Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis

The effects of hydration status on cerebral blood flow (CBF) and development of cerebrospinal fluid (CSF) lactic acidosis were evaluated in rabbits with experimental pneumococcal meningitis. As loss of cerebrovascular autoregulation has been previously demonstrated in this model, we reasoned that compromise of intravascular volume might severely affect cerebral perfusion. Furthermore, as acute exacerbation of the inflammatory response in the subarachnoid space has been observed after antibiotic therapy, animals were studied not only while meningitis evolved, but also 4-6 h after treatment with antibiotics to determine whether there would also be an effect on CBF. To produce different levels of hydration, animals were given either 50 ml/kg per 24 h of normal saline ("low fluid") or 150 ml/kg 24 h ("high fluid"). After 16 h of infection, rabbits that were given the lower fluid regimen had lower mean arterial blood pressure (MABP), lower CBF, and higher CSF lactate compared with animals that received the higher fluid regimen. In the first 4-6 h after antibiotic administration, low fluid rabbits had a significant decrease in MABP and CBF compared with, and a significantly greater increase in CSF lactate concentration than, high fluid rabbits. This study suggests that intravascular volume status may be a critical variable in determining CBF and therefore the degree of cerebral ischemia in meningitis.

The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6

The proinflammatory cytokine IL-6 seems to have an important role in the intestinal inflammation that characterizes inflammatory bowel diseases (IBDs) such as Crohn disease and ulcerative colitis. However, little is known about the molecular mechanisms regulating IL-6 production in IBD. Here, we assessed the role of the transcriptional regulator IFN regulatory factor-4 (IRF4) in this process. Patients with either Crohn disease or ulcerative colitis exhibited increased IRF4 expression in lamina propria CD3+ T cells as compared with control patients. Consistent with IRF4 having a regulatory function in T cells, in a mouse model of IBD whereby colitis is induced in RAG-deficient mice by transplantation with CD4+CD45RB(hi) T cells, adoptive transfer of wild-type but not IRF4-deficient T cells resulted in severe colitis. Furthermore, IRF4-deficient mice were protected from T cell-dependent chronic intestinal inflammation in trinitrobenzene sulfonic acid- and oxazolone-induced colitis. In addition, IRF4-deficient mice with induced colitis had reduced mucosal IL-6 production, and IRF4 was required for IL-6 production by mucosal CD90+ T cells, which it protected from apoptosis. Finally, the protective effect of IRF4 deficiency could be abrogated by systemic administration of either recombinant IL-6 or a combination of soluble IL-6 receptor (sIL-6R) plus IL-6 (hyper-IL-6). Taken together, our data identify IRF4 as a key regulator of mucosal IL-6 production in T cell-dependent experimental colitis and suggest that IRF4 might provide a therapeutic target for IBDs.

Will Whole-Tree Harvest of Jack Pine (Pinus banksiana) deplete soil nutrients in low-productivity sand soils?

In 2009 and 2010 a study was conducted on the Hiawatha National Forest (HNF) to determine if whole-tree harvest (WTH) of jack pine would deplete the soil nutrients in the very coarse-textured Rubicon soil. WTH is restricted on Rubicon sand in order to preserve the soil fertility, but the increasing construction of biomass-fueled power plants is expected to increase the demand for forest biomass. The specific objectives of this study were to estimate biomass and nutrient content of above- and below-ground tree components in mature jack pine (Pinus banksiana) stands growing on a coarse-textured, low-productivity soil, determine pools of total C and N and exchangeable soil cations in Rubicon sand, and to compare the possible impacts of conventional stem-only harvest (CH) and WTH on soil nutrient pools and the implications for productivity of subsequent rotations. Four even-aged jack pine stands on Rubicon soil were studied. Allometric equations were used to estimate above-ground biomass and nutrients, and soil samples from each stand were taken for physical and chemical analysis. Results indicate that WTH will result in cation deficits in all stands, with exceptionally large Ca deficits occurring in two stands. Where a deficit does not occur, the cation surplus is small and, chemical weathering and atmospheric deposition is not anticipated to replace the removed cations. CH will result in a surplus of cations, and will likely not result in productivity declines during the first rotation. However even under CH, the surplus is small, and chemical weathering and atmospheric deposition will not supply enough cations for the second rotation.

Inhibition of L-type amino acid transport with non-physiological amino acids in the Pahenu2 mouse model of phenylketonuria

Phenylketonuria, an autosomal recessive Mendelian disorder, is one of the most common inborn errors of metabolism. Although currently treated by diet, many suboptimal outcomes occur for patients. Neuropathological outcomes include cognitive loss, white matter abnormalities, and hypo- or demyelination, resulting from high concentrations and/or fluctuating levels of phenylalanine. High phenylalanine can also result in competitive exclusion of other large neutral amino acids from the brain, including tyrosine and tryptophan (essential precursors of dopamine and serotonin). This competition occurs at the blood brain barrier, where the L-type amino acid transporter, LAT1, selectively facilitates entry of large neutral amino acids. The hypothesis of these studies is that certain non-physiological amino acids (NPAA; DL-norleucine (NL), 2-aminonorbornane (NB; 2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid), α-aminoisobutyrate (AIB), and α-methyl-aminoisobutyrate (MAIB)) would competitively inhibit LAT1 transport of phenylalanine (Phe) at the blood-brain barrier interface. To test this hypothesis, Pah-/- mice (n=5, mixed gender; Pah+/-(n=5) as controls) were fed either 5% NL, 0.5% NB, 5% AIB or 3% MAIB (w/w 18% protein mouse chow) for 3 weeks. Outcome measurements included food intake, body weight, brain LNAAs, and brain monoamines measured via LCMS/MS or HPLC. Brain Phe values at sacrifice were significantly reduced for NL, NB, and MAIB, verifying the hypothesis that these NPAAs could inhibit Phe trafficking into the brain. However, concomitant reductions in tyrosine and methionine occurred at the concentrations employed. Blood Phe levels were not altered indicating no effect of NPAA competitors in the gut. Brain NL and NB levels, measured with HPLC, verified both uptake and transport of NPAAs. Although believed predominantly unmetabolized, NL feeding significantly increased blood urea nitrogen. Pah-/-disturbances of monoamine metabolism were exacerbated by NPAA intervention, primarily with NB (the prototypical LAT inhibitor). To achieve the overarching goal of using NPAAs to stabilize Phe transport levels into the brain, a specific Phe-reducing combination and concentration of NPAAs must be found. Our studies represent the first in vivo use of NL, NB and MAIB in Pah-/- mice, and provide proof-of-principle for further characterization of these LAT inhibitors. Our data is the first to document an effect of MAIB, a specific system A transport inhibitor, on large neutral amino acid transport.

ADVENTURES IN FRIEDMANN COSMOLOGIES---INTERACTION OF POSITIVE ENERGY DENSITIES WITH NEGATIVE ENERGY DENSITIES AND CURVATURE OF THE UNIVERSE

In this report we will investigate the effect of negative energy density in a classic Friedmann cosmology. Although never measured and possibly unphysical, the evolution of a Universe containing a significant cosmological abundance of any of a number of hypothetical stable negative energy components is explored. These negative energy (Ω < 0) forms include negative phantom energy (w<-1), negative cosmological constant (w=-1), negative domain walls (w=-2/3), negative cosmic strings (w= -1/3), negative mass (w=0), negative radiation (w=1/3), and negative ultra-light (w > 1/3). Assuming that such universe components generate pressures as perfect fluids, the attractive or repulsive nature of each negative energy component is reviewed. The Friedmann equations can only be balanced when negative energies are coupled to a greater magnitude of positive energy or positive curvature, and minimal cases of both of these are reviewed. The future and fate of such universes in terms of curvature, temperature, acceleration, and energy density are reviewed including endings categorized as a Big Crunch, Big Void, or Big Rip and further qualified as "Warped", "Curved", or "Flat", "Hot" versus "Cold", "Accelerating" versus" Decelerating" versus "Coasting". A universe that ends by contracting to zero energy density is termed a Big Poof. Which contracting universes ``bounce" in expansion and which expanding universes ``turnover" into contraction are also reviewed. The name by which the ending of the Universe is mentioned is our own nomenclature.

A 45nm CMOS DESIGN OF NEUROMORPHIC SYSTEM

Neuromorphic computing has become an emerging field in wide range of applications. Its challenge lies in developing a brain-inspired architecture that can emulate human brain and can work for real time applications. In this report a flexible neural architecture is presented which consists of 128 X 128 SRAM crossbar memory and 128 spiking neurons. For Neuron, digital integrate and fire model is used. All components are designed in 45nm technology node. The core can be configured for certain Neuron parameters, Axon types and synapses states and are fully digitally implemented. Learning for this architecture is done offline. To train this circuit a well-known algorithm Restricted Boltzmann Machine (RBM) is used and linear classifiers are trained at the output of RBM. Finally, circuit was tested for handwritten digit recognition application. Future prospects for this architecture are also discussed.

Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis

AIMS: Juvenile idiopathic arthritis (JIA) is often associated with severe chronic anterior uveitis (CAU), and immunosuppressive therapy may be required. In this study, the value of cyclosporine A (CsA) as monotherapy or as combination therapy for treating uveitis was studied in a large cohort of JIA children. METHODS: Multicentre retrospective study including 82 JIA children (girls n=60) suffering from unilateral or bilateral (n=55) CAU. The indication for CsA was active uveitis, although patients were on topical or systemic corticosteroids, MTX, or other immunosuppressive drugs. RESULTS: Inactivity of uveitis during the entire treatment period (mean 3.9 years) was obtained with CsA monotherapy in 6 of 25 (24%) patients, but more often when CsA was combined with the immunosuppressives (35/72 patients; 48.6%, P=0.037), or MTX (18/37 patients, 48.6%, P=0.065), which had already been given. With CsA (mean dosage 2.9 mg/kg), systemic immunosuppressive drugs and steroids could be reduced by >or=50% (n=19) or topical steroids reduced to

Structural and metabolic changes in language areas linked to formal thought disorder

BACKGROUND: The role of the language network in the pathophysiology of formal thought disorder has yet to be elucidated. AIMS: To investigate whether specific grey-matter deficits in schizophrenic formal thought disorder correlate with resting perfusion in the left-sided language network. METHOD: We investigated 13 right-handed patients with schizophrenia and formal thought disorder of varying severity and 13 matched healthy controls, using voxel-based morphometry and magnetic resonance imaging perfusion measurement (arterial spin labelling). RESULTS: We found positive correlations between perfusion and the severity of formal thought disorder in the left frontal and left temporoparietal language areas. We also observed bilateral deficits in grey-matter volume, positively correlated with the severity of thought disorder in temporoparietal areas and other brain regions. The results of the voxel-based morphometry and the arterial spin labelling measurements overlapped in the left posterior superior temporal gyrus and left angular gyrus. CONCLUSIONS: Specific grey-matter deficits may be a risk factor for state-related dysfunctions of the left-sided language system, leading to local hyperperfusion and formal thought disorder.

A Study of the Dissolution of Pyrolusite in Sulphuric Acid

With an eye to the future development of its re­sources, the large deposits of low-grade manganese ore within Montana's boundaries show great promise of developing an important industry. With the pre­sent war demands and the possibility of a future mar­ket it is essential that work expended to utilize this important mineral.

An Isopach Map and Discussion of the Marine Jurassic of Western United Sates and Canada

Recent demands for petroleum to carry on the war effort have resulted in widespread prospecting in the northern Great Plains. Nearly all oil wells now drilled are of a depth to penetrate the marine Jurassic formations. It is known that these strata differ in thickness from place to place, but information of distribution, thickness, and lithology has not yet been compiled.

The Bison: 2003

This digital object was funded in part through a grant from the Andrew W. Mellon Foundation. The digitalization of this object was part of a collaborative effort with the Washington Research Library Consortium and George Washington University.

Structure of alpha6 beta3 delta GABA(A) receptors and their lack of ethanol sensitivity

Delta (delta) subunit containing GABA(A) receptors are expressed extra-synaptically and mediate tonic inhibition. In cerebellar granule cells, they often form a receptor together with alpha(6) subunits. We were interested to determine the architecture of these receptors. We predefined the subunit arrangement of 24 different GABA(A) receptor pentamers by subunit concatenation. These receptors (composed of alpha(6), beta(3) and delta subunits) were expressed in Xenopus oocytes and their electrophysiological properties analyzed. Currents elicited in response to GABA were determined in presence and absence of 3alpha, 21-dihydroxy-5alpha-pregnan-20-one and to 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. alpha(6)-beta(3)-alpha(6)/delta receptors showed a substantial response to GABA alone. Three receptors, beta(3)-alpha(6)-delta/alpha(6)-beta(3), alpha(6)-beta(3)-alpha(6)/beta(3)-delta and beta(3)-delta-beta(3)/alpha(6)-beta(3), were only uncovered in the combined presence of the neurosteroid 3alpha, 21-dihydroxy-5alpha-pregnan-20-one with GABA. All four receptors were activated by 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. None of the functional receptors was modulated by physiological concentrations (up to 30 mM) of ethanol. GABA concentration response curves indicated that the delta subunit can contribute to the formation of an agonist site. We conclude from the investigated receptors that the delta subunit can assume multiple positions in a receptor pentamer composed of alpha(6), beta(3) and delta subunits.