A corpus to support eHealth Knowledge Discovery technologies. Piad-Morffis A, Gutiérrez Y, Muñoz R. J Biomed Inform. 2019 Apr 6:103172. DOI: 10.1016/j.jbi.2019.103172. [Epub ahead of print]
This paper presents and describes eHealth-KD corpus. The corpus is a collection of 1173 Spanish health-related sentences manually annotated with a general semantic structure that captures most of the content, without resorting to domain-specific labels. The semantic representation is first defined and illustrated with example sentences from the corpus. Next, the paper summarizes the process of annotation and provides key metrics of the corpus. Finally, three baseline implementations, which are supported by machine learning models, were designed to consider the complexity of learning the corpus semantics. The resulting corpus was used as an evaluation scenario in TASS 2018 [1] and the findings obtained by participants are discussed. The eHealth-KD corpus provides the first step in the design of a general-purpose semantic framework that can be used to extract knowledge from a variety of domains.
Association between Quantitative Electroencephalogram Frequency Composition and Post-Surgical Evolution in Pharmacoresistant Temporal Lobe Epilepsy Patients. Valdés Sedeño RR, Morales Chacón LM, Sánchez Coroneux A. Behav Sci (Basel). 2019 Mar 4;9(3). pii: E23. DOI: 10.3390/bs9030023
The purpose of this paper is to estimate the association between quantitative electroencephalogram frequency composition (QEEGC) and post-surgical evolution in patients with pharmacoresistant temporal lobe epilepsy (TLE) and to evaluate the predictive value of QEEGC before and after surgery. A prospective, longitudinal study was made at International Neurological Restoration Center, Havana, Cuba. Twenty-nine patients with TLE submitted to epilepsy surgery were evaluated before surgery, and six months and two years after. They were classified as unsatisfactory and satisfactory post-surgical clinical evolution using the Modified Engels Scale. Eighty-seven electroencephalograms with quantitative narrow- and broad-band measures were analyzed. A Mann Whitney test (p > 0.05) showed that QEEGC before surgery was similar between groups independently of two years post-surgical evolution. A Mann Whitney test (p ˂ 0.05) showed that subjects with two years satisfactory post-surgical evolution had greater alpha power compared to subjects with two years unsatisfactory post-surgical evolution that showed greater theta power. A Wilcoxon test (p ˂ 0.05) showed that alpha and theta power increased for two groups from pre-surgical state to post-surgical state. Logit regression (p ˂ 0.05) showed that six months after surgery, quantitative electroencephalogram frequency value with the greatest power at occipital regions shows predictive value for two years evolution. QEEGC can be a tool to predict the outcome of epilepsy surgery.
Chronic Pulmonary Aspergillosis in Patients with Underlying Respiratory Disorders in Cuba-A Pilot Study. Beltrán Rodríguez N, San Juan-Galán JL, Fernández Andreu CM, María Yera D, Barrios Pita M, Perurena Lancha MR, et al. J Fungi (Basel). 2019 Feb 22;5(1). pii: E18. DOI: 10.3390/jof5010018.
Chronic pulmonary aspergillosis (CPA) is a fungal infection with high mortality and morbidity rates. This disease is caused by several Aspergillus species and affects patients with an underlying respiratory condition. This pilot study aims to recognize CPA among patients with different respiratory diseases. Twenty-one out of 47 patients were classified as CPA based on the examination of clinical signs and symptoms, radiological findings, mycological culture of respiratory samples and analysis of Aspergillus IgG antibodies. There was a close association between high levels of Aspergillus IgG antibodies and the presence of cavities. Although Aspergillus flavus was the predominant species among clinical isolates, the number of isolates was small to reach conclusions on the prevalence of this species as main cause of CPA in Cuba. From the eleven evaluable patients for the treatment with itraconazole (Lozartil®), nine improved their health status while two did not show any recovery. This drug is included in the therapy schemes for aspergillosis in Cuba.
Comparison of the clinical and genetic features of amyotrophic lateral sclerosis across Cuban, Uruguayan and Irish clinic-based populations. Ryan M, Zaldívar Vaillant T, McLaughlin RL, Doherty MA, Rooney J, Heverin M, et al. J Neurol Neurosurg Psychiatry. 2019 Mar 7. pii: jnnp-2018-319838. DOI: 10.1136/jnnp-2018-319838. [Epub ahead of print]
Objectives This study compares the clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) within three clinic-based populations from Cuba, Uruguay and Ireland and determines the impact of known ALS-associated genetic variants on phenotypic manifestations within the Cuban population. Methods Demographic and clinical information was collected on 115 Cuban, 220 Uruguayan and 1038 Irish patients with ALS attending national specialist clinics through 1996-2017. All Cuban patients and 676 Irish patients underwent next-generation DNA sequencing and were screened for the pathogenic C9orf72 repeat expansion. Results The results mean age of onset was younger in the Cuban (53.0 years, 95% CI 50.4 to 55.6) and Uruguayan (58.2 years, 95% CI 56.5 to 60.0) populations compared with the Irish population (61.6 years, 95% CI 60.9 to 62.4). No differences in survival between populations were observed. 1.7 % (95% CI 0.6 to 4.1) of Cubans with ALS carried the C9orf72 repeat expansion compared with 9.9% (95% CI 7.8 to 12.0) of Irish patients with ALS (p=0.004). Other known variants identified in the Cuban population included ANG (one patient), CHCHD10 (one patient) and DCTN1 (three patients). Conclusions and relevance This study is the first to describe the clinical characteristics of ALS in Cuban and Uruguayan populations and report differences between the Cuban and Irish genetic signature in terms of known ALS-associated genetic variants. These novel clinical and genetic data add to our understanding of ALS across different and understudied populations.
Patel C, Kalaivani M, Karthikeyan G, Peix A, Kumar A, Massardo T, et al.
J Nucl Cardiol. 2019 Apr 11. DOI: 10.1007/s12350-019-01704-0. [Epub ahead of print]
Background We evaluated the effect of cardiac resynchronization therapy (CRT) on septal perfusion and thickening at 6 months post implantation assessed on Tc99m-MIBI Gated myocardial perfusion SPECT (GMPS).We also studied the association of change in septal perfusion and thickening with primary outcome defined as at least one [improvement in ≥1NYHA class, left ventricular ejection fraction (LVEF) by ≥ 5%, reduction of end-systolic volume (ESV) by ≥ 15%, and improvement ≥ 5 points in Minnesota living with heart failure questionnaire (MLHFQ)]. Method One hundred and five patients underwent clinical and GMPS evaluation before and at 6 months post CRT. Result Post CRT there was significant improvement in mean normalized septal perfusion uptake and in septal thickening (P value = 0.001, both). There was no significant relation between improvement in septal perfusion and primary outcome. However, improvement in septal thickening was statistically significant with favorable primary outcome (P = 0.001).There was no significant correlation between improvement of septal perfusion and improvement in LVEF, reduction in End diastolic volume (EDV), ESV, and Left ventricular Dyssynchrony (LVD). But, there was significant correlation between improvement of septal thickening and these parameters. Conclusion Improvement in septal thickening was associated with reverse remodeling, improvement in LVEF, and reduction of LVD.
Efficacy of 5-nitroimidazole compounds for giardiasis in Cuban children: systematic review and meta-analysis. Escobedo AA, Almirall P, González-Fraile E, Ballesteros J. Infez Med. 2019 Mar 1;27(1):58–67.
Five-nitroimidazole (5-NI) compounds are among the most commonly used medications in the treatment of giardiasis. However, after more than five decades of their initial indication for such treatment, there are some concerns about the efficacy of 5-NIs in giardiasis. This study sought to compare the efficacy of any 5-NI with any other antigiardial drug for the treatment of Cuban children with giardiasis. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We searched CUMED, EBSCOhost and PubMed databases. Two reviewers independently assessed trial eligibility, trial quality and extracted appropriate data. The primary outcome was the parasitological cure. The effect estimate was the pooled relative risk (RR) with 95% confidence intervals (CI). We included seven RCTs in the systematic review, involving a total of 1046 children. When the effect of 5-NIs was compared with that of benzimidazole compounds, the pooled effect was significant and favored 5-NIs [the relative risk (RR) is 1.35, 95% CI =1.05 to 1.75], with high heterogeneity (4 studies, I2 =79%). Compared with chloroquine, the pooled effects of the 5-NIs were not significant [RR is 0.96, 95% CI=0.79 to 1.18, (2 studies, I2=68%)]. Our results support the use of 5-NIs (mainly tinidazole) as first-line therapy for Cuban pediatric patients infected with Giardia and may continue being used as reference drugs in future RCTs of giardiasis. These data could help inform policy decisions in Cuba. Caution is needed in extrapolating such data in other settings.
Emotion analysis in children through facial emissivity of infrared thermal imaging. Goulart C, Valadão C, Delisle-Rodriguez D, Caldeira E, Bastos T. PLoS One. 2019 Mar 20;14(3):e0212928. DOI: 10.1371/journal.pone.0212928. eCollection 2019.
Physiological signals may be used as objective markers to identify emotions, which play relevant roles in social and daily life. To measure these signals, the use of contact-free techniques, such as Infrared Thermal Imaging (IRTI), is indispensable to individuals who have sensory sensitivity. The goal of this study is to propose an experimental design to analyze five emotions (disgust, fear, happiness, sadness and surprise) from facial thermal images of typically developing (TD) children aged 7-11 years using emissivity variation, as recorded by IRTI. For the emotion analysis, a dataset considered emotional dimensions (valence and arousal), facial bilateral sides and emotion classification accuracy. The results evidence the efficiency of the experimental design with interesting findings, such as the correlation between the valence and the thermal decrement in nose; disgust and happiness as potent triggers of facial emissivity variations; and significant emissivity variations in nose, cheeks and periorbital regions associated with different emotions. Moreover, facial thermal asymmetry was revealed with a distinct thermal tendency in the cheeks, and classification accuracy reached a mean value greater than 85%. From the results, the emissivity variations were an efficient marker to analyze emotions in facial thermal images, and IRTI was confirmed to be an outstanding technique to study emotions. This study contributes a robust dataset to analyze the emotions of 7-11-year-old TD children, an age range for which there is a gap in the literature.
Graph-Based data integration from bioactive peptide databases of pharmaceutical interest: towards an organized collection enabling visual network analysis. Aguilera-Mendoza L, Marrero-Ponce Y, Beltrán JA, Téllez Ibarra R, Guillén-Ramírez HA, Brizuela CA. Bioinformatics. 2019 Apr 17. pii: btz260. DOI: 10.1093/bioinformatics/btz260.
Motivation Bioactive peptides have gained great attention in the academy and pharmaceutical industry since they play an important role in human health. However, the increasing number of bioactive peptide databases is causing the problem of data redundancy and duplicated efforts. Even worse is the fact that the available data is non-standardized and often dirty with data entry errors. Therefore, there is a need for a unified view that enables a more comprehensive analysis of the information on this topic residing at different sites. Results After collecting web pages from a large variety of bioactive peptide databases, we organized the web content into an integrated graph database (starPepDB) that holds a total of 71, 310 nodes and 348, 505 relationships. In this graph structure, there are 45, 120 nodes representing peptides, and the rest of the nodes are connected to peptides for describing metadata. Additionally, to facilitate a better understanding of the integrated data, a software tool (starPep toolbox) has been developed for supporting visual network analysis in a user-friendly way; providing several functionalities such as peptide retrieval and filtering, network construction and visualization, interactive exploration, and exporting data options. Availability Both starPepDB and starPep toolbox are freely available at http://mobiosd-hub.com/starpep/ Supplementary information Supplementary data are available at Bioinformatics online.
Human B-1 Cells and B-1 Cell Antibodies Change With Advancing Age. Rodríguez-Zhurbenko N, Quach TD, Hopkins TJ, Rothstein TL, Hernandez AM. Front Immunol. 2019 Mar 19;10:483. DOI: 10.3389/fimmu.2019.00483. eCollection 2019.
Age-related deficits in the immune system have been associated with an increased incidence of infections, autoimmune diseases, and cancer. Human B cell populations change quantitatively and qualitatively in the elderly. However, the function of human B-1 cells, which play critical anti-microbial and housekeeping roles, have not been studied in the older age population. In the present work, we analyzed how the frequency, function and repertoire of human peripheral blood B-1 cells (CD19+CD20+CD27+CD38low/intCD43+) change with age. Our results show that not only the percentage of B-1 cells but also their ability to spontaneously secrete IgM decreased with age. Further, expression levels of the transcription factors XBP-1 and Blimp-1 were significantly lower, while PAX-5, characteristic of non-secreting B cells, was significantly higher, in healthy donors over 65 years (old) as compared to healthy donors between 20 and 45 years (young). To further characterize the B-1 cell population in older individuals, we performed single cell sequencing analysis of IgM heavy chains from healthy young and old donors. We found reduced repertoire diversity of IgM antibodies in B-1 cells from older donors as well as differences in usage of certain VH and DH specific genes, as compared to younger. Overall, our results show impairment of the human B-1 cell population with advancing age, which might impact the quality of life and onset of disease within the elderly population.
Insights into cognitive decline in spinocerebellar Ataxia type 2: a P300 event-related brain potential study. Rodríguez-Labrada R, Velázquez-Pérez L, Ortega-Sánchez R, Peña-Acosta A, Vázquez-Mojena Y, Canales-Ochoa N, et al. Cerebellum Ataxias. 2019 Mar 4;6:3.
DOI: 10.1186/s40673-019-0097-2. eCollection 2019.
Background Cognitive decline is a common non-motor feature characterizing Spinocerebellar Ataxia type 2 (SCA2) during the prodromal stage, nevertheless a reduced number of surrogate biomarkers of these alterations have been described. Objective To provide insights into cognitive dysfunction in SCA2 patients using P300 event-related potentials (ERP) and to evaluate these measures as biomarkers of the disease. Methods A cross-sectional study was performed with 30 SCA2 patients, 20 preclinical carriers and 33 healthy controls, who underwent visual, auditory P300 ERPs, and neurological examinations and ataxia scoring.
Results SCA2 patients showed significant increase in P300 latencies and decrease of P300 amplitudes for visual and auditory stimuli, whereas preclinical carriers exhibit a less severe, but significant prolongation of P300 latencies. Multiple regression analyses disclosed a significant effect of SARA score on visual P300 abnormalities in patients as well as of the time to ataxia onset on visual P300 latencies in preclinical carriers. Conclusions This paper demonstrated the role of P300 ERP for the study of attentional, discriminative and working memory abnormalities in SCA2 patients and for the search of surrogate biomarkers from prodromal to the symptomatic stages. Moreover, our findings provide psychophysiological evidences supporting the cerebellar involvement in cognitive processes and allows us to identify promising outcome measures for future trials focusing on cognitive dysfunction.
In-Vitro Evaluation of 52 Commercially-Available Essential Oils against Leishmania amazonensis. Monzote L, Herrera I, Satyal P, Setzer WN. Molecules. 2019 Mar 30;24(7). pii: E1248.
Leishmaniasis is a neglected tropical disease caused by members of the Leishmania genus of parasitic protozoa that cause different clinical manifestations of the disease. Current treatment options for the cutaneous disease are limited due to severe side effects, poor efficacy, limited availability or accessibility, and developing resistance. Essential oils may provide low cost and readily available treatment options for leishmaniasis. In-vitro screening of a collection of 52 commercially available essential oils has been carried out against promastigotes of Leishmania amazonensis. In addition, cytotoxicity has been determined for the essential oils against mouse peritoneal macrophages in order to determine selectivity. Promising essential oils were further screened against intracellular L. amazonensis amastigotes. Three essential oils showed notable antileishmanial activities: frankincense (Boswellia spp.), coriander (Coriandrum sativum L.), and wintergreen (Gualtheria fragrantissima Wall.) with IC50 values against the amastigotes of 22.1 ± 4.2, 19.1 ± 0.7, and 22.2 ± 3.5 μg/mL and a selectivity of 2, 7, and 6, respectively. These essential oils could be explored as topical treatment options for cutaneous leishmaniasis.
JM-20 protects memory acquisition and consolidation on scopolamine model of cognitive impairment. Wong-Guerra M, Jiménez-Martín J, Fonseca-Fonseca LA, Ramírez-Sánchez J, Montano-Peguero Y, Rocha JB, et al. Neurol Res. 2019 Mar 1:1–14.
DOI: 10.1080/01616412.2019.1573285. [Epub ahead of print]
Objective JM-20, a novel hybrid synthetic molecule, has been reported to have antioxidant, mitoprotective, anti-excitotoxic, anti-apoptotic and anti-inflammatory properties. However, the neuroprotective effect of JM-20 against memory impairment in preclinical AD-like models has not been analyzed. The aim of this study was to evaluate the potential neuroprotection of JM-20 that preserves essential memory process from cholinergic dysfunction and other molecular damages. Methods The effects of JM-20 on scopolamine (1 mg/kg)-induced cognitive disorders were studied. Male Wistar rats (220-230 g) were treated with JM-20 and/or scopolamine, and behavioral tasks were performed. The AChE activity, superoxide dismutase activity, catalase activity, MDA and T-SH level on brain tissue were determined by spectrophotometric methods. Mitochondrial functionality parameters were measured after behavioral tests. Histological analyses on hippocampus and prefrontal cortex were processed with hematoxylin and eosin, and neuronal and axonal damage were determined. Results The behavioral, biochemical and histopathological studies revealed that oral pre-treatment with JM-20 (8 mg/kg) significantly attenuated the scopolamine-induced memory deficits, mitochondrial malfunction, oxidative stress, and prevented AChE hyperactivity probably due to specific inhibition of AChE enzyme. It was also observed marked histological protection on hippocampal and prefrontal-cortex regions. Conclusions The multimodal action of this molecule could mediate the memory protection here observed and suggest that it may modulate different pathological aspects of memory deficits associated with AD in humans.
Methods for computing the maximum performance of computational models of fMRI responses. Lage-Castellanos A, Valente G, Formisano E, De Martino F. PLoS Comput Biol. 2019 Mar 8;15(3):e1006397. DOI: 10.1371/journal.pcbi.1006397. eCollection 2019 Mar
Computational neuroimaging methods aim to predict brain responses (measured e.g. with functional magnetic resonance imaging [fMRI]) on the basis of stimulus features obtained through computational models. The accuracy of such prediction is used as an indicator of how well the model describes the computations underlying the brain function that is being considered. However, the prediction accuracy is bounded by the proportion of the variance of the brain response which is related to the measurement noise and not to the stimuli (or cognitive functions). This bound to the performance of a computational model has been referred to as the noise ceiling. In previous fMRI applications two methods have been proposed to estimate the noise ceiling based on either a split-half procedure or Monte Carlo simulations. These methods make different assumptions over the nature of the effects underlying the data, and, importantly, their relation has not been clarified yet. Here, we derive an analytical form for the noise ceiling that does not require computationally expensive simulations or a splitting procedure that reduce the amount of data. The validity of this analytical definition is proved in simulations, we show that the analytical solution results in the same estimate of the noise ceiling as the Monte Carlo method. Considering different simulated noise structure, we evaluate different estimators of the variance of the responses and their impact on the estimation of the noise ceiling. We furthermore evaluate the interplay between regularization (often used to estimate model fits to the data when the number of computational features in the model is large) and model complexity on the performance with respect to the noise ceiling. Our results indicate that when considering the variance of the responses across runs, computing the noise ceiling analytically results in similar estimates as the split half estimator and approaches the true noise ceiling under a variety of simulated noise scenarios. Finally, the methods are tested on real fMRI data acquired at 7 Tesla.
Molecular Imaging of a Zirconium-89 Labeled Antibody Targeting Plasmodium falciparum-Infected Human Erythrocytes. Duvenhage J, Ebenhan T, Garny S, Hernández González I, Leyva Montaña R, Price R, et al. Mol Imaging Biol. 2019 Apr 19.
DOI: 10.1007/s11307-019-01360-3. [Epub ahead of print]
Purpose Nuclear imaging is an important preclinical research tool to study infectious diseases in vivo and could be extended to investigate complex aspects of malaria infections. As such, we report for the first time successful radiolabeling of a novel antibody specific to Plasmodium-infected erythrocytes (IIIB6), its in vitro assessment and molecular imaging in nude mice. Procedures In vitro confocal microscopy was used to determine the stage-specificity of Plasmodium-infected erythrocytes recognised by IIIB6. To enable micro-positron emission tomography (PET)/X-ray computed tomography (CT) imaging, IIIB6 was conjugated to Bz-DFO-NCS and subsequently radiolabeled with zirconium-89. Healthy nude mice were injected with [89Zr]IIIB6, and pharmacokinetics and organ uptake were monitored over 24 h. This was followed by post-mortem animal dissection to determine the biodistribution of [89Zr]IIIB6. Results IIIB6 recognised all the relevant stages of Plasmodium falciparum-infected erythrocytes (trophozoites, schizonts and gametocytes) that are responsible for severe malaria pathology. [89Zr]IIIB6-radiolabeling yields were efficient at 84-89 %. Blood pool imaging analysis indicated a pharmacological half-life of 9.6 ± 2.5 h for [89Zr]IIIB6. The highest standard uptake values were determined at 2-6 h in the liver followed by the spleen, kidneys, heart, stomach and lung, respectively. Minimal activity was present in muscle and bone tissues. Conclusion In vitro characterization of IIIB6 and pharmacokinetic characterization of [89Zr]IIIB6 revealed that this antibody has potential for future use in Plasmodium-infected mouse models to study malaria in a preclinical in vivo setting with PET/CT imaging.
González E, Reyes F, Otero O, Camacho F, Cuello M, Ramírez F, et al.
Methods Mol Biol. 2019;1969:181–203. DOI: 10.1007/978-1-4939-9202-7_13.
Vaccination has reduced morbidity and mortality of many diseases that previously caused devastating epidemics and deaths globally. Vaccines as a biological product may contain microorganisms or their derivatives. This aspect together with the fact that they are administered to healthy individuals (mainly children) means that approximately 70% of vaccines development time is dedicated to quality control. Monoclonal antibodies (MAbs) have become essential analytical tools for application in ELISAs, Western and Dot blotting, immunoprecipitation, and flow cytometric assays that ensure the quality control of vaccines. The aim of this work is to present a review of the methods used to obtain a platform of MAbs against Neisseria meningitidis polysaccharide antigens to use as an analytical tool for quality control of anti-meningococcal polysaccharide (Ps) vaccines. The MAbs obtained are used in five sandwich ELISAs developed for Ps quantification. The assays showed good reproducibility and repeatability, with quantitation and detection limits below 1 ng/mL. Dot Blot, as the Identity test of the Ps vaccine, was carried out to positively identify licensed and experimental vaccines. All assays described are suitable for the screening of multiple vaccine samples and could be useful for monitoring lot-to-lot consistency and stability.
Neurorehabilitation Improves the Motor Features in Prodromal SCA2: A Randomized, Controlled Trial. Velázquez-Pérez L, Rodríguez-Díaz JC, Rodríguez-Labrada R, Medrano-Montero J, Aguilera Cruz AB, Reynaldo-Cejas L, et al. Mov Disord. 2019 Apr 8.
DOI: 10.1002/mds.27676. [Epub ahead of print]
Background The search for early interventions is a novel approach in spinocerebellar ataxias, but there are few studies supporting this notion. This article aimed to assess the efficacy of neurorehabilitation treatment in prodromal spinocerebellar ataxia type 2. Methods Thirty spinocerebellar ataxia type 2 preclinical carriers were enrolled in a randomized, controlled trial using neurorehabilitation. The intervention in the treated group was 4 hours per day, 5 days per week for 12 weeks, emphasizing static balance, gait, and limb coordination. The control group did not receive rehabilitation. The primary outcome measure was the time for 5-m tandem gait over the floor. Secondary outcomes included other timed tests with increased motor complexity, as well as the scores of the SARA and the Inventory of Non-ataxia Symptoms. Results The times for 5-m tandem gait over the floor and the mattress were significantly reduced only in the rehabilitated group. Moreover, the times upholding the tandem stance over a mattress and the seesaw were notably increased only in this group. Likewise, the finger-nose and the heel-shin tests were improved in the rehabilitated group alone. The SARA score and the count of nonataxia symptoms were unchanged. Conclusions This rehabilitation program improves the subtle gait, postural and coordinative deficits in prodromal spinocerebellar ataxia type 2, which provided novel hints about the preservation of motor learning and neural plasticity mechanisms in early disease stages, leading chances for other interventional approaches in this and other spinocerebellar ataxias.
Nimotuzumab and radiotherapy for treatment of newly diagnosed diffuse intrinsic pontine glioma (DIPG): a phase III clinical study. Fleischhack G, Massimino M, Warmuth-Metz M, Khuhlaeva E, Janssen G, Graf N, et al. J Neurooncol. 2019 Mar 4. DOI: 10.1007/s11060-019-03140-z. [Epub ahead of print]
Background Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence. Methods The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3). Results All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression. Conclusions Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.
Pharmacokinetics and Biodistribution of Rhopalurus junceus Scorpion Venom in Tumor-Bearing Mice after Intravenous and Oral Administration. Díaz-García A, Pimentel González G, Basaco Bernabeu T, Rodríguez Aurrecochea JC, Rodríguez Sánchez H, Sánchez Monzón I, et al. Iran Biomed J. 2019 Jul;23(4):287–96.
Background Rhopalurus junceus scorpion venom has shown potential for anticancer treatment. However, there are no scientific evidence about venom pharmacokinetic (PK) and biodistribution (BD) in tumor-bearing mice. Methods 131I-labeled venom was administrated by intravenous (IV) and oral (PO) routes at the single dose of 12.5 mg/kg. Mice were sacrificed and blood samples, major organs, and tumor were taken at 10, 20, 40, 90, 180, 300, 480, and 1440 min. Results For IV route, maximum peak concentration (Cmax), elimination half-lives, total body clearance (CL), distribution volume (Vd), mean residence time (MRT), and area under curve (AUC) were 21.77 ± 2.45 %Dosis•h/mL, 12.65 ± 2.1 h, 4.59 ± 0.23 mL/h, 83.80 ± 12 mL, 12.49 ± 2.71 h, and 21.77 ± 2.45 %Dosis•h/mL, respectively. For PO route, they were 0.60 ± 0.07 %Dosis•h/mL, 9.33 ± 1.35 h, 36.94 ± 4.01 mL/h, 497.33 ± 30 mL, 12.40 ± 1.87 h, and 6.89 ± 1.18 %Dosis•h/mL, respectively. PK parameters (Cmax, CL, Vd, and AUC) showed significant differences between IV and PO routes. Bioavailability was 31.6 ± 4% for PO dose. Kidney, stomach, liver, and lung for IV and stomach, kidney, spleen, and lung for PO routes showed the major uptakes for 131I-labeled venom. In tumor tissue, after the maximum uptake for both routes, there was a consistent behavior of radioactivity respect to the major organs during the first 480 min. Conclusion The PK and BD of R. junceus venom in mice depend on the administration route. These data represent a starting point for future experiments with this scorpion venom in experimental models of cancer.
Predictors of Remission and Low Disease Activity State in Systemic Lupus Erythematosus: Data from a multi-ethnic, multinational Latin-American Lupus Cohort. Ugarte-Gil MF, Wojdyla D, Pons-Estel GJ, Quintana R, Gómez-Puerta JA, Catoggio LJ, et al. J Rheumatol. 2019 Mar 1. pii: jrheum.180433. DOI: 10.3899/jrheum.180433.
Objective To determine the predictors of remission and low disease activity state (LDAS) in systemic lupus erythematosus (SLE). Methods Three disease activity states were defined: Remission=SLEDAI=0 and prednisone≤5mg/d and/or immunosuppressants (maintenance dose); LDAS=SLEDAI≤4, prednisone≤7.5mg/d and/or immunosuppressants (maintenance dose); and non-optimally controlled state=SLEDAI>4 and/or prednisone>7.5mg/d and/or immunosuppressants (induction dose). Antimalarials were allowed in all groups. Patients with at least two SLEDAI reported and not optimally controlled at cohort entry were included in these analyses. Outcomes were remission and LDAS. Multivariable Cox regression models (stepwise selection procedure) were performed for remission and for LDAS. Results Of 1480 patients, 902 were non-optimally controlled at cohort entry; of them, 196 patients achieved remission (21.7%) and 314 achieved LDAS (34.8%). Variables predictive of a higher probability of remission were the absence of mucocutaneous manifestations [HR=1.571 (95%CI 1.064-2.320)], of renal involvement [HR=1.487 (95%CI 1.067-2.073)], and of hematologic involvement [HR=1.354 (95%CI 1.005-1.825)]; the use of immunosuppressive drugs before the baseline visit [HR=1.468 (95%CI 1.025-2.105)] and a lower SLEDAI at cohort entry [HR=1.028 (95%CI 1.006-1.051) per 1 unit decrease]. Older age at cohort entry, per five years increase [HR=1.050 (95%CI 1.004-1.098)]; absence of mucocutaneous manifestations [HR=1.401 (95%CI 1.016-1.930)], and renal involvement [HR=1.344 (95%CI 1.049-1.721)] as well as a lower SLEDAI at cohort entry [HR=1.025 (95%CI 1.009-1.042)] were predictive of LDAS. Conclusion The absence of mucocutaneous, renal and hematologic involvement, the use of immunosuppressive drugs and a lower disease activity early in the course of the disease were predictive of remission; older age was predictive of LDAS.
Safety and Therapeutic Profile of a GnRH-Based Vaccine Candidate Directed to Prostate Cancer. A 10-Year Follow-Up of Patients Vaccinated With Heberprovac. Junco JA, Rodríguez R, Fuentes F, Baladrón I, Castro MD, Calzada L, et al. Front Oncol. 2019 Feb 25;9:49. DOI: 10.3389/fonc.2019.00049. eCollection 2019.
Heberprovac is a GnRH based vaccine candidate containing 2.4 mg of the GnRHm1-TT peptide as the main active principle; 245 μg of the very small size proteoliposomes adjuvant (VSSP); and 350 μL of Montanide ISA 51 VG oil adjuvant. The aim of this study was to assess the safety and tolerance of the Heberprovac in advanced prostate cancer patients as well as its capacity to induce anti-GnRH antibodies, the subsequent effects on serum levels of testosterone and PSA and the patient overall survival. The study included eight patients with histologically-proven advanced prostate cancer with indication for hormonal therapy, who received seven intramuscular immunizations with Heberprovac within 18 weeks. Anti-GnRH antibody titers, testosterone and PSA levels, as well as clinical parameters were recorded and evaluated. The vaccine was well tolerated. Significant reductions in serum levels of testosterone and PSA were seen after four immunizations. Castrate levels of testosterone were observed in all patients at the end of the immunization schedule, which remained at the lowest level for at least 20 months. In a 10-year follow-up three out of six patients who completed the entire trial survived. In contrast only one out eight patients survived in the same period in a matched randomly selected group receiving standard anti-hormonal treatment. Heberprovac vaccination showed a good security profile, as well as immunological, biochemical and, most importantly, clinical benefit. The vaccinated group displayed survival advantage compared with the reference group that received standard treatment. These results warrant further clinical trials with Heberprovac involving a larger cohort.
Sleep quality and memory function in healthy ageing. Cruz T, García L, Álvarez MA, Manzanero AL. Neurologia. 2019 Apr 11. pii: S0213-4853(19)30003-9.
DOI: 10.1016/j.nrl.2018.10.001. [Epub ahead of print]
Objective To study the relationship between sleep quality and memory in healthy ageing. Methods The study included 99 people older than 50 years (69 women and 30 men; mean age, 68.74±7.18 years) with no associated diseases. Patients completed digital versions of the Word Learning and Visual Paired Associates tests and the Pittsburgh Sleep Quality Index questionnaire to assess the quality of sleep. Results Pittsburgh Sleep Quality Index score was negatively correlated with Visual Paired Associates and Word Learning test performance. Performance in these 2 memory tests decreased in line with sleep quality. In addition, performance in Visual Paired Associates test was negatively correlated with subjective sleep quality, duration, and sleep disturbances. Performance on the Word Learning test was negatively correlated with subjective sleep quality and efficiency. Participants’ sex showed a weak effect on Visual Paired Associates performance and sleep latency. Conclusions Medical professionals working with elderly patients should take into consideration the effect of poor sleep quality on memory. Cognitive impairment in these patients may be a manifestation of a neuroendocrine imbalance due to a disrupted circadian rhythm. More research is needed to prove this hypothesis.
The Statistics of EEG Unipolar References: Derivations and Properties. Hu S, Yao D, Bringas-Vega ML, Qin Y, Valdés-Sosa PA. Brain Topogr. 2019 Apr 10.
DOI: 10.1007/s10548-019-00706-y. [Epub ahead of print]
In this brief communication, which complements the EEG reference review (Yao et al. in Brain Topogr, 2019), we provide the mathematical derivations that show: (1) any EEG reference admits the general form of a linear transformation of the ideal multichannel EEG potentials with reference to infinity; (2) the average reference (AR), the reference electrode standardization technique (REST), and its regularized version (rREST) are solving the linear inverse problems that can be derived from both the maximum likelihood estimate (MLE) and the Bayesian theory; however, REST is based on more informative prior/constraint of volume conduction than that of AR; (3) we show for the first time that REST is also a unipolar reference (UR), allowing us to define a general family of URs with unified notations; (4) some notable properties of URs are ‘no memory’, ‘rank deficient by 1’, and ‘orthogonal projector centering’; (5) we also point out here, for the first time, that rREST provides the optimal interpolating function that can be used when the reference channel is missing or the ‘bad’ channels are rejected. The derivations and properties imply that: (a) any two URs can transform to each other and referencing with URs multiple times will not accumulate artifacts; (b) whatever URs the EEG data was previously transformed with, the minimum norm solution to the reference problem will be REST and AR with and without modeling volume conduction, respectively; (c) the MLE and the Bayesian theory show the theoretical optimality of REST. The advantages and limitations of AR and REST are discussed to guide readers for their proper use.
Tuberculosis vaccine candidates based on mycobacterial cell envelope components. Sarmiento ME, Álvarez N, Chin KL, Bigi F, Tirado Y, García MA, et al. Tuberculosis (Edinb). 2019 Mar;115:26–41.
Even after decades searching for a new and more effective vaccine against tuberculosis, the scientific community is still pursuing this goal due to the complexity of its causative agent, Mycobacterium tuberculosis (Mtb). Mtb is a microorganism with a robust variety of survival mechanisms that allow it to remain in the host for years. The structure and nature of the Mtb envelope play a leading role in its resistance and survival. Mtb has a perfect machinery that allows it to modulate the immune response in its favor and to adapt to the host’s environmental conditions in order to remain alive until the moment to reactivate its normal growing state. Mtb cell envelope protein, carbohydrate and lipid components have been the subject of interest for developing new vaccines because most of them are responsible for the pathogenicity and virulence of the bacteria. Many indirect evidences, mainly derived from the use of monoclonal antibodies, support the potential protective role of Mtb envelope components. Subunit and DNA vaccines, lipid extracts, liposomes and membrane vesicle formulations are some examples of technologies used, with encouraging results, to evaluate the potential of these antigens in the protective response against Mtb
Vector-borne transmission and evolution of Zika virus. Gutiérrez-Bugallo G, Piedra LA, Rodríguez M, Bisset JA, Lourenço-de-Oliveira R, Weaver SC, et al. Nat Ecol Evol. 2019 Apr;3(4)561–9.
Zika virus (ZIKV), discovered in the Zika Forest of Uganda in 1947, is a mosquito-borne flavivirus related to yellow fever, dengue and West Nile viruses. From its discovery until 2007, only sporadic ZIKV cases were reported, with mild clinical manifestations in patients. Therefore, little attention was given to this virus before epidemics in the South Pacific and the Americas that began in 2013. Despite a growing number of ZIKV studies in the past three years, many aspects of the virus remain poorly characterized, particularly the spectrum of species involved in its transmission cycles. Here, we review the mosquito and vertebrate host species potentially involved in ZIKV vector-borne transmission worldwide. We also provide an evidence-supported analysis regarding the possibility of ZIKV spillback from an urban cycle to a zoonotic cycle outside Africa, and we review hypotheses regarding recent emergence and evolution of ZIKV. Finally, we identify critical remaining gaps in the current knowledge of ZIKV vector-borne transmission.
