Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts.

BACKGROUND: During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant induced symptoms of Gulf War Illness (GWI), a multi-faceted condition that includes fatigue, pain and cognitive decrements. When studied empirically, both deployed veterans with exposures and those who meet the criteria for GWI are more likely to show deficits in the area of neuropsychological functioning. Although studies have shown cognitive impairments in small sample sizes, it is necessary to revisit these findings with larger samples and newer cohorts to see if other areas of deficit emerge with more power to detect such differences. A group of researchers and clinicians with expertise in the area of GWI have identified common data elements (CDE) for use in research samples to compare data sets. At the same time, a subgroup of researchers created a new repository to share these cognitive data and biospecimens within the GWI research community. METHODS: The present study aimed to compare cognitive measures of attention, executive functioning, and verbal memory in a large sample of GWI cases and healthy GW veteran controls using neuropsychological tests recommended in the CDEs. We additionally subdivided samples based on the specific neurotoxicant exposures related to cognitive deficits and compared exposed versus non-exposed veterans regardless of case criteria status. The total sample utilized cognitive testing outcomes from the newly collated Boston, Biorepository, Recruitment, and Integrative Network (BBRAIN) for GWI. RESULTS: Participants included 411 GW veterans, 312 GWI (cases) and 99 healthy veterans (controls). Veterans with GWI showed significantly poorer attention, executive functioning, learning, and short-and-long term verbal memory than those without GWI. Further, GW veterans with exposures to acetylcholinesterase inhibiting pesticides and nerve gas agents, had worse performance on executive function tasks. Veterans with exposure to oil well fires had worse performance on verbal memory and those with pyridostigmine bromide anti-nerve gas pill exposures had better verbal memory and worse performance on an attention task compared to unexposed veterans. CONCLUSIONS: This study replicates prior results regarding the utility of the currently recommended CDEs in determining impairments in cognitive functioning in veterans with GWI in a new widely-available repository cohort and provides further evidence of cognitive decrements in GW veterans related to war-related neurotoxicant exposures.

Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

[Clinical features and predictors of early neurological deterioration in acute isolated pontine infarction].

Objective: To investigate the clinical and imaging characteristics of early neurological deterioration (END) in acute isolated pontine infarction (AIPI) and analyze the predictive factors of END. Methods: Patients with AIPI who were confirmed by magnetic resonance imaging (MRI) in Zhengzhou University People's Hospital from January 2020 to December 2021were collected and divided into END group and non-END group (NEND group). General data and imaging characteristics of the patients were compared between the two groups, the neurological function of patients was evaluated by using the modified Rankin scale (mRS) at 1 and 3 months after stroke. Multivariate binary logistic regression model was used to analyze the risk factors of END after isolated pontine infarction, and the receiver operating characteristic curve(ROC) curve was drawn. Z-test was used to compare the area under the curve to determine the best predictor of END. Results: A total of 113 patients with AIPI were enrolled, including 72 males and 41 females, aged (62±11) years, with 40 cases in the END group and 73 cases in the NEND group. The incidence of END in AIPI was 35.4% (40/113). The National Institutes of Health Stroke Scale (NIHSS) score in the END group (5.15±1.88) was higher than that in the NEND group (4.10±1.63), and the infarcts size in the END group [(2.15±0.39) mm2] was larger than that in the NEND group [(1.61±0.46) mm2] (P=0.002 and P<0.001, respectively). Multivariate binary logistic regression analysis showed that NIHSS score on admission (OR=1.393, 95%CI: 1.017-1.909, P=0.039), infarct size (OR=11.539, 95%CI: 3.574-37.255, P<0.001) were associated with END. Comparing the area of ROC curve, infarct size [area under curve (AUC)=0.787, with a sensitivity of 0.750 and specificity of 0.545] and NIHSS score on admission (AUC=0.688, with a sensitivity of 0.700 and specificity of 0.589) showed no significant difference in the value of predicting END (P=0.056). Conclusion: Patients with AIPI had higher NIHSS score and larger infarct size on admission, and both of them exhibit good predictive performance for END.

Boston biorepository, recruitment and integrative network (BBRAIN): A resource for the Gulf War Illness scientific community.

AIMS: Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research. MAIN METHODS: BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid. KEY FINDINGS: To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received. SIGNIFICANCE: The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.

[Comparison of extracorporeal membrane oxygenation applicated in critical patients with COVID-19 and novel influenza A (H1N1) virus pneumonia].

Objective: To compare the clinical characteristics and prognosis of critical patients with COVID-19 and novel influenza A (H1N1) virus pneumonia (influenza pneumonia) applied with extracorporeal membrane oxygenation (ECMO). Methods: A total of 24 patients with influenza pneumonia treated with ECMO in respiratory intensive-care unit (ICU) of Beijing Chaoyang Hospital from March 2016 to December 2019 and 12 patients with COVID-19 hospitalized from February 1, 2020 to March 31, 2020 in 5 government designated infectious hospitals of Beijing and Hebei Province that applied with ECMO were enrolled. The demographic data, clinical manifestations, and ECMO related information were described and analyzed and all numerical variables are described as M (P25, P75). Results: The age of COVID-19 patients was 77 (66, 79) years old, which was older than influenza pneumonia patients [46 (32, 62) years old], P<0.05; acute lung injury score and respiratory ECMO survival prediction (RESP) score before ECMO application were 3.3 (3.0, 3.5) and 1 (0, 2), respectively, which were lower than influenza pneumonia patients [3.8 (3.5, 4.0) and 4 (2, 6), respectively], all P values<0.05. Thrombotic complications, bleeding complications, and ventilator-associated pneumonia occurred in ECMO applied COVID-19 patients were 4, 10 and 5 cases, respectively, which were more than that among influenza pneumonia patients (1, 9, and 2 cases, respectively), all P values<0.05. The length of ICU stay of COVID-19 patients was 31 (28, 75) d, which was longer than that of influenza pneumonia patients [27 (18, 39) d], P<0.05. The cases with successful decannulation of ECMO among COVID-19 and influenza pneumonia patients were 6 and 14 cases, respectively and mortality during ICU stay were 8 cases and 11 cases, respectively, and the difference were not statistically significant (all P values>0.05). Conclusion: COVID-19 patients applied with ECMO have more ECMO-related complications and a longer stay in the ICU than patients with influenza pneumonia.

[Product improvement and secondary development of Pudilan Xiaoyan Oral Liquid based on clinical medication].

Pudilan Xiaoyan Oral Liquid is widely used in clinical applications, with safe and effective results. Its coverage rate in the national first, second and third grade hospitals is as high as 71%. In this study, we analyzed and summarized the research progress on the material basis, quality control, production process and clinical medication of Pudilan Xiaoyan Oral Liquid based on the clinical diseases(parotitis, tonsillitis, pharyngitis), and deeply explored the intrinsic quality improvement and secondary development of Pudilan product. Pharmacodynamic material basis of Pudilan Xiaoyan Oral Liquid was explored through the network pharmacology technology and quality control indicators of the production process were optimized by cell anti-inflammatory experiments. Through these techno-logies, it would be more specific, scientific and effective to carry out process optimization of each link and multidimensional quality control of the whole process. The dosage and oral compliance for special patients(children) were explored, providing a reference for clinical pediatric medication of Pudilan Xiaoyan Oral Liquid. Simultaneously, it is helpful to expand the application market by developing Pudilan daily chemical products, and promote the traditional Chinese medicine products in terms of curative effect and daily life.

[Identification of quality markers for Pudilan Xiaoyan Oral Liquid].

On the basis of anti-inflammatory activity, combined with multiple indicators, the quality markers of Pudilan Xiaoyan Oral Liquid were screened and determined for quality control. Lipopolysaccharide(LPS) was used to induce normal human bronchial epithelial cell(NHBE) inflammation model. The anti-inflammatory effects of the main chemical components in Pudilan Xiaoyan Oral Liquid were examined one by one, and the pharmacodynamic basis for the overall anti-inflammatory efficacy of Pudilan Xiaoyan Oral Liquid was clarified to identify the quality markers of Pudilan Xiaoyan Oral Liquid and the contents of the quality markers were determined by high performance liquid chromatography(HPLC). The results showed that adenosine, epigoitrin, chlorogenic acid, caffeic acid, cichoric acid, corynoline, baicalin, wogonoside, wogonin and oroxylin A had a certain regulatory effect on inflammatory factor tumor necrosis factor(TNF-α), interleukin(IL-1ß) and IL-6 at specific concentrations in a dose-dependent manner. Considering the factors such as the IC_(50) value of each monomer component and the comprehensiveness of the quality control components, we proposed to use adenosine, cichoric acid, corynoline, baicalin and wogonin as quality markers of Pudilan Xiaoyan Oral Liquid. The contents of the five components were determined by HPLC, and the results showed that they were relatively stable in three batches of Pudilan Xiaoyan Oral Liquid. In this study, the quality control components selected by the anti-inflammatory activity test have a clear material basis, covering all four active pharmaceutical ingredients, which can fully reflect the quality of Pudilan Xiaoyan Oral Liquid, and effectively improve the quality control standard of Pudilan Xiaoyan Oral Liquid.

[Source control of Pudilan Xiaoyan Oral Liquid--research on quality of Taraxaci Herba based on ultra high performance liquid chromatography fingerprint].

Pudilan Xiaoyan Oral Liquid has been widely used in the clinical treatment of inflammatory diseases such as upper respiratory tract infections. Taraxaci Herba, as the monarch medicine in Pudilan Xiaoyan Oral Liquid, due to its multi-source, multi-origin characteristics, and the difference in the content of active ingredients in different medicinal parts, has become a potential factor for the unstable quality among different batches of Pudilan Xiaoyan Oral Liquid. In this paper, Thermo Scientific Vanquish ultra-high-performance liquid chromatography(UPLC) system was used, and the Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System(2012 Edition) issued by National Pharmacopoeia Commission was used for processing and analysis. The main common peaks were identified and contents were determined by comparison with reference substances. Fingerprints of Taraxaci Herba medicinal materials from different origins were established. 13 common peaks were identified, and 29 batches of samples from five origins had similarities above 0.90. At the same time, an ultra-high performance liquid chromatography method was developed for the determination of monocaffeoyl tartaric acid, chlorogenic acid, caffeic acid, chicoic acid, and luteolin in Taraxaci Herba. The quantitative analysis conditions were verified by methodology, and the average sample recovery was 97.30%-101.8%. The results showed that the content of the same ingredient in Taraxaci Herba from different origins and different medicinal parts was obviously different, and the fluctua-tion range was also different for different ingredients. The establishment of UPLC fingerprints for Taraxaci Herba from different regions combined with multi-component content determination methods provides a reference for improving the quality control of Taraxaci Herba medicinal materials, and also provides a source guarantee for the quality improvement of Pudilan Xiaoyan Oral Liquid.

Utility of a chemotherapy toxicity prediction tool for older patients in a community setting.

Background: Expert groups have recommended incorporation of a geriatric assessment into clinical practice for older patients starting oncologic therapy. However, that practice is not standard primarily because of resource limitations. In the present study, we evaluated the effect on treatment decisions by oncologists in the community oncology setting of a brief geriatric assessment tool that estimates risk of toxicity. Methods: This prospective longitudinal study in 5 community oncology practices in British Columbia involved patients 70 years of age and older starting a new cytotoxic chemotherapy regimen. Clinical personnel completed a brief validated geriatric assessment tool-the Cancer and Aging Research Group chemotherapy toxicity tool (carg-tt)-that estimates the risk of grade 3 or greater toxicity in older patients. Physicians were asked if the carg-tt changed their treatment plan or prompted extra supports. Patients were followed to assess the incidence of toxicity during treatment. Results: The study enrolled 199 patients between July 2016 and February 2018. Mean age was 77 years. Treatment was palliative in 61.4% of the group. Compared with physician judgment, the carg-tt predicted higher rates of toxicity. In 5 patients, treatment was changed based on the carg-tt. In 38.5% of the patients, data from the tool prompted extra supports. Within the first 3 cycles of treatment, 21.3% of patients had experienced grade 3 or greater toxicity. Conclusions: This study demonstrates that use of a brief geriatric assessment tool is possible in a broad community oncology practice. The tool modified the oncologist's supportive care plan for a significant number of older patients undertaking cytotoxic chemotherapy.

MicroRNA-31 inhibits osteosarcoma cell proliferation, migration and invasion by targeting PIK3C2A.

OBJECTIVE: To elucidate the role of microRNA-31 (miR-31) in osteosarcoma and the molecular mechanism of miR-31 in the proliferation, migration, and invasion of osteosarcoma. PATIENTS AND METHODS: Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was used to examine the expression of microRNA-31 in human osteosarcoma tissues. Pearson's chi-squared test was used to analyze the correlation between microRNA-31 and clinicopathological features. Proliferation, migration, invasion, and PI3K3C2A protein in treated osteosarcoma cells were detected by Cell Counting Kit-8 (CCK-8) assay, transwell assay without Matrigel, transwell assay with Matrigel, and Western blot analysis, respectively. RESULTS: qRT-PCR showed that miR-31 was down-regulated in osteosarcoma tissues compared with paired para-tumor bone tissues. The lower level of miR-31 was closely associated with high-grade osteosarcoma, metastasis, and poor overall survival. CCK-8 and transwell assay showed that miR-31 inhibited osteosarcoma cells proliferation, migration, and invasion. According to luciferase assay, miR-31 inhibits osteosarcoma cell proliferation, migration, and invasion through inhibiting PIK3C2A. Reversely, overexpression of PIK3C2A inhibited partial effect of miR-31 on proliferation, migration, and invasion in vitro. CONCLUSIONS: MiR-31 inhibits osteosarcoma cell proliferation, migration, and invasion by targeting PICK3C2A. MiR-31 can thus be used as a therapeutic target in osteosarcoma treatment.

Invited Article: A precise instrument to determine the Planck constant, and the future kilogram.

A precise instrument, called a watt balance, compares mechanical power measured in terms of the meter, the second, and the kilogram to electrical power measured in terms of the volt and the ohm. A direct link between mechanical action and the Planck constant is established by the practical realization of the electrical units derived from the Josephson and the quantum Hall effects. We describe in this paper the fourth-generation watt balance at the National Institute of Standards and Technology (NIST), and report our initial determination of the Planck constant obtained from data taken in late 2015 and the beginning of 2016. A comprehensive analysis of the data and the associated uncertainties led to the SI value of the Planck constant, h = 6.626 069 83(22) × 10(-34) J s. The relative standard uncertainty associated with this result is 34 × 10(-9).

The high osteotomy cut of Dega procedure for developmental dysplasia of the hip in children under 6 years of age.

BACKGROUND: Dega osteotomy has gained popularity for the acetabular reconstruction of developmental dysplasia of the hip (DDH). A high-level Dega osteotomy combining the typical Dega procedure with an age limit of under 6 years and the higher pelvic cut height of the Salter osteotomy for walking DDH patients aged 6 or younger was advocated in our department. The purpose of this retrospective study is to introduce this modified Dega procedure and report the preliminary clinical and radiological results in DDH patients under 6. MATERIALS AND METHODS: From September 2000 to September 2010, a total of 162 patients with 191 dysplastic hips between 1.5 and 6 years old were managed with this high-level Dega osteotomy. From each patient's record, clinical status was retrospectively assessed using modified McKay criteria; radiological evaluations were assessed according to the modified Severin classification, the mean acetabular index (AI), Sharp angle and center-edge (CE) angle. Any occurrence of complications was recorded postoperatively. RESULTS: The average age at surgery was 3.6 years (range 1.5 to 6.0), mean duration of follow-up 11.3 years (range 5.0 to 16.9). The latest follow-up fineness (favorable and good) rate in clinical and radiological evaluations was 92.7 % and 91.1 % respectively. There was a marked trend toward normalization of radiographic indices during the follow-up period: the mean AI changed from 38.0° to 20.8°, the mean Sharp's angle decreased from 59.9° to 39.2°, and the mean CE angle increased from -10.7° to 29.4°, preoperatively and at the latest follow-up respectively. No major complications were recorded during follow-up. CONCLUSION: The high osteotomy cut Dega procedure for patients between 1.5 and 6 years of age was found to be sufficient for improving clinical and radiographic outcomes and inducing little morbidity and few complications for late-detected pediatric walking DDH patients.

Bridging classical and quantum mechanics.

Using a watt balance and a frequency comb, a mass-energy equivalence is derived. The watt balance compares mechanical power measured in terms of the meter, the second, and the kilogram to electrical power measured in terms of the volt and the ohm. A direct link between mechanical action and the Planck constant is established by the practical realization of the electrical units derived from the Josephson and the quantum Hall effects. By using frequency combs to measure velocities and acceleration of gravity, the unit of mass can be realized from a set of three defining constants: the Planck constant h, the speed of light c, and the hyperfine splitting frequency of 133Cs.

Intracoronary infusion of Wharton's jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial.

BACKGROUND: The use of adult stem cells is limited by the quality and quantity of host stem cells. It has been demonstrated that Wharton's jelly-derived mesenchymal stem cells (WJMSCs), a primitive stromal population, could integrate into ischemic cardiac tissues and significantly improve heart function. In this randomized, controlled trial, our aim was to assess the safety and efficacy of intracoronary WJMSCs in patients with ST-elevation acute myocardial infarction (AMI). METHODS: In a multicenter trial, 116 patients with acute ST-elevation MI were randomly assigned to receive an intracoronary infusion of WJMSCs or placebo into the infarct artery at five to seven days after successful reperfusion therapy. The primary endpoint of safety: the incidence of adverse events (AEs) within 18 months, was monitored and quantified. The endpoint of efficacy: the absolute changes in myocardial viability and perfusion of the infarcted region from baseline to four months, global left ventricular ejection fraction (LVEF) from baseline to 18 months were measured using F-18-fluorodeoxyglucose positron emission computed tomography (F-18-FDG-PET) and 99mTc-sestamibi single-photon emission computed tomography (99mTc-SPECT), and two-dimensional echocardiography, respectively. RESULTS: During 18 months follow-up, AEs rates and laboratory tests including tumor, immune, and hematologic indexes were not different between the two groups. The absolute increase in the myocardial viability (PET) and perfusion within the infarcted territory (SPECT) was significantly greater in the WJMSC group [6.9 ± 0.6 % (95 %CI, 5.7 to 8.2)] and [7.1 ± 0.8 % (95 %CI, 5.4 to 8.8) than in the placebo group [3.3 ± 0.7 % (95 %CI, 1.8 to 4.7), P <0.0001] and 3.9 ± 0.6(95 %CI, 2.8 to 5.0), P = 0.002] at four months. The absolute increase in the LVEF at 18 months in the WJMSC group was significantly greater than that in the placebo group [7.8 ± 0.9 (6.0 to approximately 9.7) vs. 2.8 ± 1.2 (0.4 to approximately 5.1), P = 0.001]. Concomitantly, the absolute decreases in LV end-systolic volumes and end-diastolic volumes at 18 months in the WJMSC group were significantly greater than those in the placebo group (P = 0.0004, P = 0.004, respectively). CONCLUSIONS: Intracoronary infusion of WJMSCs is safe and effective in patients with AMI, providing clinically relevant therapy within a favorable time window. This study encourages additional clinical trials to determine whether WJMSCs may serve as a novel alternative to BMSCs for cardiac stem cell-based therapy. TRIAL REGISTRATION: Clinical Trials NCT01291329 (02/05/2011).

Clinical value of ultrasound-guided percutaneous biopsy of pulmonary lesions.

The purpose of this study was to evaluate the applica-bility of ultrasound-guided percutaneous biopsy for the diagnosis and differentiation of various pulmonary lesions in a Chinese population. A total of 338 pulmonary lesions were biopsied with 18-gauge cutting needles, guided by ultrasound, and sent for histopathological analy-sis. The ultrasonographic characteristics of these lesions, procedure complications, and histopathological diagnoses were analyzed. Suffi-cient specimen for histopathologic analysis was obtained in 95.64% (351/367), and mild complications occurred in 2.72% (10/367) of the patients. Accurate diagnosis was obtained in 94.03% (315/335) of the patients; 16 were lost to follow-up. Using the combination of shape and echogenicity to distinguish benign vs malignant lesions, diagnos-tic sensitivity and specificity were 57.39 and 95.65%, respectively. No significant difference was found between malignant and benign lesions in blood flow signals. Ultrasound-guided core biopsy is valuable for the diagnosis, management, and prognosis of unknown pulmonary lesions. Shape and echogenicity on ultrasonography correlate well with histo-pathology and provide useful information for distinguishing between benign and malignant lesions. On the contrary, color Doppler is of little value for this purpose.

Sample preincubation strategy for sensitive and quantitative detection of clenbuterol in swine urine using a fluorescent microsphere-based immunochromatographic assay.

We describe an ultrasensitive and quantitative immunochromatographic assay to determine the amount of clenbuterol (CLB) in swine urine. In this study, fluorescein isothiocyanate polystyrene fluorescent microspheres were used as probes. A sample preincubation strategy was introduced to this immunochromatographic assay. Results showed that the strategy evidently improved the sensitivity and accuracy of lateral flow assay. The method was completed in 20 min, and a half-maximal inhibitory concentration of 0.13 µg liter(-1) was obtained. The limit of detection of the proposed method to determine CLB in swine urine was 0.01 µg liter(-1), which was lower than the limit of detection of immunochromatographic assays without preincubation. Intra- and interday recoveries of spiked swine urine ranged from 85.0 to 107.5%. The relative standard deviation values of the preincubated test strip ranged from 2.7 to 12.5%. Analysis of the CLB in swine urine samples showed that the result obtained from the lateral flow assay is consistent with that obtained from a commercial enzyme-linked immunosorbent assay kit. Our results suggest that the developed fluorescent microsphere-based immunochromatographic assay may be useful as a rapid screening method to detect CLB quantitatively.

Preclinical modeling of EGFR-specific antibody resistance: oncogenic and immune-associated escape mechanisms.

To define the molecular basis of secondary resistance to epidermal growth factor receptor (EGFR)-specific antibodies is crucial to increase clinical benefit in patients. The limited access to posttreatment tumor samples constitutes the major barrier to conduct these studies, representing preclinical experimentation as a useful alternative. Anti-EGFR antibody-based therapy has been reported to mediate tumor regression by interrupting oncogenic signals and, more recently, by inducing antitumor immunological responses. However, resistance models have been focused only on tumor escape associated with EGFR blockade, whereas studies describing immune-associated escape mechanisms have not been reported thus far. To address this idea, we modeled resistance induction in D122 metastasis-bearing C57BL/6 mice treated with 7A7 (an anti-murine EGFR antibody). Similarly to patients receiving EGFR-specific antibodies, 7A7 resistance promotion represents an important drawback to successful therapy. Characterization of primary cultures derived from metastasis in 7A7-treated mice revealed a high frequency of tumor variants resistant to in vivo and in vitro antibody treatment. We showed, for the first time, the convergence of alterations in oncogenic and immunological pathways in 7A7-resistant variants. To identify key molecules behind resistance, seven 7A7-resistant variants were screened. HER3 overexpression and PTEN deficiency leading to hyperactivation of protumoral downstream signaling were found in these variants as a consequence of 7A7-mediated EGFR inhibition. Concomitantly, we found a high percentage of resistant variants carrying abnormalities in the constitutive and/or interferon gamma (IFN-γ)-inducible major histocompatibility complex I (MHC-I) expression. A significant decrease in mRNA levels for MHC-I heavy chains, ß2-microglogulin and antigen processing machinery genes as well as transcriptional alterations in IFN-γ pathway components were identified as the main mechanisms underlying MHC-I expression defects in 7A7-resistant variants. Notably, these defects have not been previously associated with EGFR-specific antibody resistance, providing novel immunological escape mechanisms. This study has strong implications for the development of new combination strategies to overcome anti-EGFR antibodies refractoriness.

Ações de teleducação interativa em saúde vocal baseadas na dinâmicado projeto jovem doutor / Activities of interactive teleducation in vocal health based on the young doctor dynamics

Introdução: as ações de promoção da saúde vocal devem atingir a população infantil, adulta e idosa, diante dos riscos que todos apresentam em desenvolver disfonia. Neste sentido, o Projeto Jovem Doutor propõe dinâmicas de capacitação para que adolescentes se tornem aptos a disseminar conhecimentos a respeito de temas em saúde para a comunidade. Objetivo: construir e avaliar o conteúdo de um Cybertutor, compondo um programa de capacitação sobre saúde vocal, seguindo a proposta do Projeto Jovem Doutor. Métodos: O Cybertutor de saúde vocal foi elaborado a partir da literatura científica. Posteriormente avaliado pelo Índice de Facilidade de Leitura de Flesch (IFLF) e por 14 alunos do ensinomédio de duas escolas. Esses alunos participaram do programa de capacitação, que consistiu de duas aulas presenciais, acesso ao cybertutor e oficina. Resultados: Os módulos obtiveram média geral de56,68% (dp±8,15) do IFLF caracterizado como nível Padrão. Quanto à avaliação subjetiva, 89,61% dos alunos classificaram a qualidade do cybertutor como excelente/satisfatório, sendo que os itens qualidadedas figuras e organização do conteúdo foram classifi cados como excelente/satisfatório em 100% da amostra. Completadas as atividades, os alunos receberam um jaleco e certificado, intitulando-os de Jovens Doutores, havendo disseminado o conhecimento adquirido para 1300 pessoas da comunidade. Conclusão: a construção e avaliação do cybertutor em saúde vocal expressou a linguagem no nível Padrão e alta satisfação dos alunos. O programa possibilitou a transmissão das informações sobre saúde vocal a um número expressivo de pessoas da comunidade pela ação intensa dos ?Jovens Doutores?.(AU)

Introduction: activities of vocal health promotion must reach the young, adult and elderly populations due to risks that everyone presents in the development of Dysphonia. In this purpose, the Young DoctorProject proposes dynamics of training to turn adolescents capable of disseminating, to the community, knowledge about health themes. Objective: to create and evaluate the content of a Cybertutor, composinga training program about vocal health, following the Young Doctor proposal. Methods: the cybertutor on vocal health was developed from the scientific literature. Subsequently, was evaluated by the Flesch Reading Facility Index (FRFI) and by 14 students of high school of two different schools. Those students participated of a training program, consisting in two classroom lectures, cybertutor access and workshop. Results: the modules obtained overall average of 56.68% (sd±8,15) of the FRFI featured as Standard level. Concerning the subjective assessment, 89.61% of students classifi ed the cybertutor quality as excellent/satisfactory, regarding that the items ?figures quality? and ?content organization? were classified as excellent/satisfactory in 100% of sample. In the end of the activities, the students received a white coat and a certificate were, named Young Doctors, disseminating the acquired knowledge to 1300 community people. Conclusion: the creation and evaluation of the cybertutor on vocal health expressed language in the Standard level and high satisfaction of students. The program enabled the communication of information about vocal health to an expressive number of community people by the intense action of the ?Young Doctors?.(AU)

Introducción: las acciones de promoción de la salud vocal deben ser llevadas a la población infantil, adulta y anciana delante de los riesgos que todos presentan para desarrolar disfonía. En este sentido, el Proyecto Joven Doctor propone dinámicas de capacitación para que adolescentes se vuelvan aptos para difundir el conocimiento sobre temas de salud para la comunidad. Objetivo: construir y evaluar el contenido de un Cybertutor, componiendo un programa de capacitación sobre la salud vocal, siguiendola propuesta del Proyecto Joven Doctor. Métodos: el Cybertutor de la salud vocal fue elaborado a partir de la literatura científica. Posteriormente evaluado por el Índice de Facilidad de Lectura Flesch (IFLF) y por 14 estudiantes de enseñanza media de dos escuelas. Estos estudiantes participaron del programa de capacitación que fue compuesto por dos clases, acceso al Cybertutor y un taller. Resultados: Los módulos obtuvieron media general de 56,68% (dp±8,15) del IFLF caracterizado como nivel Patrón. En la evaluación subjetiva, 89,61% de los estudiantes calificaron la calidad del Cybertutor como excelente/ satisfactorio, y la calidad de las figuras y organización del contenido se clasifican como excelente/ satisfactorio en 100% de la muestra. Terminadas las actividades, los estudiantes recibieron un guardapolvo y certificado, dándole el título Jóvenes Doctores, que difundieron los conocimientos adquiridos para 1300 personas de la comunidad. Conclusión: La construcción y evaluación del Cybertutor en la salud vocal expreso el lenguaje en el nivel Patrón y alta satisfacción de los alumnos. El programa permitió la transmisión de informaciones sobre la salud vocal para un número significativo de personas de la comunidad por la intensa acción de los ?Jóvenes Doctores?.(AU)

Ações de teleducação interativa em saúde vocal baseadas na dinâmicado projeto jovem doutor / Activities of interactive teleducation in vocal health based on the young doctor dynamics

Introdução: as ações de promoção da saúde vocal devem atingir a população infantil, adulta e idosa, diante dos riscos que todos apresentam em desenvolver disfonia. Neste sentido, o Projeto Jovem Doutor propõe dinâmicas de capacitação para que adolescentes se tornem aptos a disseminar conhecimentos a respeito de temas em saúde para a comunidade. Objetivo: construir e avaliar o conteúdo de um Cybertutor, compondo um programa de capacitação sobre saúde vocal, seguindo a proposta do Projeto Jovem Doutor. Métodos: O Cybertutor de saúde vocal foi elaborado a partir da literatura científica. Posteriormente avaliado pelo Índice de Facilidade de Leitura de Flesch (IFLF) e por 14 alunos do ensinomédio de duas escolas. Esses alunos participaram do programa de capacitação, que consistiu de duas aulas presenciais, acesso ao cybertutor e oficina. Resultados: Os módulos obtiveram média geral de56,68% (dp±8,15) do IFLF caracterizado como nível Padrão. Quanto à avaliação subjetiva, 89,61% dos alunos classificaram a qualidade do cybertutor como excelente/satisfatório, sendo que os itens qualidadedas figuras e organização do conteúdo foram classifi cados como excelente/satisfatório em 100% da amostra. Completadas as atividades, os alunos receberam um jaleco e certificado, intitulando-os de Jovens Doutores, havendo disseminado o conhecimento adquirido para 1300 pessoas da comunidade. Conclusão: a construção e avaliação do cybertutor em saúde vocal expressou a linguagem no nível Padrão e alta satisfação dos alunos. O programa possibilitou a transmissão das informações sobre saúde vocal a um número expressivo de pessoas da comunidade pela ação intensa dos ?Jovens Doutores?...

Introduction: activities of vocal health promotion must reach the young, adult and elderly populations due to risks that everyone presents in the development of Dysphonia. In this purpose, the Young DoctorProject proposes dynamics of training to turn adolescents capable of disseminating, to the community, knowledge about health themes. Objective: to create and evaluate the content of a Cybertutor, composinga training program about vocal health, following the Young Doctor proposal. Methods: the cybertutor on vocal health was developed from the scientific literature. Subsequently, was evaluated by the Flesch Reading Facility Index (FRFI) and by 14 students of high school of two different schools. Those students participated of a training program, consisting in two classroom lectures, cybertutor access and workshop. Results: the modules obtained overall average of 56.68% (sd±8,15) of the FRFI featured as Standard level. Concerning the subjective assessment, 89.61% of students classifi ed the cybertutor quality as excellent/satisfactory, regarding that the items ?figures quality? and ?content organization? were classified as excellent/satisfactory in 100% of sample. In the end of the activities, the students received a white coat and a certificate were, named Young Doctors, disseminating the acquired knowledge to 1300 community people. Conclusion: the creation and evaluation of the cybertutor on vocal health expressed language in the Standard level and high satisfaction of students. The program enabled the communication of information about vocal health to an expressive number of community people by the intense action of the ?Young Doctors?...

Introducción: las acciones de promoción de la salud vocal deben ser llevadas a la población infantil, adulta y anciana delante de los riesgos que todos presentan para desarrolar disfonía. En este sentido, el Proyecto Joven Doctor propone dinámicas de capacitación para que adolescentes se vuelvan aptos para difundir el conocimiento sobre temas de salud para la comunidad. Objetivo: construir y evaluar el contenido de un Cybertutor, componiendo un programa de capacitación sobre la salud vocal, siguiendola propuesta del Proyecto Joven Doctor. Métodos: el Cybertutor de la salud vocal fue elaborado a partir de la literatura científica. Posteriormente evaluado por el Índice de Facilidad de Lectura Flesch (IFLF) y por 14 estudiantes de enseñanza media de dos escuelas. Estos estudiantes participaron del programa de capacitación que fue compuesto por dos clases, acceso al Cybertutor y un taller. Resultados: Los módulos obtuvieron media general de 56,68% (dp±8,15) del IFLF caracterizado como nivel Patrón. En la evaluación subjetiva, 89,61% de los estudiantes calificaron la calidad del Cybertutor como excelente/ satisfactorio, y la calidad de las figuras y organización del contenido se clasifican como excelente/ satisfactorio en 100% de la muestra. Terminadas las actividades, los estudiantes recibieron un guardapolvo y certificado, dándole el título Jóvenes Doctores, que difundieron los conocimientos adquiridos para 1300 personas de la comunidad. Conclusión: La construcción y evaluación del Cybertutor en la salud vocal expreso el lenguaje en el nivel Patrón y alta satisfacción de los alumnos. El programa permitió la transmisión de informaciones sobre la salud vocal para un número significativo de personas de la comunidad por la intensa acción de los ?Jóvenes Doctores?...