Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2, enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. ...Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2−/− mice and OASL-deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway. cGAS was necessary for the reduced DNA virus replication observed in OASL-deficient cells. OASL directly and specifically bound to cGAS independently of double-stranded DNA, resulting in a non-competitive inhibition of the second messenger cyclic GMP-AMP production. Our findings define distinct mechanisms by which OASL differentially regulates host IFN responses during RNA and DNA virus infection and identify OASL as a negative-feedback regulator of cGAS.
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•Loss of human OASL and mouse Oasl2 inhibits DNA virus infection•OASL and Oasl2 inhibit cGAS-mediated IFN induction•OASL specifically binds to cGAS to inhibit cGAS enzyme activity•OASL binds to cGAS independently of double-stranded DNA
The interferon (IFN)-stimulated gene OASL enhances RNA-sensor RIG-I-mediated IFN induction to inhibit RNA virus replication. In contrast, Ghosh et al. show that during DNA virus infection, OASL binds to the DNA sensor cGAS to inhibit IFN induction and enhance DNA virus replication. These findings highlight the distinct regulation of IFN induction by OASL during RNA and DNA virus infection.
Advances in prostate imaging, biopsy and ablative technologies have been accompanied by growing enthusiasm for partial gland ablation, particularly using high-intensity focused ultrasound, to treat ...prostate cancer. Preserving noncancerous prostate tissue and minimizing damage to the neurovascular bundles and external urethral sphincter may improve functional outcomes.
A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using a combination of MeSH® terms, free text search and examination of relevant bibliographies using MEDLINE® and Embase® from the inception of each database through October 10, 2016. We excluded studies describing exclusively whole gland ablation, case reports and series where treatment was followed by immediate resection.
A total of 13 studies that enrolled 543 patients were included. Of the studies 11 were performed in the primary setting and 2 in the salvage setting. Median followup ranged from 6 months to 10.6 years. Rates of posttreatment erectile dysfunction and urinary incontinence ranged from 0% to 48% and 0% to 50%, respectively, with definitions varying by study. Overall there were 254 reported complications. Marked heterogeneity between studies limited the ability to pool results regarding functional and oncologic outcomes. A total of 76 patients (14%) subsequently received further oncologic treatment.
Early evidence suggests that partial gland ablation is a safe treatment option for men with localized disease. Longer term data are needed to evaluate oncologic efficacy and functional outcomes, and will aid in identifying the optimal candidates for therapy. Standardization of outcomes definitions will allow for better comparison between studies and among treatment modalities.
To evaluate differences in the incidence of benign ureteroenteric stricture, we compared stricture rates of robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC) using ...Surveillance, Epidemiology, and End Results-Medicare data.
We identified 332 RARC and 1449 ORC performed between 2009 and 2014 to determine stricture rates at 6, 12, and 24 months following surgery. We defined ureteroenteric stricture as the need for procedural intervention. Additionally, we compared the incidence of stricture diagnosis. Multivariable proportional hazards regression was performed to determine factors associated with stricture development.
The incidence of ureteroenteric stricture at 6 and 12 months was higher for RARC vs ORC at 12.1% vs 7.0% (P < .01) and 15.0% vs 9.5% (P = .01), respectively. RARC vs ORC stricture incidence at 2 years did not differ significantly at 14.6% vs 11.4% (P = .29). Similarly, the stricture diagnosis rates were significantly lower following ORC at 6, 12, and 24 months (P < .05). In adjusted analysis, RARC (HR 1.64, 95%CI 1.23-2.19) and preoperative hydronephrosis (HR 1.51, 95% CI 1.17-1.94) were associated with the development of stricture. Higher hospital volume was associated with a lower risk of stricture (HR 0.40, 95%CI 0.26-0.63).
RARC is associated with a higher rate of ureteroenteric stricture diagnosis and intervention on a population-based level that is mitigated by higher hospital volume. A significant study limitation is inability to differentiate extracorporeal vs intracorporeal diversion. However, a stricture complication compounds the financial burden of care and efforts must be pursued to improve this surgical outcome.
As incidence of operative spinal pathology continues to grow, so do the rates of lumbar spinal fusion procedures. Comorbidity indices can be used preoperatively to predict potential complications. ...However, there is a paucity of research defining the optimal comorbidity indices in patients undergoing spinal fusion surgery. We aimed to use modeling strategies to evaluate the predictive validity of various comorbidity indices and combinations thereof.
Patients who underwent spinal fusion were queried using data from the Nationwide Readmissions Database for the years 2016 through 2019. Using comorbidity indices as predictor variables, receiver operating characteristic curves were developed for pertinent complications such as mortality, nonroutine discharge, top-quartile cost, top-quartile length of stay, and 30-day readmission.
A total of 750 183 patients were included. Nonroutine discharges occurred in 161 077 (21.5%) patients. The adjusted all-payer cost for the procedure was $37 616.97 ± $27 408.86 (top quartile: $45 409.20), and the length of stay was 4.1 ± 4.4 days (top quartile: 8.1 days). By comparing receiver operating characteristics of various models, it was found that models using Frailty + Elixhauser Comorbidity Index (ECI) as the primary predictor performed better than other models with statistically significant P -values on post hoc testing. However, for prediction of mortality, the model using Frailty + ECI was not better than the model using ECI alone ( P = .23), and for prediction of all-payer cost, the ECI model outperformed the models using frailty alone ( P < .0001) and the model using Frailty + ECI ( P < .0001).
This investigation is the first to use big data and modeling strategies to delineate the relative predictive utility of the ECI and Johns Hopkins Adjusted Clinical Groups comorbidity indices for the prognostication of patients undergoing lumbar fusion surgery. With the knowledge gained from our models, spine surgeons, payers, and hospitals may be able to identify vulnerable patients more effectively within their practice who may require a higher degree of resource utilization.
Given the sparse nature of acute mania or psychosis in primary adrenal insufficiency (PAI), physicians may not be aware of the association of these two entities.
To conduct a systematic review of the ...literature for the purpose of identifying all studies reporting mania and/or psychosis in individuals with PAI.
We conducted a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the PubMed, Embase, and Web of Science databases from June 22, 1970 to June 22, 2021, for the purpose of identifying all studies reporting instances of mania or psychosis associated with PAI.
We identified nine case reports featuring nine patients (M age = 43.3 years, male = 44.4%) over eight countries that fit our inclusion/exclusion criteria. Eight (89%) of the patients had experienced psychosis. Manic and/or psychotic symptom resolution was achieved in 100% of the cases, of which steroid replacement therapy was efficacious in seven (78%) cases and was sufficient in six (67%).
Acute mania and psychosis in the context of PAI is a very rare presentation of an already uncommon disease. Resolution of acute psychiatric change is reliably achieved with the correction of underlying adrenal insufficiency.
Cerebral palsy (CP) is a chronic congenital disorder as the result of abnormal brain development. Children suffering from CP often battle debilitating chronic spasticity, which has been the focus of ...recent academic literature. In this systematic review, the authors aim to update the current neuromodulation procedures for the treatment of spasticity associated with CP in all age groups. A systematic review following was conducted using PubMed from inception to 2020. After initial title and abstract screening, 489 articles were identified, and 48 studies met the inclusion criteria for this review. In total, a majority of the published articles of treatments for CP were reporting the use of selective dorsal rhizotomy (SDR) (54%), and the remainder were of intrathecal baclofen (ITB) pumps (29%) and extracorporeal shockwave therapy (ESWT) (17%). Each method was found to have improvement of spasticity at a rate that achieved statistical significance. ITB pump therapy is an all-encompassing method of treating spasticity in children from CP, as it allows for a less invasive treatment that can be titrated to individual patient needs; however, its disadvantages include its long-term maintenance requirements. SDR appears to be an effective method for permanent spasticity relief in young patients. ESWT is a more recent and innovative technique for offering relief of spasticity while being minimally invasiveness. Further studies are needed to establish optimal frequencies and sites of application for ESWT.
Staged surgery for skull base lesions has been utilized to facilitate maximal safe resection and optimize outcomes while minimizing morbidity and complications. Conversely, staged surgery for primary ...intraparenchymal neoplasms is less commonly performed and has not been reported as extensively within the literature. As such, we performed a systematic review to examine the unique surgical indications for staging, timing between stages, specific surgical approaches utilized, and postoperative complications of staged surgery for primary intra-axial neoplasms.
A literature search was conducted in August 2021 using PubMed, Web of Science, and Cochrane databases using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations. Titles and abstracts were evaluated independently by 2 authors, after which articles were selected for final analysis based on application of strict inclusion criteria during full text screen. Each included article was then qualitatively assessed and relevant variables—including operative approaches, timing, and outcomes—were extracted for synthesis.
Of 115 results, 7 articles were included for final analysis and consisted of 17 pediatric and 4 adult patients. Staged approaches were more commonly utilized in the pediatric patient population for resection of astrocytoma and glioma. Pediatric patients had a timing of surgeries ranging from 5–10 days between operations, compared with 18 days to 4 months in adult patients. Complications in pediatric patients were most commonly hemiparesis, hydrocephalus, cranial nerve VI and VII palsies, truncal ataxia, and cerebellar mutism, while complications in adult patients included language and abstract thinking deficits, respiratory failure, and motor weakness.
This study reports the first comprehensive review of staged surgical procedures for primary, intra-axial cranial neoplasms. There exists a large degree of heterogeneity in complications resulting from staged surgeries for intra-axial neoplasms, which are similar to complications associated with single-stage surgery for intraparenchymal lesions as well as multi-stage surgeries for skull base lesions.
Dural closure is an important part of any pediatric spinal procedure with intradural pathology to prevent post-operative cerebrospinal fluid (CSF) egress and associated complications. Utilization of ...nonpenetrating titanium clips is one closure option that may have technical advantages such as ease of use and amenability to a narrow surgical corridor. No data exist on the efficacy of these clips for pediatric spinal dural closure.
A single surgeon case series of 152 pediatric patients underwent procedures involving lumbar durotomy with subsequent dural closure using the AnastoClip® nonpenetrating titanium clip closure system. Rates of infection and cerebrospinal fluid leak were measured during the follow-up period.
A total of 152 pediatric patients (mean age: 6.25 ± 5.85 years, 50.7 % female) underwent intradural surgery with clip closure. The mean follow-up time was 57.0 ± 28.5 months. All patients were initially indicated for procedures involving spinal durotomy, with a majority being isolated tethered cord release (84.2 %). Others required tethered cord release and excision of a lipomyelomeningocele, spinal meningioma or arachnoid cyst (15.8 %). Post operative CSF leak occurred in two (1.32 %) patients at 11 and 18 days. Only one (0.66 %) patient was diagnosed with an infection, which was in a separate patient from those that had CSF leaks.
The remarkably low incidence of post-operative CSF leak and infection with nonpenetrating titanium clips suggests a strong safety and efficacy profile for this form of dural closure in a pediatric cohort. Further research evaluating this technique is required to fully demonstrate its acceptability as a cost-effective alternative to traditional suture-based closure.
•152 pediatric durotomy patients subsequent dural closure using AnastoClip®.•Tethered cord release was the most common indication for initial surgery.•The simplicity of dural closure using AnastoClip® is demonstrated in this paper.•Low incidence of post-operative complications suggests strong safety and efficacy.
Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert ...beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we hypothesize that C21 may exert beneficial effects against cerebral damage and neurological deficits produced by ischemic stroke. We determined the effects of central and peripheral administration of C21 on the cerebral damage and neurological deficits in rats elicited by endothelin-1 induced middle cerebral artery occlusion (MCAO), a model of cerebral ischemia. Rats infused centrally (intracerebroventricular) with C21 before endothelin-1 induced MCAO exhibited significant reductions in cerebral infarct size and the neurological deficits produced by cerebral ischemia. Similar cerebroprotection was obtained in rats injected systemically (intraperitoneal) with C21 either before or after endothelin-1 induced MCAO. The protective effects of C21 were reversed by central administration of an AT2R inhibitor, PD123319. While C21 did not alter cerebral blood flow at the doses used here, peripheral post-stroke administration of this agent significantly attenuated the MCAO-induced increases in inducible nitric oxide synthase, chemokine (C-C) motif ligand 2 and C-C chemokine receptor type 2 mRNAs in the cerebral cortex, indicating that the cerebroprotective action is associated with an anti-inflammatory effect. These results strengthen the view that AT2R agonists may have potential therapeutic value in ischemic stroke, and provide the first evidence of cerebroprotection induced by systemic post stroke administration of a selective AT2R agonist.
•The AT2R agonist C21 exerts significant beneficial actions against ischemic stroke.•C21 is effective when applied centrally or systemically.•Cerebroprotection is obtained with systemic post-stroke injection of C21.•The beneficial effects of systemic C21 are blocked by an AT2R antagonist.•Inflammatory markers are reduced in the brains of C21 treated rats.
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