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BackgroundRight ventricular function is an important prognostic marker for pulmonary arterial hypertension. Native T1 mapping using cardiovascular magnetic resonance imaging can characterize the myocardium, but accumulating evidence indicates that T1 values of the septum or ventricular insertion points do not have predictive potential in pulmonary arterial hypertension. We aimed to elucidate whether native T1 values of the right ventricular free wall (RVT1) can predict poor outcomes in patients with pulmonary arterial hypertension.MethodsThis retrospective study included 30 patients with pulmonary arterial hypertension (median age, 45 years; mean pulmonary artery pressure, 41±13 mmHg) and 16 healthy controls (median age, 43 years) who underwent native T1 mapping. RVT1 was obtained from the inferior right ventricular free wall during end systole.ResultsPatients with pulmonary arterial hypertension had significantly higher native RVT1 than did controls (1384±74 vs. 1217±57 ms, pConclusionsRVT1 was predictive of right ventricular performance and outcomes in patients with pulmonary arterial hypertension. Thus, native T1 mapping in the right ventricular free wall may be an effective prognostic method for pulmonary arterial hypertension.

Causal relations among many statistical variables have been assessed using a Linear non-Gaussian Acyclic Model (LiNGAM). Using access to large amounts of health checkup data from Osaka prefecture obtained during the six fiscal years of years 2012-2017, we applied the DirectLiNGAM algorithm as a trial to extract causal relations among health indices for age groups and genders. Results show that LiNGAM yields interesting and reasonable results, suggesting causal relations and correlation among the statistical indices used for these analyses.

Global agriculture is under pressure to meet increasing demand for food and agricultural products. There are several global assessments of crop yields, but we know little about the uncertainties of their key findings, as the assessments are driven by the single best yield dataset available when each assessment was conducted. Recently, two different spatially explicit, global, historical yield datasets, one based on agricultural census and the other largely based on satellite remote sensing, became available. Using these datasets, we compare the similarities and differences in global yield gaps, trend patterns, growth rates and changes in year-to-year variability. We analyzed maize, rice, wheat and soybean for the period of 1981 to 2008 at four resolutions (0.083°, 0.5°, 1.0° and 2.0°). Although estimates varied by dataset and resolution, the global mean annual growth rates of 1.7-1.8%, 1.5-1.7%, 1.1-1.3% and 1.4-1.6% for maize, rice, wheat and soybean, respectively, are not on track to double crop production by 2050. Potential production increases that can be attributed to closing yield gaps estimated from the satellite-based dataset are almost twice those estimated from the census-based dataset. Detected yield variability changes in rice and wheat are sensitive to the choice of dataset and resolution, but they are relatively robust for maize and soybean. Estimates of yield gaps and variability changes are more uncertain than those of yield trend patterns and growth rates. These tendencies are consistent across crops. Efforts to reduce uncertainties are required to gain a better understanding of historical change and crop production potential to better inform agricultural policies and investments.

Double hypoglossal canal, namely a hypoglossal canal bridging, is a normal variation of the hypoglossal canal. Racial differences in the prevalence of double hypoglossal canal have been reported. We evaluated the prevalence of double hypoglossal canal in a Japanese population with multidetector computed tomography (MDCT).We reviewed five hundred and ninety consecutive patients (mean age, 61 years: range, 15-94 years: 254 men, 336 women) who underwent computed tomographic angiography (CTA) of the brain for a variety of CNS abnormalities. Two radiologists achieved consensus on the canal being single or double, and measured the sizes of single canals on CT images. Kappa statistics was used to test the reliability between the 2 investigators. A logistic regression was used to evaluate the prevalence of double hypoglossal canal and the following factors: sex, age, and laterality. Student's t-test was used to evaluate the asymmetry of single hypoglossal canal diameters. Statistical significance was accepted at P < 0.05.Double hypoglossal canal was identified in 16.9% of the patients, and was bilateral in 2.2%. Double hypoglossal canal was significantly more frequent on the left side than right (P = 0.004, odds ratio = 1.79) and in males than females (P = 0.011, odds ratio = 1.67). A larger left or right-sided canal was found in 31.6% and 12.2% of the patients, respectively, following the same side preference as that of double hypoglossal canal. Almost perfect agreement was achieved between the two readers (k = 0.975).In this Japanese population, the prevalence of a double hypoglossal canal was 16.9%, of which 2.2% were bilateral. Double hypoglossal canal was more frequent in males than females, and on the left side than right.

BACKGROUND: In the ASE/AIE-mediated genetic mechanism for age-related gene regulation, a recently identified age-related homeostasis mechanism, two genetic elements, ASE (age-related stability element) and AIE (age-related increase element as a stem-loop forming RNA), play critical roles in producing specific age-related expression patterns of genes. PRINCIPAL FINDING: We successfully identified heterogeneous nuclear ribonucleoprotein A3 (hnRNP A3) as a major mouse liver nuclear protein binding to the AIE-derived RNAs of human factor IX (hFIX) as well as mouse factor IX (mFIX) genes. HnRNP A3 bound to the AIE RNA was not phosphorylated at its Ser(359), while hnRNP A3 in the mouse liver nuclear extracts was a mixture of phosphorylated and unphosphorylated Ser(359). HepG2 cells engineered to express recombinant hFIX transduced with adenoviral vectors harboring an effective siRNA against hnRNP A3 resulted in a substantial reduction in hFIX expression only in the cells carrying a hFIX expression vector with AIE, but not in the cells carrying a hFIX expression vector without AIE. The nuclear hnRNP A3 protein level in the mouse liver gradually increased with age, while its mRNA level stayed age-stable. CONCLUSIONS: We identified hnRNP A3 as a major liver nuclear protein binding to FIX-AIE RNA. This protein plays a critical role in age-related gene expression, likely through an as yet unidentified epigenetic mechanism. The present study assigned a novel functional role to hnRNP A3 in age-related regulation of gene expression, opening up a new avenue for studying age-related homeostasis and underlying molecular mechanisms.

Background: In the ASE/AIE-mediated genetic mechanism for age-related gene regulation, a recently identified age-related homeostasis mechanism, two genetic elements, ASE (age-related stability element) and AIE (age-related increase element as a stem-loop forming RNA), play critical roles in producing specific age-related expression patterns of genes. Principal Finding: We successfully identified heterogeneous nuclear ribonucleoprotein A3 (hnRNP A3) as a major mouse liver nuclear protein binding to the AIE-derived RNAs of human factor IX (hFIX) as well as mouse factor IX (mFIX) genes. HnRNP A3 bound to the AIE RNA was not phosphorylated at its Ser359, while hnRNP A3 in the mouse liver nuclear extracts was a mixture of phosphorylated and unphosphorylated Ser359. HepG2 cells engineered to express recombinant hFIX transduced with adenoviral vectors harboring an effective siRNA against hnRNP A3 resulted in a substantial reduction in hFIX expression only in the cells carrying a hFIX expression vector with AIE, but not in the cells carrying a hFIX expression vector without AIE. The nuclear hnRNP A3 protein level in the mouse liver gradually increased with age, while its mRNA level stayed age-stable. Conclusions: We identified hnRNP A3 as a major liver nuclear protein binding to FIX-AIE RNA. This protein plays a critical role in age-related gene expression, likely through an as yet unidentified epigenetic mechanism. The present study assigned a novel functional role to hnRNP A3 in age-related regulation of gene expression, opening up a new avenue for studying age-related homeostasis and underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

Background: Clinicians in areas where malaria and typhoid fever are co-endemic often treat infected patients irrationally, which may lead to the emergence of drug resistance and extra cost to patients. This study determined the proportion of febrile conditions attributable to either malaria and/or typhoid fever and the susceptibility patterns of Salmonella spp. isolates to commonly used antimicrobial agents in Ghana. Methods: One hundred and fifty-seven (157) febrile patients attending the Ga West Municipal Hospital, Ghana, from February to May 2017 were sampled. Blood samples were collected for cultivation of pathogenic bacteria and the susceptibility of the Salmonella isolates to antimicrobial agents was performed using the Kirby-Bauer disk diffusion method with antibiotic discs on Müller Hinton agar plates. For each sample, conventional Widal test for the detection of Salmonella spp was done as well as blood film preparation for detection of Plasmodium spp. Data on the socio-demographic and clinical characteristics of the study participants were collected using an android technology software kobo-collect by interview. Results: Of the total number of patients aged 2–37 years (median age = 6 years, IQR 3–11), 82 (52.2%) were females. The proportion of febrile patients with falciparum malaria was 57/157 (36.3%), while Salmonella typhi O and H antigens were detected in 23/157 (14.6%) of the samples. The detection rate of Salmonella spp in febrile patients was 10/157 (6.4%). Malaria and typhoid fever coinfection using Widal test and blood culture was 9 (5.7%) and 3 (1.9%), respectively. The isolates were highly susceptible to cefotaxime, ceftriaxone, ciprofloxacin, and amikacin but resistant to ampicillin, tetracycline, co-trimoxazole, gentamicin, cefuroxime, chloramphenicol, and meropenem. Conclusion: Plasmodium falciparum and Salmonella spp coinfections were only up to 1.9%, while malaria and typhoid fever, individually, were responsible for 36.3% and 6.4%, respectively. Treatment of febrile conditions must be based on laboratory findings in order not to expose patients to unnecessary side effects of antibiotics and reduce the emergence and spread of drug resistance against antibiotics. [ABSTRACT FROM AUTHOR]

Introduction: Quantitative computed tomography (QCT) is used to objectively assess the degree of parenchymal impairment in COVID-19 pneumonia. Materials and methods: Retrospective study on 61 COVID-19 patients (severe and non-severe; 33 men, age 63+/-15 years) who underwent a CT scan due to tachypnea, dyspnoea or desaturation. QCT was performed using VCAR software. Patients' clinical data was collected, including laboratory results and oxygenation support. The optimal cut-off point for CT parameters for predicting death and respiratory support was performed by maximizing the Youden Index in a receiver operating characteristic (ROC) curve analysis. Results: The analysis revealed significantly greater progression of changes: ground-glass opacities (GGO) (31,42% v 13,89%, p<0.001), consolidation (11,85% v 3,32%, p<0.001) in patients with severe disease compared to non-severe disease. Five lobes were involved in all patients with severe disease. In non-severe patients, a positive correlation was found between severity of GGO, consolidation and emphysema and sex, tachypnea, chest x-ray (CXR) score on admission and laboratory parameters: CRP, D-dimer, ALT, lymphocyte count and lymphocyte/neutrophil ratio. In the group of severe patients, a correlation was found between sex, creatinine level and death. ROC analysis on death prediction was used to establish the cut-off point for GGO at 24.3% (AUC 0.8878, 95% CI 0.7889–0.9866; sensitivity 91.7%, specificity 75.5%), 5.6% for consolidation (AUC 0.7466, 95% CI 0.6009–0.8923; sensitivity 83.3%, specificity 59.2%), and 37.8% for total (GGO+consolidation) (AUC 0.8622, 95% CI 0.7525–0.972; sensitivity 75%, specificity 83.7%). The cut-off point for predicting respiratory support was established for GGO at 18.7% (AUC 0.7611, 95% CI 0.6268–0.8954; sensitivity 87.5%, specificity 64.4%), consolidation at 3.88% (AUC 0.7438, 95% CI 0.6146–0.8729; sensitivity 100%, specificity 46.7%), and total at 23.5% (AUC 0.7931, 95% CI 0.673–0.9131; sensitivity 93.8%, specificity 57.8%). Conclusion: QCT is a good diagnostic tool which facilitates decision-making regarding intensification of oxygen support and transfer to an intensive care unit in patients severely ill with COVID-19 pneumonia. QCT can make an independent and simple screening tool to assess the risk of death, regardless of clinical symptoms. Usefulness of QCT to predict the risk of death is higher than to assess the indications for respiratory support. [ABSTRACT FROM AUTHOR]

Members of the broad complex, tram track, bric-a-brac and zinc finger (BTB-ZF) family of transcription factors, such as BCL-6, ZBTB20, and ZBTB32, regulate antigen-specific B cell differentiation, plasma cell longevity, and the duration of antibody production. We found that ZBTB38, a different member of the BTB-ZF family that binds methylated DNA at CpG motifs, is highly expressed by germinal center B cells and plasma cells. To define the functional role of ZBTB38 in B cell responses, we generated mice conditionally deficient in this transcription factor. Germinal center B cells lacking ZBTB38 dysregulated very few genes relative to wild-type and heterozygous littermate controls. Accordingly, mice with hematopoietic-specific deletion of Zbtb38 showed normal germinal center B cell numbers and antibody responses following immunization with hapten-protein conjugates. Memory B cells from these animals functioned normally in secondary recall responses. Despite expression of ZBTB38 in hematopoietic stem cells, progenitors and mature myeloid and lymphoid lineages were also present in normal numbers in mutant mice. These data demonstrate that ZBTB38 is dispensable for hematopoiesis and antibody responses. These conditional knockout mice may instead be useful in defining the functional importance of ZBTB38 in other cell types and contexts. [ABSTRACT FROM AUTHOR]

Background: Combined pulmonary fibrosis with emphysema (CPFE) is a clinically meaningful syndrome characterized by coexisting upper-lobe emphysema and lower-lobe interstitial fibrosis. However, ambiguous diagnostic criteria and, particularly, the absence of objective methods to quantify emphysematous/fibrotic lesions in patients with CPFE confound the interpretation of the pathophysiology of this syndrome. We analyzed the relationship between objectively quantified computed tomography (CT) measurements and the results of pulmonary function testing (PFT) and clinical events in CPFE patients. Materials and methods: We enrolled 46 CPFE patients who underwent CT and PFT. The extent of emphysematous lesions was obtained by calculating the percent of low attenuation area (%LAA). The extent of fibrotic lesions was calculated as the percent of high attenuation area (%HAA). %LAA and %HAA values were combined to yield the percent of abnormal area (%AA). We assessed the relationships between CT parameters and other clinical indices, including PFT results. Multivariate analysis was performed to examine the association between the CT parameters and clinical events. Results: A greater negative correlation with percent predicted diffusing capacity of the lung for carbon monoxide (DLCO %predicted) existed for %AA (r = -0.73, p < 0.001) than for %LAA or %HAA alone. The %HAA value was inversely correlated with percent predicted forced vital capacity (r = -0.48, p < 0.001), percent predicted total lung capacity (r = -0.48, p < 0.01), and DLCO %predicted (r = -0.47, p < 0.01). Multivariate logistic regression analysis found that %AA showed the strongest association with hospitalization events (odds ratio = 1.20, 95% confidence interval = 1.01–1.54, p = 0.029). Conclusion: Quantitative CT measurements reflected deterioration in pulmonary function and were associated with hospitalization in patients with CPFE. This approach could serve as a useful method to determine the extent of lung morphology, pathophysiology, and the clinical course of patients with CPFE. [ABSTRACT FROM AUTHOR]

Background and purpose: MR contrast-enhanced techniques are undergoing increased scrutiny since the FDA applied a warning for gadolinium-based MR contrast agents due to gadolinium deposition within multiple organ systems. While CE-MRA provides excellent image quality, is it required in a screening carotid study? This study compares 2D TOF and 3D TOF MRA vs. CE-MRA in defining carotid stenosis in a large clinical patient population, and with multiple readers with varying experience. Materials and methods: 200 consecutive patients had their carotid bifurcations evaluated with 2D TOF, 3D TOF and CE-MRA sequences by 6 board-certified neuroradiologists. Stenosis and quality of examinations were defined for each study. Inter-rater reliability was assessed using two-way random effects intraclass correlation coefficients. Intra-reader reliability was computed via weighted Cohen's κ. Weighted Cohen's κ were also computed to assess agreement in stenosis ratings between enhanced images and unenhanced images. Results: Agreement between unenhanced and enhanced ratings was substantial with a pooled weighted κ of 0.733 (0.628–0.811). For 5 of the 6 readers, the combination of unenhanced 2D TOF and 3D TOF showed better agreement with contrast-enhanced than either 2D TOF or 3D TOF alone. Intra-reader reliability was substantial. Conclusions: The combination of 2D TOF and 3D TOF MRA showed substantial agreement with CE-MRA regarding degree of carotid stenosis in this large outpatient population across multiple readers of varying experience. Given the scrutiny that GBCA are undergoing due to concerns regarding CNS and soft tissue deposition, it seems prudent to reserve CE-MRA for cases which are not satisfactorily answered by the nonenhanced study or other noninvasive examinations. [ABSTRACT FROM AUTHOR]

Objectives: To examine potential gadolinium (Gd) accumulation in the brain of healthy mice after long-term oral administration of Gd-containing food pellets and to investigate whether Gd leads to adverse central nervous system (CNS) effects, specifically focussing on locomotor impairment in Gd exposed compared to control animals. Materials and methods: The local Animal Experimental Ethics Committee approved all procedures and applications. Fifteen female C57Bl/6 mice were orally exposed to a daily intake of 0.57 mmol Gd chloride/ kg body weight over a period of 90 weeks from the age of 4 weeks on. Gd-free, but otherwise equivalent experimental diets were given to the control group (N = 13). The animals were monitored daily by animal caretakers regarding any visible signs of distress and evaluated clinically every four weeks for the first 60 weeks and afterwards every two weeks for a better temporal resolution of potential long-term effects regarding impairment of motor performance and loss of body weight. The individual Gd content was measured using mass spectrometry in a sub-cohort of N = 6 mice. Results: The absolute brain Gd levels of the Gd-exposed mice were significantly increased compared to control mice (0.033± 0.009 vs. 0.006± 0.002 nmol Gd/ g brain tissue). Long-term oral Gd exposure over almost the entire life-span did not lead to adverse CNS effects including locomotor changes (rotarod performance, p = 0.1467) in healthy mice throughout the study period. Gd-exposed mice showed less increased body weight compared to control mice during the study period (p = 0.0423). Histopathological alterations, such as hepatocellular vacuolization due to fatty change in the liver and a loss of nucleated cells in the red pulp of the spleen, were found in peripheral organs of both groups. Conclusions: Low levels of intracerebral Gd caused by chronic oral exposure over almost the entire life span of mice did not lead to alterations in locomotor abilities in healthy mice throughout the normal aging process. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of a linear gadolinium-based contrast agent (GBCA) on the signal intensity (SI) of the deep cerebellar nuclei (DCN) in a retrospective clinical study on dogs after multiple magnetic resonance (MR) examinations with intravenous injections of gadodiamide and LA-ICP-MS analysis of a canine cerebellum after gadodiamide administration. Animals: 15 client-owned dogs of different breeds and additionally 1 research beagle dog cadaver. Procedures: In the retrospective study part, 15 dogs who underwent multiple consecutive MR imaging examinations with intravenous injection of linear GBCA gadodiamide were analyzed. SI ratio differences on unenhanced T1-weighted MR images before and after gadodiamide injections was calculated by subtracting SI ratios between DCN and pons of the first examination from the ratio of the last examination. Additionally, 1 research beagle dog cadaver was used for LA-ICP-MS (Laser ablation inductively coupled plasma mass spectrometry) analysis of gadolinium in the cerebellum as an add-on to another animal study. Descriptive and non-parametrical statistical analysis was performed and a p-value of < 0.05 was considered significant. Results: No statistically significant differences of SI ratios, between DCN and pons, were detectable based on unenhanced T1-weighted MR images. LA-ICP-MS analyses showed between 1.5 to 2.5 μg gadolinium/g tissue in the cerebellum of the examined dog, 35 months after the last of 3 MRI examination with gadodiamide (two examinations at a dose of 1 x 0.1mmol/kg, last examination at a dose of 3 x 0.05mmol/kg). Conclusion and clinical relevance: Although the retrospective MRI study did not indicate any visible effect of SI increase after multiple gadodiamide exposures, further studies based on LA-ICP-MS showed that the optical threshold was not reached for a potential visible effect. Gadolinium was detectable at a level of 1.5 to 2.5 μg gadolinium/g tissue by using LA-ICP-MS in the cerebellum 35 months after last MRI examination. The general importance of gadolinium retention of subvisible contents requires further investigation. [ABSTRACT FROM AUTHOR]

Introduction: The safety of using GBCAs to enhance the visibility of body structures is currently discussed due to possible gadolinium retention in brain structures. The aim of the study was to evaluate the effect of multiple exposures to macrocyclic GBCAs in children. Materials and methods: This retrospective, single-center study included data from 43 patients who had received ≥4 injections of macrocyclic GBCAs during MRI examinations over performed over 8 to 84 months. Signal intensity was measured on unenhanced T1-weighted MRI, and globus pallidus to thalamus (GP/Th) and dentate nucleus to pons (DN/P) ratios were calculated. The differences in ratios were tested with the Student’s t-test or the Wilcoxon rank sum test. For categorical data, Pearson's chi-squared test was used. Relationships were analyzed with the Spearman's rank correlation coefficient. Results: Patients with the mean age of 7.5 years (SD = 4.2) received 8.19 (SD = 3.63) injections of GBCAs on average. Differences in GP/Th and DN/P ratios between the first and the last measurement were insignificant. Children before the end of myelination process (≤2 years of age) had the first GP/Th ratio values significantly lower than those >2 years of age (p = 0.0284), which than increased at the final scan and reached the level similar to values obtained in the group of >2 years of age. Conclusions: Maturation of the brain may affect both signal intensity of brain structures and susceptibility to GBCAs; thus, assessment of signal intensity of the brain structures should be conducted taking into account the age of a child. [ABSTRACT FROM AUTHOR]

Pearl millet [Pennisetum glaucum (L.) R. Br.] is an important “orphan” cereal and the most widely grown of all the millet species worldwide. It is also the sixth most important cereal in the world after wheat, rice, maize, barley, and sorghum, being largely grown and used in West Africa as well as in India and Pakistan. The present study was carried out in the frame of a program designed to increase benefits and reduce potential health problems deriving from the consumption of pearl millet. The specific goal was to provide a database of information on the variability existing in pearl millet germplasm as to the amounts of phytate, the most relevant antinutrient compound, and the goitrogenic compounds C-glycosylflavones (C-GFs) accumulated in the grain.Results we obtained clearly show that, as indicated by the range in values, a substantial variability subsists across the investigated pearl millet inbred lines as regards the grain level of phytic acid phosphate, while the amount of C-GFs shows a very high variation. Suitable potential parents to be used in breeding programs can be therefore chosen from the surveyed material in order to create new germplasm with increased nutritional quality and food safety. Moreover, we report novel molecular data showing which genes are more relevant for phytic acid biosynthesis in the seeds as well as a preliminary analysis of a pearl millet orthologous gene for C-GFs biosynthesis. These results open the way to dissect the genetic determinants controlling key seed nutritional phenotypes and to the characterization of their impact on grain nutritional value in pearl millet. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the possibility of accelerated gadolinium accumulation in irradiated brain parenchyma where the blood-brain barrier was weakened. Methods: From January 2010 to June 2015, 44 patients with supratentorial glioblastoma were retrospectively identified who underwent pre- and post-radiation brain MR imaging, including R1 mapping. The mean dose of administered gadobutrol (Gadovist, Bayer, Germany) was 5.1 vials. Regions of interest (ROIs) were drawn around tumors that were located within 50–100% iso-dose lines of maximum radiation dose. ROIs were also drawn at globus pallidus, thalamus, and cerebral white matter. Averages of R1 values (unit: s-1) before and after radiation and those of R1 ratio (post-radiation R1 / pre-radiation R1) were compared by t-test or rank sum test as appropriate. Multiple linear regression analysis was performed to evaluate independent association factors for R1 value increase at irradiated parenchyma. Results: The mean R1 values in peri-tumoral areas were significantly increased after radiotherapy (0.7901±0.0977 [mean±SD] vs. 0.8146±0.1064; P <.01). The mean R1 ratio of high radiation dose areas was significantly higher than that of low dose areas (1.0055±0.0654 vs. 0.9882±0.0642; P <.01). The mean R1 ratio was lower in those who underwent hypofractionated radiotherapy (mean dose, 45.0 Gy) than those who underwent routine radiotherapy (mean dose, 61.1 Gy) (0.9913±0.0740 vs. 1.0463±0.0633; P = .08). Multiple linear regression analysis revealed that only radiotherapy type was significantly associated with increased R1 (P = .02) around tumors. Conclusions: Radiotherapy can induce R1 value increase in the brain parenchyma, which might suggest accelerated gadolinium accumulation due to damage to the blood-brain barrier. [ABSTRACT FROM AUTHOR]

In the search for novel anticancer drugs, the potassium channel KV10.1 has emerged as an interesting cancer target. Here, we report a new group of KV10.1 inhibitors, namely the purpurealidin analogs. These alkaloids are produced by the Verongida sponges and are known for their wide variety of bioactivities. In this study, we describe the synthesis and characterization of 27 purpurealidin analogs. Structurally, bromine substituents at the central phenyl ring and a methoxy group at the distal phenyl ring seem to enhance the activity on KV10.1. The mechanism of action of the most potent analog 5 was investigated. A shift of the activation curve to more negative potentials and an apparent inactivation was observed. Since KV10.1 inhibitors can be interesting anticancer drug lead compounds, the effect of 5 was evaluated on cancerous and non-cancerous cell lines. Compound 5 showed to be cytotoxic and appeared to induce apoptosis in all the evaluated cell lines. [ABSTRACT FROM AUTHOR]

Objectives: To quantify the imaging findings of patients with interstitial pneumonia (IP) and emphysema using three-dimensional curved high-resolution computed tomography (3D-cHRCT) at a constant depth from the chest wall, and compare the results to visual assessment of IP and each patient’s diffusing capacity of the lungs for carbon monoxide (DLco). Methods: We retrospectively reviewed the axial CT findings and pulmonary function test results of 95 patients with lung cancer (72 men and 23 women, aged 45–84 years) with or without IP, as follows: non-IP (n = 47), mild IP (n = 31), and moderate IP (n = 17). The 3D-cHRCT images of the lung at a 1-cm depth from the chest wall were reconstructed automatically using original software; total area (TA), high-attenuation area (HAA) >-500 HU, and low-attenuation area (LAA) <-950 HU were calculated on a workstation. The %HAA and %LAA were calculated as follows: , and . Results: The %HAA and %LAA respective values were 3.2±0.9 and 27.7±8.2, 3.9±1.2 and 27.6±5.9, and 6.9±2.2 and 25.4±8.7 in non-IP, mild IP, and moderate IP patients, respectively. There were significant differences in %HAA between the 3 groups of patients (P<0.001), but no differences in %LAA (P = 0.558). Multiple linear regression analysis revealed that %HAA and %LAA were negatively correlated with predicted DLco (standard partial regression coefficient [b*] = -0.453, P<0.001; b* = -0.447, P<0.001, respectively). Conclusions: The %HAA and %LAA values computed using 3D-cHRCT were significantly correlated with DLco and may be important quantitative parameters for both IP and emphysema. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether multiple repeated administrations of gadolinium-based macrocyclic ionic MR contrast agent (MICA) are associated with intracranial gadolinium deposition and identify the predisposing factors for deposition in various clinical situations. Materials and methods: In this institutional review board-approved retrospective study, 385 consecutive patients who underwent MICA-enhanced MR imaging were enrolled. The dentate nucleus-to-pons (DN/P) and globus pallidus-to-thalamus (GP/Th) signal intensity (SI) ratios on unenhanced T1-weighted images were recorded by 2 independent readers and averaged. The mean DN/P and GP/Th SI ratio difference between the last and the first examinations were tested using the one-sample t-test. Student’s t-test and stepwise regression analysis were used to identify the predisposing factors for deposition based on the number of administrations, time interval, hepatic and renal function, magnetic field strength, and chemo- or radiation therapy. Results: The mean DN/P SI ratio difference was not different from zero (P = .697), even in patients with ≥20 administrations (n = 33). Only patients with abnormal renal function showed an increase in the mean DN/P SI ratio difference (P = .019). The mean DN/P SI ratio difference was not associated with any predisposing factors. However, the mean GP/Th SI ratio difference showed decrease (P < .001), which was associated with age (P = .007), number of administrations (P = .01) and number of radiation therapy sessions (P = .022) on multivariate analysis. Conclusion: Multiple repeated administrations of MICA were not associated with increased T1 signal intensity in deep brain nuclei suggestive of Gd deposition in patients with normal renal function. [ABSTRACT FROM AUTHOR]

Purpose: In multiple sclerosis (MS) the sensitivity for detection of contrast enhancing lesions (CEL) in T1-weighted scans is essential for diagnostics and therapy decisions. The purpose of our study was to evaluate the sensitivity of T1w MPRAGE scans in comparison to T1w dark blood technique (T1-DB) for CEL in MS. Materials and methods: 3T MR imaging was performed in 37 MS patients, including T2-weighted imaging, T1w MPRAGE before and after gadolinium injection (unenhanced-T1 and T1-CE) and T1-DB imaging. After gadolinium application, the T1-DB scan was performed prior to T1-CE. From unenhanced-T1 and T1-CE scans, subtraction images (T1-SUB) were calculated. The number of CEL was determined separately on T1-CE and T1-DB by two raters independently. Lesions only detected on T1-DB scans then were verified on T1-SUB. Only lesions detected by both raters were included in further analysis. Results: In 16 patients, at least one CEL was detected by both rater, either on T1-CE or T1-DB. All lesions that were detected on T1-CE were also detected on T1-DB images. The total number of contrast enhancing lesions detected on T1-DB images (n = 54) by both raters was significantly higher than the corresponding number of lesions identified on T1-CE (n = 27) (p = 0.01); all of these lesions could be verified on SUB images. In 21 patients, no CEL was detected in any of the sequences. Conclusions: The application of T1-DB technique increases the sensitivity for CEL in MS, especially for those lesions that show only subtle increase in intensity after Gadolinium application but remain hypo- or iso-intense to surrounding tissue. [ABSTRACT FROM AUTHOR]

Background and purpose: Gadolinium based contrast agents (GBCAs) are widely used in magnetic resonance imaging, but recently, high signal intensity in the cerebellum structures was reported after repeated administrations of contrast- enhanced magnetic resonance images. The aim of this systematic review was to investigate the association between increased signal intensity in the dentate nucleus and globus pallidus in the brain and repeated administrations of GBCAs. Additionally, we focused on possible short- and long-term consequences of gadolinium use in those patients. Methods: Systematic review of retrospective investigations in PubMed and Medline was performed in July 2016. Primary outcomes included the presence of increased signal intensity within the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in patients following administrations of GBCAs. Two independent reviewers were responsible for search and data extraction. Results: 25 publications satisfied inclusion criteria (19 magnetic resonance images analyses, 3 case reports; 3 autopsy studies). Magnetic resonance images of 1247 patients with increased signal intensity on unenhanced T1-weighted MR images were analyzed as well as tissue specimens from 27 patients. Signal intensity correlated positively with the exposure to GBCAs and was greater after serial administrations of linear nonionic than cyclic contrast agents. Gadolinium was detected in all tissue examinations. Conclusions: High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance images were associated with previous administration of GBCAs. Signal intensity correlated negatively with stability of contrast agents. Clinical significance of gadolinium deposition in the brain remains unclear. There is a strong need for further research to identify type of gadolinium deposited in the brain as well as to gather knowledge about long-term consequences. [ABSTRACT FROM AUTHOR]

Objective: To differentiate smoking-related interstitial fibrosis (SRIF) from usual interstitial pneumonia (UIP) with emphysema on CT in combined pulmonary fibrosis and emphysema (CPFE) patients. Materials and Methods: This study was approved by the institutional review board and informed consent was waived. We included 65 patients who underwent lung biopsy under the suspicion of UIP pattern on HRCT, and after radiologic-pathologic correlation, they were divided into three groups: UIP without emphysema (n = 30), UIP with emphysema (n = 26), and SRIF (n = 9). The quantitative extent of emphysema in the entire lung was visually assessed and fibrotic patterns were qualitatively analyzed based on six characteristics (asymmetry, juxta-subpleural sparing, emphysema beside the honeycombing area, absence of ground grass attenuation/reticulation in honeycombing area, inhomogeneous honeycombing, and absence of honeycombing in the upper lobes). Kaplan-Meier analysis was used for survival analysis, and logistic regression with a receiver operating characteristic curve was used to predict the possibility of SRIF. Results: In qualitative analysis of fibrotic patterns, SRIF tended to exhibit more than three of six fibrotic features, whereas UIP with emphysema demonstrated about two of these characteristics (p = 0.035). In addition, SRIF had a higher extent of emphysema than UIP with emphysema when they have same amount of fibrosis (p = 0.014). In patients with SRIF, 5-year survival rate was 85.7%, while it was 40.7% in UIP with emphysema patients (p = 0.035). Conclusion: Fibrotic CT patterns and survival rate differed between SRIF and UIP with emphysema among CPFE patients, which explains the variable prognosis of CPFE. [ABSTRACT FROM AUTHOR]

Introduction: Emphysema and idiopathic pulmonary fibrosis (IPF) present either per se or coexist in combined pulmonary fibrosis and emphysema (CPFE). Serum surfactant proteins (SPs) A, B, C and D levels may reflect lung damage. We evaluated serum SP levels in healthy controls, emphysema, IPF, and CPFE patients and their associations to disease severity and survival. Methods: 122 consecutive patients (31 emphysema, 62 IPF, and 29 CPFE) and 25 healthy controls underwent PFTs, ABG-measurements, 6MWT and chest HRCT. Serum levels of SPs were measured. Patients were followed-up for 1-year. Results: SP-A and SP-D levels differed between groups (p = 0.006 and p<0.001 respectively). In post-hoc analysis, SP-A levels differed only between controls and CPFE (p<0.05) and CPFE and emphysema (p<0.05). SP-D differed between controls and IPF or CPFE (p<0.001 for both comparisons). In IPF SP-B correlated to pulmonary function while SP-A, correlated to the Composite Physiological Index (CPI). Controls current smokers had higher SP-A and SP-D levels compared to non-smokers (p = 0.026 and p = 0.023 respectively). SP-D levels were higher in CPFE patients with extended emphysema (p = 0.042). In patients with IPF, SP-B levels at the upper quartile of its range (≥26 ng/mL) presented a weak association with reduced survival (p = 0.05). Conclusion: In conclusion, serum SP-A and SP-D levels were higher where fibrosis exists or coexists and related to disease severity, suggesting that serum SPs relate to alveolar damage in fibrotic lungs and may reflect either local overproduction or overleakage. The weak association between high levels of SP-B and survival needs further validation in clinical trials. [ABSTRACT FROM AUTHOR]

Background: In the human visual system, different attributes of an object, such as shape, color, and motion, are processed separately in different areas of the brain. This raises a fundamental question of how are these attributes integrated to produce a unified perception and a specific response. This ''binding problem'' is computationally difficult because all attributes are assumed to be bound together to form a single object representation. However, there is no firm evidence to confirm that such representations exist for general objects. Methodology/Principal Findings: Here we propose a paired-attribute model in which cognitive processes are based on multiple representations of paired attributes. In line with the model's prediction, we found that multiattribute stimuli can produce an illusory perception of a multiattribute object arising from erroneous integration of attribute pairs, implying that object recognition is based on parallel perception of paired attributes. Moreover, in a change-detection task, a feature change in a single attribute frequently caused an illusory perception of change in another attribute, suggesting that multiple pairs of attributes are stored in memory. Conclusions/Significance: The paired-attribute model can account for some novel illusions and controversial findings on binocular rivalry and short-term memory. Our results suggest that many cognitive processes are performed at the level of paired attributes rather than integrated objects, which greatly facilitates the binding problem and provides simpler solutions for it. [ABSTRACT FROM AUTHOR]

Glomerular visceral epithelial cells (podocytes) contain interdigitated processes that form specialized intercellular junctions, termed slit diaphragms, which provide a selective filtration barrier in the renal glomerulus. Analyses of disease-causing mutations in familial nephrotic syndromes and targeted mutagenesis in mice have revealed critical roles of several proteins in the assembly of slit diaphragms. The nephrin-podocin complex is the main constituent of slit diaphragms. However, the molecular mechanisms regulating these proteins to maintain the slit diaphragms are still largely unknown. Here, we demonstrate that the PAR3-atypical protein kinase C (aPKC)-PAR6β cell polarity proteins co-localize to the slit diaphragms with nephrin. Furthermore, selective depletion of aPKCλ in mouse podocytes results in the disassembly of slit diaphragms, a disturbance in apico-basal cell polarity, and focal segmental glomerulosclerosis (FSGS). The aPKC-PAR3 complex associates with the nephrin-podocin complex in podocytes through direct interaction between PAR3 and nephrin, and the kinase activity of aPKC is required for the appropriate distribution of nephrin and podocin in podocytes. These observations not only establish a critical function of the polarity proteins in the maintenance of slit diaphragms, but also imply their potential involvement in renal failure in FSGS. [ABSTRACT FROM AUTHOR]