Miracle-dz/UniFAR-FTUs huggingface dataset:
A trial of thyroxine in acute renal failure.

UNLABELLED A trial of thyroxine in acute renal failure. BACKGROUND Acute renal failure (ARF) remains a serious medical problem with a high mortality rate. Efforts to shorten the course of ARF might reduce this mortality. Since thyroxine has been shown in experimental models to shorten the course of ARF, we designed a trial to determine if a defined course of thyroxine would alter the course or change the mortality of clinical ARF. METHODS A prospective, randomized, placebo-controlled, double-blind trial of thyroxine was carried out in patients with ARF. End points were the percentage requiring dialysis, the percentage recovering renal function, time to recovery, and mortality. RESULTS Fifty-nine patients were randomized to receive either thyroxine or placebo. The groups were well matched in terms of basal and entry creatinines, age, sex, APACHE II scores at entry, and percentage oliguric. Baseline thyroid functions, including T3, T4, rT3, and thyroid stimulating hormone (TSH) levels, were equal between the two groups and typical of patients with euthyroid sick syndrome. Thyroxine resulted in a progressive and sustained suppression of TSH levels in the treated group, but had no effect on any measure of ARF severity. Mortality was higher in the thyroxine group than the control group (43 vs. 13%) and correlated with suppression of TSH. CONCLUSIONS In contrast to the beneficial effects seen in experimental ARF, thyroxine has no effect on the course of clinical ARF and could have a negative effect on outcome through prolonged suppression of TSH. Critically ill euthyroid sick patients should not be replaced with thyroid hormone.
Potential new strategies for the treatment of ovarian infertility and degenerative diseases with autologous ovarian stem cells

The 50-year-old and currently prevailing view that all oocytes in adult human ovaries persist from the fetal period of life is controversial as it clashes with Darwinian evolutionary theory. Studies of oogenesis and follicular renewal in adult human ovaries, and of the role of hormonal signals and third-party cells (tissue macrophages and T cells), could all be helpful in providing better understanding of the causes of ovarian infertility, its prevention and potential therapy. In addition, the authors recently reported differentiation of distinct cell types and the production of new eggs in cultures derived from premenopausal and postmenopausal human ovaries. It is possible that fertilisation of such eggs will open up new opportunities for providing genetically related children to infertile women for whom conventional in vitro fertilisation has failed. As ovarian stem cells appear to represent a new type of totipotent adult stem cell, they could also be utilised for autologous stem cell therapy of degenerative diseases, without any involvement of allogeneic embryonic stem cells and somatic cell nuclear transfer.
Neurodegeneration and Neuroinflammation in Diabetic Retinopathy: Potential Approaches to Delay Neuronal Loss

In spite of the extensive research the complex pathogenesis of diabetic retinopathy (DR) has not been fully elucidated. For many years it has been thought that diabetic retinopathy manifests only with microangiopathic lesions, which are totally responsible for the loss of vision in diabetic patients. In view of the current knowledge on the microangiopathic changes in the fundus of the eye, diabetic retinopathy is perceived as a neurodegenerative disease. Several clinical tools are available to detect neuronal dysfunction at early stages of diabetes. Many functional changes in the retina can be identified before vascular pathology develops, suggesting that they result from a direct effect of diabetes on the neural retina. In the course of diabetes there is a chronic loss of retinal neurons due to increased frequency of apoptosis. The neuronal apoptosis begins very early in the course of diabetes. This observation has led to suggestions that precautions against DR should be implemented immediately after diabetes is diagnosed. Neurodegeneration cannot be reversed; therefore treatments preventing neuronal cell loss in the retina need to be developed to protect diabetic patients. This review is an attempt to summarize what is currently known about the mechanisms of neuronal apoptosis in the context of diabetic retinopathy and vascular degeneration as well as about potential treatments of DR
Imaging the 3D structure of secondary osteons in human cortical bone using phase-retrieval tomography

By applying a phase-retrieval step before carrying out standard filtered back-projection reconstructions in tomographic imaging, we were able to resolve structures with small differences in density within a densely absorbing sample. This phase-retrieval tomography is particularly suited for the three-dimensional segmentation of secondary osteons (roughly cylindrical structures) which are superimposed upon an existing cortical bone structure through the process of turnover known as remodelling. The resulting images make possible the analysis of the secondary osteon structure and the relationship between an osteon and the surrounding tissue. Our observations have revealed many different and complex 3D structures of osteons that could not be studied using previous methods. This work was carried out using a laboratory-based x-ray source, which makes obtaining these sorts of images readily accessible.
Television viewing and television in bedroom associated with overweight risk among low-income preschool children.

CONTEXT Television (TV) viewing is associated with obesity among school-aged children, adolescents, and adults, but this relationship has not been evaluated in preschool-aged children. OBJECTIVE To describe the TV/video viewing habits of a multiethnic, low-income preschool population of children and to determine whether TV/video viewing is related to their adiposity. DESIGN Cross-sectional survey of parents/guardians with measurements of children's height and weight. SETTING AND PARTICIPANTS Two thousand seven hundred sixty-one adults with children, 1 through <5 years, from 49 New York State agencies of the Supplemental Nutrition Program for Women, Infants, and Children. OUTCOME MEASURES Cross-sectional relationships between the amount of time the child spends viewing TV/video and the presence of a TV set in the child's bedroom, with the prevalence of overweight children (body mass index [BMI] >85th percentile) after adjustment for potential confounders. RESULTS Mean TV/video viewing times were higher among black children and Hispanic children than white children and increased with the child's age. In multiple logistic regression, the odds ratio of children having a BMI >85th percentile was 1.06 (95% confidence interval [CI]: 1.004-1.11) for each additional hour per day of TV/video viewed, independent of child age, child sex, parental educational attainment, and race/ethnicity. Almost 40% of children had a TV set in their bedroom; they were more likely to be overweight and spent more time (4.6 hours per week) watching TV/video than children without a TV in their bedroom. In multiple logistic regression, the odds ratio of having a BMI >85th percentile was 1.31 (95% CI: 1.01-1.69) among those with a TV in their bedroom versus those without a TV, after statistical adjustment for child age, child sex, child TV/video viewing hours per week, maternal BMI, maternal education, and race/ethnicity. CONCLUSIONS This study extends the association between TV viewing and risk of being overweight to younger, preschool-aged children. A TV in the child's bedroom is an even stronger marker of increased risk of being overweight. Because most children watch TV by age 2, educational efforts about limiting child TV/video viewing and keeping the TV out of the child's bedroom need to begin before then.
Do Survey Expectations of Stock Returns Reflect Risk-Adjustments?

Abstract To reconcile the disconnect between survey expectations of stock returns and rational expectations, researchers have hypothesized that survey participants may confound beliefs and preferences by (i) reporting risk-neutral forecasts of future returns; or (ii) reporting pessimistically-tilted forecasts reflecting ambiguity aversion or robustness concerns. We find that these hypotheses are strongly rejected by the data, albeit for different reasons: Inconsistent with hypothesis (i), survey return forecasts are reliably much higher than risk-free interest rates and survey expected excess returns are predictably time-varying. Inconsistent with (ii), agents are not always pessimistic about future returns, but often predictably optimistic and unconditionally unbiased.
Point Prevalence Surveys of Antimicrobial Use among Hospitalized Children in Six Hospitals in India in 2016

The prevalence of antimicrobial resistance in India is among the highest in the world. Antimicrobial use in inpatient settings is an important driver of resistance, but is poorly characterized, particularly in hospitalized children. In this study, conducted as part of the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children (GARPEC) project, we examined the prevalence of and indications of antimicrobial use, as well as antimicrobial agents used among hospitalized children by conducting four point prevalence surveys in six hospitals between February 2016 and February 2017. A total of 681 children were hospitalized in six hospitals across all survey days, and 419 (61.5%) were prescribed one or more antimicrobials (antibacterials, antivirals, antifungals). Antibacterial agents accounted for 90.8% (547/602) of the total antimicrobial prescriptions, of which third-generation cephalosporins (3GCs) accounted for 38.9% (213/547) and penicillin plus enzyme inhibitor combinations accounted for 14.4% (79/547). Lower respiratory tract infection (LRTI) was the most common indication for prescribing antimicrobials (149 prescriptions; 24.8%). Although national guidelines recommend the use of penicillin and combinations as first-line agents for LRTI, 3GCs were the most commonly prescribed antibacterial agents (55/149 LRTI prescriptions; 36.9%). In conclusion, 61.5% of hospitalized children were on at least one antimicrobial agent, with excessive use of 3GCs. Hence there is an opportunity to limit their inappropriate use.
Calculation of the standard binding free energy of sparsomycin to the ribosomal peptidyl‐transferase P‐site using molecular dynamics simulations with restraining potentials

The standard (absolute) binding free energy of the antibiotic sparsomycin with the 50S bacteria ribosomal subunit is calculated using molecular dynamics (MD) free energy perturbation (FEP) simulations with restraining potentials developed by Wang et al. [Biophys. J. 91:2798–2814 (2006)]. In the simulation protocol, restraining potentials are activated for the orientational and translational movements of the ligand relative to the binding site when it is decoupled from the binding pocket, and then released once the ligand fully interacts with the rest of the system. A reduced system is simulated to decrease the computational cost of the FEP/MD calculations and the effects of the surrounding atoms are incorporated using the generalized solvent boundary potential (GSBP) method. The loss of conformational freedom of the ligand upon binding is characterized using the potential of mean force (PMF) as a function of the root‐mean‐square deviation (RMSD) relative to the bound conformation. The number of water molecules in the binding pocket is allowed to fluctuate dynamically in response to the ligand during the calculations by combining FEP/MD with grand canonical Monte Carlo (GCMC) simulations. The calculated binding free energy is about −6 kcal/mol, which is in reasonable agreement with the experimental value. The information gleaned from this study provides new insight on the recognition of ribosome by sparsomycin and highlights the challenges in calculations of absolute binding free energies in these systems. Copyright © 2010 John Wiley & Sons, Ltd.
Inflammatory Cytokines Induce Production of CHI3L1 by Articular Chondrocytes*

Elevated levels of CHI3L1 (chitinase-3-like protein 1) are associated with disorders exhibiting increased connective tissue turnover, such as rheumatoid arthritis, osteoarthritis, scleroderma, and cirrhosis of the liver. This secreted protein is not synthesized in young healthy cartilage, but is produced in cartilage from old donors or patients with osteoarthritis. The molecular processes governing the induction of CHI3L1 are currently unknown. To elucidate the molecular events involved in CHI3L1 synthesis, we investigated two models of articular chondrocytes: neonatal rat chondrocytes, which do not express CHI3L1, and human chondrocytes, which express CHI3L1 constitutively. In neonatal rat chondrocytes, the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 potently induced steady-state levels of CHI3L1 mRNA and protein secretion. Treatment of chondrocytes with TNF-α for as little as 1 h was sufficient for sustained induction up to 72 h afterward. Using inhibitors selective for the major signaling pathways implicated in mediating the effects of TNF-α and interleukin-1, only inhibition of NF-κB activation was effective in curtailing cytokine-induced expression, including after removal of the cytokine, indicating that induction and continued production of CHI3L1 are controlled mainly by this transcription factor. Inhibition of NF-κB signaling also abolished constitutive expression by human chondrocytes. Thus, induction and continued secretion of CHI3L1 in chondrocytes require sustained activation of NF-κB. Selective induction of CHI3L1 by cytokines acting through NF-κB coupled with the known restriction of the catabolic responses by CHI3L1 in response to these inflammatory cytokines represents a key regulatory feedback process in controlling connective tissue turnover.
Caring Households: The Social Ties that House

Abstract Individuals turn increasingly to informal and family welfare to secure housing as housing and household pressures mount in advanced homeownership societies. This article sheds light on the role of less visible, less considered relations (beyond intergenerational assistance) that are currently being marshalled by low and middle-income households in Melbourne (Australia) and showcases the under-explored breadth of dependencies that exist between co-resident non-spousal adults. Drawing on in-depth interviews, it drills within the “giver/receiver” model to reveal diverse (inter)dependencies within families (e.g. filial, intergenerational, sibling), and between non-related, non-spousal adults (e.g. platonic, professional, e.g. AirBnB). It shows how these bidirectional transactions involve often ambiguous, asymmetrical (i.e. not-like-for-like) exchanges of material and emotional support, which are often postponed. Associated uneven power dynamics are shown to script the domestic space of these cohabiters, variously structuring householders’ use, their (perception of) control and sense of home, and also to introduce tension, including threats to household stability. Others have identified a contemporary paradox: at a time when much policy and economic practice assumes subjects liberated from the obligations of social ties, individuals rely more than ever on intimate relations. This article builds on this curiosity identifying a broad range of social ties, including beyond the family, that are essential to helping city residents stay housed. It argues that as individuals grapple with welfare shifts, financial insecurity, and housing pressures, these ties take on heightened significance but they can also be tested: the pressures that housing-related dependencies place on coresident individuals have the potential to be highly gendered and, promises and expectations of reciprocity in particular, may become untenable for some individuals to uphold in the future.
Who’s Afraid of the Big Bad Wolf? Rethinking the Core and Periphery in the Eurozone Crisis

ABSTRACT Recent literature on the eurozone crisis has begun to rethink those explanations of its origins that rely on narratives stressing the ‘immaturity’ of political and economic governance in the countries of the European periphery. These narratives are typically challenged by frameworks which understand the eurozone as a region characterised by a ‘beggar-thy-neighbour’ hierarchy between the economic growth of Germany, which leads to precarious, ‘financialised’ growth in the periphery. Yet, this article shows that core–periphery scholarship is unable to adequately challenge the immaturity thesis due to its preoccupation with German ‘victimisation’ of the European periphery. By exploring country-specific direction of trade and capital lending statistics, I shows that there is little basis for the argument that Germany is to blame for the origins of the eurozone crisis in the individual countries of the European Periphery. This article shows that by bringing core–periphery analysis into dialogue with Comparative Political Economy, a critical approach to the Eurozone crisis can be developed which leaves behind the myth of the German ‘big bad wolf’. Instead, I show that imbalances between the core and periphery are a product of a flawed construction of the Single Market and Economic and Monetary Union.
Adenosine A2A and A3 Receptors Are Involved in the Human Endothelial Progenitor Cells Migration

Abstract: Human endothelial progenitor cells (hEPC) are recruited to sites of neovascularization where they differentiate into endothelial cells. The signals/factors responsible for hEPC migration and adhesion to sites of injury are not well understood. Elevated levels of adenosine are known to increase mature endothelial cell migration in response to tissue injury. However, the understanding of the role of adenosine in the physiology of hEPC is very limited. Using quantitative polymerase chain reaction and western blot analyses, we detected the expression of the adenosine receptors A2A, A2B, and A3 in hEPC. Stimulation of adenosine receptors using adenosine or the nonselective agonist adenosine-5'-N-ethylcarboxamide (NECA) increased hEPC migration in 1.4-fold and 2.1-fold (P < 0.01), respectively. Stimulation of hEPC using the A2A-specific agonist CGS-21680 resembled the effect observed in migration when using adenosine or NECA. Consequently, NECA and CGS-21680-stimulated migration of hEPC were reverted using the A2A receptor antagonist ZM-241385. NECA-stimulated migration was inhibited in dose-dependent manner using MRS-1523 (Ki of 147 ± 0.016 nM), MRS-1754 (Ki of 1900 ± 0.02 nM), or ZM-241385 (Ki of 0.2 ± 0.01 nM). In conclusion, adenosine stimulates hEPC migration by activating A2A and A3 but not A2B receptors and provides evidence to support a role of adenosine in modulating angiogenic capacity of hEPC.
Helicobacter pylori controls NLRP3 expression by regulating hsa-miR-223-3p and IL-10 in cultured and primary human immune cells

Inflammasome-mediated production of mature IL-1β and IL-18 cytokines represents an important innate immune response against infecting pathogens. Helicobacter pylori, one of the most successful and persistent human pathogens, induces severe inflammation leading to gastritis and more serious gastric diseases. H. pylori modulates different immune responses for its survival and inflammasome signaling is manipulated by the cag pathogenicity island (cagPAI), urease and VacA cytotoxin. Here we report that H. pylori regulates NLRP3 expression, an inflammasome forming regulator, in infected THP-1 monocytes. This response was independent of the major H. pylori pathogenicity-associated factors CagA, VacA, Cgt, FlaA and cagPAI. Two NLRP3 expression controlling factors, the NLRP3 mRNA targeting microRNA hsa-miR-223-3p and cytokine IL-10, were found to work in tandem for its regulation. H. pylori infection also induced copious amount of pro-IL-1β in THP-1 monocytes/macrophages but secreted a very low amount of mature IL-1β. Moreover, secreted IL-10 correlated with the down-regulation of nigericin-induced NLRP3 inflammasome activation of LPS-primed THP-1 monocytes and human PBMCs from volunteers. However, H. pylori-treated PBMCs secreted significantly more mature IL-1β throughout the infection period, which suggests a different mode of activation. Taken together, this study demonstrates targeting of inflammasome-forming NLRP3, an important innate immunity component, and crucial manipulation of pro- and anti-inflammatory cytokines in H. pylori infection.
Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

ABSTRACT Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30–60 min after 4–5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation.
Malnutrition and high childhood mortality among the Onge tribe of the Andaman and Nicobar Islands

Abstract Objectives A study was conducted among the Onge tribe of the Andaman and Nicobar Islands with the objectives of identifying demographic factors responsible for the decline in their population and assessing their nutritional status, which is an important determinant of child survival. Study design and subjects The study included estimation of indices of fertility and child mortality, and assessment of nutritional status. All individuals of the Onge community settled on Little Andaman Island were included. Results The mean total marital fertility rate was estimated to be 5.15 live births per woman and the general fertility rate was 200 live births per 1000 married-woman-years. Although the gross reproduction rate was estimated to be 2.2 female children per married woman, the net reproduction rate was only 0.9 surviving female child per married woman. The mean infant mortality rate during the past 30 years was 192.7 per 1000 live births, and the child survival rate was found to be only 53.2%. A mild to moderate degree of malnutrition was found in 85% of children of pre-school age and severe malnutrition in 10%. The Onges had low intakes of iron, vitamin A and vitamin C. All the screened Onges were found to be infested with one or more intestinal parasites. Conclusions High childhood mortality appears to be the predominant demographic factor responsible for the decline in the Onge population. The high prevalence of undernutrition and micronutrient deficiency disorders could be important factors contributing to the high childhood mortality.