Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) represents the most common subtype of human focal epilepsies and perhaps the best-characterized disorder of this type 1 . Hippocampal sclerosis (HS) is the most common histopathologic abnormality found in adults with drugresistant mTLE 2 . The histopathologic hallmark of HS is segmental pyramidal cell loss, which can affect any field of the cornu Ammonis (CA1-4). Hippocampal neuronal cell loss is always associated with a severe pattern of astrogliosis 3 . Therewithal, disturbed homeostasis of metals is implicated in the pathology of mTLE-HS. Zinc has been considered to play a major role in epileptogenesis in relation to its involvement in the modulation of excitability and synaptic plasticity 4,5. Further, it has been shown that epileptogenic hippocampi are exposed to oxidative stress and that the development of prooxidative conditions in the CNS usually involves the loss of homeostasis of iron 6,7. Low brain levels of copper and manganese have been reported in patients with Menkes disease and in animal models of epilepsy, and linked to seizure development 8,9. Ristić et al. were the first to conduct a case-control study of total concentration of metals in tissue of human HS, and report lower concentrations of copper and manganese 10

Relationship Between Regional Distributions of Cytochrome C Oxidase and Copper-Delivering Chaperones in Sclerotic Hippocampi of Epilepsy Patients

Aims: A drop in copper level and the loss of energy homeostasis are both portrayed in mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis (HS) patients. Cytochrome c oxidase (COX) represents a crossroad of energy and copper metabolism; it is a key component of mitochondrial machinery and contains two copper centers. Our aim here was to examine the link between COX activity and the copper transporting system in HS. COX activity and the levels of mRNA of selected chaperones - COX11, COX17, Sco1 and Sco2 were determined in 13 anatomically distinct hippocampal regions. Methods: Study was performed on seven hippocampal samples, four of which had been acquired during the course of amygdalohippocampectomy treatment of medically intractable epilepsy and three control postmortem samples. Adjacent slices were used for Nissl staining, COX activity assay and mRNA in situ hybridization with autoradiography. Densitometry was performed using ImageJ. Results: Overall COX activity was decreased in HS compared to controls (P = 0.0003). However, 5 regions showed significantly lower COX activity in HS and 8 did not. Subiculum showed slightly higher activity in HS. The levels of mRNA levels were lowered in HS in 6 regions for COX11, 10 regions for COX17, two regions for Sco1 and 11 regions for Sco2. Conclusions: Our findings suggest the loss of energy homeostasis in HS may be related to pathological changes in specific components of copper delivery to COX, and that the impact may vary between different hippocampal regions

Odabir endogene kontrole za imunoblot analizu proteina u sklerotičnim hipokampusima pacijenata sa epilepsijom temporalnog režnja

Skleroza hipokampusa je najčešći neuropatološki nalaz kod epilepsije temporalnog režnja. Pored morfoloških promena odlikuju ga i promene nivoa različitih proteina u ćeliji. Imunoblot je nezamenjiva metoda za određivanje nivoa proteina i podrazumeva normalizaciju u odnosu na endogenu kontrolu (kontrolu jednakog nanošenja uzorka). Za tu svrhu se koriste proteini za koje se smatra da imaju stabilnu ekspresiju koja najmanje varira u ispitivanim uslovima, tretmanima i patofiziološkim stanjima. Ipak u nekim patofiziološkim stanjima se i ekspresija tradicionalno korišćenih endogenih kontrola menja, 1 što može dovesti do prikupljanja netačnih podataka i pogrešnog tumačenja rezultata. Cilj ovog rada je bio da se ispita stabilnost najčešće korišćenih endogenih kontrola i izabere najstabilnija koja će se koristiti za normalizaciju pri poređenju nivoa ciljnih proteina hipokampusa obolelih od epilepsije i neurološki intaktnih kontrola. Imunoblotom su detektovani β-aktin, α-tubulin, TATA-vezujući protein i gliceraldehid3-fosfat dehidrogenaza u tkivnim ekstraktima hipokampusa 9 pacijenata i 7 kontrola, i NormFinder softverom2 određene unutargrupna i međugrupna varijabilnost. Pokazano je da nivo strukturnih proteina β-aktina i α-tubulina najmanje varira u ispitivanim uslovima te se mogu koristiti za poređenje nivoa proteina u sklerotičnim i intaktnim hipokampusima. Rezultati upućuju da je odabir endogenih kontrola važan preduslov za dobijanje tačnih i pouzdanih podataka imunoblot metodom

The importance of copper in pathology of mesial temporal lobe epilepsy

More and more studies are identifying the regulation of metal homeostasis as one of the key points of central nervous system’s well-being. Epilepsy is a particularly interesting neurological condition when viewed in terms of the correlation between the amount of metals and the development of a seizure. This lecture will present contribution of our group to the field of metal biology in epilepsy by mapping brain metals in sclerotic hippocampus resected from drug resistant mesial temporal lobe epilepsy (mTLE) patients as surgical therapeutic approach. Direct insight into this epileptogenic area, by two powerful techniques, optical emission and mass spectrometry, has led us to investigation of copper turnover. Namely, among the examined metals, we found the deficiency of copper in sclerotic hippocampus on two levels: (i) in whole structure (ii) and locally in the areas of neuronal loss, with significant correlation between copper concentration and neuron density. Furthermore, analysis of copper metalloproteins showed: (i) significant increase or decrease in levels of protein that is participating in copper transport into the cell (CTR1) depending on the degree of hippocampal neuronal loss; (ii) and lower activity of an enzyme in which copper is part of the active site, cytochrome c oxidase, in sclerotic hippocampi of patients compared to control tissue. In our further investigations it remained to be determined whether changes in copper concentrations and copper metalloproteins are causal to pathology of mTLE or they represent epiphenomenon

The role of the diaphragm in prediction of respiratory function in the immediate postoperative period in lung cancer patients using a machine learning model

Abstract Background The prediction of postoperative respiratory function is necessary in identifying patients that are at greater risk of complications. There are not enough studies on the effect of the diaphragm on postoperative respiratory function prediction in lung cancer surgical patients. The objective of this study is to estimate the precision of machine learning methods in the prediction of respiratory function in the immediate postoperative period and how diaphragm function contributes to that prediction. Materials and methods Our prospective study included 79 patients who underwent lung cancer surgery. Diaphragm function was estimated by its mobility measured both ultrasonographically and radiographically and by noninvasive muscle strength tests. We present a new machine learning multilayer regression metamodel, which predicts FEV1 for each patient based on preoperative measurements. Results The proposed regression models are specifically trained to predict FEV1 in the immediate postoperative period and were proved to be highly accurate (mean absolute error in the range from 8 to 11%). Predictive models based on resected segments give two to three times less precise results. Measured FEV1 was 44.68% ± 14.07%, 50.95% ± 15.80%, and 58.0%1 ± 14.78%, and predicted postoperative (ppo) FEV1 was 43.85% ± 8.80%, 50.62% ± 9.28%, and 57.85% ± 10.58% on the first, fourth, and seventh day, respectively. By interpreting the obtained model, the diaphragm contributes to ppoFEV1 13.62% on the first day, 10.52% on the fourth, and 9.06% on the seventh day. Conclusion The machine learning metamodel gives more accurate predictions of postoperative lung function than traditional calculations. The diaphragm plays a notable role in the postoperative FEV1 prediction

Hippocampal antioxidative system in mesial temporal lobe epilepsy

ObjectiveTo examine antioxidative system in hippocampi of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS). MethodsActivity and levels of antioxidative enzymescatalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), manganese superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (CuZnSOD)were assessed in hippocampi of nine pharmacoresistant mTLE-HS patients (mean age 37.7{[}standard deviation] 6.6years) who underwent amygdalohippocampectomy, and in 10 hippocampi obtained via autopsy from five neurologically intact controls (mean age 34.49.0years). Subfield and cellular (neuron/astrocyte) distribution of CAT, GPx, and MnSOD was analyzed in detail using immunohistochemical staining. ResultsSclerotic hippocampi showed drastically increased activity of hydrogen peroxide-removing enzymes, CAT (p<0.001), GPx (p<0.001), and GR (p<0.001), and significantly higher protein levels of CAT (p=0.006), GPx (p=0.040), GR (p=0.024), and MnSOD (p=0.004), compared to controls. CAT immunofluorescence was located mainly in neurons in both controls and HS. Control hippocampi showed GPx staining in blood vessels and CA neurons. In HS, GPx-rich loci, representing bundles of astrocytes, emerged in different hippocampal regions, whereas the number of GPx-positive vessels was drastically decreased. Neurons with abnormal morphology and strong MnSOD immunofluorescence were present in all neuronal layers in HS. Small autofluorescent deposits, most likely lipofuscin, were observed, along with astrogliosis, in CA1 in HS. SignificanceAntioxidative system is upregulated in HS. This documents, for the first time, that epileptogenic hippocampi are exposed to oxidative stress. Our findings provide a basis for understanding the potential involvement of redox alterations in the pathology of epilepsy, and may open new pharmacologic perspectives for mTLE-HS treatment.Ministry of Education, Science and Technological Development of the Republic of Serbia {[}III41014, OI173014

Transorbital hybrid approach for endovascular occlusion of indirect carotid-cavernous fistulas–Case report and systematic literature review

ABSTRACT: Carotid-cavernous fistulas (CCF) are vascular malformations characterized by an aberrant shunt between one or more sources of arterial inflow and the cavernous sinus (CS). They are subdivided into direct and indirect fistulas. This last one, called dural CCF involve dural fistulous connections between branches of the internal carotid artery or the external carotid artery. When conventional routes are not eligible, surgical exposure of the vein is the only access to the fistula. We present the case of a patient successfully treated for right sided dural CCF, by a hybrid approach. Furthermore, through a literature review, we analyze the possible risks and benefits associated with this approach

“Stent-within-a-Stent” technique for the endovascular treatment of giant aneurysm of basilar artery bifurcation: A case report

Stents have become very important devices in the treatment of intracranial aneurysms. Flow diverters as high metal coverage stents are developed for hemodynamic treatment of challenging intracranial aneurysms. High level of metal coverage can also be achieved by implementing regular stents telescopically one in another. We present the case of a patient successfully treated for giant aneurysm of basilar artery bifurcation by a “Stent-within-a-Stent” technique. After stent implantation, coil embolization was performed using multiple-sized platinum helical coils. Control angiography performed at the end of the procedure revealed aneurysm occlusion. After 3 years, the patient is fully neurologically recovered, without pyramidal deficit, independently active and able to work