Publications by authors named "Andrea Bartoli"

42 Publications

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

Acta Neurochir (Wien) 2021 Mar 1. Epub 2021 Mar 1.

Department of Clinical Neurosciences, Division of Neurosurgery, Geneva University Hospitals, Geneva, Switzerland.

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.
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http://dx.doi.org/10.1007/s00701-020-04622-0DOI Listing
March 2021

Trigeminal nerve chronic motor denervation caused by cerebellar peduncle pilocytic astrocytoma.

Childs Nerv Syst 2021 Jan 22. Epub 2021 Jan 22.

Department of Pediatrics, Gynecology and Obstetrics, Division of General Pediatrics, Pediatric Hematology and Oncology Unit, University Hospitals of Geneva, Geneva, Switzerland.

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http://dx.doi.org/10.1007/s00381-021-05047-5DOI Listing
January 2021

In Reply: Treatment Options for Hydrocephalus Following Foramen Magnum Decompression for Chiari I Malformation: A Multicenter Study.

Neurosurgery 2020 Sep 5. Epub 2020 Sep 5.

Departments of Neurosurgery and Pediatric Neurosurgery Tel Aviv Medical Center and Dana Children's Hospital Tel Aviv Tel Aviv University Tel Aviv, Israel.

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http://dx.doi.org/10.1093/neuros/nyaa391DOI Listing
September 2020

Thymosin α1 protects from CTLA-4 intestinal immunopathology.

Life Sci Alliance 2020 10 14;3(10). Epub 2020 Aug 14.

Department of Experimental Medicine, University of Perugia, Perugia, Italy.

The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor-induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1-dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8 and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.
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http://dx.doi.org/10.26508/lsa.202000662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441522PMC
October 2020

Microbes in the Era of Circadian Medicine.

Front Cell Infect Microbiol 2020 5;10:30. Epub 2020 Feb 5.

Department of Experimental Medicine, University of Perugia, Perugia, Italy.

The organisms of most domains of life have adapted to circadian changes of the environment and regulate their behavior and physiology accordingly. A particular case of such paradigm is represented by some types of host-pathogen interaction during infection. Indeed, not only some hosts and pathogens are each endowed with their own circadian clock, but they are also influenced by the circadian changes of the other with profound consequences on the outcome of the infection. It comes that daily fluctuations in the availability of resources and the nature of the immune response, coupled with circadian changes of the pathogen, may influence microbial virulence, level of colonization and damage to the host, and alter the equilibrium between commensal and invading microorganisms. In the present review, we discuss the potential relevance of circadian rhythms in human bacterial and fungal pathogens, and the consequences of circadian changes of the host immune system and microbiome on the onset and development of infection. By looking from the perspective of the interplay between host and microbes circadian rhythms, these concepts are expected to change the way we approach human infections, not only by predicting the outcome of the host-pathogen interaction, but also by indicating the best time for intervention to potentiate the anti-microbial activities of the immune system and to weaken the pathogen when its susceptibility is higher.
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http://dx.doi.org/10.3389/fcimb.2020.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013081PMC
February 2020

Visual analysis of high density EEG: As good as electrical source imaging?

Clin Neurophysiol Pract 2020 30;5:16-22. Epub 2019 Nov 30.

EEG and Epilepsy Unit, University Hospital of Geneva, Geneva, Switzerland.

Objective: In this study, we sought to determine whether visual analysis of high density EEG (HD-EEG) would provide similar localizing information comparable to electrical source imaging (ESI).

Methods: HD-EEG (256 electrodes) recordings from 20 patients suffering from unifocal, drug-resistant epilepsy (13 women, mean age 29.1 ± 2.62 years, 11 with temporal lobe epilepsy) were examined. In the visual analysis condition, we identified the 5 contacts with maximal spike amplitude and determined their localization with respect to the underlying cortex. ESI was computed using the LAURA algorithm of the averaged spikes in the patient's individual MRI. We considered the localization "correct" if all 5 contacts were concordant with the resection volume underneath or if ESI was located within the resection as determined by the postoperative MRI.

Results: Twelve patients were postoperatively seizure-free (Engel Class IA), while the remaining eight were in class IB to IV. Visual analysis and ESI showed sensitivity of 58% and 75%, specificity of 75% and 87%, and accuracy of 65% and 80%, respectively. In 70% of cases, visual analysis and ESI provided concordant results.

Conclusions: Localization of the electrodes with maximal spike amplitude provides very good estimation of the localization of the underlying source. However, ESI has a higher accuracy and adds 3D information; therefore, it should remain the tool of choice for presurgical evaluation.

Significance: The present study proposes the possibility to analyze HD-EEG visually, in tandem with ESI or alone, if ESI is not accessible.
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http://dx.doi.org/10.1016/j.cnp.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939057PMC
November 2019

Localizing non-epileptiform abnormal brain function in children using high density EEG: Electric Source Imaging of focal slowing.

Epilepsy Res 2020 01 26;159:106245. Epub 2019 Nov 26.

Neurology Clinic, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland. Electronic address:

Background: Electric Source Imaging (ESI) of interictal epileptiform discharges (IED) is increasingly validated for localizing epileptic activity. In children, IED can be absent or multifocal even in cases of a focal epileptogenic zone and additional electrophysiological markers are needed. Here, we investigated ESI of pathological focal slowing (FS) recorded on EEG as a new localizing marker in children with drug-resistant epilepsy.

Methods: We selected 15 children (median: 12; range: 4-18yrs), with high-density EEG (hdEEG), presurgical evaluation and surgical resection. One patient had a non-lesional MRI. ESI of patient-specific focal slow activity was performed (distributed linear inverse solution and individual head model). The maximal average power in the band of interest was considered as the source of focal slowing (ESI-FS). The Euclidian distance between ESI-FS and the resection (5 mm margin) was compared to the localization of maximal ESI of interictal epileptiform discharges (ESI-IED), interictal FDG-PET and ictal SPECT/SISCOM.

Results: In 9/15 patients (60%), ESI of focal slowing (ESI-FS) was inside or ≤5 mm from resection margins. The remaining 6/15 cases had distances ≤15 mm. In 9/15 patients with interictal spikes, the ESI-IED was concordant with the resection. 6/15 patients with concordant ESI-FS showed also interictal concordant ESI of IED; in 3/15 patients, ESI-FS but not ESI-IED was concordant with the resection. In 10/15 patients, ESI-FS was concordant with MRI lesion and for ESI-IED this concordance was on 8/15 patients. Maximal hypometabolism and SISCOM were concordant with the resection for 7/15 and 7/12, respectively.

Conclusion: These findings suggest that "non-epileptiform" EEG activity, such as focal slowing, could be a complementary useful marker to localize the epileptogenic zone. ESI-FS may notably be applied in young patients without focal interictal spikes or multifocal spikes. This potential new marker of brain dysfunction has potential applications to other neurological disorders associated with slow EEG activity.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.106245DOI Listing
January 2020

Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease.

Life Sci Alliance 2019 12 12;2(6). Epub 2019 Nov 12.

Department of Experimental Medicine, University of Perugia, Perugia, Italy

Chronic granulomatous disease (CGD) is a genetic disorder of the NADPH oxidase characterized by increased susceptibility to infections and hyperinflammation associated with defective autophagy and increased inflammasome activation. Herein, we demonstrate that thymosin β4 (Tβ4), a g-actin sequestering peptide with multiple and diverse intracellular and extracellular activities affecting inflammation, wound healing, fibrosis, and tissue regeneration, promoted in human and murine cells noncanonical autophagy, a form of autophagy associated with phagocytosis and limited inflammation via the death-associated protein kinase 1. We further show that the hypoxia inducible factor-1 (HIF-1)α was underexpressed in CGD but normalized by Tβ4 to promote autophagy and up-regulate genes involved in mucosal barrier protection. Accordingly, inflammation and granuloma formation were impaired and survival increased in CGD mice with colitis or aspergillosis upon Tβ4 treatment or HIF-1α stabilization. Thus, the promotion of endogenous pathways of inflammation resolution through HIF-1α stabilization is druggable in CGD by Tβ4.
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http://dx.doi.org/10.26508/lsa.201900432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851533PMC
December 2019

Navigated Intraoperative 2-Dimensional Ultrasound in High-Grade Glioma Surgery: Impact on Extent of Resection and Patient Outcome.

Oper Neurosurg (Hagerstown) 2020 04;18(4):363-373

Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy.

Background: Maximizing extent of resection (EOR) and reducing residual tumor volume (RTV) while preserving neurological functions is the main goal in the surgical treatment of gliomas. Navigated intraoperative ultrasound (N-ioUS) combining the advantages of ultrasound and conventional neuronavigation (NN) allows for overcoming the limitations of the latter.

Objective: To evaluate the impact of real-time NN combining ioUS and preoperative magnetic resonance imaging (MRI) on maximizing EOR in glioma surgery compared to standard NN.

Methods: We retrospectively reviewed a series of 60 cases operated on for supratentorial gliomas: 31 operated under the guidance of N-ioUS and 29 resected with standard NN. Age, location of the tumor, pre- and postoperative Karnofsky Performance Status (KPS), EOR, RTV, and, if any, postoperative complications were evaluated.

Results: The rate of gross total resection (GTR) in NN group was 44.8% vs 61.2% in N-ioUS group. The rate of RTV > 1 cm3 for glioblastomas was significantly lower for the N-ioUS group (P < .01). In 13/31 (42%), RTV was detected at the end of surgery with N-ioUS. In 8 of 13 cases, (25.8% of the cohort) surgeons continued with the operation until complete resection. Specificity was greater in N-ioUS (42% vs 31%) and negative predictive value (73% vs 54%). At discharge, the difference between pre- and postoperative KPS was significantly higher for the N-ioUS (P < .01).

Conclusion: The use of an N-ioUS-based real-time has been beneficial for resection in noneloquent high-grade glioma in terms of both EOR and neurological outcome, compared to standard NN. N-ioUS has proven usefulness in detecting RTV > 1 cm3.
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http://dx.doi.org/10.1093/ons/opz203DOI Listing
April 2020

Treatment Options for Hydrocephalus Following Foramen Magnum Decompression for Chiari I Malformation: A Multicenter Study.

Neurosurgery 2020 04;86(4):500-508

Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel.

Background: New-onset hydrocephalus following foramen magnum decompression (FMD) for Chiari I malformation (CM-I) is rare; its natural history and pathophysiology are poorly understood.

Objective: To describe a series of patients who developed hydrocephalus following FMD for CM-I, provide possible explanations of this phenomenon, and outline treatment options.

Methods: Out of patients undergoing FMD for CM-I from 6 different tertiary centers, we evaluated patients presenting with new-onset hydrocephalus following FMD. The retrospectively collected data included demographics, clinical, and radiological findings of the CM-I and hydrocephalus patients. Time from FMD and hydrocephalus onset, treatment, and surgical techniques were assessed.

Results: Of 549 patients who underwent FMD for CM-I, 28 (5.1%) subsequently developed hydrocephalus (18 females, 10 males), with a mean age of 11.7 ± 11.9 yr (range 6 mo to 52 yr). Hydrocephalus occurred on average 2.2 ± 2.6 mo after FMD (range 1 wk to 8 mo). Four patients did not have a violation of the arachnoid during the FMD surgery. Main presenting symptoms of hydrocephalus were headaches (17, 41%), vomiting (10, 24.4%), and cerebrospinal fluid (CSF) leak or pseudomeningocele (7, 17%).Overall, 23 patients (82.1%) underwent CSF shunting, 1 patient (3.5%) had an endoscopic third ventriculostomy, 3 patients (10.7%) temporary CSF diversion only, and 1 patient (3.5%) was treated with acetazolamide.

Conclusion: Hydrocephalus following FMD for CM-I is uncommon, but important. Based on our series and literature review, its incidence is about 5% to 7% and most likely will require further surgery. Shunting appears to be the favored treatment option.
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http://dx.doi.org/10.1093/neuros/nyz211DOI Listing
April 2020

Management of median and paramedian craniofacial clefts.

J Plast Reconstr Aesthet Surg 2019 Apr 9;72(4):676-684. Epub 2019 Jan 9.

Division of Plastic, Reconstructive and Esthetic Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, 4 Rue Gabrielle Perret-Gentil, 1211 Geneva 14, Switzerland.

Background: Median and paramedian craniofacial clefts are associated with hypertelorism, anterior encephalocele, positional abnormalities of the maxilla, and nasal deformity. Cleft lip and palate, eyelid coloboma, and widow's peak are frequently present.

Methods: The authors collected data from 30 patients (mean age, 5.8 years; range, 4 months to 18 years) operated between 1986 and 2017 with median or paramedian craniofacial clefts of differing degrees of severity. Malformations of the different anatomic units and their surgical treatment were assessed, as well as complication rates.

Results: All patients presented nasal malformations and either telecanthus (n = 16) or hypertelorism (n = 14). Most patients (n = 23) had anterior encephalocele. All patients underwent nasal corrections, and most of them had medial canthopexy (n = 24). Excision of encephalocele was associated with fronto-orbital remodeling. Medialization of the orbits was performed in 11 patients, mainly by box shift (n = 9). Patients from outside Switzerland (n = 23) were operated at an older age than those in the native patient group. Because of staged reconstruction, 13 patients had more than one operation. Surgical complications included three infections and one expander exposition. One patient had bone resorption of a frontal bone flap. Nasal correction needed more than one procedure in 5 patients, and medial canthopexy had to be repeated in 7 patients. Esthetic results were satisfactory, permitting social integration.

Conclusion: Median and paramedian craniofacial clefts need adapted and carefully planned corrections respecting the growth of anatomic units. The quality of the medial canthal and nasal reconstruction is to a large extent responsible for the overall result.
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http://dx.doi.org/10.1016/j.bjps.2019.01.001DOI Listing
April 2019

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

Neurosurg Rev 2019 Sep 15;42(3):705-714. Epub 2018 Dec 15.

Departments of Neurosurgery and Pediatric Neurosurgery, Tel-Aviv Medical Center and Dana Children's Hospital Tel Aviv, Tel Aviv University, 6 Weizmann Street, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1007/s10143-018-01066-0DOI Listing
September 2019

IL-9 Integrates the Host- Cross-Talk in Vulvovaginal Candidiasis to Balance Inflammation and Tolerance.

Front Immunol 2018 20;9:2702. Epub 2018 Nov 20.

Department of Experimental Medicine, University of Perugia, Perugia, Italy.

Vulvovaginal candidiasis (VVC) is a common fungal infection caused by . The antifungal therapy represents the standard of care but due to the high costs of treatment and to the inability to prevent recurrences, the development of alternative therapeutic approaches is much-awaited. Recently, we have shown that the pathogenesis of in the gut is modulated by IL-9, a pleiotropic cytokine able to promote both inflammation and tolerance during infection. Herein, by using a mouse model of VVC, we similarly demonstrated that IL-9 might exert a dual role in VVC by contributing to inflammation during the initial immune activation and promoting resolution thereafter. Specifically, IL-9 has a pro-inflammatory activity at the onset of VVC by promoting NLRP3 inflammasome activity and mucosal mast cells expansion but a tolerogenic role in the resolution phase by promoting IL-1Ra production and connective tissue mast cells activation. We further show that a timely IL-9 neutralization at the onset of the inflammatory response ameliorated symptoms and vaginal pathology. Given that vaginal fluids from patients with recurrent VVC had higher levels of IL-9, these findings, by providing novel insights into the pathogenesis of VVC, may pave the way for alternative therapeutic strategies based on IL-9 neutralization.
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http://dx.doi.org/10.3389/fimmu.2018.02702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255860PMC
October 2019

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

Mediators Inflamm 2018 28;2018:7396136. Epub 2018 Oct 28.

Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.

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.
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http://dx.doi.org/10.1155/2018/7396136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230381PMC
February 2019

Thymosin β4 limits inflammation through autophagy.

Expert Opin Biol Ther 2018 07;18(sup1):171-175

a Department of Experimental Medicine , University of Perugia , Perugia , Italy.

Introduction: Thymosin β4 (Tβ4) is a thymic hormone with multiple and different intracellular and extracellular activities affecting wound healing, inflammation, fibrosis and tissue regeneration. As the failure to resolve inflammation leads to uncontrolled inflammatory pathology which underlies many chronic diseases, the endogenous pathway through which Tβ4 may promote inflammation resolution becomes of great interest. In this review, we discuss data highlighting the efficacy of Tβ4 in resolving inflammation by restoring autophagy.

Areas Covered: The authors provide an overview of the Tβ4's anti-inflammatory properties in several pathologies and provide preliminary evidence on the ability of Tβ4 to resolve inflammation via the promotion of non-canonical autophagy associated with the activation of the DAP kinase anti-inflammatory function.

Expert Opinion: Based on its multitasking activity in various animal studies, including tissue repair and prevention of chronic inflammation, Tβ4 may represent a potential, novel treatment for inflammatory diseases associated with defective autophagy.
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http://dx.doi.org/10.1080/14712598.2018.1473854DOI Listing
July 2018

IL-9 and Mast Cells Are Key Players of Candida albicans Commensalism and Pathogenesis in the Gut.

Cell Rep 2018 05;23(6):1767-1778

Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. Electronic address:

Candida albicans is implicated in intestinal diseases. Identifying host signatures that discriminate between the pathogenic versus commensal nature of this human commensal is clinically relevant. In the present study, we identify IL-9 and mast cells (MCs) as key players of Candida commensalism and pathogenicity. By inducing TGF-β in stromal MCs, IL-9 pivotally contributes to mucosal immune tolerance via the indoleamine 2,3-dioxygenase enzyme. However, Candida-driven IL-9 and mucosal MCs also contribute to barrier function loss, dissemination, and inflammation in experimental leaky gut models and are upregulated in patients with celiac disease. Inflammatory dysbiosis occurs with IL-9 and MC deficiency, indicating that the activity of IL-9 and MCs may go beyond host immunity to include regulation of the microbiota. Thus, the output of the IL-9/MC axis is highly contextual during Candida colonization and reveals how host immunity and the microbiota finely tune Candida behavior in the gut.
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http://dx.doi.org/10.1016/j.celrep.2018.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976578PMC
May 2018

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

Mediators Inflamm 2018 6;2018:6195958. Epub 2018 Mar 6.

Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.

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- 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.
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http://dx.doi.org/10.1155/2018/6195958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859860PMC
September 2018

Low Frequency Microstimulation Is Locally Excitatory in Patients With Epilepsy.

Front Neural Circuits 2018 4;12:22. Epub 2018 Apr 4.

Department of Neurology, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.

Deep brain stimulation (DBS) could become a palliative treatment for patients with drug-resistant epilepsy for which surgery cannot be proposed. The objective of this study was to perform microstimulation to measure the effects of DBS in epilepsy locally at the level of a few neurons, with microelectrode recordings, for the first time in patients with epilepsy. Microelectrode recordings were performed before, during and after microstimulation in nine patients with refractory epilepsy. Neuronal spikes were successfully extracted from multi-unit recordings with clustering in six out of seven patients during hippocampal and in one out of two patients during cortical dysplasia microstimulation (1 Hz, charge-balanced biphasic waveform, 60 μs/ph, 25 μA). The firing rates increased in four out of the six periods of microstimulation that could be analyzed. The firing rates were found higher than before microstimulation in all eight periods with increases reaching significance in six out of eight periods. Low-frequency microstimulation was hence sufficient to induce neuronal excitation lasting beyond the stimulation period. No inhibition was observed. This report presents the first evidence that microstimulation performed in epileptic patients produced locally neuronal excitation. Hence neuronal excitation is shown here as the local mechanism of action of DBS. This local excitation is in agreement with epileptogenic effects of low-frequency hippocampal macrostimulation.
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http://dx.doi.org/10.3389/fncir.2018.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893788PMC
February 2019

Endoscopic Transcranial Duraplasty for Rhinoliquorrhea: A Cadaveric Study.

Oper Neurosurg (Hagerstown) 2018 02;14(2):188-193

Department of Neurosurgery, Geneva University Hospitals, Faculty of Medicine, Geneva, Switzerland.

Background: Repair of the anterior skull base for cerebrospinal fluid leak requires either endoscopic endonasal approach or open transcranial approach.

Objective: To present a less invasive surgical procedure for sealing of the entire anterior fossa floor for traumatic rhinoliquorrhea.

Methods: Cadaver study in 3 head specimens. Endoscopic placement of a furled bovine pericardial patch bilaterally along the sphenoid ridge and planum in guidewire technique. Unfurling and spreading of the patch under endoscope assistance.

Results: Patch placement was feasible in all 3 specimens without visible injuries to the frontal lobes. Dissection and preservation of the olfactory tracts was only possible for 50% of olfactory tracts.

Conclusion: Endoscopic transcranial keyhole duraplasty is a promising concept for traumatic rhinoliquorrhea.
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http://dx.doi.org/10.1093/ons/opx084DOI Listing
February 2018

Syringo-Subarachnoid Shunt for the Treatment of Persistent Syringomyelia Following Decompression for Chiari Type I Malformation: Surgical Results.

World Neurosurg 2017 Dec 12;108:836-843. Epub 2017 Aug 12.

Departments of Neurosurgery and Pediatric Neurosurgery, Sourasky Medical Center and Dana Children's Hospital Tel Aviv, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Background: Approximately 30% of patients treated with foramen magnum decompression (FMD) for Chiari I-associated syringomyelia will show persistence, recurrence, or progression of the syrinx.

Objective: This study evaluates the clinical and radiologic outcomes of syringo-subarachnoid shunt (SSS) as the treatment for persistent syringomyelia after FMD.

Methods: Data were collected retrospectively. The primary outcome measurement was neurologic function (assessed with the Modified Japanese Orthopedic Association [mJOA] scale). Secondary outcome measurements were surgical complications, reoperation rate, and syrinx status on magnetic resonance imaging (MRI).

Results: Twenty-one patients (14 females [66.7%]) underwent SSS, either concurrent to the FMD or at a later stage. Two minor surgical complications were seen: a wound dehiscence and postoperative kyphosis, both requiring revision surgery. No major complication or mortality occurred. The median change in the mJOA score was an improvement of 3 out of a possible 17 points on the scale (mean follow-up, 24.9 months). Expressed as a percentage, overall improvement was 11.8% (95% confidence interval [CI], 5.9-17.6; P < 0.001). On postoperative MRI, shrinkage of the syrinx was seen in all but 1 patient in whom the syrinx remained unchanged. Expressed as percentage, the improvement of the syrinx surface was 76.3% (95% CI, 65.0-87.7; P < 0.001), and the improvement of syrinx span was 36.4% (95% CI, 21.8-50.9; P = 0.05).

Conclusion: SSS for persistent, recurrent, or increasing syrinx following FMD for Chiari I malformation is a safe and effective surgical treatment when performed selectively by an experienced neurosurgeon.
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http://dx.doi.org/10.1016/j.wneu.2017.08.002DOI Listing
December 2017

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

Neurosurg Rev 2018 Jan 10;41(1):125-132. Epub 2017 Aug 10.

Department of Neurosurgery, Faculty of Medicine, Geneva University Medical Center, Geneva, Switzerland.

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.
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http://dx.doi.org/10.1007/s10143-017-0888-yDOI Listing
January 2018

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

Virol J 2016 May 23;13:83. Epub 2016 May 23.

Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.

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.
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http://dx.doi.org/10.1186/s12985-016-0540-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877812PMC
May 2016

Cranioplasty: Is Surgical Education Safe?

World Neurosurg 2016 Jul 6;91:81-8. Epub 2016 Apr 6.

Department of Neurosurgery and Faculty of Medicine, University Hospital Geneva, Geneva, Switzerland. Electronic address:

Background: Patient safety aspects and the residents' role in spine surgery within a structured training program have recently been investigated. The current work deals with residency training safety aspects for cranioplasty (CP), a standard neurosurgical cranial procedure.

Methods: Retrospective 2-center study comparing consecutive patients undergoing CP by a supervised neurosurgery resident (teaching cases) with a consecutive series of patients operated on by a board-certified faculty neurosurgeon (nonteaching cases). The primary end point was occurrence of a postoperative complication. Secondary end points were severity (Ibañez degree) of postoperative complications, surgical site infections requiring CP removal and patients' clinical outcome measured with the modified Rankin Scale.

Results: A total of 240 CPs (137 teaching [57.1%] and 103 nonteaching [42.9%] cases) were analyzed. The mean teaching case operation time was longer (129.2 vs. 115.8 minutes; P < 0.001), and there was no difference in the estimated blood loss (mean 243.3 vs. 223.1 mL; P = 0.444). Supervised residents were as likely as board-certified faculty neurosurgeons to have a postoperative complication (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.42-1.39; P = 0.385) and the severity was comparable (Pearson χ(2) = 7.62; P = 0.106). Teaching cases were as likely as nonteaching cases to experience a surgical site infection requiring CP removal (OR, 1.66; 95% CI, 0.69-4.04; P = 0.261). Also, the likelihood for postoperative improvement on the modified Rankin Scale was similar for patients in both groups (OR, 1.11; 95% CI, 0.62-2.00; P = 0.719).

Conclusions: A relatively simple cranial procedure, such as CP, can be safely performed by a supervised neurosurgery resident without increasing complications or compromising patients' outcomes.
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http://dx.doi.org/10.1016/j.wneu.2016.03.081DOI Listing
July 2016

Pathogenic NLRP3 Inflammasome Activity during Candida Infection Is Negatively Regulated by IL-22 via Activation of NLRC4 and IL-1Ra.

Cell Host Microbe 2015 Aug;18(2):198-209

Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy. Electronic address:

Candida albicans is a well-tolerated resident of human mucosal tissues. This implies that host defense mechanisms cooperate to limit inflammation while controlling fungal burden. The cytokine IL-22 and inflammasomes are essential components of the mucosal responses to C. albicans. How these components cooperate to mediate the balance of inflammation and host defense is not explored. We find that NLRP3 inflammasome activation promotes neutrophil recruitment and inflammation during infection and that this activity is counteracted by IL-22. Mechanistically, IL-22 activated NLRC4 for sustained production of the IL-1 receptor antagonist IL-1Ra, which restrained NLRP3 activity. Symptomatic infection in mice and humans occurred under conditions of IL-1Ra deficiency and was rescued in mice by replacement therapy with the recombinant IL-1Ra anakinra. Thus, pathogenic inflammasome activity during Candida infection is negatively regulated by the IL-22/NLRC4/IL-1Ra axis. Our findings offer insights into the pathogenesis of C. albicans and suggest therapeutic avenues for candidiasis.
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http://dx.doi.org/10.1016/j.chom.2015.07.004DOI Listing
August 2015

Antifungal Th Immunity: Growing up in Family.

Front Immunol 2014 15;5:506. Epub 2014 Oct 15.

Pathology Section, Department of Experimental Medicine, University of Perugia , Perugia , Italy.

Fungal diseases represent an important paradigm in immunology since they can result from either the lack of recognition or over-activation of the inflammatory response. Current understanding of the pathophysiology underlying fungal infections and diseases highlights the multiple cell populations and cell-signaling pathways involved in these conditions. A systems biology approach that integrates investigations of immunity at the systems-level is required to generate novel insights into this complexity and to decipher the dynamics of the host-fungus interaction. It is becoming clear that a three-way interaction between the host, microbiota, and fungi dictates the types of host-fungus relationship. Tryptophan metabolism helps support this interaction, being exploited by the mammalian host and commensals to increase fitness in response to fungi via resistance and tolerance mechanisms of antifungal immunity. The cellular and molecular mechanisms that provide immune homeostasis with the fungal biota and its possible rupture in fungal infections and diseases will be discussed within the expanding role of antifungal Th cell responses.
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http://dx.doi.org/10.3389/fimmu.2014.00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197763PMC
October 2014

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

Eur J Immunol 2014 Nov 20;44(11):3192-200. Epub 2014 Oct 20.

Department of Experimental Medicine, University of Perugia, Perugia, Italy.

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.
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http://dx.doi.org/10.1002/eji.201344406DOI Listing
November 2014

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

Int J Cancer 2013 Apr 17;132(8):1940-53. Epub 2012 Oct 17.

Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy.

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.
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http://dx.doi.org/10.1002/ijc.27863DOI Listing
April 2013

Hidden aqueductal stenosis associated to bilateral idiopathic foramina of Monro stenosis mimicking a Chiari I malformation? Case report.

Acta Neurochir (Wien) 2012 Nov 7;154(11):2109-13; discussion 2113. Epub 2012 Sep 7.

Departement of Neurosurgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.

A 39-year old man came to our outpatient clinic with long history of unspecific symptoms and signs. Cerebral MRI showed herniation of the cerebellar tonsils of more than 1 cm below the foramen magnum and a triventricular hydrocephalus. A diagnosis of Chiari I malformation was retained. After an osteo-dural decompression of the posterior fossa, post-operative MRI revealed an aqueductal stenosis with triventricular hydrocephalus. An endoscopic-third- ventriculostomy showed an idiopathic stenosis of the right foramen of Monro. Residual symptoms and persistence of biventricular hydrocephalus justified a ventriculo-peritoneal shunt. Aqueductal and foramina of Monro stenosis can mimick a Chiari I malformation.
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http://dx.doi.org/10.1007/s00701-012-1438-6DOI Listing
November 2012

Accuracy of freehand fluoroscopy-guided placement of C1 lateral mass and C2 isthmic screws in atlanto-axial instability.

Acta Neurochir (Wien) 2011 Jul 21;153(7):1417-25; discussion 1425. Epub 2011 May 21.

Department of Neurosurgery, Geneva University Medical Center, Faculty of Medecine, University of Geneva, 6, Rue Perret-Gentil, 1211 Geneva, Switzerland.

Background: The C1 lateral mass and C2 isthmic stabilization, as introduced by Goel and Laheri and by Harms and Melcher, is a well-known fixation technique. We present the clinical and radiographic results with freehand fluoroscopy guided C1 lateral mass and C2 isthmic fixation in a consecutive series of 28 patients, evaluating the accuracy of screw placement.

Methods: Twenty-eight consecutive patients suffering from post-traumatic and other C1-C2 instability were operated on between 2001 and 2010. Indications for surgery were: trauma (n = 21 cases), os odontoideum (n = 1), cranio-verterbal malformation (n = 1), and arthritis (n = 3) and idiopathic instability (n = 2). C1 lateral mass and C2 isthmic screws were placed according to the usual anatomical landmarks with lateral fluoroscopy guidance. All patients underwent a postoperative CT scan. The extent of cortical lateral or medial breach was determined and classified as follows: no breach (grade A), 0-2 mm (grade B), 2-4 mm (grade C), 4-6 mm (grade D), more than 6 mm (grade E). Grade A and B screws were considered well positioned.

Results: A total of 56 C1 lateral mass and 55 C2 isthmic screws were placed. Accuracy of screw placement was as follows: 107 grade A (96.4%), four grade B (3.6%), and no grade C, D or E. Clinical and radiological follow-up showed improvement in symptoms (mainly pain) and stability of the implants at the end of the follow-up.

Conclusions: Freehand fluoroscopy-guided insertion of C1 lateral mass and C2 isthmic screws can be safely and effectively performed.
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http://dx.doi.org/10.1007/s00701-011-1039-9DOI Listing
July 2011