Entropically-driven binding of mithramycin in the minor groove of C/G-rich DNA sequences

Final full-text version available at: http://dx.doi.org/10.1093/nar/gkm037.-- Supplementary Data is available.The antitumour antibiotic mithramycin A (MTA) is a DNA minor-groove binding ligand. It binds to C/G-rich tracts as a dimer that forms in the presence of divalent cations such as Mg2+. Differential scanning calorimetry, UV thermal denaturation, isothermal titration calorimetry and competition dialysis were used, together with computations of the hydrophobic free energy of binding, to determine the thermodynamic profile of MTA binding to DNA. The results were compared to those obtained in parallel using the structurally related mithramycin SK (MSK). The binding of MTA to salmon testes DNA determined by UV melting studies (Kobs = 1.2 (±0.3) x 10^5 M–1) is tighter than that of MSK (2.9 (±1.0) x 10^4 M–1) at 25°C. Competition dialysis studies showed a tighter MTA binding to both salmon testes DNA (42% C + G) and Micrococcus lysodeikticus DNA (72% C + G). The thermodynamic analysis of binding data at 25°C shows that the binding of MTA and MSK to DNA is entropically driven, dominated by the hydrophobic transfer of the antibiotics from solution to the DNA-binding site. Direct molecular recognition between MTA or MSK and DNA through hydrogen bonding and van der Waals contacts may also contribute significantly to complex formation.Supported by a grant from the Spanish Ministry of Education and Science (SAF2005-00551) and the FEDER program of the European Community. This work was carried out within the framework of the Centre de Referencia en Biotecnologia of the Generalitat de Catalunya. Funding to pay the Open Access publication charge was provided by the Ministry of Education and Science and CSIC (Spain).Peer reviewe

Role of Neuroimaging in the Presurgical Evaluation of Epilepsy

A significant minority of patients with focal epilepsy are candidates for resective epilepsy surgery. Structural and functional neuroimaging plays an important role in the presurgical evaluation of theses patients. The most frequent etiologies of pharmacoresistant epilepsy in the adult population are mesial temporal sclerosis, malformations of cortical development, cavernous angiomas, and low-grade neoplasms. High-resolution multiplanar magnetic resonance imaging (MRI) with sequences providing T1 and T2 contrast is the initial imaging study of choice to detect these epileptogenic lesions. The epilepsy MRI protocol can be individually tailored when considering the patient's clinical and electrophysiological data. Metabolic imaging techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) visualize metabolic alterations of the brain in the ictal and interictal states. These techniques may have localizing value in patients with a normal MRI scan. Functional MRI is helpful in non-invasively identifying areas of eloquent cortex

The European Academy of Neurology NeuroCOVID-19 Task Force: A lesson for the future

Background:The COVID-19 pandemic has made its mark on world history forever causing millions of deaths, and straining health systems, economies, and societies worldwide. The European Academy of Neurology (EAN) reacted promptly. A special NeuroCOVID-19 Task Force was set up at the beginning of the pandemic to promote knowledge, research, international collaborations, and raise awareness about the prevention and treatment of COVID-19-related neurological issues. Methods Activities carried out during and after the pandemic by the EAN NeuroCOVID-19 Task Force are described. The main aim was to review all these initiatives in detail as an overarching lesson from the past to improve the present and be better prepared in case of future pandemics. Results During the pandemic, the Task Force was engaged in several initiatives: the creation of the EAN NEuro-covid ReGistrY (ENERGY); the launch of several surveys (neurological manifestations of COVID-19 infection; the pandemic's impact on patients with chronic neurological diseases; the pandemic's impact of restrictions for clinical practice, curricular training, and health economics); the publication of position papers regarding the management of patients with neurological diseases during the pandemic, and vaccination hesitancy among people with chronic neurological disorders; and the creation of a dedicated “COVID-19 Breaking News” section in EANpages. Conclusions The EAN NeuroCOVID-19 Task Force was immediately engaged in various activities to participate in the fight against COVID-19. The Task Force's concerted strategy may serve as a foundation for upcoming global neurological emergencies

Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model

IMPORTANCE: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. OBJECTIVE: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. EXPOSURES: Type of acute symptomatic seizure. MAIN OUTCOMES AND MEASURES: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). RESULTS: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. CONCLUSIONS AND RELEVANCE: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up

A plea for equitable global access to COVID‐19 diagnostics, vaccination and therapy: The NeuroCOVID‐19 Task Force of the European Academy of Neurology

Coronavirus disease 2019 (COVID‐19), a multi‐organ disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to challenge health and care systems around the globe. The pandemic has disrupted acute neurology services and routine patient care and has impacted the clinical course in patients with chronic neurological disease. COVID‐19 appears to have exposed inequalities of societies and healthcare systems and had a disproportionate impact on already vulnerable communities. The next challenge will be to set up initiatives to stop disparities in all aspects related to COVID‐19. From the medical perspective, there is a need to consider inequalities in prevention, treatment and long‐term consequences. Some of the issues of direct relevance to neurologists are summarised. With this appraisal, the European Academy of Neurology NeuroCOVID‐19 Task Force intends to raise awareness of the potential impact of COVID‐19 on inequalities in healthcare and calls for action to prevent disparity at individual, national and supranational levels

Imaging and Treatment Decisions in Seizures and Epilepsy

It has been clearly shown that magnetic resonance imaging (MRI) is the preferred modality of structural imaging for both new onset seizures and established epilepsy. MRI imaging in epilepsy requires a dedicated MRI protocol in order to detect subtle epileptogenic lesions such as focal cortical dysplasia or hippocampal sclerosis. Thin-slice thickness and orientation in the longitudinal axis of the hippocampus and perpendicular to it are the main characteristics of dedicated epilepsy MRI. An expert experienced in epilepsy and imaging should interpret epilepsy MRI. The new generation of 3 Tesla (T) MRIs is more sensitive, particularly for focal cortical dysplasia. Epilepsy-dedicated MRI is indicated particularly at the time of first seizure or new onset epilepsy, and when epilepsy becomes drug refractory. Results of a lesional MRI will assist in classifying the epilepsy syndrome and may well have an influence on treatment planning. Particularly in focal drug refractory epilepsies, a lesional MRI result may indicate a good hypothesis for presurgical assessment. If structural MRI is non-lesional, MRI post-processing may help to identify subtle epileptogenic lesions. CT scanning should only be performed in acute settings if MRI is not available or if the patient is too unwell for MRI scanning

Change of pitch due to carbamazepine and oxcarbazepine independently

İstanbul Bilim Üniversitesi, Tıp Fakültesi.Introduction; Absolute pitch (AP) is the term used to denote the cognitive ability to spontaneously and effortlessly identify and vocally produce specific musical tones without a reference note.1 Abnormalities of pitch perception are a recognized rare side effect of carbamazepine (CBZ). The mechanism of this side effect is not clear. The same symptom may also be associated with oxcarbazepine (OXC) although this is even rarer. We report a twenty-two year-old woman with partial and prolonged secondarily generalized seizures who complained of a one semitone lowering of pitch perception during CBZ therapy. After stopping CBZ and switching to OXC, she noticed that pitch perception was one semitone higher than normal.Absolute pitch (AP) is the term used to denote the cognitive ability to spontaneously and effortlessly identify and vocally produce specific musical tones without a reference note. Abnormalities of pitch perception are a recognized rare side effect of carbamazepine (CBZ). The mechanism of this side effect is not clear. The same symptom may also be associated with oxcarbazepine (OXC) although this is even rarer. We report a twenty-two year-old woman with partial and prolonged secondarily generalized seizures who complained of a one semitone lowering of pitch perception during CBZ therapy. After stopping CBZ and switching to OXC, she noticed that pitch perception was one semitone higher than normal

Prächirurgische Epilepsiediagnostik öfter ein Thema als viele denken

Epilepsiechirurgie ist eine hochwirksame Therapie mit kurativem Anspruch. Dies belegen inzwischen 3 Studien mit Klasse-1-Evidenz. Bei pharmakoresistenter fokaler Epilepsie mit einer Krankheitsdauer von fast 20 Jahren, mit kürzerer Krankheitsdauer von durchschnittlich 5 Jahren sowie bei Kindern wurde jeweils unabhängig voneinander gezeigt, dass Epilepsiechirurgie dem „best medical treatment“ hochsignifikant überlegen ist. Mithilfe multimodaler Untersuchungsmethoden (z.B. Langzeit-Video-EEG, hochauflösendes cMRT nach Epilepsieprotokoll, FDG-PET, neuropsychologische Testung, fMRT, ev. iktale SPECT-Untersuchung und Verrechnung mittels SISCOM, Postprocessing des cMRTs, „electric source imaging“ [ESI], Magnetenzephalographie [MEG], invasive Abklärung mittels Stereo-EEG-Elektroden oder subduralen Elektroden und WADA-Test) ist es in der prächirurgischen Epilepsiediagnostik nun möglich, Patienten einen epilepsiechirurgischen Eingriff anzubieten, die früher als schlechte oder aussichtslose Kandidaten für eine Epilepsiechirurgie eingeschätzt wurden.Epilepsy surgery is a highly effective therapy with the aim of long-term seizure control, i.e., to cure the epilepsy. Three different studies with class 1 evidence have shown this. In patients with drug-resistant epilepsy (DRE) lasting for nearly 20 years, shorter disease duration of about 5 years, or in children it has been shown independently that epilepsy surgery is highly superior to best medical treatment. Using multimodal techniques (e.g., long-term video EEG, high-resolution cerebral MRI according to epilepsy protocol, FDG-PET, neuropsychological testing, fMRI, ictal SPECT with SISCOM, MRI postprocessing, electric source imaging [ESI], magnetoencephalography [MEG], invasive recording with stereo-EEG electrodes or subdural electrodes and WADA test), it is possible nowadays to offer epilepsy surgery to patients who were previously not regarded as promising candidates for epilepsy surgery.(VLID)4920089Version of recor