Presentation outside office hours does not negatively influence treatment times for reperfusion therapy for acute ischemic stroke.

BACKGROUND: Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this "off-hours effect" also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands. METHODS: Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009-2015, EVT: 2014-2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values. RESULTS: In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7-4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI - 4.2 to 18.1). Clinical outcome and sICH rate also did not differ. CONCLUSION: Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

Intra-nodal nevi in sentinel node-negative patients with cutaneous melanoma does not influence survival.

BACKGROUND: Melanoma patients with intra-nodal nevi (INN) and without melanoma metastasis in the sentinel lymph node biopsy (SLNB) are generally treated as patients with negative SLNB. However, diagnosis of INN may be difficult and nodal melanoma metastases may falsely be regarded as INN. OBJECTIVES: Our aim was to evaluate the clinical significance of INN in the SLNB in patients with primary cutaneous melanoma on a nationwide level in The Netherlands by comparing survival between three groups: patients with INN and without nodal melanoma metastasis (INN group), patients without INN and without nodal melanoma metastasis (negative SLNB group) and patients with nodal melanoma metastasis irrespective of INN (positive SLNB group). METHODS: Data were obtained from 'PALGA', the Dutch Nationwide Network and Registry of Histopathology and Cytopathology, yielding a cohort of adults with histologically proven, primary, invasive cutaneous melanoma patients in The Netherlands diagnosed between 2000 and 2014 who underwent SLNB. Clinical and pathological variables were extracted from the pathology text files. Differences between patients with INN, negative SLNB and positive SLNB were analysed using Kaplan-Meier analysis. RESULTS: A total of 11 274 patients were eligible for inclusion. The prevalence of INN in the SLNB was 5.0%. Melanomas with INN had similar median Breslow thickness compared to melanomas with negative SLNB and were more frequently located on trunk and upper limbs and observed in younger patients compared to melanomas with negative and positive SLNB. Overall survival of patients with INN showed no significant difference compared with negative SLNB (median follow-up of 5.7 years of all patients). CONCLUSIONS: As there seems to be no difference in overall survival between patients with INN and negative SLNB, the diagnosis of INN seems to be reliable. Current practice to treat patients with INN as patients with negative SLNB appears to be appropriate.

The treatment of ocular hypotony after trabeculectomy with a scleral lens: A case series.

PURPOSE: Ocular hypotony after trabeculectomy may be treated medically, surgically and with a tamponade. Three cases are reported in which a scleral lens was applied to treat ocular hypotony after mitomycin C (MMC) augmented trabeculectomy. METHODS: In this retrospective case series the records of three eyes of three patients who developed ocular hypotony after they had undergone trabeculectomy augmented with MMC were evaluated. The patients were between 11 and 69 years of age and the intraocular pressure (IOP) after surgery ranged between 3 and 6 mmHg. All three patients showed a negative Seidel test; one had suspected hypotonic maculopathy and one had a collapsed anterior chamber. After unsuccessful treatment with large bandage lenses all three patients were subsequently fitted with a scleral lens. The scleral lens was fitted to fully cover and compress the bleb. Scleral lenses were worn continuously with a check-up after one night of wear and subsequent check-ups when needed. One patient continued to wear the scleral lens for a further 6.5 months on a daily wear basis. RESULTS: In all three eyes the IOP was higher after wearing the scleral lens. Two patients stopped wearing the scleral lens after the IOP was stable. One patient developed a cataract; the cataract surgery was combined with a bleb revision and scleral lens wear was therefore discontinued. DISCUSSION: The scleral lens might be a useful tool in the treatment of ocular hypotony after trabeculectomy augmented MMC surgery. The effect of the scleral lens on the ocular pressure is unpredictable. Caution is advised in vulnerable corneas due to risk factors such as hypoxia and infection. Further research is warranted to establish the safety of the procedure, the patient selection and the overall success in a larger patient group.

Disproportionate Cochlear Length in Genus Homo Shows a High Phylogenetic Signal during Apes' Hearing Evolution.

Changes in lifestyles and body weight affected mammal life-history evolution but little is known about how they shaped species' sensory systems. Since auditory sensitivity impacts communication tasks and environmental acoustic awareness, it may have represented a deciding factor during mammal evolution, including apes. Here, we statistically measure the influence of phylogeny and allometry on the variation of five cochlear morphological features associated with hearing capacities across 22 living and 5 fossil catarrhine species. We find high phylogenetic signals for absolute and relative cochlear length only. Comparisons between fossil cochleae and reconstructed ape ancestral morphotypes show that Australopithecus absolute and relative cochlear lengths are explicable by phylogeny and concordant with the hypothetized ((Pan,Homo),Gorilla) and (Pan,Homo) most recent common ancestors. Conversely, deviations of the Paranthropus oval window area from these most recent common ancestors are not explicable by phylogeny and body weight alone, but suggest instead rapid evolutionary changes (directional selection) of its hearing organ. Premodern (Homo erectus) and modern human cochleae set apart from living non-human catarrhines and australopiths. They show cochlear relative lengths and oval window areas larger than expected for their body mass, two features corresponding to increased low-frequency sensitivity more recent than 2 million years ago. The uniqueness of the "hypertrophied" cochlea in the genus Homo (as opposed to the australopiths) and the significantly high phylogenetic signal of this organ among apes indicate its usefulness to identify homologies and monophyletic groups in the hominid fossil record.

Plasma-derived human C1-esterase inhibitor does not prevent mechanical ventilation-induced pulmonary complement activation in a rat model of Streptococcus pneumoniae pneumonia.

Mechanical ventilation has the potential to cause lung injury, and the role of complement activation herein is uncertain. We hypothesized that inhibition of the complement cascade by administration of plasma-derived human C1-esterase inhibitor (C1-INH) prevents ventilation-induced pulmonary complement activation, and as such attenuates lung inflammation and lung injury in a rat model of Streptococcus pneumoniae pneumonia. Forty hours after intratracheal challenge with S. pneumoniae causing pneumonia rats were subjected to ventilation with lower tidal volumes and positive end-expiratory pressure (PEEP) or high tidal volumes without PEEP, after an intravenous bolus of C1-INH (200 U/kg) or placebo (saline). After 4 h of ventilation blood, broncho-alveolar lavage fluid and lung tissue were collected. Non-ventilated rats with S. pneumoniae pneumonia served as controls. While ventilation with lower tidal volumes and PEEP slightly amplified pneumonia-induced complement activation in the lungs, ventilation with higher tidal volumes without PEEP augmented local complement activation more strongly. Systemic pre-treatment with C1-INH, however, failed to alter ventilation-induced complement activation with both ventilation strategies. In accordance, lung inflammation and lung injury were not affected by pre-treatment with C1-INH, neither in rats ventilated with lower tidal volumes and PEEP, nor rats ventilated with high tidal volumes without PEEP. Ventilation augments pulmonary complement activation in a rat model of S. pneumoniae pneumonia. Systemic administration of C1-INH, however, does not attenuate ventilation-induced complement activation, lung inflammation, and lung injury.

Surgical and prosthetic reconsiderations in patients with maxillectomy.

The purpose of this study was to establish and evaluate new possibilities for rehabilitation of patients with obturator prosthesis who had undergone partial or total maxillectomy because of tumour ablation surgery. Eleven patients with maxillary defects were reconstructed with a computer-aided design/computer-aided manufacturing designed prosthesis. Missing retention was gained by inserting implants in the remaining bone, so that an expansion of the surgical defect to gain further retention could be avoided. All patients were treated successfully according to the previously described treatment plan. The Obturator Functioning Scale (OFS) of the Memorial Sloan-Kettering Cancer Centre was applied to evaluate the functional quality of the obturator prosthesis and patient's satisfaction. It showed good results in all fields of functional outcome and social acceptance.

CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine.

The CYP3A5*1 allele has been linked to high expression of CYP3A5 and metabolism of cyclosporine. We evaluated the role of CYP3A5*1 for long-term survival in renal transplant patients in a cohort of 399 patients who underwent cadaveric or living donor kidney allograft transplantation. All patients were treated with a similar cyclosporine-based immunosuppressive maintenance therapy protocol. The mean duration of follow-up was 8.6+/-3.7 years. In univariate survival analysis, the presence of the CYP3A5*1 allele in recipients significantly increased patient survival P=0.028 (log-rank), resulting in a hazard ratio (HR) of 0.52 (95% CI=0.29-0.94). When the presence of the CYP3A5*1 allele was included in multivariate Cox regression analyses accounting for major risk factors for patient death, CYP3A5*1 still conferred a protective effect. Further, haplotype analysis at the CYP3A5 locus confirmed that CYP3A5*1 might indeed be responsible for this survival benefit.

Neutron radiography and other NDE tests of main rotor helicopter blades.

A few nondestructive examination (NDE) techniques are extensively being used worldwide to investigate aircraft structures for all types of defects. The detection of corrosion and delaminations, which are believed to be the major initiators of defects leading to aircraft structural failures, are addressed by various NDE techniques. In a combined investigation by means of visual inspection, X-ray radiography and shearography on helicopter main rotor blades, neutron radiography (NRad) at SAFARI-1 research reactor operated by Necsa, was performed to introduce this form of NDE testing to the South African aviation industry to be evaluated for applicability. The results of the shearography, visual inspection and NRad techniques are compared in this paper. The main features and advantages of neutron radiography, within the framework of these investigations, will be highlighted.

The drying process of concrete: a neutron radiography study.

The natural drying process of concrete, which has a significant effect on its characteristics, for example durability, was studied at the neutron radiography facility at SAFARI-1 nuclear research reactor, operated by Necsa. Monitoring of the movement of the water in concrete samples, which were wet cured for one day and covered on all the sides but one, was done by means of a CCD camera system. In this paper the methodology in observing the drying process will be described together with results obtained from this investigation. The measured water content and porosity results were quantified and compared reasonably well with conventional gravimetrical measurements.

Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects.

In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is familial dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.

Long term efficacy and safety of atorvastatin in the treatment of severe type III and combined dyslipidaemia.

BACKGROUND: Fibric acid derivatives and HMG-CoA reductase inhibitors are effective in combination for treating patients with familial dysbetalipoproteinaemia and severe combined dyslipidaemia, but combination therapy affects compliance and increases the risk of side effects. AIM: To evaluate the efficacy and safety of monotherapy with atorvastatin, an HMG-CoA reductase inhibitor with superior efficacy in lowering low density lipoprotein cholesterol and triglyceride concentrations, in patients with dysbetalipoproteinaemia and severe combined dyslipidaemia. METHODS: Atorvastatin was tested as single drug treatment in 36 patients with familial dysbetalipoproteinaemia and 23 patients with severe combined dyslipidaemia. RESULTS: After 40 weeks of 40 mg atorvastatin treatment decreases in total cholesterol, triglycerides, and apolipoprotein B of 40%, 43%, and 41%, respectively, were observed in the combined dyslipidaemia group, and of 46%, 40%, and 43% in the dysbetalipoproteinaemic patients. Target concentrations of total cholesterol (< 5 mmol/l) were reached by 63% of the patients, and target concentrations of triglycerides (< 3.0 mmol/l) by 66%. Treatment with atorvastatin was well tolerated and no serious side effects were reported. CONCLUSIONS: Atorvastatin is very effective as monotherapy in the treatment of familial dysbetalipoproteinaemia and severe combined dyslipidaemia.

The effect of tibolone on the lipoprotein profile of postmenopausal women with type III hyperlipoproteinemia.

OBJECTIVE: To investigate the short-term effect of treatment with tibolone on plasma lipid and lipoprotein levels in postmenopausal women with type III hyperlipoproteinemia (HLP). DESIGN AND INTERVENTION: Patients were randomized to receive, in a double-blind cross-over fashion, a fixed dose of tibolone, 2.5 mg once daily or placebo for 8 weeks. The two treatment periods were separated by a wash-out period of 6 weeks. At each visit body weight and blood pressure were determined. Before and after each treatment period, fasting venous blood samples were obtained from the patients for biochemical measurements. SETTING: The Leiden University Medical Center. SUBJECTS: Postmenopausal women with type III HLP (aged < or = 65 years) were recruited from the Lipid Clinics of the Leiden University Medical Center, the Amsterdam Medical Center, the Utrecht Medical Center and the University Hospital Rotterdam. Five out of 25 women with type III HLP were eligible to be included in the study. Four of the five included patients completed the study according to the protocol. One patient was excluded from blinded therapy because total cholesterol levels increased above 20 mmol L(-1). MAIN OUTCOME MEASURES: A significant reduction of plasma triglyceride, total cholesterol, VLDL cholesterol and VLDL triglyceride levels. RESULTS: Plasma triglyceride and total cholesterol levels decreased from 6.82 +/- 3.58 to 2.45 +/- 1.36 mmol L(-1) and from 13.53 +/- 3.64 to 6.61 +/- 2.03 mmol L(-1), respectively (both P < 0.05). The body mass index remained unchanged. The glycated haemoglobin percentage decreased significantly from 5.8 to 5.3%. Treatment with tibolone resulted in a profound reduction in plasma apolipoprotein E, VLDL cholesterol and VLDL triglyceride levels (mean reductions of 66, 77 and 70%, respectively, P < 0.05). CONCLUSIONS: Tibolone is a valuable adjuvant to current therapy in postmenopausal women with type III HLP.

CD36 does not play a direct role in HDL or LDL metabolism.

CD36 and scavenger receptor class B, type I (SR-BI) are both class B scavenger receptors that recognize a broad variety of ligands, including oxidized low density lipoprotein (oxLDL), HDL, anionic phospholipids, and apoptotic cells. In this study we investigated the role of mouse CD36 (mCD36) as a physiological lipoprotein receptor. We compared the association of various lipoprotein particles with mCD36 and mSR-BI expressed in COS cells by adenovirus-mediated gene transfer. mCD36 bound human oxLDL and mouse HDL with high affinity. Human LDL bound poorly to mCD36, indicating that mCD36 is unlikely to play a significant role in LDL metabolism. The ability of mCD36 to mediate the selective uptake of cholesteryl esters (CE) from receptor-bound HDL was assessed. In comparison with mSR-BI, mCD36 inefficiently mediated the selective uptake of CE. Hepatic overexpression of mCD36 in C57BL/6 mice by adenovirus-mediated gene transfer did not result in significant alterations in plasma LDL and HDL levels. We conclude that mCD36, while able to bind HDL with high affinity, does not contribute significantly to HDL or LDL metabolism.

Apolipoprotein A-II modulates the binding and selective lipid uptake of reconstituted high density lipoprotein by scavenger receptor BI.

High density lipoprotein (HDL) represents a mixture of particles containing either apoA-I and apoA-II (LpA-I/A-II) or apoA-I without apoA-II (LpA-I). Differences in the function and metabolism of LpA-I and LpA-I/A-II have been reported, and studies in transgenic mice have suggested that apoA-II is pro-atherogenic in contrast to anti-atherogenic apoA-I. The molecular basis for these observations is unclear. The scavenger receptor BI (SR-BI) is an HDL receptor that plays a key role in HDL metabolism. In this study we investigated the abilities of apoA-I and apoA-II to mediate SR-BI-specific binding and selective uptake of cholesterol ester using reconstituted HDLs (rHDLs) that were homogeneous in size and apolipoprotein content. Particles were labeled in the protein (with (125)I) and in the lipid (with [(3)H]cholesterol ether) components and SR-BI-specific events were analyzed in SR-BI-transfected Chinese hamster ovary cells. At 1 microg/ml apolipoprotein, SR-BI-mediated cell association of palmitoyloleoylphosphatidylcholine-containing AI-rHDL was significantly greater (3-fold) than that of AI/AII-rHDL, with a lower K(d) and a higher B(max) for AI-rHDL as compared with AI/AII-rHDL. Unexpectedly, selective cholesterol ester uptake from AI/AII-rHDL was not compromised compared with AI-rHDL, despite decreased binding. The efficiency of selective cholesterol ester uptake in terms of SR-BI-associated rHDL was 4-5-fold greater for AI/AII-rHDL than AI-rHDL. These results are consistent with a two-step mechanism in which SR-BI binds ligand and then mediates selective cholesterol ester uptake with an efficiency dependent on the composition of the ligand. ApoA-II decreases binding but increases selective uptake. These findings show that apoA-II can exert a significant influence on selective cholesterol ester uptake by SR-BI and may consequently influence the metabolism and function of HDL, as well as the pathway of reverse cholesterol transport.

Apolipoprotein A-I conformation markedly influences HDL interaction with scavenger receptor BI.

Apolipoprotein A-I (apoA-I) is an important ligand for the high density lipoprotein (HDL) scavenger receptor class B type I (SR-BI). SR-BI binds both free and lipoprotein-associated apoA-I, but the effects of particle size, composition, and apolipoprotein conformation on HDL binding to SR-BI are not understood. We have studied the effect of apoA-I conformation on particle binding using native HDL and reconstituted HDL particles of defined composition and size. SR-BI expressed in transfected Chinese hamster ovary cells was shown to bind human HDL(2) with greater affinity than HDL(3), suggesting that HDL size, composition, and possibly apolipoprotein conformation influence HDL binding to SR-BI. To discriminate between these factors, SR-BI binding was studied further using reconstituted l-alpha-palmitoyloleoyl-phosphatidylcholine-containing HDL particles having identical components and equal amounts of apoA-I, but differing in size (7.8 vs. 9.6 nm in diameter) and apoA-I conformation. The affinity of binding to SR-BI was significantly greater (50-fold) for the larger (9.6-nm) particle than for the 7.8-nm particle. We conclude that differences in apoA-I conformation in different-sized particles markedly influence apoA-I recognition by SR-BI. Preferential binding of larger HDL particles to SR-BI would promote productive selective cholesteryl ester uptake from larger cholesteryl ester-rich HDL over lipid-poor HDL.

HDL modification by secretory phospholipase A(2) promotes scavenger receptor class B type I interaction and accelerates HDL catabolism.

During inflammatory states plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are reduced. Secretory group IIa phospholipase A(2) (sPLA(2)) is a cytokine-induced acute-phase enzyme associated with HDL. Transgenic mice overexpressing sPLA(2) have reduced HDL levels. Studies were performed to define the mechanism for the HDL reduction in these mice. HDL isolated from sPLA(2) transgenic mice have a significantly lower phospholipid content and greater triglyceride content. In autologous clearance studies, (125)I-labeled HDL from sPLA(2) transgenic mice was catabolized significantly faster than HDL from control mice (4.24 +/- 1.16 vs. 2.84 +/- 0.1 pools per day, P < 0.008). In both sPLA(2) transgenic and control mice, the cholesteryl ester component of HDL was more rapidly catabolized than the protein component, indicating a selective uptake mechanism. In vitro studies using CHO cells transfected with scavenger receptor class B type I (SR-BI) showed that sPLA(2)-modified HDL was nearly twice as efficient as a substrate for cholesteryl ester transfer. These data were confirmed in in vivo selective uptake experiments using adenoviral vector overexpression of SR-BI. In these studies, increased hepatic selective uptake was associated with increased (125)I-labeled apolipoprotein uptake in the kidney. We conclude that during inflammation sPLA(2) hydrolysis of HDL phospholipids alters the lipid composition of the particle, allowing for more efficient SR-BI-mediated selective cholesteryl ester uptake. This enhanced SR-BI activity generates HDL remnants that are preferentially catabolized in the kidney.

Increased serum amyloid a levels reflect colitis severity and precede amyloid formation in IL-2 knockout mice.

The lack of sensitive and relatively non-invasive measures has hampered monitoring the clinical course of spontaneously developing colitis in IL-2-deficient (-/-) mice. We selected (i) to study the correlation of the acute phase plasma proteins serum amyloid A (SAA) and serum amyloid P component (SAP) levels with colonic disease and (ii) to characterize the amyloidosis in the IL-2(-/-)animals. IL-2(-/-)mice exhibited increasing severity of gross intestinal inflammation with age, confined to the distal colon. Histologically, the colonic disease score increased serially in IL-2(-/-)animals. Wild-type mice showed no activity, while 16-week-old IL-2(+/-)animals had minimal colitis with small ulcers and lamina propria inflammatory infiltrate. Periportal hepatitis was present and positive Congo red staining indicated amyloidosis of the liver and spleen in 16 week IL-2(-/-)mice. SAA immunostaining in the liver and spleen was increased in the 8 week and 16 week IL-2(-/-)and 16 week IL-2(+/-)animals indicating AA amyloid deposits. Plasma SAA and SAP levels were markedly elevated, and generally preceded the onset of colitis and reflected its severity. Northern analysis showed markedly increased SAA expression in the liver and intestine of IL-2(-/-)and intestine of IL-2(+/-)16-week-old animals. Increased intestinal expression of SAA3 (lamina propria macrophages) indicates local inflammation in IL-2(+/-)animals at 16 weeks. Treatment of 3-week-old animals with systemic IL-2 or IL-1 receptor antagonist (IL-1ra) delayed inflammation, postponed the increase in SAA levels and minimized disease onset. These results further demonstrate that IL-2 plays a significant role in normal immune responses in the body and that plasma SAA levels both reflect colonic disease severity and may indicate subclinical disease in both IL-2(-/-)and IL-2(+/-)mice. Furthermore. The mechanism of IL-2-deficient induced colitis appears to be mediated in part through the increase in IL-1. In addition, the IL-2(-/-)mouse of spontaneous enterocolitis may provide a unique system for studying spontaneously developing AA amyloidosis.

Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins.

In the acute-phase response and in diseases with prolonged acute phases, normal HDL (NHDL) is converted into acute-phase HDL (APHDL) and becomes proinflammatory and unable to protect LDL against oxidative modification. Earlier work had demonstrated that these changes are associated with alterations in apolipoprotein composition and enzymatic activity of APHDL, but the effect of the acute-phase condition on the lipid composition of APHDL had remained obscure. The present study shows marked quantitative differences in lipid composition between NHDL and APHDL. Specifically, APHDL contained 25% less total lipid per milligram of protein. Up to 50% of cholesteryl ester in the lipid core of APHDL was replaced by triacylglycerol; however, the total phospholipid/total neutral lipid ratios were the same as in NHDL, both lipoproteins giving similar calculated lipid core radii. Furthermore, the phosphatidylcholine/sphingomyelin ratio in APHDL was nearly double that in NHDL, indicating a relative loss of sphingomyelin. A decrease was also seen in diacyl and alkenylacyl glycerophosphatidylethanolamine as well as in phosphatidylinositol of APHDL when compared with NHDL. APHDL contained proportionally more saturated and less polyunsaturated and isoprostane-containing species of phosphatidylcholine, as well as more saturated than unsaturated cholesteryl esters. APHDL also contained significantly more free fatty acids, lysophosphatidylcholine, and free cholesterol. These changes in the lipid composition of HDL are consistent with the alterations in the apoprotein composition and enzymatic activity of APHDL and indicate proinflammatory and proatherogenic roles for APHDL.

Apolipoprotein E2 (Lys146-->Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides.

The apolipoprotein E2 (Lys146-->Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this variant have elevated levels of plasma triglycerides, cholesterol, and apolipoprotein E (apoE). It was hypothesized that the high amounts of triglycerides in the very low density lipoprotein (VLDL) fraction are due to a disturbed lipolysis of VLDL. To test this hypothesis, apoE knockout mice were injected with an adenovirus containing the human APOE*2 (Lys146-->Gln) gene, Ad-E2(146), under the control of the cytomegalovirus promoter. ApoE knockout mice injected with an adenovirus vector encoding human apoE3 (Ad-E3) were used as controls. Five days after adenovirus injection, plasma cholesterol levels of mice injected with a high dose of Ad-E2(146) (2x10(9) plaque-forming units) were not changed compared with preinjection levels, whereas in the group who received a low dose of Ad-E2(146) (5x10(8) plaque-forming units) and in the groups injected with a low or a high dose of Ad-E3, plasma cholesterol levels were decreased 5-, 6-, and 12-fold, respectively. Plasma triglycerides were not affected in mice injected with Ad-E3. In contrast, a 7-fold increase in plasma triglycerides was observed in mice injected with the low dose of Ad-E2(146) compared with mice injected with Ad-E3. Injection with the high dose of Ad-E2(146) resulted in a dramatic increase of plasma triglycerides (50-fold compared with Ad-E3 injection). In vitro lipolysis experiments showed that the lipolysis rate of VLDLs containing normal amounts of apoE2 (Lys146-->Gln) was decreased by 54% compared with that of VLDLs containing comparable amounts of apoE3. The in vivo VLDL-triglyceride production rate of Ad-E2(146)-injected mice was not significantly different from that of Ad-E3-injected mice. These results demonstrate that expression of apoE2 (Lys146-->Gln) causes hypertriglyceridemia due to an apoE variant-specific inhibition of the hydrolysis of VLDL-triglycerides.