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Abstract Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development.

Abstract The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2519 out of 5385) of the GWAS loci examined.

Patients with type 2 diabetes mellitus (T2DM) often experience fatigue. The Multidimensional Fatigue Inventory (MFI-20) is a valid tool for evaluating fatigue; however, its psychometric properties have not been examined in Indonesian-speaking patients with T2DM. This study assessed the psychometric properties of the Indonesian version of the Multidimensional Fatigue Inventory-20 (IMFI-20) in patients with T2DM and investigated fatigue in a health-care setting. A cross-sectional design was adopted. Two hundred patients with T2DM were interviewed in clinics. Five self-structured measures were used to assess the frequency and duration of fatigue and the health-care utilization of patients with fatigue. Cronbach's alpha and intraclass correlation (ICC) were used to evaluate the internal consistency and test-retest reliability of the Indonesian version of the MFI-20 (IMFI-20). The criterion, convergent, and known-group validity of the IMFI-20 were also examined, and its underlying structure was determined using explanatory factor analysis. The STROBE checklist was used. The results revealed that approximately half of the patients experienced fatigue. Among those with fatigue, 62% reported that their fatigue was rarely or never treated by their physicians. The IMFI-20 exhibited satisfactory model fit, excellent internal consistency (Cronbach's alpha of 0.92), and test-retest ICC of 0.93. The IMFI-20 was significantly associated with the Functional Assessment of Chronic Illness Therapy-Fatigue, Beck Depression Inventory-Second Edition, and Pittsburgh Sleep Quality Index (r = 0.705, 0.670, and 0.581, respectively). The IMFI-20 exhibited known-group validity for unfavorable sleep quality and HbA1C ≥ 6.5%. Our findings suggest that patients with T2DM who experience fatigue are often overlooked by health-care providers, and that the IMFI-20, which exhibits excellent psychometric properties, can be adopted by studies that use fatigue as an endpoint in Indonesian-speaking populations.

Both high-fat diet (HFD) alone and high-fructose plus HFD (HFr/HFD) cause diet-induced non-alcoholic fatty liver disease in murine models. However, the mechanisms underlying their impacts on inducing different levels of liver injury are yet to be elucidated. This study employed a proteomic approach to elucidate further on this issue. Adult male C57BL/6J mice were allocated to the HFD or the HFr/HFD group. After feeding for 12 weeks, all mice were euthanized and samples were collected. The proteomic profiles in liver tissues were analyzed using liquid chromatography–tandem mass spectrometry followed by canonical pathway analysis. We demonstrated that the mitochondrial oxidative phosphorylation (OXPHOS) pathway was the most significantly downregulated canonical pathway in the HFr/HFD group when compared with the HFD group. Within the OXPHOS pathway, the HFr/HFD group demonstrated significant downregulation of complexes I and III and significant upregulation of complex IV when compared with the HFD group. Moreover, the HFr/HFD group had lower protein levels of NADH: ubiquinone oxidoreductase subunits S3, S6, A5, and A12 in complex I (p < 0.001, =0.03, p < 0.001), and higher protein level of cytochrome C oxidase subunit 2 in complex IV (p = 0.002), when compared with the HFD group. To summarize, we have demonstrated that the hepatic mitochondrial OXPHOS pathway is significantly downregulated in long-term HFr/HFD feeding when compared with long-term HFD feeding. These data support the concept that the hepatic mitochondrial OXPHOS pathway should be involved in mediating the effects of HFr/HFD on inducing more severe liver injury than HFD alone.

Abstract Objective To evaluate the success rate of therapeutic administration of a single calculated 131I activity for eliminating hyperthyroidism due to Graves’ disease. Methods and materials Patients with Graves’ hyperthyroidism underwent pinhole thyroid imaging, 24-h radioactive iodine uptake (RAIU) measurements and clinical examination and received a calculated 131I activity of 0.2 mCi per estimated gram of thyroid tissue, adjusted for the 24-h RAIU. The goal of RAI treatment was to achieve hypothyroidism within 3–6 months of 131I administration. Response to RAI therapy was assessed at 7 weeks and 3 months by clinical and biochemical follow-up. Results The study included 316 hyperthyroid patients with Graves’ disease (F238:M78, mean age 42.1 ± 16 y, 4–94). 179 patients (56.6%) had no prior therapeutic intervention (treatment-naive patients), whereas 6 patients had prior thyroid surgery, and 131 (41.5%) had been treated with anti-thyroid medications. The mean estimated thyroid gland size was 50.2 g ± 18, range 15–100. Mean RAIU was 0.57 ± 0.17 (normal 0.07–0.30). RAI doses ranged from 5 to 70 mCi (mean dose = 18.1 mCi). Successful treatment of hyperthyroidism at our institution was obtained after a single therapeutic 131-I activity administration in 295 of 316 (93.3%) patients. Multivariate logistic regression analysis demonstrated that failure of 131I therapy was associated with previous PTU therapy (p 90%) of patients, adjusting for the thyroid size and 24 h uptake measurement.

Endoplasmic reticulum (ER) stress mediates the effects of obesity on aggravating sepsis-induced lung injury. We investigated whether exosomes from human placenta choriodecidual membrane-derived mesenchymal stem cells (pcMSCs) can mitigate pulmonary ER stress, lung injury, and the mechanisms of inflammation, oxidation, and apoptosis in lipopolysaccharide-treated obese mice. Diet-induced obese (DIO) mice (adult male C57BL/6J mice fed with a 12-week high-fat diet) received lipopolysaccharide (10 mg/kg, i.p.; DIOLPS group) or lipopolysaccharide plus exosomes (1 × 108 particles/mouse, i.p.; DIOLPSExo group). Our data demonstrated lower levels of ER stress (upregulation of glucose-regulated protein 78, phosphorylated eukaryotic initiation factor 2α, and C/EBP homologous protein; p = 0.038, p = 0.03, p < 0.001), and apoptosis (DNA fragmentation, p = 0.003) in lung tissues, as well as lower lung injury level (decreases in tidal volume, peak inspiratory flow, and end expiratory volume; increases in resistance, injury score, and tissue water content; p < 0.001,

ABSTRACT: Objective: Postpartum thyroiditis presents as thyrotoxicosis from autoimmune thyroid inflammation that causes release of iodothyronines and diffuse, decreased thyroid uptake of both radioactive iodine and 99mTc-pertechnetate. Thyroiditis with focal “cold” thyroid nodule on thyroid scintigraphy has been previously described and attributed to localized inflammation.Methods: We report a patient diagnosed with postpartum thyroiditis, in whom an apparently “hot” nodule on initial thyroid pinhole scintigraphy was later noted to be “cold” at follow-up imaging.Results: Thyroid nodularity co-existing with subacute thyroiditis usually presents as focal “cold” nodules, attributed to localized inflammation in the thyroid. The diagnosis of postpartum thyroiditis in our patient was made more challenging due to the presence of a thyroid nodule with an evolving imaging appearance over time. This led to a potential for misdiagnosis of this “hot” nodule dependent on the timing of having the thyroscintigram performed early in the disease course. We hypothesized that the overactive focus of uptake was due to sparing of a pre-existing colloid nodule by the inflammatory process which later became “cold” in the recovery phase.Conclusion: The presence of co-existing thyroiditis and thyroid nodules, both common entities, may cause diagnostic difficulty on thyroid scintigraphy due to dynamic, temporal changes in imaging appearance and the variable findings reported in the literature. Clinical surveillance and performing repeat thyroid imaging will allow correct diagnosis and appropriate management of these challenging cases.Abbreviation: RAIU radioactive iodine uptake

Sites of infection and inflammation can be misleading in oncology PET/CT imaging because these areas commonly show 18F-FDG activity. Caution in the interpretation must be taken to avoid the misdiagnosis of malignancy. Utilization of both CT findings as well as patient history can help differentiate benign infectious and inflammatory processes from malignancy, although occasionally additional work-up may be required. This article discusses the mechanism of 18F-FDG uptake in infection and inflammation with illustrative examples.

Purpose: Hyperglycemia affects FDG uptake in the brain, potentially emulating Alzheimer’s disease in normal individuals. This study investigates global and regional cerebral FDG uptake as a function of plasma glucose in a cohort of patients. Methods: 120 consecutive male patients with FDG PET/CT for initial oncologic staging (July–Dec 2015) were reviewed. Patients with dementia, cerebrovascular accident, structural brain lesion, prior oncology treatment or high metabolic tumor burden (recently shown affecting brain FDG uptake) were excluded. 53 (24 nondiabetic) eligible patients (age 65.7 ± 2.8 mean ± SE) were analyzed with parametric computer software, MIMneuro™. Regional Z-scores were evaluated as a function of plasma glucose and age using multi variable linear mixed effects models with false discovery analysis adjusting for multiple comparisons. If the regression slope was significantly (p

Imaging techniques are an essential component of the diagnostic process for interstitial lung diseases (ILDs). Chest radiography is frequently the initial indicator of an ILD, and comparison of radiographs taken at different time points can show the rate of disease progression. However, radiography provides only limited specificity and sensitivity and is primarily used to rule out other diseases, such as left heart failure. High-resolution computed tomography (HRCT) is a more sensitive method and is considered central in the diagnosis of ILDs. Abnormalities observed on HRCT can help identify specific ILDs. HRCT also can be used to evaluate the patient's prognosis, while disease progression can be assessed through serial imaging. Other imaging techniques such as positron emission tomography-computed tomography and magnetic resonance imaging have been investigated, but they are not commonly used to assess patients with ILDs. Disease severity may potentially be estimated using quantitative methods, as well as visual analysis of images. For example, comprehensive assessment of disease staging and progression in patients with ILDs requires visual analysis of pulmonary features that can be performed in parallel with quantitative analysis of the extent of fibrosis. New approaches to image analysis, including the application of machine learning, are being developed.

Inappropriate expression of the c-met-protooncogene product (Met) and/or of its ligand, hepatocyte growth factor/scatter factor (HGF/SF), has been correlated with poor prognosis in a variety of human solid tumors. We are developing animal models for nuclear imaging of Met and HGF/SF expression in tumors in vivo. We radioiodinated a mixture of monoclonal antibodies (MAbs) that bind to human HGF/SF and to the external ligand-binding domain of human Met, and then injected the I-125-MAb mixture intravenously into mice bearing tumors either autocrine for human HGF/SF and human Met or autocrine-paracrine for murine HGF/SF and murine Met. Serial total body gamma camera images were obtained, and regional activity was determined by quantitative region-of-interest (ROI) analysis. Tumors autocrine for human HGF/SF and Met demonstrated significantly more rapid uptake and more rapid clearance of the I-125-MAb mixture than tumors expressing one or both murine homologues, reaching a mean tumor to total body activity ratio of > 0.3 by 1 day postinjection. We conclude that radioimmunodetection of tumors autocrine for human HGF/SF and Met is feasible with an I-125-MAb mixture reactive against the ligand-receptor pair.

ABSTRACT Introduction: Detection of sepsis and septic shock is essential, since any delay in initiating a proper treatment is associated with a worse prognosis. Objective: To evaluate levels of interleukin-6 (IL-6) early in the onset of the evolution of sepsis associated-organ dysfunction and its relation to the need for more advanced supportive therapies. Methods: This is a prospective study at a 43-bed mixed Medical-surgical Intensive Care Unit (ICU) in a university hospital. Patients admitted to the ICU, over 18 years of age, with severe sepsis or septic shock and who presented the first organ dysfunction in less than 48 hours of admission to the ICU were included. We monitored in a daily basis the advanced supportive therapies, need for vasopressors, mechanical ventilation, or renal replacement therapy (RRT), until hospital discharge or death. Blood samples to measure the serum IL-6 levels were collected at the time of inclusion in the study, at 12 and 24 hours later. Patients were divided into two groups according to serum IL-6 levels at admission (Low IL-6: < 1,000 pg/ml or High IL-6: > 1,000 pg/ml). Results: The need for norepinephrine was significantly higher in the group with High IL-6 (100%) than in the group with Low IL-6 (62.5%) (p = 0.009). RRT was also more frequent in patients with High IL-6 than in those with Low High IL-6 (87.5% vs. 55.5%, respectively, p = 0.056). Conclusion: These findings suggest that the evaluation of serum IL-6 level is useful in the early phase of the severe sepsis and septic shock in order to identify higher-risk patients.

PurposeBlood glucose is routinely measured prior to 18F-fluorodeoxyglucose (FDG) administration in positron emission tomography (PET) imaging to identify hyperglycemia that may affect image quality. In this study we explore the effects of blood glucose levels upon semi-quantitative standardized uptake value (SUV) measurements of target organs and tissues of interest and in particular address the relationship of blood glucose to FDG accumulation in the brain and liver.Methods436 FDG PET/CT consecutive studies performed for oncology staging in 229 patients (226 male) at the Ann Arbor Veterans Administration Healthcare System were reviewed. All patients had blood glucose measured (112.4±34.1mg/dL) prior to injection of 466.2±51.8MBq (12.6±1.4mCi) of FDG. SUV measurements of brain, aortic arch blood-pool, liver, and spleen were obtained at 64.5±10.2min' post-injection.ResultsWe found a negative inverse relationship of brain SUV with increasing plasma glucose, levels for both absolute and normalized (either to blood-pool or liver) values. Higher blood glucose levels had a mild effect upon liver and blood-pool SUV. By contrast, spleen SUV was independent of blood glucose, but demonstrated the greatest variability (deviation on linear regression). In contrast to other tissues, liver and spleen SUV normalized to blood-pool SUV were not dependent upon blood glucose levels.ConclusionThe effects of hyperglycemia upon FDG uptake in brain and liver, over a range of blood glucose values generally considered acceptable for clinical PET imaging, may have measurable effects on semi-quantitative image analysis.

Writing reflections is recommended for enhancing retention and transfer of learned material. The benefits of student reflections have been well documented, but the methods for collecting and assessing reflections can be difficult. This study presents the development and analysis of a new, straightforward rubric for assessing depth of student reflections. The psychometric properties of the depth ratings based on the rubric and preliminary validity evidence of the ratings are investigated. With this rubric, raters were able to assess the depth of reflections very reliably. Depth ratings were significantly related to GPA.