Energy composition of the Universe: time-independent internal symmetry

The energy composition of the Universe, as emerged from the Type Ia supernova observations and the WMAP data, looks preposterously complex, -- but only at the first glance. In fact, its structure proves to be simple and regular. An analysis in terms of the Friedmann integral enables to recognize a remarkably simple time-independent covariant robust recipe of the cosmic mix: the numerical values of the Friedmann integral for vacuum, dark matter, baryons and radiation are approximately identical. The identity may be treated as a symmetry relation that unifies cosmic energies into a regular set, a quartet, with the Friedmann integral as its common genuine time-independent physical parameter. Such cosmic internal (non-geometrical) symmetry exists whenever cosmic energies themselves exist in nature. It is most natural for a finite Universe suggested by the WMAP data. A link to fundamental theory may be found under the assumption about a special significance of the electroweak energy scale in both particle physics and cosmology. A freeze-out model developed on this basis demonstrates that the physical nature of new symmetry might be due to the interplay between electroweak physics and gravity at the cosmic age of a few picoseconds. The big `hierarchy number' of particle physics represents the interplay in the model. This number quantifies the Friedmann integral and gives also a measure to some other basic cosmological figures and phenomena associated with new symmetry. In this way, cosmic internal symmetry provides a common ground for better understanding of old and recent problems that otherwise seem unrelated; the coincidence of the observed cosmic densities, the flatness of the co-moving space, the initial perturbations and their amplitude, the cosmic entropy are among them.Comment: 32 page

Inflation with Ω≠1\Omega \not = 1

We discuss various models of inflationary universe with $\Omega \not = 1$. A homogeneous universe with $\Omega > 1$ may appear due to creation of the universe "from nothing" in the theories where the effective potential becomes very steep at large $\phi$, or in the theories where the inflaton field $\phi$ nonminimally couples to gravity. Inflation with $\Omega < 1$ generally requires intermediate first order phase transition with the bubble formation, and with a second stage of inflation inside the bubble. It is possible to realize this scenario in the context of a theory of one scalar field, but typically it requires artificially bent effective potentials and/or nonminimal kinetic terms. It is much easier to obtain an open universe in the models involving two scalar fields. However, these models have their own specific problems. We propose three different models of this type which can describe an open homogeneous inflationary universe.Comment: 29 pages, LaTeX, parameters of one of the models are slightly modifie

Effects of Immunosuppressive Drugs on Blood Pressure and Electrolyte Homeostasis

__Aims of the thesis__ 1. To review the recently identified roles of NCC in the regulation of sodium, potassium, and blood pressure (Chapter 2) 2. To analyze the regulation of NCC during potassium-induced natriuresis (Chapter 3) 3. To review the role of pharmacogenetics in CNI-induced hypertension (Chapter 4) 4. To test the anti-hypertensive effects of thiazide diuretics in hypertensive kidney transplant recipients using tacrolimus (Chapter 5) 5. To analyze the effects of CNIs on NCC in uEVs (Chapter 6) 6. To identify the mechanism of the anti-hypertensive effect of MMF in experimental hypertension (Chapter 7) 7. To analyze the relationship between calcineurin inhibitors, serum magnesium, and posttransplantation diabetes mellitus (Chapter 8

Finite Temperature Effective Potential for the Abelian Higgs Model to the Order e4,λ2e^4,\lambda^2

A complete calculation of the finite temperature effective potential for the abelian Higgs model to the order $e^4,\lambda^2$ is presented and the result is expressed in terms of physical parameters defined at zero temperature. The absence of a linear term is verified explicitly to the given order and proven to survive to all orders. The first order phase transition has weakened in comparison with lower order calculation, which shows up in a considerable decrease of the surface tension. The only difference from the original version is the splitting of some overlong lines causing problems with certain mailers.Comment: 13 pages LaTex ( figures not included , hardcopy available on request : [email protected] or t00heb@dhhdesy3 ) , DESY 93-08

From the Big Bang Theory to the Theory of a Stationary Universe

We consider chaotic inflation in the theories with the effective potentials phi^n and e^{\alpha\phi}. In such theories inflationary domains containing sufficiently large and homogeneous scalar field \phi permanently produce new inflationary domains of a similar type. We show that under certain conditions this process of the self-reproduction of the Universe can be described by a stationary distribution of probability, which means that the fraction of the physical volume of the Universe in a state with given properties (with given values of fields, with a given density of matter, etc.) does not depend on time, both at the stage of inflation and after it. This represents a strong deviation of inflationary cosmology from the standard Big Bang paradigm. We compare our approach with other approaches to quantum cosmology, and illustrate some of the general conclusions mentioned above with the results of a computer simulation of stochastic processes in the inflationary Universe.Comment: No changes to the file, but original figures are included. They substantially help to understand this paper, as well as eternal inflation in general, and what is now called the "multiverse" and the "string theory landscape." High quality figures can be found at http://www.stanford.edu/~alinde/LLMbigfigs

String Thermalization at a Black Hole Horizon

Susskind has recently shown that a relativistic string approaching the event horizon of a black hole spreads in both the transverse and longitudinal directions in the reference frame of an outside observer. The transverse spreading can be described as a branching diffusion of wee string bits. This stochastic process provides a mechanism for thermalizing the quantum state of the string as it spreads across the stretched horizon.Comment: 14 pages, latex, SU-ITP-94-4, NSF-ITP-94-1

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics

Background and Purpose Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. Experimental Approach We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca2+i) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. Key Results Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca2+i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G670E). Conclusions and Implications The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses

Serum magnesium, hepatocyte nuclear factor 1β genotype and post-transplant diabetes mellitus: a prospective study

BACKGROUND: Retrospective studies suggest that tacrolimus-induced hypomagnesaemia is a risk factor for post-transplant diabetes mellitus (PTDM), but prospective studies are lacking. METHODS: This was a prospective study with measurements of serum magnesium and tacrolimus at pre-specified time points in the first year after living donor kidney transplantation (KT). The role of single nucleotide polymorphisms (SNPs) in hepatocyte nuclear factor 1β (HNF1β) was also explored because HNF1β regulates insulin secretion and renal magnesium handling. Repeated measurement and regression analyses were used to analyse associations with PTDM. RESULTS: In our cohort, 29 out of 167 kidney transplant recipients developed PTDM after 1 year (17%). Higher tacrolimus concentrations were significantly associated with lower serum magnesium and increased risk of hypomagnesaemia. Patients who developed PTDM had a significantly lower serum magnesium trajectory than patients who did not develop PTDM. In multivariate analysis, lower serum magnesium, age and body mass index were independent risk factors for PTDM. In recipients, the HNF1β SNP rs752010 G > A significantly increased the risk of PTDM [odds ratio (OR) = 2.56, 95% confidence interval (CI) 1.05-6.23] but not of hypomagnesaemia. This association lost significance after correction for age and sex (OR = 2.24, 95% CI 0.90-5.57). No association between HNF1β SNPs and PTDM was found in corresponding donors. CONCLUSIONS: A lower serum magnesium in the first year after KT is an independent risk factor for PTDM. The HNF1β SNP rs752010 G > A may add to this risk through an effect on insulin secretion rather than hypomagnesaemia, but its role requires further confirmation

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome

Rationale: Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome. Methods: A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included within 24 h after meeting inclusion criteria. Intervention: A 4-day course of intravenous rh-APC (24 mcg/kg/h) (n = 33) versus saline (n = 38). Outcomes: The primary outcome parameter was the pulmonary leak index (PLI) of 67Gallium-transferrin as a measure of alveolocapillary permeability and secondary outcomes were disease severity scores and ventilator-free days, among others. Results: Baseline characteristics were similar; in 87% of patients the PLI was above normal and in 90% mechanical or noninvasive ventilation was instituted at a median lung injury score of 2.5. There was no evidence that Rh-APC treatment affected the PLI or attenuated lung injury and sequential organ failure assessment scores. Mean ventilator-free days amounted to 14 (rh-APC) and 12 days (saline, P = 0.35). 28-day mortality was 6% in rh-APC- and 18% in saline-treated patients (P = 0.12). There was no difference in bleeding events. The study was prematurely discontinued because rh-APC was withdrawn from the market. Conclusion: There is no evidence that treatment with intravenous rh-APC during 4 days for infectious or inflammatory ARDS ameliorates increased alveolocapillary permeability or the clinical course of ARDS patients. We cannot exclude underpowering. Trial Registration: Nederlands Trial Registe

Mycophenolate mofetil attenuates DOCA-salt hypertension: Effects on vascular tone

Inflammation is increasingly recognized as a driver of hypertension. Both genetic and pharmacological inhibition of B and T cells attenuates most forms of experimental hypertension. Accordingly, the immunosuppressive drug mycophenolate mofetil (MMF) reduces blood pressure in the deoxycorticosterone acetate (DOCA-) salt model. However, the mechanisms by which MMF prevent hypertension in the DOCA-salt model remain unclear. Recent studies indicate that immunosuppression can inhibit sodium transporter activity in the kidney, but its effect on vascular tone is not well characterized. Therefore, the aim of the present study was to analyze the vascular and renal tubular effects of MMF in the DOCA-salt model in rats (4 weeks without uninephrectomy). Co-treatment with MMF attenuated the rise in blood pressure from day 11 onward resulting in a significantly lower telemetric mean arterial pressure after 4 weeks of treatment (108 ± 7 vs. 130 ± 9 mmHg, P < 0.001 by two-way analysis of variance). MMF significantly reduced the number of CD3+ cells in kidney cortex and inner medulla, but not in outer medulla. In addition, MMF significantly reduced urinary interferon-γ excretion. Vascular tone was studied ex vivo using wire myographs. An angiotensin II type 2 (AT2) receptor antagonist blocked the effects of angiotensin II (Ang II) only in the vehicle group. Conversely, L-NAME significantly increased the Ang II response only in the MMF group. An endothelin A receptor blocker prevented vasoconstriction by endothelin-1 in the MMF but not in the vehicle group. MMF did not reduce the abundances of the kidney sodium transporters NHE3, NKCC2, NCC, or ENaC. Together, our ex vivo results suggest that DOCA-salt induces AT2 receptor-mediated vasoconstriction. MMF prevents this response and increases nitric oxide availability. These data provide insight in the antihypertensive mechanism of MMF and the role of inflammation in dysregulating vascular tone