Seizures Are Associated with Blood-Brain Barrier Disruption in a Piglet Model of Neonatal Hypoxic-Ischaemic Encephalopathy.

Seizures in the neonatal period are most often symptomatic of central nervous system (CNS) dysfunction and the most common cause is hypoxic-ischaemic encephalopathy (HIE). Seizures are associated with poor long-term outcomes and increased neuropathology. Blood-brain barrier (BBB) disruption and inflammation may contribute to seizures and increased neuropathology but are incompletely understood in neonatal HIE. The aim of this study was to investigate the impact of seizures on BBB integrity in a preclinical model of neonatal hypoxic-ischaemic (HI) injury. Piglets (age: <24 h) were subjected to a 30-min HI insult followed by recovery to 72 h post-insult. Amplitude-integrated electroencephalography (aEEG) was performed and seizure burden and background aEEG pattern were analysed. BBB disruption was evaluated in the parietal cortex and hippocampus by means of immunohistochemistry and Western blot. mRNA and protein expression of tight-junction proteins (zonula-occludens 1 [ZO1], occludin [OCLN], and claudin-5 [CLDN5]) was assessed using quantitative polymerase chain reaction (qPCR) and Western blot. In addition, mRNA from genes associated with BBB disruption vascular endothelial growth factor (VEGF) and matrix metalloproteinase 2 (MMP2) as well as inflammatory cytokines and chemokines was assessed with qPCR. Piglets that developed seizures following HI (HI-Sz) had significantly greater injury, as demonstrated by poorer aEEG background pattern scores, lower neurobehavioural scores, and greater histopathology. HI-Sz animals had severe IgG extravasation into brain tissue and uptake into neurons as well as significantly greater levels of IgG in both brain regions as assessed by Western blot. IgG protein in both brain regions was significantly associated with seizure burden, aEEG pattern scores, and neurobehavioural scores. There was no difference in mRNA expression of the tight junctions, however a significant loss of ZO1 and OCLN protein was observed in the parietal cortex. The inflammatory genes TGFß, IL1ß, IL8, IL6, and TNFα were significantly upregulated in HI-Sz animals. MMP2 was significantly increased in animals with seizures compared with animals without seizures. Increasing our understanding of neuropathology associated with seizure is vital because of the association between seizure and poor outcomes. Investigating the BBB is a major untapped area of research and a potential avenue for novel treatments.

Dopamine in psychiatry: a historical perspective.

Dopamine is the principal transmitter of several central nervous system pathways originating in the midbrain and critically involved in motor activity, learning and motivation, disruptions of which have been implicated in a number of disorders, including Parkinson disease and schizophrenia. Dopamine played a particularly significant role in the history of neurochemistry. Following a series of investigations between 1957 and 1965, commencing in the laboratory and completed in the clinic, the significance of chemical neurotransmission for normal CNS function was first demonstrated in the case of dopamine.

Gnomoniopsis smithogilvyi causes chestnut canker symptoms in Castanea sativa shoots in Switzerland.

A screening of Castanea sativa scions for grafting for the presence of endophytes showed that the opportunistic fungal pathogen Gnomoniopsis smithogilvyi was the most abundant member of the endophytic flora. This fungus is known as a pathogen affecting chestnut fruits in Italy and Australia. Here, we present evidence that it causes cankers very similar to the ones due to Cryphonectria parasitica infection on twigs and scions of chestnut trees. We found natural infections of G. smithogilvyi in healthy grafted plants as well as in scions from chestnut trees. The identity of the fungus isolated from asymptomatic tissues was verified by applying Koch's postulates and corroborated by DNA sequencing of four different gene regions. In contrast to C. parasitica that appears on the bark as yellow to orange pycnidia, stromata and slimy twisted tendrils, G. smithogilvyi forms orange to red and black pycnidia, gray stromata and cream-colored to beige slimy twisted tendrils on the bark. These Swiss strains are closely related to G. smithogilvyi strains from Australia and from New Zealand, Gnomoniopsis sp. and Gnomoniopsis castanea from New Zealand, Italy, France and Switzerland. While the strains from Ticino are genetically very close to G. smithogilvyi and G. castanea from Italy, the differences between the strains from Ticino and Geneva suggest two different origins. The present study supports the hypothesis that a single species named G. smithogilvyi, which is known to be the agent of chestnut rot, also causes wood cankers on chestnut.

Synthesis and Spectral Characterisation of Fabricated Cerium-Doped Magnesium Oxide Nanoparticles: Evaluation of the Antimicrobial Potential and Its Membranolytic Activity through Large Unilamellar Vesicles.

Considerable attention has been given to Magnesium oxide nanoparticles lately due to their antimicrobial potential, low toxicity to humans, high thermal stability, biocompatibility, and low cost of production. However, their successful transformation into sustainable drugs is limited due to their low membrane permeability, which reduces their bioavailability in target cells. Herein we propose Cerium-doped magnesium oxide nanoparticles (MgOCeNPs) as a powerful solution to above mentioned limitations and are compared with MgO NPs for their membrane permeability and antimicrobial activity. Both pure and Ce-doped were characterized by various spectroscopic and microscopic techniques, in which an X-ray diffraction (XRD) examination reveals the lattice patterns for doped nanoparticles. Furthermore, Atomic Force Microscopy (AFM) revealed the three-dimensional (3D) structure and height of the nanoparticle. The crystal structure (FCC) of MgO did not change with Ce doping. However, microstructural properties like lattice parameter, crystallite size and biological activity of MgO significantly changed with Ce doping. In order to evaluate the antimicrobial potential of MgOCeNPs in comparison to MgO NPs and to understand the underlying mechanisms, the antibacterial activity was investigated against human pathogenic bacteria E. coli and P. aeruginosa, and antifungal activity against THY-1, a fungal strain. MgOCeNPs were studied by several methods, which resulted in a strong antibacterial and antifungal activity in the form of an elevated zone of inhibition, reduced growth curve, lower minimum inhibitory concentration (MIC80) and enhanced cytotoxicity in both bacterial and fungal strain as compared to MgO nanoparticles. The study of the growth curve showed early and prolonged stationary phase and early decline log phase. Both bacterial and fungal strains showed dose-dependent cytotoxicity with enhancement in intracellular reactive oxygen species (ROS) generation and formation of pores in the membrane when interacting with egg-phosphatidylcholine model Large Unilamellar Vesicles (LUVs). The proposed mechanism of MgOCeNPs toxicity evidently is membranolytic activity and induction of ROS production, which may cause oxidative stress-mediated cytotoxicity. These results confirmed that MgOCeNPs are a novel and very potent antimicrobial agent with a great promise of controlling and treating other microbes.

Novel method of transpulmonary pressure measurement with an air-filled esophageal catheter.

BACKGROUND: There is a strong rationale for proposing transpulmonary pressure-guided protective ventilation in acute respiratory distress syndrome. The reference esophageal balloon catheter method requires complex in vivo calibration, expertise and specific material order. A simple, inexpensive, accurate and reproducible method of measuring esophageal pressure would greatly facilitate the measure of transpulmonary pressure to individualize protective ventilation in the intensive care unit. RESULTS: We propose an air-filled esophageal catheter method without balloon, using a disposable catheter that allows reproducible esophageal pressure measurements. We use a 49-cm-long 10 Fr thin suction catheter, positioned in the lower-third of the esophagus and connected to an air-filled disposable blood pressure transducer bound to the monitor and pressurized by an air-filled infusion bag. Only simple calibration by zeroing the transducer to atmospheric pressure and unit conversion from mmHg to cmH2O are required. We compared our method with the reference balloon catheter both ex vivo, using pressure chambers, and in vivo, in 15 consecutive mechanically ventilated patients. Esophageal-to-airway pressure change ratios during the dynamic occlusion test were close to one (1.03 ± 0.19 and 1.00 ± 0.16 in the controlled and assisted modes, respectively), validating the proper esophageal positioning. The Bland-Altman analysis revealed no bias of our method compared with the reference and good precision for inspiratory, expiratory and delta esophageal pressure measurements in both the controlled (largest bias -0.5 cmH2O [95% confidence interval: -0.9; -0.1] cmH2O; largest limits of agreement -3.5 to 2.5 cmH2O) and assisted modes (largest bias -0.3 [-2.6; 2.0] cmH2O). We observed a good repeatability (intra-observer, intraclass correlation coefficient, ICC: 0.89 [0.79; 0.96]) and reproducibility (inter-observer ICC: 0.89 [0.76; 0.96]) of esophageal measurements. The direct comparison with pleural pressure in two patients and spectral analysis by Fourier transform confirmed the reliability of the air-filled catheter-derived esophageal pressure as an accurate surrogate of pleural pressure. A calculator for transpulmonary pressures is available online. CONCLUSIONS: We propose a simple, minimally invasive, inexpensive and reproducible method for esophageal pressure monitoring with an air-filled esophageal catheter without balloon. It holds the promise of widespread bedside use of transpulmonary pressure-guided protective ventilation in ICU patients.

Synthesis and structure-activity relationship of substitutions at the C-1 position of Delta9-tetrahydrocannabinol.

A novel series of Delta9-tetrahydrocannabinol (Delta9-THC) analogues were synthesized to determine their potential as cannabinoid receptor modulators. Chemistry focused on conversion of the phenol of Delta9-THC to other functionality through palladium catalyzed reactions with an intermediate triflate 2. Two analogues with sub 100 nM affinity for the CB1 and CB2 receptors were identified.

Encephalitis lethargica and the influenza virus. III. The influenza pandemic of 1918/19 and encephalitis lethargica: neuropathology and discussion.

This is the second of two papers which critically examine the relationship between the 1918/19 influenza pandemic and encephalitis lethargica (EL). The role of influenza in the etiology of EL was vigorously debated until 1924. It is notable, however, that the unitarian camp were largely reactive in their argumentation; while the influenza skeptics provided detail descriptions of EL and the features they argued to be unique or at least unusual, influenza supporters focused on sequentially refuting the evidence of their opponents. The impression which emerges from this debate is that the individual features identified by the skeptics were not absolutely pathognomic for EL, but, on the other hand, their combination in one disorder had not previously been described for any other disease.

Encephalitis lethargica and the influenza virus. II. The influenza pandemic of 1918/19 and encephalitis lethargica: epidemiology and symptoms.

This is the first of two papers which critically examine the relationship between the 1918/19 influenza pandemic and encephalitis lethargica (EL). The role of influenza in the etiology of EL was vigorously debated until 1924. It is notable, however, that the unitarian camp were largely reactive in their argumentation; while the influenza skeptics provided detail descriptions of EL and the features they argued to be unique or at least unusual, influenza supporters focused on sequentially refuting the evidence of their opponents. The impression which emerges from this debate is that the individual features identified by the skeptics were not absolutely pathognomic for EL, but, on the other hand, their combination in one disorder had not previously been described for any other disease.

Successful clinical transplantation of hearts donated after circulatory death using normothermic regional perfusion.

BACKGROUND: Heart transplantation (HT) from donation after circulatory death (DCD) has yet to achieve wide clinical application despite the encouraging resultsreported recently. In this study we describe 2 cases of successful adult DCD HT performed at our institution using an original protocol. METHODS: Our local abdominal DCD protocol was updated to allow DCD heart procurement, and was accepted by the institutional ethics committee. The main features of the protocol include: pre-mortem insertion of peripheral venoarterial extracorporeal membrane oxygenation cannulas; thoracoabdominal normothermic regional perfusion (NRP) by clamping the 3 aortic arch vessels to exclude cerebral circulation; and in-situ heart resuscitation. The retrieved hearts were directly transplanted into recipients located in an adjoining operating room. RESULTS: The procurement warm ischemic time was 25 minutes for the first donor, and 26 minutes for the second donor. The cold ischemic time was 16 minutes for the first recipient and 17 minutes for the second recipient. The suture time was 30 minutes for the first recipient, and 53 minutes for the second recipient. Both recipients were easily weaned off cardiopulmonary bypass in sinus rhythm and inotropic support. Post-operative evaluation of cardiac function was excellent and the patients were subsequently discharged home. CONCLUSIONS: Transplantation of hearts from DCD donors is now a clinical reality.NRP is a useful tool for resuscitation, reperfusion, and preservation of transplanted hearts. It also offers the opportunity to assess the function and viability of organs before transplantation. However,due to ethical issues, some may object to ante-mortem intervention.

First report of a successful pediatric heart transplantation from donation after circulatory death with distant procurement using normothermic regional perfusion and cold storage.

Heart transplantation (HT) from donation after circulatory death (DCD) is a promising alternative to expand the heart donor pool. Cold storage can be used in a strategy to successfully retrieve and transplant DCD hearts after reconditioning using normothermic regional perfusion for distant procurement. Herein, we present the first report of a pediatric DCD heart reconditioned with normothermic regional perfusion, preserved using only cold storage while being transported to a neighboring center, and then successfully transplanted after nearly 2 hours of cold static storage. If supported by an appropriate trial, this finding could obviate the need to use expensive perfusion devices for short interhospital distances for DCD heart transportation and stimulate more centers across the world to embrace DCD HT.

A new species of Pythium with inflated sporangia and coiled antheridia, isolated from India.

Pythium kashmirense sp. nov. was isolated from soil samples taken on the Himalayas at the height of 5300 feet in the Shivalik Hill Range of the northern Indian state of Jammu and Kashmir. The oomycete has filamentous-inflated type sporangia and its antheridial filaments form loose loops around the female gametangia, and coil around the oogonial stalks. The new species is closely related to Pythium plurisporium, Pythium periilum, Pythium inflatum, and Pythium folliculosum. All of these oomycetes have filamentous-inflated type sporangia. However, P. kashmirense has its own distinguishing characteristics which can easily differentiate it among these related species. The sequences of the internal transcribed spacer (ITS) region of its rRNA and its morphological characters are unique for the genus Pythium. Taxonomic description of this new species, its comparison with related oomycetes and the sequence of the ITS region of its rRNA, are discussed here.

Achlya spiralis, a new aquatic oomycete with bent oogonial stalks, isolated from the Burgundian region of France.

Achlya spiralis sp. nov. was isolated from water samples collected in the river Tille in the Burgundian region of France. The new oomycete is described, illustrated and compared with related species of the genus Achlya. It is characterized by the presence of smooth-walled oogonia that are usually borne on bent or twisted oogonial stalks; mainly monoclinous, androgynous and diclinous antheridial branches and eccentric oospores which generally do not mature or mature after a long period of time. The internal transcribed spacer (ITS) region of its rRNA is comprised of 671 bases. The taxonomic description of this new species, its comparison with related oomycetes and the sequence of the ITS region of its rRNA are discussed here.

A new mycoparasite, Pythium lycopersicum, isolated in Isparta, Turkey: morphology, molecular characteristics, and its antagonism with phytopathogenic fungi.

Pythium lycopersicum sp. nov. has been isolated from soil samples taken in an agricultural land in the Isparta region of Southern Turkey. This oomycete is characterized by its contiguous sporangia having globose to elongated elements linked with hyphal filaments, ornamented oogonia, and monoclinous antheridia with large antheridial cells. The oomycete is reminiscent of Pythium ornamentatum described by the corresponding author in 1987 from soil samples taken in Algeria. Sequence analyses of the internal transcribed spacer (ITS) regions of rRNA show a close relationship with Pythium oligandrum and other mycoparasites possessing ornamented oogonia. Morphological and molecular features of this isolate justify its description as a new species: P. lycopersicum. When grown together with Botrytis cinerea, this oomycete shows a pronounced antagonism and suppresses the phytopathogen. The morphological details, together with the analysis of the ITS region of its rRNA, and its antagonism with some phytopathogens are discussed in this article.

Intraspecific and within-isolate sequence variation in the ITS rRNA gene region of Pythium mercuriale sp. nov. (Pythiaceae).

Sixteen Pythium isolates from diverse hosts and locations, which showed similarities in their morphology and sequences of the internal transcribed spacer (ITS) region of their rRNA gene, were investigated. As opposed to the generally accepted view, within single isolates ITS sequence variations were consistently found mostly as part of a tract of identical bases (A-T) within ITS1, and of GT or GTTT repeats within the ITS2 sequence. Thirty-one different ITS sequences obtained from 39 cloned ITS products from the 16 isolates showed high sequence and length polymorphisms within and between isolates. However, in a phylogenetic analysis, they formed a cluster distinct from those of other Pythium species. Additional sequencing of two nuclear genes (elongation factor 1 alpha and beta-tubulin) and one mitochondrial gene (nadh1) revealed high levels of heterozygosity as well as polymorphism within and between isolates, with some isolates possessing two or more alleles for each of the nuclear genes. In contrast to the observed variation in the ITS and other gene areas, all isolates were phenotypically similar. Pythium mercuriale sp. nov. (Pythiaceae) is characterized by forming thin-walled chlamydospores, subglobose to obovoid, papillate sporangia proliferating internally and smooth-walled oogonia surrounded by multiple antheridia. Maximum likelihood phylogenetic analyses based on both ITS and beta-tubulin sequence data place P. mercuriale in a clade between Pythium and Phytophthora.

Short communication: Sex-linked differences in gamma-aminobutyric acid (GABA) are related to social functioning in autism spectrum disorder.

Magnetic resonance spectroscopy (MRS) was utilized to investigate sex differences in gamma-aminobutyric acid (GABA) between adults with autism spectrum disorder (ASD) and neurotypical (NT) controls. GABA at the right superior temporal sulcus (STS) is reported for 12 ASD and 14 NT participants. The results show no group differences in GABA. There was, however, a significant positive association between GABA at the STS and autism-related social impairments in females with ASD. These findings provide preliminary support for sex differences in GABAergic distribution and processes that contribute to social functioning in ASD.

Low-frequency brain stimulation to the left dorsolateral prefrontal cortex increases the negative impact of social exclusion among those high in personal distress.

The dorsolateral prefrontal cortex (DLPFC) is thought to play a key role in the cognitive control of emotion and has therefore, unsurprisingly, been implicated in the regulation of physical pain perception. This brain region may also influence the experience of social pain, which has been shown to activate similar neural networks as seen in response to physical pain. Here, we applied sham or active low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC, previously shown to exert bilateral effects in pain perception, in healthy participants. Following stimulation, participants played the "Cyberball Task"; an online ball-tossing game in which the subject participant is included or excluded. Compared to sham, rTMS did not modulate behavioural response to social exclusion. However, within the active rTMS group only, greater trait personal distress was related to enhanced negative outcomes to social exclusion. These results add further support to the notion that the effect of brain stimulation is not homogenous across individuals, and indicates the need to consider baseline individual differences when assessing response to brain stimulation. This seems particularly relevant in social neuroscience investigations, where trait factors may have a meaningful effect.

A new species of Pythium isolated from a vineyard in France.

Pythium apiculatum sp. nov. is a new oomycete characterized by the presence of both ornamented and smooth-walled oogonia. The ornamentations are blunt, and at times, bent. The oomycete was isolated from soil samples taken in a vineyard in the Burgundian region of France. Morphologically, it resembles some species having ornamented oogonia like Pythium radiosum, Pythium echinulatum, and resembles, also the species having smooth-walled oogonia like Pythium hypogynum and Pythium acrogynum. However, the oomycete has its own distinguishing characteristics which, when combined with molecular features, enables us to describe it as a new species. The taxonomic description of this new oomycete, its comparison with related species, and the sequence of the ITS region of its rRNA gene, are described in this article.

A new species of Pythium with ornamented oogonia: morphology, taxonomy, internal transcribed spacer region of its ribosomal RNA, and its comparison with related species.

Pythium spiculum sp. nov. was isolated from soil samples taken in a vineyard in the Burgundian region of France and from different locations in Spain and Portugal. The oomycete has spiny oogonia and does not sporulate readily. It resembles Pythium mamillatum Meurs, but has its own distinguishing characteristics. It also exhibits sickle-shaped as well as spherical appressoria which at times are associated with sex organs like those found in Pythium abappressorium Paulitz and Pythium contiguanum Paul. Sequencing of the internal transcribed spacer region of its nuclear ribosomal DNA and a close look at its morphological characters have now enabled us to describe it as a new species. The internal transcribed spacer region of its rRNA gene sequence is comprised of 945 bases. This oomycete is closely related to the members that form ornamented or spiny oogonia like Pythiummamillatum, Pythium spinosum and Pythium irregulare but also with those producing smooth-walled oogonia like Pythium paroecandrum, Pythium sylvaticum and Pythium cylindrosporum. Taxonomic description of this new species, its comparison with related oomycetes, the sequence of the internal transcribed spacer region of its rRNA gene and the phylogenetic tree, are given here.

Morphological and molecular taxonomy of Pythium longisporangium sp. nov. isolated from the Burgundian region of France.

During the course of an investigation on the Pythiaceous oomycetes occurring in the Burgundian vineyards, some species of Pythium possessing mainly hypogynous antheridia were found. These had been classified as oomycetes belonging to the "Pythium rostratum" group for a long time. Three of these isolates, having similar structures and growth, are very closely related to a recently described species, Pythium bifurcatum Paul. A close look at these, however, underlines some fundamental differences with the latter. Not all of them produce zoospores but have very large sporangia. The type specimen is F-1200 (B 76a) which is a medium-slow growing saprophyte. The sequence of the ITS region of the rDNA also shows a very close relationship with P. bifurcatum. On the basis of morphological and molecular analysis, we now describe this species as Pythium longisporangium sp. nov. Morphological features of this new species, the sequences of the ITS region of its nuclear ribosomal DNA, and its comparison with related species are discussed.