Geographic constraints on social network groups

Social groups are fundamental building blocks of human societies. While our social interactions have always been constrained by geography, it has been impossible, due to practical difficulties, to evaluate the nature of this restriction on social group structure. We construct a social network of individuals whose most frequent geographical locations are also known. We also classify the individuals into groups according to a community detection algorithm. We study the variation of geographical span for social groups of varying sizes, and explore the relationship between topological positions and geographic positions of their members. We find that small social groups are geographically very tight, but become much more clumped when the group size exceeds about 30 members. Also, we find no correlation between the topological positions and geographic positions of individuals within network communities. These results suggest that spreading processes face distinct structural and spatial constraints.Comment: 10 pages, 5 figure

Searching for network modules

When analyzing complex networks a key target is to uncover their modular structure, which means searching for a family of modules, namely node subsets spanning each a subnetwork more densely connected than the average. This work proposes a novel type of objective function for graph clustering, in the form of a multilinear polynomial whose coefficients are determined by network topology. It may be thought of as a potential function, to be maximized, taking its values on fuzzy clusterings or families of fuzzy subsets of nodes over which every node distributes a unit membership. When suitably parametrized, this potential is shown to attain its maximum when every node concentrates its all unit membership on some module. The output thus is a partition, while the original discrete optimization problem is turned into a continuous version allowing to conceive alternative search strategies. The instance of the problem being a pseudo-Boolean function assigning real-valued cluster scores to node subsets, modularity maximization is employed to exemplify a so-called quadratic form, in that the scores of singletons and pairs also fully determine the scores of larger clusters, while the resulting multilinear polynomial potential function has degree 2. After considering further quadratic instances, different from modularity and obtained by interpreting network topology in alternative manners, a greedy local-search strategy for the continuous framework is analytically compared with an existing greedy agglomerative procedure for the discrete case. Overlapping is finally discussed in terms of multiple runs, i.e. several local searches with different initializations.Comment: 10 page

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease

BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

<p>Abstract</p> <p>Background</p> <p>The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare.</p> <p>Methods</p> <p>We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m²BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS), tumor burden, pretreatment with temozolomide (TMZ), type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model.</p> <p>Results</p> <p>The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15), median overall survival 22 weeks (95% CI: 18-27). The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression). No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off).</p> <p>Conclusion</p> <p>In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are available.</p

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Chemotherapy with BCNU in recurrent glioma: Analysis of clinical outcome and side effects in chemotherapy-naïve patients

Background: To date, standardized strategies for the treatment of recurrent glioma are lacking. Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, particularly the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma. Methods: Survival data of 34 mostly chemotherapy-naïve glioblastoma patients treated with BCNU at 1st relapse were compared to 29 untreated control patients, employing a multiple Cox regression model which considered known prognostic factors including MGMT promoter hypermethylation. Additionally, medical records of 163 patients treated with BCNU for recurrent glioma WHO grade II to IV were retrospectively evaluated for BCNU-related side effects classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0. Results: In recurrent glioblastoma, multiple regression survival analysis revealed a significant benefit of BCNU-based chemotherapy on survival after relapse (p = 0.02; HR = 0.48; 95 % CI = 0.26–0.89) independent of known clinical and molecular prognostic factors. Exploratory analyses suggested that survival benefit was most pronounced in MGMT-hypermethylated, BCNU-treated patients. Moreover, BCNU was well tolerated by 46 % of the 163 patients analyzed for side effects; otherwise, predominantly mild side effects occurred (CTCAE I/II; 45 %). Severe side effects CTCAE III/IV were observed in 9 % of patients including severe hematotoxicity, thromboembolism, intracranial hemorrhage and injection site reaction requiring surgical intervention. One patient presented with a clinically apparent pulmonary fibrosis CTCAE IV requiring temporary mechanical ventilation. Conclusion: In this study, BCNU was rarely associated with severe side effects, particularly pulmonary toxicity, and, in case of recurrent glioblastoma, even conferred a favorable outcome. Therefore BCNU appears to be an appropriate alternative to other nitrosoureas although the efficacy against newer drugs needs further evaluation

Antiproliferative effects of Tubi-bee propolis in glioblastoma cell lines

Propolis is a resin formed by a complex chemical composition of substances that bees collect from plants. Since ancient times, propolis has been used in folk medicine, due to its biological properties, that include antimicrobial, anti-inflammatory, antitumoral and immunomodulatory activities. Glioblastoma is the most common human brain tumor. Despite the improvements in GBM standard treatment, patients’ prognosis is still very poor. The aim of this work was to evaluate in vitro the Tubi-bee propolis effects on human glioblastoma (U251 and U343) and fibroblast (MRC-5) cell lines. Proliferation, clonogenic capacity and apoptosis were analyzed after treatment with 1 mg/mL and 2 mg/mL propolis concentrations for different time periods. Additionally, glioblastoma cell lines were submitted to treatment with propolis combined with temozolomide (TMZ). Data showed an antiproliferative effect of tubi-bee propolis against glioblastoma and fibroblast cell lines. Combination of propolis with TMZ had a synergic anti-proliferative effect. Moreover, propolis caused decrease in colony formation in glioblastoma cell lines. Propolis treatment had no effects on apoptosis, demonstrating a cytostatic action. Further investigations are needed to elucidate the molecular mechanism of the antitumor effect of propolis, and the study of its individual components may reveal specific molecules with antiproliferative capacity

Dose dense 1 week on/1 week off temozolomide in recurrent glioma: a retrospective study

Alternative temozolomide regimens have been proposed to overcome O6-methylguanine-DNA methyltransferase mediated resistance. We investigated the efficacy and tolerability of 1 week on/1 week off temozolomide (ddTMZ) regimen in a cohort of patients treated with ddTMZ between 2005 and 2011 for the progression of a glioblastoma during or after chemo-radiation with temozolomide or a recurrence of another type of glioma after radiotherapy and at least one line of chemotherapy. Patients received ddTMZ at 100–150 mg/m2/d (days 1–7 and 15–21 in cycles of 28-days). All patients had a contrast enhancing lesion on MRI and the response was assessed by MRI using the RANO criteria; complete and partial responses were considered objective responses. Fifty-three patients were included. The median number of cycles of ddTMZ was 4 (range 1–12). Eight patients discontinued chemotherapy because of toxicity. Two of 24 patients with a progressive glioblastoma had an objective response; progression free survival at 6 months (PFS-6) in glioblastoma was 29%. Three of the 16 patients with a recurrent WHO grade 2 or 3 astrocytoma or oligodendroglioma or oligo-astrocytoma without combined 1p and 19q loss had an objective response and PFS-6 in these patients was 38%. Four out of the 12 evaluable patients with a recurrent WHO grade 2 or 3 oligodendroglioma or oligo-astrocytoma with combined 1p and 19q loss had an objective response; PFS-6 in these patients was 62%. This study indicates that ddTMZ is safe and effective in recurrent glioma, despite previous temozolomide and/or nitrosourea chemotherapy. Our data do not suggest superior efficacy of this schedule as compared to the standard day 1–5 every 4 weeks schedule

A Rapid Crosstalk of Human γδ T Cells and Monocytes Drives the Acute Inflammation in Bacterial Infections

Vγ9/Vδ2 T cells are a minor subset of T cells in human blood and differ from other T cells by their immediate responsiveness to microbes. We previously demonstrated that the primary target for Vγ9/Vδ2 T cells is (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), an essential metabolite produced by a large range of pathogens. Here we wished to study the consequence of this unique responsiveness in microbial infection. The majority of peripheral Vγ9/Vδ2 T cells shares migration properties with circulating monocytes, which explains the presence of these two distinct blood cell types in the inflammatory infiltrate at sites of infection and suggests that they synergize in anti-microbial immune responses. Our present findings demonstrate a rapid and HMB-PP-dependent crosstalk between Vγ9/Vδ2 T cells and autologous monocytes that results in the immediate production of inflammatory mediators including the cytokines interleukin (IL)-6, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and oncostatin M (OSM); the chemokines CCL2, CXCL8, and CXCL10; and TNF-related apoptosis-inducing ligand (TRAIL). Moreover, under these co-culture conditions monocytes differentiate within 18 hours into inflammatory dendritic cells (DCs) with antigen-presenting functions. Addition of further microbial stimuli (lipopolysaccharide, peptidoglycan) induces CCR7 and enables these inflammatory DCs to trigger the generation of CD4+ effector αβ T cells expressing IFN-γ and/or IL-17. Importantly, our in vitro model replicates the responsiveness to microbes of effluent cells from peritoneal dialysis (PD) patients and translates directly to episodes of acute PD-associated bacterial peritonitis, where Vγ9/Vδ2 T cell numbers and soluble inflammatory mediators are elevated in patients infected with HMB-PP-producing pathogens. Collectively, these findings suggest a direct link between invading pathogens, microbe-responsive γδ T cells, and monocytes in the inflammatory infiltrate, which plays a crucial role in the early response and the generation of microbe-specific immunity