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Background PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) increases LDL cholesterol (LDL-C) levels by stimulating the degradation of Low Density Lipoprotein receptors (LDL-r). This protein is now of high interest because antibodies which inhibit its effect on LDL-r are being developed. A severe hypercholesterolemia and / or an elevation of lipoprotein(a) can be treated with lipoprotein apheresis (LA) in high-risk patients. Methods We measured serum PCSK9 levels in patients eligible for the extracorporeal treatment: in 40 patients (Cohort I) who were treated with different systems before and after apheresis sessions and in the intervals between sessions. 10 patients (Cohort II) who were eligible but did not start LA yet served as controls. Results Patients' baseline serum PCSK9 levels were elevated relative to healthy volunteers and LA sessions acutely reduced the mean PCSK9 concentrations by 51%. Comparison of the effectiveness of the different LA methods demonstrated the DSA and HELP were more effective than the DALI system. After 24 h PCSK9 levels had returned to baseline compared to 8 days for the LDL-C concentrations to return to its pre-apheresis levels. In Cohort II baseline PCSK9 levels were similar to those in Cohort I. Conclusion The acute reductions of PCSK9 by apheresis may be beneficial with respect to increasing the effectiveness of lipid-lowering drugs and with respect to an anti-atherosclerotic effect. In the future, antagonists to PCSK9 will probably be combined with or possibly replace LA in patients with a very high cardiovascular risk.

Untreated pediatric patients with homozygous familial hypercholesterolemia usually have myocardial infarctions, heart failure, or death by the teenage years. Low-density lipoprotein (LDL) apheresis effectively lowers LDL cholesterol in the short term, but there is little published information on the long-term safety and efficacy of this treatment in children. An analysis was performed of a registry of all 29 patients who began LDL apheresis before 18 years of age at 15 sites during the 11 years since approval by the United States Food and Drug Administration. A chart review of 9 patients treated at The Rogosin Institute was also performed to obtain additional details about lipid lowering, adverse events, and cardiovascular status. Of the 29 patients, 20 are currently treated, with a mean age at the start of treatment of 9 +/- 4 years (range 3 to 15) and a mean treatment duration of 6 +/- 4 years (range 2 to 21). The baseline LDL cholesterol (521 +/- 126 mg/dl) is acutely lowered by 75% and chronically lowered by 48% with biweekly sessions. Systemic adverse events have been uncommon. Atherosclerotic disease of the coronary arteries and/or aorta or aortic valve was evident by angiography and/or echocardiography in 12 patients (60%) at baseline and progressed to more severe, symptomatic disease in 6 (30%). In conclusion, LDL apheresis is well tolerated for decades by even very young pediatric patients with homozygous familial hypercholesterolemia. It effectively lowers LDL cholesterol, but target LDL levels are not achieved, and some patients will show progression of cardiovascular disease.

Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited, life-threatening, metabolic disorder of low-density lipoprotein (LDL) receptor function characterized by elevated serum LDL cholesterol (LDL-C) and rapidly progressive atherosclerotic cardiovascular disease (ACVD). Since LDL receptors are predominantly found on hepatocytes, orthotopic liver transplantation (OLT) has emerged as a viable intervention for HoFH because LDL receptor activity is restored. This study assessed the effects of OLT on ACVD and ACVD risk factors in pediatric patients with HoFH. We analyzed lipids, lipoproteins, body mass index, glucose, blood pressure, and cardiovascular imaging in 8 pediatric patients who underwent OLT for HoFH. Total serum cholesterol, LDL-C, lipoprotein (a), and apolipoprotein B/apolipoprotein A1 ratio decreased to normal values in all subjects (p values0.001) at 1 month after OLT and were maintained for the length of follow-up (2 to 6 years). There were few complications related to surgery or immunosuppressive therapy. Two patients developed mild hypertension. In the first 4 subjects monitored for 4 to 6 years after OLT, coronary artery disease did not develop or progress except in 1 minor artery in 1 subject and actually regressed in 2 subjects with50% stenosis. However, aortic valve stenosis progressed in 2 of 4 subjects. In conclusion, OLT is an effective therapeutic option for patients with HoFH with coronary artery disease and persistently elevated serum LDL-C despite maximum medical therapy. Aortic valvular disease may progress. Long-term data are needed to evaluate the true risk-benefit ratio of this surgical approach.

Monocyte chemoattractant protein-1 (MCP-1) is essential in atherogenesis. Oxidized lipids regulate MCP-1 expression and release from mononuclear cells. In this study we investigated (1) whether statin therapy reduces lipopolysaccharide (LPS)–stimulated MCP-1 production in human whole-blood samples and (2) the relationships between in vitro low-density lipoprotein (LDL) oxidation and MCP-1 production. Fasting blood samples were obtained from 55 healthy nonsmoking adults with moderate hypercholesterolemia who were participating in a randomized double-blind 8-week trial comparing the effects of statin therapy with those of placebo on cytokine production. Samples were analyzed for resistance to copper-mediated LDL oxidation (lag time in minutes), as well as MCP-1– and interleukin-8 (IL-8)–stimulated production. Statin therapy reduced MCP-1 production (mean ± SD) −161 ± 399 pg/mL/mm 3 white cells) compared with 267 ± 985 pg/mL/mm 3 in the placebo group, but changes were not different between active and placebo groups ( P = .13). Statin therapy also increased lag times (median [interquartile range]; 20.5 [7.0–51.2] minutes vs −17.0 [−5.3–16.5] minutes; P = .067 for group difference). Inhibition of MCP-1 production correlated with prolongation of lag time ( r = .46, P = .0056) in statin-treated subjects. Statin therapy reduced MCP-1 production in the whole blood of human subjects and these changes were correlated with improvement in LDL oxidative resistance.

Objective This study was undertaken to demonstrate the safety and efficacy of in vitro, radioallergosorbent test (RAST)-based inhalant allergen immunotherapy. Study design and setting Prospective 22 year single site clinical study, with outcome evaluations of 480 perennial allergic rhinitis patients, including 96 with concomitant asthma. Results Rhinitis symptom control after 2 years of immunotherapy was excellent in 32.5% of patients, good in 45.6%, and fair in 14.2%. There was no improvement in 7.7%. For patients with asthma, 81% had good or excellent pulmonary symptom improvement, and no patient failed to improve. No severe reactions occurred, but there were 5 limited systemic reactions, or 0.008% of injections, during a 2.5-year mean immunotherapy treatment course. Conclusion RAST-based immunotherapy is safe and effective for patients with perennial allergic rhinitis, with or without concomitant asthma. Significance This is the first large, multiyear study of safety and efficacy of RAST-based immunotherapy for treatment of perennial allergic rhinitis and asthma. EBM rating: C.

Decreased concentrations of total cholesterol, lipoproteins, and lipoprotein cholesterols occur early in the course of critical illness. Low cholesterol concentrations correlate with high concentrations of cytokines such as interleukin (IL)-6 and IL-10, and may be due to decreased synthesis or increased catabolism of cholesterol. Low cholesterol concentrations have been associated clinically with several adverse outcomes, including the development of nosocomial infections. The study was performed to test the hypothesis that a low cholesterol concentration predicts mortality and secondarily predicts the development of organ dysfunction in critical surgical illness.A prospective study was undertaken of 215 patients admitted to a university surgical ICU with systemic inflammatory response syndrome (SIRS). Serial blood samples were collected within 24 h of admission, as well as on the morning of days 2, 4, and 7 of the ICU stay for as long as the patients were in the ICU. Demographic data and predetermined outcomes were noted.One hundred nine patients had at least two samples drawn and form the population for analysis. Sixty-two of the patients had three samples obtained, whereas 42 patients had four samples obtained. By univariate analysis, non-survivors were more severely ill on admission (APACHE III), more likely to have been admitted to the ICU as an emergency, more likely to develop a nosocomial infection, and more likely to develop severe organ dysfunction (MODS) (all, p0.05). Death was associated on day 1 with increased concentrations of sIL2R, IL-6, IL-10, and sTNFR-p75 (all, p0.01), but there were initially no differences in serum lipid concentrations. However, by day 2, concentrations of IL-6, IL-10, and cholesterol had decreased significantly (all, p0.05) from day 1 in non-survivors but not in survivors; the difference in serum cholesterol concentration persisted to day 7 (p0.05). Persistently elevated concentrations of IL-6 and IL-10 were observed in patients who developed severe MODS. By logistic regression, increased APACHE III score, development of a nosocomial infection, and decreased cholesterol concentration were independently associated with mortality.Decreased serum cholesterol concentration is an independent predictor of mortality in critically ill surgical patients. Repletion of serum lipids is a feasible therapeutic approach for the management of critical illness.

Endotoxemia is associated with rapid and marked declines in serum levels of LDL and HDL by unknown mechanisms. Six normal volunteers received a single, small intravenous (iv) dose of endotoxin (Escherichia coli 0113, 2 ng/kg) or saline in a random order, cross-over design. After endotoxin treatment, volunteers had mild, transient flu-like symptoms and markedly increased serum levels of tumor necrosis factor and its soluble receptors, interleukin-6, cortisol, serum amyloid A, and C-reactive protein. Triglyceride (TG), VLDL-TG, and nonesterified fatty acid increased (peak at 3–4 h), then TG declined (nadir at 9 h), and then cholesterol, LDL cholesterol, apolipoprotein B (apoB), and phospholipid declined (nadirs at 12–24 h). HDL cholesterol and apoA-I levels were not affected, but half of the decrease in phospholipid was HDL phospholipid. Lipopolysaccharide binding protein (LBP) rose 3-fold (peak at 12 h), with smaller and later decreases in the activities of phospholipid transfer protein and cholesteryl ester transfer protein. In conclusion, a decline in LDL was rapidly induced in normal volunteers with a single iv dose of endotoxin. The selective loss of phospholipid from HDL may have been mediated by LBP and, after more intense or prolonged inflammation, could result in increased HDL clearance and reduced HDL levels.

Treatment to low-density lipoprotein (LDL) cholesterol targets has become a focus in the management of patients with coronary heart disease (CHD). Many patients with familial hypercholesterolemia (FH) are unable to reach targets because of drug intolerance or extremely high baseline LDL cholesterol levels. Consequently, LDL apheresis has become a useful modality for the treatment of patients with severe hypercholesterolemia. Commonly used LDL apheresis systems utilize immunoadsorption columns, dextran sulfate cellulose columns, or heparin precipitation. A new and simpler treatment modality is emerging which uses whole blood compatible columns. All systems require systemic anticoagulation, extracorporeal processing of blood, and venous vascular access. Acute LDL lowering is 70% to 80% and time-averaged LDL lowering is 40% to 50%. Lipoprotein(a) is also substantially lowered. Clinical efficacy has been shown in several studies. Mechanisms for clinical improvement in addition to regression of atherosclerotic plaque have been suggested by recent research.

The short-term effectiveness of low-density lipoprotein (LDL) apheresis using a dextran sulfate cellulose adsorption column technique was previously examined in a 9-center, 22-week controlled trial in 64 patients with familial hypercholesterolemia (FH) who did not adequately respond to diet and drug therapy. Forty-nine patients (40 treatment, 9 controls) subsequently received LDL apheresis procedures as part of an optional follow-up phase. This study reports on the long-term safety, lipid lowering, and clinical efficacy of LDL apheresis for the 5-year period that includes both the initial controlled study and follow-up phase. During this time, patients received a total of 3,902 treatments of which 3,314 treatments were given during the follow-up phase. Adverse events were infrequent, occurring in 142 procedures (3.6%). Immediate reduction in LDL cholesterol was 76% both in homozygotes and in heterozygotes. Patients with homozygous FH had a progressive decrease in pretreatment LDL cholesterol level along with an increase in high-density lipoprotein (HDL) cholesterol level. There was no appreciable change in pretreatment lipoprotein level over time in heterozygotes. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy. These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with heterozygous and homozygous FH who are inadequately controlled with drug therapy.

The use of LDL-apheresis to treat patients with severe hypercholesterolemia has gained wider clinical acceptance during the past 2-3 years, particularly in patients with coronary artery disease. Systems utilizing immunoadsorption columns, dextran sulfate cellulose columns and heparin precipitation have been most commonly employed. New or improved technologies include whole-blood compatible columns, double-filtration plasmapheresis and lipoprotein (a)-apheresis. The mechanisms for clinical improvement extend beyond simple regression of atherosclerotic plaque.

A subset of patients with familial hypercholesterolemia (FH) have an inadequate lipid-lowering response to diet and drug treatment and should be considered for low-density lipoprotein (LDL)-apheresis therapy. This procedure selectively removes apolipoprotein B-containing particles [LDL, very-low-density lipoprotein, lipoprotein(a)] from plasma independent of diet and drug therapy. Methods for performing LDL-apheresis include dextran sulfate cellulose adsorption, immunoadsorption, and heparin-induced extracorporeal precipitation. The Liposorber Study Group evaluated LDL removal using the Liposorber® LA-15 LDL-apheresis System in 64 patients with FH who had not responded adequately to diet and maximal drug therapy. Mean acute reductions in LDL cholesterol (LDL-C) were 76% in heterozygous FH (HtFH) patients and 81% in homozygous FH (HoFH) patients. Time-averaged levels of LDL-C were lowered 41% in HtFH and 53% in HoFH patients. Hypotension was the most frequent side effect, occurring in 3% of procedures. The Liposorber® LA-15 System has been approved by the Food and Drug Administration and is recommended for 1) patients with functional homozygous FH (LDL-C level >500 mg/dL; 2) patients with coronary artery disease (CAD) and LDL-C levels ≥200 mg/dL; 3) patients without CAD, but an LDL-C level ≥300 mg/dL. © 1996 Wiley-Liss, Inc.

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for vascular disease and a potential link between coagulation, lipoproteins, and the development of atherosclerosis. Its role in the vascular complications of patients with chronic renal disease is unclear. We review methodologic issues involved in measuring Lp(a), particularly as they relate to studies of patients with chronic renal disease. The accurate measurement of Lp(a) is difficult because all the commercially available assays are sensitive to apolipoprotein(a) isoform size, Lp(a) behaves like an acute phase reactant, and levels vary markedly among ethnic groups. The results of 12 studies that included data on median Lp(a) levels in controls and patients receiving renal replacement therapy were analyzed. Although there was variation among studies, most found elevated levels of Lp(a) in patients receiving hemodialysis (range of medians, 9.0 to 38.4 mg/dL) compared with controls (range of medians, 4.7 to 19.7 mg/dL). With the exception of one study, Lp(a) levels also were elevated in patients receiving continuous ambulatory peritoneal dialysis compared with controls and patients receiving hemodialysis. In one study, an elevated Lp(a) level in patients receiving hemodialysis correlated with subsequent development of vascular events. A separate study associated the occurrence of vascular access occlusion with Lp(a) level. Following renal transplantation, Lp(a) levels decreased in all four studies, which included data before and after transplantation. Although variability in results were seen, Lp(a) levels appear to be elevated in patients receiving renal replacement therapy. Renal transplantation at least partially reverses this effect. The variability in results is probably related to methodologic difficulties in measuring Lp(a) and failure to segregate ethnic groups in study design and analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Low-density lipoprotein (LDL) apheresis offers an additional approach to lipid lowering in patients with severe hypercholesterolemia who fail to respond adequately to diet and drug therapy. Well-defined criteria for patient selection have yet to be established for LDL apheresis. This study proposes guidelines based on whether coronary artery disease (CAD) is present and on the degree of LDL cholesterol elevation after treatment with diet and maximal drug therapy. It is reasonable to consider LDL apheresis therapy for: (1) patients with CAD and LDL cholesterol levels >190 mg/dl; (2) patients without CAD, but at high risk for disease due to an LDL cholesterol level >250 mg/dl, a first-degree relative with premature CAD, and the presence of ≥1 additional risk factor. In addition, LDL apheresis is recommended for the management of all patients with homozygous familial hypercholesterolemia due to the very high risk of CAD and the poor response to usual lipid-lowering treatments.

Lowering total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels is widely recommended for the prevention of coronary heart disease (CHD) and for the management of patients with existing CHD. In most patients, dietary modification and drug therapy are often sufficient to lower LDL-C levels to within acceptable ranges as recommended by the National Cholesterol Education Program Guidelines. However, for some patients, particularly those with familial hypercholesterolemia (FH), additional therapy may be required to achieve desired cholesterol levels. In those patients for whom diet and maximum drug therapy are either ineffective or not tolerated, LDL-apheresis has been shown to be a safe and effective procedure. The Liposorber® LA-15 system is an LDL-apheresis system that selectively removes apolipoprotein B-containing lipoproteins, including LDL-C, very-low-density lipoprotein, and lipoprotein(a). In addition to its role in treating patients with FH, preliminary data also suggest that LDL-apheresis may be beneficial in the prevention of restenosis after percutaneous transluminal coronary angioplasty, the treatment of focal glomerular sclerosis, and the management of arteriosclerosis obliterans. The present paper discusses the main components of the Liposorber LA-15 system, the principles that underlie LDL-apheresis, and the clinical conditions in which the system has been used effectively.

LDL-apheresis is an extracorporeal plasma-perfusion method that selectively removes apolipoprotein B-containing lipoproteins from the blood. It is indicated for patients with homozygous and drug-resistant heterozygous familial hypercholesterolemia. Clinical and angiographic regression of coronary artery disease has been demonstrated in patients treated with cholesterol-lowering programs that include LDL-apheresis.

Objectives: PCSK9 plays an important role in the regulation of LDLcholesterol concentrations via its influence on catabolism of the LDL receptors. It is known that PCSK9 levels are higher in patients with familial hypercholesterolemia than in normolipidemic controls. We wanted to estimate PCSK9 levels in patients currently undergoing apheresis or eligible to be treated by LA and look into the acute effects of LA on PCSK9 concentrations. Methods: We measured total serum PCSK9 levels (using an ELISA-method) in 2 cohorts: Cohort I consisted of patients actively undergoing lipoprotein apheresis as part of their routine care (n 40; 21 males, 19 females; age 55.6 years (range 32-73 years)). Blood was drawn before and immediately after 3 apheresis sessions (paying attention to standardized conditions). The following LA methods were used: Dextran Sulfate cellulose Adsorption (DSA), Heparin Extracorporeal LDL Precipitation (HELP) system, Double filtration plasmapheresis (DFPP), Direct Adsorption of Lipoproteins (DALI), and “other” systems. Cohort II consisted of patients who were eligible for lipoprotein apheresis but not undergoing the procedure (n 10; 3 males, 7 females; age 61.1 years (range 50-78 years)). Results: Mean PCSK9 pre-apheresis levels were 253.70 ng/mL in Cohort I, were decreased by approximately 50 % by LA, but returned to the preapheresis levels on the second dayafter the apheresis. It appeared that when compared with the DSA method HELP showed a more pronounced decline in PCSK9 concentrations, whereas DALI was associated with a less pronounced reduction than DSA. In Cohort II mean PCSK9 levels were 287.00 ng/mL. Conclusion: LA treatment reduced PCSK9 by approximately 50%, with the extent of reduction being dependent upon the type of apheresis method used. The PCSK9 concentrations were slightly higher in subjects eligible for, but not undergoing, apheresis compared to patients that were actively undergoing apheresis.

A subgroup of patients with familial hypercholesterolemia (FH) respond inadequately to standard diet and drug therapy, and are therefore at high risk for the premature development or progression of coronary artery disease. This study evaluated low-density lipoprotein (LDL) cholesterol and lipoprotein (a) removal in a multicenter, controlled trial with a new LDL apheresis procedure (Liposorber LA-15 System). The study comprised patients with FH who had not responded adequately to diet and maximal drug therapy. There were 54 patients with heterozygous FH (45 randomized to treatment and 9 control subjects) and 10 with homozygous FH (all of whom received LDL apheresis). The study included three 6-week treatment phases and a 4-week rebound phase. Treatments were administered at 7- to 14-day intervals. Mean acute reductions in LDL cholesterol were 76% in heterozygous FH patients and 81% in homozygous ones. Time-averaged levels of LDL cholesterol were reduced 41% (243 to 143 mg/dl) in heterozygous FH patients and 53% (447 to 210 mg/dl) in homozygous ones. The substantial acute reduction of lipoprotein (a) (means: 65%, heterozygous FH; 68%, homozygous FH) has not been reported with other therapies. The Liposorber LA-15 System represents an important therapeutic option in FH patients who respond inadequately to diet and drug therapy.

ADAMTS13 mediated thrombotic thrombocytopenic purpura (TTP) is an immunological disease that is very difficult to treat. Plasma exchange, with plasma replacement and steroids have been the first line of treatment for this condition. Ten to 20% of the patients either have no response or a partial response to the treatment. Refractory TTP has been treated in few case reports with anti-CD20 agents, intravenous gamma globulin, vincristine and splenectomy. We report two cases of refractory TTP that responded to multimodality immunosuppressive therapy that included splenectomy, intravenous gamma globulin, and cyclosporine after numerous plasma exchange treatments, steroids, rituximab and vincristine had failed to induce remission. Combining drugs that target T and B lymphocytes is a standard in organ transplantation and deserves more consideration in the treatment of severe and refractory autoimmune diseases such as TTP.

Comparison of open food challenge (OFC) with double-blind placebo-controlled food challenge (DBPCFC).Prospective sequential randomized challenges.Twenty adults with chronic allergy symptoms and at least 1 positive intradermal food wheal response recorded symptoms during DBPCFC and OFC provoked using organic foods, normal portions, and normal food preparation. Acoustic Rhinometry and biochemical tests were done during DBPCFC.All patients reacted to at least 1 food and to all challenges with the same food, with multiorgan symptoms in the nose, nervous system, throat, and lung. There was a correlation in the type and severity of symptoms (P = 0.015) for OFC and DBPCFC, and both were significantly (P0.01) more severe than placebo. Compared with DBPCFC, OFC sensitivity was 66%, and positive predictive value was 89%.This is the first study showing both concordance of OFC and DBPCFC and also that intradermal tests can identify reactive foods that can be verified by DBPCFC. Because most tests for IgE-mediated food allergy were negative, observed reactions were probably non-IgE mediated.

The effect of statins on bone mass and fracture rates is uncertain. Therefore, we investigated whether statin therapy acutely altered bone turnover as measured by changes in bone serum markers (bone-specific alkaline phosphatase, osteocalcin, and type I collagen N-telopeptide cross-links). Fasting blood samples were obtained from 55 (M/F 39/16) healthy nonsmoking adults (mean +/- standard deviation: age, 50.4+/-7.5 years; body mass index, 27.8+/-4.9 kg/m(2)) with low-density lipoprotein cholesterol concentrations between 3.38-4.90 mmol/l. Subjects were randomized to four possible 8-week treatment regimens: placebo (n =14), pravastatin 40 mg/daily (n =12), simvastatin 20 mg/daily (n =14) or simvastatin 80 mg/daily (n =15). High-dose simvastatin (80 mg/daily) produced a significant reduction in bone-specific alkaline phosphatase as compared with other treatment regimens (p =0.009). However, there were no changes in urinary N-telopeptide cross-links, a sensitive marker of bone resorption. Short-term use of high-dose simvastatin lowers the level of the serum bone marker bone-specific alkaline phosphatase, which suggests the possibility of reduced bone turnover.

Adipose tissue expression of tumor necrosis factor-alpha (TNF-α) has been implicated in the pathogenesis of obesity-linked insulin resistance and the dyslipoproteinemia of insulin resistance. This study has two aims: (1) to compare select inflammatory mediators in non-smoking, normoglycemic male subjects with and without the atherogenic dyslipoproteinemia (ADL), and (2) to determine the effects of statin therapy on select inflammatory mediators. ADL subjects had higher levels of insulin (16.7 ± 7.5 versus 11.6 ± 5.9μIU/mL, P = 0.008), soluble TNF receptor superfamily 1B (sTNFRSF1B) (3.3 ± 0.7 versus 2.7 ± 0.5ng/mL, P = 0.005), and interleukin-6 (IL-6) (2.6 ± 2.2 versus 1.3 ± 1.8pg/mL, P = 0.006) as compared to those of the non-ADL subjects. After adjustment for age, sTNFRSF1B ( P = 0.003) was more predictive of ADL than high-sensitivity C-reactive protein (hs-CRP) ( P = 0.047). Statin therapy did not change sTNFRSF1B, TNF-α, IL-6, hs-CRP, whereas soluble TNF receptor superfamily 1A (sTNFRSF1A) increased slightly ( P = 0.048). A high level of sTNFRSF1B is a strong marker of the pro-inflammatory state in this sample of male ADL subjects.

The goal of this study was to determine the relationship among lipid concentrations, cytokine concentrations, and clinical outcomes of burn patients. Twenty-eight patients admitted within 24 hours of burn injury, segregated based on burn size, had blood samples drawn 24 and 48 hours after burn injury and then weekly for 3 weeks. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, interleukin (IL)-6, soluble IL-2 receptor, and soluble necrosis factor p55 and p75 receptors. Infection, length of stay (LOS), and survival were monitored. Cholesterol and lipoprotein concentrations decreased by at least 40% in patients with burns >20% total body surface area and inversely correlated with IL-6. Lower cholesterol and higher IL-6 values correlated with higher infection rates and longer LOS. IL-6 was the strongest predictor for LOS. In conclusion, outcomes after burn injury are related to low cholesterol and elevated IL-6 levels.

Through the efforts of Edward H. Ahrens, LDL apheresis became available for the treatment of patients, often with familial hypercholesterolemia, who have no alternative therapy for severely elevated LDL cholesterol levels. In the U.S., the FDA has approved this treatment for individuals on maximum diet and drugs with an LDL cholesterol greater than 300 mg/dL or greater than 200 mg/dL with coronary artery disease. Unlike plasmapheresis, apolipoprotein B-containing lipoproteins (LDL, Lp(a), and VLDL) are selectively removed by heparin precipitation or columns containing dextran sulfate cellulose or antibodies to apolipoprotein B. The acute lowering of LDL-cholesterol by a typical 2 - 3 h treatment is up to 80%, and the time-averaged lowering in the 1 to 2 week interval between treatments is up to 50%, with very few side effects. The lowering of LDL-cholesterol and other cardioprotective effects of LDL apheresis have reduced chest pain, prevented new disability and prolonged life. Whole blood compatible columns in development offer the possibility of simpler and less expensive treatments.

The United States Liposorber Study was a 22 week randomized controlled study of low-density lipoprotein (LDL) apheresis with an optional follow-up phase. The procedure was found to acutely lower LDL cholesterol by up to 81%, have good tolerability, and produce a reduction in the frequency of cardiovascular events. Studies outside the United States have found therapy with LDL apheresis to be associated with a favorable clinical outcome including improved myocardial perfusion, but variable regression of coronary artery disease (CAD). Improvement in blood viscosity and endothelial function may help explain the symptomatic benefits observed with relatively small changes in angiography. Based upon favorable clinical experience, LDL apheresis using dextran sulfate cellulose columns has recently received approval for commercialization in the United States in patients with inadequate responses to diet and drug therapy and LDL levels > or = 200 mg with CAD present or LDL levels > or = 300 mg/dl without CAD.

Objectives To determine the prevalence and clinical significance of hypolipidemia found in critically ill patients, and whether the addition of a reconstituted lipoprotein preparation could inhibit the generation of tumor necrosis factor-alpha (TNF-alpha) in acute-phase blood taken from these patients. Setting Surgical intensive care unit (ICU) of a large urban university hospital. Design Prospective case series. Patients A total of 32 patients with a variety of critical illnesses had lipid and lipoprotein concentrations determined. Six patients and six age- and gender-matched control subjects had whole blood in vitro studies of the effect of lipoprotein on lipopolysaccharide mediated TNF-alpha production. Interventions Blood samples were drawn on admission to the ICU and over a subsequent 8-day period. Measurements and Main Results Mean serum lipid and lipoprotein values obtained from patients within 24 hrs of transfer to the surgical ICU were extremely low: mean total cholesterol was 117 mg/dL (3.03 mmol/L), low-density lipoprotein cholesterol 71 mg/dL (1.84 mmol/L), and high-density lipoprotein cholesterol 25 mg/dL (0.65 mmol/L). Only the mean triglyceride concentration of 105 mg/dL (1.19 mmol/L), and the mean lipoprotein(a) concentration of 25 mg/dL (0.25 g/L) were within the normal range. During the first 8 days following surgical ICU admission, there were trends toward increasing lipid and lipoprotein concentrations that were significant for triglycerides and apolipoprotein B. Survival did not correlate with the lipid or lipoprotein concentrations, but patients with infections had significantly lower (p equals .008) high-density lipoprotein cholesterol concentrations compared with noninfected patients. Lipopolysaccharide-stimulated production of TNF-alpha in patient and control blood samples was completely suppressed by the addition of 2 mg/mL of a reconstituted high-density lipoprotein preparation. Conclusions Patients who are critically ill from a variety of causes have extremely low cholesterol and lipoprotein concentrations. Correction of the hypolipidemia by a reconstituted highdensity lipoprotein preparation offers a new strategy for the prevention and treatment of endotoxemia.

Abstract 4666 Background: Case reports and two prospective, controlled trials document the efficacy of anti-C5 monoclonal antibody eculizumab in the treatment of refractory atypical hemolytic uremic syndrome (aHUS) as well as in aHUS patients requiring chronic plasma exchange. It has shown efficacy in the presence and absence of defects in complement (C) and C regulatory proteins. However, eculizumab has not been previously used in TTP associated with low ADAMTS13 activity, despite the many shared clinical and pathologic features of TTP with aHUS. Case report: A 27 y.o. white male with a history of inflammatory bowel disease presented with fever, thrombocytopenia, and microangiopathic hemolytic anemia, and rapidly developed renal failure, seizures, and coma. ADAMTS13 activity was Relevant clinical data: Figure and C1q and complement regulatory proteins: factors H, I, and B: normal. Outcome: In remission four months after initial presentation, receiving biweekly eculizumab infusions as an outpatient. Conclusion: Eculizumab was associated with remission induction in a patient with classic idiopathic TTP refractory to plasma exchange. Although multiple, overlapping initial therapies obfuscate assignment of efficacy to a single agent during initial treatment, remission obtained with eculizumab alone on relapse suggests its efficacy. Eculizumab should be considered in patients with refractory TTP. Eculizumab treatment is ongoing in this patient, but the duration of the treatment period remains to be elucidated. Our study also emphasizes that vascular C activation, possibly triggered by endothelial cell injury, may be a critical factor in at least some cases of TTP. C5b-9 induces a secretory response in endothelium to elaborate ultra high molecular weight von Willebrand factor multimers which would be ineffectually cleaved in patients with antibodies to ADAMTS13. This could lead to a dysregulated thrombotic microangiopathy. Blocking C5 formation may thus address a critical upstream pathway relevant to TTP as well as aHUS. Disclosures: Off Label Use:Eculizumab treatment of TTP is an off-label use.

The effect of lipid lowering on hard exudates was determined in six consecutive patients with insulin-dependent diabetes mellitus. Diet and hypolipidemic drug therapy including the use of pravastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase, were used to treat patients for one year. The total cholesterol concentration decreased from a mean baseline value of 231 mg/dl to a treatment mean value of 165 mg/dl. The mean low-density lipoprotein cholesterol concentration decreased from 157 mg/dl to 93 mg/dl. Masked grading of fundus photographs indicated an improvement in hard exudates in all six patients and a decrease in microaneurysms in four patients. Visual acuity improved in one patient and did not change (one line or less change) in five patients. No remarkable side effects resulting from treatment were observed. Our pilot study suggests that aggressive therapy of diabetic patients with hyperlipidemia may have a beneficial effect on background retinopathy.

To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events.Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level4.14 mmol/L [160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment.Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups.Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.

Plasma high density lipoprotein (HDL) concentrations were increased in five hypercholesterolemic normoglyceridemic patients after removal of plasma low density lipoprotein (LDL) by LDL-pheresis. In each patient up to 80% of circulating LDL was removed by passing plasma through immunoadsorption columns containing antibody to apolipoprotein B immobilized to Sepharose. Rebound of LDL was slow after the procedure: 5-7 days in four non-familial hypercholesterolemic patients and greater than 14 days in one patient with homozygous familial hypercholesterolemia. Plasma HDL rose above the pretreatment baseline during the interval between treatments in four of the five patients. When treatments were repeated weekly, time-averaged plasma LDL was lowered by 40-70%, while plasma HDL cholesterol and apolipoprotein AI were increased up to 2-fold, depending on the degree of LDL lowering. Plasma HDL concentrations fell back to their baseline values when LDL-pheresis was stopped and rose again when treatment was restarted. Thus, LDL-pheresis may augment the therapeutic effectiveness of LDL lowering by raising plasma HDL levels and the concentration of HDL relative to LDL.

Plasma exchange (PE) and intravenous gammaglobulin (IVGG) are potentially effective therapies in immune thrombocytopenic purpura (ITP). In this study, eight patients refractory to IVGG and to prednisone were treated with a protocol of combined PE and IVGG therapy using a single PE on each of 3 consecutive days, followed by 2 consecutive days of IVGG at 1 g per kg. Four of the eight patients responded to the combined therapy with a mean peak platelet count of 132,000 per microliter (range, 74,000 to 225,000/microliter). Responses lasted approximately 2 weeks. These four patients were among the five who had initially responded to IVGG before becoming refractory; none of the three patients without an initial response to IVGG responded to the combined therapy. Age, duration of disease, and splenectomy status did not appear to be related to response to the combined therapy. Two patients began maintenance treatment (1 PE followed by 1 g/kg IVGG on the same day), but both became unresponsive after three treatments. PE combined with IVGG may be a useful treatment for some patients with refractory ITP who have uncontrollable bleeding or require major surgery. The development of resistance to IVGG effect may be mediated by an increase in the level of antiplatelet antibodies. PE, by lowering antiplatelet antibody levels, may then allow IVGG infusion to be effective again in elevating the platelet count.