The search for biomarkers for the early diagnosis of neurodegenerative diseases is a growing area. Numerous investigations are exploring minimally invasive and cost-effective biomarkers, with the ...detection of phosphorylated Tau (pTau) protein emerging as one of the most promising fields. pTau is the main component of the paired helical filaments found in the brains of Alzheimer’s disease cases and serves as a precursor in the formation of neurofibrillary tangles (NFTs). Recent research has revealed that analysis of p-Tau181, p-Tau217 and p-Tau231 in blood may be an option for detecting the preclinical stage of Alzheimer’s disease. In this study, we have analyzed the values of pTau 181 in the serum of Syrian hamsters during hibernation. Naturally, over the course of hibernation, these animals exhibit a reversible accumulation of pTau in the brain tissue, which rapidly disappears upon awakening. A biosensing system based on the interferometric optical detection method was used to measure the concentration of pTau181 protein in serum samples from Syrian hamsters. This method eliminates the matrix effect and amplifies the signal obtained by using silicon dioxide nanoparticles (SiO2 NPs) biofunctionalized with the αpTau181 antibody. Our results indicate a substantial increase in the serum concentration of pTau in threonine-181 during hibernation, which disappears completely 2–3 h after awakening. Investigating the mechanism by which pTau protein appears in the blood non-pathologically may enhance current diagnostic techniques. Furthermore, since this process is reversible, and no tangles are detected in the brains of hibernating hamsters, additional analysis may contribute to the discovery of improved biomarkers. Additionally, exploring drugs targeting pTau to prevent the formation of tangles or studying the outcomes of any pTau-targeted treatment could be valuable.
Objectives: To analyze the characteristics and the predictive factors of the use of rituximab and belimumab in daily practice in patients from the inception cohort Registro Español de Lupus (RELES). ...Material and methods: The study included 518 patients. We considered patients treated with biologics who received at least one dose of rituximab or belimumab, and possible indications of those manifestations registered at the same time or in the previous 2 months of the start of the therapy. Results: In our cohort, 37 (7%) patients received at least one biological treatment. Rituximab was prescribed in 26 patients and belimumab in 11. Rituximab was mainly prescribed for hemolytic anemia or thrombocytopenia (11 patients, 42%), lupus nephritis and neuropsychiatric lupus (5 patients each, 19%). Belimumab was mostly used for arthritis (8 patients, 73%). In the univariate analysis, the predictive factors at diagnosis for the use of biologic therapy were younger age (p = 0.022), a higher SLEDAI (p = 0.001) and the presence of psychosis (p = 0.011), organic mental syndrome (SOCA) (p = 0.006), hemolytic anemia (p = 0.001), or thrombocytopenia (p = 0.01). In the multivariant model, only younger age, psychosis, and hemolytic anemia were independent predictors of the use of biologics. Conclusions: Rituximab is usually given to patients with hematological, neuropsychiatric and renal involvement and belimumab for arthritis. Psychosis, hemolytic anemia and age at the diagnosis of lupus were independent predictive factors of the use of biological agents. Their global effects are beneficial, with a significant reduction in SLE activity and a low rate of side effects.
Objectives
Using data of patients from the inception cohort Registro Español de Lupus Eritematoso Sistémico (RELES), we aimed to analyse the incidence of severe infection in the first two years of ...follow-up and how predictors of infection change during the course of systemic lupus erythematosus (SLE).
Material and methods
The study included 282 patients. Markers of lupus activity, prednisone doses and immunosuppressive therapy were compared between patients with and without infections in the first and second year of the disease. Drug therapy administered during the first month of follow-up has been considered as a potential predictor of infections during the first year and medications administered during the first year have been considered potential predictors of infections during the second.
Results
Nineteen patients (6.4%) had a documented episode of major infection during the first year of follow-up and 16 patients (5.67%) during the second. The following variables were associated with infections during the first year: hypocomplementaemia at diagnosis (p < 0.01), nephritis at diagnosis (p = 0.03), SLEDAI score (p < 0.01), prednisone >30 mg/day (p = 0.01), methylprednisolone pulses (p = 0.05) and mycophenolate use (p = 0.02). The independent variables in the final model were hypocomplementaemia (odds ratio (OR) 4.41, 95% confidence interval (CI) 0.96–20.20, p = 0.05) and a dose of prednisone >30 mg/day (OR 6.60, 95% CI 1.34–32.42, p = 0.02). The following variables were associated with infections during the second year: dose of prednisone > 7.5 mg/day (p = 0.05), methylprednisolone pulses (p = 0.07), duration of therapy with antimalarials (p = 0.09), therapy with mycophenolate (p = 0.01), therapy with cyclophosphamide (p = 0.05). The independent variables in the final model were a dose of prednisone >7.5 mg/day (OR 4.52, 95% CI 0.99–21, p = 0.054) and duration of therapy with antimalarials as a protective factor (OR 0.99, 95% CI 0.99–1.00, p = 0.053).
Conclusions
The low incidence of early infections in the RELES cohort is partially explained by the extended use of antimalarials and by the general avoidance of prolonged high doses of prednisone. Patients with high baseline activity are at a higher risk of infection during the first months but therapy with medium–high doses of prednisone is the main predictor of infectious events. Thus, every effort should be made to limit oral glucocorticoid use from the very beginning of the SLE course.
Currently employed in aerospace, defense, oil, and gas applications, Inconel 718 (IN718) is an indispensable alloy with excellent thermo-mechanical properties and hot corrosion resistance. Inconel ...(IN718) has become the gold standard to manufacture turbine blades, bearing housing parts, compressor seals, drive couple gears, side pocket mandrels, wellheads, packers, and safety valves. Additive Manufacturing (AM) or 3D printing technology is a promising alternative to fabricate and repair nickel-based superalloy components, characterized by challenging processing through conventional methods due to the mechanical strength of the alloys or the geometric complexity of the piece. Furthermore, many applications require surface protection features, such as high hardness, corrosion, and wear resistance. These properties can be achieved by applying hard coatings and/or surface thermochemical treatments such as plasma nitriding. This study reports the effect of plasma nitriding applied on Laser Powder Bed Fusion (LPBF) additively manufactured IN718. Depending on the time, the treatment produced a 1.5–2.8 μm nitrided protective bi-layer composed by an outer CrN containing layer followed by an inner austenitic expanded γN layer. The growing kinetics analysis shows that the nitriding process follows a parabolic behavior. The nitriding process also increases the surface roughness as a result of case hardening formation reaching ~ 60 nm within 2 h. No measurable wear on the plasma nitrided additively manufactured IN718 alloy was recorded.
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•Homogeneous nitrided bi-layer was built on additively manufactured IN718 upon plasma nitriding.•There is a linear growing of the nitrided layer indicating that the process was limited by N-diffusion.•The results suggest the formation of a Cr-depleted phase through the reaction γN ➔ γCr-depleted + c-CrN nano-grains.•No wear was measured on the plasma nitrided additively manufactured IN718.
Objectives
We performed a network meta‐analysis of PEP randomized clinical trials to evaluate the best regimen.
Methods
After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) ...comparing at least 2 PEP three‐drug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavir‐boosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistat‐boosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP non‐completion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to follow‐up and adverse events.
Results
Participants were mostly men who have sex with men (n = 832, 75%) with non‐occupational exposure to HIV (89.86%). Four‐hundred fifty‐four (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP non‐completion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58–1.56; EVG/c: OR 0.65 95% CI 0.30–1.37; RAL: OR 0.68 95% CI 0.41–1.13; and MVC: OR 0.69 95% CI 0.47–1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP non‐completion at day 28, switching, lost to follow‐up or adverse events and MVC for PEP discontinuations due to adverse events.
Conclusions
Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a Single‐Tablet Regimen.
Resumen
La enfermedad de Alzheimer (EA) es la forma más común de demencia y tiene una elevada morbilidad y mortalidad. La EA se caracteriza principalmente por la presencia de dos estructuras ...aberrantes en el cerebro de los pacientes, placas seniles formadas por péptido-β-amiloide (Aβ) y ovillos neurofibrilares cuyo principal componente es la proteína tau fosforilada. Aunque actualmente no se conoce bien la etiopatogenia, cada vez son más los estudios que demuestran un efecto causal del microbioma intestinal sobre la EA y las funciones cognitivas, a través del "eje microbiota intestino-cerebro". Las evidencias científicas sugieren un posible efecto protector de los polifenoles del vino frente a los trastornos neurodegenerativos aunque se desconocen los mecanismos y, hasta el momento, los estudios para evaluar de forma exhaustiva el efecto del vino sobre la etiopatogenia de la EA son muy escasos. El objetivo principal de la línea de investigación que enmarca este trabajo es entender cómo la dieta, y especialmente los polifenoles presentes en los alimentos vegetales, y otros factores del estilo de vida interactúan con el microbioma oral e intestinal, en relación con la salud digestiva y el deterioro cognitivo. Para ello, se está llevando a cabo una aproximación experimental que tiene como finalidad evaluar el posible efecto protector de los polifenoles del vino, mediante la suplementación de la dieta en dos modelos murinos de la EA (patología Aß y Tau), y, por otro lado, se está profundizando en el estudio de los mecanismos de protección mediante la evaluación de los efectos del ácido protocatéquico sobre la actividad eléctrica del cerebro.
Alzheimer's disease (AD) is the most common form of age-related dementia with high morbidity and mortality. AD is mainly characterized by the presence of two aberrant structures in the brain of patients, senile plaques formed by peptide-β-amyloid (Aβ) and neurofibrillary tangles whose main component is phosphorylated tau protein. Although the etiopathogenesis is currently not well understood, an increasing number of studies demonstrate a causal effect of the gut microbiome on AD and cognitive functions, through the "gut-brain microbiota axis". Scientific evidence suggests a possible protective effect of wine polyphenols against neurodegenerative disorders although the mechanisms are unknown and, so far, studies to evaluate comprehensively the effect of wine on the etiopathogenesis of AD are very scarce. The main objective of the research line that frames this work is to understand how diet, and especially the polyphenols present in plant foods, and other lifestyle factors interact with the oral and intestinal microbiome in relation to digestive health and cognitive impairment. To this end, an experimental approach is being carried out to evaluate the possible protective effect of wine polyphenols through dietary supplementation in two murine models of AD (Aß and Tau pathology), and, on the other hand, the study of the protective mechanisms is being deepened by evaluating the effects of protocatechuic acid on the electrical activity of the brain.
Resumen Introducción La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in ...vitro. Material y métodos Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43 días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82 días tras la cirugía. Resultados Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobre expresión de cistatina C, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B. Conclusiones Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad.
INTRODUCTIONPatient registries are useful tools for assessing rare diseases. Our objective is to present the Spanish registry of patients with systemic lupus erythematosus (Registro español de ...pacientes con lupus eritematoso sistémico, RELES). PATIENTS AND METHODSRELES was started in 2008 as an observational, prospective, multicentre cohort registry that included patients from the time they were diagnosed. The registry's objective is to analyse the incidence and noninflammatory complications of systemic lupus erythematosus (SLE). The departments of internal medicine of 38 Spanish hospitals participate in this registry. RESULTSA total of 298 patients with a mean age of 40.8±15.7 years were included, 88.9% of whom were women and 85.6% of whom were white. In the first visit, there was a predominance of joint manifestations (74.5%). One hundred and seventy-seven patients (59.4%) were positive for anti-native DNA. In these patients, there was a higher rate of lupus nephritis (26.7% vs. 14%, p=.009; relative risk RR, 1.33), haemolytic anaemia (13.6% vs. 4.1%, p=.07; RR, 1.46) and lymphopenia (55.4% vs. 43.8%, p=.05; RR, 1.21). The median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) score was 9.64 points (interquartile range, 4-13). The patients treated with antimalarial drugs before the diagnosis of SLE had a median SLEDAI score in the first visit of 5, compared with 8 for those who were not treated with these drugs (p=.02). CONCLUSIONSRELES constitutes the first Spanish patient cohort with SLE recorded from the time of the diagnosis. The presence of anti-DNA has been related to severe manifestations such as nephritis and haemolytic anaemia. Treatment with antimalarial drugs before the diagnosis was associated with less active disease at the initial presentation.
AimTo study the influence of prednisone dose during the first month after systemic lupus erythematosus (SLE) diagnosis (prednisone-1) on glucocorticoid burden during the subsequent 11 months ...(prednisone-2–12).Methods223 patients from the Registro Español de Lupus Eritematoso Sistémico inception cohort were studied. The cumulative dose of prednisone-1 and prednisone-2–12 were calculated and recoded into a four-level categorical variable: no prednisone, low dose (up to 7.5 mg/day), medium dose (up to 30 mg/day) and high dose (over 30 mg/day). The association between the cumulative prednisone-1 and prednisone-2–12 doses was tested. We analysed whether the four-level prednisone-1 categorical variable was an independent predictor of an average dose >7.5 mg/day of prednisone-2–12. Adjusting variables included age, immunosuppressives, antimalarials, methyl-prednisolone pulses, lupus nephritis and baseline SLE Disease Activity Index (SLEDAI).ResultsWithin the first month, 113 patients (51%) did not receive any prednisone, 24 patients (11%) received average low doses, 46 patients (21%) received medium doses and 40 patients (18%) received high doses. There was a strong association between prednisone-1 and prednisone-2–12 dose categories (p<0.001). The cumulative prednisone-1 dose was directly associated with the cumulative prednisone-2–12 dose (p<0.001). Compared with patients on no prednisone, patients taking medium (adjusted OR 5.27, 95% CI 2.18 to 12.73) or high-dose prednisone-1 (adjusted OR 10.5, 95% CI 3.8 to 29.17) were more likely to receive prednisone-2–12 doses of >7.5 mg/day, while patients receiving low-dose prednisone-1 were not (adjusted OR 1.4, 95% CI 0. 0.38 to 5.2). If the analysis was restricted to the 158 patients with a baseline SLEDAI of ≥6, the model did not change.ConclusionThe dose of prednisone during the first month after the diagnosis of SLE is an independent predictor of prednisone burden during the following 11 months.
Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons.
We selected CSF with previously reported cytotoxic effects ...from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82days after surgery.
Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatin C, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins.
Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease.
La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in vitro.
Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82días tras la cirugía.
Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobreexpresión de cistatinaC, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B.
Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad.
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