Miracle-dz/UniFAR-FTUs huggingface dataset:
Glatiramer Acetate Stimulates Regulatory B Cell Functions

The control of the activities of regulatory B (Breg) cells in immune disorders is an emerging therapeutic strategy for the recovery of immune homeostasis. Manipulating B cells using numerous drugs in vivo affect their regulatory functions, although a direct link has not yet been demonstrated. Glatiramer acetate (GA) is a synthetic polypeptide that is used in the treatment of inflammatory and autoimmune diseases. We experimented on an in vitro coculture system to determine its direct effects on the Breg cell properties of human B cells. We found that GA improves the B cell–dependent control of T cells’ immune responses. When B cells are stimulated by GA, the T cell proliferation and their Th1 IFN-γ production are further inhibited, whereas the B cell production of IL-10 is further enhanced. GA binds preferentially to the memory B cells and the activation of sorted B cell subsets shows that GA-dependent increased Breg cell activities are specifically supported by the B cells’ memory compartment. Moreover, we found that the defective regulations that emerge from the B cells of systemic lupus erythematosus patients can be restored by GA stimulation. Overall, these data demonstrate that GA stimulates the Breg functions mainly by shifting the memory B cells known to contribute to the T cell–dependent inflammatory response into Breg cells. Our results also indicate that GA treatment could be a useful therapy for recovering the Breg cells in autoimmune situations in which their activities are defective.
Toward an understanding of bisretinoid autofluorescence bleaching and recovery.

PURPOSE To understand molecular mechanisms underlying photobleaching of the RPE fluorophores responsible for fundus autofluorescence. METHODS ARPE-19 cells were allowed to accumulate the bisretinoid, A2E, and were irradiated at 430 nm. For some experiments, the cells were pretreated with vitamin E or sulforaphane and N-acetylcysteine; samples included A2E-free cells. The cells were analyzed by fluorescence microscopy and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) analysis. A2E free cells were also irradiated and analyzed. Cell death was quantified by double labeling with a membrane impermeable dye and 4',6'-diamino-2-phenylindole (DAPI). RESULTS A2E that had accumulated in ARPE-19 cells exhibited irradiation-associated autofluorescence bleaching despite the absence of appreciable cell death. Chromatographic analysis with absorbance, fluorescence, and mass spectrometry detection revealed that irradiation of A2E was associated with A2E photoisomerization, photooxidation, and photodegradation. Pretreatment with vitamin E favored fluorescence recovery; this finding was consistent with a process involving photooxidation. A2E that was not cell-associated underwent irradiation-induced bleaching, but fluorescence recovery was not observed. CONCLUSIONS Using cell-associated A2E as a model of RPE bisretinoid behavior, photobleaching and autofluorescence recovery was observed; these changes were similar to RPE autofluorescence reduction in vivo. The potential for autofluorescence recovery is dependent on light dose and antioxidant status. Fluorescence bleaching of bisretinoid involves photooxidative and photodegradative processes.
Comparative Characterization of Human and Equine Mesenchymal Stromal Cells: A Basis for Translational Studies in the Equine Model

Multipotent mesenchymal stromal cells (MSCs) have gained tremendous attention as potential therapeutic agents for the treatment of orthopedic diseases. Promising results have been obtained after application of MSCs for treatment of tendon and joint disease in the equine model, making it appear favorable to use these results as a basis for the translational process of the therapy. However, while the horse is considered a highly suitable model for orthopedic diseases, knowledge is lacking regarding the level of analogy of equine MSCs and their human counterparts. Therefore, the aim of this study was to assess the properties of human and equine adipose-and tendon-derived MSCs in a direct comparison. Basic properties of human and equine MSCs from both tissues were similar. The cells expressed CD29, CD44, CD90, and CD105 and lacked expression of CD73, CD14, CD34, CD45, CD79a, and MCHII/HLA-DR. No significant differences were found between proliferation potential of human and equine MSCs in early passages, but recovery of nucleated cells after tissue digestion as well as proliferation in later passages was higher in equine samples (p < 0.01). All samples showed a good migration capacity and multilineage differentiation potential. However, while osteogenic differentiation was achieved in all equine samples, it was only evident in five out of nine human tendon-derived samples. Human MSCs further showed a higher expression of collagen IIIA1 and tenascin-C, but lower expression of decorin and scleraxis (p < 0.01). Although revealing some potentially relevant differences, the study demonstrates a high level of analogy between human and equine MSCs, providing a basis for translational research in the equine model according to the guidelines issued by the authorities.
Rod Photoresponse Kinetics Limit Temporal Contrast Sensitivity in Mesopic Vision

The mammalian visual system operates over an extended range of ambient light levels by switching between rod and cone photoreceptors. Rod-driven vision is sluggish, highly sensitive, and operates in dim or scotopic lights, whereas cone-driven vision is brisk, less sensitive, and operates in bright or photopic lights. At intermediate or mesopic lights, vision transitions seamlessly from rod-driven to cone-driven, despite the profound differences in rod and cone response dynamics. The neural mechanisms underlying such a smooth handoff are not understood. Using an operant behavior assay, electrophysiological recordings, and mathematical modeling we examined the neural underpinnings of the mesopic visual transition in mice of either sex. We found that rods, but not cones, drive visual sensitivity to temporal light variations over much of the mesopic range. Surprisingly, speeding up rod photoresponse recovery kinetics in transgenic mice improved visual sensitivity to slow temporal variations, in the range where perceptual sensitivity is governed by Weber's law of sensation. In contrast, physiological processes acting downstream from phototransduction limit sensitivity to high frequencies and temporal resolution. We traced the paradoxical control of visual temporal sensitivity to rod photoresponses themselves. A scenario emerges where perceptual sensitivity is limited by: (1) the kinetics of neural processes acting downstream from phototransduction in scotopic lights, (2) rod response kinetics in mesopic lights, and (3) cone response kinetics as light levels rise into the photopic range. SIGNIFICANCE STATEMENT Our ability to detect flickering lights is constrained by the dynamics of the slowest step in the visual pathway. Cone photoresponse kinetics limit visual temporal sensitivity in bright (photopic) lights, whereas mechanisms in the inner retina limit sensitivity in dim (scotopic) lights. The neural mechanisms underlying the transition between scotopic and photopic vision in mesopic lights, when both rods are cones are active, are unknown. This study provides a missing link in this mechanism by establishing that rod photoresponse kinetics limit temporal sensitivity during the mesopic transition. Surprisingly, this range is where Weber's Law of Sensation governs temporal contrast sensitivity in mouse. Our results will help guide future studies of complex and dynamic interactions between rod–cone signals in the mesopic retina.
Safety of Pregnancy After Cerebral Venous Thrombosis: A Systematic Review

Background and Purpose— Pregnancy and puerperium are associated with an increased risk of venous thrombotic events (VTEs), including cerebral venous thrombosis (CVT). We aimed to systematically review, in pregnant woman with previous CVT, (1) the risk of recurrence of CVT or other VTE; (2) the result of pregnancy; and (3) the association of antithrombotic prophylaxis with these outcomes. Methods— We searched MEDLINE, Cochrane Database of Systematic Reviews, clinicaltrials.gov (from inception to July 2015), and reference lists of included studies and review articles. We considered observational studies reporting original data on the frequency of CVT or other VTE associated with pregnancy or puerperium in women with history of CVT. Results— Thirteen studies were included. A simple pooled analysis of individual patient data and meta-analysis of proportions using a random effect model were performed. (1) 1 CVT recurrences/217 pregnancies (9 per 1000; 95% confidence interval, 3–33) and 5 noncerebral VTE/186 pregnancies (27 per 1000; 95% confidence interval, 12–61). (2) Pregnancy outcome: 33 spontaneous abortions/186 pregnancies (17.7%; 95% confidence interval, 13–24). (3) Data on the risk of CVT/extracerebral VTE according to antithrombotic prophylaxis was limited. Miscarriage did not differ significantly in women undergoing antithrombotic therapy or not (11.3% versus 18.8%; P=0.34). Conclusions— In women with previous CVT, the absolute risk of pregnancy-related venous thrombosis is low but the relative risk of noncerebral VTE is 16-fold higher and the recurrence of CVT is 80-fold higher than the baseline risk described in general population studies. The rate of miscarriage is not significantly different from that estimated for the general population.
Patient-Reported Outcomes and Readmission after Ileostomy Creation in Older Adults

Because of the concern about risk of poor outcome, ileostomy creation is sometimes avoided in older adults. We sought to evaluate the effect of a rigorous postoperative pathway and checklist on readmission and self-efficiacy in older surgical patients. After implementing a self-care checklist and standardized care pathway at our institution, we performed a retrospective review of patients between June 2013 and June 2016 and compared characteristics and outcomes for patients aged <65 and ≥65 years. Using logistic regression, we identified independent predictors of readmission. We also conducted a survey of patient self-efficacy after discharge to assess independence. There were 288 younger patients and 72 older patients. The older group had more patients with an American Society of Anesthesiologists >2 (53.0% vs 81.4%, P < 0.01) and were more likely to have had surgery for cancer (22.9% vs 48.5%, P < 0.01). In the multivariable analyses, age was not a predictor of readmission but American Society of Anesthesiologist and length of stay were. In the 57 patients surveyed after discharge, we found that older and younger patients reported similar self-efficacy scores. In our study, older and younger patients have similar rates of readmission and similar ability to independently care for their themselves after ileostomy creation.
Targeting Thioredoxin Reductase by Ibrutinib Promotes Apoptosis of SMMC-7721 Cells

Ibrutinib (IBT), the first-in-class inhibitor of Bruton’s tyrosine kinase (BTK), has demonstrated clinical activity against various B-cell malignancies. Aside from its therapeutic mechanism through BTK inhibition, IBT has other target sites reported for cancer therapy, leading us to investigate whether IBT has unreported targets. Our study revealed that IBT can inhibit SMMC-7721 cells through irreversible inhibition of mammalian thioredoxin reductase enzymes. Further study demonstrated that IBT can cause cellular reactive oxygen species elevation and induce cancer cell apoptosis. The discovery of a new target of IBT sheds light on better understanding its anticancer mechanisms and provides a theoretical foundation for its further use in clinical therapy.
Visuospatial Ability and Memory Are Associated with Falls Risk in Older People

Background/Aims: Our purpose was to examine whether falls risk is associated with cognitive functions beyond executive function/attention and processing speed. Methods: Cognitive function was measured in a population-based sample (n = 300) of people aged 60–86 years. The physiological profile assessment was used to estimate the falls risk. Results: After adjusting for confounders, visual construction (p < 0.01), executive function/attention and memory (both p < 0.05) were independently associated with falls risk. The associations for visual construction (p < 0.01) and memory (p < 0.01) remained after adjusting for executive function/ attention. Conclusions: The neural basis underlying the associations of visuospatial function and memory with falls risk require further study.
Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model

AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. ABSTRACT AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline antituberculosis agent isoniazid.
DSM‐5 Alcohol Use Disorder Severity as a Function of Sexual Orientation Discrimination: A National Study

BACKGROUND Sexual minorities are more likely than their heterosexual counterparts to develop alcohol use disorder (AUD), and understanding the underlying reasons for this heightened risk is a public health priority. This study examined relationships between sexual orientation discrimination and DSM-5 AUD severity. METHODS The 2012 to 2013 National Epidemiologic Survey on Alcohol and Related Conditions III conducted in-person interviews with a nationally representative sample of U.S. adults (N = 36,309). Approximately 2.8% of the target population self-identified as lesbian, gay, or bisexual, 3.1% had at least 1 past-year same-sex sexual partner, and 8.3% reported same-sex sexual attraction. RESULTS Adults who identified as lesbian, gay, bisexual, heterosexual with same-sex attraction and/or current same-sex sexual partners, and those not sure of their sexual identity, had higher rates of individual DSM-5 AUD criteria than heterosexual-identified adults with only opposite-sex attraction and sexual partners. Respondents who were bisexual or unsure of their sexual identity consistently had the highest probabilities of endorsing each of these AUD criteria relative to the other subgroups. Differences in AUD severity across sexual orientation subgroups were much larger among women than among men. Sexual minorities who experienced higher levels of sexual orientation discrimination had significantly higher levels of AUD severity than sexual minorities who experienced lower levels or no discrimination. In particular, greater levels of sexual orientation discrimination increased the odds of impaired control criteria and pharmacologic criteria. Associations between prior-to-past-year sexual orientation discrimination and AUD severity were not as robust as those involving past-year discrimination. CONCLUSIONS Sexual minorities are at substantially greater risk of severe DSM-5 AUD, and this is particularly true among those who experience high levels of sexual orientation discrimination. Findings indicate that proximal experiences of discrimination are more salient than distal experiences. AUD treatment should address recent sexual orientation discrimination given that such experiences are associated with more severe AUD.
Comparison of Rigid and Soft-Brace Treatments for Acute Osteoporotic Vertebral Compression Fracture: A Prospective, Randomized, Multicenter Study

While bracing is the standard conservative treatment for acute osteoporotic compression fracture, the efficacy of different brace treatments has not been extensively studied. We aimed to clarify and compare the preventive effect of the different brace treatments on the deformity of the vertebral body and other clinical results in this patient cohort. This multicenter nationwide prospective randomized study included female patients aged 65–85 years with acute one-level osteoporotic compression fractures. We assigned patients within four weeks of injury to either a rigid-brace treatment or a soft-brace treatment. The main outcome measure was the anterior vertebral body compression percentage at 48 weeks. Secondary outcome measures included scores on the European Quality of Life-5 Dimensions (EQ-5D), visual analog scale (VAS) for lower back pain, and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ). A total of 141 patients were assigned to the rigid-brace group, whereas 143 patients were assigned to the soft-brace group. There were no statistically significant differences in the primary outcome and secondary outcome measures between groups. In conclusion, among patients with fresh vertebral compression fractures, the 12-week rigid-brace treatment did not result in a statistically greater prevention of spinal deformity, better quality of life, or lesser back pain than soft-brace.
Clinical trials in traumatic brain injury: cellular therapy and outcome measures

Clinical trials for traumatic brain injury (TBI) have not successfully produced a new therapeutic for neuroprotection or neurorestoration, despite multiple attempts. Stem cell–based therapies and/or cellular therapies have been developed over the past 20 years such that clinical trials are now in Phase II and III stages for neurologic diseases such as TBI and stroke. Many of the vexing issues from past clinical failures still exist today, namely, preclinical data that may not translate to clinical trial because of design and injury heterogeneity that poorly stratifies enrolled patients. Recognition of these problems has led us to advocate for outcome measures that are clinically meaningful, but do not represent a global functional “score. ” Specifically, we seek to measure those early physiologically relevant outcomes (intracranial pressure, edema, and therapeutic intensity) and later structural outcomes in regions of interest that are linked to putative mechanisms of action of cell based therapies. Early approval of therapeutics that are successful by these metrics would then allow further access to treatments that could be further tested via patient registries and other surveillance for ultimate adoption. Continuing to do the same thing with each iterative trial will assure the same results.
Changes in risk behaviors among Thai men who have sex with men and transgender women enrolled in the test and treat cohort

ABSTRACT The test-and-treat approach has the potential to reduce high-risk sexual behaviors by linking high-risk individuals to health education, although this has not been proven yet. We used longitudinal data from the Test and Treat Demonstration Project among Thai men who have sex with men (MSM) and transgender women (TGW) who were not known to be HIV-positive to analyze changes in risk behaviors during the 24-month study period categorized by three groups: HIV-negative without seroconversion, seroconverters, and HIV-positive at enrollment. Five binary risk behavior outcomes – laboratory-diagnosed sexually transmitted infections (STIs); multiple sexual partners, unprotected anal intercourse, self-perceived HIV risk, and amphetamine-type stimulants use in the past month – were assessed. Among 689 participants, with a mean (SD) age of 23.1 (6.2) years, 165 participants were diagnosed with HIV: 115 at enrollment and 50 with seroconversions. HIV-positive participants at enrollment showed significant reductions in all five behavioral risk outcomes. Seroconverters demonstrated higher risks at enrollment than HIV-negative participants, and continued to practice high-risk behaviors even after seroconversion despite a significant reduction in self-perceived moderate-to-high HIV risk. Continuation of risk behaviors among seroconverters could negatively affect the ending AIDS goal, thus the integration of other effective preventive measures into HIV/STIs management programs are needed.
Functional Imaging of the Implicit Association of the Self With Life and Death.

OBJECTIVE A critical need exists to identify objective markers of suicide ideation. One potential suicide risk marker is the Suicide Implicit Association Task (S-IAT), a behavioral task that uses differential reaction times to compare the implicit association between the self and death to the implicit association between the self and life. Individuals with a stronger association between the self and death on the S-IAT are more likely to attempt suicide in the future. To better understand the neural underpinnings of the implicit association between self and either life or death, a functional magnetic resonance imaging (fMRI) version of the S-IAT was adapted and piloted in healthy volunteers. METHOD An fMRI version of the S-IAT was administered to 28 healthy volunteers (ages 18-65, 14F/14M). RESULTS Behavioral results were comparable to those seen in non-scanner versions of the task. The task was associated with patterns of neural activation in areas relevant to emotional processing, specifically the insula and right ventrolateral prefrontal cortex. CONCLUSIONS Performance on the S-IAT fMRI task may reflect scores obtained outside of the scanner. In future evaluations, this task could help assess whether individuals at increased risk of suicide display a different pattern of neural activation in response to self/death and self/life stimuli.
Colostrum immunoglobulins and oxidative capacity may be affected by infant sex and maternal age and parity

Background/aim The aims of this study were to determine the levels of the total antioxidant status (TAS), the total oxidant status (TOS), the oxidative stress index (OSI), and the concentration of immunoglobulin A (IgA) and M (IgM) in colostrum, and evaluate relationships between these parameters and maternal age, maternal parity, and infant sex. Materials and methods The analysis was performed in serum samples of colostrum which were collected from 90 mothers on the first day of lactation between 10:00 and 12:00 AM. Results The measurements established that no significant association existed between the TAS level of colostrum and parity, maternal age, or infant sex. However, mothers 18 to 30 years of age had significantly lower colostrum TOS and OSI levels compared with mothers older than 30 years of age. IgA and IgM values of the colostrum of primiparous mothers were significantly higher than those of multiparous mothers, whereas no correlations existed with the age of the mother. Additionally, significantly higher colostrum IgA and IgM values were observed in female infants fed colostrum compared with male infants. Conclusion In conclusion, sex-based hormonal changes in mothers during pregnancy may be associated with the different colostral immunoglobulin levels for male and female infants.