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.

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.

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.

[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.

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.

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.

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.

Intracellular Localization and intercellular heterogeneity of the human DNA repair protein O(6)-methylguanine-DNA methyltransferase.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl adducts from DNA and may be important in tumor resistance to alkylation chemotherapy. MGMT was visualized in human cells and tumor tissues with monoclonal antibodies against MGMT and immunofluorescence microscopy, and fluorescent signals were quantified by digital image analysis. MGMT was found both in the cytoplasm and the nucleus, and in either locale the protein reacts with alkylated DNA bases and becomes inactivated and lost from the cell. Cell lines in culture and xenografts showed a broad normal distribution of nuclear MGMT levels, but human brain tumors often showed a skewed distribution, with a significant fraction of cells with high levels of MGMT. O(6)-Benzylguanine, a suicide substrate inactivator for MGMT activity, reduced MGMT in human cells and in a mouse xenograft to levels undetectable by antibody assay 1 h post-treatment. In melanoma specimens taken from a patient 3 h post-treatment with temozolomide, MGMT levels were reduced by 70%. This quantitative immunofluorescence assay can be used to monitor MGMT and it depletion in human tumors to improve the use of alkylating agents in cancer chemotherapy.

Intra-arterial and intravenous chemotherapy for the treatment of malignant glioma. Preliminary results.

Twenty-one patients with malignant glioma were treated with cis-diamminedichloroplatinum II (CDDP II) 60-90 mg/m2 intra-arterial (I.A.) bolus on day 1 and Carmustine (BCNU) 100 mg/m2 intravenously (I.V.) on days 1 and 2. Three patients received additional Aziridinylbenzoquinone (AZQ) 7 mg/m2 (I.V.) on days 1 and 2. At the time of this treatment, seven patients had local recurrence after previous surgery and radiotherapy. Nine patients had subtotal tumor resection or biopsy, one patient had macroscopic tumor resection, and four patients had no previous surgery because of medical contraindication. Six patients received five or more courses of I.A. and I.V. chemotherapy. Five of these patients showed complete remission (CR) and one had a partial remission (PR) by brain computerized tomography (CT scan). Another 15 patients treated with two to four courses of I.A., and I.V. chemotherapy showed eight partial responses (PR), and seven showed no changes (NC) by brain CT scan. Five patients died with disease. Patients who achieved CR also received radical radiotherapy for remission consolidation. Sixteen patients are still alive; five patients are off treatment, four of these with no evidence of disease (NED), one alive with disease (AWD); and the remaining 11 patients are still on treatment. Toxicity, symptomatic neurological recovery, disease stabilization, and causes of death will be discussed.

Doctors' decision-making on giving information to cancer patients.

A major focus in the literature about doctor-patient communication is information-giving. In the case of cancer patients, one significant issue is which factors determine whether and how, general practitioners and oncologists give information to their patients. Whatever may be the content of information, the most important choice for the doctor is to give information or not. Our research group at the Department of Health Psychology has conducted investigations in order to identify the significant determinants of decisions concerning giving information to cancer patients. A sample of 60 doctors from Alicante province in Spain were asked their criteria for giving information about a cancer diagnosis. Results showed that perceived intelligence and emotional control in the patients were the best predictors of the decision by doctors to give information. Age and socio-economic status were also significantly associated with the doctors' information-giving practices. These data suggest that the criteria for giving information to cancer patients are subjective and show a strong cultural influence.

[Carcinoid syndrome: advances in diagnosis and treatment]. / Síndrome carcinoide: avances en diagnóstico y tratamiento.

Carcinoid is the most common endocrine digestive tumor. The carcinoid syndrome resulting from the variety of amines and peptides produced by this tumor is usually apparent once there are metastases to the liver. Tumors with direct systemic venous drainage seldom produce a carcinoid syndrome without the presence of liver metastasis. This may occur because the hormone escapes the normal metabolic pathway (monoamine oxidase) in the liver. The most significant and important advance in diagnosis for tumor localization has been the introduction of scintigraphy using 111In-labeled octreotide. Current management of carcinoid syndrome should consider the spontaneous course of the disease and the severity of clinical symptoms, and includes different therapeutic options as hepatic resection, chemoembolization, medical treatment with the long-acting analogues of somatostatin and liver transplantation.

[Acute hepatitis due to heatstroke]. / Hepatitis aguda grave causada por golpe de calor.

The hepatic injury is a nearly constant event in the course of a heatstroke, which rarely evolves to a severe liver failure. In these cases, the patient's survival is conditioned to an early treatment and, sometimes, an orthotopic liver transplantation is needed. We report a case of severe acute hepatitis in a 17-year-old man, due to a heatstroke during a vigorous exercise in a training program. High ambient temperature and a long time without training predisposed to the development of heatstroke in this patient. Outcome was favourably, with a total recovery in a few weeks.

[The pathophysiological basis of dystonia]. / Bases fisiopatológicas de la distonía.

OBJECTIVE: We review the mechanisms that may involved in the pathophysiology of dystonia. DEVELOPMENT: The role of basal ganglia, spinal and brainstem interneurons, and primary motor cortex in dystonia will be discussed. Abnormalities in the discharge pattern of internal pallidum or thalamus, secondary to basal ganglia disorders might be the cause of disbalance between excitatory and inhibitory mechanisms in motor cortex. Other factors such as excessive repetition of a movement or abnormal sensory afferent discharges may be participating in cortical reorganization. CONCLUSIONS: Overlapping of the cortical representation of dystonic muscles due to enlargement of cortical maps could explain overflow and co-contraction phenomena. The study of the exact role of these factors in each type of dystonia is a challenge for the future that opens the door for new therapeutic approaches.

[Lemièrre's syndrome. Report of 2 new cases and review of the literature]. / Síndrome de Lemièrre. Descripción de dos nuevos casos y revisión de la literatura.

Septic thrombophlebitis of internal jugular vein following oropharyngeal infections, referred to as postanginal sepsis, was first described at the beginning of the century by Lemièrre. For diagnostic of Lemièrre's syndrome, distant metastatic abscesses from septic embolization are required. These are placed most frequently in the lungs, but also occurred in soft tissues. Two cases of this unusual syndrome seen in a year period, are reported in this brief communication. We described the first liver metastatic infection, in the syndrome. Successful result was observed when we use a low molecular weight heparin as treatment in the septic thrombophlebitis of internal jugular vein.

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.

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.