Mechanical responses produced by high potassium solution (high-K), norepinephrine (noradrenaline; NA) and phenylephrine (Phe) were examined in the thoracic aorta isolated from control (WKY) and spontaneously hypertensive rats (SHR). In the SHRs the tissues showed increased sensitivity to high potassium compared with those from the control rats. Mechanical removal of endothelium in tissues from the controls did not change the response. The effects produced by NA and Phe were also increased in tissues from SHRs. The amplitudes of contractions were enhanced after removal of the endothelium in tissues from the controls. The relaxation in response to endothelium-dependent vasodilators (acetylcholine and histamine) was significantly depressed in aortic rings from SHRs. Experiments using modified sandwich preparations suggest that the defect in the relaxant ability of vascular smooth muscle is coupled to a reduced functionality of the endothelium.

Acetylcholine↗

PubMedDate not supplied

In human monocytes IL-1 stimulates a phospholipase C active on phosphatidylcholine and inactive on phosphatidylinositol.

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Calcimycin↗

PubMedDate not supplied

Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing.

The de minimis concept acknowledges a human exposure threshold value for chemicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulation on substances used in food-contact articles. Further to this, the principle of Threshold of Toxicological Concern (TTC) has been developed and is now used by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in their evaluations. Establishing an accepted TTC would benefit consumers, industry and regulators, since it would preclude extensive toxicity evaluations when human intakes are below such threshold, and direct considerable time and cost resources towards testing substances with the highest potential risk to human health. It was questioned, however, whether specific endpoints that may potentially give rise to low-dose effects would be covered by such threshold. In this review, the possibility of defining a TTC for chemical substances present in the diet was examined for general toxicity endpoints (including carcinogenicity), as well as for specific endpoints, namely neurotoxicity and developmental neurotoxicity, immunotoxicity and developmental toxicity. For each of these endpoints, a database of specific no-observed-effect levels (NOELs) was compiled by screening oral toxicity studies. The substances recorded in each specific database were selected on the basis of their demonstrated adverse effects. For the neurotoxicity and developmental neurotoxicity databases, it was intended to cover all classes of compounds reported to have either a demonstrated neurotoxic or developmentally neurotoxic effect, or at least, on a biochemical or pharmacological basis were considered to have a potential for displaying such effects. For the immunotoxicity endpoint, it was ensured that only immunotoxicants were included in the database by selecting most of the substances from the Luster et al. database, provided that they satisfied the criteria for immunotoxicity defined by Luster. For the developmental toxicity database, substances were selected from the Munro et al. database that contained the lowest NOELs retrieved from the literature for more than 600 compounds. After screening these, substances showing any effect which could point to developmental toxicity as broadly defined by the US were recorded in the database. Additionally, endocrine toxicity and allergenicity were addressed as two separate cases, using different approaches and methodology. The distributions of NOELs for the neurotoxicity, developmental neurotoxicity and developmental toxicity endpoints were compared with the distribution of NOELs for non-specific carcinogenic endpoints. As the immunotoxicity database was too limited to draw such a distribution of immune NOELs, the immunotoxicity endpoint was evaluated by comparing immune NOELs (or LOELs-lowest-observed-effect levels-when NOELs were not available) with non-immune NOELs (or LOELs), in order to compare the sensitivity of this endpoint with non-specific endpoints. A different methodology was adopted for the evaluation of the endocrine toxicity endpoint since data currently available do not permit the establishment of a clear causal link between endocrine active chemicals and adverse effects in humans. Therefore, this endpoint was analysed by estimating the human exposure to oestrogenic environmental chemicals and evaluating their potential impact on human health, based on their contribution to the overall exposure, and their estrogenic potency relative to endogenous hormones. The allergenicity endpoint was not analysed as such. It was addressed in a separate section because this issue is not relevant to the overall population but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e. labelling) than the Threshold of Toxicological Concern approach. (ABSTRACT TRUNCATED)

Animals↗

PubMedDate not supplied

A new formula for echo-Doppler estimation of right ventricular systolic pressure.

The Doppler formulas currently used for right ventricular systolic pressure (RVSP) evaluation include right ventricular-right atrial (RV-RA) gradient and RA pressure. The former is expressed by the velocity of the trans-tricuspid regurgitant flow; the latter is generally assumed and is different from one formula to another. In 110 patients with cardiac disease with normal or elevated pulmonary pressure, we tested a new echo-Doppler formula for the evaluation of RVSP based on the estimation of RA pressure by means of the inferior vena cava collapsibility index (IVCCI) and compared this method with two traditional formulas (methods A and B) and with cardiac catheterization values. Patients were classified into three groups on the basis of IVCCI (group 1 > 45%, group 2 between 35% and 45%, and group 3 < 35%). RVSP was evaluated by method A (RV-RA gradient + 10), method B (RV-RA gradient x 1.1 + 14), and our new method, method C, which assigns 6, 9, and 16 mmHg to RA pressure in the presence of normal (> 45%), moderately reduced (between 35% and 45%), or markedly reduced (< 35%) IVCCI, respectively. IVCCI correctly identified RA pressure in the three groups (group 1, 6.8 mmHg; group 2, 10.8 mm Hg; and group 3, 13.1 mmHg); a high correlation existed between Doppler-derived and invasively determined RV-RA gradient (r = 0.99). Method C improved noninvasive estimation of RVSP in groups 1 and 3 compared with the other methods; in group 2, Doppler estimation of RVSP by methods A and C were comparable, whereas method B significantly overestimated the actual values.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Function, Right↗

PubMedDate not supplied

Recent advances in the biology of n-6 fatty acids.

The intensive research carried out in the last 10 years on the unique biological functions of n-3 fatty acids (FA), has promoted comparative investigations on various aspects (metabolic, functional) of the biology of n-6 FA. The involvement of peroxisomes in fatty acid metabolism, initially described for the n-3 acids, has now been shown also for the n-6 FA (formation of 22 carbon delta 4 unsaturated FA, formation of newly identified products of beta-oxidation of arachidonic acid, AA). Additional pathways of AA conversion, beyond the classical eicosanoids, give rise to a series of biologically active products, such as the epoxides, involved in the modulation of vascular functions, through the cytochrome p450 system, and to the AA-ethanolamide, anandamide, an endogenous ligand of the cannabinoid receptors, through a phospholipase-mediated process. Finally, nonenzymatic oxidation products of AA, the isoprostanes, isomers of prostaglandins, also endowed of potent biological activities, are generated both in in vitro-induced lipid oxidation and in vivo, being considered as reliable markers of in vivo oxidative stress. As to the nutritional aspects of the n-6 FA, attention is now paid to the intake of preformed long-chain polyunsaturated FA (PUFA) in the n-6 series, mainly AA, through the diet, in analogy with the intake of the long-chain n-3 FA, in fish-eating populations. The importance of the dietary intake of preformed AA is now recognized in newborns, through maternal milk. The ranges of the intakes of AA in population groups, not currently adequately estimated, appear to be wider than generally assumed, and the elevated intakes in some population groups, in the order of several hundred milligrams per day, may be partly responsible of yet unexplored population-based differences in physiologic variables. Recent research on the functional effects of n-6 FA has confirmed their lipid-lowering effects, which can be observed also in neonates, and has shown that, in cooperation with the n-3, they directly and indirectly contribute to modulate functional parameters at the cellular level, such as receptor function, ion channels, and gene expression. From a nutritional point of view, it is clear that PUFA represent the biologically most active component of dietary fat, and the n-6 are quantitatively the most relevant fraction in our diet. In the light of the diversified activities of n-6 and n-3 PUFA, a correct balance between the various fatty acids is recommended.

Adult↗

PubMedDate not supplied

GBV-C/HGV: a new human hepatitis-related virus.

Two novel potentially hepatotropic flavi-like viruses were recently identified in patients with acute or chronic hepatitis and were provisionally called GBV-C and hepatitis G virus (HGV). The sequence identity analysis of these two viruses clearly indicated that GBV-C and HGV are two isolates of the same virus. In addition, the phylogenic analysis of the aligned viral polyprotein sequences showed that the GBV-C and HGV isolates are closely related to two Flaviviruses (GBV-A and GBV-B) that cause hepatitis in tamarins, and are distantly related to hepatitis C virus (HCV). Taken together, these results demonstrate that GBV-C/HGV belongs to the Flaviviridae family. GBV-C/HGV genomic RNA is detectable in both acute and chronic non-A, nonE hepatitis as well as in a minor proportion of patients with fulminant hepatic failure, hepatocellular carcinoma and in blood donors with or without abnormal alanine aminotransferase. However, the majority of patients with prospectively followed HGV infections have no evidence of liver damage. The high frequency of GBV-C/HGV infections in patients who are coinfected with HBV and/or HCV suggests that these viruses can share a common mode of transmission.

Flaviviridae↗