Forward and Inverse Energy Cascade in Fluid Turbulence Adhere to Kolmogorov's Refined Similarity Hypothesis.

We study fluctuations of the local energy cascade rate Φ_{ℓ} in turbulent flows at scales (ℓ) in the inertial range. According to the Kolmogorov refined similarity hypothesis (KRSH), relevant statistical properties of Φ_{ℓ} should depend on ε_{ℓ}, the viscous dissipation rate locally averaged over a sphere of size ℓ, rather than on the global average dissipation. However, the validity of KRSH applied to Φ_{ℓ} has not yet been tested from data. Conditional averages such as ⟨Φ_{ℓ}|ε_{ℓ}⟩ as well as of higher-order moments are measured from direct numerical simulations data, and results clearly adhere to the predictions from KRSH. Remarkably, the same is true when considering forward (Φ_{ℓ}>0) and inverse (Φ_{ℓ}<0) cascade events separately. Measured ratios of forward and inverse cascade probability densities conditioned on ε_{ℓ} also confirm the applicability of the KRSH to analysis of the fluctuation relation from nonequilibrium thermodynamics.

Turbulence is an Ineffective Mixer when Schmidt Numbers Are Large.

We solve the advection-diffusion equation for a stochastically stationary passive scalar θ, in conjunction with forced 3D Navier-Stokes equations, using direct numerical simulations in periodic domains of various sizes, the largest being 8192^{3}. The Taylor-scale Reynolds number varies in the range 140-650 and the Schmidt number Sc≡ν/D in the range 1-512, where ν is the kinematic viscosity of the fluid and D is the molecular diffusivity of θ. Our results show that turbulence becomes an ineffective mixer when Sc is large. First, the mean scalar dissipation rate ⟨χ⟩=2D⟨|∇θ|^{2}⟩, when suitably nondimensionalized, decreases as 1/logSc. Second, 1D cuts through the scalar field indicate increasing density of sharp fronts on larger scales, oscillating with large excursions leading to reduced mixing, and additionally suggesting weakening of scalar variance flux across the scales. The scaling exponents of the scalar structure functions in the inertial-convective range appear to saturate with respect to the moment order and the saturation exponent approaches unity as Sc increases, qualitatively consistent with 1D cuts of the scalar.

Small-Scale Isotropy and Ramp-Cliff Structures in Scalar Turbulence.

Passive scalars advected by three-dimensional Navier-Stokes turbulence exhibit a fundamental anomaly in odd-order moments because of the characteristic ramp-cliff structures, violating small-scale isotropy. We use data from direct numerical simulations with grid resolution of up to 8192^{3} at high Péclet numbers to understand this anomaly as the scalar diffusivity, D, diminishes, or as the Schmidt number, Sc=ν/D, increases; here ν is the kinematic viscosity of the fluid. The microscale Reynolds number varies from 140 to 650 and Sc varies from 1 to 512. A simple model for the ramp-cliff structures is developed and shown to characterize the scalar derivative statistics very well. It accurately captures how the small-scale isotropy is restored in the large-Sc limit, and additionally suggests a possible correction to the Batchelor length scale as the relevant smallest scale in the scalar field.

Oscillations Modulating Power Law Exponents in Isotropic Turbulence: Comparison of Experiments with Simulations.

Inertial-range features of turbulence are investigated using data from experimental measurements of grid turbulence and direct numerical simulations of isotropic turbulence simulated in a periodic box, both at the Taylor-scale Reynolds number R_{λ}∼1000. In particular, oscillations modulating the power-law scaling in the inertial range are examined for structure functions up to sixth-order moments. The oscillations in exponent ratios decrease with increasing sample size in simulations, although in experiments they survive at a low value of 4 parts in 1000 even after massive averaging. The two datasets are consistent in their intermittent character but differ in small but observable respects. Neither the scaling exponents themselves nor all the viscous effects are consistently reproduced by existing models of intermittency.

Steep Cliffs and Saturated Exponents in Three-Dimensional Scalar Turbulence.

The intermittency of a passive scalar advected by three-dimensional Navier-Stokes turbulence at a Taylor-scale Reynolds number of 650 is studied using direct numerical simulations on a 4096^{3} grid; the Schmidt number is unity. By measuring scalar increment moments of high orders, while ensuring statistical convergence, we provide unambiguous evidence that the scaling exponents saturate to 1.2 for moment orders beyond about 12, indicating that scalar intermittency is dominated by the most singular shocklike cliffs in the scalar field. We show that the fractal dimension of the spatial support of steep cliffs is about 1.8, whose sum with the saturation exponent value of 1.2 adds up to the space dimension of 3, thus demonstrating a deep connection between the geometry and statistics in turbulent scalar mixing. The anomaly for the fourth and sixth order moments is comparable to that in the Kraichnan model for the roughness exponent of 4/3.

Extreme events in computational turbulence.

We have performed direct numerical simulations of homogeneous and isotropic turbulence in a periodic box with 8,192(3) grid points. These are the largest simulations performed, to date, aimed at improving our understanding of turbulence small-scale structure. We present some basic statistical results and focus on "extreme" events (whose magnitudes are several tens of thousands the mean value). The structure of these extreme events is quite different from that of moderately large events (of the order of 10 times the mean value). In particular, intense vorticity occurs primarily in the form of tubes for moderately large events whereas it is much more "chunky" for extreme events (though probably overlaid on the traditional vortex tubes). We track the temporal evolution of extreme events and find that they are generally short-lived. Extreme magnitudes of energy dissipation rate and enstrophy occur simultaneously in space and remain nearly colocated during their evolution.

Abnormalities in left inferior frontal gyral thickness and parahippocampal gyral volume in young people at high genetic risk for bipolar disorder.

BACKGROUND: Fronto-limbic structural brain abnormalities have been reported in patients with bipolar disorder (BD), but findings in individuals at increased genetic risk of developing BD have been inconsistent. We conducted a study in adolescents and young adults (12-30 years) comparing measures of fronto-limbic cortical and subcortical brain structure between individuals at increased familial risk of BD (at risk; AR), subjects with BD and controls (CON). We separately examined cortical volume, thickness and surface area as these have distinct neurodevelopmental origins and thus may reflect differential effects of genetic risk. METHOD: We compared fronto-limbic measures of grey and white matter volume, cortical thickness and surface area in 72 unaffected-risk individuals with at least one first-degree relative with bipolar disorder (AR), 38 BD subjects and 72 participants with no family history of mental illness (CON). RESULTS: The AR group had significantly reduced cortical thickness in the left pars orbitalis of the inferior frontal gyrus (IFG) compared with the CON group, and significantly increased left parahippocampal gyral volume compared with those with BD. CONCLUSIONS: The finding of reduced cortical thickness of the left pars orbitalis in AR subjects is consistent with other evidence supporting the IFG as a key region associated with genetic liability for BD. The greater volume of the left parahippocampal gyrus in those at high risk is in line with some prior reports of regional increases in grey matter volume in at-risk subjects. Assessing multiple complementary morphometric measures may assist in the better understanding of abnormal developmental processes in BD.

Cancellation exponents in isotropic turbulence and magnetohydrodynamic turbulence.

Small-scale characteristics of turbulence such as velocity gradients and vorticity fluctuate rapidly in magnitude and oscillate in sign. Much work exists on the characterization of magnitude variations, but far less on sign oscillations. While in homogeneous turbulence averages performed on large scales tend to zero because of the oscillatory character, those performed on increasingly smaller scales will vary with the averaging scale in some characteristic way. This characteristic variation at high Reynolds numbers is captured by the so-called cancellation exponent, which measures how local averages tend to cancel out as the averaging scale increases, in space or time. Past experimental work suggests that the exponents in turbulence depend on whether one considers quantities in full three-dimensional (3D) space or uses their one- or two-dimensional cuts. We compute cancellation exponents of vorticity and longitudinal as well as transverse velocity gradients in isotropic turbulence at Taylor-scale Reynolds numbers up to 1300 on 8192^{3} grids. The 2D cuts yield the same exponents as those for full 3D, while the 1D cuts yield smaller numbers, suggesting that the results in higher dimensions are more reliable. We make the case that the presence of vortical filaments in isotropic turbulence leads to this conclusion. This effect is particularly conspicuous in magnetohydrodynamic turbulence, where an increased degree of spatial coherence develops along the direction of an imposed magnetic field.

Reynolds number scaling of velocity increments in isotropic turbulence.

Using the largest database of isotropic turbulence available to date, generated by the direct numerical simulation (DNS) of the Navier-Stokes equations on an 8192^{3} periodic box, we show that the longitudinal and transverse velocity increments scale identically in the inertial range. By examining the DNS data at several Reynolds numbers, we infer that the contradictory results of the past on the inertial-range universality are artifacts of low Reynolds number and residual anisotropy. We further show that both longitudinal and transverse velocity increments scale on locally averaged dissipation rate, just as postulated by Kolmogorov's refined similarity hypothesis, and that, in isotropic turbulence, a single independent scaling adequately describes fluid turbulence in the inertial range.

Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac.

Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1(-/-)) or Epac2 (Epac2(-/-)) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2(-/-) mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2(-/-) mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2(-/-) mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis.

Refined similarity hypothesis using three-dimensional local averages.

The refined similarity hypotheses of Kolmogorov, regarded as an important ingredient of intermittent turbulence, has been tested in the past using one-dimensional data and plausible surrogates of energy dissipation. We employ data from direct numerical simulations, at the microscale Reynolds number R(λ)∼650, on a periodic box of 4096(3) grid points to test the hypotheses using three-dimensional averages. In particular, we study the small-scale properties of the stochastic variable V=Δu(r)/(rε(r))(1/3), where Δu(r) is the longitudinal velocity increment and ε(r) is the dissipation rate averaged over a three-dimensional volume of linear size r. We show that V is universal in the inertial subrange. In the dissipation range, the statistics of V are shown to depend solely on a local Reynolds number.

Synthesis, characterization, and Ca2+ antagonistic activity of diltiazem metabolites.

Diltiazem is a calcium antagonist widely used in the treatment of angina and hypertension. The contributions of metabolites of diltiazem to the vasorelaxant effects of diltiazem were investigated. The synthesis and spectroscopic characterization of eight major cis-diltiazem metabolites are described. Three of the compounds--N, O-didemethylated metabolite (21), O-demethylated metabolite (22), and diltiazem N-oxide (27)--have been recently reported and have not previously been synthesized. The identities of all eight synthetic metabolites have been verified with samples obtained from human urine using combined LC-MS/MS. The Ca2+ antagonistic activities of diltiazem and its metabolites (except 27) were studied on hamster aorta preparations depolarized with KCl. The order of potencies (IC50 +/- SE, microM) is as follows: diltiazem (0.98 +/- 0.47) greater than 17 (2.46 +/- 0.38) greater than or equal to 23 (3.27 +/- 1.02) greater than 26 (20.2 +/- 10.5) greater than 22 (40.4 +/- 15.4) greater than or equal to 25 (45.5 +/- 18.1) greater than 21 (112.2 +/- 33.2) greater than or equal to 24 (126.7 +/- 24.2). Structure-activity relationships are also discussed.

VEGF-2 (St Elizabeth's Medical Center).

St Elizabeth's Medical Center of Boston is developing VEGF gene therapy for the potential treatment of angina and diabetic neuropathy. The center is studying three isoforms of VEGF, although the expression of phVEGF165 has yielded the most positive results [312563]. VEGF-2 gene therapy augments perfusion of ischemic myocardium that contributes to improved clinical outcomes in patients with chronic myocardial ischemia as assessed by NOGA electromechanical mapping [390786]. Phase I trials demonstrated that gene transfer directly into the heart of the patient facilitates blood flow to the primary muscles of the heart, providing relief of angina [348564]. Reduced angina was reported by 28 out of 30 patients and tolerance of exercise increased from 240 to 410 s up to 180 days post-therapy [348632].

Technology evaluation: transgenic antithrombin III (rhAT-III), Genzyme Transgenics.

AT-III LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery such as cardiopulmonary bypass.

Effect of diltiazem on intraarterial blood pressure and heart rate during stress testing in patients with angina: a gender comparison study.

The purpose of this study was to measure the blood pressure and electrocardiographic responses of a small, matched group of women (n = 8) and men (n = 9) who experienced typical, effort angina during an exercise on the treadmill (up to the second stage of a Bruce protocol). These responses were measured before and after therapy with diltiazem (60 mg four times daily for 1 week). Reports of previous studies have described significant gender differences in blood pressure responses to diltiazem in healthy volunteers tested with the same protocol. In contrast to the data in healthy individuals, gender differences in blood pressure responses to exercise before and after diltiazem administration were not observed. Results of analysis of pulse pressure responses to exercise were also similar in male and female patients with angina. A significant postexercise drop in blood pressure was observed, which was augmented by diltiazem. These data suggest that gender differences in drug action may be difficult to demonstrate in patients with vascular disease.

Erythrocyte adenosine transport. A rapid screening test for cardiovascular drugs.

An erythrocyte (RBC) model based on whole blood was used to investigate the effect of cardiovascular drugs on the uptake of adenosine in vitro. Fresh whole blood obtained from healthy volunteers was allowed to equilibrate with various concentrations (5-1000 microM) of a tested agent. (2-3H)-Adenosine was used as a substrate, and the reaction was terminated after 2 sec of incubation at room temperature by rapid addition of a "Stopping Solution" which was a mixture of erythro-9-(2-hydroxy-3-nonyl)adenine, dipyridamole, and EDTA. The mixture was centrifuged (1760 g, 4 degrees C, 10 min), and the radioactivity of an aliquot of the supernatant was determined by a scintillation counter. The results showed that dipyridamole was the most potent agent tested (IC50 = 0.2 microM). Amongst the calcium antagonists studied, isradipine was most potent, followed by verapamil, clentiazem, diltiazem, and then nifedipine. The racemates of two metabolites of diltiazem, MX and MB, were more potent than the parent drug. The antiarrhythmic agents, amiodarone and sotalol, the two new lipid peroxidation inhibitors, U-74389F and U-78517F, and the anxiolytic agent, alprazolam, were as active as verapamil. The beta-receptor antagonist propranolol and the angiotensin converting enzyme (ACE) inhibitor, enalapril, were practically inactive. In addition, the model was stereoselective such that the S(-)-enantiomer of verapamil was considerably more potent than the R(+)-antipote, whereas d(+)-sotalol was practically inactive compared to racemic sotalol.

High-performance liquid chromatographic assay of diltiazem and six of its metabolites in plasma: application to a pharmacokinetic study in healthy volunteers.

A sensitive and specific reversed-phase high-performance liquid chromatographic assay for simultaneous determination of plasma concentrations of diltiazem and six of its metabolites known to occur in humans is reported. Using 2 mL of plasma, the lower limit of quantitation of the assay was less than 10 ng/mL of diltiazem and each of the metabolites, with coefficients of variation of less than 10%. The assay was successfully applied to determine the kinetics of diltiazem and its major metabolites in four healthy volunteers after each received a single 90-mg oral dose of diltiazem. In addition to the previously reported two major metabolites in humans, deacetyl diltiazem (M1) and N-monodemethyl diltiazem (MA), another previously unreported major metabolite, deacetyl N-monodemethyl diltiazem (M2), was present at comparable concentrations to M1 and MA in all four volunteers. In addition, another metabolite, deacetyl diltiazem N-oxide (M1-NO), which was previously found most abundant in urine, was also estimated in the plasma of two volunteers. Two other known human metabolites, deacetyl O-demethyl diltiazem (M4) and deacetyl N,O-didimethyl diltiazem (M6), were not detected in any of the four study subjects. The average maximum plasma concentrations of M1, M2, MA, and M1-NO were 10, 15, 26, and 13%, respectively, of the mean maximum diltiazem concentrations.

Determination of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in human plasma by a simple and rapid high-performance liquid chromatography assay.

In order to study the pharmacodynamic effects of drugs on dopamine and serotonin metabolism, a reversed-phase HPLC assay coupled with electrochemical detection (ECD) for measuring plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) was developed. The system was operated isocratically using a mobile phase of aqueous 0.03 M KH2PO4 buffer containing 0.15 mM EDTA in methanol (8.75:1.25), with a final pH of 4.0. The flow rate was set at 1.5 mL/min, and potentials at +450 mV. Using a signal to noise ratio of > 3, the minimum detection limit assessed by direct on-column injection of a standard solution for DOPAC and 5-HIAA was < 1 pg. The assays were linear from basal concentrations (1-10 ng/mL) to 100 ng/mL. The intra- and interassay variations were < 10% and < 20%, respectively.

Radioimmunoassay for the N-oxide metabolite of chlorpromazine in human plasma and its application to a pharmacokinetic study in healthy humans.

Antibodies specific to chlorpromazine N-oxide (CPZNO) were produced in rabbits immunized with a hapten-bovine serum albumin conjugate, which was prepared by linking the 7-position of the phenothiazine ring of the metabolite to the protein via a 4-carbon bridge. An extraction radioimmunoassay (RIA) was developed using this antiserum and shown to have adequate sensitivity and specificity for determination of plasma concentrations of CPZNO in the presence of chlorpromazine (CPZ) and its major metabolites. It was used together with the previously developed RIAs for CPZ, chlorpromazine sulfoxide (CPZSO), and 7-hydroxychlorpromazine (7-OHCPZ) to study the pharmacokinetics of CPZ and these metabolites in five healthy volunteers after they received a single 50-mg oral dose of CPZ. It is interesting to note that peak plasma concentrations of CPZNO were considerably higher than CPZ, and the apparent elimination half-lives of this metabolite were shorter than those of CPZ.

Transgenic antithrombin III (Genzyme).

ATIII LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB). GTC has a license from Behringwerke (Hoechst Marion Roussel; now Aventis Pharma) to develop transgenic AT-III. Behringwerke retains exclusive worldwide marketing rights to the product, but has to purchase its entire supply of transgenic AT-III from GTC [156364]. In March 1997, GTC signed an agreement with SMIG, a joint venture formed by GTC and Sumitomo Metals, under which SMIG has the rights to develop rhAT-III in Asia in return for US dollar 4.4 million in additional funding for the continued transgenic development of rhAT-III. The dollar 4.4 million will be paid upon reaching certain milestones, which GTC expected to complete in 1997 [240202]. In December 1998, US-05843705 was issued covering rhAT-III production in transgenic goats [302263]. In January 2000, the results of the European phase III trial, which were significant in meeting the trial's primary endpoint of reduction in the use of fresh frozen plasma were reported. The trial was also significant in two of three secondary endpoints, maintenance of normal AT-III levels and changes in D-dimer and fibrin monomer [352041,353372]. Three phase III trials were initiated in the second quarter of 1998. Two identical trials, one in Europe and one in the US, evaluated the safety and efficacy of rhAT-III compared to placebo in restoring heparin sensitivity to heparin-resistant patients scheduled for elective cardiac surgery requiring CPB. The third trial, in both the US and Europe, will determine whether rhAT-III matches, at equivalent doses, the ability of plasma-derived AT-III to restore heparin sensitivity among heparin-resistant patients undergoing CPB [292235,292861]. Full enrollment onto the US trial was complete by the end of first quarter 2000 [363589], and the companies aim to complete trials and submit a filing by the end of 2000 [353372]. Clinical trials of the proteins in Japan were expected to begin in 1998 [286086].