The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury.

In this single-center, double-blind, randomized, sham-controlled, prospective trial at the U.S. Air Force School of Aerospace Medicine, the effects of 2.4 atmospheres absolute (ATA) hyperbaric oxygen (HBO2) on post-concussion symptoms in 50 military service members with at least one combat-related, mild traumatic brain injury were examined. Each subject received 30 sessions of either a sham compression (room air at 1.3 ATA) or HBO2 treatments at 2.4 ATA over an 8-week period. Individual and total symptoms scores on Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT®) and composite scores on Post-traumatic Disorder Check List-Military Version (PCL-M) were measured just prior to intervention and 6 weeks after completion of intervention. Difference testing of post-intervention means between the sham-control and HBO2 group revealed no significant differences on the PCL-M composite score (t=-0.205, p=0.84) or on the ImPACT total score (t=-0.943, p=0.35), demonstrating no significant effect for HBO2 at 2.4 ATA. PCL-M composite scores and ImPACT total scores for sham-control and HBO(2) groups revealed significant improvement over the course of the study for both the sham-control group (t=3.76, p=0.001) and the HBO2 group (t=3.90, p=0.001), demonstrating no significant HBO2 effect. Paired t-test results revealed 10 ImPACT scale scores in the sham-control group improved from pre- to post-testing, whereas two scale scores significantly improved in the HBO2 group. One PCL-M measure improved from pre- to post-testing in both groups. This study showed that HBO2 at 2.4 ATA pressure had no effect on post-concussive symptoms after mild TBI.

Hyperbaric oxygen for post-concussion syndrome: design of Department of Defense clinical trials.

The current wars in the Middle East have resulted in between 10-20% of U.S. service members with mild traumatic brain injury (mTBI). While anecdotal reports have associated hyperbaric oxygen (HBO2) with improved outcomes after mTBI, controlled research is lacking. The Department of Defense (DoD), in collaboration with the Department of Veterans Affairs (DVA), has a comprehensive program examining this issue. The DoD's four randomized controlled trials will enroll a total of 242 service members with post-concussion syndrome and expose them to a range of control, sham and HBO2 conditions for 40 sessions over a period of eight to 11 weeks. Compression pressures will range from 1.2 atm abs (sham) to 2.4 atm abs, and oxygen concentration will range from room air (sham and control) to 100%. Outcomes measures include both subjective and objective measures performed at baseline, at exposure completion, and at three to 12 months' follow-up. This integrated program of clinical trials investigating the efficacy of HBO2 in service members with persistent symptoms following mTBI exposure will be important to define practice guidelines and, if needed, for the development of definitive clinical trials in this population.

Tissue-specific increases in endogenous all-trans retinoic acid: possible contributing factor in ethanol toxicity.

All-trans retinoic acid (atRA) is required for neurogenesis and dendritic growth in the hippocampus. The toxic effects of ethanol include developmental defects, cognitive dysfunction, and increased risk of cancer and have some similarities to the detrimental effects of excess atRA, the active form of vitamin A. It is therefore possible that disruption of atRA homeostasis would contribute to the deleterious effects of ethanol. However, previous work, using very high exogenous doses of retinol, found that ethanol toxicity led to decreased formation of atRA, apparently due to competitive inhibition of alcohol dehydrogenase, which is purportedly involved in the conversion of retinol to retinal. A new study, using assays that are highly sensitive for endogenous atRA, has reported that ethanol toxicity in mice actually increased atRA concentration in certain tissues, including brain hippocampus, apparently due to a mobilization of hepatic retinyl esters that led to increased retinol and atRA in specific tissues.

Endogenous ligand for an orphan receptor.

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) can be activated pharmacologically by fibrate drugs, lowering triglycerides and raising high-density lipoprotein. However, until recently, the endogenous ligand of PPARalpha had been unknown. A new study reports the identity of a physiologically relevant endogenous PPARalpha ligand as a phospholipid that is dependent upon a nutritionally responsive enzyme, fatty acid synthase. Mass spectrometry identified this phospholipid as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16/18-GPC) and as the endogenous ligand of PPARalpha. In vivo experiments involving portal vein infusion of 16/18-GPC induced PPARalpha-dependent expression of the fatty acid metabolism genes acyl CoA oxidase and carnitine palmitoyl transferase.

Retinoic acid activation of peroxisome proliferation-activated receptor delta represses obesity and insulin resistance.

Retinoic acid (RA) was found to be a ligand for peroxisome proliferation-activated receptor delta (PPARdelta) as well as the classical RA receptor (RAR). Carrier proteins that move the RA from the cytosol into the nucleus are the fatty acid-binding protein 5 (FABP5), activating PPARdelta, and the cellular retinoic acid-binding protein II (CRABPII), activating RAR. The ratio of FABP5/CRABPII concentrations determines which receptor is activated. By activating PPARdelta, RA was found to induce expression of genes affecting lipid and glucose homeostasis, in particular, leading to expression of the insulin-signaling gene PDK1 and improvement of insulin action. Hence, RA stimulates lipolysis and reduces triglyceride content. In vivo, obesity has led to downregulation of adipose PPARdelta expression. RA implantation into obese mice has caused upregulation of levels of PPARdelta and consequent weight loss as well as increased expression of PPARdelta target genes, including the insulin-signaling gene PDK1.

Adipose-specific phospholipase as regulator of adiposity.

A white adipose-tissue-specific intracellular phospholipase, which releases arachidonic acid from position sn-2 of phospholipids, was recently discovered and named AdPLA. When AdPLA was induced by feeding or by insulin treatment, the arachidonic acid released from phospholipids acted as a precursor for the formation of prostaglandin E(2) (PGE(2)). Subsequent activation of the prostaglandin receptor EP3 caused decreased levels of cAMP that led to decreased lipolysis and increased adiposity. Ablation of AdPLA in knockout mice resulted in the reverse sequence of events, with a decline in arachidonic acid release and prostaglandin synthesis and an increase in levels of cAMP, leading to increased lipolysis and a decline in adiposity, even though food intake was not affected. The newly discovered AdPLA enzyme in white adipose tissue functions as a regulator of lipolysis by acting as an antilipolytic agent mediated by increased PGE(2) formation and decreased intracellular cAMP.

Brown adipose tissue: the molecular mechanism of its formation.

The function of brown adipose tissue (BAT) is to oxidize fat and to dissipate the energy produced as heat, providing a source of heat to the organism. Preadipocytes are stimulated by expression of the PRDM16 gene to differentiate into BAT cells. The PRDM16 protein is greatly enriched in BAT and causes increased expression of mitochondrial genes and greater density of mitochondria. It increases expression of the uncoupling factor UCP1 and thereby causes a large stimulation of uncoupled respiration with resultant heat production, enhanced by cAMP. Recent evidence strongly supports the idea that the PRDM16 gene determines BAT identity.

New insights into thiol-mediated regulation of adiponectin secretion.

Adiponectin is a protein secreted into the circulation exclusively by adipocytes. It acts as an anti-diabetic and anti-atherogenic adipokine. Its plasma level is lowered in conditions of obesity, diabetes, and atherosclerosis. Within adipocytes, it is retained in the lumen of the endoplasmic reticulum by binding to the thiol protein ERp44 and released by another thiol protein, Ero1-Lalpha. Nuclear receptor PPARgamma ligand agonists appear to regulate its retention-release mechanism.

Role of fatty acids in the development of insulin resistance and type 2 diabetes mellitus.

Insulin resistance is defined as the reduced responsiveness to normal circulating levels of insulin. It is the basic condition of type 2 diabetes mellitus, in which both experimental animals and humans accumulate lipids intracellularly in skeletal muscle and liver. Measurement of these lipids in humans, using nuclear magnetic resonance spectroscopy after lipid infusion, indicated they could cause inhibition of the glucose transporter GLUT4, thereby suppressing glucose entry into cells and inhibiting glucose oxidation and glycogen synthesis in muscle. Furthermore, it is known that the enzyme acetyl-CoA carboxylase2 (ACC2) suppresses the oxidation of fatty acids by inhibiting the entry of fatty acids into mitochondria. Further support for the lipocentric hypothesis of the pathogenesis of insulin resistance was provided by knocking out the gene coding for ACC2 in mice; this led to greater fatty acid oxidation, reduced fat mass and, in consequence, greatly enhanced insulin sensitivity. These studies suggest that a specific inhibitor of ACC2 would have therapeutic potential for type 2 diabetes mellitus.

Energy regulation by the skeleton.

Bones of the skeleton are constantly remodeled through bone resorption by cells called osteoclasts and bone formation by cells called osteoblasts. Both cell types are under multi-hormone control. New research findings demonstrate that bone formation by osteoblasts is negatively regulated by the hormone leptin, which is secreted by adipocytes and acts through the leptin receptor in the central nervous system and ultimately through the sympathetic nervous system. Leptin deficiency leads to increased osteoblast activity and increased bone mass. Reciprocally, expression of the Esp gene, exclusive to osteoblasts, regulates glucose homeostasis and adiposity through controlling the osteoblastic secretion of the hormone-like substance osteocalcin. An undercarboxylated form of osteocalcin acts as a regulator of insulin in the pancreas and adiponectin in the adipocyte to modulate energy metabolism. Osteocalcin deficiency in knockout mice leads to decreased insulin and adiponectin secretion, insulin resistance, higher serum glucose levels and increased adiposity.

Retinoic acid as cause of cell proliferation or cell growth inhibition depending on activation of one of two different nuclear receptors.

Retinoic acid can combine with the nuclear retinoic acid receptor (RAR), leading to cell growth inhibition, as in certain tumors. Retinoic acid can also bind to the orphan nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta), resulting in stimulation of cell growth and inhibition of apoptosis. To bind to RAR, retinoic acid is carried into the nucleus by the cytosolic cellular retinoic acid-binding protein-II; to bind to PPAR beta/delta, it is transported into the nucleus by the cytosolic fatty acid-binding protein 5.

Identification of a membrane receptor for retinol-binding protein functioning in the cellular uptake of retinol.

Retinol-binding protein (RBP) is the transport protein that carries retinol in the circulation from the liver to its target tissues. The existence of a cell-surface receptor on the target cells, which mediates the uptake of retinol from RBP, has been known since 1975. Recently, it was identified as an integral transmembrane protein named STRA6 that is inducible by retinoic acid in certain cancer cells. The receptor was found to be highly specific for RBP, with high affinity, and to be localized in all tissues known to require retinol for their function, particularly the pigment epithelium of the eye.

Serum retinol-binding protein: a link between obesity, insulin resistance, and type 2 diabetes.

Insulin resistance occurs under conditions of obesity, metabolic syndrome, and type 2 diabetes. It was found to be accompanied by down-regulation of the insulin-responsive glucose transporter GLUT4. Decreased adipocyte GLUT4 caused secretion by adipocytes of the serum retinol-binding protein RBP4. Enhanced levels of serum RBP4 appeared to be the signal for the development of systemic insulin resistance both in experimental animals and in humans. In mice, increased levels of serum RBP4 led to impaired glucose uptake into skeletal muscle and increased glucose production by liver, whereas lowered serum RBP4 levels greatly enhanced insulin sensitivity. Thus, a link has been established between obesity and insulin resistance: RBP4, the vitamin A-transport protein secreted into the circulation by adipocytes.

Estimation of the human daily requirement of vitamin E by turnover kinetics of labeled RRR-alpha-tocopherol.

The human daily requirement of alpha-tocopherol was estimated by a determination of the turnover kinetics of deuterium-labeled RRR-alpha-tocopherol in two women and three men. The amount of alpha-tocopherol absorbed varied in proportion to the amount of fat eaten with the vitamin, increasing by 0.43 mg for each gram of fat consumed. A fat-free method for administering alpha-tocopherol was developed by vacuum impregnation of apples with the vitamin. Even in the absence of fat, about 10% of the administered alpha-tocopherol was absorbed. The daily requirement of alpha-tocopherol when consumed with a diet containing 21% fat was estimated to be 15 +/- 2 mg, an amount close to the current Estimated Average Requirement (EAR) of 12 mg/d. The study showed that vacuum-impregnated fruit might be a useful way to supplement vitamin E in people eating a low-fat diet.

Identification of proton-coupled high-affinity human intestinal folate transporter mutated in human hereditary familial folate malabsorption.

The human folate transporter of the small intestine has been identified and characterized. It functions optimally at the low pH (6.0-6.2) characteristic of the microenvironment of the duodenal brush border membrane, where dietary folates are mainly absorbed. The transporter, named PCFT/HCP1, is a protein of approximately 50 kDa and functions as a reversible, electrogenic, proton-coupled high-affinity folate transporter (PCFT). It shows high specificity for folates and anti-folates. This protein was previously identified as an intestinal heme carrier protein HCP1. Patients suffering from hereditary familial folate malabsorption were found to be homozygous for a mutation of the PCFT/HCP1 gene due to loss of a particular exon coding for 28 amino acids.

The regulation of food intake by hypothalamic malonyl-coenzyme A: the MaloA hypothesis.

In animals, food intake and therefore energy balance is regulated by a center in the hypothalamus of the brain. Neurons there release appetite-inhibiting (anorexigenic) or appetite-stimulating (orexigenic) peptide hormones according to whether energy intake exceeds or is less than expenditure, respectively. Recent evidence for the "malonyl coenzyme A hypothesis" showed that the level of malonyl coenzyme A (MalCoA) in the arcuate nucleus of the hypothalamus determines the stimulation or inhibition of food intake. A high level of MalCoA, indicative of energy surplus, signals the release of anorexigenic neuropeptides, resulting in decreased food intake; a low level of MalCoA, due to an energy deficit such as during fasting, signals the release of orexigenic neuropeptides, stimulating food intake.

Carbon sequestration via aqueous olivine mineral carbonation: role of passivating layer formation.

CO2 sequestration via carbonation of widely available low-cost minerals, such as olivine, can permanently dispose of CO2 in an environmentally benign and a geologically stable form. We report the results of studies of the mechanisms that limit aqueous olivine carbonation reactivity under the optimum sequestration reaction conditions observed to date: 1 M NaCl + 0.64 M NaHCO3 at Te 185 degrees C and P(CO2) approximately equal to 135 bar. A reaction limiting silica-rich passivating layer (PL) forms on the feedstock grains, slowing carbonate formation and raising process cost. The morphology and composition of the passivating layers are investigated using scanning and transmission electron microscopy and atomic level modeling. Postreaction analysis of feedstock particles, recovered from stirred autoclave experiments at 1500 rpm, provides unequivocal evidence of local mechanical removal (chipping) of PL material, suggesting particle abrasion. This is corroborated by our observation that carbonation increases dramatically with solid particle concentration in stirred experiments. Multiphase hydrodynamic calculations are combined with experimentto better understand the associated slurry-flow effects. Large-scale atomic-level simulations of the reaction zone suggest that the PL possesses a "glassy" but highly defective SiO2 structure that can permit diffusion of key reactants. Mitigating passivating layer effectiveness is critical to enhancing carbonation and lowering sequestration process cost.

How an increased intake of alpha-tocopherol can suppress the bioavailability of gamma-tocopherol.

alpha-Tocopherol is the only form of vitamin E in vitamin supplements, whereas gamma-tocopherol is the predominant form of vitamin E in the US diet. gamma-Tocopherol has beneficial properties as an anti-inflammatory and possibly anti-atherogenic and anticancer agent. Excess a-tocopherol taken in supplements causes a reduction of gamma-tocopherol concentration in plasma. The biochemical mechanism of this effect, which is important to human nutrition, has recently been elucidated.