Integrating metabolomics profiling measurements across multiple biobanks.

To optimize the quality of large scale mass-spectrometry based metabolomics data obtained from semiquantitative profiling measurements, it is important to use a strategy in which dedicated measurement designs are combined with a strict statistical quality control regime. This assures consistently high-quality results across measurements from individual studies, but semiquantitative data have been so far only comparable for samples measured within the same study. To enable comparability and integration of semiquantitative profiling data from different large scale studies over the time course of years, the measurement and quality control strategy has to be extended. We introduce a strategy to allow the integration of semiquantitative profiling data from different studies. We demonstrate that lipidomics data generated in samples from three different large biobanks acquired in the time course of 3 years can be effectively combined when using an appropriate measurement design and transfer model. This strategy paves the way toward an integrative usage of semiquantitative metabolomics data sets of multiple studies to validate biological findings in another study and/or to increase the statistical power for discovery of biomarkers or pathways by combining studies.

Influence of predispositions on post-traumatic stress disorder: does it vary by trauma severity?

BACKGROUND: Only a minority of trauma victims (<10%) develops post-traumatic stress disorder (PTSD), suggesting that victims vary in predispositions to the PTSD response to traumas. It is assumed that the influence of predispositions is inversely related to trauma severity: when trauma is extreme predispositions are assumed to play a secondary role. This assumption has not been tested. We estimate the influence of key predispositions on PTSD induced by an extreme trauma - associated with a high percentage of PTSD - (sexual assault), relative to events of lower magnitude (accidents, disaster, and unexpected death of someone close). METHOD: The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is representative of the adult population of the USA. A total of 34 653 respondents completed the second wave in which lifetime PTSD was assessed. We conducted three series of multinomial logistic regressions, comparing the influence of six predispositions on the PTSD effect of sexual assault with each comparison event. Three pre-existing disorders and three parental history variables were examined. RESULTS: Predispositions predicted elevated PTSD risk among victims of sexual assault as they did among victims of comparison events. We detected no evidence that the influence of predispositions on PTSD risk was significantly lower when the event was sexual assault, relative to accidents, disasters and unexpected death of someone close. CONCLUSIONS: Important predispositions increase the risk of PTSD following sexual assault as much as they do following accidents, disaster, and unexpected death of someone close. Research on other predispositions and alternative classifications of event severity would be illuminating.

Safety and tolerability of linagliptin: a pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes mellitus.

AIMS: To assess the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes. METHODS: Data were pooled from eight randomized, double-blind, placebo-controlled Phase III clinical trials lasting ≤24 weeks. Incidences were calculated with descriptive statistics for the overall population and for subgroups of elderly and renally impaired patients. RESULTS: A total of 2523 patients received linagliptin 5 mg once daily and 1049 patients received placebo. The overall incidence of adverse events (AEs) or serious AEs with linagliptin was similar to placebo (AEs 55.8% vs. 55.0%; serious AEs 2.8% vs. 2.7%). Overall aggregated infection incidence was 19.5% for linagliptin and 21.4% for placebo. Similar or reduced incidence of AEs versus placebo were seen with linagliptin for upper respiratory tract infection (3.3% vs. 4.9%), headache (2.9% vs. 3.1%), urinary tract infection (2.2% vs. 2.7%), blood and lymphatic disorders (1.0% vs. 1.2%), hypersensitivity (0.1% vs. 0.1%), hepatic enzyme increase (0.1% and 0.1%) and serum creatinine increase (0.0% and 0.1%). There was a slight increased frequency of nasopharyngitis (5.9% vs. 5.1%) and cough (1.7% vs. 1.0%) with linagliptin. Hypoglycaemia incidence was 8.2% for linagliptin and 5.1% for placebo; incidence was higher in patients with a background of sulphonylurea therapy (20.7% and 13.3%, respectively). In patients not receiving concomitant sulphonylurea, the hypoglycaemic incidence with linagliptin was very low in both the total population (<1%), and elderly and renally impaired patients (both <1%). CONCLUSIONS: This pooled analysis shows that linagliptin is well tolerated, with a low risk of hypoglycaemia.

Stability and suitability for storage and distribution of Ad26.ZEBOV/MVA-BN®-Filo heterologous prime-boost Ebola vaccine.

The stability profile of a vaccine has important implications for storage, cold chain management and field deployment. The heterologous prime-boost Janssen Ebola vaccine regimen demonstrated an acceptable safety profile and durability of Ebola-specific immune responses in Phase I studies in healthy adults. Potency (infectious titre) of both components of the Ad26.ZEBOV/MVA-BN-Filo regimen were assessed using qPCR-based potency assay and flow cytometry during real-time and accelerated stability studies, conducted between -80 °C and 25 °C. Additionally, vaccine potency was assessed following agitation, temperature cycling, freeze-thawing and while in the injection system. Ad26.ZEBOV remained stable for 24 months when frozen and at 2-8 °C; MVA-BN-Filo remained stable for 24 months frozen and 12 months at 2-8 °C. Potency of both vaccines was maintained during temperature cycling, agitation and freeze-thawing. When exposed to high temperatures (up to 40 °C) in a syringe/needle both vaccines remained stable for at least 6 h. The vaccines are expected to maintain potency for 36 months when frozen (based on extrapolation of observed stability). The findings of this study indicate that the stability of the Ad26.ZEBOV/MVA-BN-Filo is likely suitable for field deployment in regions at risk of Ebola outbreaks, where cold chain maintenance is challenging owing to infrastructure and resource limitations.

Vascular effects of 5-HT1B/1D-receptor agonists in patients with migraine headaches.

OBJECTIVES: Second-generation triptans are believed to have fewer cardiovascular effects than sumatriptan. This was investigated in vivo by comparing the vascular effects of equipotent therapeutic dosages of selective 5-HT1B/1D-receptor agonists. METHODS: Sixteen patients with migraine headaches completed a double-blind, placebo-controlled, four-way crossover study. With ultrasonography and applanation tonometry used 1.5 hours after the oral intake of sumatriptan (50 mg), rizatriptan (10 mg), zolmitriptan (2.5 mg), or placebo arterial vessel wall properties, blood flow and pressure waveforms were measured in common carotid, brachial, and temporal arteries. At the brachial artery, flow-induced vasodilation (an endothelium-dependent process) was evaluated, and blood pressures were recorded. RESULTS: Mean arterial pressure, 91 +/- 2 mm Hg after placebo, increased (P < .05) by 4% to 6% after administration of each triptan. Each active treatment decreased (P < .001) both brachial and carotid artery diameter. Isobaric compliance of the brachial artery, 0.077 +/- 0.010 mm2/kPa after placebo, decreased (P < .01) by 11% +/- 8%, 11% +/- 11%, and 23% +/- 7% after administration of sumatriptan, rizatriptan, and zolmitriptan, respectively. Isobaric compliance of the carotid artery was 1.31 +/- 0.10 mm2/kPa after placebo (no change). Zolmitriptan was the only triptan that decreased temporal artery diameter significantly (by 12% +/- 3%, P < .001). The resistance of the temporal artery vascular bed increased after administration of sumatriptan (by 26% +/- 11%, P < .05) and zolmitriptan (by 40% +/- 9%, P = .001). Flow-induced vasodilation was unaffected. CONCLUSIONS: Selective 5-HT1B/1D-receptor agonists induce vasoconstriction and decrease compliance of conduit arteries. These effects are more pronounced at muscular (temporal, brachial) compared with elastic (carotid) arteries. Resistance is only increased at the temporal artery vascular bed, suggesting cranioselectivity for resistance vessels. Endothelial function is not differently affected by any of the triptans tested.

Chronic traumatic brain injury in professional soccer players.

OBJECTIVE: To determine the presence of chronic traumatic brain injury in professional soccer players. METHODS: Fifty-three active professional soccer players from several professional Dutch soccer clubs were compared with a control group of 27 elite noncontact sport athletes. All participants underwent neuropsychological examination. The main outcome measures were neuropsychological tests proven to be sensitive to cognitive changes incurred during contact and collision sports. RESULTS: The professional soccer players exhibited impaired performances in memory, planning, and visuoperceptual processing when compared with control subjects. Among professional soccer players, performance on memory, planning, and visuoperceptual tasks were inversely related to the number of concussions incurred in soccer and the frequency of "heading" the ball. Performance on neuropsychological testing also varied according to field position, with forward and defensive players exhibiting more impairment. CONCLUSION: Participation in professional soccer may affect adversely some aspects of cognitive functioning (i.e., memory, planning, and visuoperceptual processing).

Surface reflectances and human color constancy: comment on Dannemiller (1989)

Dannemiller's (1989) computational approach to color constancy is discussed in relation to human color constancy. A reflectance channel that requires a priori information is shown to be less plausible for the human visual system than Dannemiller argued. The resemblance of Dannemiller's hypothetical visual system to the human visual system is misleading because it implies that surface reflectance is the illuminant-invariant object color descriptor that the human visual system uses to achieve color constancy. However, an alternative type of descriptor is available that is not used to recover reflectance spectra. It has the advantage of allowing an interpretation that is preferable from a human perceptual point of view.

Apoptosis in the rat spinal cord during postnatal development; the effect of perinatal asphyxia on programmed cell death.

The aim of our study was to investigate the effect of perinatal asphyxia on developmental apoptosis in the cervical and lumbar spinal cord in the neonatal rat. Perinatal asphyxia was induced by keeping pups at term in utero in a water bath at 37 degrees C for 20 min, followed by resuscitation. Effects of this treatment on developmental apoptosis were studied on postnatal days 2, 5 and 8 using terminal deoxynucleotidyl transferase (TdT)-dUTP-biotin nick end labelling (TUNEL) and caspase-3 staining. TUNEL positive cells were identified using double immunostaining. On postnatal day 2 an increase of 215% in TUNEL positive cells was detected (P=0.005) in laminae IV-VII of the lumbar spinal cord of rats which underwent perinatal asphyxia compared to controls. An increase of 55% compared to controls (P=0.03) was seen in laminae I-III of the lumbar spinal cord at postnatal day 8. TUNEL positive cells could be partly identified as microglia cells (ED1 positive) and oligodendrocytes (O4 positive). The effect of perinatal asphyxia on programmed cell death in the neonatal rat spinal cord was mainly observed in the intermediate zone and dorsal horn of the lumbar spinal cord. We conclude that perinatal asphyxia has a pronounced effect on the survival of cells in a specific region of the spinal cord and thus may have a profound effect on the development of motor networks.

Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study.

We treated 24 patients with narcolepsy for 4 weeks with gammahydroxybutyrate (GHB), 60 mg/kg/night, in a randomized double-blind placebo-controlled cross-over trial. Both clinical and polysomnographic criteria were used to assess the results. Compared to placebo, GHB reduced the daily number of hypnagogic hallucinations (from 0.87 to 0.28; p = 0.008), daytime sleep attacks (from 2.27 to 1.40; p = 0.001) and the severity of subjective daytime sleepiness (from 1.57 to 1.24 on a 0-4 scale; p = 0.028). The number of daily cataplexy attacks was reduced from 1.26 at baseline to 0.56 after 4 weeks of GHB intake. This reduction, however, was not statistically significantly different from the difference between baseline and placebo. GHB stabilized nocturnal rapid eye movement (REM) sleep, i.e. it reduced the percentage of wakefulness during REM sleep (p = 0.007) and the number of awakenings out of REM sleep (p = 0.016), and tended to increase slow wave sleep (p = 0.053). Adverse events were few and mild. We conclude that GHB is an effective and well-tolerated treatment for narcolepsy.

Ritanserin, a 5-HT2 receptor blocker, as add-on treatment in narcolepsy.

In a double-blind placebo-controlled trial, ritanserin (a 5-HT2 receptor blocker) 5 mg/day or placebo was added to the usual medication in 28 patients with narcolepsy during 4 wk. The effect was assessed by means of polysomnography, daily and weekly subjective evaluations, and Multiple sleep latency tests (MSLT). During the night ritanserin increased the amount of nonrapid eye movement slow wave sleep and reduced wakefulness after sleep onset. It improved the feeling of being refreshed in the morning after awakening and reduced subjective daytime sleepiness. The drug did not significantly influence sleep latency in the MSLT.

Determinants of success of inpatient clinical information systems: a literature review.

We reviewed the English and Dutch literature on evaluations of patient care information systems that require data entry by health care professionals published from 1991 to 2001. Our objectives were to identify attributes that were used to assess the success of such systems and to test the ability of a framework developed by Delone and McLean for management information systems(1) to categorize these attributes correctly. The framework includes six dimensions or success factors: system quality, information quality, usage, user satisfaction, individual impact, and organizational impact. Thirty-three papers were selected for complete review. Types of study design included descriptive, correlational, comparative, and case studies. A variety of relevant attributes could be assigned to the six dimensions in the Delone and McLean framework, but some attributes, predominantly in cases of failure, did not fit any of the categories. They related to contingent factors, such as organizational culture. Our review points out the need for more thorough evaluations of patient care information systems that look at a wide range of factors that can affect the relative success or failure of these systems.

Child psychiatric diagnoses in a population of Dutch schoolchildren aged 6 to 8 years.

OBJECTIVE: To determine the prevalence rates of child psychiatric diagnoses in a school-based population of children aged 6 to 8 years in the south of the province of Limburg (The Netherlands). METHOD: In a two-stage design 1,317 children were screened with the Child Behavior Checklist. From 403 of these children, child psychiatric information was obtained with the Amsterdam Diagnostic Interview for Children and Adolescents (ADIKA, DSM-III-R/IV). Data were generalized to the responder group (n = 1,317) and to the entire cohort (N = 2,290). For the latter procedure, a prediction model was used to generalize ADIKA results to the nonresponders (n = 973). RESULTS: Estimates of the prevalence of different ADIKA diagnoses in the responder group were quite comparable with those for the entire cohort. Twenty-four percent of the entire cohort met criteria for a single disorder, and 21.0% met criteria for two or more disorders. However, in only 5.7% of the cases parents did report a need for help. CONCLUSIONS: Where other studies generalize psychiatric diagnoses to the responder group only, this report adds new information by generalizing the prevalence to a school-based cohort of children aged 6 to 8 years. These prevalence estimates are of importance with regard to the demand for care for child psychopathology.

Localization and age-related changes of nitric oxide- and ANP-mediated cyclic-GMP synthesis in rat cervical spinal cord: an immunocytochemical study.

An immunocytochemical technique was used to study the localization and developmental aspects of cyclic GMP (cGMP)-synthesizing structures in the cervical spinal cord of 2-week and 3-month-old Lewis rats in response to the nitric oxide (NO) donor sodium nitroprusside (SNP) and/or atrial natriuretic peptide (ANP). By using cell-specific markers, the cell structures involved were investigated. To visualize cGMP, a combined technique of low- and high-power magnification, using a confocal laser scanning microscope was used. NOS-mediated cGMP synthesis was observed in the cervical spinal cord in laminae I, II and III in 14-day-old rats, which activity was mainly absent at the age of 3 months. The involvement of NO in the NMDA-mediated increase in cGMP immunostaining (cGMP-IS) was demonstrated by the absence of cGMP-IS in slices incubated in the presence of NMDA together with the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). This NO-mediated effect of NMDA on cGMP-IS was completely absent in the 3-month-old rats. ANP-mediated cGMP synthesis resulted in an increase in cGMP in laminae I and II, which was generally similar at both ages. Astrocytes in both white and gray matter were found to be cGMP-IS in the basal, NO- and ANP-stimulated conditions. Using confocal laser microscopy, NO-mediated cGMP synthesis was observed in large cholinergic terminals nearby motor neurons in the ventral horn. An extensive colocalization between NO-stimulated cGMP synthesis and parvalbumin-positive (GABAergic) neurons and fibers was observed in all laminae. In the ANP-stimulated condition, a colocalization with parvalbumin structures was found in laminae II and III. No NO- or ANP-mediated cGMP synthesis was found in fibers immunopositive for the presynaptic glutamate transporter, serotonin, or tyrosine hydroxylase.

Abnormal warm and cold sensation thresholds suggestive of small-fibre neuropathy in sarcoidosis.

OBJECTIVE: A substantial number of sarcoidosis patients report apparently non-specific symptoms such as pain, for which no organic substrate has yet been found. Recently we observed symptoms suggestive of small-fibre neuropathy in a group of sarcoidosis patients. The aim of the present study was to verify this observation using various electrophysiological tests. METHODS: In 74 sarcoidosis patients complaining of symptoms suggestive of small-fibre neuropathy, thresholds for warm (WS) and cold sensation (CS) as well as for heat pain were determined at the thenar eminence and the foot dorsum. Furthermore, sympathetic skin responses (SSR), nerve conduction studies and concentric needle electromyography were performed. In 31 patients, cardiovascular autonomic testing was carried out. RESULTS: Thermal threshold testing (TTT) revealed abnormalities in 51 of the 74 patients. Abnormalities showed an asymmetrical distribution. WS was affected more often than CS and feet more often than hands. Nerve conduction studies in the legs showed slightly abnormal results in 6 patients; all of these had abnormal TTT results. The SSR was absent at the foot in 7 patients. Cardiovascular autonomic testing was abnormal in only a single patient. CONCLUSIONS: In a subgroup of sarcoidosis patients we found TTT abnormalities suggestive of small-fibre neuropathy. SSR and cardiovascular autonomic testing appeared to be of little diagnostic value. Small-fibre neuropathy may be the cause of a number of hitherto unexplained symptoms in sarcoidosis.

Baclofen inhibits ANP-mediated cyclic GMP synthesis in the rat cervical spinal cord.

The neurotransmitter gamma-aminobuteric acid (GABA) is believed to have a controlling action on spinal locomotor networks. In spasticity, spinal locomotor networks are thought to play a role. A well known drug in the treatment of spasticity is the GABA(B) agonist Baclofen. We report an inhibitory effect of Baclofen on the ANP-mediated cGMP synthesis in the superficial dorsal horn (laminae I-III) of the rat cervical spinal cord. This inhibitory effect of Baclofen could not be detected after incubation with the NO donor SNP. The clinical effect of Baclofen on the reduction of spasticity might be explained by an enhancement of GABAergic inhibition of ANP mediated cGMP concentration in the spinal cord dorsal horn, thus reducing afferent input.

Human leucocyte alpha-L-fucosidase.

1. Human alpha-L-fucosidase (EC 3.2.1.51) was studied from leucocytes, urine and serum. 2. The leucocyte and urine enzymes are similar in many properties (KM, pH optimum, electrophoretic pattern, heat stability). 3. The serum alpha-L-fucosidase differs from the leucocyte and 4rine enzyme wit,respect to: electrophoretic pattern, pH optimum and heat stapility. 4. The molecular weight of leucocyte alpha-L-fucosidase was determined to be 80 000 +/- 5000. 5. Cu2+, Hg2+ and PCMB are strong inhibitors of leucocyte alpha-L-fucosidase. This inhibition could be completely reversed by beta-mercaptoethanol, indicating that thiol groups are essential for catalytic activity.

Characterization of alpha-L-fucosidase from two different families with fucosidosis.

1. Two different families with a different type of fucosidase deficiency are described. 2. In the first family the activity of alpha-L-fucosidase in leucocytes of two patients with fucosidosis type I was about 4 to 8% of the normal value. The activity of alpha-L-fucosidase in the leucocytes of the father and the mother are in the heterozygote range, while a sister of the propositus showed normal values. 3. The activity of alpha-L-fucosidase of the propositus from urine, serum and liver were also severely decreased. The activity of alpha-L-fucosidase in the urine of the parents and the healthy sister of thr propositus were about 5% of the mean normal value. However in the serum these values were above 50%. 4. The KM value for alpha-L-fucosidase from leucocytes of the patient was increased about 10 times and in serum this value was even higher. The KM values from the enzyme of the parents were in the normal range. 5. The abnormal enzyme from the propositus is unique in its thermal behaviour since after heating its activity increased. 6. In the second fanily the activity of alpha-L-fucosidase in the leucocytes of the patient is about 30% of the mean normal value, while the arylsulphatase A activity is also decreased (25% of the mean normal value). 7. The activity of alpha-L-fucosidase from the leucocytes of the father and the healthy brother are about 50% of the mean normal level, while the enzyme of the mother showed a normal activity. 8. The alpha-L-fucosidase activity in the urine and the liver of the propositus is also decreased. The serum enzyme activity however was in the normal range. 9. The KM value of alpha-L-fucosidase and heat stability of the enzyme of the patient were normal. In the leectrophoretic pattern of the whole family one bond was missing.

Prognostic value of blood pressure in acute stroke.

Manipulation of blood pressure (BP) in acute stroke may improve outcome. Despite various studies, data on the prognostic significance of early BP in stroke remain unclear. Therefore, we studied the relationship between various BP variables in the acute phase of stroke and functional outcome at 3 months. Blood pressures were collected by reviewing BP records of 817 patients who were admitted to our stroke unit between 1987 and 1992. Besides the first systolic and diastolic admission BP (SBP and DBP), we also used the mean of the daytime as well as the night-time systolic and diastolic BP values. Finally, we studied the relationship between the decrease in BP between day 0 and 4 and outcome. As dependent outcome variable we used the Rankin handicap score at 3 months dichotomized in a score >3 (poor outcome) vs a score 3 (good outcome). A total of 430 patients were admitted within 24 h following stroke onset. There was no significant relationship between the systolic and diastolic BP and the outcome at 3 months. Only night-time systolic BP 165 mm Hg (odds ratio (OR) 2.8; 95% CI 1.1-6.8), night-time diastolic BP 60 mm Hg (OR 8.1; 95% CI 1.1-58.3), and a decrease in daytime diastolic BP between day 0 and 4 of 10 mm Hg (OR 3.0; 95% CI 1.1-7.9) showed a significant relationship with poor outcome. Our findings suggest that admission BP values may not reliably reflect any impact of BP on stroke outcome. They also suggest a potential differential effect of BP manipulation: increasing or decreasing BP may be beneficial for patients with BP extremes in one direction, but detrimental for those with BP values in the opposite direction.

Transparent layer constancy.

Perceived transparency was studied as a constancy problem. In the episcotister (E-) model of scission, luminances are partitioned into layer and background components; four luminances determine values of two layer parameters that specify constancy of a transparent layer on different backgrounds. The E-model was tested in an experiment in which 12 Ss matched 24 pairs of four-luminance patterns by adjusting two luminances of the comparison pattern. Both the standard and the comparison were perceived as a transparent layer on a checkerboard. The E-model predicts matches when layer values are identical in the two patterns. One parameter was constant, constraining the adjustment along the second dimension. Obtained values corresponded well with E-predictions. Alternative models based on local luminance or average contrast ratios accounted for less variability. Results indicate that transparency models should utilize luminance, not reflectance, as the independent variable.

Binocular measurements of chromatic adaptation.

In this paper we present asymmetric matching data that were obtained with a binocular presentation method. Our main motivation was the question whether chromatic adaptation, one of the important mechanisms that contribute to colour constancy, has evolved towards a better performance in the range of colours that are present in the natural image. For the eye adapted to a bluish illuminant for example the presence of an object with a deep yellow colour is very unlikely. So, it was expected that the colour difference between adapting light and target has an influence on the extent of chromatic adaptation. It was found that the colour shift in the observers' matches that can be attributed to chromatic adaptation indeed has a maximum. The location of the maximum, however, was unexpected, i.e. colour differences between target and adapting light that lie around 0.05 u'v'-chromaticity units. Additionally, several models for chromatic adaptation were fitted to our data. It was found that, except for the simple von Kries model, Retinex Theory and difference contrast, a number of models gave good predictions for the L-wave and M-wave fundamental systems, but that predictions for the S-wave system were less accurate.