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Effect of hemorrhage and anoxia on hepatic gluconeogenesis and potassium balance in the rat.

Previous investigations have demonstrated impairment of hepatic gluconeogenic activity during both hypovolemia and sepsis, but the mechanisms responsible remain unclear. The present study was designed to determine the influence of lack of oxygen on gluconeogenesis independent of humoral factors, products of ischemic peripheral tissues or pH changes. Livers obtained from Sprague-Dawley rats fasted 24 hours were perfused with Krebs-Henseleit buffer containing 5 mM lactate for 30 minutes. In the control group (n = 8) perfusion was continued; in others, anoxia was induced by perfusing with buffer equilibrated with 95% N2 and 5% CO2 for periods of 15, 30, or 60 minutes (n = 4, 5, and 5, respectively). The initial conditions were then reinstituted for an additional 45 minutes. Anoxia caused hepatic release of K+, indicative of disordered hepatic cellular ionic gradients and an abrupt cessation of gluconeogenesis. Reoxygenation partially reversed these alterations but some impairment of gluconeogenesis persisted and the degree of uptake of K+ from the perfusion media was decreased as the duration of anoxia increased. The degree of restoration of gluconeogenesis after a period of anoxia was closely associated with restoration of cellular uptake of K+. By comparison, livers taken from hypovolemic animals maintained at a mean arterial blood pressure of 40 mm Hg until the beginning of the decompensatory stage of shock exhibited a gluconeogenic capacity of only 41% of control animals and was comparable to the compromise induced by between 30 and 60 minutes of anoxia. These results suggest that the abilities to restore hepatic electrolyte balance and gluconeogenesis after oxygen deprivation are affected in parallel and may reflect a common dependence on the restoration of ATP stores after the insult.

Animals↗

Murine M2-10B4 and SL/SL cell lines differentially affect the balance between CD34+ cell expansion and maturation.

The ability of bone marrow stroma to modulate hematopoietic progenitor cell expansion is of considerable interest for gene transfer strategies and transplantation of limited stem cell numbers. We compared the capacity of 2 murine stromal cell lines to affect the balance between maturation and proliferation of human CD34+ cells in short-term expansion cultures. In 7-day serum-free cultures, cytokine-induced amplification of granulocyte-macrophage colony-forming cells (CFC-GM), erythroid burst-forming units (BFU-E), and total cells was significantly increased by the presence of genetically engineered Sl/Sl and M2-10B4 stromal cells in a 1:1 ratio (Sl/M2 cells) compared with stroma-free cultures (P < .05). Sl/M2 cultures generated 21-fold more mature CD15+ cells than stroma-free cultures, without further amplifying the number of CD34+ cells. The addition of serum led to a further increase of CFC-GM, total cells, and CD15+ cells, whereas BFU-E were no longer maintained. Pure Sl/Sl stromal layers were likewise superior to stroma-free cultures in expansion of CD34+ cells and total cells when serum was present. However, the differentiation of CD34+ cells was less pronounced in Sl/Sl cultures compared with Sl/M2 layers, as demonstrated by a lower content of CD15+ cells. Neutralization experiments revealed differential contributions of Flt3 ligand and thrombopoietin to the support of total cell and CFC expansion by Sl/M2 and Sl/Sl stromal feeders.

Adjuvants, Immunologic↗

Prenatal exposure to anticonvulsant drugs and spatial ability in adulthood.

By disturbing steroid hormone balances in the fetus, the anticonvulsant drugs phenobarbital and phenytoin may affect certain aspects of cognitive functioning. In order to test this hypothesis, we studied hormone related cognitive functioning in 72 men and 75 women who had been prenatally exposed to these drugs and equal numbers of matched control subjects. The groups did not differ on word fluency, dichotic listening and a Water Level Test. On Card Rotations, however, anticonvulsant-exposed males and females obtained significantly lower scores than control subjects. These results suggest that in both males and females prenatal exposure to phenobarbital and phenytoin may affect holistic spatial processing.

Adult↗

Partial weight-bearing gait retraining for persons following traumatic brain injury: preliminary report and proposed assessment scale.

The objectives of this investigation were to (1) document the recovery patterns of walking ability in two patients recovering from traumatic brain injury receiving partial weight-bearing gait retraining, and (2) introduce a new assessment scale of gait progress for patients receiving partial weight support therapy. The two patients were categorized as acute (< 6 months) and chronic (> 2 years) injury. Each patient received extensive in-patient rehabilitation, including physical therapy designed with twice-weekly partial body support gait training. The subjects made improvements in all measured indicators of gait ability (i.e. muscle strength, spasticity, standing balance). However, assessment of their improvement using standard assessment scales showed little progress. The newly devised Missouri Assisted Gait (MAG) scale, which includes developmental components of gait ability measured dramatic gains. This added precision of measurement was useful in communicating progress to both patients and providers.

Adult↗

A functional role for complex gangliosides: motor deficits in GM2/GD2 synthase knockout mice.

Although gangliosides are abundant molecular determinants on all vertebrate nerve cells (comprising approximately 1.5% of brain dry weight) their functions have remained obscure. We report that mice engineered to lack a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase), and which express only the simple ganglioside molecular species GM3 and GD3, develop significant and progressive behavioral neuropathies, including deficits in reflexes, strength, coordination, and balance. Quantitative indices of motor abilities, applied at 8 and 12 months of age, also revealed progressive gait disorders in complex ganglioside knockout mice compared to controls, including reduced stride length, stride width, and increased hindpaw print length as well as a marked reduction in rearing. Compared to controls, null mutant mice tended to walk in small labored movements. Twelve-month-old complex ganglioside knockout mice also displayed significant incidence of tremor and catalepsy. These comprehensive neurobehavioral studies establish an essential role for complex gangliosides in the maintenance of normal neural physiology in mice, consistent with a role in maintaining axons and myelin (Sheikh, K. A. , J. Sun, Y. Liu, H. Kawai, T. O. Crawford, R. L. Proia, J. W. Griffin, and R. L. Schnaar. 1999. Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc. Natl. Acad. Sci. USA 96: 7532-7537), and may provide insights into the mechanisms underlying certain neural degenerative diseases.

Animals↗

Balance marks cognitive changes in old age because it reflects global brain atrophy and cerebro-arterial blood-flow.

In healthy old age biomarkers such as Balance robustly correlate with measures of mental abilities such as scores on tests of intelligence, reaction times and memory. A plausible explanation is that balance reflects general physiological fitness and so also neurophysiological integrity, but direct evidence is lacking. Brain scans measured age-associated loss of brain volume and cerebro-arterial blood flow (CBf) in 69 volunteers aged from 62 to 81 years who also took the Tinetti Balance test battery, 3 tests of fluid intelligence, 3 tests of decision speed and a memory test. Balance, but not atrophy or CBf, predicted intelligence test scores. Balance, atrophy, and CBf all independently predicted speed and memory scores but, after variance in atrophy and CBf had been considered, predictions from Balance were no longer significant. It appears that in these tests Balance marks cognitive performance in old age because it reflects gross age-related neurophysiological changes.

Aged↗

Age-related changes in rate and magnitude of ankle torque development: implications for balance control.

BACKGROUND: One of the key components of postural control is the motor system's ability to produce appropriate torques to counteract perturbations that may lead to a loss of balance. Evidence exists to show that there is an age-related decline in absolute strength and in the ability to rapidly produce torque. The relationship between age-related decreases in these voluntary torque production capabilities and the ability to rapidly produce torques in a reactive balance task has not been studied. Thus, the purpose of this study was to examine the magnitude and rate of torque production in younger and older adults under reactive balance conditions. METHODS: Older (OA) and younger (YA) adults received forward and backward support surface translations of varying amplitudes and velocities. Maximum ankle muscle torque (maxMa) and rate of change of ankle muscle torque (Ma) following a perturbation were calculated. RESULTS: Two balance responses emerged: a no-step and a step response. With increasing perturbation difficulty, YA and OA used different responses. The no-step and step responses were examined for age-group differences in the force characteristics. No significant age-group differences were found for maxMa or rate of change of Ma within either no-step or step responses. CONCLUSION: The results of this study suggest that neither the magnitude nor rate of ankle muscle torque production, as produced during the initial balance response in this set of reactive balance control tasks, determines the different balance responses seen in younger versus older adults.

Adult↗

Physiological characterization of Taxol-induced large-fiber sensory neuropathy in the rat.

The cancer chemotherapeutic agent Taxol (paclitaxel) causes a dose-related peripheral neuropathy in humans. We produced a dose-dependent large-fiber sensory neuropathy, without detrimental effects on general health, in mature rats by using two intravenous injections 3 days apart. Tests of other dosing schedules demonstrated the dependence of the severity of the neuropathy and of animal health on both the dose and the frequency of dosing. Pathologically, severe axonal degeneration and hypomyelination were observed in sections of dorsal roots, whereas ventral roots remained intact. Electrophysiologically, H-wave amplitudes in the hindlimb and amplitudes of predominantly sensory compound nerve action potentials in the tail were reduced. These effects persisted for at least 4 months after treatment. Motor amplitudes were not affected, but both motor and sensory conduction velocities decreased. The ability of rats to remain balanced on a narrow beam was impaired, indicating proprioceptive deficits. Muscle strength, measured by hindlimb and forelimb grip strength, and heat nociception, measured by tail-flick and hindlimb withdrawal tests, were not affected by Taxol. This model of Taxol-induced neuropathy in mature rats, with minimal effects on general health, parallels closely the clinical syndrome observed after Taxol treatment in humans.

Animals↗

DNA base trimers: empirical and quantum chemical ab initio calculations versus experiment in vacuo.

A complete scan of the potential-energy surfaces for selected DNA base trimers has been performed by a molecular dynamics/quenching technique using the force field of Cornell et al. implemented in the AMBER7 program. The resulting most stable/populated structures were then reoptimized at a correlated ab initio level by employing resolution of the identity, Møller-Plesset second-order perturbation theory (RI-MP2). A systematic study of these trimers at such a complete level of electronic structure theory is presented for the first time. We show that prior experimental and theoretical interpretations were incorrect in assuming that the most stable structures of the methylated trimers corresponded to planar systems characterized by cyclic intermolecular hydrogen bonding. We found that stacked structures of two bases with the third base in a T-shape arrangement are the global minima in all of the methylated systems: they are more stable than the cyclic planar structures by about 10 kcal mol(-1). The different behaviors of nonmethylated and methylated trimers is also discussed. The high-level geometries and interaction energies computed for the trimers serve also as a reference for the testing of recently developed density functional theory (DFT) functionals with respect to their ability to correctly describe the balance between the electrostatic and dispersion contributions that bind these trimers together. The recently reported M052X functional with a polarized triple-zeta basis set predicts 11 uracil trimer interaction energies with a root-mean-square error of 2.3 kcal mol(-1) relative to highly correlated ab initio theoretical calculations.

Chemistry, Physical↗

Inflammatory cell participation in coagulation.

Vascular cells, and leukocytes in particular, have evolved a formidable machinery to initiate and amplify coagulation. Through multiple, receptor-mediated recognitions this process provides a cellular microenvironment of limited proteolytic activation that contributes to the maintenance of the hemostatic balance in vivo. However, the ability of leukocytes to generate thrombin is also a fundamental aspect of inflammatory responses, and has far-reaching implications in the pathophysiology of vascular diseases. The scope of this article is to revisit the most recent contributions to the cellular and molecular mechanisms of leukocyte-mediated coagulation, and to highlight their role in the pathogenesis of vascular injury.

Blood Coagulation↗

Ammonia uptake and its effects on ionoregulation in the freshwater crayfish Pacifastacus leniusculus (Dana).

Exposure of adult crayfish Pacifastacus leniusculus to Artificial Freshwater (AFW) media containing 1.5 m and 0.15 mmol x l(-1) total ammonia [Tamm; 0.1 x acute lethal concentration (24 h LC50) and 0.01 x 24 h LC50] and adjusted to pH 6.5, pH 8.2 and pH 10.5 resulted in significant increases in haemolymph ammonia over a 24-h period. Ammonia accumulated most rapidly at pH 10.5. These media were chosen to expose animals to a range of different un-ionised ammonia (UIA) [NH3] and ionised ammonia [NH4+] concentrations. From comparisons of measured transepithelial potential differences (PDte) with calculated Nernst potentials (PDNH4+) for the known haemolymph-to-medium gradients of [NH4+], it was deduced that, in pH 8.2 and pH 6.5 AFW, NH4+ was not in thermodynamic equilibrium across the integument (presumably gill epithelium). In pH 10.5 AFW with 1.5 mmol x l(-1) Tamm (predominantly NH3), the accumulation of ammonia in the haemolymph was in the NH4+ form due to haemolymph pH regulation by the crayfish in this alkaline external medium. Measured net fluxes of ammonia (Jamm(net)) were inwardly directed and maximal when [NH3] was the main component externally, but were also significant at pH 8.2 with high [NH4+] ([NH4+]:[NH3] approximately 20:1). Haemolymph Na+ depletion was significant and, over the 24-h exposure period, most rapid in high [NH3] medium but [Cl-] was unaffected. However, paradoxically, sodium uptake (measured JNa(in) on immediate transfer to high Tamm medium) was not significantly inhibited when [NH3] was the predominant ammonia species. In 1.5 mmol x l(-1) Tamm (mainly [NH4+), VNa(in) (the active component of JNa(in)) was significantly inhibited, particularly at low external [Na+]. This inhibition could not be demonstrated as one of competition at an Na+/NH4+ apical gill exchange site. The resultant net efflux of sodium from the animal showed that the ability of the animals to balance sodium losses at low external [Na+] was severely affected. Longer exposure to pH 10.5 AFW with high [NH3] (12 h) resulted in significantly increased JNa(out), while not significantly affecting JNa(in). Analysis of urinary Na+ losses showed that, while urinary flow rate and water reabsorption was most likely unaffected by ammonia exposure, final urine [Na+] was significantly elevated. The resulting urinary Na+ loss accounted for 63% of the increased JNa(out) in high [NH3] medium.

Ammonia↗

Quantitative assessment of neuromotor function in adolescents with high functioning autism and Asperger Syndrome.

BACKGROUND: Motor impairment in children with Asperger Syndrome (AS) or High functioning autism (HFA) has been reported previously. This study presents results of a quantitative assessment of neuromotor skills in 14-22 year old HFA/AS. METHODS: 16 HFA/AS and 16 IQ-matched controls were assessed by the Zurich Neuromotor Assessment (ZNA). RESULTS: The HFA/AS group showed strongest impairments of dynamic balance skills and diadochokinesis. Motor abilities were associated with degree of social withdrawal in the full sample and severity of current autistic symptoms in the HFA/AS group. CONCLUSION: Similar motor patterns as in younger children were found in the older adolescents. The association of autistic symptoms with motor performance points towards an essential role of motor impairment in autism spectrum disorders.

Adolescent↗

Brief report: the impact of subcortical band heterotopia and associated complications on the neuropsychological functioning of a 13-year-old child.

Motor impairment in children with Asperger syndrome (AS) or high functioning autism (HFA) has been reported previously. This study presents results of a quantitative assessment of neuromotor skills in 14-22 year old HFA/AS. Sixteen HFA/AS and 16 IQ-matched controls were assessed by the Zurich Neuromotor Assessment (ZNA). The HFA/AS group showed strongest impairments of dynamic balance skills and diadochokinesis. Motor abilities were associated with degree of social withdrawal in the full sample and severity of current autistic symptoms in the HFA/AS group. Similar motor patterns as in younger children were found in the older adolescents. The association of autistic symptoms with motor performance points towards an essential role of motor impairment in autism spectrum disorders.

Adolescent↗

Bone marrow regeneration under cytotoxic drug regimens: behaviour ranging from homeostasis to unpredictability in a model for hemopoietic differentiation.

In the process of hemopoiesis, bone marrow stem cells differentiate into the various types of mature blood cells. We present a model for bone marrow dynamics, which retrieves its ability to continuously modulate the balance between self-renewal and differentiation, even under periodic cytodestructive perturbations. Yet, a temporally stochastic perturbation results in chaotic-like behaviour which has no deterministic source.

Animals↗

Adenosine treatment delays postischemic hippocampal CA1 loss after cardiac arrest and resuscitation in rats.

Resuscitation from cardiac arrest results in reperfusion injury that leads to increased postresuscitation mortality and delayed neuronal death. One of the many consequences of resuscitation from cardiac arrest is a derangement of energy metabolism and the loss of adenylates, impairing the tissue's ability to regain proper energy balance. In this study, we investigated the effects of adenosine (ADO) on the recovery of the brain from 12 min of ischemia using a rat model of cardiac arrest and resuscitation. Compared to the untreated group, treatment with adenosine (7.2 mg/kg) initiated immediately after resuscitation increased the proportion of rats surviving to 4 days and significantly delayed hippocampal CA1 neuronal loss. Brain blood flow was increased significantly in the adenosine-treated rats 1 h after cardiac arrest and resuscitation. Adenosine-treated rats exhibited less edema in cortex, brainstem and hippocampus during the first 48 h of recovery. Adenosine treatment significantly lowered brain temperature during recovery, and a part of the neuroprotective effects of adenosine treatment could be ascribed to adenosine-induced hypothermia. With this dose, adenosine may have a delayed transient effect on the restoration of the adenylate pool (AXP = ATP + ADP + AMP) 24 h after cardiac arrest and resuscitation. Our findings suggested that improved postischemic brain blood flow and ADO-induced hypothermia, rather than adenylate supplementation, may be the two major contributors to the neuroprotective effects of adenosine following cardiac arrest and resuscitation. Although adenosine did not prevent eventual CA1 neuronal loss in the long term, it did delay neuronal loss and promoted long-term survival. Thus, adenosine or specific agonists of adenosine receptors should be evaluated as adjuncts to broaden the window of opportunity in the treatment of the reperfusion injury following cardiac arrest and resuscitation.

Adenosine↗

Regulators of nonsulfur purple phototrophic bacteria and the interactive control of CO2 assimilation, nitrogen fixation, hydrogen metabolism and energy generation.

For the metabolically diverse nonsulfur purple phototrophic bacteria, maintaining redox homeostasis requires balancing the activities of energy supplying and energy-utilizing pathways, often in the face of drastic changes in environmental conditions. These organisms, members of the class Alphaproteobacteria, primarily use CO2 as an electron sink to achieve redox homeostasis. After noting the consequences of inactivating the capacity for CO2 reduction through the Calvin-Benson-Bassham (CBB) pathway, it was shown that the molecular control of many additional important biological processes catalyzed by nonsulfur purple bacteria is linked to expression of the CBB genes. Several regulator proteins are involved, with the two component Reg/Prr regulatory system playing a major role in maintaining redox poise in these organisms. Reg/Prr was shown to be a global regulator involved in the coordinate control of a number of metabolic processes including CO2 assimilation, nitrogen fixation, hydrogen metabolism and energy-generation pathways. Accumulating evidence suggests that the Reg/Prr system senses the oxidation/reduction state of the cell by monitoring a signal associated with electron transport. The response regulator RegA/PrrA activates or represses gene expression through direct interaction with target gene promoters where it often works in concert with other regulators that can be either global or specific. For the key CO2 reduction pathway, which clearly triggers whether other redox balancing mechanisms are employed, the ability to activate or inactivate the specific regulator CbbR is of paramount importance. From these studies, it is apparent that a detailed understanding of how diverse regulatory elements integrate and control metabolism will eventually be achieved.

Alphaproteobacteria↗

Intradermal DNA immunization by using jet-injectors in mice and monkeys.

We have used spring powered jet injectors to deliver a solution of a naked DNA vaccine encoding the influenza hemagglutinin HA into the skin of mice and monkeys. We compared the immune responses induced by this needleless injection technique into the skin to the responses induced by a classical i.m. immunization. Both routes of immunization induced significant ELISA antibody titers and hemagglutination inhibition (HI) titers that were above the usual threshold values predictive of protection against influenza in mice and monkeys. In mice, both ways of immunization were equally efficient in inducing HA-specific CTL responses. Regarding antibody isotypes, the IgG1/IgG2a ratio was in favour of the IgG2a isotype for i.m. immunization and more balanced for i.d. immunization. The ability of the two injection techniques to induce immunity in mice did not correlate with transgene expression in the site of administration. In fact, local gene expression was 10-100 fold more important in the injected muscle as compared to the jet-injected skin when assessed by using the luciferase reporter system.

Animals↗

T lymphocyte-dependent effector mechanisms of immunity to Toxoplasma gondii.

Immunity to the opportunistic pathogen, Toxoplasma gondii, is highly dependent upon the effector activity of IFN-gamma-producing T lymphocytes. While IFN-gamma is required to survive infection, an understanding of its function remains incomplete. During infection, T. gondii simultaneously induces downregulatory antiinflammatory cytokines, thereby avoiding major host pathology mediated by proinflammatory cytokines such as IFN-gamma. The ability to induce the correct balance between these two opposing host responses likely accounts for the success of this organism as a parasite.

Animals↗