MEAD: an interdisciplinary study of the marine effects of atmospheric deposition in the Kattegat.

This paper summarises the results of the EU funded MEAD project, an interdisciplinary study of the effects of atmospheric nitrogen deposition on the Kattegat Sea between Denmark and Sweden. The study considers emissions of reactive nitrogen gases, their transport, transformations, deposition and effects on algal growth together with management options to reduce these effects. We conclude that atmospheric deposition is an important source of fixed nitrogen to the region particularly in summer, when nitrogen is the limiting nutrient for phytoplankton growth, and contributes to the overall eutrophication pressures in this region. However, we also conclude that it is unlikely that atmospheric deposition can, on its own, induce algal blooms in this region. A reduction of atmospheric nitrogen loads to this region will require strategies to reduce emissions of ammonia from local agriculture and Europe wide reductions in nitrous oxide emissions.

Enhanced thermogenic responsiveness during chronic ephedrine treatment in man.

The thermogenic effect of a single oral dose of ephedrine (1 mg/kg body weight) was studied by indirect calorimetry in five women with 14% overweight before, during and 2 mo after 3 mo of chronic ephedrine treatment (20 mg, perorally, three times daily). Before treatment and 2 mo after its cessation a similar thermogenic response to ephedrine was observed. The total extra consumption of oxygen was 1.3 1 before and 1.2 1 after cessation of the chronic treatment. After 4 and 12 wk of treatment ephedrine elicited a more sustained response, the extra oxygen consumption in the 3 h following ephedrine intake being 7.0 and 6.9 1, respectively. The ratio of serum T3 to T4 increased significantly after 4 wk of treatment (15.6 +/- 1.3 vs 19.4 +/- 2.4; p less than 0.05), but decreased below the initial value after 12 wk treatment. The mean body weight was significantly reduced after 4 and 12 wk of treatment (2.5 and 5.5 kg, respectively). An improved capacity for beta-adrenergic induced thermogenesis may be useful in the treatment of obesity.

What do pharmacological approaches to obesity management offer? Linking pharmacological mechanisms of obesity management agents to clinical practice.

Obesity is characterised by pathophysiological defects affecting both sides of the energy balance equation. Individuals with a predisposition to obesity have impaired appetite control when diets are fat-rich and energy dense. They also exhibit a lower than expected resting metabolic rate (RMR). A low RMR, in concert with a sedentary lifestyle, contributes to a low total energy output, which may lead to obesity if continued over a period of years. A low metabolic rate seems to be genetically determined, and is partly caused by low sympathetic nervous system activity. Classical treatment programmes for obesity do not provide a satisfactory long-term outcome for the majority of patients. Patients who achieve only a small weight loss during dietary therapy, and have a tendency to weight regain, are characterised by lower energy expenditure, lower sympathetic activity, and a reduced ability to mobilise fat stores, compared with patients who are more successful at losing weight. It is reasonable to improve or normalise these traits by supporting the dietary approach with pharmacological manipulation of central and peripheral pathways. Agents which stimulate adrenergic neurons are particularly suitable because they offer mechanisms for inhibiting hunger and for stimulating energy expenditure, lipolysis and fat oxidation. Sympathomimetic compounds can reduce appetite and increase energy expenditure. Energy expenditure can be increased by 5-10% via stimulation of a combination of beta-adrenoceptors; beta3-adrenoceptors may predominate during chronic therapy. This increased energy expenditure increases the relative proportion of fat oxidation; as this is not fully compensated by increased energy intake, a negative energy balance occurs. This mechanism may be responsible for the long-term weight loss efficiency of agents like ephedrine/caffeine and sibutramine. Pharmacotherapy can be used to support short-term induction of weight loss or long-term weight maintenance. In the latter case, adrenergic agents enable a greater proportion of patients to maintain a satisfactory weight loss, compared with patients treated with conventional programmes alone. Pharmacotherapy which stabilises the size of fat stores at a lower level contributes indirectly to a pronounced improvement of risk factors, leading to a decreased potential for cardiovascular disease, type 2 diabetes and associated morbidity.

[Evaluation of patients with below knee amputation with respect to postoperative prosthesis fitting]. / Evaluering af crusamputerede patienter med henblik på postoperativ proteseforsyning.

A follow-up of 78 patients who underwent amputations just below the knee at Herlev University Hospital in the county of Copenhagen during the period 1985-88 is reported. The examination was carried out at an average of 39 months later. There was a high early mortality postoperatively as well as in the subsequent years. Of the survivors, about 87% were found to be candidates for prosthetic fitting. Nearly all of these patients became functional ambulators. The long-term survival rate was primarily correlated to a reduced occurrence of concurrent medical diseases, especially of cardiovascular nature. All women with diabetes mellitus were deceased at the time of examination. This is a well-known phenomenon, relating diabetes with a six times higher mortality risk. The study indicates that the effort and expense of fitting and training patients with prostheses may be well worthwhile.

[Daytime sedation measured after intake of nitrazepam and lorazepam, respectively, as hypnotics for 10 days]. / Dagsedation målt efter indtagelse af henholdsvis nitrazepam og lorazepam som hypnotikum gennem ti døgn.

A prospective double-blind cross-over investigation was undertaken among 46 geriatric patients (62-92 years) in which either 5 mg nitrazepam or 1 mg lorazepam were administered as hypnotics for two periods of ten days. No significant differences were observed in the quality of sleep but the objective psychomotor tests and the patients' subjective experience of hang-overs showed that there were significant differences in the frequencies of side effects in favour of lorazepam. It is concluded that daytime sedation after repetitive administration of a benzodiazepine preparation depends upon the half-life and that side effects are revealed better by psychomotor tests than by intellectual, cognitive tests and that lorazepam should be given preference to nitrazepam as a hypnotic for elderly patients.

[Increased urea synthesis in patients with active inflammatory bowel disease]. / Accelereret urinstofsyntese hos patienter med aktiv inflammatorisk tarmsygdom.

Patients with active inflammatory bowel disease are often reported to be in negative nitrogen balance. Therefore, we examined basal and amino acid stimulated urea synthesis in 11 patients with active inflammatory bowel disease and in 10 patients with non-active disease. A primed continuous infusion of an amino acid mixture was given from t = 1 h to t = 5 h; during the first and the last two hours no amino acid infusion was given. Urea nitrogen synthesis rate was quantified independently of changes in blood amino acid concentration by means of the functional hepatic nitrogen clearance, i.e. the linear slope of the regression of urea nitrogen synthesis rate on blood amino acid concentration. Basal and amino acid stimulated urea nitrogen synthesis rate as well as functional hepatic nitrogen clearance were elevated twofold in the patients with active disease. No differences between the two groups were observed as regards basal or stimulated plasma glucagon, cortisol, catecholamines and serum levels of interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6. The results show that liver function related to conversion of amino-nitrogen to urea is increased and may contribute to the less efficient nitrogen economy in patients with active inflammatory bowel disease.

Intra-articular sodium hyaluronate 2 mL versus physiological saline 20 mL versus physiological saline 2 mL for painful knee osteoarthritis: a randomized clinical trial.

OBJECTIVE: Methodological constraints weaken previous evidence on intra-articular viscosupplementation and physiological saline distention for osteoarthritis. We conducted a randomized, patient- and observer-blind trial to evaluate these interventions in patients with painful knee osteoarthritis. METHODS: We centrally randomized 251 patients with knee osteoarthritis to four weekly intra-articular injections of sodium hyaluronate 2 mL (Hyalgan 10.3 mg/mL) versus physiological saline 20 mL (distention) versus physiological saline 2 mL (placebo) and followed patients for 26 weeks. Inclusion criteria were age over 59 years and daily knee pain more than 20 mm on a 100-mm visual analogue scale (VAS) without satisfactory response to analgesics. During the trial, rescue analgesic were allowed. The primary outcome was pain on movement. The secondary outcomes were pain at rest, pain during the night, Knee Injury and Osteoarthritis Outcome Score (KOOS), Osteoarthritis Research Society International (OARSI) criteria, and global assessment of the patient's condition. RESULTS: The mean age of the patients was 69.4 years; 55% were women. The effects of hyaluronate 2 mL, physiological saline 20 mL, and physiological saline 2 mL did not differ significantly in reducing knee pain, knee function, or consumption of analgesics. Using OARSI criteria, no significant differences were found. The VAS and KOOS outcomes all improved significantly over time (p<0.0005), regardless of intervention group. No adverse events were reported. CONCLUSIONS: Intra-articular hyaluronate or distention with physiological saline did not significantly reduce pain compared with physiological saline placebo in patients with osteoarthritis of the knee.

Subnormal energy expenditure: a putative causal factor in the weight gain induced by treatment of hyperthyroidism.

AIMS: To examine the causes of weight gain occurring as an adverse effect of treatment of hyperthyroidism. METHODS: We measured 24-h energy expenditure (EE), body composition and spontaneous physical activity (SPA) in eight patients before and 1 year after treatment of hyperthyroidism was initiated, and eight controls. RESULTS: One year after initiation of treatment thyrotropin was normalized, thyroid hormones had fallen to the lower end of the reference range and fat mass had increased by 3.5 kg (p < 0.001). Twenty-four hour EE adjusted for fat-free mass (FFM) was 15% higher in hyperthyroid patients before treatment than in controls (p = 0.003), and treatment decreased 24-h EE by 1.9 MJ/day (p = 0.001). After treatment, 24-h EE, adjusted for FFM, was similar to the controls. Multiple regression analyses showed that the suppressed EE could partly be attributed to an iatrogenic suppression of thyroid hormones, resulting in lower sleeping EE. Twenty-four hour SPA was normal in the hyperthyroid state, but decreased after treatment by 21% (p = 0.045), to a level not significantly different, but still below that of the controls. CONCLUSIONS: The study suggests that weight gain during treatment of hyperthyroidism might be due to subnormal levels of EE and SPA caused by a suppression of the thyroid hormone to a level in the lower end of the normal range.

Sibutramine and energy balance.

Obesity develops from a combination of low energy expenditure and increased energy intake. The current treatment strategy aims at reducing energy intake by a low-fat, high-complex-carbohydrate diet and increasing energy expenditure by increased physical activity. In a major proportion of obese patients, however, this treatment is ineffective and does not produce a satisfactory long-term result. Among the risk factors for weight gain and for an unsuccessful diet-induced weight loss in obese patients is a low metabolic rate, which can be attributed in part to a low sympathetic nervous system (SNS) activity. The low SNS activity may also have an adverse effect on appetite control. Pharmacological enhancement of the SNS may have a role in the normalization of the autonomic control of the disturbed energy balance in obesity. In animal studies, sibutramine causes a negative fat balance and weight loss, by a dual mechanism of action. Sibutramine enhances satiety by a combined noradrenergic and serotonergic effect, thus decreasing food intake. In addition, sibutramine stimulates thermogenesis by activating the SNS. Recent studies have demonstrated that sibutramine also enhances satiety, stimulates thermogenesis and diminishes the weight-loss induced decline in energy expenditure in humans, so the dual effect on energy balance seems to be responsible for the efficient fat loss and weight maintenance found in clinical trials on obese patients. In conclusion, sibutramine can contribute to normalization of the disturbed energy balance in obesity, by enhancing satiety and by the stimulation of energy expenditure.

Iliofemoral bypass surgery for lower limb ischaemia. A follow-up of 62 patients.

This study evaluates iliofemoral bypass reconstruction in limb-salvage, graft patency, and appearance of contralateral symptoms. The study included 62 consecutive iliofemoral bypass reconstructions during 1980-82. The indication for surgery was disabling intermittent claudication in 19% of the patients and severe ischaemia in 81%. At follow-up 42 patients were examined, 16 were dead and 4 were lost to follow-up. The primary mortality was 5%. At 3 years postoperatively the survival rate was 78%, ipsilateral limb-salvage 88%, graft patency 83%, and patency of the contralateral iliofemoral segment 92%. During the follow-up period reconstructive vascular surgery on the contralateral aortoiliac segment was performed in only 3 patients. The results of the iliofemoral bypass reconstruction in this study were comparable to the results of aortic bifurcation grafts, and the patency of the contralateral iliofemoral segment was higher than might have been expected. The iliofemoral bypass reconstruction seems to be useful for patients with unilateral affection of the iliofemoral segment, for limb-salvage concerning patients in poor general condition, and for patients who have had a contralateral amputation.

Increased hepatic urea synthesis in patients with active inflammatory bowel disease.

BACKGROUND/METHODS: Patients with active inflammatory bowel disease are often reported to be in negative nitrogen balance. Therefore, we examined basal and amino acid stimulated urea synthesis in 11 patients with active inflammatory bowel disease (six with Crohn's disease and five with ulcerative colitis) and in 10 patients with non-active disease (six with Crohn's disease and four with ulcerative colitis). A primed continuous infusion of an amino acid mixture was given from t = 1 h to t = 5 h; during the first and the last 2 h no amino acid infusion was given. Urea nitrogen synthesis rate was calculated in hourly intervals for 7 consecutive hours. Urea nitrogen synthesis rate was quantified independent of changes in blood amino acid concentration by means of the functional hepatic nitrogen clearance, i.e. the linear slope of the regression of urea nitrogen synthesis rate of blood amino acid concentration. RESULTS: Basal urea nitrogen synthesis rate was 24.5 +/- 2.9 mmol/h in the patients with no disease activity and 43.8 +/- 2.2 mmol/h in patients with active disease (p < 0.01). During amino acid infusion urea nitrogen synthesis rate was elevated two-fold in the patients with active disease. Functional hepatic nitrogen clearance was 28.2 +/- 1.5 1/h in patients with no disease activity and 56.1 +/- 4.1 1/h in patients with active disease (p < 0.01). No differences between the two groups were observed as regards basal or stimulated plasma glucagon and cortisol and serum levels of interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor alpha and interleukin-6. CONCLUSIONS: The results show that the liver function related to conversion of amino-nitrogen to urea is increased in patients with active inflammatory bowel disease. No differences among known and possible regulators of urea synthesis were found between the two groups. The accelerated hepatic amino-nitrogen conversion contributes to the less efficient nitrogen economy in patients with active inflammatory bowel disease.

Increased in vivo antibody activity against interferon alpha, interleukin-1alpha, and interleukin-6 after high-dose Ig therapy.

High-avidity antibodies against interferon alpha (IFN alpha), interleukin-1alpha (IL-1alpha), and IL-6 have been demonstrated in preparations of normal human IgG, and in vivo modulation of these cytokines may therefore account for immunomodulatory and anti-inflammatory effects of high-dose intravenous IgG therapy. We have investigated the in vivo recovery and the effect on serum cytokine levels of antibodies to IFN alpha, IL-1alpha, and IL-6 infused with IgG preparations. Fifteen treatment series of 0.4 g IgG/kg/d were administered over 3 days to eight patients with autoimmune diseases. All IgG preparations contained variable amounts of antibodies binding to 125I-labeled human IFN alpha2A, -IL-1alpha, and -IL-6, and the contents of these molecules correlated with increased levels in serum anticytokine activities after IgG infusion. The infused anti-IL-1alpha antibody activity was fully recovered, whereas the recovery of anti-IFN alpha2A antibodies was significantly reduced. Serum antiviral activities were significantly reduced after IgG therapy (before, 0 to 5.6 IU/mL; after, 0 to 0.6 IU/mL). In contrast, enzyme-linked immunosorbent assay (ELISA) showed no significant reduction in the serum levels of IL-6 (before, 1 to 70 pg/mL; after, 2 to 55 pg/mL), and the levels of IL-1alpha were consistently below the detection limit (<30 pg/mL). In conclusion, increased levels of antibodies to IFN alpha2A, IL-1alpha, and IL-6 occurred in patients receiving IgG and this reduced the serum antiviral activity.