[Novel psychoactive substances: a worldwide problem that requires an adequate approach]. / Les nouveles susbtances psychoactives: un problème mondial nècessitant une prise en charge adaptèe.

The use of new psychoactive substances (NPSI is increasing worldwide. Each year the number of NPS which are found through seizures in Belgium rises. The prevalence in the general population is unknown. In the Belgian nightlife at least 7% has already consumed an NPS at least once. NPS are alternatives for traditional illicit drugs (cannabis, cocaine, ecstasy, ...) made legal by adding a small modification within the chemical structure. But these modified substances are often more dangerous because there is little known about the acute and chronic effects, which could lead quickly to overdosing. Current legislation in Belgium uses a nominative list. However, this procedure is not suited to respond fast enough to the dynamic nature of NPS. In 2014 a new legislation based on generic classification was introduced as a solution and should be in place in 2015 in Belgium to reduce the rising number of legal drugs. An important consequence of generic classification is that certain medicines and other useful compounds will be included by this new law, which is a problem for the pharmaceutical industry and pharmacy. I cooperation with the FAGG exceptions for these substances were made.

How appropriate is therapeutic drug monitoring for lithium? Data from the Belgian external quality assessment scheme.

BACKGROUND: Lithium remains a mainstay in the management of mood disorders. As with many psychotropic drugs, lithium treatment requires continuous observation for adverse effects and strict monitoring of serum concentrations. The present study aimed to assess the appropriateness of lithium assays used by Belgian laboratories, and to evaluate acceptability of their clinical interpretations. METHODS: Nine in-house serum samples spiked with predetermined concentrations of lithium were distributed to 114 participants in the Belgian external quality assessment scheme. Laboratories were requested to report the assay technique, lithium measurements and interpretations with regard to measured concentrations. Inter/intramethod imprecision and bias were reported and acceptability of clinical interpretations was assessed. The intramethod variability was evaluated by selecting methods used by 6 laboratories or more. Flame photometry (IL 943) was considered as the reference method. RESULTS: Laboratories returned assay results using colorimetry (69.3%), ion selective electrode (15.8%), flame photometry (8.8%), atomic absorption spectroscopy (5.2%) or mass spectrometry (0.9%). Lithium concentrations were systematically higher when measured with the Vitros assay (median bias: 4.0%), and were associated with consecutive biased interpretations. In contrast, the Thermo Scientific Infinity assay showed a significant negative bias (median bias: 9.4%). 36.0% of laboratories reported numerical values below their manufacturer cut-off for the blank sample; 16.6% of these laboratories detected residual lithium concentrations. CONCLUSIONS: The present study revealed assay-related differences in lithium measurements and their interpretations. Overall, there appeared to be a need to continue EQA of therapeutic drug monitoring for lithium in Belgium.

The effect of non-surgical weight loss interventions on urinary incontinence in overweight women: a systematic review and meta-analysis.

Although the aetiology of urinary incontinence can be multifactorial, in some cases weight loss could be considered as a part of the therapeutic approach for urinary incontinence in people who are overweight. The objective of this study was to review and meta-analyse the effect of non-surgical weight loss interventions on urinary incontinence in overweight women. Web of Science, PubMed, Pedro, SPORTDiscus and Cochrane were systematically searched for clinical trials that met the a priori set criteria. Data of women who participated in non-surgical weight loss interventions (diet, exercise, medication or a combination) were included in the meta-analysis. After removing duplicates, 62 articles remained for screening on title, abstract and full text. Six articles (totalling 2,352 subjects in the intervention groups) were included for meta-analysis. The mean change in urinary incontinence (reported as frequency or quantity, depending on the study) after a non-surgical weight loss intervention, expressed as standardized effect size and corrected for small sample sizes (Hedges' g), was -0.30 (95%CI = -0.47 to -0.12). This systematic review and meta-analysis shows evidence that a non-surgical weight loss intervention has the potential to improve urinary incontinence and should be considered part of standard practice in the management of urinary incontinence in overweight women.

Assessment of human exposure to indoor organic contaminants via dust ingestion in Pakistan.

UNLABELLED: Ingestion of indoor dust has been acknowledged as an important route of exposure to organic contaminants (OCs). We investigated the presence of polybrominated diphenyl ethers (PBDEs), novel brominated flame retardants (NBFRs), organophosphate flame retardants (OPFRs), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs) in indoor floor dust from rural homes (N=31) and mosques (N=12) in Gujrat, Pakistan. Low concentrations were observed for most contaminants. OPFRs were the principle contaminants, with tri-(2-butoxyethyl)-phosphate (TBEP) and tri-phenyl-phosphate (TPP) having medians of 66 and 109 ng/g, respectively. PBDEs were only minor constituents in the investigated samples, with BDE 209 (median 40 ng/g) being the most important congener. Levels and profile of ∑PBDEs, ∑NBFRs, ∑HCHs, ∑DDTs, and ∑PCBs revealed no difference (P<0.05) between samples of dust from homes and mosques, indicating similar emission sources. Exposure scenarios using 5th percentile, median, mean, and 95th percentile levels were estimated for both adult and toddlers. Typical high-end, using median levels and high dust ingestion, exposure for adults were 0.02, 0.02, 0.03, <0.01, and 0.65 ng/kg bw/day and for toddlers 0.39, 0.45, 0.69, 0.01, and 15.2 ng/kg bw/day for ∑PBDEs, ∑NBFRs, ∑OCPs, ∑PCBs, and ∑OPFRs, respectively. To the authors' knowledge, this is the first study to document the presence of indoor OCs in Pakistani dust. PRACTICAL IMPLICATIONS: This is the first report on the analysis of various contaminants in indoor dust from Pakistan. Some of these chemicals are currently being used in different consumer products. The study will help to further an understanding of the levels of different organic contaminants (OCs) in Pakistani indoor environments and will enlighten the generally ignored area of environmental pollution in Pakistan. Furthermore, studies based on animal models have shown that some of the analyzed chemicals can cause different types of chronic toxicities. However, our results showed that the levels of estimated exposure via dust ingestion for all chemicals were several orders of magnitude lower than their reference dose (RfD) values or than those reported in studies from Belgium, China, Singapore, and the UK (Ali et al., 2011a; Harrad et al., 2008; Tan et al., 2007a,b; Van den Eede et al., 2011a; Wang et al., 2010).

Polychlorinated biphenyl and organochlorine pesticide contamination signatures in deep-sea fish from the Mediterranean Sea.

Polychlorinated biphenyl (PCB) and OCP concentrations were determined in the livers of two deep-sea fish species, roughsnout grenadier and hollowsnout grenadier, from the Adriatic Sea. In both species, contaminant concentrations were in the following order: PCBs>DDTs>>HCB. Contaminant load was higher in roughsnout grenadier (PCB: 12,327ngg(-1); DDTs: 5357ngg(-1); HCB: 13.1ngg(-1)) than in hollowsnout grenadier (PCB: 1234ngg(-1); DDTs: 763ngg(-1); HCB 6.3ngg(-1)). PCB patterns were dominated by higher chlorinated congeners (hexa-CBs: 50.3-52.1%, hepta-CBs: 29.6-35.5%, penta-CBs: 8.0-11.1% and octa-CBs :5.2-5.4%). PCBs 138, 153 180 and 187 were the most abundant. Regarding the DDT pattern, p,p'-DDE was prevalent in both species (roughsnout grenadier: 99.7%, hollowsnout grenadier: 90%), suggesting no recent DDT input. In both species, the total 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalent (TEQ) concentrations (roughsnout grenadier: mean 43.77pg/g, hollowsnout grenadier: mean 20.49pg/g), calculated from non- and mono-ortho PCBs, reached those encountered in marine organisms at higher levels in the trophic chain.

Adding lactate to the prime solution during hypothermic cardiopulmonary bypass: a quantitative acid-base analysis.

BACKGROUND: The effect of adding lactate to the cardiopulmonary bypass (CPB) prime was investigated using Stewart's quantitative acid-base approach. According to this quantitative model, serum pH and bicarbonate are determined by three independent factors: the partial pressure of carbon dioxide (PCO(2)), the total concentration of weak acids (e.g. albumin), and the strong ion difference. The apparent strong ion difference is calculated as the sum of sodium, potassium, magnesium and calcium minus chloride concentrations. The pH decreases with a smaller strong ion difference and vice versa. METHODS: Twenty patients scheduled for coronary surgery were studied prospectively. All patients were treated identically, except for the prime, which either contained lactate or was lactate free. Just before bypass and before coming off bypass, haemoglobin, glucose, plasma osmolality and colloid osmotic pressure were determined; albumin, lactate, sodium, potassium, ionized calcium, magnesium, phosphate, arterial pH, PCO(2), bicarbonate, and base excess were measured for use in Stewart's analysis. RESULTS: Metabolic acidosis had resolved by the end of bypass with the lactated prime. Although the strong ion gap (apparent minus effective strong ion difference) increased significantly in both groups, its composition differed significantly between the groups. The Stewart technique detected polyanionic gelatin as a weak acid component contributing to the unidentified anion fraction. Colloid osmotic pressure was maintained in both groups. CONCLUSION: Exogenous lactate attenuates acidosis related to CPB. The oncotic and weak acid deficits produced by hypoalbuminaemia may be compensated for temporarily during CPB by polyanionic synthetic colloids such as succinylated gelatin.

Quality assessment for prostate-specific antigen (PSA) in relation to ERSPC: report of the PSA committee.

OBJECTIVE: To assess the application of a quality control scheme for total prostate-specific antigen (PSA) as used for participants of the European Randomized Study for Screening of Prostate Cancer (ERSPC) during 1996-2002. METHODS: From 1996, the first complete year being 1997, an external scheme was organized by the Dutch Quality Assessment Foundation especially for the ERSPC. This scheme consists of one control round every 2 months with two different human serum samples and is only meant to compare the recovery of methods. From 1998 an internal scheme was also applied by adding two distinct samples to every round. RESULTS: Initially there was a wide variation (coefficient of variation of +/- 15% at threshold PSA of 4.0 ng/mL) among all ERSPC participants who were all using the Tandem assay (Hybritech Inc, USA). After introducing the internal scheme the performance of some intra-ERSPC group comparisons for PSA and the introduction of the completely automated Beckman-Access analyser in 2001 there was state-of-the-art precision for PSA of +/- 5% in the 2002 surveys. CONCLUSIONS: The ERSPC group measurements of PSA have considerably improved since 1996 because of the application of a quality-assessment scheme and with the introduction of complete automation of the PSA assay. Both findings are in line with earlier developments in clinical chemistry.

Driving and intrathecal morphine administration.

Since Belgian law recently set a limit to morphine concentration detectable in blood and urine while driving a vehicle, questions arose about the implications for the medical use of opiates. We determined morphine concentrations in whole blood and urine by gas chromatography-mass spectrometry in 15 patients on continuous intrathecal morphine administration. Effects on blood and urine concentration after water intake and the correlation with the intrathecal morphine daily dose were also evaluated. Our results confirm that, in all patients examined, the legally determined maximum blood morphine concentration of 20 ng/ml was never exceeded. Even patients on high intrathecal morphine dose schedules did never reach the maximum legal blood concentration. However, morphine concentration in urine reached levels which exceeded by far the legally determined maximum concentration of 300 ng/ml. Although legal actions against driving under the influence of morphine can only be taken after a positive urine and a subsequent positive blood sample, drivers on intrathecal opiates must be aware of the possibility of a positive roadside drug test.

Pedophilia is accompanied by increased plasma concentrations of catecholamines, in particular epinephrine.

Plasma epinephrine and norepinephrine concentrations were measured in pedophiles and normal men both in placebo conditions and after administration of meta-chlorophenylpiperazine (mCPP), a post-synaptic 5-HT2 receptor agonist. The plasma concentrations of catecholamines, in particular epinephrine, were significantly increased in pedophiles. It is concluded that pedophiles may have an increased activity of the sympathoadrenal system.

Reference values for plasma dipeptidyl-peptidase IV activity and their association with other laboratory parameters.

In blood, the exopeptidase dipeptidyl-peptidase IV (DPPIV; EC 3.4.14.5) is predominantly present in a soluble form in plasma/serum and as an activation antigen on the membrane of lymphocytes (CD26). It modifies some important biologically active peptides (neuropeptides, chemokines), and a regulatory role for DPPIV/CD26 in immune and endocrine processes has been demonstrated. The aim of this study was to determine reference values for plasma/serum DPPIV activity and to study the association of this activity with a series of biochemical and hematological parameters and baseline characteristics such as age, gender, blood pressure and body mass index. We studied 481 healthy subjects aged between 19 and 61 years. The group consisted of 213 men and 268 women equally divided between the different categories of age. Among the women, 127 were taking hormone therapy (contraception/hormone replacement) and 141 were not. A multiple regression model shows that DPPIV activity decreases significantly with age. The activity in women is slightly lower than in men. We observed an important association with liver, muscle and lipid metabolism-related parameters. In this model, no significant contribution of body mass index, blood pressure or hormone therapy could be stated.

The prolonged P(300) latency in recently detoxified alcohol-dependent patients is related to activation of the inflammatory response system.

The aims of this study were to examine the late components of the auditory event-related potentials (AERPs), i.e. N(100), P(200) and P(300), in recently detoxified alcohol-dependent patients compared to normal controls and to investigate whether there is a relationship between alterations in these AERPs and signs of activation of the inflammatory response system (IRS). The study subjects consisted of 14 healthy volunteers and 14 recently detoxified alcohol-dependent patients. All subjects performed a two-tone auditory discrimination task, using a standard "oddball" paradigm. The alcohol-dependent patients had their blood sampled to examine IRS markers, such as erythrocyte sedimentation rate (ESR), serum copper concentrations and the number of leukocytes. The P(300) latency was significantly greater in recently detoxified alcohol-dependent patients than in normal controls. There were significant correlations between the P(300) latency and the ESR (r = 0.84, p = 0.009), serum copper concentrations (r = 0.73, p = 0.01) and number of monocytes (r = 0.71, p = 0.006). It is concluded that the P(300) latency is prolonged in detoxified, chronic alcohol-dependent patients and is positively related to indicators of IRS activation. It is hypothesized that activation of the IRS may play a role in the delayed P(300) latency in recently detoxified, alcohol-dependent patients.

Determination of carbohydrate-deficient transferrin using capillary zone electrophoresis.

BACKGROUND: Current methods for carbohydrate-deficient transferrin (CDT) often suffer from low precision, complexity, or risk of false positives attributable to genetic variants. In this study, a new capillary zone electrophoresis (CZE) method for CDT was developed. METHODS: CZE was performed on a P/ACE 5000 using fused-silica capillaries [50 microm (i.d.) x 47 cm] and the CEOFIX CDT buffer system with addition of 50 microL of anti-C3c and 10 microL of anti-hemoglobin. Native sera were loaded by high-pressure injection for 3 s, separated at 28 kV over 12 min, and monitored at 214 nm. RESULTS: CDT was completely resolved by differences in migration times (di-trisialotransferrin, 9.86 +/- 0.05 min; monosialotransferrin, 9.72 +/- 0.05 min; asialotransferrin, 9.52 +/- 0.04 min), with a CV of 0.15%. The number of theoretical plates was 312,000 +/- 21,000 for the mono- and 199 000 +/- 6500 for the di-trisialylated transferrin. Genetic CB and CD variants showed prominent peaks with migration times of 10.12 +/- 0.06 and 9.89 +/- 0.03 min, respectively, and the carbohydrate-deficient glycoprotein syndrome could be detected, excluding false-positive results. CZE results (as a percentage; y) correlated with the Axis %CDT TIA (x) values by Deming regression analysis: y = 1.92x - 7.29; r = 0.89. CDT values in 130 healthy nonalcoholics were determined. The 2.5th and 97.5th percentiles were 1.84% and 6.79%. CONCLUSIONS: CZE without sample pretreatment can determine CDT with good precision, allows detection of variants, and correlates with ion-exchange chromatography.

The haptoglobin 2-2 phenotype affects serum markers of iron status in healthy males.

BACKGROUND: Human iron status is influenced by environmental and genetic factors. We hypothesized that the genetic polymorphism of haptoglobin (Hp), a hemoglobin-binding plasma protein, could affect iron status. METHODS: Reference values of serum iron status markers were compared according to Hp phenotypes (Hp 1-1, Hp 2-1, Hp 2-2; determined by starch gel electrophoresis) in 717 healthy adults. Iron storage was investigated in peripheral blood monocyte-macrophages by measuring cytosolic L- and H-ferritins and by in vitro uptake of radiolabeled ((125)I) hemoglobin-haptoglobin complexes. RESULTS: In males but not in females, the Hp 2-2 phenotype was associated with higher serum iron (P <0.05), transferrin saturation (P <0.05), and ferritin (P <0.01) concentrations than Hp 1-1 and 2-1, whereas soluble transferrin receptor concentrations were lower (P <0.05). Moreover, serum ferritin correlated with monocyte L-ferritin content (r = 0.699), which was also highest in the male Hp 2-2 subgroup (P <0.01). In vitro, monocyte-macrophages took up a small fraction of (125)I-labeled hemoglobin complexed to Hp 2-2 but not to Hp 1-1 or 2-1. CONCLUSIONS: The Hp 2-2 phenotype affects serum iron status markers in healthy males and is associated with higher L-ferritin concentrations in monocyte-macrophages because of a yet undescribed iron delocalization pathway, selectively occurring in Hp 2-2 subjects.

Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness.

OBJECTIVE: Major depression is associated with defective antioxidant defenses. Vitamin E is the major fat soluble antioxidant in the body. The aim of the present study is to examine serum vitamin E concentrations in major depressed patients versus normal volunteers. METHOD: Serum vitamin E concentrations were measured in 26 healthy volunteers and 42 major depressed patients by means of HPLC. Since vitamin E is a fat soluble vitamin, and serum vitamin E concentrations are strongly related to these of low-density-lipoprotein cholesterol (LDL-C) and triglycerides, we have adjusted the results for possible differences in these lipids. The numbers of peripheral blood leukocytes were measured. RESULTS: Patients with major depression had significantly lower serum vitamin E concentrations than healthy controls. The area under the ROC (receiver operating characteristics) curve was 83%. There were significant and negative correlations between serum vitamin E and number of total leukocytes and neutrophils. CONCLUSIONS: Major depression is accompanied by significantly lower serum vitamin E concentrations, suggesting lower antioxidant defenses against lipid peroxidation. The results could, in part, explain previous findings, which suggest increased lipid peroxidation in major depression.

In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress.

BACKGROUND: Psychologic stress in humans induces the production of proinflammatory cytokines, such as interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6), and that of the negative immunoregulatory cytokine, IL-10. An imbalance of omega6 to omega3 polyunsaturated fatty acids (PUFAs) in the peripheral blood causes an overproduction of proinflammatory cytokines. The omega3 PUFAs reduce the production of proinflammatory cytokines. METHODS: This study examines whether an imbalance in omega6 to omega3 PUFAs in human blood predicts a greater production of proinflammatory cytokines in response to psychologic stress. Twenty-seven university students had serum sampled a few weeks before and after as well as 1 day before a difficult oral examination. We determined the omega6 and omega3 fractions in serum phospholipids as well as the ex vivo production of IFN-gamma, TNF-alpha, IL-6, IL-10, and IL-5 by diluted whole blood stimulated with polyclonal activators. RESULTS: Academic examination stress significantly increased the ex vivo, stimulated production of IFN-gamma, TNF-alpha and IL-10, and the IFN-gamma/IL-5 production ratio. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had significantly greater stress-induced TNF-alpha and IFN-gamma responses than subjects with higher serum omega3 PUFAs and a lower omega6/omega3 ratio, respectively. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had a significantly higher stress-induced increase in the IFN-gamma/IL-5 ratio than the remaining subjects. CONCLUSIONS: Psychologic stress induces a Th-1-like or proinflammatory response in some subjects. An imbalance in the omega6 to omega3 PUFA ratio appears to predispose humans toward an exaggerated Th-1-like response and an increased production of monocytic cytokines, such as TNF-alpha, in response to psychologic stress. The results suggest that increased omega3 PUFA levels may attenuate the proinflammatory response to psychologic stress.

Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.