Metformin:A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice

Comparison of the RNA-amplification based methods RT–PCR and NASBA for the detection of circulating tumour cells

Increasingly, reverse transcriptase polymerase chain reaction (RT–PCR) is used to detect clinically significant tumour cells in blood or bone marrow. This may result in a redefinition of disease-free and clinical relapse. However, its clinical utility may be limited by lack of automation or reproducibility. Recent studies have suggested nucleic acid sequence-based amplification of target RNA may be more robust. In this study, nucleic acid sequence-based amplification was established to detect melanoma, colorectal and prostate cancer cells. Nucleic acid sequence-based amplification and RT–PCR both successfully amplified target RNA in peripheral blood samples from patients with melanoma and colorectal cancer, but only RT–PCR detected PSA in blood samples from patients with prostate cancer. There was relatively good agreement between sample replicates analyzed by RT–PCR (Kappa values of one for tyrosinase, 0.67 for CK-20 and one for PSA), but less agreement when analyzed by nucleic acid sequence-based amplification. This may limit the routine use of NASBA for the detection of clinically significant disease. In summary, RT–PCR appears at present to be the most reliable and reproducible method for the detection of low-level disease in cancer patients, although prospective studies are warranted to assess the clinical utility of different molecular diagnostic methods

Diffusive propagation of cosmic rays from supernova remnants in the Galaxy. II: anisotropy

We investigate the effects of stochasticity in the spatial and temporal distribution of supernova remnants on the anisotropy of cosmic rays observed at Earth. The calculations are carried out for different choices of the diffusion coefficient D(E) for propagation in the Galaxy. The propagation and spallation of nuclei are taken into account. At high energies we assume that $D(E)\sim(E/Z)^{\delta}$, with $\delta=1/3$ and $\delta=0.6$ being the reference scenarios. The large scale distribution of supernova remnants in the Galaxy is modeled following the distribution of pulsars with and without accounting for the spiral structure of the Galaxy. Our calculations allow us to determine the contribution to anisotropy resulting from both the large scale distribution of SNRs in the Galaxy and the random distribution of the nearest remnants. The naive expectation that the anisotropy amplitude scales as D(E) is shown to be an oversimplification which does not reflect in the predicted anisotropy for any realistic distribution of the sources. The fluctuations in the anisotropy pattern are dominated by nearby sources, so that predicting or explaining the observed anisotropy amplitude and phase becomes close to impossible. We find however that the very weak energy dependence of the anisotropy amplitude below $10^{5}$ GeV and the rise at higher energies, can best be explained if the diffusion coefficient is $D(E)\sim E^{1/3}$. Faster diffusion, for instance with $\delta=0.6$, leads in general to an exceedingly large anisotropy amplitude. The spiral structure introduces interesting trends in the energy dependence of the anisotropy pattern, which qualitatively reflect the trend seen in the data. For large values of the halo size we find that the anisotropy becomes dominated by the large scale regular structure of the source distribution, leading indeed to a monotonic increase of $\delta_A$ with energy.Comment: 21 Pages, to appear in JCA

Changes in active site histidine hydrogen bonding trigger cryptochrome activation

Cryptochrome (CRY) is the principal light sensor of the insect circadian clock. Photoreduction of the Drosophila CRY (dCRY) flavin cofactor to the anionic semiquinone (ASQ) restructures a C-terminal tail helix (CTT) that otherwise inhibits interactions with targets that include the clock protein Timeless (TIM). All-atom molecular dynamics (MD) simulations indicate that flavin reduction destabilizes the CTT, which undergoes large-scale conformational changes (the CTT release) on short (25 ns) timescales. The CTT release correlates with the conformation and protonation state of conserved His378, which resides between the CTT and the flavin cofactor. Poisson-Boltzmann calculations indicate that flavin reduction substantially increases the His378 pKa. Consistent with coupling between ASQ formation and His378 protonation, dCRY displays reduced photoreduction rates with increasing pH; however, His378Asn/Arg variants show no such pH dependence. Replica-exchange MD simulations also support CTT release mediated by changes in His378 hydrogen bonding and verify other responsive regions of the protein previously identified by proteolytic sensitivity assays. His378 dCRY variants show varying abilities to light-activate TIM and undergo self-degradation in cellular assays. Surprisingly, His378Arg/Lys variants do not degrade in light despite maintaining reactivity toward TIM, thereby implicating different conformational responses in these two functions. Thus, the dCRY photosensory mechanism involves flavin photoreduction coupled to protonation of His378, whose perturbed hydrogen-bonding pattern alters the CTT and surrounding regions

A trans-Indian Ocean hydrographic section at latitude 32°South : data report of RRS Charles Darwin cruise #29

A trans-Indian Ocean hydrographic section employing CTD/O2 profilers was conducted between Africa and Australia during austral spring 1987. The cruise track ranged between 29°S and 34°S; the average latitude of the crossing was 32°S. The purpose of the cruise was to explore various aspects of the South Indian Ocean including the characteristics of the core water masses of this ocean, the strength of the subtropical gyre, the structure and transport of deep western-boundary currents, and the net meridional heat flux. A total of 109 CTD/O2 profiles with associated rosette water sample measurements and 347 XBT profiles were collected, supplemented by underway upper ocean velocity, bathymetric and sea surface temperature and salinity data. This report detals the data collection, calibration, and reduction methods, and summarizes the hydrographic observations.Funding was provided by the National Science Foundation through Grant No. OCE 86-14497

Swine Influenza A Outbreak, Fort Dix, New Jersey, 1976

Published literature and events surrounding the outbreak are reviewed

PCR-based detection of mobile genetic elements in total community DNA

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Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae

<p>Abstract</p> <p>Background</p> <p>The risk of mortality from pneumonia caused by <it>Streptococcus pneumoniae </it>is increased in patients with cirrhosis. However, the specific pneumococcal virulence factors and host immune defects responsible for this finding have not been clearly established. This study used a cirrhotic rat model of pneumococcal pneumonia to identify defect(s) in innate pulmonary defenses in the cirrhotic host and to determine the impact of the pneumococcal toxin pneumolysin on these defenses in the setting of severe cirrhosis.</p> <p>Results</p> <p>No cirrhosis-associated defects in mucociliary clearance of pneumococci were found in these studies, but early intrapulmonary killing of the organisms before the arrival of neutrophils was significantly impaired. This defect was exacerbated by pneumolysin production in cirrhotic but not in control rats. Neutrophil-mediated killing of a particularly virulent type 3 pneumococcal strain also was significantly diminished within the lungs of cirrhotic rats with ascites. Levels of lysozyme and complement component C3 were both significantly reduced in bronchoalveolar lavage fluid from cirrhotic rats. Finally, complement deposition was reduced on the surface of pneumococci recovered from the lungs of cirrhotic rats in comparison to organisms recovered from the lungs of control animals.</p> <p>Conclusion</p> <p>Increased mortality from pneumococcal pneumonia in this cirrhotic host is related to defects in both early pre-neutrophil- and later neutrophil-mediated pulmonary killing of the organisms. The fact that pneumolysin production impaired pre-neutrophil-mediated pneumococcal killing in cirrhotic but not control rats suggests that pneumolysin may be particularly detrimental to this defense mechanism in the severely cirrhotic host. The decrease in neutrophil-mediated killing of pneumococci within the lungs of the cirrhotic host is related to insufficient deposition of host proteins such as complement C3 on their surfaces. Pneumolysin likely plays a role in complement consumption within the lungs. Our studies, however, were unable to determine whether pneumolysin more negatively impacted this defense mechanism in cirrhotic than in control rats. These findings contribute to our understanding of the defects in innate pulmonary defenses that lead to increased mortality from pneumococcal pneumonia in the severely cirrhotic host. They also suggest that pneumolysin may be a particularly potent pneumococcal virulence factor in the setting of cirrhosis.</p

The Microcirculation Is Unchanged in Neonates with Severe Respiratory Failure after the Initiation of ECMO Treatment

Purpose. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is known to improve cardiorespiratory function and outcome in neonates with severe respiratory failure. We tested the hypothesis that VA-ECMO therapy improves the microcirculation in neonates with severe respiratory failure. Methods. This single-center prospective observational pilot study took place in an intensive care unit of a level III university children's hospital. Twenty-one-term neonates, who received VA-ECMO treatment, were included. The microcirculation was assessed in the buccal mucosa, using Orthogonal Polarization Spectral imaging, within 24 hours before (T1) and within the first 24 hours after initiation of ECMO treatment (T2). Data were compared to data of a ventilated control group (N = 7). Results. At baseline (T1), median functional capillary density (FCD), microvascular flow index (MFI), and heterogeneity index (HI) did not differ between the ECMO group and the control group. At T2 the median FCD was lower in the control group (median [range]: 2.4 [1.4–4.2] versus 4.3 [2.8–7.4] cm/cm2; P value <0.001). For MFI and HI there were no differences at T2 between the two groups. Conclusion. The perfusion of the microcirculation does not change after initiation of VA-ECMO treatment in neonates with severe respiratory failure

Precision electroweak calculation of the production of a high transverse-momentum lepton pair at hadron colliders

We present a detailed study of the production of a high transverse-momentum lepton pair at hadron colliders, which includes the exact O(alpha) electroweak corrections properly matched with leading logarithmic effects due to multiple photon emission, as required by the experiments at the Fermilab Tevatron and the CERN LHC. Numerical results for the relevant observables of single Z-boson production at hadron colliders are presented. The impact of the radiative corrections is discussed in detail. The presence in the proton of a photon density is considered and the effects of the photon-induced partonic subprocesses are analyzed. The calculation has been implemented in the new version of the event generator HORACE, which is available for precision simulations of the neutral and charged current Drell-Yan processes.Comment: October 2007, 22p