Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey

Background Clozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men. Methods We investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness. Results Mean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27–0.79) mg/L] compared with men [0.44 (0.26–0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0–45.3)] for females compared with 32.5 (25.2–41.0) for males. Overall, BMI increased by 0.7 kg/m 2 over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose ≤6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (χ2  = 18.6, p < 0.0001). Conclusions We have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism

Herbert Simon's decision-making approach: Investigation of cognitive processes in experts

This is a post print version of the article. The official published can be obtained from the links below - PsycINFO Database Record (c) 2010 APA, all rights reserved.Herbert Simon's research endeavor aimed to understand the processes that participate in human decision making. However, despite his effort to investigate this question, his work did not have the impact in the “decision making” community that it had in other fields. His rejection of the assumption of perfect rationality, made in mainstream economics, led him to develop the concept of bounded rationality. Simon's approach also emphasized the limitations of the cognitive system, the change of processes due to expertise, and the direct empirical study of cognitive processes involved in decision making. In this article, we argue that his subsequent research program in problem solving and expertise offered critical tools for studying decision-making processes that took into account his original notion of bounded rationality. Unfortunately, these tools were ignored by the main research paradigms in decision making, such as Tversky and Kahneman's biased rationality approach (also known as the heuristics and biases approach) and the ecological approach advanced by Gigerenzer and others. We make a proposal of how to integrate Simon's approach with the main current approaches to decision making. We argue that this would lead to better models of decision making that are more generalizable, have higher ecological validity, include specification of cognitive processes, and provide a better understanding of the interaction between the characteristics of the cognitive system and the contingencies of the environment

Zipf law in the popularity distribution of chess openings

We perform a quantitative analysis of extensive chess databases and show that the frequencies of opening moves are distributed according to a power-law with an exponent that increases linearly with the game depth, whereas the pooled distribution of all opening weights follows Zipf's law with universal exponent. We propose a simple stochastic process that is able to capture the observed playing statistics and show that the Zipf law arises from the self-similar nature of the game tree of chess. Thus, in the case of hierarchical fragmentation the scaling is truly universal and independent of a particular generating mechanism. Our findings are of relevance in general processes with composite decisions.Comment: 5 pages, 4 figure

Rotational symmetry of self-similar solutions to the Ricci flow

Let (M,g) be a three-dimensional steady gradient Ricci soliton which is non-flat and \kappa-noncollapsed. We prove that (M,g) is isometric to the Bryant soliton up to scaling. This solves a problem mentioned in Perelman's first paper.Comment: Final version, to appear in Invent. Mat

Optimal waveform estimation for classical and quantum systems via time-symmetric smoothing

Classical and quantum theories of time-symmetric smoothing, which can be used to optimally estimate waveforms in classical and quantum systems, are derived using a discrete-time approach, and the similarities between the two theories are emphasized. Application of the quantum theory to homodyne phase-locked loop design for phase estimation with narrowband squeezed optical beams is studied. The relation between the proposed theory and Aharonov et al.'s weak value theory is also explored.Comment: 13 pages, 5 figures, v2: changed the title to a more descriptive one, corrected a minor mistake in Sec. IV, accepted by Physical Review

Rigidity of compact Riemannian spin Manifolds with Boundary

In this article, we prove new rigidity results for compact Riemannian spin manifolds with boundary whose scalar curvature is bounded from below by a non-positive constant. In particular, we obtain generalizations of a result of Hang-Wang \cite{hangwang1} based on a conjecture of Schroeder and Strake \cite{schroeder}.Comment: English version of "G\'eom\'etrie spinorielle extrins\`eque et rigidit\'es", Corollary 6 in Section 3 added, to appear in Letters Math. Phy

936-86 Plasma Fibrinogen Level Predicts Severity of Intimal Thickening After Cardiac Transplantation

Diffuse atherosclerosis is the primary reason for late graft failure after cardiac transplantation. Because there is increasing evidence that imbalances in the hemostatic and fibrinolytic pathways are associated with allogeneic rejection, we hypothesized that atherothrombotic risk factors may contribute to accelerated atherosclerosis. We therefore prospectively evaluated the burden of coronary atherosclerosis by intravascular ultrasound (IVUS) in 20 patients and measured plasma fibrinogen (FGN). lipoprotein (a) (Lp(a)) and net fibrinolytic activity of plasma using a standard fibrin plate assay. Intimal thickening was quantified using IVUS by measuring the intimal index (li=intimal area/[intimal area+luminal area]) in 2–5 segments of the LAD using planimetry. The maximal Ii per patient was calculated and indexed to the time post-transplant (Mxli/Yr). FGN predicted severity of Mxli/Yr (r2=0.41, p=0.008). In patients with decreased plasma fibrinolytic activity (lytic zone <100 mm2). Mxli/Yr was increased ten-fold (0.21±0.17 vs. 0.02±0.02, p=0.002). Because Lp(a) colocalizes with fibrinogen in the vessel wall and inhibits fibrinolysis, we correlated plasma Lp(a) levels with the degree of intimal thickening. Lp(a) did not predict Mxli/Yr (p=NS). In conclusion, these data suggest that plasma FGN and net fibrinolytic activity predict the degree of intimal thickening and that fibrin deposition may play an integral role in diffuse coronary atherosclerosis after cardiac transplantation

Relation between positional specific heat and static relaxation length: Application to supercooled liquids

A general identification of the {\em positional specific heat} as the thermodynamic response function associated with the {\em static relaxation length} is proposed, and a phenomenological description for the thermal dependence of the static relaxation length in supercooled liquids is presented. Accordingly, through a phenomenological determination of positional specific heat of supercooled liquids, we arrive at the thermal variation of the static relaxation length $\xi$, which is found to vary in accordance with $\xi \sim (T-T_0)^{-\nu}$ in the quasi-equilibrium supercooled temperature regime, where $T_0$ is the Vogel-Fulcher temperature and exponent $\nu$ equals unity. This result to a certain degree agrees with that obtained from mean field theory of random-first-order transition, which suggests a power law temperature variation for $\xi$ with an apparent divergence at $T_0$. However, the phenomenological exponent $\nu = 1$, is higher than the corresponding mean field estimate (becoming exact in infinite dimensions), and in perfect agreement with the relaxation length exponent as obtained from the numerical simulations of the same models of structural glass in three spatial dimensions.Comment: Revised version, 7 pages, no figures, submitted to IOP Publishin

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

The mechanisms that generate itch are poorly understood at both the molecular and cellular levels despite its clinical importance. To explore the peripheral neuronal mechanisms underlying itch, we assessed the behavioral responses (scratching) produced by s.c. injection of various pruritogens in PLCβ3- or TRPV1-deficient mice. We provide evidence that at least 3 different molecular pathways contribute to the transduction of itch responses to different pruritogens: 1) histamine requires the function of both PLCβ3 and the TRPV1 channel; 2) serotonin, or a selective agonist, α-methyl-serotonin (α-Me-5-HT), requires the presence of PLCβ3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLCβ3 or TRPV1. To determine whether the activity of these molecules is represented in a particular subpopulation of sensory neurons, we examined the behavioral consequences of selectively eliminating 2 nonoverlapping subsets of nociceptors. The genetic ablation of MrgprD^+ neurons that represent ≈90% of cutaneous nonpeptidergic neurons did not affect the scratching responses to a number of pruritogens. In contrast, chemical ablation of the central branch of TRPV1+ nociceptors led to a significant behavioral deficit for pruritogens, including α-Me-5-HT and ET-1, that is, the TRPV1-expressing nociceptor was required, whether or not TRPV1 itself was essential. Thus, TRPV1 neurons are equipped with multiple signaling mechanisms that respond to different pruritogens. Some of these require TRPV1 function; others use alternate signal transduction pathways

Effect of spin-orbit impurity scattering in the superconducting state of t-J model

We study the effect of magnetic impurities in the d_{x^2-y^2}-wave superconducting (SC) state of the two dimensional t-J model.The spin-orbit and the spin-exchange interactions are examined by treating the impurity as a classical spin. The Bogoliubov de Gennes equation derived within a slave-boson mean-field approximation is solved numerically at T = 0. The spin-exchange scattering induces spin-triplet p-wave SC order parameters near the impurity, while a SC state with broken time-reversal symmetry and a spontaneous current appears in the presence of the spin-orbit interaction. When both interactions coexist, it turns out that a state which carries a spontaneous spin current occurs.Comment: 4 pages, 7 figure