Vismodegib for periocular basal cell carcinoma: an international multicentre case series.

INTRODUCTION: Vismodegib (Erivedge, Genentech) is a first-in-class inhibitor of the hedgehog (Hh) pathway, which is licensed for use in locally advanced basal cell carcinoma (BCC) and metastatic BCC. The National Institute for Health and Care Excellence withdrew recommendation for use of vismodegib secondary to a lack of data comparing vismodegib to standard supportive care. The purpose of this multicentre, international case series is to report outcomes of patients with locally advanced periocular BCC who have been treated with vismodegib. METHODS: The medical records of all patients treated with vismodegib were retrospectively reviewed across seven institutions in the United Kingdom, Australia, and New Zealand. RESULTS: Thirteen patients were identified. Seven (54%) patients were male. All BCCs were ill-defined, with seven (58%) having orbital involvement at presentation. Median treatment time was 7 months (range 2-36 months). Eleven out of 13 patients developed side effects, the most common being fatigue in six patients (46%). Median follow-up was 24 months (range 12-48 months). Complete response was found in 5/13 patients (38%) and a partial response in 8/13 patients (62%). Six patients had further surgery after vismodegib, with three classed as globe-sparing operations. Three patients developed recurrence (23%). Three patients (23%) ultimately underwent exenteration. DISCUSSION: This study demonstrates vismodegib to be a well-tolerated treatment which may, in some cases, facilitate globe-sparing surgery and hence avoid disfiguring operations such as exenteration. Uncertainty does remain regarding the long-term outcomes of patients treated with vismodegib.

Reduced emotional empathy in adults with subclinical ADHD: evidence from the empathy and systemizing quotient.

Studies in children with ADHD suggest impairments in social cognitive functions, whereas studies in adults with ADHD are scarce and inconclusive. The aim of this study was to investigate the relationship between ADHD traits and self-reported social cognitive style in a sample of adults from the general population. For this purpose, a community sample of 685 adults filled out online self-report questionnaires about ADHD symptoms (ADHD Rating Scale, ARS), social cognitive functioning and friendships. The Empathy Quotient (EQ) with the subscales Cognitive Empathy (CE), Emotional Empathy (EE) and Social Skills (SS), and the Systemizing Quotient (SQ) were included for measuring social cognitive style and the Friendship Questionnaire (FQ) for the quality of friendships. Participants who met the DSM-5 criteria on the ARS ('subclinical ADHD'; n = 56) were compared regarding their social cognitive functioning scores with a control group (n = 56) that was matched for age, sex and student status. With small effect sizes, the subclinical ADHD group showed reduced EE scores on the EQ and a more male social cognitive profile. This result was not influenced by sex or ADHD subtype. This study points to a relationship between traits of ADHD and the emotional aspect of empathy, whereas more complex aspects of empathy were unrelated. These findings should be corroborated in clinical patients with ADHD, employing neuropsychological tests rather than self-report questionnaires.

Phosphocholine - an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors.

We demonstrated previously that phosphocholine and phosphocholine-modified macromolecules efficiently inhibit ATP-dependent release of interleukin-1ß from human and murine monocytes by a mechanism involving nicotinic acetylcholine receptors (nAChR). Interleukin-1ß is a potent pro-inflammatory cytokine of innate immunity that plays pivotal roles in host defence. Control of interleukin-1ß release is vital as excessively high systemic levels cause life threatening inflammatory diseases. In spite of its structural similarity to acetylcholine, there are no other reports on interactions of phosphocholine with nAChR. In this study, we demonstrate that phosphocholine inhibits ion-channel function of ATP receptor P2X7 in monocytic cells via nAChR containing α9 and α10 subunits. In stark contrast to choline, phosphocholine does not evoke ion current responses in Xenopus laevis oocytes, which heterologously express functional homomeric nAChR composed of α9 subunits or heteromeric receptors containing α9 and α10 subunits. Preincubation of these oocytes with phosphocholine, however, attenuated choline-induced ion current changes, suggesting that phosphocholine may act as a silent agonist. We conclude that phophocholine activates immuno-modulatory nAChR expressed by monocytes but does not stimulate canonical ionotropic receptor functions.

Oxytocin enhances orienting to social information in a selective group of high-functioning male adults with autism spectrum disorder.

OBJECTIVE: The study investigated the effects of nasally administered oxytocin on neurophysiological orienting to empathy-evoking pictures in normally intelligent male adults with and without an autism spectrum disorder (ASD). It further investigated whether these effects might be moderated by the individual's approach and avoidance tendencies. METHODS: All subjects participated in a randomised double-blind placebo controlled crossover trial where either oxytocin (OXT) or placebo was administered preceding the viewing of affective pictures.The pictures, selected from the International Affective Picture System (IAPS), represented a systematic variation of pleasant, unpleasant and neutral scenes with and without humans. Both cardiac (ECR) and cortical (LPP) evoked orienting responses were measured and both were enhanced for the pictures with humans, in particular for the unpleasant ones. RESULTS: No significant group differences were found, nor were there any treatment effects. Moderator analysis, however, demonstrated that OXT did enhance orienting to affective pictures with humansin male adults with ASD who are easily distressed when seeing others in stressful situations and in healthy males who are highly sensitive to anticipated punishment and criticism or have a low drive for goal achievement. CONCLUSION: Individual differences in stress-related avoidance tendencies should be taken into account when considering OXT as a treatment of social deficiencies in autism.

The Empathy and Systemizing Quotient: The Psychometric Properties of the Dutch Version and a Review of the Cross-Cultural Stability.

The 'Empathy Quotient' (EQ) and 'Systemizing Quotient' (SQ) are used worldwide to measure people's empathizing and systemizing cognitive styles. This study investigates the psychometric properties of the Dutch EQ and SQ in healthy participants (n = 685), and high functioning males with autism spectrum disorder (n = 42). Factor analysis provided support for three subscales of the abridged 28-item EQ: Cognitive Empathy, Emotional Empathy and Social Skills. Overall, the Dutch EQ and SQ appeared reliable and valid tools to assess empathizing and systemizing cognitive style in healthy adults and high functioning adults with autism. The literature showed good cross-cultural stability of the SQ and EQ in Western countries, but in Asian countries EQ is less stable and less sensitive to sex differences.

Cardiac adaptivity to attention-demanding tasks in children with a pervasive developmental disorder not otherwise specified (PDD-NOS).

BACKGROUND: Decreases in heart rate variability (HRV) have been repeatedly demonstrated to be an index of effort allocation to attention-demanding tasks. Children with autistic-type problems in social interaction and in adapting to unfamiliar situations (DSM-IV: PDD-NOS) have been shown to have specific attention deficits. These children were hypothesized to exhibit less cardiac adaptivity to attention-demanding tasks. METHODS: Two groups of 18 children with PDD-NOS, judged to be hyperactive and nonhyperactive, were compared to 18 healthy children with respect to their performances on a visual attention task and the differences in HRV measured during periods of task performance and periods of rest. RESULTS: Compared to the control group, both clinical groups were found to have a stronger capacity limitation in processing high loads of information, and to be less capable of maintaining a stable task performance throughout the whole task. Both clinical groups showed significantly less decreases in HRV during the periods of task performance. The magnitude of rest-task differences in HRV was found to correlate significantly with a behavioral measure of resistance to unexpected changes in daily routines. CONCLUSIONS: Children with PDD-NOS are significantly less flexible in their autonomic adaptation to attention-demanding tasks. The findings are interpreted as reflecting a deficiency in the functional organization of those neural pathways that provide cortical control of the visceral efferents.

Erythromycin increases plasma concentrations of alpha-dihydroergocryptine in humans.

OBJECTIVE: Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)-inhibiting agents such as erythromycin and the dopamine agonist alpha-dihydroergocryptine (DHEC). METHODS: The study was carried out as a single-center, controlled, nonblinded, 2-way crossover clinical trial with randomly allocated period-balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4-day treatment (days -2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2-25.1 kg x m(-2)) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol. RESULTS: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24-hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay). CONCLUSIONS: The concomitant use of erythromycin or similarly CYP3A4-inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.

Lack of effect of clonidine on stuttering in children.

OBJECTIVE: The authors studied the effects of the alpha 2-receptor agonist clonidine on stuttering in children. METHOD: Using a double-blind crossover study, they gave placebo or 4 micrograms/kg body weight per day to 25 stuttering children who were 6-13 years old. Stuttering was measured by counting the occurrences of four elementary speech difficulties and by asking parents and teachers to give an overall impression of the amount of stuttering, as well as their impression of how troublesome the stuttering was to the children. RESULTS: Clonidine did not improve stuttering. CONCLUSIONS: Clonidine cannot be recommended as a useful drug for treating children who stutter.

Joint occurrence of collagen mRNA containing cells and macrophages in human atherosclerotic vessels.

Cells with enhanced levels of collagen type I and III mRNA were identified and localized in frozen tissue sections from samples of human atherosclerotic renal and common iliac arteries by in situ hybridization using complementary 35S-labeled RNA probes. Serial sections were immunohistochemically stained for smooth muscle cells, monocytes, and differentiated macrophages. In the fibromuscular intima and in the fibrous plaques, cells with enhanced transcriptional activity were located mainly in the vicinity of differentiated macrophages. In three patients, lack of enhanced transcriptional activity in a proliferated intima was connected with complete absence of macrophages, thus indicating a quiescent stage of atherosclerosis. Immunohistochemical staining of serial sections for smooth muscle cells (SMC) revealed the presence of this cell type throughout the proliferated intima in atherosclerotic arteries including those areas in which enhanced collagen mRNAs were detected. The present results support the idea that macrophages play an important role in the activation of collagen synthesis in SMC of atherosclerotic vessel walls.

Localization of cytoplasmic collagen mRNA in human aortic coarctation: mRNA enhancement in high blood pressure-induced intimal and medial thickening.

Enhanced synthesis and deposition of extracellular matrix components, including collagen, contribute significantly to arteriosclerotic changes in the arterial vessel wall. We localized cells actively synthesizing collagen by hybridizing 35S-labeled RNA probes complementary to type I and III collagen mRNA with cytoplasmic mRNA in frozen sections of surgically removed aortic coarctations. These were chosen as a model for comparing mRNA levels in areas of high blood pressure-induced wall thickening and in unaffected post-stenotic areas. In situ hybridization revealed increased expression of type I and III collagen mRNA in intimal cells and in cells adjacent to the medial-adventitial border in the pre-stenotic part of the coarctation. In contrast, cells of the post-stenotic area showed only a very low signal. No immunohistologically detectable macrophages were seen in the pre-stenotic subendothelial areas where mRNA levels were enhanced. Higher collagen mRNA levels therefore occur in particular regions of high blood pressure-induced arterial wall thickening in the absence of macrophages. The results suggest that in situ hybridization is suitable for detection of locally occurring transcriptional activation of cells for collagens in the vessel wall.