Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters.

Leishmania is an intracellular parasite with different species pathogenic to humans and causing the disease leishmaniasis. Leishmania donovani causes visceral leishmaniasis (VL) that manifests as hepatosplenomegaly, fever, pancytopenia and hypergammaglobulinemia. If left without treatment, VL can cause death, especially in immunocompromised people. Current treatments have often significant adverse effects, and resistance has been reported in some countries. Determining the metabolites perturbed during VL can lead us to find new treatments targeting disease pathogenesis. We therefore compared metabolic perturbation between L. donovani-infected and uninfected hamsters across organs (spleen, liver, and gut). Metabolites were extracted, analyzed by liquid chromatography-mass spectrometry, and processed with MZmine and molecular networking to annotate metabolites. We found few metabolites commonly impacted by infection across all three sites, including glycerophospholipids, ceramides, acylcarnitines, peptides, purines and amino acids. In accordance with VL symptoms and parasite tropism, we found a greater overlap of perturbed metabolites between spleen and liver compared to spleen and gut, or liver and gut. Targeting pathways related to these metabolite families would be the next focus that can lead us to find more effective treatments for VL

Fatal progression of experimental visceral leishmaniasis is associated with intestinal parasitism and secondary infection by commensal bacteria, and is delayed by antibiotic prophylaxis.

Leishmania donovani causes visceral leishmaniasis (VL), which is typically fatal without treatment. There is substantial variation between individuals in rates of disease progression, response to treatment and incidence of post-treatment sequelae, specifically post-kala-azar dermal leishmaniasis (PKDL). Nevertheless, the majority of infected people are asymptomatic carriers. Hamsters and mice are commonly used as models of fatal and non-fatal VL, respectively. Host and parasite genetics are likely to be important factors, but in general the reasons for heterogeneous disease presentation in humans and animal models are poorly understood. Host microbiota has become established as a factor in cutaneous forms of leishmaniasis but this has not been studied in VL. We induced intestinal dysbiosis in mice and hamsters by long-term treatment with broad-spectrum antibiotics in their drinking water. There were no significant differences in disease presentation in dysbiotic mice. In contrast, dysbiotic hamsters infected with L. donovani had delayed onset and progression of weight loss. Half of control hamsters had a rapid progression phenotype compared with none of the ABX-treated animals and the nine-month survival rate was significantly improved compared to untreated controls (40% vs. 10%). Antibiotic-treated hamsters also had significantly less severe hepatosplenomegaly, which was accompanied by a distinct cytokine gene expression profile. The protective effect was not explained by differences in parasite loads or haematological profiles. We further found evidence that the gut-liver axis is a key aspect of fatal VL progression in hamsters, including intestinal parasitism, bacterial translocation to the liver, malakoplakia and iron sequestration, none of which occurred in non-progressing murine VL. Diverse bacterial genera were cultured from VL affected livers, of which Rodentibacter was specifically absent from ABX-treated hamsters, indicating this pathobiont may play a role in promoting disease progression. The results provide experimental support for antibiotic prophylaxis against secondary bacterial infections as an adjunct therapy in human VL patients

Pediatric colloid cysts: a multinational, multicenter study. An IFNE-ISPN-ESPN collaboration

OBJECTIVE Colloid cysts (CCs) are rare at all ages, and particularly among children. The current literature on pediatric CC is limited, and often included in mixed adult/pediatric series. The goal of this multinational, multicenter study was to combine forces among centers and investigate the clinical course of pediatric CCs. METHODS A multinational, multicenter retrospective study was performed to attain a large sample size, focusing on CC diagnosis in patients younger than 18 years of age. Collected data included clinical presentation, radiological characteristics, treatment, and outcome. RESULTS One hundred thirty-four children with CCs were included. Patient age at diagnosis ranged from 2.4 to 18 years (mean 12.8 ± 3.4 years, median 13.2 years, interquartile range 10.3–15.4 years; 22% were \u3c 10 years of age). Twenty-two cases (16%) were diagnosed incidentally, including 48% of those younger than 10 years of age. Most of the other patients had symptoms related to increased intracranial pressure and hydrocephalus. The average follow-up duration for the entire group was 49.5 ± 45.8 months. Fifty-nine patients were initially followed, of whom 28 were eventually operated on at a mean of 19 ± 32 months later due to cyst growth, increasing hydrocephalus, and/or new symptoms. There was a clear correlation between larger cysts and symptomatology, acuteness of symptoms, hydrocephalus, and need for surgery. Older age was also associated with the need for surgery. One hundred three children (77%) underwent cyst resection, 60% using a purely endoscopic approach. There was 1 death related to acute hydrocephalus at presentation. Ten percent of operated patients had some form of complication, and 7.7% of operated cases required a shunt at some point during follow-up. Functional outcome was good; however, the need for immediate surgery was associated with educational limitations. Twenty operated cases (20%) experienced a recurrence of their CC at a mean of 38 ± 46 months after the primary surgery. The CC recurrence rate was 24% following endoscopic resection and 15% following open resections (p = 0.28). CONCLUSIONS CCs may present in all pediatric age groups, although most that are symptomatic present after the age of 10 years. Incidentally discovered cysts should be closely followed, as many may grow, leading to hydrocephalus and other new symptoms. Presentation of CC may be acute and may cause life-threatening conditions related to hydrocephalus, necessitating urgent treatment. The outcome of treated children with CCs is favorable

Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression

Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression

Event reconstruction for KM3NeT/ORCA using convolutional neural networks

The KM3NeT research infrastructure is currently under construction at two locations in the Mediterranean Sea. The KM3NeT/ORCA water-Cherenkov neutrino de tector off the French coast will instrument several megatons of seawater with photosensors. Its main objective is the determination of the neutrino mass ordering. This work aims at demonstrating the general applicability of deep convolutional neural networks to neutrino telescopes, using simulated datasets for the KM3NeT/ORCA detector as an example. To this end, the networks are employed to achieve reconstruction and classification tasks that constitute an alternative to the analysis pipeline presented for KM3NeT/ORCA in the KM3NeT Letter of Intent. They are used to infer event reconstruction estimates for the energy, the direction, and the interaction point of incident neutrinos. The spatial distribution of Cherenkov light generated by charged particles induced in neutrino interactions is classified as shower-or track-like, and the main background processes associated with the detection of atmospheric neutrinos are recognized. Performance comparisons to machine-learning classification and maximum-likelihood reconstruction algorithms previously developed for KM3NeT/ORCA are provided. It is shown that this application of deep convolutional neural networks to simulated datasets for a large-volume neutrino telescope yields competitive reconstruction results and performance improvements with respect to classical approaches

Event reconstruction for KM3NeT/ORCA using convolutional neural networks

The KM3NeT research infrastructure is currently under construction at two locations in the Mediterranean Sea. The KM3NeT/ORCA water-Cherenkov neutrino detector off the French coast will instrument several megatons of seawater with photosensors. Its main objective is the determination of the neutrino mass ordering. This work aims at demonstrating the general applicability of deep convolutional neural networks to neutrino telescopes, using simulated datasets for the KM3NeT/ORCA detector as an example. To this end, the networks are employed to achieve reconstruction and classification tasks that constitute an alternative to the analysis pipeline presented for KM3NeT/ORCA in the KM3NeT Letter of Intent. They are used to infer event reconstruction estimates for the energy, the direction, and the interaction point of incident neutrinos. The spatial distribution of Cherenkov light generated by charged particles induced in neutrino interactions is classified as shower- or track-like, and the main background processes associated with the detection of atmospheric neutrinos are recognized. Performance comparisons to machine-learning classification and maximum-likelihood reconstruction algorithms previously developed for KM3NeT/ORCA are provided. It is shown that this application of deep convolutional neural networks to simulated datasets for a large-volume neutrino telescope yields competitive reconstruction results and performance improvements with respect to classical approaches

Supratentorial Pediatric Midline Tumors and Tumor-like Lesions: Clinical Spectrum, Natural History and Treatment Options

Childhood Central Nervous System tumors account for 25% of all pediatric tumors. Large availability and broadening of indications to imaging has made incidental findings more common. Among these, midline lesions have different clinical relevance depending on their intrinsic pattern of behaviour and on their specific location. In this narrative review we describe the natural history and treatment options of midline lesions in children

Supratentorial Pediatric Midline Tumors and Tumor-like Lesions: Clinical Spectrum, Natural History and Treatment Options

Childhood Central Nervous System tumors account for 25% of all pediatric tumors. Large availability and broadening of indications to imaging has made incidental findings more common. Among these, midline lesions have different clinical relevance depending on their intrinsic pattern of behaviour and on their specific location. In this narrative review we describe the natural history and treatment options of midline lesions in children