Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study.

RATIONALE & OBJECTIVE: In this pilot study, we hypothesized that autosomal dominant polycystic kidney disease (ADPKD) is characterized by impaired kidney oxidative metabolism that associates with kidney size and cyst burden. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Twenty adults with ADPKD (age, 31±6 years; 65% women; body mass index [BMI], 26.8 [22.7-30.4] kg/m2; estimated glomerular filtration rate [eGFR, 2021 CKD-EPI creatinine], 103±18mL/min/1.73m2; height-adjusted total kidney volume [HTKV], 731±370mL/m; Mayo classifications 1B [5%], 1C [42%], 1D [21%], and 1E [32%]) and 11 controls in normal weight category (NWC) (age, 25±3 years; 45% women; BMI, 22.5 [21.7-24.2] kg/m2; eGFR, 113±15mL/min/1.73m2; HTKV, 159±31mL/m) at the University of Colorado Anschutz Medical Campus. PREDICTORS: ADPKD status (yes/no) and severity (Mayo classifications). OUTCOME: HTKV and cyst burden by magnetic resonance imaging, kidney oxidative metabolism, and perfusion by 11C-acetate positron emission tomography/computed tomography, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]). ANALYTICAL APPROACH: For categorical variables, χ2/Fisher's exact tests, and for continuous variables t tests/Mann-Whitney U tests. Pearson correlation was used to estimate the relationships between variables. RESULTS: Compared with NWC individuals, the participants with ADPKD exhibited lower mean±SD M/I ratio (0.586±0.205 vs 0.424±0.171 [mg/kg lean/min]/(µIU/mL), P=0.04), lower median cortical perfusion (1.93 [IQR, 1.80-2.09] vs 0.68 [IQR, 0.47-1.04] mL/min/g, P<0.001) and lower median total kidney oxidative metabolism (0.17 [IQR, 0.16-0.19] vs. 0.14 [IQR, 0.12-0.15] min-1, P=0.001) in voxel-wise models excluding cysts. HTKV correlated inversely with cortical perfusion (r: -0.83, P < 0.001), total kidney oxidative metabolism (r: -0.61, P<0.001) and M/I (r: -0.41, P = 0.03). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSIONS: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements. FUNDING: Grants from government (National Institutes of Health, Centers for Disease Control and Prevention) and not-for-profit (JDRF) entities. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study numbers NCT04407481 and NCT04074668. PLAIN-LANGUAGE SUMMARY: In our study, we explored how a common genetic kidney condition, autosomal dominant polycystic kidney disease (ADPKD), relates to kidney metabolism. ADPKD leads to the growth of numerous cysts in the kidneys, which can impact their ability to work properly. We wanted to understand the kidneys' ability to process oxygen and blood flow in ADPKD. Our approach involved using advanced imaging techniques to observe kidney metabolism and blood flow in people with ADPKD compared with healthy individuals. We discovered that those with ADPKD had significant changes in kidney oxygen metabolism even when their kidney function was still normal. These findings are crucial as they provide deeper insights into ADPKD, potentially guiding future treatments to target these changes.

Improving microbial phylogeny with citizen science within a mass-market video game.

Citizen science video games are designed primarily for users already inclined to contribute to science, which severely limits their accessibility for an estimated community of 3 billion gamers worldwide. We created Borderlands Science (BLS), a citizen science activity that is seamlessly integrated within a popular commercial video game played by tens of millions of gamers. This integration is facilitated by a novel game-first design of citizen science games, in which the game design aspect has the highest priority, and a suitable task is then mapped to the game design. BLS crowdsources a multiple alignment task of 1 million 16S ribosomal RNA sequences obtained from human microbiome studies. Since its initial release on 7 April 2020, over 4 million players have solved more than 135 million science puzzles, a task unsolvable by a single individual. Leveraging these results, we show that our multiple sequence alignment simultaneously improves microbial phylogeny estimations and UniFrac effect sizes compared to state-of-the-art computational methods. This achievement demonstrates that hyper-gamified scientific tasks attract massive crowds of contributors and offers invaluable resources to the scientific community.

Brown adipose tissue metabolism in women is dependent on ovarian status.

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

The effects of the ß1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

AIM: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a ß3-adrenergic receptor (ß3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a ß1-AR antagonist could suppress these unwanted effects and increase the stimulation of the ß3-AR and ß2-AR in BAT. METHODS: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the ß1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. RESULTS: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. CONCLUSION: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

Cardiorenal ketone metabolism: a positron emission tomography study in healthy humans.

Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, 11C-acetoacetate (11C-AcAc), in the heart and kidney compared to 11C-acetate (11C-Ac), which is a well-validated metabolic radiotracer. Both tracers were highly metabolized by the left ventricle and the renal cortex. In the heart, kinetic rates were similar for both tracers. But in the renal cortex, uptake of 11C-Ac was higher compared to 11C-AcAc, while the reverse was observed for the clearance. Interestingly, infusion of 11C-AcAc led to a significantly delayed release of radioactivity in the renal medulla and pelvis, a phenomenon not observed with 11C-Ac. This suggests an equilibrium of 11C-AcAc with the other ketone, 11C-D-beta-hydroxybutyrate, and a different clearance profile. Overall, this suggests that in the kidney, the absorption and metabolism of 11C-AcAc is different compared to 11C-Ac. This dual tracer PET protocol provides the opportunity to explore the relative importance of ketone metabolism in cardiac and renal diseases, and to improve our mechanistic understanding of new metabolic interventions targeting these two organs.

High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome.

Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.

Exercise Capacity and Perceived Exertion on Treadmill Stress Test Performed While Wearing vs Without a Surgical Mask: A Randomized Clinical Trial in Healthy Adults.

Background: The graded exercise treadmill stress test (GXT) is among the most frequently performed tests in cardiology. The COVID-19 pandemic led many healthcare facilities to require patients to wear a mask during the test. This study evaluated the effect of wearing a surgical face mask on exercise capacity and perceived exertion. Methods: In this prospective, randomized crossover trial, 35 healthy adults performed a GXT using the Bruce protocol while wearing a surgical mask, and without a mask. The primary outcome was exercise capacity in metabolic equivalents (MET), and the secondary outcome was exercise perception on the modified Borg scale (from 0 to 10). Effort duration, heart rate, oxygen saturation, and blood pressure were also analyzed. Results: Exercise capacity was reduced by 0.4 MET (95% confidence interval [CI] -0.7 to -0.2) during the GXT with a mask (11.8 ± 2.7 vs 12.3 ± 2.5 MET, P = 0.001), and the final perceived effort increased by 0.5 points (95% CI 0.2 to 0.8; 8.4 ± 1.3 vs 7.9 ± 1.6, P = 0.004). Effort duration was cut down by 24 seconds (CI -0:39 to -0:09; 10:03 ± 2:30 vs 10:27 ± 2:16 [minutes:seconds], P = 0.003). Oxygen saturation was slightly lower at the end of the test when participants wore a mask. No significant differences occurred in heart rate or blood pressure during the test. Conclusion: Wearing a surgical mask causes a statistically significant decrease in exercise capacity and increase in perceived exertion. This small effect is not clinically significant for the interpretation of test results.

Introduction: L'épreuve d'effort gradué sur tapis roulant (GXT, de l'anglais graded exercise test) compte parmi les épreuves les plus fréquemment réalisées en cardiologie. La pandémie de COVID-19 a poussé de nombreux établissements de soins de santé à exiger aux patients le port du masque durant l'épreuve. La présente étude portait sur l'évaluation des effets du port du masque chirurgical sur la capacité à l'effort et l'effort perçu. Méthodes: Dans cet essai croisé prospectif, 35 adultes en bonne santé ont réalisé une GXT selon le protocole de Bruce, avec le port du masque chirurgical et sans le port du masque. Le principal critère d'évaluation était la capacité à l'effort exprimée en équivalents métaboliques (MET, de l'anglais Metabolic Equivalent of Task), et le critère secondaire était la perception de l'effort selon l'échelle de Borg modifiée (de 0 à 10). La durée de l'effort, la fréquence cardiaque, la saturation en oxygène et la pression artérielle ont également fait l'objet de l'analyse. Résultats: La capacité à l'effort était réduite de 0,4 MET (intervalle de confiance [IC] à 95 % de ­0,7 à ­0,2) durant la GXT réalisée avec le port du masque (11,8 ± 2,7 vs 12,3 ± 2,5 MET, P = 0,001), et l'effort perçu final avait augmenté de 0,5 point (IC à 95 % de 0,2 à 0,8 ; 8,4 ± 1,3 vs 7,9 ± 1,6, P = 0,004). La durée de l'effort était réduite de 24 secondes (IC à 95 % de ­0:39 à ­0:09 ; 10:03 ± 2:30 vs 10:27 ± 2:16 [minutes:secondes], P = 0,003). La saturation en oxygène était légèrement plus faible à la fin de l'épreuve lorsque les participants portaient le masque. Aucune différence significative de la fréquence cardiaque et de la pression artérielle n'est apparue durant l'épreuve. Conclusion: Le port du masque chirurgical entraîne une diminution statistiquement significative de la capacité à l'effort et une augmentation de l'effort perçu. Cet effet minime n'est pas cliniquement significatif pour l'interprétation des résultats de l'épreuve.

Basketball videos presented on a computer screen appear slower than in virtual reality.

Decision-making skills are essential to successful performance. To train them, coaches frequently use video replays to show their athletes how to best respond when facing specific situations. Recently, it has been shown that presenting the videos in virtual reality (VR) led to enhanced transfer, from the laboratory to the playing field, compared to when the videos were presented on a standard computer screen (CS). Interestingly, although the videos were identical, many participants informally reported that the VR videos felt accelerated compared to those they usually see on television. Here, we tested this claim by having varsity-level basketball players perform a decision-making task concomitantly with a playback speed estimation task. All participants observed the same video clips in the VR and CS conditions, and the video clips were either presented at their normal speed or had been accelerated or decelerated by 10%. Our results revealed that participants perceived the VR videos as significantly faster than the CS videos (mean perceived playback speed of 100.7% ± 2.35% and 94.9% ± 2.24%, respectively). This difference was, however, caused by the CS videos appearing slower than they truly were. Our results indicate that VR videos appear immune to the speed underestimation frequently reported with CS videos.

DeepImageTranslator: A free, user-friendly graphical interface for image translation using deep-learning and its applications in 3D CT image analysis.

The advent of deep-learning has set new standards in an array of image translation applications. At present, the use of these methods often requires computer programming experience. Non-commercial programs with graphical interface usually do not allow users to fully customize their deep-learning pipeline. Therefore, our primary objective is to provide a simple graphical interface that allows researchers with no programming experience to easily create, train, and evaluate custom deep-learning models for image translation. We also aimed to test the applicability of our tool in CT image semantic segmentation and noise reduction. DeepImageTranslator was implemented using the Tkinter library, the standard Python interface to the Tk graphical user interface toolkit; backend computations were implemented using data augmentation packages such as Pillow, Numpy, OpenCV, Augmentor, Tensorflow, and Keras libraries. Convolutional neural networks (CNNs) were trained using DeepImageTranslator. The effects of data augmentation, deep-supervision, and sample size on model accuracy were also systematically assessed. The DeepImageTranslator a simple tool that allows users to customize all aspects of their deep-learning pipeline, including the CNN, training optimizer, loss function, and the types of training image augmentation scheme. We showed that DeepImageTranslator can be used to achieve state-of-the-art accuracy and generalizability in semantic segmentation and noise reduction. Highly accurate 3D segmentation models for body composition can be obtained using training sample sizes as small as 17 images. In conclusion, an open-source deep-learning tool for accurate image translation with a user-friendly graphical interface was presented and evaluated. This standalone software can be downloaded at: https://sourceforge.net/projects/deepimagetranslator/.

Fat Cell Size: Measurement Methods, Pathophysiological Origins, and Relationships With Metabolic Dysregulations.

The obesity pandemic increasingly causes morbidity and mortality from type 2 diabetes, cardiovascular diseases and many other chronic diseases. Fat cell size (FCS) predicts numerous obesity-related complications such as lipid dysmetabolism, ectopic fat accumulation, insulin resistance, and cardiovascular disorders. Nevertheless, the scarcity of systematic literature reviews on this subject is compounded by the use of different methods by which FCS measurements are determined and reported. In this paper, we provide a systematic review of the current literature on the relationship between adipocyte hypertrophy and obesity-related glucose and lipid dysmetabolism, ectopic fat accumulation, and cardiovascular disorders. We also review the numerous mechanistic origins of adipocyte hypertrophy and its relationship with metabolic dysregulation, including changes in adipogenesis, cell senescence, collagen deposition, systemic inflammation, adipokine secretion, and energy balance. To quantify the effect of different FCS measurement methods, we performed statistical analyses across published data while controlling for body mass index, age, and sex.

Effects of the pandemic on caregivers of individuals with neuropsychomotor disorders / Efeitos da pandemia em cuidadores de indivíduos com alterações neuropsicomotoras

Abstract Introduction Since social isolation during the COVID-19 pandemic can influence a patient's and informal caregiver's health, the present study was carried out to understand and improve the latter's quality of life. Objective To analyze the physical, mental and quality of life effects on caregivers of patients with neurological sequelae and developmental delay during the COVID-19 pandemic. Methods: Thirty informal caregivers divided into two groups (G1: Psychomotor disorders and syndromes; G2: Neurological sequelae) were evaluated using questionnaires on general data, burden and quality of life. Chi-square tests with Bonferroni post-hoc correction were performed to compare the response rate between the dependent variables and the level of burden. The student's t-test was applied to determine the correlation between groups and quality of life, obtaining significant findings (p ≤ 0.05). Results No or minimal burden was found in 33.3% of the caregivers, and mild to moderate in 66.7% of each group, with no significant effect between them. In terms of quality of life, a decline was found in all domains, with a significant intergroup difference in social aspects and G1 exhibiting the highest declines (G1: 70.00 ± 23.99%; G2: 86.66 ± 20.84%). Conclusion There was a mild-to-moderate impact on physical burden, with a change in the quality of life of caregivers evaluated during the COVID-19 pandemic. Caregivers of children with psychomotor disorders and syndromes were the most affected in the social aspect domain.

Resumo Introdução O isolamento social durante a pandemia de COVID-19 pode influenciar a saúde do paciente e do cuidador informal. No intuito de compreender e orientar a melhora da qualidade de vida destes cuidadores, este estudo foi realizado. Objetivo Analisar os efeitos físicos, mentais e a qualidade de vida de cuidadores de pacientes com sequelas neurológicas e atraso do desenvolvimento durante a pandemia de COVID-19. Métodos Trinta cuidadores informais divididos em dois grupos (G1: distúrbios psicomotores e síndromes; G2: sequelas neurológicas) foram avaliados com questionários sobre dados gerais, sobrecarga e qualidade de vida. Foram realizados os testes qui-quadrado com pós-teste de Bonferroni para comparar a taxa de resposta entre as variáveis dependentes e o nível de sobrecarga. Para a correlação entre os grupos e a qualidade de vida, utilizou-se o teste t de Student não pareado, sendo significativo os achados com p ≤ 0,05. Resultados Encontrou-se ausência de sobrecarga ou sobrecarga mínima em 33,3% e sobrecarga leve a moderada em 66,7% dos cuidadores em cada grupo, sem efeito significativo entre estes. Na qualidade de vida foi encontrado déficit em todos os domínios, com diferença significativa entre os grupos no domínio de aspectos sociais, tendo o G1 apresentado maiores déficits (G1: 70,00 ± 23,99%; G2: 86,66 ± 20,84%). Conclusão Conclui-se que houve impacto de leve a moderado na sobrecarga física, com alteração na qualidade de vida dos cuidadores avaliados durante a pandemia de COVID-19, sendo os cuidadores de crianças com distúrbios psicomotores e síndromes os mais acometidos no aspecto social.

Lipocalin 2 modulates dendritic cell activity and shapes immunity to influenza in a microbiome dependent manner.

Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.

Contribution of perfusion to the 11 C-acetate signal in brown adipose tissue assessed by DCE-MRI and 68 Ga-DOTA PET in a rat model.

PURPOSE: Determine if dynamic contrast enhanced (DCE) -MRI and/or 68 gallium 1,4,7,10-tetraazacyclododecane N, N', N″, N‴-tretraacetic acid (68 Ga-DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold-stimulated and heat-inhibited BAT. Determine if the 11 C-acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. METHODS: Rats were split into three groups. In group 1 (N = 6), DCE-MRI with gadobutrol was compared directly to 68 Ga-DOTA PET following exposure to 10 °C for 48 h. 11 C-Acetate PET was also performed to assess oxidation. In group 2 (N = 4), only 68 Ga-DOTA PET was acquired following exposure to 10 °C for 48 h. Finally, in group 3 (N = 10), perfusion was assessed with DCE-MRI in rats exposed to 10 °C or 30 °C for 48 h, and oxidation was measured with 11 C-acetate. Perfusion was quantified with a two-compartment pharmacokinetic model, while oxidation was assessed by a four-compartment model. RESULTS: DCE-MRI and 68 Ga-DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10 °C or 30 °C did not affect the perfusion measures, but the 11 C-acetate signal increased in BAT at 10 °C. Without prior information about blood volume, the 11 C-acetate compartment model overestimated blood volume and underestimated oxidation in 10 °C BAT. CONCLUSION: Precise assessment of oxidation via 11 C-acetate PET requires prior information about blood volume which can be obtained by DCE-MRI or 68 Ga-DOTA PET. Since perfusion can change rapidly, simultaneous PET-MRI would be preferred.

SLAMF1 is required for TLR4-mediated TRAM-TRIF-dependent signaling in human macrophages.

Signaling lymphocytic activation molecule family 1 (SLAMF1) is an Ig-like receptor and a costimulatory molecule that initiates signal transduction networks in a variety of immune cells. In this study, we report that SLAMF1 is required for Toll-like receptor 4 (TLR4)-mediated induction of interferon ß (IFNß) and for killing of Gram-negative bacteria by human macrophages. We found that SLAMF1 controls trafficking of the Toll receptor-associated molecule (TRAM) from the endocytic recycling compartment (ERC) to Escherichia coli phagosomes. In resting macrophages, SLAMF1 is localized to ERC, but upon addition of E. coli, it is trafficked together with TRAM from ERC to E. coli phagosomes in a Rab11-dependent manner. We found that endogenous SLAMF1 protein interacted with TRAM and defined key interaction domains as amino acids 68 to 95 of TRAM as well as 15 C-terminal amino acids of SLAMF1. Interestingly, the SLAMF1-TRAM interaction was observed for human but not mouse proteins. Overall, our observations suggest that SLAMF1 is a new target for modulation of TLR4-TRAM-TRIF inflammatory signaling in human cells.

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M.

Positive-stranded RNA viruses, such as hepatitis C virus (HCV), assemble their viral replication complexes by remodeling host intracellular membranes to a membranous web. The precise composition of these replication complexes and the detailed mechanisms by which they are formed are incompletely understood. Here we show that the human immunity-related GTPase M (IRGM), known to contribute to autophagy, plays a previously unrecognized role in this process. We show that IRGM is localized at the Golgi apparatus and regulates the fragmentation of Golgi membranes in response to HCV infection, leading to colocalization of Golgi vesicles with replicating HCV. Our results show that IRGM controls phosphorylation of GBF1, a guanine nucleotide exchange factor for Arf-GTPases, which normally operates in Golgi membrane dynamics and vesicle coating in resting cells. We also find that HCV triggers IRGM-mediated phosphorylation of the early autophagy initiator ULK1, thereby providing mechanistic insight into the role of IRGM in HCV-mediated autophagy. Collectively, our results identify IRGM as a key Golgi-situated regulator that links intracellular membrane remodeling by autophagy and Golgi fragmentation with viral replication.

An adolescent with large cell calcifying sertoli cell tumor of the testis and undiagnosed Carney Complex: A case report.

Carney Complex (CNC) is a rare autosomal dominant condition with characteristic clinical presentation, tumor development, and unique genetic mutation. We present a unique case and literature review of CNC in which two neoplasms characteristic of this complex were initially diagnosed through cytological fine needle aspirate specimens, leading to the identification of CNC, with subsequent surgical and cytogenetic confirmation. Diagn. Cytopathol. 2017;45:634-639. © 2017 Wiley Periodicals, Inc.

The Arabidopsis DNA mismatch repair gene PMS1 restricts somatic recombination between homeologous sequences.

The eukaryotic DNA mismatch repair (MMR) system contributes to maintaining the fidelity of genetic information by correcting replication errors and preventing illegitimate recombination events. This study aimed to examine the function(s) of the Arabidopsis thaliana PMS1 gene (AtPMS1), one of three homologs of the bacterial MutL gene in plants. Two independent mutant alleles (Atpms1-1 and Atpms1-2) were obtained and one of these (Atpms1-1) was studied in detail. The mutant exhibited a reduction in seed set and a bias against the transmission of the mutant allele. Somatic recombination, both homologous and homeologous, was examined using a set of reporter constructs. Homologous recombination remained unchanged in the mutant while homeologous recombination was between 1.7- and 4.8-fold higher than in the wild type. This increase in homeologous recombination frequency was not correlated with the degree of sequence divergence. In RNAi lines, a range of increases in homeologous recombination were observed with two lines showing a 3.3-fold and a 3.6-fold increase. These results indicate that the AtPMS1 gene contributes to an antirecombination activity aimed at restricting recombination between diverged sequences.

Estimating Medicare Part D's impact on medication access among dually eligible beneficiaries with mental disorders.

OBJECTIVE: Medicare drug benefit (Part D) plans may restrict psychotropic medications more than state Medicaid programs do. This may have important implications for patients dually eligible for Medicare and Medicaid whose medications previously were covered under Medicaid. The objective of this study was to estimate rates of medication switching among dually eligible beneficiaries using antidepressants, antipsychotics, and mood stabilizers attributable to their enrollment in Medicare drug plans. METHODS: Baseline data on medication usage patterns among 467 dually eligible beneficiaries with mental disorders from the Medicare Current Beneficiary Survey, formulary data from a sample of Medicare drug plans, and estimates of the utilization response to pharmacy management tools from the Medicaid literature were used to estimate the likelihood of switching medications conditional on use of drugs and assignment to particular Medicare drug plans. RESULTS: Restrictions on psychotropic medications were common among the drug plans studied. Estimated rates of medication switching attributable to Medicare Part D were 6%-10% among dually eligible beneficiaries using antipsychotics, 5%-7% among those using antidepressants, and 2%-4% among those using mood stabilizers. Switching rates varied substantially across plans. CONCLUSIONS: On average, relatively few dually eligible beneficiaries with mental disorders are likely to experience treatment disruptions because of formulary restrictions and utilization controls used by Medicare drug plans. However, beneficiaries in some plans will experience significant barriers to medication access. Given the substantial variation among Medicare drug plans' management of psychotropic medication use, clinicians and social service agencies should counsel their beneficiaries with mental disorders in navigating the complex Medicare drug plan market.