Precision dosing-based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers:a virtual clinical trial pharmacokinetics study

Objective: Paroxetine has been demonstrated to undergo gestation-related reductions in plasma concentrations, to an extent which is dictated by the polymorphic state of CYP 2D6. However, knowledge of appropriate dose titrations is lacking. Methods: A pharmacokinetic modelling approach was applied to examine gestational changes in trough plasma concentrations for CYP 2D6 phenotypes, followed by necessary dose adjustment strategies to maintain paroxetine levels within a therapeutic range of 20–60 ng/ml. Key findings: A decrease in trough plasma concentrations was simulated throughout gestation for all phenotypes. A significant number of ultrarapid (UM) phenotype subjects possessed trough levels below 20 ng/ml (73–76%) compared to extensive metabolisers (EM) (51–53%). Conclusions: For all phenotypes studied, there was a requirement for daily doses in excess of the standard 20 mg dose throughout gestation. For EM, a dose of 30 mg daily in trimester 1 followed by 40 mg daily in trimesters 2 and 3 is suggested to be optimal. For poor metabolisers (PM), a 20 mg daily dose in trimester 1 followed by 30 mg daily in trimesters 2 and 3 is suggested to be optimal. For UM, a 40 mg daily dose throughout gestation is suggested to be optimal

Asymptomatic bacteriuria in type 2 Iranian diabetic women: a cross sectional study

BACKGROUND: The risk of developing infection in diabetic patients is higher and urinary tract is the most common site for infection. Serious complications of urinary infection occur more commonly in diabetic patients. To study the prevalence and associates of asymptomatic bacteriuria (ASB) in women with type 2 diabetes mellitus in the Iranian population, this study was conducted. METHODS: Between February 10, 2004 and October 15, 2004; 202 nonpregnant diabetic (type 2) women (range: 31 to 78 years old) with no abnormalities of the urinary tract system were included in this clinic based study. We defined ASB as the presence of at least 10(5 )colony-forming units/ml of 1 or 2 bacterial species, in two separated cultures of clean-voided midstream urine. All the participants were free from any symptoms of urinary tract infection (UTI). Associates for developing bacteriuria was assessed and compared in participants with and without bacteriuria. RESULTS: In this study, the prevalence of ASB was 10.9% among diabetic women. E. coli was the most prevalent microorganism responsible for positive urine culture. Most of the isolated microorganisms were resistant to Co-trimoxazole, Nalidixic acid and Ciprofloxacin. Pyuria (P < 0.001) and glucosuria (P < 0.05) had a meaningful relationship with bacteriuria but no association was evident between age (P < 0.45), duration of diabetes (P < 0.09), macroalbuminuria (P < 0.10) and HbA(1c )level (P < 0.75), and the presence of ASB. CONCLUSION: The prevalence of ASB is higher in women with type 2 diabetes, for which pyuria and glucosuria can be considered as associates. Routine urine culture can be recommended for diabetic women even when there is no urinary symptom

The Molecular Assembly of Amyloid Aβ Controls Its Neurotoxicity and Binding to Cellular Proteins

Accumulation of β-sheet-rich peptide (Aβ) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. Aβ species are potent neurotoxins, however the molecular mechanism responsible for Aβ toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of Aβ 1–40 and Aβ 1–42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that Aβ toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as Aβ receptors in N2a cells, triggering a multi factorial toxicity

A Search for Dark Higgs Bosons

Recent astrophysical and terrestrial experiments have motivated the proposal of a dark sector with GeV-scale gauge boson force carriers and new Higgs bosons. We present a search for a dark Higgs boson using 516 fb-1 of data collected with the BABAR detector. We do not observe a significant signal and we set 90% confidence level upper limits on the product of the Standard Model-dark sector mixing angle and the dark sector coupling constant.Comment: 7 pages, 5 postscript figures, published version with improved plots for b/w printin

Magnesium Limitation Is an Environmental Trigger of the Pseudomonas aeruginosa Biofilm Lifestyle

Biofilm formation is a conserved strategy for long-term bacterial survival in nature and during infections. Biofilms are multicellular aggregates of cells enmeshed in an extracellular matrix. The RetS, GacS and LadS sensors control the switch from a planktonic to a biofilm mode of growth in Pseudomonas aeruginosa. Here we detail our approach to identify environmental triggers of biofilm formation by investigating environmental conditions that repress expression of the biofilm repressor RetS. Mg2+ limitation repressed the expression of retS leading to increased aggregation, exopolysaccharide (EPS) production and biofilm formation. Repression of retS expression under Mg2+ limitation corresponded with induced expression of the GacA-controlled small regulatory RNAs rsmZ and rsmY and the EPS biosynthesis operons pel and psl. We recently demonstrated that extracellular DNA sequesters Mg2+ cations and activates the cation-sensing PhoPQ two-component system, which leads to increased antimicrobial peptide resistance in biofilms. Here we show that exogenous DNA and EDTA, through their ability to chelate Mg2+, promoted biofilm formation. The repression of retS in low Mg2+ was directly controlled by PhoPQ. PhoP also directly controlled expression of rsmZ but not rsmY suggesting that PhoPQ controls the equilibrium of the small regulatory RNAs and thus fine-tunes the expression of genes in the RetS pathway. In summary, Mg2+ limitation is a biologically relevant environmental condition and the first bonafide environmental signal identified that results in transcriptional repression of retS and promotes P. aeruginosa biofilm formation

The mechanisms by which polyamines accelerate tumor spread

Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions

The role of morphine in regulation of cancer cell growth

Morphine is considered the “gold standard” for relieving pain and is currently one of the most effective drugs available clinically for the management of severe pain associated with cancer. In addition to its use in the treatment of pain, morphine appears to be important in the regulation of neoplastic tissue. Although morphine acts directly on the central nervous system to relieve pain, its activities on peripheral tissues are responsible for many of the secondary complications. Therefore, understanding the impact, other than pain control, of morphine on cancer treatment is extremely important. The effect of morphine on tumor growth is still contradictory, as both growth-promoting and growth-inhibiting effects have been observed. Accumulating evidence suggests that morphine can affect proliferation and migration of tumor cells as well as angiogenesis. Various signaling pathways have been suggested to be involved in these extra-analgesic effects of morphine. Suppression of immune system by morphine is an additional complication. This review provides an update on the influence of morphine on the growth and migration potential of tumor cells

B0 meson decays to rho0 K*0, f0 K*0, and rho-K*+, including higher K* resonances

We present branching fraction measurements for the decays B0 -> rho0 K*0, B0 -> f0 K*0, and B0 -> rho- K*+, where K* is an S-wave (K pi)_0* or a K*(892) meson; we also measure B0 -> f0 K_2*(1430)^0. For the K*(892) channels, we report measurements of longitudinal polarization fractions (for rho final states) and direct CP-violation asymmetries. These results are obtained from a sample of (471.0 +/- 2.8) x 10^6 BBbar pairs collected with the BaBar detector at the PEP-II asymmetric-energy e+ e- collider at the SLAC National Accelerator Laboratory. We observe rho0 K*(892)^0, rho0 (K pi)_0^{*0}, f0 K*(892)^0, and rho- K*(892)+ with greater than 5 sigma significance, including systematics. We report first evidence for f0 (K pi)_0^{*0} and f0 K_2*(1430)^0, and place an upper limit on rho- (K pi)_0^{*+}. Our results in the K*(892) channels are consistent with no direct CP-violation.Comment: 17 pages, 6 postscript figures, submitted to Phys. Rev.