Generalized phantom energy

We examine cosmological models with generalized phantom energy (GPE). Generalized phantom energy satisfies the supernegative equation of state, but its evolution with the scale factor is generally independent, i.e. not determined by its equation of state. The requirement of general covariance makes the gravitational constant time-dependent. It is found that a large class of distinct GPE models with different evolution of generalized phantom energy density and gravitational constant, but the same equation of state of GPE have the same evolution of the scale factor of the universe in the distant future. The time dependence of the equation of state parameter determines whether the universe will end in a de Sitter-like phase or diverge in finite time with the accompanying "Big Rip" effect on the bound structures.Comment: v1: 9 pages. v2: version to appear in Phys. Lett.

Cosmology with Self-Adjusting Vacuum Energy Density from a Renormalization Group Fixed Point

Cosmologies with a time dependent Newton constant and cosmological constant are investigated. The scale dependence of $G$ and $\Lambda$ is governed by a set of renormalization group equations which is coupled to Einstein's equation in a consistent way. The existence of an infrared attractive renormalization group fixed point is postulated, and the cosmological implications of this assumption are explored. It turns out that in the late Universe the vacuum energy density is automatically adjusted so as to equal precisely the matter energy density, and that the deceleration parameter approaches $q = -1/4$. This scenario might explain the data from recent observations of high redshift type Ia Supernovae and the cosmic microwave background radiation without introducing a quintessence field.Comment: v2: published version, two references update

Brain stem adenosine receptors modulate centrally mediated hypotensive responses in conscious rats: A review

Abbreviations: A2A, adenosine subtype A2A receptor; A1, adenosine subtype A1 receptor; ABC, avidin biotin complex; ABD rat, aortic barodenervated rat; α2 AR, alpha 2 adrenergic receptor; αMNE, alpha methyl norepinephrine; ATP, adenosine triphosphate; BP, blood pressure; cAMP, cyclic adenosine monophosphate; CGS21680, 2-[4-[(2-carboxyethyl)phenyl]ethylaminophenyl]ethylamino]-5′-N-ethylcarboxamidoadenosine. Selective A2A receptor agonist; CNS, central nervous system; CPA, N6-cyclopentyladenosine. Selective A1 receptor agonist; DAG, diacylglycerol; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine. Selective A1 receptor antagonist; I1, imidazoline subtype 1 receptor; I.C., intracisternal; IP3, Inositol Triphosphate; I.V., intravenous; JNK, C-Jun N-terminal kinase; L-NAME, Nω-nitro-l-arginine methyl ester hydrochloride. Non-selective nitric oxide synthase inhibitor; NOS, nitric oxide synthase; NO, nitric oxide; NTS, nucleus tractus solitarius; PC-PLC, phosphatidyl choline-selective phospholipase C; PC12 cells, pheochromocytoma cells; PD98059, selective extracellular signal regulated kinase inhibitor; ERK1/2, extracellular signal regulated kinase; PDE, phosphodiesterase; PKA, protein kinase A; RVLM, rostral ventrolateral medulla; SAPK, stress activated protein kinase; SCH58261, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-∈]-1,2,4-triazolo[1,5-c]pyrimidine. Selective adenosine A2A antagonist; SHR, spontaneously hypertensive rat; SND, sympathetic neuronal discharge; SO, sham operated = conscious normotensive rats; 8-SPT, 8-(p-sulfophenyl)-theophylline. Non-selective adenosine receptor blocker; WKY, Wistar Kyoto ra

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future

The Core/E1 domain of Hepatitis C virus genotype 4a in Egypt does not contain viral mutations or strains specific for hepatocellular carcinoma

[EN] Background: Hepatitis C virus (HCV) infection is a well-documented etiological factor for hepatocellular carcinoma (HCC). As HCV shows remarkable genetic diversity, an interesting and important issue is whether such a high viral genetic diversity plays a role in the incidence of HCC. Prior data on this subject are conflicting. Objectives: Potential association between HCV genetic mutations or strain variability and HCC incidence has been examined through a comparative genetic analysis merely focused on a single HCV subtype (genotype 4a) in a single country (Egypt). Study design: The study focused on three HCV sequence datasets with explicit sampling dates and disease patterns. An overlapping HCV Core/E1 domain from three datasets was used as the target for comparative analysis through genetic and phylogenetic approaches. Results: Based on partial Core/E1 domain (387 bp), genetic and phylogenetic analysis did not identify any HCC-specific viral mutations and strains, respectively. Conclusions: The Core/E1 domain of HCV genotype 4a in Egypt does not contain HCC-specific mutations or strains. Additionally, sequence errors resulting from the polymerase chain reaction, together with a strong evolutionary pressure on HCV in patients with end-stage liver disease, have significant potential to bias data generation and interpretation. (C) 2011 Elsevier B.V. All rights reserved.This work was supported by NIH grants R01 DK80711 (Dr. Xiaofeng Fan), R21 AI076834 (Dr. Adrian M. Di Bisceglie) and USA and Egypt Science and Technology Joint Fund BIO6-002-004 (Dr. Adrian M. Di Bisceglie).Zhang, X.; Ryu, SH.; Xu, Y.; Elbaz, T.; Zekri, AN.; Abdelaziz, AO.; Abdel-Hamid, M.... (2011). The Core/E1 domain of Hepatitis C virus genotype 4a in Egypt does not contain viral mutations or strains specific for hepatocellular carcinoma. Journal of Clinical Virology. 52(4):333-338. https://doi.org/10.1016/j.jcv.2011.08.022S33333852

Ontogeny of midazolam glucuronidation in preterm infants

Purpose: In preterm infants, the biotransformation of midazolam (M) to 1-OH-midazolam (OHM) by cytochrome P450 3A4 (CYP3A4) is developmentally immature, but it is currently unknown whether the glucuronidation of OHM to 1-OH-midazolam glucuronide (OHMG) is also decreased. The aim of our study was to investigate the urinary excretion of midazolam and its metabolites OHM and OHMG in preterm neonates following the intravenous (IV) or oral (PO) administration of a single M dose. Methods: Preterm infants (post-natal age 3-13 days, gestational age 26-34 4/7 weeks) scheduled to undergo a stressful procedure received a 30-min IV infusion (n=15) or a PO bolus dose (n=7) of 0.1 mg/kg midazolam. The percentage of midazolam dose excreted in the urine as M, OHM and OHMG up to 6 h post-dose was determined. Results: The median percentage of the midazolam dose excreted as M, OHM and OHMG in the urine during the 6-h interval after the IV infusion was 0.44% (range 0.02-1.39%), 0.04% (0.01-0.13%) and 1.57% (0.36-7.7%), respectively. After administration of the PO bolus dose, the median percentage of M, OHM and OHMG excreted in the urine was 0.11% (0.02-0.59%), 0.02% (0.00-0.10%) and 1.69% (0.58-7.31%), respectively. The proportion of the IV midazolam dose excreted as OHMG increased significantly with postconceptional age (r=0.73, p <0.05). Conclusion: The glucuronidation of OHM appears immature in preterm infants less than 2 weeks of age. The observed increase in urinary excretion of OHMG with postconceptional age likely reflects the combined maturation of glucuronidation and renal function

Germline BAP1 Inactivation Is Preferentially Associated with Metastatic Ocular Melanoma and Cutaneous-Ocular Melanoma Families

Background: BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome. Design: To characterize BAP1’s contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds. Results: Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8 % vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29 % vs. 0.52%, p =.003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain i