Pentylenetetrazole-induced Seizure Susceptibility in the Tau58/4 Transgenic Mouse Model of Tauopathy

In several tauopathies such as Alzheimer's disease (AD), an increased incidence of seizures is observed. Tau, one of the major proteins implicated in AD pathology, is an important regulator of neural network excitability and might participate in the underlying epileptic cascade. However, the mechanisms underlying this relationship are not fully elucidated. We aim to investigate this mechanism by analyzing seizure susceptibility to the convulsant pentylenetetrazole (PTZ) in a novel rodent tauopathy model. A single dose of PTZ was systemically injected in Tau58/4 transgenic mice. To investigate whether young and aged heterozygous (HET) mice exhibit a higher susceptibility to seizures in comparison with wild-type (WT) littermates, video electroencephalography (EEG) in combination with behavioral scoring according to a modified Racine scale was used. The employment of different dosage groups enabled us to characterize the dose range reliably inducing seizures. Here, we report an increased seizure susceptibility in young but not in old HET Tau58/4 mice. Young HET animals displayed more severe seizures and had a reduced latency to the first seizure compared to WTs. Also, age-related differences in susceptibility could be demonstrated for both genotypes. Identification and targeting of secondary diseases such as epilepsy, which aggravate dementia and lead to earlier institutionalization, is key. This study finds that tau pathology itself is sufficient to alter seizure susceptibility in a rodent model, indicating that the disease process is crucial in the emergence of epilepsy in patients with tauopathy

The FOAM study : Is Hysterosalpingo foam sonography (HyFoSy) a cost-effective alternative for hysterosalpingography (HSG) in assessing tubal patency in subfertile women? Study protocol for a randomized controlled trial

This is an investigator initiated trial, VU medical center Amsterdam is the sponsor, contact information: prof. CJM de Groot, Department of Obstetrics and Gynaecology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands, Tel: + 31-204444444. This study is funded by ZonMw, a Dutch organization for Health Research and Development, project number 837001504. ZonMW gives financial support for the whole project. IQ Medical Ventures provides the ExEm FOAM® kits. The funding bodies have no role in the design of the study; collection, analysis, and interpretation of data; and in writing the manuscript.Peer reviewedPublisher PD

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial

Funding Information: The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foamVR kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Peer reviewedPublisher PD

Progressive Motor Deficit is Mediated by the Denervation of Neuromuscular Junctions and Axonal Degeneration in Transgenic Mice Expressing Mutant (P301S) Tau Protein

Tauopathies include a variety of neurodegenerative diseases associated with the pathological aggregation of hyperphosphorylated tau, resulting in progressive cognitive decline and motor impairment. The underlying mechanism for motor deficits related to tauopathy is not yet fully understood. Here, we use a novel transgenic tau mouse line, Tau 58/4, with enhanced neuron-specific expression of P301S mutant tau to investigate the motor abnormalities in association with the peripheral nervous system. Using stationary beam, gait, and rotarod tests, motor deficits were found in Tau 58/4 mice already 3 months after birth, which deteriorated during aging. Hyperphosphorylated tau was detected in the cell bodies and axons of motor neurons. At the age of 9 and 12 months, significant denervation of the neuromuscular junction in the extensor digitorum longus muscle was observed in Tau 58/4 mice, compared to wild-type mice. Muscle hypotrophy was observed in Tau 58/4 mice at 9 and 12 months. Using electron microscopy, we observed ultrastructural changes in the sciatic nerve of 12-month-old Tau 58/4 mice indicative of the loss of large axonal fibers and hypomyelination (assessed by g-ratio). We conclude that the accumulated hyperphosphorylated tau in the axon terminals may induce dying-back axonal degeneration, myelin abnormalities, neuromuscular junction denervation, and muscular atrophy, which may be the mechanisms responsible for the deterioration of the motor function in Tau 58/4 mice. Tau 58/4 mice represent an interesting neuromuscular degeneration model, and the pathological mechanisms might be responsible for motor signs observed in some human tauopathies

Neuroimaging of subacute brain inflammation and microstructural changes predicts long-term functional outcome after experimental traumatic brain injury

There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to controlled cortical impact (CCI) injury, sham surgery, or skin incision (naive). CCI-injured (n=18) and sham-operated rats (n=6) underwent positron emission tomography (PET) imaging with the translocator protein 18kDa (TSPO) radioligand [F-18]PBR111 and diffusion tensor imaging (DTI) in the subacute phase (3 weeks post-injury) to quantify inflammation and microstructural alterations. CCI-injured, sham-operated, and naive rats (n=8) underwent behavioral testing in the chronic phase (5.5-10 months post-injury): open field and sucrose preference tests, two one-week video-electroencephalogram (vEEG) monitoring periods, pentylenetetrazole (PTZ) seizure susceptibility tests, and a Morris water maze (MWM) test. In vivo imaging revealed pronounced neuroinflammation, decreased fractional anisotropy, and increased diffusivity in perilesional cortex and ipsilesional hippocampus of CCI-injured rats. Behavioral analysis revealed disinhibition, anhedonia, increased seizure susceptibility, and impaired learning in CCI-injured rats. Subacute TSPO expression and changes in DTI metrics significantly correlated with several chronic deficits (Pearson's |r|=0.50-0.90). Certain specific PET and DTI parameters had good sensitivity and specificity (area under the receiver operator characteristic [ROC] curve=0.85-1.00) to distinguish between TBI animals with and without particular behavioral deficits. Depending on the investigated behavioral deficit, PET or DTI data alone, or the combination, could very well predict the variability in functional outcome data (adjusted R-2=0.54-1.00). Taken together, both TSPO PET and DTI seem promising prognostic biomarkers to predict different chronic TBI sequelae

Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis

PURPOSE DPYD-guided fluoropyrimidine dosing improves patient safety in carriers of DPYD variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis. METHODS Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G&gt;A and c.2846A&gt;T) or 50% (DPYD*2A and c.1679T&gt;G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. RESULTS In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G&gt;A, 25 DPYD*2A, 13 c.2846A&gt;T, and—when pooled—93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P 5 .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P 5 .698) were not negatively affected by DPYD-guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P 5 .007) was found in c.1236G&gt;A variant carriers, whereas no differences were found for DPYD*2A and c.2846A&gt;T carriers. CONCLUSION In this exploratory analysis, DPYD-guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G&gt;A carriers receiving a reduced starting dose.</p

Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis

PURPOSE: -guided fluoropyrimidine dosing improves patient safety in carriers of variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between variant carriers treated with a reduced dose and wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis. METHODS: Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which variant carriers received a 25% (c.1236G&gt;A and c.2846A&gt;T) or 50% ( *2A and c.1679T&gt;G) reduced dose and data from variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each variant carrier was matched to three wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. RESULTS: In total, 156 variant carriers and 775 wild-type controls were available for analysis. Sixty-one c.1236G&gt;A, 25 *2A, 13 c.2846A&gt;T, and-when pooled-93 variant carriers could each be matched to three unique wild-type controls. For pooled variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; = .698) were not negatively affected by -guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; = .007) was found in c.1236G&gt;A variant carriers, whereas no differences were found for *2A and c.2846A&gt;T carriers. CONCLUSION: In this exploratory analysis, -guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G&gt;A carriers receiving a reduced starting dose

Can Hysterosalpingo-Foam Sonography Replace Hysterosalpingography as First-Choice Tubal Patency Test? A Randomized Non-inferiority Trial

(Abstracted from Hum Reprod 2022;37:969-979) A main cause of female infertility is tubal pathology, with 11% to 30% of cases resulting from previous surgery, infections (such as sexually transmitted diseases), or endometriosis. Hysterosalpingography (HSG) is considered as the first choice for a tubal patency test during fertility workup, but the more patient-friendly hysterosalpingo-contrast sonography option has also been introduced