The flavonoid kaempferol protects the fruit fly Drosophila melanogaster against the motor impairment produced by exposure to the insecticide fipronil.

Exposure to pesticides across species has been associated with cognitive and motor impairments. As the problem impacts ecosystem stability, food production and public health, it is urgent to develop multifactorial solutions, from regulatory legislation to pharmacological alternatives that ameliorate the impairments. Fipronil, a commonly used insecticide, acts as a GABAA receptor (GABAAR) antagonist and induces motor impairments in vertebrates and invertebrates. Here, we hypothesized that kaempferol, a secondary metabolite derived from plants, acting as an allosteric modulator of GABAARs, would protect against the negative effects induced by the administration of fipronil in adults of the fruit fly Drosophila melanogaster. We further evaluated our hypothesis via co-administration of flumazenil, a competitive antagonist on the GABAAR, and through in silico analyses. We administered kaempferol prophylactically at three concentrations (10, 30 and 50 µmol l-1) and evaluated its protective effects against motor impairments induced by fipronil. We then used a single dose of kaempferol (50 µmol l-1) to evaluate its protective effect while administering flumazenil. We found that oral administration of fipronil impaired motor control and walking ability. In contrast, kaempferol was innocuous and protected flies from developing the motor-impaired phenotype, whereas the co-administration of flumazenil counteracted these protective effects. These results are supported by the binding of the ligands with the receptor. Together, our results suggest that kaempferol exerts a protective effect against fipronil via positive allosteric modulation of GABAARs, probably within brain areas such as the central complex and the mushroom bodies. These findings further support current attempts to use metabolites derived from plants as protectors against impairments produced by pesticides.

Diagnostic accuracy of semi-automatic quantitative metrics as an alternative to expert reading of CT myocardial perfusion in the CORE320 study.

AIMS: To determine the diagnostic accuracy of semi-automatic quantitative metrics compared to expert reading for interpretation of computed tomography perfusion (CTP) imaging. METHODS: The CORE320 multicenter diagnostic accuracy clinical study enrolled patients between 45 and 85 years of age who were clinically referred for invasive coronary angiography (ICA). Computed tomography angiography (CTA), CTP, single photon emission computed tomography (SPECT), and ICA images were interpreted manually in blinded core laboratories by two experienced readers. Additionally, eight quantitative CTP metrics as continuous values were computed semi-automatically from myocardial and blood attenuation and were combined using logistic regression to derive a final quantitative CTP metric score. For the reference standard, hemodynamically significant coronary artery disease (CAD) was defined as a quantitative ICA stenosis of 50% or greater and a corresponding perfusion defect by SPECT. Diagnostic accuracy was determined by area under the receiver operating characteristic curve (AUC). RESULTS: Of the total 377 included patients, 66% were male, median age was 62 (IQR: 56, 68) years, and 27% had prior myocardial infarction. In patient based analysis, the AUC (95% CI) for combined CTA-CTP expert reading and combined CTA-CTP semi-automatic quantitative metrics was 0.87(0.84-0.91) and 0.86 (0.83-0.9), respectively. In vessel based analyses the AUC's were 0.85 (0.82-0.88) and 0.84 (0.81-0.87), respectively. No significant difference in AUC was found between combined CTA-CTP expert reading and CTA-CTP semi-automatic quantitative metrics in patient based or vessel based analyses(p > 0.05 for all). CONCLUSION: Combined CTA-CTP semi-automatic quantitative metrics is as accurate as CTA-CTP expert reading to detect hemodynamically significant CAD.

Umbilical Granuloma in a 2-Month-Old Patient: Histopathology of a Common Clinical Entity.

Umbilical granulomas are the most common anomaly of the umbilicus in neonates and infants. These lesions are characterized by an overgrowth of granulation tissue that persists at the base of the umbilical cord after its separation. Histologically, they consist of granulation tissue, which is composed of fibroblasts, inflammatory cells, and vascular endothelial cells set in an edematous stroma. Although umbilical granulomas are commonly seen clinically, there are no reports of their histopathology in the literature. The authors present the histology of this clinical finding in a 2-month-old infant, as it is important for the pathologist to be aware of this benign entity and distinguish it from other umbilical anomalies that may be of greater clinical significance.

Magnetic, Angular Rate and Gravity Sensor System Fusion for Orientation Estimation.

This paper presents the development of a fusion strategy to integrate and calibrate signals from magnetometers, gyroscopes and accelerometers to implement a magnetic, angular rate and gravity (MARG) sensor system. The aim of such algorithms is to capture signals from the individual sensors and identify, compensate and reduce external and internal errors such as bias, scale factor and drifts, which highly depend on the noise levels. The necessary calibrations to ensure the reliability of captured data are also presented. The orientation data obtained by the proposed algorithm will be compared with a commercial motion capture system, which are currently being used by researchers in biomechanical analysis and in clinical motor rehabilitation studies.

Asthma in the elderly: what we know and what we have yet to know.

In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients.

Immune cell profile in infants' lung tissue.

Little is known about the normal immune cell profile in the lungs of infants without pulmonary disease. Normal lung samples obtained at autopsy of 10 infants that died either due to incidental or inflicted causes or non-pulmonary diseases were stained for antibodies against B and T lymphocytes, macrophages, NK cells, cytotoxic cells, dendritic cells and mast cells. Cells were quantified in the airway epithelial layer, inner layer (between the epithelium and the outer smooth muscle border), outer layer (between the outer smooth muscle border and the external limits of the airway) and alveolar septa. Basement membrane or alveolar septa lengths were assessed by image analysis. Results were expressed as cells/mm. The median age of patients was 6.8 months, ranging from 11 to 840 days. The inner layer of the airways was the region with the smallest density of cells. There was a predominance of cells related to the innate immunity such as CD56+, Granzyme B+ and CD68+ cells in the epithelial layer and alveolar parenchyma. The outer layer and the lung parenchyma presented the highest cellular density. There were very few CD4+ T cells or dendritic cells in most of the lung compartments. The numbers of CD3+ T and granzyme B+ cells correlated positively with age. There was a compartmentalization of immune cells along airways and parenchyma, which may be related to the development of innate and acquired lung defense mechanisms.

Extracellular matrix composition in COPD.

Extracellular matrix (ECM) composition has an important role in determining airway structure. We postulated that ECM lung composition of chronic obstructive pulmonary disease (COPD) patients differs from that observed in smoking and nonsmoking subjects without airflow obstruction. We determined the fractional areas of elastic fibres, type-I, -III and -IV collagen, versican, decorin, biglycan, lumican, fibronectin and tenascin in different compartments of the large and small airways and lung parenchyma in 26 COPD patients, 26 smokers without COPD and 16 nonsmoking control subjects. The fractional area of elastic fibres was higher in non-obstructed smokers than in COPD and nonsmoking controls, in all lung compartments. Type-I collagen fractional area was lower in the large and small airways of COPD patients and in the small airways of non-obstructed smokers than in nonsmokers. Compared with nonsmokers, COPD patients had lower versican fractional area in the parenchyma, higher fibronectin fractional area in small airways and higher tenascin fractional area in large and small airways compartments. In COPD patients, significant correlations were found between elastic fibres and fibronectin and lung function parameters. Alterations of the major ECM components are widespread in all lung compartments of patients with COPD and may contribute to persistent airflow obstruction.

Clinical characteristics and possible phenotypes of an adult severe asthma population.

BACKGROUND: Currently, there are no studies of well-characterized severe asthmatics in Brazil. We aimed to study a population of severe treated asthmatics still uncontrolled to characterize them and define possible phenotypes. METHODS: Descriptive cross-sectional outpatient study of severe asthmatics, evaluating functional and inflammatory markers, health-related quality of life, anxiety and depression symptoms, clinical control status, and characteristics related to atopy, age of asthma onset, induced sputum eosinophil levels, and airflow limitation. We also grouped the subgroups characteristics to identify phenotypes. The study is registered on ClinicalTrial.gov NCT 01089322. RESULTS: From 128 eligible patients with severe/uncontrolled asthma, 74 fulfilled the inclusion criteria. The cohort was comprised of 85% women, frequently with a body mass index higher than 31 kg m(-2), atopy (60%), early-onset disease (50%), sputum eosinophilia (80%), comorbidities, and reduced quality of life. Nonatopics had significant higher asthma onset (19 y.a.) and twice level of induced sputum eosinophil. Late-onset patients had significantly less atopy (57%) and higher levels of induced sputum eosinophils. Non-eosinophilics had lower levels of inflammatory markers. Patients with airflow limitation had more intensive care unit admissions (56%) and 1.5 times more airway resistance. Subgroups characteristics identified a priori four well-characterized phenotypes, with 55% presenting sputum eosinophilia. CONCLUSION: Our data emphasize the high burden of disease, the persistence of inflammation and the existence of clinical possible phenotypes population sharing common features with published cohorts. Despite the necessity of further investigation into pathogenic mechanisms, this study with clinically difficult patient group may help to improve future asthma care.

Diagnostic performance of combined noninvasive coronary angiography and myocardial perfusion imaging using 320 row detector computed tomography: design and implementation of the CORE320 multicenter, multinational diagnostic study.

Multidetector coronary computed tomography angiography (CTA) is a promising modality for widespread clinical application because of its noninvasive nature and high diagnostic accuracy as found in previous studies using 64 to 320 simultaneous detector rows. It is, however, limited in its ability to detect myocardial ischemia. In this article, we describe the design of the CORE320 study ("Combined coronary atherosclerosis and myocardial perfusion evaluation using 320 detector row computed tomography"). This prospective, multicenter, multinational study is unique in that it is designed to assess the diagnostic performance of combined 320-row CTA and myocardial CT perfusion imaging (CTP) in comparison with the combination of invasive coronary angiography and single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). The trial is being performed at 16 medical centers located in 8 countries worldwide. CT has the potential to assess both anatomy and physiology in a single imaging session. The co-primary aim of the CORE320 study is to define the per-patient diagnostic accuracy of the combination of coronary CTA and myocardial CTP to detect physiologically significant coronary artery disease compared with (1) the combination of conventional coronary angiography and SPECT-MPI and (2) conventional coronary angiography alone. If successful, the technology could revolutionize the management of patients with symptomatic CAD.

Kidney transplantation with Belzer or Custodiol solution: a randomized prospective study.

PURPOSE: The purpose of this study was to compare the Belzer vs Custodiol solutions for cadaveric kidney perfusion in relation to delayed graft function, renal function, acute rejection episodes, and patient and graft survivals. METHODS: This randomized prospective study included 42 kidneys and 9 simultaneous kidney and pancreas recipients from December 2002 to February 2004, namely 24 in the Custodiol arm and 27 in the Belzer arm. We analyzed delayed graft function frequency, acute rejection episodes (biopsy proven), renal function (creatinine at 1, 6, and 12 months), as well as graft and patient survivals. Categorical and continuous variables were evaluated as appropriate. RESULTS: We failed to observe a difference in the immunosuppressant drug protocol, cold ischemia time, or mean recipient or donor age. The prevalence of delayed graft function was 63% among the Belzer arm, and 50% among the Custodiol arm (P = NS). The renal function was the same in both arms at 1, 6, and 12 months. The graft survival after 3 months was 94% among the Belzer group (death from sepsis), and 95% among the Custodiol group (nonfunctioning graft). At 1 year, the results were 78% among the Belzer group (4 deaths from cardiovascular or infectious complications and 2 graft losses), and 79% among the Custodiol group (3 deaths, 1 primary nonfunctioning graft, and 1 graft loss; P = NS). After 12 months follow-up, patient survival was 84% among the Belzer group, and 86% among the Custodiol group. In the first year, the incidences of biopsy-proven acute rejection episodes were 37% among the Belzer group, and 33% among the Custodiol group. CONCLUSION: Custodiol solution achieved similar results compared with Belzer solution.

Lymphocytic inflammation in childhood bronchiolitis obliterans.

Childhood bronchiolitis obliterans (CBO) is an infrequent, severe disorder characterized by persistent obstructive respiratory symptoms after an acute episode of bronchiolitis. The viral etiology is most common, and adenovirus is the most frequently identified causative agent. Pathologically, the disease is characterized as constrictive type BO, with variable degrees of chronic inflammation and fibrosis in the bronchioles. The nature of the cellular infiltrate is largely unknown, and its characterization may provide better understanding of the disease and offer clues for therapy. Therefore, the aim of the present study was to characterize the inflammatory infiltrate in the bronchioles of 23 open lung biopsies of children with CBO and to compare this to the infiltrate in histologically normal airways. Our results show that CD3+ T cells were the most frequent cell type observed in CBO, with a predominance of the CD8+ T-cell subtype. When compared to the control group, there was a larger number of CD8+, CD4+, CD20+, granzyme B+, and perforin+ lymphocytes in the CBO group. Further studies are needed to address the role of different cell types in the development of CBO.

Histologic patterns of lung infiltration of B-cell, T-cell, and Hodgkin lymphomas.

Secondary lung infiltration by lymphomas occurs frequently. To our knowledge, however, no recent studies have attempted to discriminate histologic patterns of lung infiltration in the lymphoma subtypes. We retrospectively evaluated the frequency of lung infiltration and the respective infiltration patterns by lymphomas at autopsy, during an 11-year period. Lymphomas were classified according to the 2001 World Health Organization Classification of hematologic malignancies in B-cell, T-cell, and Hodgkin lymphomas (HLs). In 21,157 autopsies, 414 reports with lymphoma diagnosis were reviewed histologically, and 85 showed lung infiltration (20.5%). We studied 14 HLs, 43 B-cell lymphomas, and 20 T-cell lymphomas. Five infiltration patterns were identified: peribronchial-perivascular, nodular alveolar, interstitial, and pleural. Approximately half of the lymphomas had more than 1 infiltration pattern (mean, 1.7); peribronchial-perivascular and pleural were the most frequent. The frequency of nodular infiltration was larger in HL than in B-cell lymphomas. T-cell lymphomas had a larger frequency of the interstitial infiltration pattern compared with B-cell lymphomas. Recognizing the frequency and patterns of lung infiltration in the light of a more recent classification is certainly useful for physicians dealing with lymphoma diagnostic procedures, such as radiologists and pathologists.