Autonomic cardiac control in animal models of cardiovascular diseases II. Variability analysis in transgenic rats with alpha-tropomyosin mutations Asp175Asn and Glu180Gly

Animal models of cardiovascular diseases allow to investigate relevant pathogenetic mechanisms in detail. In the present study, the mutations Asp175Asn and Glu180Gly in alpha-tropomyosin (TPM1), known cause familiar hypertrophic cardiomyopathy (FHC) were studied for changes in hemodynamic parameters and spontaneous baroreflex regulation in transgenic rats in comparison to transgenic and non-transgenic controls by telemetry. Heart rate variability (HRV) and blood pressure variability (BPV) were analyzed using time- and frequency domain, as well as non-linear measures. The dual sequence method was used for the estimation of the baroreflex regulation. In transgenic rats harboring mutated TPM1, changes in HRV were detected during exercise, but not at rest. Both mutations, Asp175Asn and Glu180Gly, caused increased low frequency power. In addition, in animals with mutation Asp175Asn a reduced total HRV was observed. BPV did not show any differences between all transgenic animal lines. During exercise, a strong increase in the number of bradycardic and tachycardic fluctuations accompanied with decreased baroreflex sensitivity (BRS) was detected in animals with either TPM1 mutation, Asp175Asn or Glu180Gly. These data suggest, that the analysis of cardiac autonomic control, particularly of baroreflex regulation, represents a powerful non-invasive approach to investigate the effects of subtle changes in sarcomeric architecture on cardiac physiology in vivo. In case of mutations Asp175Asn or Glu180Gly in TPM1, early detection of alterations in autonomic cardiac control could help to prevent sudden cardiac death in affected persons

Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection (authors reply inN Engl J Med. 2005 May 12;352(19):2027-8)

BACKGROUND: Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients. METHODS: We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT1) receptor might be involved. RESULTS: Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor-activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-κB. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody-mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model. CONCLUSIONS: A non-HLA, AT1-receptor-mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT 1-receptor antibodies or from pharmacologic blockade of AT 1 receptors

Закономерности изменения физико-механических свойств сплава Zr-1%Nb при комплексном ионно-плазменном модифицировании поверхности и наводороживании

В работе были изучены особенности изменения морфологии, структуры и физико-механических свойств циркониевого сплава Zr-1%Nb, подвергнутого комплексному ионно-плазменному модифицированию поверхности методами плазменно-иммерсионной ионной имплантации титана и осаждения покрытий нитрида титана. Показана высокая эффективность защиты сформированных структур от проникновения водорода в циркониевый сплав. Изучены механизмы сорбции и захвата водорода в титансодержащем модифицированном слое.In the present work, the features of the change in the morphology, structure, and physico-mechanical properties of zirconium alloy Zr-1%Nb subjected to complex ion-plasma surface modification by the methods of plasma-immersion titanium ion implantation and deposition of titanium nitride coatings were studied. The high protective properties of the formed structures against hydrogen permeation into the zirconium alloy is shown. Mechanisms of sorption and capture of hydrogen in a titanium-doped modified layer are studied

Технологические решения для строительства разведочной вертикальной скважины глубиной 2650 метров на нефтяном месторождении (Тюменская область)

Объектом исследования является разведочная вертикальная скважина глубиной 2650 метров на нефтяном месторождении (Тюменская область). Целью работы является – спроектировать технологическое решения для бурения вертикальной разведочной скважины, геолого-технический наряд, компоновки низа бурильной колонны, интервалы бурении и спуск обсадных колонн, интервалы цементирования.The object of the study is a vertical exploratory well with a depth of 2,650 meters in an oil field (Tyumen Oblast). The aim of the work is to design technological solutions for drilling a vertical exploration well, geological and technical outfit, layouts of the bottom of the drill string, drilling intervals and running of the casing strings, cementing intervals

Anthrax Toxins Induce Shock in Rats by Depressed Cardiac Ventricular Function

Anthrax infections are frequently associated with severe and often irreversible hypotensive shock. The isolated toxic proteins of Bacillus anthracis produce a non-cytokine-mediated hypotension in rats by unknown mechanisms. These observations suggest the anthrax toxins have direct cardiovascular effects. Here, we characterize these effects. As a first step, we administered systemically anthrax lethal toxin (LeTx) and edema toxin (EdTx) to cohorts of three to twelve rats at different doses and determined the time of onset, degree of hypotension and mortality. We measured serum concentrations of the protective antigen (PA) toxin component at various time points after infusion. Peak serum levels of PA were in the µg/mL range with half-lives of 10–20 minutes. With doses that produced hypotension with delayed lethality, we then gave bolus intravenous infusions of toxins to groups of four to six instrumented rats and continuously monitored blood pressure by telemetry. Finally, the same doses used in the telemetry experiments were given to additional groups of four rats, and echocardiography was performed pretreatment and one, two, three and twenty-four hours post-treatment. LeTx and EdTx each produced hypotension. We observed a doubling of the velocity of propagation and 20% increases in left ventricular diastolic and systolic areas in LeTx-treated rats, but not in EdTx-treated rats. EdTx-but not LeTx-treated rats showed a significant increase in heart rate. These results indicate that LeTx reduced left ventricular systolic function and EdTx reduced preload. Uptake of toxins occurs readily into tissues with biological effects occurring within minutes to hours of serum toxin concentrations in the µg/mL range. LeTx and EdTx yield an irreversible shock with subsequent death. These findings should provide a basis for the rational design of drug interventions to reduce the dismal prognosis of systemic anthrax infections

Animal models for hypertension/blood pressure recording

Hypertension is an important disease with polygenic inheritance. In order to identify the genes involved in blood pressure regulation, hypertensive rat and mouse models have been developed either by selective breeding or by transgenic technology. The most essential technological prerequisite in these studies is a reliable assessment of the blood pressure in rodents. Three methods are used most frequently for this purpose: tail cuff plethysmography, intra-arterial catheters, and radiotelemetry. Plethysmography is noninvasive, relatively simple, and suitable for a large number of animals, but also imprecise. Intra-arterial catheters are more precise, but require surgery. And both methods restrain and thereby stress the animals, which leads to alterations in blood pressure. Therefore, the telemetric blood pressure measurement, which allows the study of conscious, freely moving animals, has become the gold standard for measuring blood pressure in rodents. However, this method is extremely expensive. Thus, for each experiment the costs have to be put in relation to the quality of data required. This chapter will describe blood pressure measurement methods in technical detail

Interaction between blood pressure quantitative trait loci in rats in which trait variation at chromosome 1 is conditional upon a specific allele at chromosome 10

We have used inbred and congenic rat strains in F2 segregation studies to discover epistasis in a polygenic model of hypertension. Previously, we have found evidence that the presence of a blood pressure quantitative trait locus (QTL) on chromosome 1 is conditional upon the allele status of chromosome 10. To prove the existence of an epistatic interaction we have analyzed congenic strains for chromosome 1 and 10 carrying high blood pressure QTL alleles from the spontaneously hypertensive rat on a normotensive background of the Wistar–Kyoto (WKY) rat. Additionally, a double congenic strain was developed with both chromosome 1 and 10 high blood pressure QTL alleles on the WKY background. Analysis of variance for blood pressure phenotypes as determined by radiotelemetry showed a significant effect for chromosome 10 but not chromosome 1 QTL alleles and demonstrated a significant interaction between the two loci (P<0.05). The interaction accounted for 5 mmHg of blood pressure. Thus, the identification of epistasis is critical to the understanding of the quantitative nature of blood pressure genetics