate of already active MUs. Which strategy the nervous system uses when the synaptic drive onto GG motoneurons increases is not known. Here we report on GG whole muscle and tonic MU activities under conditions that mimic sleep, i.e., mild-moderate elevations in CO(2) (3% inspired CO(2) or the addition of a 1.0 l dead space) and elevated airway resistance. Based on previous work in rat, we hypothesized that mild hypercapnia would increase the firing rates of tonic MUs and that these effects would be further potentiated by a modest increase in airway resistance. Fine wire and tungsten microelectrodes were inserted into the GG to record whole muscle and single MU activities in 21 subjects (13 women, 8 men; 20-55 yr). Either 3% inspired CO(2) or added dead space resulted in a 200-300% increase in the amplitude of both tonic and phasic components of the whole muscle GG EMG and a doubling of minute ventilation. Despite these changes, recordings obtained from a total of 84 tonically discharging GG single MUs provide no evidence of a change in firing rate under any of the conditions. On this basis we conclude that in healthy adults, the increase in the tonic component of the whole muscle GG EMG secondary to mild hypercapnia is due almost exclusively to the recruitment of previously inactive MUs.

Clinical judgement of near pupil responses provides a useful indicator of focusing ability in children with cerebral palsy.

Accommodation is often reduced in cerebral palsy (CP). Knowledge about accommodative facility is valuable when investigating a child's visual needs and developing strategies for education. With normal accommodation, changing focus from distance to near results in pupil constriction. We compared quality of near pupil responses (NPR) with objective measures of accommodative function obtained with dynamic retinoscopy (DR) to investigate the utility of NPR in indicating accommodative facility. NPR and accommodative function of 90 children with CP (56 males, 34 females; median age 11y, range 4-18y) were assessed. A total of 93% of participants had spastic CP (71.3% bilateral involvement, 28.7% hemiplegia). The severity of motor impairment ranged from very mild (n=7) to severe (no independent walking, n=28). NPR was classified subjectively as normal, reduced, or absent and compared with DR measures of accommodative response. A total of 9.8% of pupil responses were judged absent, 25.6% reduced, and 64.6% normal. Participants with reduced or absent pupil responses demonstrated significantly poorer levels of accommodation with DR (one-way analysis of variance p<0.01). Sensitivity and specificity of NPR in identifying participants with reduced accommodation were 83% (95% confidence interval [CI] 65.5-92.4%) and 72% (95% CI 58.4-82.0%) respectively. NPR provides a rapid, useful indicator of accommodative function in children with CP.