A teljesexom-szekvenálás jelentősége a ritka neurológiai betegségek diagnosztikájában – saját tapasztalatok egy ataxiás eset kapcsán

Next generation sequencing (NGS) technologies reshape the diagnostics of rare neurological diseases. In the background of certain neurological symptoms, such as ataxia, many acquired and genetic causes may be present. Variations in a given gene can present with variable phenotypes, too. Because of this phenomenon, the conventional one gene sequencing approach often fails to identify the genetic background of a disease. Next generation sequencing panels allow to sequence 50-100 genes simultaneously, and if the disease stratification is not possible based on the clinical symptoms, whole exome sequencing can help in the diagnostic of genetic disorders with atypical presentation. This case study is about the exome sequencing of a patient with cerebellar ataxia. Genetic investigations identified rare variants in the SPG11 gene in association with the clinical phenotype, which gene was originally described in the background of hereditary spastic paraparesis. Our article highlights that in certain cases the variability of the leading presenting symptom makes it hard to select the correct gene panel. In our case the variants in the gene, formerly associated to hereditary spastic paraparesis, resulted in cerebellar ataxia initially, so even an ataxia NGS gene panel would not detect those. Orv Hetil. 2018; 159(28): 1163-1169

Májáttétes betegek sztereotaxiás ablatív sugárkezelésével (SABRT) elért első eredményeink

Recently the prevalence of oligometastatic patients is increasing. A common site of distant spread is the liver. The standard of care is curative surgical resection, however, the resecability rate is only 10-20%. Alternatively, radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) may be used. Stereotactic ablative body radiotherapy (SABRT) makes it possible to deliver curative radiation dose without radiation injury to the healthy liver tissue. We delivered SABRT to three patients with inoperable hepatic metastases. The primary tumors were rectal (2) and lung (1). The dose was 3x20 Gy every other day. We observed one grade 1 side effect. All the metastases showed complete remission and no local recurrence or late side effect occurred during the one year of follow-up. One patient is tumor-free, one has stable disease, in one patient two new hepatic metastases appeared and receives chemo-biological therapy. SABRT of liver metastases is safe and highly effective. It can be expected that in the near future it will become one of the standard treatments of hepatic tumors

Epidemiology of acute kidney injury in Hungarian intensive care units: a multicenter, prospective, observational study

<p>Abstract</p> <p>Background</p> <p>Despite the substantial progress in the quality of critical care, the incidence and mortality of acute kidney injury (AKI) continues to rise during hospital admissions. We conducted a national, multicenter, prospective, epidemiological survey to evaluate the importance of AKI in intensive care units (ICUs) in Hungary. The objectives of this study were to determine the incidence of AKI in ICU patients; to characterize the differences in aetiology, illness severity and clinical practice; and to determine the influencing factors of the development of AKI and the patients' outcomes.</p> <p>Methods</p> <p>We analysed the demographic, morbidity, treatment modality and outcome data of patients (n = 459) admitted to ICUs between October 1^st, 2009 and November 30^th, 2009 using a prospectively filled in electronic survey form in 7 representative ICUs.</p> <p>Results</p> <p>The major reason for ICU admission was surgical in 64.3% of patients and medical in the remaining 35.7%. One-hundred-twelve patients (24.4%) had AKI. By AKIN criteria 11.5% had Stage 1, 5.4% had Stage 2 and 7.4% had Stage 3. In 44.0% of patients, AKI was associated with septic shock. Vasopressor treatment, SAPS II score, serum creatinine on ICU admission and sepsis were the independent risk factors for development of any stage of AKI. Among the Stage 3 patients (34) 50% received renal replacement therapy. The overall utilization of intermittent renal replacement therapy was high (64.8%). The overall in-hospital mortality rate of AKI was 49% (55/112). The ICU mortality rate was 39.3% (44/112). The independent risk factors for ICU mortality were age, mechanical ventilation, SOFA score and AKI Stage 3.</p> <p>Conclusions</p> <p>For the first time we have established the incidence of AKI using the AKIN criteria in Hungarian ICUs. Results of the present study confirm that AKI has a high incidence and is associated with high ICU and in-hospital mortality.</p

Island in the neoliberal stream: energy security and soft re-nationalisation in Hungary

Since 2010, the Hungarian Government has increased its stake in the country’s energy sector at the expense of foreign-owned energy companies. This ‘soft re-nationalisation’ is driven by both exogenous and endogenous factors, especially the country’s external dependence on gas imports, its previous commitment to a European model of energy liberalisation, public dissatisfaction with high energy prices and the emergence of an ‘illiberal state’. The case of Hungary’s ‘soft re-nationalisation’ yields two central findings. Firstly, conceptually, there is a need to move away from just focusing on the radical re-nationalisation of energy in the form of resource nationalism, and instead understand re-nationalisation as consisting of a broad spectrum of state interventions into the energy market. Secondly, Hungary’s recent ‘statist turn’ in the energy sector highlights inherent tensions within EU energy policy as it threatens attempts to establish a fully liberalised and marketised energy market across the continen

Magnetic field effects on the vestibular system: calculation of the pressure on the cupula due to ionic current-induced Lorentz force

Large static magnetic fields may be employed in magnetic resonance imaging (MRI). At high magnetic field strengths (usually from about 3 tesla and above) it is possible for humans to perceive a number of effects. One such effect is mild vertigo. Recently, Roberts et al (Current Biology 21:1635-1640 2011) proposed a Lorentz-force mechanism resulting from the ionic currents occurring naturally in the endolymph of the vestibular system. In the present work a more detailed calculation of the forces and resulting pressures in the vestibular system is carried out using a numerical model. Firstly, realistic 3D finite element conductivity and fluid maps of the utricle and a single semi-circular canal containing the current sources (dark cells) and sinks (hair cells) of the utricle and ampulla were constructed. Secondly, the electrical current densities in the fluid are calculated. Thirdly, the developed Lorentz force is used directly in the Navier-Stokes equation and the trans-cupular pressure is computed. Since the driving force field is relatively large in comparison with the advective acceleration, we demonstrate that it is possible to perform an approximation in the Navier-Stokes equations that reduces the problem to solving a simpler Poisson equation. This simplification allows rapid and easy calculation for many different directions of applied magnetic field. At 7 tesla a maximum cupula pressure difference of 1.6 mPa was calculated for the combined ampullar (0.7 μA) and utricular (3.31 μA) distributed current sources, assuming a hair-cell resting current of 100 pA per unit. These pressure values are up to an order of magnitude lower than those proposed by Roberts et al using a simplistic model and calculation, and are in good agreement with the estimated pressure values for nystagmus velocities in head rotation/caloric experiments. This modeling work supports the hypothesis that the Lorentz force mechanism is a significant contributor to the perception of magnetic field induced vertigo

Charge stabilization by reaction center protein immobilized to carbon nanotubes functionalized by amine groups and poly(3-thiophene acetic acid) conducting polymer

A large number of studies have indicated recently that photosynthetic reaction center proteins (RC) bind successfully to nanostructures and their functional activity is largely retained. The major goal of current research is to find the most efficient systems and conditions for the photoelectric energy conversion and for the stability of this bio-nanocomposite. In our studies, we immobilized the RC protein on multiwalled carbon nanotubes (MWNT) through specific chemical binding to amine functional groups and through conducting polymer (poly(3-thiophene acetic acid), PTAA). Both structural (TEM, AFM) and functional (absorption change and conductivity) measurements has shown that RCs could be bound effectively to functionalized CNTs. The kinetics of the light induced absorption change indicated that RCs were still active in the composite and there was an interaction between the protein cofactors and the CNTs. The light generated photocurrent was measured in an electrochemical cell with transparent CNT electrode designed specially for this experiment. (C) 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei

MicroRNA-25-dependent up-regulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative/nitrative stress and subsequent dysfunction in the heart

Diet-induced hypercholesterolemia leads to oxidative/nitrative stress and subsequent myocardial dysfunction. However, the regulatory role of microRNAs in this phenomenon is unknown. We aimed to investigate, whether hypercholesterolemia-induced myocardial microRNA alterations play a role in the development of oxidative/nitrative stress and in subsequent cardiac dysfunction. Male Wistar rats were fed with 2% cholesterol/0.25% cholate-enriched or standard diet for 12weeks. Serum and tissue cholesterol levels were significantly elevated by cholesterol-enriched diet. Left ventricular end-diastolic pressure was significantly increased in cholesterol-fed rats both in vivo and in isolated perfused hearts, indicating diastolic dysfunction. Myocardial expression of microRNAs was affected by cholesterol-enriched diet as assessed by microarray analysis. MicroRNA-25 showed a significant down-regulation as detected by microarray analysis and QRT-PCR. In silico target prediction revealed NADPH oxidase 4 (NOX4) as a putative target of microRNA-25. NOX4 protein showed significant up-regulation in the hearts of cholesterol-fed rats, while NOX1 and NOX2 remained unaffected. Cholesterol-feeding significantly increased myocardial oxidative/nitrative stress as assessed by dihydroethidium staining, protein oxidation assay, and nitro-tyrosine ELISA, respectively. Direct binding of microRNA-25 mimic to the 3' UTR region of NOX4 was demonstrated using a luciferase reporter assay. Transfection of a microRNA-25 mimic into primary cardiomyocytes decreased superoxide production, while a microRNA-25 inhibitor resulted in an up-regulation of NOX4 protein and an increase in oxidative stress that was attenuated by the NADPH oxidase inhibitor diphenyleneiodonium. Here we demonstrated for the first time that hypercholesterolemia affects myocardial microRNA expression, and by down-regulating microRNA-25 increases NOX4 expression and consequently oxidative/nitrative stress in the heart. We conclude that hypercholesterolemia-induced microRNA alterations play an important role in the regulation of oxidative/nitrative stress and in consequent myocardial dysfunction

Novel, selective EPO receptor ligands lacking erythropoietic activity reduce infarct size in acute myocardial infarction in rats

Erythropoietin (EPO) has been shown to protect the heart against acute myocardial infarction in pre-clinical studies, however, EPO failed to reduce infarct size in clinical trials and showed significant safety problems. Here, we investigated cardioprotective effects of two selective non- erythropoietic EPO receptor ligand dimeric peptides (AF41676 and AF43136) lacking erythropoietic activity, EPO, and the prolonged half-life EPO analogue, darbepoetin in acute myocardial infarction (AMI) in rats. In a pilot study, EPO at 100U/mL significantly decreased cell death compared to vehicle (33.8+/-2.3% vs. 40.3+/-1.5%, p<0.05) in rat neonatal cardiomyocytes subjected to simulated ischemia/reperfusion. In further studies (studies 1-4), in vivo AMI was induced by 30min coronary occlusion and 120min reperfusion in male Wistar rats. Test compounds and positive controls for model validation (B-type natriuretic peptide, BNP or cyclosporine A, CsA) were administered iv. before the onset of reperfusion. Infarct size (IS) was measured by standard TTC staining. In study 1, 5000U/kg EPO reduced infarct size significantly compared to vehicle (45.3+/-4.8% vs. 59.8+/-4.5%, p<0.05). In study 2, darbepoetin showed a U-shaped dose-response curve with maximal infarct size-reducing effect at 5mug/kg compared to the vehicle (44.4+/-5.7% vs. 65.9+/-2.7%, p<0.01). In study 3, AF41676 showed a U-shaped dose-response curve, where 3mg/kg was the most effective dose compared to the vehicle (24.1+/-3.9% vs. 44.3+/-2.5%, p<0.001). The positive control BNP significantly decreased infarct size in studies 1-3 by approximately 35%. In study 4, AF43136 at 10mg/kg decreased infarct size, similarly to the positive control CsA compared to the appropriate vehicle (39.4+/-5.9% vs. 58.1+/-5.4% and 45.9+/-2.4% vs. 63.8+/-4.1%, p<0.05, respectively). This is the first demonstration that selective, non-erythropoietic EPO receptor ligand dimeric peptides AF41676 and AF43136 administered before reperfusion are able to reduce infarct size in a rat model of AMI. Therefore, non-erythropoietic EPO receptor peptide ligands may be promising cardioprotective agents