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A characteristic surface structure is observed on the samples prepared by plasma polymerization of n-hexane and n-heptane microwave discharge. This typical structure depends on the deposition conditions. The interpretation of the structural changes was based on the nature of the plasma polymer, one result of which is the frost effect that we observed. [ABSTRACT FROM AUTHOR]

A DC planar electromagnetron in an unbalanced mode has been used for the deposition of hydrogenated amorphous carbon (a-C:H) films using butane/argon mixture as a working gas. We have studied the electrical conductivity of these samples without breaking vacuum and also in the air. The film absorbance in the visible region was also measured. The relations between the deposition processes, the film microstructure and resulting film properties (especially optical and electrical) are discussed. [ABSTRACT FROM AUTHOR]

Phosphotyrosine (pTyr) recognition coordinates the assembly of protein complexes, thus controlling key events of cell cycle, cell development and programmed cell death. Although many aspects of membrane receptor function and intracellular signal transduction have been deciphered in the last decades, the details of how phosphorylation alters protein-protein interaction and creates regulating switches of protein activity and localization often remains unclear. We developed a synthetic route to a protected phophotyrosine building block with isolated 13 C- 1 H spins in the aromatic ring. The compound can be used for solid phase peptide synthesis (SPPS) and readily applied to study affinity, dynamics and interactions on an atomic level using NMR spectroscopy. As a first example, we prepared an isotopologue of a pTyr containing 12mer peptide (pY1021) as part of the platelet-derived growth factor to analyze the binding to the phospholipase C-γ (PLCγ-1) SH2 domain., (© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

Side chain isotope labelling is a powerful tool to study protein structure and interactions by NMR spectroscopy. 1 H, 13 C labelling of side-chain methyl groups in a deuterated background allows studying large molecules, while side-chain aromatic groups are highly sensitive to the interaction with ligands, drugs, and other proteins. In E. coli, side chain labelling is performed by substituting amino acids with isotope-labelled precursors. However, proteins that can only be produced in mammalian cells require expensive isotope-labelled amino acids. Here we provide a simple and cost-effective method to label side chains in mammalian cells, which exploits the reversible reaction catalyzed by endogenous transaminases to convert isotope-labelled α-ketoacid precursors. We show by in-cell and in-lysate NMR spectroscopy that replacing an amino acid in the medium with its cognate precursor is sufficient to achieve selective labelling without scrambling, and how this approach allows monitoring conformational changes such as those arising from ligand binding., (© 2024. The Author(s).)

Background: Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease., Methods: We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models., Results: TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced., Conclusion: TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting., (© 2024. The Author(s).)

Background:  Ventriculostomy (VST) is a frequent neurosurgical procedure. Freehand catheter placement represents the standard current practice. However, multiple attempts are often required. We present augmented reality (AR) headset guided VST with in-house developed head models. We conducted a proof of concept study in which we tested AR-guided as well as freehand VST. Repeated AR punctures were conducted to investigate if a learning curve can be derived., Methods:  Five custom-made 3D-printed head models, each holding an anatomically different ventricular system, were filled with agarose gel. Eleven surgeons placed two AR-guided as well as two freehand ventricular drains per head. A subgroup of four surgeons did a total of three series of AR-guided punctures each to test for a learning curve. A Microsoft HoloLens served as the hardware platform. The marker-based tracking did not require rigid head fixation. Catheter tip position was evaluated in computed tomography scans., Results:  Marker-tracking, image segmentation, and holographic display worked satisfactorily. In freehand VST, a success rate of 72.7% was achieved, which was higher than under AR guidance (68.2%, difference not statistically significant). Repeated AR-guided punctures increased the success rate from 65 to 95%. We assume a steep learning curve as repeated AR-guided punctures led to an increase in successful attempts. Overall user experience showed positive feedback., Conclusions:  We achieved promising results that encourage the continued development and technical improvement. However, several more developmental steps have to be taken before an application in humans can be considered. In the future, AR headset-based holograms have the potential to serve as a compact navigational help inside and outside the operating room., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: A new-onset adrenocortical insufficiency (NAI) is the most critical postoperative endocrinological complication after transsphenoidal surgery for macroadenomas. Because of increased mortality risk, arginine vasopressin deficiency (AVP-D) is also a relevant postoperative complication. This study aimed to identify easy-to-acquire magnet resonance imaging (MRI) aspects of the pituitary stalk to predict these insufficiencies after transsphenoidal surgery., Methods: Pituitary stalk morphology was reviewed intraoperatively and three months postoperatively in the MRIs of 48 transsphenoidal surgeries for macroadenomas. NAI was validated in endocrinological follow-up controls 10-14 months post-surgery., Results: Intraoperative pituitary stalk diameters were 0.5 mm larger in patients who developed NAI and AVP-D. The odds ratio was 29 for NAI and 6 for AVP-D in binary regression analysis. A value of 2.9 mm was identified as the optimal cut-off for the minimal pituitary stalk diameter regarding NAI, with a high specificity of 89%. There was no difference in pituitary stalk diameter regarding these insufficiencies three months post-surgery., Conclusions: We identified an increased pituitary stalk diameter in intraoperative MRIs as a predictive factor of NAI and AVP-D after transsphenoidal surgery. These findings might improve the early detection of NAI and, thus, optimal management. However, validating these retrospective findings in prospective studies is obligatory.

Background: More than 2 billion peripheral vascular cannulas are introduced globally each year. It is the most frequently performed invasive procedure in medicine worldwide. There is a group of patients with difficult intravenous access (DIVA). In experts' hands, ultrasound-guided vascular access appears to be a significantly better method. Investigators hypothesize that UGVA is superior also in short-term patency of cannula and even for blood draw through cannula. Repeated cannula pricks in the operating room setting not only puts a lot of stress on the patient and medical staff, but they also waste OR time., Methods: This investigator-initiated prospective randomized monocentric controlled trial is designed to randomly allocate 200 patients undergoing elective primary total joint arthroplasty of hip or knee to one of two groups as follows: Group C (control group) - peripheral venous cannula insertion by palpation or Group USG (intervention) - cannula insertion by ultrasound-guided vascular access. Our primary endpoint is to compare the number of attempts for ultrasound-guided insertion of the peripheral venous cannula with common palpation insertion of the peripheral venous cannula in overweight/obese patients (BMI ≥ 25). The secondary endpoint is a failure rate of the peripheral venous cannula to administer intravenous therapy up to 5 days postoperatively. Tertiary endpoints include a portion of long PVCs that are able to ensure blood draw up to 5 days postoperatively, time needed to insert PVC in each group, number of needle tip redirections in both groups, and reinsertion of PVC needed in both groups for any reason., Discussion: This study is pragmatic and is looking for clinically relevant data. After completion, it will answer the question of whether it is clinically relevant to use ultrasound-guided vascular access in the context of not only short-term benefit of insertion, but also up to 5 days after insertion. Also, if this method can ensure blood draw through a peripheral vein cannula, it can save resources in the perioperative period - valuable especially considering the ongoing shortage of medical staff worldwide. If this hypothesis is confirmed, this finding could contribute to more widespread implementation of ultrasound-guided peripheral vascular access in the perioperative period., Trial Registration: ClinicalTrials.gov NCT05156008. Registered on 13.12.2021., (© 2023. The Author(s).)

The surgical treatment of recurrent adenomas can be challenging. Intraoperative magnetic resonance imaging (iMRI) can improve the orientation and increase the safe extent of resection. We conducted a quantitative and qualitative retrospective analysis of recurrent adenomas treated by endoscopic or microscopic iMRI-assisted transsphenoidal surgery. A total number of 59 resections were selected. Detailed volumetric measurements, tumor characteristics, and MRI features of intraoperative remnants were evaluated. Intraoperative MRI increased the gross total resection (GTR) rate from 33.9% to 49.2%. Common locations of tumor remnants after iMRI were the clivus, the wall of the cavernous sinus or the perforation of the diaphragm. Increasing tumor volume and the microscopic technique were significantly associated with further resection after iMRI in the univariate analysis ( p = 0.004, OR 1.6; p = 0.009, OR 4.4). Only the increasing tumor volume was an independent predictor for further resection ( p = 0.007, OR 1.5). A significantly higher proportion of GTRs was achieved with the endoscopic technique ( p = 0.001). Patients with a large recurrent pituitary adenoma who underwent microscopic transsphenoidal resection were the most likely to benefit from iMRI regarding the extent of resection. Occult invasions of the cavernous sinus and/or the clivus were the most common findings leading to further resection of tumor remnants after iMRI.

Objective: Despite evidence of a relationship among obstructive sleep apnea (OSA), metabolic dysregulation, and diabetes, it is uncertain whether OSA treatment can improve metabolic parameters. We sought to determine effects of long-term continuous positive airway pressure (CPAP) treatment on glycemic control and diabetes risk in patients with cardiovascular disease (CVD) and OSA., Research Design and Methods: Blood, medical history, and personal data were collected in a substudy of 888 participants in the Sleep Apnea cardioVascular Endpoints (SAVE) trial in which patients with OSA and stable CVD were randomized to receive CPAP plus usual care, or usual care alone. Serum glucose and glycated hemoglobin A 1c (HbA 1c ) were measured at baseline, 6 months, and 2 and 4 years and incident diabetes diagnoses recorded., Results: Median follow-up was 4.3 years. In those with preexisting diabetes ( n = 274), there was no significant difference between the CPAP and usual care groups in serum glucose, HbA 1c , or antidiabetic medications during follow-up. There were also no significant between-group differences in participants with prediabetes ( n = 452) or new diagnoses of diabetes. Interaction testing suggested that women with diabetes did poorly in the usual care group, while their counterparts on CPAP therapy remained stable., Conclusions: Among patients with established CVD and OSA, we found no evidence that CPAP therapy over several years affects glycemic control in those with diabetes or prediabetes or diabetes risk over standard-of-care treatment. The potential differential effect according to sex deserves further investigation., (© 2020 by the American Diabetes Association.)

Aim: Obtain an overview of the current sleep habits and sleep hygiene practices in a group of intermediate-aged students, and establish whether these students achieve adequate sleep according to the New Zealand education and health guidelines., Methods: A standardised sleep health questionnaire and seven-day sleep diary were completed by 163 participants (aged 11-13; 62% female) from a cross-section of five Christchurch schools., Results: In this group, 71% of students reported 9-11 hours of sleep per night (averaged over seven days). Total sleep time was independent of gender and the day of the week. Bedtimes and wake-times were earlier from Monday-Thursday compared to the weekend (p<0.0001). Fifty-nine percent of students used a device in the hour before bed. Pre-bedtime device users were more likely to achieve less sleep than non-device users (p<0.001). The majority of students (66%) did not choose their bedtime., Conclusions: In this group of students, the majority achieved a sleep duration within the advised Ministry of Education and Sleep Health Foundation guidelines, despite non-recommended sleep hygiene practices in the pre-bed routine. Parental guidance, with respect to bed times and reduction in device usage before sleep are two factors that could be employed to improve sleep in this group., Competing Interests: Nil.

Background: Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma., Methods: Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM)., Results: ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM., Conclusion: Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.

Aim To investigate risk factors for the development of prosthetic joint infection. Methods A group of 50 patients with periprosthetic infection was compared with a group of 100 randomly selected patients with total hip or knee arthroplasty without infectious complications. Twelve risk factors in both groups were analysed. Results Five factors showed to be significant: body mass index higher than 40, diabetes mellitus on insulin therapy, kidney and liver disease, vascular disease of the lower extremities and positive drain tip culture. Conclusion One of the ways to reduce the incidence of periprosthetic infection is the maximum possible elimination of risk factors in patients who have a high probability of endoprosthesis infection. If this elimination is not possible for a long time, it is advisable to consider abandoning the planned operation., (Copyright© by the Medical Assotiation of Zenica-Doboj Canton.)

Background and Purpose: Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti-cancer activity. In this study, we examined whether inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma., Experimental Approach: We applied 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays to assess cellular proliferation. Annexin V/propidium iodide and tetramethylrhodamine, ethyl ester staining were used to examine apoptosis. Western blotting, RT-PCR, and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action., Key Results: Bcl-2/Bcl-xL inhibition exerted synergistic anti-proliferative effects across established, primary cultured, and stem-like glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its proposed original concentration (CUSP9-LD). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9-LD counteracted ABT263-mediated up-regulation of Mcl-1. Silencing of Mcl-1 enhanced ABT263-mediated apoptosis which indicates that down-regulation of Mcl-1 is crucial for the induction of cell death by the combination treatment., Conclusion and Implications: These data suggest that Bcl-2/Bcl-xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl-2/Bcl-xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP., (© 2019 The British Pharmacological Society.)

Purpose: Anti-apoptotic and pro-migratory phenotypes are hallmarks of neoplastic diseases, including primary brain malignancies. In this work, we examined whether reprogramming of the apoptotic and migratory machineries through a multi-targeting approach would induce enhanced cell death and enhanced inhibition of the migratory capacity of glioblastoma cells., Methods: Preclinical testing and molecular analyses of combined inhibition of Bcl-2/Bcl-xL and RAC1 were performed in established, primary cultured and stem-like glioblastoma cell systems., Results: We found that the combined inhibition of Bcl-2/Bcl-xL and RAC1 resulted in synergistic pro-apoptotic and anti-migratory effects in a broad range of different glioblastoma cells. At the molecular level, we found that RAC1 inhibition led to a decreased expression of the deubiquitinase Usp9X, followed by a decreased stability of Mcl-1. We also found that the combined inhibition led to a significantly decreased migratory activity and that tumor formation of glioblastoma cells on chorion allantoic membranes of chicken embryos was markedly impaired following the combined inhibition., Conclusions: Our data indicate that concomitant inhibition of RAC1 and Bcl-2/Bcl-xL induces pro-apoptotic and anti-migratory glioblastoma phenotypes as well as synergistic anti-neoplastic activities. The clinical efficacy of this inhibitory therapeutic strategy warrants further evaluation.

Background: Although recent evidence suggests that OSA treatment may cause weight gain, the long-term effects of CPAP on weight are not well established., Methods: This study was a post hoc analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) study, a multicenter, randomized trial of CPAP plus standard care vs standard care alone in adults with a history of cardiac or cerebrovascular events and moderate to severe OSA. Participants with weight, BMI, and neck and waist circumferences measured at baseline and during follow-up were included. Linear mixed models were used to examine sex-specific temporal differences, and a sensitivity analysis compared high CPAP adherers (≥ 4 h per night) with propensity-matched control participants., Results: A total of 2,483 adults (1,248 in the CPAP group and 1,235 in the control group) were included (mean 6.1 ± 1.5 measures of weight available). After a mean follow-up of 3.78 years, there was no difference in weight change between the CPAP and control groups, for male subjects (mean [95% CI] between-group difference, 0.07 kg [-0.40 to 0.54]; P = .773) or female subjects (mean [95% CI] between-group difference, -0.14 kg [-0.37 to 0.09]; P = .233). Similarly, there were no significant differences in BMI or other anthropometric measures. Although male participants who used CPAP ≥ 4 h per night gained slightly more weight than matched male control subjects without CPAP (mean difference, 0.38 kg [95% CI, 0.04 to 0.73]; P = .031), there were no between-group differences in other anthropometric variables, nor were there any differences between female high CPAP adherers and matched control subjects., Conclusions: Long-term CPAP use in patients with comorbid OSA and cardiovascular disease does not result in clinically significant weight change., Trial Registry: ClinicalTrials.gov; No.: NCT00738179; URL: www.clinicaltrials.gov., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

OBJECTIVEThe gold standard for evaluation of ventriculoperitoneal (VP) shunt position, dislocation, or disconnection is conventional radiography. Yet, assessment with this modality can be challenging because of low image quality and can result in repetitive radiation exposure with high fluctuation in the radiation dose. Recently, CT-based radiation doses have been significantly reduced by using low-dose protocols. Thus, whole-body low-dose CT (LDCT) has become applicable for routine use in VP shunt evaluation. The authors here compared image quality and approximate radiation dose between radiography and LDCT in patients with implanted VP shunt systems.METHODSVentriculoperitoneal shunt systems have been investigated with LDCT scanning at the authors' department since 2015. A consecutive series of 57 patients (70 investigations) treated between 2015 and 2016 was retrospectively assessed. A historical patient cohort that had been evaluated with radiography was compared with the LDCT patients in terms of radiation dose and image quality. Three independent observers evaluated projection of the valve pressure level and correct intraperitoneal position, as well as complete shunt projection, using a Likert-type scale of 1-5, where 1 indicated "not assessable" and 5 meant "assessable with high accuracy." Descriptive statistics and the Mann-Whitney U-test were used for analysis.RESULTSTwenty-seven radiographs (38.6%) and 43 LDCT scans (61.4%) were analyzed. The median dose-length product (DLP) of the LDCT scans was 100 mGy·cm (range 59.9-183 mGy·cm). The median total dose-area product (DAP) of the radiographic images was 3177 mGy·cm2 (range 641-13,833 mGy·cm2). The estimated effective dose (EED) was significantly lower with the LDCT scan (p < 0.001). The median EED was 4.93 and 1.90 mSv for radiographs and LDCT, respectively. Significantly better identification of the abdominal position of the distal shunt catheter was achieved with LDCT (p < 0.001). Simultaneously, significantly improved visualization of the entire shunt system was realized with this technique (p < 0.001). On the contrary, identification of the valve settings was significantly worse with LDCT (p < 0.001).CONCLUSIONSWhole-body LDCT scanning allows good visualization of the distal catheter after VP shunt placement. Despite the fact that only a rough estimation of effective doses is possible in a direct comparison of LDCT and radiography, the data showed that shunt assessment via LDCT does not lead to greater radiation exposure. Thus, especially in difficult anatomical conditions, as in patients who have undergone multiple intraabdominal surgeries, have a high BMI, or are immobile, the use of LDCT shunt evaluation has high clinical value. Further data are needed to determine the value of LDCT for the evaluation of complications or radiation dose in pediatric patients.

Objectives: At present, there is no standard therapy approved for recurrent glioblastoma (rGB). In particular, the counselling of patients with an unmethylated O 6 -methylguanine-DNA methyltransferase (MGMT) promoter GB remains a challenge. Our aim was to compare the overall survival (OS) and progression free survival (PFS) in patients treated surgically and non-surgically at the time of GB recurrence. This was evaluated with particular reference to the impact of recurrent surgery for patients with unmethylated MGMT promoter rGB., Patients and Methods: The clinical and radiological data from 127 consecutive cases of rGB was retrospectively identified and evaluated. The PFS and OS from cohorts of surgically and non-surgically treated patients at time of GB recurrence were compared using Kaplan Meier estimations and Log-Rank tests. Multivariate Cox regression analysis included the major influencing variables (surgical resection, MGMT promoter methylation status, Karnofsky performance scale (KPS), age, eloquent tumor location) to analyze the survival benefit. Subgroup analysis of cases depending on the MGMT promoter methylation status was performed., Results: Multiple Cox regression analysis revealed inferior OS (p = 0.029, OR = 1.731, CI 95% 1.059-2.829) of patients treated non-surgically (14 vs. 31 months). MGMT promoter methylation and age were related to longer OS (p < 0.001, OR 2.683, CI 95% 1.631-4.414 and p = 0.009, OR = 1.029, CI95% 1.007-0.052 respectively). Gross total resection (GTR) in comparison to subtotal resection (STR) lead to a median OS of 39 months vs. 22 months and a PFS of seven vs. four months respectively. In the subgroup of cases with unmethylated MGMT promoter rGB, those who underwent GTR survived significantly longer (OS: 31 months) than patients who underwent STR (OS: 15 months, p = 0.024). PFS was six vs. four months after GTR and STR respectively., Conclusion: Surgical management for recurrent glioblastoma appears to be a safe procedure which results in longer OS in comparison to non-surgical management. GTR may be of particular benefit to patients with unmethylated MGMT promoter rGB., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale: Obstructive sleep apnea (OSA) is associated with impaired renal function, but uncertainty exists over whether OSA treatment can influence renal outcomes., Objectives: To determine the effects of continuous positive airway pressure (CPAP) on renal function in subjects with coexisting OSA and cardiovascular disease., Methods: This was a substudy of the international SAVE (Sleep Apnea Cardiovascular Endpoints) trial, in which 2,717 patients with moderate to severe OSA and established coronary or cerebrovascular disease were randomized to receive either CPAP plus usual care or usual care alone. Renal function and adverse renal events were compared between the CPAP (n = 102) and usual care (n = 98) groups. Glomerular filtration rate was estimated at randomization and at the end of follow-up, and the urinary albumin-to-creatinine ratio was measured at study exit., Measurements and Main Results: In 200 substudy participants (mean age, 64 yr; median, 4% oxygen desaturation index; 20 events/h; mean estimated glomerular filtration rate at baseline, 82 ml/min/1.73 m 2 ), the median (interquartile range) changes in estimated glomerular filtration rate (ml/min/1.73 m 2 /yr) were -1.64 (-3.45 to -0.740) in the CPAP group and -2.30 (-4.53 to -0.71) in the usual care group (P = 0.21) after a median of 4.4 years. There were no between-group differences in end-of-study urinary albumin-to-creatinine ratio or in the occurrence of serious renal or urinary adverse events during the trial. The level of CPAP adherence did not influence the findings., Conclusions: CPAP treatment of OSA in patients with cardiovascular disease does not alter renal function or the occurrence of renal adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT00738179).

Background: Glioblastoma multiforme (GBM), a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM., Methods: Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively., Results: Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA) and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival., Conclusions: Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention.

Background: The presence of residual tumor is crucial in decision-making for low-grade gliomas (LGGs), because patients older than 40 years of age with residual tumor are considered for adjuvant treatment. There are hints that early postoperative fluid-attenuated inversion recovery (FLAIR) and T2 (within 48 hours) may overestimate residual tumor volume in LGG. Intraoperative magnetic resonance imaging (MRI) without subsequent resection or ultra-early postoperative MRI may assess the amount of residual tumor more adequately. To evaluate the utility of postoperative imaging in LGG, we volumetrically analyzed intraoperative, early, and late (3-4 months after surgery) postoperative MRIs of LGGs., Patients and Methods: A total of 33 patients with LGG were assessed retrospectively. Residual tumor was defined as signal-enhanced tissue in T2 and FLAIR. Volumetric assessment was performed with intraoperative, early, and late postoperative T2/FLAIR via Brainlab-iPlan 3.0. Wilcoxon and χ(2) tests were used for statistical analysis., Results: A significant difference of FLAIR/T2 abnormalities was found in intraoperative and early postoperative MRIs (FLAIR mean volume = 5.433 cm(3), T2 mean volume = 3.374 cm(3) vs. FLAIR mean volume = 14.090 cm(3), P = 0.002, T2 mean volume = 7.597 cm(3), P = 0.006). There was no significant difference between intraoperative and late postoperative FLAIR/T2 abnormalities (late postoperative FLAIR/T2 mean volume = 5.560 cm(3) and 2.370 cm(3), P = 0.520, P = 0.398), whereas a significant difference was detected between early and late postoperative images (FLAIR, P < 0.0001; T2, P < 0.00001)., Conclusion: Intraoperative MRI without further resection or ultra-early postoperative MRI seems to reflect the actual volume of residual tumor in LGG more precisely compared with early postoperative MRI and therefore seems to be more useful regarding decisions for adjuvant therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Study Objectives: To investigate gray matter volume and concentration and cerebral perfusion in people with untreated obstructive sleep apnea (OSA) while awake., Design: Voxel-based morphometry to quantify gray matter concentration and volume. Arterial spin labeling perfusion imaging to quantify cerebral perfusion., Setting: Lying supine in a 3-T magnetic resonance imaging scanner in the early afternoon., Participants: 19 people with OSA (6 females, 13 males; mean age 56.7 y, range 41-70; mean AHI 18.5, range 5.2-52.8) and 19 controls (13 females, 6 males; mean age: 50.0 y, range 41-81)., Interventions: N/A., Measurements and Results: There were no differences in regional gray matter concentration or volume between participants with OSA and controls. Neither was there any difference in regional perfusion between controls and people with mild OSA (n = 11). However, compared to controls, participants with moderate-severe OSA (n = 8) had decreased perfusion (while awake) in three clusters. The largest cluster incorporated, bilaterally, the paracingulate gyrus, anterior cingulate gyrus, and subcallosal cortex, and the left putamen and left frontal orbital cortex. The second cluster was right-lateralized, incorporating the posterior temporal fusiform cortex, parahippocampal gyrus, and hippocampus. The third cluster was located in the right thalamus., Conclusions: There is decreased regional perfusion during wakefulness in participants with moderate-severe obstructive sleep apnea, and these are in brain regions which have shown decreased regional gray matter volume in previous studies in people with severe OSA. Thus, we hypothesize that cerebral perfusion changes are evident before (and possibly underlie) future structural changes., (© 2015 Associated Professional Sleep Societies, LLC.)

The poor prognosis of patients with glioblastoma fuels the search for more effective therapeutic compounds. We previously hypothesised that the neuroleptic olanzapine may enhance antineoplastic effects of temozolomide the standard chemotherapeutic agent used in this disease. This study tested this hypothesis. The anti-proliferative effect of olanzapine was examined by MTT assays and cell count analysis. Soft-agar assays were performed to examine colony-forming ability. In addition, the inhibitory effect of olanzapine on the migratory capacity of U87MG and A172 cells was analyzed by Transwell(®) assays. Moreover, staining for annexin V/propidium iodide or carboxyfluorescein succinimidyl ester was performed prior to flow cytometric analysis in order to better understand the subjacent cellular mechanism. Our initial hypothesis that olanzapine may enhance temozolomide's anti-tumor activity could be confirmed in U87MG and A172 glioblastoma cell lines. Moreover, treatment with olanzapine alone resulted in a marked anti-proliferative effect on U87MG, A172 and two glioma stem-like cells with IC50 values ranging from 25 to 79.9 µM. In U87MG cells, anchorage-independent growth was dose-dependently inhibited. In A172 cells, migration was also shown to be inhibited in a dose-dependent manner. In addition, olanzapine was shown to exert a cell line-dependent pleomorphism with respect to the induction of apoptosis, necrosis and/or cytostasis. Our data show that the neuroleptic olanzapine enhances the anti-tumor activity of temozolomide against glioblastoma cell lines. Moreover, this is the first study to show that olanzapine provides on its own anti-cancer activity in glioblastoma and thus may have potential for repurposing.

Introduction: In low-grade glioma (LGG) surgery, intraoperative differentiation between tumor and most likely tumor-free brain tissue can be challenging. Intraoperative ultrasound can facilitate tumor resection. The aim of this study is to evaluate the accuracy of linear array ultrasound in comparison to conventional intraoperative ultrasound (cioUS) and intraoperative high-field MRI (iMRI)., Methods: We prospectively enrolled 13 patients harboring a LGG of WHO Grade II. After assumed near total removal, a resection control was performed using navigated cioUS, navigated lioUS, and iMRI. We harvested 30 navigated biopsies from the resection cavity and compared the histopathological findings with the respective imaging results. Spearman's rho was calculated to test for significant correlations. Sensitivity and specificity as well as receiver operating characteristics (ROC) were calculated to assess test performance of each imaging modality., Results: Imaging results of lioUS correlated significantly (p < 0.009) with iMRI. Both iMRI and lioUS correlated significantly with final histopathological diagnosis (p < 0.006, p < 0.014). cioUS did not correlate with other imaging findings or with final diagnosis. The highest sensitivity for residual tumor detection was found in iMRI (83 %), followed by lioUS (79 %). The sensitivity of cioUS was only 21 %. Specificity was highest in cioUS (100 %), whereas iMRI and lioUS both achieved 67 %. ROC curves showed fair results for iMRI and lioUS and a poor result for cioUS., Conclusions: Intraoperative resection control in LGGs using lioUS reaches a degree of accuracy close to iMRI. Test results of lioUS are superior to cioUS. cioUS often fails to discriminate solid tumors from "normal" brain tissue during resection control. Only in lesions <10 cc cioUS does show good accuracy.

Objective: Conventional curved or sector array ultrasound (cioUS) is the most commonly used intraoperative imaging modality worldwide. Although highly beneficial in various clinical applications, at present the impact of linear array intraoperative ultrasound (lioUS) has not been assessed for intracranial use. We provide a technical description to integrate an independent lioUS probe into a commercially available neuronavigation system and evaluate the use of navigated lioUS as a resection control in glioblastoma surgery., Methods: We performed a prospective study assessing residual tumor detection after complete microsurgical resection using either cioUS or lioUS in 15 consecutive patients. We compared the imaging findings of both ultrasound modalities in 44 sites surrounding the resection cavity. The respective findings were correlated with the histopathologic findings of tissue specimen obtained from those sites., Results: Use of cioUS leaded to an additional resection in 9 patients, whereas lioUS detected residual tumor during all surgeries. A further resection was performed at 33 of 44 intraoperative sites (75%) based on results of lioUS alone. Resected tissue was solid tumor in 66% and infiltration zone in 34%. No false-positive or false-negative findings were seen using lioUS. There was no case of a tumor detection in cioUS combined with a negative finding in lioUS. The difference of imaging results between cioUS and lioUS was significant (sign test, P<0.001)., Conclusions: lioUS can be used as a safe and precise tool for intracranial image-guided resection control of glioblastomas. It can be integrated in a commercially available navigation system and shows a significant higher detection rate of residual tumor compared with conventional cioUS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Perry syndrome consists of autosomal dominant Parkinsonism, depression, weight loss, and central hypoventilation. Eight mutations in 16 families have been reported: p.F52L, p.G67D, p.G71R, p.G71E, p.G71A, p.T72P, p.Q74P, and p.Y78C located in exon 2 of the dynactin 1 (DCTN1) gene on chromosome 2p13.1., Methods: Genealogical, clinical, genetic, and functional studies were performed in three kindreds from New Zealand, the United States, and Colombia. A diaphragmatic pacemaker was implanted in the proband from the Colombian family to treat her respiratory insufficiency. Dopaminergic therapy was initiated in probands from two families., Results: Besides the probands, 17 symptomatic relatives from all families were identified. The cardinal signs of Perry syndrome were present in all three probands with symptomatic disease onset in their fifth or sixth decade of life. Parkinsonism was moderate with a partial response to dopaminergic treatment. All affected persons but two died of respiratory insufficiency. The proband from the Colombian family is alive most likely due to early diagnosis and implantation of a diaphragmatic pacemaker. Two-and-a-half-year follow-up examination has revealed that the diaphragmatic pacemaker is optimally functioning without any major complications. In the Colombian and US families, the DCTN1 p.G71R and in the New Zealand family the DCTN1 p.Y78C mutations were identified. In functional assays, both mutations altered microtubule binding consistent with a pathogenic role., Conclusions: Perry syndrome is a rare condition, but new cases are expected to be diagnosed worldwide. Early diagnosis prevents life-threatening acute respiratory failure. Diaphragmatic pacemakers should be considered as an effective symptomatic treatment option., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Object: Intraoperative MRI (iMRI) provides updated information for neuronavigational purposes and assessments on the status of resection during transsphenoidal surgery (TSS). The high-field technique additionally provides information about vascular structures at risk and precise information about extrasellar residual tumor, making it readily available during the procedure. The imaging, however, extends the duration of surgery. To evaluate the benefit of this technique, the authors conducted a retrospective study to compare postoperative outcome and residual tumor in patients who underwent conventional microsurgical TSS with and without iMRI., Methods: A total of 143 patients were assessed. A cohort of 67 patients who had undergone surgery before introduction of iMRI was compared with 76 patients who had undergone surgery since iMRI became routine in TSS at the authors' institution. Residual tumor, complications, hormone dependency, biochemical remission rates, and improvement of vision were assessed at 6-month follow-up. A volumetric evaluation of residual tumor was performed in cases of parasellar tumor extension., Results: The majority of patients in both groups suffered from nonfunctioning pituitary adenomas. At the 6-month follow-up assessment, vision improved in 31% of patients who underwent iMRI-assisted surgery versus 23% in the conventional group. One instance of postoperative intrasellar bleeding was found in the conventional group. No major complications were found in the iMRI group. Minor complications were seen in 9% of patients in the iMRI group and in 5% of those in the conventional group. No differences between groups were found for hormone dependency and biochemical remission rates. Time of surgery was significantly lower in the conventional treatment group. Overall a residual tumor was found after surgery in 35% of the iMRI group, and 41% of the conventional surgery group harbored a residual tumor. Total resection was achieved as intended significantly more often in the iMRI group (91%) than in the conventional group (73%) (p < 0.034). Patients with a planned subtotal resection showed higher mean volumes of residual tumor in the conventional group. There was a significantly lower incidence of intrasellar tumor remnants in the iMRI group than in the conventional group. Progression-free survival after 30 months was higher according to Kaplan-Meier analysis with the use of iMRI, but a statistically significant difference could not be shown., Conclusions: The use of high-field iMRI leads to a significantly higher rate of complete resection. In parasellar tumors a lower residual volume and a significantly lower rate of intrasellar tumor remnants were shown with the technique. So far, long-term follow-up is limited for iMRI. However, after 2 years Kaplan-Meier analyses show a distinctly higher progression-free survival in the iMRI group. No significant benefit of iMRI was found for biochemical remission rates and improvement of vision. Even though the surgical time was longer with the adjunct use of iMRI, it did not increase the complication rate significantly. The authors therefore recommend routine use of high-field iMRI for pituitary surgery, if this technique is available at the particular center.

Object: High-grade gliomas (HGGs) and metastasis (MET) are the most common intracranial lesions in neurosurgical routine. Both of them show an invasive growth pattern extending into neural tissue beyond the margins of contrast enhancement on MRI. These "undetected" areas might be the origin of early tumor recurrence. The aim of the present study was to evaluate whether 5-aminolevulinic acid (5-ALA) fluorescence provides an additional benefit in detection of invasive tumor compared with intraoperative MRI (iMRI)., Methods: The authors prospectively enrolled 45 patients harboring contrast-enhancing lesions, in whom gross-total resection was intended. All patients had surgery in which iMRI and 5-ALA-guided resection were used following a specific protocol. First, a typical white light tumor resection was performed. Then, spatial location of residual fluorescence was marked. After that, an iMRI was performed and residual uptake of contrast was marked. Navigated biopsy samples were taken from all marked areas and from additional sites according to the surgeon's judgment. Cross tables and receiver operating characteristic curves were calculated, assessing performance of the imaging methods for tumor detection alone and for combined detection of infiltration zone and solid tumor (pathological tissue). Also, correlations of histopathological findings with imaging results were tested using Spearman rho., Results: Thirty-four patients with HGGs and 11 with METs were enrolled. Three patients harboring a MET showed no 5-ALA enhancement and were excluded; 127 histopathological samples were harvested in the remaining patients. In HGG, sensitivity for tumor detection was significantly higher (p < 0.001) in 5-ALA (0.85) than in iMRI (0.41). Specificity was significantly lower (p < 0.001) in 5-ALA (0.43) than in iMRI (0.70). For detection of pathological tissue, 5-ALA significantly exceeded iMRI in specificity (0.80 vs 0.60) and sensitivity (0.91 vs 0.66) (p < 0.001). Imaging results of iMRI and 5-ALA did not correlate significantly; only 5-ALA showed a significant correlation with final histopathological diagnosis of the specimen and with typical histopathological features of HGGs. In METs, sensitivity and specificity for tumor detection were equal in 5-ALA and iMRI. Both techniques showed high values for sensitivity (0.75) and specificity (0.80). The odds ratio for detection of tumor tissue was 12 for both techniques. Concerning pathological tissue, no statistically significant difference was found either. Imaging results of iMRI and 5-ALA correlated significantly (p < 0.022), as with final histopathological diagnosis in METs., Conclusions: In METs, due to the rate of nonenhancing lesions, the authors found no additional benefit of 5-ALA compared with iMRI. In HGG, imaging results of 5-ALA and iMRI are significantly different at the border zone; 5-ALA has a higher sensitivity and a lower specificity for tumor detection than Gd-DTPA-enhanced iMRI. For detection of infiltrating tumor at the border of the resection cavity, 5-ALA is superior to Gd-DTPA-enhanced iMRI concerning both sensitivity and specificity. Thus, use of 5-ALA in addition to iMRI might be beneficial to maximize extent of resection. Clinical synergistic effects will be evaluated in a prospective randomized trial.

Objectives: The aim of this paper was to demonstrate the long-term results following microsurgery in a single surgeon's continuous series of patients with Cushing disease (CD), to assess the influence of changes in surgical procedures, and to compare the results with those of other treatment modalities. In particular, preoperative diagnosis, tumor size, results of histological examination, and complications were considered., Methods: Between 1971 and 2004, 426 patients suffering from newly diagnosed CD underwent primary surgery. Pre-operative measures included clinical examination, endocrinological workup (testing of the hypothalamic-pituitary-adrenal axis, and 2- and 8-mg dexamethasone overnight suppression tests), sellar imaging (polytomography, computed tomography, and magnetic resonance [MR] imaging), and in patients with negative results on imaging studies, inferior petrosal sinus sampling. Follow-up examinations consisting of endocrinological workup, and imaging took place 1 week and 3 months after surgery and then at yearly intervals., Results: During microsurgery as first treatment, the adenoma finding rate was 86.6%. After selective adenomectomy, the remission rate was 75.9%, and this rate showed no improvement over the years. The best results were achieved in microadenomas confirmed on MR imaging or histopathological investigation. The recurrence rate (15%) and the complication rate (5.9%) declined over the years. If no adenoma was found, exploration of the sella turcica was performed in 45.6%, hypophysectomy in 3.5%, and hemihypophysectomy in 50.9% of these patients, leading to an early remission in 37.9%. In case of persistence or recurrence, further treatment (repeated operation, adrenalectomy, radio-therapy, or medical treatment) was used to control the disease., Conclusions: Microsurgery remains the treatment of first choice in CD, even though no improvement in remission rates was observed over the years, because complication or remission rates for other treatment options are comparable or worse.