Cardiac autonomic regulation and repolarization during acute experimental hypoglycemia in Type 2 diabetes

Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes (T2DM). We previously observed an increase in arrhythmias during spontaneous prolonged hypoglycemia in T2DM patients. Our aim was to examine changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and eleven age, BMI-matched nondiabetic controls underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0mmol/L) or hypoglycemia (2.5mmol/L) for one hour. Heart rate, blood pressure, heart rate variability were assessed every thirty minutes and corrected QT (QTc) and T wave morphology every 60 minutes. Heart rate initially increased in T2DM participants but then fell towards baseline despite maintained hypoglycemia at 1 hour, accompanied by reactivation of vagal tone. In nondiabetic participants, vagal tone remained depressed during sustained hypoglycemia. Diabetic participants exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T wave symmetry and Principal Component Analysis (PCA) ratio compared with the nondiabetic group. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears time-dependent. T2DM individuals demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes

Predicting postpartum hemorrhage (PPH) during cesarean delivery using the Leicester PPH Predict tool: a retrospective cohort study.

Objective: The aim of the present study was to develop a toolkit combining various risk factors to predict the risk of developing a postpartum hemorrhage (PPH) during a cesarean section. Study Design: A retrospective cohort study of 24,230 women who had cesarean delivery between January 2003 and December 2013 at a tertiary care teaching ho spital within the United Kingdom serving a multi-ethnic population. Data was extracted from hospital databases and risk factors for PPH were identified. Hothorn et al.s Recursive Partitioning algorithm was used to infer a conditional decision tree. For each of the identified combinations of risk factors two probabilities were calculated: the probability of a patient pro ducing 1000ml blood loss and 2000ml blood loss. Results: The Leicester PPH Predict Score was then tested on the randomly s elected remaining 25% (n=6095) of the data for internal validity. Reliability te sting showed intraclass correlation of 0.98 and mean absolute error 239.8ml with the actual outcome. Conclusion: The proposed toolkit, which is available online, enables clinicians to predict the risk of postpartum hemorrhage. As a result, preventative measures f or postpartum hemorrhage could be undertaken. Further external validation of the current toolkit is required

HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α

Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic

Electrically Small Supergain Arrays

The theory, computer simulations, and experimental measurements are presented for electrically small two-element supergain arrays with near optimal endfire gains of 7 dB. We show how the difficulties of narrow tolerances, large mismatches, low radiation efficiencies, and reduced scattering of electrically small parasitic elements are overcome by using electrically small resonant antennas as the elements in both separately driven and singly driven (parasitic) two-element electrically small supergain endfire arrays. Although rapidly increasing narrow tolerances prevent the practical realization of the maximum theoretically possible endfire gain of electrically small arrays with many elements, the theory and preliminary numerical simulations indicate that near maximum supergains are also achievable in practice for electrically small arrays with three (and possibly more) resonant elements if the decreasing bandwidth with increasing number of elements can be tolerated.Comment: 10 pages, 11 figures, submitted to IEEE Transactions on Antennas and Propagation (December 2006

Compact and Planar End-fire Antenna for PicoSat and CubeSat Platforms to Support Deployable Systems

A miniaturized planar Yagi-Uda antenna for integration with PicoSats or other SmallSat missions is proposed. Miniaturization techniques, such as meandering and 1-D artificial dielectric concepts to reduce the guided wavelength, are employed to overcome space constraints imposed by the SmallSat footprint while still maintaining good performance for the FR-4 antenna. Simulations and measurements have been carried out on the Unicorn-2 PicoSat chassis from Alba Orbital and are in good agreement. Also, antenna dimensions have been reduced between 15% and 66% when compared to a more conventional planar Yagi-Uda antenna working at the same frequency. This compactness allows for simple integration with the deployable solar panel array of the Unicorn-2 PicoSat spacecraft. Full end-fire radiation is achieved and peak gain values are about 5 dBi for the antenna when fully integrated on the satellite chassis, offering an attractive solution for downlink connectivity. This compact antenna design can also be used within an array for beam steering or integrated within the solar cell modules of other PicoSats, CubeSats and SmallSats. Applications include Earth observation, remote sensing, as well as SmallSat to ground station communications. The planar Yagi-Uda antenna may also be useful wherever end-fire radiation is required from a compact antenna structure

Протеом липопротеинов высокой плотности

БЕЛКИЛИПОПРОТЕИНЫ, ЛВППРОТЕО

Satisfaction with the Use of Different Technologies for Insulin Delivery and Glucose Monitoring Among Adults with Long-Standing Type 1 Diabetes and Problematic Hypoglycemia: 2-Year Follow-Up in the HypoCOMPaSS Randomized Clinical Trial

Background In the HypoCOMPaSS trial, adults with long-standing type 1 diabetes and problematic hypoglycaemia were randomised to compare insulin pump (CSII) vs multiple daily injections (MDI) and real-time continuous glucose monitoring (RT-CGM) vs conventional self-monitoring (SMBG). Our aim was to investigate participants\u27 satisfaction with these technologies at 6-month RCT endpoint and at 2-year follow-up. Methods Participants completed the Insulin Treatment Satisfaction Questionnaire (ITSQ) subscales \u27device delivery\u27 and \u27hypoglycaemia control\u27; and Glucose Monitoring Experience Questionnaire (GME-Q), assessing \u27convenience\u27, \u27effectiveness\u27, \u27intrusiveness\u27 and \u27total satisfaction\u27. We assessed change over time and between group differences by insulin and monitoring modalities. Results Participants (N=96) were: 64% women, aged 49\ub112 years, diabetes duration 29\ub112 years. At 6 months, participants reported improvements compared to baseline (all p<0.001) in satisfaction with insulin \u27delivery device\u27 (r=0.39) and \u27hypoglycaemia control\u27 (r=0.52), and trends towards significance in perceived \u27effectiveness\u27 (r=0.42) and \u27intrusiveness\u27 (r=0.27) of monitoring device (but not \u27convenience\u27, p=0.139). All improvements were sustained at 2 years. At 6 months, the only difference between arms was that greater satisfaction with insulin \u27delivery device\u27 was reported in the CSII group compared to MDI (p<0.001, r=0.40). No between-group differences were observed at 2 years. Conclusions Overall, significant improvements in participant satisfaction with diabetes technologies were observed over the 6-month RCT, in all domains except \u27convenience\u27, maintained at 2 years. While HypoCOMPaSS demonstrated non-inferiority of SMBG versus CGM, and MDI versus CSII in terms of biomedical outcomes, detailed assessments confirm participants\u27 satisfaction with delivery device was greater in those allocated to CSII than MDI

Prolonged prothrombotic effects of antecedent hypoglycemia in individuals with type 2 diabetes

OBJECTIVE Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes. RESEARCH DESIGN AND METHODS Twelve individuals with type 2 diabetes with no history of CV disease and 11 age- and BMI-matched volunteers without diabetes underwent paired hyperinsulinemic-euglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy. RESULTS Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased Δ 1.15 ± 0.28 fibers/μm2 at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only. CONCLUSIONS Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short- and medium-term risk of CV mortality

Production, characterization and anticancer activity of <em>Candida bombicola</em> sophorolipids by means of solid state fermentation of sunflower oil cake and soybean oil

The production of sophorolipids by <em>Candida bombicola</em> NRRL Y- 17069 grown in a mixture of sunflower oil cake and crude soybean oil as economic substrates with different fermentation techniques was studied. The highest yield (49.5 g·100 g⁻¹ substrates) was obtained from solid state fermentation after employing a new concept for extraction by methanol (E I) followed by ethyl acetate (E II), then partially purified with hexane (E III). The course of time of fermentation was also studied, and E I extracted of the 12^th day showed the minimum surface tension (45 mN·m⁻¹) at a critical micelle dilution (CMD) of 10% concentration. The produced sophorolipids were characterized and confirmed by FTIR and ¹H NMR spectroscopy. The anticancer activity of the produced compounds was assessed against MCF-7, HepG2, A549, HCT116 cancer cell lines and the results revealed that E III and E IV (a mixture of E I & E III) act as promising anticancer agents in HepG2 and A549 by inhibiting urokinase and histone deacetylase activities.<br><br>Se estudió la producción de soforolípidos por <em>Candida bombicola</em> NRRL Y- 17069 cultiva con diferentes técnicas de fermentación en una mezcla de torta de girasol y aceite de soja crudo, como sustratos económicos. El rendimiento más alto (49,5 g·100 g⁻¹ de sustrato) se obtuvo por fermentación en estado sólido después de extraer con metanol (IE) seguido de acetato de etilo (EII), y de purificación parcial con hexano (EIII). También se estudió el tiempo de fermentación, considerando que el extracto IE de 12 días mostró una tensión superficial mínima (45 mN·m⁻¹) a una dilución micelar crítica (CMD) de concentración 10 %. Los soforolípidos producidos se caracterizaron y se confirmaron mediante espectroscopia FTIR y RMN de ¹H. La actividad anticancerígena de los compuestos producidos se evaluó en células MCF-7, HepG2, A549, líneas celulares de cáncer de HCT116 y los resultados revelaron que EIII y EIV (una mezcla de EI y EIII) actúan como prometedores agentes anticancerígenos en HepG2 y A549 inhibiendo las actividades de uroquinasa e histona desacetilasa

Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation.

Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 5'-terminal mRNA cap structure (m7GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design cap-binding inhibitors of eIF4E by modifying the N7-substituent of m7GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N'-(2-methyl-propyl)-N-(phenyl-methyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 5'-deoxy-5'-(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7-methyl-guanosine (4a), N7-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7-benzyl-5'-deoxy-5'-(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents