An AMP Kinase-pathway dependent integrated stress response regulates ageing and longevity.

The purpose of this article is to investigate the role of the AMP-kinase pathway (AMPK pathway) in the induction of a concomitant set of health benefits by exercise, numerous drugs, and health ingredients, all of which are adversely affected by ageing. Despite the AMPK pathway being frequently mentioned in relation to both these health effects and ageing, it appears challenging to understand how the activation of a single biochemical pathway by various treatments can produce such a diverse range of concurrent health benefits, involving so many organs. We discovered that the AMPK pathway functions as an integrated stress response system because of the presence of a feedback loop in it. This evolutionary conserved stress response system detects changes in AMP/ATP and NAD/NADH ratios, as well as the presence of potential toxins, and responds by activating a common protective transcriptional response that protects against aging and promotes longevity. The inactivation of the AMPK pathway with age most likely explains why ageing has a negative impact on the above-mentioned set of health benefits. We conclude that the presence of a feedback loop in the AMP-kinase pathway positions this pathway as an AMPK-ISR (AMP Kinase-dependent integrated stress response) system that responds to almost any type of (moderate) environmental stress by inducing various age-related health benefits and longevity.

Supramolecular surface functionalization via catechols for the improvement of cell-material interactions.

Optimization of cell-material interactions is crucial for the success of synthetic biomaterials in guiding tissue regeneration. To do so, catechol chemistry is often used to introduce adhesiveness into biomaterials. Here, a supramolecular approach based on ureido-pyrimidinone (UPy) modified polymers is combined with catechol chemistry in order to achieve improved cellular adhesion onto supramolecular biomaterials. UPy-modified hydrophobic polymers with non-cell adhesive properties are developed that can be bioactivated via a modular approach using UPy-modified catechols. It is shown that successful formulation of the UPy-catechol additive with the UPy-polymer results in surfaces that induce cardiomyocyte progenitor cell adhesion, cell spreading, and preservation of cardiac specific extracellular matrix production. Hence, by functionalizing supramolecular surfaces with catechol functionalities, an adhesive supramolecular biomaterial is developed that allows for the possibility to contribute to biomaterial-based regeneration.

Amino acid profile during exercise and training in Standardbreds.

The objective of this study is to assess the influence of acute exercise, training and intensified training on the plasma amino acid profile. In a 32-week longitudinal study using 10 Standardbred horses, training was divided into four phases, including a phase of intensified training for five horses. At the end of each phase, a standardized exercise test, SET, was performed. Plasma amino acid concentrations before and after each SET were measured. Training significantly reduced mean plasma aspartic acid concentration, whereas exercise significantly increased the plasma concentrations of alanine, taurine, methionine, leucine, tyrosine and phenylalanine and reduced the plasma concentrations of glycine, ornithine, glutamine, citrulline and serine. Normally and intensified trained horses differed not significantly. It is concluded that amino acids should not be regarded as limiting training performance in Standardbreds except for aspartic acid which is the most likely candidate for supplementation.

The incidence and severity of gastric ulceration does not increase in overtrained Standardbred horses.

REASONS FOR PERFORMING STUDY: Gastric ulceration can be caused by different pathophysiological mechanisms including dietary factors, psychological stress and exercise. Overtraining is a medical syndrome in performance horses associated with altered hormone levels, altered feed intake, altered behaviour and decreased performance. These components might lead to a higher incidence of gastric ulceration in overtrained horses. OBJECTIVES: To investigate whether the incidence of gastric ulceration is increased in overtrained compared to control horses. METHODS: A longitudinal training study with twelve 1.5 years old Standardbred horses was performed on a treadmill for a total of 32 weeks. Training was divided into 4 periods: (1) acclimatisation (2) training (3) intensified training, and (4) detraining. In period 3, the horses were randomly divided into 2 groups: control (C) and intensified trained group (IT). At the end of each period, gastroscopy was performed in conscious horses after withholding feed for 12 h and water for 6 h using a 3.5 m video gastroendoscope. Lesion scores were assigned to areas of the stomach and graded 1-4. Logistic regression was used for statistical calculations. RESULTS: Evaluation of the stomach revealed only minor changes (grades 1 or 2) on each occasion. There were no significant differences in gastric lesion scores between groups or periods. Most lesions (70%) were found around the minor curvature. After detraining no lesions (0%) were found in contrast to periods 1 (40%, P = 0.056), 2 (30%) and 3 (30%). CONCLUSIONS: Experimentally-induced overtraining does not increase the incidence of gastric ulceration in normally fed Standardbred horses and detraining appears to reduce gastric ulceration.

Normal function of the hypothalamic-pituitary growth axis in three dwarf Friesian foals.

Serial blood samples were collected from three dwarf Friesian foals to examine their endogenous growth hormone (GH) profiles, and the integrity of the GH-insulin-like growth factor-1 (IGF-1) axis was tested in one of them by examining its responses to the administration of GH-releasing hormone (GHRH) and to 10 days of treatment with recombinant equine GH. The basal serum concentrations of IGF-1 in the three dwarf foals were compared with those in nine age-matched normal foals. All the dwarf foals secreted endogenous GH. Stimulation with 7.0 microg/kg GHRH led to a 1400 per cent increase in plasma GH concentration in the dwarf foal tested, and 10 daily subcutaneous treatments with 20 microg/kg recombinant equine GH led to a 100 per cent increase in its serum IGF-1 concentration. The basal serum concentrations of IGF-1 in the dwarf foals were not significantly different from those of the normal foals.

Overtrained horses alter their resting pulsatile growth hormone secretion.

The influence of intensified and reduced training on nocturnal growth hormone (GH) secretion and elimination dynamics was studied in young (1.5 yr) Standardbred geldings to detect potential markers indicative for early overtraining. Ten horses trained on a treadmill for 32 wk in age-, breed-, and gender-matched fixed pairs. Training was divided into four phases (4, 18, 6, and 4 wk, respectively): 1) habituation to high-speed treadmill trotting, 2) normal training, in which speed and duration of training sessions were gradually increased, 3) in this phase, the horses were divided into 2 groups: control (C) and intensified trained (IT) group. In IT, training intensity, duration, and frequency were further increased, whereas in control these remained unaltered, and 4) reduced training (RT). At the end of phases 2, 3, and 4, blood was sampled overnight every 5 min for 8 h for assessment of GH secretory dynamics using pulse detection, deconvolution analysis, and approximate entropy (ApEn). Intensified training induced overtraining (performance decreased by 19% compared with C), which was associated with an increase in concentration peaks number (3.6 vs. 2.0, respectively), a smaller peak secretion pattern with a prolonged half-life (15.2 vs. 7.3 min, respectively), and an increased ApEn (0.89 vs. 0.49, respectively). RT did not lead to full recovery for the overtrained horses. The increased irregularity of nocturnal GH pulsatility pattern is indicative of a loss of coordinated control of GH regulation. Longer phases of somatostatin withdrawal are hypothesized to be the underlying mechanism for the observed changes in GH pulsatility pattern.

Toxicological evaluation of pomegranate seed oil.

In this manuscript, the toxicology and safety of pomegranate seed oil (PSO) was evaluated by in vitro (Ames, chromosomal aberration), and in vivo toxicity tests (acute toxicity and 28-day toxicity in Wistar rats). No mutagenicity of PSO was observed in the absence and presence of metabolic activation up to precipitating concentrations of 5000 microg/plate (Ames test) or 333 microg/ml (chromosome aberration test). The acute oral toxicity study revealed no significant findings at 2000 mg PSO/kg body weight. In the 28-day dietary toxicity study PSO was dosed at concentrations of 0, 10,000, 50,000 and 150,000 ppm, which resulted in a mean intake of 0-0, 825-847, 4269-4330 and 13,710-14,214 mg PSO/kg body weight per day in males-females, respectively. At 150,000 ppm dietary exposure to PSO, a much higher dose than the level of PSO that elicits antidiabetic and anti-inflammatory efficacy, increased hepatic enzyme activities determined in plasma (aspartate, alanine aminotransferase and alkaline phosphatase) and increased liver-to-body weight ratios were observed. However, these effects might be the result of a physiological response to exposure to a very high level of a fatty acid which is not part of the normal diet, and are most likely not toxicologically relevant. The no observable adverse effect level (NOAEL) was 50,000 ppm PSO (=4.3 g PSO/kg body weight/day).

Long-standing, insulin-treated type 2 diabetes patients with complications respond well to short-term resistance and interval exercise training.

OBJECTIVE: To determine the feasibility and the benefits of combined resistance and interval exercise training on phenotype characteristics and skeletal muscle function in deconditioned, type 2 diabetes (T2D) patients with polyneuropathy. DESIGN: Short-term, single-arm intervention trial. METHODS: Eleven male T2D patients (age: 59.1+/-7.5 years; body mass index: 32.2+/-4.0 kg/m2) performed progressive resistance and interval exercise training thrice a week for 10 weeks. Besides primary diabetes outcome measures, muscle strength (MUST), maximal workload capacity (Wmax), whole-body peak oxygen uptake (VO2peak) and muscle oxidative capacity (MUOX), intramyocellular lipid (IMCL) and glycogen (IMCG) storage, and systemic inflammation markers were determined before and after training. Daily exogenous insulin requirements (EIR) and historic individualized EIR were gathered and analysed. RESULTS: MUST and Wmax increased with 17% (90% confidence intervals 9-24%) and 14% (6-21) respectively. Furthermore, mean arterial blood pressure declined with 5.5 mmHg (-9.7 to -1.4). EIR dropped with 5.0 IU/d (-11.5 to 1.5) compared with baseline. A decline of respectively -0.7 mmol/l (-2.9 to 1.5) and -147 micromol/l (-296 to 2) in fasting plasma glucose and non-esterified fatty acids concentrations were observed following the intervention, but these were not accompanied by changes in VO2peak, MUOX, IMCL or IMCG, and blood glycolysated haemoglobin, adiponectin, tumor necrosis factor-alpha and/or cholesterol concentrations. CONCLUSION: Short-term resistance and interval exercise training is feasible in deconditioned T2D patients with polyneuropathy and accompanied by moderate improvements in muscle function and blood pressure. Such a specific exercise regimen may provide a better framework for future exercise intervention programmes in the treatment of deconditioned T2D patients.

Hormonal responses to acute exercise, training and overtraining. A review with emphasis on the horse.

Overtraining is an imbalance between training and recovery leading to symptoms associated with a neuroendocrine dysbalance called the overtraining syndrome, a disease characterized by behavioral, emotional and physical symptoms similar with depression. Although the prevalence of overtraining is high in human and equine athletes, at present no sensitive and specific test is available to prevent or diagnose overtraining. Nowadays, it is believed that combination of different (hormonal) parameters appear to be the best indicators of overtraining. Therefore, this review provides a summary of previous literature examining the response of the hypothalamic-pituitary-adrenal (HPA) axis and the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis to acute and chronic exercise as well as overtraining in humans and horses. The exercise induced hormonal responses seem to be equal for the equine as well as the human athlete, which makes comparisons possible. Repeated bouts of exercise are suggested to provide a way to detect subtle changes in hormonal responses in the individual athlete, which may make them an important tool in detecting early overtraining. This should be combined with corticotropin releasing hormone (CRH) stimulation tests and basal ACTH and GH pulsatility determination. Further research is needed to establish the correct training intensity and rest period for the exercise test in equines.

Skeletal muscle uncoupling protein-3 restores upon intervention in the prediabetic and diabetic state: implications for diabetes pathogenesis?

AIM: Skeletal muscle uncoupling protein-3 (UCP3) is reduced in type 2 diabetes, and in the pre-diabetic condition of impaired glucose tolerance (IGT). Here we examined whether intervention programs known to improve insulin sensitivity are paralleled by an increase in skeletal muscle UCP3 protein levels. METHODS: Skeletal muscle UCP3 protein content was measured before and after one year of an exercise intervention in muscle biopsies of eight diabetic subjects. In addition, UCP3 was measured in IGT subjects before and after 1 year of following a lifestyle-intervention program or serving as control. RESULTS: In the diabetic patients a significant increase of approximately 75% in UCP3 protein was found after 1 year of exercise training (P < 0.05). In IGT subjects UCP3 protein increased in the intervention group (P = 0.02), while UCP3 remained unaltered in the control group (P = 0.64). CONCLUSION: Both, exercise training and a lifestyle-intervention program increase UCP3 protein content in skeletal muscle of subjects with reduced glycaemic control, indicating a restoration towards normal UCP3 levels. These data support the idea that UCP3 has a role in the aetiology of type 2 diabetes mellitus.

Substrate source utilisation in long-term diagnosed type 2 diabetes patients at rest, and during exercise and subsequent recovery.

AIMS/HYPOTHESIS: Disturbances in substrate source metabolism and, more particularly, in fatty acid metabolism, play an important role in the aetiology and progression of type 2 diabetes. However, data on substrate source utilisation in type 2 diabetes are inconclusive. METHODS: [U-(13)C]palmitate and [6,6-(2)H(2)]glucose tracers were used to assess plasma NEFA and glucose oxidation rates and to estimate the use of muscle- and/or lipoprotein-derived triacylglycerol and muscle glycogen. Subjects were ten male patients who had a long-term (7 +/- 1 years) diagnosis of type 2 diabetes and were overweight, and ten matched healthy, male control subjects. Muscle biopsy samples were collected before and after exercise to assess muscle fibre type-specific intramyocellular lipid and glycogen content. RESULTS: At rest and during exercise, the diabetes patients had greater values than the controls for palmitate rate of appearance (Ra) (rest, 2.46 +/- 0.18 and 1.85 +/- 0.20 respectively; exercise, 3.71 +/- 0.36 and 2.84 +/- 0.20 micromol kg(-1) min(-1)) and rate of disappearance (Rd) (rest, 2.45 +/- 0.18 and 1.83 +/- 0.20; exercise, 3.64 +/- 0.35 and 2.80 +/- 0.20 micromol kg(-1) min(-1) respectively). This was accompanied by significantly higher fat oxidation rates at rest and during recovery in the diabetes patients (rest, 0.11 +/- 0.01 in diabetes patients and 0.09 +/- 0.01 in controls; recovery, 0.13 +/- 0.01 and 0.11 +/- 0.01 g/min respectively), despite significantly greater plasma glucose Ra, Rd and circulating plasma glucose concentrations. Furthermore, exercise significantly lowered plasma glucose concentrations in the diabetes patients, as a result of increased blood glucose disposal. CONCLUSION: This study demonstrates that substrate source utilisation in long-term-diagnosed type 2 diabetes patients, in whom compensatory hyperinsulinaemia is no longer present, shifts towards an increase in whole-body fat oxidation rate and is accompanied by disturbances in fat and carbohydrate handling.

The effect of long-term exercise on glucose metabolism and peripheral insulin sensitivity in standardbred horses.

REASONS FOR PERFORMING STUDY: To study the possible long-term effect of improved glucose tolerance in horses after long-term training, as the impact of exercise training on glucose metabolism is still unclear in the equine species. It is not known whether there is a direct long-term effect of training or if the measurable effect on glucose metabolism is the residual effect of the last exercise session. OBJECTIVES: To determine the chronic effect on glucose metabolism and peripheral insulin sensitivity of long-term training in horses by use of the euglycaemic hyperinsulinaemic clamp technique. METHODS: Eleven Standardbred horses were acclimatised to running on the high-speed treadmill for 4 weeks (Phase 1) followed by training for 18 weeks with an alternating endurance (approximately 60% HRmax) high intensity training programme (approximately 80% HRmax) (Phase 2). Training frequency was 4 days/week. At the end of Phase 1, a euglycaemic hyperinsulinaemic clamp was performed 72 h after the last bout of exercise in all horses. At the end of Phase 2, the horses were clamped 24 h or 72 h after the last bout of exercise. RESULTS: Glucose metabolism rate did not change significantly after 18 weeks of training, measured 72 h after the last exercise bout (0.018 +/- 0.009 and 0.022 +/- 0.006 mmol/kg bwt/min, respectively). Peripheral insulin sensitivity also did not change significantly following training (7.6 +/- 5.7 x 10(-6) and 8.0 +/- 3.1 x 10(-6), respectively). The same measurements 24 h after the last bout of exercise showed no significant differences. CONCLUSIONS: Results indicated that long-term training in Standardbreds neither changed glucose metabolism or insulin sensitivity 72 h after the last bout of exercise. POTENTIAL RELEVANCE: The fact that the beneficial effect of increased insulin sensitivity after acute exercise diminishes quickly in horses and no long-term effects on insulin sensitivity after chronic exercise have as yet been found in horses, implies that exercise should be performed on a regular basis in horses to retain the beneficial effect of improved insulin sensitivity.

Functional outcome 5 years after non-operative treatment of type A spinal fractures.

This study was conducted to study the functional outcome after non-operative treatment of type A thoracolumbar spinal fractures without neurological deficit. Functional outcome was determined following the International Classification of Functioning, Disability and Health, measuring restrictions in body function and structure, restrictions in activities, and restrictions in participation/quality of life. All patients were treated non-operatively for a type A thoracolumbar (Th11-L4) spinal fracture at the University Hospital Groningen, The Netherlands. Thirty-three of the eighty-one selected patients agreed to participate in the study (response-rate 41%). Respondents were older than non-respondents (mean 50.5 years vs. 39.2 years), but did not differ from each other concerning injury-related variables. Patients with a neurological deficit were excluded. Treatment consisted either of mobilisation without brace, or of bedrest followed by wearing a brace. Restrictions in body function and structure were measured by physical tests (dynamic lifting test and bicycle ergometry test); restrictions in activities were measured by means of questionnaires, the Roland Morris Disability Questionnaire (RMDQ) and Visual Analogue Scale Spine Score (VAS). Restrictions in participation/quality of life were assessed with the Short Form 36 (SF-36) and by means of return to work status. Thirty-seven per cent of the patients were not able to perform the dynamic lifting test within normal range. In the ergometry test, 40.9% of the patients performed below the lowest normal value, 36.4% of the patients achieved a high VO(2)-max. Mean RMDQ-score was 5.2, the mean VAS-score was 79. No significant differences between patients and healthy subjects were found in SF-36 scores, neither were differences found between braced and unbraced patients in any of the outcome measures. Concerning the return to work status, 10% of the subjects had stopped working and received social security benefits, 24% had arranged changes in their work and 14% had changed their job. We conclude that patients do reasonably well 5 years after non-operative treatment of a thoracolumbar fracture, although outcome is diverse in the different categories and physical functioning seems restricted in a considerable number of patients.

Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients.

AIMS/HYPOTHESIS: In the present study, we investigated the consequences of adipose tissue lipolytic inhibition on skeletal muscle substrate use in type 2 diabetic patients. MATERIALS AND METHODS: We studied ten type 2 diabetic patients under the following conditions: (1) at rest; (2) during 60 min of cycling exercise at 50% of maximal workload capacity and subsequent recovery. Studies were done under normal, fasting conditions (control trial: CON) and following administration of a nicotinic acid analogue (low plasma non-esterified fatty acid trial: LFA). Continuous [U-13C]palmitate and [6,6 -2H2]glucose infusions were applied to quantify plasma NEFA and glucose oxidation rates, and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected before and after exercise to determine net changes in lipid and glycogen content specific to muscle fibre type. RESULTS: Following administration of the nicotinic acid analogue (Acipimox), the plasma NEFA rate of appearance was effectively reduced, resulting in lower NEFA concentrations in the LFA trial (p<0.001). Plasma NEFA oxidation rates were substantially reduced at rest, during exercise and subsequent recovery in the LFA trial. The lower plasma NEFA oxidation rates were compensated by an increase in IMTG and endogenous carbohydrate use (p<0.05). Plasma glucose disposal rates did not differ between trials. In accordance with the tracer data, a greater net decline in type I muscle fibre lipid content was observed following exercise in the LFA trial (p<0.05). CONCLUSIONS/INTERPRETATION: This study shows that plasma NEFA availability regulates IMTG use, and that adipose tissue lipolytic inhibition, in combination with exercise, could be an effective means of augmenting intramuscular lipid and glycogen use in type 2 diabetic patients in an overnight fasted state.

Physiological, biochemical and psychological markers of strenuous training-induced fatigue.

The purpose of the study was to investigate whether severe fatigue, possibly leading to overreaching, could be diagnosed at an early stage by a combination of parameters. Seven well-trained male subjects (age [mean +/- SD]: 25.3 +/- 4.7 yr; body mass: 76 +/- 6.6 kg; VO2max: 61.1 +/- 7 ml.kg(-1).min(-1)) increased their training load by doubling their training volume and increasing the intensity by 15 % over a period of two weeks. Before and after this intensified training period subjects underwent a series of tests including a maximal incremental cycle ergometer test (Wmax) with continuous ventilatory measurements and blood lactate values, time trial, basal blood parameter tests (red and white blood profile), hormones [growth hormone (GH), insulin-like growth factor 1(IGF-1), adreno-corticotropic hormone (ACTH), cortisol], neuro-endocrine stress test [short insulin tolerance test (SITT), combined anterior pituitary test (CAPT) and exercise], a shortened Profile of Mood State (POMS), the estimated rate of perceived exertion (RPE) and a cognitive reaction time test. The intensified training period resulted in a significant increase of the training load (p <0.01), training monotony (p <0.01) and training strain (p <0.01). The RPE during training increased significantly (p <0.01) during the intensified training period. Total mood score obtained from the POMS tended to increase (p=0.06), reflecting an increase in worse mood state. A novel finding was that reaction times increased significantly, indicating that overreaching might adversely affect speed of information processing by the brain, especially for the most difficult conditions. After the intensified training period, neither changes in exercise-induced plasma hormone values, nor SITT values were observed. During the CAPT only cortisol showed a significant decrease after the intensified training period. Hemoglobin showed a significant decrease after the intensified training period whereas hematocrit, red blood cell count (RBC) and MCV tended to decrease. The intensified training had no effect on physical performance (Wmax or time trial), maximal blood lactate, maximal heart rate and white blood cell profile. The most sensitive parameters for detecting overreaching are reaction time performance (indicative for cognitive brain functioning), RPE and to a lesser extend the shortened POMS. This strongly suggests, that central fatigue precedes peripheral fatigue. All other systems,including the neuro-endocrine, are more robust and react most likely at a later stage in exhaustive training periods.

Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a).

OBJECTIVES: To investigate the effects of two different regimens of androgenic-anabolic steroid (AAS) administration on serum lipid and lipoproteins, and recovery of these variables after drug cessation, as indicators of the risk for cardiovascular disease in healthy male strength athletes. METHODS: In a non-blinded study (study 1) serum lipoproteins and lipids were assessed in 19 subjects who self administered AASs for eight or 14 weeks, and in 16 non-using volunteers. In a randomised double blind, placebo controlled design, the effects of intramuscular administration of nandrolone decanoate (200 mg/week) for eight weeks on the same variables in 16 bodybuilders were studied (study 2). Fasting serum concentrations of total cholesterol, triglycerides, HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C), HDL3-cholesterol (HDL3-C), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), and lipoprotein (a) (Lp(a)) were determined. RESULTS: In study 1 AAS administration led to decreases in serum concentrations of HDL-C (from 1.08 (0.30) to 0.43 (0.22) mmol/l), HDL2-C (from 0.21 (0.18) to 0.05 (0.03) mmol/l), HDL3-C (from 0.87 (0.24) to 0.40 (0.20) mmol/l, and Apo-A1 (from 1.41 (0.27) to 0.71 (0.34) g/l), whereas Apo-B increased from 0.96 (0.13) to 1.32 (0.28) g/l. Serum Lp(a) declined from 189 (315) to 32 (63) U/l. Total cholesterol and triglycerides did not change significantly. Alterations after eight and 14 weeks of AAS administration were comparable. No changes occurred in the controls. Six weeks after AAS cessation, serum HDL-C, HDL2-C, Apo-A1, Apo-B, and Lp(a) had still not returned to baseline concentrations. Administration of AAS for 14 weeks was associated with slower recovery to pretreatment concentrations than administration for eight weeks. In study 2, nandrolone decanoate did not influence serum triglycerides, total cholesterol, HDL-C, HDL2-C, HDL3-C, Apo-A1, and Apo-B concentrations after four and eight weeks of intervention, nor six weeks after withdrawal. However, Lp(a) concentrations decreased significantly from 103 (68) to 65 (44) U/l in the nandrolone decanoate group, and in the placebo group a smaller reduction from 245 (245) to 201 (194) U/l was observed. Six weeks after the intervention period, Lp(a) concentrations had returned to baseline values in both groups. CONCLUSIONS: Self administration of several AASs simultaneously for eight or 14 weeks produces comparable profound unfavourable effects on lipids and lipoproteins, leading to an increased atherogenic lipid profile, despite a beneficial effect on Lp(a) concentration. The changes persist after AAS withdrawal, and normalisation depends on the duration of the drug abuse. Eight weeks of administration of nandrolone decanoate does not affect lipid and lipoprotein concentrations, although it may selectively reduce Lp(a) concentrations. The effect of this on atherogenesis remains to be established.

Compassionate use programme of irinotecan in colorectal cancer patients in The Netherlands.

BACKGROUND: Irinotecan is an effective treatment for metastatic colorectal cancer. However, its use may be associated with troublesome adverse effects such as delayed diarrhoea, acute cholinergic syndrome and neutropenic infection. The manufacturer decided to release irinotecan for compassionate use in The Netherlands prior to its regulatory approval (June 1998) and first introduction for second-line treatment of metastatic colorectal cancer. In view of the drug's adverse effect profile this was done in a carefully controlled manner. METHODS: Irinotecan was made available to patients with colorectal cancer with elaborate precautions. Treating physicians requesting irinotecan for compassionate use received a protocol, providing recommendations for the proper use and the prevention/management of potentially troublesome adverse events. Limited demographic, toxicity and efficacy data were collected. RESULTS: Between June 1997 and September 1998, 112 patients were registered for this programme, 103 of whom actually received irinotecan. The percentage of patients experiencing grade 3-4 adverse effects was relatively low: delayed diarrhoea in 17%, nausea and vomiting 17%, acute cholinergic syndrome 6%, febrile neutropenia 4% and neutropenic infection 2%. Five partial tumour responses and a high proportion of patients with 'no change' were noted. CONCLUSIONS: The carefully controlled release of irinotecan for compassionate use with a very detailed protocol for guidance and advice on safety precautions seems to have contributed to the relatively safe use of the drug outside the setting of a formal clinical trial.

(R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function: in vitro and in vivo evaluation.

The mdr1 gene product P-glycoprotein (P-gp) is involved in the bioavailability and pharmacokinetics of various drugs. Racemic [(11)C]verapamil has been used to image P-gp expression in vivo. A racemic tracer, however, is not suitable for quantification. The purpose of the present study was to identify the most appropriate enantiomer of [(11)C]verapamil as a potential PET-tracer for quantifying P-gp function. The two enantiomers, (R)- and (S)-[(11)C]verapamil, were synthesized and studied in vivo. For the in vivo model mdr1a/1b double gene knock-out and wild type mice were used. The in vitro study made use of the LLC-PK1 MDR cell line to examine the P-gp mediated transport of both enantiomers. The biodistribution of (R)- and (S)-[(11)C]verapamil in dKO and WT mice demonstrated no stereoselectivity of verapamil for P-gp in the blood-brain barrier and in the testes. In addition, no significant differences in P-gp transport for both enantiomers were observed in the in vitro experiments. Previous studies have shown that (R)-verapamil is metabolized less in man and that it has lower affinity for calcium channels. Since (R)- and (S)-verapamil have equal transport for P-gp, the (R)-enantiomer seems to be the best and safest candidate as PET-tracer for measuring P-gp function in vivo.

Effect of testosterone and endurance training on glycogen metabolism in skeletal muscle of chronic hyperglycaemic female rats.

OBJECTIVES: To investigate in glycolytic and oxidative muscles of trained (nine weeks) and untrained hyperglycaemic female rats the effect of hyperandrogenicity and/or endurance training on energy metabolic properties. METHODS: Glycogen content and activity of muscle enzymes with regulatory functions in glycogen synthesis were examined. RESULTS: Testosterone treatment increased glycogen content of extensor digitorum longus (EDL) and soleus muscles of hyperglycaemic sedentary (18% and 84% respectively) and hyperglycaemic trained (7% and 16% respectively) rats. In both types of muscle of the hyperglycaemic testosterone treated exercised subgroup, less depletion of glycogen was found than in the untreated group (38% and 87% for EDL and soleus respectively). CONCLUSIONS: The mechanisms by which training and/or hyperandrogenism alone or in combination elicits their specific effects are complex. Differences in sex, surgery, levels of hormones administered, and exercise model used may be the main reasons for the observed discrepancies. Conclusions from the results: (a) hyperandrogenism is not a primary cause of the development of insulin resistance; (b) glycogen content of slow and fast twitch muscle is increased by training through increased glycogen synthase activity. The most plausible explanation for differences between different muscle fibre types is the different levels of expression of androgen receptors in these fibres. Hyperandrogenicity therefore acts on energy metabolic variables of hyperglycaemic animals by different mechanisms in glycolytic and oxidative muscle fibres.

Functional outcome in patients with thoracolumbar burst fractures treated with dorsal instrumentation and transpedicular cancellous bone grafting.

The aim of the study was to develop an insight into the impairments in spinal fracture patients, operatively treated with an internal fixator, and also into their ability to participate in daily living, return to work and quality of life as defined by the World Health Organization. Nineteen patients operated for a type A fracture of the thoracolumbar spine (T9-L4) between 1993 and 1998 in the University Hospital Groningen, the Netherlands, aged between 18 and 60 years, without neurological deficit were included in the study. Operative treatment consisted of fracture reduction and internal fixation using the Universal Spine System, combined with transpedicular cancellous bone grafting and dorsal spondylodesis. No ventral fusion operations, laminectomies or discectomies were done. Restrictions in body function and structure were measured on radiographs and in functional capacity tests, such as lifting tests and ergometry. Restrictions in activities were studied with the Visual Analogue Scale (VAS) Spine Score and the Roland Morris Disability Questionnaire (RMDQ). Restrictions in participation/quality of life were analysed with the Short Form 36 (SF36) and described in the return to work status. The radiological results are comparable to the literature. The reduction of the anterior wedge angle was followed by a gradual partial loss of intervertebral angle and regional angle. The maximum oxygen uptake (VO2-max) was reduced in only 8.3% of the patients. Arm and trunk lift was within the normal range in 87% and 80% of the patients respectively, but only 53% of the patients were able to perform a leg lift within the normal range. A mean RMDQ score of 4.0 positive items (SD 6.0) was found, and the mean VAS Spinal Score was 79.4 (SD 25.0), both better than in other series. No significant differences compared to the values of a comparable (healthy) age group could be identified in any variable of the SF36. A high correlation was seen between RMDQ, VAS Spine Score and the SF36 categories. No correlation was found between the anterior wedge angle and the regional angle on the one hand, and functional capacity tests or questionnaire scores on the other. Of the patients in paid employment before the trauma, 87% had returned to work at follow-up. About 50% of the patients had been obliged to change the intensity of their work or the kind of work they performed after the injury and treatment. In this matter, leg (muscle) performance seems a more important factor than overall condition (VO2-max). The results of the study indicate that patients with thoracolumbar spinal fractures without neurological deficit, treated with dorsal instrumentation, perform like healthy people 3-8 years after injury, according to the RMDQ, VAS Spine Score and SF36 results. Physical capacity tests reveal that leg (muscle) performance seems a more important factor in impairment than arm lift or overall condition.