Fostamatinib effectiveness and safety for immune thrombocytopenia in clinical practice.

ABSTRACT: Fostamatinib, a recently approved Syk inhibitor used in adult primary immune thrombocytopenia (ITP), has been shown to be safe and effective in this disorder. However, clinical trial results may not be similarly reproduced in clinical practice. Here, 138 patients with ITP (both primary and secondary) from 42 Spanish centers who had been treated with fostamatinib were evaluated prospectively and retrospectively. The median age of our cohort (55.8% women) was 66 years (interquartile range [IQR], 56-80). The median time since ITP diagnosis at fostamatinib initiation was 51 months (IQR, 10-166). The median number of therapies before fostamatinib initiation was 4 (IQR, 2-5), including eltrombopag (76.1%), romiplostim (57.2%), and IV immunoglobulins (44.2%). Fifty-eight patients (42.0%) had signs/symptoms of bleeding in the month before treatment initiation. Seventy-nine percent of patients responded to fostamatinib with 53.6% complete responses (platelet count > 100 × 109/L). Eighty-three patients (60.1%) received fostamatinib monotherapy, achieving a high response rate (85.4%). The proportion of time in response during the 27-month period examined was 83.3%. The median time to platelet response was 11 days (IQR, 7-21). Sixty-seven patients (48.5%) experienced adverse events, mainly grade 1 to 2; the commonest of which were diarrhea (n = 28) and hypertension (n = 21). One patient had deep venous thrombosis, and one patient developed acute myocardial infarction. Fostamatinib was shown to be effective with good safety profile in patients with primary and secondary ITP across a wide age spectrum in this real-world study.

Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49fhigh cells. The disruption of the S100A enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.

Neuroplastin genetically interacts with Cadherin 23 and the encoded isoform Np55 is sufficient for cochlear hair cell function and hearing.

Mammalian hearing involves the mechanoelectrical transduction (MET) of sound-induced fluid waves in the cochlea. Essential to this process are the specialised sensory cochlear cells, the inner (IHCs) and outer hair cells (OHCs). While genetic hearing loss is highly heterogeneous, understanding the requirement of each gene will lead to a better understanding of the molecular basis of hearing and also to therapeutic opportunities for deafness. The Neuroplastin (Nptn) gene, which encodes two protein isoforms Np55 and Np65, is required for hearing, and homozygous loss-of-function mutations that affect both isoforms lead to profound deafness in mice. Here we have utilised several distinct mouse models to elaborate upon the spatial, temporal, and functional requirement of Nptn for hearing. While we demonstrate that both Np55 and Np65 are present in cochlear cells, characterisation of a Np65-specific mouse knockout shows normal hearing thresholds indicating that Np65 is functionally redundant for hearing. In contrast, we find that Nptn-knockout mice have significantly reduced maximal MET currents and MET channel open probabilities in mature OHCs, with both OHCs and IHCs also failing to develop fully mature basolateral currents. Furthermore, comparing the hearing thresholds and IHC synapse structure of Nptn-knockout mice with those of mice that lack Nptn only in IHCs and OHCs shows that the majority of the auditory deficit is explained by hair cell dysfunction, with abnormal afferent synapses contributing only a small proportion of the hearing loss. Finally, we show that continued expression of Neuroplastin in OHCs of adult mice is required for membrane localisation of Plasma Membrane Ca2+ ATPase 2 (PMCA2), which is essential for hearing function. Moreover, Nptn haploinsufficiency phenocopies Atp2b2 (encodes PMCA2) mutations, with heterozygous Nptn-knockout mice exhibiting hearing loss through genetic interaction with the Cdh23ahl allele. Together, our findings provide further insight to the functional requirement of Neuroplastin for mammalian hearing.

Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell­ and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFß1). Blocking TGFß signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cell­stem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

A comprehensive assessment of care competence and maternal experience of first antenatal care visits in Mexico: Insights from the baseline survey of an observational cohort study.

BACKGROUND: Comprehensive antenatal care (ANC) must prioritize competent, evidence-based medical attention to ensure a positive experience and value for its users. Unfortunately, there is scarce evidence of implementing this holistic approach to ANC in low- and middle-income countries, leading to gaps in quality and accountability. This study assessed care competence, women's experiences during the first ANC visit, and the factors associated with these care attributes. METHODS AND FINDINGS: The study analyzed cross-sectional baseline data from the maternal eCohort study conducted in Mexico from August to December 2023. The study adapted the Quality Evidence for Health System Transformation (QuEST) network questionnaires to the Mexican context and validated them through expert group and cognitive interviews with women. Pregnant women aged 18 to 49 who had their first ANC visit with a family physician were enrolled in 48 primary clinics of the Instituto Mexicano del Seguro Social across 8 states. Care competence and women's experiences with care were the primary outcomes. The statistical analysis comprised descriptive statistics, multivariable linear and Poisson regressions. A total of 1,390 pregnant women were included in the study. During their first ANC visit, women received only 67.7% of necessary clinical actions on average, and 52% rated their ANC experience as fair or poor. Women with previous pregnancies (adjusted regression coefficient [aCoef.] -3.55; (95% confidence intervals [95% CIs]): -4.88, -2.22, p < 0.001), at risk of depression (aCoef. -3.02; 95% CIs: -5.61, -0.43, p = 0.023), those with warning signs (aCoef. -2.84; 95% CIs: -4.65, -1.03, p = 0.003), common pregnancy discomforts (aCoef. -1.91; 95% CIs: -3.81, -0.02, p = 0.048), or those who had a visit duration of less than 20 minutes (<15 minutes: aCoef. -7.58; 95% CIs: -10.21, -4.95, p < 0.001 and 15 to 19 minutes: aCoef. -2.73; 95% CIs: -4.79, -0.67, p = 0.010) and received ANC in the West and Southeast regions (aCoef. -5.15; 95% CIs: -7.64, -2.66, p < 0.001 and aCoef. -5.33; 95% CIs: -7.85, -2.82, p < 0.001, respectively) had a higher probability of experiencing poorer care competence. Higher care competence (adjusted prevalence ratio [aPR] 1.004; 95% CIs:1.002, 1.005, p < 0.001) and receiving care in a small clinic (aPR 1.19; 95% CIs: 1.06, 1.34, p = 0.003) compared to a medium-sized clinic were associated with a better first ANC visit experience, while common pregnancy discomforts (aPR 0.94; 95% CIs: 0.89, 0.98, p = 0.005) and shorter visit length (aPR 0.94; 95% CIs: 0.88, 0.99, p = 0.039) were associated with lower women's experience. The primary limitation of the study is that participants' responses may be influenced by social desirability bias, leading them to provide socially acceptable responses. CONCLUSIONS: We found important gaps in adherence to ANC standards and that care competence during the first ANC visit is an important predictor of positive user experience. To inform quality improvement efforts, IMSS should institutionalize the routine monitoring of ANC competencies and ANC user experience. This will help identify poorly performing facilities and providers and address gaps in the provision of evidence-based and women-centered care.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Sub-Doppler spectroscopy of the Cs atom 6S1/2-7P1/2 transition at 459 nm in a microfabricated vapor cell.

We report on the characterization of sub-Doppler resonances detected by probing the 6S1/2 - 7P1/2 transition of the Cs atom at 459 nm in a microfabricated vapor cell. The dependence of the sub-Doppler resonance (linewidth, amplitude) on some key experimental parameters, including the laser intensity and the cell temperature, is investigated. These narrow atomic resonances are of interest for high-resolution spectroscopy and instrumentation and may constitute the basis of a high-stability microcell optical standard.

ZnO-Salen NPs Employed as Chemosensor for Detection of Al3+ and K+ in Aqueous Medium, Developing Human Cell Images.

ZnO nanoparticles (NPs) were prepared and characterized by different analytical methods and then they were used to decorate with N, N´-bis(salicylidene)ethylenediamine (salen) in order to perform as receptor for the metal ions in an aqueous medium. The results show that ZnO-salen selectively detects Al3+ ions in aqueous medium since the intensity of fluorescence has been enhanced significantly. However, the presence of K+ in the medium further intensified the fluorescence emission for the [ZnO-salen-Al3+] system. The above system has been applied to recognize Al3+ and K+ in cells by developing the cell images, for which, the fluorescence image is brightened if a human glioblastoma U251 cell contains [ZnO-salen-Al3+] + K+ ions, consisting of the fluorescence titration. The binding global constant for Al3+ and the subsequent recognition of K+ by ZnO-salen resulted in ß2(Al3+) = 6.61 × 103 and ß2(K+) = 3.71 × 103 with a detection limit of 36.51 µM for Al3+ and 17.39 µM for K+. In the cell toxicity analysis, the cell viability was over 85% for the ZnO-salen even in the concentration as high as 100 mM.

The order of stimuli matters when learning second-order transitional probabilities.

The order of stimuli within sequences and the transitional probabilities (TPs) it generates are central information in sequence processing. However, less is known about what type of information and how it is extracted by general learning mechanisms. The present study focused on statistical learning of second-order TPs. Second-order TPs are involved when only the combination of two stimuli predicts the third. In a first experiment, TPs depended crucially on the order of presentation of a pair A - B , which led to different predictions depending on the order of the stimuli (i.e., ABC vs. BAF). Eight visuomotor sequences governed by second-order TPs were used and response times (RTs) were recorded for each transition. The task included a learning phase followed by a switch phase during which the second-order TP were reversed (e.g., the sequences ABC and BAF became respectively ABF and BAC). A decrease of RTs between the second and the third stimulus during the learning phase and an increase of RTs during the switch phase suggested that variations of orders within second-order TPs could be learned. Further analyses, however, indicated that such learning was difficult for most participants. A second experiment showed that the difficulty of learning was not solely due to the difficulty to pick up the effect of order of presentation, but that learning second-order transitional probabilities in addition to order would be the main obstacle. These experiments suggest that statistical learning is capable of learning complex associations, even if this remains a challenge for human cognition.

PTVR - A software in Python to make virtual reality experiments easier to build and more reproducible.

Researchers increasingly use virtual reality (VR) to perform behavioral experiments, especially in vision science. These experiments are usually programmed directly in so-called game engines that are extremely powerful. However, this process is tricky and time-consuming as it requires solid knowledge of game engines. Consequently, the anticipated prohibitive effort discourages many researchers who want to engage in VR. This paper introduces the Perception Toolbox for Virtual Reality (PTVR) library, allowing visual perception studies in VR to be created using high-level Python script programming. A crucial consequence of using a script is that an experiment can be described by a single, easy-to-read piece of code, thus improving VR studies' transparency, reproducibility, and reusability. We built our library upon a seminal open-source library released in 2018 that we have considerably developed since then. This paper aims to provide a comprehensive overview of the PTVR software for the first time. We introduce the main objects and features of PTVR and some general concepts related to the three-dimensional (3D) world. This new library should dramatically reduce the difficulty of programming experiments in VR and elicit a whole new set of visual perception studies with high ecological validity.

[Association between transtheoretical model and physical activity in patients with hypertension]. / Modelo transteórico y su asociación con la actividad física en pacientes con hipertensión arterial.

OBJECTIVE: To identify the association between the transtheoretical model (TTM) and physical activity (PA) carried out in free time in patients with arterial hypertension in the central region of Mexico. DESIGN: Comparative cross-sectional study. SITE: The study was carried out in the Family Medicine Unit No.1 (UFM1) of the Mexican Social Security Institute in Aguascalientes, Mexico. PARTICIPANTS: Four hundred thirty-five adults aged 40 to 70 with arterial hypertension who attended the outpatient clinic at UFM1 were included. INTERVENTIONS: The Global Physical Activity Questionnaire and the Stages of Change algorithm from the TTM were applied. MAIN MEASUREMENTS: A descriptive, bivariate analysis and ordinal logistic regression were performed to evaluate the association between TTM stages and PA. RESULTS: As patients progress through the stages of change, their weekly PA increased. Individuals in the action, maintenance and consolidation stages were significantly more likely to perform higher levels of exercise: 20 times more likely in the action stage with an ordinal odds ratio (OR) of 20.07 (CI95%: 10,52-38,25), 24 times more in the maintenance stage with OR 24 (CI95%: 12,79-47,63) and 40 times more in the consolidation stage with OR 40,35 (IC95%: 19,25-84,59). CONCLUSIONS: The strong association between the stages of change and PA reveals the importance of applying the TTM to achieve success in programs to promote healthy habits by designing strategies that suit each subject.

Macrophage-mediated PDGF Activation Correlates With Regenerative Outcomes Following Musculoskeletal Trauma.

OBJECTIVE: Our objective was to identify macrophage subpopulations and gene signatures associated with regenerative or fibrotic healing across different musculoskeletal injury types. BACKGROUND: Subpopulations of macrophages are hypothesized to fine tune the immune response after damage, promoting either normal regenerative, or aberrant fibrotic healing. METHODS: Mouse single-cell RNA sequencing data before and after injury were assembled from models of musculoskeletal injury, including regenerative and fibrotic mouse volumetric muscle loss (VML), regenerative digit tip amputation, and fibrotic heterotopic ossification. R packages Harmony , MacSpectrum , and Seurat were used for data integration, analysis, and visualizations. RESULTS: There was a substantial overlap between macrophages from the regenerative VML (2 mm injury) and regenerative bone models, as well as a separate overlap between the fibrotic VML (3 mm injury) and fibrotic bone (heterotopic ossification) models. We identified 2 fibrotic-like (FL 1 and FL 2) along with 3 regenerative-like (RL 1, RL 2, and RL 3) subpopulations of macrophages, each of which was transcriptionally distinct. We found that regenerative and fibrotic conditions had similar compositions of proinflammatory and anti-inflammatory macrophages, suggesting that macrophage polarization state did not correlate with healing outcomes. Receptor/ligand analysis of macrophage-to-mesenchymal progenitor cell crosstalk showed enhanced transforming growth factor ß in fibrotic conditions and enhanced platelet-derived growth factor signaling in regenerative conditions. CONCLUSION: Characterization of macrophage subtypes could be used to predict fibrotic responses following injury and provide a therapeutic target to tune the healing microenvironment towards more regenerative conditions.

Spotlight on mycobacterial lipid exploitation using nanotechnology for diagnosis, vaccines, and treatments.

Tuberculosis (TB), historically the most significant cause of human morbidity and mortality, has returned as the top infectious disease worldwide, under circumstances worsened by the COVID-19 pandemic's devastating effects on public health. Although Mycobacterium tuberculosis, the causal agent, has been known of for more than a century, the development of tools to control it has been largely neglected. With the advancement of nanotechnology, the possibility of engineering tools at the nanoscale creates unique opportunities to exploit any molecular type. However, little attention has been paid to one of the major attributes of the pathogen, represented by the atypical coat and its abundant lipids. In this review, an overview of the lipids encountered in M. tuberculosis and interest in exploiting them for the development of TB control tools are presented. Then, the amalgamation of nanotechnology with mycobacterial lipids from both reported and future works are discussed.

Iron-Catalyzed Reductive Cross-Coupling of Alkyl Electrophiles with Olefins.

In terms of its abundance and its minimal toxicity, iron has advantages relative to other transition metals. Although alkyl-alkyl bond construction is central to organic synthesis, examples of iron-catalyzed alkyl-alkyl couplings of alkyl electrophiles are relatively sparse. Herein we report an iron catalyst that achieves cross-coupling reactions of alkyl electrophiles wherein olefins, in the presence of a hydrosilane, are used in place of alkylmetal reagents. Carbon-carbon bond formation proceeds at room temperature, and the method employs commercially available components (Fe(OAc)2 , Xantphos, and Mg(OEt)2 ); interestingly, this set of reagents can be applied directly to a distinct hydrofunctionalization of olefins, hydroboration. Mechanistic studies are consistent with the generation of an alkyl radical from the alkyl electrophile, as well as with reversibility for elementary steps that precede carbon-carbon bond formation (olefin binding to iron and ß-migratory insertion).

Recovery of polyclonal immunoglobulins during treatment in patients ineligible for autologous stem-cell transplantation is a prognostic marker of longer progression-free survival and overall survival.

Immunoparesis is the suppression of normal polyclonal immunoglobulins and is present in most patients with newly diagnosed multiple myeloma (MM). The association of immunoparesis at diagnosis, and particularly its recovery along with treatment, with survival in patients ineligible for autologous stem-cell transplantation (ASCT) has not been well established. This retrospective study evaluated the impact of immunoparesis in 431 patients diagnosed with MM, ineligible for ASCT, with a median overall survival of 36 months [95% confidence interval (CI): 31-40]. Immunoparesis was present in 81.2% of patients at diagnosis and was associated with a trend to a worse overall response rate (ORR: 84.8% vs. 74.9%; OR 1.88 (95% CI: 0.97-3.63), shorter progression-free survival (PFS) [22.0 vs. 18.2 months; hazard ratio (HR) 0.775; 95%CI: 0.590-1.018; p = 0.066], and overall survival (OS) (45.9 vs. 34.2 months; HR 0.746; 95% CI: 0.551-1.010; p = 0.057). Twenty-four per cent of patients who had immunoparesis at diagnosis recovered polyclonal immunoglobulins in the follow-up period. Interestingly, these patients had a better ORR (96.3% vs. 68.2%; OR 12.29 (95% CI: 3.77-40.06), PFS (HR 0.703; 95CI%: 0.526-0.941; p = 0.018) and OS (HR 0.678; 95 CI%: 0.503-0.913; p = 0.011) than patients who did not recover it. In summary, restoring a healthy immune system along with first-line treatment in patients with MM, not receiving ASCT, is associated with better outcomes.

TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features.

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3'IGH (del-3'IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3'IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3'IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3'IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3'IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3'IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.

Tuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis.

Myeloid cells are critical to the development of fibrosis following muscle injury; however, the mechanism of their role in fibrosis formation remains unclear. In this study, we demonstrate that myeloid cell-derived TGF-ß1 signaling is increased in a profibrotic ischemia reperfusion and cardiotoxin muscle injury model. We found that myeloid-specific deletion of Tgfb1 abrogates the fibrotic response in this injury model and reduces fibro/adipogenic progenitor cell proliferation while simultaneously enhancing muscle regeneration, which is abrogated by adaptive transfer of normal macrophages. Similarly, a murine TGFBRII-Fc ligand trap administered after injury significantly reduced muscle fibrosis and improved muscle regeneration. This study ultimately demonstrates that infiltrating myeloid cell TGF-ß1 is responsible for the development of traumatic muscle fibrosis, and its blockade offers a promising therapeutic target for preventing muscle fibrosis after ischemic injury.

Matrix metalloproteinase-2 and matrix metalloproteinase-9 serum levels in patients with vertebrobasilar dolichoectasia with and without stroke: case-control study.

PURPOSE: To describe the differences in the serum levels of MMP-2 and MMP-9 of patients with vertebrobasilar dolichoectasia (VBD) with and without acute stroke. METHODS: Case-control study. From an outpatient clinic, we recruited 14 controls and 19 patients with VBD. We also recruited 33 patients with stroke from two emergency departments, 14 without VBD (S/-VBD) and 19 with VBD (S/ + VBD). All the patients underwent serum MMP-2 and MMP-9 measurements and a non-contrast CT scan. Two investigators assessed the intracranial vertebral arteries (VA) and the basilar artery (BA) at the mid-pons. Diagnosis of VBD was made if the BA diameter was ≥ 4.5 mm. RESULTS: The mean age of the 66 patients studied was 57.6 + 16.0 years, 41% female. In the 33 patients with stroke, the median NIHSS was 8 (range 15); there were no differences in the NIHSS scores between both groups with stroke. Median MMP-2 levels were lower in the S/-VBD when compared to controls. Median MMP-9 serum levels were higher in both groups with VBD when compared to controls and the S/-VDB group. Both groups with stroke exhibited higher MMP-9 serum levels than controls but were not statistically different from those found in patients with VBD. Serum levels of MMP-9 were significantly correlated with the diameters of the BA (r = 0.344, p = 0.01) and the left VA (r = 0.305, p = 0.05). CONCLUSION: This study found that high serum levels of MMP-9 are associated with VBD independently of stroke and correlated with the degree of VBD.

Content and Quality of Information about Stroke in Wikipedia across Multiple Languages.

BACKGROUND: Given the high contribution of stroke to the global burden of disease, there is a need for good-quality information on Web platforms such as Wikipedia. AIMS: This study aimed to describe the quality of the Wikipedia articles on stroke written in different languages. METHODS: We studied the world's 30 most spoken languages. With the DISCERN score, we evaluated the quality of the information within the Wikipedia articles. Three investigators assessed each of the texts translated to English. We also registered the word count, the number of references, and if the text referred to the emergency status of stroke, cues to suspect a stroke, and allusions to endovascular treatment. RESULTS: There is a Wikipedia article for stroke in 23 out of the 30 languages. The mean DISCERN score was 35 29.9 ± 9.2. Overall quality ranged from 3/5 in 26.1% to 1/5 in 17.4%. Word count had a mean of 36 3,145.8 ± 3,048.9 words, and the texts included a mean of 43.1 ± 57.3 references; 69.6% of the articles referred to stroke as a medical emergency, 52.2% included awareness symptoms, and 34.8% included endovascular management among the stroke treatments. Three pages included steroids as part of the stroke treatment. The DISCERN score was not correlated with the number of speakers, but it was positively correlated with the number of references (r = 0.90, p < 0.001) and the number of words (r = 0.78, p < 0.001) in the articles. CONCLUSION: The analyzed Wikipedia articles do not contain relevant and up-to-date information to the general population. Further, the content varies widely across the different languages and is missing for some of them. The missing versions disproportionally affect millions of potential information seekers in undeveloped countries.

Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation.

Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of ß-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and Hacl1-/- mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the Hacl1-/- liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in Hacl1-/- mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1-/- mice in better understanding disease mechanism in fatty acid α-oxidation disorders.