Melatonin as a treatment for mood disorders: a systematic review.

OBJECTIVE: Melatonin has been widely studied in the treatment of sleep disorders and evidence is accumulating on a possible role for melatonin influencing mood. Our aim was to determine the efficacy and acceptability of melatonin for mood disorders. METHOD: We conducted a comprehensive systematic review of randomized clinical trials on patients with mood disorders, comparing melatonin to placebo. RESULTS: Eight clinical trials were included; one study in bipolar, three in unipolar depression and four in seasonal affective disorder. We have only a small study on patients with bipolar disorder, while we have more studies testing melatonin as an augmentation strategy for depressive episodes in major depressive disorder and seasonal affective disorder. The acceptability and tolerability were good. We analyzed data from three trials on depressive episodes and found that the evidence for an effect of melatonin in improving mood symptoms is not significant (SMD = 0.37; 95% CI [-0.05, 0.37]; P = 0.09). The small sample size and the differences in methodology of the trials suggest that our results are based on data deriving from investigations occurring early in this field of study. CONCLUSION: There is no evidence for an effect of melatonin on mood disorders, but the results are not conclusive and justify further research.

Bone health in multiple sclerosis.

People who are disabled with multiple sclerosis (MS) may be at increased risk of osteoporosis. This review discusses issues relevant to bone health in MS and makes practical recommendations regarding prevention and screening for osteoporosis and fracture risk in MS. A search of the literature up until 5 April 2011 was performed using key search terms, and articles pertinent to bone health in MS were analysed. Bone mineral density (BMD) is reduced at the lumbar spine, hip and total body in MS, with the degree of reduction being greatest at the hip. A strong relationship exists between the disability level, measured by the Expanded Disability Status Score, and BMD at the lumbar spine and femoral neck, particularly the latter. The rate of loss of BMD also correlates with the level of disability. Pulsed corticosteroids for acute episodes of MS, even with a high cumulative steroid dose, do not significantly affect BMD, but an effect on fracture risk is yet to be elucidated. There appears to be no correlation between vitamin D levels and BMD, and the relationship between disability and vitamin D levels remains unclear. Falls and fractures are more common than in healthy controls, and the risk rises with increasing levels of disability. The principal factor resulting in low BMD and increased fracture risk in MS is immobility. Antiresorptive therapy with bisphosphonates and optimising vitamin D levels are likely to be effective interventions although there are no randomised studies of this therapy.

Future directions for monitoring and human health research for the Arctic Monitoring and Assessment Programme.

For the last two and a half decades, a network of human health experts under the Arctic Monitoring and Assessment Program (AMAP) has produced several human health assessment reports. These reports have provided a base of scientific knowledge regarding environmental contaminants and their impact on human health in the Arctic. These reports provide scientific information and policy-relevant recommendations to Arctic governments. They also support international agreements such as the Stockholm Convention on Persistent Organic Pollutants (POPs) and the Minamata Convention on Mercury. Key topics discussed in this paper regarding future human health research in the circumpolar Arctic are continued contaminant biomonitoring, health effects research and risk communication. The objective of this paper is to describe knowledge gaps and future priorities for these fields.

Regulation of the production and catabolism of plasma low density lipoproteins in hypertriglyceridemic subjects. Effect of weight loss.

In subjects with hypertriglyceridemia, plasma concentrations of low density lipoprotein (LDL) cholesterol are often normal or reduced. Perturbations that alter plasma very low density lipoprotein (VLDL) concentrations are associated with opposite changes in plasma LDL levels. To determine the mechanisms regulating plasma LDL levels, we used 131I-VLDL and 125I-LDL to measure the fractional catabolic rates (FCR), production rates (PR), and rates of interconversion of apoprotein B (apo B) in VLDL, intermediate density lipoprotein, and LDL in six hypertriglyceridemic subjects pre- and post-weight reduction. [2-3H]glycerol was used to quantitate VLDL triglyceride PR. All data are presented as mean +/- SD. Percent ideal body weight fell from 132 +/- 17.9 to 119 +/- 15.9% in the group, P less than 0.05. After weight loss, plasma VLDL triglyceride (486.0 +/- 364.1 vs. 191.3 +/- 65.4 mg/dl, P less than 0.05) and VLDL apo B (32.2 +/- 12.0 vs. 14.8 +/- 6.8 mg/dl, P less than 0.05) concentrations were reduced. VLDL triglyceride PR also fell after weight reduction (56.6 +/- 39.0 vs. 28.6 +/- 23.1 mg/kg per h, P less than 0.05), as did VLDL apo B PR (47.9 +/- 41.4 vs. 19.0 +/- 14.1 mg/kg per d, P less than 0.05). Pre-weight loss, plasma LDL cholesterol and apo B levels were low-normal or reduced (64.0 +/- 12.6 and 58.4 +/- 11.9 mg/dl, respectively) despite normal or elevated LDL apo B PR (17.4 +/- 7.2 mg/kg per d). The reduced cholesterol and apo B levels were associated with increased FCRs (0.68 +/- 0.29 d-1) and reduced cholesterol/protein ratios (1.01 +/- 0.18) in LDL. The plasma levels of LDL cholesterol and apo B rose after weight reduction (84.8 +/- 24.9, P less than 0.05; and 69.5 +/- 14.3 mg/dl, P less than 0.05, respectively, vs. base line). These increased concentrations resulted from a combination of events. First, the FCR for LDL apo B fell in five of six subjects with a significant reduction for the group as a whole (0.48 +/- 0.11 d-1, P less than 0.05 vs. base line). Second, the cholesterol/protein ratio increased in all six subjects with a significantly greater mean after weight loss (1.25 +/- 0.27, P less than 0.05 vs. base line). In contrast, the LDL apo B PR fell or was essentially unchanged in the six subjects after weight loss (mean, 14.4 +/- 2.8 mg/kg per d; NS vs. pre-weight loss). The changes in LDL catabolism and composition were associated with changes in the source of LDL apo B. Pre-weight loss, 73.3% of LDL was derived from VLDL, while 26.7% was directly secreted into plasma. Post-weight reduction, VLDL-derived LDL fell to 46.8% of total, while direct secretion accounted for 53.2% of LDL production. These changes were significant; P < 0.95. Thus, all subjects had direct secretion of LDL apo B and the magnitude of this source of VLDL triglyceride secretion. These results indicate that the regulation of plasma LDL levels in hypertriglyceridemic subjects is quite complex and that the rise in LDL levels after weight loss results from reduction in the fractional catabolism of this lipoprotein. The fall in the FCR is associated with changes in the source of LDL and in its composition.

Effect of heparin-induced lipolysis on the distribution of apolipoprotein e among lipoprotein subclasses. Studies with patients deficient in hepatic triglyceride lipase and lipoprotein lipase.

In normal subjects, apolipoprotein E (apo E) is present on very low density lipoproteins (VLDL) (fraction I) and on particles of a size intermediate between VLDL and low density lipoproteins (LDL) (fraction II). The major portion of apo E is, however, on particles smaller than LDL but larger than the average high density lipoproteins (HDL) (fraction III). To investigate the possible role of the vascular lipases in determining this distribution of apo E among the plasma lipoproteins, we studied subjects with primary deficiency of either hepatic lipase or of lipoprotein lipase and compared them with normal subjects. Subjects with familial hepatic triglyceride lipase deficiency (n = 2) differ markedly from normal in that fraction II is the dominant apo E-containing group of lipoproteins. When lipolysis of VLDL was enhanced in these subjects upon release of lipoprotein lipase by intravenous heparin, a shift of the apo E from VLDL into fractions II and III was observed. In contrast, apolipoproteins CII and CIII (apo CII and CIII, respectively) did not accumulate in intermediate-sized particles but were shifted markedly from triglyceride rich lipoproteins to HDL after treatment with heparin. In subjects with primary lipoprotein lipase deficiency (n = 4), apo E was confined to fractions I and III. Release of hepatic triglyceride lipase by heparin injection in these subjects produced a shift of apo E from fraction I to III with no significant increase in fraction II. This movement of apo E from large VLDL and chylomicron-sized particles occurred with little hydrolysis of triglyceride and no significant shift of apo CII or CIII into HDL from triglyceride rich lipoproteins. When both lipoprotein lipase and hepatic triglyceride lipase were released by intravenous heparin injection into normal subjects (n = 3), fraction I declined and the apo E content of fraction III increased by an equivalent amount. Either moderate or no change was noted in the intermediate sized particles (fraction II). These data strongly support the hypothesis that fraction II is the product of the action of lipoprotein lipase upon triglyceride rich lipoproteins and is highly dependent on hepatic triglyceride lipase for its further catabolism. In addition, the hydrolysis by hepatic triglyceride lipase of triglyceride rich lipoproteins in general results in a preferential loss of apo E and its transfer to a specific group of large HDL.

Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo.

Previous data suggest that apolipoprotein (apo) CIII may inhibit both triglyceride hydrolysis by lipoprotein lipase (LPL) and apo E-mediated uptake of triglyceride-rich lipoproteins by the liver. We studied apo B metabolism in very low density (VLDL), intermediate density (IDL), and low density lipoproteins (LDL) in two sisters with apo CIII-apo AI deficiency. The subjects had reduced levels of VLDL triglyceride, normal LDL cholesterol, and near absence of high density lipoprotein (HDL) cholesterol. Compartmental analysis of the kinetics of apo B metabolism after injection of 125I-VLDL and 131I-LDL revealed fractional catabolic rates (FCR) for VLDL apo B that were six to seven times faster than normal. Simultaneous injection of [3H]glycerol demonstrated rapid catabolism of VLDL triglyceride. VLDL apo B was rapidly and efficiently converted to IDL and LDL. The FCR for LDL apo B was normal. In vitro experiments indicated that, although sera from the apo CIII-apo-AI deficient patients were able to normally activate purified LPL, increasing volumes of these sera did not result in the progressive inhibition of LPL activity demonstrable with normal sera. Addition of purified apo CIII to the deficient sera resulted in 20-50% reductions in maximal LPL activity compared with levels of activity attained with the same volumes of the native, deficient sera. These in vitro studies, together with the in vivo results, indicate that in normal subjects apo CIII can inhibit the catabolism of triglyceride-rich lipoproteins by lipoprotein lipase.

Coseismic seafloor deformation in the trench region during the Mw8.8 Maule megathrust earthquake.

The Mw 8.8 megathrust earthquake that occurred on 27 February 2010 offshore the Maule region of central Chile triggered a destructive tsunami. Whether the earthquake rupture extended to the shallow part of the plate boundary near the trench remains controversial. The up-dip limit of rupture during large subduction zone earthquakes has important implications for tsunami generation and for the rheological behavior of the sedimentary prism in accretionary margins. However, in general, the slip models derived from tsunami wave modeling and seismological data are poorly constrained by direct seafloor geodetic observations. We difference swath bathymetric data acquired across the trench in 2008, 2011 and 2012 and find ~3-5 m of uplift of the seafloor landward of the deformation front, at the eastern edge of the trench. Modeling suggests this is compatible with slip extending seaward, at least, to within ~6 km of the deformation front. After the Mw 9.0 Tohoku-oki earthquake, this result for the Maule earthquake represents only the second time that repeated bathymetric data has been used to detect the deformation following megathrust earthquakes, providing methodological guidelines for this relatively inexpensive way of obtaining seafloor geodetic data across subduction zone.

In vitro metabolism of apolipoprotein E.

Apolipoprotein E plays a major role in the uptake of chylomicrons and of very-low-density lipoprotein (VLDL) remnants by the liver. It has also been clearly demonstrated that apolipoprotein E rapidly and spontaneously exchanges between lipoproteins. To assess whether all lipoprotein-bound apolipoprotein E is available to participate in spontaneous transfer and/or exchange, the present study followed the fate of radiolabeled apolipoprotein E in an in vitro system. The results show that in vitro, apolipoprotein E can be considered as having both a spontaneously exchangeable pool and a nonexchangeable pool. Based upon specific radioactivity data, only a limited amount of apolipoprotein E originating in VLDL or in high-density lipoproteins (HDL) was capable of in vitro exchange with that in other lipoprotein fractions. Lipolysis of VLDL triacylglycerol by milk lipoprotein lipase, however, resulted in complete transfer of VLDL apolipoprotein E mass and radioactivity to HDL, supporting the potential for transformation of exchangeable apolipoprotein to a transferable pool in vivo. The results of these studies indicate that during the course of lipoprotein metabolism, conformational changes occur which alter the accessibility of apolipoprotein E. Such dynamic heterogeneity may have implications for the regulation of lipoprotein metabolism.

Plasma apolipoprotein secretion by human monocyte-derived macrophages.

Apolipoprotein E has been demonstrated to be a major secretory protein of human monocyte macrophages. The synthesis of the other plasma apolipoproteins by these cells has not been documented. Human monocyte macrophages cultured for 17-76 days were preincubated for 24 h in RPMI 1640/0.2% bovine serum albumin with or without malondialdehyde-LDL (100 micrograms/ml), followed by an additional 24 h incubation in RPMI 1640/0.2% bovine serum albumin. The media from the two incubation periods were analyzed for apolipoproteins A-I, B, C-II, C-III and E by specific radioimmunoassays. No apolipoprotein B mass was detected with a specific radioimmunoassay capable of detecting 10 ng apolipoprotein B. No apolipoproteins A-I, C-II or C-III mass was detected, even though the radioimmunoassays for these apolipoproteins were as sensitive as that for apolipoprotein E (detection limit of 0.2 ng). In contrast, significant levels of macrophage-secreted apolipoprotein E were quantified. Baseline apolipoprotein E production ranged from 0.64 to 2.82 micrograms/mg cell protein per 24 h. Preincubation in the presence of malondialdehyde-LDL (100 micrograms/ml) stimulated a 1.6-3.0-fold increase in apolipoprotein E secretion. The identification of the immunoreactive material as apolipoprotein E was confirmed by labelling the cells with [35S]methionine, followed by fractionation of the 35S-labelled secretory products by anti-apolipoprotein E affinity chromatography and SDS-gel electrophoresis. We thus report the absence of synthesis of apolipoproteins A-I, B, C-II and C-III by cultured human monocyte macrophages. These cells, however, can synthesize microgram levels of apolipoprotein E on a per mg protein basis.

Immunoaffinity isolation of apolipoprotein E-containing lipoproteins.

Discrete apolipoprotein E-containing lipoproteins can be identified when EDTA plasma is fractionated on columns of 4% agarose. The present study has demonstrated, by physical and metabolic criteria, that these apolipoprotein E-containing lipoprotein subclasses may be further isolated by immunoaffinity chromatography. Whole plasma was first bound to an anti-apolipoprotein E immunoadsorbent prior to gel filtration on 4% agarose. After elution from the affinity column and dialysis, the bound fraction was chromatographed on 4% agarose. Discrete subfractions of apolipoprotein E could be demonstrated within elution volumes similar to those observed in the original plasma. When whole plasma was first submitted to gel filtration and the apolipoprotein E-containing lipoproteins of either intermediate- or of high-density lipoprotein (HDL) size were subsequently bound to anti-apolipoprotein E columns, the bound eluted fractions maintained their size and physical properties as shown by electron microscopy and by rechromatography on columns of 4% agarose. The metabolic integrity of apolipoprotein E-containing very-low-density lipoproteins (VLDL) was examined by coinjection into a cynomolgus monkey of 125I-labeled apolipoprotein E-rich and 131I-labeled apolipoprotein E-deficient human VLDL which had been separated by immunoaffinity chromatography. The plasma specific activity time curves of the apolipoprotein B in VLDL, intermediate-density (IDL) and low-density (LDL) lipoproteins demonstrated rates of decay and precursor-product relationships similar to those obtained after injection of whole labeled VLDL, supporting the metabolic integrity of VLDL isolated by immunoaffinity chromatography.

Multidisciplinary education for oxygen prescription. A continuous quality improvement study.

OBJECTIVES: To examine the oxygen-prescribing habits and monitoring patterns on a medical teaching ward and to review the literature in this area. DESIGN: A continuous quality improvement study. SETTING: A 29-bed medical clinical teaching unit in a 453-bed university-affiliated tertiary care hospital. PATIENTS: We studied 50 consecutive patients who required 79 oxygen treatments. METHODS: We recorded the indication, prescriber, documentation of prior hypoxemia, method and mode of delivery, oxygenation assessment after initiation, and duration of therapy. RESULTS: Patients received oxygen for a mean (+/- SD) of 4.7 +/- 4.5 days. Oxygen therapy was ordered on a continuous basis 60.3% of the time. It was ordered by house staff in 54 cases (68%); nurses initiated oxygen therapy in 14 cases (18%) but discontinued it more often than any other health care workers. The most common indications for starting oxygen therapy were dyspnea and tachypnea. In 15 patients (30%), none of the American College of Chest Physicians and National Heart, Lung, and Blood Institute criteria for starting oxygen therapy were fulfilled. For 16 patients (32%), arterial blood gas values were measured within 1 hour of oxygen administration; for 29 patients, oximetry was performed. For 9 patients (18%), no testing of adequate oxygenation was performed within 24 hours. Oxygenation status was assessed daily for 23 patients (46%). CONCLUSIONS: Oxygen prescribing and monitoring practices were suboptimal on our busy medical teaching ward. Practice guidelines based on best available evidence are needed to increase the efficiency of oxygen use. A physiologic, multidisciplinary educational focus on the benefits and hazards of supplemental oxygen is necessary, and randomized trials of such educational interventions should be conducted.

The influence of a wide range of absorbed cholesterol on plasma cholesterol levels in man.

The influence of absorbed dietary cholesterol on plasma cholesterol concentration was studied in two populations, one Seventh Day Adventist (SDA) vegetarian and one nonvegetarian, representing a broad range of plasma cholesterol values and dietary cholesterol intakes. As a group, the SDA vegetarians had significantly lower levels of plasma cholesterol and triglycerides than did the nonvegetarians. This hypolipidemic pattern in the SDA vegetarians was apparently closely related to dietary habits, sinceanother group of SDA who were nonvegetarian had significantly higher plasma cholesterol and triglyceride levels than their vegetarian counterparts. Both the dietary intake of cholesterol and the percentage absorption of cholesterol were lower in vegetarians than in nonvegetarians. The mass of cholesterol absorbed increased linearly with the mass of cholesterol ingested in all groups, but no relationship could be demonstrated between absorbed cholesterol and plasma cholesterol concentration.

Effect of lipoprotein lipase and hepatic triglyceride lipase activity on the distribution of apolipoprotein E among the plasma lipoproteins.

The independent roles of human lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in determining the distribution of apolipoprotein E (apo E) among the plasma lipoproteins has been studied in vitro. In one series of three studies, postheparin plasma (10%) was incubated for 2 h with autologous plasma and the changes in the lipoprotein association of apo E after lipase exposure were determined after lipoprotein fractionation on 4% agarose columns. Specificity for LPL or HTGL was achieved by inhibition with goat anti-human HTGL or with 1 M NaCl, respectively. In another study, LPL and HTGL were partially purified from human postheparin plasma. The independent effects of these enzymes on the lipoprotein association of apo E were then examined after incubation of plasma in the absence or presence of one or both lipases. Data from both types of in vitro study showed that LPL-mediated triglyceride hydrolysis in the absence of HTGL activity was accompanied by a loss of apo E from triglyceride-rich lipoproteins, a gain or no change in the apo E-containing lipoproteins the size of intermediate density lipoproteins (IDL) and inconsistent changes in the apo E mass associated with high density lipoproteins (HDL). HTGL activity, on the other hand, in the absence of LPL, resulted in a redistribution of apo E from lipoproteins the size of IDL and a gain by those of HDL size. These studies thus support previous in vivo studies which pointed toward a specific role for HTGL in the processing of apo E containing IDL.

The ansamycins: a novel class of hypolipidemic agents with a high affinity for lipoproteins.

The ansamycins are derivatives of 3-piperazino rifamycin with potent hypolipidemic activity in nonprimate and primate species. Since the cholesterol reduction results from increased uptake and catabolism of lipoprotein cholesterol, it was hypothesized that the hydrophobicity of the ansamycins could result in a lipoprotein association which facilitates clearance. When radiolabeled ansamycins CGP 43371 or CGS 24565 were incubated with human plasma, > 95% was lipoprotein-bound up to drug levels of 25 microM. With plasma from chow-fed rats, radiolabeled compounds again distributed with the lipoproteins. Feeding a cholesterol/cholic acid diet to rats shifted the cholesterol distribution to lower density lipoproteins and in vitro incubation resulted in a shift of radiolabeled drug to lower density lipoproteins as well. Intravenous administration of radiolabeled ansamycins to chow-fed or cholesterol-fed rats resulted in a plasma lipoprotein binding profile indistinguishable from the corresponding in vitro incubations. When [14C]-CGP 43371 bound in vitro to high density lipoprotein (HDL) was reincubated with increasing concentrations of low density lipoprotein (LDL), a concentration-dependent fall in HDL association and increase in LDL binding was observed. Thus, the ansamycins have a high affinity for all plasma lipoproteins and can transfer between lipoprotein fractions. When [125I]-labeled LDL or HDL was incubated with CGP 43371 and Hep G2 cells, the cell association of the 125I label was significantly increased in a dose-dependent manner. In addition, plasma clearance of [14C]cholesterol oleate-labeled HDL coinjected with CGP 43371 was accelerated relative to control rats and radioactivity was specifically increased in livers of CGP 43371-treated rats. The physical association of the ansamycins with lipoproteins may thus lead to subtle conformational changes and enhanced hepatic uptake.

The effects of plasma exchange on cholesterol metabolism.

Four patients heterozygous for familial hypercholesterolaemia were treated by repeated plasma exchange with or without lipid-lowering drugs. Repeated plasma exchange without drug therapy in 3 patients was associated with a significant 18--28% decrement in plasma cholesterol level, comparing control with plateau values observed 3 weeks after exchange. Further decrements in plateau values followed the addition of lipid-lowering drugs used in combination, clofibrate--nicotinic acid or clofibrate--nicotinic acid--cholestyramine (range of total decrement 39--50%). Plasma exchange was associated with an increased excretion of endogenous faecal steroids, but this increase was completely abolished by the subsequent administration of clofibrate--nicotinic acid. This therapy prevented any increase in bile acid excretion with concomitant use of cholestyramine resin. Plasma exchange with drug therapy was associated with a sustained rise in plasma cholesterol specific radioactivity. In a fourth patient, clofibrate--nicotinic acid was administered prior to plasma exchange and led to a 24% fall in plasma cholesterol. Subsequent plasma exchange in this patient produced no sustained change in plasma cholesterol plateau level. In two patients, withdrawal of drugs allowed plasma cholesterol to return to pre-exchange control levels. These observations suggest that plasma exchange probably produced an increase in endogenous cholesterol synthesis and a mobilisation of tissue cholesterol. In relation to plateau cholesterol values 3 weeks after an exchange, the data suggested that the reduction in plasma cholesterol level with plasma exchange and drug therapy could have been achieved by intensive drug therapy alone.

Effect of a novel series of macrocyclic hypolipidemic agents on plasma lipid and lipoprotein levels of four non-primate species.

The ansamycins are structurally novel hypolipidemic agents derived from rifampicin, but lacking antibacterial activity. Oral or intravenous administration resulted in rapid lowering of plasma cholesterol in rats, hamsters, guinea pigs and dogs. In the chow-fed rat, three related compounds (CGP 43371, CGS 23810 and CGS 24565) exhibited ED50 values of 13.7, 3.1 and 0.18 mg/kg, respectively. A feature common to the lipid lowering documented in these four species was the concomitant reduction of low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol. In the chow-fed rat, however, apolipoprotein AI (apo AI) levels were much less affected than were those of HDL cholesterol. CGP 43371 at 3 and 10 mg/kg, lowered HDL cholesterol by 20% and 39%, respectively, whereas plasma apo AI was reduced by only 1% and 12%. Similarly, in lipoprotein fractions separated by ultracentrifugation, apo AI was unchanged in the d = 1.019-1.21 g/ml fraction after treatment with 3 or 10 mg/kg of CGP 43371, but HDL cholesterol was reduced 12% and 26% in this fraction at the two dose levels. Plasma and lipoprotein apo B levels, on the other hand, were reduced to a level equivalent to that of the reduction in cholesterol. The ansamycins thus represent a new structural series which may possess a novel mechanism of action as well, involving differential effects on HDL cholesterol and protein.

Isolation of apolipoprotein E-containing lipoproteins by immunoaffinity chromatography.

These data suggest that subfractionation of lipoproteins by immunoaffinity chromatography according to apolipoprotein content provides a valuable method for physical isolation of intact lipoprotein subclasses. While this study has focused specifically on apoE-containing lipoproteins, the technique of immunoaffinity isolation clearly has wider application. It must be emphasized that antibodies differ with regard to affinity and avidity, and that both binding and elution conditions may need to be adjusted for each group of antibodies. Maintenance of physical integrity of lipoproteins thus isolated must also be evaluated independently for each antibody. Nevertheless, immunoaffinity isolation of apolipoprotein-specific subclasses offers a powerful tool for preparing lipoproteins which should reflect physical and/or metabolic properties conferred by the apolipoprotein of interest.

An evaluation of multidisciplinary intervention for chronic fatigue syndrome with long-term follow-up, and a comparison with untreated controls.

Individuals meeting the Fukuda et al definition for chronic fatigue syndrome completed a multidisciplinary assessment that included medical, psychiatric, behavioral, and psychological evaluations. Patients were then offered a comprehensive multidisciplinary intervention that included (1) bringing the patient under optimal medical management; (2) treating any ongoing affective or anxiety disorder pharmacologically; and (3) implementing a comprehensive cognitive-behavioral treatment program. Fifty-one patients proceeded to treatment. The cognitive-behavioral component was carried out through the use of a therapist working with the patients in their own environments. The program was individually tailored to patients, but included (1) structured physical exercise and activation; (2) sleep management strategies; (3) careful activity management; (4) regulation of stimulant intake and reductions in use of symptomatic medications; (5) cognitive intervention designed to deal with patients' beliefs concerning the nature of their disorder; (6) participation of patients' family; and (7) efforts to establish specific vocational and avocational goals. Third parties were encouraged to collaborate cooperatively. Employers were urged to provide employment opportunities and facilitate a graduated but time-targeted return to work. Disability carriers were encouraged to provide interim financial support in the form of disability benefits, support therapeutic intervention, but also to establish a clear time-frame to access to benefits. Of 51 treated patients, 31 returned to gainful employment, 14 were functioning at a level equivalent to employment, and 6 remained significantly disabled. Twenty of the original 71 patients were contacted an average of 33 months later. Patients who had been treated showed good maintenance of gains. Untreated patients showed improvement in only a minority of cases.

Abnormalities in lipoprotein metabolism in Gaucher type 1 disease.

We have previously described an association between Gaucher type 1 disease and reduced levels of total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol. Plasma concentrations of apolipoprotein B and apolipoprotein AI were reduced in these subjects, while plasma apolipoprotein E (apoE), which can be synthesized and secreted by macrophages, was increased. To study the pathophysiologic basis for these changes in lipoprotein and apolipoprotein levels, we studied very low density lipoprotein (VLDL), LDL, and HDL metabolism in-depth in four subjects with Gaucher disease. Gel filtration of their plasma revealed that apoE was present in essentially a single population of lipoproteins in the large HDL range. In subject no. 4, studied presplenectomy and post-splenectomy, plasma apoE levels fell after surgery in association with a redistribution of apoE among the plasma lipoproteins to a pattern seen in normal subjects. Determination of the rates of secretion and catabolism of VLDL apoB and triglyceride were within normal limits. The reduced plasma levels of LDL and HDL cholesterol, and of both plasma apoB and apoAI, were associated with increased fractional catabolic rates of these apolipoproteins in LDL and HDL. These results indicate that the hypocholesterolemia present in subjects with Gaucher type 1 disease is associated with increased fractional catabolism of LDL and HDL. These findings, together with the evidence for alternations in plasma apoE metabolism in this disorder, suggest a role for the macrophage as the basis for these abnormalities.

Plasma lipoprotein abnormalities associated with acquired hepatic triglyceride lipase deficiency.

Two enzymes, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), are released into human plasma after intravenous injection of heparin. LPL is the major enzyme responsible for initiating catabolism of chylomicrons and very-low-density lipoproteins (VLDL). The physiological role of HTGL is less certain. HTGL has been postulated to be an alternate enzyme to LPL in hydrolysis of triglyceride in VLDL and to be an important enzyme for removal of phospholipid from both low-density lipoproteins (LDL) and high-density lipoproteins (HDL). In this latter role, this enzyme would convert larger, lighter lipoprotein particles to smaller denser particles. HTGL deficiency has been found in severe liver disease and with a genetic deficiency of this enzyme. A unique patient is described with acquired hepatic triglyceride lipase deficiency and vitamin A intoxication. This patient developed hypercholesterolemia with an increase in both LDL and HDL. An increased proportion of lighter LDL (LDL1) and HDL (HDL2) was noted. In addition, after administration of heparin there was no shift in the distribution of apoE in plasma fractionated using a column containing 4% agarose. These findings are consistent with a postulated role of HTGL in metabolism of light LDL and HDL particles and some classes of apoE containing lipoproteins.