Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

The role of brain-derived neurotrophic factor in learned fear processing: an awake rat fMRI study.

Brain-derived neurotrophic factor (BDNF) signaling is implicated in the etiology of many psychiatric disorders associated with altered emotional processing. Altered peripheral (plasma) BDNF levels have been proposed as a biomarker for neuropsychiatric disease risk in humans. However, the relationship between peripheral and central BDNF levels and emotional brain activation is unknown. We used heterozygous BDNF knockdown rats (BDNF(+/-)) to examine the effects of genetic variation in the BDNF gene on peripheral and central BDNF levels and emotional brain activation as assessed by awake functional magnetic resonance imaging (fMRI). BDNF(+/-) and control rats were trained to associate a flashing light (conditioned stimulus; CS) with foot-shock, and brain activation in response to the CS was measured 24 h later in awake rats using fMRI. Central and peripheral BDNF levels were decreased in BDNF(+/-) rats compared with control rats. Activation of fear circuitry (amygdala, periaqueductal gray, granular insular) was seen in control animals; however, activation of this circuitry was absent in BDNF(+/-) animals. Behavioral experiments confirmed impaired conditioned fear responses in BDNF(+/-) rats, despite intact innate fear responses. These data confirm a positive correlation [r = 0.86, 95% confidence interval (0.55, 0.96); P = 0.0004] between peripheral and central BDNF levels and indicate a functional relationship between BDNF levels and emotional brain activation as assessed by fMRI. The results demonstrate the use of rodent fMRI as a sensitive tool for measuring brain function in preclinical translational studies using genetically modified rats and support the use of peripheral BDNF as a biomarker of central affective processing.

[PENS (papular epidermal nevus with "skyline" basal cell layer)]. / Syndrome PENS (papular epidermal nevus with "skyline" basal cell layer).

BACKGROUND: PENS is a rare neuro-cutaneous syndrome that has been recently described. It involves one or more congenital epidermal hamartomas of the papular epidermal nevus with "skyline" basal cell layer type (PENS) as well as non-specific neurological anomalies. Herein, we describe an original case in which the epidermal hamartomas are associated with autism spectrum disorder (ASD). PATIENTS AND METHODS: A 6-year-old boy with a previous history of severe ASD was referred to us for asymptomatic pigmented congenital plaques on the forehead and occipital region. Clinical examination revealed a light brown verrucous mediofrontal plaque in the form of an inverted comma with a flat striated surface comprising coalescent polygonal papules, and a clinically similar round occipital plaque. Repeated biopsies revealed the presence of acanthotic epidermis covered with orthokeratotic hyperkeratosis with occasionally broadened epidermal crests and basal hyperpigmentation, pointing towards an anatomoclinical diagnosis of PENS. DISCUSSION: A diagnosis of PENS hamartoma was made on the basis of the clinical characteristics and histopathological analysis of the skin lesions. This condition is defined clinically as coalescent polygonal papules with a flat or rough surface, a round or comma-like shape and light brown coloring. Histopathological examination showed the presence of a regular palisade "skyline" arrangement of basal cell epidermal nuclei which, while apparently pathognomonic, is neither a constant feature nor essential for diagnosis. Association of a PENS hamartoma and neurological disorders allows classification of PENS as a new keratinocytic epidermal hamartoma syndrome. The early neurological signs, of varying severity, are non-specific and include psychomotor retardation, learning difficulties, dyslexia, hyperactivity, attention deficit disorder and epilepsy. There have been no reports hitherto of the presence of ASD as observed in the case we present. CONCLUSION: This new case report of PENS confirms the autonomous nature of this neuro-cutaneous disorder associated with keratinocytic epidermal hamartoma syndromes.

Cluster-based computational methods for mass univariate analyses of event-related brain potentials/fields: A simulation study.

BACKGROUND: In recent years, analyses of event related potentials/fields have moved from the selection of a few components and peaks to a mass-univariate approach in which the whole data space is analyzed. Such extensive testing increases the number of false positives and correction for multiple comparisons is needed. METHOD: Here we review all cluster-based correction for multiple comparison methods (cluster-height, cluster-size, cluster-mass, and threshold free cluster enhancement - TFCE), in conjunction with two computational approaches (permutation and bootstrap). RESULTS: Data driven Monte-Carlo simulations comparing two conditions within subjects (two sample Student's t-test) showed that, on average, all cluster-based methods using permutation or bootstrap alike control well the family-wise error rate (FWER), with a few caveats. CONCLUSIONS: (i) A minimum of 800 iterations are necessary to obtain stable results; (ii) below 50 trials, bootstrap methods are too conservative; (iii) for low critical family-wise error rates (e.g. p=1%), permutations can be too liberal; (iv) TFCE controls best the type 1 error rate with an attenuated extent parameter (i.e. power<1).

Neural dissociation of phonological and visual attention span disorders in developmental dyslexia: FMRI evidence from two case reports.

A dissociation between phonological and visual attention (VA) span disorders has been reported in dyslexic children. This study investigates whether this cognitively-based dissociation has a neurobiological counterpart through the investigation of two cases of developmental dyslexia. LL showed a phonological disorder but preserved VA span whereas FG exhibited the reverse pattern. During a phonological rhyme judgement task, LL showed decreased activation of the left inferior frontal gyrus whereas this region was activated at the level of the controls in FG. Conversely, during a visual categorization task, FG demonstrated decreased activation of the parietal lobules whereas these regions were activated in LL as in the controls. These contrasted patterns of brain activation thus mirror the cognitive disorders' dissociation. These findings provide the first evidence for an association between distinct brain mechanisms and distinct cognitive deficits in developmental dyslexia, emphasizing the importance of taking into account the heterogeneity of the reading disorder.

[Necrotic arachnidism in the south of France: two clinical cases of loxoscelism]. / Envenimation nécrotique dans le Sud de la France : deux observations de loxoscélisme cutané

BACKGROUND: loxosceles spiders are found throughout the world and are responsible for numerous cases of envenomation in America and Southern Europe. We describe, to our knowledge for the first time in France, two clinical cases of cutaneous loxoscelism. CASE REPORT: two cases of skin necrosis arising after supposed spider bites were grouped together because of their similar clinical presentation: an initial painless bite and rapid development of an inflammatory and painful cutaneous lesion with a central hemorrhagic bulla surrounded by a perimeter of blanched skin (the "red, white, and blue" sign). The outcome in both cases was deep skin necrosis and chronic ulceration requiring surgical treatment. DISCUSSION: loxoscelism can result in dermonecrosis. Although our cases were not documented by capture of the spider, the diagnosis of cutaneous loxoscelism was supported by the characteristic appearance of the lesion, a typical clinical course, elimination of differential diagnoses, and the confirmed presence of Loxosceles rufescens in the region. CONCLUSION: loxoscelism can occur in the south of France and although rare, must be considered in this region as a possible cause of skin necrosis.

Parafoveal-on-foveal and foveal word priming are different processes: behavioral and neurophysiological evidence.

Parafoveal-on-foveal priming refers to the presentation of an item (the prime) in parafoveal vision followed by the presentation of an item (the target) in foveal vision. In natural reading, the 'parafoveal preview benefit' subserves fluent reading as, e.g., reading times increase when such information is not available. Yet, the neural correlates of reading are mostly studied with foveally presented stimuli and little is known of this parafoveal influence. Here, we used complementary information from a behavioral study and a magnetoencephalography experiment to clarify the relationship between parafoveal-on-foveal and foveal priming. Unlike foveal priming, parafoveal-on-foveal priming was present only at short prime-to-target delay (<100 ms). Behaviorally, the parafoveal priming effect was influenced by the prime visual field (left/right) and target lexical type (word/non-word), suggesting emphasis on perceptual analysis for LVF primes and on conceptual analysis for RVF primes. At the neural level, the overall sequence of activation was similar for foveal and parafoveal primes followed by foveal word targets, but the priming effects were bilateral for foveal primes versus left-lateralized for RVF primes. No neural effects of priming appeared for LVF primes, in line with the RVF preference imposed by the Western writing system. These results highlight the role of the left hemisphere in linguistic analysis and point out possible limitations of foveal stimulus presentation for drawing conclusions about natural reading.

[Infarction in the per-operative period: check-up, results, treatment, surveillance]. / Infarctus et période péri-opératoire: quel bilan? Quel traitement? Quelle surveillance?

Peroperative infarction (POI) is a frequent and serious event, which is associated with an increase in morbidity and mortality; the risk is aggravated to varying degrees by the techniques of anaesthesia and surgery used. The preoperative evaluation of risk, which combines clinical and paraclinical criteria is described in the algorithm of the new AHA/ACC guidelines. In order to avert these ischemic episodes, beta-blockers must be continued or introduced during vascular surgery. In other types of surgery, they must be considered. It is difficult to diagnose MI in a per-operative context. The electrocardiogram print out and troponin kinetics will identify patients in the postoperative phase that should be oriented towards cardiovascular evaluation and therapy.

Lateral masking, levels of processing and stimulus category: a comparative study between normal and dyslexic readers.

The lateral masking effect results in lower performance on letter recognition when items are flanked by other stimuli. Using a new paradigm based on discrimination (feature analysis) and categorization (memory access) tasks, we investigated the influence of level of processing (as addressed, respectively, by these two tasks) and stimulus type (Latin letters, Korean letters and geometrical figures) on lateral masking. In addition, performance of dyslexic and non-dyslexic adult readers was compared. The non-dyslexic participants demonstrated a classical lateral masking effect with lower performance for flanked items than isolated ones. In addition, lateral masking was stronger in the categorization than in the discrimination task and was restricted to familiar items, i.e., Latin letters and geometrical figures. Dyslexic participants showed poorer performance than non-dyslexics on processing isolated items, and the pattern of decrease in performance for lateral masking was similar to non-dyslexics. However, they also showed a stronger decrease in performance in categorization and a stronger decrease related to the lateral masking for this categorization task. Our results in normal readers suggest that lateral masking relies on the interference between the target and the flankers during feature integration that may result in marked impairment of memory access (categorization task). Poorer performance in dyslexic readers may reflect impaired parafoveal/peripheral low-level processing during feature integration that may have worsened during the flanked condition due to a target selection/spatial-attentional disorder. Moreover, dyslexic subjects presented an additional categorization deficit that may relate to a specific left-hemispheric disorder.

Anatomy and time course of discrimination and categorization processes in vision: an fMRI study.

Studies investigating the cerebral areas involved in visual processes generally oppose either different tasks or different stimulus types. This work addresses, by fMRI, the interaction between the type of task (discrimination vs. categorization) and the type of stimulus (Latin letters, well-known geometrical figures, and Korean letters). Behavioral data revealed that the two tasks did not differ in term of percentage of errors or correct responses, but a delay of 185 ms was observed for the categorization task in comparison with the discrimination task. All conditions activated a common neural network that includes both striate and extrastriate areas, especially the fusiform gyri, the precunei, the insulae, and the dorsolateral frontal cortex. In addition, interaction analysis revealed that the right insula was sensitive to both tasks and stimuli, and that stimulus type induced several significant signal variations for the categorization task in right frontal cortex, the right middle occipital gyrus, the right cuneus, and the left and right fusiform gyri, whereas for the discrimination task, significant signal variations were observed in the right occipito-parietal junction only. Finally, analyzing the latency of the BOLD signal also revealed a differential neural dynamics according to tasks but not to stimulus type. These temporal differences suggest a parallel hemisphere processing in the discrimination task vs. a cooperative interhemisphere processing in the categorization task that may reflect the observed differences in reaction time.