Effects of a self-guided, web-based activity programme for patients with persistent musculoskeletal pain in primary healthcare: A randomized controlled trial.

BACKGROUND: Web-based interventions for pain management are increasingly used with possible benefits, but never used in addition to multimodal rehabilitation (MMR). MMR is recommended treatment for persistent pain in Sweden. The aim was to evaluate the effects of a self-guided, web-based programme added to MMR for work ability, pain, disability and health-related quality of life. METHODS: We included 99 participants with persistent musculoskeletal pain in a randomized study with two intervention arms: (1) MMR and web-based intervention, and (2) MMR. Data was collected at baseline, 4 and 12 months. Outcome measures were work ability, working percentage, average pain intensity, pain-related disability, and health-related quality of life. RESULTS: There were no significant effects of adding the web-based intervention to MMR regarding any of the outcome variables. CONCLUSIONS: This trial provides no support for adding a self-guided, web-based activity programme to MMR for patients with persistent musculoskeletal pain. SIGNIFICANCE: The comprehensive self-guided, web-based programme for activity, Web-BCPA, added to multimodal treatment in primary health care had no effect on work ability, pain, disability or health-related quality of life. Future web-based interventions should be tailored to patients' individual needs and expectations.

The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence.

Recent clinical studies show that hypoglycaemia is associated with increased risk of death, especially in patients with coronary artery disease or acute myocardial infarction. This paper reviews data from cellular and clinical research supporting the hypothesis that acute hypoglycaemia increases the risk of malignant ventricular arrhythmias and death in patients with diabetes by generating the two classic abnormalities responsible for the proarrhythmic effect of medications, i.e. QT prolongation and Ca(2+) overload. Acute hypoglycaemia causes QT prolongation and the risk of ventricular tachycardia by directly suppressing K(+) currents activated during repolarisation, a proarrhythmic effect of many medications. Since diabetes itself, myocardial infarction, hypertrophy, autonomic neuropathy and congestive heart failure also cause QT prolongation, the arrhythmogenic effect of hypoglycaemia is likely to be greatest in patients with pre-existent cardiac disease and diabetes. Furthermore, the catecholamine surge during hypoglycaemia raises intracellular Ca(2+), thereby increasing the risk of ventricular tachycardia and fibrillation by the same mechanism as that activated by sympathomimetic inotropic agents and digoxin. Diabetes itself may sensitise myocardium to the arrhythmogenic effect of Ca(2+) overload. In humans, noradrenaline (norepinephrine) also lengthens action potential duration and causes further QT prolongation. Finally, both hypoglycaemia and the catecholamine response acutely lower serum K(+), which leads to QT prolongation and Ca(2+) loading. Thus, hypoglycaemia and the subsequent catecholamine surge provoke multiple, interactive, synergistic responses that are known to be proarrhythmic when associated with medications and other electrolyte abnormalities. Patients with diabetes and pre-existing cardiac disease may therefore have increased risk of ventricular tachycardia and fibrillation during hypoglycaemic episodes.

Taurine in plasma and CSF: a study in healthy male volunteers.

In order to explore the interrelationship between plasma and cerebrospinal fluid taurine concentrations, three consecutive 6-ml fractions of cerebrospinal fluid were drawn from 30 healthy male volunteers in the early morning after 8 h in the fasting condition. Repeated plasma samples were drawn over 24 h the day before lumbar puncture. Taurine in plasma and cerebrospinal fluid was determined by high performance liquid chromatography. The subjects were categorized as extensive or poor metabolizers with respect to the cytochrome P450 2D6 genotype. The taurine cerebrospinal fluid/plasma ratio at 8 a.m. was negatively influenced by the plasma taurine concentration at 4 p.m. the previous day. It was also negatively influenced by body mass index and positively by the intraspinal pressure. Three poor metabolizers of cytochrome P450 2D6 had higher plasma taurine areas under the curve than 27 extensive metabolizers. Hypothetically, cytochrome P450 2D6 influences the transport of taurine across the blood-brain barrier.

CSF cholecystokinin, gamma-aminobutyric acid and neuropeptide Y in pathological gamblers and healthy controls.

The sulphated cholecystokinin (CCK) octapeptide (CCK-8S), the CCK tetrapeptide (CCK-4), neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA) were determined in cerebrospinal fluid (CSF) obtained from 11 pathological male gamblers and 11 healthy male controls. Compared with healthy controls, pathological male gamblers displayed higher concentrations of CCK-8S, CCK-4 and GABA (but not NPY). A gradient with decreasing concentrations from the first to the third 6-ml CSF fraction was found for CCK-8S, CCK-4 and NPY, but only in pathological gamblers. Disrupted gradients were found for GABA and for NPY in healthy controls. Given that CCK is a modulator of dopamine in the reward process, the increase in CCK-8S and CCK-4 is not unexpected. The high level of GABA in pathological gamblers is in conformity with a compensatory inhibitory action on noradrenergic neurons. The CSF gradient of CCK-8S and CCK-4 in pathological male gamblers (but not healthy controls) might indicate a difference in diurnal variation. The results obtained are in line with an altered CCK and GABA function in pathological gambling.

Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia.

Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n=49) and male patients with schizophrenia (n=90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM+/-0.10 vs. 1.06 nM+/-0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM+/-0.19, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM+/-0.17, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM+/-0.10, n=19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.

Tactile stimulus and neurohormonal response: a pilot study.

The effects of tactile stimuli on plasma oxytocin and neuropeptide Y (NPY) were investigated in 21 volunteers exposed to massage. Blood samples for basal values were drawn immediately before and immediately after finishing the massage. A third sample was drawn after 60 min of restricted rest. On focusing on the difference between oxytocin concentrations before and immediately after massage, we found a sex difference. An opposite sex difference was found for NPY. The results imply that there might be sex-related difference in neurohormonal response to tactile stimuli such as in massage, and the results contradict those of previously reported animal experiments.

Body mass index influences plasma concentration of neuropeptide Y in healthy female volunteers: a pilot study.

Neuropeptide Y (NPY) was measured in plasma obtained from healthy female volunteers twice in the natural menstrual cycle or the hormonal cycle caused by oral contraceptives about 2 weeks apart. The ratio between the NPY plasma concentration in the second sample and the first sample was influenced negatively by body mass index (BMI). There were no differences in NPY plasma concentrations on comparing the first and second samples. Age and the use or non-use of oral contraceptives did not exert any influence. BMI might be a confounding factor when determining NPY in the plasma of healthy women.

Quantitative pharmacogenetics of nortriptyline: a novel approach.

OBJECTIVE: To quantitatively model nortriptyline clearance as a function of the cytochrome P450 (CYP) 2D6 genotype and to estimate the contribution of genotype to the interindividual variability in steady-state plasma concentration and metabolic clearance. DESIGN: Modelling study using data from two previously published studies. PARTICIPANTS: 20 healthy volunteers receiving single oral doses of nortriptyline and 20 patients with depression on steady-state oral treatment. METHODS: A total of 275 nortriptyline plasma concentrations were analysed by standard nonlinear regression and nonlinear mixed effect models. The pharmacokinetic model was a 1-compartment model with first order absorption and elimination. All participants had previously been genotyped with respect to the CYP2D6 polymorphism. RESULTS: A model in which the intrinsic clearance is a linear function of the number of functional CYP2D6 genes and hepatic blood flow is fixed to 60 L/h gave the closest fit of the pharmacokinetic model to the data. Stable estimates were obtained for population pharmacokinetic parameters and interindividual variances. Assuming 100% absorption, the model allows systemic clearance and bioavailability to be estimated. Bioavailability was found to vary between 0.17 and 0.71, depending on the genotype. Using the frequency distribution of CYP2D6 genotype with the above results we estimate that, in compliant Swedish individuals on nortriptyline monotherapy, the number of functional CYP2D6 genes could explain 21% of the total interindividual variance in oral clearance of nortriptyline and 34% of that in steady-state plasma concentrations. CONCLUSION: Nonlinear mixed-effects modelling can be used to quantify the influence of the number of functional CYP2D6 genes on the metabolic clearance and plasma concentration of drugs metabolised by this enzyme. Gene dose has a significant impact on drug pharmacokinetics and prior knowledge of it may aid in predicting plasma concentration of the drug and thus tailoring patient-specific dosage regimens.

Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia.

Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate-receptor. Mounting evidence indicate that the compound is significantly involved in basal neurophysiological processes in the brain. In the present investigation, cerebrospinal fluid (CSF) level of kynurenic acid was analyzed in 28 male schizophrenic patients and 17 male healthy controls by means of high pressure liquid chromatography and fluorescence detection. Schizophrenic patients showed elevated CSF levels of kynurenic acid (1.67+/-0.27 nM) compared to the control group (0.97+/-0.07 nM). Furthermore, CSF levels of kynurenic acid in schizophrenic patients were also found to correlate with age. The present finding is indicative of a contribution of kynurenic acid in the pathogenesis of schizophrenia.

Intraspinal pressure influences CSF disposition of tryptophan and 5-HIAA.

Cerebrospinal fluid (CSF) concentrations of monoamine compounds are influenced by factors such as age, gender, height, body weight, tapping time, and atmospheric pressure. We have now examined the role of intraspinal pressure. Thirteen male volunteers underwent lumbar puncture in the right decubitus position without preceding strict bed rest. The intraspinal pressure was recorded, and monoamine precursors, transmitters, and metabolites were analyzed in two consecutively collected CSF fractions. Tryptophan in 12 ml of CSF and the 5-hydroxyindoleacetic acid concentration ratio [fraction II (7--12 ml CSF)/fraction I (0--6 ml CSF)] correlated with the intraspinal pressure. Hypothetically, the intraspinal pressure may be a confounding factor for a correct interpretation of CSF tryptophan and 5-hydroxyindoleacetic acid concentrations, and this is an issue that has to be addressed in future CSF studies.

Depressive symptoms in hypothyroid disorder with some observations on biochemical correlates.

Lumbar punctures and ratings of depressive symptoms were done in hypothyroid patients before and during L-thyroxine therapy. Before treatment, the most prominent symptoms were concentration difficulties, lassitude, and reduced sexual interest. All patients suffered from sleep disturbances. Suicidal thoughts did not occur at all. Inner tension was negatively correlated with the anxiogenic cholecystokinin tetrapeptide (CCK-4) in the cerebrospinal fluid (CSF), while reduced sexual interest was negatively correlated with CSF tryptophan. Furthermore, failing memory correlated negatively with T3 as well as T4 in serum. A positive correlation was found between failing memory and serum TSH. All patients improved significantly during treatment. No biochemical correlates were found. In conclusion, hypothyroidism is associated with major depressive symptoms. CSF CCK-4 and tryptophan, as well as serum thyroid hormones, may constitute biochemical correlates for some of these symptoms.

Prevalence of depressive symptoms in late pregnancy and postpartum.

BACKGROUND: Postnatal depression refers to a non-psychotic depressive episode that begins in or extends into the postpartum period. The aims of this study were to examine the prevalence of depressive symptoms in a pregnant and later postnatal population, to determine the natural course of these symptoms and whether there is an association between antenatal and postnatal depressive symptomatology. METHODS: A longitudinal study with a total population of 1,558 consecutively registered pregnant women in the southeast region of Sweden. Presence of depressive symptoms was measured with the Edinburgh Postnatal Depression Scale on four occasions namely in gestational week 35-36, in the maternity ward, 6-8 weeks and 6 months postpartum. RESULTS: The prevalence of depressive symptoms during late pregnancy was 17%; in the maternity ward 18%; 6-8 weeks postnatally 13%; and 6 months postnatally, 13%. A correlation between antenatal and postnatal depressive symptoms was found (r=0.50, p<0.0001). CONCLUSION: Detection of women at risk for developing postnatal depressive symptoms can be done during late pregnancy. Antenatal care clinics constitute a natural and useful environment for recognition of women with depressive symptoms.

Monoamine compounds in cerebrospinal fluid of healthy subjects punctured without preceding strict bed rest: a pilot study.

The interpretation of data on compounds in the lumbar cerebrospinal fluid (CSF) is limited by several confounding factors, e.g. motor activity for which strict bed rest prior to lumbar puncture is recommended for standardisation. Now we report data from 14 healthy males employing the standardised procedure except for the requirement of strict bed rest. The levels of serotonin, noradrenaline, 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid and 4-hydroxy-3-methoxyphenylglycol in the second CSF fraction (7-12 ml) were significantly higher than those in the first fraction (0-6 ml), indicating the presence of concentration gradients. 5-HIAA was negatively influenced by age and the neuraxis distance in the lying position and positively by atmospheric pressure. Storage time and atmospheric pressure contributed to the variance in dopamine. Both tyrosine, tryptophan and dopamine were linearly correlated with storage time. We also found a significant curvilinear correlation between tapping time and atmospheric pressure. On comparing with previous studies, the results support the notion that the issue of strict bed rest or not prior to lumbar puncture might have to be taken into consideration when interpreting lumbar monoamine CSF data.

CSF collection time at lumbar puncture is influenced by plasma cholesterol and triglycerides.

It is a fairly well-known fact that the CSF collection time (tapping time) at lumbar puncture may influence CSF levels of monoamine compounds (e.g. the serotonin metabolite 5-hydroxyindoleacetic acid, 5-HIAA) and some neuropeptides. Since serum levels of cholesterol and triglycerides and low CSF levels of 5-HIAA have been linked to violent behaviour and impulsivity, we investigated retrospectively whether serum cholesterol and triglycerides affect CSF collection time. The series consists of 14 healthy males lumbar punctured at the L(4-5) level. We found that both serum cholesterol and serum triglycerides influenced the CSF collection time for 12 ml of CSF (R = 0.77; p = 0.0067). There was no correlation between cholesterol in serum and CSF, nor between cholesterol in the CSF and collection time. However, we accidentally found a correlation between cholesterol in the CSF and age. The proposed hypothesis tries to explain why cholesterol- and triglyceride-rich lipoprotein particles modify the CSF collection time and influence endothelial function with a subsequent effect on CSF production and/or intraspinal pressure. Thus, it may be of interest to pay attention to serum cholesterol and triglycerides, their effect on CSF collection time and, in the next step, their putative impact on levels of various compounds in the CSF.

Enantioselective analysis of citalopram and metabolites in adolescents.

Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.

Cerebrospinal fluid levels of monoamine compounds and cholecystokinin peptides after exposure to standardized barometric pressure.

BACKGROUND: Connections between mood changes and weather have been described throughout the ages, and in more recent years, there have been reports on a relationship between atmospheric pressure and neurotransmitter levels in cerebrospinal fluid. METHODS: To further investigate this issue under strictly standardized conditions, we have lumbar-punctured 8 healthy males under low (963 hPa) and high (1064 hPa) barometric pressure, using a pressure chamber. RESULTS: Under high pressure, the tyrosine concentrations in the cerebrospinal fluid (CSF) were lower, while the cholecystokinin tetrapeptide (CCK-4) levels were higher. No differences between low and high pressure were found for tryptophan, 5-hydroxyindolacetic acid (5-HIAA), dopamine (DA), and sulphated cholecystokinin octapeptide (CCK-8S). The serum level of CCK-8S was higher under high pressure. On comparing concentration ratios between the second and the first CSF fraction, we found significantly increased ratios for homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylglycol (HMPG), but a decreased ratio for tyrosine under high pressure. The difference in the concentration ratios of HVA between low and high pressure correlated negatively with age. Intraspinal pressure correlated negatively with tapping time at low pressure. CONCLUSION: Our results are in line with the hypothesis that atmospheric pressure influences CSF levels of monoamine compounds and cholecystokinin peptides.