Cerebral venous hemodynamic abnormalities in episodic and chronic migraine

Alterations of cerebral venous drainage have been demonstrated in chronic migraine (CM), suggesting that cerebral venous hemodynamic abnormalities (CVHAs) play a role in this condition. The aim of the present study was to look for a correlation between CM and CVHAs. We recruited 33 subjects suffering from CM with or without analgesic overuse, 29 episodic migraine (EM) patients with or without aura, and 21 healthy subjects as controls (HCs). CVHAs were evaluated by transcranial and extracranial echo-color Doppler evaluation of five venous hemodynamic parameters. CVHAs were significantly more frequent in the CM and EM patients than in the HCs. In the migraine patients, CVHAs were not correlated with clinical features. Cerebral venous hemodynamic abnormalities in episodic and chronic migraine The significantly greater frequency of CVHAs observed in the migraineurs may reflect a possible relationship between migraine and these abnormalities. Prospective longitudinal studies are needed to investigate whether CVHAs have a role in the processes of migraine chronification

GM1 OLIGOSACCHARIDE ACCOUNTS FOR GM1 ROLE IN ENHANCING NEURONAL DEVELOPMENT ACTING ON TRKA-MAPK PATHWAY

Il ganglioside GM1 \ue8 un glicosfingolipide mono-sialilato presente nello strato esterno della membrana plasmatica cellulare ed \ue8 particolarmente abbondante nei neuroni. Numerosi studi in vitro e in vivo evidenziano il ruolo del GM1 non solo come componente strutturale ma anche come regolatore di diversi processi cellulari. Infatti, l'arricchimento di GM1 nei microdomini di membrana promuove il differenziamento e la protezione neuronale. Inoltre il contenuto di GM1 \ue8 essenziale per la sopravvivenza e il mantenimento dei neuroni. Nonostante vi siano numerose evidenze sugli effetti neuronotrofici mediati dal GM1, la conoscenza del meccanismo d'azione sottostante \ue8 scarsa. Recentemente, la catena oligosaccaridica del GM1 (oligoGM1) \ue8 stata identificata come responsabile delle propriet\ue0 neuritogeniche del ganglioside GM1 nelle cellule di neuroblastoma. Gli effetti mediati dall\u2019oligoGM1 dipendono dal suo legame con il recettore specifico dell\u2019 NGF, il TrkA, determinando cos\uec l'attivazione della via TrkA-MAPK. In questo contesto, il mio lavoro di dottorato mirava a confermare il ruolo dell\u2019oligoGM1, come componente bioattiva dell\u2019intero ganglioside GM1, capace di stimolare i processi di differenziaziamento e maturazione dei neuroni granulari cerebellari di topo. Come prima cosa, abbiamo eseguito analisi morfologiche in time -course sui neuroni primari coltivati in presenza o in assenza dei gangliosidi GM1 o GD1a (il quale rappresenta il diretto precursore catabolico del GM1), somministrati esogenamente. Abbiamo osservato che entrambi i gangliosidi aumentavano l\u2019aggregazione e l'arborizzazione dei neuroni. Dopo successiva somministrazione dei rispettivi oligosaccaridi, abbiamo osservato che solo l\u2019oligoGM1 favoriva la migrazione dei neuroni, mentre l\u2019oligoGD1a non induceva nessun effetto discriminante rispetto alle cellule controllo. Questo risultato suggerisce l'importanza della specifica struttura saccaridica del GM1 nella mediazione degli effetti neuronotrofici del ganglioside. Quindi abbiamo caratterizzato biochimicamente l'effetto mediato dall\u2019oligoGM1 nei neuroni e abbiamo osservato un pi\uf9 elevato tasso di fosforilazione delle proteine FAK e Src, le quali rappresentano i regolatori intracellulari chiave della motilit\ue0 neuronale. Inoltre, in presenza dell\u2019 oligoGM1 i neuroni granulari cerebellari mostravano un aumento del livello di marcatori neuronali specifici (ad es. \u3b23-Tubulina, Tau, Neuroglicano C, Sinapsina), suggerendo uno stadio di maturazione pi\uf9 avanzato rispetto ai controlli. Inoltre, abbiamo scoperto che l'oligoGM1 accelera l'espressione del pattern di gangliosidi tipico dei neuroni maturi che \ue8 caratterizzato da alti livelli di gangliosidi complessi (cio\ue8 GM1, GD1a, GD1b e GT1b) e basso livello del ganglioside pi\uf9 semplice GM3. Per studiare il meccanismo d'azione dell'oligoGM1, abbiamo usato il suo derivato marcato con il trizio e abbiamo scoperto che l'oligoGM1 interagisce con la superficie cellulare senza entrare nelle cellule. Questa scoperta suggerisce la presenza di un bersaglio biologico sulla membrana plasmatica neuronale. \uc8 interessante notare che abbiamo riscontrato una precoce attivazione della via di segnalazione del TrkA associata alle MAP chinasi in seguito alla somministrazione dell\u2019oligoGM1 nelle culture neuronali. Questo risultato suggerisce che questo evento rappresenti un punto di partenza degli effetti dell\u2019 oligoGM1 nei neuroni. I nostri dati rivelano che gli effetti del ganglioside GM1 sul differenziamento e la maturazione neuronale sono mediati dalla sua porzione di oligosaccaride. Infatti, l\u2019oligoGM1 interagisce con la superficie cellulare, innescando cos\uec l'attivazione di processi biochimici intracellulari che sono responsabili della migrazione neuronale, dell'emissione dei dendriti e della crescita degli assoni. Nel complesso, i nostri risultati sottolineano l'importanza dell\u2019 oligoGM1 come un nuovo e promettente fattore neurotrofico.The GM1 ganglioside is a mono-sialylated glycosphingolipid present in the outer layer of the cell plasma membrane and abundant in neurons. Numerous in vitro and in vivo studies highlight the role of GM1 not only as a structural component but also as a functional regulator. Indeed, GM1 enrichment in membrane microdomains promotes neuronal differentiation and protection, and the GM1 content is essential for neuronal survival and maintenance. Despite many lines of evidence on the GM1-mediated neuronotrophic effects, our knowledge on the underlying mechanism of action is scant. Recently, the oligosaccharide chain of GM1 (oligoGM1) has been identified as responsible for the neuritogenic properties of the GM1 ganglioside in neuroblastoma cells. The oligoGM1-mediated effects depend on its binding to the NGF specific receptor TrkA, thus resulting in the TrkA-MAPK pathway activation. In this context, my PhD work aimed to confirm the role of the oligoGM1, as the bioactive portion of the entire GM1 ganglioside, capable of enhancing the differentiation and maturation processes of mouse cerebellar granule neurons. First, we performed time course morphological analyses on mouse primary neurons plated in the presence or absence of exogenously administered gangliosides GM1 or GD1a (direct GM1 catabolic precursor). We found that both gangliosides increased neuron clustering and arborization, however only oligoGM1 and not oligoGD1a induced the same effects in prompting neuron migration. This result suggests the importance of the specific GM1 saccharide structure in mediating neuronotrophic effects. Then we characterized biochemically the oligoGM1-mediated effect in mouse primary neurons, and we observed a higher phosphorylation rate of FAK and Src proteins which are the intracellular key regulators of neuronal motility. Moreover, in the presence of oligoGM1 cerebellar granule neurons showed increased level of specific neuronal markers (e.g., \u3b23-Tubulin, Tau, Neuroglycan C, Synapsin), suggesting an advanced stage of maturation compared to controls. In addition, we found that the oligoGM1 accelerates the expression of the typical ganglioside pattern of mature neurons which is characterized by high levels of complex gangliosides (i.e., GM1, GD1a, GD1b, and GT1b) and low level of the simplest one, the GM3 ganglioside. To study the mechanism of action of the oligoGM1, we used its tritium labeled derivative and we found that the oligoGM1 interacts with the cell surface without entering the cells. This finding suggests the presence of a biological target at the neuronal plasma membrane. Interestingly, we observed the TrkA-MAP kinase pathway activation as an early event underlying oligoGM1 effects in neurons. Our data reveal that the effects of GM1 ganglioside on neuronal differentiation and maturation are mediated by its oligosaccharide portion. Indeed, oligoGM1 interacts with the cell surface, thus triggering the activation of intracellular biochemical pathways that are responsible for neuronal migration, dendrites emission and axon growth. Overall, our results point out the importance of oligoGM1 as a new promising neurotrophic player

Intravesical administration of combined hyaluronic acid (HA) and chondroitin sulfate (CS) for the treatment of female recurrent urinary tract infections: a European multicentre nested case-control study.

Published onlineJournal ArticleMulticenter StudyObservational StudyResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.OBJECTIVES: To compare the clinical effectiveness of the intravesical administration of combined hyaluronic acid and chondroitin sulfate (HA+CS) versus current standard management in adult women with recurrent urinary tract infections (RUTIs). SETTING: A European Union-based multicentre, retrospective nested case-control study. PARTICIPANTS: 276 adult women treated for RUTIs starting from 2009 to 2013. INTERVENTIONS: Patients treated with either intravesical administration of HA+CS or standard of care (antimicrobial/immunoactive prophylaxis/probiotics/cranberry). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was occurrence of bacteriologically confirmed recurrence within 12 months. Secondary outcomes were time to recurrence, total number of recurrences, health-related quality of life and healthcare resource consumption. Crude and adjusted results for unbalanced characteristics are presented. RESULTS: 181 patients treated with HA+CS and 95 patients treated with standard of care from 7 centres were included. The crude and adjusted ORs (95% CI) for the primary end point were 0.77 (0.46 to 1.28) and 0.51 (0.27 to 0.96), respectively. However, no evidence of improvement in terms of total number of recurrences (incidence rate ratio (95% CI), 0.99 (0.69 to 1.43)) or time to first recurrence was seen (HR (95% CI), 0.99 (0.61 to 1.61)). The benefit of intravesical HA+CS therapy improves when the number of instillations is ≥ 5. CONCLUSIONS: Our results show that bladder instillations of combined HA+CS reduce the risk of bacteriologically confirmed recurrences compared with the current standard management of RUTIs. Total incidence rates and hazard rates were instead non-significantly different between the 2 groups after adjusting for unbalanced factors. In contrast to what happens with antibiotic prophylaxis, the effectiveness of the HA+CS reinstatement therapy improves over time. TRIAL REGISTRATION NUMBER: NCT02016118.This study was funded by an unrestricted grant from the TETI Association—study group for urogenital diseases. Members of the association were involved in the data collection and revised the manuscript

Starving leukemia to induce differentiation

A new study shows that fasting induces the differentiation and elimination of some types of leukemia in mice, which implicates fasting or its mimetics as a novel strategy for the treatment of this disease

Klebsiella pneumoniae bacteraemia complicating rotavirus gastroenteritis in two infants with glucocorticoid deficiency

Rotavirus gastroenteritis was complicated by Klebsiella Pneumoniae bacteraemia in two infants with glucocorticoid deficient conditions who were treated with 'stress dose' hydrocortisone during their illness. Delayed healing in the context of glucocorticoid administration combined with damage from rotavirus infection may result in increased risk of mucosal invasion by gastrointestinal bacteria and subsequent enteric gram-negative bacteraemia

Inkjet printing and cell seeding thermoreversible photocurable gel structures

We have developed a biocompatible fluid suitable for inkjet delivery that gels by a tandem mechanism of a rapid physical gelation followed by a photoactivated chemical cross-linking. We prepared 20 vol% aqueous solutions of acrylate functionalised Pluronic F127, a poly(ethylene glycol-b-propylene glycol-b-ethylene glycol) (PEO-PPO), with triethanolamine and eosin Y as a photocurable cross-linker combination; poly(ethylene glycol) diacrylate was also added to the solution to improve the sol-gel transition. This fluid has a viscosit

Novel insights on GM1 and Parkinson's disease: A critical review

GM1 is a crucial component of neuronal membrane residing both in the soma and nerve terminals. As reported in Parkinson’s disease patients, the reduction of GM1 determines the failure of fundamental functional processes leading to cumulative cell distress up to neuron death. This review reports on the role of GM1 in the pathogenesis of the disease, illustrating the current data available but also hypotheses on the additional mechanisms in which GM1 could be involved and which require further study. In the manuscript we discuss these points trying to explain the role of diminished content of brain GM1, particularly in the nigro-striatal system, in Parkinson’s disease etiology and progression

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Many species of ganglioside GM1, differing for the sialic acid and ceramide content, have been characterized and their physico\u2010chemical properties have been studied in detail since 1963. Scientists were immediately attracted to the GM1 molecule and have carried on an ever\u2010increasing number of studies to understand its binding properties and its neurotrophic and neuroprotective role. GM1 displays a well balanced amphiphilic behavior that allows to establish strong both hydrophobic and hydrophilic interactions. The peculiar structure of GM1 reduces the fluidity of the plasma membrane which implies a retention and enrichment of the ganglioside in specific membrane domains called lipid rafts. The dynamism of the GM1 oligosaccharide head allows it to assume different conformations and, in this way, to interact through hydrogen or ionic bonds with a wide range of membrane receptors as well as with extracellular ligands. After more than 60 years of studies, it is a milestone that GM1 is one of the main actors in determining the neuronal functions that allows humans to have an intellectual life. The progressive reduction of its biosynthesis along the lifespan is being considered as one of the causes underlying neuronal loss in aged people and severe neuronal decline in neurodegenerative diseases. In this review, we report on the main knowledge on ganglioside GM1, with an emphasis on the recent discoveries about its bioactive component

Atrial Fibrillation Ablation without Interruption of Anticoagulation

Atrial fibrillation (AF) can be cured by pulmonary vein antrum isolation (PVAI) in a substantial proportion of patients. The high efficacy of PVAI is partially undermined by a small but concrete periprocedural risk of complications, such as thromboembolic events and bleeding. A correct management of anticoagulation is essential to prevent such complications. Performing PVAI without interruption of oral anticoagulation has been demonstrated feasible by our group in previous studies. Recently, we reported that continuation of therapeutic warfarin during radiofrequency catheter ablation consistently reduces the risk of periprocedural stroke/transient ischemic attack without increasing the risk of hemorrhagic events. Of note, interrupting warfarin anticoagulation may actually increase the risk of stroke even when bridged with heparin. The latter strategy is also associated with an increased risk of minor bleeding. With regard to major bleeding, we found no significant difference between patients with a therapeutic INR and those who were bridged with heparin. Therefore, continuation of therapeutic warfarin during ablation of AF appears to be the best anticoagulation strategy. In this paper we summarize our experience with AF ablation without interruption of anticoagulation