Characteristics of augmented breaths provoked by almitrine bismesylate in cats.

The contribution of almitrine bismesylate to the occurrence and pattern of augmented breaths was studied in fifteen spontaneously breathing, anaesthetized cats. Breathing was via a tracheostomy, while the laryngeal resistance to airflow was measured with the larynx isolated in situ. Almitrine bismesylate at a dose of 0.5 mg kg-1 of body weight was injected intravenously in the intact animals and following bilateral vagotomy which spared the right recurrent laryngeal nerve. Almitrine injected intravenously elicited augmented breaths within the first 45 s in thirteen cats and within 1 min in the remaining two cats. During augmented breaths inspiratory and expiratory airflows rose, the mean increases being 385.2 and 159.6% respectively above the controls (P less than 0.01). The inspiratory laryngeal resistance declined to 77.7% of the control (P less than 0.01) and expiratory laryngeal resistance increased by 95.4% above the control level (P less than 0.01). The inspiratory and expiratory times were prolonged by 56 and 58% compared with baseline breathing. Following the augmented breaths the respiratory airflows exceeded baseline values, the respiratory timing was slightly reduced, and the inspiratory laryngeal resistance was significantly lowered below the control level (P less than 0.01). The expiratory laryngeal resistance showed the same trend without statistical significance. Bilateral vagotomy abolished the occurrence of augmented breaths following almitrine injection.     

Hypertensive-diabetic cardiomyopathy in the rat: an experimental model of human disease.

The authors recently described a group of diabetic patients with severe congestive heart failure, hypertension, and minimal coronary artery disease, who had significant myocardial degeneration apparently secondary to the combined effects of high blood pressure and diabetes on the heart. To evaluate the effects of hypertension and diabetes mellitus more fully, the authors studied four groups of rats with either no disease, streptozotocin-induced diabetes mellitus, renovascular hypertension, or a combination of hypertension and diabetes. They employed semiquantitative light microscopy, which revealed significantly greater replacement fibrosis in the hypertensive-diabetic rats when compared with the other three groups. Interstitial fibrosis was increased in the hypertensive-diabetic animals, though it was just below the 5% level of significance when compared with the hypertensives. Further analysis, however, revealed that those hypertensive-diabetic animals with the greatest relative cardiac hypertrophy, as measured by the heart weight/body weight ratio, had significantly increased interstitial fibrosis. Surprisingly, diabetes mellitus alone produced no morphologic light-microscopic alterations; yet 8 weeks of combined hypertension and diabetes mellitus led to myocardial degeneration similar to the human disease. These changes do not appear to be secondary to abnormalities of intramyocardial muscular vessels. Measurement of 3 parameters of vascular disease revealed that hypertensive animals with less myocardial damage had greater vascular changes than the more severely affected hypertensive-diabetics. This study provides evidence that the combination of diabetes mellitus and hypertension produces significantly greater myocardial lesions than either disease alone. The similarity of the lesions with those observed in human patients suggests that the hypertensive-diabetic rat is a useful model for elucidating the pathogenesis of clinical myocardial disease in patients with hypertension and diabetes mellitus.     

Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH 4-10

The heptapeptide Semax, an analogue of the N-terminal adrenocorticotropic hormone fragment (4-10) (ACTH(4-10)), has been shown to exert a number of neuroprotective effects. There are some investigations that connected these effects with the increase of neurotrophin gene expression under the peptide drug application in neuron cell cultures [M.I. Shadrina, O.V. Dolotov, I.A. Grivennikov, P.A. Slominsky, L.A. Andreeva, L.S. Inozemtseva, S.A. Limborska, N.F. Myasoedov, Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analogue, Neurosci. Lett. 308 (2001) (2) 115-118]. In this work, we examined the action of Semax on rapid changes of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) gene expression in vivo. Male Wistar rats were treated for 1h with Semax (50 microg/kg, single intranasal application) and neurotrophin gene expression in rat brain was analyzed by real-time polymerase chain reaction (PCR). It was revealed that an intranasal application of Semax increased the expression of both neurotrophin genes in rat hippocampus. Bdnf gene expression also increased in the brainstem and cerebellum. Ngf gene expression decreased in rat frontal cortex. Thus, Semax induces rapid, gene- and region-specific changes in neurotrophin gene expression in normal rat brain.     

Identification of early disease progression in an ALS rat model

Transgenic rat models of amyotrophic lateral sclerosis (ALS) have recently been developed. Most assays of ALS-symptoms in these models monitor disease onset accurately, but do not identify individuals that will develop these symptoms before the motor deficits become apparent. Peak bodyweight has recently been shown to indicate affected individuals before motor deficits become apparent. However, it must be determined retrospectively due to weight fluctuation. Here, we report that exploratory activities detected by a photobeam activity system (PAS) and wire mesh ascending test can be used to detect slight motor deficits in the early phase of ALS. Thus, these tests may be used in addition to peak bodyweight to monitor early disease progression and to assay efficacy of new therapeutic interventions.     

低氧性肺动脉高压大鼠肺组织硫化氢的变化

本文旨在探讨低氧对大鼠内源性硫化氢体系的变化。采用生化反应方法测定血浆中硫化氢的含量和肺组织中硫化氢合酶的活性 ,采用定量竞争性RT PCR的方法检测肺组织中胱硫醚 γ 裂解酶 (CSE)mRNA的含量。结果显示 ,与对照组相比 ,低氧组大鼠的血浆硫化氢含量明显减少 [(1 92 2± 2 2 1 ) μmol Lvs (30 1 6± 32 4 ) μmol L ,P <0 0 1 ) ],肺组织中硫化氢合酶的活性明显下降 [(0 1 2 7± 0 0 2 3)vs (0 2 78± 0 0 99)nmol mgwettissue·min ,P <0 0 1 ],CSEmR NA的含量明显减少 [(1 0 2± 0 1 5 )× 1 0 - 6 fmolvs (2 1 7± 0 2 2 )× 1 0 - 6 fmol,P <0 0 1 ]。以上研究表明 ,低氧对大鼠的内源性硫化氢体系有抑制作用     

Double-blind study on the action of almitrine in patients with polycythemia of high altitude

Chronic polycythaemia in people living at high altitude is associated with hypoxaemia due to a marked reduction in hypoxic and hypercapnic drives. The effect of almitrine, a chemoreceptor stimulant, was evaluated in 40 patients, with haematocrit values over 57%, living in La Pa2 (3,600-4,000 m). Two studies were carried out. The aim of the first was to assess the ventilatory response, and the increase in PaO2 due to almitrine in a double blind, placebo controlled protocol including 40 patients (mean haematocrit 66.8%). Almitrine was given orally at a dose of 3 mg X kg-1. Variance analysis showed that three hours later there was a significant increase in PaO2 (+0.46 kPa), pH and respiratory frequency, with a significant reduction in PaCO2 (-0.4 kPa). The increase in ventilation (+17%) was not significant. The aim of the second study was to assess the effect of almitrine on the polycythaemia. It was given orally at a dose of 1.5 mg X kg-1 X day-1 to twelve patients over a four week period. Blood gases, ventilation (VE), oxygen consumption (VO2), carbon dioxide, production (VCO2) and haematocrit were measured every week. There was a slight but significant reduction in haematocrit (-3.5%). PaO2 and all the other measured parameters (VE, PaCO2, pH, VO2 VCO2) remained constant. The reduction in haematocrit was not therefore due to an increase in diurnal PaO2 but is perhaps due to the improvement in pulmonary ventilation during sleep.     

Stochastio morphological model of the rat lung

The laboratory rat is often used as a human surrogate in aerosol inhalation studies. Here we present a new stochastic model for the rat lung analogous to that for the human lung. Morphometric data on the tracheobronchial geometry of the rat lung provided by the Lovelace Inhalation Toxicology Research Institute were analyzed. The results of this statistical analysis reveal significant differences in diameters and branching angles between major and minor daughter tubes starting from the same bifurcation. As a consequence of the more monopodial airway branching in the rat lung compared to the more dichotomous structure of the human lung, we recommend classifying the rat lung airways by their diameters and not by generation numbers. The distributions of the gemetric airway parameters and the correlations among them will be used for Monte Carlo deposition calculations.     

Structural analysis of fetal rat lung development.

The primary aim of this morphological investigation was to elaborate a concept allowing us to coherently define reference spaces for morphometric analysis of fetal lung development. Beyond this quantitative goal, morphological analysis of cell types, definition of compartments, and reflection about the prospective fate of their constituents provided per se new insights into the developmental processes. Lungs of rat fetuses aged 17-23 days and newborns aged 20 hours were fixed with an osmium tetroxide and glutaraldehyde mixture and their volume determined. Left lungs were embedded in Epon and investigated by light and electron microscopy. The right lung of one animal per group was embedded in methacrylate and step sections obtained to precisely locate the airways within the mesenchyme. The various cell types, their topographical relationships, and their morphological alterations with ongoing development were analyzed with regard to their prospective potentials of differentiation. The developing lung could be partitioned into four zones further subdivided into defined compartments. Zone I forms a superficial mantle around the lobes and the future acini. Consisting of primitive mesenchymal cells, it represents a zone of growth which disappears with the onset of the saccular stage. Zone II is mainly a zone of differentiation. Its interstitium stains intensely due to a dense population of dark cells. Up to gestational day 19, zone II contains future conductive airways with their vessels. After day 21, it comprises the whole prospective gas exchange region. Zones III and IV contain the elements of the airway tree and vascular system, zone IV corresponding to the most proximal generations with an adventitial layer. For all differentiation processes, a centrifugal directionality is manifested.     

Stochastic morphological model of the rat lung

The laboratory rat is often used as a human surrogate in aerosol inhalation studies. Here we present a new stochastic model for the rat lung analogous to that for the human lung. Morphometric data on the tracheobronchial geometry of the rat lung provided by the Lovelace Inhalation Toxicology Research Institute were analyzed. The results of this statistical analysis reveal significant differences in diameters and branching angles between major and minor daughter tubes starting from the same bifurcation. As a consequence of the more monopodial airway branching in the rat lung compared to the more dichotomous structure of the human lung, we recommend classifying the rat lung airways by their diameters and not by generation numbers. The distributions of the geometric airway parameters and the correlations among them will be used for Monte Carlo deposition calculations.     

Curcuminoids enhance memory in an amyloid-infused rat model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease. There are a limited number of therapeutic options available for the treatment of AD. Curcuminoids (a mixture of bisdemethoxycurcumin, demethoxycurcumin and curcumin) is the main chemical constituent found in turmeric, a well known curry spice, having potential in the treatment of AD. The objective of this study was to investigate the effects of curcuminoid mixture and individual constituents on spatial learning and memory in an amyloid-beta (Aβ) peptide-infused rat model of AD and on the expression of PSD-95, synaptophysin and camkIV. Curcuminoid mixture showed a memory-enhancing effect in rats displaying AD-like neuronal loss only at 30 mg/kg, whereas individual components were effective at 3–30 mg/kg. A shorter duration treatment with test compounds showed that the curcuminoid mixture and bisdemethoxycurcumin increased PSD-95 expression in the hippocampus at 3–30 mg/kg, with maximum effect at a lower dose (3 mg/kg) with respective values of 470.5 and 587.9%. However, after a longer duration treatment, two other compounds (demethoxycurcumin and curcumin) also increased PSD-95 to 331.7 and 226.2% respectively at 30 mg/kg. When studied for their effect on synaptophysin in the hippocampus after the longer duration treatment, the curcuminoid mixture and all three individual constituents increased synaptophysin expression. Of these, demethoxycurcumin was the most effective showing a 350.1% increase (P<0.01) at 30 mg/kg compared to the neurotoxin group. When studied for their effect on camkIV expression after longer treatment in the hippocampus, only demethoxycurcumin at 30 mg/kg increased levels to 421.2%. These compounds salvaged PSD-95, synaptophysin and camkIV expression levels in the hippocampus in the rat AD model, which suggests multiple target sites with the potential of curcuminoids in spatial memory enhancing and disease modifying in AD.     

Deregulation of hypothalamic-pituitary-adrenal axis functions in an Alzheimer's disease rat model

Elevated cortisol evidence in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD. We investigated the hypothalamic-pituitary-adrenal (HPA) axis activity, functionality, and reactivity for up to 6 weeks after an intracerebroventricular injection of amyloid-β_25–35 peptide (Aβ_25–35) in rat, a validated acute model of AD. Aβ_25–35 induces memory impairment, alteration of anxiety responses, HPA axis hyperactivity, and glucocorticoid (GR) and mineralocorticoid (MR) receptor increases in brain regions related to HPA axis functions. GR are progressively translocated in neurons nucleus, while membrane version of MR is evidenced in all structures considered. The MR/GR ratio was modified in all structures considered. Aβ_25–35 induces a subtle disturbance in the feedback of the HPA axis, without modifying its functionality. The reactivity alteration is long-lasting, suggesting that amyloid toxicity affects the HPA axis adaptive response to stress. These findings are evidence of progressive HPA axis deregulation after Aβ_25–35, which is associated with an imbalance of MR/GR ratio and a disruption of the glucocorticoid receptors nucleocytoplasmic shuttling, and suggest that elevated glucocorticoids observed in AD could be first a consequence of amyloid toxicity.     

An adaptive analogue tracker for automatic measurement of lung parameters

This paper describes the design and results obtained using simple electronic circuits specially designed for implementing a simple lung-parameter tracking algorithm for identification of the mechanical properties of the lung. Unlike the commonly used loop-flattening technique, the adaptive electronic tracker is able to monitor continuously the mechanical properties of the respiratory sysem. It is capable of tracking the rapid changes in lung parameters as the frequency of breathing changes. The design of the adaptive tracker is based on equation-error formulation and the global asymptotic stability of the adaptive tracking equations is guaranteed. The cheapness and simplicity of the tracker makes it suitable for clinical applications.     

帕金森病大鼠模型的建立及MRI分析

目的:从行为学和MRI表现上评价6-OHDA分别毁损大鼠黑质及纹状体制备的偏侧帕金森病模型。方法:40只Wistar雄性大鼠随机分为3组:黑质毁损组20只,纹状体毁损组18只,假手术组2只。应用立体定向仪,分别作单点黑质毁损与两点纹状体毁损术。观察术后不同时期阿朴吗啡诱导的大鼠旋转行为,并进一步用高场强MRI活体检测帕金森病大鼠黑质、纹状体的毁损情况。结果:黑质毁损后第2周内有7只大鼠诱发出明显的旋转行为,且旋转次数>7转/min,模型成功率为35％。纹状体毁损后第2周有11只大鼠诱发出旋转行为,旋转次数<4转/min,第3周内旋转次数<5转/min,至术后第5周达到7转/min以上并保持稳定,模型成功率为61.1％。MRI显示:模型大鼠第3周内毁损侧黑质和纹状体较对侧出现了明显的MRI低信号区,且随着时间的延长低信号区逐渐减小,至第5周已基本消失。结论:应用6-OHDA小剂量两点毁损纹状体制备的偏侧帕金森病大鼠模型更加符合临床帕金森病病人的病程进展并具有较高的成功率,是帕金森病研究较为理想的模型。MRI扫描可以活体连续观察帕金森病大鼠模型的毁损情况,是客观评价和检测帕金森病大鼠模型的一种有效工具。