Canine urothelial carcinoma: genomically aberrant and comparatively relevant.

Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.

A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors.

The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.

Attenuated psychosis symptoms are related to working alliance between therapist and service user.

AIM: Many trials have demonstrated the efficacy of specific therapy modalities for individuals with attenuated psychosis symptoms (APS). Less is known regarding mechanisms behind positive outcomes, including the role of nonspecific therapeutic factors. This study explored working alliance (WA) in a clinic serving individuals with APS to see how WA changed across the course of treatment and its relation to APS. METHODS: Session level APS and WA data was available for 12 individuals of diverse racial and gender identity, (M = 48 sessions each). Multilevel models with random intercepts tested change in WA and APS over time, and cross-sectional and prospective relations. RESULTS: WA increased and APS decreased over time. Cross sectionally, WA and APS were inversely related. Prospective relations were non-significant. CONCLUSION: When symptoms increase, therapists for individuals with APS should be attentive to potential disruptions in WA, though strong WA may be a cross-sectional protective factor.

Using search engine data to gauge public interest in mental health, politics and violence in the context of mass shootings.

Despite significant potential for providing insight to private perceptions and behaviors, search engine data has yet to be utilized as a means of gauging the U.S. public's interest and understanding of mental health in the context of gun violence and politics. An analysis of Google Trends revealed that Mental health searches increased in volume starting in the beginning of the current decade. Notably, both "mental health" and "gun(s)" were searched with greater frequency the week after the mass shooting events occurred. Related searches after the event also observed a significant increase in interest in mental health and gun regulation, legal reform, mass shootings, and gun(s). Results suggest that the American public's perception of mental illness increasingly incorporates associations with themes of violence and politics, which becomes more apparent surrounding mass shooting events. Future studies are needed to determine implications for stigmatization of vulnerable groups, and possible relations to media coverage.

Effect of walking surface, late-cueing, physiological characteristics of aging, and gait parameters on turn style preference in healthy, older adults.

Turning while walking is a crucial component of locomotion, often performed on irregular surfaces with little planning time. Turns can be difficult for some older adults due to physiological age-related changes. Two different turning strategies have been identified in the literature. During step turns, which are biomechanically stable, the body rotates about the outside limb, while for spin turns, generally performed with closer foot-to-foot distance, the inside limb is the main pivot point. Turning strategy preferences of older adults under challenging conditions remains unclear. The aim of this study was to determine how turning strategy preference in healthy older adults is modulated by surface features, cueing time, physiological characteristics of aging, and gait parameters. Seventeen healthy older adults (71.5 ±â€¯4.2 years) performed 90° turns for two surfaces (flat, uneven) and two cue conditions (pre-planned, late-cue). Gait parameters were identified from kinematic data. Measures of lower-limb strength, balance, and reaction-time were also recorded. Generalized linear (logistic) regression mixed-effects models examined the effect of (1) surface and cuing, (2) physiological characteristics of ageing, and (3) gait parameters on turn strategy preference. Step turns were preferred when the condition was pre-planned (p < 0.001) (model 1) and when the gait parameters of stride regularity and maximum acceleration decreased (p = 0.010 and p = 0.039, respectively) (model 3). Differences in turn strategy selection under dynamic conditions ought to be evaluated in future fall-risk research and rehabilitation utilizing real-world activity monitoring.

Machine learning algorithms can classify outdoor terrain types during running using accelerometry data.

BACKGROUND: Running is a popular physical activity that benefits health; however, running surface characteristics may influence loading impact and injury risk. Machine learning algorithms could automatically identify running surface from wearable motion sensors to quantify running exposures, and perhaps loading and injury risk for a runner. RESEARCH QUESTION: (1) How accurately can machine learning algorithms identify surface type from three-dimensional accelerometer sensors? (2) Does the sensor count (single or two-sensor setup) affect model accuracy? METHODS: Twenty-nine healthy adults (23.3 ±â€¯3.6 years, 1.8 ±â€¯0.1 m, and 63.6 ±â€¯8.5 kg) participated in this study. Participants ran on three different surfaces (concrete, synthetic, woodchip) while fit with two three-dimensional accelerometers (lower-back and right tibia). Summary features (n = 208) were extracted from the accelerometer signals. Feature-based Gradient Boosting (GB) and signal-based deep learning Convolutional Neural Network (CNN) models were developed. Models were trained on 90% of the data and tested on the remaining 10%. The process was repeated five times, with data randomly shuffled between train-test splits, to quantify model performance variability. RESULTS: All models and configurations achieved greater than 90% average accuracy. The highest performing models were the two-sensor GB and tibia-sensor CNN (average accuracy of 97.0 ±â€¯0.7 and 96.1 ±â€¯2.6%, respectively). SIGNIFICANCE: Machine learning algorithms trained on running data from a single- or dual-sensor accelerometer setup can accurately distinguish between surfaces types. Automatic identification of surfaces encountered during running activities could help runners and coaches better monitor training load, improve performance, and reduce injury rates.

Adenovirus detection in Guthrie cards from paediatric leukaemia cases and controls.

Archived neonatal blood cards (Guthrie cards) from children who later contracted leukaemia and matched normal controls were assayed for adenovirus (AdV) C DNA content using two highly sensitive methods. In contrast to a previous report, AdV DNA was not detected at a higher frequency among neonates who later developed leukaemia, when compared with controls.

Aging may negatively impact movement smoothness during stair negotiation.

Stairs represent a barrier to safe locomotion for some older adults, potentially leading to the adoption of a cautious gait strategy that may lack fluidity. This strategy may be characterized as unsmooth; however, stair negotiation smoothness has yet to be quantified. The aims of this study were to assess age- and task-related differences in head and body center of mass (COM) acceleration patterns and smoothness during stair negotiation and to determine if smoothness was associated with the timed "Up and Go" (TUG) test of functional movement. Motion data from nineteen older and twenty young adults performing stair ascent, stair descent, and overground straight walking trials were analyzed and used to compute smoothness based on the log-normalized dimensionless jerk (LDJ) and the velocity spectral arc length (SPARC) metrics. The associations between TUG and smoothness measures were evaluated using Pearson's correlation coefficient (r). Stair tasks increased head and body COM acceleration pattern differences across groups, compared to walking (p < 0.05). LDJ smoothness for the head and body COM decreased in older adults during stair descent, compared to young adults (p ≤ 0.015) and worsened with increasing TUG for all tasks (-0.60 ≤ r ≤ -0.43). SPARC smoothness of the head and body COM increased in older adults, regardless of task (p < 0.001), while correlations showed improved SPARC smoothness with increasing TUG for some tasks (0.33 ≤ r ≤ 0.40). The LDJ outperforms SPARC in identifying age-related stair negotiation adaptations and is associated with performance on a clinical test of gait.

Gait adaptations of older adults on an uneven brick surface can be predicted by age-related physiological changes in strength.

BACKGROUND: Outdoor falls in community-dwelling older adults are often triggered by uneven pedestrian walkways. It remains unclear how older adults adapt to uneven surfaces typically encountered in the outdoor built-environment and whether these adaptations are associated to age-related physiological changes. RESEARCH QUESTION: The aims of this study were to (1) compare gait parameters over uneven and flat brick walkways, (2) evaluate the differences between older and young adults for these two surfaces, and (3) assess if physiological characteristics could predict adaptations in older adults. METHODS: Balance, strength, reaction-time, full-body marker positions, and acceleration signals from a trunk-mounted inertial measurement unit were collected in seventeen older (71.5 ±â€¯4.2 years) and eighteen young (27.0 ±â€¯4.7 years) healthy adults to compute lower-limb joint kinematics, spatio-temporal parameters, dynamic stability, and accelerometry-derived metrics (symmetry, consistency, and smoothness). RESULTS: Both groups increased hip flexion at foot-strike, while decreasing ankle dorsiflexion, margin of stability, symmetry, and consistency on the uneven, compared to flat, surface. Older, compared to young, adults showed a larger increase in knee flexion at foot-strike and a larger decrease in smoothness on the uneven surface. Only young adults decreased hip abduction on the uneven surface. Strength, not balance nor reaction-time, was the main predictor of hip abduction in older adults on both surfaces. SIGNIFICANCE: While older adults may be especially vulnerable, uneven surfaces negatively impact gait, irrespective of age, and could represent a risk to all pedestrians.

Machine learning algorithms based on signals from a single wearable inertial sensor can detect surface- and age-related differences in walking.

The aim of this study was to investigate if a machine learning algorithm utilizing triaxial accelerometer, gyroscope, and magnetometer data from an inertial motion unit (IMU) could detect surface- and age-related differences in walking. Seventeen older (71.5 ±â€¯4.2 years) and eighteen young (27.0 ±â€¯4.7 years) healthy adults walked over flat and uneven brick surfaces wearing an inertial measurement unit (IMU) over the L5 vertebra. IMU data were binned into smaller data segments using 4-s sliding windows with 1-s step lengths. Ninety percent of the data were used as training inputs and the remaining ten percent were saved for testing. A deep learning network with long short-term memory units was used for training (fully supervised), prediction, and implementation. Four models were trained using the following inputs: all nine channels from every sensor in the IMU (fully trained model), accelerometer signals alone, gyroscope signals alone, and magnetometer signals alone. The fully trained models for surface and age outperformed all other models (area under the receiver operator curve, AUC = 0.97 and 0.96, respectively; p ≤ .045). The fully trained models for surface and age had high accuracy (96.3, 94.7%), precision (96.4, 95.2%), recall (96.3, 94.7%), and f1-score (96.3, 94.6%). These results demonstrate that processing the signals of a single IMU device with machine-learning algorithms enables the detection of surface conditions and age-group status from an individual's walking behavior which, with further learning, may be utilized to facilitate identifying and intervening on fall risk.

Soldier-relevant body borne load impacts minimum foot clearance during obstacle negotiation.

Soldiers often trip and fall on duty, resulting in injury. This study examined ten male soldiers' ability to negotiate an obstacle. Participants had lead and trail foot minimum foot clearance (MFC) parameters quantified while crossing a low (305 mm) and high (457 mm) obstacle with (19.4 kg) and without (6 kg) body borne load. To minimize tripping risk, participants increased lead foot MFC (p = 0.028) and reduced lead (p = 0.044) and trail (p = 0.035) foot variability when negotiating an obstacle with body borne load. While obstacle height had no effect on MFC (p = 0.273 and p = 0.126), placing the trail foot closer to the high obstacle when crossing with body borne load, resulted in greater lead (R = 0.640, b = 0.241, p = 0.046) and trail (R = 0.636, b = 0.287, p = 0.048) MFC. Soldiers, when carrying typical military loads, may be able to minimize their risk of tripping over an obstacle by creating a safety margin via greater foot clearance with reduced variability.

Lower limb flexion posture relates to energy absorption during drop landings with soldier-relevant body borne loads.

Fifteen military personnel performed 30-cm drop landings to quantify how body borne load (light, ∼6 kg, medium, ∼20 kg, and heavy, ∼40 kg) impacts lower limb kinematics and knee joint energy absorption during landing, and determine whether greater lower limb flexion increases energy absorption while landing with load. Participants decreased peak hip (P = 0.002), and knee flexion (P = 0.007) posture, but did not increase hip (P = 0.796), knee (P = 0.427) or ankle (P = 0.161) energy absorption, despite exhibiting greater peak hip (P = 0.003) and knee (P = 0.001) flexion, and ankle (P = 0.003) dorsiflexion angular impulse when landing with additional load. Yet, when landing with the light and medium loads, greater hip (R(2) = 0.500, P = 0.003 and R(2) = 0.314, P = 0.030) and knee (R(2) = 0.431, P = 0.008 and R(2) = 0.342, P = 0.022) flexion posture predicted larger knee joint energy absorption. Thus, military training that promotes hip and knee flexion, and subsequently greater energy absorption during landing, may potentially reduce risk of musculoskeletal injury and optimize soldier performance.

Minor physical anomalies, dermatoglyphic asymmetries, and cortisol levels in adolescents with schizotypal personality disorder.

OBJECTIVE: A relationship between schizotypal personality disorder and schizophrenia has been documented in behavioral genetic studies, and there are similarities in the cognitive deficits and brain abnormalities associated with these disorders. Adolescents with schizotypal personality disorder are of particular interest because the postpubertal period is a critical one for the development of a DSM axis I disorder. It is likely that some schizotypal adolescents will remain stable over time, some will improve, and a subgroup will develop schizophrenia. This study tested the hypotheses that, like schizophrenic patients, schizotypal adolescents manifest an elevated rate of minor physical and dermatoglyphic anomalies, both of which suggest prenatal neurodevelopmental abnormalities. Cortisol release is also of interest because of evidence that the hypothalamic-pituitary-adrenal axis may influence the behavioral expression of vulnerability to schizophrenia. METHOD: Minor physical anomalies, dermatoglyphic asymmetries, and salivary cortisol levels were measured in three groups of adolescents: 20 with schizotypal personality disorder, 20 with other personality disorders, and 26 with no disorder. Assessments began at noon, and four saliva samples were obtained at hourly intervals. RESULTS: The schizotypal personality disorder group showed more minor physical anomalies and dermatoglyphic asymmetries than the normal comparison group and higher cortisol levels than both of the other groups. Group differences in cortisol level were most pronounced at the beginning of the evaluation. Cortisol level and age were positively correlated. CONCLUSIONS: The findings support the assumption that schizotypal personality disorder is associated with perturbations in fetal neurodevelopment and, under some circumstances, a heightened cortisol response.

Does neuroretinitis rule out multiple sclerosis?

Neuroretinitis, a form of optic neuritis, is characterized by papillitis and a stellate macular exudate, or "macular star." The star implies the presence of a disc vasculopathy and secondary leakage of lipoproteinaceous material into the macula. Demyelinating optic neuritis would not be expected to produce a secondary macular exudate. We reviewed the literature on the risk of multiple sclerosis developing in a patient after an attack of optic neuritis, and rarely found a comment on the presence of a macular star. We then reviewed two series of 40 patients who had neuroretinitis and added ten patients of our own. Signs of multiple sclerosis had not developed in the 13 patients contacted retrospectively, nor in the patients followed up prospectively. We also noted that in our patients, neuroretinitis may be accompanied by other neurologic manifestations; neuroretinitis may be bilateral and may be staggered; papillitis may present without a macular star, only to have typical exudates develop up to two weeks later; and the macular exudate may take up to 12 months to resolve. We suggest that patients who demonstrate acute papillitis with a normal macula be reevaluated within two weeks for the development of a macular star. Its presence militates strongly against the subsequent development of multiple sclerosis.

Post-irradiation neuromyotonia affecting trigeminal nerve distribution: an unusual presentation.

We describe two patients who developed neuromyotonia of the floor of the mouth after irradiation of a motor branch (V3) of the trigeminal nerve. The neuromyotonia manifested as sustained muscle contraction due to peripheral nerve dysfunction. The neuromyotonia in both patients was controlled with carbamazepine. Radiation-exposed nerves can become symptomatic months or years after completion of radiation therapy.

Influence of transcutaneous oxygen monitoring on the incidence of retinopathy of prematurity.

This study was performed to determine whether the use of continuous transcutaneous oxygen tension (tcPO2) monitoring could reduce the incidence of retinopathy of prematurity in preterm infants receiving oxygen therapy. A total of 296 infants with birth weights less than or equal to 1,300 g were randomly assigned to a continuous monitoring or a standard care group. Infants in the continuous monitoring group had tcPO2 monitored continuously as long as they required supplemental oxygen, and infants in the standard care group had tcPO2 monitored only during the more acute state of their illness. Management of both groups was otherwise identical. Of 148 infants in the continuous monitoring group, 101 survived; of the 148 patients in the standard care group, 113 survived. Mean birth weights and gestational ages were similar for both groups. Duration of mechanical ventilation and oxygen therapy was also similar. The overall incidence of retinopathy of prematurity was 51% in the continuous monitoring group and 59% in the standard care group. As birth weight for infants greater than or equal to 1,000 g increased, a higher risk of retinopathy of prematurity developing was noted in the standard care group. Cicatricial retinopathy of prematurity developed in four infants in the continuous monitoring group and five in the standard care group. These results suggest that continuous tcPO2 monitoring may reduce the incidence of retinopathy of prematurity in infants with birth weights greater than 1,000 g but not in the smaller infants in whom this complication occurs more frequently and is more severe.

Differential cell adhesion and expression of N-cadherin among retinoblastoma cell lines.

Retinoblastoma (RB) is the most common intraocular childhood cancer, but little is known regarding its cellular biology and the factors that might regulate its progression and metastatic potential. Although alterations in cell-adhesion interactions could contribute to the metastatic behavior of RB, no specific cell-adhesion molecules have been identified in RB cells. The current study examined the adhesive properties of three RB cell lines (Weri-Rb1, Weri-Rb27, and Y79) and determined whether N-cadherin, a specific cell-adhesion protein expressed during normal retinal development, was expressed by these cell lines. This study revealed marked differences in the cell-adhesive properties of the three cell lines with respect to several parameters assayed, including cell morphology, calcium dependence of the cell adhesion, and the presence of N-cadherin. N-cadherin was expressed by human RB cells, but the level of expression, determined both functionally and biochemically, varied among different RB cell lines.

In vitro efficacy of carboplatin and hyperthermia in a murine retinoblastoma cell line.

PURPOSE: To determine the cell-killing activity of varying doses of carboplatin, graded hyperthermia, and the combination of carboplatin and hyperthermia in the treatment of a transgenic murine retinoblastoma cell line. METHODS: Replicate cell wells (more than six wells per dose point) from an established transgenic murine retinoblastoma cell line (Rb-6) were exposed to a single application of hyperthermia for 15, 30, 60, and 120 minutes at temperatures of 37 degrees C (control), 40 degrees C, and 43 degrees C. Carboplatin dose response treatment was studied at doses of 2000, 1000, 500, 400, 300, 200, 100, and 50 ng per well. Combined treatment studies used these carboplatin dosages with each of the graded hyperthermia exposure temperatures at each exposure time. At 24 hours, all wells were pulsed with 3H-thymidine for 24 hours, washed three times, harvested, and counted. Raw counts (3H-thymidine) were fitted to a linear regression model to calculate the lethal dose for 50% (LD50) of cells. RESULTS: The LD50 for carboplatin exposure at 37 degrees C occurred at 542 ng. The LD50 for hyperthermia at 40 degrees C occurred at 90 minutes and at 43 degrees C it occurred at 62 minutes. Combined hyperthermia and carboplatin exposure yielded a synergistic interaction with an LD50 of 327 ng at 43 degrees C for 30 minutes. Determination of a thermal enhancement ratio yielded an enhancement range of 1.1 to 25.8. CONCLUSIONS: The synergistic cytocidal interaction of heat and carboplatin in a transgenic murine retinoblastoma cell line has been established in this study. The increased thermal enhancement ratio documents the potential utility of combined treatment applications in reducing treatment levels of single-modality therapy, potentially allowing for a decrease in treatment-related morbidity.

Some factors related to coronary heart disease incidence in Honolulu Japanese men: the Honolulu Heart Study.

Eight thousand and six Japanese men born in the years 1900-1919 participated in the baseline examination of the Honolulu Heart Study. Of the survivors, 94.6 per cent participated in a second examination two years later. All but 23 of the second exam refusers were contacted about their health. These procedures identified 101 men who had developed coronary heart disease (CHD) for the first time during this two-year interval. This incidence was associated with elevated levels of serum cholesterol, blood pressure, relative weight, uric acid, and cigarette smoking. Considered by itself, non-fasting serum triglyceride was related to CHD incidence, but in the context of other (non-lipid) characteristics this apparent association was not significant. Cigarette smoking was related to CHD other than angina pectoris (AP) but not to AP alone, while the reverse was true for glucose intolerance. In this cohort, the association between relative weight and CHD was as strong as that between serum cholesterol and CHD.