Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

Through the orbit and beyond: Current state and future perspectives in endoscopic orbital surgery on behalf of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Introduction: Orbital surgery has always been disputed among specialists, mainly neurosurgeons, otorhinolaryngologists, maxillofacial surgeons and ophthalmologists. The orbit is a borderland between intra- and extracranial compartments; Krönlein's lateral orbitotomy and the orbitozygomatic infratemporal approach are the historical milestones of modern orbital-cranial surgery. Research question: Since its first implementation, endoscopy has significantly impacted neurosurgery, changing perspectives and approaches to the skull base. Since its first application in 2009, transorbital endoscopic surgery opened the way for new surgical scenario, previously feasible only with extensive tissue dissection. Material and methods: A PRISMA based literature search was performed to select the most relevant papers on the topic. Results: Here, we provide a narrative review on the current state and future trends in endoscopic orbital surgery. Discussion and conclusion: This manuscript is a joint effort of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Surgical management of anterior clinoidal meningiomas: consensus statement on behalf of the EANS skull base section.

BACKGROUND: The optimal management of clinoidal meningiomas (CMs) continues to be debated. METHODS: We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of these tumors. The data from the literature along with contemporary practice patterns were discussed within the task force to generate consensual recommendations. RESULTS AND CONCLUSION: This article represents the consensus opinion of the task force regarding pre-operative evaluations, patient's counselling, surgical classification, and optimal surgical strategy. Although this analysis yielded only Class B evidence and expert opinions, it should guide practitioners in the management of patients with clinoidal meningiomas and might form the basis for future clinical trials.

Petroclival meningiomas: update of current treatment and consensus by the EANS skull base section.

BACKGROUND: The optimal management of petroclival meningiomas (PCMs) continues to be debated along with several controversies that persist. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the management of these tumors. To achieve this, the task force reviewed in detail the literature in this field and had formal discussions within the group. RESULTS: The constituted task force dealt with the existing definitions and classifications, pre-operative radiological investigations, management of small and asymptomatic PCMs, radiosurgery, optimal surgical strategies, multimodal treatment, decision-making, and patient's counselling. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the management of PCMs.

Factors associated with unsuccessful return-to-work following work-related upper extremity injury.

BACKGROUND: Returning to work following occupational injury is a key outcome for both workers' compensation boards and injured workers. Predictive factors for returning remain unclear. AIMS: To describe factors associated with unsuccessful return-to-work (RTW) in a hand injury population to identify target areas through which occupational rehabilitation programmes can help injured workers achieve successful RTW outcomes. METHODS: Demographic data, functional, pain and psychosocial scores were recorded for injured workers discharged between April 2011 and September 2015 from a multidisciplinary upper extremity treatment programme. The primary outcome of RTW status was assessed at programme discharge. Bivariate analyses and multivariable logistic regression were used to identify factors associated with being unable to RTW. RESULTS: Of 872 participants who met the inclusion criteria, 65% were male and the mean age was 46 (standard deviation [SD] 11) years. In unadjusted bivariate analyses, the group with an unsuccessful RTW outcome had higher mean baseline pain, catastrophizing and QuickDASH scores; a higher baseline prevalence of depression, and reported a high level of pain more frequently than those who were working at discharge. In the adjusted logistic regression model, not working at baseline, higher QuickDASH score and presence of depression at baseline were independently associated with unsuccessful work status outcome. CONCLUSIONS: Negative baseline work status, greater self-reported functional disability and presence of depression were associated with greater odds of unsuccessful RTW following a workplace upper extremity injury. Integrating mental healthcare provision with occupational rehabilitation is a potential programmatic approach to improve RTW.

A western route of prehistoric human migration from Africa into the Iberian Peninsula.

Being at the western fringe of Europe, Iberia had a peculiar prehistory and a complex pattern of Neolithization. A few studies, all based on modern populations, reported the presence of DNA of likely African origin in this region, generally concluding it was the result of recent gene flow, probably during the Islamic period. Here, we provide evidence of much older gene flow from Africa to Iberia by sequencing whole genomes from four human remains from northern Portugal and southern Spain dated around 4000 years BP (from the Middle Neolithic to the Bronze Age). We found one of them to carry an unequivocal sub-Saharan mitogenome of most probably West or West-Central African origin, to our knowledge never reported before in prehistoric remains outside Africa. Our analyses of ancient nuclear genomes show small but significant levels of sub-Saharan African affinity in several ancient Iberian samples, which indicates that what we detected was not an occasional individual phenomenon, but an admixture event recognizable at the population level. We interpret this result as evidence of an early migration process from Africa into the Iberian Peninsula through a western route, possibly across the Strait of Gibraltar.

Preoperative platelet transfusions to reverse antiplatelet therapy for urgent non-cardiac surgery: an observational cohort study.

Essentials An increasing number of patients requiring surgery receive antiplatelet therapy (APT). We analyzed 181 patients receiving presurgery platelet transfusions to reverse APT. No coronary thrombosis occurred after platelet transfusion. This justifies a prospective trial to test preoperative platelet transfusions to reverse APT. SUMMARY: Background Patients receiving antiplatelet therapy (APT) have an increased risk of perioperative bleeding and cardiac adverse events (CAE). Preoperative platelet transfusions may reduce the bleeding risk but may also increase the risk of CAE, particularly coronary thrombosis in patients after recent stent implantation. Objectives To analyze the incidence of perioperative CAE and bleeding in patients undergoing non-cardiac surgery using a standardized management of transfusing two platelet concentrates preoperatively and restart of APT within 24-72 h after surgery. Methods A cohort of consecutive patients on APT treated with two platelet concentrates before non-cardiac surgery between January 2012 and December 2014 was retrospectively identified. Patients were stratified by the risk of major adverse cardiac and cerebrovascular events (MACCE). The primary objective was the incidence of CAE (myocardial infarction, acute heart failure and cardiac troponine T increase). Secondary objectives were incidences of other thromboembolic events, bleedings, transfusions and mortality. Results Among 181 patients, 88 received aspirin, 21 clopidogrel and 72 dual APT. MACCE risk was high in 63, moderate in 103 and low in 15 patients; 67 had cardiac stents. Ten patients (5.5%; 95% CI, 3.0-9.9%) developed a CAE (three myocardial infarctions, four cardiac failures and three troponin T increases). None was caused by coronary thrombosis. Surgery-related bleeding occurred in 22 patients (12.2%; 95% CI, 8.2-17.7%), making 12 re-interventions necessary (6.6%; 95% CI, 3.8-11.2%). Conclusion Preoperative platelet transfusions and early restart of APT allowed urgent surgery and did not cause coronary thromboses, but non-thrombotic CAEs and re-bleeding occurred. Randomized trials are warranted to test platelet transfusion against other management strategies.

Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis.

Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R-/- mice had lower symptom scores, neutrophil-recruitment mediators (colonic interleukin-6 (IL-6), CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient KitW-sh/W-sh mice reconstituted with histidine decarboxylase-deficient (HDC-/-) bone marrow-derived MCs compared with WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2-/- × H4R-/- mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2-/- mice, revealing an innate protective antibacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.

Endoscopic Third Ventriculostomy before Posterior Fossa Tumor Surgery in Adult Patients.

OBJECTIVE: Obstructive hydrocephalus in patients with posterior fossa tumors is frequently seen. Treatment options include immediate tumor removal or prior cerebrospinal fluid (CSF) diversion procedures. The necessity and feasibility of an ETV in these situations has not yet been proven in adult patients. METHODS: We retrospectively reviewed our prospectively maintained database for ETVs before surgery of posterior fossa tumors in adults. The primary focus of data analyses was the question of whether the ETV was suitable to treat the acute situation of hydrocephalus without an increased rate of complications due to the special anatomical situation with a posterior fossa tumor. We also analyzed whether any further CSF diverting procedures were necessary. RESULTS: A total of 40 adult patients who underwent an ETV before posterior fossa tumor surgery were analyzed. Overall, 33 patients (82.5%) had clinical signs of hydrocephalus, and all of them improved in their clinical course after ETV. Seven patients (17.5%) did not demonstrate clinical signs of hydrocephalus, but ETV was performed with prophylactic or palliative intent in six patients and one patient, respectively. No complications were observed due to ETV itself. No permanent shunting procedure was necessary in a mean follow-up of 76.5 months. Early additional CSF diverting procedures (redo ETV, external ventricular drain) were performed in five patients (12.5%). CONCLUSION: The present series confirms the feasibility and safety of ETV before posterior fossa tumor surgery in adult patients. If patients had symptomatic hydrocephalus before tumor surgery, an ETV can be performed, followed by early elective tumor surgery. A prophylactic ETV in asymptomatic patients is not advised. Early elective tumor surgery should be performed in these patients.

The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice.

Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.

A Pilot Study of Femoropopliteal Artery Revascularisation with a Low Dose Paclitaxel Coated Balloon: Is Predilatation Necessary?

OBJECTIVE/BACKGROUND: The objective was to compare 2 year outcomes in patients treated with or without predilatation prior to drug coated balloon (DCB) angioplasty for symptomatic femoropopliteal lesions. METHODS: This prospective multicentre pilot study was conducted at three sites in Germany. It compared claudicants undergoing predilatation with a bare percutaneous transluminal angioplasty (PTA) balloon before DCB (predilatation group) with patients undergoing direct DCB (direct DCB group). Patients were followed for 2 years. Outcomes included late lumen loss at 6 months, and ankle brachial index (ABI), major adverse events, and primary patency at 2 years. A Clinical Events Committee and core laboratories analysed adverse events and angiographic/duplex images, respectively. RESULTS: Between December 2011 and November 2012, 50 patients were enrolled to the predilatation group (12% total occlusions) and 28 to the direct DCB group (5% total occlusions). Follow-up compliance at the 2 year visit was 88% (n = 44) and 86% (n = 24), respectively. Late lumen loss at 6 months was lower in the direct DCB group (0.03 ± 0.68 mm vs. 0.54 ± 0.97 mm; p = .01). Major adverse events over 2 years occurred in seven (15%) patients who underwent predilatation and in five (19%) after direct DCB. Mean ABI at 2 years was 0.94 ± 0.15 after predilatation and 1.0 ± 0.12 after direct DCB. Over 2 years, primary patency (80.3% vs. 78.2%; p = .55) was not statistically different between the groups. After propensity score adjustments, 2 year findings remained unchanged. CONCLUSION: Paclitaxel coated PTA, with or without bare predilatation, is effective over 2 years in symptomatic patients with femoropopliteal stenotic lesions. Adequately powered randomised controlled comparisons are required to confirm these preliminary results.

Platelet transfusion to reverse antiplatelet therapy before decompressive surgery in patients with intracranial haemorrhage.

BACKGROUND: Platelet concentrates (PC) are transfused to improve primary haemostasis before urgent neurosurgery in patients with intracranial haemorrhage (ICH) receiving antiplatelet therapy (APT). It is unresolved, whether PCs increase the risk for major cardio- and cerebrovascular adverse events. We evaluated a standardized transfusion regimen to reverse APT in patients with ICH who required decompressive neurosurgery. METHODS: Analysed were consecutive patients between 2012 and 2014. The primary outcome was the frequency of new arterial thrombotic complications. The secondary outcome was the frequency of recurrent ICH. RESULTS: Of 72 patients, 14 received acetylsalicylic acid and a P2Y12 inhibitor, 53 received acetylsalicylic acid and five clopidogrel. No acute coronary syndrome (95% CI: 0-5·07) and one ischaemic stroke occurred (1·4%; 95% CI: 0·25-7·46). In contrast, 26·4% of patients developed recurrent ICH (95% CI: 17·59-37·58). The risk of bleeding was significantly higher compared to the risk of arterial thrombosis (P < 0·00001) and was increased for patients with chronic ICH (OR: 4·78; 95% CI: 1·57-14·55) and those receiving clopidogrel (OR: 2·78; 95% CI: 0·90-8·57). CONCLUSION: Platelet concentrate transfusion before cranial decompressive surgery in patients with ICH complicating APT showed a low risk for cardio-cerebral thrombotic complications. However, the risk of rebleeding remains high, especially in patients with chronic ICH and those pretreated with clopidogrel.

Clinical and morphological aspects of adenocarcinomas of the intestinal type in the inner nose: a retrospective multicenter analysis.

Clinical and histological parameters from 117 patients with wood dust-related sinonasal adenocarcinomas of intestinal type (ITAC) were analyzed and correlated with a follow-up period of 5 years at least. The rate of survival for 5 years was 53.1 % and for 10 years 30.2 %. Only 33 patients were free of disease. 74.2 % of patients with recurrences died in relation to ITAC. As expected, tumors of T4-category had the worst prognosis. The mucus content of a tumor was the most important histological parameter. Endonasal methods of surgery had no more positive survival rates after 5 years. An effect of radiotherapy has to be in discussion. The high incidence of tumor recurrences requires control examinations consistently.

Endoscopic Biopsy for Intra- and Paraventricular Tumors: Rates of Complications, Mortality, and Tumor Cell Dissemination.

BACKGROUND AND STUDY AIM: Intra- and paraventricular tumors are frequently associated with cerebrospinal fluid (CSF) pathway obstruction. Thus the aim of an endoscopic approach is to restore patency of the CSF pathways and to obtain a tumor biopsy. Because endoscopic tumor biopsy may increase tumor cell dissemination, this study sought to evaluate this risk. PATIENTS, MATERIALS, AND METHODS: Forty-four patients who underwent endoscopic biopsies for ventricular or paraventricular tumors between 1993 and 2011 were included in the study. Charts and images were reviewed retrospectively to evaluate rates of adverse events, mortality, and tumor cell dissemination. Adverse events, mortality, and tumor cell dissemination were evaluated. RESULTS: Postoperative clinical condition improved in 63.0% of patients, remained stable in 30.4%, and worsened in 6.6%. One patient (2.2%) had a postoperative thalamic stroke leading to hemiparesis and hemineglect. No procedure-related deaths occurred. Postoperative tumor cell dissemination was observed in 14.3% of patients available for follow-up. CONCLUSIONS: For patients presenting with occlusive hydrocephalus due to tumors in or adjacent to the ventricular system, endoscopic CSF diversion is the procedure of first choice. Tumor biopsy in the current study did not affect safety or efficacy.

Metastatic behaviour of sinonasal adenocarcinomas of the intestinal type (ITAC).

The relative frequency of regional lymphogenic versus distant hematogenic metastases was evaluated in 369 patients with sinonasal adenocarcinoma of the intestinal type (ITAC). We assessed the results of neck dissections for a limited number of patients undergoing this surgical intervention. 117 ITAC patients were followed up for at least 5 years. Neck dissections were performed in 18 cases (15 primary and 3 secondary operations), 4 of which revealed carcinoma-positive lymph nodes. Metastases in lymph nodes were also diagnosed clinically in three other patients adding up to a total of seven individuals (6 % of 117) with lymphogenic metastases. In comparison, distant hematogenic metastases were identified in 15.4 % of these 117 patients. In the second group of 252 patients, the occurrence of distant hematogenic metastases and colorectal adenocarcinomas was registered but no formal follow-up procedure was applied. 50 neck dissections were performed in this group, 46 of which exhibited no histological evidence for metastases in lymph nodes, while in 1 case they were carcinoma-positive. Three additional cases showed clinical signs of metastases in regional lymph nodes. Taken together, our observations indicate that regional lymphogenic metastases are rather rare (about 2 %) in patients with sinonasal adenocarcinoma of the intestinal type. Therefore, the surgery of neck dissection appears not advised as routine intervention in these cases. ITAC patients show a normal prevalence of colorectal adenocarcinomas.

Use of digital images to aid in the decision-making for acute upper extremity trauma referral.

UNLABELLED: This study evaluated the use of digital smartphone images in the decision-making for acute upper extremity trauma referrals. Surgeons (n = 15) were presented with ten upper limb trauma scenarios for consideration of immediate transfer. Based on verbal history and with additional images, participants were asked questions regarding diagnosis, injured tissues, recommended management and diagnostic and treatment confidence. Statistical analyses evaluated confidence level changes and relationships between confidence levels and independent variables. Confidence levels for diagnosis and treatment were increased with the provision of smartphone images, and this was statistically significant. The decision to transfer was changed in 22%. The photographs were more useful for amputation versus non-amputation injuries (diagnosis and treatment) and hand versus forearm injuries (diagnosis), and these differences reached statistical significance. Smartphone digital images were shown to be useful for decision-making in acute upper extremity trauma referrals. This improved communication may have implications for health cost savings and patient burden by minimizing unnecessary acute transfers. LEVEL OF EVIDENCE: Diagnostic Level III.

[BREAST CANCER: FROM TARGETED THERAPY TO PRECISION MEDICINE]. / CANCER DU SEIN : DE LA THÉRAPIE CIBLÉE À LA MÉDECINE PERSONNALISÉE.

The authors review the principles of systemic therapy in breast cancer. They analyze the degree of treatment individualization in our current approach. New technologies allow the detection of genomic alterations in cancer cells. Unfortunately, we do not know yet how to best use this knowledge for routine patient care. Most genomic alterations are rare events complicating further drug development. Temporal and spatial heterogeneity in tumors also has to be taken into account. An intense international collaboration is ongoing to try and demonstrate that precision medicine will really improve treatment outcome.