Monitoring Neural Activity with Bioluminescence during Natural Behavior

Existing techniques for monitoring neural activity in awake, freely behaving vertebrates are invasive and difficult to target to genetically identified neurons. We used bioluminescence to non-invasively monitor the activity of genetically specified neurons in freely behaving zebrafish. Transgenic fish with the Ca$^{2+}$-sensitive photoprotein green fluorescent protein (GFP)-Aequorin in most neurons generated large and fast bioluminescent signals that were related to neural activity, neuroluminescence, which could be recorded continuously for many days. To test the limits of this technique, we specifically targeted GFP-Aequorin to the hypocretin-positive neurons of the hypothalamus. We found that neuroluminescence generated by this group of ~20 neurons was associated with periods of increased locomotor activity and identified two classes of neural activity corresponding to distinct swim latencies. Our neuroluminescence assay can report, with high temporal resolution and sensitivity, the activity of small subsets of neurons during unrestrained behavior.Molecular and Cellular Biolog

Galectin-1 serum levels reflect tumor burden and adverse clinical features in classical Hodgkin lymphoma

Galectin-1 (Gal1) is a member of a highly conserved family of carbohydrate-binding proteins that modulates innate and adaptive immune responses and fosters tumor-immune escape. Hodgkin lymphoma (HL) Reed-Sternberg (RS) cells overexpress and secrete Gal1, which selectively kills Th1,Th17 and cytotoxic T cells and promotes the immunosuppressive Th2/Treg-predominant HL microenvironment. We developed a sandwich ELISA and assessed serum Gal1 levels in 315 newly diagnosed, previously untreated HL patients enrolled on 3 risk-adapted clinical trials. Serum Gal1 levels were significantly higher in HL patients than in normal controls (p < .0001). Gal1 serum levels also increased with Ann Arbor stage (p < .0001), areas of nodal involvement (p = .0001) and the International Prognostic Score (IPS) (2-7, p = .006). We conclude that Gal1 serum levels are significantly associated with tumor burden and additional adverse clinical characteristics in newly diagnosed HL Patients.Fil: Ouyang, Jing. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos de América;Fil: Plütschow, Annette. German Hodgkin Study Group; Alemania;Fil: Von Strandmann, Elke Pogge. University Hospital of Cologne. Laboratory for Immunotherapy; Alemania;Fil: Reiners, Katrin S.. University Hospital of Cologne. Laboratory for Immunotherapy; Alemania;Fil: Ponader, Sabine. German Hodgkin Study Group; Alemania;Fil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Neuberg, Donna. Dana-Farber Cancer Institute. Department of Biostatistics; Estados Unidos de América;Fil: Engert, Andreas. German Hodgkin Study Group; Alemania;Fil: Shipp, Margaret A.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos de América

Poorer outcome of elderly patients treated with extended-field radiotherapy compared with involved-field radiotherapy after chemotherapy for Hodgkin's lymphoma: an analysis from the German Hodgkin Study Group

Background: The optimal treatment of elderly patients with Hodgkin's lymphoma (HL) is still a matter of debate. Since many of these patients receive combined modality treatment, we evaluated the impact of different radiation field sizes, that is extended-field (EF) or involved-field (IF) technique when given after four cycles of chemotherapy. Patients and methods: In the multicenter HD8 study of the German Hodgkin Study Group, 1204 patients with early-stage unfavorable HL were randomized to receive four cycles of chemotherapy followed by either radiotherapy (RT) of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). A total of 1064 patients were assessable for the analysis. Of these, 89 patients (8.4%) were 60 years or older. Results: Elderly patients had a poorer risk profile. Acute toxicity from RT was more pronounced in elderly patients receiving EF-RT compared with IF-RT [World Health Organization (WHO) grade 3/4: 26.5% versus 8.6%)]. Freedom from treatment failure (FFTF, 64% versus 87%) and overall survival (OS, 70% versus 94%) after 5 years was lower in elderly patients compared with younger patients. Importantly, elderly patients had poorer outcome when treated with EF-RT compared with IF-RT in terms of FFTF (58% versus 70%; P = 0.034) and OS (59% versus 81%; P = 0.008). Conclusion: Elderly patients with early-stage unfavorable HL generally have a poorer risk profile and outcome when compared with younger patients. Treatment with EF-RT instead of IF-RT after chemotherapy has a negative impact on survival of elderly patients and should be avoide

Self-organized critical neural networks

A mechanism for self-organization of the degree of connectivity in model neural networks is studied. Network connectivity is regulated locally on the basis of an order parameter of the global dynamics which is estimated from an observable at the single synapse level. This principle is studied in a two-dimensional neural network with randomly wired asymmetric weights. In this class of networks, network connectivity is closely related to a phase transition between ordered and disordered dynamics. A slow topology change is imposed on the network through a local rewiring rule motivated by activity-dependent synaptic development: Neighbor neurons whose activity is correlated, on average develop a new connection while uncorrelated neighbors tend to disconnect. As a result, robust self-organization of the network towards the order disorder transition occurs. Convergence is independent of initial conditions, robust against thermal noise, and does not require fine tuning of parameters.Comment: 5 pages RevTeX, 7 figures PostScrip

You turn me cold: evidence for temperature contagion

Introduction During social interactions, our own physiological responses influence those of others. Synchronization of physiological (and behavioural) responses can facilitate emotional understanding and group coherence through inter-subjectivity. Here we investigate if observing cues indicating a change in another's body temperature results in a corresponding temperature change in the observer. Methods Thirty-six healthy participants (age; 22.9±3.1 yrs) each observed, then rated, eight purpose-made videos (3 min duration) that depicted actors with either their right or left hand in visibly warm (warm videos) or cold water (cold videos). Four control videos with the actors' hand in front of the water were also shown. Temperature of participant observers' right and left hands was concurrently measured using a thermistor within a Wheatstone bridge with a theoretical temperature sensitivity of <0.0001°C. Temperature data were analysed in a repeated measures ANOVA (temperature × actor's hand × observer's hand). Results Participants rated the videos showing hands immersed in cold water as being significantly cooler than hands immersed in warm water, F(1,34) = 256.67, p0.1). There was however no evidence of left-right mirroring of these temperature effects p>0.1). Sensitivity to temperature contagion was also predicted by inter-individual differences in self-report empathy. Conclusions We illustrate physiological contagion of temperature in healthy individuals, suggesting that empathetic understanding for primary low-level physiological challenges (as well as more complex emotions) are grounded in somatic simulation

Increased angiogenic factor secretion by decidual natural killer cells from pregnancies with high uterine artery resistance alters trophoblast function.

STUDY QUESTION Are the concentrations of factors secreted by decidual natural killer (dNK) cells from pregnancies at high risk of poor spiral artery remodelling different to those secreted from pregnancies at low risk? SUMMARY ANSWER Expression levels of PLGF, sIL-2R, endostatin and angiogenin were significantly increased by dNK cells from high-risk pregnancies, and angiogenin and endostatin were found to alter trophoblast function. WHAT IS KNOWN ALREADY During early pregnancy, maternal uterine spiral arteries are remodelled from small diameter, low-flow, high-resistance vessels into larger diameter, higher flow vessels, with low-resistance. This change is essential for the developing fetus to obtain sufficient oxygen and nutrients. dNK cells have been implicated in this process. STUDY DESIGN, SIZE, DURATION dNK cells were isolated from first trimester terminations of pregnancies (obtained with local ethical approval) screened for normal- or high-resistance index, indicative of cases least (21%) likely to have developed pre-eclampsia had the pregnancy not been terminated (n = 18 each group). Secreted factors and the effects of these on the trophoblast cell line, SGHPL-4, were assessed in vitro. PARTICIPANTS/MATERIALS, SETTING, METHODS A multiplex assay was used to assess dNK cell-secreted factors. SGHPL-4 cell functions were assessed using time-lapse microscopy, 3D invasion assays, endothelial-like tube formation ability and western blot analysis. MAIN RESULTS AND THE ROLE OF CHANCE The expression levels of PLGF (P < 0.01), sIL-2R (P < 0.01), endostatin (P < 0.05) and angiogenin (P < 0.05) were significantly increased by dNK cells from high-risk pregnancies. Endostatin significantly decreased SGHPL-4 invasion (P < 0.05), SGHPL-4 tube formation (P < 0.05) and SGHPL-4 Aktser473 phosphorylation (P < 0.05). Angiogenin significantly decreased SGHPL-4 invasion (P < 0.05), but increased SGHPL-4 tube formation (P < 0.01) and decreased SGHPL-4 Aktser473 phosphorylation (P < 0.05). LIMITATIONS, REASONS FOR CAUTION The culture of dNK cells and protein concentrations in vitro may not fully represent the in vivo situation. Although SGHPL-4 cells are extravillous trophoblast derived, further studies would be needed to confirm the roles of angiogenin and endostatin in vivo. WIDER IMPLICATIONS OF THE FINDINGS The altered expression of secreted factors of dNK cells may contribute to pregnancy disorders associated with poor spiral artery remodelling. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Wellcome Trust (project reference 091550). R.F. was a recipient of a PhD studentship from the Division of Biomedical Sciences, St. George's, University of London. The authors have no conflict of interests

Therapy-Related Myeloid Neoplasms in Patients Treated for Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a malignancy of the lymphatic system with an incidence of 2-3/100.000/year in developed countries. With modern multi-agent chemotherapy protocols optionally combined with radiotherapy (RT), 80% to 90% of HL patients achieve long-term remission and can be considered cured. However, current standard approaches bear a considerable risk for the development of treatment-related late effects. Thus, one major focus of current clinical research in HL is reducing the incidence of these late effects that include heart failure, infertility, chronic fatigue and therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML). In previous analyses, t-MDS/t-AML after treatment for HL was associated with a poor prognosis. Nearly all patients died rapidly after diagnosis. However, more recent analyses indicated an improved outcome among patients with t-MDS/t-AML who are eligible for modern anti-leukemic treatment and allogeneic stem cell transplantation (aSCT). This article gives an overview of recent reports on the incidence and the treatment of t-MDS/t-AML after HL therapy and describes the efforts currently made to reduce the risk to develop this severe late effect

Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial

Background In the HD14 trial, 2× BEACOPPescalated+2× ABVD (2+2) has improved the primary outcome. Compared with 4× ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. Patients and methods Women ≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. Results Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women ≥30 years (A: 21%, B: 25%). Conclusions Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation tim

Active flow control systems architectures for civil transport aircraft

Copyright @ 2010 American Institute of Aeronautics and AstronauticsThis paper considers the effect of choice of actuator technology and associated power systems architecture on the mass cost and power consumption of implementing active flow control systems on civil transport aircraft. The research method is based on the use of a mass model that includes a mass due to systems hardware and a mass due to the system energy usage. An Airbus A320 aircraft wing is used as a case-study application. The mass model parameters are based on first-principle physical analysis of electric and pneumatic power systems combined with empirical data on system hardware from existing equipment suppliers. Flow control methods include direct fluidic, electromechanical-fluidic, and electrofluidic actuator technologies. The mass cost of electrical power distribution is shown to be considerably less than that for pneumatic systems; however, this advantage is reduced by the requirement for relatively heavy electrical power management and conversion systems. A tradeoff exists between system power efficiency and the system hardware mass required to achieve this efficiency. For short-duration operation the flow control solution is driven toward lighter but less power-efficient systems, whereas for long-duration operation there is benefit in considering heavier but more efficient systems. It is estimated that a practical electromechanical-fluidic system for flow separation control may have a mass up to 40% of the slat mass for a leading-edge application and 5% of flap mass for a trailing-edge application.This work is funded by the Sixth European Union Framework Programme as part of the AVERT project (Contract No. AST5-CT-2006-030914

BRCA2 variants and cardiovascular disease in a multi-ethnic study.

BACKGROUND: Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD). METHODS: Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP), the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART), and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS). RESULTS: Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studies resulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06). CONCLUSIONS: Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnic population, these results were not replicated in two South Asian case-control studies of incident MI. Future studies exploring the association between BRCA variants and cardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVD pathogenesis.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are