Background/Objectives
Puberty seems to be a turning point in cluster headache (CH) onset. To verify its influence on CH phenotype, we focused on cases with onset ≤13 years. A review of the literature ...follows.
Method
We considered CH cases with age‐of‐onset ≤13 years evaluated at our center between 1975 and 2015; these cases were matched by sex to two consecutive patients with age‐of‐onset as close as possible (±2 years) to the median age‐of‐onset of the overall CH population.
Results
Of the overall 808 cases (585 men and 223 women, M:F ratio = 2.6), 38 patients (20 men and 18 women, M:F ratio = 1.1) had pediatric onset (PO). The diagnostic delay was significantly higher among cases with PO (21.2 ± 12.4 years, P < .0001). In this group, females had more frequently a chronic course and a familiarity for CH. Men with PO had some significant distinctive features, including higher frequency and longer duration of headache attacks, and higher proportion of various cranial autonomic and migraine‐like symptoms.
Conclusions
We confirmed that CH with childhood onset does not show a male predominance, which was actually inverted for chronic cases. Furthermore, males with PO seem to have a specific clinical phenotype.
Non-motor symptoms of Parkinson's disease (PD) such as dysautonomia and REM sleep behavior disorder (RBD) are recognized to be important prodromal symptoms that may also indicate clinical subtypes of ...PD with different pathogenesis. Unbiased clustering analyses showed that subjects with dysautonomia and RBD symptoms, as well as early cognitive dysfunction, have faster progression of the disease. Through analysis of the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we tested the hypothesis that symptoms of dysautonomia and RBD, which are readily assessed by standard questionnaires in an ambulatory care setting, may help to independently prognosticate disease progression. Although these two symptoms associate closely, dysautonomia symptoms predict severe progression of motor and non-motor symptoms better than RBD symptoms across the 3-year follow-up period. Autonomic system involvement has not received as much attention and may be important to consider for stratification of subjects for clinical trials and for counseling patients.
Increasing evidence suggests that lycopene, the major carotenoid present in tomato, may be preventive against smoke-induced cell damage. However, the mechanisms of such a prevention are still ...unclear. The aim of this study was to investigate the role of lycopene on the production of the pro-inflammatory cytokine IL-8 induced by cigarette smoke and the possible mechanisms implicated. Therefore, human THP-1 macrophages were exposed to cigarette smoke extract (CSE), alone and following a 6-h pre-treatment with lycopene (0.5-2 µM). CSE enhanced IL-8 production in a time- and a dose-dependent manner. Lycopene pre-treatment resulted in a significant inhibition of CSE-induced IL-8 expression at both mRNA and protein levels. NF-kB controlled the transcription of IL-8 induced by CSE, since PDTC prevented such a production. Lycopene suppressed CSE-induced NF-kB DNA binding, NF-kB/p65 nuclear translocation and phosphorylation of IKKα and IkBα. Such an inhibition was accompanied by a decrease in CSE-induced ROS production and NOX-4 expression. Lycopene further inhibited CSE-induced phosphorylation of the redox-sensitive ERK1/2, JNK and p38 MAPKs. Moreover, the carotenoid increased PPARγ levels which, in turn, enhanced PTEN expression and decreased pAKT levels in CSE-exposed cells. Such effects were abolished by the PPARγ inhibitor GW9662. Taken together, our data indicate that lycopene prevented CSE-induced IL-8 production through a mechanism involving an inactivation of NF-kB. NF-kB inactivation was accompanied by an inhibition of redox signalling and an activation of PPARγ signalling. The ability of lycopene in inhibiting IL-8 production, NF-kB/p65 nuclear translocation, and redox signalling and in increasing PPARγ expression was also found in isolated rat alveolar macrophages exposed to CSE. These findings provide novel data on new molecular mechanisms by which lycopene regulates cigarette smoke-driven inflammation in human macrophages.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Histamine Intolerance (HIT) is a multifaceted pseudoallergic disorder possibly due to defective histamine metabolism. Diamine oxidase (DAO) contributes to histamine degradation and can be ...measured in the serum. The role of DAO measurement in the diagnostic work-up of HIT still remains unclear, and conflicting results have been reported in the literature. Therefore, we aimed to evaluate the possible clinical usefulness and consistency of DAO value ranges as provided by the assay manufacturer and verify whether they could predict the response to treatment. Methods: We retrospectively analyzed 192 outpatients with HIT symptoms and measured serum DAO values at baseline. Patients were prescribed either with low-histamine diet and/or enzymatic supplementation according to symptom severity and re-evaluated six to eight months later. Patients were stratified into three groups according to DAO levels: <3 U/mL, 3−10 U/mL, and >10 U/mL. HIT severity was assessed on a scale of 1 to 5 before and after treatment. Results: A total of 146 patients completed the study. Gastrointestinal and cutaneous symptoms, often associated with headache, were more frequent in subjects with DAO < 10 U/mL. Symptom severity and DAO ranges were correlated. Patients with intermediate DAO levels (3−10 U/mL) showed a more complex clinical phenotype but also a more significant improvement in symptom severity (score reduction 50%, interquartile range (IQR) = 33−60%) when compared to patients with low DAO (40%, IQR = 20−60%; p = 0.045) or high DAO (33%, IQR = 0−50%; p < 0.001). Complex clinical phenotypes were also more frequent in patients with intermediate DAO levels. Conclusions: HIT is characterized by typical symptoms and low levels of DAO activity. Symptom severity was associated with the degree of DAO deficiency. Patients with DAO values between 3 and 10 U/mL show the best response to treatment (low-histamine diet and/or DAO supplementation). DAO value could arguably be considered as a predictor of clinical response to treatment. Prospective studies are needed to confirm these data.
Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these ...diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression.
A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October Formula: see text, 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random-effects empirical Bayes model.
Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of Formula: see text points (CI Formula: see text, Formula: see text) in the BDI scale, of Formula: see text points (CI Formula: see text, Formula: see text) in the BDI-II scale and of Formula: see text points (CI Formula: see text, Formula: see text) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of Formula: see text (CI Formula: see text, Formula: see text) points in the HIT6 scale, Formula: see text (CI Formula: see text, Formula: see text) in the MIDAS scale, Formula: see text (CI Formula: see text, Formula: see text) points in the VAS scale and of Formula: see text (CI Formula: see text, Formula: see text) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores.
Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features.
TDP1 removes transcription-blocking topoisomerase I cleavage complexes (TOP1ccs), and its inactivating H493R mutation causes the neurodegenerative syndrome SCAN1. However, the molecular mechanism ...underlying the SCAN1 phenotype is unclear. Here, we generate human SCAN1 cell models using CRISPR-Cas9 and show that they accumulate TOP1ccs along with changes in gene expression and genomic distribution of R-loops. SCAN1 cells also accumulate transcriptional DNA double-strand breaks (DSBs) specifically in the G1 cell population due to increased DSB formation and lack of repair, both resulting from abortive removal of transcription-blocking TOP1ccs. Deficient TDP1 activity causes increased DSB production, and the presence of mutated TDP1 protein hampers DSB repair by a TDP2-dependent backup pathway. This study provides powerful models to study TDP1 functions under physiological and pathological conditions and unravels that a gain of function of the mutated TDP1 protein, which prevents DSB repair, rather than a loss of TDP1 activity itself, could contribute to SCAN1 pathogenesis.
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•Generation of human SCAN1 cells with homozygous TDP1 H493R mutation by CRISPR-Cas9•SCAN1 cells accumulate TOP1ccs and G1 phase-specific transcriptional DSBs•DSB accumulation in SCAN1 results from enhanced DSB formation and defective repair•Mutated TDP1 protein hampers DSB repair by a TDP2-dependent backup pathway
Geraud et al. generate human SCAN1 cells by CRISPR-Cas9 to study SCAN1 disease. SCAN1 cells accumulate transcriptional DSBs specifically in G1 phase due to enhanced DSB formation and defective repair. The presence of mutated TDP1, rather than loss of its activity, causes defective repair by hampering a TDP2-dependent backup pathway.
We modeled an unprecedentedly large dataset of complete fusion cross section data using a novel artificial intelligence approach. Our analysis aims especially to unveil, in a data-driven way, nuclear ...structure effects on the fusion between heavy ions and to suggest a universal formula capable to describe all previously available data. The study focused on light-to-mediummass nuclei, where incomplete fusion phenomena are more difficult to occur and less likely to contaminate the data. The method used to derive the models exploits a state-of-the-art hybridization of genetic programming and artificial neural networks and is capable to derive an analytical expression that serves to predict integrated cross section values. For the first time, we analyzed a comprehensive set of nuclear variables, including quantities related to the nuclear structure of projectile and target. In this manuscript, we describe the derivation of two computationally simple models that can satisfactorily describe, with a reduced number of variables and only a few parameters, a large variety of lightto- intermediate-mass collision systems in an energy domain ranging approximately from the Coulomb barrier to the oncet of multi-fragmentation phenomena. The underlying methods are particularly innovative and are of potential use for a broad domain of applications in the nuclear field.
Epilepsy is reported in 29–52% of patients with glioblastoma (GBM) and has an important role in the natural history of this tumor and patients’ life quality. Although GBM is less epileptogenic than ...lower-grade gliomas, seizures are usually more difficult to control with common antiseizure medications; drug resistance is found in 20% of cases. Recent studies suggest that seizures at the onset of GBM could be a possible favorable independent prognostic factor in patients. Moreover, a growing body of evidence shows that many molecular mechanisms that influence epileptogenesis often regulate GBM growth and invasiveness, sometimes favoring or counteracting the tumor, respectively. The better-characterized players include glutamate, γ-aminobutyric acid, aquaporin-4, and hypoxia-activated molecules. However, currently available data on the molecular basis of epileptogenesis, tumorigenesis, and their relationship is incomplete or discordant and further research is urgently needed on this topic.
Current therapies for Non-Small Cell Lung Cancer (NSCLC) still fail to significantly increase its survival rate. Here we asked whether Interleukin(IL)-27, which has revealed powerful antitumor ...activity and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients. IL-27's effects were tested on Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) cell lines and xenograft models. IL-27Receptor(R) expression was assessed in lung tissues from 78 NSCLC patients. In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROγ/MIP2β expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with Nestin, SNAI1/SNAIL, SNAI2/SLUG and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease. Our data suggest that even immunocompromised or advancer NSCLC patients may benefit from IL-27's antitumor properties based on its ability to drive myeloid cells towards antitumor activities, and down-regulate stemness- and EMT-related genes in cancer cells.
This paper introduces the Supervisor Evolutionary Algorithm, a novel technique that allows for self-adapt almost all the internal parameters in parallel distributed client-server genetic programming. ...This novel adapting mechanism, is itself of an evolutionary nature, so we have a double evolutionary tool. The upper level, as is usual in evolutionary computing, has its own customized selection, crossover, and mutation mechanisms. The lower stage used here is the Brain Project a parallel-distributed software tool for formal modelling of numerical data using a hybrid neural-genetic programming technique. As demonstrated by the experiment reported in this paper, our approach works well adapting continuously its internal parameters.
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