Comparative acute effects of the calcium channel blockers tiapamil, nisoldipine, and nifedipine on blood pressure and some regulatory factors in normal and hypertensive subjects

To clarify the pharmacological profile of the two new calcium channel blockers tiapamil and nisoldipine in humans, their acute effects as compared with those of the reference agent nifedipine were assessed in 10 normal subjects and 10 patients with essential hypertension. Blood pressure (BP), heart rate (HR), plasma and urinary catecholamine, sodium and potassium, plasma renin and aldosterone levels, and urinary prostaglandin E2 and F2 excretion rates were determined before and up to 4 or 5 h (urine values) after intravenous injection of placebo (20 ml 0.9% NaCl), tiapamil 1 mg/kg body weight, nisoldipine 6 micrograms/kg, or nifedipine 15 micrograms/kg. The four studies were performed at weekly intervals according to Latin square design. All three calcium channel blockers significantly (p less than 0.05 or lower) lowered BP and distinctly increased sodium excretion in hypertensive patients, but had only little influence on these parameters in normal subjects. HR was increased in both groups. Changes in BP and HR were maximal at 5 min and largely dissipated 3 h after drug injection. Effects on BP and HR, as well as concomitant mild increases in plasma norepinephrine and renin levels that occurred in both groups, tended to be more pronounced (about double) following nisoldipine than following tiapamil or nifedipine at the dosages given. Plasma aldosterone, epinephrine levels, and prostaglandin excretion rates were not consistently modified. These findings demonstrate that tiapamil and nisoldipine possess distinct antihypertensive properties in humans. Different chronotropic and renin-activating effects of different calcium channel blockers may be determined, at least in part, by a different influence on sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel chloride channel mutations leading to mild myotonia among Chinese

We describe two Chinese families with a mild form of the myotonia congenita due to novel chloride channel (ClCN1) mutations. In one case, heterozygous I553F and H555N mutations were found. The patient shared the I553F mutation with his healthy father, and his mother had a history of mild myotonia when she was younger. In another family, autosomal dominant myotonia congenita was due to a L844F change. The physiological effects of the mutations were examined by using the two-electrode voltage-clamp technique after expression of the channels in Xenopus oocytes. All mutations drastically shifted the voltage required for half-maximal activation, more under conditions mimicking the homozygous situation, than under conditions mimicking the heterozygous situation. The larger effect was seen in the compound heterozygous situation combining the I553F and the H555N mutations. Our data suggest that myotonia congenita caused by CLCN1 mutations in Chinese have similar variable features to those found in the West.

Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport

Maternal-fetal calcium (Ca(2+)) transport is crucial for fetal Ca(2+) homeostasis and bone mineralization. In this study, the physiological significance of the transient receptor potential, vanilloid 6 (TRPV6) Ca(2+) channel in maternal-fetal Ca(2+) transport was investigated using Trpv6 knockout mice. The Ca(2+) concentration in fetal blood and amniotic fluid was significantly lower in Trpv6 knockout fetuses than in wildtypes. The transport activity of radioactive Ca(2+) ((45)Ca) from mother to fetuses was 40% lower in Trpv6 knockout fetuses than in wildtypes. The ash weight was also lower in Trpv6 knockout fetuses compared with wildtype fetuses. TRPV6 mRNA and protein were mainly localized in intraplacental yolk sac and the visceral layer of extraplacental yolk sac, which are thought to be the places for maternal-fetal Ca(2+) transport in mice. These expression sites were co-localized with calbindin D(9K) in the yolk sac. In wildtype mice, placental TRPV6 mRNA increased 14-fold during the last 4 days of gestation, which coincides with fetal bone mineralization. These results provide the first in vivo evidence that TRPV6 is involved in maternal-fetal Ca(2+) transport. We propose that TRPV6 functions as a Ca(2+) entry pathway, which is critical for fetal Ca(2+) homeostasis.

Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation

The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a (45)Ca(2+) uptake assay (7.11 +/- 1.93 versus 3.61 +/- 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuria.

Irradiation of intracerebral 9L gliosarcoma by a single array of microplanar x-ray beams from a synchrotron: balance between curing and sparing

The purpose of this work was the understanding of microbeam radiation therapy at the ESRF in order to find the best compromise between curing of tumors and sparing of normal tissues, to obtain a better understanding of survival curves and to report its efficiency. This method uses synchrotron-generated x-ray microbeams. Rats were implanted with 9L gliosarcomas and the tumors were diagnosed by MRI. They were irradiated 14 days after implantation by arrays of 25 microm wide microbeams in unidirectional mode, with a skin entrance dose of 625 Gy. The effect of using 200 or 100 microm center-to-center spacing between the microbeams was compared. The median survival time (post-implantation) was 40 and 67 days at 200 and 100 microm spacing, respectively. However, 72% of rats irradiated at 100 microm spacing showed abnormal clinical signs and weight patterns, whereas only 12% of rats were affected at 200 microm spacing. In parallel, histological lesions of the normal brain were found in the 100 microm series only. Although the increase in lifespan was equal to 273% and 102% for the 100 and 200 microm series, respectively, the 200 microm spacing protocol provides a better sparing of healthy tissue and may prove useful in combination with other radiation modalities or additional drugs.

VMC++ versus BEAMnrc: a comparison of simulated linear accelerator heads for photon beams

BEAMnrc, a code for simulating medical linear accelerators based on EGSnrc, has been bench-marked and used extensively in the scientific literature and is therefore often considered to be the gold standard for Monte Carlo simulations for radiotherapy applications. However, its long computation times make it too slow for the clinical routine and often even for research purposes without a large investment in computing resources. VMC++ is a much faster code thanks to the intensive use of variance reduction techniques and a much faster implementation of the condensed history technique for charged particle transport. A research version of this code is also capable of simulating the full head of linear accelerators operated in photon mode (excluding multileaf collimators, hard and dynamic wedges). In this work, a validation of the full head simulation at 6 and 18 MV is performed, simulating with VMC++ and BEAMnrc the addition of one head component at a time and comparing the resulting phase space files. For the comparison, photon and electron fluence, photon energy fluence, mean energy, and photon spectra are considered. The largest absolute differences are found in the energy fluences. For all the simulations of the different head components, a very good agreement (differences in energy fluences between VMC++ and BEAMnrc <1%) is obtained. Only a particular case at 6 MV shows a somewhat larger energy fluence difference of 1.4%. Dosimetrically, these phase space differences imply an agreement between both codes at the <1% level, making VMC++ head module suitable for full head simulations with considerable gain in efficiency and without loss of accuracy.

Testing the GlaaS algorithm for dose measurements on low- and high-energy photon beams using an amorphous silicon portal imager

The GLAaS algorithm for pretreatment intensity modulation radiation therapy absolute dose verification based on the use of amorphous silicon detectors, as described in Nicolini et al. [G. Nicolini, A. Fogliata, E. Vanetti, A. Clivio, and L. Cozzi, Med. Phys. 33, 2839-2851 (2006)], was tested under a variety of experimental conditions to investigate its robustness, the possibility of using it in different clinics and its performance. GLAaS was therefore tested on a low-energy Varian Clinac (6 MV) equipped with an amorphous silicon Portal Vision PV-aS500 with electronic readout IAS2 and on a high-energy Clinac (6 and 15 MV) equipped with a PV-aS1000 and IAS3 electronics. Tests were performed for three calibration conditions: A: adding buildup on the top of the cassette such that SDD-SSD = d(max) and comparing measurements with corresponding doses computed at d(max), B: without adding any buildup on the top of the cassette and considering only the intrinsic water-equivalent thickness of the electronic portal imaging devices device (0.8 cm), and C: without adding any buildup on the top of the cassette but comparing measurements against doses computed at d(max). This procedure is similar to that usually applied when in vivo dosimetry is performed with solid state diodes without sufficient buildup material. Quantitatively, the gamma index (gamma), as described by Low et al. [D. A. Low, W. B. Harms, S. Mutic, and J. A. Purdy, Med. Phys. 25, 656-660 (1998)], was assessed. The gamma index was computed for a distance to agreement (DTA) of 3 mm. The dose difference deltaD was considered as 2%, 3%, and 4%. As a measure of the quality of results, the fraction of field area with gamma larger than 1 (%FA) was scored. Results over a set of 50 test samples (including fields from head and neck, breast, prostate, anal canal, and brain cases) and from the long-term routine usage, demonstrated the robustness and stability of GLAaS. In general, the mean values of %FA remain below 3% for deltaD equal or larger than 3%, while they are slightly larger for deltaD = 2% with %FA in the range from 3% to 8%. Since its introduction in routine practice, 1453 fields have been verified with GLAaS at the authors' institute (6 MV beam). Using a DTA of 3 mm and a deltaD of 4% the authors obtained %FA = 0.9 +/- 1.1 for the entire data set while, stratifying according to the dose calculation algorithm, they observed: %FA = 0.7 +/- 0.9 for fields computed with the analytical anisotropic algorithm and %FA = 2.4 +/- 1.3 for pencil-beam based fields with a statistically significant difference between the two groups. If data are stratified according to field splitting, they observed %FA = 0.8 +/- 1.0 for split fields and 1.0 +/- 1.2 for nonsplit fields without any significant difference.

Three dimensional finite element simulation of polymer melting and flow in a single-screw extruder : optimization of screw channel geometry

Single-screw extrusion is one of the widely used processing methods in plastics industry, which was the third largest manufacturing industry in the United States in 2007 [5]. In order to optimize the single-screw extrusion process, tremendous efforts have been devoted for development of accurate models in the last fifty years, especially for polymer melting in screw extruders. This has led to a good qualitative understanding of the melting process; however, quantitative predictions of melting from various models often have a large error in comparison to the experimental data. Thus, even nowadays, process parameters and the geometry of the extruder channel for the single-screw extrusion are determined by trial and error. Since new polymers are developed frequently, finding the optimum parameters to extrude these polymers by trial and error is costly and time consuming. In order to reduce the time and experimental work required for optimizing the process parameters and the geometry of the extruder channel for a given polymer, the main goal of this research was to perform a coordinated experimental and numerical investigation of melting in screw extrusion. In this work, a full three-dimensional finite element simulation of the two-phase flow in the melting and metering zones of a single-screw extruder was performed by solving the conservation equations for mass, momentum, and energy. The only attempt for such a three-dimensional simulation of melting in screw extruder was more than twenty years back. However, that work had only a limited success because of the capability of computers and mathematical algorithms available at that time. The dramatic improvement of computational power and mathematical knowledge now make it possible to run full 3-D simulations of two-phase flow in single-screw extruders on a desktop PC. In order to verify the numerical predictions from the full 3-D simulations of two-phase flow in single-screw extruders, a detailed experimental study was performed. This experimental study included Maddock screw-freezing experiments, Screw Simulator experiments and material characterization experiments. Maddock screw-freezing experiments were performed in order to visualize the melting profile along the single-screw extruder channel with different screw geometry configurations. These melting profiles were compared with the simulation results. Screw Simulator experiments were performed to collect the shear stress and melting flux data for various polymers. Cone and plate viscometer experiments were performed to obtain the shear viscosity data which is needed in the simulations. An optimization code was developed to optimize two screw geometry parameters, namely, screw lead (pitch) and depth in the metering section of a single-screw extruder, such that the output rate of the extruder was maximized without exceeding the maximum temperature value specified at the exit of the extruder. This optimization code used a mesh partitioning technique in order to obtain the flow domain. The simulations in this flow domain was performed using the code developed to simulate the two-phase flow in single-screw extruders.

Utilizing Gaussian-Schell model beams to mitigate atmospheric turbulence in free space optical communications / by Kyle R. Drexler.

Turbulence affects traditional free space optical communication by causing speckle to appear in the received beam profile. This occurs due to changes in the refractive index of the atmosphere that are caused by fluctuations in temperature and pressure, resulting in an inhomogeneous medium. The Gaussian-Schell model of partial coherence has been suggested as a means of mitigating these atmospheric inhomogeneities on the transmission side. This dissertation analyzed the Gaussian-Schell model of partial coherence by verifying the Gaussian-Schell model in the far-field, investigated the number of independent phase control screens necessary to approach the ideal Gaussian-Schell model, and showed experimentally that the Gaussian-Schell model of partial coherence is achievable in the far-field using a liquid crystal spatial light modulator. A method for optimizing the statistical properties of the Gaussian-Schell model was developed to maximize the coherence of the field while ensuring that it does not exhibit the same statistics as a fully coherent source. Finally a technique to estimate the minimum spatial resolution necessary in a spatial light modulator was developed to effectively propagate the Gaussian-Schell model through a range of atmospheric turbulence strengths. This work showed that regardless of turbulence strength or receiver aperture, transmitting the Gaussian-Schell model of partial coherence instead of a fully coherent source will yield a reduction in the intensity fluctuations of the received field. By measuring the variance of the intensity fluctuations and the received mean, it is shown through the scintillation index that using the Gaussian-Schell model of partial coherence is a simple and straight forward method to mitigate atmospheric turbulence instead of traditional adaptive optics in free space optical communications.

Length of the annular regime for condensing flows inside a horizontal channel - the experimental determination of its values and its trends

The experiments observe and measure the length of the annular regime in fully condensing quasi-steady (steady-in-the-mean) flows of pure FC-72 vapor in a horizontal condenser (rectangular cross-section of 2 mm height, 15 mm width, and 1 m length). The sides and top of the duct are made of clear plastic that allows flow visualization. The experimental system in which this condenser is used is able to control and achieve different quasi-steady mass flow rates, inlet pressures, and wall cooling conditions (by adjustment of the temperature and flow rate of the cooling water flowing underneath the condensing-plate). The reported correlations and measurements for the annular length are also vital information for determining the length of the annular regime and proposing extended correlation (covering many vapors and a larger parameter set than the experimentally reported version here) by ongoing independent modeling and computational simulation approach.

Accelerating Diffraction-free Beams in Photonic Lattices

We study nondiffracting accelerating paraxial optical beams in periodic potentials, in both the linear and the nonlinear domains. In particular, we show that only a unique class of z-dependent lattices can support a true accelerating diffractionless beam. Accelerating lattice solitons, autofocusing beams and accelerating bullets in optical lattices are systematically examined.

Geology of Smoke Hollow Area 8 Miles Southeast of Deerlodge, Powell County, Montana

This investigation was undertaken primarily as a problem in geologic mapping. The stratigraphy was studied as to the character, age, and sequence of the geologic formations that are exposed. The conclusions were based principally on the field relationships and lithology because no fossils were found.