[Dental anxiety and alexithymia; research on anxiety acquisition]. / Behandelangst en alexithymie, onderzoek naar angstleerprocessen.

People with alexithymia have difficulty identifying and describing feelings, have little imagination and mental processes largely orientated towards facts and less towards inner experience. It occurs in about 1 in 10 people and therefore in the dental office, too. A positive association has been found between alexithymia and the development of dental anxiety. With the help of an anxiety-conditioning experiment, the acquisition and the extinction of anxiety can be studied. To gain more knowledge about these processes of acquisition in people with alexithymia, such an experiment was conducted among 32 people with severe dental anxiety, 13 of whom with (possible) alexithymia. Relatively little anxiety conditioning occurred during the experiment. This may be explained by the aversive stimulus and the context in which the experiment was conducted. However, it emerged that for people with alexithymia, a physical outcome measure may be a better indicator of anxiety than a subjective score on a visual analogue scale.

Safety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients.

INTRODUCTION: Cetuximab is registered for use in colorectal cancer (CRC) patients with RAS wild-type tumours only. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification (prenylation) of KRAS. We hypothesize that the activated KRAS pathway in KRAS mutant tumors can be inhibited by simvastatin rendering these tumors sensitive to the EGFR inhibitor cetuximab. METHODS: A Simon two-stage, single-arm, phase II study was performed to test the efficacy and safety of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their CRC tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens. The primary endpoint was to test the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40% was free from progression, comparable to, though slightly lower than in KRAS wild-type patients. RESULTS: Four of 18 included patients (22.2%) were free from progression at the primary endpoint time. The time to progression in these 4 patients ranged from 20.3 to 47 weeks. CONCLUSION: Based on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation.

Effects of cannabidiol on fear conditioning in anxiety disorders: decreased threat expectation during retention, but no enhanced fear re-extinction.

RATIONALE: Preclinical research suggests that pharmacologically elevating cannabinoid levels may attenuate fear memory expression and enhance fear extinction. OBJECTIVES: We studied the effects of cannabidiol (CBD) on fear memory expression and fear re-extinction in 69 patients with panic disorder with agoraphobia or with social anxiety disorder. Moderation by sex, diagnosis, and serotonergic antidepressant (AD) use was explored. METHODS: A cued fear conditioning paradigm was applied before the first treatment session with 300 mg CBD/placebo augmented exposure therapy. Study medication was administered orally preceding 8 weekly sessions. Fear acquisition and suboptimal extinction took place prior to the first medication ingestion (T0). After the first medication ingestion (T1), we investigated effects on fear memory expression at retention and fear re-extinction. Subjective fear, shock expectancy, skin conductance, and startle responses to conditioned (CS+) and safety stimulus (CS-) were measured. RESULTS: Across the sample, CBD reduced shock expectancy at retention under low and ambiguous threat of shock, but fear re-extinction at T1 was unaffected by CBD. However, in AD users, re-extinction of subjective fear was impaired in the CBD condition compared to placebo. In female AD users, CBD interfered with safety learning measured with fear-potentiated startle. CONCLUSIONS: The current findings provide no evidence for enhanced fear re-extinction by CBD. However, CBD acutely decreased threat expectation at retention, without affecting other indices of fear. More studies are needed to elucidate possible interactions with AD use and sex, as well as potential effects of CBD on threat expectancies.

[Hindering the immune system by tumours in the head and neck area]. / Remming van het immuunsysteem door tumoren in het hoofd-halsgebied.

Head and neck tumours possess several mechanisms to hinder an appropriate immune response against the tumour cell. In the first place, the tumour cells attempt to suppress the presentation of tumour-associated antigens to the cells of the immune system. Tumours also have a negative effect on the surface structures of the efferent blood vessel epithelium, thereby inhibiting the recruitment of immune cells. In addition, proteins are secreted capable of inactivating immune cells. These immunosuppressive activities of the tumour result in a deterioration of life expectancy. Several experimental methods to improve the immune response of the patient against tumour cells are currently being explored.

Genetic polymorphisms of the dopamine and serotonin systems modulate the neurophysiological response to feedback and risk taking in healthy humans.

Genetic differences in the dopamine and serotonin systems have been suggested as potential factors underlying interindividual variability in risk taking and in brain activation during the processing of feedback. Here, we studied the effects of dopaminergic (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT]) and serotonergic (serotonin transporter [5HTTLPR]) polymorphisms on risk taking and brain responses following feedback in 60 healthy female subjects. The subjects completed a well-established experimental gambling paradigm while an electroencephalogram was recorded. During the task, risk-taking behavior and prefrontal brain responses (feedback-related negativity [FRN]) following monetary gains and losses were assessed. FRN amplitudes were enhanced for nine-repeat-allele carriers of the DAT1 and short-allele carriers of 5HTTLPR, which are both presumably linked to less transporter activity and higher neurotransmitter levels. Moreover, nine-repeat DAT1 carriers displayed a trend toward increased risk taking in general, whereas 5HTTLPR short-allele carriers showed decreased risk taking following gains. COMT val158met genotype was unrelated to FRN amplitude and average risk taking. However, COMT met/met carriers showed a pronounced feedback P3 amplitude independent of valence, and a gradual increase in risk taking during the gambling task. In sum, the present findings underline the importance of genetic variability in the dopamine and serotonin systems regarding the neurophysiology of feedback processing.

Discontinuity in Equilibrium Wave-Current Ripple Size and Shape and Deep Cleaning Associated With Cohesive Sand-Clay Beds.

Mixtures of cohesive clay and noncohesive sand are widespread in many aquatic environments. Ripple dynamics in sand-clay mixtures have been studied under current-alone and wave-alone conditions but not combined wave-current conditions, despite their prevalence in estuaries and the coastal zone. The present flume experiments examine the effect of initial clay content, C 0, on ripples by considering a single wave-current condition and, for the first time, quantify how changing clay content of substrate impacts ripple dimensions during development. The results show inverse relationships between C 0 and ripple growth rates and clay winnowing transport rates out of the bed, which reduce as the ripples develop toward equilibrium. For C 0 ≤ 10.6%, higher winnowing rates lead to clay loss, and thus the presence of clean sand, far below the base of equilibrium ripples. This hitherto unquantified "deep-cleaning" of clay does not occur for C 0 > 10.6%, where clay-loss rates are much lower. The clay-loss behavior is associated with two distinct types of equilibrium combined flow ripples: (a) Large asymmetric ripples with dimensions and plan geometries comparable to their clean-sand counterparts for C 0 ≤ 10.6% and (b) small, flat ripples for C 0 > 10.6%. The 10.6% threshold, which may be specific to the experimental conditions, corresponds to a more general 8% threshold found beneath the ripple base, suggesting that clay content here must be <8% for clean-sand-like ripples to develop in sand-clay beds. This ripple-type discontinuity comprises a threefold reduction in ripple height, with notable implications for bed roughness.

The Role of the Endocannabinoids 2-AG and Anandamide in Clinical Symptoms and Treatment Outcome in Veterans with PTSD.

Background: Although current treatments for Post-Traumatic Stress Disorder (PTSD) in war veterans are effective, unfortunately 30-50% still do not benefit from these treatments. Trauma-focused therapies, eg exposure therapy, are primarily based on extinction processes in which the endocannabinoid system (ECS) plays a significant role. Therefore, it can be hypothesized that poor treatment response on trauma-focused therapy due to extinction deficits may be associated with a poorly functioning ECS. The present study examined whether the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) are associated with post-treatment symptom reduction. Methods: Blood plasma levels of AEA and 2-AG were determined in war veterans with a PTSD diagnosis (n = 54) and combat controls (n = 26) before and after a 6-8 month interval. During this period veterans with PTSD received trauma-focused therapy (eg cognitive behavioral therapy with exposure or eye-movement desensitization and reprocessing). Clinical symptoms were assessed before and after therapy with the Clinician Administered PTSD Scale (CAPS), State-Trait Anxiety Inventory (STAI) and Mood and Anxiety Symptom Questionnaire (MASQ). Results: Regression analysis demonstrated that pretreatment endocannabinoid levels were not predictive of PTSD symptom reduction. Additionally, baseline endocannabinoid levels did not differ between either PTSD and combat controls or between combat controls, treatment responders, and non-responders. Only cortisol levels significantly decreased over time from pre- to posttreatment (p = .041). Endocannabinoid levels were significantly lower in individuals who reported cannabis use during their lifetime, independent of PTSD diagnosis. Furthermore, correlation analysis revealed that pretreatment 2-AG levels in PTSD were positively correlated with anxious arousal (r = .354, p = .015) and negatively with avoidance symptoms (r = -.271, p = .048). Both posttreatment AEA and 2-AG were positively correlated with trait anxiety (AEA r = .459, p = .003; 2-AG r = .423, p = .006), anxious arousal (AEA r = .351, p = .024; 2-AG r = .311, p = .048) and general distress depression symptoms (AEA r = .414, p = .007; 2-AG r = .374, p = .016). Conclusion: Since endocannabinoids are mainly generated 'on demand', future work could benefit by investigating endocannabinoid circulation under both baseline and stressful conditions. In line with previous research cannabis use was associated with lower endocannabinoid levels. The correlation analysis between pre- and posttreatment endocannabinoid levels and pre- and posttreatment clinical symptomatology were exploratory analysis and should be replicated in future research.

Trajectories of fear learning in healthy participants are able to distinguish groups that differ in individual characteristics, chronicity of fear and intrusions.

BACKGROUND AND OBJECTIVES: Studies on the development and treatment of anxiety disorders mostly focus on the comparison of predefined groups. An alternative approach is to use data-driven latent class growth analyses (LCGA) to determine differentiation between groups based on particular mechanistic factors. This study validated the use of LCGA on responses in a compact fear conditioning task and whether specific characteristics are associated with maladaptive fear learning trajectories. METHODS: Healthy subjects (N = 300) completed a fear conditioning task that included uninstructed and instructed acquisition and extinction phases. Subjective fearfulness and US expectancy were used as outcome measures. Latent classes in the responses to the CS+ (coupled with a scream) and the CS- (control stimulus) were determined based on trajectories across the experimental phases. State and trait anxiety were measured during testing, and return of fear and intrusions were measured one and six weeks later. RESULTS: Fear learning trajectories of poor extinction in responding to the CS+ and generalization of fear to the CS- were associated with higher state and trait anxiety. Individuals belonging to these trajectories reported more intrusions, fear and had higher US expectancy ratings after 1 week. LIMITATIONS: Only 56% of participants completed the six weeks follow-up measures. CONCLUSION: Fear learning trajectories are associated with individual characteristics, return of fear and intrusions. Next, this task will be implemented in clinical practice to assess its predictive power for the extent to which patients benefit from exposure treatments.

Failure to condition to a cue is associated with sustained contextual fear.

The acquisition of a conditioned fear response is adaptive, as it enables the organism to appropriately respond to predictors of aversive events. Consequently, the absence of predictive cues can be used as a signal for safety. We aimed to study whether deficient fear conditioning might lead to maladaptive fear. Following previous work, we predicted that failure to learn the CS-US association would result in higher contextual fear, and that participants who failed to learn would tend to exhibit higher trait anxiety. Conditioning took place in a virtual environment with two contexts. In one of the two contexts, offset of a CS (light) was associated with a shock. Each participant visited two places (a house and an apartment) in each of 12 blocks. In one of these places shocks were administered at the offset of an 8-s period of lights on (CS). The results showed that half of the participants demonstrated differential shock expectancy between situations in the shock context in which the CS was present versus absent. This indicates that these participants learned the contingencies between the shocks and both the context and the light CS. In contrast, the other half of the participants learned only the association with the context. As predicted, learning the CS-US contingency resulted in reduced self-reported fear in the absence of the CS in the danger context compared to the presence of the CS. On the other hand, participants who failed to learn the association displayed a sustained aversive state throughout the duration of the danger context. Skin conductance measures confirmed this pattern of results. Fear-potentiated startle during the threat context compared to the safe context was significant in both groups, while startle was only potentiated during the CS in the threat context in the group that learned the CS association (trend-level significant). Finally, scores on Spielberger's self-report scale of trait anxiety tended to be higher in the group of participants who did not learn the CS-shock association in the danger context compared to participants who did. In conclusion, these results confirm higher contextual fear in participants who did not acquire a conditioned response to the cue in comparison to participants who did. Also, virtual reality contexts provide a useful tool for the study of context conditioning.

Pharmacokinetics and safety of panitumumab in a patient with chronic kidney disease.

PURPOSE: Data on panitumumab dosing in cancer patients with renal insufficiency are lacking. Here, we report a 63-year-old metastatic colorectal cancer patient with chronic kidney injury with a glomerular filtration rate of approximately 11 mL/min. METHODS: Pharmacokinetic parameters, including dose-normalized area under the curve, clearance and elimination half-life (T 1/2) after the 11th and 12th infusions were estimated using trapezoidal non-compartmental methods. Data were compared to previous reported pharmacokinetic data from studies in patients with normal renal function. RESULTS: The results show that the pharmacokinetic data in this patient with kidney failure are comparable to those in patients with adequate renal function. Moreover the treatment was well tolerated in this patient. CONCLUSION: This study suggests that panitumumab can be safely used in cancer patients with renal impairment without dose adjustment.

Scaling relationships based on partition coefficients and body sizes have similarities and interactions.

The LC(50) of compounds with a similar biological effect, at a given exposure period, is frequently plotted log-log against the octanol-water partition coefficient and a straight line is fitted for interpolation purposes. This is also frequently done for physiological properties, such as the weight-specific respiration rate, as function of the body weight of individuals. This paper focuses on the remarkable observation that theoretical explanations for these relationships also have strong similarities. Both can be understood as result of the covariation of the values of parameters of models of a particular type for the underlying processes, while this covariation follows logically from the model structure. The one-compartment model for the uptake and elimination of compounds by organisms is basic to the BioConcentration Factor (BCF), or the partition coefficient; the standard Dynamic Energy Budget model is basic to the (ultimate) body size. The BCF is the ratio of the uptake and the elimination rates; the maximum body length is the ratio of the assimilation (i.e. uptake of resources) and the maintenance (i.e. use of resources) rates. This paper discusses some shortcomings of descriptive approaches and conceptual aspects of theoretical explanations. The strength of the theory is in the combination of why metabolic transformation depends both on the BCF and the body size. We illustrate the application of the theory with several data sets from the literature.

A fatal case of metastatic squamous cell carcinoma in a patient with myositis ossificans traumatica.

Myositis ossificans traumatica is a rare disease associated with chronic wounds and fistulae. Chronic ulcers, fistulae and wounds can transform into squamous cell carcinoma, the so-called Marjolin's ulcer. We describe a rapid, progressive and fulminant course of a metastatic squamous cell carcinoma arising from a chronic wound in a patient with myositis ossificans traumatica.

Human fear acquisition deficits in relation to genetic variants of the corticotropin-releasing hormone receptor 1 and the serotonin transporter--revisited.

We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears.

Extending standard testing period in honeybees to predict lifespan impacts of pesticides and heavy metals using dynamic energy budget modelling.

Concern over reported honeybee (Apis mellifera spp.) losses has highlighted chemical exposure as a risk. Current laboratory oral toxicity tests in A. mellifera spp. use short-term, maximum 96 hour, exposures which may not necessarily account for chronic and cumulative toxicity. Here, we use extended 240 hour (10 day) exposures to examine seven agrochemicals and trace environmental pollutant toxicities for adult honeybees. Data were used to parameterise a dynamic energy budget model (DEBtox) to further examine potential survival effects up to 30 day and 90 day summer and winter worker lifespans. Honeybees were most sensitive to insecticides (clothianidin > dimethoate ≫ tau-fluvalinate), then trace metals/metalloids (cadmium, arsenic), followed by the fungicide propiconazole and herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). LC50s calculated from DEBtox parameters indicated a 27 fold change comparing exposure from 48 to 720 hours (summer worker lifespan) for cadmium, as the most time-dependent chemical as driven by slow toxicokinetics. Clothianidin and dimethoate exhibited more rapid toxicokinetics with 48 to 720 hour LC50s changes of <4 fold. As effects from long-term exposure may exceed those measured in short-term tests, future regulatory tests should extend to 96 hours as standard, with extension to 240 hour exposures further improving realism.

A simple mechanistic model to interpret the effects of narcotics.

In this research we will show the advantages of using a time-independent dose metric in a mechanistic model to evaluate toxic effects for different narcotic compounds on different species. We will show how different already existing QSARs can be combined within a mechanistic framework to 1) make predictions of lethal thresholds; 2) show some limitations in the use of existing QSARs; 3) show how a mechanistic framework solves some conceptual problems in current approaches and 4) show how such a framework can be used to be of aid in an experimental setup in predicting the outcome of a survival experiment. The approach we chose is based on the simplest mechanistic model available, a scaled one-compartment model to describe uptake and elimination and hazard model to link the exposure to effects on survival. Within this theoretical framework a prediction for an internal threshold for effects on survival of 3 mmol/kg bw can be made, which should be similar for different species and independent of the partitioning characteristics of the toxicant. To demonstrate this, a threshold for 51 different species was derived, which indeed appeared to lie in a relatively small range, typically between 1 and 10 mmol/kg bw.

Predictive value of indium-111 antimyosin uptake for improvement of left ventricular wall motion after thrombolysis in acute myocardial infarction.

In 21 patients treated with thrombolysis for acute myocardial infarction (AMI), the degree of myocardial uptake of indium-111 monoclonal antimyosin antibodies injected within 24 hours after onset of AMI was compared with the degree and extent of regional asynergy on admission and discharge, as assessed by 2-dimensional echocardiography. On the first day of AMI, 80 MBq of indium-111 antimyosin was injected and planar images were made 24 hours later. Indium-111 antimyosin uptake was evaluated for count density index (count density of infarct zone/left lung count density) in the left anterior oblique projection, in which the infarction zone was well displayed in all patients. Using 2-dimensional echocardiography, the left ventricle was divided into 13 segments and evaluated for regional asynergy, which was considered severe (akinesia or dyskinesia) or mild (hypokinesia). The extent of regional asynergy was measured by the number of asynergic segments. All 21 patients had severe regional asynergy on admission. Nine of 21 showed only mild regional asynergy on discharge and 12 of 21 had persistent severe regional asynergy in at least 1 segment. The count density index was significantly lower in patients with mild regional asynergy on discharge compared with patients with severe regional asynergy (1.63 +/- 0.27 vs 2.50 +/- 0.42, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Spin-singlet clusters in the ladder compound NaV2O5

The space group of alpha(')-NaV2O5 turns below T(c) = 34 K from Pmmn with all V sites equivalent, into Fmm2 with three independent vanadium sites per layer. This is incompatible with models of charge ordering into V4+ and V5+. Our structure determination indicates that the phase transition consists of a charge ordering with three distinct valence states, formally V4+, V4.5+, and V5+. The singlet formation is not associated with dimerization on the spin ladder, but with the formation of spin clusters. Finally, we ascribe the quadrupling of the c axis to the large polarizability of the V2O5 skeleton.

Threat-induced cortical processing and startle potentiation.

This paper presents cortical responses as reflected in event-related potentials (ERP) in an instructed fear paradigm. Safe cues and threat cues that predict shock were presented at an unprecedented fast rate (mean SOA of 2.1 s). Startle and subjective measures confirmed that threat relative to safe cues elicited fear. Several ERP correlates of fear processing were predicted and confirmed: modulation of exogenous sensory components, frontal selection positivity, and increase of P3. Furthermore, a frontal negative slow wave was observed. These results are discussed in relation to attentional selection models and emotional processing.

On the processing of spatial frequencies as revealed by evoked-potential source modeling.

OBJECTIVES AND METHODS: Visually evoked potentials (VEPs) are known to be sensitive to spatial frequency, especially in the time range between 50 and 100 ms post-stimulus. In two experiments we localized the cortical activity elicited by stimuli of varying spatial frequency in scalp-recorded brain potentials, using multi-electrode recordings and dipole-source analysis. RESULTS: Low spatial frequencies (<1 c/d) activated relatively lateral occipital areas, the orientation of the neural ensembles involved being predominantly perpendicular to the scalp surface. In contrast, high spatial frequencies (>4 c/d) induced activation of more medial occipital areas with the predominant orientation of the sources being much more parallel to the scalp surface. Furthermore, at about 100 ms latency the lateral-occipital response to low spatial frequencies was stronger in the right hemisphere; no such asymmetry was found for the responses to the high spatial frequencies. These findings were consistent across varying recording conditions, individual subjects, subject populations, stimulus characteristics (grating orientation, grating vs. checkerboard), and task conditions (active vs. passive). CONCLUSION: The results indicate that there are differences in sensitivity to specific spatial frequencies between primary and secondary visual areas, as well as between the right and the left hemispheres.

Stimulus-preceding negativity induced by fear: a manifestation of affective anticipation.

The Stimulus-Preceding Negativity (SPN), a slow cortical potential, has been studied in relation to anticipatory attention. A review of the literature suggests that most instances of SPN are observed in anticipation of motivational stimuli, such as aversive stimuli and stimuli that provide Knowledge of Results. In the present study, SPN was recorded in 12 subjects in a threat-of-shock experiment. This manipulation induced fear, as shown by subjective ratings and potentiation of the eyeblink startle. The fear-induced SPN showed a frontocentral maximum and coarse source analysis suggested that it was generated in midline frontal areas, possibly by the anterior cingulate cortex. It is concluded that the fear-induced SPN is a manifestation of affective anticipation. Possible thalamocortical and amygdalocortical contributions to its generation are discussed.