Promises and pitfalls of untargeted metabolomics

Metabolomics is one of the newer omics fields, and has enabled researchers to complement genomic and protein level analysis of disease with both semi-quantitative and quantitative metabolite levels, which are the chemical mediators that constitute a given phenotype. Over more than a decade, methodologies have advanced for both targeted (quantification of specific analytes) as well as untargeted metabolomics (biomarker discovery and global metabolite profiling). Untargeted metabolomics is especially useful when there is no a priori metabolic hypothesis. Liquid chromatography coupled to mass spectrometry (LC-MS) has been the preferred choice for untargeted metabolomics, given the versatility in metabolite coverage and sensitivity of these instruments. Resolving and profiling many hundreds to thousands of metabolites with varying chemical properties in a biological sample presents unique challenges, or pitfalls. In this review, we address the various obstacles and corrective measures available in four major aspects associated with an untargeted metabolomics experiment: (1) experimental design, (2) pre-analytical (sample collection and preparation), (3) analytical (chromatography and detection), and (4) post-analytical (data processing).     

Dietary Therapies: Emerging Paradigms in Therapy of Drug Resistant Epilepsy in Children

About one-third of childhood epilepsy ultimately becomes drug resistant epilepsy. Only about one-third of drug resistant epilepsy is amenable for epilepsy surgery. Epilepsy surgery and vagal nerve stimulation is still beyond the reach of huge proportion of children with pharmacoresistant epilepsy. Ketogenic diet (KD) has been in use for almost a century now all over the world for drug resistant epilepsy, although in between there was a decline in its popularity with advent of newer antiepileptic drugs like valproate, phenytoin and carbamazepine. Again from 1990s there was resurgence of interest in KD for pharmacoresistant epilepsy and in the last two decades several randomized controlled trials and systemic reviews have proved its efficacy beyond any suspicion. Ketogenic diet is a high fat low carbohydrate and low protein diet, which has been found to reduce epileptogenesis in body most probably by production of ketone bodies. Modified Atkin’s Diet (MAD) first introduced in 2003 and Low Glycemic Index Treatment (LGIT) first introduced in 2005 are another two dietary therapies, which are less restrictive, more palatable with fewer adverse effects and comparable efficacy. MAD is also a high fat, low carbohydrate diet, in which high sugar foods are discouraged and protein and fluids are unrestricted. In LGIT, only carbohydrates with Glycemic Index <50 are allowed and carbohydrate intake is restricted to 40–60 g per day. Medium Chain Triglyceride KD (MCT KD) is another alternative, in which there are more food choices as compared to classic KD, with comparable efficacy.     

Financial incentives,timing of births,and infant health: a closer look into the delivery room

As a result of strong financial incentives created by the German parental leave reform on January 1, 2007, some 1000 births have been shifted from the last days of 2006 to the first days of 2007, especially by working mothers. This fact is already described in the literature, yet there is no evidence as to the mechanisms and only scarce evidence regarding the effects on newborn health. I use new data to study the timing of C-sections and the induction of births around the day the reform took effect. I estimate that postponed C-sections and inductions account for nearly 80 % of the pre-reform shortfall and nearly 90 % of the post-reform excess number of births. Despite concerns voiced by doctors before the reform, hardly any evidence can be found for detrimental health effects of those shifts, as measured by changes in gestational age, birth weight, APGAR scores, neonatal mortality, or hospitalization.     

Expression and Role of Voltage-Gated Sodium Channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7, Species Differences,and Regulation by Paclitaxel

Voltage-gated sodium channels(Navs) play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion(hDRG) tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Nav1.7(~50% of total Nav expression) and lower expression of Nav1.8(~12%), whereas the mouse DRG has higher expression of Nav1.8(~45%) and lower expression of Nav1.7(~18%). To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel(0.1-1 μmol/L) for 24 h. Paclitaxel increased the Nav 1.7 but not Nav1.8 expression and also increased the transient Na~+ currents and action potential firing frequency in small-diameter(50 μm) hDRG neurons. Thus, the hDRG provides a translational model in which to study"human pain in a dish" and test new pain therapeutics.     

Pediatric Concerns Due to Expanded Cannabis Use: Unintended Consequences of Legalization

An “unintended consequence” of marijuana legalization is the impact on the pediatric population. From prenatal exposure to unintentional childhood exposures, through concerns of adolescence abuse and marijuana use for medicinal indications in children, marijuana exposure can affect pediatric patients at every stage in childhood. Regardless of the stage or reason of exposure, concerns exist about short-term and long-term consequences in a child’s physical and mental health. The use of cannabidiol (CBD) may have some benefit for the treatment of epilepsy, but emphasis needs to be on rigorous clinical trials to evaluate efficacy and safety. As more states allow both medical and recreational marijuana, availability and prevalence of use will likely increase and more surveillance and research is needed to evaluate the consequences on the pediatric population.     

Impact of surgery and radiation therapy on spinal high-grade gliomas: a population-based study

Cerebral radiation necrosis (CRN) is a known complication of radiation therapy. Treatment options are limited and include steroids, bevacizumab, and surgery. This study seeks to determine the safety of laser interstitial thermal therapy (LITT) for CRN and identify the pattern of post-ablation volume change over time. Patients undergoing LITT for tumor treatment at Henry Ford Hospital between November 2013 and January 2016 with biopsy-confirmed CRN were prospectively collected and retrospectively reviewed with attention to ablation volume, survival, demographic data, steroid dose, and complications. Imaging occurred at set intervals beginning pre-ablation. Ten patients with 11 ablations were evaluated. Four patients had a primary diagnosis of high-grade glioma, while six had metastatic lesions. An average of 86% of CRN volume was ablated. Ablation volume increased to 430% of initial CRN volume at 1–2 weeks before decreasing to 69% after 6 months. No patient had a decline in baseline neurological examination while in the hospital. Four patients developed delayed neurological deficits likely due to post-operative edema, of which three improved back to baseline. The 6-month survival was 77.8% and the 1-year survival was 64.8% based on Kaplan–Meier curve estimates. In this study, LITT was a relatively safe treatment for CRN, providing both a diagnostic and therapeutic solution for refractory patients. Significant increase in ablation volume was noted at 1–2 months, gradually decreasing in size to less than the original volume by 6 months. Further studies are needed to better define the role of LITT in the treatment of CRN.