Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

BackgroundAlthough the contrast-enhancing (CE) lesion on T1-weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T2-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden.MethodsFifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy.ResultsThe Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data.ConclusionsThe similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM

Transcriptional landscape of epithelial and immune cell populations revealed through FACS-seq of healthy human skin.

Human skin consists of multiple cell types, including epithelial, immune, and stromal cells. Transcriptomic analyses have previously been performed from bulk skin samples or from epithelial and immune cells expanded in cell culture. However, transcriptomic analysis of bulk skin tends to drown out expression signals from relatively rare cells while cell culture methods may significantly alter cellular phenotypes and gene expression profiles. To identify distinct transcriptomic profiles of multiple cell populations without substantially altering cell phenotypes, we employed a fluorescence activated cell sorting method to isolate keratinocytes, dendritic cells, CD4+ T effector cells, and CD8+ T effector cells from healthy skin samples, followed by RNA-seq of each cell population. Principal components analysis revealed distinct clustering of cell types across samples, while differential expression and coexpression network analyses revealed transcriptional profiles of individual cell populations distinct from bulk skin, most strikingly in the least abundant CD8+ T effector population. Our work provides a high resolution view of cutaneous cellular gene expression and suggests that transcriptomic profiling of bulk skin may inadequately capture the contribution of less abundant cell types

Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy

Evaluation of bile salt hydrolase inhibitor efficacy for modulating host bile profile and physiology using a chicken model system

Gut microbial enzymes, bile salt hydrolases (BSHs) are the gateway enzymes for bile acid (BA) modification in the gut. This activity is a promising target for developing innovative non-antibiotic growth promoters to enhance animal production and health. Compelling evidence has shown that inhibition of BSH activity should enhance weight gain by altering the BA pool, host signalling and lipid metabolism. We recently identified a panel of promising BSH inhibitors. Here, we address the potential of them as alternative, effective, non-antibiotic feed additives, for commercial application, to promote animal growth using a chicken model. In this study, the in vivo efficacy of three BSH inhibitors (caffeic acid phenethylester, riboflavin, carnosic acid) were evaluated. 7-day old chicks (10 birds/group) were either untreated or they received one of the specific BSH inhibitors (25 mg/kg body weight) via oral gavage for 17 days. The chicks in treatment groups consistently displayed higher body weight gain than the untreated chicks. Metabolomic analysis demonstrated that BSH inhibitor treatment led to significant changes in both circulating and intestinal BA signatures in support of blunted intestinal BSH activity. Consistent with this finding, liver and intestinal tissue RNA-Seq analysis showed that carnosic acid treatment significantly altered expression of genes involved in lipid and bile acid metabolism. Taken together, this study validates microbial BSH activity inhibition as an alternative target and strategy to antibiotic treatment for animal growth promotion

Prospective comparison of long-term pain relief rates after first-time microvascular decompression and stereotactic radiosurgery for trigeminal neuralgia

OBJECTIVE Common surgical treatments for trigeminal neuralgia (TN) include microvascular decompression (MVD), stereotactic radiosurgery (SRS), and radiofrequency ablation (RFA). Although the efficacy of each procedure has been described, few studies have directly compared these treatment modalities on pain control for TN. Using a large prospective longitudinal database, the authors aimed to 1) directly compare long-term pain control rates for first-time surgical treatments for idiopathic TN, and 2) identify predictors of pain control. METHODS The authors reviewed a prospectively collected database for all patients who underwent treatment for TN between 1997 and 2014 at the University of California, San Francisco. Standardized collection of data on preoperative clinical characteristics, surgical procedure, and postoperative outcomes was performed. Data analyses were limited to those patients who received a first-time procedure for treatment of idiopathic TN with > 1 year of follow-up. RESULTS Of 764 surgical procedures performed at the University of California, San Francisco, for TN (364 SRS, 316 MVD, and 84 RFA), 340 patients underwent first-time treatment for idiopathic TN (164 MVD, 168 SRS, and 8 RFA) and had > 1 year of follow-up. The analysis was restricted to patients who underwent MVD or SRS. Patients who received MVD were younger than those who underwent SRS (median age 63 vs 72 years, respectively; p 5 years of follow-up (60 of 164 and 64 of 168 patients, respectively). Immediate or short-term (< 3 months) postoperative pain-free rates (Barrow Neurological Institute Pain Intensity score of I) were 96% for MVD and 75% for SRS. Percentages of patients with Barrow Neurological Institute Pain Intensity score of I at 1, 5, and 10 years after MVD were 83%, 61%, and 44%, and the corresponding percentages after SRS were 71%, 47%, and 27%, respectively. The median time to pain recurrence was 94 months (25th–75th quartiles: 57–131 months) for MVD and 53 months (25th–75th quartiles: 37–69 months) for SRS (p = 0.006). A subset of patients who had MVD also underwent partial sensory rhizotomy, usually in the setting of insignificant vascular compression. Compared with MVD alone, those who underwent MVD plus partial sensory rhizotomy had shorter pain-free intervals (median 45 months vs no median reached; p = 0.022). Multivariable regression demonstrated that shorter preoperative symptom duration (HR 1.005, 95% CI 1.001–1.008; p = 0.006) was associated with favorable outcome for MVD and that post-SRS sensory changes (HR 0.392, 95% CI 0.213–0.723; p = 0.003) were associated with favorable outcome for SRS. CONCLUSIONS In this longitudinal study, patients who received MVD had longer pain-free intervals compared with those who underwent SRS. For patients who received SRS, postoperative sensory change was predictive of favorable outcome. However, surgical decision making depends upon many factors. This information can help physicians counsel patients with idiopathic TN on treatment selection

Cluster randomized trial of the impact of an obesity prevention intervention on child care center nutrition and physical activity environment over two years

Objective: The prevalence of obesity among preschool-aged children in the United States remains unacceptably high. Here we examine the impact of Healthy Caregivers-Healthy Children (HC2) Phase 2, a child care center (CCC)-based obesity prevention intervention on changes in the CCC nutrition and physical activity environment over two school years. Design: This was a cluster randomized trial with 12 CCC receiving the HC2 intervention arm and 12 in the control arm. The primary outcome was change in the Environment and Policy Assessment and Observation (EPAO) tool over two school years (Fall-2015, Spring-2016 and Spring-2017). Changes in EPAO physical activity and nutrition score were analyzed via a (1) random effects mixed models and (2) mixed models to determine the effect of HC2 versus control. Setting: The study was conducted in 24 CCCs serving low-income, ethnically diverse families in Miami-Dade County. Participants: Intervention CCCs received (1) teachers/parents/children curriculum; (2) snack, beverage, physical activity, and screen time policies; and (3) menu modifications. Results: Two-year EPAO nutrition score changes in intervention CCCs were almost twice that of control CCCs. The EPAO physical activity environment scores only slightly improved in intervention CCCs versus control CCCs. Intervention CCCs showed higher combined EPAO physical activity and nutrition scores compared to control CCCs over the 2-year study period (β=0.09, P=0.05). Conclusions: Obesity prevention programs can have a positive impact on the CCC nutrition environment and can promote healthy weight in early childhood. CCCs may need consistent support to improve the physical activity environment to ensure the policies remain intact

Measuring service quality and assessing its relationship to contraceptive discontinuation: A prospective cohort study in Pakistan and Uganda

Background: The quality of contraceptive counseling that women receive from their provider can influence their future contraceptive continuation. We examined (1) whether the quality of contraceptive service provision could be measured in a consistent way by using existing tools from 2 large-scale social franchises, and (2) whether facility quality measures based on these tools were consistently associated with contraceptive discontinuation.Methods: We linked existing, routinely collected facility audit data from social franchise clinics in Pakistan and Uganda with client data. Clients were women aged 15-49 who initiated a modern, reversible contraceptive method from a sampled clinic. Consented participants completed an exit interview and were contacted 3, 6, and 12 months later. We collapsed indicators into quality domains using theory-based categorization, created summative quality domain scores, and used Cox proportional hazards models to estimate the relationship between these quality domains and discontinuation while in need of contraception.Results: The 12-month all-modern method discontinuation rate was 12.5% among the 813 enrolled women in Pakistan and 5.1% among the 1,185 women in Uganda. We did not observe similar associations between facility-level quality measures and discontinuation across these 2 settings. In Pakistan, an increase in the structural privacy domain was associated with a 60% lower risk of discontinuation, adjusting for age and baseline method (PP=.005).Conclusions: We were not able to leverage existing, widely used quality measurement tools to create quality domains that were consistently associated with discontinuation in 2 study settings. Given the importance of contraceptive service quality and recent advances in indicator standardization in other areas, we recommend further effort to harmonize and simplify measurement tools to measure and improve contraceptive quality of care for all