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.

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.

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.

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.

Mid-line clefts of the atlas: a diagnostic dilemma.

Congenital clefts and other developmental anomalies of the atlas vertebra are rarely encountered. They are incidental findings discovered while investigating the cervical spine following trauma. Differentiation of developmental variants of the atlas from the burst fracture of Jefferson is essential to prevent unnecessary medical intervention.

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.

Prevalence of deep venous thrombosis in the lower extremities of children in the intensive care unit.

PURPOSE: To determine the prevalence of lower extremity deep venous thrombosis (LE-DVT) in children who spent at least 72 h in the pediatric intensive care unit (ICU). MATERIALS AND METHODS: Children up to the age of 17 years who spent at least 72 h in the ICU underwent lower extremity venous ultrasound at the end of their stay. Prevalence range for the sample size was calculated with a confidence interval of 95%. RESULTS: Among 76 children who spent 3-141 days in the ICU, the prevalence of acute (and silent) DVT was 4% (confidence interval 0-9%). All three affected children had femoral venous catheters in that leg during their ICU stay (17 unaffected children also had catheters). CONCLUSION: Children in an ICU setting are at significantly lower risk for thrombosis than adults in the same setting.

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 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 ansamycins: hypolipidemic agents stimulating cholesterol removal by nonclassical mechanisms.

The ansamycins CGP 43371 and CGS 24565 are derivatives of the antibiotic rifamycin that reduce plasma cholesterol levels in both primate and nonprimate species. In vivo, a striking accumulation of macrophage cholesteryl ester was seen in ansamycin-treated rats and hamsters, but carbon clearance studies and reticuloendothelial system blockade by gadolinium chloride indicated that phagocytosis was not involved. Simple addition of an ansamycin to macrophages or monocytes in vitro failed to stimulate radiolabeled lipoprotein cholesteryl ester association or mass accumulation. In contrast to mononuclear cells, however, the ansamycins did enhance radiolabeled lipoprotein cholesteryl ester association by liver cells in vitro. Primary hepatocyte cultures prepared from rats treated with radiolabeled CGP 43371 secreted CGP 43371 over an 18-h period in a fraction floating at d < 1.02 g/ml after density gradient ultracentrifugation that was relatively enriched in apoA-I. The medium containing this secreted [14C]GP 43371-labeled lipoprotein was capable of enhancing the cholesteryl ester content of macrophages in vitro, suggesting that ansamycin-induced liver modification of lipoproteins might be involved. These drugs may serve as valuable tools for studying mechanisms of lipoprotein uptake.

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.

Hypolipidaemic activity of a novel acyclic ansamycin derivative. Synthesis and pharmacokinetic and pharmacodynamic studies in rodents.

Certain classes of the antibacterial agent rifamycin SV have recently been shown to possess marked hypolipidaemic activity. An acyclic oxazolylrifamycin has been prepared and its hypolipidaemic properties evaluated; it was found to be significantly more potent when administered orally to Wistar and Sprague-Dawley rats than other previously described rifamycin hypolipidaemics. The plasma decay rate of a bolus of intravenously administered 125I-LDL (low density lipoprotein) was significantly greater in treated rats than in rats receiving vehicle alone, compatible with a drug-induced increase in LDL catabolism. A bolus of radiolabelled drug was rapidly removed from the circulation by the liver, the presumed target organ. Compound 3 constitutes the first example of a new class of acyclic hypolipidaemic ansamycins.

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.

Independent regulation of plasma apolipoprotein C-II and C-III concentrations in very low density and high density lipoproteins: implications for the regulation of the catabolism of these lipoproteins.

Apolipoproteins C-II (apoC-II) and C-III (apoC-III) are distributed among all the major lipoprotein classes, particularly very low density (VLDL) and high density lipoproteins (HDL). We have determined concentrations of apoC-II and apoC-III in VLDL and HDL in subjects with a wide range of VLDL triglyceride and HDL cholesterol levels, and correlated these levels with fractional catabolic rates (FCR) of VLDL triglyceride and HDL apolipoprotein A-I (apoA-I). Both apoC-II and apoC-III levels increased in VLDL as VLDL apolipoprotein B (apoB) and triglyceride levels rose. The rate of rise of VLDL apoC-III, however, was approximately 3 times greater than that of apoC-II, and positive correlations were present between the ratio of VLDL apoC-III/apoC-II and both VLDL apoB (r = 0.59; P less than 0.01) and VLDL triglyceride (r = 0.70; P less than 0.005) levels. Univariate analysis demonstrated that the FCR for VLDL triglyceride was inversely related to the ratio of apoC-III/apoC-II in VLDL (r = -0.58; P less than 0.05), although this relationship was not significant in a multivariate analysis. In HDL, concentrations of apoC-III and apoA-I were correlated (r = 0.73; P less than 0.005) while no correlation was observed between apoC-II and apoA-I levels. Univariate analyses of HDL variables revealed inverse correlations between the concentration of apoC-III and the FCR for apoA-I (r = -0.67; P less than 0.005) and between the ratio of apoC-III/apoA-I and the FCR for apoA-I (r = -0.66; P less than 0.005). Multivariate analysis confirmed the latter relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

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 distribution of apolipoprotein E in familial hypercholesterolemia.

Although familial hypercholesterolemia (FH) has been well characterized in terms of the etiology of the major lipoprotein abnormality, that of low density lipoproteins (LDL), less information is available on changes in other lipoproteins which could influence the atherogenic process in this disorder. The present study has focused on such potential abnormalities by studying in detail the lipoprotein association of apolipoprotein E (apo E) in a large group of subjects homozygous for FH. Total plasma apo E levels in homozygous subjects were significantly elevated (p less than 0.001) relative to heterozygous subjects which were, in turn, significantly greater (p less than 0.001) than controls (137.6 micrograms/ml, 69.4 micrograms/ml, 46.5 micrograms/ml respectively). After separation of plasma lipoproteins by 4% agarose chromatography, an increased mass of apo E in lipoproteins of intermediate size was present; this may reflect the absence of LDL receptors that normally mediate their clearance. Homozygous FH subjects also demonstrated an increased mass of apo E-enriched high density lipoproteins (HDL) of large size, but a reduction in HDL cholesterol and apo A-I. The increase in the potentially atherogenic remnant lipoproteins and the decrease in HDL are associated with an increased risk for atherosclerosis, even in the absence of the LDL elevation, which is characteristic of FH. The increase in apo E-enriched HDL could reflect a compensatory mechanism that permits reverse cholesterol transport in the absence of LDL receptors.

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.

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.