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OBJECTIVE: Dizziness is a symptom of acute mountain sickness (AMS). This study tested whether immediate fall in systolic blood pressure (BP) on standing was more severe at altitude and whether this was associated with symptoms of dizziness. METHODS: Eighty-five lowlanders flew into La Paz, Bolivia (3650 m), and after 4 to 5 days of acclimatization ascended in 90 minutes to the Chacaltaya Laboratory (5200 m) by road. Blood pressure was measured on 5 occasions, 3 times at 5200 m and twice at sea level, before and after the expedition using a mercury sphygmomanometer. Both a supine and an erect (within 15 seconds of standing) BP measurement were recorded. Participants recorded whether they felt dizzy on standing. A mixed-effect model was used to test for a difference in the change in BP for time and altitude. RESULTS: The immediate fall in systolic BP observed on standing was significantly greater (P < .001) on all 3 altitude study days (18.2, 23.4, and 20.7 mm Hg) than at sea level (12.2 and 12.4 mm Hg). There was no significant difference in the change in diastolic BP or change in mean arterial BP between sea level and altitude. CONCLUSIONS: The immediate drop in systolic BP observed on standing was greater at altitude. However, mean arterial pressure was maintained, and we found no association between the degree of immediate fall in BP and dizziness or AMS.

Objectives: To investigate the effect of Antarctic residence on energy dynamics and aerobic fitness over the course of a year in over-wintering personnel. Study design: A prospective longitudinal observational study. Methods: A convenience sample of personnel over-wintering at Rothera Research Station in Antarctica was studied. Body weight, body fat, food intake, activity and aerobic fitness were recorded every 30 days for 1 year. Body weight, body fat and food intake were measured using weighing scales, skinfold callipers and diet records, respectively; activity was measured using accelerometer-based activity trackers and aerobic fitness using a treadmill protocol. Climate markers of temperature and sunlight hours were also recorded. Results: Twenty-one subjects took part in the study over the 12-month period. A statistically significant increase in body weight and body fat in winter was observed (p=0.012 and p=0.049, respectively). There were no statistically significant trends in activity, food intake or aerobic fitness. Conclusions: There were significant seasonal changes in body weight and body fat, with both measures increasing in winter but no significant changes in the other main outcome measures. Keywords: Antarctica; energy dynamics; fitness; Antarctic residence. (Published: 19 March 2012) Citation: Int J Circumpolar Health 2012, 71 : 17227 - DOI: 10.3402/ijch.v71i0.17227

Both tissue hypoxia in vitro, and whole-body hypoxia in vivo, have been found to promote the release of reactive oxygen species (ROS) that are potentially damaging to the cardiovascular system. Antioxidant systems protect against oxidative damage by ROS and may exhibit some degree of responsiveness to oxidative stimuli. Production of urate, a potent soluble antioxidant, is increased in hypoxic conditions. We aimed to determine whether urate is an important antioxidant defense in healthy subjects exposed to hypoxia.We conducted a cohort study of 25 healthy lowland volunteers during acute exposure to high altitude (4 days at 3,600 m, followed by 10 days at 5,200 m) on the Apex high-altitude research expedition to Bolivia. We measured markers of oxidative stress (8-isoprostane F2), serum urate concentration, and total plasma antioxidant activity by two techniques: 2,2'-amino-di-[3-ethylbenzthiazole sulfonate] spectrophotometry (total antioxidant status [TAS]) and enhanced chemiluminescence (ECL).On ascent, F2-isoprostane levels were significantly elevated compared with those at sea level (p0.01). After 1 week at high altitude, plasma antioxidant capacity (AOC) by both TAS and ECL, and serum urate concentration were significantly elevated (each p0.01 vs sea level), and F2-isoprostane levels were reduced to values at sea level. There was a highly significant correlation between plasma urate and AOC at this stage (ECL, r(2) = 0.59, p = 0.0001; TAS, r(2) = 0.30, p = 0.0062).Our results support the hypothesis that urate may act as a responsive endogenous antioxidant in high-altitude hypoxia.

Context Prompt reperfusion therapy in acute ST-segment elevation myocardial infarction (STEMI) improves outcomes and is therefore a key part of the management of affected patients. Primary percutaneous coronary intervention (PPCI) is preferred over thrombolysis; however, when PPCI is not available within an acceptable time frame, thrombolysis should be administered without delay. When thrombolysis is contraindicated, this can lead to delays in achieving coronary artery reperfusion, and making therapeutic decisions is more challenging. Issues A 57-year-old woman with hereditary haemorrhagic telangiectasia (HHT) presented with chest pain to local medical services on a Scottish island. Initial assessment including 12-lead ECG was performed without delay and led to a diagnosis of infero-lateral STEMI. Initial treatment was with antiplatelets, nitrate and opiate analgesia. Immediate reperfusion therapy with thrombolysis was considered; however, this was contraindicated due to the diagnosis of HHT. Following discussion with the regional centre she was treated with heparin and urgently transferred to the nearest catheterisation laboratory for PPCI. Unfortunately delays in transfer were caused by inclement weather conditions, which precluded the use of an air ambulance. The patient reached a cardiac catheterisation laboratory by road. A total occlusion of a distal branch of the circumflex artery was found to be the culprit lesion and despite wiring and ballooning good blood flow was not restored. However, she made a good recovery and was discharged home on secondary prevention therapy, which was modified to take into account her increased bleeding risk associated with her pre-existing HHT. Lessons learned In this case, the patient presented early to medical services following the onset of symptoms and was immediately assessed, resulting in a prompt accurate diagnosis at first medical contact. Despite this, the presence of HHT, and the particularities of living in a remote area compounded by unfavourable weather conditions, resulted in a delay in definitive treatment that would have been available to a similar patient presenting in an urban setting. In remote regions where reperfusion therapy for acute STEMI relies more often on thrombolysis, an increased awareness of the issues around the contraindication of thrombolysis, together with early discussion with a regional cardiology service leads to the most efficient way of establishing the best treatment plan for individual patients. Despite this, rural patients may remain at a disadvantage.

Gene-directed enzyme-prodrug therapy (GDEPT) using nitroreductase (NTR), with efficient adenoviral delivery, and CB1954 (CB), is an effective means of directly killing tumours. However, an immune-mediated bystander effect remains an important product of GDEPT since it is often critical to the elimination of untransduced tumour cells both locally and at distal metastatic sites through generation of tumour-specific immunity without the need for tumour antigen identification or the generation of a personalised vaccine. The mode of induced tumour cell death is thought to contribute to the immunisation process, together with the induction and release of stress proteins. Here, RM-9 murine prostate tumour cells were efficiently killed by adenovirally delivered NTR/CB treatment both in vitro and in vivo, and bystander effects were observed. Cells appeared to die by pathways that suggest necrosis more than that of classical apoptosis. NTR/CB-induced expression of a range of stress proteins was determined by proteomic analysis, revealing chiefly heat shock protein (HSP)25 and HSP70 upregulation, whilst immune responses in vivo were weak. In an attempt to enhance the anti-tumour effect, an adenoviral vector was constructed that co-expressed NTR and HSP70, the latter being a known immune stimulator and chaperone of antigen. This combination elicited significantly enhanced protection over NTR alone for both the treated tumour and a subsequent re-challenge. Protection was CD4+ and CD8+ T cell-dependent and was associated with tumour-specific CTL, IFNgamma and IL-5 responses. The use of such a cytotoxic and immunomodulatory gene combination in cancer therapy warrants further pursuit.

Immunization with dendritic cells (DCs) transfected with genes encoding tumor-associated antigens (TAAs) is a highly promising approach to cancer immunotherapy. We have developed a system, using complexes of plasmid DNA expression constructs with the cationic peptide CL22, that transfects human monocyte-derived DCs much more efficiently than alternative nonviral agents. After CL22 transfection, DCs expressing antigens stimulated autologous T cells in vitro and elicited primary immune responses in syngeneic mice, in an antigen-specific manner. Injection of CL22-transfected DCs expressing a TAA, but not DCs pulsed with a TAA-derived peptide, protected mice from lethal challenge with tumor cells in an aggressive model of melanoma. The CL22 system is a fast and efficient alternative to viral vectors for engineering DCs for use in immunotherapy and research.

Extreme sports such as paragliding are increasing in popularity, providing continued challenges for the development of safe practice techniques. In January and February 2013, the Wings of Kilimanjaro expedition aimed to launch 95 paragliders from the summit of Mount Kilimanjaro, 5790 m above sea level. A safe launch was paramount but risked being impaired by adverse environmental conditions, in particular the pathophysiological effects of high altitude. There are no existing scores to assess fitness for high-altitude paraglider launches present in the literature. A novel scoring system, the Kilimanjaro Score, was therefore developed to rapidly assess pilots pre-flight. The Kilimanjaro Score aimed to assess cognition, memory, and visual-spatial skill within the context of standard pre-flight checks. Further testing, including the Lake Louise Score, was to be performed if the pilot's Kilimanjaro Score was deemed unsatisfactory. We present the Kilimanjaro Score here for comment and refinement, and we invite other parties to consider its use in the field for high altitude paragliding activities.

Objective. To review the current literature that describes the effect of Antarctic residence on energy dynamics and aerobic fitness. Study design. Literature review. Methods. Published literature on energy dynamics and aerobic fitness in the polar environment was reviewed. Energy dynamics were represented by body weight, body fat, food intake and energy expenditure. Consideration was given to seasonal variation and possible explanations for the apparent high metabolic cost of Antarctic residence. The influence of cold exposure was discussed and comment was made on the differences between temperate and polar residence. Results. Food intake and energy expenditure are found to increase with Antarctic residence. There is often an associated increase in body weight and body fat. Seasonal variation is common but not universal, with an increase in body weight and body fat in winter. Variation in aerobic fitness appears to be related to the specific study sample rather than Antarctic residence per se. Conclusions. In most instances, Antarctic residence has effects on energy dynamics and aerobic fitness. Explanations for the observed changes may include physiological adaptations, such as a raised basal metabolic rate and increased thermogenesis. However, cold-induced changes are less likely when cold exposure is minimized by heated buildings and insulated clothing. Activity patterns related to work and leisure thus represent a more likely cause. The majority of the research is several decades old; further research would help to elucidate the patterns of energy dynamics of modern Antarctic workers. (Int J Circumpolar Health 2010; 69(3):220–235) Keywords: energy dynamics, aerobic fitness, Antarctic residence

Since the mid-1970s technology has enabled extraction of the UK’s oil and gas reserves in a cost-effective manner using subsea wells rather than individual platforms. In 2008, 43% of the UK’s oil and gas production was by subsea wells (The United Kingdom Offshore Oil and Gas Industry Association, 2010). Centrica Energy performed an extended well test on a subsea high-pressure, high-temperature (HPHT) appraisal well in the North Sea and monitored the test using a permanently installed optical distributed temperature sensor (DTS) system. The high temperatures and pressures, together with a subsea installation, created specific challenges for monitoring the completion integrity and flow from the multizone reservoir during the well test. In this paper the authors outline the deployment of the DTS system and present an interpretation of the acquired data. The completion was installed in one trip, with tubing-conveyed perforating (TCP) guns run at the bottom of the string. The firing of the guns, the completion integrity, and the fluid flow were monitored using a DTS optical fiber connected through the wellhead via an optical wet-connector and extending past the packer to the bottom of the guns. The same cable was used to operate a downhole electrical pressure gauge above the packer. Interpretation of the continuous temperature data enabled Centrica Energy to: identify leaks at gas lift mandrels while pressure testing the production tubing during commissioning, allowing time saving decisions to be made on how to proceed with the installation. check that all the perforating guns fired correctly to confirm that the whole reservoir was open to flow. monitor the flow from different reservoir intervals over the 2-week well test to compare the flow profile from the reservoir to model predictions. minimize QHSE risks associated with a well intervention.

A vast range of immunotherapeutic strategies are being considered for the treatment of cancer, only some of which are discussed above. Immunotherapy is unlikely to become a stand-alone treatment for cancer; it is far more likely that it will be used as a method to treat minimal residual disease or recurrence following more conventional treatment, such as surgical removal of primary tumour masses. This is emphasized by the fact that the effectiveness of treatment in animal models is more striking in the preventative, rather than the therapeutic, setting. The ultimate measure for the success of these approaches is clinical efficacy, but practical considerations must also be taken into account. For example, assuming equivalent efficacy and toxicity, relatively simple procedures such as cytokine administration will be preferable to manipulated autologous cell therapies. The immune status of patients is also a critical consideration when designing clinical trials and assessing results; many cancer patients are immunosuppressed either as a result of the cancer or of previous treatments.Assessment of the relative efficacy of the different approaches is currently very difficult because relative potency in animal models is rarely tested and, even if it were, would probably not be predictive of the potency in patients. However, over the next few years, as the results of ongoing, or imminent, clinical trials become available, a clearer picture of the potential of immunotherapy for the treatment of cancer will hopefully emerge, and, specifically, there might be indications as to which approaches show the most potency, with least toxicity, in patients. Thus, we hope to gain insights into the most promising approaches to help the immune system win this battle.

SummaryVentilatory control undergoes profound changes on ascent to high altitude. We hypothesized that the fall in citric acid cough threshold seen on ascent to altitude is mediated by changes in the central control of cough and would parallel changes in central ventilatory control assessed by the hypercapnic ventilatory response (HCVR). Twenty-five healthy volunteers underwent measurements of HCVR and citric acid sensitivity at sea level and during a 9 day sojourn at 5200m. None of the subjects had any evidence of respiratory infection. Citric acid cough threshold fell significantly on ascent to 5200m. The slope, S, of the HCVR increased significantly on ascent to 5200m and during the stay at altitude. There was no correlation between citric acid sensitivity and HCVR. We conclude that the change in citric acid cough threshold seen on exposure to hypobaric hypoxia is unlikely to be mediated by changes in the central control of cough. Sensitivity to citric acid may be due to early subclinical pulmonary edema stimulating airway sensory nerve endings.

Gene-directed enzyme prodrug therapy (GDEPT) is a promising approach to local management of cancer through targeted chemotherapy. Killing localized tumors by GDEPT in a manner that induces strong antitumor cellular immune responses might improve local management and allow benefit in disseminated cancer. Here we evaluated the combination of nitroreductase (NTR)/CB1954 GDEPT with high-level expression of heat shock protein 70 (HSP70, a stress protein that can shuttle cytosolic peptides into antigen-presenting cells) for induction of antitumor immunity using adenovirus gene delivery in an aggressive and nonimmunogenic BALB/c syngeneic 4T1 breast cancer model. The mechanism of cell death and spectrum of stress proteins induced are likely to be important determinants of the resulting immune responses. We showed that NTR/CB1954 treatment of 4T1 cells gave both apoptotic and nonapoptotic killing. In vivo killing of 4T1 cells expressing NTR gave weak antitumor immunity and very limited induction of stress proteins including HSP70. High-level coexpression of HSP70 during NTR/CB1954-mediated killing of 4T1 cells in vivo gave much greater protection from tumor challenge (67% long-term survivors compared to 17%) and induced 4T1-specific cytotoxic T-cell responses. The enhancement of antitumor responses resulting from HSP70 coexpression was similar to that conferred by coexpression of GM-CSF.

We recently published the construction and evaluation of a beta-catenin-dependent, highly active promoter, CTP1, and its possible application for the treatment of colorectal cancer using gene-directed enzyme prodrug therapy with adenoviral (Ad) vectors. Alternative Ad-based approaches such as tumor-specific, replication-competent vectors and/or exploiting therapeutic gene products with intrinsic toxic activity, such as gibbon ape leukemia virus fusogenic membrane glycoprotein, diphtheria toxin A (DTA), and ricin, would demand a very tightly regulated promoter to avoid breakthrough replication and toxicity in nontumor tissue and Ad producer cell lines. In this study we optimized the activity/specificity profile of the synthetic beta-catenin-dependent promoter by varying its basal promoter, the number of Tcf binding sites, and the distance between these and the basal promoter. The optimal promoter, CTP4, showed virtually undetectable expression in cells with normal beta-catenin regulation but high level expression in cells deregulated for beta-catenin. Using CTP4 we were able to generate, for the first time to our knowledge, an Ad vector expressing fully active wild-type DTA without the need for time-consuming and cumbersome production systems. CTP4 should be the promoter of choice for Ad-based gene therapies of tumors deregulated for beta-catenin. We provide preliminary evidence that these may include prostate and ovarian as well as colorectal cancer.

Condensing peptide-DNA complexes have great potential as nonviral agents for gene delivery. To date, however, such complexes have given transfection activities greatly inferior to adenovirus and somewhat inferior to cationic lipid-DNA complexes, even for cell lines and primary cells in vitro. We report here the identification of a novel condensing peptide, CL22, which forms DNA complexes that efficiently transfect many cell lines, as well as primary dendritic and endothelial cells. We report studies with sequence and structure variants that define some properties of the peptide that contribute to efficient transfection. We demonstrate that the superior transfection activity of CL22 compared with other DNA condensing peptides is conferred at a step after uptake of the complexes into cells. We show that CL22-DNA complexes have transfection activity that is at least equivalent to the best available nonviral agents.

The hCMV promoter is very commonly used for high level expression of transgenes in mammalian cells, but its utility is hindered by transcriptional silencing. Large genomic fragments incorporating the CpG island region of the HNRPA2B1 locus are resistant to transcriptional silencing. In this report we describe studies on the use of a novel series of vectors combining the HNRPA2B1 CpG island with the hCMV promoter for expression of transgenes in CHO-K1 cells. We show that the CpG island gives at least twenty-fold increases in the levels of EGFP and EPO observed in pools of transfectants, and that transgene expression levels remain high in such pools for more than 100 generations. These novel vectors also allow facile isolation of clonal CHO-K1 cell lines showing stable, high-level transgene expression. Vectors incorporating the hnRPA2B1 CpG island give major benefits in transgene expression from the hCMV promoter, including substantial improvements in the level and stability of expression. The utility of these vectors for the improved production of recombinant proteins in CHO cells has been demonstrated.