Search

PrPSc, a misfolded, aggregation-prone isoform of the cellular prion protein (PrPC), is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals. PrPSc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, posing challenges for the development of effective therapies. Since PrPC is the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity, it represents an attractive therapeutic target for prion diseases. In this minireview, we briefly outline the approaches to target PrPC and discuss our recent identification of Zn(II)-BnPyP, a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action. We argue that in-depth understanding of the molecular mechanism by which Zn(II)-BnPyP targets PrPC may lead toward the development of a new class of dual mechanism anti-prion compounds.

Engaging patients as partners in biomedical research has gradually gained consensus over the last two decades. They provide a different perspective on health priorities and help to improve design and outcomes of clinical studies. This paper describes the relationship established between scientists and members of a large family at genetic risk of very rare lethal disease, fatal familial insomnia (FFI). This interaction led to a clinical trial based on the repurposing of doxycycline – an antibiotic with a known safety profile and optimal blood–brain barrier passage – which in numerous preclinical and clinical studies had given evidence of its potential therapeutic effect in neurodegenerative disorders, including prion diseases like FFI. The design of this trial posed several challenges, which were addressed jointly by the scientists and the FFI family. Potential participants excluded the possibility of being informed of their own FFI genotype; thus, the trial design had to include both carriers of the FFI mutation (10 subjects), and non-carriers (15 subjects), who were given placebo. Periodic clinical controls were performed on both groups by blinded examiners. The lack of surrogate outcome measures of treatment efficacy has required to compare the incidence of the disease in the treated group with a historical dataset during 10 years of observation. The trial is expected to end in 2023. Regardless of the clinical outcome, it will provide worthwhile knowledge on the disease. It also offers an important example of public engagement and collaboration to improve the quality of clinical science.

Late formation of pseudoaneurysm related to stent fracture is rarely described in the literature. We describe a case of spontaneous 8-cm femoral superficial artery pseudoaneurysm rupture that had developed from fracture of a stent implanted 3 years previously. Surgical repair was performed with fractured stent removal and reverse saphenous vein bypass. Keywords: Stent, Fracture, Superficial artery, Pseudoaneurysm

Objective: The adjunctive use of Heli-FX EndoAnchors (EAs) in endovascular aneurysm repair has been proposed for the treatment or prevention of type Ia endoleaks. The aim of this study was to evaluate the impact of the penetration of EAs on endograft textile structure from two aortic endografts that had been explanted for persistent type Ia endoleak despite the implantation of EAs. Methods: An Aorfix aortic endograft was implanted in an 85 year old man. Six months later, six EAs were implanted for Ia endoleak. The endograft was explanted as an emergency seven months later for aneurysm rupture. An Endurant II aortic endograft was implanted in an 80 year old man. Seven EAs were implanted 24 months later for type Ia endoleak. A proximal cuff extension with bilateral renal and superior mesenteric artery chimneys was performed 18 months later to treat a persistent type Ia endoleak. Endograft explantation was performed six months later owing to persistent type Ia endoleak and aneurysm sac enlargement. Explant analysis in both cases was performed at GEPROVAS. Results: Systematic analysis of both explants, including the 13 EAs, revealed the following lesions: (1) alteration of textile structure directly linked to several penetrations of the fabric with the same EA and tears of the textile fibres in two cases; (2) tears of the binding threads as the EA had passed through them in five cases; and (3) interactions between EA and endograft stents in four cases. Conclusion: The site of EA penetration into the endograft might contribute to endograft fabric damage and to a loss of stability of the endograft at the level of the aortic neck.

Abstract Syphilitic aortitis is a rare complication of tertiary syphilis, which can lead to aortic aneurysm formation, aortic valvular insufficiency, and ostial coronary stenosis. Syphilis has re-emerged worldwide over recent decades and vascular surgeons should be aware of its cardiovascular manifestations. Atypical clinical presentation, such as hemoptysis and a computed tomography angiography pattern of a thicker aneurysmal wall with ulcer-like aneurysm projections, should raise suspicion of syphilitic aortic aneurysm. An early diagnosis and appropriate surgical and medical therapies significantly contribute to successful treatment and favorable prognosis. Herein is reported the case of an 82-year-old male patient, positive for syphilis infection, with impending aortic arch aneurysm rupture treated with a hybrid arch repair. After 7 months, the patient was brought to the emergency room in cardiac arrest. Unsuccessful cardiopulmonary resuscitation maneuvers were performed, and an autopsy showed cardiac tamponade due to rupture of the ascending aorta.

Fatal familial insomnia (FFI) is a dominantly inherited prion disease linked to the D178N mutation in the gene encoding the prion protein (PrP). Symptoms, including insomnia, memory loss and motor abnormalities, appear around 50 years of age, leading to death within two years. No treatment is available. A ten-year clinical trial of doxycycline (doxy) is under way in healthy individuals at risk of FFI to test whether presymptomatic doxy prevents or delays the onset of disease.To assess the drug's effect in a tractable disease model, we used Tg(FFI-26) mice, which accumulate aggregated and protease-resistant PrP in their brains and develop a fatal neurological illness highly reminiscent of FFI. Mice were treated daily with 10 mg/kg doxy starting from a presymptomatic stage for twenty weeks. Doxy rescued memory deficits and restored circadian motor rhythmicity in Tg(FFI-26) mice. However, it did not prevent the onset and progression of motor dysfunction, clinical signs and progression to terminal disease. Doxy did not change the amount of aggregated and protease-resistant PrP, but reduced microglial activation in the hippocampus. Presymptomatic doxy treatment rescues cognitive impairment and the motor correlates of sleep dysfunction in Tg(FFI-26) mice but does not prevent fatal disease.

Traumatic brain injury (TBI) is associated with widespread tau pathology in about 30% of patients surviving late after injury. We previously found that TBI in mice induces the formation of an abnormal form of tau (tauTBI) which progressively spreads from the site of injury to remote brain regions. Intracerebral inoculation of TBI brain homogenates into naïve mice induced progressive tau pathology, synaptic loss and late cognitive decline, suggesting a pivotal role of tauTBI in post-TBI neurodegeneration. However, the possibility that tauTBI was a marker of TBI-associated neurodegeneration rather than a toxic driver of functional decline could not be excluded.Here we employed the nematode C. elegans as a biosensor to test the pathogenic role of TBI generated tau. The motility of this nematode depends on efficient neuromuscular transmission and is exceptionally sensitive to the toxicity of amyloidogenic proteins, providing a tractable model for our tests. We found that worms exposed to brain homogenates from chronic but not acute TBI mice, or from mice in which tauTBI had been transmitted by intracerebral inoculation, had impaired motility and neuromuscular synaptic transmission. Results were similar when worms were given brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, suggesting that TBI-induced and mutant tau have similar toxic properties. P301L brain homogenate toxicity was similar in wild-type and ptl-1 knock-out worms, indicating that the nematode tau homolog protein PTL-1 was not required to mediate the toxic effect. Harsh protease digestion to eliminate the protein component of the homogenates, pre-incubation with anti-tau antibodies or tau depletion by immunoprecipitation, abolished the toxicity. Homogenates of chronic TBI brains from tau knock-out mice were not toxic to C. elegans, whereas oligomeric recombinant tau was sufficient to impair their motility.This study indicates that tauTBI impairs motor activity and synaptic transmission in C. elegans and supports a pathogenic role of tauTBI in the long-term consequences of TBI. It also sets the groundwork for the development of a C. elegans-based platform for screening anti-tau compounds.

Abstract Isolated dissection of the internal carotid artery (ICA) is rare in young patients and is a cause for strong suspicion of fibromuscular dysplasia (FMD), especially when associated with artery elongation and tortuosity. The natural history of cerebrovascular FMD is unknown and management of symptomatic patients can be challenging. We report the case of a 44-year-old female patient with a history of transient ischemic attack in the absence of cardiovascular risk factors, associated with an isolated left ICA dissection and kinking. Carotid duplex ultrasound confirmed the diagnosis of dissection and demonstrated severe stenosis of the left ICA. The patient underwent surgical repair and histopathological evaluation confirmed the diagnosis of FMD with dissection. An autogenous great saphenous vein bypass was performed and the patient had an uneventful recovery. Cervical carotid artery dissection can be related to underlying arterial pathologies such as FMD, and the presence of ICA tortuosity highlights certain peculiarities for optimal management, which might be surgical.

BackgroundCarotid artery stenosis (CAS) is a multifaceted disease characterized by possible ocular involvement. Treatment with carotid endarterectomy helps to restore cerebral perfusion, which may prevent ocular and cerebral complications. The main aim was to assess retinal and choroidal vascular perfusion changes before and after endarterectomy in patients affected by CAS.MethodsThe design of the study was prospective and observational, including patients affected by CAS and healthy controls. The follow-up was 3 months. We performed quantitative optical coherence tomography (OCT) angiography (OCTA) analyses of retinal perfusion changes, before and after endarterectomy. The main outcome measures were the quantitative changes of choroidal thickness (CT), retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL); vessel density (VD); and vessel tortuosity (VT) OCTA metrics were also measured.ResultsSixty eyes of 30 patients affected by CAS and 30 eyes of 30 controls were included. We separately considered the ipsilateral eyes to CAS, the contralateral eyes to CAS, and the healthy eyes. Visual symptoms were absent in all the patients. RNFL and GCL resulted similar between patients and controls (p > 0.05). CT was significantly thinner in ipsilateral eyes than controls (p < 0.01), and it resulted unchanged after surgery (p > 0.05). VD resulted significantly altered only in some plexa of the ipsilateral eyes (p < 0.01), whereas VT disclosed decreased values of the entire retinal vascular network, both in ipsilateral and contralateral eyes (p < 0.05). Endarterectomy was followed by statistically significant improvement of retinal perfusion (p < 0.05).ConclusionOptical coherence tomography angiography can noninvasively detect postendarterectomy retinal perfusion improvements in CAS patients with baseline diabetes and hypertension as a systemic risk factor.

Abstract External iliac artery endofibrosis is a rare pathology that affects high-level endurance athletes, especially cyclists. Classical symptoms include pain, loss of power, and/or cramp in the affected limb while training at maximal effort. The patient’s lack of atherosclerotic risk factors makes clinical suspicion of arteriopathy challenging. Moreover, the best management of such patients is still a subject of discussion. We report the case of a 36-year-old professional female endurance cyclist who presented with lower extremity pain during training. Right external iliac artery endofibrosis was diagnosed and the patient underwent surgical treatment. At two-months follow-up, she reported significant improvement in symptoms. This case highlights the importance of diagnosing peripheral vascular disease in young patients and athletes, who do not fit the ordinary profile of patients with atherosclerotic risk factors.

Plasma electrolytic oxidation (PEO) is proven as a scalable method for surface treatment of titanium (Ti) providing a thick oxide layer with porous micro-nano morphology. Despite the lack of antibacterial performance, this modification has potential to improve the osseointegration properties of Ti-based implant. To address this limitation, we demonstrated a new concept, showing that partial incorporation of graphene oxide (GO) to porous-PEO Ti-surface can significantly improve its antibacterial performance. Our idea for partial coating compared with a full surface coverage of GO was motivated to create a mixed surface with porous PEO and GO to improve antibacterial ability, while maintaining the osseointegration properties. To achieve these goals, we combined PEO and electrophoretic deposition process (EPD) to deposit GO sheets over the titanium PEO-treated substrate. The SEM, EDS, optical profilometry, XRD and Raman spectroscopy confirmed the growth of unique multi-structured porous PEO structures decorated with GO patches. The bio-mineralization test provided the evidence of hydroxyapatite formation over the PEO-GO surface, indicating its good bioactivity. Finally, PEO-GO samples demonstrated a superior antibacterial rate of ~80% against E.coli and ~100% against S. aureus. These results indicate that PEO-GO modified titanium substrates are very promising for the development of advanced biomedical implants.

Infection is a severe complication in chronic wounds, often leading to morbidity or mortality. Current treatments rely on dressings, which frequently contain silver as a broad-spectrum antibacterial agent, although improper dosing can result in severe side effects. This work proposes a novel methylcellulose (MC)-based hydrogel designed for the topical release of silver nanoparticles (AgNPs) via an intelligent mechanism activated by the pH variations in infected wounds. A preliminary optimization of the physicochemical and rheological properties of MC hydrogels allowed defining the optimal processing conditions in terms of crosslinker (citric acid) concentration, crosslinking time, and temperature. MC/AgNPs nanocomposite hydrogels were obtained via an in situ synthesis process, exploiting MC both as a capping and reducing agent. AgNPs with a 12.2 ± 2.8 nm diameter were obtained. MC hydrogels showed a dependence of the swelling and degradation behavior on both pH and temperature and a noteworthy pH-triggered release of AgNPs (release ~10 times higher at pH 12 than pH 4). 1H-NMR analysis revealed the role of alkaline hydrolysis of the ester bonds (i.e., crosslinks) in governing the pH-responsive behavior. Overall, MC/AgNPs hydrogels represent an innovative platform for the pH-triggered release of AgNPs in an alkaline milieu.

[This corrects the article DOI: 10.1371/journal.ppat.1008654.].

Background and aims: Extent of subclinical atherosclerosis has been associated with brain parenchymal loss in community-dwelling aged subjects. Identification of patient-related and plaque-related markers could identify subjects at higher risk of brain atrophy, independent of cerebrovascular accidents. Aim of the study was to investigate the relation between extent and characteristics of carotid plaques and brain atrophy in asymptomatic patients with no indication for revascularization. Methods and results: Sixty-four patients (aged 69 ± 8 years, 45% females) with carotid stenosis

Titanium oxide nanotube arrays are extremely promising materials for localized drug delivery in orthopedic implants due to their excellent properties and facile preparation. TiO2 nanotubes can act as an effective drug reservoir to prevent bacterial colonization and implant infection and, at the same time, could promote tissue regeneration and effective osseointegration. Here, highly ordered TiO2 nanotubes (NTs) were synthesized by electrochemical anodization of titanium foils and the process parameters were varied in order to obtain a large range of NT diameters to evaluate its influence. The effect of NTs’ diameter on gentamicin loading/release and on osteosarcoma cell and bacterial adhesion was assessed. Anodization was confirmed as an easy and effective method to prepare highly ordered, open top nanotubes with predictable diameter as a function of imposed voltage. A lower amount of bacteria Staphylococcus Aureus adhesion was found on unloaded NTs surfaces at 24 h. When gentamicin was loaded, protracted release and antibacterial action was observed and bacteria adhesion was prevented on all NTs dimension. However, higher cell proliferation and a more favorable cell morphology was observed on smaller nanotubes, to support the indication toward a reduction in NTs diameter for the preparation of effective implant surfaces.

Prion protein (PrP) mutations are linked to genetic prion diseases, a class of phenotypically heterogeneous neurodegenerative disorders with invariably fatal outcome. How mutant PrP triggers neurodegeneration is not known. Synaptic dysfunction precedes neuronal loss but it is not clear whether, and through which mechanisms, disruption of synaptic activity ultimately leads to neuronal death. Here we show that mutant PrP impairs the secretory trafficking of AMPA receptors (AMPARs). Specifically, intracellular retention of the GluA2 subunit results in synaptic exposure of GluA2-lacking, calcium-permeable AMPARs, leading to increased calcium permeability and enhanced sensitivity to excitotoxic cell death. Mutant PrPs linked to different genetic prion diseases affect AMPAR trafficking and function in different ways. Our findings identify AMPARs as pathogenic targets in genetic prion diseases, and support the involvement of excitotoxicity in neurodegeneration. They also suggest a mechanistic explanation for how different mutant PrPs may cause distinct disease phenotypes.

Prion diseases arise from the conformational conversion of the cellular prion protein (PrPC) into a self-replicating prion isoform (PrPSc). Although this process has been studied mostly in neurons, a growing body of evidence suggests that astrocytes express PrPC and are able to replicate and accumulate PrPSc. Currently, prion diseases remain incurable, while downregulation of PrPC represents the most promising therapy due to the reduction of the substrate for prion conversion. Here we show that the astrocyte-specific genetic ablation or pharmacological inhibition of the calcium-activated phosphatase calcineurin (CaN) reduces PrPC expression in astrocytes. Immunocytochemical analysis of cultured CaN-KO astrocytes and isolation of synaptosomal compartments from the hippocampi of astrocyte-specific CaN-KO (ACN-KO) mice suggest that PrPC is downregulated both in vitro and in vivo. The downregulation occurs without affecting the glycosylation of PrPC and without alteration of its proteasomal or lysosomal degradation. Direct assessment of the protein synthesis rate and shotgun mass spectrometry proteomics analysis suggest that the reduction of PrPC is related to the impairment of global protein synthesis in CaN-KO astrocytes. When WT-PrP and PrP-D177N, a mouse homologue of a human mutation associated with the inherited prion disease fatal familial insomnia, were expressed in astrocytes, CaN-KO astrocytes showed an aberrant localization of both WT-PrP and PrP-D177N variants with predominant localization to the Golgi apparatus, suggesting that ablation of CaN affects both WT and mutant PrP proteins. These results provide new mechanistic details in relation to the regulation of PrP expression in astrocytes, suggesting the therapeutic potential of astroglial cells.

Abstract In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1β) release that may influence MMP9 generation, thus their possible modulation through acting on P2X7 was investigated. P2X7-related machinery was characterized and the effects of P2X7 antagonists (A740003, KN62) and MMPs inhibitors (Batimastat, Ro28-2653) were studied in ex-vivo tissue cultures of human PL’s vs. non-atherosclerotic internal mammary artery (IMA) by using molecular biology, immune-biochemical and microscopy methodologies. We highlighted atherosclerosis-related differences between PLs and IMAs molecular patterns, and their responsivity to P2X7 antagonism. High IL-1β tissue content was associated with PLs morphology and instability/vulnerability. We demonstrated that A740003, but not KN62, decreased IL-1β and MMP9 independently from NLR family pyrin domain containing 3, but in relationship with patient’s smoking status. Acting downstream P2X7 by MMPs inhibitors, diminished IL-1β mRNA without transcriptional effect at MMP9, possibly because the assumption of statin by patients. These data firstly demonstrated A740003 suitability as a specific tool to decrease inflammatory status in human vessels and might support the design of studies applying P2X7 antagonists for the local targeting and tailored therapy of atherosclerosis.

The ubiquitously expressed SUMO proteins regulate a plethora of cellular pathways and processes. While they have a predominantly nuclear localization, extranuclear roles of SUMO isoforms at the synapse have also been described, making SUMOylation one of the major post-translational regulators of nerve functions. These findings have however recently been challenged, at least for SUMO1, by the analysis of knock-in mice expressing His6-HA-SUMO1, where the authors failed to detect the protein at the synapse. In the ongoing dispute, the subcellular distribution in neurons of SUMO2/3 and of the E2 SUMO ligase Ubc9 has not been examined. To investigate whether SUMO proteins do or do not localize at the synapse, we studied their localization in hippocampal primary neurons by super resolution microscopy. We found that SUMO1, SUMO2/3, and Ubc9 are primarily nuclear proteins, which also colocalize partially with pre- and post-synaptic markers such as synaptophysin and PSD95.

Prion diseases typically involve brain deposition of abnormally folded prion protein, which is associated with activated glia and increased cytokine production. Cyclophilin A (CypA) is a ubiquitous protein with peptidyl prolyl cis-trans isomerase activity, which regulates protein folding, and can be secreted by cells in response to inflammatory stimuli. On the basis of in vitro studies, CypA was proposed to mediate glial activation during prion infection. To investigate the role of CypA in vivo, we inoculated CypA+/+, CypA+/− and CypA−/− mice with the RML prion strain, and recorded the time to onset of neurological signs and to terminal disease, and the astrocyte and microglia response at presymptomatic and symptomatic stages. Time to onset of disease and survival were significantly shorter in CypA-deficient mice than CypA-expressing controls. CypA-deficient mice had significantly greater microglial activation in the presymptomatic stage, and analysis of anti- and pro-inflammatory microglial markers indicated a shift towards a pro-inflammatory phenotype. There was no difference in astrocyte activation. This suggests that CypA contributes to dampening the pro-inflammatory microglial response during the early stage of RML-induced prion disease.

Introduction: The technique of sealing is a widely accepted procedure for prevention of caries. The aim of our in vitro study was to compare the effect of two different curing units (traditional LED source and innovative laser diode lamp) on the integrity of fissure sealant material and its interface with tooth enamel. Materials and methods: Sixty healthy third molars were randomly assigned to two groups. In group A were teeth intended for polymerization by LED B lamp, and group B comprised teeth to be polymerized by an innovative laser diode. Both groups were treated with the traditional sealing technique, subjected to a metallization process, and analyzed by scanning electron microscope. Results: Micro-gaps between the sealant and the enamel were found in specimens in both A (43%) and B (40%) groups ( p =0.793), and sealant shrinkage was seen. Significant differences between the groups emerged in the percentage of perimetric micro-erosion sites (80% vs. 100%, p =0.010) and the presence of holes and micro-bubbles on the sealant surface (21% vs. 63%, p =0.001). Conclusions: Although macroscopic clinical polymerization occurred with both instruments, the microscopic evaluation showed significant differences between the studied groups in terms of perimetric micro-erosion sites and micro-bubbles, which were higher in laser-cured samples.

Background: Plaque composition may predict the evolution of carotid artery stenosis rather than its sole extent. The grey scale median (GSM) value is a reproducible and standardized value to report plaque echogenicity as an indirect measure of its composition. We monitored plaque composition in asymptomatic subcritical carotid stenosis and evaluated the effect of an oral modulating calcification factor (vitamin K2). Methods: Carotid plaque composition was assessed by GSM value. Monitoring the effects of standard therapy (acetylsalicylic acid and low–medium dosage statin) (acetylsalicylic acid (ASA) arm) or standard therapy plus vitamins K2 oral supplementation (ASA + K2 arm) over a 12 months period was conducted using an ultrasound scan in a prospective, open-label, randomized controlled trial (PLAK2). Results: Sixty patients on low–medium dosage statin therapy were enrolled and randomized (30 per arm) to either ASA + K2 or ASA alone. Thirty-seven patients (61.6%) showed at 12 months a stable plaque with a mean increase in the GSM value in respect to the baseline of 2.6% with no differences between the two study arms (p = 0.66). Fifteen patients (25%) showed an 8% GSM value reduction respect the baseline with no differences between the two study arms (p = 0.99). At multivariable analysis, the adjusted mean (95% confidence interval) GSM change per month from baseline was greater in the ASA + K2 arm (−0.55 points, p = 0.048) compared to ASA alone (−0.18 points, p = 0.529). Conclusions: Carotid plaque composition monitoring through GSM value represents a laborious procedure. Although its use may not be applied to everyday practice, a specific application consists in evaluating the effect of pharmacological therapy on plaque composition. This 12 months randomized trial showed that the majority of subcritical asymptomatic carotid plaque on treatment with low–medium dosage statin presented a stable or increased echogenicity. Although vitamin K2 beyond standard therapy did not determine a significant change in plaque composition, for those who presented with GSM reduction it did enhance a GSM monthly decline.

Many years following transplantation, heart transplant recipients may require noncardiac major surgeries. Anesthesia in such patients may be challenging due to physiological and pharmacological problems regarding allograft denervation and difficult immunosuppressive management. Massive hemorrhage, hypoperfusion, renal, respiratory failure, and infections are some of the most frequent complications related to thoracic aorta aneurysm repair. Understanding how to optimize hemodynamic and infectious risks may have a substantial impact on the outcome. This case report aims at discussing risk stratification and anesthetic management of a 54-year-old heart transplant female recipient, affected by Marfan syndrome, undergoing thoracic aorta aneurysm repair.

Artificial substrates supporting the healing of skin wounds require specific structural and chemical architectures that promote a recapitulation of the complexity of the native organ. Bottom-up fabrication technologies are emerging as effective strategies to fine tune biochemical, morphological, and structural features intended for regenerative applications. Here, we proposed an electrophoretic replica deposition (EPrD) approach to realize chitosan three-dimensional structures specifically designed to treat patients with serious cutaneous damages or losses. The EPrD process has been optimized to consistently obtain random porosity vs. hierarchical lattice structures, showing mechanical properties in the range of skin tissue (E = 0.2–20 MPa). The obtained patches were tested in vivo via a one-stage grafting procedure in a full thickness skin wound rat model. Chitosan patches showed no adverse reactions throughout the experimental period (14 days). Hair follicles and sebaceous glands were observed in histological sections, indicating the regeneration of a thin epidermal layer with more skin appendages. Immunohistochemistry results demonstrated that keratin 10 was mostly expressed in basal and suprabasal layers, like normal skin, in structures with random porosity and with smaller lattice structures. The obtained results show the potential of EPrD to innovate the design of artificial substrates in skin healing therapies.

Background. Extracranial vertebral artery aneurysms are a rare cause of embolic stroke; surgical and endovascular therapy options are debated and long-term complication may occur. Case Report. A 53-year-old man affected by neurofibromatosis type 1 (NF1) came to our attention for recurrent vertebrobasilar embolic strokes, caused by a primary giant, partially thrombosed, fusiform aneurysm of the left extracranial vertebral artery. The aneurysm was treated by endovascular approach through deposition of Guglielmi Detachable Coils in the proximal segment of the left vertebral artery. Six years later the patient presented stroke recurrence. Cerebral angiography and Color Doppler Ultrasound well characterized the unique hemodynamic condition developed over the years responsible for the new embolic event: the aneurysm had been revascularized from its distal portion by reverse blood flow coming from the patent vertebrobasilar axis. A biphasic Doppler signal in the left vertebral artery revealed a peculiar behavior of the blood flow, alternately directed to the aneurysm and backwards to the basilar artery. Surgical ligation of the distal left vertebral artery and excision of the aneurysm were thus performed. Conclusion. This is the first described case of NF1-associated extracranial vertebral artery aneurysm presenting with recurrent embolic stroke. Complete exclusion of the aneurysm from the blood circulation is advisable to achieve full resolution of the embolic source.

We report the case of a 72-year-old patient presenting with an isolated common iliac aneurysm with occlusion of contralateral common iliac artery and severe kyphoscoliosis. Because of high risk for open surgery due to chronic obstructive pulmonary disease, this patient was treated with an endovascular approach using an aortomonoiliac stent graft, followed by a femoro-femoral crossover bypass. This report illustrates the usefulness of a minimally invasive approach, and feasibility even for patients with difficult anatomy.Relatamos o caso de um paciente de 72 anos com aneurisma isolado de ilíaca, oclusão contralateral de artéria ilíaca comum e cifoescoliose grave. Devido ao alto risco para cirurgia convencional em razão de doença pulmonar obstrutiva crônica, o paciente foi tratado com abordagem endovascular, utilizando uma endoprótese aortomonoilíaca, seguida de uma derivação fêmoro-femoral cruzada. Este relato ilustra a utilidade de uma abordagem minimamente invasiva e demonstra que, mesmo para pacientes com anatomia difícil, é factível.

We report a case of a 72-year-old patient considered unfit for open surgery, presenting with paraanastomotic aneurysms of all three anastomoses, 13 years after an open aortobiiliac reconstruction for abdominal aortic aneurysm. This patient was successfully treated with an endovascular approach using a left aortouniiliac endograft and a right iliac tubular endograft, followed by crossover femorofemoral bypass. This report illustrates the usefulness of a minimally invasive approach for solving this complication of aortic open surgery and discusses technical issues related to endovascular devices in this particular setting.Relatamos um caso de um paciente de 72 anos não considerado elegível para cirurgia aberta, apresentando aneurismas para-anastomóticos das três anastomoses, 13 anos após uma reconstrução aberta aorto-biilíaca para aneurisma aórtico abdominal. Este paciente foi tratado com sucesso através de abordagem endovascular usando uma endoprótese aorto-uniilíaca esquerda e uma endoprótese tubular ilíaca direita, seguida por derivação cruzada fêmoro-femoral. Este relato ilustra a utilidade de uma abordagem minimamente invasiva para o tratamento desta complicação da cirurgia aórtica aberta e discute questões técnicas relacionadas a dispositivos endovasculares neste contexto em especial.

BACKGROUND: Endovascular approach to the aortic arch is an appealing solution for selected patients. OBJECTIVE: To compare the technical and clinical success recorded in the different anatomical settings of endografting for aortic arch disease. METHODS: Between June 1999 and October 2006, among 178 patients treated at our institution for thoracic aorta disease with a stent-graft, the aortic arch was involved in 64 cases. According to the classification proposed by Ishimaru, aortic zone 0 was involved in 14 cases, zone 1 in 12 cases and zone 2 in 38 cases. A hybrid surgical procedure of supra-aortic debranching and revascularization was performed in 37 cases. RESULTS: Zone 0. Proximal neck length: 44±6 mm. Initial clinical success was 78.6%: two deaths (stroke), one type Ia endoleak. At a mean follow-up of 16.4±11 months the midterm clinical success was 85.7%. Zone 1. Proximal neck length: 28±5 mm. Initial clinical success was 66.7%: 0 deaths, four type Ia endoleaks. At a mean follow-up of 16.9±17.2 months the midterm clinical success was 75.0%. Zone 2. Proximal neck length: 30±5 mm. Initial clinical success was 84.2%: two deaths (one cardiac arrest, one multiorgan embolization), three type Ia endoleaks, one case of open conversion. Two cases of delayed transitory paraparesis/paraplegia were observed. At a mean follow-up of 28.0±17.2 months the midterm clinical success was 89.5%. CONCLUSIONS: This study and a literature review demonstrated that hybrid procedure for aortic arch pathology is feasible in selected patients at high risk for conventional surgery. Our experience is still limited by the relatively small sample size. We propose to reserve zone 1 for patients unfit for sternotomy or in cases with aortic neck length > 30 mm following left common carotid artery debranching. We recommend to perform complete aortic rerouting of the aortic arch in cases with lesser comorbidities and shorter aortic neck.CONTEXTO: O tratamento endovascular dos aneurismas do arco aórtico é uma solução interessante para pacientes selecionados. OBJETIVO: Comparar os sucessos técnico e clínico registrados nas diferentes regiões anatômicas do arco aórtico após a colocação de endoprótese. MÉTODOS: Entre junho de 1999 e outubro de 2006, 178 pacientes foram tratados na nossa instituição devido a doenças da aorta torácica com a colocação de endoprótese, sendo que o arco aórtico estava envolvido em 64 casos. De acordo com a classificação proposta por Ishimaru, a zona aórtica 0 estava envolvida em 14 casos, zona 1 em 12 casos e zona 2 em 38 casos. Procedimentos de debranching do arco aórtico e revascularização extra-anatômica dos troncos supra-aórticos foram realizados em 37 casos para obter um adequado colo aórtico proximal. RESULTADOS: Zona 0. Comprimento do colo proximal: 44±6 mm. Sucesso clínico inicial de 78,6%: dois óbitos (acidente vascular cerebral), um vazamento do tipo Ia. Seguimento médio de 16,4±11 meses com sucesso clínico a médio prazo de 85,7%. Zona 1. Comprimento do colo proximal: 28±5 mm. Sucesso clínico inicial de 66,7%: 0 óbitos, quatro vazamentos do tipo Ia. Seguimento médio de 16,9±17,2 meses com sucesso clínico a médio prazo de 75%. Zona 2. Comprimento do colo proximal: 30±5 mm. Sucesso clínico inicial de 84,2%: dois óbitos (um infarto cardíaco e uma embolização de múltiplos órgãos), três vazamentos do tipo Ia, um caso de conversão para operação aberta. Dois casos de paraparesia/paraplegia transitória tardia foram observados. Seguimento médio de 28,0±17,2 meses com sucesso clínico a médio prazo de 89,5%. CONCLUSÃO: Este estudo e a análise da literatura demonstram que o procedimento híbrido para moléstia do arco aórtico é factível em pacientes selecionados com alto risco para a operação convencional. Nossa experiência ainda é limitada pelo tamanho relativamente pequeno da amostra. Sugerimos reservar a zona 1 para pacientes inadequados para esternotomia ou em casos de comprimento do colo aórtico proximal > 30 mm apos revascularização da artéria carótida comum esquerda. Sugerimos realizar revascularização completa do arco aórtico em pacientes adequados com um colo aórtico proximal mais curto.

Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

The prion protein (PrPC) is highly expressed within the nervous system. Similar to other GPI-anchored proteins, PrPC is found in lipid rafts, membrane domains enriched in cholesterol and sphingolipids. PrPC raft association, together with raft lipid composition, appears essential for the conversion of PrPC into the scrapie isoform PrPSc, and the development of prion disease. Controversial findings were reported on the nature of PrPC-containing rafts, as well as on the distribution of PrPC between rafts and non-raft membranes. We investigated PrPC/ganglioside relationships and their influence on PrPC localization in a neuronal cellular model, cerebellar granule cells. Our findings argue that in these cells at least two PrPC conformations coexist: in lipid rafts PrPC is present in the native folding (α-helical), stabilized by chemico-physical condition, while it is mainly present in other membrane compartments in a PrPSc-like conformation. We verified, by means of antibody reactivity and circular dichroism spectroscopy, that changes in lipid raft-ganglioside content alters PrPC conformation and interaction with lipid bilayers, without modifying PrPC distribution or cleavage. Our data provide new insights into the cellular mechanism of prion conversion and suggest that GM1-prion protein interaction at the cell surface could play a significant role in the mechanism predisposing to pathology.

A great deal of effort has been devoted during the past 20 years to defining the chemical nature of prions, the infectious agents responsible for transmissible spongiform encephalopathies. In contrast, much less attention has been paid to elucidating how prions actually damage the central nervous system. Although it is commonly assumed that PrPSc, the protein constituent of infectious prions, is the primary culprit, increasing evidence indicates that this may not be the case. Several alternative molecular forms of PrP are reasonable candidates for the neurotoxic species in prion diseases, although it is still too early to tell whether these or other ones will turn out to be the true instigating factors. The cellular pathways activated by neurotoxic forms of PrP that ultimately result in neuronal death are also being investigated, and several possible mechanisms have been uncovered, including the operation of quality control processes in the endoplasmic reticulum. Elucidating the distinction between the infectious and neurotoxic forms of PrP has important implications for designing therapy of prion diseases, as well as for understanding pathogenic mechanisms operative in other neurodegenerative disorders and the role of prion-like states in biology.

A nine-octapeptide insertional mutation in the prion protein (PrP) gene is associated with an inherited variant of Creutzfeldt–Jakob disease in humans. Transgenic mice that express the mouse PrP homologue of this mutation (designated PG14) under control of a PrP promoter display a progressive neurological disorder characterized by ataxia, apoptosis of cerebellar granule cells, and accumulation in the brain of mutant PrP molecules that display the biochemical hallmarks of PrPSc, the pathogenic isoform of PrP. In this report, we have investigated the expression of PG14 PrP in the peripheral tissues of these mice. We found highest levels of mutant PrP in the brain and spinal cord, intermediate levels in skeletal muscle, heart, and testis and low levels in kidney, lung, spleen, intestine, and stomach. Up to 70% of the PG14 PrP expressed in peripheral tissues was detergent-insoluble, and digestion with low concentrations of proteinase K yielded a PrP 27–30 fragment. These results suggest that the mutant protein was converted to a physical state reminiscent of PrPSc, although its infectivity remains to be determined. Histological analysis of skeletal muscle, one of the peripheral tissues with the highest level of PG14 PrP, revealed features indicative of a progressive, primary myopathy, including central nuclei, necrotic and regenerating fibers, and variable fiber size. These results indicate that the PG14 mutation structurally alters the protein in a way that promotes conversion to a PrPSc-like state, regardless of the tissue context, and suggest that accumulation of PrPSc can have deleterious effects on skeletal muscle cells as well as on neurons.

ObjectiveStatins are among the most prescribed drugs worldwide and their recently discovered anti-inflammatory effect seems to have an important role in inhibiting proinflammatory cytokine production, chemokines expression and counteracting the harmful effects of sepsis on the coagulation system. We decided to perform a meta-analysis of all randomized controlled trials ever published on statin therapy in septic patients to evaluate their effect on survival and length of hospital stay.Data sources and study selectionArticles were assessed by four trained investigators, with divergences resolved by consensus. BioMedCentral, PubMed, Embase and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and comparison of statins versus any comparator in septic patients.Data extraction and synthesisData from 650 patients in 5 randomized controlled studies were analyzed. No difference in mortality between patients receiving statins versus control (44/322 [14%] in the statins group vs 50/328 [15%] in the control arm, RR = 0.90 [95% CI 0.65 to 1.26], p = 0.6) was observed. No differences in hospital stay (p = 0.7) were found.ConclusionsPublished data show that statin therapy has no effect on mortality in the overall population of adult septic patients. Scientific evidence on statins role in septic patients is still limited and larger randomized trials should be performed on this topic.

Synaptic dysfunction is an important cause of neurological symptoms in prion diseases, a class of clinically heterogeneous neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC). Experimental data suggest that accumulation of misfolded PrPC in the endoplasmic reticulum (ER) may be crucial in synaptic failure, possibly because of the activation of the translational repression pathway of the unfolded protein response. Here, we report that this pathway is not operative in mouse models of genetic prion disease, consistent with our previous observation that ER stress is not involved. Building on our recent finding that ER retention of mutant PrPC impairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfolded PrPC results in loss of function or gain of toxicity of PrPC-interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases.

Coronary atherosclerosis, the main condition predisposing to acute myocardial infarction, has an inflammatory component caused by stimuli that are yet unknown. We molecularly investigated the nature of the immune response within human coronary lesion in four coronary plaques obtained by endoluminal atherectomy from four patients. We constructed phage-display libraries containing the IgG1/kappa antibody fragments produced by B-lymphocytes present in each plaque. By immunoaffinity, we selected from these libraries a monoclonal antibody, arbitrarily named Fab7816, able to react both with coronary and carotid atherosclerotic tissue samples. We also demonstrated by confocal microscopy that this monoclonal antibody recognized human transgelin type 1, a cytoskeleton protein involved in atherogenesis, and that it co-localized with fibrocyte-like cells transgelin+, CD68+, CD45+ in human sections of coronary and carotid plaques. In vitro fibrocytes obtained by differentiating CD14+ cells isolated from peripheral blood mononuclear cells also interacted with Fab7816, thus supporting the hypothesis of a specific recognition of fibrocytes into the atherosclerotic lesions. Interestingly, the same antibody, cross-reacted with the outer membrane proteins of Proteus mirabilis and Klebsiella pneumoniae (and possibly with homologous proteins of other enterobacteriaceae present in the microbiota). From all the other three libraries, we were able to clone, by immunoaffinity selection, human monoclonal antibodies cross-reacting with bacterial outer membrane proteins and with transgelin. These findings demonstrated that in human atherosclerotic plaques a local cross-reactive immune response takes place.

Insight into the normal function of PrP(C), and how it can be subverted to produce neurotoxic effects, is provided by PrP molecules carrying deletions encompassing the conserved central region. The most neurotoxic of these mutants, Δ105-125 (called ΔCR), produces a spontaneous neurodegenerative illness when expressed in transgenic mice, and this phenotype can be dose-dependently suppressed by co-expression of wild-type PrP. Whether the toxic activity of ΔCR PrP and the protective activity or wild-type PrP are cell-autonomous, or can be exerted on neighboring cells, is unknown. To investigate this question, we have utilized co-cultures of differentiated neural stem cells derived from mice expressing ΔCR or wild-type PrP. Cells from the two kinds of mice, which are marked by the presence or absence of GFP, are differentiated together to yield neurons, astrocytes, and oligodendrocytes. As a surrogate read-out of ΔCR PrP toxicity, we assayed sensitivity of the cells to the cationic antibiotic, Zeocin. In a previous study, we reported that cells expressing ΔCR PrP are hypersensitive to the toxic effects of several cationic antibiotics, an effect that is suppressed by co-expression of wild type PrP, similar to the rescue of the neurodegenerative phenotype observed in transgenic mice. Using this system, we find that while ΔCR-dependent toxicity is cell-autonomous, the rescuing activity of wild-type PrP can be exerted in trans from nearby cells. These results provide important insights into how ΔCR PrP subverts a normal physiological function of PrP(C), and the cellular mechanisms underlying the rescuing process.

The cellular pathways activated by mutant prion protein (PrP) in genetic prion diseases, ultimately leading to neuronal dysfunction and degeneration, are not known. Several mutant PrPs misfold in the early secretory pathway and reside longer in the endoplasmic reticulum (ER) possibly stimulating ER stress-related pathogenic mechanisms. To investigate whether mutant PrP induced maladaptive responses, we checked key elements of the unfolded protein response (UPR) in transgenic mice, primary neurons and transfected cells expressing two different mutant PrPs. Because ER stress favors the formation of untranslocated PrP that might aggregate in the cytosol and impair proteasome function, we also measured the activity of the ubiquitin proteasome system (UPS). Molecular, biochemical and immunohistochemical analyses found no increase in the expression of UPR-regulated genes, such as Grp78/Bip, CHOP/GADD153, or ER stress-dependent splicing of the mRNA encoding the X-box-binding protein 1. No alterations in UPS activity were detected in mutant mouse brains and primary neurons using the Ub(G76V)-GFP reporter and a new fluorogenic peptide for monitoring proteasomal proteolytic activity in vivo. Finally, there was no loss of proteasome function in neurons in which endogenous PrP was forced to accumulate in the cytosol by inhibiting cotranslational translocation. These results indicate that neither ER stress, nor perturbation of proteasome activity plays a major pathogenic role in prion diseases.

BackgroundA promising strategy to create stimuli-responsive gene delivery systems is to exploit the redox gradient between the oxidizing extracellular milieu and the reducing cytoplasm in order to disassemble DNA/cationic lipid complexes (lipoplexes). On these premises, we previously described the synthesis of SS14 redox-sensitive gemini surfactant for gene delivery. Although others have attributed the beneficial effects of intracellular reducing environment to reduced glutathione (GSH), these observations cannot rule out the possible implication of the redox milieu in its whole on transfection efficiency of bioreducible transfectants leaving the determinants of DNA release largely undefined.Methodology/principal findingsWith the aim of addressing this issue, SS14 was here formulated into binary and ternary 100 nm-extruded liposomes and the effects of the helper lipid composition and of the SS14/helper lipids molar ratio on chemical-physical and structural parameters defining transfection effectiveness were investigated. Among all formulations tested, DOPC/DOPE/SS14 at 25:50:25 molar ratio was the most effective in transfection studies owing to the presence of dioleoyl chains and phosphatidylethanolamine head groups in co-lipids. The increase in SS14 content up to 50% along DOPC/DOPE/SS14 liposome series yielded enhanced transfection, up to 2.7-fold higher than that of the benchmark Lipofectamine 2000, without altering cytotoxicity of the corresponding lipoplexes at charge ratio 5. Secondly, we specifically investigated the redox-dependent mechanisms of gene delivery into cells through tailored protocols of transfection in GSH-depleted and repleted vs. increased oxidative stress conditions. Importantly, GSH specifically induced DNA release in batch and in vitro.Conclusions/significanceThe presence of helper lipids carrying unsaturated dioleoyl chains and phosphatidylethanolamine head groups significantly improved transfection efficiencies of DOPC/DOPE/SS14 lipoplexes. Most importantly, this study shows that intracellular GSH levels linearly correlated with transfection efficiency while oxidative stress levels did not, highlighting for the first time the pivotal role of GSH rather than oxidative stress in its whole in transfection of bioreducible vectors.

A key pathogenic role in prion diseases was proposed for a cytosolic form of the prion protein (PrP). However, it is not clear how cytosolic PrP localization influences neuronal viability, with either cytotoxic or anti-apoptotic effects reported in different studies. The cellular mechanism by which PrP is delivered to the cytosol of neurons is also debated, and either retrograde transport from the endoplasmic reticulum or inefficient translocation during biosynthesis has been proposed. We investigated cytosolic PrP biogenesis and effect on cell viability in primary neuronal cultures from different mouse brain regions.Mild proteasome inhibition induced accumulation of an untranslocated form of cytosolic PrP in cortical and hippocampal cells, but not in cerebellar granules. A cyclopeptolide that interferes with the correct insertion of the PrP signal sequence into the translocon increased the amount of untranslocated PrP in cortical and hippocampal cells, and induced its synthesis in cerebellar neurons. Untranslocated PrP boosted the resistance of cortical and hippocampal neurons to apoptotic insults but had no effect on cerebellar cells.These results indicate cell type-dependent differences in the efficiency of PrP translocation, and argue that cytosolic PrP targeting might serve a physiological neuroprotective function.

BACKGROUND:Prion diseases are fatal neurodegenerative disorders that can arise sporadically, be genetically inherited or acquired through infection. The key event in these diseases is misfolding of the cellular prion protein (PrP(C)) into a pathogenic isoform that is rich in beta-sheet structure. This conformational change may result in the formation of PrP(Sc), the prion isoform of PrP, which propagates itself by imprinting its aberrant conformation onto PrP(C) molecules. A great deal of effort has been devoted to developing protocols for purifying PrP(Sc) for structural studies, and testing its biological properties. Most procedures rely on protease digestion, allowing efficient purification of PrP27-30, the protease-resistant core of PrP(Sc). However, protease treatment cannot be used to isolate abnormal forms of PrP lacking conventional protease resistance, such as those found in several genetic and atypical sporadic cases. PRINCIPAL FINDINGS:We developed a method for purifying pathological PrP molecules based on sequential centrifugation and immunoprecipitation with a monoclonal antibody selective for aggregated PrP. With this procedure we purified full-length PrP(Sc) and mutant PrP aggregates at electrophoretic homogeneity. PrP(Sc) purified from prion-infected mice was able to seed misfolding of PrP(C) in a protein misfolding cyclic amplification reaction, and mutant PrP aggregates from transgenic mice were toxic to cultured neurons. SIGNIFICANCE:The immunopurification protocol described here isolates biologically active forms of aggregated PrP. These preparations may be useful for investigating the structural and chemico-physical properties of infectious and neurotoxic PrP aggregates.

Introduction: Women are generally underrepresented in trials focusing on aortic aneurysm. Nevertheless, sex-related differences have recently emerged from several studies and registries. The aim of this research was to assess whether sex-related anatomical disparities existed in fenestrated and branched aortic repair candidates and whether these discrepancies could influence endovascular repair outcomes. Methods: Data from all consecutive patients treated during the 2008–2019 period within the Italian Multicenter fenestrated or branched endovascular aortic repair (F/BEVAR) Registry were included in the present study. Propensity matching was performed using a logistic regression model adjusted for demographic data and comorbidities to obtain comparable male and female samples. The selection model led to a final study population of 176 patients (88 women and 88 men) among the total initial cohort of 596. Study endpoints were technical and clinical success, overall survival, aneurysm-related death, and reintervention rates evaluated at 30 days and during follow-up. Results: Twenty-eight patients (15.9%) received urgent/emergent repair. In most of the cases (71.6%), women received treatment for extensive thoracoabdominal pathology (Crawford type I, II, or III aneurysm rather than type IV or juxta-pararenal) versus 46.6% of men (p=0.001). Female patients presented with more challenging iliac accesses with at least one side considered hostile in 27.3% of the cases (vs 13.6% in male patients, p=0.039). Finally, women had significantly smaller visceral vessels. Women had significantly worse operative outcomes, with an 86.2% technical success rate versus 96.6% in the male population (p=0.016). No differences were recorded in terms of 30-day reinterventions between men and women. The 5-year estimate of freedom from late reintervention, according to Kaplan-Meier analysis, was 85.6% in men versus 81.6% in women (p=ns). No aneurysm-related death was recorded during follow-up (median observational time, 23 months [interquartile range, 7–45 months]). Conclusion: Women presented a significantly higher incidence of thoracoabdominal aneurysms, smaller visceral vessels, and more complex iliofemoral accesses, resulting in a significantly lower technical success after F/BEVAR. Further studies assessing sex-related differences are needed to properly determine the impact on outcomes and stratify procedural risks. Clinical Impact: Women are generally underrepresented in trials focusing on aortic aneurysms. Aiming to assess whether sex may affect outcomes after a complex endovascular aortic repair, a propensity score selection was applied to a total population of 596 patients receiving F/BEVAR aortic repair with the Cook platform, matching each treated female patient with a corresponding male patient. Women presented more frequently a thoracoabdominal aneurysm extent, smaller visceral vessels, and complex iliofemoral accesses, resulting in significantly worse operative outcomes, with an 86.2% technical success versus 96.6% (p=0.016). No differences were recorded in terms of short-term and mid-term reinterventions. According to these results, careful and critical assessment should be posed in case of female patients receiving complex aortic repair, especially regarding preoperative anatomical evaluation and clinical selection with appropriate surgical risk stratification. [ABSTRACT FROM AUTHOR]