IL-2 Regulates Expression of C-MAF in Human CD4 T Cells

Blockade of IL-2R with humanized anti-CD25 Abs, such as daclizumab, inhibits Th2 responses in human T cells. Recent murine studies have shown that IL-2 also plays a significant role in regulating Th2 cell differentiation by activated STAT5. To explore the role of activated STAT5 in the Th2 differentiation of primary human T cells, we studied the mechanisms underlying IL-2 regulation of C-MAF expression. Chromatin immunoprecipitation studies revealed that IL-2 induced STAT5 binding to specific sites in the C-MAF promoter. These sites corresponded to regions enriched for markers of chromatin architectural features in both resting CD4 and differentiated Th2 cells. Unlike IL-6, IL-2 induced C-MAF expression in CD4 T cells with or without prior TCR stimulation. TCR-induced C-MAF expression was significantly inhibited by treatment with daclizumab or a JAK3 inhibitor, R333. Furthermore, IL-2 and IL-6 synergistically induced C-MAF expression in TCR-activated T cells, suggesting functional cooperation between these cytokines. Finally, both TCR-induced early IL4 mRNA expression and IL-4 cytokine expression in differentiated Th2 cells were significantly inhibited by IL-2R blockade. Thus, our findings demonstrate the importance of IL-2 in Th2 differentiation in human T cells and support the notion that IL-2R–directed therapies may have utility in the treatment of allergic disorders

Fingerprinting the Substrate Specificity of M1 and M17 Aminopeptidases of Human Malaria, Plasmodium falciparum

Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs.To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria.This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment

Epidemiology of pediatric hydrocephalus in Haiti: analysis of a surgical case series

OBJECTIVEHydrocephalus is recognized as a common disabling pediatric disease afflicting infants and children disproportionately in the developing world, where access to neurosurgical care is limited and risk of perinatal infection is high. This surgical case series describes the Project Medishare Hydrocephalus Specialty Surgery (PMHSS) program experience treating hydrocephalus in Haiti between 2008 and 2015.METHODSThe authors conducted a retrospective review of all cases involving children treated for hydrocephalus within the PMHSS program in Port-au-Prince, Haiti, from 2008 through 2015. All relevant epidemiological information of children treated were prospectively collected including relevant demographics, birth history, hydrocephalus etiology, head circumference, and operative notes. All appropriate associations and statistical tests were performed using univariate and multivariate logistic regression analyses.RESULTSAmong the 401 children treated within PMHSS, postinfectious hydrocephalus (PIH) accounted for 39.4% (n = 158) of cases based on clinical, radiographic, and endoscopic findings. The majority of children with hydrocephalus in Haiti were male (54.8%, n = 197), born in the rainy season (59.7%, n = 233), and born in a coastal/inland location (43.3%, n = 61). The most common surgical intervention was endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) (45.7%, n = 175). Multivariate logistic regression analysis yielded coastal birth location (OR 3.76, 95% CI 1.16–12.18) as a statistically significant predictor of PIH. Increasing head circumference (adjusted OR 1.06, 95% CI 0.99–1.13) demonstrated a slight trend toward significance with the incidence of PIH.CONCLUSIONSThis information will provide the foundation for future clinical and public health studies to better understand hydrocephalus in Haiti. The 39.4% prevalence of PIH falls within observed rates in Africa as does the apparently higher prevalence for those born during the rainy season. Although PIH was the most frequent etiology seen in almost all birth locations, the potential relationship with geography noted in this series will be the focus of further research in an effort to understand the link between climate and PIH in Haiti. The ultimate goal will be to develop an appropriate public health strategy to reduce the burden of PIH on the children of Haiti

Combined transcranial-orbital approach for resection of optic nerve gliomas: a clinical and anatomical study

To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis. A retrospective, noncomparative, interventional case series. All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010. A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn. The proximal transected edge of the nerve is examined intraoperatively for tumor margin clearance. Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn. A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn. Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence. Eleven patients underwent resection of optic nerve gliomas using this technique. No patients had tumor recurrence or developed postoperative paralytic ptosis. The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis

RARE-31. TREATMENT OUTCOME OF CHILDREN WITH PLEOMORPHIC XANTHOASTROCYTOMA: RETROSPECTIVE ANALYSIS – A SINGLE INSTITUTION EXPERIENCE

Abstract BACKGROUND Pleomorphic xanthoastrocytoma (PXA) and anaplastic pleomorphic xanthoastrocytoma (APXA) are two types of rare astrocytomas in pediatrics. There is limited literature reporting their outcomes. METHODS A retrospective analysis of pediatric patients with diagnosis of PXA and APXA treated at Nicklaus Children’s Hospital was conducted using descriptive measures. RESULTS A chart review of patients with brain tumors from 2001 to 2019 revealed that 13 patients (median age 6 years, range 2–17 years) were diagnosed with non-metastatic PXA (n=12) and APXA (n=1). Six patients (46%) were male. Clinical presentation included seizures (n=8), headaches (n=2) cranial nerve palsies (n=2). Diagnostic imaging showed tumor in the temporal lobe (n=5), parietal lobe (n=2), temporoparietal lobe (n=2), frontal lobe (n=1), occipital lobe (n=1), others (n=2). BRAF V600E mutation were identified in three of five analyzed tumors including PXA (n=4) and APXA (n=1). Surgical intervention consisted of gross total resection (n=8) and near/subtotal resection (n=5). Ten patients (76%) required a second surgery (median 2; range 1–4) due to local recurrence. The median time to recurrence was 3 years (range 6 months - 7 years). Three patients (23%) had malignant transformation of PXA, which occurred three to eight years from the initial surgery; one of them also had extensive spinal metastasis. Focal radiation was given to six patients (46%) due to multiple recurrence (n=2), malignant transformation (n=3), APXA (n=1). At a median follow up of 8 years (range 3 to 20 years), eight patients remain alive, three patients had lost to follow up, two patients died from progressive disease. Long-term sequelae varied as follows; seizures (n=5), motor weakness (n=4), cranial nerve palsies (n=2), and learning disability (n=1). CONCLUSION PXA is associated with high local recurrence rate and uncommonly malignant transformation to APXA in pediatrics, which requires close follow-up due to unpredictable biological behavior of these tumors

Genetic support of carbapenemases : a One Health systematic review and meta-analysis of current trends in Africa

Antimicrobial resistance (AMR) is a public health threat globally. Carbapenems are β-lactam antibiotics used as last-resort agents for treating antibiotic-resistant infections. Mobile genetic elements (MGEs) play an important role in the dissemination and expression of antimicrobial resistance genes (ARGs), including the mobilization of ARGs within and between species. The presence of MGEs around carbapenem-hydrolyzing enzymes, called carbapenemases, in bacterial isolates in Africa is concerning. The association between MGEs and carbapenemases is described herein. Specific plasmid replicons, integrons, transposons, and insertion sequences were found flanking specific and different carbapenemases across the same and different clones and species isolated from humans, animals, and the environment. Notably, similar genetic contexts have been reported in non-African countries, supporting the importance of MGEs in driving the intra- and interclonal and species transmission of carbapenemases in Africa and globally. Technical and budgetary limitations remain challenges for epidemiological analysis of carbapenemases in Africa, as studies undertaken with whole-genome sequencing remained relatively few. Characterization of MGEs in antibiotic-resistant infections can deepen our understanding of carbapenemase epidemiology and facilitate the control of AMR in Africa. Investment in genomic epidemiology will facilitate faster clinical interventions and containment of outbreaks.SUPPLEMENTARY MATERIAL : Appendix S1. The role of MGEs in antimicrobial resistance (A) and the clonality (MLST) of isolates hosting resistance genes (B).Dataset S1. Raw data of the information extracted from included articles and statistical analysis.Figure S1. A PRISMA diagram showing the literature search strategy, inclusion and exclusion criteria, and the final number of included articles.Table S1. (A–E) The sequence types of species harboring carbapenemases in Africa.https://nyaspubs.onlinelibrary.wiley.com/journal/174966322022-11-09hj2022Medical Microbiolog

Endoscopic Fenestration of Middle Fossa Arachnoid Cysts: A Technical Description and Case Series

Background: Arachnoid cysts are intra-arachnoidal cerebrospinal fluid collections most frequently seen in the middle cranial fossa. The optimal method of treatment for symptomatic arachnoid cysts remains controversial and includes cyst shunting, open craniotomy and endoscopic fenestration. All these techniques, however, have been associated with the development of postoperative subdural fluid collections. We describe a new endoscopic transcortical technique that attempts to avoid this complication. Methods: Six patients with middle cranial fossa arachnoid cysts were treated with endoscopic fenestration at our institution between January 2002 and December 2005. Three cases were approached directly through the cyst, while the other 3 were approached by passing the endoscope through the rim of adjacent cortex. Results: All six endoscopic fenestrations were successful in treating the arachnoid cysts. Among the 3 patients treated via a direct cyst entry, 2 cases developed significant subdural hygromas, 1 of which required aspiration. On the other hand, 1 of the 3 cases treated using a transcortical technique developed an insignificant postoperative extra-axial collection that resolved at 3 months without intervention. Conclusion: Endoscopic fenestration is an effective treatment for symptomatic arachnoid cysts. Endoscopic fenestration via a transcortical approach attempts to minimize cerebrospinal fluid drainage into the subdural space, avoiding the development of significant postoperative extra-axial collections, while promoting flow into the basal cisterns

Engorged epidural venous plexus and cervical myelopathy due to cerebrospinal fluid overdrainage: a rare complication of ventricular shunts. Case report

The authors report on a 17-year-old boy with cervical myelopathy from dilated epidural veins due to cerebrospinal fluid (CSF) overdrainage. The patient had a long-standing subdural-peritoneal shunt and presented with incapacitating spastic tetraparesis. Magnetic resonance imaging revealed significant cervical spinal cord compression from a markedly dilated epidural venous plexus. The shunt was externalized so that CSF flow dynamics could be assessed, and the patient was found to have low intracranial pressure (ICP). The patient was gradually acclimated to higher ICPs, and a new shunt was placed with an antisiphon device and a programmable valve set at the higher pressure. Postoperatively the child experienced significant clinical improvement, and reduction of spinal cord compression was evident on images. Compensatory engorgement of the epidural venous plexus due to long-term shunt usage should be considered in the differential diagnosis when cervical myelopathy due to a dilated epidural venous plexus is present