Severe Central Nervous System Research Articles

Acute Transverse Myelitis Related to Mycoplasma pneumonia

AbstractWe present a case of transverse myelitis caused by Mycoplasma pneumonia. Clinical findings were muscle weakness and decreased deep tendon reflexes of the lower extremities, total sensory loss below T8 level, including loss of superficial cutaneous abdominal reflexes bilaterally, and urinary and stool incontinence. Magnetic resonance imaging revealed segmental edema extending from the cervical to the lumbar cord. Serological criteria were used for the diagnosis of acute infection caused by M. pneumonia. The patient recovered completely after a 15-day treatment of intravenous clarithromycin accompanied by pulsed methylprednisolone. This report emphasizes that myelitis is one of the most severe central nervous system complications related to M. pneumonia infections, and early treatment helps to avoid complications.

Experiences from the first 10 years of a perinatal palliative care program: A retrospective chart review.

Perinatal palliative care is a relatively new component of paediatric palliative care which supports families who are expecting the birth of a child with a life-limiting condition. This study seeks to understand the characteristics of the infants and families referred for perinatal palliative care and the context for referrals in terms of diagnoses, referral characteristics, interventions, and outcomes. A retrospective chart review of infants with prenatally diagnosed life-limiting conditions that were referred for perinatal palliative care. Eighty-five referrals were made for perinatal palliative care during the 10-year period, of which, 84 chose to continue with the service. Average gestational age at diagnosis was 23 weeks, and the mean time between diagnosis and referral to palliative care was 7 weeks. Stillbirths were common, occurring in 29% cases. Of livebirths, 59% of the infants survived for 2 days, and 80% died within 30 days. The most commonly referred conditions were trisomy 13 or 18 (24%), severe central nervous system malformations (20%), and severe congenital cardiac disease (16%). Referrals were most often made by neonatologists (39%), and maternal-fetal medicine specialists (36%). Our study confirms previously observed characteristics of diagnosis, referrals, and outcomes, while providing the most detailed account of lifespans for particular diagnoses to date. Our findings validate the need for perinatal palliative care, as 99% of those referred continued with the service. Future research should adopt a prospective approach to identify critical factors affecting decision making of families and physicians in the wake of a life-limiting diagnosis.

Antiviral efficacy of bromo-anilino substituents of 4,5-dihydrofuran-3-carboxylate compound CW-33 against Japanese encephalitis virus.

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, occasionally causes severe central nervous system disorders in the risk zone where more than 3 billion people reside. Our prior studies demonstrated antiviral potential of 4,5-dihydrofuran-3-carboxylate compound CW-33 (ethyl 2-(3',5'-dimethylanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate) and its derivative CW-33A ((ethyl 2-(2-fluoroanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate) against JEV infection ((Int. J. Mol. Sci. 2016, 17: E1386; Sci. Rep. 2018, 8: 16595). This study synthesized six new CW-33 derivatives containing chloro, or bromo groups at the C-2, C-3, or C-4 of anilino ring of CW-33, and assessed the antiviral activity and mechanisms of these chloro- and bromo-anilino substitutedderivatives. CW-33K, CW-33L and CW-33M had the bromo-substituents at the C-2, C-3, or C-4 of anilino ring of CW-33, respectively, showing the higher anti-JEV activity than CW-33 and other derivatives. CW-33K (ethyl 2-(2-bromoanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate) exhibited the highest antiviral efficacy and therapeutic index. The IC50 value of CW-33K was less than 5 μM for reducing JEV-induced cytopathic effect, virus infectivity and virus yield. CW-33K significantly inhibited the JEV replication at the early and late stages, suppressing viral RNA synthesis and intracellular JEV particle production. The study demonstrated that the CW-33 derivative with a bromosubstitutionat the C-2 anilino ring improved the antiviral activity JEV, providing the structure-antiviral activity relationship for the development of anti-JEV agents.

Research progress of role of inflammasome in spinal cord functional recovery after spinal cord injury

Spinal cord injury is a severe central nervous system damage. The inflammatory response plays a critical role in the secondary injury of spinal cord injury. Inflammasomes which promote the processing, maturation and secretion of interleukin (IL)-1β and IL-18 by regulating the activation of caspase-1 consequentially trigger and aggravate the inflammatory response after spinal cord injury. Targeting upstream and downstream pathways of inflammasomes to interfere with inflammatory response can significantly promote functional repair after spinal cord injury. This review will focus on the inflammasome types, the mode of activation and the treatment strategies of inflammasomes after spinal cord injury, so as to provide reference for researches on inflammation and spinal injury repair. Key words: Spinal cord injuries; Inflammation; Caspase-1

Imaging appearance of acute disseminated encephalomyelitis: a study of 22 cases

L'Encéphalomyélite aiguë disséminée (ADEM) est une cause rare d'encéphalite de l'adulte, caractérisée par des lésions inflammatoires de la substance blanche du système nerveux central (SNC). Le tableau clinique initial peut mimer un tableau sévère d'infection du SNC avec fièvre, encéphalopathie, crises convulsives, ou un tableau de sclérose en plaque. Le but de notre travail est de rapporter les caractéristiques épidémiologiques, cliniques, radiologiques, thérapeutiques et évolutives de l'ADEM, aussi évaluer l'apport des séquences IRM dans le diagnostic, le suivi et le pronostic de la maladie. Il s'agit d'une étude rétrospective des dossiers cliniques et radiologiques d'ADEM sur 11 ans (janvier 2006-janvier 2017) portant sur 22 cas suivis au service de neurologie et explorés au niveau du service d'imagerie médicale de l'Hôpital Militaire d'Instruction Mohammed V de Rabat. L'âge moyen des patients était de 35 ans [12-57ans]. Une notion d'infection récente était retrouvée dans 31%, une vaccination récente dans 4%. La symptomatologie était dominée par un déficit neurologique focal avec un pourcentage de 72%. La TDM était normale dans 78%. L'IRM a montré un hyper signal FLAIR de la SB sus et sous tentoriel dans 70%, sans restriction de la diffusion dans la totalité des cas, avec rehaussement des lésions dans 27%, l'atteinte de la moelle cervicale estimait à 68%. L'évolution clinique et radiologique était favorable dans la totalité des cas.

Intravenous delivery of a chemically modified sulfamidase efficiently reduces heparan sulfate storage and brain pathology in mucopolysaccharidosis IIIA mice

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) characterized by severe central nervous system (CNS) degeneration. The disease is caused by mutations in the SGSH gene coding for the lysosomal enzyme sulfamidase. Sulfamidase deficiency leads to accumulation of heparan sulfate (HS), which triggers aberrant cellular function, inflammation and eventually cell death. There is currently no available treatment against MPS IIIA. In the present study, a chemically modified recombinant human sulfamidase (CM-rhSulfamidase) with disrupted glycans showed reduced glycan receptor mediated endocytosis, indicating a non-receptor mediated uptake in MPS IIIA patient fibroblasts. Intracellular enzymatic activity and stability was not affected by chemical modification. After intravenous (i.v.) administration in mice, CM-rhSulfamidase showed a prolonged exposure in plasma and distributed to the brain, present both in vascular profiles and in brain parenchyma. Repeated weekly i.v. administration resulted in a dose- and time-dependent reduction of HS in CNS compartments in a mouse model of MPS IIIA. The reduction in HS was paralleled by improvements in lysosomal pathology and neuroinflammation. Behavioral deficits in the MPS IIIA mouse model were apparent in the domains of exploratory behavior, neuromuscular function, social- and learning abilities. CM-rhSulfamidase treatment improved activity in the open field test, endurance in the wire hanging test, sociability in the three-chamber test, whereas other test parameters trended towards improvements. The unique properties of CM-rhSulfamidase described here strongly support the normalization of clinical symptoms, and this candidate drug is therefore currently undergoing clinical studies evaluating safety and efficacy in patients with MPS IIIA.

Anti-inflammatory and antiviral effects of minocycline in enterovirus 71 infections

Enterovirus 71 (EV71) brainstem encephalitis (BE) is divided into—uncomplicated BE, autonomic nervous system (ANS) dysregulation, and pulmonary edema (PE)—based on cytokine-mediated severe systemic and central nervous system (CNS) inflammatory responses. Minocycline has been found to have anti-inflammatory and immunomodulatory properties in infectious and inflammatory neurological disease models. The effects of minocycline on EV71 infection were studied in vitro and in vivo experiments. The minocycline treatment (100–300 μg/mL) on cytokine expressions and viral replications were investigated in rhabdomyosarcoma (RD), U-87MG, and THP-1 cells. The mouse-adapted-EV71 strain (MP4)-infected 7-day-old ICR mice model was used to explore the anti-inflammatory and antiviral effects of minocycline (1 and 5 μg/g) for the treatment of EV71 infection. In in vitro, minocycline reduced cytopathic effects (CPEs), viral protein expressions, viral titers, the levels of interleukin (IL)-6 and IL-8 and relative mRNA expressions of IL-12p40, IL-1β, and tumor necrosis factor (TNF) after EV71 infection. The levels of TNF, IL-1β, IL-6, and IL-8 decreased with a single dose of minocycline in EV71-infected THP-1 cells. Double-dose minocycline treatment demonstrated more effective reduction in cytokines. In the MP4-infected animal model, clinical scores, mortality rates and viral titers in various brain tissues were decreased evidently after double-dose minocycline treatment. Minocycline inhibited IL-6 and granulocyte colony-stimulating factor (G-CSF) in plasma and TNF in the cerebellum. Minocycline has properties that enable it to function both as an anti-inflammatory and antiviral agent in EV71 infection. These results evidence its potential usefulness in clinical treatment.

Fetal aqueductal stenosis: Prenatal diagnosis and intervention.

Fetal severe central nervous system ventriculomegaly is associated with poor neurologic outcomes, usually driven by a primary malformation, deformation, or disruption of brain parenchyma. In utero shunting of excess cerebrospinal fluid (CSF) in hopes of improving neurologic outcomes was attempted in the 1980s but was abandoned due to perceived lack of effect, likely due to technological limitations of the time that precluded proper patient selection. Little progress on the antenatal management of severe ventriculomegaly has been made in the intervening decades. A multidisciplinary, evidence-based reassessment of ventriculoamniotic shunting for isolated fetal aqueductal stenosis (FAS), a unique form of severe ventriculomegaly (supratentorial intracranial hypertension), is currently underway. An accurate diagnosis of FAS must precede in utero intervention. Magnetic resonance imaging (MRI) will be an excellent adjunct to high-resolution prenatal ultrasound and next-generation genetic testing to correctly diagnose FAS in a timely fashion while excluding other intracranial and extracranial anomalies. This manuscript will briefly discuss the history, current management, and future directions of the prenatal diagnosis and potential intervention for FAS.

Arsenic Neurotoxicity in Humans.

Arsenic (As) contamination affects hundreds of millions of people globally. Although the number of patients with chronic As exposure is large, the symptoms and long-term clinical courses of the patients remain unclear. In addition to reviewing the literature on As contamination and toxicity, we provide useful clinical information on medical care for As-exposed patients. Further, As metabolite pathways, toxicity, speculated toxicity mechanisms, and clinical neurological symptoms are documented. Several mechanisms that seem to play key roles in As-induced neurotoxicity, including oxidative stress, apoptosis, thiamine deficiency, and decreased acetyl cholinesterase activity, are described. The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers. A sural nerve biopsy showed the axonal degeneration of peripheral nerves mainly in small myelinated and unmyelinated fibers. Exposure to high concentrations of As causes severe central nervous system impairment in infants, but no or minimal impairment in adults. The exposure dose–response relationship was observed in various organs including neurological systems. The symptoms caused by heavy metal pollution (including As) are often nonspecific. Therefore, in order to recognize patients experiencing health problems caused by As, a multifaceted approach is needed, including not only clinicians, but also specialists from multiple fields.

A retrospective cohort study of plasma exchange in central nervous system demyelinating events in children

BackgroundPlasma exchange (PLEX) may improve recovery of acute central nervous system (CNS) demyelinating events related to multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), and MOG-antibody associated demyelination (MOG) if recovery with pulse steroids (PS) is incomplete. Although there is a single randomized controlled trial in adults, there are limited case series in children. We aimed to describe the effectiveness and safety of PLEX in children with acute events of MS, NMOSD, TM, ADEM, and MOG with limited improvement after PS. MethodsThis was a retrospective cohort study of children with acute CNS demyelinating events seen at a single tertiary referral center who received PLEX as a second- or third-line therapy between 2006 and 2018. Through chart review of clinical notes, presence of clinical improvement by physician assessment was recorded pre- and post-PS and pre- and post-PLEX. Expanded Disability Status Scale (EDSS) scores were collected pre- and post-PLEX. We evaluated the number who improved clinically with PLEX and compared pre- and post-PLEX EDSS with Wilcoxon matched pairs signed-rank test. Results26 patients followed at the Pediatric MS Center at the University of California, San Francisco received PLEX for acute events of MS (n = 15), NMOSD (n = 7), MOG (n = 2), TM (n = 1), and ADEM (n = 1). At time of PLEX initiation, median age was 13.5 years (range 3–17) and median time between the acute event onset and PLEX initiation was 22 days (range 3–94). 14 of 24 patients had documented clinical improvement after PS. Of those who improved during PS (n = 14), 13 had additional improvement after PLEX. Of those with no improvement after PS (n = 10), 8 improved after PLEX. 16 of 26 patients had pre- and post-PLEX EDSS scores available. Median pre-PLEX EDSS score was 4.0 (range 3.0–8.0), and median post-PLEX EDSS score was 3.75 (range 0–8.0) (p = 0.062). 5 patients had improved EDSS scores by 1 or more points. Adverse events during PLEX included hypotension (n = 3), nausea (n = 2), headache (n = 2), hypocalcemia (n = 2), hypofibrinogenemia (n = 2), thrombocytopenia (n = 1), spinal cord hemorrhage (n = 1), acute non-occlusive thrombosis of internal jugular vein (n = 1), occlusion of the central line (n = 1), edema of the neck (n = 1), and gastrointestinal discomfort (n = 1). ConclusionsPLEX is an overall well-tolerated second-line treatment option for pediatric patients with severe acute CNS demyelinating events with limited response to PS.

Nörolojik tutulumu olmayan brusellozlu çocuk ve ergenlerin depresyon açısından değerlendirilmesi

Purpose: Brucella infection may appear with varying clinical manifestations, from subclinical infection to severe bacteremia or central nervous system infections. The aim of this study was to compare depression rates in brucellosis cases without neurobrucellosis with a non-brucellosis control group.Materials and Methods: One hundred and twenty children and adolescents, 60 with brucellosis and 60 controls, were included in the study. All subjects were administered the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children -Present and Lifetime Version-Turkish Version (K-SADS-PL-T), and psychiatric evaluation was performed on the basis of DSM-5 diagnostic criteria. Subjects were also assessed with the administration of the Children's Depression Inventory (CDI) and a detailed information form.Results:Depression was diagnosed in 16 (26.7%) of the patients with brucellosis, and in 3 (5%) of the control group, the incidence being significantly higher in the case group (p=0.002). CDI scores were also higher in the case group than in the control group (p< 0.001).Conclusion:The higher rate of depression in children and adolescents with brucellosis, even in the absence of neurological involvement, suggests the importance of these cases being evaluated in psychological terms.

Pathological Findings in Lowland Tapirs (Tapirus terrestris) Killed by Motor Vehicle Collision in the Brazilian Cerrado

The lowland tapir (Tapirus terrestris) is the largest land mammal in South America. The species faces steady population decline due to poaching, habitat loss and fragmentation, road-kill, pesticide pollution, competition with domestic livestock and fires, among other threats. The lowland tapir is currently listed as vulnerable to extinction. Little information is available about natural disease processes for the species. This study aimed to report the pathological findings recorded in a cohort of 35 lowland tapirs killed by motor vehicle collision (MVC) on highways of Mato Grosso do Sul State, Brazil, between 2015 and 2018. The main gross pathological findings were those associated with MVC, primarily involving skeletal fractures and internal multiorgan damage with extensive bleeding and/or severe central nervous system injury. The most prevalent concurrent histopathological findings, unrelated to the cause of death, were: adrenal gland degeneration, necrosis and loss of fascicular and reticular cells with replacement fibrosis and cortical atrophy (9/15; 60%); interstitial pneumonia (20/34; 59%); glossitis (9/24; 38%); pulmonary anthracosis (12/34; 35%); colitis (9/28; 32%); and cholangitis/pericholangitis (9/35; 26%). The aetiopathogeneses and clinicopathological significance of some of these findings are unclear; however, parasitic infections appear to be common. Our results highlight the importance of wildlife health information obtained through the study of carcasses of roadkills.

Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection.

Meningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs.

Enterovirus A71 VP1 Variation A289T Decreases the Central Nervous System Infectivity via Attenuation of Interactions between VP1 and Vimentin In Vitro and In Vivo.

Vimentin (VIM) is a surface receptor for enterovirus-A71, mediating the initial binding and subsequent increase in EV-A71 infectivity. The caspid protein VP1 variation, A289T, is reportedly closely associated with less severe central nervous system (CNS) infections in humans. However, it is unclear whether VIM is associated with a reduction in CNS infections of EV-A71 in the presence of A289T. We investigated whether VIM served as a receptor for EV-A71 in the presence of an A298T substitution in VP1. EV-A71-289A and EV-A71-289T were used to infect human rhabdomyosarcoma cells, control human brain microvascular endothelial cells (HBMECs), and VIM-knockout (KO) HBMECs and inoculated BALB/c mice, SV129 mice, and VIM-KO SV129 mice. Furthermore, we cloned VP1-289A-Flag and VP1-289T-Flag proteins for co-immunoprecipitation analysis. Analysis of viral function revealed that the capacity of viral attachment, replication, and protein synthesis and secretion decreased in HBMECs during an EV-A71-289A infection, the infectivity being higher than that of EV-A71-289T upon VIM-KO. Histopathological and immunohistochemical analyses of brain tissue revealed that cerebral cortical damage was more extensive in EV-A71-289A than in EV-A71-289T infections in control SV129 mice; however, no significant difference was observed upon VIM-KO. Co-immunoprecipitation analysis revealed an interaction between VP1 and VIM, which was attenuated in VP1 harboring A289T; however, this attenuation was reversed by VIM (1-58) peptide. The A289T variation of VP1 specifically decreased the virulence of EV-A71 in HBMECs, and the attenuated interaction between VP1 harboring the A289T variation and VIM essentially decreased the CNS infectivity of EV-A71 in vitro and vivo.

OAS1 gene polymorphism is associated with central nervous system involvement in children with enterovirus 71 infection

We investigated the association between OAS1 gene polymorphism and susceptibility to central nervous system (CNS) involvement of enterovirus (EV)71 infection. This case-control study was conducted among 180 children with EV71 infection, including 72 with mild infections without any complications and 108 with severe infections and CNS involvement; 201 children undergoing routine physical examination served as the healthy controls. For all the participants, the single nucleotide polymorphisms (SNPs) at OAS1 rs2660 and rs1131454 were analyzed using SNPscan multiple SNP typing methods. No significant differences were found between the case and control groups in genotype or allele distributions of rs2660 and rs1131454. OAS1 rs2660 polymorphism was significantly different between the children with CNS involvement and those with mild EV71 infection, and the genotype AG frequency was higher and the genotype GG frequency was lower in children with CNS involvement. No significant difference was found in the distribution of genotypes or alleles of rs1131454 between the children with CNS involvement and those with mild EV71 infection. OAS1 gene rs2660 and rs1131454 SNPs are not associated with the susceptibility to or CNS involvement of EV71 infection, but OAS1 rs2660 SNPs are significantly correlated with the susceptibility to CNS involvement in EV71 infection. Children carrying OAS1 rs2660 AG genotype are more likely to have CNS involvement after EV71 infection.

Severe Central and Peripheral Nervous System Toxicity Associated with Vinblastine in the Treatment of Hodgkins Lymphoma (P3.4-025)

Severe Central and Peripheral Nervous System Toxicity Associated with Vinblastine in the Treatment of Hodgkins Lymphoma (P3.4-025)

The Trp73 Mutant Mice: A Ciliopathy Model That Uncouples Ciliogenesis From Planar Cell Polarity.

p73 transcription factor belongs to one of the most important gene families in vertebrate biology, the p53-family. Trp73 gene, like the other family members, generates multiple isoforms named TA and DNp73, with different and, sometimes, antagonist functions. Although p73 shares many biological functions with p53, it also plays distinct roles during development. Trp73 null mice (p73KO from now on) show multiple phenotypes as gastrointestinal and cranial hemorrhages, rhinitis and severe central nervous system defects. Several groups, including ours, have revisited the apparently unrelated phenotypes observed in total p73KO and revealed a novel p73 function in the organization of ciliated epithelia in brain and trachea, but also an essential role as regulator of ependymal planar cell polarity. Unlike p73KO or TAp73KO mice, tumor-prone Trp53−/− mice (p53KO) do not present ependymal ciliary or planar cell polarity defects, indicating that regulation of ciliogenesis and PCP is a p73-specific function. Thus, loss of ciliary biogenesis and epithelial organization might be a common underlying cause of the diverse p73KO-phenotypes, highlighting Trp73 role as an architect of the epithelial tissue. In this review we would like to discuss the data regarding p73 role as regulator of ependymal cell ciliogenesis and PCP, supporting the view of the Trp73-mutant mice as a model that uncouples ciliogenesis from PCP and a possible model of human congenital hydrocephalus.

The clinical significance of severe human parechovirus infections in newborns and infants in Hungary

Most human parechovirus (HPeV, family Picornaviridae) infections are asymptomatic but may cause gastroenteritis in children. New reports show that HPeVs can be associated with severe central nervous system symptoms and sepsis-like syndromes in infants. The clinical significance of HPeVs in Hungary has not been investigated before. The aim of this study was to detect genotype HPeV in faecal samples of children and analysis of the clinical symptoms. For the detection and genotyping of HPeV strains, reverse transcription-polymerase chain reaction and sequencing methods were used from faecal samples of children with gastroenteritis divided into three groups: group A) hospitalised children younger than 10 years (n = 75); group B) 0-12 months infants (n = 237) and group C) children less than 18 years of age with sepsis-like/neurological symptoms (n = 105) were tested. Three HPeV positive samples (3/75, 4%) were found in group A, two of them belong to the HPeV type 1, the third was non-typeable. All positive samples were from infants of 7 to 11 months of age. In group B, HPeV was detected in 6.8% (16/237) of the samples. Five were HPeV1, six were HPeV3 and five were non-typeable. While most of the infants with HPeV1 (4/5) did not require hospitalisation, 83% of the HPeV3 infected infants (5/6) did. Five (4.8%) HPeV strains detected from children less than 18 years of age with sepsis-like/neurological symptoms (group C) belonged to HPeV1 (three) and HPeV3 (two). All positive samples were from hospitalised infants less than 2 months of age. HPeV1 infections are less severe in infants than HPeV3 infections. The leading symptom of HPeV1 was diarrhoea, although in infants less than 1-2 months neurological symptoms (somnolence, lassitude) were also present. HPeV3 infections were more common among newborns. The main symptoms of severe HPeV3 infection are: gastroenteritis (7/8), fever ≥38 °C (6/7), loss of appetite (6/7), rash (4/7), somnolence/lassitude (3/7), sepsis-like syndrome (3/7) and respiratory symptoms (2/7). Orv Hetil. 2019; 160(10): 386-395.

Neuronanomedicine: An Up-to-Date Overview.

The field of neuronanomedicine has recently emerged as the bridge between neurological sciences and nanotechnology. The possibilities of this novel perspective are promising for the diagnosis and treatment strategies of severe central nervous system disorders. Therefore, the development of nano-vehicles capable of permeating the blood–brain barrier (BBB) and reaching the brain parenchyma may lead to breakthrough therapies that could improve life expectancy and quality of the patients diagnosed with brain disorders. The aim of this review is to summarize the recently developed organic, inorganic, and biological nanocarriers that could be used for the delivery of imaging and therapeutic agents to the brain, as well as the latest studies on the use of nanomaterials in brain cancer, neurodegenerative diseases, and stroke. Additionally, the main challenges and limitations associated with the use of these nanocarriers are briefly presented.

Classical dopamine agonists.

The pioneering work of Arvid Carlsson has laid the foundation for a number of innovative therapies for severe central nervous system (CNS) diseases. He was awarded the Nobel Price for the discovery of the crucial role of dopamine (DA) as a neurotransmitter in the CNS, thereby forming the basis for the symptomatic therapy of Parkinson's disease (PD) with L-DOPA and subsequently dopaminergic drugs. Parenteral apomorphine has a short lasting effect in PD, bromocriptine can be administered orally and has a long-lasting effects but is poorly tolerated. Lisuride on the other hand has a high affinity to DA receptors and can be administered orally, parenterally or via the transdermal route of administration. Last but not least Carlsson developed the concepts of presynaptic effects of DA agonists as well as DA partial agonism potentially innovative mechanisms for treatment of PD and schizophrenia.