Prevalence of urinary tract cancer in the Spanish cohort of the IDENTIFY study.

INTRODUCTION: Malignant tumors of the urinary tract are associated with high morbidity and mortality, and their prevalence can vary worldwide. Recently, the IDENTIFY study has published results on the prevalence of urinary tract cancer at a global level. This study evaluates the prevalence of cancer within the Spanish cohort of the IDENTIFY study to determine whether the published results can be extrapolated to our population. PATIENTS AND METHODS: An analysis of the data from the Spanish cohort of patients in the IDENTIFY study was performed. This is a prospective cohort of patients referred to secondary care with suspected cancer, predominantly due to hematuria. Patients were recruited between December 2017 and December 2018. RESULTS: A total of 706 patients from 9 Spanish centers were analyzed. Of these, 277 (39.2%) were diagnosed with cancer: 259 (36.7%) bladder cancer, 10 (1.4%) upper tract urothelial carcinoma, 9 (1.2%) renal cancer and 5 (0.7%) prostate cancer. Increasing age (OR 1.05 (95% CI 1.03-1.06; P < 0.001)), visible hematuria (VH) OR 2.19 (95% CI 1.13-4.24; P = 0.02)) and smoking (ex-smokers: OR 2.11(95% CI 1.30-3.40; P = 0.002); smokers: OR 2.36 (95% CI 1.40-3.95; P = 0.001)) were associated with higher probability of bladder cancer. CONCLUSION: This study highlights the risk of bladder cancer in patients with VH and smoking habits. Bladder cancer presented the highest prevalence; higher than the prevalence reported in previous series and presented in the IDENTIFY study. Future work should evaluate other associated factors that allow us to create cancer prediction models to improve the detection of cancer in our patients.

Comparing the effect of electron beam, beta and ultraviolet C exposure on the luminescence emission of commercial dosimeters.

This paper reports on the luminescence characterization of TLD-100 (LiF: Ti, Mg), TLD-200 (CaF2: Dy), TLD-400 (CaF2: Mn) and GR-200 (LiF: Mg, Cu, P) dosimeters exposed to electro beam, beta and ultraviolet C radiation -UVC-. All of them show high sensitivity to radiation regardless of whether it is ionizing or partially ionizing radiation based on their luminescence properties (cathodoluminescence -CL- or thermoluminescence -TL-). CL emission differs significantly among them in shape and intensity due to their chemical compositions. LiF samples display three maxima at: (i) 300-450 nm linked to intrinsic and structural defects, (ii) a green waveband probably due to F3+ centres or the presence of hydroxyl groups and (iii) the red-infrared emission band associated with F2 centres. However, CL spectra from the CaF2 dosimeters display meaningful differences due to the dopant. TLD-200 is characterized by an emission with four sharp individual peaks in the green-IR spectral region (due to the Dy3+), whilst TLD-400 exhibits a broad maximum peaked at Ì´500 nm (linked to the Mn2+). On the other hand, the variation in the TL glow curves allows to discriminate the TLDs exposed to beta and UVC radiation since they give rise to different chemical-physical processes and that have been studied from the estimation of the kinetic parameters by means of the Computerised Glow Curve Deconvolution (CGCD) method.

Synergistic activation of AMPK prevents from polyglutamine-induced toxicity in Caenorhabditis elegans.

Expression of abnormally long polyglutamine (polyQ) tracks is the source of a range of dominant neurodegenerative diseases, such as Huntington disease. Currently, there is no treatment for this devastating disease, although some chemicals, e.g., metformin, have been proposed as therapeutic solutions. In this work, we show that metformin, together with salicylate, can synergistically reduce the number of aggregates produced after polyQ expression in Caenorhabditis elegans. Moreover, we demonstrate that incubation polyQ-stressed worms with low doses of both chemicals restores neuronal functionality. Both substances are pleitotropic and may activate a range of different targets. However, we demonstrate in this report that the beneficial effect induced by the combination of these drugs depends entirely on the catalytic action of AMPK, since loss of function mutants of aak-2/AMPKα2 do not respond to the treatment. To further investigate the mechanism of the synergetic activity of metformin/salicylate, we used CRISPR to generate mutant alleles of the scaffolding subunit of AMPK, aakb-1/AMPKß1. In addition, we used an RNAi strategy to silence the expression of the second AMPKß subunit in worms, namely aakb-2/AMPKß2. In this work, we demonstrated that both regulatory subunits of AMPK are modulators of protein homeostasis. Interestingly, only aakb-2/AMPKß2 is required for the synergistic action of metformin/salicylate to reduce polyQ aggregation. Finally, we showed that autophagy acts downstream of metformin/salicylate-related AMPK activation to promote healthy protein homeostasis in worms.

Asymptomatic LTP sensitisation is common in plant-food allergic children from the Northeast of Spain

BACKGROUND: The sensitisation profile at molecular level in plant-food allergy is complex. Several allergens may be involved, with different potential for severe reactions. lipid transfer proteins (LTP) are considered the most relevant plant-food allergens in adults in Mediterranean countries, but less is known in children. AIM: To describe the clinical pattern and sensitisation profile of children with plant-food allergy and LTP sensitisation from Northeast Spain. METHODS: Children with history of immediate reaction to plant-food(s), positive skin-prick-test to the culprit plant-food(s) and specific-IgE to plant-food LTPs were analysed. RESULTS: 130 children were included. 69.2% (90/130) had reacted to ≥2 taxonomically unrelated plant-foods. Peach, walnut, hazelnut and peanut were most frequently involved. Reactions severity ranged from anaphylaxis (45.4%, 59/130) to oral symptoms only. Sensitisation to a particular plant-food LTP not always caused clinical symptoms with that plant-food; 69% (40/58) and 63% (17/27) of peach- and walnut-tolerant subjects had positive rPru p 3 and nJug r 3 specific IgE, respectively. 65.4% (85/130) of children were also sensitised to storage proteins, which was associated to anaphylaxis and nut allergy. However, 60% of patients without nuts/seeds allergy were sensitised to storage proteins. Specific-IgE levels to LTPs and/or storage proteins were not useful to predict allergy (vs. tolerance) to peach, walnut, peanut or hazelnut. CONCLUSIONS: Sensitisation to LTP and/or storage proteins without clear clinical significance is relatively common. Prospective longitudinal studies are required to evaluate the relevance of these silent sensitisations over time. Caution is required when interpreting the results of molecular-based diagnostic tools in clinical practice

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Asymptomatic LTP sensitisation is common in plant-food allergic children from the Northeast of Spain.

BACKGROUND: The sensitisation profile at molecular level in plant-food allergy is complex. Several allergens may be involved, with different potential for severe reactions. lipid transfer proteins (LTP) are considered the most relevant plant-food allergens in adults in Mediterranean countries, but less is known in children. AIM: To describe the clinical pattern and sensitisation profile of children with plant-food allergy and LTP sensitisation from Northeast Spain. METHODS: Children with history of immediate reaction to plant-food(s), positive skin-prick-test to the culprit plant-food(s) and specific-IgE to plant-food LTPs were analysed. RESULTS: 130 children were included. 69.2% (90/130) had reacted to ≥2 taxonomically unrelated plant-foods. Peach, walnut, hazelnut and peanut were most frequently involved. Reactions severity ranged from anaphylaxis (45.4%, 59/130) to oral symptoms only. Sensitisation to a particular plant-food LTP not always caused clinical symptoms with that plant-food; 69% (40/58) and 63% (17/27) of peach- and walnut-tolerant subjects had positive rPru p 3 and nJug r 3 specific IgE, respectively. 65.4% (85/130) of children were also sensitised to storage proteins, which was associated to anaphylaxis and nut allergy. However, 60% of patients without nuts/seeds allergy were sensitised to storage proteins. Specific-IgE levels to LTPs and/or storage proteins were not useful to predict allergy (vs. tolerance) to peach, walnut, peanut or hazelnut. CONCLUSIONS: Sensitisation to LTP and/or storage proteins without clear clinical significance is relatively common. Prospective longitudinal studies are required to evaluate the relevance of these silent sensitisations over time. Caution is required when interpreting the results of molecular-based diagnostic tools in clinical practice.

Nonsteroidal anti-inflammatory drugs enhance IgE-mediated activation of human basophils in patients with food anaphylaxis dependent on and independent of nonsteroidal anti-inflammatory drugs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) act as cofactors worsening the allergic reactions induced by food allergens. AIM: The aim of this study was to evaluate the effect of both lysine acetylsalicylate (L-ASA) (non-selective cyclooxygenase (COX) inhibitor) and valdecoxib (selective COX-2 inhibitor) in basophils activated by peach lipid transfer protein (Pru p 3) in patients with food-dependent NSAID-induced anaphylaxis (FDNIA). METHODS: Twenty Pru p 3-allergic patients with FDNIA group, eleven peach anaphylaxis not exacerbated by NSAIDs (no-NSAID group) and 5 healthy volunteers were recruited. Basophil activation (BA) was measured as expression of CD63 (Flow(2) CAST(™) ; Bühlmann(®) ), after stimulation with Pru p 3, both alone and in combination with L-ASA (1.13, 3.38 and 6.78 mm) or valdecoxib (0.87, 7.8 and 31.25 µm). RESULTS: Basophils from no-NSAID group were significantly more reactive and sensitive to Pru p 3 than those from the FDNIA group. In both groups, an increase in BA was observed when basophils were exposed to Pru p 3 and L-ASA. In the FDNIA group, valdecoxib partially terminates the BA induced by Pru p 3, whereas in the no-NSAID group, a dual effect was observed depending on the concentration tested. CONCLUSIONS: This study indicates that subjects with food-induced anaphylaxis differ from FDNIA subjects in the higher reactivity and sensitivity of their basophils to allergen challenge. We have shown a direct effect of NSAIDs on basophils using a human model of FDNIA. Our results also suggest that selective COX2 inhibitors might be a safe alternative. BA test may be a useful tool in the study of the pathogenic mechanism of the cofactor phenomenon.

Amiloidosis leptomeníngea debida a la mutación A25T TTR. A propósito de un caso / Leptomeningeal amyloidosis due to A25T TTR mutation: a case report

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Functional reorganization of the forepaw cortical representation immediately after thoracic spinal cord hemisection in rats.

Spinal cord injury may produce long-term reorganization of cortical circuits. Little is known, however, about the early neurophysiological changes occurring immediately after injury. On the one hand, complete thoracic spinal cord transection of the spinal cord immediately decreases the level of cortical spontaneous activity and increases the cortical responses to stimuli delivered to the forepaw, above the level of the lesion. On the other hand, a thoracic spinal cord hemisection produces an immediate cortical hyperexcitability in response to preserved spinothalamic inputs from stimuli delivered to the hindpaw, below the level of the lesion. Here we show that a thoracic spinal cord hemisection also produces a bilateral increase of the responses evoked in the forepaw cortex by forepaw stimuli, associated with a bilateral decrease of cortical spontaneous activity. Importantly, the increased cortical forepaw responses are immediate in the cortex contralateral to the hemisection (significant within 30min after injury), but they are progressive in the cortex ipsilateral to the hemisection (reaching significance only 2.5h after injury). Conversely, the decreased cortical spontaneous activity is progressive both ipsilaterally and contralaterally to the hemisection (again reaching significance only 2.5h after injury). In synthesis, the present work reports a functional reorganization of the forepaw cortical representation immediately after thoracic spinal cord hemisection, which is likely important to fully understand the mechanisms underlying long-term cortical reorganization after incomplete spinal cord injuries.

Characterization of Spanish honeys with protected designation of origin "Miel de Granada" according to their mineral content.

Honey attributes such as geographical origin or specified botanical sources often command a premium price due to their organoleptic or pharmacoactive properties. "Miel de Granada" is a highly quality product with protected designation of origin (PDO) which includes six monofloral honeys and two multifloral honeys. Our objective was the characterization of "Miel de Granada" according to their metal content. Metal content was specific enough and allowed discrimination from honeys of different botanical and geographical origins and confirmed the authenticity of PDO labelling as Granada product with the determination of only five elements (K, Na, Ca, Mg and Zn). Chemometric techniques as cluster analysis and ANOVA were used to classify honeys according to their botanical and geographical origin in the metal data. Metal content marks the differences in honey samples and can be used as a tool to assess the quality of honeys. ANOVA showed significant differences among rosemary honeys from different geographical areas despite the botanical factor weight. Our research contributes to the groundwork studies to determine the geographical origin of Spanish honeys.

Lipid transfer protein syndrome: clinical pattern, cofactor effect and profile of molecular sensitization to plant-foods and pollens.

BACKGROUND: Multiple plant-food sensitizations with a complex pattern of clinical manifestations are a common feature of lipid transfer protein (LTP)-allergic patients. Component-resolved diagnosis permits the diagnosis of the allergen sensitization profile. OBJECTIVE: We sought to clinically characterize and describe the plant-food and pollen molecular sensitization profile in patients with LTP syndrome. METHODS: Forty-five subjects were recruited, after being diagnosed with multiple plant-food allergies sensitized to LTP, but not to any other plant-food allergen, according to the molecular allergen panel tested (Pru p 3 (LTP), Pru p 1 (Bet v 1-like), Pru p 4 (profilin) and those included in a commercial microarray of 103 allergenic components). IgE-mediated food-allergy symptoms and pollinosis were collected. Patients were skin prick tested with a plant-food and pollens panel, and specific IgE to Tri a 14 was evaluated. RESULTS: A heterogeneous group of plant-foods was involved in local and systemic symptoms: oral allergy syndrome (75.6%), urticaria (66.7%), gastrointestinal disorders (55.6%) and anaphylaxis (75.6%), 32.4% of which were cofactor dependent (Non-Steroidal Anti-inflammatory Drugs, exercise). All tested subjects were positive to peach and Pru p 3, Tri a 14 and to some of the LTPs included in the microarray. Pollinosis was diagnosed in 75.6% of subjects, with a broad spectrum of pollen and pollen-allergen sensitization. Plane tree and mugwort were the statistically significant pollens associated with Pru p 3. CONCLUSIONS AND CLINICAL RELEVANCE: Several plant-foods, taxonomically unrelated, independent of peach involvement, are implicated in LTP syndrome. Local symptoms should be evaluated as a risk marker for anaphylaxis because they are frequently associated with cofactor-dependent anaphylaxis. The association of these symptoms with pollinosis, especially plane tree pollinosis, could be part of this syndrome in our area.

Hirano body-rich subtypes of Creutzfeldt-Jakob disease.

BACKGROUND: In definite Creutzfeldt-Jakob disease (CJD), morphological and immunohistochemical patterns are useful to identify molecular subtypes. Severe cerebellar pathology and hippocampal involvement helps to identify VV subtypes. The rare VV1 variant (<1%), more frequent in young individuals, is additionally characterized by the presence of ballooned neurones in affected areas. In 1985, Cartier et al. described a family cluster of three individuals with an ataxic CJD form, showing, in addition to severe cerebellar and hippocampal involvement, the presence of frequent Hirano bodies (HB) in CA1 pyramidal neurones. HB are frequently found in aged individuals with Alzheimer pathology although they are not a specific finding. AIMS AND METHODS: In this study, we evaluated the presence of HB in hippocampi of 54 genetically and molecularly characterized CJD cases, aiming to elucidate whether additional morphological features could be helpful to point to molecular subtypes. RESULTS: We identified nine cases (four VV1, one out of three MV2K, three out of six MV2K+2C and one MV carrying a 96-base pair insertion) with abundant, partly bizarre and clustered HB in CA1 sector, not observed in other subtypes. The presence of HB was independent of hippocampal involvement by the disease itself. CONCLUSIONS: Clusters of abundant HB might be found in rare CJD subtypes such as VV1, MV2K/MV2K+2C and some genetic cases. In addition to histopathological and PrP immunohistochemical deposition patterns, their presence might be a useful additional morphologic feature that could point to the molecular subtype, especially when genetic and/or Western blot analyses are not available.

Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice.

An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay.

PICOGEN: experiencia de 5 años de un programa de asesoramiento genético en demencia / PICOGEN: Five years experience with a genetic counselling program for dementia

Introducción: Describimos la experiencia del Programa de Información y Consejo Genético para demencias familiares (PICOGEN) en sus 5 a˜nos de funcionamiento. Métodos: Todos los sujetos fueron asesorados por un neurólogo que seleccionó los candidatos a estudio genético según la historia familiar y el diagnóstico (enfermedad de Alzheimer [EA], degeneración lobular frontotemporal [DLFT] o enfermedad priónica). Los sujetos asintomáticos que decidieron conocer su estatus genético siguieron un protocolo estructurado de evaluación antes y después de la realización del test genético. Resultados: Ochenta y siete pacientes de 72 familias fueron candidatos a estudio genético, 20 de 72 familias presentaban historia familiar autosómica dominante de inicio precoz (HADp). En 22 se detectó una mutación patogénica (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 no descritas previamente. Todos los casos con mutación, excepto uno PSEN1 (12,5%) y 4 PRNP (50%) presentaban HADp. En 3 casos con HADp (15%) no se encontró ninguna mutación. 24 de 54 sujetos asintomáticos de familias con mutación conocida decidieron realizarse el estudio presintomático, 10 resultaron portadores. En el seguimiento de los sujetos que realizaron el estudio predictivo no se observó ninguna complicación psiquiátrica mayor. Conclusiones: En nuestra serie la HADp resultó un criterio sensible para la detección de mutaciones patogénicas en EA y DLFT, pero no en enfermedades priónicas. Un 15% de los casos HADp no presentaron alteraciones genéticas causales en estudios diagnósticos convencionales. El 43% de los sujetos en riesgo que recibieron asesoramiento genético individual realizaron el estudio presintomático. El estudio presintomático resultó seguro en este contexto (AU)

Introduction: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). Methods: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. Results: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the presymptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. Conclusions: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of presymptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions (AU)

Estradiol synthesis within the human brain.

Estradiol biosynthesis is catalyzed by the enzyme aromatase, the product of the CYP19A1 gene. Aromatase is expressed in the brain, where it is involved not only in the control of neuroendocrine events and reproduction, but also in the regulation of neural development, synaptic plasticity and cell survival. In this review we summarize the existing data related with the detection of aromatase in human brain, with particular emphasis in the so-called "non-primary reproductive" areas. Besides hypothalamus, amygdala and preoptic/septal areas, aromatase is expressed in certain regions of basal forebrain, cerebral cortex, hippocampus, thalamus, cerebellum and brainstem of the human brain. Aromatase in human brain is produced by neurons, but there is also an astrocyte subpopulation that constitutively expresses the enzyme. The use of different methodological approaches, including the in vivo analysis by positron emission tomography of human subjects, has permitted to draw a general map of human brain aromatase, but the detailed distribution map is still far to be completed. On the other hand, despite the fact that there is only one aromatase protein, there are multiple mRNA transcripts that differ in the 5'-untranslated region, where regulatory elements reside. To date, some of the aromatase transcripts characteristic of cerebral cortex, as well as of human cell lines of neural origin, have been identified. This characteristic may confer tissue or even region-specific regulation of the expression and therefore it is conceivable to develop selective aromatase modulators to regulate the expression of the enzyme in the human brain. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

PICOGEN: five years experience with a genetic counselling program for dementia.

INTRODUCTION: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). METHODS: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. RESULTS: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the pre-symptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. CONCLUSIONS: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of pre-symptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions.

Cortical hyperexcitability in response to preserved spinothalamic inputs immediately after spinal cord hemisection.

Chronic injury of the main somatosensory pathways ascending along the spinal cord - the dorsal columns and the spinothalamic tract - can produce both changes in the organization of cortical somatotopic maps and neuropathic pain. Little is known, however, about the early neurophysiological changes occurring immediately after injury. We bilaterally recorded the neural activity of the hindpaw representation of the primary somatosensory cortex evoked by stimuli delivered to the hindpaws before and immediately after a thoracic spinal cord hemisection in anesthetized rats. This unilateral spinal cord injury allowed us to separately investigate the cortical effects of deafferenting the dorsal column (stimuli ipsilateral to the hemisection) or the spinothalamic tract (stimuli contralateral to the hemisection). The hemisection produced immediate bilateral changes in the cortical responses evoked by stimuli delivered to the hindpaw ipsilateral to the hemisection (deafferented dorsal column): an expected loss of classical short-latency cortical responses, accompanied by an unexpected appearance of long-latency activations. At the population level, these activations reflected a progressive stimulus-induced transition of the hindpaw somatosensory cortex from up-and-down states to a sustained activated state. At the single-cell level, these cortical activations resembled the "wind-up" typically observed - with the same type of stimuli - in the dorsal horn cells originating the spinothalamic tract. Virtually no changes were observed in the responses evoked by stimuli delivered to the hindpaw contralateral to the hemisection (deafferented spinothalamic tract). These results suggest that spinal cord hemisection immediately produces an abnormal hyperexcitability of the primary somatosensory cortex in response to preserved spinothalamic inputs from the hindpaw. This immediate cortical hyperexcitability could be important to understand the long-term development of cortical reorganization and neuropathic pain after incomplete spinal cord lesions.

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation.

Transient reactive oxygen species (ROS) production is currently proving to be an important mechanism in the regulation of intracellular signalling, but reports showing the involvement of ROS in important biological processes, such as cell differentiation, are scarce. In this study, we show for the first time that ROS production is required for megakaryocytic differentiation in K562 and HEL cell lines and also in human CD34(+) cells. ROS production is transiently activated during megakaryocytic differentiation, and such production is abolished by the addition of different antioxidants (such as N-acetyl cysteine, trolox, quercetin) or the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium. The inhibition of ROS formation hinders differentiation. RNA interference experiments have shown that a p22(phox)-dependent NADPH oxidase activity is responsible for ROS production. In addition, the activation of ERK, AKT and JAK2 is required for differentiation, but the activation of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase seems to be less important. When ROS production is prevented, the activation of these signalling pathways is partly inhibited. Taken together, these results show that NADPH oxidase ROS production is essential for complete activation of the main signalling pathways involved in megakaryocytopoiesis to occur. We suggest that this might also be important for in vivo megakaryocytopoiesis.

Possible association between NOD2 variants and joint surgery in psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) has been inconsistently associated with common NOD2 gene variants, although some of these studies did not include patient stratification by clinical phenotype. OBJECTIVES: To analyse the association between the three common NOD2 variants (R702W, G908R and L1007fs) and clinical phenotypes of PsA, particularly with surrogate markers of severe joint destruction. PATIENTS AND METHODS: A total of 183 unrelated PsA patients and 187 controls were included. Demographic, clinical, biological and immunological characteristics were collected. Genotypes for the three common NOD2 gene variants were obtained by PCR and direct sequencing. RESULTS: NOD2 variants in PsA patients (7.6%) are just as prevalent as in healthy controls (7.5%). 18.5% of PsA patients carrying at least one NOD2 variant underwent joint surgery compared with 4.5% of those without these variants (p=0.019). Multivariate analysis confirmed this finding (OR 8.82, CI 1.7-46.3). There was no requirement for early surgery in patients carrying the NOD2 variants but there was an increased possibility of requiring surgery at similar times of disease duration. No other association with clinical features and NOD2 status carrier was found. CONCLUSIONS: Common NOD2 gene variants are not associated with PsA, but might increase the risk of undergoing joint replacement surgery, suggesting that this autoinflammatory-associated gene could act as a phenotypic modifier gene in PsA patients by increasing the risk of joint destruction. Given the small number of PsA patients with joint surgery included, we consider our findings a new hypothesis that will need further testing.