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The new complexes [Zn(ITZ)2Cl2] (1) and [Zn(ITZ)2(OH)2] (2) were synthetized by a reaction of itraconazole with their respective zinc salts under reflux. These Zn-ITZ complexes were characterized by elemental analyses, molar conductivity, mass spectrometry, 1H and 13C1H nuclear magnetic resonance, UV-vis and infrared spectroscopies. The antiparasitic and antifungal activity of Zn-ITZ complexes was evaluated against three protozoans of medical importance, Leishmania amazonensis, Trypanosoma cruzi and Toxoplasma gondii, and two fungi, Sporothrix brasiliensis and Sporothrix schenckii The Zn-ITZ complexes exhibited a broad spectrum of action, with antiparasitic and antifungal activity in low concentrations. The strategy of combining zinc with ITZ was efficient to enhance ITZ activity, since Zn-ITZ-complexes were more active than the azole alone. This study opens perspectives for future applications of these Zn-ITZ-complexes in the treatment of parasitic diseases and sporotrichosis. Copyright © 2020 American Society for Microbiology.Type I and III IFNs play diverse roles in bacterial infections, being protective for some but deleterious for others. Using RNA-sequencing transcriptomics we investigated lung gene expression responses to Bordetella pertussis infection in adult mice, revealing that type I and III IFN pathways may play an important role in promoting inflammatory responses. In B. pertussis-infected mice, lung type I/III IFN responses correlated with increased proinflammatory cytokine expression and with lung inflammatory pathology. In mutant mice with increased type I IFN receptor (IFNAR) signaling, B. pertussis infection exacerbated lung inflammatory pathology, whereas knockout mice with defects in type I IFN signaling had lower levels of lung inflammation than wild-type mice. Curiously, B. pertussis-infected IFNAR1 knockout mice had wild-type levels of lung inflammatory pathology. However, in response to infection these mice had increased levels of type III IFN expression, neutralization of which reduced lung inflammation. In support of this finding, B. pertussis-infected mice with a knockout mutation in the type III IFN receptor (IFNLR1) and double IFNAR1/IFNLR1 knockout mutant mice had reduced lung inflammatory pathology compared with that in wild-type mice, indicating that type III IFN exacerbates lung inflammation. In marked contrast, infant mice did not upregulate type I or III IFNs in response to B. pertussis infection and were protected from lethal infection by increased type I IFN signaling. These results indicate age-dependent effects of type I/III IFN signaling during B. pertussis infection and suggest that these pathways represent targets for therapeutic intervention in pertussis. Copyright © 2020 by The American Association of Immunologists, Inc.CRISPR/Cas9 technologies have revolutionized our understanding of gene function in complex biological settings, including T cell immunology. Current CRISPR-mediated gene editing strategies in T cells require in vitro stimulation or culture that can both preclude the study of unmanipulated naive T cells and alter subsequent differentiation. In this study, we demonstrate highly efficient gene editing within uncultured primary naive murine CD8+ T cells by electroporation of recombinant Cas9/sgRNA ribonucleoprotein immediately prior to in vivo adoptive transfer. Using this approach, we generated single and double gene knockout cells within multiple mouse infection models. Strikingly, gene deletion occurred even when the transferred cells were left in a naive state, suggesting that gene deletion occurs independent of T cell activation. Finally, we demonstrate that targeted mutations can be introduced into naive CD8+ T cells using CRISPR-based homology-directed repair. This protocol thus expands CRISPR-based gene editing approaches beyond models of robust T cell activation to encompass both naive T cell homeostasis and models of weak activation, such as tolerance and tumor models. Copyright © 2020 by The American Association of Immunologists, Inc.The advance in the human genetic field has permitted to identify small chromosome alterations and associate them to a specific phenotype. However, there are many mutations that have not yet been described in the literature. We describe the clinical case of a term newborn with appropriate weight to its gestational age, without perinatal background of interest that, at birth, presented macrocephaly, hypertelorism, low-set ears, prominent forehead, micrognathia, camptodactyly, bilateral cryptorchidism, inspiratory stridor with the cry, multifocal systolic murmur, wide anterior fontanel and hypotonia of mixed characteristics and in whom a deletion of the 1q44 cytoband and a pathogenic duplication in the 9q32q34.3 cytoband were detected. We perform a review of the literature. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.Young man with acute onset nausea, vomiting, joint pain, abdominal pain, fever and weight loss was found to have gait ataxia and positive B rucella titres. He deteriorated despite appropriate antibiotics and developed confusion and disorientation. Lumbar puncture revealed lymphocytosis with high protein and low glucose. MRI showed diffuse demyelination. Pulse steroids resulted in rapid clinical, biochemical and radiological recovery. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.A 73-year-old woman was referred to a tertiary centre with isolated splenic metastasis from previous pT1aNo stage 1a lung adenocarcinoma. The patient underwent a right lower lobe lobectomy and mediastinal lymph node dissection 2 years ago for invasive adenocarcinoma with no adjuvant therapy. An incidental finding of new splenic cyst was noted on surveillance imaging, which was fluorodeoxyglucose positive on positron emission tomography, and confirmed on cytology to be metastatic lung adenocarcinoma. After multi-disciplinary team's review, the patient underwent splenectomy, with partial excision of diaphragm due to local infiltration. Her postoperative course was eventful, and was complicated by a simple fluid collection in the surgical bed (amylase negative), a left sided pneumonia and atelectasis and left sided pleural effusion, requiring antibiotics and radiological drainage of the abdominal and pleural collection. The patient recovered well and is currently doing well 9 months postoperatively with no evidence of recurrence or metastatic disease. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.The use of indwelling pleural catheters (IPC) is well established in the treatment of malignant pleural effusions. They allow symptom management with intermittent drainage without requiring overnight admission to hospital. However, little is known about their effectiveness in the treatment of pleural infections. Here, we present a case where an IPC is used in the therapeutic management of tuberculous empyema. The IPC enabled outpatient treatment, allowed the patient to return to work and reduced the cost of treatment and the risk of hospital-acquired complications. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.The overall kidney survival among lupus nephritis patients has improved with currently used induction immunosuppression regimens of corticosteroids and either cyclophosphamide or mycophenolate mofetil; however, there still remains a significant number of lupus nephritis patients who do not achieve remission with these regimens. Investigators have looked at other immunosuppressive regimens for lupus nephritis, and there has been interest in the use of calcineurin inhibitors in this regard. Calcineurin inhibitors are potentially an attractive option because of their established ability to inhibit T cell function, attenuate proteinuria through non-immunologic means, and their safety in pregnancy and lactation. In this review, we discuss the findings and limitations of selected trials that evaluated the use of calcineurin inhibitors in the treatment of lupus nephritis, either with corticosteroids alone or as a component of multitarget therapy when combined with mycophenolate mofetil. There may be a role for calcineurin inhibitors among patients with heavy proteinuria, as well as younger patients with refractory lupus nephritis. The multitarget therapy trials reveal higher rates of remission compared with mycophenolate mofetil alone and cyclophosphamide; however, some trials highlight the possibility of more infectious adverse events. We discuss the need for further study of calcineurin inhibitors in more diverse patient populations and the need for trials with longer follow-up with "hard" endpoints beyond proteinuria reduction, such as worsening CKD or repeat protocol biopsies, given the calcineurin inhibitors ability to reduce proteinuria non-immunologically and thus increased rate of relapse when the drug is tapered. While there may indeed be a space for calcineurin inhibitors to help increase remission rates in lupus nephritis patients, more work is needed to help address the questions the studies available to date have yet to answer. Copyright © 2020 by the American Society of Nephrology.BACKGROUND AND OBJECTIVES Residual kidney function is important to the health and wellbeing of patients with ESKD. We tested whether the kidney clearances of proximal tubular secretory solutes are associated with burden of uremic and heart failure symptoms among patients on peritoneal dialysis with residual kidney function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We enrolled 29 patients on incident peritoneal dialysis with residual urine output >250 ml daily. We used targeted liquid chromatography-mass spectrometry to quantify plasma, 24-hour urine, and peritoneal dialysate concentrations of ten tubular secretory solutes. We calculated the kidney and peritoneal dialysis clearances of each secretory solute, creatinine, and urea, and we estimated a composite kidney and peritoneal secretion score. We assessed for uremic symptoms using the Dialysis Symptom Index and heart failure-related symptoms using the Kansas City Cardiomyopathy Questionnaire. We used linear regression to determine associations of compo dialysis clearances. Kidney clearances of secretory solutes are associated with patient-reported uremic and heart failure-related symptoms. learn more Copyright © 2020 by the American Society of Nephrology.Glaucoma is a leading cause of blindness affecting up to 70 million people worldwide. High intraocular pressure (IOP) is a major risk factor for glaucoma. Inefficient aqueous humor (AqH) outflow resulting from structural or functional alterations in ocular drainage tissues are well established to cause high IOP, but the genes and pathways involved are poorly understood. We previously demonstrated that mutations in the gene encoding the serine protease PRSS56 induces ocular angle-closure and high IOP in mice and identified reduced ocular axial length as a potential contributing factor. Here we show that Prss56 -/- mice also exhibits an abnormal iridocorneal angle configuration characterized by a posterior shift of ocular drainage structures relative to the ciliary body and iris. Notably, we show that retina-derived PRSS56 is required between postnatal days 13 and 18 for proper iridocorneal configuration and that abnormal positioning of the ocular drainage tissues is not dependent on ocular size reduction in Prss56 -/- mice.
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