Characterization and modulation of voltage-gated potassium channels in human lymphocytes in schizophrenia.

BACKGROUND: It is known that the immune system is dysregulated in schizophrenia, having a state similar to chronic neuroinflammation. The origin of this process is unknown, but it is known that T and B lymphocytes, which are components of the adaptive immune system, play an important role in the pathogenic mechanisms of schizophrenia. METHODS: We analysed the membrane of PBMCs from patients diagnosed with schizophrenia through proteomic analysis (n = 5 schizophrenia and n = 5 control). We found the presence of the Kv1.3 voltage-gated potassium channel and its auxiliary subunit ß1 (KCNAB1) and ß2 (KCNAB2). From a sample of 90 participants, we carried out a study on lymphocytes with whole-cell patch-clamp experiments (n = 7 schizophrenia and n = 5 control), western blot (n = 40 schizophrenia and n = 40 control) and confocal microscopy to evaluate the presence and function of different channels. Kv in both cells. RESULTS: We demonstrated the overexpression of Kv1.1, Kv1.2, Kv1.3, Kv1.6, Kv4.2, Kv4.3 and Kv7.2 channels in PBMCs from patients with schizophrenia. This study represents a groundbreaking exploration, as it involves an electrophysiological analysis performed on T and B lymphocytes from patients diagnosed of schizophrenia compared to healthy participants. We observed that B lymphocytes exhibited an increase in output current along with greater peak current amplitude and voltage conductance curves among patients with schizophrenia compared with healthy controls. CONCLUSIONS: This study showed the importance of the B lymphocyte in schizophrenia. We know that the immune system is altered in schizophrenia, but the physiological mechanisms of this system are not very well known. We suggest that the B lymphocyte may be relevant in the pathophysiology of schizophrenia and that it should be investigated in more depth, opening a new field of knowledge and possibilities for new treatments combining antipsychotics and immunomodulators. The limitation is that all participants received antipsychotic medication, which may have influenced the differences observed between patients and controls. This implies that more studies need to be done where the groups can be separated according to the antipsychotic drug.

Photosensitive EGFR-Targeted Nanocarriers for Combined Photodynamic and Local Chemotherapy.

The major limitation of any cancer therapy lies in the difficulty of precisely controlling the localization of the drug in the tumor cells. To improve this drawback, our study explores the use of actively-targeted chemo-photo-nanocarriers that recognize and bind to epidermal growth factor receptor-overexpressing cells and promote the local on-demand release of the chemotherapeutic agent doxorubicin triggered by light. Our results show that the attachment of high concentrations of doxorubicin to cetuximab-IRDye700DX-mesoporous silica nanoparticles yields efficient and selective photokilling of EGFR-expressing cells mainly through singlet oxygen-induced release of the doxorubicin from the nanocarrier and without any dark toxicity. Therefore, this novel triply functionalized nanosystem is an effective and safe nanodevice for light-triggered on-demand doxorubicin release.

Changes in the Brain Extracellular Matrix Composition in schizophrenia: A Pathophysiological Dysregulation and a Potential Therapeutic Target.

The brain extracellular matrix (ECM) is involved in crucial processes of neural support, neuronal and synaptic plasticity, extrasynaptic transmission, and neurotransmission. ECM is a tridimensional fibrillary meshwork composed of macromolecules that determine its bioactivity and give it unique characteristics. The characterization of the brain ECM is critical to understand its dynamic in SZ. Thus, a comparative study was developed with 71 patients with schizophrenia (SZ) and 70 healthy controls. Plasma of participants was analysed by label-free liquid chromatography-tandem mass spectrometry, and the results were validated using the classical western blot method. Lastly, immunostaining of post-mortem human brain tissue was performed to analyse the distribution of the brain ECM proteins by confocal microscopy. The analysis identified four proteins: fibronectin, lumican, nidogen-1, and secreted protein acidic and rich in cysteine (SPARC) as components of the brain ECM. Statistical significance was found for fibronectin (P = 0.0166), SPARC (P = 0.0003), lumican (P = 0.0012), and nidogen-1 (P < 0.0001) that were decreased in the SZ group. Fluorescence imaging of prefrontal cortex (PFC) sections revealed a lower expression of ECM proteins in SZ. Our study proposes a pathophysiological dysregulation of proteins of the brain ECM, whose abnormal composition leads to a progressive neuronal impairment and consequently to neurodegenerative processes due to lack of neurophysiological support and dysregulation of neuronal homeostasis. Moreover, the brain ECM and its components are potential pharmacological targets to develop new therapeutic approaches to treat SZ.

Perfil proteómico y metabólico de pacientes crónicos con esquizofrenia tras un programa de actividad física: estudio piloto / Proteomic and metabolic profiling of chronic patients with schizophrenia induced by a physical activity program: Pilot study

Introducción: La esquizofrenia es una enfermedad crónica que suele ir acompañada de trastornos metabólicos como la diabetes, la obesidad y problemas cardiovasculares asociados muchas veces a estilos de vida poco saludables, así como a problemas neuroendocrinos ocasionados por la propia enfermedad. Los cambios en el estilo de vida, como la práctica de ejercicio físico regular, tienen un efecto positivo sobre los trastornos metabólicos y la salud mental. Sin embargo, se desconocen los cambios moleculares y su consecuente repercusión en los pacientes diagnosticados con esquizofrenia. Con este estudio se pretenden analizar los cambios moleculares inducidos por el ejercicio físico en pacientes crónicos con esquizofrenia.MétodosVeintiún pacientes con esquizofrenia crónica fueron sometidos a un programa de entrenamiento aeróbico diario durante 6 meses. El grupo de pacientes se dividió en 2 subgrupos: un subgrupo que completó en su totalidad el programa de entrenamiento (12 pacientes) y un segundo subgrupo que abandonó el programa el primer día (9 pacientes). Se analizaron los datos bioquímicos y clínicos de cada paciente y se estudió el perfil proteómico del plasma mediante ESI-LC-MS/MS de tipo shotgun.ResultadosEl análisis proteómico reconoció 21.165 proteínas y péptidos diferentes en el plasma de los pacientes. Concretamente, 4.657 proteínas sufrieron variaciones significativas, de las cuales fueron identificadas 1.812 proteínas relacionadas con las vías metabólicas y de regulación biológica. Tras el análisis de los parámetros clínicos en estos pacientes, se encontraron diferencias significativas en el peso, el IMC, el perímetro abdominal, la presión arterial diastólica y los niveles de colesterol HDL. La puntuación en la Escala de Autoevaluación de Anhedonia fue el cambio más significativo, siendo más elevada en el subgrupo que abandonó el programa de entrenamiento en comparación con el subgrupo activo. (AU)

Introduction: Schizophrenia is a chronic illness often accompanied by metabolic disorders, diabetes, obesity and cardiovascular problems often associated with unhealthy lifestyles, as well as neuroendocrine problems caused by the disease itself. Lifestyle changes, such as regular physical exercise, have a positive effect on metabolic disorders and mental health, although the molecular changes that occur in this type of patient and how they explain the changes in their response are unknown. This study wants to analyze in a novel way the proteins and molecular pathways involved in critical plasmatic proteins in plasma to reveal the pathways involved in the implementation of physical exercise and the changes that occur among patients who participate in such programs with those who leave.MethodsTwenty-one patients with chronic schizophrenia underwent a daily, 6-month aerobic training program. We divided them into a group that completed the program (12 patients) and a second group that left the training program (9 patients). The biochemical and clinical data of each patient were analyzed and the proteomic profile of the plasma was studied using ESI-LC-MS/MS.ResultsProteomic analysis recognizes 21.165 proteins and peptides in each patient, of which we identified 1,812 proteins that varied between both groups linked to the metabolic and biological regulation pathways. After clinical analysis of each patient we found significant differences in weight, BMI, abdominal perimeter, diastolic blood pressure, and HDL cholesterol levels. The main change that vertebrates both groups is the Self-Assessment Anhedonia Scale, where we detected higher levels in the dropout group (no physical activity) compared to the active group. (AU)

Proteomic and metabolic profiling of chronic patients with schizophrenia induced by a physical activity program: Pilot study.

INTRODUCTION: Schizophrenia is a chronic illness often accompanied by metabolic disorders, diabetes, obesity and cardiovascular problems often associated with unhealthy lifestyles, as well as neuroendocrine problems caused by the disease itself. Lifestyle changes, such as regular physical exercise, have a positive effect on metabolic disorders and mental health, although the molecular changes that occur in this type of patient and how they explain the changes in their response are unknown. This study wants to analyze in a novel way the proteins and molecular pathways involved in critical plasmatic proteins in plasma to reveal the pathways involved in the implementation of physical exercise and the changes that occur among patients who participate in such programs with those who leave. METHODS: Twenty-one patients with chronic schizophrenia underwent a daily, 6-month aerobic training program. We divided them into a group that completed the program (12 patients) and a second group that left the training program (9 patients). The biochemical and clinical data of each patient were analyzed and the proteomic profile of the plasma was studied using ESI-LC-MS/MS. RESULTS: Proteomic analysis recognizes 21.165 proteins and peptides in each patient, of which we identified 1.812 proteins that varied between both groups linked to the metabolic and biological regulation pathways. After clinical analysis of each patient we found significant differences in weight, BMI, abdominal perimeter, diastolic blood pressure, and HDL cholesterol levels. The main change that vertebrates both groups is the Self-Assessment Anhedonia Scale, where we detected higher levels in the dropout group (no physical activity) compared to the active group. CONCLUSION: The benefits of physical exercise are clear in chronic patients with schizophrenia, as it substantially improves their BMI, as well as their clinical and biochemical parameters. However, our study reveals the biological and molecular pathways that affect physical exercise in schizophrenia, such as important metabolic proteins such as ApoE and ApoC, proteins involved in neuronal regulation such as tenascin and neurotrophins, neuroinflammatory regulatory pathways such as lipocalin-2 and protein 14-3-3, as well as cytoskeleton proteins of cells such as spectrins and annexines. Understanding these molecular mechanisms opens the door to future therapies in the chronicity of schizophrenia.

The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia.

The neurobiology of schizophrenia is multifactorial, comprising the dysregulation of several biochemical pathways and molecules. This research proposes a peripheral biomarker for schizophrenia that involves the second extracellular loop of norepinephrine transporter (NEText), the tropomyosin receptor kinase C (TrkC), and the neurotrophin-3 (NT-3) in T cells. The study of NEText, NT-3, and TrkC was performed in T cells and plasma extracted from peripheral blood of 54 patients with schizophrenia and 54 healthy controls. Levels of NT-3, TrkC, and NET were significantly lower in plasma and T cells of patients compared to healthy controls. Co-immunoprecipitation (co-IPs) showed protein interactions with Co-IP NEText-NT-3 and Co-IP NEText-TrkC. Computational modelling of protein-peptide docking by CABS-dock provided a medium-high accuracy model for NT-3-NEText (4.6935 Å) and TrkC-NEText (2.1365 Å). In summary, immunocomplexes reached statistical relevance in the T cells of the control group contrary to the results obtained with schizophrenia. The reduced expression of NT-3, TrkC, and NET, and the lack of molecular complexes in T cells of patients with schizophrenia may lead to a peripheral dysregulation of intracellular signaling pathways and an abnormal reuptake of norepinephrine (NE) by NET. This peripheral molecular biomarker underlying schizophrenia reinforces the role of neurotrophins, and noradrenergic and immune systems in the pathophysiology of schizophrenia.

Self-Assembled Binaphthyl-Bridged Amphiphilic AABB Phthalocyanines: Nanostructures for Efficient Antimicrobial Photodynamic Therapy.

Herein, the photodynamic activity of phthalocyanine (pc)-assembled nanoparticles against bacterial strains is demonstrated. The photosensitizers (PS) studied in this work are two chiral ZnII Pcs (PS-1 and PS-2), with an AABB geometry (where A and B refer to differently substituted isoindole constituents). They contain differently functionalized, chiral binaphthyloxy-linked A isoindole units, which determine the hydrophobicity of the system, and cationic methyl pyridinium moieties in the other two isoindoles to embody hydrophilicity. Both compounds have the ability to self-assemble into nanoparticles in aqueous media and have proved efficient in the photo-inactivation of Staphylococcus aureus and Escherichia coli, selected as models of Gram-positive and Gram-negative bacteria. The average size of the nanoparticles was determined by substitution at the binaphthyl core and, in turn, influences the toxicity of the PS. Thus, PS-1, presenting a nonsubstituted binaphthyl core, forms larger nanoparticles with a larger cationic surface than the octyl-functionalized PS-2. Although both PSs present similar structure and photophysical features, the self-assembled nanostructures of PS-1 are more effective at killing both types of strain, showing an outstanding photo-inactivation capacity with the Gram-negative E. coli.

Catéter central de inserción periférica en trasplante de progenitores hematopoyéticos. Infusión de células hematopoyéticas y complicaciones / Peripherally inserted central catheter in haematopoietic stem cell transplantation. Infusion of haematopoietic cells and complications

OBJETIVO: Analizar la incidencia de complicaciones relacionadas con el catéter central de inserción periférica y la viabilidad de la infusión de las células madre hematopoyéticas mediante bombas de perfusión volumétrica. MÉTODO: Estudio descriptivo prospectivo que incluye a todos los pacientes que recibieron un trasplante hematopoyético en el Servicio de Hematología del Hospital Clínico de Valencia entre enero y diciembre de 2016 (n=73). A todos se les colocó un catéter central de inserción periférica. Se utilizó el programa informático SPSS® V.22 para realizar el análisis descriptivo de las principales variables utilizando un intervalo de confianza del 95%. Se realizó el análisis de la t de Student para comparar las medias de 2 muestras independientes suponiendo varianzas desiguales. RESULTADO: El 63% (n=73) de los catéteres se mantuvieron sin problemas durante todo el procedimiento. La principal causa de retirada del catéter fue la fiebre de origen desconocido (28,8%). La mediana de días para la recuperación hematológica en el trasplante autólogo fue de 12,5 días y en el alogénico de 15 días. CONCLUSIONES: El catéter central de inserción periférica presenta pocas complicaciones relacionadas con la inserción. La administración de las células hematopoyéticas a través de este tipo de catéteres y con bombas de perfusión volumétrica no supone un retraso en la recuperación hematológica. Se constata una buena aceptación por parte del paciente

AIMS: To analyze the incidence of complications related to the central peripheral insertion catheter and the viability of the infusion of haematopoietic stem cells through volumetric perfusion pumps. METHOD: Prospective descriptive study that includes all patients who received a haematopoietic transplant in the Haematology Service of the Hospital Clínico de Valencia between January and December 2016 (n=73). All of them received a central peripheral insertion catheter. SPSS™ v22 was used to perform the descriptive analysis of the main variables using a confidence interval of 95%. The student's t-test was used to compare the means of two independent samples assuming unequal variances. RESULTS: The 63% (n=73) of the catheters remained without problems throughout the procedure. Fever of unknown origin (28.8%) was the main cause of catheter removal. The median number of days for haematological recovery was 12.5 for the autologous transplants and 15 for the allogeneic transplants. CONCLUSIONS: The central peripheral insertion catheter presents few complications related to insertion. The administration of haematopoietic cells through these catheters with volumetric perfusion pumps does not imply a delay in haematological recovery. Good acceptance by the patient is confirmed

Plasma ß-III tubulin, neurofilament light chain and glial fibrillary acidic protein are associated with neurodegeneration and progression in schizophrenia.

Schizophrenia is a progressive disorder characterized by multiple psychotic relapses. After every relapse, patients may not fully recover, and this may lead to a progressive loss of functionality. Pharmacological treatment represents a key factor to minimize the biological, psychological and psychosocial impact of the disorder. The number of relapses and the duration of psychotic episodes induce a potential neuronal damage and subsequently, neurodegenerative processes. Thus, a comparative study was performed, including forty healthy controls and forty-two SZ patients divided into first-episode psychosis (FEP) and chronic SZ (CSZ) subgroups, where the CSZ sub group was subdivided by antipsychotic treatment. In order to measure the potential neuronal damage, plasma levels of ß-III tubulin, neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) were performed. The results revealed that the levels of these proteins were increased in the SZ group compared to the control group (P < 0.05). Moreover, multiple comparison analysis showed highly significant levels of ß-III tubulin (P = 0.0002), Nf-L (P = 0.0403) and GFAP (P < 0.015) in the subgroup of CSZ clozapine-treated. In conclusion, ß-III tubulin, Nf-L and GFAP proteins may be potential biomarkers of neurodegeneration and progression in SZ.

c(RGDfK)- and ZnTriMPyP-Bound Polymeric Nanocarriers for Tumor-Targeted Photodynamic Therapy.

Active targeting strategies are currently being extensively investigated in order to enhance the selectivity of photodynamic therapy. The aim of the present research was to evaluate whether the external decoration of nanopolymeric carriers with targeting peptides could add more value to a photosensitizer formulation and increase antitumor therapeutic efficacy and selectivity. To this end, we assessed PLGA-PLA-PEG nanoparticles (NPs) covalently attached to a hydrophilic photosensitizer 5-[4-azidophenyl]-10,15,20-tri-(N-methyl-4-pyridinium)porphyrinato zinc (II) trichloride (ZnTriMPyP) and also to c(RGDfK) peptides, in order to target αv ß3 integrin-expressing cells. In vitro phototoxicity investigations showed that the ZnTriMPyP-PLGA-PLA-PEG-c(RGDfK) nanosystem is effective at submicromolar concentrations, is devoid of dark toxicity, successfully targets αv ß3 integrin-expressing cells and is 10-fold more potent than related nanosystems where the PS is occluded instead of covalently bound.

Brainwaves Oscillations as a Potential Biomarker for Major Depression Disorder Risk.

Major depressive disorder (MDD) is a multidimensional disorder that is characterized by the presence of alterations in mood, cognitive capacity, sensorimotor, and homeostatic functions. Given that about half of the patients diagnosed with MDD do not respond to the various current treatments, new techniques are being sought to predict not only the course of the disease but also the characteristics that differentiate responders from non-responders. Using the electroencephalogram, a noninvasive and inexpensive tool, most studies have proposed that patients with MDD have some lateralization in brain electrical activity, with alterations in alpha and theta rhythms being observed, which would be related to dysfunctions in emotional capacity such as the absence or presence of responses to the different existing treatments. These alterations help in the identification of subjects at high risk of suffering from depression, in the differentiation into responders and nonresponders to various therapies (pharmacological, electroconvulsive therapy, and so on), as well as to establish in which period of the disease the treatment will be more effective. Although the data are still inconclusive and more research is needed, these alpha and theta neurophysiological markers could support future clinical practice when it comes to establishing an early diagnosis and treating state disorders more successfully and accurately of mood disorders.

Peripherally inserted central catheter in haematopoietic stem cell transplantation. Infusion of haematopoietic cells and complications. / Catéter central de inserción periférica en trasplante de progenitores hematopoyéticos. Infusión de células hematopoyéticas y complicaciones.

AIMS: To analyze the incidence of complications related to the central peripheral insertion catheter and the viability of the infusion of haematopoietic stem cells through volumetric perfusion pumps. METHOD: Prospective descriptive study that includes all patients who received a haematopoietic transplant in the Haematology Service of the Hospital Clínico de Valencia between January and December 2016 (n=73). All of them received a central peripheral insertion catheter. SPSS™ v22 was used to perform the descriptive analysis of the main variables using a confidence interval of 95%. The student's t-test was used to compare the means of two independent samples assuming unequal variances. RESULTS: The 63% (n=73) of the catheters remained without problems throughout the procedure. Fever of unknown origin (28.8%) was the main cause of catheter removal. The median number of days for haematological recovery was 12.5 for the autologous transplants and 15 for the allogeneic transplants. CONCLUSIONS: The central peripheral insertion catheter presents few complications related to insertion. The administration of haematopoietic cells through these catheters with volumetric perfusion pumps does not imply a delay in haematological recovery. Good acceptance by the patient is confirmed.

Proteomics in Schizophrenia: A Gateway to Discover Potential Biomarkers of Psychoneuroimmune Pathways.

Schizophrenia is a severe and disabling psychiatric disorder with a complex and multifactorial etiology. The lack of consensus regarding the multifaceted dysfunction of this ailment has increased the need to explore new research lines. This research makes use of proteomics data to discover possible analytes associated with psychoneuroimmune signaling pathways in schizophrenia. Thus, we analyze plasma of 45 patients [10 patients with first-episode schizophrenia (FES) and 35 patients with chronic schizophrenia] and 43 healthy subjects by label-free liquid chromatography-tandem mass spectrometry. The analysis revealed a significant reduction in the levels of glia maturation factor beta (GMF-ß), the brain-derived neurotrophic factor (BDNF), and the 115-kDa isoform of the Rab3 GTPase-activating protein catalytic subunit (RAB3GAP1) in patients with schizophrenia as compared to healthy volunteers. In conclusion, GMF-ß, BDNF, and 115-kDa isoform of RAB3GAP1 showed significantly reduced levels in plasma of patients with schizophrenia, thus making them potential biomarkers in schizophrenia.

Dermoscopic features of skin lesions in patients with mastocytosis.

OBJECTIVES: To evaluate dermoscopic features in a group of 127 patients with mastocytosis in the skin and to investigate the relationship between different dermoscopic patterns and other clinical and biological characteristics of the disease. DESIGN: Clinical and laboratory data were compared among patients with mastocytosis grouped according to the different dermoscopic patterns. SETTING: Patients were selected from the Instituto de Estudios de Mastocitosis de Castilla La Mancha and the Department of Dermatology of Hospital Universitario Ramón y Cajal from April 1 through September 30, 2009. Patients Overall, 127 consecutive patients (70 females [55.1%] and 57 males [44.9%]; median age, 17 years; range, 0-81 years) with mastocytosis in the skin were included in the study. MAIN OUTCOME MEASURES: Evaluation of dermoscopic patterns and investigation of potential predictive factors for more symptomatic forms of the disease according to the need for daily antimediator therapy. RESULTS: Four distinct dermoscopic patterns were observed: yellow-orange blot, pigment network, reticular vascular pattern, and (most frequently) light-brown blot. A reticular vascular pattern was identified in all telangiectasia macular eruptiva and some maculopapular mastocytosis. In turn, all patients with mastocytoma displayed the yellow-orange blot pattern. The reticular vascular dermoscopic pattern was associated with the need for daily antimediator therapy; this pattern, together with serum tryptase levels and plaque-type mastocytosis, represented the best combination of independent factors to predict the need for maintained antimediator therapy. CONCLUSIONS: Dermoscopy is a feasible method for the subclassification of mastocytosis. Of note, a reticular vascular pattern is more frequently associated with the need for antimediator therapy.

Dermatoscopy for in vivo diagnosis of malignant melanoma.

A man, 59 years of age, presented with a pigmented lesion that was discovered on lung auscultation by a family physician. Clinically, a 12 mm long, slightly elevated, brown lesion with variegate pigmentation was observed on his back. Dermatoscopy revealed a multicomponent pattern characterised by irregular pigmented network, radial streaming and pseudopods along with extensive blue-grey areas and a dark brown patch.

Phakomatosis pigmentovascularis: Clinical findings in 15 patients and review of the literature.

INTRODUCTION: Phakomatosis pigmentovascularis (PPV) is a rare syndrome characterized by the association of a vascular nevus with an extensive pigmentary nevus. OBJECTIVE: We sought to study and evaluate clinical findings in patients with PPV referred to the laser department of our hospital. METHODS: We revised the clinical findings of 15 patients with PPV and reclassified them according to Happle's new classification. RESULTS: We studied 11 female patients and 4 male patients with a mean age of 21 years. Thirteen had phakomatosis cesioflammea, one cesiomarmorata, and one an unclassifiable form. Of 15 patients, 12 had nevus of Ota. The vascular involvement was extensive in our PPV population and 14 patients were affected in two or more areas. The mosaicism pattern in 13 patients was patchy and without a midline separation. The most frequent associations found were Sturge-Weber syndrome, Klippel-Trénaunay syndrome, and melanosis oculi. LIMITATIONS: Limitations include the methods of case collection, that this is a retrospective study, and that there were a relatively small number of patients. CONCLUSIONS: PPV are rare syndromes with a wide variability in their clinical expression. Most of the publications in the literature have only reported isolated cases.