Spinal cord injury and the human microbiome: beyond the brain-gut axis.

In addition to standard management for the treatment of the acute phase of spinal cord injury (SCI), implementation of novel neuroprotective interventions offers the potential for significant reductions in morbidity and long-term health costs. A better understanding of the systemic changes after SCI could provide insight into mechanisms that lead to secondary injury. An emerging area of research involves the complex interplay of the gut microbiome and the CNS, i.e., a brain-gut axis, or perhaps more appropriately, a CNS-gut axis. This review summarizes the relevant literature relating to the gut microbiome and SCI. Experimental models in stroke and traumatic brain injury demonstrate the bidirectional communication of the CNS to the gut with postinjury dysbiosis, gastrointestinal-associated lymphoid tissue-mediated neuroinflammatory responses, and bacterial-metabolite neurotransmission. Similar findings are being elucidated in SCI as well. Experimental interventions in these areas have shown promise in improving functional outcomes in animal models. This commensal relationship between the human body and its microbiome, particularly the gut microbiome, represents an exciting frontier in experimental medicine.

Quantification of tetrabromo benzoic acid and tetrabromo phthalic acid in rats exposed to the flame retardant Uniplex FPR-45.

The first withdrawal of certain polybrominated diphenyl ethers flame retardants from the US market occurred in 2004. Since then, use of brominated non-PBDE compounds such as bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (BEH-TEBP) and 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) in commercial formulations has increased. Assessing human exposure to these chemicals requires identifying metabolites that can potentially serve as their biomarkers of exposure. We administered by gavage a dose of 500 mg/Kg bw of Uniplex FRP-45 (>95 % BEH-TEBP) to nine adult female Sprague-Dawley rats. Using authentic standards and mass spectrometry, we positively identified and quantified 2,3,4,5-tetrabromo benzoic acid (TBBA) and 2,3,4,5-tetrabromo phthalic acid (TBPA) in 24-h urine samples collected 1 day after dosing the rats and in serum at necropsy, 2 days post-exposure. Interestingly, TBBA and TBPA concentrations correlated well (R (2) = 0.92). The levels of TBBA, a known metabolite of EH-TBB, were much higher than the levels of TBPA both in urine and serum. Because Uniplex FRP-45 was technical grade and EH-TBB was present in the formulation, TBBA likely resulted from the metabolism of EH-TBB. Taken together, our data suggest that TBBA and TBPA may serve as biomarkers of exposure to non-PBDE brominated flame retardant mixtures. Additional research can provide useful information to better understand the composition and in vivo toxicokinetics of these commercial mixtures.

Quantification of 21 metabolites of methylnaphthalenes and polycyclic aromatic hydrocarbons in human urine.

Polycyclic aromatic hydrocarbons (PAHs) and their alkylated derivatives, such as methylnaphthalenes (MeNs), are harmful pollutants ubiquitously present in the environment. Exposure to PAHs has been linked to a variety of adverse health effects and outcomes, including cancer. Alkyl PAHs have been proposed as petrogenic source indicators because of their relatively high abundance in unburned petroleum products. We report a method to quantify 11 urinary methylnaphthols (Me-OHNs), metabolites of 1- and 2-methylnaphthalenes, and 10 monohydroxy PAH metabolites (OH-PAHs), using automated liquid-liquid extraction and isotope dilution gas chromatography tandem mass spectrometry (GC-MS/MS). After spiking urine (1 mL) with (13)C-labeled internal standards, the conjugated target analytes were hydrolyzed enzymatically in the presence of ascorbic acid. Then, their free species were preconcentrated into 20 % toluene in pentane, derivatized and quantified by GC-MS/MS. The 11 Me-OHNs eluted as 6 distinct chromatographic peaks, each representing 1 - 3 isomers. Method detection limits were 1.0- 41 pg/mL and the coefficients of variation in quality control materials were 4.7 - 19 %. The method was used to analyze two National Institute of Standards and Technology's Standard Reference Materials® and samples from 30 smokers and 30 non-smokers. Geometric mean concentrations were on average 37 (Me-OHNs) and 9.0 (OH-PAHs) fold higher in smokers than in non-smokers. These findings support the usefulness of Me-OHNs as potential biomarkers of non-occupational exposure to MeNs and sources containing MeNs.

Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite.

Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.

Minimally invasive tubular access for posterior cervical foraminotomy with three-dimensional microscopic visualization and localization with anterior/posterior imaging.

BACKGROUND CONTEXT: Posterior cervical foraminotomy allows decompression of the nerve root with preservation of motion. A previously described endoscopic technique utilizes minimally invasive muscle splitting with routine outpatient discharge. PURPOSE: The approach allows a modified tubular retraction system to be used with three-dimensional visualization and anterior/posterior fluoroscopic imaging, thus allowing easy visualization even in large patients. This approach also allows safe docking of the retractor system on the lateral mass, thus avoiding the cervical spinal canal during exposure. STUDY DESIGN: Prone position is utilized, with localization and docking of instrumentation accomplished with anterior/posterior fluoroscopy. Surgery is performed with microscope-facilitated, three-dimensional visualization. METHODS: Patients were placed in the prone position. Spinal needle localization was used for initial localization followed by a stab wound and placement of a 14-mm tube using sequentially enlarging dilators. Frequent use of anterior/posterior fluoroscopy avoided inadvertent medial placement of the instruments in the canal. A standard neurocapable operating microscope was used with 10X magnification and 400-mm focal length. RESULTS: A new minimally invasive posterior cervical approach was performed on 222 patients without dural penetration. CONCLUSIONS: Posterior foraminal cervical surgery with three-dimensional access and localization with anterior/posterior fluoroscopic imaging allows safe, reproducible docking on the cervical spine with subsequent exploration of the foramen and routine outpatient discharge. Complications related to difficulty with lateral localization in the lower cervical spine, and with inadvertent entry into the cervical spinal canal with possible catastrophic result are thus avoided.

Measurement of urinary Benzo[a]pyrene tetrols and their relationship to other polycyclic aromatic hydrocarbon metabolites and cotinine in humans.

Biomonitoring of exposure to polycyclic aromatic hydrocarbons (PAHs) typically uses measurement of metabolites of PAHs with four or less aromatic rings, such as 1-hydroxypyrene, even though interest may be in exposure to larger and carcinogenic PAHs, such as benzo[a]pyrene (B[a]P). An improved procedure for measuring two tetrol metabolites of B[a]P has been developed. Using 2 mL urine, the method includes enzymatic deconjugation of the tetrol conjugates, liquid-liquid extraction, activated carbon solid phase extraction (SPE) and Strata-X SPE, and gas chromatography-electron capture negative ionization-tandem mass spectrometric determination. Limits of detection were 0.026 pg/mL (benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydrotetrol, BPT I-1) and 0.090 pg/mL (benzo[a]pyrene-r-7,t-8,c-9,c-10-tetrahydrotetrol, BPT II-1). We quantified BPT I-1 and BPT II-1 in urine from a volunteer who consumed one meal containing high levels of PAHs (barbequed chicken). We also measured urinary concentrations of BPT I-1 and BPT II-1 in smokers and nonsmokers, and compared these concentrations with those of monohydroxy PAHs (OH-PAHs) and cotinine. Urinary elimination of BPT I-1 and BPT II-1 as a function of time after dietary exposure was similar to that observed previously for OH-PAHs. While the median BPT I-1 concentration in smokers' urine (0.069 pg/mL) significantly differs from nonsmokers (0.043 pg/mL), BPT I-1 is only weakly correlated with cotinine. The urinary concentration of BPT I-1 shows a weaker relationship to tobacco smoke than metabolites of smaller PAHs, suggesting that other routes of exposure such as for example dietary routes may be of larger quantitative importance.

Minimally invasive tubular access for posterior cervical foraminotomy.

BACKGROUND: Minimally invasive tubular access for posterior cervical foraminotomy can be an effective and safe technique for decompression of the nerve root utilizing minimally invasive muscle splitting with routine outpatient discharge. This technique has come under scrutiny calling into question the associated learning curve, a subjective limited exposure provided, and an argument that the risks and complications are largely unknown. In response to previously published critiques, this study aims to describe the outcomes and complications associated with this technique in a large patient series. METHODS: A retrospective chart review was performed from 1999 to 2013 capturing a single surgeon's experience with the minimally invasive tubular access for posterior cervical foraminotomy technique from a single institution, encompassing 463 patients. Surgical outcome documented at follow-up and complications were obtained from this patient series. Additional variables analyzed include: Hospital length of stay, number of levels operated, targeted root for decompression, side operated, length of surgery, and estimated blood loss. RESULTS: Outpatient discharge was achieved in 91.6% of cases. There were 10 complications (2.2%) among the 463 patients undergoing this technique from 1999 to 2013. Patients were followed for an average of 1 year and 2 months postoperatively. Improvement from the preoperative condition was observed in 98.2% of patients and excellent outcomes with patients reporting complete relief of symptoms with no or mild residual discomfort was seen in 92.2%. CONCLUSIONS: Compared with open techniques, minimally invasive tubular access for posterior cervical foraminotomy demonstrates comparable, if not superior, complication rates, and patient outcomes.

Pornography addiction - a supranormal stimulus considered in the context of neuroplasticity.

Addiction has been a divisive term when applied to various compulsive sexual behaviors (CSBs), including obsessive use of pornography. Despite a growing acceptance of the existence of natural or process addictions based on an increased understanding of the function of the mesolimbic dopaminergic reward systems, there has been a reticence to label CSBs as potentially addictive. While pathological gambling (PG) and obesity have received greater attention in functional and behavioral studies, evidence increasingly supports the description of CSBs as an addiction. This evidence is multifaceted and is based on an evolving understanding of the role of the neuronal receptor in addiction-related neuroplasticity, supported by the historical behavioral perspective. This addictive effect may be amplified by the accelerated novelty and the 'supranormal stimulus' (a phrase coined by Nikolaas Tinbergen) factor afforded by Internet pornography.

A method for rapid, non-targeted screening for environmental contaminants in household dust.

Household dust can be a major source of human exposure to environmental contaminants such as polybrominated diphenyl ethers, pesticides, and other compounds. This work shows a screening technique that may be used to identify components in an environmental sample as xenobiotics based on mass spectral characteristics of classes of compounds that may be expected to be present in the environment. Household dust (SRM-2585) from the National Institute of Standards and Technology (NIST) was extracted with hexane using accelerated solvent extraction. Large molecules, such as triglycerides and fatty acids were removed with gel permeation chromatography. The extract was then concentrated and analyzed by comprehensive two dimensional gas chromatography coupled to a time of flight mass spectrometer. The resulting peak table was automatically filtered to identify compound classes such as phthalates, polycyclic aromatic hydrocarbons and their heterocyclic analogs, chlorinated compounds, brominated compounds, and nitro compounds. While phthalates can be identified by abundances at specific masses, the identification of the remaining classes is based on the identification of the molecular ion and identification of isotope clusters or other spectral characteristics. The technique detected compounds identified and quantified by NIST as well as compounds not identified by NIST in the sample. By comparison with concentrations determined by NIST for the analytes found, the technique is able to identify analytes in these compound classes at concentrations as low as 10-20 ng/g dust.