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 .

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.

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.

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.

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.

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.

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.

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.

Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance?

OBJECTIVE: The aetiology of idiopathic intracranial hypertension (IIH) is not known, but its association with obesity is well-recognized. Recent studies have linked obesity with abnormalities in circulating inflammatory and adiposity related cytokines. The aim of this study was to characterize adipokine and inflammatory cytokine profiles in IIH. DESIGN: Paired serum and cerebrospinal fluid (CSF) specimens were collected from 26 patients with IIH and compared to 62 control subjects. Samples were analysed for leptin, resistin, adiponectin, insulin, IL-1beta, IL-6, IL-8 (CXCL8), TNFalpha, MCP-1 (CCL2), hepatocyte growth factor, nerve growth factor and PAI-1 using multiplex bead immunoassays. RESULTS: CSF leptin was significantly higher in patients with IIH (P = 0.001) compared to controls after correction for age, gender and body mass index (BMI). In the control population, BMI correlated with serum leptin (r = 0.34; P = 0.007) and CSF leptin (r = 0.51; P < 0.0001), but this was not the case for the IIH population. Profiles of other inflammatory cytokines and adipokines did not differ between IIH patients and controls once anthropometric factors had been accounted for. CONCLUSIONS: IIH was characterized by significantly elevated CSF leptin levels which did not correlate with BMI. We suggest that CSF leptin may be important in the pathophysiology of IIH and that obesity in IIH may occur as a result of hypothalamic leptin resistance.

The effect of exercise and training status on platelet activation: do cocoa polyphenols play a role?

Sedentary and trained men respond differently to the same intensity of exercise, this is probably related to their platelet reactivity and antioxidant capacity. There is growing interest in the utilization of antioxidant-rich plant extracts as dietary food supplements. The aim of this study was to investigate the effect of an acute bout of sub maximal exercise on platelet count and differential response of platelet activation in trained and sedentary subjects and to observe if cocoa polyphenols reverse the effect of exercise on platelet function. The practical significance of this study was that many sedentary people engage in occasional strenuous exercise that may predispose them to risk of heart disease. Fasting blood samples were collected from 16 male subjects, pre and post 1-h cycling exercise at 70% of maximal aerobic power (VO2max) before and after consumption of cocoa or placebo. Agonist stimulated citrated whole blood was utilized for measuring platelet aggregation, adenosine triphosphate (ATP) release and platelet activation. Baseline platelet count (221 +/- 33 x 10(9)/L) and ATP release (1.4 +/- 0.6 nmol) increased significantly (P < 0.05) after exercise in all subjects. Baseline platelet numbers in the trained were higher (P < 0.05) than in the sedentary (235 +/- 37 vs. 208 +/- 34 x 10(9)/L), where as platelet activation in trained was lower (P < 0.05) than sedentary (51 +/- 6 vs. 59 +/- 5%). Seven days of cocoa polyphenol supplementation had little effect on any of the parameters measured. We conclude that trained subjects show decreased activation of stimulated platelets when compared to the sedentary subjects and short-term cocoa polyphenol supplementation did not decrease platelet activity in response to exercise independent of prior training status.

Exploitation of a non-apoptotic caspase to regulate the abundance of the cdkI p27(KIP1) in transformed lymphoid cells.

Expression of the cyclin dependent kinase inhibitor p27(KIP1) is intimately linked to the control of proliferation, and is itself regulated by transcription, translation, phosphorylation, protein stability or sequestration. p27(KIP1) is also regulated during apoptosis; cleavage occurs at DPSD(139)S and ESQD(108)V, by a sub-set of Z-VAD-fmk-sensitive caspases. We have identified a related but distinct mechanism that regulates p27(KIP1) in proliferating lymphoid cell lines. In a B-lymphoid cell line (BJAB), the abundance of p27(KIP1) oscillates inversely to proliferation; loss of full-length p27(KIP1) correlates with the appearance of a truncated version corresponding to cleavage at DPSD(139)S. A direct correlation exists between the appearance of truncated p27(KIP1) and the presence of an activity able to cleave peptides representing DPSD(139)S and a caspase-8 substrate (Ac-IETD-AMC) in vitro. This activity is inhibited by Ac-IETD-CHO but not Z-VAD-fmk in vitro. Furthermore a requirement for caspase-8 has been excluded. The activity differs from the apoptosis related p27(KIP1)-cleaving activity; indeed few cells undergoing apoptosis are present in the population of proliferating cells. The activity is further distinguished by its inability to cleave a peptide based on ESQD(108)V in vitro, together with the lack of a corresponding cleavage product in vivo. Inhibition of the caspase activity in vivo promotes an accumulation of full length p27(KIP1), as well as a decrease in cell proliferation. Together these studies highlight the importance of non-apoptotic caspases in regulating p27(KIP1) in transformed lymphoid cells.

Biophysical analysis of natural variants of the multimerization region of Epstein-Barr virus lytic-switch protein BZLF1.

BZLF1 plays a key role in the induction of Epstein-Barr virus (EBV) replication. On the basis of limited sequence homology and mutagenesis experiments, BZLF1 has been described as a member of the bZip family of transcription factors, but this prospect has not been rigorously tested to date. Here, we present biophysical analysis of the multimerization domain of BZLF1, from three natural variants of EBV, and demonstrate for the first time that the region between amino acids 196 and 227 is sufficient to direct folding as a coiled-coil dimer in vitro.

p27KIP1 is down-regulated by two different mechanisms in human lymphoid cells undergoing apoptosis.

The cyclin-dependent kinase inhibitor p27KIP1 is a crucial component of the mammalian restriction point, and as such is subject to multiple regulatory mechanisms. It has recently been shown that the abundance of p27KIP1 is also regulated during apoptosis; p27KIP1 is cleaved by a Z-VAD-fmk-sensitive caspase during apoptosis induced by growth factor deprivation in endothelial cells, and also following exposure of myeloid leukaemia cells to etoposide. Here, we investigate p27KIP1 regulation in B- and T-lymphoid cells undergoing apoptosis. We observe that p27KIP1 is down-regulated following exposure to a variety of apoptotic stimuli including an agonistic anti-Fas antibody, cycloheximide and etoposide. Further investigation revealed the existence of two different routes of p27KIP1 regulation in lymphoid cells undergoing apoptosis. The first pathway is utilized by lymphoid cells stimulated through Fas, is abrogated in a caspase-8-deficient T-cell line, and is blocked by the caspase inhibitors Z-VAD-fmk and Boc-D-fmk. In contrast, the loss of p27KIP1 in cells exposed to cycloheximide and etoposide occurs in the absence of caspase-8 or any Z-VAD-fmk- or Boc-D-fmk-sensitive caspase activities. Thus the down-regulation of p27KIP1 is a common occurrence in lymphoid cells undergoing apoptosis but, depending on the apoptotic trigger, this can be affected by two different mechanisms.

Selected micronutrient intake and status in men with differing meat intakes, vegetarians and vegans.

Dietary factors play a critical role in human health. The aim of this cross-sectional study was to examine micronutrient intake and status of subjects who were habitual meat eaters eating different quantities of meat with those who were habitual vegetarians or vegans. One hundred and thirty-nine healthy male subjects (vegan, n = 18; ovolacto-vegetarian, n = 46; moderate meat-eater, n = 65; and high meat-eater, n = 18) aged 20-55 years were recruited in metropolitan Melbourne. Each volunteer completed a semiquantitative Food Frequency Questionnaire (FFQ) and gave a fasting venous blood sample. Dietary sodium/potassium ratio was significantly lower and vitamin C, fibre and iron intakes were higher in vegetarians than in meat-eaters. High meat-eaters had a significantly higher calcium, retinol and zinc intake than did the other three dietary groups; moderate meateaters had the lowest mean intake of fibre, vitamin C and ß-carotene. Vegans had a significantly higher ß-carotene intake than did the other groups. Serum ferritin and vitamin B12 levels, and haemoglobin concentration were significantly lower in vegetarians than in meat-eaters. Vegans had a significantly higher serum folate concentration than did ovolacto-vegetarian and moderate meat-eater groups. There was no significant difference in serum α-tocopherol concentration. There are differences between the four diet groups that have potential to affect the subjects' health and susceptibility to chronic diseases including cardiovascular disease and cancer. Based on the present data, high meat-eaters may particularly benefit from altering their dietary pattern to reduce their sodium and saturated fat intake, and moderate meat-eaters from increasing their fibre and antioxidant consumption. Vegetarians, especially vegans, may need to increase their vitamin B12 and zinc intakes.

Divergent requirements for the MAPK(ERK) signal transduction pathway during initial virus infection of quiescent primary B cells and disruption of Epstein-Barr virus latency by phorbol esters.

Quiescent primary B lymphocytes and Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines express components of the extracellular response kinase arm of the mitogen-activated protein kinase (MAPK(ERK)) signal transduction pathway and transmit signals through the pathway when exposed to appropriate stimuli. Although the MAPK(ERK) pathway is activated following infection with EBV, MAPK/ERK kinase (MEK1) activity is not required to drive the proliferation of infected cells. However, MEK1 contributes to EBV latency control.

Loss of functional pRB is not a ubiquitous feature of B-cell malignancies.

Human cancers frequently sustain genetic mutations that alter the function of their G1 cell cycle control check point. These include changes to the retinoblastoma gene and to the genes that regulate its phosphorylation, such as the cyclin-dependent kinase inhibitor p16INK4a. Altered expression of retinoblastoma protein (pRb) is associated with non-Hodgkin's lymphoma, particularly centroblastic and Burkitt's lymphomas. pRb is expressed in normal B-cells and its regulatory phosphorylation pathway is activated in response to a variety of stimuli. Since human B-lymphoma-derived cell lines are often used as in vitro model systems to analyse the downstream effects of signal transduction, we examined the functional status of pRb in a panel of human B-cell lines. We identified eleven cell lines which express the hyperphosphorylated forms of pRb. Furthermore, we suggest that the pRb protein appears to be functional in these cell lines.