Network Analysis Reveals Distinct Clinical Syndromes Underlying Acute Mountain Sickness

Acute mountain sickness (AMS) is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS), we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject-days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25). These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Activation of macrophages to express cytocidal activity correlates with inhibition of their responsiveness to macrophage colony-stimulating factor (CSF-1): involvement of a pertussis toxin-sensitive reaction

Bone marrow-derived murine macrophages were used to study the relationship between the proliferative response of macrophages to macrophage colony-stimulating factor (CSF-1) and their activation for cytocidal activity against tumour cells. Macrophage activation required two sequential signals. Lymphokines (gamma interferon, interleukin-4) provided the first (priming) signal; bacterial products (lipopolysaccharide, lipophilic muramyl tripeptide, lipopeptide 31362, pertussis toxin) provided the second (triggering) signal. Both priming and triggering agents inhibited [H]-thymidine uptake by macrophages stimulated with CSF-1. The antiproliferative activity of priming and triggering stimuli was synergistic. Pretreatment with triggering stimuli at 37°C caused a rapid reduction of the subsequent binding of [I]-CSF-1 to the cell surface at 4°C, whereas priming agents had relatively little effect. Growth inhibition by both priming and triggering agents was largely reversible by washing the cells, and occurred even when they were added as long as 24 h after the growth factor. The ability of pertussis toxin to both inhibit CSF-1-induced proliferation and trigger cytotoxicity in macrophages suggests the involvement of a regulatory GTP-binding protein (G protein) in both processes

Transcriptional regulatory networks in macrophages

The functions of macrophages in the innate immune system require the constitutive expression of a wide range of myeloid-specific genes, including various pattern recognition receptors, as well as the inducible expression of a suite of genes required to initiate inflammation and eliminate pathogens. Our overall aim is to understand the transcriptional networks that underlie both macrophage-specific transcription and the response to pathogen components such as lipopolysaccharide (LPS). The approaches used include detailed functional analysis of specific promoters, such as that of the CSF1 receptor, global cDNA microarray expression profiling, high throughput real-time PCR analysis of all the transcription factors encoded by the mammalian genome, full length cDNA library construction and sequencing, CAGE analysis to identify specific promoters used in macrophages and motif analysis to detect candidate cis-acting elements in co-regulated genes in macrophages. This review discusses some of the progress in moving towards a transcriptional network model for mouse macrophage activation by LPS, as well as insight into the role of alternative promoter usage and polyadenylation in generating functional protein variants that impact on signalling in macrophages. Copyrigh

The role of macrophages in experimental arthritis induced by Streptococcus agalactiae sonicate: Actions of macrophage colony-stimulating factor (CSF-1) and other macrophage-modulating agents

Intraperitoneal injection of Streptococcus agalactiae sonicated cells into Wistar rats causes a chronic relapsing polyarthritis resembling human rheumatoid arthritis. We report evidence favoring a role for macrophages in the pathology of this disease. S. agalactiae injected ip induced a high level of tumor necrosis factor release by peritoneal macrophages isolated subsequently, and had a similar effect when added to control peritoneal macrophages in culture. Ia antigen was induced on macrophages in both the peritoneum and affected joints following S. agalactiae injection. The role of macrophages in the disease process was studied by treating animals prior to S. agalactiae injection with varying concentrations of bacterial lipopolysaccharide (LPS), silica, and carrageenan, agents known to have a biphasic effect on macrophage function. They aggravated the pathology at low doses but prevented the disease at high doses. The most specific alteration of macrophage levels was achieved by injection of recombinant human macrophage colony-stimulating factor (CSF-1). Treatment with CSF-1 early in the disease lead to significant worsening of the pathology. Administration of CSF-1 after 2 weeks reactivated the disease and extended the chronic phase. These data in combination with previous findings are consistent with nonimmune, macrophage-mediated pathology for this model of arthritis. The results have implications for therapeutic application of CSF-1

Growth hormone and colony-stimulating factor 1 share multiple response elements in the c-fos promoter

The c-fos protooncogene is induced by GH rapidly, but transiently. Induction requires C kinase activation and the serum response element, and recent binding studies have also implicated the sis-inducible element (SIE). However, no systematic study of the promoter elements responsible for transactivation by GH has been undertaken. Here we used Chinese hamster ovary K1 cells transiently cotransfected with rabbit GH receptor and c-fos promoter-luciferase constructs to demonstrate that the major region responsible for GH induction is located between 284-396 base pairs upstream of the transcription start site. Full induction by GK requires all of the known elements located in this region to be intact, including the SIE or signal transducer and activator of transcription binding element. We also report novel negative elements located around -216 upstream of the start site that reduce induction by GH and provide gel shift evidence for factors binding in this region