Proposed Definition of Experimental Secondary Ischemia for Mouse Subarachnoid Hemorrhage.

Inconsistency in outcome parameters for delayed cerebral ischemia (DCI) makes it difficult to compare results between mouse studies, in the same way inconsistency in outcome parameters in human studies has for long obstructed adequate comparison. The absence of an established definition may in part be responsible for the failed translational results. The present article proposes a standardized definition for DCI in experimental mouse models, which can be used as outcome measure in future animal studies. We used a consensus-building approach to propose a definition for "experimental secondary ischemia" (ESI) in experimental mouse subarachnoid hemorrhage that can be used as an outcome measure in preclinical studies. We propose that the outcome measure should be as follows: occurrence of focal neurological impairment or a general neurological impairment compared with a control group and that neurological impairment should occur secondarily following subarachnoid hemorrhage (SAH) induction compared with an initial assessment following SAH induction. ESI should not be used if the condition can be explained by general anesthesia or if other means of assessments sufficiently explain function impairment. If neurological impairment cannot reliably be evaluated, due to scientific setup. Verification of a significant secondary impairment of the cerebral perfusion compared with a control group is mandatory. This requires longitudinal examination in the same animal. The primary aim is that ESI should be distinguished from intervention-related ischemia or neurological deficits, in order establish a uniform definition for experimental SAH in mice that is in alignment with outcome measures in human studies

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Evaluation of P-glycoprotein function at the blood-brain barrier using [F-18]MC225-PET

P-glycoprotein (P-gp) is an ATP-dependent efflux transporter located at the blood–brain barrier (BBB), involved in the transport of a variety of neurotoxic substances out of the brain. Alterations in P-gp function play an essential role in the pathophysiological mechanisms underlying neurodegenerative disorders

External validation of a model to predict the survival of patients presenting with a spinal epidural metastasis

The surgical treatment of spinal metastases is evolving. The major problem is the selection of patients who may benefit from surgical treatment. One of the criteria is an expected survival of at least 3 months. A prediction model has been previously developed. The present study has been performed in order to validate externally the model and to demonstrate that this model can be generalized to other institutions and other countries than the Netherlands. Data of 356 patients from five centers in Germany, Spain, Sweden, and the Netherlands who were treated for metastatic epidural spinal cord compression were collected. Hazard ratios in the test population corresponded with those of the developmental population. However, the observed and the expected survival were different. Analysis revealed that the baseline hazard function was significantly different. This tempted us to combine the data and develop a new prediction model. Estimating iteratively, a baseline hazard was composed. An adapted prediction model is presented. External validation of a prediction model revealed a difference in expected survival, although the relative contribution of the specific hazard ratios was the same as in the developmental population. This study emphasized the need to check the baseline hazard function in external validation. A new model has been developed using an estimated baseline hazar

Long-term outcome after anterior cervical discectomy without fusion

To retrospectively study the long-term outcome of patients after anterior cervical discectomy without fusion (ACD) compared to results published on the long-term outcome after ACD with fusion (ACDF). We reviewed the charts of all patients receiving ACD surgery between 1985 and 2000 to analyze the direct post-operative results as well as complications of the surgery. Moreover, 102 patients, randomly selected, were interviewed with the neck disability index to study possible persisting complaints up to 18 years after ACD surgery. A total of 551 Patients were identified. Two months post-operative follow up at the outpatient clinic revealed that 90.1% of patients were satisfied with the result of ACD surgery. At the time of the survey, this percentage had dropped to 67.6%. In addition, 20.6% and 11.8% had obtained moderate to severe complaints, respectively, in daily-life activities. Complaints were mainly localized in the neck region and occasionally provoked radiating pain in the arm. On the short term, ACD leads to a satisfied outcome. Over the longer term, patients report increasing complaints. The increase in complaints at the time of the survey may be the result of ongoing degenerative effects. Compared to published data on ACDF, there is no superiority of any fusion technique compared to ACD alone

Factor Structure, Reliability and Criterion Validity of the Autism-Spectrum Quotient (AQ): A Study in Dutch Population and Patient Groups

The factor structure of the Dutch translation of the Autism-Spectrum Quotient (AQ; a continuous, quantitative measure of autistic traits) was evaluated with confirmatory factor analyses in a large general population and student sample. The criterion validity of the AQ was examined in three matched patient groups (autism spectrum conditions (ASC), social anxiety disorder, and obsessive–compulsive disorder). A two factor model, consisting of a “Social interaction” factor and “Attention to detail” factor could be identified. The internal consistency and test–retest reliability of the AQ were satisfactory. High total AQ and factor scores were specific to ASC patients. Men scored higher than women and science students higher than non-science students. The Dutch translation of the AQ is a reliable instrument to assess autism spectrum conditions