Efficacy and safety of peri-procedural bridging therapy with low molecular weight heparin in atrial fibrillation patients under vitamin K antagonists.

BACKGROUND: The clinical effect of peri-operative bridging therapy in atrial fibrillation (AF) patients remains unclear given that it may increase bleeding risk without providing significant benefits. We aimed to investigate peri-procedural events in relation to peri-operative use of bridging therapy in AF patients under Vitamin K Antagonists (VKAs). METHODS: We included AF patients stable the previous 6 months on VKAs. During a median follow-up of 6.5 years (IQR 4.3-7.9), we recorded all invasive procedures and the peri-operative clinical management. All peri-procedural events (ischaemic stroke/transient ischaemic attack/systemic embolism, clinically relevant non-major bleeding and major bleeding) and severe peri-procedural events (ischaemic stroke/transient ischaemic attack/systemic embolism and major bleeding) suffered until the 30-days post-intervention period were recorded. RESULTS: We included 1361 patients (48.7% male, median age 76 [IQR 71-81] years). There were 1100 (70.9%) procedures performed using bridging therapy. The rate of any (4.5% vs. 0.7%, P < 0.001) and severe (2.3% vs. 0.0%, P = 0.002) peri-procedural events were higher in patients receiving bridging therapy. Adjusted logistic regressions demonstrated that the bleeding risk of the procedure was related with higher risk of severe peri-procedural events (OR 3.51, 95% CI 1.54-8.01) and peri-procedural events (OR 2.77, 95% CI 1.56-4.91). Importantly, the use of bridging therapy was also independently associated with higher risk of any peri-procedural events (OR 4.32, 95% CI 1.28-14.51). CONCLUSIONS: In this study including AF patients under VKA therapy, the use of bridging therapy as part of the clinical management during an invasive procedure was independently associated with higher risk of any peri-procedural event.

Cutaneous involvement in an 8-year-old boy with Ras-associated autoimmune leucoproliferative disorder (RALD).

Ras-associated autoimmune leucoproliferative disorder (RALD) is a nonmalignant syndrome associated with somatic KRAS mutations. We report a patient with RALD and cutaneous lesions, the first such case reported, to our knowledge. An 8-year-old boy presented with erythematous plaques on his face and body, along with lymphadenopathies and spleen enlargement without systemic symptoms. An increased number of monocytes were found in skin biopsy, peripheral blood and bone marrow (BM). Juvenile myelomonocytic leukaemia (JMML) was suspected. Genetic study using peripheral blood showed no mutations in the KRAS, PTPN11, NRAS, CBL or BCR-ABL genes, but bone marrow analysis revealed a mutation (p-G12S/c.34 G>A) in the KRAS gene. The karyotype was normal. No KRAS mutations were found using molecular analysis of saliva. The diagnosis of RALD was proposed. The differential diagnosis between RALD and JMML is challenging because there are no established criteria to differentiate between them. The clinical course of RALD is uncertain, so long-term follow-up is recommended.

Brain correlates of the intrinsic subjective cost of effort in sedentary volunteers.

One key aspect of motivation is the ability of agents to overcome excessive weighting of intrinsic subjective costs. This contribution aims to analyze the subjective cost of effort and assess its neural correlates in sedentary volunteers. We recruited a sample of 57 subjects who underwent a decision-making task using a prospective, moderate, and sustained physical effort as devaluating factor. Effort discounting followed a hyperbolic function, and individual discounting constants correlated with an indicator of sedentary lifestyle (global physical activity questionnaire; R=-0.302, P=0.033). A subsample of 24 sedentary volunteers received a functional magnetic resonance imaging scan while performing a similar effort-discounting task. BOLD signal of a cluster located in the dorsomedial prefrontal cortex correlated with the subjective value of the pair of options under consideration (Z>2.3, P<0.05; cluster corrected for multiple comparisons for the whole brain). Furthermore, effort-related discounting of reward correlated with the signal of a cluster in the ventrolateral prefrontal cortex (Z>2.3, P<0.05; small volume cluster corrected for a region of interest including the ventral prefrontal cortex and striatum). This study offers empirical data about the intrinsic subjective cost of effort and its neural correlates in sedentary individuals.

Do physicians correctly calculate thromboembolic risk scores? A comparison of concordance between manual and computer-based calculation of CHADS2 and CHA2 DS2 -VASc scores.

BACKGROUND: Clinical risk scores, CHADS2 and CHA2 DS2 -VASc scores, are the established tools for assessing stroke risk in patients with atrial fibrillation (AF). AIM: The aim of this study is to assess concordance between manual and computer-based calculation of CHADS2 and CHA2 DS2 -VASc scores, as well as to analyse the patient categories using CHADS2 and the potential improvement on stroke risk stratification with CHA2 DS2 -VASc score. METHODS: We linked data from Atrial Fibrillation Spanish registry FANTASIIA. Between June 2013 and March 2014, 1318 consecutive outpatients were recruited. We explore the concordance between manual scoring and computer-based calculation. We compare the distribution of embolic risk of patients using both CHADS2 and CHA2 DS2 -VASc scores RESULTS: The mean age was 73.8 ± 9.4 years, and 758 (57.5%) were male. For CHADS2 score, concordance between manual scoring and computer-based calculation was 92.5%, whereas for CHA2 DS2 -VASc score was 96.4%. In CHADS2 score, 6.37% of patients with AF changed indication on antithrombotic therapy (3.49% of patients with no treatment changed to need antithrombotic treatment and 2.88% of patients otherwise). Using CHA2 DS2 -VASc score, only 0.45% of patients with AF needed to change in the recommendation of antithrombotic therapy. CONCLUSION: We have found a strong concordance between manual and computer-based score calculation of both CHADS2 and CHA2 DS2 -VASc risk scores with minimal changes in anticoagulation recommendations. The use of CHA2 DS2 -VASc score significantly improves classification of AF patients at low and intermediate risk of stroke into higher grade of thromboembolic score. Moreover, CHA2 DS2 -VASc score could identify 'truly low risk' patients compared with CHADS2 score.

Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans.

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population.

[Paramedian forehead flap for the reconstruction of extensive nasal defects]. / Colgajo fronto-nasal paramedial en la reconstrucción de defectos nasales extensos.

BACKGROUND: The Department of Dermatology at Hospital Universitario de Guadalajara in Spain is a referral center for Mohs micrographic surgery. Consequently, we are regularly faced with the problem of repairing large surgical defects on the nose. The paramedian forehead flap is currently one of the techniques of choice for the repair of such defects. MATERIALS AND METHODS: We review our experience in the repair of nasal defects using the paramedian forehead flap over the period from 2004 to 2008. We describe the surgical technique, complications, and final results. RESULTS: Ten patients (mean age, 75.1 years) were treated using this flap. Two patients also required cartilage grafts and reconstruction of the internal nasal lining. The most common complications were bleeding (60%) and partial necrosis (10%). The final cosmetic and functional results were considered good or excellent in 90% of cases. CONCLUSIONS: The forehead flap continues to be one of the best options for the closure of surgical defects of the nasal pyramid larger than 2 cm. Adequate knowledge and careful application of the technique allows excellent results to be obtained with few complications.

Right parietal dominance in spatial egocentric discrimination.

Egocentric tactile perception is crucial for skilled hand motor control. In order to better understand the brain functional underpinnings related to this basic sensorial perception, we performed a tactile perception functional magnetic resonance imaging (fMRI) experiment with two aims. The first aim consisted of characterizing the neural substrate of two types of egocentric tactile discrimination: the spatial localization (SLD) and simultaneity succession discrimination (SSD) in both hands to define hemispheric dominance for these tasks. The second goal consisted of characterizing the brain activation related to the spatial attentional load, the functional changes and their connectivity patterns induced by the psychometric performance (PP) during SLD. We used fMRI in 25 right-handed volunteers, applying pairs of sinusoidal vibratory stimuli on eight different positions in the palmar surface of both hands. Subjects were required either to identify the stimulus location with respect to an imaginary midline (SLD), to discriminate the simultaneity or succession of a stimuli pair (SSD) or to simply respond to stimulus detection. We found a fronto-parietal network for SLD and frontal network for SSD. During SLD we identified right hemispheric dominance with increased BOLD activation and functional interaction of the right supramarginal gyrus with contralateral intra-parietal sulcus for right and left hand independently. Brain activity correlated to spatial attentional load was found in bilateral structures of intra-parietal sulcus, precuneus extended to superior parietal lobule, pre-supplementary motor area, frontal eye fields and anterior insulae for both hands. We suggest that the right supramarginal gyrus and its interaction with intra-parietal lobule may play a pivotal role in the phenomenon of tactile neglect in right fronto-parietal lesions.

Assessment of Bradykinesia in Parkinson's disease patients through a multi-parametric system.

The aim of this paper is to describe and present the results of the automatic detection and assessment of bradykinesia in motor disease patients using wireless, wearable accelerometers. The current work is related to a module of the PERFORM system, a FP7 project from the European Commission, that aims at providing an innovative and reliable tool, able to evaluate, monitor and manage patients suffering from Parkinson's disease. The assessment procedure was carried out through a developed C# library that detects the activities of the patient using an activity recognition algorithm and classifies the data using a Support Vector Machine trained with data coming from previous test phases. The accuracy between the output of the automatic detection and the evaluation of the clinician both expressed with the Unified Parkinson's disease Rating Scale, presents an average value of [68.3 ± 8.9]%. A meta-analysis algorithm is used in order to improve the accuracy to an average value of [74.4 ± 14.9]%. Future work will include a personalized training of the classifiers in order to achieve a higher level of accuracy.

Gait assessment in Parkinson's disease patients through a network of wearable accelerometers in unsupervised environments.

Parkinson's disease (PD) predominantly alters the motor performance of the affected individuals. In particular, the loss of dopaminergic neurons compromises the speed, the automaticity and fluidity of movements. As the disease evolves, PD patient's motion becomes slower and tremoric and the response to medication fluctuates along the day. In addition, the presence of involuntary movements deteriorates voluntary movement in advanced state of the disease. These changes in the motion can be detected by studying the variation of the signals recorded by accelerometers attached in the limbs and belt of the patients. The analysis of the most significant changes in these signals make possible to build an individualized motor profile of the disease, allowing doctors to personalize the medication intakes and consequently improving the response of the patient to the treatment. Several works have been done in a laboratory and supervised environments providing solid results; this work focused on the design of unsupervised method for the assessment of gait in PD patients. The development of a reliable quantitative tool for long-term monitoring of PD symptoms would allow the accurate detection of the clinical status during the different PD stages and the evaluation of motor complications. Besides, it would be very useful both for routine clinical care as well as for novel therapies testing.

Analysis of the GIGYF2 gene in familial and sporadic Parkinson disease in the Spanish population.

BACKGROUND AND PURPOSE: Linkage analysis in familial Parkinson's disease (PD) identified a locus in 2q36-37 (PARK11). Sequencing of GIGYF2 identified several variants only present amongst PD individuals. METHODS: We analyzed the presence of disease-associated GIGYF2 variants in familial and sporadic PD from Spanish origin by sequencing of 147 PD individuals. The entire GIGYF2 coding sequence was analyzed in 122 familial PD individuals and exons 2, 4, 8-11, 14 and 25-26 were sequenced in 25 sporadic PD to identify disease-associated variants. RESULTS: We found no variants associated with PD and failed to identify any of previously PD-associated GIGYF2 variants in our sample. We identified four novel missense changes in GIGYF2. p.Met48Ile was found in a PD individual who also was a carrier of two PARKIN mutations. p.Q1244_Q1247del variant was present only in one PD individual but not found in 70 controls. However, its location in the highly polymorphic GIGYF2 glutamine/proline-rich region does not support a role in PD. Two variants (p.P1238insAGC and p.Q1249del) were present both in PD subjects and in controls. Additionally, the p.L1230_Q1237del variant, which was previously considered as a PD-associated change, was found in one control. CONCLUSION: Our findings suggest that GIGYF2 mutations are not a frequent cause of PD in the Spanish population, since we found no clearly segregating variants. We propose further analyses in PD subjects from different populations to define the role of GIGYF2. A clear pathogenic mutation in other gene at 2q36-37 in the PARK11-linked PD families would definitively disprove GIGYF2 as the responsible gene.

Complex modular structure of large-scale brain networks.

Modular structure is ubiquitous among real-world networks from related proteins to social groups. Here we analyze the modular organization of brain networks at a large scale (voxel level) extracted from functional magnetic resonance imaging signals. By using a random-walk-based method, we unveil the modularity of brain webs and show modules with a spatial distribution that matches anatomical structures with functional significance. The functional role of each node in the network is studied by analyzing its patterns of inter- and intramodular connections. Results suggest that the modular architecture constitutes the structural basis for the coexistence of functional integration of distant and specialized brain areas during normal brain activities at rest.

Forceps minor region signal abnormality "ears of the lynx": an early MRI finding in spastic paraparesis with thin corpus callosum and mutations in the spatacsin gene (SPG11) on chromosome 15.

BACKGROUND AND PURPOSE: A thin corpus callosum on magnetic resonance imaging (MRI) characterizes a type of autosomal recessive disorder with progressive spastic paraparesis and cognitive impairment. Known as Hereditary Spastic Paraparesis with Thin Corpus Callosum (HSP-TCC), it has been associated with mutations of the SPG11 gene. No other specific MRI findings have been reported. METHODS: We studied with MRI four patients from three families with HSP-TCC who had identified causal mutations in the SPG11 gene. RESULTS: In all individuals studied the region of the forceps minor of the corpus callosum, corresponding to the genu fibers, appeared bright on T2-weighted and dark on T1-weighted images. On axial sections, the frontal horn region bore a remarkable resemblance to the ears of a lynx, with the areas of abnormal signal reminiscent of the tufts of hair crowning the tips of the ears of this animal. Less specific findings included a box-shape appearance of the calloso-caudate angle and diffusely increased signal in the hemispheric white matter. CONCLUSION: Abnormal MRI signal in the region of the forceps minor of the corpus callosum is a characteristic early imaging finding of HSP-TCC with SPG11 mutations.

Frequency-specific coupling in the cortico-cerebellar auditory system.

Induced oscillatory activity in the auditory cortex peaks at around 40 Hz in humans. Using regional cerebral blood flow and positron emission tomography we previously confirmed frequency-selective cortical responses to 40-Hz tones in auditory primary cortices and concomitant bilateral activation of the cerebellar hemispheres. In this study, using functional magnetic resonance imaging (fMRI) we estimated the influence of 40-Hz auditory stimulation on the coupling between auditory cortex and superior temporal sulcus (STS) and Crus II, using a dynamic causal model of the interactions between medial geniculate nuclei, auditory superior temporal gyrus (STG)/STS, and the cerebellar Crus II auditory region. Specifically, we tested the hypothesis that 40-Hz-selective responses in the cerebellar Crus II auditory region could be explained by frequency-specific enabling of interactions in the auditory cortico-cerebellar-thalamic loop. Our model comparison results suggest that input from auditory STG/STS to cerebellum is enhanced selectively at gamma-band frequencies around 40 Hz.

SPG11 compound mutations in spastic paraparesis with thin corpus callosum.

BACKGROUND: Autosomal recessive hereditary spastic paraparesis with thin corpus callosum (ARHSP-TCC) is being increasingly recognized as a variety of spastic paraplegia with mental retardation. SPG11 gene mutations have been reported to be associated with ARHSP-TCC. METHODS: As an independent group, we investigated SPG11 gene involvement in four individuals not previously described with either recessive or sporadic HSP-TCC presentation. RESULTS: Chromosome 15q13-15 segregating autosomal disease haplotypes were different across the kindreds and sequencing of SPG11 identified four novel frameshift/nonsense segregating mutations and the R2034X mutation, which were in heterozygous compound status. The affected examined had decreased thalamic and bilateral paracentral frontal lobe metabolism on (18)F-flurodeoxyglucose PET. CONCLUSIONS: Loss-of-function SPG11 mutations are the major cause of autosomal recessive hereditary spastic paraparesis with thin corpus callosum in Southern Europe, even in apparently sporadic cases. Decreased thalamic metabolism was consistently a phenotypical SPG11 mutation hallmark.

[Aquagenic keratoderma: 3 new cases and a review of the literature]. / Queratodermia acuagénica: tres nuevos casos y revisión de la literatura.

Aquagenic keratoderma is a rare type of transient acquired keratoderma that is triggered or exacerbated by immersion of the palms or soles in water. It is characterized by whitish or translucent papules with central punctate depressions that coalesce in macerated edematous plaques. It appears within a few minutes of exposure to water and subsides soon after drying. We describe 3 new cases of aquagenic keratoderma in a 28-year-old man with a history of Behçet disease, an 18-year-old woman, and a 20-year-old man. We discuss the clinical and histopathologic features, treatment options, and course of the lesions in the cases described in the literature.

Putaminal activity is related to perceptual certainty.

We have investigated the neural basis of perceptual certainty using a simple discrimination paradigm. Psychophysical experiments have shown that a pair of identical electrical stimuli to the skin or a pair of auditory clicks to the ears are consistently perceived as two separate events in time when the inter-stimulus interval (ISIs) is long, and perceived as simultaneous events when the ISIs are very short. The perceptual certainty of having received one or two stimuli decreases when the ISI lies between these two extremes and this is reflected in inconsistent reporting of the percept across trials. In two fMRI experiments, 14 healthy subjects received either paired electrical pulses delivered to the forearm (ISIs=5-110 ms) or paired auditory clicks presented binaurally (ISIs=1-20 ms). For each subject and modality, we calculated a consistency index (CI) representing the level of perceptual certainty. The task activated pre-SMA and anterior cingulate cortex, plus the cerebellum and the basal ganglia. Critically, activity in the right putamen was linearly dependent on CI for both tactile and auditory discrimination, with topographically distinct effects in the two modalities. These results support a role for the human putamen in the "automatic" perception of temporal features of tactile and auditory stimuli.

Topography of cortical activation differs for fundamental and harmonic frequencies of the steady-state visual-evoked responses. An EEG and PET H215O study.

In humans, visual flicker stimuli of graded frequency (2-90 Hz) elicit an electroencephalographic (EEG) steady-state visual-evoked response (SSVER) with the same fundamental frequency as the stimulus and, in addition, a series of harmonic responses. The fundamental component of the SSVER is generated by increased synaptic activity in primary visual cortex (V1). We set out to determine the cortical origin of the harmonic responses in humans. For this purpose, we recorded the SSVERs at 5 different frequencies (5, 10, 15, 25, and 40 Hz) and measured regional cerebral blood flow (rCBF) with positron emission tomography-H(2)(15)O at rest and during visual stimulation at the same frequencies. The rCBF contrast weighted by the amplitude of the SSVERs first harmonics showed activation of a swath of cortex perpendicular to V1, including mostly the inferior half of the parieto-occipital sulcus. This area overlapped minimally with the primary visual cortex activated by the fundamental frequency. A different method, estimating EEG cortical source current density with low-resolution brain electromagnetic tomography, gave the same results. Our finding suggests that the inferior portion of the banks of the parieto-occipital sulci contains association visual cortex involved in the processing of stimuli that can be as simple as a flickering light source.