Clinical Neuroscience

Electrophysiological alterations and general toxic signs obtained by subacute administration of titanium dioxide nanoparticles to the airways of rats

HORVÁTH Tamara, PAPP András, KOVÁCS Dávid, KÁLOMISTA Ildikó, KOZMA Gábor, VEZÉR Tünde

MARCH 30, 2017

Clinical Neuroscience - 2017;70(03-04)


Introduction and aims - Particles of titanium dioxide (TiO2) with typical size below 100 nm have gained a broad range of application by now, partly involving direct human exposure. Their known properties - high specific surface, mobility within the organism, induction of oxidative stress, release of inflammation mediators etc. - raise the possibility of nervous system damage but the available data regarding this are scarce and contradictory. Based on that, and the experiences with other metal oxide nanoparticles, the aim of the present study was to investigate certain general end nervous system toxic effects of TiO2 nanoparticles applied in the airways of rats. Materials and methods - Young adult Wistar rats (5 groups of 10 rats each) received, daily for 28 days, intratracheal instillations of titanium dioxide nanoparticles of ca. 10 nm diameter, suspended in 1% hydroxyethyl cellulose dissolved in phosphate-buffered saline, in the doses of 1, 3, and 10 mg/kg b. w. Vehicle controls received the suspension medium and there was also an untreated control group. During treatment, the rats’ body weight was measured, and their clinical state observed, daily. After the 28 days, spontaneous cortical activity, sensory evoked potentials and tail nerve action potential was recorded in urethane anesthesia, then the rats were dissected and tissue samples were taken for Ti level determination and biochemical measurements of some oxidative stress indicators. Results - The two higher doses reduced the rate of body weight gain significantly. Sensory evoked potentials and tail nerve action potential were significantly slowed, but the change in the spectrum of spontaneous cortical activity was not significant. Correlation of moderate strength was found between certain evoked potential parameters and brain Ti level and oxidative stress data. Conclusion - Our results underlined the possible neurotoxicity of TiO2 NPs but also the need for further investigations.



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Clinical Neuroscience

Procedural learning and its consolidation in autism spectrum disorder


Children with autism spectrum disorder (ASD) show altered learning and memory. A number of recent studies have debated whether procedural learning in ASD is intact or not. Our aim was to further assess the question of whether the implicit, non-conscious form of procedural learning in ASD children is intact or not, furthermore, how shifts towards a more explicit, attention-demanding task setting can alter this performance. We administered a modified version of the Alternating Serial Reaction Time (ASRT) Task to children with ASD and IQ- and age-matched typically developing (TD) children. The task consisted of alternating blocks of cued (explicit) and uncued (implicit probe) blocks, and was repeated after a 16-hour delay. We found that ASD and TD children showed similar sequence-specific learning in cued explicit blocks, however, on the uncued probe blocks ASD children performed better compared to TD children. After the 16-hour delay both groups showed retention of the previously acquired knowledge. Finally, when we investigated the performance in different parts of the blocks, we found that ASD children did not show an effect of fatigue by the second part of the blocks. Our results suggest that children with ASD have increased implicit procedural learning skills compared to TD children. Differences in cued (explicit) and uncued (implicit) settings indicate that children with ASD are not affected by the lack of explicit instructions in probe blocks, suggesting a resistance for changes in task settings. These findings can help in a more thorough planning of cognitive therapeutic setups for ASD children.

Clinical Neuroscience

[Relationship between sport and traumatic brain injury - risks and sequelaes]

TAMÁS Viktória, KOVÁCS Noémi, BÜKI András

[Traumatic brain injury represents major public health problem worldwide. A typical form of brain injuries is the injury suffered during sports, which according to severity ranges from mild injuries to fatal damages. The significance of the sport related minor head injuries derives form the high incidence, the excessive involvement of the younger age groups, and their potential repetitive nature. The repeated mild head injuries may accumulate, leading to complex structural, neurochemical, neuroendocrine, and psychological alterations, which in long term may result in changes of the patients quality of life and in significant deterioration of participation in the everyday activity. Actually we neither have enough knowledge about the ne-gative consequences, nor the way of prevention, or protection against the harmful long term results. With this study summary we would like to draw attention to the potential hazards emerging from sport injuries, moreover we would like to emphasize the importance of study participation and follow up of articles in this field.]

Clinical Neuroscience

Surveillance and management of patients with tuberous sclerosis complex

FOGARASI András, GYORSOK Zsuzsanna, BODÓ Tímea

Tuberous sclerosis complex (TSC) is an autosomal dominant disease due to the uncontrolled differentiation, proliferation, and migration of cells in several organs. Clinical expression is highly variable, from mild skin findings and asymptomatic brain lesions to seizures, mental retardation, autism, and potentially fatal kidney, cardiac, or pulmonary disease. Aim of this paper is to summarize the diagnostic criteria, surveillance and therapeutic issues of this multisystemic disorder emphasizing the most important neurological consequences. Presenting the state-of-the-art management recommendations and comparing them with the local protocols, we hope that our review might help in the proper assessment of one of the most important single gene disorder.

Clinical Neuroscience

[A családorvosok alvási apnoéval kapcsolatos ismeretei és attitűdjei. Megvalósul-e az OSAS szűrése a járművezetők egészségi alkalmasságának vizsgálata során?]


[Objective - Obstructive sleep apnea syndrome (OSAS) without treatment can cause serious cardiovascular, cardiorespiratory, neurological and other complications. Family physicians have an important role in recognizing the disease. The aim of the study is to assess the knowledge and attitude of family physicians related to sleep apnea. Whether OSAS screening is realized during the general medical checkup for drivers. Methods - In the cross-sectional study we used a validated OSAKA questionnaire in mandatory continuous medical education courses, supplemented with four additional questions. Results - 116 family physicians and 103 family medicine residents filled out the questionnaire. Hungarian family physicians, especially male doctors lack the adequate knowledge of sleep apnea. The average score of female physicians was significantly higher than that of males (13.4±1.8 vs. 11.7±2.6, p=0.005). The more sprecializations the doctor has, the higher the score. Zero or one special examination holders reached 12.5±2.3 points, two special examination holders 12.7±2.2 points. three or four special examination holders reached 14.0±2.1 (p=0.05). Residents’ average score was 12.1±2.4 points, which is higher than that of family doctors (p=0.012). Female residents also had higher average points than male residents (12.6±2.0 vs. 11.3±2.7; p=0.008). The size, location and type of the practice or the doctor’s age did not show any statistically significant correlation with the number of points achieved. According to our regression analysis, corrected to variables in the model, we found correlation between gender and medical knowledge, but there was no correlation between age, number of specialities, body mass index and the theoretical knowledge of the doctors. In terms of attitude female GPs had higher average scores than male GPs (3.5±0.6 vs. 2.9±0.6, p<0.001). Despite the modification of the 13/1992 regulation only 39% of the practices carried out regularly the required OSAS screening as part of the medical examination for a driving licence. Conclusions - Despite the high prevalence and clinical importance of OSAS, GPs often do not recognize sleep apnea and they have difficulty in treating their patients for this problem.]

Clinical Neuroscience

[Multilocus genetic analysis implicates neurodevelopment and immune system in the etiology of schizophrenia]

PULAY Attila József, KOLLER Júlia, NAGY László, MOLNÁR Mária Judit, RÉTHELYI János

[Background - Schizophrenia is a severe psychiatric disorder of poorly understood etiology, characterized by high heritability, multifactorial inheritance and high heterogeneity. Multilocus associaton methods may reduce the genetic heterogeneity and improve the probability of replication between analyses. Objectives - The aims of our study were twofold: 1. To analyse genetic risk factors of schizophrenia by using multilocus genetic tests. 2. To assess the replication probability attributable to the various multilocus tests. Subjects - Discovery set: case-parent trios of unaffected parents and affected probands with a DSM-IV schizophrenia diagnosis (n=16); replication set: schizophrenia cases and unaffected controls (n=5337). Methods - Associations of single nucleotide and indel markers were transferred to gene- and geneset-based associations, furthermore to geneset-enrichment tests and functional annotation cluster analyses in a two-staged designs. Associations with p<0.1 from the discovery set were tested in the replication sample. Familywise p-value correction for multiple comparisons were performed during the replication step. Results - After correction for multiplicity, no significant association or enrichment were detected for gene-based nor canonical pathway analyses, but significant association of the 14q31 cytoband and enrichments of the 5q31 and Xq13 cytobands were found (p_corr: 0.002, 0.006 and 0.048, respectively). Functional annotation clustering yielded statistically significant enrichment scores for clusters of splicing/alternative splicing, neurodevelopment and embryonic development. Improvements in replication probabilty were found with increased test complexity (P_rep: 0, 0.015, 0.21). Conclusions - Our results corroborate the involvement of neurodevelopment, synaptic plasticity and immune mechanisms in the etiology of schizophrenia. Also, our findings indicated improvement of replication probability by using multilocus genetic analyses. ]

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Clinical Neuroscience

A case with reversible neurotoxicity induced by metronidazole

EREN Fulya, ALDAN Ali Mehmet, DOGAN Burcu Vasfiye, GUL Gunay, SELCUK Hatem Hakan, SOYSAL Aysun

Background - Metronidazole is a synthetic antibiotic, which has been commonly used for protozoal and anaerobic infections. It rarely causes dose - and duration - unrelated reversible neurotoxicity. It can induce hyperintense T2/FLAIR MRI lesions in several areas of the brain. Although the clinical status is catastrophic, it is completely reversible after discontinuation of the medicine. Case report - 36-year-old female patient who had recent brain abscess history was under treatment of metronidazole for 40 days. She admitted to Emergency Department with newly onset myalgia, nausea, vomiting, blurred vision and cerebellar signs. She had nystagmus in all directions of gaze, ataxia and incompetence in tandem walk. Bilateral hyperintense lesions in splenium of corpus callosum, mesencephalon and dentate nuclei were detected in T2/FLAIR MRI. Although lumbar puncture analysis was normal, her lesions were thought to be related to activation of the brain abscess and metronidazole was started to be given by intravenous way instead of oral. As lesions got bigger and clinical status got worse, metronidazole was stopped. After discontinuation of metronidazole, we detected a dramatic improvement in patient’s clinical status and MRI lesions reduced. Conclusion - Although metronidazole induced neurotoxicity is a very rare complication of the treatment, clinicians should be aware of this entity because its adverse effects are completely reversible after discontinuation of the treatment.

Clinical Neuroscience

[The role of β-amyloid and mitochondrial dysfunction in the pathogenesis of Alzheimer’s disease]


[Alzheimer’s disease is the most common form of dementia in mid- and late life. The 7-10% of the population over 65 and the 50-60% of the population over 85 are affected by this disease. On the contrary of its prevalence the pathogenesis of the disease is not well defined and there is no effective neuroprotective therapeutic agent. Three predominant neuropathological features of the Alzheimer’s disease brain are intracellular neurofibrillary tangles consisting mainly of the hyperphosphorylated protein t; the extracellular amyloid deposits (neuritic plaques) consisting of amyloid b peptide; and the extensive neuronal cell loss in the hippocampus and in portions of the cerebral cortex. The possible reason of the extensive neuronal cell loss can be the mitochondrial dysfunction observed in Alzheimer’s disease. Beyond the unclarified pathogenesis the causality of these characteristic neuropathologic phenomena are still unknown. In this study we would like to deal with two actual hypotheses, with the amyloid cascade and with the mitochondrial cascade hypotheses. We try to give an overview of these two hypotheses and to depict their interrelationship.]

Hypertension and nephrology

[Plasma ortho-tyrosine/para-tyrosine ratio predicts hyporesponsiveness to erythropoiesis-stimulating agents in dialyzed patients]

KUN Szilárd, MIKOLÁS Esztella, MOLNÁR Gergő Attila, SÉLLEY Eszter, LACZY Boglárka, CSIKY Botond, KOVÁCS Tibor, WITTMANN István

[Objectives: Patients suffering from end-stage renal failure (ESRF) are mostly treated with erythropoiesis-stimulating agents (ESAs). They often show hyporesponsiveness to ESA, which condition is associated with elevated production of free radicals. Phenylalnine (Phe) is converted into para- and ortho-tyrosine (p- and o- Tyr) by hydroxyl free radical. o-Tyr is produced exclusively in this way. However, physiological isomer p-Tyr is formed in significantly higher amounts by phenylalaninehydroxylase, mainly in the kidney. It has been shown that p-Tyr production is decreased in ESRF. As a result, p-Tyr can be replaced by o-Tyr in proteins, e.g. in proteins playing part in signal transduction of erythropoietin. We aimed to study the association of different Tyr isoforms with ESA-responsiveness. Methods: Four groups of volunteers were involved in our cross-sectional study: healthy volunteers (CONTR; n=16), patients on hemodialysis without ESA-treatment (non-ESA-HD; n=8), hemodialyzed patients with ESA-treatment (ESA-HD; n=40) and patients on continuous peritoneal dialysis (CAPD; n=21). Plasma p-, o-Tyr and Phe levels were detected using a high performance liquid chromatography (HPLC)-method, with fluorescence detection. ESA-demand was expressed as ESA-dose, ESAdose/ body weight and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). Multivariate regression models were used to examine predictors of ESA-demand. In these models, most of the known predictors of ESA-hyporesponsiveness were included. Results: Lower p-Tyr levels were found in dialyzed patients compared with control subjects. In contrast, o-Tyr levels and o-Tyr/p-Tyr ratios were higher in dialyzed patients. Regarding dialyzed patients, o-Tyr level and o-Tyr/p-Tyr ratio were higher in ESA-HD than in non-ESA-HD and CAPD groups. Weekly ESA-dose/body weight and ERI1 correlated with o-Tyr/p-Tyr ratio (r=0.441, p=0.001; r=0.434, p=0.001, respectively). Finally, o-Tyr/p-Tyr ratio proved to be an independent predictor of ERI1 (β=0.330, p=0.016). Discussion: Our results suggest that elevation of o-Tyr/p-Tyr ratio could be responsible for ESA-hyporesponsiveness in dialyzed patients.]

Clinical Neuroscience

[Calcium ion is a common denominator in the pathophysiological processes of amyotrophic lateral sclerosis]

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[Amyotrophic lateral sclerosis (ALS), the most frequent motor neuron disease is characterized by progressive muscle weakness caused by the degeneration of the motor neurons in the spinal cord and motor cortex. However, according to the recent observations, ALS is a rather complex syndrome which frequently involves symptoms of cognitive impairment. Therefore, ALS cases can be interpreted in a clinico-pathological spectrum spanning from the classical ALS involving only the motor system to the fronto-temporal dementia. The progression of the disease, however, manifested in the degeneration of the upper and lower motor neurons, is based on the same complex pathobiology. The main elements of the pathomechanism, such as oxidative stress, excitotoxicity, immune/inflammatory processes and mitochondrial dysfunction are well described already, which operate in orchestrated way and amplify the deleterious effect of each other. It is assumed that calcium ions act as a catalyst in this interaction, hence each of the individual mechanisms has strong, positive and reciprocal calcium dependence thus may combine the individual pathological processes into a unified escalating mechanism of neuronal destruction. This review provides an overview of the role of calcium in connecting and amplifying the major mechanisms which lead to degeneration of the motor neurons in ALS. ]

Lege Artis Medicinae

[Systemic diseases in pseudoexfoliation syndrome]


[Pseudoexfoliation syndrome is a condition associated with the production and accumulation of a pathological protein (pseudoexfoliation material). Originally, the syndrome was recognised on the basis of its intraocular symptoms and had been considered to be an isolated eye disease for a long time. However, some 20 years ago it became clear that in pseudoexfoliation syndrome pseudoexfoliation material is present all over in the body. In the past decade, vascular dysfunction associated with this syndrome has been also recognised. Recent studies have shown that pseudoexfoliation syndrome is caused by genetic alterations affecting a lysil oxidaselike (LOXL) protein, LOXL1. LOXL1 has an important role in the synthesis of extracellular material. To our current knowledge, pseudoexfoliation syndrome is a systemic elastosis associated with oxidative stress. Its complications are in part ocular (development of nuclear cataract, zonular damage and development of pseudoexfoliative glaucoma) and in part systemic (dysfunction of capillaries, muscular and elastic arteries, impairment of baroreflex function, increase of arterial rigidity, development of aorta aneurism, recurrent venous occlusions and neurosensory hearing loss). Despite the recognition of the above complications, currently it is not possible to set guidelines of a potential cardiovascular screening for patients with pseudoexfoliation syndrome, since the frequency and significance of systemic complications vary across different populations.]