Discovery and insights from DSX mission's high-power VLF wave transmission experiments in the radiation belts.

Space weather phenomena can threaten space technologies. A hazard among these is the population of relativistic electrons in the Van Allen radiation belts. To reduce the threat, artificial processes can be introduced by transmitting very-low-frequency (VLF) waves into the belts. The resulting wave-particle interactions may deplete these harmful electrons. However, when transmitting VLF waves in space plasma, the antenna, plasma, and waves interact in a manner that is not well-understood. We conducted a series of VLF transmission experiments in the radiation belts and measured the power and radiation impedance under various frequencies and conditions. The results demonstrate the critical role played by the plasma-antenna-wave interaction around high-voltage space antennae and open the possibility to transmit high power in space. The physical insight obtained in this study can provide guidance to future high-power space-borne VLF transmitter developments, laboratory whistler-mode wave injection experiments, and the interpretation of various astrophysical and optical phenomena.

Intracranial pressure directly predicts headache morbidity in idiopathic intracranial hypertension.

OBJECTIVE: Headache is the predominant disabler in idiopathic intracranial hypertension (IIH). The aim was to characterise headache and investigate the association with intracranial pressure. METHODS: IIH:WT was a randomised controlled parallel group multicentre trial in the United Kingdom investigating weight management methods in IIH. Participants with active IIH (evidenced by papilloedema) and a body mass index (BMI) ≥35 kg/m2 were recruited. At baseline, 12 months and 24 months headache characteristics and quality of life outcome measures were collected and lumbar puncture measurements were performed. RESULTS: Sixty-six women with active IIH were included with a mean age of 32.0 years (SD ± 7.8), and mean body mass index of 43.9 ± 7.0 kg/m2. The headache phenotype was migraine-like in 90%. Headache severity correlated with ICP at baseline (r = 0.285; p = 0.024); change in headache severity and monthly headache days correlated with change in ICP at 12 months (r = 0.454, p = 0.001 and r = 0.419, p = 0.002 respectively). Cutaneous allodynia was significantly correlated with ICP at 12 months. (r = 0.479, p < 0.001). Boot strap analysis noted a positive association between ICP at 12 and 24 months and enabled prediction of both change in headache severity and monthly headache days. ICP was associated with significant improvements in quality of life (SF-36). CONCLUSIONS: We demonstrate a positive relationship between ICP and headache and cutaneous allodynia, which has not been previously reported in IIH. Those with the greatest reduction in ICP over 12 months had the greatest reduction in headache frequency and severity; this was associated with improvement of quality of life measures. TRIAL REGISTRATION: This work provides Class IIa evidence of the association of raised intracranial pressure and headache. ClinicalTrials.gov number, NCT02124486 .

Differing presenting features of idiopathic intracranial hypertension in the UK and US.

AIM: Demographic factors potentially influencing the presentation and severity of idiopathic intracranial hypertension (IIH) in the US vs. UK populations include obesity and ethnicity. We aimed to compare the presenting features of IIH between populations in the UK and US tertiary referral centres, to assess what population differences exist and whether these cause different presentations and impact on visual function. METHODS: Clinical data were collected on 243 consecutive UK IIH patients and 469 consecutive US IIH patients seen after 2012 in two tertiary centres. Visual function was defined as severe visual loss when Humphrey visual field mean deviation was <-15 dB, when Goldmann visual fields showed constriction or when visual acuity was <20/200. RESULTS: US patients were more commonly of self-reported black race (58.9% vs. 7.1%) than UK patients, but had a similar mean body mass index (38.3 ± 0.63kg/m2 UK vs. 37.7 ± 0.42kg/m2 US; p = 0.626). The UK cohort had lower presenting Frisén grade (median 1 vs. 2; p < 0.001) and severe visual loss less frequently (15.4% vs. 5%; p = 0.014), but there was no difference in mean cerebrospinal fluid-opening pressure (CSF-OP) (35.8 ± 0.88cmH2O UK vs. 36.3 ± 0.52cmH2O US; p = 0.582). African Americans had poorer visual outcomes compared with US whites (19.4% vs. 10% severe visual loss; p = 0.011). Visual function was weakly associated with CSF-OP (R2 = 0.059; p = 0.001), which was similar between UK and US patients. CONCLUSIONS: The UK and the US cohorts had a similar average presenting BMI. However, the worse presenting visual function in the US IIH cohort was partially attributable to differences in the black populations in the two countries.

Deintensification of hypoglycaemic medications-use of a systematic review approach to highlight safety concerns in older people with type 2 diabetes.

IMPORTANCE: Intensive treatment of older people with diabetes is common placing them at increased risk of adverse events such as hypoglycaemia and hospitalisation for drug errors. Little is known about when, how or for whom to deintensify hypoglycaemic medications. OBJECTIVE: To explore the characteristics of patients for whom deintensification is appropriate and to determine the outcome of deintensification. EVIDENCE REVIEW: Medline, Google scholar and EmBase search from 1997 to present was performed using keywords relating to diabetes mellitus, polypharmacy, hypoglycaemia, hospitalisation, deintensification, deprescribing and reduction, simplification or withdrawal of hypoglycaemic medications. Only English language articles were selected. Articles were reviewed for relevance by abstract. A manual review of citations in retrieved articles was performed in addition to the electronic literature search. FINDINGS: Those who are over treated appear to be of older age group, frail with weight loss and have multiple medical morbidities especially renal impairment and dementia. Simplification, reduction or even complete withdrawal of hypoglycaemic medications in these patients appears to be feasible without deterioration of glycaemic control. CONCLUSIONS: Over treatment is common in frail older people with multiple comorbidities and deintensification appears safe in this group of patients. Current recommendations emphasise preventing underuse rather than overuse of medications, and therefore, a change in guidelines advice may be warranted.

Introduction of pharmacy technicians onto a busy oncology ward as part of the nursing team.

A project was planned to explore the practicality of using pharmacy technicians to support the workload of nursing teams on a busy haematology oncology ward of 28 beds in a university acute care children's hospital of 300 beds. The question asked was, could pharmacy technicians be part of the nursing team to undertake what has traditionally been considered a nursing role? Three pharmacy technicians were trained and participated in the study. Assisting in the preparation and administration of 509 intravenous injections out of a possible 1123 (45%) of all intravenous injections prepared on the ward during the study period. The results indicated a reduction in adverse events of 1-2 a day during the study period, a reduction in work-related stress by nursing staff associated with preparing complex medication and releasing a nurse, 4 hours a day to enable them additional time to care for patients.

Examining factors associated with excess mortality in older people (age ≥ 70 years) with diabetes - a 10-year cohort study of older people with and without diabetes.

AIMS: To compare all-cause mortality in older people with or without diabetes and consider the associated risk of comorbidity and polypharmacy. METHODS: A 10-year cohort study using data from the Health Innovation Network database (2003-2013) comparing mortality in people aged ≥ 70 years with diabetes (DM cohort) (n = 35 717) and without diabetes (No DM cohort) (n = 307 918). RESULTS: The mean age of the DM cohort was 78.1 ± 5.8 years vs. 79.0 ± 6.3 years in the No DM cohort. Mean diabetes duration was 8.2 ± 8.1 years, and 30% had diabetes for > 10 years. The DM cohort had a greater comorbidity load and people in this cohort were prescribed more therapies than the No DM cohort. The 5- and 10-year survival rates were lower in the DM cohort at 64% and 39%, respectively, compared with 72% and 50% in the No DM cohort. The excess mortality in the DM cohort was greatest in those aged < 75 years with longer duration diabetes, the relative hazard for mortality was higher in females. Although comorbidity and polypharmacy were associated with increased mortality risk in the DM cohort, this risk was lower compared with the No DM cohort. The hazard ratios (95% confidence interval) for comorbidities > 4 and medicines ≥ 7 were 1.29 (1.19 to 1.41) and 1.34 (1.25 to 1.43) in the DM cohort and 1.63 (1.57 to 1.70) and 1.48 (1.40 to 1.56) in the No DM cohort, respectively. CONCLUSIONS: There is significant excess mortality in older people with diabetes, which is unexplained by comorbidity or polypharmacy. This excess is greatest in the younger old with longer disease duration, suggesting that it may be related to the effect of diabetes exposure.

Synthesis, analysis and biological evaluation of novel indolquinonecryptolepine analogues as potential anti-tumour agents.

A small library of cryptolepine analogues were synthesised incorporating halogens and/or nitrogen containing side chains to optimise their interaction with the sugar-phosphate backbone of DNA to give improved binding, interfering with topoisomerase II hence enhancing cytotoxicity. Cell viability, DNA binding and Topoisomerase II inhibition is discussed for these compounds. Fluorescence microscopy was used to investigate the uptake of the synthesised cryptolepines into the nucleus. We report the synthesis and anti-cancer biological evaluation of nine novel cryptolepine analogues, which have greater cytotoxicity than the parent compound and are important lead compounds in the development of novel potent and selective indoloquinone anti-neoplastic agents.

Treating diabetes mellitus in older and oldest old patients.

There is a rapidly growing number of persons reaching extreme age limits. Indeed, the fastest growth is found in those over the age of 80 years or octogenarians. Along with this continuous rise, there is a significant increase in type 2 diabetes in this population. Unfortunately, individuals living past 80 years of age are often accompanied by numerous comorbidities and geriatric conditions, all which render anti-diabetic treatment options challenging. Indeed the principles of managing type 2 diabetes are similar to younger patients. Special considerations in this delicate group are essential due to the increased prevalence of comorbidities and relative inability to tolerate adverse effects of medication and severe hypoglycemia. It is important to recall that octogenarians have shown to have a greater prevalence for cognitive impairment, physical disability, ren al and hepatic dysfunction, and syndromes, such as frailty compared to younger elders. The frailty syndrome is considered one of the most important limitations when treating octogenarians with type 2 diabetes in polypharmacy. Due to the lack of evidence for specific targets of glucose and glycated hemoglobin (A1C) levels in the elderly, available treatment guidelines are based on data extrapolation from younger adults and expert opinion citing reliable evidence. Overall, the most important conclusion emerging from these groups is to accomplish a moderate glycemic control (A1C levels between 7 -8%) in complex elderly patients. However, the risk of hypoglycemia from some treatments may present the greatest significant barrier to optimal glycemic control for the very old. The present review discusses the highlights from the latest guidelines for treating older persons and underlines the need for specific considerations when treating the very old in order to maintain a balance between treating comorbidities and maintaining quality of life.

Radiation endurance of piezoelectric ultrasonic transducers--a review.

A literature survey is presented on the radiation endurance of piezoelectric ultrasonic transducer components and complete transducer assemblies, as functions of cumulative gamma dose and neutron fluence. The most extensive data on this topic has been acquired in CANDU electrical generating stations, which use piezoelectric ultrasonic transducers manufactured commercially with minor accommodation for high radiation fields. They have been found to be reliable for cumulative gamma doses of up to approximately 2 MegaGrays; a brief summary is made of the associated accommodations required to the transducer design, and the ultimate expected failure modes. Outside of the CANDU experience, endurance data have been acquired under a diverse spectrum of operating conditions; this can impede a direct comparison of the information from different sources. Much of this data is associated with transducers immersed in liquid metal coolants associated with advanced reactor designs. Significant modifications to conventional designs have led to the availability of custom transducers that can endure well over 100 MegaGrays of cumulative gamma dose. Published data on transducer endurance against neutron fluence are reviewed, but are either insufficient, or were reported with inadequate description of test conditions, to make general conclusions on transducer endurance with high confidence. Several test projects are planned or are already underway by major laboratories and research consortia to augment the store of transducer endurance data with respect to both gamma and neutron radiation.

Diabetes and dementia in older people: a Best Clinical Practice Statement by a multidisciplinary National Expert Working Group.

Both dementia and diabetes mellitus are long-term disabling conditions and each may be a co-morbidity of the other. Type 2 diabetes is associated with a 1.5- to 2-fold higher risk of dementia. Diabetes also may occur for the first time in many individuals with mental ill health, including cognitive impairment and dementia, and this may complicate management and lead to difficulties in self-care. Case finding is often poor for cognitive impairment in medical settings and for diabetes in mental health settings and this needs to be addressed in the development of care pathways for both conditions. Many other deficiencies in quality care (both for dementia and diabetes) currently exist, but we hope that this Best Clinical Practice Statement will provide a platform for further work in this area. We have outlined the key steps in an integrated care pathway for both elements of this clinical relationship, produced guidance on identifying each condition, dealt with the potentially hazardous issue of hypoglycaemia, and have outlined important competencies required of healthcare workers in both medical/diabetes and mental health settings to enhance clinical care.

Targeting survival pathways in chronic myeloid leukaemia stem cells.

UNLABELLED: Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population. LINKED ARTICLES: This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8.

Brief report: Use of the Mini-Cog as a screening tool for cognitive impairment in diabetes in primary care.

The Mini-Cog was shown to be a brief, acceptable and practical cognitive screen for older people with diabetes when administered by a primary care nurse. It could be integrated easily into the annual diabetes review and help to identify those who may benefit from extra help with their management.

Insulin resistance: a risk marker for disease and disability in the older person.

Clinical metabolic studies have demonstrated that insulin action declines progressively with age in humans. In addition to its close association with Type 2 diabetes, which reduces life expectancy in older people, age-related insulin resistance is implicated in pathogenesis of several highly prevalent disorders for which ageing is a major risk factor. These include atherosclerotic cardiovascular disease, dementia, frailty and cancer. Accordingly, insulin resistance may be viewed as biomarker of age-related ill health and reduced lifespan. The rapidly rising number of older people, coupled with a high prevalence of insulin resistance resulting from obesity and sedentary lifestyles, presents unprecedented public health and societal challenges. Studies of centenarians have shown that preserved whole-body sensitivity to insulin is associated with longevity. The mechanisms through which insulin action is associated with age-related diseases remain unclear. Changes in body composition, i.e. sarcopenia and excess adiposity, may be more potent than age per se. Moreover, the impact of insulin resistance has been difficult to disentangle from the clustering of vascular risk factors that co-segregate with the insulin resistance-hyperinsulinaemia complex. Potentially modifiable mediators of age-related changes in insulin sensitivity include alterations in adipocytokines, impaired skeletal myocyte mitochondrial function and brown fat activity. The hypothesis that improving or maintaining insulin sensitivity preserves health and extends lifespan merits further evaluation. Practical non-pharmacological interventions directed against age-related insulin resistance remain underdeveloped. Novel metabolically active pharmacological agents with theoretical implications for some age-related disorders are entering clinical trials. However, recent adverse experiences with the thiazolidinediones suggest the need for a cautious approach to the use of insulin sensitizing drugs in older people. This could be particularly important in the absence of diabetes where the risk to benefit analysis may be less favourable.

Bioimpedance analysis for the characterization of breast cancer cells in suspension.

The bioimpedance spectroscopy (BIS) technique is potentially a useful tool to differentiate malignancy based on the variation of electrical properties presented by different tissues and cells. The different tissues and cells present variant electrical resistance and reactance when excited at different frequencies. The main purpose of this area of research is to use impedance measurements over a low-frequency bandwidth ranging from 1 kHz to 3 MHz to 1) differentiate the pathological stages of cancer cells under laboratory conditions and 2) permit the extraction of electrical parameters related to cellular information for further analysis. This provides evidence to form the basis of bioimpedance measurement at the cellular level and aids the potential future development of rapid diagnostics from biopsy materials. Three cell lines, representing normal breast epithelia and different pathological stages of breast cancer, have been measured using a standard impedance analyzer driving a four-electrode chamber filled with different cell suspensions. We identify the specific BIS profile for each cell type and determine whether these can be differentiated. In addition, the electrical parameters, e.g., the intracellular conductivity, membrane capacitance/capacity, characteristic frequency, are extracted by the use of equivalent circuit models and physical models to provide details of the cell electric signatures for further analysis of cancer cell pathology.

Barriers and opportunities of empowerment as applied in diabetes settings: a focus on health care professionals' experiences.

This exploratory study examines the opportunities and barriers health care professionals (HCPs) working with diabetes patients face when they try to implement the rhetoric of patient empowerment in practice. A small sample of diabetes HCPs (N=13), from National Health Service (NHS) hospital, walk-in and general practitioner (GP) clinics in South-East England, was interviewed through in-depth semi-structured interviews. Interviews were recorded, transcribed verbatim and analysed thematically. The analysis showed that empowerment was seen as beneficial for patients and HCPs. Time and resources could be moved from successfully empowered patients and focussed on more complex patients, this was termed 'selective empowerment'. The main barriers to empowerment were identified as a lack of resources, time and HCPs trained in empowerment techniques. Empowerment is a popular concept in theory, and presents HCPs with several opportunities but also important barriers in its practical, clinical implementation day-to-day.

Prescribed medicines for elderly frail people with diabetes resident in nursing homes-issues of polypharmacy and medication costs.

AIMS: To describe the numbers and costs of medications prescribed to people living with diabetes resident in nursing homes in one primary care trust in the UK. METHODS: A retrospective case notes review of 75 people with known diabetes who were resident in the 11 nursing homes in the Coventry teaching primary care trust. RESULTS: Sixty-three residents (84%) were being prescribed four or more medications. Forty-four residents (59%) were prescribed anti-platelet drugs for prevention of cardiovascular disease, including aspirin, clopidogrel and dipyridamole, and 31 residents (41%) were on statin therapy. Eighteen (24%) residents had a monthly medication cost that was above £101 per month. On detailed review, these were largely residents who were being prescribed special order liquid preparations, usually for secondary cardiovascular disease prevention. CONCLUSION: Polypharmacy, defined as taking four or more drugs per day per resident, is highly prevalent within this population of care home residents with diabetes. A high proportion of residents are prescribed drugs for cardiovascular disease prevention, which may be entirely inappropriate in this population with limited life expectancy. Regular medication review of care home residents with diabetes should be undertaken as it has the potential to reduce costs, minimize adverse drug reactions and increase health gain.

The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells.

The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the extracellular signal-regulated kinase (ERK) pathway, downstream of BCR-ABL, by treating CD34+ CML stem/progenitor cells with a highly selective adenosine triphosphate (ATP) non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared with BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, -8 and -9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant-negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease.

Idiopathic intracranial hypertension associated with iron deficiency anaemia: a lesson for management.

AIM: To document the causal association of iron deficiency anaemia (IDA) and intracranial hypertension (IH). METHODS: A consecutive case note review of patients with a clinical diagnosis of idiopathic intracranial hypertension (IIH) and anaemia presenting to a tertiary referral unit over a 2.5-year period. Demographics, aetiology and clinical details were recorded and analysed. RESULTS: Eight cases were identified from 77 new cases presenting with IIH. All 8 had documented microcytic anaemia with clinical evidence of raised intracranial pressure. There was no evidence of venous sinus thrombosis on MRI and MR venography in 7 subjects and on repeated CT venography in 1. On correction of anaemia alone, 7 cases resolved. One patient with severe progressive visual loss underwent ventriculoperitoneal shunt in addition to treatment of anaemia, with good outcome. The incidence of this association is 10.3%. CONCLUSION: These cases present an association between IDA and IH, in the absence of cerebral sinus thrombosis. As a clinically significant proportion of cases presenting with signs of IIH have IDA, we recommend all patients presenting with IIH have full blood counts and if they are found to be anaemic, they should be treated appropriately.

Fatty acids and obesity.

Obesity is becoming a major public health problem worldwide. Its prevalence is increasing as well as the burden of diet-related chronic diseases including hypertension, diabetes, cardiovascular disease, stroke, and certain cancers. The link between obesity and chronic diseases is well established. Obese individuals are two to three times more likely to die prematurely than their lean counterparts, primarily due to the association between obesity and type 2 diabetes and CHD. Over the past 20 years, there has been an increase in the scientific interest in the impact of omega-3 and omega- 6 fatty acids on human health. Several epidemiological and experimental studies have been published on the cardiovascular (CV) benefits of omega-3 fatty acids. Fish and fish oil are rich sources of omega- 3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Alpha-linolenic acid (ALA) is an omega-3 fatty acid present in seeds and oils, green leafy vegetables, and nuts and beans. Linoleic acid (LA), an omega-6 fatty acid, is present in grains, meats, and the seeds of most plants. In addition, conjugated linoleic acid (CLA), a group of positional and geometric isomers of linoleic acid characterized by the presence of conjugated dienes, seems to confer specific cardiovascular benefits. The potential for unsaturated fatty acids to counteract the negative effects of obesity is substantial and deserves further investigation.