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Abstract Background It is unclear how changes in quantitative muscle magnetic resonance imaging (MRI) relate to changes in clinical outcome in facioscapulohumeral muscular dystrophy (FSHD), although this information is crucial for optimal use of MRI as imaging biomarker in trials. We therefore assessed muscle MRI and clinical outcome measures in a large longitudinal prospective cohort study. Methods All patients were assessed by MRI at baseline and at 5‐year follow‐up, employing 2pt‐Dixon and turbo inversion recovery magnitude (TIRM) sequences, after which fat fraction and TIRM positivity of 19 leg muscles were determined bilaterally. The MRI compound score (CoS) was defined as the mean fat fraction of all muscles weighted for cross‐sectional area. Clinical outcome measures included the Ricci‐score, FSHD clinical score (FSHD‐CS), MRC sumscore (MRC‐SS), and motor‐function‐measure (MFM). Results We included 105 FSHD patients [mean age 54 ± 14 years, median Ricci‐score 7 (range 0–10)]. The median change over 5 years' time in the MRI‐CoS was 2.0% (range −4.6 to +12.1; P

Abstract Background Postcancer fatigue is a frequently occurring, severe, and invalidating problem, impairing quality of life. Although it is possible to effectively treat postcancer fatigue with cognitive behaviour therapy, the nature of the underlying (neuro)physiology of postcancer fatigue remains unclear. Physiological aspects of fatigue include peripheral fatigue, originating in muscle or the neuromuscular junction; central fatigue, originating in nerves, spinal cord, and brain; and physical deconditioning, resulting from a decreased cardiopulmonary function. Studies on physiological aspects of postcancer fatigue mainly concentrate on deconditioning. Peripheral and central fatigue and brain morphology and function have been studied for patients with fatigue in the context of chronic fatigue syndrome and neuromuscular diseases and show several characteristic differences with healthy controls. Methods/design Fifty seven severely fatigued and 21 non-fatigued cancer survivors will be recruited from the Radboud University Nijmegen Medical Centre. Participants should have completed treatment of a malignant, solid tumour minimal one year earlier and should have no evidence of disease recurrence. Severely fatigued patients are randomly assigned to either the intervention condition (cognitive behaviour therapy) or the waiting list condition (start cognitive behaviour therapy after 6 months). All participants are assessed at baseline and the severely fatigued patients also after 6 months follow-up (at the end of cognitive behaviour therapy or waiting list). Primary outcome measures are fatigue severity, central and peripheral fatigue, brain morphology and function, and physical condition and activity. Discussion This study will be the first randomized controlled trial that characterizes (neuro)physiological factors of fatigue in disease-free cancer survivors and evaluates to which extent these factors can be influenced by cognitive behaviour therapy. The results of this study are not only essential for a theoretical understanding of this invalidating condition, but also for providing an objective biological marker for fatigue that could support the diagnosis and follow-up of treatment. Trial registration The study is registered at http://ClinicalTrials.gov (NCT01096641).

Heskamp et al. perform quantitative MRI analysis of end-to-end muscle fat fractions in a series of patients with facioscapulohumeral dystrophy. The authors report that disease initiation commonly occurs at the distal end of affected muscles, with wave-like progression to the proximal end.

Chronic intake of high amounts of fructose has been linked to the development of metabolic disorders, which has been attributed to the almost complete clearance of fructose by the liver. However, direct measurement of hepatic fructose uptake is complicated by the fact that the portal vein is difficult to access. Here we present a new, non-invasive method to measure hepatic fructose uptake and metabolism with the use of deuterium metabolic imaging (DMI) upon administration of [6,6’-2H2]fructose. Using both [6,6’-2H2]glucose and [6,6’-2H2]fructose, we determined differences in the uptake and metabolism of glucose and fructose in the mouse liver with dynamic DMI. The deuterated compounds were administered either by fast intravenous (IV) bolus injection or by slow IV infusion. Directly after IV bolus injection of [6,6’-2H2]fructose, a more than two-fold higher initial uptake and subsequent 2.5-fold faster decay of fructose was observed in the mouse liver as compared to that of glucose after bolus injection of [6,6’-2H2]glucose. In contrast, after slow IV infusion of fructose, the 2H fructose/glucose signal maximum in liver spectra was lower compared to the 2H glucose signal maximum after slow infusion of glucose. With both bolus injection and slow infusion protocols, deuterium labeling of water was faster with fructose than with glucose. These observations are in line with a higher extraction and faster turnover of fructose in the liver, as compared with glucose. DMI with [6,6’-2H2]glucose and [6,6’-2H2]fructose could potentially contribute to a better understanding of healthy human liver metabolism and aberrations in metabolic diseases.

Efforts to increase genetic gains in breeding programs of flowering plants depend on making genetic crosses. Time to flowering, which can take months to decades depending on the species, can be a limiting factor in such breeding programs. It has been proposed that the rate of genetic gain can be increased by reducing the time between generations by circumventing flowering through the in vitro induction of meiosis. In this review, we assess technologies and approaches that may offer a path towards meiosis induction, the largest current bottleneck for in vitro plant breeding. Studies in non-plant, eukaryotic organisms indicate that the in vitro switch from mitotic cell division to meiosis is inefficient and occurs at very low rates. Yet, this has been achieved with mammalian cells by the manipulation of a limited number of genes. Therefore, to experimentally identify factors that switch mitosis to meiosis in plants, it is necessary to develop a high-throughput system to evaluate a large number of candidate genes and treatments, each using large numbers of cells, few of which may gain the ability to induce meiosis.

Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

Purpose: Prostate tissue has a complex microstructure, mainly composed of epithelial and stromal cells, and of extracellular (acinar‐luminal) spaces. Diffusion‐weighted MR spectroscopy (DW‐MRS) is ideally suited to explore complex microstructure in vivo with metabolites selectively distributed in different subspaces. To date, this technique has been applied to brain and muscle. This study presents the development and pioneering utilization of 1H‐DW‐MRS in the prostate, accompanied by in vitro studies to support interpretations of in vivo findings. Methods: Nine healthy volunteers underwent a prostate MR examination (mean age, 56 years; range, 31–66). Metabolic complexation was studied in vitro using solutions with major compounds found in prostatic fluid of the lumen. DW‐MRS was performed at 3 T with a non–water‐suppressed single‐voxel sequence with metabolite‐cycling to concurrently measure metabolite and water signals. The water signal was used in postprocessing as a reference in a motion‐compensation scheme. The spectra were fitted simultaneously in the spectral and diffusion‐weighting dimensions. Apparent diffusion coefficients (ADCs) were derived by fitting signal decays that were assumed to be mono‐exponential for metabolites and biexponential for water. Results: DW‐MRS of the prostate revealed relatively low ADCs for Cho and Cr compounds, aligning with their intracellular location and higher ADCs for citrate and spermine supporting their luminal origin. In vitro assessments of the ADCs of citrate and spermine demonstrated their complex formation and protein binding. Tissue concentrations of MRS‐detectable metabolites were as expected for the voxel location. Conclusions: This work successfully demonstrates the feasibility of 1H‐DW‐MRS of the prostate and its potential for providing valuable microstructural information. [ABSTRACT FROM AUTHOR]

IntroductionIn situ tumor ablation releases a unique repertoire of antigens from a heterogeneous population of tumor cells. High-intensity focused ultrasound (HIFU) is a completely noninvasive ablation therapy that can be used to ablate tumors either by heating (thermal (T)-HIFU) or by mechanical disruption (mechanical (M)-HIFU). How different HIFU ablation techniques compare with respect to their antigen release profile, their activation of responder T cells, and their ability to synergize with immune stimuli remains to be elucidated.Methods and resultsHere, we compare the immunomodulatory effects of T-HIFU and M-HIFU ablation with or without the TLR9 agonist CpG in the ovalbumin-expressing lymphoma model EG7. M-HIFU ablation alone, but much less so T-HIFU, significantly increased dendritic cell (DC) activation in draining lymph nodes (LNs). Administration of CpG following T- or M-HIFU ablation increased DC activation in draining LNs to a similar extend. Interestingly, ex vivo co-cultures of draining LN suspensions from HIFU plus CpG treated mice with CD8+ OT-I T cells demonstrate that LN cells from M-HIFU treated mice most potently induced OT-I proliferation. To delineate the mechanism for the enhanced anti-tumor immune response induced by M-HIFU, we characterized the RNA, DNA and protein content of tumor debris generated by both HIFU methods. M-HIFU induced a uniquely altered RNA, DNA and protein profile, all showing clear signs of fragmentation, whereas T-HIFU did not. Moreover, western blot analysis showed decreased levels of the immunosuppressive cytokines IL-10 and TGF-β in M-HIFU generated tumor debris compared to untreated tumor tissue or T-HIFU.ConclusionCollectively, these results imply that M-HIFU induces a unique context of the ablated tumor material, enhancing DC-mediated T cell responses when combined with CpG.

Abstract Objective The aim of this review is to describe approaches to ostomy management utilizing algorithmic approaches found within the literature. Design An integrative review approach was used based on a modified Cooper's five‐stage research review framework. Data Sources Systematic searches occurred using the CINAHL and MEDLINE databases searching for peer‐reviewed, English publications. Review Methods There were 640 articles identified through the review process, 608 of which were excluded based on title and abstract review. The remaining 12 articles were assessed in full text after which two studies were removed as duplicates and six studies were excluded based on inclusion/exclusion criteria. Four studies were included in this synthesis. Studies were critically analysed using a critical appraisal tool developed for both qualitative and quantitative study assessments. Results Utilizing inductive content analysis, included literature was presented within two categories: validation of ostomy algorithms and implementation of ostomy algorithms in practice. Four themes emerged from these categories including the following: algorithm validation, identifying underlying causes, focus on accessories and large‐scale implementation. Conclusion No currently available validated algorithms published in full were found during this literature review. Current literature demonstrates the potential benefit for ostomy management algorithms to standardize and improve ostomy patient care. Impact This study sought to determine the availability and supporting research of ostomy management algorithms which may assist in standardizing and improving ostomy care. This review has demonstrated a lack of available ostomy management algorithms. Given the potential benefit of ostomy algorithms identified within the literature, further studies should be completed to develop, validate and test new ostomy management algorithms.

Abstract Background Current multiparametric MRI (mp-MRI) in routine clinical practice has poor-to-moderate diagnostic performance for transition zone prostate cancer. The aim of this study was to evaluate the potential diagnostic performance of novel 1H magnetic resonance spectroscopic imaging (MRSI) using a semi-localized adiabatic selective refocusing (sLASER) sequence with gradient offset independent adiabaticity (GOIA) pulses in addition to the routine mp-MRI, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI) and quantitative dynamic contrast enhancement (DCE) for transition zone prostate cancer detection, localization and grading. Methods Forty-one transition zone prostate cancer patients underwent mp-MRI with an external phased-array coil. Normal and cancer regions were delineated by two radiologists and divided into low-risk, intermediate-risk, and high-risk categories based on TRUS guided biopsy results. Support vector machine models were built using different clinically applicable combinations of T2WI, DWI, DCE, and MRSI. The diagnostic performance of each model in cancer detection was evaluated using the area under curve (AUC) of the receiver operating characteristic diagram. Then accuracy, sensitivity and specificity of each model were calculated. Furthermore, the correlation of mp-MRI parameters with low-risk, intermediate-risk and high-risk cancers were calculated using the Spearman correlation coefficient. Results The addition of MRSI to T2WI + DWI and T2WI + DWI + DCE improved the accuracy, sensitivity and specificity for cancer detection. The best performance was achieved with T2WI + DWI + MRSI where the addition of MRSI improved the AUC, accuracy, sensitivity and specificity from 0.86 to 0.99, 0.83 to 0.96, 0.80 to 0.95, and 0.85 to 0.97 respectively. The (choline + spermine + creatine)/citrate ratio of MRSI showed the highest correlation with cancer risk groups (r = 0.64, p

Introduction: Parents and adolescents are often discrepant in their reports of adolescent psychosocial factors. Few studies have addressed parent–adolescent discrepancies in subjective ratings of familial dysfunction and depression as longitudinal predictor variables, and none have done so in a treatment setting for adolescents with acute suicidality. This study examined how parent–adolescent discrepancies in familial dysfunction and depression impact adolescent treatment response in an intensive outpatient program for suicidality. Methods: Adolescents (N = 315) were assessed at treatment entry and exit for familial dysfunction, depression, and suicidal ideation. Parents received parallel assessments of familial dysfunction and adolescent depression at each time point. A polynomial regression was conducted to determine whether parent–adolescent discrepancies in reports of familial dysfunction and depression at entry related to the treatment outcome of adolescent‐reported depression and suicide ideation at exit. Results: Significant discrepancies were present with on average adolescents reporting more depression and familial dysfunction than parents. Entry discrepancy in familial dysfunction (but not depression) predicted suicide ideation at exit. Conclusions: Our results suggest that parent–adolescent discrepancies in perception of familial dysfunction is a risk factor for poor outcomes in suicidal youth and might be a fruitful target in treatment programs. [ABSTRACT FROM AUTHOR]

PurposeTo evaluate the value of convolutional neural network (CNN) in the diagnosis of human brain tumor or Alzheimer's disease by MR spectroscopic imaging (MRSI) and to compare its Matthews correlation coefficient (MCC) score against that of other machine learning methods and previous evaluation of the same data. We address two challenges: 1) limited number of cases in MRSI datasets and 2) interpretability of results in the form of relevant spectral regions.MethodsA shallow CNN with only one hidden layer and an ad-hoc loss function was constructed involving two branches for processing spectral and image features of a brain voxel respectively. Each branch consists of a single convolutional hidden layer. The output of the two convolutional layers is merged and fed to a classification layer that outputs class predictions for the given brain voxel.ResultsOur CNN method separated glioma grades 3 and 4 and identified Alzheimer's disease patients using MRSI and complementary MRI data with high MCC score (Area Under the Curve were 0.87 and 0.91 respectively). The results demonstrated superior effectiveness over other popular methods as Partial Least Squares or Support Vector Machines. Also, our method automatically identified the spectral regions most important in the diagnosis process and we show that these are in good agreement with existing biomarkers from the literature.ConclusionShallow CNNs models integrating image and spectral features improved quantitative and exploration and diagnosis of brain diseases for research and clinical purposes. Software is available at https://bitbucket.org/TeslaH2O/cnn_mrsi.

In in vivo 1H-MRSI of the prostate, small matrix sizes can cause voxel bleeding extending to regions far from a voxel, dispersing a signal of interest outside that voxel and mixing extra-prostatic residual lipid signals into the prostate. To resolve this problem, we developed a three-dimensional overdiscretized reconstruction method. Without increasing the acquisition time from current 3D MRSI acquisition methods, this method is aimed to improve the localization of metabolite signals in the prostate without compromising on SNR. The proposed method consists of a 3D spatial overdiscretization of the MRSI grid, followed by noise decorrelation with small random spectral shifts and weighted spatial averaging to reach a final target spatial resolution. We successfully applied the three-dimensional overdiscretized reconstruction method to 3D prostate 1H-MRSI data at 3T. Both in phantom and in vivo, the method proved to be superior to conventional weighted sampling with Hamming filtering of k-space. Compared with the latter, the overdiscretized reconstructed data with smaller voxel size showed up to 10% less voxel bleed while maintaining higher SNR by a factor of 1.87 and 1.45 in phantom measurements. For in vivo measurements, within the same acquisition time and without loss of SNR compared with weighted k-space sampling and Hamming filtering, we achieved increased spatial resolution and improved localization in metabolite maps.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

In this study, we investigated the potential of the multivariate curve resolution alternating least squares (MCR‐ALS) algorithm for analyzing three‐dimensional (3D) 1H‐MRSI data of the prostate in prostate cancer (PCa) patients. MCR‐ALS generates relative intensities of components representing spectral profiles derived from a large training set of patients, providing an interpretable model. Our objectives were to classify magnetic resonance (MR) spectra, differentiating tumor lesions from benign tissue, and to assess PCa aggressiveness. We included multicenter 3D 1H‐MRSI data from 106 PCa patients across eight centers. The patient cohort was divided into a training set (N = 63) and an independent test set (N = 43). Singular value decomposition determined that MR spectra were optimally represented by five components. The profiles of these components were extracted from the training set by MCR‐ALS and assigned to specific tissue types. Using these components, MCR‐ALS was applied to the test set for a quantitative analysis to discriminate tumor lesions from benign tissue and to assess tumor aggressiveness. Relative intensity maps of the components were reconstructed and compared with histopathology reports. The quantitative analysis demonstrated a significant separation between tumor and benign voxels (t‐test, p < 0.001). This result was achieved including voxels with low‐quality MR spectra. A receiver operating characteristic analysis of the relative intensity of the tumor component revealed that low‐ and high‐risk tumor lesions could be distinguished with an area under the curve of 0.88. Maps of this component properly identified the extent of tumor lesions. Our study demonstrated that MCR‐ALS analysis of 1H‐MRSI of the prostate can reliably identify tumor lesions and assess their aggressiveness. It handled multicenter data with minimal preprocessing and without using prior knowledge or quality control. These findings indicate that MCR‐ALS can serve as an automated tool to assess the presence, extent, and aggressiveness of tumor lesions in the prostate, enhancing diagnostic capabilities and treatment planning of PCa patients. [ABSTRACT FROM AUTHOR]

Disruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects of di-n-octyltin dichloride (DOTC) on maternal and developing immune systems of rats in an extended one-generation reproductive toxicity study according to the OECD 443 test guideline. We hypothesize that the DOTC-induced changes in the immune system can affect neurodevelopment. Therefore, we used in-vivo MRI and PET imaging and genomics, in addition to behavioral testing and neuropathology as proposed in OECD test guideline 443, to investigate the effect of DOTC on structural and functional brain development. Male rats were exposed to DOTC (0, 3, 10, or 30 mg/kg of diet) from 2 weeks prior to mating of the F0-generation until sacrifice of F1-animals. The brains of rats, exposed to DOTC showed a transiently enlarged volume of specific brain regions (MRI), altered specific gravity, and transient hyper-metabolism ([18F]FDG PET). The alterations in brain development concurred with hyper-responsiveness in auditory startle response and slight hyperactivity in young adult animals. Genomics identified altered transcription of key regulators involved in neurodevelopment and neural function (e.g. Nrgrn, Shank3, Igf1r, Cck, Apba2, Foxp2); and regulators involved in cell size, cell proliferation, and organ development, especially immune system development and functioning (e.g. LOC679869, Itga11, Arhgap5, Cd47, Dlg1, Gas6, Cml5, Mef2c). The results suggest the involvement of immunotoxicity in the impairment of the nervous system by DOTC and support the hypothesis of a close connection between the immune and nervous systems in brain development. [ABSTRACT FROM AUTHOR]

Abstract Background Mutations in isocitrate dehydrogenase 1 (IDH1) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of D-2-hydroxyglutarate (D-2-HG) at the expense of α-ketoglutarate (α-KG) and NADPH. To overcome metabolic stress induced by these alterations, IDH-mutated (IDH mut ) cancers utilize rescue mechanisms comprising pathways in which glutaminase and glutamate dehydrogenase (GLUD) are involved. We hypothesized that inhibition of glutamate processing with the pleiotropic GLUD-inhibitor epigallocatechin-3-gallate (EGCG) would not only hamper D-2-HG production, but also decrease NAD(P)H and α-KG synthesis in IDH mut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy. Methods We performed 13C-tracing studies to show that HCT116 colorectal cancer cells with an IDH1 R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D-2-HG. We treated HCT116 cells, HCT116-IDH1 R132H cells, and HT1080 cells (carrying an IDH1 R132C mutation) with EGCG and evaluated D-2-HG production, cell proliferation rates, and sensitivity to radiotherapy. Results Significant amounts of 13C from glutamate accumulate in D-2-HG in HCT116-IDH1 wt/R132H but not in HCT116-IDH1 wt/wt . Preventing glutamate processing in HCT116-IDH1 wt/R132H cells with EGCG resulted in reduction of D-2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1 mut cells and at high doses sensitized cancer cells to ionizing radiation. Effects of EGCG in IDH-mutated cell lines were diminished by treatment with the IDH1mut inhibitor AGI-5198. Conclusions This work shows that glutamate can be directly processed into D-2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for IDH mut cancers.