ADHD Adults Show Lower Interindividual Similarity in Ex-Gaussian Reaction Time Vectors for Congruent Stimuli Compared to Control Peers.

OBJECTIVE: Interindividual similarity refers to how similarly individuals respond when receiving the same stimulus or intervention. In this study, we aimed to examine interindividual similarity in adults with ADHD. METHOD: We used the cosine similarity index of ex-Gaussian reaction time (RT) vectors of mu, sigma, and tau parameters during a Stroop task. RESULTS: Our results demonstrate that the ADHD group exhibits a reduced interindividual similarity index in their ex-Gaussian RT vectors for congruent stimuli compared to the healthy control group. Importantly, we did not find significant differences in the interindividual similarity index to incongruent stimuli between both groups, thus suggesting that this reduced index was selective for congruent stimuli. CONCLUSION: Our findings highlight that ADHD adults exhibit more significant interindividual differences in cognitive functioning when processing congruent stimuli than healthy controls. These results provide new insights into the selective mechanisms underlying ADHD and may contribute to developing new targeted interventions for this disorder.

Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.

Hyaluronic acid (HA), through its interactions with the cluster of differentiation 44 (CD44), acts as a potent modulator of the tumor microenvironment, creating a wide range of extracellular stimuli for tumor growth, angiogenesis, invasion, and metastasis. An innovative antitumor treatment strategy based on the development of a nanodevice for selective release of an inhibitor of the HA-CD44 interaction is presented. Computational analysis was performed to evaluate the interaction of the designed tetrahydroisoquinoline-ketone derivative (JE22) with CD44 binding site. Cell viability, efficiency, and selectivity of drug release under acidic conditions together with CD44 binding capacity, effect on cell migration, and apoptotic activity were successfully evaluated. Remarkably, the conjugation of this CD44 inhibitor to the nanodevice generated a reduction of the dosis required to achieve a significant therapeutic effect.

Antipsychotic-Associated Weight Gain and Clinical Improvement Under Clozapine Treatment.

BACKGROUND: Antipsychotic-associated weight gain is a common adverse effect with several negative outcomes in the clinical evolution of patients, which might also affect patients' self-identity from physical appearance and imply treatment discontinuation. However, recent research has drawn attention to an unexpected clinical improvement associated with weight gain, mostly in patients under treatment with clozapine or olanzapine. METHODS: Twenty-three treatment-resistant psychosis patients initiating clozapine were evaluated. Longitudinal psychopathological assessment through the Positive and Negative Syndrome Scale (PANSS) and anthropometric evaluation were performed at baseline, week 8, and 18. RESULTS: Body mass index (BMI) change during clozapine treatment was associated with clinical improvement measured with PANSS total score at week 8 (P = 0.021) while showed a trend at week 18 (P = 0.058). The PANSS general score was also associated with weight gain at week 8 (P = 0.022), whereas negative subscale score showed a trend at week 8 (P = 0.088) and was associated between week 8 and 18 (P = 0.018). Sex differences applied at week 8 for PANSS total score, where clinical improvement was significantly associated with BMI in male subjects (P = 0.024). We also stratified for time to initiate clozapine, finding significant associations in negative symptom at week 8 (P = 0.023) and week 18 (P = 0.003) for subjects, which started clozapine after 3 years of illness. CONCLUSIONS: Our results suggest that in subjects initiating clozapine, clinical improvement is associated with BMI increase, mostly in negative symptom and in patients after 3 years of antipsychotic use. Our findings were already described in the preantipsychotic era, suggesting some pathophysiological mechanism underlying both conditions.

Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study.

Objective: To analyze those factors contributing to the diagnostic delay in ALS. Methods: Consecutive ALS patients were categorized as those studied in departmental hospitals and those studied in a referral ALS center. Demographic and clinical variables, together with data of the diagnostic pathway were collected. Multivariable models were used to assess their effect in the time between symptoms onset and the first neurologist visit (time symptoms-neurologist), in the time between the first neurologist visit and the diagnosis (time neurologist-diagnosis) and in the diagnostic delay. Results: 166 ALS patients with a median diagnostic delay of 11.53 months (IQR: 6.68, 15.23) were included. The median diagnostic delay was 8.57 months (5.16, 11.61) in the referral center vs. 12.08 months (6.87, 16.8) in departmental centers. Bulbar onset, fast progression rate, upper motor neuron predominant phenotype and an early referral to the neurologist were associated with a shorter time between symptoms-neurologist. Being studied in a referral center was associated with a shorter time between neurologist-diagnosis. Comorbidities, familial ALS, bulbar onset, early referral to the neurologist and being studied in a referral center were associated with a shorter diagnostic delay. For patients studied in departmental hospitals, fast progression rate was also strongly associated with a shorter time between neurologist-diagnosis and diagnostic delay. Conclusion: Unmodifiable factors (comorbidities, familial ALS, bulbar onset, and progression rate) as well as modifiable factors (early referral to the neurologist and the evaluation in an ALS referral center) have an independent effect in the diagnostic delay. The universalization of ALS Units is probably the most efficient measure to reduce the diagnostic delay.

Drug "Clicking" on Cell-Penetrating Fluorescent Nanoparticles for In Cellulo Chemical Proteomics.

Chemical proteomics approaches are widely used to identify molecular targets of existing or novel drugs. This manuscript describes the development of a straightforward approach to conjugate azide-labeled drugs via click chemistry to alkyne-tagged cell-penetrating fluorescent nanoparticles as a novel tool to study target engagement and/or identification inside living cells. A modification of the Baeyer test for alkynes allows monitoring the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, guaranteeing the presence of the drug on the solid support. As a proof of concept, the conjugation of the promiscuous kinase inhibitor dasatinib to Cy5-labeled nanoparticles is presented. Dasatinib-decorated fluorescent nanoparticles efficiently inhibited its protein target SRC in vitro, entered cancer cells, and colocalized with SRC in cellulo.

Do FSH/LH ratio and gonadal hormone levels predict clinical improvement in postmenopausal schizophrenia women?

Menopause is a process characterized by a decline in estrogen levels and is therefore a period of biological vulnerability for psychotic relapse in women with schizophrenia. Our goal was to correlate not only gonadal hormone levels but also follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels with improvement in specific clinical symptoms. Thirty-seven acutely ill postmenopausal schizophrenia women with a newly initiated, clinically determined change in antipsychotic medication participated in a 12-week prospective observational outcome study. Scales used were the PANSS scale for psychotic symptoms, the PSP for functioning, and CGI for global clinical impression. Circulating FSH, LH, estradiol, progesterone, and testosterone serum levels were determined by chemiluminescent immunoassay. Partial correlational analyses were performed along with a Bonferroni significance correction (p < 0.0007). After adjustment for confounding factors, the FSH/LH ratio correlated positively with mean changes in PANSS positive scores, and there was a correlation with worsening of CGI total and cognitive scores. Testosterone was also positively associated with improvement in PANSS positive scores. However, after correction for multiple testing, the initial correlations were no longer statistically significant. In summary, while the hormone assays we did in this small sample did not prove to be significantly linked to clinical improvement in any of the schizophrenia symptom domains, we recommend further investigation of pituitary, adrenal, and gonadal hormone ratios as potential markers of clinical improvement in this population.

Tracking cell proliferation using a nanotechnology-based approach.

AIM: To develop an efficient nanotechnology fluorescence-based method to track cell proliferation to avoid the limitations of current cell-labeling dyes. MATERIAL & METHODS: Synthesis, PEGylation, bifunctionalization and labeling with a fluorophore (Cy5) of 200 nm polystyrene nanoparticles (NPs) were performed. These NPs were characterized and assessed for in vitro long-term monitoring of cell proliferation. RESULTS: The optimization and validation of this method to track long-term cell proliferation assays have been achieved with high reproducibility, without cell cycle disruption. This method has been successfully applied in several adherent and suspension cells including hard-to-transfect cells and isolated human primary lymphocytes. CONCLUSION: A novel approach to track efficiently cellular proliferation by flow cytometry using fluorescence labeled NPs has been successfully developed. [Formula: see text].

Novel bead-based platform for direct detection of unlabelled nucleic acids through Single Nucleobase Labelling.

Over the last decade, circulating microRNAs have received attention as diagnostic and prognostic biomarkers. In particular, microRNA122 has been demonstrated to be an early and more sensitive indicator of drug-induced liver injury than the widely used biomarkers such as alanine aminotransferase and aspartate aminotransferase. Recently, microRNA122 has been used in vitro to assess the cellular toxicity of new drugs and as a biomarker for the development of a rapid test for drug overdose/liver damage. In this proof-of-concept study, we report a PCR-free and label-free detection method that has a limit of detection (3 standard deviations) of 15 fmoles of microRNA122, by integrating a dynamic chemical approach for "Single Nucleobase Labelling" with a bead-based platform (Luminex®) thereby, in principle, demonstrating the exciting prospect of rapid and accurate profiling of any microRNAs related to diseases and toxicology.

Antipsychotic Response Worsens With Postmenopausal Duration in Women With Schizophrenia.

BACKGROUND: The loss of estrogens in the menopause may lead to increased vulnerability for psychotic relapse, poor clinical outcome, and a need for increased antipsychotic dose. However, confounders such as cumulative estrogen exposure and time since menopause have been inadequately studied. Our aim was to investigate potential variables capable of influencing antipsychotic response in a sample of postmenopausal women with schizophrenia. METHODS: Sixty-four postmenopausal schizophrenic women were followed in a 12-week prospective treatment-by-clinical requirement study. Duration of reproductive years was considered an indirect measure of lifetime cumulative estrogens exposure. Psychopathological assessment included the following: Positive and Negative Syndrome Scale, Personal and Social Performance, and Clinical Global Impression-Schizophrenia Scale. Response was defined as a reduction of 30% or more of Positive and Negative Syndrome Scale total scores. Antipsychotic adherence was assessed by plasma level monitoring at 4 weeks. Regression analyses were performed to investigate the association between potential confounding factors and antipsychotic response. RESULTS: Forty-two participants (66%) were found to be antipsychotic responders. Time since menopause was significantly and negatively associated with overall antipsychotic response, explaining almost 42% of the variance of the model used. Smoking and cumulative estrogen exposures were associated with improvement in negative symptoms. Smoking and time since menopause were associated with improvement in excitement symptoms, and smoking was positively associated with improvement in depressive and cognitive symptoms. DISCUSSION: Time since menopause was significantly negatively associated with antipsychotic response in postmenopausal schizophrenic women, suggesting a decline in antipsychotic response after menopause. The neurobiological basis for antipsychotic response may include a role for estrogen and nicotine receptors.

Number of Nanoparticles per Cell through a Spectrophotometric Method - A key parameter to Assess Nanoparticle-based Cellular Assays.

Engineered nanoparticles (eNPs) for biological and biomedical applications are produced from functionalised nanoparticles (NPs) after undergoing multiple handling steps, giving rise to an inevitable loss of NPs. Herein we present a practical method to quantify nanoparticles (NPs) number per volume in an aqueous suspension using standard spectrophotometers and minute amounts of the suspensions (up to 1 µL). This method allows, for the first time, to analyse cellular uptake by reporting NPs number added per cell, as opposed to current methods which are related to solid content (w/V) of NPs. In analogy to the parameter used in viral infective assays (multiplicity of infection), we propose to name this novel parameter as multiplicity of nanofection.

Cellular response to empty and palladium-conjugated amino-polystyrene nanospheres uptake: a proteomic study.

Amino polystyrene nanospheres are shown to be efficient and controllable delivery devices, capable of transporting several bioactive cargoes. Recently, the design of a new device for prodrug activation, using these nanospheres with palladium encapsulated onto them, has been developed successfully. To study the influence of the cellular uptake of these nanodevices, we investigated the cellular response of human embryonic kidney cells (HEK-293T) and murine fibroblasts (L929) treated with empty or palladium-conjugated amino polystyrene nanospheres. To identify differentially expressed proteins, we performed an exhaustive proteomic analysis. In accordance with genomic data previously obtained, the uptake of the empty nanospheres did not induce significant variation in protein expression levels. Following the treatment with palladium-conjugated nanospheres, some changes in protein profiles in both cell lines were observed; these alterations affect proteins involved in cell metabolism and intracellular transport. No key regulator of the cell cycle result was differentially expressed after the treatment, confirming that these innovative drug delivery systems are harmless and well tolerated by the cells.

In vitro nanoparticle-mediated intracellular delivery into human adipose-derived stem cells.

Adipose-derived stem cells (ASCs) are multipotent cells that are emerging as an extremely promising therapeutic agent for tissue regeneration. The ability to manipulate ASC phenotypes by the delivery of biologically active cargoes is essential to understand their role and to design novel therapeutic strategies based on the use of ASCs. Here we describe a simple and efficient protocol for the conjugation and efficient delivery of biological materials into ASCs based on the use of polystyrene nanoparticles as carrier system.

Multimodal navigation in the functional microsurgical resection of intrinsic brain tumors located in eloquent motor areas: role of tractography.

OBJECT: Nowadays the role of microsurgical management of intrinsic brain tumors is to maximize the volumetric resection of the tumoral tissue, minimizing the postoperative morbidity. The purpose of this paper was to study the benefits of an original protocol developed for the microsurgical treatment of tumors located in eloquent motor areas where the navigation and electrical stimulation of motor subcortical pathways have been implemented. METHODS: A total of 17 patients who underwent resection of cortical or subcortical tumors in motor areas have been included in the series. The preoperative planning for multimodal navigation was done by integrating anatomical studies, motor functional MR (fMR) imaging, and subcortical pathway volumes generated by diffusion tensor (DT) imaging. Intraoperative neuromonitoring included motor mapping by direct cortical stimulation (CS) and subcortical stimulation (sCS), and localization of the central sulcus by using cortical multipolar electrodes and the N20 wave inversion technique. The location of all cortically and subcortically stimulated points with positive motor response was stored in the navigator and correlated with the cortical and subcortical motor functional structures defined preoperatively. RESULTS: The mean tumoral volumetric resection was 89.1 +/- 14.2% of the preoperative volume, with a total resection (> or = 100%) in 8 patients. Preoperatively a total of 58.8% of the patients had some kind of motor neurological deficit, increasing 24 hours after surgery to 70.6% and decreasing to 47.1% at 1 month later. There was a great correlation between anatomical and functional data, both cortically and subcortically. A total of 52 cortical points submitted to CS had positive motor response, with a positive correlation of 83.7%. Also, a total of 55 subcortical points had positive motor response; in these cases the mean distance from the stimulated point to the subcortical tract was 7.3 +/- 3.1 mm. CONCLUSIONS: The integration of anatomical and functional studies allows a safe functional resection of the brain tumors located in eloquent areas. Multimodal navigation allows integration and correlation among preoperative and intraoperative anatomical and functional data. Cortical motor functional areas are anatomically and functionally located preoperatively thanks to MR and fMR imaging and subcortical motor pathways with DT imaging and tractography. Intraoperative confirmation is done with CS and N20 inversion wave for cortical structures and with sCS for subcortical pathways. With this protocol the authors achieved a good volumetric resection in cortical and subcortical tumors located in eloquent motor areas, with an increase in the incidence of neurological deficits in the immediate postoperative period that significantly decreased 1 month later. Ongoing studies must define the safe limits for functional resection, taking into account the intraoperative brain shift. Finally, it must be demonstrated whether this protocol has any long-term benefit for patients by prolonging the disease-free interval, the time to recurrence, or the survival time.