Optimizing outcomes with maintenance IV UST in highly bio-exposed patients with IBD. Efficacy and Adjusted Regimen in Real World.

BACKGROUND AND AIMS: Ustekinumab is an effective treatment for inflammatory bowel diseases. However, some patients do not respond to conventional doses. The aim of the study was to evaluate the effectiveness of intravenous maintenance Ustekinumab in patients with secondary failure. METHODS: Single-center, retrospective study in adult patients with intravenous maintenance ustekinumab. The reduction of biochemical activity markers, ustekinumab trough levels and clinical indices of activity were evaluated. Biological remission was defined as the percentage decrease fecal calprotectin ≥ 80% and/or final fecal calprotectin ≤ 250 and C reactive protein < 5mg/L. RESULTS: 31 patients were included: Crohn's disease 77.4%. All included patients were bio-exposed and 61.3% had carried ≥ 2 biologics. Pre-intravenous maintenance mean Harvey-Bradshaw Index was 6.5±4,38 vs 5±3,1 at week 8 (p=0.024) vs 4.1±3.1 at week 24 (p=0.019). The median ustekinumab trough levels pre-intravenous maintenance were 1.40µg/ml [IQR 2.3] vs 5.35µg/ml [IQR 4.1] at week 8 (p<0.001) vs 4.8µg/ml [IQR 3.9] at week 24 (p<0.001). The pre-intravenous maintenance median fecal calprotectin was 809µg/g [IQR: 2256] vs 423µg/g [IQR: 999] at week 8 (p=0.025) vs 333µg/g [508] (p=0.001) at week 24. At the end of follow-up 48% went into biological remission. The presence of perianal disease was associated with lower biological remission (70.6% vs 27.3%, p=0.025). Median intravenous ustekinumab maintenance time was 8.55 [IQR 23.9] months. In 83.9% of patients no serious infections or malignancy were documented. CONCLUSIONS: The use of maintenance intravenous ustekinumab appears to be an effective and safe strategy that can be evaluated as a salvage treatment especially in highly bioexposed patients.

Anisotropic Spin-Acoustic Resonance in Silicon Carbide at Room Temperature.

We report on acoustically driven spin resonances in atomic-scale centers in silicon carbide at room temperature. Specifically, we use a surface acoustic wave cavity to selectively address spin transitions with magnetic quantum number differences of ±1 and ±2 in the absence of external microwave electromagnetic fields. These spin-acoustic resonances reveal a nontrivial dependence on the static magnetic field orientation, which is attributed to the intrinsic symmetry of the acoustic fields combined with the peculiar properties of a half-integer spin system. We develop a microscopic model of the spin-acoustic interaction, which describes our experimental data without fitting parameters. Furthermore, we predict that traveling surface waves lead to a chiral spin-acoustic resonance that changes upon magnetic field inversion. These results establish silicon carbide as a highly promising hybrid platform for on-chip spin-optomechanical quantum control enabling engineered interactions at room temperature.

Current and emerging avenues for Alzheimer's disease drug targets.

Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aß) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aß and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.

Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Acoustically driven arrayed waveguide grating.

We demonstrate compact tunable phased-array wavelength-division multiplexers driven by surface acoustic waves (SAWs) in the low GHz range. The devices comprise two couplers, which respectively split and combine the optical signal, linked by an array of single-mode waveguides (WGs). Two different layouts are presented, in which multi-mode interference couplers or free propagating regions were separately employed as couplers. The multiplexers operate on five equally distributed wavelength channels, with a spectral separation of 2 nm. A standing SAW modulates the refractive index of the arrayed WGs. Each wavelength component periodically switches paths between the output channel previously asigned by the design and the adjacent channels, at a fixed applied acoustic power. The devices were monolithically fabricated on (Al,Ga)As. A good agreement between theory and experiment is achieved.

Resistance training does not have an effect on cognition or related serum biomarkers in nonagenarians: a randomized controlled trial.

The aim of this randomized controlled trial was to determine the effects of 8-week exercise-intervention on cognition and related serum biochemical markers in nonagenarians. We also studied the effects of a 4-week training cessation ('detraining') period on our study variables. Participants were randomly allocated to a standard-care (control) or intervention (exercise) group [n=20 (16 women)/group]. The intervention focused on supervised, light-to-moderate-intensity aerobic and resistance exercises (mainly leg press), and included 3 weekly sessions. Cognitive status was determined by the mini-mental state examination and geriatric depression scale. We analysed proteins with reported relation with mechanisms behind cognition changes such as serum levels of angiotensin converting enzyme, amyloid-precursor protein, epidermal growth factor, brain-derived neural factor and tumor necrosis factor. No significant change (P>0.05) in any of the variables studied was found following the exercise intervention compared with the standard-care group. Similarly, no significant changes (P>0.05) were observed following the detraining period compared with the standard-care group. Overall changes after the exercise intervention in serum biomarkers were not associated with changes in functional capacity and cognitive measures. An 8-week exercise intervention focusing on resistance exercises neither benefits cognitive function nor affects the levels of the serum proteins analysed in nonagenarians.

Pathways to Alzheimer's disease.

Recent trials of anti-amyloid agents have not produced convincing improvements in clinical outcome in Alzheimer's disease; however, the reason for these poor or inconclusive results remains unclear. Recent genetic data continue to support the amyloid hypothesis of Alzheimer's disease with protective variants being found in the amyloid gene and both common low-risk and rare high-risk variants for disease being discovered in genes that are part of the amyloid response pathways. These data support the view that genetic variability in how the brain responds to amyloid deposition is a potential therapeutic target for the disease, and are consistent with the notion that anti-amyloid therapies should be initiated early in the disease process.

High-frequency acoustic charge transport in GaAs nanowires.

The oscillating piezoelectric fields accompanying surface acoustic waves are able to transport charge carriers in semiconductor heterostructures. Here, we demonstrate high-frequency (above 1 GHz) acoustic charge transport in GaAs-based nanowires deposited on a piezoelectric substrate. The short wavelength of the acoustic modulation, smaller than the length of the nanowire, allows the trapping of photo-generated electrons and holes at the spatially separated energy minima and maxima of conduction and valence bands, respectively, and their transport along the nanowire with a well defined acoustic velocity towards indium-doped recombination centers.

Acoustically driven photon antibunching in nanowires.

The oscillating piezoelectric field of a surface acoustic wave (SAW) is employed to transport photoexcited carriers, as well as to spatially control exciton recombination in GaAs-based nanowires (NWs) on a subns time scale. The experiments are carried out in core-shell NWs transferred to a SAW delay line on a LiNbO(3) crystal. Carriers generated in the NW by a focused laser spot are acoustically transferred to a second location, leading to the remote emission of subns light pulses synchronized with the SAW phase. The dynamics of the carrier transport, investigated using spatially and time-resolved photoluminescence, is well-reproduced by computer simulations. The high-frequency contactless manipulation of carriers by SAWs opens new perspectives for applications of NWs in opto-electronic devices operating at gigahertz frequencies. The potential of this approach is demonstrated by the realization of a high-frequency source of antibunched photons based on the acoustic transport of electrons and holes in (In,Ga)As NWs.

Electrical suppression of spin relaxation in GaAs(111)B quantum wells.

Spin dephasing via the spin-orbit interaction (SOI) is a major mechanism limiting the electron spin lifetime in III-V zincblende quantum wells (QWs). The dephasing can be suppressed in GaAs(111) quantum wells by applying an electric field. The suppression has been attributed to the compensation of the intrinsic SOI associated with the bulk inversion asymmetry of the GaAs lattice by a structural induced asymmetry SOI term induced by an electric field. We provide direct experimental evidence for this mechanism by demonstrating the transition between the bulk inversion asymmetry-dominated to a structural induced asymmetry-dominated regime via photoluminescence measurements carried out over a wide range of applied fields. Spin lifetimes exceeding 100 ns are obtained near the compensating electric field, thus making GaAs(111) QWs excellent candidates for the electrical storage and manipulation of spins.

Guidelines for enhanced recovery after cardiac surgery. Consensus document of Spanish Societies of Anesthesia (SEDAR), Cardiovascular Surgery (SECCE) and Perfusionists (AEP). / Vía clínica de recuperación intensificada en cirugía cardiaca. Documento de consenso de la Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor (SEDAR), la Sociedad Española de Cirugía Cardiovascular y Endovascular (SECCE) y la Asociación Española de Perfusionistas (AEP).

The ERAS guidelines are intended to identify, disseminate and promote the implementation of the best, scientific evidence-based actions to decrease variability in clinical practice. The implementation of these practices in the global clinical process will promote better outcomes and the shortening of hospital and critical care unit stays, thereby resulting in a reduction in costs and in greater efficiency. After completing a systematic review at each of the points of the perioperative process in cardiac surgery, recommendations have been developed based on the best scientific evidence currently available with the consensus of the scientific societies involved.

Fibrin glue treatment associated or not with diathermy for recurrent tracheoesophageal fistula: our results after more than 20 years' experience. / Tratamiento con adhesivo de fibrina asociado o no a diatermia para las fístulas traqueoesofágicas recurrentes: resultados tras más de 20 años de experiencia.

INTRODUCTION: Recurrent tracheoesophageal fistula (RTEF) is a frequent complication (5-10%) in patients with esophageal atresia (EA). Open RTEF surgery has a high morbidity and mortality, so the endoscopic approach represents a promising alternative. We present the long-term results of fibrin glue (FG) bronchoscopic application in patients with RTEF secondary to EA, which was first used by our team in 1994. MATERIAL AND METHODS: A retrospective review of all patients diagnosed with RTEF following EA repair and treated with FG bronchoscopic application from 1993 to 2019 was carried out. In most cases, diathermy was applied prior to FG sealing. The maximum number of endoscopic sessions was 5. In case of persistent RTEF following the fifth session, open surgery was performed. RESULTS: 14 RTEF patients were treated with FG. In all but the first 3 cases (11 patients, 78.6%), diathermy was applied concomitantly. Mean first treatment day was day 85 of life (range: 14-770). Patients received a mean of 2.1 (1-5) endoscopic sessions. Mean follow-up was 12.1 (10-20) years. Overall success rate was 71.4%, without significant differences according to whether diathermy was concomitantly applied or not (72.7% vs. 66.6%). CONCLUSIONS: Fibrin glue bronchoscopic application associated or not associated with diathermy is an excellent option for RTEF treatment in EA patients. The endoscopic approach should be considered as the first-choice treatment for RTEF.

INTRODUCCION: La fístula traqueoesofágica recurrente (FTER) representa una complicación frecuente (5-10%) en los pacientes con atresia de esófago (AE). La cirugía abierta de FTER implica una alta morbimortalidad, por lo que los abordajes endoscópicos suponen una alternativa prometedora. Presentamos los resultados a largo plazo de la aplicación broncoscópica de adhesivo de fibrina (AF) en pacientes con FTER secundaria a AE, técnica utilizada por primera vez en 1994 por nuestro equipo. METODOS: Revisión retrospectiva de 1993 a 2019, incluyendo a todos los pacientes diagnosticados de FTER tras la reparación de AE, y tratados con aplicación broncoscópica de AF. En la mayoría de los casos se aplicó diatermia previamente al sellado con AF. El número máximo de sesiones endoscópicas se estableció en cinco; en caso de persistir FTER tras la quinta sesión, se procedió a cirugía abierta. RESULTADOS: 14 pacientes con FTER fueron tratados con AF; en todos salvo los primeros 3 casos (11 pacientes, 78,6%) se aplicó diatermia concomitante. El día promedio del primer tratamiento fue el día 85 de vida (14 a 770). Los pacientes recibieron una media de 2,1 (1-5) sesiones endoscópicas. El seguimiento medio fue de 12,1 (10-20) años. El éxito global fue del 71,4%, sin apenas variar con la aplicación o no de diatermia concomitante (72,7% vs. 66,6%). CONCLUSIONES: La aplicación broncoscópica de adhesivo de fibrina asociado o no a diatermia representa una excelente opción para el tratamiento de FTER en pacientes con AE. El abordaje endoscópico debe considerarse como tratamiento de primera elección para FTER.

[Adaptive functioning in adults with intellectual deficiency: Role of skills during childhood, age, and IQ in a preliminary study of 16 adults]. / Étude du fonctionnement adaptatif d'adultes présentant une déficience intellectuelle : rôles des apprentissages réalisés dans l'enfance, de l'âge et du quotient intellectuel ; étude préliminaire observationnelle de 16 adultes.

The objective of this study was to investigate the adaptive functioning of adults who had a slight to moderate intellectual deficiency, in regard of age and intellectual quotient (IQ). Cognitive and adaptive functioning were evaluated using the WAIS and VINELAND scales in 16 adults who accepted to participate in this study. We found a correlation between global IQ and each domain of the adaptive score, mostly communication skills. We also found that there was an age effect on socialization skills. Most skills were learned during infancy and adolescence, especially communication skills, which are highly stable at different ages and highly correlated with IQ. However, some abilities are still acquired in adulthood, mostly socialization skills, especially in persons with the lowest IQ. These data are of particular interest for people caring for disabled adults.

Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer's disease.

Strong evidence indicates oxidative stress in the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Abeta) has been implicated in both oxidative stress mechanisms and in neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) are antioxidants that can inhibit apoptosis signal-regulating kinase (ASK1). We examined levels of GRX1 and TRX1 in AD brain as well as their effects on Abeta neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that Abeta causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Abeta toxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, Abeta neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. Deregulation of GRX1 and TRX1 antioxidant systems could be important events in AD pathogenesis.

[Neuropsychological impairment in patients with intracranial aneurysms: surgical versus endovascular treatment]. / Alteraciones neuropsicológicas en pacientes con aneurismas cerebrales: tratamiento quirúrgico versus tratamiento endovascular.

OBJECTIVES: To describe the neuropsychological status of patients with intracranial aneurysms and to compare the cognitive status of patients with intracranial aneurysm treated by surgical or endovascular methods. MATERIAL AND METHODS: Ninety-three cases with intracranial aneurysms treated with surgery (n = 56) or embolization (n = 37) were included. A neuropsychological assessment was applied to both groups retrospectively, at least one year after treatment. RESULTS: Neuropsychological impairment was found in both groups. 35.7% of the patients treated with surgery and 43.2%, of those treated with embolization did not show any cognitive impairment. Visual Memory and Cued Recall of verbal information are better in patients treated by embolization. CONCLUSIONS: Our results show that a large proportion of patients with intracranial aneurysms have cognitive impairment after treatment. Endovascular management may cause less impairment in visual and verbal memory. However, bleeding may be the most important factor to explain these cognitive impairments.

Protein kinase C and amyloid precursor protein processing in skin fibroblasts from sporadic and familial Alzheimer's disease cases.

Non-amyloidogenic alpha-secretase processing of amyloid precursor protein (APP) is stimulated by protein kinase C (PKC). Levels and activity of PKC are decreased in sporadic Alzheimer's disease skin fibroblasts. We investigated whether alterations in PKC and PKC-mediated APP processing occur also in fibroblasts established from individuals with familial Alzheimer's disease APP KM670/671NL, PS1 M146V and H163Y mutations. These pathogenic mutations are known to alter APP metabolism to increase Abeta. PKC activities, but not levels, were decreased by 50% in soluble fractions from sporadic Alzheimer's disease cases. In contrast, familial Alzheimer's disease fibroblasts showed no significant changes in PKC enzyme activity. Fibroblasts bearing the APP KM670/671NL mutation showed no significant differences in either PKC levels or PKC-mediated soluble APP (APPs) secretion, compared to controls. Fibroblasts bearing PS1 M146V and H163Y mutations showed a 30% increase in soluble PKC levels and a 40% decrease in PKC-mediated APPs secretion. These results indicate that PKC deficits are unlikely to contribute to increased Abeta seen with APP and PS1 mutations, and also that PS1 mutations decrease alpha-secretase derived APPs production independently of altered PKC activity.

[The value of the internal capsule signs in the stimulation of the subthalamic nucleus in Parkinson's disease]. / Valor de los signos de cápsula interna en la estimulación del núcleo subtalámico de la enfermedad de Parkinson.

INTRODUCTION: The effectiveness of stimulating the subthalamic nucleus (DBS-STN) in advanced Parkinson's disease (PD) largely depends on the correct placement of the electrodes. Since the sensory-motor region of the STN lies beside the internal capsule (IC), we believe that the motor effectiveness of DBS-STN could be related to the stimulation threshold in which IC signs appear (IC threshold). PATIENTS AND METHODS: An examination of 17 consecutive patients with advanced PD who had been submitted to bilateral DBS-STN (one case was unilateral) was carried out to determine the motor improvement on each side of the body (n = 33) and the energy consumption one year after surgery according to the IC threshold obtained during the programming. RESULTS: A 45% improvement was observed in the UPDRS III in off and there was a 24% reduction in the equivalent dose of levodopa with bilateral DBS-STN. When the electrodes were considered, there was a statistically significant improvement that depended on the IC threshold. Energy consumption differed significantly between electrodes with an IC threshold of 3-7 V (1.5 +/- 1.2 microW) and those with an IC threshold > 7 V (8.3 +/- 9.4 microW). CONCLUSIONS: During the stimulation phase and following the correct location of the STN, which was achieved by neurophysiological recording, the IC threshold has prognostic implications in medium-long term motor effectiveness and in the consumption of the battery in the generator.

[Thrombolysis in stroke: inappropriate consideration of the 'window period' as the time available]. / Trombólisis en el ictus: consideración inapropiada del 'período de ventana' como tiempo disponible.

AIMS: The earlier r-TPA is administered in ischaemic strokes, the more effective it is. The aim of this study is to analyse the delay times in health care afforded in a consecutive series of cases that had received treatment, with a view to shortening them. PATIENTS AND METHODS: We analysed the medical records of the first patients to be treated in our centre. The paper describes several variables involving demographic and clinical factors, as well as the delay in entering the Emergency department, performing a CAT scan and especially the time elapsed between the CAT scan and starting treatment. We have examined the existence of an inappropriate correlation between delays that should be independent of one another. RESULTS: The mean age of the 17 patients treated was 68 years and they had a stroke severity score of 17 points on the NIHSS. The mean time of delay until arrival, arrival-CAT, and CAT-treatment were slightly under 1 hour each, and onset-treatment delay was 165 minutes, which is very close to the limit of the therapeutic window period. We found a strong inverse linear association between the time elapsed between onset and the CAT scan, and from the latter to the beginning of treatment (Spearman's r: -0.664, p = 0.004). CONCLUSIONS: Findings indicate that in our hospital, as in other centres in the initial phases of implementation, the therapeutic time window for intravenous thrombolysis in ischaemic stroke tends to run out. It must be highlighted that the resolve of the physician who indicates the treatment exerts a decisive effect on the delay.

Apolipoprotein E isoform-specific disruption of phosphoinositide hydrolysis: protection by estrogen and glutathione.

The mechanism(s) by which the E4 isoform of apolipoprotein E (apoE4) influences Alzheimer's disease (AD) are not fully known. We report that apoE4, but not apoE3, disrupts carbachol-stimulated phosphoinositide (PI) hydrolysis in SH-SY5Y neuroblastoma cells. Carbachol responses were also disrupted by beta-amyloid (Abeta) (1-42) and apoE4/Abeta(1-42) complexes, but not by apoE3/Abeta(1-42). Glutathione and estrogen protected against apoE4 and Abeta(1-42) effects, as well as those of H(2)O(2). Estrogen protection was partially blocked by wortmannin, suggesting the involvement of phosphatidylinositol 3-kinase. An apoE4-induced disruption of acetylcholine muscarinic receptor-mediated signalling may explain the lower effectiveness of cholinergic replacement treatments in apoE4 AD patients. Also, the beneficial effect of estrogen in AD may be partially due to its ability to protect against apoE4- and Abeta(1-42)-mediated disruption of PI hydrolysis.

Apolipoprotein E and beta A4-amyloid: signals and effects.

In humans, the apolipoprotein E gene (APOE) is polymorphic with the alleles APOE epsilon 2, 3 and 4 coding for apolipoproteins (Apo) E2, 3 and 4. Apart from age, the APOE epsilon 4 allele represents the most important risk factor in sporadic Alzheimer's disease (AD). Compared to APOE epsilon 3 homozygotes, the histopathological onset of tau pathology is found 1-2 decades earlier but progresses with the same speed. ApoE dose-dependently and specifically increases free intraneuronal calcium levels in the order ApoE4 > ApoE3 > ApoE2. This effect is amplified in the presence of beta A4-peptide. The ApoE effects on calcium are not affected by the blockade of action potentials with tetrodotoxin, or by inhibition of common ApoE binding sites. The calcium channel involved has been identified as a P/Q-type-like channel. Brain tissue ApoE levels differ with respect to APOE alleles and Braak-stage for Alzheimer-histopathology. The production of ApoE in astrocytes is controlled by several receptor/effector systems such as adrenoceptors and cAMP. In the presence of beta A4-peptide fragments, astrocytes stop their synthesis of ApoE resulting in a massive reduction in the bioavailability of ApoE. In the periphery, ApoE directs cholesterol transport and thereby influences its cellular concentrations. In neurons, changes in the concentration of cholesterol influence the phosphorylation status of the microtubule-associated protein tau at sites known to be altered in AD.