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Cranioplasty using Hydroxyapatite prosthesis is a conceptually simple procedure, but it may harbor several challenges for the surgeons. Several papers in the literature deal with cranioplasty using porous hydroxyapatite. The results are not homogeneous both because of the variability of the patients treated but also because Hydroxyapatite requires a more careful surgical technique to achieve maximum performance. The aim of the present study is to offer an insight of a single institution, multidisciplinary experience with custom-made Hydroxyapatite cranioplasty with surgical tips and tricks based on personal opinion and literature evidence. We will provide an overview of all the fundamental steps we believe to be useful to optimize surgical outcomes, including preoperative planning of cranioplasty; as cranioplasty flap/soft tissue coverage planning, infectious prophylaxis, patient positioning, incisional patterns, tissue dissection, primary bone demolition, and preparation of the craniectomy margins before implant positioning. The authors will also discuss methods for dural suspension, implant fixation and anchorage, margins polishing, drainage, suturing, and dressing. Cranioplasty using hydroxyapatite prosthesis is a valuable alternative for skull reconstruction with heterologous implants, and in our opinion a multidisciplinary approach integrating plastic surgeons and neurosurgeons' specific skills can facilitate surgical planning, reducing complications and allowing to achieve better functional and aesthetic results., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Notch and its ligands play a critical role in rheumatoid arthritis (RA) pathogenesis. Hence, studies were conducted to delineate the functional significance of the Notch pathway in RA synovial tissue (ST) cells and the influence of RA therapies on their expression. Morphological studies reveal that JAG1, DLL4, and Notch1 are highly enriched in RA ST lining and sublining CD68 + CD14 + MΦs. JAG1 and DLL4 transcription is jointly upregulated in RA MΦs reprogrammed by TLR4/5 ligation and TNF, whereas Syntenin-1 exposure expands JAG1, DLL4, and Notch1 expression levels in these cells. Single-cell RNA-seq data exhibit that JAG1 and Notch3 are overexpressed on all fibroblast-like synoviocyte (FLS) subpopulations, in parallel, JAG2, DLL1, and Notch1 expression levels are modest on RA FLS and are predominately potentiated by TLR4 ligation. Intriguingly, JAG1, DLL1/4, and Notch1/3 are presented on RA endothelial cells, and their expression is mutually reconfigured by TLR4/5 ligation in the endothelium. Synovial JAG1/JAG2/DLL1 or Notch1/3 transcriptomes were unchanged in patients who received disease-modifying anti-rheumatic drugs (DMARDs) or IL-6R Ab therapy regardless of disease activity score. Uniquely, RA MΦs and endothelial cells rewired by IL-6 displayed DLL4 transcriptional upregulation, and IL-6R antibody treatment disrupted RA ST DLL4 transcription in good responders compared to non-responders or moderate responders. Nevertheless, the JAG1/JAG2/DLL1/DLL4 transcriptome was diminished in anti-TNF good responders with myeloid pathotype and was unaltered in the fibroid pathotype except for DLL4. Taken together, our findings suggest that RA myeloid Notch ligands can serve as markers for anti-TNF responsiveness and trans-activate Notch receptors expressed on RA FLS and/or endothelial cells., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes (FLS). Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9, IL-1β, IL-6, and CCL2 through SDC-1 ligation and HIF1α, or mTOR activation. Mechanistically, Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling. In Syntenin-1 reprogrammed endothelial cells, the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors, AMPK, PGC-1α, citrate, and inactive oxidative phosphorylation. Conversely, RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity. The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression. We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS, which are also represented in RA explants. Similar to RA explants, morphological and transcriptome studies authenticated the importance of VEGFR1/2, Notch1, RAPTOR, and HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired synovial angiogenic imprint amplified by Syntenin-1. In conclusion, since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood, targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy., (© 2023. The Author(s), under exclusive licence to CSI and USTC.)

Since ancient history, men have been attempting to intervene when skull trauma occurs. The majority of traumas were always linked to war injuries, and in the modern era, the culprit was reached during World War I. Cranial traumas in wartime were very common, and consequently, physicians in wartime became particularly interested in the subject of cranial traumatology. In the following text, we want to bring to light the experience of some of the pioneers of cranial surgery in Italy during the First Great War. In fact before the war, very few medical officers had received training in central nervous system surgery. In addition, the surgical instruments for that clinical activity were inadequate and obsolete, but to deal with the medical emergency that had arisen on the front lines, the Italian government established Battlefield Medical Schools. And it is also from the reports and lectures of surgeons working on the front lines that the next generations of neurosurgeons were able to develop this surgical field into the complex and well-established surgical specialty that it is today., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Burr holes in the cranial vault are usually made during trephination for craniotomy or drainage of chronic subdural hematomas. The resulting cranial defect might bring to unsatisfactory esthetic outcome. In the current study the authors report clinical data regarding a cohort of patients who were treated with 3 different types of burr hole covers; autologous bone dust from skull trephination, and 2 different types of cylindric plug made out of porous hydroxyapatite in order to evaluate medium and long-term esthetic and radiological outcomes. Twenty patients were consecutively enrolled in the study and in each patient all 3 types of materials were used to cover different holes. Clinical and radiological outcomes at 6 and 12 months, were analyzed for all 3 types of plugs in terms of thickness of the graft coaptation of margins, remodeling, fractures, mobilization, and contour irregularities. In all craniotomy holes filled with autologous bone dust the authors have observed partial or complete bone reabsorption at 1 year and in 60% of the cases a visible and palpable cranial vault contour irregularity was reported. Both types of bone substitutes gave satisfactory results, comparable to autologous bone dust at 6 months and superior at 12 months, especially in terms of thickness and esthetic appearance. Hydroxyapatite plugs have shown better esthetic and biomechanical results and higher patients' satisfaction compared to autologous bone dust while not giving any additional complications., Competing Interests: A.N. is consultant for FinCeramica. The remaining authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)

Background and Purpose: Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. CVST-VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST-VITT patients who underwent decompressive surgery are described and predictors of in-hospital mortality in these patients are explored., Methods: Data from an ongoing international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680-1689), were included., Results: Decompressive surgery was performed in 34/128 (27%) patients with CVST-VITT. In-hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non-surgical group (p < 0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non-comatose; p < 0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p = 0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow-up of 6 months, 8/10 of surgical CVST-VITT who survived admission were functionally independent., Conclusions: Almost two-thirds of surgical CVST-VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Retrospective cohort study., Objective: The authors' goal was to clarify whether a bone substitute combined with antibiotics might gain a hold in spinal surgery as a preventive treatment for early infections (EIs)., Background: A relatively infrequent but severe complication in spinal surgery is the occurrence of EIs., Methods: The authors retrospectively compared a population undergoing posterolateral fusion with Mg-enriched hydroxyapatite paste mixed with 60 mg rifampicin powder, with a matched population treated with autologous bone without antibiotics. A total of 30 patients from 2020 to 2021 were included in our study. We estimated EI's relative risk and the number needed to treat. Statistical analyses were performed using the R statistical package v3.4.1 (http://www.r-project.org)., Results: No early infections occurred in the population treated with antibiotic-combined bone substitutes, compared with 6.7% of patients treated with autologous bone without antibiotics. The relative risk of EIs was 0.33 ( P=. 49; 95% CI = 0.01-7.58) and the number needed to treat was 15., Conclusions: The results support the hypothesis that combining bone substitutes with antibiotics may decrease the risk of EIs and could be a viable option to improve spinal surgery outcomes. However, a larger sample size would be needed to confirm the benefit of rifampicin-combined Mg-enriched hydroxyapatite substitutes over autologous bone for surgical site infection prevention., Level of Evidence: Level 3., Competing Interests: The authors declare they have no financial or other conflict of interests in relation to this research and its publication., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA., Methods: RA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape., Results: Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14 + CD86 + GLUT1 + MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80 + iNOS + RAPTOR + MΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1 -/- animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation., Conclusion: The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

To improve solid spinal fusion while avoiding the morbidity associated with autograft harvesting procedures, numerous alternatives have been investigated, including allograft, demineralized bone matrix (DBM), cell-based therapies and growth factors (i.e., bone morphogenetic proteins, platelet concentrates), and ceramic-based biomaterials. Even though all of these approaches have the potential to improve the outcome of spinal fusion procedures, most of them have not yet been validated by evidence-based clinical results, and thus they are not strongly advisable for clinical use, in addition to being particularly expensive. Here, we give an overview of the current clinical evidence for bone graft alternatives for spine surgery procedures. We will also evaluate the pros and cons of their use and briefly review the more relevant literature.

Abstract: Cranioplasty is a common neurosurgical procedure performed to reconstruct cranial defects. The most common cranioplasty materials used today can be divided into 2 types: autologous bone and bone substitutes, such as polyetheretherketone, titanium mesh, poly-methyl methacrylate, and Hydroxyapatite (HA). Infection represents one of the most feared complications, ranging from 2.3% to 20%. Early implant infections occur within 30 days from the operation and are mostly due to pathogens from the skin and the paranasal cavity. The authors aim to demonstrate the efficacy of our preoperative antibiotic immersion protocol of custom-made HA prosthesis, to prevent early implant infections. The authors compare this population to cranioplasties without preoperative antibiotic elution and those with anonstandardized antibiotic elution. The authors retrospectively analyzed data from patients referred to 6 different hospitals in northern Italy, in the period 2000 to 2020. Inclusion criteria were patients requiring reconstruction of thecal bone with HA prosthesis after post-traumatic decompressive surgery; age more than 18 years; detailed patient history and clinical data; and follow-up of minimum 6 months. A total of 77 cranioplasties were included in the study, along with 120 retrospective cases in comparison. Infections occurred in 2.6% of cranioplasties with antibiotic immersion compared to 7.8% of cranioplasties without. Even if nonsignificant, these results support our hypothesis that pretreatment of HA implants with antibiotic appears to prevent cranioplasty infections and could be a viable option to improve cranioplasty outcomes in the future., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)

Recent studies show a connection between glycolysis and inflammatory response in rheumatoid arthritis (RA) macrophages (MΦs) and fibroblasts (FLS). Yet, it is unclear which pathways could be targeted to rebalance RA MΦs and FLS metabolic reprogramming. To identify novel targets that could normalize RA metabolic reprogramming, TLR7-mediated immunometabolism was characterized in RA MΦs, FLS and experimental arthritis. We uncovered that GLUT1, HIF1α, cMYC, LDHA and lactate were responsible for the TLR7-potentiated metabolic rewiring in RA MΦs and FLS, which was negated by IRAK4i. While in RA FLS, HK2 was uniquely expanded by TLR7 and negated by IRAK4i. Conversely, TLR7-driven hypermetabolism, non-oxidative PPP (CARKL) and oxidative phosphorylation (PPARγ) were narrowly dysregulated in TLR7-activated RA MΦs and FLS and was reversed by IRAK4i. Consistently, IRAK4i therapy disrupted arthritis mediated by miR-Let7b/TLR7 along with impairing a broad-range of glycolytic intermediates, GLUT1, HIF1α, cMYC, HK2, PFKFB3, PKM2, PDK1 and RAPTOR. Notably, inhibition of the mutually upregulated glycolytic metabolites, HIF1α and cMYC, was capable of mitigating TLR7-induced inflammatory imprint in RA MΦs and FLS. In keeping with IRAK4i, treatment with HIF1i and cMYCi intercepted TLR7-enhanced IRF5 and IRF7 in RA MΦs, distinct from RA FLS. Interestingly, in RA MΦs and FLS, IRAK4i counteracted TLR7-induced CARKL reduction in line with HIF1i. Whereas, cMYCi in concordance with IRAK4i, overturned oxidative phosphorylation via PPARγ in TLR7-activated RA MΦs and FLS. The blockade of IRAK4 and its interconnected intermediates can rebalance the metabolic malfunction by obstructing glycolytic and inflammatory phenotypes in RA MΦs and FLS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis (RA) patients could reflect activation of innate immune mechanisms. Herein, we show that a TLR7 GU-rich endogenous ligand, miR-Let7b, potentiates synovitis by amplifying RA monocyte and fibroblast (FLS) trafficking. miR-Let7b ligation to TLR7 in macrophages (MΦs) and FLSs expanded the synovial inflammatory response. Moreover, secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell differentiation. We showed that IRAK4 inhibitor (i) therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦ or FLS activation, as well as monokine-modulated Th1/Th17 cell polarization. IRAK4i therapy also disrupted RA osteoclastogenesis, which was amplified by miR-Let7b ligation to joint myeloid TLR7. Hence, the effectiveness of IRAK4i was compared with that of a TNF inhibitor (i) or anti-IL-6R treatment in collagen-induced arthritis (CIA) and miR-Let7b-mediated arthritis. We found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480 + iNOS + MΦs, the expression of certain monokines, and Th1 cell differentiation. Unexpectedly, these biologic therapies were unable to alleviate miR-Let7b-induced arthritis. The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480 + iNOS + MΦs, vimentin + fibroblasts, and CD3 + T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells., (© 2020. CSI and USTC.)

Gap junctional intercellular communication (GJIC) is a homeostatic process mediated by membrane channels composed of a protein family known as connexins. Alterations to channel activity can modulate suppression or facilitation of cancer progression. These varying roles are influenced by the cancer cell genetic profile and the context-dependent mechanisms of a dynamic extracellular environment that encompasses fluctuations to nutrient availability. To better explore the effects of altered cellular metabolism on GJIC in breast cancer, we generated a derivative of the triple-negative breast cancer cell line MDA-MB-231 optimized for growth in low-glucose. Reduced availability of glucose is commonly encountered during tumor development and leads to metabolic reprogramming in cancer cells. MDA-MB-231 low-glucose adapted cells exhibited a larger size with improved cell-cell contact and upregulation of cadherin-11. Additionally, increased protein levels of connexin 43 and greater plasma membrane localization were observed with a corresponding improvement in GJIC activity compared to the parental cell line. Since GJIC has been shown to affect cellular invasion in multiple cancer cell types, we evaluated the invasive qualities of these cells using multiple three-dimensional Matrigel growth models. Results of these experiments demonstrated a significantly more invasive phenotype. Moreover, a decrease in invasion was noted when GJIC was inhibited. Our results indicate a potential response of triple-negative breast cancer cells to reduced glucose availability that results in changes to GJIC and invasiveness. Delineation of this relationship may help elucidate mechanisms by which altered cancer cell metabolism affects GJIC and how cancer cells respond to nutrient availability in this regard.

Background: Cranioplasty is a common neurosurgical procedure with the goal of restoring skull integrity. Custom-made porous hydroxyapatite prostheses have long been used for cranial reconstruction in patients with traumatic brain injury. We present a large consecutive series of 2 groups of patients undergoing cranioplasty with hydroxyapatite custom bone and compare the adverse events (AEs) between the 2 groups., Methods: We examined a series of consecutive patients who underwent cranioplasty using custom-made porous hydroxyapatite implants following tumor resection and traumatic brain injury at a single center between March 2003 and May 2018. The implants were designed and produced according to the surgeon's specifications and based on the patient's computed tomography scan data obtained through a standardized protocol. AEs were recorded., Results: Information on 38 patients with tumor and 39 patients with traumatic brain injury was collected and analyzed. A significant difference in the timing of surgery was found between the 2 groups; single-stage surgery was performed in 84% of patients in the tumor versus 8% of those in the traumatic brain injury group (P < 0.0001). The rate of AEs was not significantly different between the 2 groups (P = 0.4309) and was not related to the timing of surgery., Conclusions: Custom-made hydroxyapatite cranioplasty is a solution for cranial reconstruction in patients with cranial tumors. The low incidence of AEs in a consecutive series of patients with either trauma or tumors demonstrates that these prostheses represent a safe solution independent of the characteristics of cases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In rheumatoid arthritis (RA), synovial tissue abundantly expresses CCL21, a chemokine strongly associated with RA susceptibility. In this study, we aimed to characterize the functional significance of CCL21/CCR7 signaling in different phases of RA pathogenesis. We determined that CCR7 is a hallmark of RA M1 synovial fluid (SF) macrophages, and its expression in RA monocytes and in vitro differentiated macrophages is closely associated with disease activity score (DAS28). In early stages of RA, monocytes infiltrate the synovial tissue. However, blockade of SF CCL21 or CCR7 prevents RA SF-mediated monocyte migration. CCR7 expression in the newly migrated macrophages can be accentuated by LPS and IFNγ and suppressed by IL-4 treatment. We also uncovered that CCL21 stimulation increases the number of M1-polarized macrophages (CD14+CD86+), resulting in elevated transcription of IL-6 and IL-23. These CCL21-induced M1 cytokines differentiate naïve T cells to Th17 cells, without affecting Th1 cell polarization. In the erosive stages of disease, CCL21 potentiates RA osteoclastogenesis through M1-driven Th17 polarization. Disruption of this intricate crosstalk, by blocking IL-6, IL-23, or IL-17 function, impairs the osteoclastogenic capacity of CCL21. Consistent with our in vitro findings, we establish that arthritis mediated by CCL21 expands the joint inflammation to bone erosion by connecting the differentiation of M1 macrophages with Th17 cells. Disease progression is further exacerbated by CCL21-induced neovascularization. We conclude that CCL21 is an attractive novel target for RA therapy, as blockade of its function may abrogate erosive arthritis modulated by M1 macrophages and Th17 cell crosstalk.

Background: The growing impact of the emergency neurology of trauma centers and of mechanical thrombectomy for the treatment of acute ischemic stroke is revolutionizing the domain of eurosciences., Methods: A census focused on the demographic distribution of the three main cohorts of neurosciences (neurologists, neuroradiologists, and neurosurgeons) was conducted in Italy between December 2015 and February 2017, and results were compared to the estimated retirement rates and loss for other reasons., Results: The total number of neurosciences specialists active in Italy was 4394 at the end of the period of the survey. The estimated retirement rates and losses seem not be supplied by the physicians in training in the same period., Conclusions: A proper redistribution of the resources and the modification of the training programs seem to be mandatory to maintain acceptable standards of care for the Italian neurosciences during the next decade.

Herpes simplex virus type-1 (HSV-1) is a significant pathogen that affects vision by targeting multiple regions in the human eye including iris. Using a focused library of synthetic non-saccharide glycosaminoglycan mimetics (NSGMs), we identified sulfated pentagalloylglucoside (SPGG) as a potent inhibitor of HSV-1 entry and cell-to-cell spread in the primary cultures of human iris stromal (HIS) cells isolated from eye donors. Using in vitro β-galactosidase reporter assay and plaque reduction assay, SPGG was found to inhibit HSV-1 entry in a dosage-dependent manner (IC 50 ∼6.0 μM). Interestingly, a pronounced inhibition in HSV-1 entry and spread was observed in HIS cells, or a cell line expressing specific gD-receptor, when virions were pre-treated with mimetics suggesting a possible interaction between SPGG and the HSV-1 glycoprotein. To examine the significance of gD-SPGG interaction, HIS cells were pretreated with SPGG, which showed a significant reduction in gD binding. Taken together, our results provide strong evidence of SPGG being a novel viral entry inhibitor against ocular HSV infection., (Copyright © 2018. Published by Elsevier B.V.)

After failing of autologous cranioplasty or when the bone flap is unavailable, the alloplastic (heterologous) materials are the choice for cranial reconstruction. No agreement has been reported about the material with a significant lower risk of septic complications. This is due to extremely heterogeneous prognostic factors related not only to the material used but also to the surgical procedures and/or to the timing of the procedure. More attention should be focused on the material whose characteristic could enable a delay in bacterial colonization, where an antibiotic therapy could be effective, without need of prosthesis removal. Four cases of severe septic complication following cranioplasty with porous hydroxyapatite (HA) prosthesis are presented. Patients were conservatively treated, without heterologous bone flap removal. All of our patients presented reasons for delaying HA cranioplasty removal: patients #1, 3, and 4 had an associated shunted hydrocephalus and the need for not removing the prosthesis was related to the predictable recurrence of overshunting and/or sinking skin flap syndrome. In patient #4, the revision surgery would have also damaged the microvascular flap with latissimus dorsi muscle used by plastic surgeon for skin reconstruction. In patient #2, the patient refused revision surgery. In all cases, systemic and/or radiological signs of infection were observed. In patient #2 the infective process surrounded completely the HA prosthesis, while it was located in the epidural region in patients #1 and 4. In patient #3, a surgical curettage of the infected wound was performed over the HA prosthesis. Following prosthesis retention management with antibiotic therapy, all patients revealed systemic and/or radiological signs of sepsis resolution at follow-up. The possibility to avoid a prosthesis removal with effective antibiotic treatment is mainly due to the combination of three factors: targeted antibiotic therapy, good anatomical area revascularization (resulting of an "in situ" intake of antibiotics), and the biomimetism of HA prosthesis. Further investigations in a larger number of cases need to confirm these observations.

When a cranioplasty implant becomes infected, standard operating procedure dictates its removal and the initiation of a long course of antibiotic therapy. However, removing such a prosthesis can have a series of adverse consequences, including delayed cognitive and motor recovery, lack of brain tissue protection, unsightly deformity, and the need for two additional surgical procedures, not to mention the additional costs involved. To maintain the advantages of cranioplasty, we opted for a conservative approach (levofloxacin and rifampicin every 24 hours for 8 weeks) in a 68-year-old woman whose custom-made porous hydroxyapatite implant, fitted following aneurysm clipping, had become infected. The tissues overlying the implant were curettaged, and the patient's clinical condition, blood markers, and infection course were continuously monitored (local monitoring was performed by single-photon emission computed tomography [SPECT]/computed tomography [CT after intravenous administration of Tc-labeled antigranulocyte antibody). Blood tests and SPECT/CT evidenced a progressive reduction in phlogosis indices and infection locus, even 1 month after antibiotic therapy was commenced, and at 2 years from cranioplasty, the same tests and clinical examination were negative. At 6-year follow-up, clinical assessment revealed nothing out of the ordinary.Hence, specific cases (hydroxyapatite prosthesis, intact dura, cranial CT and magnetic resonance imaging negative for empyema, well-vascularized scalp, antibiotic-responsive bacteria) of infected cranial implant can be treated using a conservative approach consisting of appropriate antibiotic therapy, accompanied by local debridement where necessary, and assiduous monitoring of phlogosis indices and local verification via labeled-leukocyte scintigraphy. Our report, which was compiled after a long-term follow-up period, shows that this conservative procedure appears to be a viable option in cases of infected, custom-made hydroxyapatite cranioplasty, provided that some basic rules concerning clinical and instrumental standards are adhered to, as clearly stated in our report.

Liposarcoma is a malignant soft tissue tumor that originates from adipose tissue and is one of the most frequently diagnosed soft tissue sarcomas in humans. There is great interest in identifying novel chemotherapeutic options for treating liposarcoma based upon molecular alterations in the cancer cells. The Aurora kinases have been identified as promising chemotherapeutic targets based on their altered expression in many human cancers and cellular roles in mitosis and cytokinesis. In this study, we investigated the effects of an Aurora kinase A inhibitor (MK-5108), an Aurora kinase B inhibitor (AZD1152-HQPA), and a pan-Aurora kinase inhibitor (AMG 900) on undifferentiated SW-872 and well-differentiated 93T449 human liposarcoma cells. Treatment of the SW-872 and 93T449 cells with MK-5108 (0-1000 nM), AZD1152-HQPA (0-1000 nM), and AMG 900 (0-1000 nM) for 72 h resulted in a dose-dependent decrease in the total viable cell number. Based upon the EC 50 values, the potency of the three Aurora kinase inhibitors in the SW-872 cells was as follows: AMG 900 (EC 50  = 3.7 nM) > AZD1152-HQPA (EC 50  = 43.4 nM) > MK-5108 (EC 50  = 309.0 nM), while the potency in the 93T449 cells was as follows: AMG 900 (EC 50  = 6.5 nM) > AZD1152-HQPA (EC 50  = 74.5 nM) > MK-5108 (EC 50  = 283.6 nM). The percentage of polyploidy after 72 h of drug treatment (0-1000 nM) was determined by propidium iodide staining and flow cytometric analysis. AMG 900 caused a significant increase in polyploidy starting at 25 nM in the SW-872 and 93T449 cells, and AZD1152-HQPA caused a significant increase starting at 100 nM in the SW-872 cells and 250 nM in the 93T449 cells. The Aurora kinase A inhibitor MK-5108 did not significantly increase the percentage of polyploid cells at any of the doses tested in either cell line. The expression of Aurora kinase A and B was evaluated in the SW-872 cells versus differentiated adipocytes and human mesenchymal stem cells by real-time RT-PCR and Western blot analysis. Aurora kinase A and B mRNA expression was significantly increased in the SW-872 cells versus the differentiated adipocytes and human mesenchymal stem cells. Western blot analysis revealed a ~ 48 kDa immunoreactive band for Aurora kinase A that was not present in the differentiated adipocytes or the human mesenchymal stem cells. A ~ 39 kDa immunoreactive band for Aurora kinase B was detected in the SW-872 cells, differentiated adipocytes, and human mesenchymal stem cells. A smaller immunoreactive band for Aurora kinase B was detected in the SW-872 cells but not in the differentiated adipocytes and human mesenchymal stem cells, and this may reflect the expression of a truncated splice variant of Aurora kinase B that has been associated with poor patient prognosis. The 93T449 cells demonstrated decreased expression of Aurora kinase A and B mRNA and protein compared to the SW-872 cells, and also expressed the truncated form of Aurora kinase B. The results of these in vitro studies indicate that Aurora kinase inhibitors should be further investigated as possible chemotherapeutic agents for human liposarcoma.

Cranioplasty remains a difficult procedure for all craniofacial surgeons, particularly when concerning the reconstruction of large lacunae in the skull. Considering the significant clinical and economic impact of the procedure, the search for materials and strategies to provide more comfortable and reliable surgical procedures is one of the most important challenges faced by modern craniofacial medicine.The purpose of this study was to compare the available data regarding the safety and clinical efficacy of materials and techniques currently used for the reconstruction of the skull. Accordingly, the scientific databases were searched for the following keywords autologous bone, biomaterials, cranial reconstruction, cranioplasty, hydroxyapatite, polyetheretherketone, polymethylmethacrylate, and titanium. This literature review emphasizes the benefits and weaknesses of each considered material commonly used for cranioplasty, especially in terms of infectious complications, fractures, and morphological outcomes.As regards the latter, this appears to be very similar among the different materials when custom three-dimensional modeling is used for implant development, suggesting that this criterion is strongly influenced by implant design. However, the overall infection rate can vary from 0% to 30%, apparently dependent on the type of material used, likely in virtue of the wide variation in their chemico-physical composition. Among the different materials used for cranioplasty implants, synthetics such as polyetheretherketone, polymethylmethacrylate, and titanium show a higher primary tear resistance, whereas hydroxyapatite and autologous bone display good biomimetic properties, although the latter has been ascribed a variable reabsorption rate of between 3% and 50%.In short, all cranioplasty procedures and materials have their advantages and disadvantages, and none of the currently available materials meet the criteria required for an ideal implant. Hence, the choice of cranioplasty materials is still essentially reliant on the surgeon's preference.

Genital chlamydial infections lead to severe upper reproductive tract pathology in a subset of untreated women. We demonstrated previously that tumor necrosis factor (TNF)-α-producing CD8(+) T cells contribute significantly to chlamydial upper genital tract pathology in female mice. In addition, we observed that minimal chlamydial oviduct pathology develops in OT-1 transgenic (OT-1) mice, wherein the CD8(+) T-cell repertoire is restricted to recognition of the ovalbumin peptide Ova(257-264), suggesting that non-Chlamydia-specific CD8(+) T cells may not be responsible for chlamydial pathogenesis. In the current study, we evaluated whether antigen-specific CD8(+) T cells mediate chlamydial pathology. Groups of wild-type (WT) C57BL/6J, OT-1 mice, and OT-1 mice replete with WT CD8(+) T cells (1 × 10(6) cells per mouse intravenously) were infected intravaginally with C. muridarum (5 × 10(4) IFU/mouse). Serum total anti-Chlamydia antibody and total splenic anti-Chlamydia interferon (IFN)-γ and TNF-α responses were comparable among the three groups of animals. However, Chlamydia-specific IFN-γ and TNF-α production from purified splenic CD8(+) T cells of OT-1 mice was minimal, whereas responses in OT-1 mice replete with WT CD8(+) T cells were comparable to those in WT animals. Vaginal chlamydial clearance was comparable between the three groups of mice. Importantly, the incidence and severity of oviduct and uterine horn pathology was significantly reduced in OT-1 mice but reverted to WT levels in OT-1 mice replete with WT CD8(+) T cells. Collectively, these results demonstrate that Chlamydia-specific CD8(+) T cells contribute significantly to upper genital tract pathology.

Objective: Iliac crest bone graft (ICBG) is considered the gold standard for spine surgical procedures to achieve a successful fusion, because of its known osteoinductive and osteoconductive properties. Considering its autogenous origin, the use of ICBG has not been associated to an increase of intraoperative or postoperative complications directly related to the surgery. However, complications related to the harvesting procedure and to the donor site morbidity have been largely reported in the literature, favoring the development of a wide range of alternative products to be used as bone graft extenders or substitutes for spine fusion. The family of ceramic-based bone grafts has been widely used and studied during the last years for spine surgical procedures in order to reduce the need for iliac crest bone grafting and the consequent morbidity associated to the harvesting procedures., Patients and Methods: We report here the results of a post-market surveillance analysis performed on four independent cohorts of patients (115 patients) to evaluate the safety of three different formulations of hydroxyapatite-derived products used as bone graft extenders/substitutes for lumbar arthrodesis., Results: No intraoperative or post-operative complications related to the use of hydroxyapatite-derived products were detected, during medium and long follow up period (minimum 12 months-maximum 5 years)., Conclusions: This post-market surveillance analysis evidenced the safety of ceramic products as bone graft extenders or substitutes for spine fusion. Moreover, the evidence of the safety of hydroxyapatite-derived products allows to perform clinical studies aimed at evaluating the fusion rates and the clinical outcomes of these materials as bone graft extenders/substitutes, in order to support their use as an alternative to ICBG for spine fusion.

Purpose: Cranioplasty is a surgical intervention aimed at reestablishing the integrity of skull defects. Autologous bone is still considered the treatment of choice for cranioplasty. The aims of this study were to characterize and evaluate the efficacy of porous hydroxyapatite (HA) to fill skull defects based on its biomimetic characteristics., Methods: The authors analyzed the postmarketing data of all patients treated with custom-made porous HA prostheses (CustomBone Service). Characterization data in terms of physicochemical analysis and mechanical performance of the porous HA prostheses were also reported., Results: The low incidence of adverse events (5.72%) due to the use of HA porous custom-made prostheses for cranioplasty is related to the biomimetic performance of the prostheses. The composition and morphology of the porosity enable it to be a useful biomimetic prosthesis for the reconstruction of large and complex skull defects, also able to promote osteointegration., Conclusions: These collected and analyzed data demonstrate that porous HA is a suitable material to produce custom-made prostheses to repair craniolacunia. It is a biomimetic implant well-tolerated in both adult and pediatric patients and has been shown to be an effective and good alternative for cranial reconstruction.

Human cytomegalovirus (HCMV) has emerged as a clinically opportunistic pathogen that targets multiple types of ocular cells and tissues, including the iris region of the uveal tract during anterior uveitis. In this report, we used primary cultures of human iris stroma (HIS) cells derived from human eye donors to investigate HCMV entry. The following lines of evidence suggested the role of 3-O-sulfated heparan sulfate (3-OS HS) during HCMV-mediated entry and cell-to-cell fusion in HIS cells. First, 3-O-sulfotransferase-3 (3-OST-3) expression in HIS cells promoted HCMV internalization, while pretreatment of HIS cells with heparinase enzyme or with anti-3-OS HS (G2) peptide significantly reduced the HCMV-mediated formation of plaques/foci. Second, coculture of the HCMV-infected HIS cells with CHO-K1 cells expressing 3-OS HS significantly enhanced cell fusion. Finally, a similar trend of enhanced fusion was observed with cells expressing HCMV glycoproteins (gB, gO, and gH-gL) cocultured with 3-OS HS cells. Taken together, these results highlight the role of 3-OS HS during HCMV plaque formation and cell-to-cell fusion and identify a novel target for future therapeutic interventions., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Although the porous hydroxyapatite (PHA) used in custom-made cranioplasty implants is a material appreciated for its biomimetic properties, before osteointegration it is initially very fragile. Nevertheless, we wondered whether this primary fragility is entirely due to brittleness or whether the surgeon's actions may influence the behavior of the material., Methods: To study the influence of the surgeon's behavior, we made a virtual model of a custom-made PHA cranioplasty implant and submitted it to three implant procedural variables using finite element methods. In the first test, a scenario in which the surgeon's design, validation, and positioning techniques are impeccable, the edges of the implant adhered well to the craniectomy margins. In the second test, a discrepancy between a portion of the perimeter of the craniectomy and the profile of the prosthesis was modeled, and in the third test, several gaps were simulated between the implant and the craniectomy margins., Results: Our mathematical model showed that when local and general discontinuities were included in the test scenarios, there was an increase in the load coming to bear on the cranioplasty implant, which amounted to 80 and 50 %, respectively., Conclusions: The fragility of custom-made PHA cranioplasty implants increases if the surgeon fails to achieve a precise design and validation, and/or an accurate surgical procedure. Nevertheless, careful attention during these phases helps to maintain the strength of the implant, given the more favorable mechanical conditions, without interfering with its biomimetic capacity.

Introduction: To optimize the functional and esthetic result of cranioplasty, it is necessary to choose appropriate materials and take steps to preserve and support tissue vitality. As far as materials are concerned, custom-made porous hydroxyapatite implants are biomimetic, and therefore, provide good biological interaction and biointegration. However, before it is fully integrated, this material has relatively low mechanical resistance. Therefore, to reduce the risk of postoperative implant fracture, it would be desirable to accelerate regeneration of the tissues around and within the graft., Objectives: The objective was to determine whether integrating growth-factor-rich platelet gel or supportive dermal matrix into hydroxyapatite implant cranioplasty can accelerate bone remodeling and promote soft tissue regeneration, respectively., Materials and Methods: The investigation was performed on cranioplasty patients fitted with hydroxyapatite cranial implants between 2004 and 2010. In 7 patients, platelet gel was applied to the bone/prosthesis interface during surgery, and in a further 5 patients, characterized by thin, hypotrophic skin coverage of the cranial lacuna, a sheet of dermal matrix was applied between the prosthesis and the overlying soft tissue. In several of the former groups, platelet gel mixed with hydroxyapatite granules was used to fill small gaps between the skull and the implant. To confirm osteointegration, cranial computed tomography (CT) scans were taken at 3-6 month intervals for 1-year, and magnetic resonance imaging (MRI) was used to confirm dermal integrity., Results: Clinical examination performed a few weeks after surgery revealed good dermal regeneration, with thicker, healthier skin, apparently with a better blood supply, which was confirmed by MRI at 3-6 months. Furthermore, at 3-6 months, CT showed good biomimetism of the porous hydroxyapatite scaffold. Locations at which platelet gel and hydroxyapatite granules were used to fill gaps between the implant and skull appeared to show more rapid integration of the implant than untreated areas. Results were stable at 1-year and remain so to date in cases where follow-up is still ongoing., Conclusions: Bone remodeling time could be reduced by platelet gel application during cranioplasty with porous hydroxyapatite implants. Likewise, layering dermal matrix over such implants appears to promote dermal tissue regeneration and the oshtemo mimetic process. Both of these strategies may, therefore, reduce the likelihood of postsurgical fracture by promoting mechanical resistance.

Ocular herpes simplex virus 1 (HSV-1) infection can lead to multiple complications, including iritis, an inflammation of the iris. Here, we use human iris stroma cells as a novel in vitro model to demonstrate HSV-1 entry and the inflammatory mediators that can damage the iris. The upregulated cytokines observed in this study provide a new understanding of the intrinsic immune mechanisms that can contribute to the onset of iritis.

Background: Cranioplasty is a surgical intervention aimed at reestablishing the integrity of skull defects, and should be considered the conclusion of a surgical act that began with bone flap removal. Autologous bone is still considered the treatment of choice for cranioplasty. An alternative choice is bioceramic porous hydroxyapatite (HA) as it is one of the materials that meets and comes closest to the biomimetic characteristics of bone., Methods: The authors analyzed the clinical charts, compiled by the neurosurgeon, of all patients treated with custom-made porous HA devices (Custom Bone Service Fin-Ceramica, Faenza) from which epidemiological and pathological data as well as material-related complications were extrapolated., Results: From November 1997 to December 2010, 1549 patients underwent cranioplasty with the implantation of 1608 custom-made porous HA devices. HA was used in 53.8% of patients for decompressive craniectomy after trauma or intracranial hemorrhage, while the remaining cases were for treated for comminuted fracture, cutaneous or osseous resection, cranial malformation, autologous bone reabsorption or infection or rejection of previously implanted material. The incidence of adverse events in patients treated for cranioplasty, as first line treatment was 4.78% (56 events/1171 patients), and 5.02%, (19 events/378 patients) at second line., Conclusion: This study demonstrates that HA is a safe and effective material, is well tolerated in both adult and pediatric patients, and meets the requirements necessary to repair craniolacunia.

Introduction: Large cranial defects still represent a challenge in neurosurgery. Currently different biomaterials are available for cranial reconstruction including titanium, acrylic mesh and different types of calcium phosphate-based bone grafts. The goal of surgery is a perfect fit of the implant without infection and absorption, and a good aesthetic result. This paper describes a surgical method for cranioplasty, using a customised porous hydroxyapatite (HA) prosthesis., Materials and Methods: Sixty patients treated surgically with a customised porous-HA prosthesis for large cranial defects, were followed retrospectively. A two-year follow-up was carried out with periodic visits and CT scans. Safety (the incidence of adverse events and fractures of the implant) and clinical performance (biological and cosmetic results) were evaluated., Results: Fifty one patients were followed-up, no rejection occurred and only one case of infection was recorded. Five patients had minor surgery-related complications, and no spontaneous implant fractures or mobilisation were reported. Three patients exhibited implant fractures as a result of trauma and all healed spontaneously. All patients showed a satisfactory clinical outcome with good cosmetic appearance in the early postoperative period and after a long-term follow-up., Conclusions: Cranioplasty performed with a customised porous-HA prosthesis gave a positive outcome, showing it to be an appropriate technique for use in large and complex cranial reconstruction., (Copyright © 2011 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Benign angiopathy of the central nervous system is a clinical syndrome with evidence of reversible cerebral vasoconstriction (RCVS). Haemorrhagic stroke, either subarachnoid or intracerebral is an unusual presentation of RCVS. We describe a case of RCVS presenting with a subarachnoid haemorrhage (SAH), with rebleeding and onset of hydrocephalus during the first week, and, notably, delayed evidence of typical angiographic features after two negative prior exams. Normalization of the angiographic vasculitic-like lesions was documented at month +6. Repeated cerebral angiograms are mandatory to exclude this kind of disease, and the uncommon presentation of this case reinforces this concept.

Aims and Background: The present study evaluated toxicity, local control, and survival in patients with relapsed high-grade glioma after surgery and external beam radiation therapy and treated with re-operation and GliaSite brachytherapy., Methods: Between 2006 and 2008, 15 patients with recurrent high-grade glioma underwent re-operation and GliaSite brachytherapy. Ten patients were males and 5 females. Median age was 40 years (range, 20-71). Karnofsky performance status was ≥70. All patients but one received GliaSite irradiation of the surgical cavity wall at the dose of 4500 cGy at a depth of 1 cm., Results: No severe acute side effects were observed during GliaSite brachytherapy. Pathologically documented, symptomatic late radiation necrosis was observed in 3 patients (20%); 2 subsequently died of further complications. Two patients were alive at a median follow-up 13 months (range, 1-30). Median overall survival after GliaSite brachytherapy was 13 months., Conclusions: Patients with recurrent high-grade glioma can be treated with additional surgery and GliaSite brachytherapy, delivering 4500 cGy at 1 cm depth without significant acute side effects but with a significant rate (20%) of late radiation necrosis, resulting in 13% of treatment-related deaths. Compared with the literature, survival results in our study appear to be satisfactory, but they may be related to patient selection criteria. Re-intervention followed by GliaSite brachytherapy should not be offered as a standard treatment for recurrent high-grade glioma, because of the high rate of late complications, treatment-related deaths, and high treatment costs.