ß-Cyclodextrins alter the energy metabolism-related enzyme activities in rats.

Although widely used in medicine, separation technology, and other fields, the effects of cyclodextrins on the activities of phosphoryl transfer enzymes have not been previously evaluated. In vivo studies evaluated the function of cyclodextrins as active compounds. Despite the use of cyclodextrins as active compounds, the effects of cyclodextrins on hepatic and renal tissues remain to be fully elucidated. The primary objective of this study was to evaluate the effects of ß- cyclodextrins, methyl-ß-cyclodextrin (M-ß- cyclodextrins), and (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-cyclodextrins) on enzyme activities regulating the maintenance of energy homeostasis in the kidney and liver tissues in relation to toxicity. Serum levels of liver and kidney markers were measured, and oxidative stress parameters were assessed. After 60-day treatments, we observed that the administration of ß-cyclodextrins and M-ß-cyclodextrins inhibited the hepatic activity of pyruvate kinase, an irreversible enzyme within the glycolytic pathway. Additionally, administration of HP-ß-cyclodextrins inhibited creatine kinase activity and increased the total sulfhydryl content in kidneys. Here, we demonstrated for the first time that ß-cyclodextrins, M-ß-cyclodextrins, and HP-ß-cyclodextrins cause bioenergetic dysfunction in renal and hepatic tissues. These findings suggest that understanding the balance between cyclodextrins' efficacy and adverse effects is essential for better accepting their use in medicine.

Potential clinical utility of 68Ga-DOTATATE PET/CT for detection and response assessment in cardiac sarcoidosis.

BACKGROUND: Somatostatin receptor is expressed in sarcoid granulomas, and preliminary clinical studies have shown that myocardial sarcoidosis can be identified on somatostatin receptor-targeted PET. We examined the potential clinical use of 68Ga-DOTATATE PET/CT for diagnosis and response assessment in cardiac sarcoidosis compared to 18F-FDG PET/CT. METHODS: Eleven cardiac sarcoidosis patients with 18F-FDG PET/CT were prospectively enrolled for cardiac 68Ga-DOTATATE PET/CT. The two PET/CT studies were interpreted independently and were compared for patient-level and segment-level concordance, as well as for the degree of radiotracer uptake. Follow-up 68Ga-DOTATATE PET/CT was performed in eight patients. RESULTS: Patient-level concordance was 91%: ten patients had multifocal DOTATATE uptake (active cardiac sarcoidosis) and one patient showed diffuse DOTATATE uptake. Segment-level agreement was 77.1% (Kappa 0.53 ± 0.07). The SUVmax-to-blood pool ratio was lower on 68Ga-DOTATATE PET/CT (3.2 ± 0.6 vs. 4.9 ± 1.5, P = 0.006 on paired t test). Follow-up 68Ga-DOTATATE PET/CT showed one case of complete response and one case of partial response, while 18F-FDG PET/CT showed four cases of response, including three with complete response. CONCLUSION: Compared to 18F-FDG PET/CT, 68Ga-DOTATATE PET/CT can identify active cardiac sarcoidosis with high patient-level concordance, but with moderate segment-level concordance, low signal-to-background ratio, and underestimation of treatment response.

Fatigue following type 2 diabetes: Psychometric testing of the Indonesian version of the multidimensional fatigue Inventory-20 and unmet fatigue-related needs.

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.

High-Fructose/High-Fat Diet Downregulates the Hepatic Mitochondrial Oxidative Phosphorylation Pathway in Mice Compared with High-Fat Diet Alone.

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, <0.001, and <0.001, respectively), lower protein level of cytochrome C in complex III (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.

Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells Mitigate Endoplasmic Reticulum Stress, Inflammation, and Lung Injury in Lipopolysaccharide-Treated Obese Mice.

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, <0.001, and <0.001, respectively), inflammation (activation of nuclear factor-kB, hypoxia-inducible factor-1α, macrophages, and NLR family pyrin domain containing 3; upregulation of tumor necrosis factor-α, interleukin-1ß, and interleukin-6; p = 0.03, <0.001, <0.001, <0.001, <0.001, <0.001, and <0.001, respectively), lipid peroxidation (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, <0.001, <0.001, <0.001, <0.001, and =0.002, respectively) in the DIOLPSExo group than in the DIOLPS group. In conclusion, exosomes from human pcMSCs mitigate pulmonary ER stress, inflammation, oxidation, apoptosis, and lung injury in lipopolysaccharide-treated obese mice.

Histopathologic features predictive of metastasis and survival in 230 patients with cutaneous squamous cell carcinoma of the head and neck and non-head and neck locations: a single-center retrospective study.

BACKGROUND: Staging systems for cutaneous squamous cell carcinoma (cSCC) produce inconsistent risk stratification. OBJECTIVE: The aim of this study was to identify further prognostic parameters for better stratification. METHODS: We retrospectively analysed the prognostic significance of clinicopathologic parameters of 230 patients who underwent primary excision of invasive cSCC of the head and neck (n = 115) and non-head and non-neck (n = 115) locations. In addition to known high-risk features, we analysed tumour nest shape, invasion pattern, lymphoid response pattern and tumour budding. RESULTS: On multivariable analysis, lymphovascular invasion (LVI) and high tumour budding predicted worse disease-specific survival, and ulceration, LVI and high tumour budding predicted worse overall survival. Only ulceration was independently associated with risk of nodal metastasis. CONCLUSION: High tumour budding, LVI and ulceration are independently associated with poor outcome in cSCC and may be used to refine cSCC prognostic stratification, which is crucial to optimize clinical decision and to identify patients who are more likely to benefit from more aggressive interventions or clinical trials.

Analysis of single nucleotide polymorphisms in chronic beryllium disease.

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.

Exploiting the GTEx resources to decipher the mechanisms at GWAS loci.

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.

The impact of infection and inflammation in oncologic 18F-FDG PET/CT imaging.

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.

Effects of plasma glucose levels on regional cerebral 18F-fluorodeoxyglucose uptake: Implications for dementia evaluation with brain PET imaging.

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 < 0.05) different than zero, hyperglycemia effect was present. RESULTS: There was a negative inverse relationship (p < 0.001) between global brain FDG uptake and hyperglycemia. No regional hyperglycemia effect on uptake were present when subjects were normalized using pons or cerebellum. However, regional hyperglycemia effects were seen (p < 0.047-0.001) when normalizing by the whole brain. No obvious pattern was seen in the regions affected. Age had a significant effect using whole brain normalization (p < 0.04-0.01). CONCLUSIONS: Cortical variation in FDG uptake were identified when subjects were hyperglycemic. However, these variations didn't fit a particular pattern of dementia and the severity of the affect is not likely to alter clinical interpretation.

Nuclear Medicine Therapy With 223Radium-dichloride for Osseous Metastases in Prostate Carcinoma.

Painful osseous metastasis resulting from castration-resistant prostate carcinoma is a common clinical problem. Historically, nuclear medicine offered several palliative beta-emitting radiopharmaceuticals targeting the skeleton with the goal of decreasing pain. However, these have largely been replaced by the alpha-emitting agent 223radium (Ra). 223Ra received Food and Drug Administration approval in 2013 for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases without visceral metastases. 223Ra offers an improved therapeutic profile due to its alpha-particle emissions resulting in a relatively higher linear energy transfer and lower particle range compared with beta-emitters. 223Ra also has demonstrated to increase overall survival in patients and to delay adverse skeletal events. Running a successful clinical nuclear therapy program with Ra requires a multidisciplinary team approach and this article suggests an implementation strategy from the authors' institution. Potential new nuclear radiopharmaceuticals still under investigation offering the future possibility of radioligand therapy are also discussed briefly.

Synchronous Metastatic Breast Carcinoma and Parathyroid Adenoma on 18F-FDG PET/CT and 99mTc-Sestamibi Imaging.

In addition to nuclear cardiac and breast imaging, Tc-sestamibi scintigraphy is often used to localize parathyroid adenomas. F- fluorodeoxyglucose (FDG) PET is heavily utilized in oncology, although its use in identifying parathyroid adenomas is limited. We describe a case of a 57-year-old woman who underwent parathyroid scintigraphy and F-FDG PET/CT in the same week due to hyperparathyroidism and an enlarging breast mass, respectively. A right paratracheal mediastinal mass that otherwise would be suspicious for nodal metastases by CT alone was correctly identified to be an ectopic parathyroid adenoma using a combination of the nuclear medicine studies performed.

Comparison of Microbial Growth Between Commercial Formula and Blenderized Food for Tube Feeding.

BACKGROUND: Many healthcare facilities and providers prohibit blenderized tube feeding (BTF) for patients who request it due to concerns of high microbial load. The current project compared microbial loads of a standard ready-to-feed polymeric commercial formula (CF), a BTF made using baby food (BTF-BF), and a BTF prepared from blending whole food (BTF-WF), following food safety standards expected of U.S. hospitals. METHODS: Three tube-feeding formulas (CF, BTF-BF, BTF-WF) were prepared in a U.S. hospital and delivered in vitro to an unoccupied patient room. Samples were collected at zero hour, 2 hours, and 4 hours and compared for growth of aerobic microorganisms, Staphylococus aureus, coliforms, and Escherichia coli. The experiment was conducted in triplicate, 1 week apart. RESULTS: No S. aureus or coliform/E. coli were detected at any time point following preparation, and total bacterial count was well below acceptable limits. All 3 feeding formulas at zero hour, 2 hours, and 4 hours for each of the 3 sampling dates were acceptable for human consumption. CONCLUSION: Judicious BTF recipe selection and adherence to safe food handling provide a safe feeding substrate equivalent to CF in the hospital setting. Due to increased use and interest in BTF by patients and their caregivers, healthcare facilities may need to reexamine their policies prohibiting BTF use.

Role of imaging in progressive-fibrosing interstitial lung diseases.

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.

Efficacy of radioactive iodine treatment of graves' hyperthyroidism using a single calculated 131I dose.

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 <  0.001).The mean response time after successful RAI therapy was 110.2 days, with cumulative response of 25% at 61 days, 50% by 84 days and 75% by 118 days after radioiodine administration. The mean time to respond for those on prior PTU medications was 297 days compared to 116 days for those on MMI and 109 days for those not previously treated with antithyroid medications. In patients with persistent hyperthyroidism, failure of RAI therapy was documented in 16 patients (76.2%) within (less than) one year after 131I administration and in 5 patients (23.8%) more than one year after initial therapy, considered late failure. CONCLUSION: Successful 131I therapy for Graves' hyperthyroidism with a single calculated dose can be achieved in the majority (> 90%) of patients, adjusting for the thyroid size and 24 h uptake measurement.

Effects of Tumor Burden on Reference Tissue Standardized Uptake for PET Imaging: Modification of PERCIST Criteria.

Purpose To examine the effect metabolic burden (tumor and/or cardiac myocyte uptake) has on fluorine 18 fluorodeoxyglucose (FDG) distribution in organs and tissues of interest. Materials and Methods Positron emission tomographic (PET)/computed tomographic (CT) scans at the Ann Arbor Veterans Affairs hospital from January to July 2015 were reviewed. A total of 107 scans (50 patients; mean age, 64.3 years ± 13.2 [standard deviation]) had metabolic tissue burden assessed by using total lesion glycolysis (TLG) obtained from autosegmentation of the tumor and/or cardiac tissue. Standardized uptake value (SUV) and subsequent normalized SUV uptake in target organs and tissues were compared with 436 FDG PET/CT scans previously reported in 229 patients as a function of TLG to describe the effect(s) that metabolic burden has on reference tissue (blood pool, liver, and brain) FDG uptake. Subsequent regression by using linear mixed-effects models was used. If the slope of the regression was significantly (P < .05) different than zero, then an effect from TLG was present. Results There was a negative inverse relationship (P < .0001) between FDG uptake within reference tissues (blood pool, liver, and brain) and TLG in comparison to the study population at similar blood glucose levels. This TLG effect was no longer statistically significant (P > .05) when FDG uptake was normalized to a reference tissue (eg, blood pool or liver). Conclusion Metabolic tissue burden can have a significant effect on SUV measurements for PET imaging. This effect can be mitigated by normalizing FDG uptake to a reference tissue. © RSNA, 2018.

Microbial Lineages in Sarcoidosis. A Metagenomic Analysis Tailored for Low-Microbial Content Samples.

RATIONALE: The etiology of sarcoidosis is unknown, but microbial agents are suspected as triggers. OBJECTIVES: We sought to identify bacterial, fungal, or viral lineages in specimens from patients with sarcoidosis enriched relative to control subjects using metagenomic DNA sequencing. Because DNA from environmental contamination contributes disproportionately to samples with low authentic microbial content, we developed improved methods for filtering environmental contamination. METHODS: We analyzed specimens from subjects with sarcoidosis (n = 93), control subjects without sarcoidosis (n = 72), and various environmental controls (n = 150). Sarcoidosis specimens consisted of two independent sets of formalin-fixed, paraffin-embedded lymph node biopsies, BAL, Kveim reagent, and fresh granulomatous spleen from a patient with sarcoidosis. All specimens were analyzed by bacterial 16S and fungal internal transcribed spacer ribosomal RNA gene sequencing. In addition, BAL was analyzed by shotgun sequencing of fractions enriched for viral particles, and Kveim and spleen were subjected to whole-genome shotgun sequencing. MEASUREMENTS AND MAIN RESULTS: In one tissue set, fungi in the Cladosporiaceae family were enriched in sarcoidosis compared with nonsarcoidosis tissues; in the other tissue set, we detected enrichment of several bacterial lineages in sarcoidosis but not Cladosporiaceae. BAL showed limited enrichment of Aspergillus fungi. Several microbial lineages were detected in Kveim and spleen, including Cladosporium. No microbial lineage was enriched in more than one sample type after correction for multiple comparisons. CONCLUSIONS: Metagenomic sequencing revealed enrichment of microbes in single types of sarcoidosis samples but limited concordance across sample types. Statistical analysis accounting for environmental contamination was essential to avoiding false positives.