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Abstract: High plasma levels of lipoprotein(a) [Lp(a)] are considered a risk factor for the development of coronary artery disease. In vitro experiments have shown that oxidized Lp(a) is able to impair the arterial endothelium-dependent dilation, thus suggesting a possible role of Lp(a) in the genesis of essential hypertension. The aim of our work was to investigate the correlation of blood pressure levels with plasma Lp(a) concentration, apo(a) isoform size, and peroxidative stress in patients with essential hypertension. The study was performed in 54 untreated hypertensive patients whose blood pressure was monitored for 24 h by ambulatory blood pressure monitoring. Lp(a) concentration was measured by a double monoclonal antibody-based enzyme immunoassay demonstrated to be insensitive to apo(a) size heterogeneity. Apo(a) isoforms were determined by a high-resolution SDS-agarose gel electrophoresis followed by immunoblotting. A significant correlation was found between Lp(a) levels and the night-time systolic and diastolic pressures (r=0.32, P<0.05, and r=0.30, P<0.05, respectively), as well as with the mean night-time fall in systolic and diastolic blood pressures (r=0.28, P<0.05 and r=0.29, P<0.05, respectively). These relationships were further potentiated when peroxidative stress data were taken into consideration (r=0.37 and r=0.40, P<0.01 for the night-time systolic and diastolic pressures, respectively and r=0.34 and r=0.38, P<0.01 for the night-time fall in systolic and distolic blood pressures, respectively). Apo(a) isoform size did not affect these relationships. Our data suggest that Lp(a) and peroxidative stress may be involved as cofactors in essential hypertension, with a mechanism that remains to be elucidated.

1. INTRODUCTION 68 1.1 Receptor patterns in the plasma membrane 68 1.2 Different types of receptor patterns 71 2. METHODS TO INVESTIGATE NON-RANDOM RECEPTOR CLUSTERING 73 2.1 Fluorescence resonance energy transfer 73 2.2 Flow cytometric energy transfer measurement 78 2.3 Fluorescence anisotropy and energy transfer 79 2.4 Photobleaching energy transfer on single cells 81 2.5 Two-dimensional mapping of receptor superstructures 82 2.6 Detecting single receptor molecules 85 2.7 Chemical identification of receptor clusters 86 2.8 Electron microscopy 87 2.9 Scanning force microscopy 88 3. CONFORMATIONAL STATES OF RECEPTORS 90 3.1 Multi-subunit receptor structures 90 3.2 Physical parameters influencing conformational states 91 3.3 Chemical interactions and receptor conformations 92 4. ON THE ORIGIN OF NATURALLY OCCURRING RECEPTOR CLUSTERS 93 4.1 Synthesis of receptors and their localization in the plasma membrane 93 4.2 Lipid domain structure of the plasma membrane 94 4.3 The validity of the Singer–Nicolson model 94 5. CONCLUSIONS 96 6. ACKNOWLEDGEMENTS 96 7. REFERENCES 97

Food restriction (FR) is a well-recognized method of extending mean and maximum longevity of rodents, but the mode of its action remains to be uncovered. This article reviews the effect of FR on the physical-chemical properties and lipid peroxidizability of cellular membranes. FR prevents the age-dependent increase in microviscosity and peroxidizability of cellular membranes. It has been suggested that a decrease in the body temperature occurring in undernourished animals may play a fundamental role in the process. Indeed, the lowering of average body temperature occurring in FR animals may induce a modification in membrane lipid composition, stimulating the cells to counteract the rigidifying effect of lower temperature. Thus, membranes are maintained in a proper functional state by a mechanism similar to that found in poikilotherm animals.Food restriction (FR) is a well-recognized method of extending mean and maximum longevity of rodents, but the mode of its action remains to be uncovered. This article reviews the effect of FR on the physical-chemical properties and lipid peroxidizability of cellular membranes. FR prevents the age-dependent increase in microviscosity and peroxidizability of cellular membranes. It has been suggested that a decrease in the body temperature occurring in undernourished animals may play a fundamental role in the process. Indeed, the lowering of average body temperature occurring in FR animals may induce a modification in membrane lipid composition, stimulating the cells to counteract the rigidifying effect of lower temperature. Thus, membranes are maintained in a proper functional state by a mechanism similar to that found in poikilotherm animals.

The selection of signal transducing pathways of T cells depends on the type of triggers. Antigens, antibodies or lectins induce the T cell receptor-CD3 operated pathway, and IL-2 transmits its activation signal via the IL-2 receptor. It has been demonstrated that bretylium, a quaternary ammonium ion, can significantly inhibit the first pathway at the same dose range that stimulates cell activation through the IL-2 receptor system. In the light of the different complexity of the two pathways at the plasma membrane level, and the non-toxic and reversible behavior of the drug, it is suggested that the bretylium induced sustained membrane hyperpolarization is responsible for the observation. This finding may open new possibilities in studying the mechanism of different signal transducing pathways.

Using the patch-clamp technique, we determined that bretylium tosylate, a quaternary ammonium compound possessing immunomodulating activity, decreased the whole-cell K+ current in human T lymphocytes, in a dose-dependent manner, in the 0.05-5 mM extracellular concentration range. Bretylium tosylate prolonged the recovery from inactivation and accelerated the inactivation and deactivation of the K+ current but did not influence the kinetics of activation or the voltage dependence of activation and steady state inactivation of the K+ conductance. The percentage of drug-induced block was independent of membrane potential. K+ channel block by bretylium tosylate was partially and slowly removable by washing with drug-free extracellular solution. Bovine serum albumin (10 mg/ml) in the bath lifted the drug-induced block almost instantaneously, although not completely. In control experiments bovine serum albumin increased the inactivation time constant of the K+ channels but left the peak K+ current amplitude unaffected. On the basis of the experimental evidence, a gating-dependent allosteric interaction is suggested for the mechanism of drug action. The effective dose range, time of exposure, and reversibility of bretylium tosylate-induced K+ channel block correlated well with the same parameters of the drug-induced inhibition of T lymphocyte activation. The reported effects of bretylium tosylate on T cell mitogenesis can be regarded partly as a consequence of its blocking effects on voltage-gated K+ channels.

An age-dependent increase of thermal stability of DNA in situ has been demonstrated in rat liver by means of microfluorimetry, which was reversed to a great extent in old regenerated liver.

Backgroundrespiratory morbidity is common in patients with sickle cell anaemia (SCA). The quality of care and environmental factors might have an influence on their respiratory health.Aimsto compare spirometry lung function in children and adolescents attending sickle cell centres in UK and Italy.Methodsanthropometry and spirometry were undertaken in SCA-patients (SS,Sb0) aged 6–17 years. Exclusion criteria: SCArelated morbidity within the last two weeks and inability to perform an adequate spirometry. Portable spirometers (Pony FX, Cosmed-IT, Easy-on PC, NDD-CH) were used. Z-scores of anthropometric and spirometric data were derived, respectively, from CDC2000 and GLI-black equation (Quanjer, ERJ2012). Spirometry patterns were classified as normal, obstructive (zFEV1/FVC < 1.64) or restrictive (zFVC < 1.64 +zFEV1/ FVC 31.64). Differences between groups were assessed by ttests and considered statistically significant for p values<0.05.ResultsEighty-five subjects of African ancestry were included (n.46 UK; n.39 Italy; 42% girls; age-range: 6.2–17.9 years). Prevalence of obstructive pattern was higher in SCA-patients from UK, while a restrictive pattern was more common in subjects living in Italy (table). Mean FEV1/FVC was ~0.6 z-scores lower in SCA patients from UK (p<0.01). Age was negatively correlated (p<0.05) with both zFEV1(R20.19) and zFVC(R20.136).Conclusionobstructive lung disease is more common among paediatric subjects with SCA living in UK than in Italy. Differences in the level of ambient air pollution and prevalence of allergies, could have contributed to these findings. It seems that SCA patients from Italy develop earlier a restrictive picture. These results need further confirmation.Abstract G112(P) Table 1Mean (SD) values, unless otherwise specifiedIndexSickle cell UKSickle cell ITADiff between means (95% CI)n (%male)46 (54%)39 (61%)Age (years)11.8 (2.9)11.3 (3.5)0.5 (-0.9 to 1.9)Height z-score-0.11 (1.23)-0.08 (1.09)-0.03 (-0.53 to 0.47)BMI z-score-0.26 (1.20)-0.55 (1.17)0.29 (-0.24 to 0.82)FEV1 z-score-1.15 (1.09)-0.80 (0.97)-0.35 (-0.81 to 0.08)FVC z-score-0.79 (1.04)-0.71 (0.83)-0.08 (-0.53 to 0.32)FEV1/FVC z-score-0.87 (0.93)-0.27 (0.93)-0.60 (-1.0 to -0.019)Spirometry patternObstructive (% of total)10 (21.7%)3 (7.7%)Restrictive (% of total)5 (10.8%)8 (20.5%)

Relative DNA-contents of hepatocyte nuclei have been determined in young, old, and thymus-grafted old mice. There is an age-dependent increase in the occurrence of tetraploid nuclei, which is in agreement with previous data regarding the nuclear volume of hepatocytes. The neonatal thymus grafted into old recipients decreased the percentage of tetraploid cells to a statistically significant extent.

* This paper was original published in 2002, as a chapter of Managing for healthy ecosystems(William L. Lasley, David J. Rapport, Ardeshir B. Damania, Dennis E. Rolston, N . Ole Nielsen, and Calvin O. Qualset). This paper is reprinted with permission from CRC Press LLC with minor editing privileges.