Aryl Hydrocarbon Receptor Agonism Antagonizes the Hypoxia-driven Inflammation in Cystic Fibrosis.

Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by HIF-1α (hypoxia-inducible factor 1α) inhibition demands a better comprehension of downstream hypoxia-dependent pathways that are amenable for manipulation. We assessed here whether hypoxia may interfere with the activity of AhR (aryl hydrocarbon receptor), a versatile environmental sensor highly expressed in the lungs, where it plays a homeostatic role. We used murine models of Aspergillus fumigatus infection in vivo and human cells in vitro to define the functional role of AhR in CF, evaluate the impact of hypoxia on AhR expression and activity, and assess whether AhR agonism may antagonize hypoxia-driven inflammation. We demonstrated that there is an important interferential cross-talk between the AhR and HIF-1α signaling pathways in murine and human CF, in that HIF-1α induction squelched the normal AhR response through an impaired formation of the AhR:ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF-1ß heterodimer. However, functional studies and analysis of the AhR genetic variability in patients with CF proved that AhR agonism could prevent hypoxia-driven inflammation, restore immune homeostasis, and improve lung function. This study emphasizes the contribution of environmental factors, such as infections, in CF disease progression and suggests the exploitation of hypoxia:xenobiotic receptor cross-talk for antiinflammatory therapy in CF.

Combined sclerotherapy followed by surgical resection of a large extracranial venous malformation in a 14-month-old child: preoperative workup and technical note.

INTRODUCTION: Venous malformations affect around 2 per 10,000 newborn and are the most common type of congenital vascular malformation. They are always present at birth and are often misdiagnosed with hemangiomas. Accurate diagnosis and adequate targeted therapy through a multidisciplinary approach is advocated for a successful treatment, considering a combination of modalities in complex cases. We present here the workup and treatment of a venous malformation in a 14 month old child by combining a preoperative sclerotherapy with sodium tetradecyl sulfate (STS) followed by complete surgical excision respecting the calvarium. CASE PRESENTATION: A large right extracranial fronto-parietal venous malformation and scalloping of the underlying calvarium, attached to the pericranium, surgically excised after preoperative sclerotherapy with STS in a 14-month-old child. RESULTS: The patient had an uneventful postoperative course with complete resection of the lesion, satisfying cosmetic appearance and no complications. Histopathological examination confirmed a venous malformation. CONCLUSION: We demonstrated the workup and the rationale of the combined sclerotherapy followed by surgical resection of a large growing extracranial venous malformation. Preoperative direct contrast injection and sclerotherapy allowed to rule out significative extracranial to intracranial venous inflow and reduce blood loss for the surgical procedure, respectively. Complete removal of the malformation minimized the impact on future growth of the calvarium.

Decompressive hemicraniectomy in pediatric malignant arterial ischemic stroke: a case-based review.

PURPOSE: Malignant stroke is a life-threatening emergency, with a high mortality rate (1-3). Despite strong evidence showing decreased morbidity and mortality in the adult population, decompressive hemicraniectomy (DCH) has been scarcely reported in the pediatric stroke population, and its indication remains controversial, while it could be a potential lifesaving option. METHODS AND RESULTS: We performed an extensive literature review on pediatric malignant arterial ischemic stroke (pmAIS) and selected 26 articles reporting 97 cases. Gathering the data together, a 67% mortality rate is observed without decompressive therapy, contrasting with a 95.4% survival rate with it. The median modified Rankin score (mRS) is 2.1 after surgery with a mean follow-up of 31.8 months. For the 33% of children who survived without surgery, the mRS is 3 at a mean follow-up of 19 months. As an illustrative case, we report on a 2-year-old girl who presented a cardioembolic right middle cerebral artery stroke with subsequent malignant edema and ongoing cerebral transtentorial herniation in the course of a severe myocarditis requiring ECMO support. A DCH was done 32 h after symptom onset. At the age of 5 years, she exhibits an mRS of 3. CONCLUSION: Pediatric stroke with malignant edema is a severe condition with high mortality rate if left untreated and often long-lasting consequences. DCH might minimize the vicious circle of cerebral swelling, increasing intracranial pressure and brain ischemia. Our literature review underscores DCH as an efficient therapeutic measure management of pmAIS even when performed after a significant delay; however, long-lasting morbidities remain high.

Severe Basilar impression in osteogenesis imperfecta treated with halo gravity traction, occipitocervicothoracic fusion, foramen magnum and upper cervical decompression and expansive duroplasty: a technical note.

Osteogenesis imperfecta (OI) is a rare bone disease due to an abnormal synthesis of 1-type collagen. OI is frequently associated with basilar impression (BI), defined by the elevation of the clivus and floor of the posterior fossa with subsequent migration of the upper cervical spine and the odontoid peg into the base of the skull. Bone intrinsic fragility leading to fractures and deformity, brainstem compression and impaired CSF circulation at cranio-vertebral junction (CVJ) makes the management of these conditions particularly challenging. Different surgical strategies, including posterior fossa decompression with or without instrumentation, transoral or endonasal decompression with posterior occipito-cervical fusion, or halo gravity traction with posterior instrumentation have been reported, but evidence about best modalities treatment is still debated. In this technical note, we present a case of a 16-years-old patient, diagnosed with OI and BI, treated with halo traction, occipito-cervico-thoracic fixation, foramen magnum and upper cervical decompression, and expansive duroplasty. We focus on technical aspects, preoperative work up and postoperative follow up. We also discuss advantages and limitations of this strategy compared to other surgical techniques.

Natural history and treatment options of radiation-induced brain cavernomas: a systematic review.

Radiation-induced cavernous malformations (RICMs) are delayed complications of brain irradiation during childhood. Its natural history is largely unknown and its incidence may be underestimated as RCIMS tend to develop several years following radiation. No clear consensus exists regarding the long-term follow-up or treatment. A systematic review of Embase, Cochrane Library, PubMed, Google Scholar, and Web of Science databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed. Based on our inclusion/exclusion criteria, 12 articles were included, totaling 113 children with RICMs, 86 were treated conservatively, and 27 with microsurgery. We were unable to precisely define the incidence and natural history from this data. The mean age at radiation treatment was 7.3 years, with a slight male predominance (54%) and an average dose of 50.0 Gy. The mean time to detection of RICM was 9.2 years after radiation. RICM often developed at distance from the primary lesion, more specifically frontal (35%) and temporal lobe (34%). On average, 2.6 RICMs were discovered per child. Sixty-seven percent were asymptomatic. Twenty-one percent presented signs of hemorrhage. Clinical outcome was favorable in all children except in 2. Follow-up data were lacking in most of the studies. RICM is most often asymptomatic but probably an underestimated complication of cerebral irradiation in the pediatric population. Based on the radiological development of RICMs, many authors suggest a follow-up of at least 15 years. Studies suggest observation for asymptomatic lesions, while surgery is reserved for symptomatic growth, hemorrhage, or focal neurological deficits.

Syndrome of the trephined: clinical spectrum, risk factors, and impact of cranioplasty on neurologic recovery in a prospective cohort.

Syndrome of the trephined (SoT) is an underrecognized complication after decompressive craniectomy. We aimed to investigate SoT incidence, clinical spectrum, risk factors, and the impact of the cranioplasty on neurologic recovery. Patients undergoing a large craniectomy (> 80 cm2) and cranioplasty were prospectively evaluated using modified Rankin score (mRS), cognitive (attention/processing speed, executive function, language, visuospatial), motor (Motricity Index, Jamar dynamometer, postural score, gait assessment), and radiologic evaluation within four days before and after a cranioplasty. The primary outcome was SoT, diagnosed when a neurologic improvement was observed after the cranioplasty. The secondary outcome was a good neurologic outcome (mRS 0-3) 4 days and 90 days after the cranioplasty. Logistic regression models were used to evaluate the risk factors for SoT and the impact of cranioplasty timing on neurologic recovery. We enrolled 40 patients with a large craniectomy; 26 (65%) developed SoT and improved after the cranioplasty. Brain trauma, hemorrhagic lesions, and shifting of brain structures were associated with SoT. After cranioplasty, a shift towards a good outcome was observed within 4 days (p = 0.025) and persisted at 90 days (p = 0.005). Increasing delay to cranioplasty was associated with decreased odds of improvement when adjusting for age and baseline disability (odds ratio 0.96; 95% CI, 0.93-0.99, p = 0.012). In conclusion, SoT is frequent after craniectomy and interferes with neurologic recovery. High suspicion of SoT should be exercised in patients who fail to progress or have a previous trauma, hemorrhage, or shifting of brain structures. Performing the cranioplasty earlier was associated with improved and quantifiable neurologic recovery. Graphical abstract.

Atlantoaxial posterior screw fixation using intra-operative spinal navigation with three-dimensional isocentric C-arm fluoroscopy.

PURPOSE: Intra-operative image acquisition coupled with navigation aims to increase screw placement accuracy, and it is particularly helpful in complex spinal procedures. The aim of this study is to analyze the accuracy and reliability of posterior atlanto-axial fixation using spinal navigation combined with intra-operative 3D isocentric C-arm. METHODS: We retrospectively reviewed all patients presenting with C1-C2 instability and treated by posterior atlanto-axial fixation in our center between December 2016 and September 2018. Screw positioning was guided by intra-operative navigation, registered with surface matching procedure on a previously obtained CT scan and controlled by intra-operative 3D isocentric C-arm. Age, sex, pre- and post-operative neurological status, duration of surgery, presence/absence of vertebral artery injury, and screw placement were retrospectively collected from patients' records. All patients underwent clinical and radiological follow-up at three months after surgery. Radiological assessment of screw positioning was performed by an independent radiologist using the Gertzbein and Robbins grading. RESULTS: N = 11 (7F, 4 M) consecutive patients were included, with a mean age of 72 years (range from 51 to 85). N = 44 navigated screws were inserted and controlled with intra-operative 3D fluoroscopy at the end of the procedure. An acceptable screw positioning (Gertzbein-Robbins grade A and B) was obtained in all cases (100%). No vertebral artery injury was observed. Mean operating time was 123 minutes. At three months, no screw loosening or displacement was observed. CONCLUSION: In our experience, spinal navigation coupled with intra-operative 3D fluoroscopy proved to be reliable and safe for C1-C2 screw placement.

Isolated subarachnoid hemorrhage in mild traumatic brain injury: is a repeat CT scan necessary? A single-institution retrospective study.

BACKGROUND: Traumatic brain injury (TBI) with isolated subarachnoid hemorrhage (iSAH) is a common finding in the emergency department. In many centers, a repeat CT scan is routinely performed 24 to72 h following the trauma to rule out further radiological progression. The aim of this study is to assess the clinical utility of the repeat CT scan in clinical practice. METHODS: We reviewed the medical charts of all patients who presented to our institution with mild TBI (mTBI) and isolated SAH between January 2015 and October 2017. CT scan at admission and control after 24 to 72 h were examined for each patient in order to detect any possible change. Neurological deterioration, antiplatelet/anticoagulant therapy, coagulopathy, SAH location, associated injuries, and length of stay in hospital were analyzed. RESULTS: Of the 649 TBI patients, 106 patients met the inclusion criteria. Fifty-four patients were females and 52 were males with a mean age of 68.2 years. Radiological iSAH progression was found in 2 of 106 (1.89) patients, and one of them was under antiplatelet therapy. No neurological deterioration was observed. Ten of 106 (9.4%) patients were under anticoagulation therapy, and 28 of 106 (26.4%) were under antiplatelet therapy. CONCLUSION: ISAH in mTBI seems to be a radiological stable entity over 72 h with no neurological deterioration. The clinical utility of a repeat head CT in such patients is questionable, considering its radiation exposure and cost. Regardless of anticoagulation/antiplatelet therapy, neurologic observation and symptomatic treatment solely could be a reasonable alternative.

Managing the Cloud Continuum: Lessons Learnt from a Real Fog-to-Cloud Deployment.

The wide adoption of the recently coined fog and edge computing paradigms alongside conventional cloud computing creates a novel scenario, known as the cloud continuum, where services may benefit from the overall set of resources to optimize their execution. To operate successfully, such a cloud continuum scenario demands for novel management strategies, enabling a coordinated and efficient management of the entire set of resources, from the edge up to the cloud, designed in particular to address key edge characteristics, such as mobility, heterogeneity and volatility. The design of such a management framework poses many research challenges and has already promoted many initiatives worldwide at different levels. In this paper we present the results of one of these experiences driven by an EU H2020 project, focusing on the lessons learnt from a real deployment of the proposed management solution in three different industrial scenarios. We think that such a description may help understand the benefits brought in by a holistic cloud continuum management and also may help other initiatives in their design and development processes.

A Shifted Composition of the Lung Microbiota Conditions the Antifungal Response of Immunodeficient Mice.

The microbiome, i.e., the communities of microbes that inhabit the surfaces exposed to the external environment, participates in the regulation of host physiology, including the immune response against pathogens. At the same time, the immune response shapes the microbiome to regulate its composition and function. How the crosstalk between the immune system and the microbiome regulates the response to fungal infection has remained relatively unexplored. We have previously shown that strict anaerobes protect from infection with the opportunistic fungus Aspergillus fumigatus by counteracting the expansion of pathogenic Proteobacteria. By resorting to immunodeficient mouse strains, we found that the lung microbiota could compensate for the lack of B and T lymphocytes in Rag1-/- mice by skewing the composition towards an increased abundance of protective anaerobes such as Clostridia and Bacteroidota. Conversely, NSG mice, with major defects in both the innate and adaptive immune response, showed an increased susceptibility to infection associated with a low abundance of strict anaerobes and the expansion of Proteobacteria. Further exploration in a murine model of chronic granulomatous disease, a primary form of immunodeficiency characterized by defective phagocyte NADPH oxidase, confirms the association of lung unbalance between anaerobes and Proteobacteria and the susceptibility to aspergillosis. Consistent changes in the lung levels of short-chain fatty acids between the different strains support the conclusion that the immune system and the microbiota are functionally intertwined during Aspergillus infection and determine the outcome of the infection.

Treatment failure of syringomyelia associated with Chiari I malformation following foramen magnum decompression: how should we proceed?

The preferred treatment of patients with persistent, recurrent, or progressive syringomyelia after foramen magnum decompression (FMD) for Chiari I (CMI)-associated syringomyelia is controversial, and may include redo FMD, stabilization, or shunting procedures (such as syringopleural or syringo-subarachnoid shunts). We describe our experience in treating these patients and discuss the treatment modalities for these patients. We retrospectively collected data of CMI patients with persistent, recurrent, or progressive syringomyelia after FMD. In addition to baseline characteristics, surgical treatments and neurological and radiological outcomes were assessed. Further, we assessed through uni- and multivariate analyses possible technical, surgical, and radiological factors which might lead to failed FMD. Between 1998 and 2017, 48 consecutive patients (35 females (73%), average age 16.8 ± 11.5 years) underwent FMD for a syringomyelia-Chiari complex. Twenty-four patients (50%) underwent surgical treatment for a persistent (n = 10), progressive (n = 12), or recurrent (n = 2) syringomyelia 21.4 ± 27.9 months (median 14.6 months, range 12 days-134.9 months) after FMD. Of all analyzed factors, only extradural FMD was significantly associated with lower failure rates. Two patients (8%) underwent redo FMD, 18 (75%) underwent 19 syringo-subarachnoid-shunts, and 4 (17%) had 6 cranial CSF diversion procedures. The overall follow-up time was 40.1 ± 47.4 months (median 25 months, range 3-230 months). Based on our results, 50% of the patients undergoing FMD for syringomyelia-Chiari complex may require further surgical treatment due to persistent, progressive, or recurrent syringomyelia. Treatment should be tailored to the suspected underlying pathology. A subgroup of patients may be managed conservatively; however, these patients need close clinical and radiological follow-ups. The technical aspects of FMD in CMI-syrinx complex should be the focus of larger studies, as an effort to improve failure rates.

The Mast Cell-Aryl Hydrocarbon Receptor Interplay at the Host-Microbe Interface.

Mast cells are increasingly being recognized as crucial cells in the response of the organism to environmental agents. Interestingly, the ability of mast cells to sense and respond to external cues is modulated by the microenvironment that surrounds mast cells and influences their differentiation. The scenario that is emerging unveils a delicate equilibrium that balances the effector functions of mast cells to guarantee host protection without compromising tissue homeostasis. Among the environmental components able to mold mast cells and fine-tune their effector functions, the microorganisms that colonize the human body, collectively known as microbiome, certainly play a key role. Indeed, microorganisms can regulate not only the survival, recruitment, and maturation of mast cells but also their activity by setting the threshold required for the exploitation of their different effector functions. Herein, we summarize the current knowledge about the mechanisms underlying the ability of the microorganisms to regulate mast cell physiology and discuss potential deviations that result in pathological consequences. We will discuss the pivotal role of the aryl hydrocarbon receptor in sensing the environment and shaping mast cell adaptation at the host-microbe interface.

Autophagy and LAP in the Fight against Fungal Infections: Regulation and Therapeutics.

Phagocytes fight fungi using canonical and noncanonical, also called LC3-associated phagocytosis (LAP), autophagy pathways. However, the outcomes of autophagy/LAP in shaping host immune responses appear to greatly vary depending on fungal species and cell types. By allowing efficient pathogen clearance and/or degradation of inflammatory mediators, autophagy proteins play a broad role in cellular and immune homeostasis during fungal infections. Indeed, defects in autophagic machinery have been linked with aberrant host defense and inflammatory states. Thus, understanding the molecular mechanisms underlying the relationship between the different forms of autophagy may offer a way to identify drugable molecular signatures discriminating between selective recognition of cargo and host protection. In this regard, IFN-γ and anakinra are teaching examples of successful antifungal agents that target the autophagy machinery. This article provides an overview of the role of autophagy/LAP in response to fungi and in their infections, regulation, and therapeutic exploitation.

What to do in failed hemispherotomy? Our clinical series and review of the literature.

Hemispherotomy is an established surgical technique to cure or palliate selected, mostly young patients suffering from refractory epilepsy. However, a few patients continue to have seizures despite the surgical hemispherical disconnection. We present a case series of patients who underwent redo hemispherotomy after a first unsuccessful hemispherical disconnection and provide a roadmap for subsequent workup and treatment. The institutional database of epilepsy surgery was reviewed. Twenty-four patients who underwent hemispherotomies for refractory epilepsy were identified between 2007 and 2016. Patients' notes were checked for demographics, history, clinical presentation, preoperative workup, medical treatment, age at first hemispherotomy, and surgical technique. Complications, histopathology, postoperative antiepileptic drug, and postoperative neurological follow-up were documented. Engel class was used to determine the outcome after surgery. Three patients (one hemimegalencephaly, one perinatal stroke, and one Rasmussen's disease) underwent redo hemispherotomy after electroencephalography and MRI studies with particular importance given to diffusion tensor imaging (DTI) to demonstrate residual connection between hemispheres. In one case, redo disconnection followed by a frontal lobectomy rendered the patient seizure-free (Engel class I). In one case, the seizure frequency remained the same but generalized seizures disappeared (Engel class III), and in one case, seizure frequency was considerably reduced after the redo disconnection (Engel class II), with a minimum follow-up of 2 years. Surgical aspects, possible reasons of failure of first hemispherotomy, and rationale that led to second-look surgery are presented. Reasons for failure can be related to patient's selection and/or surgical aspects. Hemispherotomy is a technically demanding procedure and requires accurate preoperative workup. Redo hemispherotomy is a valid option on the basis of further epileptological and radiological workup to demonstrate residual interhemispheric connections and/or rule out bi-hemispheric epileptic activity.

Herpes simplex encephalitis as a complication of neurosurgical procedures: report of 3 cases and review of the literature.

BACKGROUND: Herpes simplex virus (HSV) is the most common identified cause of focal encephalitis worldwide. However, postoperative HSV encephalitis (HSVE) is a rare complication of neurosurgical procedures and a significant clinical challenge METHOD: We describe 3 cases of postoperative HSVE and review all published reports. A total of 23 cases were identified. DISCUSSION: Clinical heterogeneity represents a diagnostic challenge in the postoperative setting. Cerebral magnetic resonance imaging showed typical findings in a minority of patients only, whereas HSV-specific polymerase chain reaction on the cerebrospinal fluid proved to be a valuable test. The postoperative viral pathophysiology remains a subject of debate. The rate of adverse outcome is high and early antiviral treatment seems to be a strong predictor of clinical outcome. CONCLUSION: We recommend early empirical treatment for any patient presenting with post-neurosurgical lymphocytic meningo-encephalitis, and prophylactic antiviral treatment for patients with a history of previous HSVE who will undergo a neurosurgical procedure.

Microbiota control of a tryptophan-AhR pathway in disease tolerance to fungi.

An increased understanding of the importance of microbiota in shaping the host's immune and metabolic activities has rendered fungal interactions with their hosts more complex than previously appreciated. The aryl hydrocarbon receptor (AhR) has a pivotal role in connecting tryptophan catabolism by microbial communities and the host's own pathway of tryptophan metabolite production with the orchestration of T-cell function. AhR activation by a Lactobacillus-derived AhR ligand leads to the production of IL-22 to the benefit of mucosal defense mechanisms, an activity upregulated in the absence of the host tryptophan catabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO1), which is required for protection from fungal diseases ("disease tolerance"). As AhR activation in turn leads to the activation-in a feedback fashion-of IDO1, the regulatory loop involving AhR and IDO1 may have driven the coevolution of commensal fungi with the mammalian immune system and the microbiota, to the benefit of host survival and fungal commensalism. This review will discuss the essential help the microbiota provides in controlling the balance between the dual nature of the fungal-host relationship, namely, commensalism vs. infection.

γ-Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down-regulation.

γ-Secretase inhibitors (GSIs) have been proposed for combined therapies of malignancies with a dysregulated Notch signaling. GSI I (Z-Leu-Leu-Nle-CHO) induces apoptosis of some tumor cells by inhibiting proteasome and Notch activity. Alterations in these two cell survival regulators contribute to apoptosis resistance of chronic lymphocytic leukemia (CLL) cells. Here, we investigated the mechanisms whereby GSI I increases apoptosis of primary CLL cells. Time-course studies indicate that initial apoptotic events are inhibition of proteasome activity, concomitant with an increased endoplasmic reticulum (ER) stress apoptotic signaling, and a consistent Noxa protein up-regulation. These events precede, and some of them contribute to, mitochondrial alterations, which occur notwithstanding Mcl-1 accumulation induced by GSI I. In CLL cells, GSI I inhibits Notch1 and Notch2 activation only in the late apoptotic phases, suggesting that this event does not initiate CLL cell apoptosis. However, Notch inhibition may contribute to amplify GSI I-induced CLL cell apoptosis, given that Notch activation sustains the survival of these cells, as demonstrated by the evidence that both Notch1 and Notch2 down-regulation by small-interfering RNA accelerates spontaneous CLL cell apoptosis. Overall, our results show that GSI I triggers CLL cell apoptosis by inhibiting proteasome activity and enhancing ER stress, and amplifies it by blocking Notch activation. These findings suggest the potential relevance of simultaneously targeting these three important apoptosis regulators as a novel therapeutic strategy for CLL.

Pediatric Posterior Fossa ATRT: A Case Report, New Treatment Strategies and Perspectives.

Posterior fossa atypical teratoid rhabdoid tumor (ATRT) is a rare childhood tumor usually associated with a dismal prognosis. Although upfront surgical gross total resection (GTR) has classically been the first line of treatment, new multimodal treatments, including two-stage surgery, are showing promising results in terms of overall survival (OS) and complication rate. We present a case of a 9-month-old child treated with two-staged surgery and chemotherapy. When deemed risky, multimodal treatments, including staged surgeries, can be a safe alternative to reduce surgical mortality and morbidity. At 23 months old, the patient had normal global development and no major impact on quality of life. We, therefore, discuss the most recent advancements from a treatment perspective, including molecular targeting.