Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the
MECP2
gene. Since the
MECP2
gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent
MECP2
mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed
MECP2
transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.
Background and purpose
Stroke mimics (SMs) account for a significant number of patients attended as stroke code (SC) with an increasing number over the years. Recent studies show perfusion computed tomography (PCT) alterations in some SMs, especially in seizures. The objective of our study was to evaluate the clinical characteristics and PCT alterations in SMs attended as SC in order to identify potential predictors of PCT alterations in SMs.
Methods
A retrospective study was performed including all SC activations undergoing a multimodal CT study including non‐enhanced computed tomography (CT), CT angiography and PCT, as part of our SC protocol, over 39 months. Patients with a final diagnosis of SM after complete diagnosis work‐up were therefore selected. Clinical variables, diagnosis, PCT alteration patterns and type of map affected (Tmax or time to peak, cerebral blood flow and cerebral blood volume) were registered.
Results
Stroke mimics represent up to 16% (284/1761) of SCs with a complete multimodal study according to our series. Amongst SMs, 26% (74/284) showed PCT alterations. PCT abnormalities are more prevalent in seizures and status epilepticus and the main pattern is alteration of the time to peak map, of unilateral hemispheric distribution or of non‐vascular territory. In our series, the independent predictors of alteration in PCT in SMs are aphasia, female sex and older age.
Conclusions
Perfusion computed tomography alterations can be found amongst almost a third of SMs attended as SC, especially older women presenting with aphasia with a final diagnosis of epileptic seizures and status epilepticus.
Traumatic brain injury (TBI) and stroke are major causes of morbidity and mortality worldwide. Despite major advances in the comprehension of the molecular mechanisms determining brain injury in stroke and TBI, the history of clinical translation of experimentally successful trials of neuroprotective drugs is plagued with failures. Although with certain differences, the reasons for the failures of clinical trials are similar, from insufficient data on animal experiments and too many assumptions in translation to insufficient acknowledgement and control of clinical heterogeneity, poor data handling and standardization and restricted outcome measurement and analysis. Realization of these reasons with improved experimental conception and testing of the potentially active compound, including the use of different strains, sexes, models and outcome analyses, with replication of preclinical data in different laboratories, as well as better planning and analysis of clinical trials, could finally allow the development of an effective therapeutic strategy.
Aims: Epilepsy is one of the most prevalent neurological diseases. A third of patients with epilepsy remain drug-resistant. The exact aetiology of drug-resistant epilepsy (DRE) is still unknown. Neuronal tetraploidy has been associated with neuropathology. The aim of this study was to assess the presence of tetraploid neurons and astrocytes in DRE.Methods: For that purpose, cortex, hippocampus and amygdala samples were obtained from patients subjected to surgical resection of the epileptogenic zone. Post-mortem brain tissue of subjects without previous records of neurological, neurodegenerative or psychiatric diseases was used as control.Results: The percentage of tetraploid cells was measured by immunostaining of neurons (NeuN) or astrocytes (S100β) followed by flow cytometry analysis. The results were confirmed by image cytometry (ImageStream X Amnis System Cytometer) and with an alternative astrocyte biomarker (NDRG2). Statistical comparison was performed using univariate tests. A total of 22 patients and 10 controls were included. Tetraploid neurons and astrocytes were found both in healthy individuals and DRE patients in the three brain areas analysed: cortex, hippocampus and amygdala. DRE patients presented a higher number of tetraploid neurons (p = 0.020) and astrocytes (p = 0.002) in the hippocampus than controls. These results were validated by image cytometry.
Conclusions:We demonstrated the presence of both tetraploid neurons and astrocytes in healthy subjects as well as increased levels of both cell populations in DRE patients.Herein, we describe for the first time the presence of tetraploid astrocytes in healthy subjects. Furthermore, these results provide new insights into epilepsy, opening new avenues for future treatment.
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