Cerebral blood flow regulation following hypoxic attacks and seizures in the newborn piglet

Asphyxia affects approximately 5-10 % of the newborn infants and may have life-long adverse consequences, such as mental retardation and epileptiform seizures. Both hypoxic attacks, including asphyxia and cerebral ischemia, and seizures disrupt the coupling between cerebral metabolic needs and blood supply thereby lead to neuronal damage and impaired cerebrovascular reactivity and function. Although hypoxia is reversed the fastest by ventilation with 100% oxygen (O2) upon resuscitation, hyperoxygenation may cause additional damage. We tested if reventilation with room air (RA, 21% O2) or 100% O2 after asphyxia would differentially affect haemodynamic events and neuronal damage in different brain areas of newborn pigs. We found O2 toxicity after asphyxia in the hippocampus and cerebellum, but not in the cerebral cortex or basal ganglia. The observed regional differences may be associated with local haemodynamic factors, since reactive hyperemia was significantly higher in the cerebellum than in the cerebral cortex. Carbon dioxide (CO2) is a powerful dilator of the cerebral vessels by a mechanism involving cyclooxygenase (COX) metabolites in the newborn. This responsiveness to CO2/hypercapnia is sensitive to hypoxia/ischemia and is used as a measure of the cerebrovascular function. Acetazolamide (AZD), a carbonic anhydrase inhibitor, produces cerebral vasodilation presumably due to CO2 retention and acidosis. We examined if cerebrovascular effects of AZD were similar to hypercapnia in the newborn pig. The mechanism of AZD-induced cerebral vasodilation appears to be similar/identical to hypercapnia, since both reactions were abolished by the non-selective COX-inhibitor indomethacin, unaltered by ibuprofen and L-NAME and were significantly attenuated after ischemia/reperfusion. Cerebrovascular function is protected against seizure-induced damage by enhanced endogenous carbon monoxide (CO) production by heme oxygenase. We hypothesized that exogenous CO derived from the CO releasing molecule-A1 (CORM-A1) exerts protective effects on the cerebral microvasculature. Seizures reduced postictal cerebrovascular responsiveness to physiologically relevant vasodilators (bradykinin, hemin, and isoproterenol), which was prevented by CORM-A1-pretreatment. We provided novel data on the cerebrovascular regulation in the hypoxic and epileptic newborn

Novel heterozygous STUB1 gene mutation causes SCA48 in a Hungarian patient

Spinocerebellar ataxia type 48 (SCA48) is an autosomal dominantly inherited disease characterized by gait and limb ataxia, cerebellar dysarthria, cognitive impairment, psychiatric abnormalities and variable types of movement disorders. To date, more than 30 STUB1 gene (NM_005861.4) mutations have been described in the genetic background of SCA48.The aim of this short report was to demonstrate the first Hungarian SCA48 patient caused by a novel STUB1 missense mutation (c.788G>C, p.Arg263Pro). The characteristics of detailed neurological phenotype, brain MRI and genetic assessment are presented and compared to previously published cases. The most important neurological findings of the patient were gait ataxia, dysarthria, cognitive decline and psychiatric problems including depression, anxiety and mild impulsivity. The brain MRI demonstrated cerebellar atrophy with posterolateral predominance and frontal lobe cortical atrophy. Clinical exome sequencing examination identified the above-mentioned missense variant located in the significant ubiquitinase domain of the CHIP protein.In this paper the first Hungarian SCA48 patient was described with characteristic neuropsychiatric signs and brain MRI abnormalities, due to a novel STUB1 gene missense mutation

The clinical manifestations of two novel SPAST mutations

The purpose of this chapter is to give an overview of the main issues in regard to software patenting in the 21st century. The focus is on the question of patentability of software, since this is the area which has caused the most problems for patent offices and courts. The main systems of concern are the European and U.S. patent systems. The chapter begins with a presentation of the concept of software in section 2, followed by section 3 with a presentation of IP and patents and the international legal context as well as the European and U.S. patent systems. In section 4 the debate regarding the patent system as a proper protection system for software is discussed. Section 5 outlines the international patent rules pertaining to software which are contained in the TRIPS agreement. Section 6 concentrates on the European approach to software and business methods’ patentability, while Section 7 explores the corresponding U.S. approach. Finally there are some brief final words in Section 8

Acetazolamide induces indomethacin and ischaemia-sensitive pial arteriolar vasodilation in the piglet

Aim: Acetazolamide (AZD) produces cerebral vasodilation. The underlying mechanism is unclear, but it is assumed to be largely due to CO2 retention and acidosis. We tested if cerebrovascular effects of AZD were similar to hypercapnia in the newborn pig. Methods: We used the closed cranial window/intravital microscopy technique to determine pial arteriolar diameters simultaneously with laser-Doppler flowmetry (LDF) to monitor cortical blood perfusion. Anaesthetized (Na-thiopenthal + alpha-chloralose), ventilated, 1-day-old instrumented piglets (n = 38) were divided into five experimental groups: time control (n = 11), indomethacin, ibuprofen, N-omega-nitro-L-arginine methyl ester (L-NAME) treatments (1, 30, 15 mg/kg, i.v., n = 6, 6, 4, respectively), and global ischaemia/reperfusion (I/R, 10 min induced by elevated intracranial pressure, n = 11). Responses to 5-10% inhaled CO2 were recorded before and after the treatments, and then in a similar manner to AZD (10-20 mg/kg, i.v.). Results: Hypercapnia and AZD produced pial arteriolar vasodilation and increases in cortical perfusion. Consistent with previous data, hypercapnia-induced changes were abolished by indomethacin, unaltered by ibuprofen and L-NAME and were significantly attenuated after I/R. AZD-induced vasodilation was also sensitive to indomethacin and I/R and was unaltered by ibuprofen or L-NAME

Spectrum of neurodevelopmental disabilities: a cohort study in Hungary

The spectrum of neurodevelopmental disabilities was studied in a cohort of patients in Hungary. A search for etiologies and assessment of the degree of intellectual disability were carried out. The study included 241 (131 boys) patients. Disability occurred without any prenatal, perinatal, and/or neonatal adverse events in 167 patients. They were classified into the following subgroups: genetic syndromes with recognized etiology, global developmental delay/intellectual disability in association with dysmorphic features but unknown etiology, global developmental delay/intellectual disability without dysmorphic features and recognized etiology, brain malformations, inborn errors of metabolism, leukoencephalopathies, epileptic syndromes, developmental language impairment, and neuromuscular disorders. Adverse events occurred in 74 children classified into subgroups such as cerebral palsy after delivery preterm or at term, and disabilities without cerebral palsy. The etiology was identified in 66.4%, and genetic diagnosis was found in 19.5%. Classification of neurodevelopmental disorders contribute to etiological diagnosis, proper rehabilitation, and genetic counseling

Reventilation with room air or 100% oxygen after asphyxia differentially affects cerebral neuropathology in newborn pigs

Aim: To test if reventilation with room air ( RA) or 100% oxygen ( O-2) after asphyxia would differentially affect neuronal damage in different brain areas of newborn pigs. Methods: Anaesthetized piglets were subjected to 10 min asphyxia ( n = 27) or served as time controls ( n = 7). Reventilation started with either RA or O-2 for 1 h, and was continued with RA for an additional 1 - 3 h. Cortical or cerebellar blood flow was assessed with laser-Doppler flowmetry ( LDF). Haematoxylin/eosin-stained sections from six brain regions were prepared for blinded neuropathological examination and scoring. Results: Asphyxia resulted in significant neuronal damage compared to time controls in all areas examined except the pons. O2 ventilation elicited greater neuronal lesions in the hippocampus and the cerebellum but smaller damage in the basal ganglia compared to RA. The assessed physiological parameters including the LDF signals were similar in both ventilation groups, except for PaO2 in the first hour of reventilation ( RA 75 +/- 5 mmHg, O-2 348 +/- 57 mmHg; p < 0.05). Interestingly, however, reactive hyperaemia was much higher in the O-2-sensitive cerebellum as compared with the cortex ( 1101 +/- 227 vs 571 +/- 73; p < 0.05, area under the curve). Conclusion: O-2 toxicity after asphyxia was demonstrated in the piglet hippocampus and cerebellum but not in the cerebral cortex or basal ganglia. The observed regional differences may be associated with local haemodynamic factors

A novel de novo truncating variant in a Hungarian patient with CTNNB1 neurodevelopmental disorder

We aimed to elucidate the underlying disease in a Hungarian family, with only one affected family member, a 16-year-old male Hungarian patient, who developed global developmental delay, cognitive impairment, behavioral problems, short stature, intermittent headaches, recurrent dizziness, strabismus, hypermetropia, complex movement disorder and partial pituitary dysfunction. After years of detailed clinical investigations and careful pediatric care, the exact diagnosis of the patient and the cause of the disease was still unknown.We aimed to perform whole exome sequencing (WES) in order to investigate whether the affected patient is suffering from a rare monogenic disease.Using WES, we identified a novel, de novo frameshift variant (c.1902dupG, p.Ala636SerfsTer12) of the catenin beta-1 (CTNNB1) gene. Assessment of the novel CTNNB1 variant suggested that it is a likely pathogenic one and raised the diagnosis of CTNNB1 neurodevelopmental disorder (OMIM 615,075).Our manuscript may contribute to the better understanding of the genetic background of the recently discovered CTNNB1 neurodevelopmental disorder and raise awareness among clinicians and geneticists. The affected Hungarian family demonstrates that based on the results of the clinical workup is difficult to establish the diagnosis and high-throughput genetic screening may help to solve these complex cases