Mechanisms and pathways underlying the therapeutic effect of transcranial magnetic stimulation.

It has been almost 40 years since Barker, Jalinous, and Freeston designed and used the first device of transcranial magnetic stimulation (TMS). From then until now, this technique has evolved vertiginously, appearing a lot of new protocols and device modifications, which associated with new technologies complement and enhance the versatility of this technique. TMS has demonstrated to be a safe technology and become a key tool in the study of the complex brain processes. Despite this, it is as a therapeutic tool where this technique has caused a revolution. In this regard, this type of non-invasive brain stimulation has been proven useful in a variety of neurodegenerative and psychiatric disorders due to its biochemical, molecular, and cellular effects, with depression being the paradigm of the therapeutic effectiveness of this technique. This review focuses on a detailed vision of how this type of radiation modifies different biochemical and cellular processes that induce the mechanisms and pathways underlying the therapeutic effects of TMS.

Red Light Enhances Plant Adaptation to Spaceflight and Mars g-Levels.

Understanding how plants respond and adapt to extraterrestrial conditions is essential for space exploration initiatives. Deleterious effects of the space environment on plant development have been reported, such as the unbalance of cell growth and proliferation in the root meristem, or gene expression reprogramming. However, plants are capable of surviving and completing the seed-to-seed life cycle under microgravity. A key research challenge is to identify environmental cues, such as light, which could compensate the negative effects of microgravity. Understanding the crosstalk between light and gravity sensing in space was the major objective of the NASA-ESA Seedling Growth series of spaceflight experiments (2013-2018). Different g-levels were used, with special attention to micro-g, Mars-g, and Earth-g. In spaceflight seedlings illuminated for 4 days with a white light photoperiod and then photostimulated with red light for 2 days, transcriptomic studies showed, first, that red light partially reverted the gene reprogramming induced by microgravity, and that the combination of microgravity and photoactivation was not recognized by seedlings as stressful. Two mutant lines of the nucleolar protein nucleolin exhibited differential requirements in response to red light photoactivation. This observation opens the way to directed-mutagenesis strategies in crop design to be used in space colonization. Further transcriptomic studies at different g-levels showed elevated plastid and mitochondrial genome expression in microgravity, associated with disturbed nucleus-organelle communication, and the upregulation of genes encoding auxin and cytokinin hormonal pathways. At the Mars g-level, genes of hormone pathways related to stress response were activated, together with some transcription factors specifically related to acclimation, suggesting that seedlings grown in partial-g are able to acclimate by modulating genome expression in routes related to space-environment-associated stress.

Clinical characteristics of full thickness macular holes that closed without surgery.

PURPOSE: To ascertain the anatomic factors that help achieve non-surgical sealing in full thickness macular hole (FTMH). METHODS: Retrospective collaborative study of FTMH that closed without surgical intervention. RESULTS: A total of 78 patients (mean age 57.9 years) included 18 patients with blunt ocular trauma, 18 patients that received topical or intravitreal therapies and 42 patients with idiopathic FTMH. Mean±SD of the initial corrected visual acuity (VA) in logMAR improved from 0.65±0.54 to 0.34±0.45 (p<0.001) at a mean follow-up of 33.8±37.1 months. FTMH reopened in seven eyes (9.0%) after a mean of 8.6 months. Vitreomacular traction was noted in 12 eyes (15.8%), perifoveal posterior vitreous detachment in 42 (53.8%), foveal epiretinal membrane in 10 (12.8%), cystoid macular oedema (CME) in 49 (62.8%) and subretinal fluid (SRF) in 20 (25.6%). By multivariate analysis, initial VA correlated to the height (p<0.001) and narrowest diameter of the hole (p<0.001) while final VA correlated to the basal diameter (p<0.001). Time for closure of FTMH (median 2.8 months) correlated to the narrowest diameter (p<0.001) and the presence of SRF (p=0.001). Mean time for closure (in months) was 1.6 for eyes with trauma, 4.3 for eyes without trauma but with therapy for CME, 4.4 for eyes without trauma and without therapy in less than 200 µm in size and 24.7 for more than 200 µm. CONCLUSION: Our data suggest an observation period in new onset FTMH for non-surgical closure, in the setting of trauma, treatment of CME and size <200 µm.

Analysis of Graviresponse and Biological Effects of Vertical and Horizontal Clinorotation in Arabidopsis thaliana Root Tip.

Clinorotation was the first method designed to simulate microgravity on ground and it remains the most common and accessible simulation procedure. However, different experimental settings, namely angular velocity, sample orientation, and distance to the rotation center produce different responses in seedlings. Here, we compare A. thaliana root responses to the two most commonly used velocities, as examples of slow and fast clinorotation, and to vertical and horizontal clinorotation. We investigate their impact on the three stages of gravitropism: statolith sedimentation, asymmetrical auxin distribution, and differential elongation. We also investigate the statocyte ultrastructure by electron microscopy. Horizontal slow clinorotation induces changes in the statocyte ultrastructure related to a stress response and internalization of the PIN-FORMED 2 (PIN2) auxin transporter in the lower endodermis, probably due to enhanced mechano-stimulation. Additionally, fast clinorotation, as predicted, is only suitable within a very limited radius from the clinorotation center and triggers directional root growth according to the direction of the centrifugal force. Our study provides a full morphological picture of the stages of graviresponse in the root tip, and it is a valuable contribution to the field of microgravity simulation by clarifying the limitations of 2D-clinostats and proposing a proper use.

Antioxidant-like effects and protective action of transcranial magnetic stimulation in depression caused by olfactory bulbectomy.

We studied the effects of transcranial magnetic stimulation (TMS, 60 Hz and 0.7 mT for 4 h/day for 14 days) on oxidative and cell damage caused by olfactory bulbectomy (OBX) in Wistar rats. The levels of lipid peroxidation products and caspase-3 were enhanced by OBX, whereas it prompted a reduction in reduced glutathione (GSH) content and antioxidative enzymes activities. The treatment with TMS reverted towards normality the biomarkers indicative of oxidative stress and apoptosis. In conclusion, our data show that TMS induced a protection against cell and oxidative damage induced by OBX, as well as they support the hypothesis that oxidative stress may play an important role in depression.

Immunotherapy, Cancer and Rheumatological Diseases: A Review of the Literature and a Series of Cases in a University Hospital. / Inmunoterapia, cáncer y enfermedades reumatológicas: revisión de la literatura y serie de casos en un hospital universitario.

The appearance in the field of oncology of therapeutic molecules in the form of monoclonal antibodies, whose objective is to stimulate the patient's own immune system to be responsible for destroying cancer cells, has revolutionized the treatment of many cancers in recent years. This type of therapy, called immunotherapy, is also characterized by presenting side effects in the form of autoimmune diseases that we are still beginning to understand. From the point of view of the immune-mediated rheumatological side effects, we can find musculoskeletal manifestations, mechanical, inflammatory or systemic autoimmune diseases. The therapeutic approach to these side effects remains uncertain due to the absence of clinical trials and validated recommendations. The multidisciplinary management is crucial to successfully treat such cases. In the following manuscript, we will describe our case reports of rheumatologic immune-related adverse events in a university hospital.

RNAseq Analysis of the Response of Arabidopsis thaliana to Fractional Gravity Under Blue-Light Stimulation During Spaceflight.

Introduction: Traveling to nearby extraterrestrial objects having a reduced gravity level (partial gravity) compared to Earth's gravity is becoming a realistic objective for space agencies. The use of plants as part of life support systems will require a better understanding of the interactions among plant growth responses including tropisms, under partial gravity conditions. Materials and Methods: Here, we present results from our latest space experiments on the ISS, in which seeds of Arabidopsis thaliana were germinated, and seedlings grew for six days under different gravity levels, namely micro-g, several intermediate partial-g levels, and 1g, and were subjected to irradiation with blue light for the last 48 h. RNA was extracted from 20 samples for subsequent RNAseq analysis. Transcriptomic analysis was performed using the HISAT2-Stringtie-DESeq pipeline. Differentially expressed genes were further characterized for global responses using the GEDI tool, gene networks and for Gene Ontology (GO) enrichment. Results: Differential gene expression analysis revealed only one differentially expressed gene (AT4G21560, VPS28-1 a vacuolar protein) across all gravity conditions using FDR correction (q < 0.05). However, the same 14 genes appeared differentially expressed when comparing either micro-g, low-g level (< 0.1g) or the Moon g-level with 1g control conditions. Apart from these 14-shared genes, the number of differentially expressed genes was similar in microgravity and the Moon g-level and increased in the intermediate g-level (< 0.1g), but it was then progressively reduced as the difference with the Earth gravity became smaller. The GO groups were differentially affected at each g-level: light and photosynthesis GO under microgravity, genes belonged to general stress, chemical and hormone responses under low-g, and a response related to cell wall and membrane structure and function under the Moon g-level. Discussion: Transcriptional analyses of plants under blue light stimulation suggests that root blue-light phototropism may be enough to reduce the gravitational stress response caused by the lack of gravitropism in microgravity. Competition among tropisms induces an intense perturbation at the micro-g level, which shows an extensive stress response that is progressively attenuated. Our results show a major effect on cell wall/membrane remodeling (detected at the interval from the Moon to Mars gravity), which can be potentially related to graviresistance mechanisms.

Spanish Registry of Recent-onset Psoriatic Arthritis (REAPSER study): Aims and methodology. / Registro Español de Artritis Psoriásica de Reciente Comienzo (estudio REAPSER). Objetivos y metodología.

AIMS: To describe the methodology of REAPSER (Spanish Registry of Recent-onset Psoriatic Arthritis), its strengths and limitations. The aim of this study is to identify prognostic factors for the clinical and radiographic course in a cohort of patients with psoriatic arthritis (PsA) diagnosed within 2years of symptom evolution. METHODS: Multicenter, observational and prospective study (with 2-year follow-up including annual visits). Baseline visit intended to reflect patient situation before the disease course was modified by treatments prescribed in rheumatology departments. Patients were invited to participate consecutively in one of their routine visits to the rheumatologist. 211 patients were included. Following data were collected: sociodemographic variables; employment situation; family history; personal history and comorbidities; anthropometric data; lifestyle; use of healthcare services; clinical situation at the time of PsA diagnosis; joint involvement and spinal pain; pain and overall assessment; enthesitis, dactylitis and uveitis; skin and nail involvement; functional situation and quality of life; radiographic evaluation; analytical determinations; treatment; axial and peripheral flare-ups. CONCLUSIONS: The REAPSER study includes a cohort of patients with recent-onset PsA, before the disease course was modified by disease-modifying antirheumatic drugs prescribed in rheumatology departments. Exhaustive information collected in each visit is expected to be an important data source for future analysis.

Rituximab therapy in necrotizing autoimmune myopathy associated with anti-SRP antibody: A clinical case review. / Tratamiento con rituximab para las miopatías necrosantes autoinmunes asociadas al anti-SRP: caso clínico y revisión de la evidencia.

Necrotizing autoimmune myopathy (NAM) is a rare and emerging entity of idiopathic inflammatory myopathy (IIM). They have been associated with connective tissue disorders, viral infections, malignancy, anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase protein (with or without the use of statins). Anti-SRP associated NAM has different clinical and histological characteristics that differentiate them from other IIM, resulting in a poor prognosis. Very few cases treated with rituximab have been published, with varying clinical response. Here we describe a case of anti-SRP associated NAM refractory to conventional immunosuppressants and its successful long-term management with the combination of rituximab, corticosteroids and methotrexate.

Extraction of nuclear proteins from root meristematic cells.

Fractionation and extraction of nuclear proteins are techniques intended to facilitate dedicated plant proteomic studies. These techniques rely on subcellular fractionation, which makes it possible to define and characterize the proteome of a subcellular organelle, in this case the cell nucleus. Nuclear protein fractionation is proposed as a method to be carried out according to the solubility of proteins in buffers of increasing ionic strength. This physical criterion, accompanied in some steps by the use of additional reagents, such as detergents or enzymes, produces fractions that have been demonstrated to have functional significance. The proposed procedure yields five fractions, the first of them containing proteins associated with the nuclear envelope and remnants of the cytoskeleton. The second fraction, which is soluble at low ionic strength, contains ribonucleoproteins active in nuclear RNA metabolism. After increasing ionic strength and digesting with DNase, the result is the chromatin fraction. Finally, the fourth and fifth fractions correspond to the nuclear matrix and are obtained, respectively, by solubilization in high salt concentration and in the form of the residual pellet, which is only soluble in 7 M urea under sonication. This procedure offers a wide range of applicability, even in the cases in which the genome of the particular species investigated is not sequenced. In general, the functional criteria driving the extraction method described here will make this method capable of generating valuable and useful information.

Structural and antigenic preservation of plant samples by microwave-enhanced fixation, using dedicated hardware, minimizing heat-related effects.

We explored the use of microwave technology in fixation with the objective of achieving quicker fixation regimes, lower concentrations of toxic and volatile reagents, and enhanced antigen detection. We used a modified domestic microwave oven (900 W) and a low-power (5 W) microwave bench. The work was done on plant materials. The oven was supplemented with a cooling device, a stirring system, and a record of the sample temperature and the time of effective irradiation. The sample, immersed in a fixative solution of 1% paraformaldehyde (PFA) in PBS, was irradiated for only 10 minutes. The sample temperature did not exceed 37 degrees C. In these mild conditions, the quality of the (ultra)structural preservation of the samples, morphometrically assessed, was at the same level as obtained with the same fixative, using conventional methods. On the contrary, samples fixed in the same conditions without irradiation showed a poor structural preservation. The antigenic preservation of the irradiated samples was excellent, since the labeling levels of two nucleolar proteins, detected by immunogold, were three times higher than in conventionally fixed samples. In the so-called microwave bench, the pathway of microwaves is guided, so that low-power microwaves directly hit the sample and there is no dispersion of energy. Temperature of fixative did not increase after microwave irradiation. Fixation in the bench with either 4% PFA, or 1% PFA, for 20 minutes resulted in structural preservation of samples similar in quality as obtained with conventional fixation and in a similar or better level of antigen preservation. Therefore, controlling temperature and effective irradiation is crucial in order to obtain optimal structural and antigen preservation with microwave-enhanced fixation. The dramatic differences observed between microwave-irradiated samples and samples fixed in the same conditions without irradiation, strongly support the existence of specific effects of microwaves on fixation, independent from the mere heating of the samples.

Mechanisms of disruption of meristematic competence by microgravity in Arabidopsis seedlings.

Experiments performed in actively proliferating plant cells both in space and simulated microgravity have evidenced a common effect: cell proliferation appears enhanced whereas cell growth is depleted. Coordination of cell growth and proliferation, called meristematic competence, is a major feature of meristematic cells and its disruption may lead to important alterations in the developmental pattern of the plant. Auxin is known to be a mediator of the transduction of the gravitropic signal and a regulator of the rates of growth and proliferation in meristematic cells, as well as of their further differentiation. Therefore, gravity sensing, gravitropism, auxin levels, and meristematic competence are mutually interrelated. However, our experiments in simulated microgravity, using both mechanical and magnetic levitation technologies, have revealed that this interdependence is neither strict nor univocal and may include additional factors and mechanisms. Available data indicate that altered gravity may affect cell growth and proliferation by mechanisms alternative to the transduction of the gravitropic signal perceived by columella cells in the root tip. These mechanisms would include gravity sensing independent from statolith displacement and transduction mediators other than polar auxin transport.

Microgravity induces changes in microsome-associated proteins of Arabidopsis seedlings grown on board the international space station.

The "GENARA A" experiment was designed to monitor global changes in the proteome of membranes of Arabidopsis thaliana seedlings subjected to microgravity on board the International Space Station (ISS). For this purpose, 12-day-old seedlings were grown either in space, in the European Modular Cultivation System (EMCS) under microgravity or on a 1 g centrifuge, or on the ground. Proteins associated to membranes were selectively extracted from microsomes and identified and quantified through LC-MS-MS using a label-free method. Among the 1484 proteins identified and quantified in the 3 conditions mentioned above, 80 membrane-associated proteins were significantly more abundant in seedlings grown under microgravity in space than under 1 g (space and ground) and 69 were less abundant. Clustering of these proteins according to their predicted function indicates that proteins associated to auxin metabolism and trafficking were depleted in the microsomal fraction in µg space conditions, whereas proteins associated to stress responses, defence and metabolism were more abundant in µg than in 1 g indicating that microgravity is perceived by plants as a stressful environment. These results clearly indicate that a global membrane proteomics approach gives a snapshot of the cell status and its signaling activity in response to microgravity and highlight the major processes affected.

Microsome-associated proteome modifications of Arabidopsis seedlings grown on board the International Space Station reveal the possible effect on plants of space stresses other than microgravity.

Growing plants in space for using them in bioregenerative life support systems during long-term human spaceflights needs improvement of our knowledge in how plants can adapt to space growth conditions. In a previous study performed on board the International Space Station (GENARA A experiment STS-132) we evaluate the global changes that microgravity can exert on the membrane proteome of Arabidopsis seedlings. Here we report additional data from this space experiment, taking advantage of the availability in the EMCS of a centrifuge to evaluate the effects of cues other than microgravity on the relative distribution of membrane proteins. Among the 1484 membrane proteins quantified, 227 proteins displayed no abundance differences between µ g and 1 g in space, while their abundances significantly differed between 1 g in space and 1 g on ground. A majority of these proteins (176) were over-represented in space samples and mainly belong to families corresponding to protein synthesis, degradation, transport, lipid metabolism, or ribosomal proteins. In the remaining set of 51 proteins that were under-represented in membranes, aquaporins and chloroplastic proteins are majority. These sets of proteins clearly appear as indicators of plant physiological processes affected in space by stressful factors others than microgravity.

[Acute posterior multifocal placoid pigment epitheliopathy. A rare cause of ischaemic stroke]. / Epiteliopatía pigmentaria placoide multifocal posterior aguda. Una rara causa de ictus isquémico.

INTRODUCTION: Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a rare inflammatory disease, generally of unknown aetiology, affecting the choriocapillaris, the pigment epithelium and the outer retina. It predominantly affects young patients and in some cases may involve the central nervous system in the form of strokes or meningoencephalitis. We report the clinical case of a young female with APMPPE that was complicated by stroke and intracranial hypertension. CASE REPORT: Our patient was a 16-year-old female who began with intense headaches suggesting intracranial hyper-tension, as well as with an acute deficit in the left hemisphere. A magnetic resonance scan of the head revealed embolic or vasculitic lesions in different territories. No evidence of meningoencephalitis was found in the cerebrospinal fluid analysis, but signs of associated intracranial hypertension were observed. The presence of very specific lesions in the posterior pole of the eye led to a diagnosis of APMPPE complicated by ischaemic stroke, probably caused by a vasculitic mechanism. An extensive aetiological study failed to identify a clear precipitating factor underlying the process. Treatment with corticoids was established, with good clinical and radiological progression. CONCLUSIONS: APMPPE is an infrequent condition that generally has a good prognosis. In some cases, however, complications may arise owing to involvement of the central nervous system, and ischaemic stroke secondary to vasculitis is the most severe complication. In young patients with stroke who present visual symptoms and chorioretinital lesions, APMPPE must be considered in the aetiological diagnosis.

TITLE: Epiteliopatia pigmentaria placoide multifocal posterior aguda. Una rara causa de ictus isquemico.Introduccion. La epiteliopatia pigmentaria placoide multifocal posterior aguda (EPPMPA) es una enfermedad inflamatoria rara, generalmente de etiologia indeterminada, de la coriocapilar, el epitelio pigmentario y la retina externa. Afecta predominantemente a pacientes jovenes y en algunos casos puede involucrar al sistema nervioso central en forma de ictus o de meningoencefalitis. Presentamos el caso clinico de una mujer joven con EPPMPA complicada con ictus e hipertension intracraneal. Caso clinico. Mujer de 16 anos que comienza con cefalea intensa sugestiva de hipertension intracraneal, asi como con un deficit agudo hemisferico izquierdo. La resonancia magnetica craneal ponia de manifiesto lesiones embolicas o vasculiticas en diferentes territorios. No se evidenciaron datos de meningoencefalitis en el estudio del liquido cefalorraquideo, pero si de hipertension intracraneal asociada. La presencia de lesiones muy especificas en el polo ocular posterior permitio el diagnostico de EPPMPA complicada con ictus isquemico, probablemente por mecanismo vasculitico. Un amplio estudio etiologico fue negativo para identificar un factor desencadenante claro del proceso. Se inicio tratamiento corticoideo con buena evolucion clinica y radiologica. Conclusiones. La EPPMPA es una entidad rara que generalmente entrana buen pronostico; sin embargo, en algunos casos puede complicarse con afectacion del sistema nervioso central, y el ictus isquemico secundario a vasculitis es la complicacion mas grave. Ante un paciente joven con ictus que presente sintomatologia visual y lesiones coriorretinianas, debe considerarse la EPPMPA en su diagnostico etiologico.

[Can the medication in patients with rheumatoidarthritis in remission be stopped?]. / ¿Se puede suspender la medicación en los pacientes con artritis reumatoide en remisión?

Rheumatoid arthritis is a chronic systemic inflammatory disease that causes significant morbidity and mortality. The combined use of methotrexate and biological agents directed against tumor necrosis factor (TNF) has achieved significant improvement in clinical, radiographic and functional parameters not seen previously and has revolutionized the therapeutic goal of achieving remission in clinical, structural and functional parameters. The next goal should be to achieve remission without the use of biological drugs and later without medication. Although there is evidence about the efficacy and safety of TNF inhibitors, there is none on remission without the use of biological agents or disease modifying drugs.

Use of nonmydriatic spectral-domain optical coherence tomography for diagnosing diabetic macular edema.

PURPOSE: To evaluate the accuracy of 3 spectral-domain (SD) optical coherence tomography (OCT) devices (Topcon 3D-1000 [Topcon]; Cirrus HD [Carl Zeiss Meditec, Inc], and Spectralis OCT [Heidelberg Engineering]) before and after mydriasis for the diagnosis of diabetic macular edema. DESIGN: Cross-sectional study. METHODS: Sixty-two eyes of 62 consecutive patients with diabetes without recent loss of vision referred for retinal control were assessed. Two scans were performed for each SD OCT instrument. Central retinal thickness was measured before and after pupil dilation. Pupil dynamic was studied using pMetrics pupillometer (iVIS Technologies), and lens opacity was measured by Pentacam densitometry (Oculus). The diagnostic accuracy of SD OCT devices was assessed by sensitivity, specificity, and area under the receiver operating characteristic curve. Logistic regression analysis was used to assess the effect of pupil size and lens opacity on the reliability of SD OCT in the acquisition of adequate images. RESULTS: The area under the receiver operating characteristic curve for the Topcon 3D OCT device was 0.84, that for the Cirrus HD OCT device was 0.93, and that for the Spectralis OCT device was 0.91. Significant differences in area under the receiver operating characteristic curve before and after pupillary dilatation were not found. Sensitivity and specificity associated with the cutoff value for the best performance were 82% and 74% for the Topcon 3D OCT device, 90% and 87% for the Cirrus HD OCT device, and 90% and 84% for the Spectralis OCT device, respectively. The Topcon 3D OCT device had an 11.3% segmentation algorithm failure rate for the central millimeter of the fovea, and the nuclear lens density was significantly greater in these eyes than in those without failure (17.1 ± 1.1 mm vs 10.4 ± 0.2 mm; P < .05). CONCLUSIONS: SD OCT is a useful tool to detect and to measure diabetic macular edema without the need for pupil dilatation.

Q-fever can simulate a lupus flare.

Fever is a diagnostic challenge in the patient with lupus. Infections can mimic a lupus flare which further complicates the diagnostic approach. Moreover, immunosuppressive treatment of SLE may promote the development of infections and poor outcome. We report the case of a patient with SLE with an initial diagnosis of lupus flare, who was found to have Q fever showing an excellent response to treatment with doxycycline.