Cardiotoxicity of mitoxantrone treatment in a german cohort of 639 multiple sclerosis patients

Background and Purpose: The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment. Methods: Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. Results: None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. Conclusions: The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically)

Background Independence and Asymptotic Safety in Conformally Reduced Gravity

We analyze the conceptual role of background independence in the application of the effective average action to quantum gravity. Insisting on a background independent renormalization group (RG) flow the coarse graining operation must be defined in terms of an unspecified variable metric since no rigid metric of a fixed background spacetime is available. This leads to an extra field dependence in the functional RG equation and a significantly different RG flow in comparison to the standard flow equation with a rigid metric in the mode cutoff. The background independent RG flow can possess a non-Gaussian fixed point, for instance, even though the corresponding standard one does not. We demonstrate the importance of this universal, essentially kinematical effect by computing the RG flow of Quantum Einstein Gravity in the ``conformally reduced'' Einstein--Hilbert approximation which discards all degrees of freedom contained in the metric except the conformal one. Without the extra field dependence the resulting RG flow is that of a simple $\phi^4$-theory. Including it one obtains a flow with exactly the same qualitative properties as in the full Einstein--Hilbert truncation. In particular it possesses the non-Gaussian fixed point which is necessary for asymptotic safety.Comment: 4 figures

Acceleration of Diffusional Jumps of Interstitial Fe with Increasing Ge Concentration in Si1 − x Ge x Alloys Observed by Mössbauer Spectroscopy

Radioactive 57Mn isotopes have been implanted into Si1 − x Ge x crystals (x ≤ 0.1) at elevated temperatures for Mössbauer studies of the diffusion of interstitial 57Fe daughter atoms. The atomic jump frequency is found to increase upon Ge alloying. This is attributed to a lowering of the activation energy, i.e. the saddle point energy at hexagonal interstitial sites with Ge neighbour atom

Casimir effect: running Newton constant or cosmological term

We argue that the instability of Euclidean Einstein gravity is an indication that the vacuum is non perturbative and contains a condensate of the metric tensor in a manner reminiscent of Yang-Mills theories. As a simple step toward the characterization of such a vacuum the value of the one-loop effective action is computed for Euclidean de Sitter spaces as a function of the curvature when the unstable conformal modes are held fixed. Two phases are found, one where the curvature is large and gravitons should be confined and another one which appears to be weakly coupled and tends to be flat. The induced cosmological constant is positive or negative in the strongly or weakly curved phase, respectively. The relevance of the Casimir effect in understanding the UV sensitivity of gravity is pointed out.Comment: Final, slightly extended version, to appear in Classical and Quantum Gravit

Hints of (trans-Planckian) asymptotic freedom in semiclassical cosmology

We employ the semiclassical approximation to the Wheeler-DeWitt equation in the spatially flat de Sitter Universe to investigate the dynamics of a minimally coupled scalar field near the Planck scale. We find that, contrary to naive intuition, the effects of quantum gravitational fluctuations become negligible and the scalar field states asymptotically approach plane-waves at very early times. These states can then be used as initial conditions for the quantum states of matter to show that each mode essentially originated in the minimum energy vacuum. Although the full quantum dynamics cannot be solved exactly for the case at hand, our results can be considered as supporting the general idea of asymptotic safety in quantum gravity.Comment: 11 pages, 2 figures; replaced to match content of published versio

Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques

We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6±1.0 years, BMI 31.5±0.4 kg/m2; 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6–62H2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39–56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r2 = 27–32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations

Spin half fermions with mass dimension one: theory, phenomenology, and dark matter

We provide the first details on the unexpected theoretical discovery of a spin-one-half matter field with mass dimension one. It is based upon a complete set of dual-helicity eigenspinors of the charge conjugation operator. Due to its unusual properties with respect to charge conjugation and parity, it belongs to a non-standard Wigner class. Consequently, the theory exhibits non-locality with (CPT)^2 = - I. We briefly discuss its relevance to the cosmological `horizon problem'. Because the introduced fermionic field is endowed with mass dimension one, it can carry a quartic self-interaction. Its dominant interaction with known forms of matter is via Higgs, and with gravity. This aspect leads us to contemplate the new fermion as a prime dark matter candidate. Taking this suggestion seriously we study a supernova-like explosion of a galactic-mass dark matter cloud to set limits on the mass of the new particle and present a calculation on relic abundance to constrain the relevant cross-section. The analysis favours light mass (roughly 20 MeV) and relevant cross-section of about 2 pb. Similarities and differences with the WIMP and mirror matter proposals for dark matter are enumerated. In a critique of the theory we bare a hint on non-commutative aspects of spacetime, and energy-momentum space.Comment: 78 pages [Changes: referee-suggested improvements, additional important references, and better readability

A new measurement of the properties of the rare decay K -> pi+ e+ e-

A large low-background sample of events (10300) has been collected for the rare decay of kaons in flight K+ -> pi+ e+ e- by experiment E865 at the Brookhaven AGS. The decay products were accepted by a broad band high-resolution charged particle spectrometer with particle identification. The branching ratio (2.94 +- 0.05(stat.) +- 0.13(syst.) +- 0.05(model))*10**{-7} was determined normalizing to events from the decay chain K+ -> pi+ pi0; pi0 -> e+ e- gamma. From the analysis of the decay distributions the vector nature of this decay is firmly established now, and limits on scalar and tensor contributions are deduced. From the (e+ e-) invariant mass distribution the decay form factor f(z)=f0(1+ delta*z) (z=M(ee)**2/m(K)**2) is determined with delta=2.14 +- 0.13 +- 0.15. Chiral QCD perturbation theory predictions for the form factor are also tested, and terms beyond leading order O(p**4) are found to be important.Comment: 4 pages, 5 figure

Strategic responses to global challenges: The case of European banking, 1973–2000

In applying a strategy, structure, ownership and performance (SSOP) framework to three major clearing banks (ABN AMRO, UBS, Barclays), this article debates whether the conclusions generated by Whittington and Mayer about European manufacturing industry can be applied to the financial services sector. While European integration plays a key role in determining strategy, it is clear that global factors were far more important in determining management actions, leading to significant differences in structural adaptation. The article also debates whether this has led to improved performance, given the problems experienced with both geographical dispersion and diversification, bringing into question the quality of decision-making over the long term