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To examine the sequence of environmental and entomological events prior to a substantial increase in Ross River virus (RRV) and Barmah Forest virus (BFV) notifications with a view to informing future public health response.Rainfall, tidal, mosquito and human arboviral notification data were analysed to determine the temporality of events.Following two extremely dry years, there was a substantial increase in the abundance of mosquitoes along coastal New South Wales (NSW) two weeks after a significant rainfall event and high tides in February 2020. Subsequently, RRV and BFV notifications in north east NSW began to increase eight and nine weeks respectively after the high rainfall, with RRV notifications peaking 12 weeks after the high rainfall.Mosquito bite avoidance messaging should be instigated within two weeks of high summer rainfall, especially after an extended dry period.Intense summertime rain events, which are expected to increase in frequency in south-east Australia with climate change, can lead to significant increases in arboviral disease. These events need to be recognised by public health practitioners to facilitate timely public health response. This has taken on added importance since the emergence of Japanese encephalitis virus in southeastern Australia in 2022.

Background Childhood interstitial lung disease (chILD) represents a rare heterogeneous group of respiratory disorders. In the absence of randomized controlled clinical trials, global collaborations have utilized case series with an aim to standardising approaches to diagnosis and management. Australasian data are lacking. The aim of this study was to calculate prevalence and report the experience of chILD in Australasia over a decade. Methods Paediatric pulmonologists in Australia and New Zealand involved in the care of patients aged 0–18 years with chILD completed a questionnaire on demographics, clinical features and outcomes, over a 10 year period. These data, together with data from the 2 reference genetics laboratories, were used to calculate prevalence. Results One hundred fifteen cases were identified equating to a period prevalence (range) of 1.5 (0.8–2.1) cases/million for children aged 0–18years. Clinical data were provided on 106 patients: the

The NSW (New South Wales) Climate Change Policy Framework, launched by the NSW Government in 2016, recognises that climate change presents risks to health and wellbeing. Risks to health and wellbeing come from direct impacts of extreme weather events, and from indirect impacts through effects on air, water, food and ecosystems. Responding to these challenges offers an opportunity to protect and promote health by enhancing environmental amenities, and building adaptive capacity and resilience in populations and systems. To develop policy that effectively protects and promotes health in the face of climate change in NSW it is necessary to define the expected impacts of climate change on health and wellbeing in NSW.

This article briefly reviews evidence of health effects associated with exposure to particulate matter (PM) air pollution from five common outdoor emission sources: traffic, coal-fired power stations, diesel exhaust, domestic wood combustion heaters, and crustal dust. The principal purpose of this review is to compare the evidence of health effects associated with these different sources with a view to answering the question: Is exposure to PM from some emission sources associated with worse health outcomes than exposure to PM from other sources? Answering this question will help inform development of air pollution regulations and environmental policy that maximises health benefits. Understanding the health effects of exposure to components of PM and source-specific PM are active fields of investigation. However, the different methods that have been used in epidemiological studies, along with the differences in populations, emission sources, and ambient air pollution mixtures between studies, make the comparison of results between studies problematic. While there is some evidence that PM from traffic and coal-fired power station emissions may elicit greater health effects compared to PM from other sources, overall the evidence to date does not indicate a clear ‘hierarchy’ of harmfulness for PM from different emission sources. Further investigations of the health effects of source-specific PM with more advanced approaches to exposure modeling, measurement, and statistics, are required before changing the current public health protection approach of minimising exposure to total PM mass.

SummaryObjectives Childhood interstitial lung disease (chILD) is a group of rare chronic and complex disorders of variable pathology. There has been no systematic review of published chILD research. This study aimed to describe chILD classification systems, epidemiology, morbidity, treatments, outcomes, and the impact of chILD on families and the burden on health services. Methods A systematic literature search for original studies on chILD was undertaken in the major biomedical databases to the end of December 2013. Epidemiological studies, case series and studies describing classification systems were included. Single case studies were excluded. Results The search yielded 37 publications that met study criteria. Four different chILD classification systems have been proposed in the past decade. The incidence of chILD has been estimated at 0.13–16.2 cases/100,000 children/year. One to five new cases presented to individual hospitals each year. In developed countries, the median mortality was 13% (6–19%). Morbidity and outcomes were highly variable and not systematically reported. Corticosteroids and hydroxychloroquine were the most common treatments. The impact of chILD on families and the burden on health services has not been studied. Conclusions The heterogeneity of the chILD group of disorders, different determinations of what constitutes a chILD disorder and, a paucity of large epidemiological studies precludes consolidation of results across studies. Consensus on chILD classification is needed to support diagnosis and allow direct comparisons of research evidence. Active disease surveillance and international patient registries are required to advance understanding and management of chILD. Pediatr Pulmonol. 2015; 50:1383–1392. © 2015 Wiley Periodicals, Inc.

Changes in natural hazards related to climate change are evident in New South Wales (NSW), Australia, and are projected to become more frequent and intense. The impacts of climate change may adversely affect health and wellbeing, directly via extreme weather events such as heatwaves, storms and floods, and indirectly via impacts on food security, air and water quality, and other environmental amenities. The NSW Government's Climate Change Policy Framework recognises the need to reduce the effects of climate change on health and wellbeing. A conceptual framework can support the aims and objectives of the policy framework by depicting the effects of climate change on health, and individual and social wellbeing, and areas for policy actions and responses. A proposed conceptual framework has been developed, modelled on the Driving force, Pressure, State, Exposure, Effect and Action (DPSEEA) framework of the World Health Organization - a framework which shows the link between exposures and health effects as well as entry points for interventions. The proposed framework presented in this paper was developed in consultation with researchers and policy makers. The framework is guiding current research examining vulnerabilities to climate change and the effects of a range of exposures on health and wellbeing.

Objective— Animal and clinical studies have suggested that polyphenols in fruits, red wine, and tea may delay the development of atherosclerosis through their antioxidant and anti-inflammatory properties. We investigated whether individual dietary polyphenols representing different polyphenolic classes, namely quercetin (flavonol), (−)-epicatechin (flavan-3-ol), theaflavin (dimeric catechin), sesamin (lignan), or chlorogenic acid (phenolic acid), reduce atherosclerotic lesion formation in the apolipoprotein E (ApoE) −/− gene–knockout mouse. Methods and Results— Quercetin and theaflavin (64-mg/kg body mass daily) significantly attenuated atherosclerotic lesion size in the aortic sinus and thoracic aorta ( P −/− control mice). Quercetin significantly reduced aortic F 2 -isoprostane, vascular superoxide, vascular leukotriene B 4 , and plasma-sP-selectin concentrations; and augmented vascular endothelial NO synthase activity, heme oxygenase-1 protein, and urinary nitrate excretion ( P −/− mice). Theaflavin showed similar, although less extensive, significant effects. Although (−)-epicatechin significantly reduced F 2 -isoprostane, superoxide, and endothelin-1 production ( P −/− mice), it had no significant effect on lesion size. Sesamin and chlorogenic acid treatments exerted no significant effects. Quercetin, but not (−)-epicatechin, significantly increased the expression of heme oxygenase-1 protein in lesions versus ApoE −/− controls. Conclusion— Specific dietary polyphenols, in particular quercetin and theaflavin, may attenuate atherosclerosis in ApoE −/− gene–knockout mice by alleviating inflammation, improving NO bioavailability, and inducing heme oxygenase-1. These data suggest that the cardiovascular protection associated with diets rich in fruits, vegetables, and some beverages may in part be the result of flavonoids, such as quercetin.

An initial step in reverse cholesterol transport is the movement of unesterified cholesterol from peripheral cells to high-density lipoproteins (HDLs). This transfer usually occurs in extracellular spaces, such as the subendothelial space of a vessel wall, and is promoted by the interaction of lipid-free or lipid-poor apolipoprotein (apo)AI with ATP binding cassette A1 cellular transporters on macrophages (MΦ). Because HDL does not interact with MΦ ATP binding cassette A1 and apoAI is not synthesized by macrophages, this apoAI must be generated from spherical HDL. In this brief review, we propose that spherical apoAI is derived from HDL by remodeling events that are accomplished by proteins secreted by cholesteryl ester–loaded foam cells, including the lipid transfer proteins, phospholipid transfer protein, and cholesteryl ester transfer protein, and the triglyceride hydrolases hepatic lipase and lipoprotein lipase.

Human plasma HDLs are classified on the basis of apolipoprotein composition into those that contain apolipoprotein A-I (apoA-I) without apoA-II [(A-I)HDL] and those containing apoA-I and apoA-II [(A-I/A-II)HDL]. ApoA-I enters the plasma as a component of discoidal particles, which are remodeled into spherical (A-I)HDL by LCAT. ApoA-II is secreted into the plasma either in the lipid-free form or as a component of discoidal high density lipoproteins containing apoA-II without apoA-I [(A-II)HDL]. As discoidal (A-II)HDL are poor substrates for LCAT, they are not converted into spherical (A-II)HDL. This study investigates the fate of apoA-II when it enters the plasma. Lipid-free apoA-II and apoA-II-containing discoidal reconstituted HDL [(A-II)rHDL] were injected intravenously into New Zealand White rabbits, a species that is deficient in apoA-II. In both cases, the apoA-II was rapidly and quantitatively incorporated into spherical (A-I)HDL to form spherical (A-I/A-II)HDL. These particles were comparable in size and composition to the (A-I/A-II)HDL in human plasma. Injection of lipid-free apoA-II and discoidal (A-II)rHDL was also accompanied by triglyceride enrichment of the endogenous (A-I)HDL and VLDL as well as the newly formed (A-I/A-II)HDL. We conclude that, irrespective of the form in which apoA-II enters the plasma, it is rapidly incorporated into spherical HDLs that also contain apoA-I to form (A-I/A-II)HDL.

This study compares the kinetics of hepatic lipase (HL)-mediated phospholipid and triacylglycerol hydrolysis in spherical, reconstituted high-density lipoproteins (rHDL) that contain either apolipoprotein E2 (apoE2), apoE3, apoE4, or apoA-I as the sole apolipoprotein. HL-mediated phospholipid hydrolysis was assessed by incubating various concentrations of rHDL that contained only cholesteryl esters (CE) in their core, (E2/CE)rHDL, (E3/CE)rHDL, (E4/CE)rHDL, and (A-I/CE)rHDL, with a constant amount of HL. The rate of phospholipid hydrolysis was determined as the formation of nonesterified fatty acid mass. HL-mediated triacylglycerol hydrolysis was assessed in rHDL containing CE, unlabeled triacylglycerol, and [(3)H]triacylglycerol in their core, (E2/TG)rHDL, (E3/TG)rHDL, (E4/TG)rHDL, and (A-I/TG)rHDL. Triacylglycerol hydrolysis was determined as the ratio of (3)H-labeled hydrolysis products to (3)H-labeled unhydrolyzed triacylglycerol. The rates of phospholipid hydrolysis in the (E2/CE)rHDL, (E3/CE)rHDL, and (E4/CE)rHDL were significantly greater than that in the (A-I/CE)rHDL. The rates of triacylglycerol hydrolysis were also greater in the (E2/TG)rHDL, (E3/TG)rHDL, and (E4/TG)rHDL compared to the (A-I/TG)rHDL, although to a lesser degree than observed with phospholipid hydrolysis. Furthermore, the rates of both phospholipid and triacylglycerol hydrolyses were greater in the (E2)rHDL than in either the (E3)rHDL or the (E4)rHDL. These results show that apoE increases the rate of HL-mediated phospholipid and triacylglycerol hydrolysis in rHDL and that this influence is isoform dependent.

The objective of this study was to determine the combined effects of HL and cholesteryl ester transfer protein (CETP), derived exclusively from bone marrow (BM), on plasma lipids and atherosclerosis in high-fat-fed, atherosclerosis-prone mice. We transferred BM expressing these proteins into male and female double-knockout HL-deficient, LDL receptor-deficient mice (HL(-/-)LDLr(-/-)). Four BM chimeras were generated, where BM-derived cells expressed 1) HL but not CETP, 2) CETP and HL, 3) CETP but not HL, or 4) neither CETP nor HL. After high-fat feeding, plasma HDL-cholesterol (HDL-C) was decreased in mice with BM expressing CETP but not HL (17 ± 4 and 19 ± 3 mg/dl, female and male mice, respectively) compared with mice with BM expressing neither CETP nor HL (87 ± 3 and 95 ± 4 mg/dl, female and male mice, respectively, P < 0.001 for both sexes). In female mice, the presence of BM-derived HL mitigated this CETP-mediated decrease in HDL-C. BM-derived CETP decreased the cholesterol component of HDL particles and increased plasma cholesterol. BM-derived HL mitigated these effects of CETP. Atherosclerosis was not significantly different between BM chimeras. These results suggest that BM-derived HL mitigates the HDL-lowering, HDL-modulating, and cholesterol-raising effects of BM-derived CETP and warrant further studies to characterize the functional properties of these protein interactions.

Childhood interstitial lung disease (chILD) is a group of rare chronic and complex disorders of variable pathology. There has been no systematic review of published chILD research. This study aimed to describe chILD classification systems, epidemiology, morbidity, treatments, outcomes, and the impact of chILD on families and the burden on health services.A systematic literature search for original studies on chILD was undertaken in the major biomedical databases to the end of December 2013. Epidemiological studies, case series and studies describing classification systems were included. Single case studies were excluded.The search yielded 37 publications that met study criteria. Four different chILD classification systems have been proposed in the past decade. The incidence of chILD has been estimated at 0.13-16.2 cases/100,000 children/year. One to five new cases presented to individual hospitals each year. In developed countries, the median mortality was 13% (6-19%). Morbidity and outcomes were highly variable and not systematically reported. Corticosteroids and hydroxychloroquine were the most common treatments. The impact of chILD on families and the burden on health services has not been studied.The heterogeneity of the chILD group of disorders, different determinations of what constitutes a chILD disorder and, a paucity of large epidemiological studies precludes consolidation of results across studies. Consensus on chILD classification is needed to support diagnosis and allow direct comparisons of research evidence. Active disease surveillance and international patient registries are required to advance understanding and management of chILD.

It is well established that cholesteryl ester transfer protein (CETP) changes the size of high density lipoproteins (HDL) during incubation in vitro. It has been suggested that HDL.CETP.HDL ternary complex formation is involved in these changes. The present results, which are consistent with CETP changing the size of spherical reconstituted HDL (rHDL) by a mechanism involving fusion, support the ternary complex hypothesis. When rHDL containing a core of cholesteryl esters and either three molecules of apolipoprotein (apo) A-I/particle, (A-I)rHDL, or six molecules of apoA-II/particle, (A-II)rHDL, were incubated individually with CETP, their respective diameters decreased from 9.4 to 7.8 nm and from 9.8 to 8.8 nm. The small (A-I)rHDL and (A-II)rHDL contained, respectively, two molecules of apoA-I/particle and four molecules of apoA-II/particle. As all of the rHDL lipids and apolipoproteins were quantitatively recovered at the end of the incubations, it was apparent that there was a 50% increase in the number of particles. This increase in the number of particles can be explained as follows: (i) sequential binding of two rHDL to CETP to generate a ternary complex, (ii) fusion of the rHDL in the ternary complex, and (iii) rearrangement of the fusion product into three small particles. Various spectroscopic techniques were used to show that the small rHDL were structurally distinct from the original rHDL. These results provide the first evidence that CETP mediates the fusion of spherical rHDL.

The effect of sphingomyelin (SPM) on the structure and function of discoidal and spherical reconstituted high density lipoproteins (rHDL) has been studied. Three preparations of discoidal rHDL with 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC)/SPM/unesterified cholesterol (UC)/apolipoprotein (apo)A-I molar ratios of 99.6/0. 0/10.2/1.0, 86.0/13.6/10.8/1.0, and 72.5/26.3/11.4/1.0 were prepared by cholate dialysis. SPM did not affect discoidal rHDL size or surface charge. Esterification of cholesterol by lecithin:cholesterol acyltransferase (LCAT) was inhibited in the SPM-containing discoidal rHDL. When the discoidal rHDL of POPC/SPM/UC/apoA-I molar ratio 99.6/0.0/10.2/1.0 were incubated with low density lipoproteins (LDL) and LCAT, SPM transferred spontaneously from the LDL to the rHDL (t1/2 = 0.8 h) and spherical particles with a POPC/SPM/UC/CE/apoA-I molar ratio of 24.6/4.9/3. 6/24.9/1.0 were formed. Depleting the spherical rHDL of SPM head groups by incubation with sphingomyelinase increased the negative charge on the surface, but did not change their size. Cholesteryl ester transfer protein (CETP)-mediated transfers of cholesteryl esters and triglyceride between spherical rHDL and Intralipid were not affected by SPM head group depletion. The effect of SPM on rHDL structure was assessed spectroscopically. SPM increased POPC acyl chain and head group packing in the discoidal rHDL. When the spherical rHDL were depleted of SPM head groups, POPC acyl chain packing order decreased, but head group packing order was not affected. SPM inhibited the lipid-water interfacial hydration of discoidal rHDL. This parameter was not affected when the spherical rHDL were depleted of SPM head groups. The SPM molecule and the SPM head group, respectively, inhibited the unfolding of apoA-I in discoidal and spherical rHDL. It is concluded that (i) SPM influences the structure of discoidal and spherical rHDL, (ii) SPM inhibits the LCAT reaction in discoidal rHDL, and (iii) the SPM head group does not affect CETP-mediated lipid transfers into or out of spherical rHDL.

Publisher Summary This chapter discusses the role of cholesteryl ester transfer protein (CETP) in high density lipoprotein (HDL) metabolism. CETP exchanges neutral lipids and phospholipids between lipoproteins. CETP-mediated exchange of neutral lipids results in the net mass transfer of triglycerides from triglyceride-rich very low density lipoproteins (VLDL) to HDL and the net transfer of cholesteryl esters from HDL to VLDL. This study reveals that CETP-mediated net mass transfers occur in the lipoprotein milieu in blood. The CETP-mediated exchange of neutral lipids changes the molecular structure of lipoproteins. Because HDL is smallest in size of the various lipoprotein classes, and therefore has fewer neutral lipids per particle, it is the movement of neutral lipids in and out of these particles that has particularly profound effects. These effects change HDL structure and consequently function and metabolism. The study also reveals that a combination of data obtained from transgenic research animals, different animal species, CETP-deficient humans, epidemiology, inhibitors of CETP, and in vitro studies provides ample evidence that CETP activity has fundamental effects on HDL metabolism. The most consistent effect is that CETP activity reduces plasma HDL cholesteryl ester concentration via neutral lipid exchange with other lipoproteins. This is primarily viewed as an atherosclerosis promoting effect due to the independent inverse association between HDL cholesterol and atherosclerosis risk. However, the link between CETP, HDL metabolism, and atherosclerosis is not independent of other modulators of lipid metabolism and atherogenesis.

High-density lipoproteins (HDLs) have been well established to protect against the development of atherosclerotic cardiovascular disease. It has become apparent that in addition to the promotion of reverse cholesterol transport, HDLs possess a number of additional functional properties that may contribute to their beneficial influence on the arterial wall. A number of exciting therapeutic strategies have been developed that target HDL and its ability to protect against the development of atherosclerotic plaque. This paper will review how the promotion of the functional properties of HDL inhibits the formation of atherosclerotic plaque and stabilises lesions in patients with established disease.

This study examines hepatic lipase (HL) mediated phospholipid hydrolysis in mixtures of apolipoprotein-specific, spherical reconstituted high-density lipoproteins (rHDL). We have shown previously that apolipoprotein A-I (apoA-I) and apoA-II have a major influence on the kinetics of HL-mediated phospholipid and triacylglycerol hydrolysis in well-characterized, homogeneous preparations of spherical rHDL [Hime, N. J., Barter, P. J., and Rye, K.-A. (1998) J. Biol. Chem. 273, 27191-27198]. In the present study, phospholipid hydrolysis was assessed in mixtures of rHDL containing either apoA-I only, (A-I)rHDL, apoA-II only, (A-II)rHDL, or both apoA-I and apoA-II, (A-I/A-II)rHDL. The rHDL contained trace amounts of radiolabeled phospholipid, and hydrolysis was measured as the formation of radiolabeled nonesterified fatty acids (NEFA). As predicted from our previous kinetic studies, the (A-II)rHDL acted as competitive inhibitors of HL-mediated phospholipid hydrolysis in (A-I)rHDL. Less expected was the observation that the rate of phospholipid hydrolysis in (A-II)rHDL was enhanced when (A-I)rHDL were also present in the incubation mixture. The rate of phospholipid hydrolysis in (A-I/A-II)rHDL was also greater than in (A-II)rHDL, indicating that apoA-I enhances phospholipid hydrolysis when it is present as a component of (A-I/A-II)rHDL. It is concluded that apoA-I enhances HL-mediated phospholipid hydrolysis in apoA-II containing rHDL, irrespective of whether the apoA-I is present in the same particle as the apoA-II [as in (A-I/A-II)rHDL] or whether it is present as a component of a different particle, such as when (A-I)rHDL are added to incubations of (A-II)rHDL.

This study describes the influence of apolipoproteins on the hepatic lipase (HL)-mediated hydrolysis of phospholipids and triacylglycerol in high density lipoproteins (HDL). HL-mediated hydrolysis was assessed in well characterized, homogeneous preparations of spherical reconstituted high density lipoproteins (rHDL). The rHDL were comparable in size and lipid composition and contained either apoA-I ((A-I)rHDL) or apoA-II ((A-II)rHDL) as their sole apolipoprotein constituent. Preparations of rHDL containing only cholesteryl esters (CE) in their core, (A-I/CE)rHDL and (A-II/CE)rHDL, were used to assess phospholipid hydrolysis. Preparations of rHDL that contained triacylglycerol as their predominant core lipid, (A-I/TG)rHDL and (A-II/TG)rHDL, were used to assess both triacylglycerol and phospholipid hydrolysis. The rHDL contained trace amounts of either radiolabeled phospholipid or radiolabeled triacylglycerol. Hydrolysis was measured as the release of radiolabeled nonesterified fatty acids (NEFA) from the rHDL. Kinetic analysis showed that HL had a greater affinity for the phospholipids in (A-II/CE)rHDL (Km(app) = 0.2 mM) than in (A-I/CE)rHDL (Km(app) = 3.1 mM). This was also evident when hydrolysis was measured directly by quantitating NEFA mass. HL also had a greater affinity for the phospholipids and triacylglycerol in (A-II/TG)rHDL than in (A-I/TG)rHDL. The Vmax for phospholipid hydrolysis was, by contrast, greater for (A-I/CE)rHDL than for (A-II/CE)rHDL: 309.3 versus 49.1 nmol of NEFA formed/ml of HL/h. Comparable Vmax values were obtained for the hydrolysis of the phospholipids in (A-II/TG)rHDL and (A-I/TG)rHDL. In the case of triacylglycerol hydrolysis, the respective Vmax values for (A-I/TG)rHDL and (A-II/TG)rHDL were 1154.8 and 240.2 nmol of NEFA formed/ml of HL/h. These results show that apolipoproteins have a major influence on the kinetics of HL-mediated phospholipid and triacylglycerol hydrolysis in rHDL.

Background Rare chronic diseases of childhood are often complex and associated with multiple health issues. Such conditions present significant demands on health services, but the degree of these demands is seldom reported. This study details the utilisation of hospital services and associated costs in a single case of surfactant protein C deficiency, an example of childhood interstitial lung disease. Methods Hospital records and case notes for a single patient were reviewed. Costs associated with inpatient services were extracted from a paediatric hospital database. Actual costs were compared to cost estimates based on both disease/procedure-related cost averages for inpatient hospital episodes and a recently implemented Australian hospital funding algorithm (activity-based funding). Results To age 8 years and 10 months the child was a hospital inpatient for 443 days over 32 admissions. A total of 298 days were spent in paediatric intensive care. Investigations included 58 chest x-rays, 9 bronchoscopies, 10 lung function tests and 11 sleep studies. Comprehensive disease management failed to prevent respiratory decline and a lung transplant was required. Costs of inpatient care at three tertiary hospitals totalled $966,531 (Australian dollars). Disease- and procedure-related cost averages underestimated costs of paediatric inpatient services for this patient by 68%. An activity-based funding algorithm that is currently being adopted in Australia estimated the cost of hospital health service provision with more accuracy. Conclusions Health service usage and inpatient costs for this case of rare chronic childhood respiratory disease were substantial. This case study demonstrates that disease- and procedure-related cost averages are insufficient to estimate costs associated with rare chronic diseases that require complex management. This indicates that the health service use for similar episodes of hospital care is greater for children with rare diseases than other children. The impacts of rare chronic childhood diseases should be considered when planning resources for paediatric health services.

The effect of cholesteryl ester transfer protein (CETP) on the size, composition, and structure of spherical, reconstituted HDL (rHDL) which contain apolipoprotein (apo) A-I as their sole apolipoprotein has been studied. Spherical rHDL were incubated with CETP and Intralipid for up to 24 h. During this time CETP promoted transfers of cholesteryl esters (CE) and triglyceride (TG) between rHDL and Intralipid. As a result, the rHDL became depleted of CE and enriched in TG. However, as the loss of CE from the rHDL was greater than the gain of TG, the concentration of core lipids in the rHDL decreased. The decrease in the concentration of rHDL core lipids, which was evident throughout the incubation, was accompanied by a reduction in rHDL diameter from 9.2 to 8.0 nm, the dissociation of apoA-I from rHDL and a decrease in the number of apoA-I molecules, from three/particle in the 9.2-nm rHDL, to two/particle in the 8.0-nm rHDL. Spectroscopic studies showed that the lipid-water interface and phospholipid packing of the 8.0-nm rHDL were, respectively, more polar and less ordered than those of the 9.2-nm rHDL. Quenching studies with KI revealed that the number of exposed apoA-I Trp residues in the 9.2- and 8.0-nm rHDL was two and three, respectively. Circular dichroism established that the 9.2- and 8.0-nm rHDL had identical apoA-I alpha-helical contents. The 9.2- and 8.0-nm rHDL also had identical surface charges as determined by agarose gel electrophoresis. Denaturation studies with guanidine hydrochloride demonstrated that apoA-I is more stable in 8.0-nm rHDL than in 9.2-nm rHDL. It is concluded that CETP converts rHDL to small, TG-enriched, apoA-I-depleted particles with increased lipid-water interfacial hydration and less ordered phospholipid packing. These changes are associated with enhanced stability and minor changes to the conformation of the apoA-I which remains associated with the rHDL.

Aortic ring preparations from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated with N omega-nitro-L-arginine (NOLA, 10(-4) M). This produced a sustained contraction in preparations from SHR but not WKY rats. A similar contraction in aortic ring preparations from the SHR was produced with methylene blue (10(-5) M) and NG-monomethyl-L-arginine (10(-5) M). The NOLA-induced contraction was reversed with indomethacin (8 x 10(-6) M), ridogrel (10(-5) M) and SQ 29548 (10(-6) M) thus confirming the involvement of thromboxane A2/prostaglandin H2 processes. Subsequent experiments demonstrated that the thromboxane-like contraction was not dependent upon the presence of endothelial cells and occurred in preparations from young, prehypertensive (5 week) and older (17 week) SHRs. The thromboxane-like contraction was markedly suppressed with chronic captopril treatment and reinstated 4 weeks after withdrawal from captopril. The addition of saralasin (10(-6) M) or captopril (10(-6) M) to aortic ring preparations did not suppress the thromboxane-like contractions. The foregoing findings support the presence of a nonendothelial cell thromboxane-like constrictor agent in the aorta of the SHR that is revealed after impairment of nitric oxide production. The activity of the thromboxane-like constrictor process is not tightly linked to prevailing blood pressure, but is reduced with chronic in vivo inhibition of the angiotensin-converting enzyme.