Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Sensitivity of Mycobacteria to Isoniazid Is Related to Differences in KatG-Mediated Enzymatic Activation of the Drug

Isoniazid (INH) is a cornerstone of antitubercular therapy. Mycobacterium tuberculosis complex bacteria are the only mycobacteria sensitive to clinically relevant concentrations of INH. All other mycobacteria, including M. marinum and M. avium subsp. paratuberculosis are resistant. INH requires activation by bacterial KatG to inhibit mycobacterial growth. We tested the role of the differences between M. tuberculosis KatG and that of other mycobacteria in INH sensitivity. ABSTRACT Isoniazid (INH) is a cornerstone of antitubercular therapy. Mycobacterium tuberculosis complex bacteria are the only mycobacteria sensitive to clinically relevant concentrations of INH. All other mycobacteria, including M. marinum and M. avium subsp. paratuberculosis are resistant. INH requires activation by bacterial KatG to inhibit mycobacterial growth. We tested the role of the differences between M. tuberculosis KatG and that of other mycobacteria in INH sensitivity. We cloned the M. bovis katG gene into M. marinum and M. avium subsp. paratuberculosis and measured the MIC of INH. We recombinantly expressed KatG of these mycobacteria and tested in vitro binding to, and activation of, INH. Introduction of katG from M. bovis into M. marinum and M. avium subsp. paratuberculosis rendered them 20 to 30 times more sensitive to INH. Analysis of different katG sequences across the genus found KatG evolution diverged from RNA polymerase-defined mycobacterial evolution. Biophysical and biochemical tests of M. bovis and nontuberculous mycobacteria (NTM) KatG proteins showed lower affinity to INH and substantially lower enzymatic capacity for the conversion of INH into the active form in NTM. The KatG proteins of M. marinum and M. avium subsp. paratuberculosis are substantially less effective in INH activation than that of M. tuberculosis, explaining the relative INH insensitivity of these microbes. These data indicate that the M. tuberculosis complex KatG is divergent from the KatG of NTM, with a reciprocal relationship between resistance to host defenses and INH resistance. Studies of bacteria where KatG is functionally active but does not activate INH may aid in understanding M. tuberculosis INH-resistance mechanisms, and suggest paths to overcome them.
Pitfall prayer marks: Recognition and appropriate treatment: A case report and review of literature

Prayer marks are asymptomatic callosities resulting from repeated, extended pressure, and friction exerted on bony prominences when praying on hard ground. A 41‐year‐old woman with ulcerative colitis treated with infliximab was referred to our clinic due to skin changes on her feet that were suspected to be drug eruptions. The patient presented several asymptomatic, hyperpigmented, and hyperkeratotic plaques over the lateral malleoli suggesting that the lesions had a mechanical cause. Further exploration revealed that the patient, a practicing Muslim, prays in a sitting position called “Julus” several times a day. After color marking, the lesions over the lateral feet left a precise imprint on the underlay when the patient was asked to imitate the praying posture—thus proving the origin of the skin lesions. We searched the database on July 31, 2019 using the terms «prayer marks» OR «prayer nodules» OR “prayer callosities. ” Only electronically available publications were reviewed. Recognition of prayer marks is important to avoid misdiagnosis, performance of unnecessary diagnostic procedures, and to enhance the intercultural competence of clinicians who practice in multicultural societies.
Extrathyroidal congenital defects in children with congenital hypothyroidism - observations from a single paediatric centre in Central Europe with a review of literature.

INTRODUCTION Patients with congenital hypothyroidism (CH) can have an increased risk of occurrence of extrathyroidal defects compared to the general population, which could influence their development. The abnormalities occur mainly in organ systems whose development and function is dependent on genes that are also responsible for proper organogenesis of the thyroid gland and thyroid hormone synthesis. AIM OF THE STUDY The aim of the study was to evaluate the frequency of extrathyroidal defects in CH patients, taking into consideration the cause of this co-occurrence and the role of genetic tests. MATERIAL AND METHODS The study included 54 newborns with positive screening test for CH based on elevated TSH level, in the years 2010-2017, from South-Eastern Poland. The data was retrieved retrospectively from patients' medical records. RESULTS Twenty of 54 newborns with CH (37%) had congenital defects of other organs. In 10 (18.5%) cardiac defects were found, in 5 (9.25%) abnormal symptoms of the respiratory system, 7 (12.96%) had abnormalities of the gastrointestinal system, five (9.25%) had genitouri-nary abnormalities, 3 (5.55%) had abnormalities of the nervous system, and 6 (11.1%) had musculoskeletal abnormalities. CONCLUSIONS The analysis of our data and current literature suggests that genetic factors play the most important role in the development of extrathy-roidal abnormalities in newborns with CH. Identifying the mutation causing CH, the potential defects that can accompany newborns with CH, screening could be offered for these patients in order to obtain an earlier diagnosis and implement early and appropriate treat-ment.
Enhanced Anti-Diabetogenic Effect of Intravenous Immune Globulin Modified by Ferrous Ion Exposure

The aim of this study was to investigate the immunomodulatory capacity of native and Fe(II)-exposed intravenous immune globulin (IVIg) in multiple low dose streptozotocin-induced diabetes and to delineate the mechanisms of their influence on immune cell functions. Optimal doses (200–600mg/kg) of IVIg prevented the development of hyperglycemia, glycosuria and attenuated mononuclear cell infiltration in pancreatic islets. Fe(II) exposure of IVIg decreased their optimal therapeutic dose to 100mg/kg which significantly decreased the serum levels of proinflammatory cytokines compared to the same dose of native IVIg. This was accompanied by lower numbers of TNF-α, IFN-γ and IL-17 producing CD4+ T cells and increased frequencies of CD4+IL-10+ and CD4+IL-4+ T cells in the pancreatic lymph nodes and islets on day 16 after diabetes induction. Ferrous ion-exposed IVIg enhanced the bias towards Th2 response while the regulatory Foxp3+ T cells were not affected.
Niobium-Treated Titanium Implants with Improved Cellular and Molecular Activities at the Tissue–Implant Interface

There have been several attempts to improve the cellular and molecular interactions at the tissue–implant interface. Here, the biocompatibility of titanium-based implants (e.g., Grade 2 Titanium alloy (Ti-40) and titanium–niobium alloy (Ti-Nb)) has been assessed using different cellular and molecular examinations. Cell culture experiments were performed on three substrates: Ti-40, Ti-Nb, and tissue culture polystyrene as control. Cells number and growth rate were assessed by cell counting in various days and cell morphology was monitored using microscopic observations. The evaluation of cells’ behavior on the surface of the implants paves the way for designing appropriate biomaterials for orthopedic and dental applications. It was observed that the cell growth rate on the control sample was relatively higher than that of the Ti-40 and Ti-Nb samples because of the coarse surface of the titanium-based materials. On the other hand, the final cell population was higher for titanium-based implants; this difference was attributed to the growth pattern, in which cells were not monolayered on the surface. Collagen I was not observed, while collagen III was secreted. Furthermore, interleukin (IL)-6 and vascular endothelial growth factor (VEGF) secretion were enhanced, and IL-8 secretion decreased. Moreover, various types of cells can be utilized with a series of substrates to unfold the cell behavior mechanism and cell–substrate interaction.
Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells

Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory properties and have been used as immune regulators for the treatment of graft-versus-host disease (GVHD). Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to BM-MSCs for potential clinical applications because of their accessibility and easy preparation. The aim of this in vitro study was to compare MSCs from dental pulp (DP-MSCs), gingival tissue (G-MSCs), and periodontal ligament (PDL-MSCs) in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells to determine which MSCs would be the most appropriate for in vivo immunoregulatory applications. BM-MSCs were included as the gold standard. Our results demonstrated, in vitro, that MSCs from DP, G, and PDL showed immunoregulatory properties similar to those from BM, in terms of the cellular proliferation inhibition of both CD4+- and CD8+-activated T-cells. This reduced proliferation in cell co-cultures correlated with the production of interferon-γ and tumor necrosis factor alpha (TNF-α) and the upregulation of programmed death ligand 1 (PD-L1) in MSCs and cytotoxic T-cell-associated Ag-4 (CTLA-4) in T-cells and increased interleukin-10 and prostaglandin E2 production. Interestingly, we observed differences in the production of cytokines and surface and secreted molecules that may participate in T-cell immunosuppression in co-cultures in the presence of DT-MSCs compared with BM-MSCs. Importantly, MSCs from four sources favored the generation of T-cell subsets displaying the regulatory phenotypes CD4+CD25+Foxp3+ and CD4+CD25+CTLA-4+. Our results in vitro indicate that, in addition to BM-MSCs, MSCs from all of the dental sources analyzed in this study might be candidates for future therapeutic applications.
Comparison of the Diagnostic Utility of Manual Screening and the ThinPrep Imaging System in Liquid-Based Cervical Cytology

Objective: To compare the diagnostic results of the ThinPrep manual method (TPMM) and ThinPrep automated method (TPAM) in liquid-based cytology and present the advantages and disadvantages of both methods. Material and Method: A total of 1.500 randomized ThinPrep Pap tests that were screened manually and archived in 2015 were reviewed by a blinded researcher manually and by the ThinPrep automatic method. Results: There was a 83.3% increase in the detection of ASCUS (Atypical squamous cells of undetermined significance) with the TPAM compared to the TPMM, and with respect to the reference results, the accuracy was higher for the TPAM than for the TPMM. We also noted a 33.3% increase in the rate of LSIL (Low grade squamous intraepithelial lesion) and 20% increase in the rate of HSIL (High grade squamous intraepithelial lesion) by the TPAM. Concordance was best between the TPAM and reference cytologic diagnoses. The sensitivity was higher for the TPAM and the specificity was similar for both methods. The false positive rate was higher for the TPAM than the TPMM but the false negative rate was higher for the TPMM. We determined a 30% gain in screening time per smear by the TPAM. However, rejection of many samples by the system, especially because of air bubbles, was a limitation of the TPAM. Conclusion: The TPAM has advantages over the TPMM as well as disadvantages such as limiting features and a high false positive rate. The TPAM should be supported by the manual method to decrease the false positive rate.
Minimal Effect of Bevacizumab Treatment on Residual Vestibular Schwannomas after Partial Resection in Young Neurofibromatosis Type 2 Patients

Hearing-preserving partial resection of neurofibromatosis type 2 (NF2) associated vestibular schwannomas (VS) is a preferred treatment strategy, particularly for children and adolescents. However, the residual tumors do grow and lead at some point to continued hearing deterioration. An adjuvant bevacizumab treatment may provide an option for slowing down this process. In this retrospective study, we reviewed tumor volume and hearing data of 16 operated VS in nine patients younger than 30 years over a period of 63 to 142 months. All these patients had one or more bevacizumab treatment periods and most of them had a non-treatment period after surgery. Four different patterns of growth were observed for the residual tumors: (1) growth in the non-treatment periods, which slowed down in the treatment periods; (2) growth slowed down in one but not in another on-period; (3) unaffected growth; (4) no or minimal growth regardless of the treatment. Neither radiological regression of tumor volume nor hearing improvement were observed in the treatment periods. Accelerated hearing deterioration was observed in several non-treatment periods, but also in some treatment periods. No straightforward correlation can be drawn between tumor growth and hearing scores. Tumor growth and worsening of hearing between two measurement points were slightly less in the treatment periods; however, the differences were not significant, because variations were large. In conclusion, our comprehensive follow-up on 16 VS in nine NF2 patients did show heterogenous effects of bevacizumab on small residual vestibular schwannomas after surgery both regarding tumor size and hearing preservation. Thus, smaller and slower growing tumor residuals seem to behave differently to bevacizumab than reported for not-operated faster growing VS.
Analysis of Toxic Metals in Liquid from Electronic Cigarettes

As the technology of electronic nicotine delivery systems (ENDS), including e-cigarettes, evolves, assessing metal concentrations in liquids among brands over time becomes challenging. A method for quantification of chromium, nickel, copper, zinc, cadmium, tin, and lead in ENDS liquids using triple quadrupole inductively coupled plasma mass spectrometry was developed. The method’s limits of detection (LODs) were 0.031, 0.032, 3.15, 1.27, 0.108, 0.099, 0.066 µg/g for Cr, Ni, Cu, Zn, Cd, Sn, and Pb respectively. Liquids analyzed were from different brands and flavors of refill bottles or single-use, rechargeable, and pod devices from different years. Scanning electron microscopy with energy dispersive spectroscopy further evaluated the device components’ compositions. Refill liquids before contacting a device were below lowest reportable levels (LRL) for all metals. Copper and zinc were elevated in liquids from devices containing brass. Cadmium was <LRL in all liquids and was not observed in device components. Cr, Ni, Cu, Zn, Sn, and Pb, reported in µg/g, ranged from <LRL to 0.396, 4.04, 903, 454, 0.898, and 13.5 respectively. Elevated metal concentrations in the liquid were also elevated in aerosol from the corresponding device. The data demonstrates the impact of device design and materials on toxic metals in ENDS liquid.
Overall Survival and Adjuvant Therapy in Women with Ovarian Carcinosarcoma: A Single-Institution Experience

Background: Carcinosarcoma of the ovary (CSO) is a rare and aggressive variant of ovarian cancer. Due to the rare nature of the disease there is insufficient evidence to make recommendations regarding standard management and overall prognosis. Methods: An Institutional Review Board-approved study identified all our patients with CSO between January 2011 and May 2018. Demographic and outcome measures were abstracted from the medical records and tumor board files. Cox proportional hazard models, log rank tests, and comparisons of means were used to calculate significance (p < 0.05). Results: 27 women with CSO were identified. The median age at diagnosis was 65 years (range 48–91). Five women (18%) presented with early stage disease (Stage I or II) and 22 patients (82%) presented with late stage III or IV disease. Twenty patients (74%) received intravenous platinum-based combination chemotherapy. Seven patients did not receive chemotherapy during their treatment course. The median overall survival was 23 months (range 2–68 months). Overall survival was not significantly worsened by the stage of disease at diagnosis. There was no difference in survival based on the age at diagnosis, tobacco status or ethnicity (p > 0.05). Conclusion: This is one of the largest single institution experiences with CSO. The majority of our patients presented with advanced stage disease and received adjuvant platinum-based chemotherapy after cytoreductive surgery. The median overall survival of 23 months was not affected by the stage of the disease. The optimal management of this rare disease needs further study with collaborative, prospective multi-institutional trials.
Proactive and Reactive Aggressive Behaviors: Dimensionality of Self-Report Scales

Abstract The literature distinguishes aggressive behavior as being either proactive or reactive; however, despite being highly comorbid, they appear to possess unique correlation patterns to external variables. We propose to assess the dimensionality and latent profiles that emerged based on the Peer Aggressive Behavior Scale (PAB-S) and the Peer Aggressive and Reactive Behavior Questionnaire (PARB-Q). Confirmatory Factor Analysis (CFA) and Latent Profile Analysis (LPA) was conducted on two self-report scales in a non-representative Brazilian sample composed by 2,517 students of elementary school (1,275 girls; 50.7%), aged from seven to 16 years. CFA analyses showed inconclusive results regarding the dimensionality of the data. LPA results, for both instruments, indicated the interdependence between proactive and reactive factors. We suggest that dimensionality issues concerning human aggression might depend, at least in part, on the method used to assess the phenomenon.
Multiplex CRISPR/Cas9‐mediated metabolic engineering increases soya bean isoflavone content and resistance to soya bean mosaic virus

Summary Isoflavonoids, which include a variety of secondary metabolites, are derived from the phenylpropanoid pathway and are distributed predominantly in leguminous plants. These compounds play a critical role in plant–environment interactions and are beneficial to human health. Isoflavone synthase (IFS) is a key enzyme in isoflavonoid synthesis and shares a common substrate with flavanone‐3‐hydroxylase (F3H) and flavone synthase II (FNS II). In this study, CRISPR/Cas9‐mediated multiplex gene‐editing technology was employed to simultaneously target GmF3H1, GmF3H2 and GmFNSII‐1 in soya bean hairy roots and plants. Various mutation types and frequencies were observed in hairy roots. Higher mutation efficiencies were found in the T0 transgenic plants, with a triple gene mutation efficiency of 44.44%, and these results of targeted mutagenesis were stably inherited in the progeny. Metabolomic analysis of T0 triple‐mutants leaves revealed significant improvement in isoflavone content. Compared with the wild type, the T3 generation homozygous triple mutants had approximately twice the leaf isoflavone content, and the soya bean mosaic virus (SMV) coat protein content was significantly reduced by one‐third after infection with strain SC7, suggesting that increased isoflavone content enhanced the leaf resistance to SMV. The isoflavone content in the seeds of T2 triple mutants was also significantly increased. This study provides not only materials for the improvement of soya bean isoflavone content and resistance to SMV but also a simple system to generate multiplex mutations in soya bean, which may be beneficial for further breeding and metabolic engineering.
Negative life events and suicide risk in college students: Conditional indirect effects of hopelessness and self-compassion

Abstract Objective Suicide risk is a significant public health concern for college students and may be exacerbated by hopelessness resulting from negative life events (NLE), yet may be ameliorated by self-compassion. We examined the mediating role of hopelessness in the relation between NLE and suicidal behavior, and the moderating influence of self-compassion on all model paths. Participants: Participants were 338 undergraduates (89% white; 67% female). Data were collected from December 2014 to December 2015. Methods: Participants completed the Life Events Checklist for College Students, Beck Hopelessness Inventory, Self-Compassion Scale, and Suicidal Behaviors Questionnaire – Revised. Results: Negative life events were related to greater hopelessness and, in turn, to more suicidal behavior, yet self-compassion attenuated this effect. Conclusions: Self-compassion may buffer the NLE–hopelessness linkage, thereby reducing suicide risk among college students. Therapeutic promotion of self-compassion, and reduction of hopelessness, may be important suicide prevention strategies on college campuses.
Glucose-lowering therapies in patients with type 2 diabetes and cardiovascular diseases

Type 2 diabetes mellitus is a major risk factor for developing cardiovascular disease, and many patients with diabetes have prevalent cardiovascular complications. Recent cardiovascular outcome clinical trials suggest that certain new glucose-lowering drugs are accompanied by additional cardioprotective properties. Indeed, selected glucagon-like peptide-1 receptor agonists have a proved cardiovascular benefit in terms of a reduced incidence of ischaemic events, while sodium/glucose co-transporter-2 inhibitors have also shown significant protection, with a striking effect on heart failure and renal endpoints. These findings have been integrated in recent guidelines which now recommend prescribing (when initial metformin monotherapy fails) a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor with clinical trial-confirmed benefit in patients with diabetes and atherosclerotic cardiovascular disease, and a sodium/glucose co-transporter-2 inhibitor in such patients with heart failure or chronic kidney disease at initial stages. Furthermore, the new 2019 European Society of Cardiology guidelines in collaboration with the European Association for the Study of Diabetes recommend a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor in treatment-naive patients with type 2 diabetes mellitus with pre-existing cardiovascular disease or at high cardiovascular risk. Future research will disentangle the mechanisms underpinning these beneficial effects and will also establish to what extent these results are generalisable to the whole diabetes population. In the meantime, available evidence should prompt a wide diffusion of these two classes of drugs among patients with diabetes and cardiovascular disease. Here, we briefly summarise recent findings emerging from cardiovascular outcome clinical trials, discuss their impact on treatment algorithms and propose new possible approaches to improve our knowledge further regarding the cardiovascular effect of glucose-lowering medications.