Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

Cardioprotective effect of ornitho-kinin in an anesthetized, open-chest chicken model of acute coronary occlusion

The generation of bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in blood and kallidin (Lys-BK) in tissues by the action of the kallikrein-kinin system has received little attention in non-mammalian vertebrates. In mammals, kallidin can be generated by the coronary endothelium and myocytes in response to ischemia, mediating cardioprotective events. The plasma of birds lacks two key components of the kallikrein-kinin system: the low molecular weight kininogen and a prekallikrein activator analogous to mammalian factor XII, but treatment with bovine plasma kallikrein generates ornitho-kinin [Thr6,Leu8]-BK. The possible cardioprotective effect of ornitho-kinin infusion was investigated in an anesthetized, open-chest chicken model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. The iv injection of a low dose of ornitho-kinin (4 µg/kg) reduced mean arterial pressure from 88 ± 12 to 42 ± 7 mmHg and increased heart rate from 335 ± 38 to 402 ± 45 bpm (N = 5). The size of the infarct was reduced by pretreatment with ornitho-kinin (500 µg/kg infused over a period of 5 min) from 35 ± 3 to 10 ± 2% of the area at risk. These results suggest that the physiological role of the kallikrein-kinin system is preserved in this animal model in spite of the absence of two key components, i.e., low molecular weight kininogen and factor XII.

Keratoconus prediction using a finite element model of the cornea with local biomechanical properties

PURPOSE: The ability to predict and understand which biomechanical properties of the cornea are responsible for the stability or progression of keratoconus may be an important clinical and surgical tool for the eye-care professional. We have developed a finite element model of the cornea, that tries to predicts keratoconus-like behavior and its evolution based on material properties of the corneal tissue. METHODS: Corneal material properties were modeled using bibliographic data and corneal topography was based on literature values from a schematic eye model. Commercial software was used to simulate mechanical and surface properties when the cornea was subject to different local parameters, such as elasticity. RESULTS: The simulation has shown that, depending on the corneal initial surface shape, changes in local material properties and also different intraocular pressures values induce a localized protuberance and increase in curvature when compared to the remaining portion of the cornea. CONCLUSIONS: This technique provides a quantitative and accurate approach to the problem of understanding the biomechanical nature of keratoconus. The implemented model has shown that changes in local material properties of the cornea and intraocular pressure are intrinsically related to keratoconus pathology and its shape/curvature.

EVALUATING VIBRATIONS ON A SMALL-SCALE MODEL OF A TIMBER FOOTBRIDGE

In Brazil, the study of pedestrian-induced vibration on footbridges has been undertaken since the early 1990s, for concrete and steel footbridges. However, there are no recorded studies of this kind for timber footbridges. Brazilian code ABNT NBR 7190 (1997) gives design requirements only for static loads in the case of timber footbridges, without considering the serviceability limit state from pedestrian-induced vibrations. The aim of this work is to perform a theoretical dynamic, numerical and experimental analysis on simply-supported timber footbridges, by using a small-scale model developed from a 24 m span and 2 m width timber footbridge, with two main timber beams. Span and width were scaled down (1:4) to 6 m e 0.5 in, respectively. Among the conclusions reached herein, it is emphasized that the Euler-Bernoulli beam theory is suitable for calculating the vertical and lateral first natural frequencies in simply-supported timber footbridges; however, special attention should be given to the evaluation of lateral bending stiffness, as it leads to conservative values.

Bronchus-Associated Lymphoid Tissue (BALT) and Survival in a Vaccine Mouse Model of Tularemia

Background: Francisella tularensis causes severe pulmonary disease, and nasal vaccination could be the ideal measure to effectively prevent it. Nevertheless, the efficacy of this type of vaccine is influenced by the lack of an effective mucosal adjuvant. Methodology/Principal Findings: Mice were immunized via the nasal route with lipopolysaccharide isolated from F. tularensis and neisserial recombinant PorB as an adjuvant candidate. Then, mice were challenged via the same route with the F. tularensis attenuated live vaccine strain (LVS). Mouse survival and analysis of a number of immune parameters were conducted following intranasal challenge. Vaccination induced a systemic antibody response and 70% of mice were protected from challenge as showed by their improved survival and weight regain. Lungs from mice recovering from infection presented prominent lymphoid aggregates in peribronchial and perivascular areas, consistent with the location of bronchus-associated lymphoid tissue (BALT). BALT areas contained proliferating B and T cells, germinal centers, T cell infiltrates, dendritic cells (DCs). We also observed local production of antibody generating cells and homeostatic chemokines in BALT areas. Conclusions: These data indicate that PorB might be an optimal adjuvant candidate for improving the protective effect of F. tularensis antigens. The presence of BALT induced after intranasal challenge in vaccinated mice might play a role in regulation of local immunity and long-term protection, but more work is needed to elucidate mechanisms that lead to its formation.

Intestinal Anti-Inflammatory Activity of Baccharis dracunculifolia in the Trinitrobenzenesulphonic Acid Model of Rat Colitis

Baccharis dracunculifolia DC (Asteraceae) is a Brazilian medicinal plant popularly used for its antiulcer and anti-inflammatory properties. This plant is the main botanical source of Brazilian green propolis, a natural product incorporated into food and beverages to improve health. The present study aimed to investigate the chemical profile and intestinal anti-inflammatory activity of B. dracunculifolia extract on experimental ulcerative colitis induced by trinitrobenzenosulfonic acid (TNBS). Colonic damage was evaluated macroscopically and biochemically through its evaluation of glutathione content and its myeloperoxidase (MPO) and alkaline phosphatase activities. Additional in vitro experiments were performed in order to test the antioxidant activity by inhibition of induced lipid peroxidation in the rat brain membrane. Phytochemical analysis was performed by HPLC using authentic standards. The administration of plant extract (5 and 50 mgkg(-1)) significantly attenuated the colonic damage induced by TNBS as evidenced both macroscopically and biochemically. This beneficial effect can be associated with an improvement in the colonic oxidative status, since plant extract prevented glutathione depletion, inhibited lipid peroxidation and reduced MPO activity. Caffeic acid, p-coumaric acid, aromadendrin-4-O-methyl ether, 3-prenyl-p-coumaric acid, 3,5-diprenyl-p-coumaric acid and baccharin were detected in the plant extract.

Human Dental Pulp Cells: A New Source of Cell Therapy in a Mouse Model of Compressive Spinal Cord Injury

Strategies aimed at improving spinal cord regeneration after trauma are still challenging neurologists and neuroscientists throughout the world. Many cell-based therapies have been tested, with limited success in terms of functional outcome. In this study, we investigated the effects of human dental pulp cells (HDPCs) in a mouse model of compressive spinal cord injury (SCI). These cells present some advantages, such as the ease of the extraction process, and expression of trophic factors and embryonic markers from both ecto-mesenchymal and mesenchymal components. Young adult female C57/BL6 mice were subjected to laminectomy at T9 and compression of the spinal cord with a vascular clip for 1 min. The cells were transplanted 7 days or 28 days after the lesion, in order to compare the recovery when treatment is applied in a subacute or chronic phase. We performed quantitative analyses of white-matter preservation, trophic-factor expression and quantification, and ultrastructural and functional analysis. Our results for the HDPC-transplanted animals showed better white-matter preservation than the DMEM groups, higher levels of trophic-factor expression in the tissue, better tissue organization, and the presence of many axons being myelinated by either Schwann cells or oligodendrocytes, in addition to the presence of some healthy-appearing intact neurons with synapse contacts on their cell bodies. We also demonstrated that HDPCs were able to express some glial markers such as GFAP and S-100. The functional analysis also showed locomotor improvement in these animals. Based on these findings, we propose that HDPCs may be feasible candidates for therapeutic intervention after SCI and central nervous system disorders in humans.

Renal denervation in an animal model of diabetes and hypertension: Impact on the autonomic nervous system and nephropathy

Background: The effects of renal denervation on cardiovascular reflexes and markers of nephropathy in diabetic-hypertensive rats have not yet been explored. Methods: Aim: To evaluate the effects of renal denervation on nephropathy development mechanisms (blood pressure, cardiovascular autonomic changes, renal GLUT2) in diabetic-hypertensive rats. Forty-one male spontaneously hypertensive rats (SHR) similar to 250 g were injected with STZ or not; 30 days later, surgical renal denervation (RD) or sham procedure was performed; 15 days later, glycemia and albuminuria (ELISA) were evaluated. Catheters were implanted into the femoral artery to evaluate arterial pressure (AP) and heart rate variability (spectral analysis) one day later in conscious animals. Animals were killed, kidneys removed, and cortical renal GLUT2 quantified (Western blotting). Results: Higher glycemia (p < 0.05) and lower mean AP were observed in diabetics vs. nondiabetics (p < 0.05). Heart rate was higher in renal-denervated hypertensive and lower in diabetic-hypertensive rats (384.8 +/- 37, 431.3 +/- 36, 316.2 +/- 5, 363.8 +/- 12 bpm in SHR, RD-SHR, STZ-SHR and RD-STZ-SHR, respectively). Heart rate variability was higher in renal-denervated diabetic-hypertensive rats (55.75 +/- 25.21, 73.40 +/- 53.30, 148.4 +/- 93 in RD-SHR, STZ-SHR-and RD-STZ-SHR, respectively, p < 0.05), as well as the LF component of AP variability (1.62 +/- 0.9, 2.12 +/- 0.9, 7.38 +/- 6.5 in RD-SHR, STZ-SHR and RD-STZ-SHR, respectively, p < 0.05). GLUT2 renal content was higher in all groups vs. SHR. Conclusions: Renal denervation in diabetic-hypertensive rats improved previously reduced heart rate variability. The GLUT2 equally overexpressed by diabetes and renal denervation may represent a maximal derangement effect of each condition.

Frustration and anomalous behavior in the Bell-Lavis model of liquid water

We have reconsidered the Bell-Lavis model of liquid water and investigated its relation to its isotropic version, the antiferromagnetic Blume-Emery-Griffiths model on the triangular lattice. Our study was carried out by means of an exact solution on the sequential Husimi cactus. We show that the ground states of both models share the same topology and that fluid phases (gas and low- and high-density liquids) can be mapped onto magnetic phases (paramagnetic, antiferromagnetic, and dense paramagnetic, respectively). Both models present liquid-liquid coexistence and several thermodynamic anomalies. This result suggests that anisotropy introduced through orientational variables play no specific role in producing the density anomaly, in agreement with a similar conclusion discussed previously following results for continuous soft core,models. We propose that the presence of liquid anomalies may be related to energetic frustration, a feature common to both models.

Mechanism and model of the oscillatory electro-oxidation of methanol

A mechanism for the kinetic instabilities observed in the galvanostatic electro-oxidation of methanol is suggested and a model developed. The model is investigated using stoichiometric network analysis as well as concepts from algebraic geometry (polynomial rings and ideal theory) revealing the occurrence of a Hopf and a saddle-node bifurcation. These analytical solutions are confirmed by numerical integration of the system of differential equations. (C) 2010 American Institute of Physics

Exercise training reduces cardiac angiotensin II levels and prevents cardiac dysfunction in a genetic model of sympathetic hyperactivity-induced heart failure in mice

The role of exercise training (ET) on cardiac renin-angiotensin system (RAS) was investigated in 3-5 month-old mice lacking alpha(2A-) and alpha(2C-)adrenoceptors (alpha(2A)/alpha(2C)ARKO) that present heart failure (HF) and wild type control (WT). ET consisted of 8-week running sessions of 60 min, 5 days/week. In addition, exercise tolerance, cardiac structural and function analysis were made. At 3 months, fractional shortening and exercise tolerance were similar between groups. At 5 months, alpha(2A)/alpha(2C)ARKO mice displayed ventricular dysfunction and fibrosis associated with increased cardiac angiotensin (Ang) II levels (2.9-fold) and increased local angiotensin-converting enzyme activity (ACE 18%). ET decreased alpha(2A)/alpha(2C)ARKO cardiac Ang II levels and ACE activity to age-matched untrained WT mice levels while increased ACE2 expression and prevented exercise intolerance and ventricular dysfunction with little impact on cardiac remodeling. Altogether, these data provide evidence that reduced cardiac RAS explains, at least in part, the beneficial effects of ET on cardiac function in a genetic model of HF.

Intracellular mechanisms of specific beta-adrenoceptor antagonists involved in improved cardiac function and survival in a genetic model of heart failure

beta-blockers, as class, improve cardiac function and survival in heart failure (HF). However, the molecular mechanisms underlying these beneficial effects remain elusive. In the present study, metoprolol and carvedilol were used in doses that display comparable heart rate reduction to assess their beneficial effects in a genetic model of sympathetic hyperactivity-induced HF (alpha(2A)/alpha(2C)-ARKO mice). Five month-old HF mice were randomly assigned to receive either saline, metoprolol or carvedilol for 8 weeks and age-matched wild-type mice (WT) were used as controls. HF mice displayed baseline tachycardia, systolic dysfunction evaluated by echocardiography, 50% mortality rate, increased cardiac myocyte width (50%) and ventricular fibrosis (3-fold) compared with WT. All these responses were significantly improved by both treatments. Cardiomyocytes from HF mice showed reduced peak [Ca(2+)](i) transient (13%) using confocal microscopy imaging. Interestingly, while metoprolol improved [Ca(2+)](i) transient, carvedilol had no effect on peak [Ca(2+)](i) transient but also increased [Ca(2+)] transient decay dynamics. We then examined the influence of carvedilol in cardiac oxidative stress as an alternative target to explain its beneficial effects. Indeed, HF mice showed 10-fold decrease in cardiac reduced/oxidized glutathione ratio compared with WT, which was significantly improved only by carvedilol treatment. Taken together, we provide direct evidence that the beneficial effects of metoprolol were mainly associated with improved cardiac Ca(2+) transients and the net balance of cardiac Ca(2+) handling proteins while carvedilol preferentially improved cardiac redox state. (C) 2008 Elsevier Inc. All rights reserved.

The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking alpha(2A) and alpha(2C) adrenoceptor knockout (alpha(2A)/alpha(2C) ARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, alpha(2A)/alpha(2C)ARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT(1) receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

Extending the kinetic solution of the classic Michaelis-Menten model of enzyme action

The principal aim of studies of enzyme-mediated reactions has been to provide comparative and quantitative information on enzyme-catalyzed reactions under distinct conditions. The classic Michaelis-Menten model (Biochem Zeit 49:333, 1913) for enzyme kinetic has been widely used to determine important parameters involved in enzyme catalysis, particularly the Michaelis-Menten constant (K (M) ) and the maximum velocity of reaction (V (max) ). Subsequently, a detailed treatment of the mechanisms of enzyme catalysis was undertaken by Briggs-Haldane (Biochem J 19:338, 1925). These authors proposed the steady-state treatment, since its applicability was constrained to this condition. The present work describes an extending solution of the Michaelis-Menten model without the need for such a steady-state restriction. We provide the first analysis of all of the individual reaction constants calculated analytically. Using this approach, it is possible to accurately predict the results under new experimental conditions and to characterize and optimize industrial processes in the fields of chemical and food engineering, pharmaceuticals and biotechnology.

A transient three-dimensional heat transfer model of the human body

The objective of this work is to develop an improved model of the human thermal system. The features included are important to solve real problems: 3D heat conduction, the use of elliptical cylinders to adequately approximate body geometry, the careful representation of tissues and important organs, and the flexibility of the computational implementation. Focus is on the passive system, which is composed by 15 cylindrical elements and it includes heat transfer between large arteries and veins. The results of thermal neutrality and transient simulations are in excellent agreement with experimental data, indicating that the model represents adequately the behavior of the human thermal system. (C) 2009 Elsevier Ltd. All rights reserved.