Polygenic contributions to performance on the Balloon Analogue Risk Task.

Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.

Does acute stress play a role in the lasting therapeutic effects of psychedelic drugs?

Psychedelic drugs, when used in the context of psychotherapy, can produce significant and long-lasting memories with enduring beneficial effects. Yet, the behavioral and neurobiological mechanisms that underlie these beneficial effects remain a mystery. Here, we suggest that both the quality and durability of memories of the drug-facilitated therapeutic experience may be mediated, in part, by the acute stress responses induced by the drugs. It is known that high doses of psychedelic drugs activate autonomic and hormonal stress responses. For evolutionarily adaptive reasons, acute stress is known to i) instill meaning to the immediate context in which it is experienced, and ii) lead to the formation of salient and lasting memories of the events surrounding the stress. Thus, the stress-inducing effect of psychedelic drugs may contribute to the reported sense of meaning, as well as the durability of the memory of the drug experience. When used in a therapeutic context these actions may i) enhance the salience of insights gained during the experience and ii) strengthen the memories formed by these experiences. Future empirical studies will help to determine whether acute stress contributes to the emotional significance and lasting effects of psychedelic-assisted psychotherapy.

[Medication and comedication in COVID-19 patients]. / Geneesmiddelen bij COVID-19.

This paper discusses the possible effects of comedication on COVID-19 and the current treatment options for this infection. It is very doubtful that comedication has a disadvantageous effect on the course of the disease. NSAIDs should be avoided in any patient with a possible severe disease, because of potential side effects. Inhibitors of the renin-angiotensin aldosterone system should be continued when there is a solid indication, and stopped in case of hemodynamic problems. There is no preference for either ACE inhibitors or angiotensin II receptor inhibitors. Currently, chloroquine and remdesivir are possible treatment options. There is no sound evidence for either treatment. Chloroquine has side effects (nausea, QT prolongation) and there are several drug interactions. The treatment should be reconsidered in the event of side effects and when inferior medication for comorbidity must be prescribed because of possible interactions. Lopinavir/ritonavir is not effective. Supportive care is at present the mainstay of the treatment.

Natural organic matter fractions and their removal in full-scale drinking water treatment under cold climate conditions in Nordic capitals.

Drinking water treatment plants (DWTPs) designed to remove natural organic matter (NOM) are challenged as concentrations of NOM in raw waters are increasing. Here, we assess seasonal differences in NOM quality and quantity, from raw waters to the distribution network, at three large DWTPs in Oslo, Stockholm and Helsinki. Samples, collected during stable stratification in both winter and summer and during the autumnal turnover, were analysed for NOM concentrations and composition. The NOM was characterized by common routine parameters, size and content (TFF, LC-OCD, fluorescence) and biodegradability. The NOM concentration decreased to 2.5 mg/L (55%), 4.0 mg/L (48%) and 5.7 mg/L (76%) at the respective DWTPs in Oslo, Stockholm and Helsinki. The NOM in raw waters were predominantly in the largest size fraction (>50 kDa), in particular from Oslo. High MW fractions >50 kDa and humics remained the largest fractions with minimum 30% and maximum 80% of the total NOM. The BDOC in treated water <0.3 mg/L and the conditions in the distribution network imply low probability for bacteria regrowth. The multi-step treatment consisting of coagulation/flocculation, sedimentation, rapid sand filtration, ozonation and biological activated carbon filtration (BAC) was most effective in removing NOM. Coagulation/flocculation followed by sedimentation and sand filtration were critical, especially for the removal of biopolymers and humics, and somewhat for building blocks. The sand filtration provided up to 25% additional removal of biopolymers and below 7% removal of other fractions. The ozonation and BAC was more effective and removed 11% of biopolymers, and about 35% of building blocks and LMW neutrals.

The use of an electronic clinical rule to discontinue chronically used benzodiazepines and related Z drugs.

PURPOSE: The chronic use of benzodiazepines and benzodiazepine-related drugs (BZ/Z) in older people is common and not without risks. The objective of this study was to evaluate whether the implementation of a clinical rule promotes the discontinuation of chronically used BZ/Z for insomnia. METHODS: A clinical rule, generating an alert in case of chronic BZ/Z use, was created and applied to the nursing home (NH) setting. The clinical rule was a one-off intervention, and alerts did not occur over time. Reports of the generated alerts were digitally sent to NH physicians with the advice to phase out and eventually stop the BZ/Z. In cases where the advice was adopted, a follow-up period of 4 months on the use of BZ/Z was taken into account in order to determine whether the clinical rule alert led to a successful discontinuation of BZ/Z. RESULTS: In all, 808 NH patients were screened. In 161 (19.1%) of the patients, BZ/Z use resulted in a clinical rule alert. From these, the advice to phase out and stop the BZ/Z was adopted for 27 patients (16.8%). Reasons for not following the advice consisted of an unsuccessful attempt in the past (38 patients), patients family and/or patient resistance (37 patients), the non-continuous use of BZ/Z (32 patients) and indication still present (27 patients). Of the 12 NH physicians, seven adopted the advice. CONCLUSIONS: The success rate of a clinical rule for discontinuation of chronically used BZ/Z for insomnia was low, as reported in the present study. Actions should be taken to help caregivers, patients and family members understand the importance of limiting BZ/Z use to achieve higher discontinuation rates.

A cost-controlling treatment strategy of adding liraglutide to insulin in type 2 diabetes.

BACKGROUND: Addition of the GLP-1 receptor agonist liraglutide to insulin can reverse insulin-associated weight gain, improve HbA1c and decrease the need for insulin, but is expensive. From a cost perspective, such treatment should be discontinued when it is clear that treatment targets will not be achieved. Our aim was to find the best cost-controlling treatment strategy: the shortest possible trial period needed to discriminate successfully treated patients from those failing to achieve predefined targets of treatment success. METHODS: We used data from the 'Effect of Liraglutide on insulin-associated wEight GAiN in patients with Type 2 diabetes' (ELEGANT) trial, comparing additional liraglutide (n = 47) and standard insulin therapy (n = 24) during 26 weeks, to calculate the costs associated with different trial periods. Treatment success after 26 weeks was defined by having achieved ≥ 2 of the following: ≥ 4% weight loss, HbA1c ≤ 53 mmol/mol (7%), and/or discontinuation of insulin. RESULTS: The additional direct costs of adding liraglutide for 26 weeks were € 699 per patient, or € 137 per 1 kg weight loss, compared with standard therapy. The best cost-controlling treatment strategy (identifying 21 of 23 responders, treating four non-responders) was to continue treatment in patients showing ≥ 3% weight loss or ≥ 60% decrease in insulin dose at 8 weeks, with a total cost of € 246 for this t rial period, saving € 453 in case of early discontinuation. CONCLUSION: An 8-week trial period of adding liraglutide to insulin in patients with insulin-associated weight gain is an effective cost-controlling treatment strategy if the liraglutide is discontinued in patients not showing an early response regarding weight loss or insulin reduction.

Immune dysregulation in offspring of a bipolar parent. Altered serum levels of immune growth factors at adolescent age.

Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.

Brain-derived Neurotrophic Factor (BDNF) and gray matter volume in bipolar disorder.

INTRODUCTION: Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC). METHODS: We studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was P<0.05, Family Wise Error (FWE) corrected for multiple comparisons. All the analyses were controlled for the effect of nuisance covariates known to influence GM volumes, such as age, gender and lithium treatment. RESULTS: BD patients showed significantly higher serum BDNF levels compared with HC. Reduced GM volumes in BD patients compared to HC were observed in several brain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD. DISCUSSION: Our study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF.

A dynamic course of T cell defects in individuals at risk for mood disorders.

OBJECTIVES: T cell abnormalities have been repeatedly reported in adult patients with mood disorders, suggesting a role of these cells in the pathogenesis of these disorders. In the present study, we explored the dynamics of circulating T cell subsets over time in a population at high familial risk for developing a mood disorder. METHODS: Children of a parent with bipolar disorder (bipolar offspring, N=140) were assessed at three time-points: adolescence, young adulthood and adulthood. We carried out a detailed fluorescence-activated cell sorting (FACS) analysis to determine various T cell subsets from frozen stored peripheral blood mononuclear cells of bipolar offspring and age- and gender-matched healthy controls at each time-point. RESULTS: Throughout the period of observation reduced levels of CD3+ and CD3+ CD4+ T cells were observed. In bipolar offspring Th1, Th2, Th17 and natural T regulatory cells (Tregs) followed a dynamic course over time with reduced levels of Tregs in adolescence and a reduced relative number of Th1, Th17 cells in young adulthood. In post hoc analysis Tregs were inversely associated with the pro-inflammatory monocyte state determined previously (rs=-0.220, p=0.001). Significant associations between T cell subset abnormalities and psychopathology such as mood disorders were not found. CONCLUSIONS: A subtle partial T cell defect was present in bipolar offspring from adolescence through adulthood. Within this defect the dynamic change of inflammatory and regulatory T cell subsets suggests a high inflammatory state during adolescence, a reduced inflammatory state during young adulthood and a virtually normalized state at adulthood.

Usually Available Clinical and Laboratory Data Are Insufficient for a Valid Medication Review: A Crossover Study.

OBJECTIVES: To establish the quality of medication reviews performed by nursing home physicians, general practitioners and pharmacists. DESIGN AND SETTING: 15 Pharmacists, 13 general practitioners and 18 nursing home physicians performed a medication review for three cases (A, B and C), at three evaluation moments. First, they received the medication list. Secondly, they also received laboratory results and reason for admission and finally, we added medical history. Remarks were divided into 6 categories, i.e. indication without medication, medication without indication, contraindications/ interactions, dosage problems, double medication and wrong medication. Remarks were compared to the remarks made by our expert panel and scored according to our grading model as appropriate (0 to +3) or missed or potentially harmful (-1). For each medication error category, the percentage of participants who made this error was computed. RESULTS: After the first evaluation moment, the overall estimated mean percentage score was -1.7% for case A, 3.9% for case B, and 8.7% for case C. After the second review, this score was 15.0% for case A, 19.8% for case B, and 22.2% for case C. This further increased to 30.0% for case A, 36.7% for case B and 44% for case C at the final evaluation. The absence of medication where there was an indication (indication without medication) was frequently missed and did not improve after adding the extra information regarding laboratory results, reason for admission and finally medical history. CONCLUSION: Increasing clinical information helps physicians and pharmacists to improve their medication reviews, however, additional information was still related with a high margin of error. Detection of certain errors becomes easier with additional information, whereas other errors remain undetected. To achieve a high standard of medication review, we have to change the way medication reviews should be performed.

Durable efficacy of liraglutide in patients with type 2 diabetes and pronounced insulin-associated weight gain: 52-week results from the Effect of Liraglutide on insulin-associated wEight GAiN in patients with Type 2 diabetes' (ELEGANT) randomized controlled trial.

BACKGROUND: Pronounced weight gain frequently complicates insulin therapy in patients with type 2 diabetes (T2DM). We have previously reported that addition of liraglutide for 26 weeks can reverse insulin-associated weight gain, decrease insulin dose and improve glycaemic control, as compared with continuation of standard insulin treatment. OBJECTIVES: To investigate whether the beneficial effects of liraglutide are sustained up to 52 weeks and whether similar effects could be obtained when liraglutide is added 6 months later. METHODS: Adult T2DM patients with ≥ 4% weight gain within 16 months of insulin therapy completing the first 26-week trial period of open-label addition of liraglutide 1.8 mg day(-1) (n = 26) versus continuation of standard insulin therapy (n = 24) were all treated with liraglutide for another 26 weeks. Results were analysed according to the intention-to-treat principle. RESULTS: Overall, 24 (92%) and 18 (75%) patients originally assigned to liraglutide and standard therapy, respectively, completed the study. Addition of liraglutide decreased body weight to a similar extend when given in the first 26 weeks (liraglutide group) or second 26 weeks (original standard therapy group): -4.4 vs. -4.3 kg (difference -0.32 kg, 95% confidence interval -2.2 to 1.6 kg; P = 0.74). Similar results were also seen in the two groups with regard to decrease in haemoglobin A1c (HbA1c ) (-0.77 vs. -0.66%; P = 0.23) and insulin dose (-28 vs. -26 U day(-1) ; P = 0.32). In both groups, 22% of patients could discontinue insulin. Continuation of liraglutide until 52 weeks led to sustained effects on body weight, HbA1c and insulin-dose requirements. CONCLUSION: In T2DM patients with pronounced insulin-associated weight gain, addition of liraglutide within 2 years leads to sustained reversal of body weight, improved glycaemic control and decrease in insulin dose. Thus, liraglutide offers a valuable therapeutic option.

Insulin administered by needle-free jet injection corrects marked hyperglycaemia faster in overweight or obese patients with diabetes.

AIMS: To test whether jet injection of insulin resulted in faster correction of marked hyperglycaemia than when insulin is injected by a conventional pen in patients with diabetes. METHODS: Adult, overweight or obese (BMI ≥25 and ≤40 kg/m(2)) patients with type 1 diabetes (n = 10) or insulin-treated type 2 diabetes (n = 10) were enrolled in a randomized, controlled, crossover study. On two separate occasions, patients were instructed to reduce insulin dose(s) to achieve marked hyperglycaemia (18-23 mmol/l). Subsequently, insulin aspart was administered either by jet injection or by conventional pen, in a dose based on estimated individual insulin sensitivity. Pharmacodynamic and pharmacokinetic profiles were derived from plasma glucose and insulin levels, measured for 6 h after injection. RESULTS: After conventional injection, plasma glucose concentration dropped by ≥10 mmol/l after 192.5 ± 13.6 min. The jet injector advanced this time to 147.9 ± 14.4 min [difference 44.6 (95% confidence interval 4.3, 84.8); P = 0.03], except in 3 patients who failed to reach this endpoint. The time advantage exceeded 1.5 h in patients with a BMI above the median. Jet injection also reduced the hyperglycaemic burden during the first 2 h (2042 ± 37.2 vs 2168 ± 26.1 mmol/min; P = 0.01) and the time to peak insulin levels (40.5 ± 3.2 vs 76.8 ± 7.7 min; P < 0.001), but did not increase the risk for hypoglycaemia. CONCLUSIONS: Administration of rapid-acting insulin by jet injection results in faster correction of marked hyperglycaemia in overweight or obese patients with insulin-requiring diabetes.

Circadian rhythm of circulating levels of the endocannabinoid 2-arachidonoylglycerol.

CONTEXT: The endocannabinoid (eCB) system is involved in the regulation of food intake and of peripheral metabolism. Although the cross talk between energy metabolism and the circadian system is well documented, little is known about a potential circadian modulation of human eCB activity. OBJECTIVE: The objective of the study was to define the 24-hour profile of circulating levels of the most abundant endogenous ligand of the CB1 receptor, 2-arachidonoylglycerol (2-AG), in healthy young nonobese adults studied under controlled bedtime, dietary, and activity conditions. METHODS: Fourteen subjects participated in this 4-day laboratory study with fixed light-dark cycles, standardized meals, and bedtimes. Sleep was recorded each night. On the third day, blood sampling at 15- to 30-minute intervals began at 9:30 pm and continued for 24 hours. Cortisol, leptin, and ghrelin were assayed on all samples, whereas the levels of 2-AG and its structural analog, 2-oleoylglycerol (2-OG), were measured at 60-minute intervals. RESULTS: All participants exhibited a large circadian variation of 2-AG serum concentrations with a nadir around midsleep, coincident with the middle of the overnight fast. Levels of 2-AG increased continually across the morning, peaking in the early to midafternoon. Peak values represented, on average, a nearly 3-fold increase above nocturnal nadir levels. Concentrations of 2-OG followed a similar pattern, although with a shorter morning increase and lower amplitude. CONCLUSIONS: The findings demonstrate that activity of the eCB system is profoundly modulated by circadian rhythmicity and suggest that its impact on the regulation of food intake is suppressed during sleep and is maximal during early to midafternoon.

Does COMT genotype influence the effects of d-amphetamine on executive functioning?

In a widely cited study, Mattay et al. reported that amphetamine (0.25 mg/kg oral, or 17 mg for a 68 kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5, 10, and 20 mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research.

MIDD or MELAS : that's not the question MIDD evolving into MELAS : a severe phenotype of the m.3243A>G mutation due to paternal co-inheritance of type 2 diabetes and a high heteroplasmy level.

Maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) are different syndromes, but are caused by the same m.3243A>G mutation in mitochondrial DNA. Why some patients develop MIDD while others MELAS is unknown, but may be related to heteroplasmy level. Progression from MIDD to MELAS has not been described. Here we report a patient with MIDD who over time developed severe insulin resistance and symptoms and signs consistent with MELAS. The most likely explanation here was paternal co-inheritance of type 2 diabetes in combination with a high heteroplasmy level. The present case showing evolution of MIDD to MELAS supports the concept that both syndromes can be regarded as two phenotypes of the same disease.

OPRM1 gene variants modulate amphetamine-induced euphoria in humans.

The µ-opioid receptor is involved in the rewarding effects of not only opioids like morphine but also psychostimulants like amphetamine. This study aimed to investigate associations between subjective response to amphetamine and genetic polymorphisms and haplotypes in the µ-opioid receptor including the exonic variant rs1799971 (Asp40Asn). One hundred and sixty-two Caucasian volunteers participated in three sessions receiving either placebo or d-amphetamine (10 and 20 mg). Associations between levels of self-reported Euphoria, Energy and Stimulation [Addiction Research Center Inventory 49-item questionnaire (ARCI-49)] after d-amphetamine ingestion and polymorphisms in OPRM1 were investigated. The intronic single nucleotide polymorphisms (SNPs) rs510769 and rs2281617 were associated with significantly higher ratings of Euphoria, Energy and Stimulation after 10 mg amphetamine. Feelings of Euphoria, Energy and Stimulation were also found to be associated with a two-SNP haplotype formed with rs1799971 and rs510769 and a three-SNP haplotype formed with rs1918760, rs2281617 and rs1998220. These results support the hypothesis that genetic variability in the µ-opioid receptor gene influences the subjective effects of amphetamine and may suggest new strategies for prevention and treatment of psychostimulant abuse.

Endothelial function in familial combined hyperlipidaemia.

BACKGROUND: Familial combined hyperlipidaemia (FCH) is characterized by dyslipidaemia, visceral obesity and insulin resistance, and is associated with an increased intima-media thickness (IMT) and an increased risk for cardiovascular disease. In the present study, we investigated whether FCH is associated with early functional vascular wall changes, as represented by endothelial dysfunction, and we determined whether endothelial function in FCH is related to any of the cardiovascular risk factors associated with the FCH phenotype, or to the (increased) IMT. DESIGN: In 98 patients with FCH [mean age 51 (48-54) years, 43% male] and 230 unaffected relatives [mean age 44 (42-46) years, 48% male], venous blood was drawn in the fasting state after discontinuation of lipid lowering drugs for at least 4 weeks (if used). IMT was measured by B-mode ultrasound and endothelial function was assessed by determination of flow mediated dilation (FMD) and by measurement of plasma concentrations of various soluble adhesion molecules, including soluble vascular cell adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM) and soluble E-selectin. RESULTS: There were no significant differences between FCH patients and their non-affected relatives in FMD [2.9 (2.3-3.6%) vs. 2.8 (2.5-3.2%)] or in the plasma concentrations of the various adhesion molecules. None of the individual clinical and biochemical cardiovascular risk factors was an independent predictor of endothelial function in patients with FCH, nor was IMT. However, subgroup analysis revealed that IMT was an independent and powerful predictor of FMD in subjects with carotid artery plaques (St. beta = 4.11, P < 0.004), whereas IMT was no significant predictor in subjects without plaques. CONCLUSIONS: FCH patients have no impaired endothelial function when compared to their unaffected relatives. IMT is an important predictor of FMD when advanced morphological wall changes are present. Our results question the value of FMD measurements for cardiovascular risk stratification in populations with an anticipated high cardiovascular risk.