Chronic mild hyperhomocysteinemia induces anxiety-like symptoms, aversive memory deficits and hippocampus atrophy in adult rats: New insights into physiopathological mechanisms.

In the last decade, increased homocysteine levels have been implicated as a risk factor for neurodegenerative and psychiatric disorders. We have developed an experimental model of chronic mild hyperhomocysteinemia (HHcy) in order to observe metabolic impairments in the brain of adult rodents. Besides its known effects on brain metabolism, the present study sought to investigate whether chronic mild HHcy could induce learning/memory impairments associated with biochemical and histological damage to the hippocampus. Adult male Wistar rats received daily subcutaneous injections of homocysteine (0.03 µmol/g of body weight) twice a day, from the 30th to the 60th day of life or saline solution (Controls). After injections, anxiety-like and memory tests were performed. Following behavioral analyses, brains were sliced and hippocampal volumes assessed and homogenized for redox state assessment, antioxidant activity, mitochondrial functioning (chain respiratory enzymes and ATP levels) and DNA damage analyses. Behavioral analyses showed that chronic mild HHcy may induce anxiety-like behavior and impair long-term aversive memory (24 h) that was evaluated by inhibitory avoidance task. Mild HHcy decreased locomotor and/or exploratory activities in elevated plus maze test and caused hippocampal atrophy. Decrease in cytochrome c oxidase, DNA damage and redox state changes were also observed in hippocampus of adult rats subjected to mild HHcy. Our findings show that chronic mild HHcy alters biochemical and histological parameters in the hippocampus, leading to behavioral impairments. These findings might be considered in future studies aiming to search for alternative strategies for treating the behavioral impairments in patients with mild elevations in homocysteine levels.

Galantamine administration reduces reactive astrogliosis and upregulates the anti-oxidant enzyme catalase in rats submitted to neonatal hypoxia ischemia.

Neonatal hypoxia ischemia (HI) plays a role in the etiology of several neurological pathologies and causes severe sequelae. Acetylcholine is a neurotransmitter in the central nervous system and cholinesterase inhibitors have demonstrated a positive action over HI induced deficits. In order to evaluate the effects of pre and post-hypoxia administrations of galantamine, a cholinesterase inhibitor, in a model of perinatal HI, Wistar rats in the post-natal day 7 (PND7) were subjected to a combination of unilateral occlusion of the right carotid artery with the exposure to a 1h hypoxia. Intraperitoneal injections of galantamine were administered in two different protocols: one pre and other post-hypoxia. The analysis of brain structures volume at PND45 showed that pre-hypoxia galantamine treatment prevented tissue injury to the ipsilesional hippocampus. Also, immunofluorescence showed HI-induced increase in the number of astrocytes that was prevented by pre-hypoxia treatment. Biochemical analysis was performed in the ipsilesional hippocampus at PND8 and revealed that pre-hypoxia galantamine treatment: 1) prevented the neuronal loss induced by HI; 2) reduced the HI-induced hypertrophy of astrocytes; and 3) caused an increase in the activity of the anti-oxidant enzyme catalase. Overall, treatment with galantamine was able to prevent the brain damage, increase the survival of neurons, reduce astrocytic reaction and increase the activity of the anti-oxidant enzyme catalase in rats submitted to neonatal hypoxia ischemia.

Exploring synergies between transit investment and dense redevelopment: a scenario analysis in a rapidly urbanizing landscape.

Like many urban areas around the world, Durham and Orange counties in North Carolina, USA are experiencing population growth and sprawl that is putting stress on the transportation system. Light rail and denser transit-oriented development are being considered as possible solutions. However, local agencies and stakeholders are concerned the light rail may worsen housing affordability and have questioned whether investment in both light rail and dense redevelopment are necessary to achieve community goals. We developed an integrated system dynamics model to quantitatively explore the outcomes of these land use and transportation options across multiple societal dimensions. The model incorporates feedbacks among the land, transportation, economic, equity, and energy sectors. This paper uses the results of four model scenarios, run between 2000 and 2040, to address two main questions: (1) what role does redevelopment play in capturing the socioeconomic benefits of transit infrastructure investment? And (2) how do redevelopment and light-rail transit interact to affect housing and transportation affordability? We find that transit investment and dense redevelopment combine synergistically to better achieve the goals of the light-rail line, including economic development, mobility, and compact growth. However, housing affordability does worsen in the combined scenario, as transportation-cost savings are not sufficient to offset the rise in housing costs. We emphasize that model users may input their own assumptions to explore the dynamics of alternative scenarios. We demonstrate how spatially-aggregated systems models can complement traditional land use and transportation models in the regional planning process.

Administration of Huperzia quadrifariata Extract, a Cholinesterase Inhibitory Alkaloid Mixture, has Neuroprotective Effects in a Rat Model of Cerebral Hypoxia-Ischemia.

Neonatal hypoxia-ischemia (HI) is an etiologic component of several neurologic pathologies associated to cognitive impairment. The mechanisms involved in HI-induced tissue damage start immediately after HI and extend for days. Acetylcholine is an important neurotransmitter in the central nervous system and exerts a protector effect on tissue damage by modulating inflammation, and cholinesterase inhibitors have shown neuroprotective properties and their action are often attributed to inhibition of the immune response. The administration of Huperzia quadrifariata alkaloid extract (HqAE), with potent and selective cholinesterase inhibitor properties, will reduce the HI induced behavioral deficits and tissue damage. A total of 84 newborn Wistar rat pups at post natal day 7 (PND7) were subjected to right carotid occlusion followed by 1 h of hypoxia (8% of O2) and i.p. injections of saline, vehicle or HqAE (10 mg/kg). Morris Water Maze and inhibitory avoidance tests were used to assess the cognitive function. Flow cytometry was performed at PND11. Histological analysis was performed at PND45. HqAE treatment was able to prevent the HI induced cognitive deficits in both tests and, at PND45, histological analysis showed that HqAE treatment reduced hippocampus tissue damage. Flow cytometry of the injured hippocampus revealed that the treatment was able to reduce cellular death and the number of infiltrating T cells. Altogether, these results show the therapeutic potential of the Huperzia quadrifariata alkaloid extract to prevent cognitive deficits and histological damage caused by neonatal hypoxia-ischemia, probably by reducing cellular death and T cell mobilization.

Are the consequences of neonatal hypoxia-ischemia dependent on animals' sex and brain lateralization?

Hypoxia-ischemia on 3-day-old rats (HIP3) allows the investigation of HI damage in the immature brain. HIP3 is characterized for neurological disabilities caused by white matter injury. This study investigates the relationship between animals' sex and injured hemisphere on HIP3 consequences. Male and female Wistar rats had their right or left common carotid artery occluded under halotane anesthesia and exposed to 8% O2 for 1.5 h. Control rats received sham surgery and exposure to 1.5 h of room air in isolation of their mothers. Sex and injured hemisphere influence in Na+/K+ -ATPase activity 24h after lesion: females and the right brain hemispheres showed decreased enzymatic activity after HIP3. Cognitive impairment was observed in step-down inhibitory avoidance, in which females HIP3 left injured were the most damaged. Histological analysis showed a trend to white matter damage in females left injured without hemispherical nor hippocampal volume decrease in HIP3 rats at postnatal day 21. However, at PND90, hemisphere and sex effects were noted in hemispherical volume and myelination: left brain hemisphere and the females evidenced higher histological damage. Our results points to an increased resistance of male rats and right brain hemisphere to support the impairment caused in Na+/K+ -ATPase activity early after HIP3, and evidencing more discrete behavioral impairments and histological damage at adulthood. Present data adds new evidence of distinct effects of brain lateralization and sex vulnerability on biochemical, behavioral and histological parameters after hypoxia-ischemia.

Isolation stress during the prepubertal period in rats induces long-lasting neurochemical changes in the prefrontal cortex.

Social isolation during postnatal development leads to behavioral and neurochemical changes, and a particular susceptibility of the prefrontal cortex to interventions during this period has been suggested. In addition, some studies showed that consumption of a palatable diet reduces some of the stress effects. Therefore, our aim is to investigate the effect of isolation stress in early life on some parameters of oxidative stress and energy metabolism (Na(+),K(+)-ATPase activity, respiratory chain enzymes activities and mitochondrial mass and potential) in prefrontal cortex of juvenile and adult male rats. We also verified if the consumption of a palatable diet during the prepubertal period would reduce stress effects. The results showed that, in juvenile animals, isolation stress increased superoxide dismutase and Complex IV activities and these effects were still observed in the adulthood. An interaction between stress and diet was observed in catalase activity in juveniles, while only the stress effect was detected in adults, reducing catalase activity. Access to a palatable diet increased Na(+),K(+)-ATPase activity in juveniles, an effect that was reversed after removing this diet. On the other hand, isolation stress induced a decreased activity of this enzyme in adulthood. No effects were observed on glutathione peroxidase, total thiols and free radicals production, as well as on mitochondrial mass and potential. In conclusion, isolation stress in the prepubertal period leads to long-lasting changes on antioxidant enzymes and energetic metabolism in the prefrontal cortex of male rats, and a palatable diet was not able to reverse these stress-induced effects.

H-RAS gene expression in human multinodular goiter.

The RAS protooncogene has an important, although not yet established role in thyroid neoplasia. In this study, we evaluated the H-RAS mRNA and protein levels in human samples of nontoxic and toxic multinodular goiter samples, according to serum TSH levels. The mean of H-RAS mRNA levels in nodules of nontoxic nodular goiter were significantly increased compared to nonnodular tissue (1.49+/-1.21 vs. 0.94+/-0.81 AU, P=0.016). Nine of the 18 specimens (50%) of nontoxic multinodular goiter exhibited increased levels of H-RAS mRNA. The increased H-RAS mRNA levels were paralleled by inRAcreased H-Ras protein levels in about 90% of the cases. Interestingly, no differences were observed in H-RAS expression between nodules and adjacent nonnodular tissue in toxic nodular goiters (0.58+/-0.27 vs. 0.58+/-0.20 AU, P=0.88). None of the 10 samples from toxic multinodular goiters exhibited overexpression of H-RAS. The H-RAS expression was positively correlated with thyroglobulin expression (r2=0.51; P=0.04). In conclusion, we demonstrated increased levels of H-RAS mRNA and protein in samples of nontoxic multinodular goiter, indicating that it might be involved in goiter pathogenesis. In contrast, H-RAS overexpression was not detected in any of the samples of toxic multinodular goiter, suggesting different mechanisms for cell proliferation in nodular goiter according to thyroid status.

Effects of changes in articulator settings on generated occlusal tracings. Part II: Immediate side shift, intercondylar distance, and rear and top wall settings.

An occlusal scribing device attached to a fully adjustable articulator was used to generate occlusal tracings. The tracings were analyzed to determine the effect changes in immediate side shift, intercondylar distance, and rear and top wall settings had on molar occlusal morphology. When ranked from greatest to least effect, a 0.2 mm change in the immediate side shift setting had the greatest effect on the occlusion, whereas a 5-degree change in the rear and top wall settings had the least effect.

Effects of changes in articulator settings on generated occlusal tracings. Part I: Condylar inclination and progressive side shift settings.

An occlusal scribing device attached to a fully adjustable articulator was used to generate occlusal tracings. The tracings were analyzed to determine the effect changes in progressive side shift and condylar inclination settings had on molar occlusal morphology. The progressive side shift adjustment affected the cusp height and ridge and groove position, primarily in the nonworking excursion. The condylar inclination adjustment affected the cusp heights in the protrusive and nonworking excursion without affecting the working excursion.

A graphic comparison of mandibular border movements generated by various articulators. Part II: Results.

A method was described in Part I in which mandibular border movements of a subject can be compared with the movements generated by various articulators (fully adjustable Denar SE and semiadjustable Denar Mark II) by using an electronic pantograph, the Pantronic. The mean values of 12 sets of plots from this device were calculated and graphs were generated. For the subject studied, differences were detected by the Pantronic pantograph between human border movements and those generated by each articulator and method of adjusting it. In the horizontal table, the semiadjustable articulator without immediate side shift always showed the potential of greater errors, especially as excursions started. When the semiadjustable instrument was programmed with immediate side shift, its movements were comparable with the fully adjustable articulator. Neither articulator exactly simulated the subjects' movements.

A graphic comparison of mandibular border movements generated by various articulators. Part I: Methodology.

A method was described by which mandibular border movement of a subject can be compared with the movements generated by various articulators. The fully adjustable articulator, Denar SE, and the semiadjustable instrument, Denar Mark II, were used in this study. The movements were recorded by an electronic pantograph, the Pantronic. The mean values of 12 sets of print-out plots from this device were calculated by using Microsoft Excel software. These mean values were then used by CricatGraph software to generate combined graphs. Both software programs were used with an Apple Macintosh Plus personal computer. The clinical significance of the findings will be discussed in Part II of this study.

Evaluation of a digitizer and computer system designed to analyze articulator-generated occlusal tracings.

Occlusal tracings generated on a Denar fully adjustable articulator were photographed, projected, digitized, and stored in a computer data file. These steps were accomplished with sufficient accuracy for clinical analysis. This study demonstrated that appropriately referenced tracing data can be transferred accurately into a machine-readable form. Studies of pantographic tracings for mandibular movements are facilitated by this convenient and accurate method of handling data.

The use of ketanserin, a 5-hydroxytryptamine receptor antagonist, for treatment of postoperative hypertension following coronary artery bypass surgery.

In patients developing hypertension following coronary artery bypass surgery (CABG) the possible role of 5-hydroxytryptamine (5-HT; serotonin) was investigated by injecting ketanserin, a specific 5-HT2-receptor antagonist. Ketanserin was administered intravenously when intraarterial systolic blood pressure (SAP) exceeded 150 mm Hg either as a 10-mg bolus (group 1, N = 15), or as a 10-mg bolus followed by infusion of 4 mg/h for either 2.5 h (group 2, N = 15) or for 1 h (group 3, N = 10). In 33 patients (82.5%), SAP and diastolic arterial pressure decreased significantly within 5 min after the 10-mg bolus. In group 1, SAP gradually increased after 30-50 min but in groups 2 and 3 SAP remained normal. The triple index (TI) decreased significantly in all groups. Heart rate decreased slightly but significantly in groups 2 and 3. Central venous and left atrial pressures did not change substantially in any of the three groups. Cardiac output increased significantly (0.51 +/- 0.158 L/min); hence, systemic vascular resistance (SVR) decreased significantly (452.1 +/- 50.57 dyn . s . cm-5--group 3). No rebound increase in SAP occurred after terminating the infusions (groups 2 and 3). These findings indicate that 5-HT plays a role in the majority of patients who develop hypertension following CABG. The decrease of SVR without reflex tachycardia is a favorable effect of ketanserin.