Influence of anti-carbamylated protein antibodies on disease activity and joint erosions in seronegative and seropositive rheumatoid arthritis.

Anti-carbamylated protein (anti-CarP) antibodies are promising biomarkers in rheumatoid arthritis (RA), although their significance in seronegative disease (SNRA) remains uncertain. To assess the influence of anti-CarP antibodies on disease activity and erosive joint damage in SNRA patients. In RA patients, rheumatoid factor (RF), anti-citrullinated protein antibodies, and anti-CarP antibodies were measured. Disease activity was assessed using DAS28-CRP and SDAI indices, while musculoskeletal ultrasound identified bone erosions. A total of 77 patients were enrolled, comprising 49 with seropositive RA (SPRA) and 28 with SNRA. Notably, 28% of SPRA and 10% of SNRA patients were positive to anti-CarP antibodies. Anti-CarP-positive patients exhibited elevated C-reactive protein (median 10.6, interquartile range 4.6-20.0 vs. 3.4, 1.7-9.9 mg/L; p = 0.005), erythrocyte sedimentation rate (34, 19-46 vs. 16, 7-25 mm/h; p = 0.002), DAS28-CRP (3.2, 2.6-4.2 vs. 2.6, 1.9-3.5; p = 0.048), and SDAI (19.9, 6.3-32.1 vs. 10.9, 5.5-18.1; p = 0.034) indices. Multivariate analysis revealed RF positivity as the sole predictor for anti-CarP antibodies (odds ratio [OR] = 5.9). Musculoskeletal ultrasound revealed bone erosions in 36% of RA patients; 35% among anti-CarP-negative patients and 40% among anti-CarP-positive patients. Notably, RF presence (OR = 44.3) and DAS28-CRP index (OR = 2.4) emerged as predictors of musculoskeletal ultrasound-confirmed erosive joint disease. Anti-CarP antibodies are detected at similar frequencies among both SPRA and SNRA patients. While associated with increased disease activity, these antibodies did not correlate with increased erosive joint damage.

Virtual reality and augmented reality as strategies for teaching social skills to individuals with intellectual disability: A systematic review.

Virtual reality (VR) and augmented reality (AR) programs have proliferated significantly in recent years and they are finding their way into different educational and therapeutic purposes. This systematic review aims at analyzing the virtual reality and augmented reality programs designed to promote the development of social skills in individuals with intellectual disability. Searches were carried out in the Scopus, Science Direct, Springer and Web of Science databases in the period from 2005 to 2020. A total of six articles met the inclusion criteria. A descriptive data analysis was performed. The results show that the clinical profile of the individuals who participated in the interventions is diverse. It can be concluded that there is some scientific evidence that points to the usefulness of VR and AR in the development of intervention programs to improve the social skills of individuals diagnosed with developmental deficits. However, it is necessary to acknowledge methodological limitations such as the lack of control groups, follow-up measures and of generalization of the results.

Ultrasmall Manganese Ferrites for In Vivo Catalase Mimicking Activity and Multimodal Bioimaging.

Manganese ferrite nanoparticles display interesting features in bioimaging and catalytic therapies. They have been recently used in theranostics as contrast agents in magnetic resonance imaging (MRI), and as catalase-mimicking nanozymes for hypoxia alleviation. These promising applications encourage the development of novel synthetic procedures to enhance the bioimaging and catalytic properties of these nanomaterials simultaneously. Herein, a cost-efficient synthetic microwave method is developed to manufacture ultrasmall manganese ferrite nanoparticles as advanced multimodal contrast agents in MRI and positron emission tomography (PET), and improved nanozymes. Such a synthetic method allows doping ferrites with Mn in a wide stoichiometric range (Mnx Fe3-x O4 , 0.1 ≤ x ≤ 2.4), affording a library of nanoparticles with different magnetic relaxivities and catalytic properties. These tuned magnetic properties give rise to either positive or dual-mode MRI contrast agents. On the other hand, higher levels of Mn doping enhance the catalytic efficiency of the resulting nanozymes. Finally, through their intracellular catalase-mimicking activity, these ultrasmall manganese ferrite nanoparticles induce an unprecedented tumor growth inhibition in a breast cancer murine model. All of these results show the robust characteristics of these nanoparticles for nanobiotechnological applications.

Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model.

Age-related Macular degeneration (AMD) is a degenerative disease of the macula affecting the elderly population. Treatment options are limited, partly due to the lack of understanding of AMD pathology and the lack of suitable research models that replicate the complexity of the human macula and the intricate interplay of the genetic, aging and lifestyle risk factors contributing to AMD. One of the main genetic risks associated with AMD is located on the Complement Factor H (CFH) gene, leading to an amino acid substitution in the Factor H (FH) protein (Y402H). However, the mechanism of how this FH variant promotes the onset of AMD remains unclear. Previously, we have shown that FH deprivation in RPE cells, via CFH silencing, leads to increased inflammation, metabolic impairment and vulnerability toward oxidative stress. In this study, we established a novel co-culture model comprising CFH silenced RPE cells and porcine retinal explants derived from the visual streak of porcine eyes, which closely resemble the human macula. We show that retinae exposed to FH-deprived RPE cells show signs of retinal degeneration, with rod cells being the first cells to undergo degeneration. Moreover, via Raman analyses, we observed changes involving the mitochondria and lipid composition of the co-cultured retinae upon FH loss. Interestingly, the detrimental effects of FH loss in RPE cells on the neuroretina were independent of glial cell activation and external complement sources. Moreover, we show that the co-culture model is also suitable for human retinal explants, and we observed a similar trend when RPE cells deprived of FH were co-cultured with human retinal explants from a single donor eye. Our findings highlight the importance of RPE-derived FH for retinal homeostasis and provide a valuable model for AMD research.

Albinism in Artibeus planirostris (Chiroptera, Phyllostomidae) in the Caatinga biome and updated list of albino bats in Brazil.

Albinism is a genetic disorder that results in a deficiency in melanin production. This type of chromatic alteration may affect several vertebrate species, but is rarely observed in nature. In Brazil, for the bat group, only 15 albino individuals have been registered. Here we present a new case for Artibeus planirostris. A pregnant female of this species with alopecia was captured in the Caatinga biome. A compilation of the distribution of albino bats in Brazil is presented.

A novel AAGAB mutation in a Peruvian family with punctate palmoplantar keratoderma.

Buschke-Fischer-Brauer (BFB) disease is a rare keratoderma characterized by multiple hyperkeratotic lesions on the palms and soles, with an autosomal dominant pattern. In several countries, some genetic alterations have been associated with this clinical entity. A 68-year-old Peruvian woman presenting with hyperkeratotic lesions on both her palms and soles was diagnosed with BFB keratoderma. After sequencing of the genes that had previously been related to this disease, a mutation (c.249C>G) that was predicted to generate a termination codon (Tyr83*) was found in the alpha and gamma adaptin binding protein P34 gene (AAGAB). After treatment with 30% urea plus 10% salicylic acid, the patient experienced an improvement in her condition. Here we report a novel mutation in the AAGAB gene of a patient diagnosed with BFB keratoderma and a treatment that improved her symptoms.

Survey of mosquito-borne flaviviruses in the Cuitzmala River Basin, Mexico: do they circulate in rodents and bats?

BACKGROUND: RNA viruses commonly infect bats and rodents, including mosquito-borne flaviviruses (MBFV) that affect human and animal health. Serological evidence suggests past interactions between these two mammalian orders with dengue viruses (DENV), West Nile virus (WNV), and yellow fever virus (YFV). Although in Mexico there are reports of these viruses in both host groups, we know little about their endemic cycles or persistence in time and space. METHODS: Rodents and bats were captured at the Cuitzmala River Basin on the Pacific coast of Jalisco state, Mexico, where MBFV, such as DENV, have been reported in both humans and bats. Samples were taken during January, June, and October 2014, at locations adjacent to the river. Tissue samples were collected from both bats and rodents and serum samples from rodents only. Highly sensitive serological and molecular assays were used to search for current and past evidence of viral circulation. RESULTS: One thousand nine hundred forty-eight individuals were captured belonging to 21 bat and 14 rodent species. Seven hundred sixty-nine liver and 764 spleen samples were analysed by means of a specific molecular protocol used to detect flaviviruses. Additionally, 708 serum samples from rodents were examined in order to demonstrate previous exposure to dengue virus serotype 2 (which circulates in the region). There were no positive results with any diagnostic test. DISCUSSION: To our knowledge, this is the first survey of rodents and only the second survey of bats from the Pacific Coast of Mexico in a search for MBFV. We obtained negative results from all samples. We validated our laboratory tests with negative and positive controls. Our findings are consistent with other empirical and experimental studies in which these mammalian hosts may not replicate mosquito-borne flaviviruses or present low prevalence. CONCLUSIONS: True-negative results are essential for the construction of distribution models and are necessary to identify potential areas at risk. Negative results should not be interpreted as the local absence of MBFV in the region. On the contrary, we need to establish a long-term surveillance programme to find MBFV presence in the mosquito trophic networks, identifying the potential role of rodents and bats in viral dynamics.

Transcriptional Profiling of Immune-Related Genes in Leishmania infantum-Infected Mice: Identification of Potential Biomarkers of Infection and Progression of Disease.

Leishmania spp. is a protozoan parasite that affects millions of people around the world. At present, there is no effective vaccine to prevent leishmaniases in humans. A major limitation in vaccine development is the lack of precise understanding of the particular immunological mechanisms that allow parasite survival in the host. The parasite-host cell interaction induces dramatic changes in transcriptome patterns in both organisms, therefore, a detailed analysis of gene expression in infected tissues will contribute to the evaluation of drug and vaccine candidates, the identification of potential biomarkers, and the understanding of the immunological pathways that lead to protection or progression of disease. In this large-scale analysis, differential expression of 112 immune-related genes has been analyzed using high-throughput qPCR in spleens of infected and naïve Balb/c mice at four different time points. This analysis revealed that early response against Leishmania infection is characterized by the upregulation of Th1 markers and M1-macrophage activation molecules such as Ifng, Stat1, Cxcl9, Cxcl10, Ccr5, Cxcr3, Xcl1, and Ccl3. This activation doesn't protect spleen from infection, since parasitic burden rises along time. This marked difference in gene expression between infected and control mice disappears during intermediate stages of infection, probably related to the strong anti-inflammatory and immunosuppresory signals that are activated early upon infection (Ctla4) or remain activated throughout the experiment (Il18bp). The overexpression of these Th1/M1 markers is restored later in the chronic phase (8 wpi), suggesting the generation of a classical "protective response" against leishmaniasis. Nonetheless, the parasitic burden rockets at this timepoint. This apparent contradiction can be explained by the generation of a regulatory immune response characterized by overexpression of Ifng, Tnfa, Il10, and downregulation Il4 that counteracts the Th1/M1 response. This large pool of data was also used to identify potential biomarkers of infection and parasitic burden in spleen, on the bases of two different regression models. Given the results, gene expression signature analysis appears as a useful tool to identify mechanisms involved in disease outcome and to establish a rational approach for the identification of potential biomarkers useful for monitoring disease progression, new therapies or vaccine development.

The Challenge of Stability in High-Throughput Gene Expression Analysis: Comprehensive Selection and Evaluation of Reference Genes for BALB/c Mice Spleen Samples in the Leishmania infantum Infection Model.

The interaction of Leishmania with BALB/c mice induces dramatic changes in transcriptome patterns in the parasite, but also in the target organs (spleen, liver…) due to its response against infection. Real-time quantitative PCR (qPCR) is an interesting approach to analyze these changes and understand the immunological pathways that lead to protection or progression of disease. However, qPCR results need to be normalized against one or more reference genes (RG) to correct for non-specific experimental variation. The development of technical platforms for high-throughput qPCR analysis, and powerful software for analysis of qPCR data, have acknowledged the problem that some reference genes widely used due to their known or suspected "housekeeping" roles, should be avoided due to high expression variability across different tissues or experimental conditions. In this paper we evaluated the stability of 112 genes using three different algorithms: geNorm, NormFinder and RefFinder in spleen samples from BALB/c mice under different experimental conditions (control and Leishmania infantum-infected mice). Despite minor discrepancies in the stability ranking shown by the three methods, most genes show very similar performance as RG (either good or poor) across this massive data set. Our results show that some of the genes traditionally used as RG in this model (i.e. B2m, Polr2a and Tbp) are clearly outperformed by others. In particular, the combination of Il2rg + Itgb2 was identified among the best scoring candidate RG for every group of mice and every algorithm used in this experimental model. Finally, we have demonstrated that using "traditional" vs rationally-selected RG for normalization of gene expression data may lead to loss of statistical significance of gene expression changes when using large-scale platforms, and therefore misinterpretation of results. Taken together, our results highlight the need for a comprehensive, high-throughput search for the most stable reference genes in each particular experimental model.

Drinking water quality in a Mexico city university community: perception and preferences.

A transversal study was conducted at the University City campus of the National Autonomous University of Mexico (UNAM) in Mexico City, with the goal of estimating the university community preference for drinking either tap water or bottled water and the reasons for their selection. A representative sample of three university community subpopulations (students, workers/administrative staff, and academic personnel) were interviewed with respect to their water consumption habits. The results showed that 75% of the university community drinks only bottled water and that the consumption of tap water is low. The interviewees responded that the main reason for this preference is the organoleptic features of tap water independent of quality. In general, the participants in this study do not trust the quality of the tap water, which could be caused by the facilities that distribute bottled water encouraging a general disinterest in learning about the origin and management of the tap water that is distributed on campus.

C2-domain abscisic acid-related proteins mediate the interaction of PYR/PYL/RCAR abscisic acid receptors with the plasma membrane and regulate abscisic acid sensitivity in Arabidopsis.

Membrane-delimited abscisic acid (ABA) signal transduction plays a critical role in early ABA signaling, but the molecular mechanisms linking core signaling components to the plasma membrane are unclear. We show that transient calcium-dependent interactions of PYR/PYL ABA receptors with membranes are mediated through a 10-member family of C2-domain ABA-related (CAR) proteins in Arabidopsis thaliana. Specifically, we found that PYL4 interacted in an ABA-independent manner with CAR1 in both the plasma membrane and nucleus of plant cells. CAR1 belongs to a plant-specific gene family encoding CAR1 to CAR10 proteins, and bimolecular fluorescence complementation and coimmunoprecipitation assays showed that PYL4-CAR1 as well as other PYR/PYL-CAR pairs interacted in plant cells. The crystal structure of CAR4 was solved, which revealed that, in addition to a classical calcium-dependent lipid binding C2 domain, a specific CAR signature is likely responsible for the interaction with PYR/PYL receptors and their recruitment to phospholipid vesicles. This interaction is relevant for PYR/PYL function and ABA signaling, since different car triple mutants affected in CAR1, CAR4, CAR5, and CAR9 genes showed reduced sensitivity to ABA in seedling establishment and root growth assays. In summary, we identified PYR/PYL-interacting partners that mediate a transient Ca(2+)-dependent interaction with phospholipid vesicles, which affects PYR/PYL subcellular localization and positively regulates ABA signaling.

Modeling potential effects of reduced calories in kids' meals with toy giveaways.

BACKGROUND: Given the large proportion of daily calories attributable to fast food, there is growing interest in considering whether ordinances that restrict calories in kids' meals with toy giveaways could avert weight gain among children. METHODS: Based upon a literature review and stakeholder feedback, a model was developed to estimate the potential number of children that could be affected by a statewide toy giveaway ordinance and the caloric savings should such a policy effectively reduce the number of calories in kids' meals with toy giveaways. Assumptions included the estimated number of children that eat fast food each day, the proportion that choose a kids' meal with a toy, the caloric savings of a kids' meal that meets nutrition standards, and the degree to which these savings could result in weight gain averted per child per year. RESULTS: Using New York as a case study, the model estimates that, on a typical day, 5% (163,571) of children 0-12 years of age in New York could be affected by a toy ordinance. A child who typically consumes fast food two times per week could avoid gaining approximately 2 pounds per year with an ordinance requiring kids' meals to be ≤550 calories. The amount of weight gain averted would vary according to the calorie limit set by the law and the frequency of consumption per week. CONCLUSIONS: Our model indicates that a reduction in calories in kids' meals with toy giveaways has the potential to positively affect weight gain in a considerable percentage of children. Limitations of the model are considered.

Invasive lionfish (Pterois volitans): a potential human health threat for ciguatera fish poisoning in tropical waters.

Invasive Indo-Pacific lionfish (Pterois volitans) have rapidly expanded in the Western Atlantic over the past decade and have had a significant negative impact on reef fish biodiversity, habitat, and community structure, with lionfish out-competing native predators for resources. In an effort to reduce this population explosion, lionfish have been promoted for human consumption in the greater Caribbean region. This study examined whether the geographical expansion of the lionfish into a known ciguatera-endemic region can pose a human health threat for ciguatera fish poisoning (CFP). More than 180 lionfish were collected from waters surrounding the US Virgin Islands throughout 2010 and 2011. Ciguatoxin testing included an in vitro neuroblastoma cytotoxicity assay for composite toxicity assessment of sodium-channel toxins combined with confirmatory liquid chromatography tandem mass spectrometry. A 12% prevalence rate of ciguatoxic lionfish exceeding the FDA guidance level of 0.1 µg/kg C-CTX-1 equivalents was identified in fish from the U.S. Virgin Islands, highlighting a potential consumption risk in this region. This study presents the first evidence that the invasive lionfish, pose a direct human health risk for CFP and highlights the need for awareness and research on this food safety hazard in known endemic areas.

Mercury, lead and cadmium levels in the urine of 170 Spanish adults: a pilot human biomonitoring study.

Human biomonitoring is a well-recognized tool for estimating the exposure of human populations to environmental pollutants. However, information regarding biomarker concentrations of many environmental chemicals in the general population is limited for many countries. The Spanish Environment Ministry has recently funded a human biomonitoring study on the Spanish general population. This study aims to determine reference levels for several biomarkers, especially heavy metals, persistent organic pollutants (POPs) and cotinine, in urine, whole blood, serum and hair, and will involve 2000 volunteers throughout Spain. Samples were taken during 2009-2010 and analyses are currently underway. The results presented herein were obtained in a pilot study carried out in the Madrid region. The study group comprised 170 volunteers, of which 79% were female and 21% male (age: 23-66 years). All participants were asked to complete a questionnaire regarding diet and living habits and provides a morning urine sample. The geometric means for total mercury (Hg), lead (Pb) and cadmium (Cd) were 1.23, 1.11 and 0.25 µg/g creatinine, respectively. Levels of Pb and Hg were higher than those reported for the general population in the USA and Germany, whereas Cd was in the same range (CDC, 2009; Becker et al., 2003). The values reported here are similar to those reported in other Spanish studies.

Toxic diatoms and domoic acid in natural and iron enriched waters of the oceanic Pacific.

Near-surface waters ranging from the Pacific subarctic (58°N) to the Southern Ocean (66°S) contain the neurotoxin domoic acid (DA), associated with the diatom Pseudo-nitzschia. Of the 35 stations sampled, including ones from historic iron fertilization experiments (SOFeX, IronEx II), we found Pseudo-nitzschia at 34 stations and DA measurable at 14 of the 26 stations analyzed for DA. Toxin ranged from 0.3 fg·cell(-1) to 2 pg·cell(-1), comparable with levels found in similar-sized cells from coastal waters. In the western subarctic, descent of intact Pseudo-nitzschia likely delivered significant amounts of toxin (up to 4 µg of DA·m(-2)·d(-1)) to underlying mesopelagic waters (150-500 m). By reexamining phytoplankton samples from SOFeX and IronEx II, we found substantial amounts of DA associated with Pseudo-nitzschia. Indeed, at SOFeX in the Antarctic Pacific, DA reached 220 ng·L(-1), levels at which animal mortalities have occurred on continental shelves. Iron ocean fertilization also occurs naturally and may have promoted blooms of these ubiquitous algae over previous glacial cycles during deposition of iron-rich aerosols. Thus, the neurotoxin DA occurs both in coastal and oceanic waters, and its concentration, associated with changes in Pseudo-nitzschia abundance, likely varies naturally with climate cycles, as well as with artificial iron fertilization. Given that iron fertilization in iron-depleted regions of the sea has been proposed to enhance phytoplankton growth and, thereby, both reduce atmospheric CO(2) and moderate ocean acidification in surface waters, consideration of the potentially serious ecosystem impacts associated with DA is prudent.

Comparison of functional regression and nonfunctional regression approaches to the study of the walking velocity effect in force platform measures.

The effect of walking velocity on force platform measures is examined by means of functional regression and nonfunctional regression analyses. The two techniques are compared using a data set of ground reaction forces. Functional data analysis avoids the need to identify significant points, and provides more information along the waveform.

Polytene chromosomal maps of 11 Drosophila species: the order of genomic scaffolds inferred from genetic and physical maps.

The sequencing of the 12 genomes of members of the genus Drosophila was taken as an opportunity to reevaluate the genetic and physical maps for 11 of the species, in part to aid in the mapping of assembled scaffolds. Here, we present an overview of the importance of cytogenetic maps to Drosophila biology and to the concepts of chromosomal evolution. Physical and genetic markers were used to anchor the genome assembly scaffolds to the polytene chromosomal maps for each species. In addition, a computational approach was used to anchor smaller scaffolds on the basis of the analysis of syntenic blocks. We present the chromosomal map data from each of the 11 sequenced non-Drosophila melanogaster species as a series of sections. Each section reviews the history of the polytene chromosome maps for each species, presents the new polytene chromosome maps, and anchors the genomic scaffolds to the cytological maps using genetic and physical markers. The mapping data agree with Muller's idea that the majority of Drosophila genes are syntenic. Despite the conservation of genes within homologous chromosome arms across species, the karyotypes of these species have changed through the fusion of chromosomal arms followed by subsequent rearrangement events.

Inspiring healthy adolescent choices: a rationale for and guide to strength promotion in primary care.

The social, emotional, and biological health of adolescents requires their development as autonomous beings who make responsible decisions about their own health. Clinicians can assist in this development by adopting a strength-based approach to adolescent health care, which applies concepts from positive youth development to the medical office setting.