Cerebral rituximab uptake in multiple sclerosis: A 89Zr-immunoPET pilot study.

Previous studies have demonstrated that the chimeric monoclonal antibody rituximab significantly reduces clinical and radiological disease activity in relapsing-remitting multiple sclerosis as early as 4 weeks after the first administration. The exact mechanisms leading to this rapid effect have not yet been clarified. The aim of this positron emission tomography study was to assess central nervous system penetration as a possible explanation, using zirconium-89-labelled rituximab. No evidence was found for cerebral penetration of [89Zr]rituximab.

Adipose derived mesenchymal stem cells express keratinocyte lineage markers in a co-culture model.

Cutaneous wound healing is a complex type of biological event involving proliferation, differentiation, reprograming, trans/de-differentiation, recruitment, migration, and apoptosis of a number of cells (keratinocytes, fibroblasts, endothelial cells, nerve cells and stem cells) to regenerate a multi-layered tissue that is damaged by either internal or external factors. The exact regeneration mechanism of damaged skin is still unknown but the epithelial and other kinds of stem cells located in skin play crucial roles in the healing process. In this work, a co-culture model composed of adipose derived mesenchymal stem cells and keratinocytes was developed to understand the cellular differentiation behaviour in wound healing. Human mesenchymal stem cells were isolated from waste lipoaspirates. Keratinocytes were isolated from neonatal rats skin as well from human adult skin. Both types of cells were cultured and their culturing behaviour was observed microscopically under regular intervals of time. The identity of both cells was confirmed by flow cytometry and qRT-PCR. Cells were co-cultured under the proposed co-culturing model and the model was observed for 7, 14 and 21 days. The cellular behaviour was studied based on change in morphology, colonization, stratification, migration and expression of molecular markers. Expression of molecular markers was studied at transcriptional level and change in cellular morphology and migration capabilities was observed under the invert microscope regularly. Successfully isolated and characterized mesenchymal stem cells were found to express keratinocyte lineage markers i.e. K5, K10, K14, K18, K19 and Involucrin when co-cultured with keratinocytes after 14 and 21 days. Their expression was found to increase by increasing the time span of cell culturing. The keratinocyte colonies started to disappear after 10 days of culturing which might be due to stratification process initiated by possibly transdifferentiated stem cells. It can be concluded that mesenchymal stem cells can regenerate the damaged skin if transplanted to damaged area but for their successful differentiation and enhanced regeneration, they need a population of keratinocytes in situ which need further experiments for validation of co-culture model and its potential for being used in clinics.

The role of microRNAs in the resistance to colorectal cancer treatments.

Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Several approaches such as surgery, chemotherapy, radiotherapy, targeted therapy, or combinations thereof have been used to treat CRC patients. However, the fact that many patients develop a drug resistance during the course of the treatment is a major obstacle. Understanding the mechanisms underlying resistance is critical in order to develop more effective targeted treatments. Recently, several studies have reported on the regulatory role of microRNAs (miRNAs) in the response to anti-cancer drugs and suggested them as a source of predictive biomarkers for the purpose of patient stratification and for the prognosis of treatment success. For example, overexpressing miR-34a, a master regulator of tumor suppression attenuates chemoresistance to 5-FU by downregulating silent information regulator 1 (SIRT1) and E2F3. MRX34, a miR-34a replacement is the first synthetic miRNA mimic to enter clinical testing. MiR-34a antagonizes cancer stemness, metastasis, and chemoresistance processes that are necessary for cancer viability. This example shows that miRNAs are coming into focus for the design of enhanced cancer therapies that aim to sensitise tumor cells for anti-cancer drugs. In this review, we provide an overview on the role of miRNAs in the resistance to current colorectal cancer therapies. Furthermore, we discuss the value of miRNAs as biomarkers for predicting chemosensitivity and their potential to enhance treatment strategies.

Gender differences in the expression of genes involved during cardiac development in offspring from dams on high fat diet.

Previously we have demonstrated that maternal high fat diet (HF) during pregnancy increase cardiovascular risk in the offspring, and pharmacological intervention using statins in late pregnancy reduced these risk factors. However the effects of maternal HF-feeding and statin treatment during pregnancy on development of heart remain unknown. Hence we measured expression of genes involved in cell cycle progression (cyclin G1), ventricular remodelling brain natriuretic peptide (BNP), and environmental stress response small proline-rich protein 1A (SPRR 1A) in the offspring left ventricle (LV) from dams on HF with or without statin treatment. Female C57 mice were fed a HF diet (45% kcal fat) 4 weeks prior to conception, during pregnancy and lactation. From the second half of the pregnancy and throughout lactation, half of the pregnant females on HF diet were given a water-soluble statin (Pravastatin) in their drinking water (HF + S). At weaning offspring were fed HF diet to adulthood (generating dam/offspring dietary groups HF/HF and HF + S/HF). These groups were compared with offspring from dams fed standard chow (C 21% kcal fat) and fed C diet from weaning (C/C). LV mRNA levels for cyclin G1, BNP and SPRR 1A were measured by RT-PCR. Heart weights and BP in HF/HF offspring were higher versus C/C group. Maternal Pravastatin treatment reduced BP and heart weights in HF + S/HF female offspring to levels found in C/C group. LV cyclin G1 mRNA levels were lower in HF/HF versus both C/C and HF + S/HF offspring. BNP mRNA levels were elevated in HF/HF females but lower in males versus C/C. BNP gene expression in HF + S/HF offspring was similar to HF/HF. SPRR 1A mRNA levels were similar in all treatment groups. Statins given to HF-fed pregnant dams reduced cardiovascular risk in adult offspring, and this is accompanied by changes in expression of genes involved in adaptive remodelling in the offspring LV and that there is a gender difference.

Procedural Outcomes With Femoral, Radial, Distal Radial, and Ulnar Access for Coronary Angiography: A Network Meta-Analysis.

BACKGROUND: Radial artery access for coronary angiography or percutaneous coronary intervention (PCI) reduces the risk of death, bleeding, and vascular complications and is preferred over femoral artery access, leading to a class 1 indication by clinical practice guidelines. However, alternate upper extremity access such as distal radial and ulnar access are not mentioned in the guidelines despite randomized trials. We aimed to evaluate procedural outcomes with femoral, radial, distal radial, and ulnar access sites in patients undergoing coronary angiography or PCI. METHODS: PubMed, EMBASE, and clinicaltrials.gov databases were searched for randomized clinical trials that compared at least 2 of the 4 access sites in patients undergoing PCI or angiography. Primary outcomes were major bleeding and access site hematoma. Intention-to-treat mixed treatment comparison meta-analysis was performed. RESULTS: From 47 randomized clinical trials that randomized 38 924 patients undergoing coronary angiography or PCI, when compared with femoral access, there was a lower risk of major bleeding with radial access (odds ratio [OR], 0.46 [95% CI, 0.35-0.59]) and lower risk of access site hematoma with radial (OR, 0.34 [95% CI, 0.24-0.48]), distal radial (OR, 0.33 [95% CI, 0.20-0.56]), and ulnar (OR, 0.50 [95% CI, 0.31-0.83]) access. However, when compared with radial access, there was higher risk of hematoma with ulnar access (OR, 1.48 [95% CI, 1.03-2.14]). CONCLUSIONS: Data from randomized trials support guideline recommendation of class 1 for the preference of radial access over femoral access in patients undergoing coronary angiography or PCI. Moreover, distal radial and ulnar access can be considered as a default secondary access site before considering femoral access. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: 42024512365.

Extracorporeal membrane oxygenation support in a situation of diagnostic dilemma.

Severe acute respiratory distress syndrome (ARDS) in children carries a high morbidity and mortality. High frequency ventilation and extracorporeal membrane oxygenation (ECMO) are used as rescue modes of support in difficult situations. Malignancy may be considered to be a relative contraindication to ECMO support. We report a case where the decision was made to support the patient with ECMO for fulminant Epstein-Barr (EBV) infection while investigations were being done to exclude an underlying malignancy.

Current state and upcoming opportunities for immunoPET biomarkers in lung cancer.

Immune oncology therapy (IO) has now become an important treatment option for patients with a non-small cell lung cancer (NSCLC). However, a substantial proportion of patients still fails to benefit from IO. Predictive biomarkers and biomarkers that provide insights in the biological processes at the tumor microenvironment (TME) level could enhance the beneficial impact of IO, and lead to improved drug development strategies. Immune positron emission tomography (immunoPET) has the potential to provide such biomarkers, by using highly-specific, radiolabeled tracers to investigate key targets in the TME with PET imaging. This review will highlight developments in immunoPET biomarkers, and the corresponding tracers and radionuclides used in cancer, and more specifically NSCLC. We will focus on available clinical tracers as well as those under development, providing an overview of each TME target, and the available clinical validation. Recent advances that could improve immunoPET in the upcoming years will be discussed.

Amyloid-ß, cortical thickness, and subsequent cognitive decline in cognitively normal oldest-old.

OBJECTIVE: To investigate the relationship between amyloid-ß (Aß) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition. METHODS: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aß status determined by [18 F]-flutemetamol PET (normal = Aß - vs. abnormal = Aß+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aß on cognitive decline were mediated by atrophy of specific anatomical brain areas. RESULTS: Subjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aß+. Compared to Aß-, Aß+ individuals showed steeper decline on memory (ß ± SE = -0.26 ± 0.09), and processing speed (ß ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aß+ individuals was mediated through parahippocampal atrophy. INTERPRETATION: These results show that Aß abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aß pathology.

White matter microstructure disruption in early stage amyloid pathology.

INTRODUCTION: Amyloid beta (Aß) accumulation is the first pathological hallmark of Alzheimer's disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cognitively unimpaired cohort. METHODS: We included 179 individuals from the European Medical Information Framework for AD (EMIF-AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract-level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomography (PET) imaging to assess amyloid burden. RESULTS: Regression analyses showed a non-linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingulate cortex strongly related to AxD and RD measures in the genu CC. DISCUSSION: Early amyloid deposition is associated with changes in WM microstructure. The non-linear relationship might reflect multiple stages of axonal damage.

Spatial concordance of DNA methylation classification in diffuse glioma.

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. RESULTS: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. CONCLUSION: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease.

Tumor necrosis factor-alpha (TNF-alpha) is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases. The location of its gene within major histocompatibility complex and biological activities has raised the possibility that polymorphisms within this locus may contribute to the pathogenesis of wide range of autoimmune and infectious diseases. For example, a bi-allelic single nucleotide substitution of G (TNFA1 allele) with A (TNFA2 allele) polymorphism at -308 nucleotides upstream from the transcription initiation site in the TNF-alpha promoter is associated with elevated TNF-alpha levels and disease susceptibilities. However, it is still unclear whether TNF-alpha -308 polymorphism plays a part in the disease process, in particular whether it could affect transcription factor binding and in turn influence TNF-alpha transcription and synthesis. Several studies have suggested that TNFA2 allele is significantly linked with the high TNF-alpha-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF-alpha levels and a more severe outcome in diseases. This review discusses the genetics of the TNF-alpha -308 polymorphism in selected major diseases and evaluates its common role in health and disease.

Enhancing the efficiency of slit-coupling to surface-plasmon-polaritons via dispersion engineering.

We describe a simple method for enhancing the efficiency of coupling from a free-space transverse-magnetic (TM) plane-wave mode into a surface-plasmon-polariton (SPP) mode. The coupling structure consists a metal film with a dielectric-filled slit and a planar, dielectric layer on the slit-exit side of the metal film. By varying the dielectric layer thickness, the wavevector of the SPP mode on the metal surface can be tuned to match the wavevector magnitude of the modes emanating from the slit exit, enabling high-efficiency radiation coupling into the SPP mode at the slit exit. An optimal dielectric layer thickness of approximately 100 nm yields a visible-frequency SPP coupling efficiency approximately 4 times greater than the SPP coupling efficiency without the dielectric layer. Commensurate coupling enhancement is observed spanning the free-space wavelength range 400 nm < or = lambda(0) < or = 700 nm. We map the dependence of the SPP coupling efficiency on the slit width, the dielectric-layer thickness, and the incident wavelength to fully characterize this SPP coupling methodology.

High-throughput diffraction-assisted surface-plasmon-polariton coupling by a super-wavelength slit.

We propose a novel SPP coupling scheme capable of high SPP throughput and high SPP coupling efficiency based on a slit of width greater than the wavelength, immersed in a uniform dielectric. The dispersive properties of the slit are engineered such that the slit sustains a low-loss higher-order waveguide mode just above cutoff, which is shown to be amenable to wavevector matching to the SPP mode at the slit exit. The SPP throughput and SPP coupling efficiency are quantified by numerical simulations of visible light propagation through the slit for varying width and dielectric refractive index. An optimal SPP coupling configuration satisfying wavevector matching is shown to yield an order-of-magnitude greater SPP throughput than a comparable slit of sub-wavelength width and a peak SPP coupling efficiency ≃ 68%. To our knowledge, this is the first investigation of coupling between higher-order waveguide modes in slits of super-wavelength width and SPP modes.

The effects of smoking on fracture healing.

Tobacco smoking is the single most avoidable cause of premature death worldwide. In fracture healing, it has been found to be a contributory factor to delayed union, and smokers are significantly disadvantaged, as healing times are often prolonged. The orthopaedic surgeon is likely to be knowledgeable about the detrimental effects of smoking on healing bones, as the problem has been known for some time. Smoking adversely affects bone mineral density, lumbar disc degeneration, the incidences of hip fractures and the dynamics of bone and wound healing. Clinical trials and demographic studies have been more widespread than biochemical analyses, and have reported poor prognosis for fracture patients who smoke. Scientific research has elucidated some of the negative impacts of tobacco use and investigations involving several animal models in cellular and humoral analyses have shown damage caused by various toxicological processes. Cessation of the habit perioperatively, therefore, is routinely advised to improve outcomes for patients. The current review describes some of the consequences of tobacco smoking in fracture healing.

Improved detection of diffuse glioma infiltration with imaging combinations: a diagnostic accuracy study.

BACKGROUND: Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/fluid attenuated inversion recovery (FLAIR)-weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as the new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. METHODS: We included 20 consecutive adults with newly diagnosed non-enhancing glioma (7 diffuse astrocytomas, isocitrate dehydrogenase [IDH] mutant; 1 oligodendroglioma, IDH mutant and 1p/19q codeleted; 1 glioblastoma IDH wildtype) or enhancing glioma (glioblastoma, 9 IDH wildtype and 2 IDH mutant). Standardized preoperative imaging (T1-, T2-, FLAIR-weighted, and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multiregion stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by 2 neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. RESULTS: A total of 174 biopsies were obtained (63 from 9 non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of apparent diffusion coefficient (ADC) with [18F]FET PET (area under the curve [AUC], 95% CI: 0.89, 0.79‒0.99) detected tumor better than T1G MRI (0.56, 0.39‒0.72; P < 0.001) and [18F]FET PET (0.76, 0.66‒0.86; P = 0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65-0.98) compared with 0.69 (0.56-0.81; P = 0.019) for [18F]FET PET. CONCLUSION: Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy.

Visual and quantitative evaluation of [18F]FES and [18F]FDHT PET in patients with metastatic breast cancer: an interobserver variability study.

PURPOSE: Correct identification of tumour receptor status is important for treatment decisions in breast cancer. [18F]FES PET and [18F]FDHT PET allow non-invasive assessment of the oestrogen (ER) and androgen receptor (AR) status of individual lesions within a patient. Despite standardised analysis techniques, interobserver variability can significantly affect the interpretation of PET results and thus clinical applicability. The purpose of this study was to determine visual and quantitative interobserver variability of [18F]FES PET and [18F]FDHT PET interpretation in patients with metastatic breast cancer. METHODS: In this prospective, two-centre study, patients with ER-positive metastatic breast cancer underwent both [18F]FES and [18F]FDHT PET/CT. In total, 120 lesions were identified in 10 patients with either conventional imaging (bone scan or lesions > 1 cm on high-resolution CT, n = 69) or only with [18F]FES and [18F]FDHT PET (n = 51). All lesions were scored visually and quantitatively by two independent observers. A visually PET-positive lesion was defined as uptake above background. For quantification, we used standardised uptake values (SUV): SUVmax, SUVpeak and SUVmean. RESULTS: Visual analysis showed an absolute positive and negative interobserver agreement for [18F]FES PET of 84% and 83%, respectively (kappa = 0.67, 95% CI 0.48-0.87), and 49% and 74% for [18F]FDHT PET, respectively (kappa = 0.23, 95% CI - 0.04-0.49). Intraclass correlation coefficients (ICC) for quantification of SUVmax, SUVpeak and SUVmean were 0.98 (95% CI 0.96-0.98), 0.97 (95% CI 0.96-0.98) and 0.89 (95% CI 0.83-0.92) for [18F]FES, and 0.78 (95% CI 0.66-0.85), 0.76 (95% CI 0.63-0.84) and 0.75 (95% CI 0.62-0.84) for [18F]FDHT, respectively. CONCLUSION: Visual and quantitative evaluation of [18F]FES PET showed high interobserver agreement. These results support the use of [18F]FES PET in clinical practice. In contrast, visual agreement for [18F]FDHT PET was relatively low due to low tumour-background ratios, but quantitative agreement was good. This underscores the relevance of quantitative analysis of [18F]FDHT PET in breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01988324. Registered 20 November 2013, https://clinicaltrials.gov/ct2/show/NCT01988324?term=FDHT+PET&draw=1&rank=2.

Collaboration Around Rare Bone Diseases Leads to the Unique Organizational Incentive of the Amsterdam Bone Center.

In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and may be hindered by competition and non-equivalent cooperation inherent in a hierarchical structure. Here we describe the "collaborative organizational model" of the Amsterdam Bone Center (ABC), which emerged from and benefited the rare bone disease team. This team is often confronted with pathologically complex and under-investigated diseases. We describe the benefits of this model that still guarantees the autonomy of each team member, but combines and focuses our collective expertise on a clear shared goal, enabling us to capture synergistic and innovative opportunities for the patient, while avoiding self-interest and possible harmful competition.

Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice.

In rodents, adverse prenatal nutrition, such as a maternal diet rich in fat during pregnancy, enhances susceptibility of the offspring to hypertension, type 2 diabetes and other features of the human metabolic syndrome in adulthood. However, previous experimental studies were confined to short-term modifications of the maternal diet during pregnancy and/or lactation periods, a situation uncommon in humans. Moreover in humans, the offspring may also consume a high-fat diet, which may take them beyond the range to which their development has adapted them to respond healthily. We examined in C57 mice the effects on offspring of feeding their mothers a high-fat (HF) or standard chow (C) diet from weaning through pregnancy and lactation, and whether there are additive phenotypic effects of feeding the offspring an HF diet from weaning to adulthood (dam-offspring dietary group HF-HF). This group was compared with offspring from HF-fed dams fed a C diet from weaning to adulthood (HF-C) and offspring from C-fed mothers fed the C or HF diet (C-C and HF-C, respectively). HF-HF, HF-C and C-HF adult female offspring were heavier, fatter, and had raised serum cholesterol and blood pressure compared with C-C female offspring. We observed a similar trend in male offspring except for the HF-C group which was not heavier or fatter than male C-C offspring. Histology showed lipid vacuoles within hepatocytes in the HF-HF, HF-C and C-HF but not the CC offspring. Serum C-reactive protein was elevated in female (C-HF and HF-HF) but not in male offspring. Elevated blood pressure in the HF-C and C-HF groups was attenuated in the HF-HF group in males but not in females. These findings indicate that long-term consumption of an HF diet by the mother predisposes her offspring to developing a metabolic syndrome-like phenotype in adult life, although cardiovascular effects of an HF diet are related to sex specificity in the HF-HF group.

In Situ Oxidative Stress and Atrial Cell Deaths in Patients with Valve Disease.

BACKGROUND: Left ventricular hypertrophy and myocardial remodeling occur with aortic valve disease and may lead to heart failure. Although increased oxidative stress and inflammatory factors have been implicated in heart failure, their role in the progression of valve disease remains unclear. OBJECTIVES: We investigated the role of oxidative stress and inflammatory factors in valve disease whether this relates to cell death. METHODS: Blood samples were taken from 24 patients with valve disease before surgery and the results were compared with those from blood samples from 30 control healthy subjects. Myocardial biopsies from patients with valve disease were also collected before cannulation of the right atrial appendage. NF-κB activities in atrial and mononuclear cells nuclear extracts were determined by electrophoretic mobility shift assay. RESULTS: Nuclear factor kappaB activities were significantly greater in mononuclear cells from AVD patients compared with healthy controls and the antigens were detectable in atrial tissues valve disease patients. Plasma C-reactive protein, B-natriuretic peptides, plasma tumor necrosis factor alpha and soluble tumor necrosis factor receptor 1 and 3-nitrotyrosine levels were significantly higher in valve disease patients. Inducible nitric oxide and 3-nitrotyrosine antigens and cells expressing CD45 antigens were detected within atrial tissues obtained from valve disease patients suggesting oxidative stress originated from in situ leukocytes. CONCLUSION: The findings suggest that oxidative stress originating from in situ leukocytes within the atrial myocardium may be the potential trigger for excessive transcriptional activities and apoptotic cell death within the atrial myocardium of valve disease patients. This represents a potential therapeutic target.

Healthy Tissue Uptake of 68Ga-Prostate-Specific Membrane Antigen, 18F-DCFPyL, 18F-Fluoromethylcholine, and 18F-Dihydrotestosterone.

PET is increasingly used for prostate cancer (PCa) diagnostics. Important PCa radiotracers include 68Ga-prostate-specific membrane antigen HBED-CC (68Ga-PSMA), 18F-DCFPyL, 18F-fluoromethylcholine (18F-FCH), and 18F-dihydrotestosterone (18F-FDHT). Knowledge on the variability of tracer uptake in healthy tissues is important for accurate PET interpretation, because malignancy is suspected only if the uptake of a lesion contrasts with its background. Therefore, the aim of this study was to quantify uptake variability of PCa tracers in healthy tissues and identify stable reference regions for PET interpretation. Methods: A total of 232 PCa PET/CT scans from multiple hospitals was analyzed, including 87 68Ga-PSMA scans, 50 18F-DCFPyL scans, 68 18F-FCH scans, and 27 18F-FDHT scans. Tracer uptake was assessed in the blood pool, lung, liver, bone marrow, and muscle using several SUVs (SUVmax, SUVmean, SUVpeak). Variability in uptake between patients was analyzed using the coefficient of variation (COV%). For all tracers, SUV reference ranges (95th percentiles) were calculated, which could be applicable as image-based quality control for future PET acquisitions. Results: For 68Ga-PSMA, the lowest uptake variability was observed in the blood pool (COV, 19.9%), which was significantly more stable than all other tissues (COV, 29.8%-35.2%; P = 0.001-0.024). For 18F-DCFPyL, the lowest variability was observed in the blood pool and liver (COV, 14.4% and 21.7%, respectively; P = 0.001-0.003). The least variable 18F-FCH uptake was observed in the liver, blood pool, and bone marrow (COV, 16.8%-24.2%; P = 0.001-0.012). For 18F-FDHT, low uptake variability was observed in all tissues, except the lung (COV, 14.6%-23.6%; P = 0.001-0.040). The different SUV types had limited effect on variability (COVs within 3 percentage points). Conclusion: In this multicenter analysis, healthy tissues with limited uptake variability were identified, which may serve as reference regions for PCa PET interpretation. These reference regions include the blood pool for 68Ga-PSMA and 18F-DCFPyL and the liver for 18F-FCH and 18F-FDHT. Healthy tissue SUV reference ranges are presented and applicable as image-based quality control.