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Film‐substrate interactions of YBa2Cu3O7−x (YBCO) thin films grown by pulsed laser deposition on alkaline earth fluoride substrates were investigated. X‐ray photoelectron spectroscopy, atomic force microscopy, and x‐ray‐diffraction measurements showed that the quality of the film and amount of chemical reaction between film and substrate were dependent on the substrate material and deposition temperature. The reaction of YBCO films with CaF2 and MgF2 substrates forms BaF2 and calcium or magnesium oxide species. The reacted film is insulating and has a microscopically rough surface. No reaction was detected in films deposited on BaF2 and SrF2. Physical and thermodynamic properties which may explain the observed order of reactivity are examined.

Finasteride is a novel therapeutic agent that selectively inhibits the enzyme 5 alpha-reductase, thereby reducing prostatic dihydrotestosterone (DHT) levels and prostate size. In men with symptomatic benign prostatic hyperplasia (BPH), these effects have been associated with improvements in peak urinary flow rate and urological symptoms; withdrawal from therapy, however, results in regrowth of the adenoma and long term therapy is therefore necessary. Although the magnitude of clinical improvement seen with finasteride has been perceived to be modest [especially when compared with that associated with transurethral resection of the prostate (TURP)], it has been maintained in the medium term (up to 2 years) and thus may represent significant reversal of disease progression. Such beneficial effects, however, may not become apparent until completion of at least 6 months of therapy. Furthermore, since clinical studies have been unable to proactively identify a responsive subgroup, a trial period of 6 or possibly 12 months is necessary to assess patient responsiveness. Despite these potential shortcomings, the benefits of therapy appear to outweigh the risks. Indeed, finasteride is well tolerated; most adverse events have been related to sexual dysfunction (decreased libido, ejaculation disorders and impotence) and occurred in only a small proportion (about 2 to 3%) of patients. Moreover, although there has been concern that finasteride might mask the detection of prostate cancer through its decremental effects on serum prostate specific antigen (PSA) levels, careful monitoring in clinical trials appears to have avoided this problem. Thorough pretreatment assessment and periodic follow-up examinations for malignancy are therefore required in clinical practice. The role of finasteride in the treatment of patients with BPH is still emerging and will no doubt gain in clarity with further planned investigations. TURP (or other invasive procedures such as the insertion of prostatic stents in patients unsuitable for resection), continues to be the mainstay of therapy for those patients with severe symptomatic BPH. However, available data support a first line role for finasteride in the treatment of patients with uncomplicated symptomatic BPH. Within this setting, finasteride appears to offer a needed additional treatment option for those patients in whom surgery is not indicated, and may be of special benefit to the considerable proportion of patients who opt not to undergo prostatectomy.

The scope and limitations of the enzymatic resolution of α,α-disubstituted α-amino acid amides by an amino acid amidase from Mycobacterium neoaurum and of the corresponding ethyl esteis with Pig liver estetase (PLE) have been studied. Moderate enantiomeric excesses were obtained with PLE, with only a narrow substrate specificity. Mycobacterium neoaurum on the contrary yields a broad range of S-α,α-disubstituted α-amino acids 1 and the corresponding R-amides 2.

In two previous studies [J. Chem. Phys. 91, 1287 (1989); 95, 1234 (1991)] we had examined the dynamics of coupled, internal translational, and rotational motions in a rigid or pseudorigid N‐sphere macromolecular model using the rotational–translational Brownian dynamics algorithm of Dickinson et al. [J. Chem. Soc. Faraday Trans. 2 81, 591 (1985)]. In the present study, those works are generalized to include all possible internal flexible motions in an N‐sphere macromolecular model. In general, for the N‐sphere system there are 6(N‐1) degrees of configurational freedom, although not all modes may be active in any particular application. Using the language of small oscillation theory, the deviations in the generalized coordinates associated with the ‘‘joints’’ connecting the spheres to one another are described in terms of quadratic potentials. From these potentials, the components of the generalized forces (torques and forces) are obtained for subsequent use in the Brownian dynamics algorithm. The degree o...

In this paper high-performance liquid chromatography—UV data are analyzed by multivariate techniques in order to obtain information about a specific analyte of interest in the presence of interfering compounds. It will be shown that small model errors can be encountered in practice and their effect on the results of multivariate data analysis will be demonstrated. The results will be explained in the context of the results from previous evaluation studies. In the first experiment target testing is used in order to test for the presence of N -benzyl- p -aminophenol- o -glucuronide in samples of patients' urine. Malinowski's F -test is compared with the target testing algorithm of Ho, Christian and Davidson. In the second experiment generalized rank annihilation factor analysis (GRAFA) and iterative target transformation factor analysis (ITTFA) are used for the quantitative analysis of anthracene in the presence of an interfering compound (phenanthrene). Anthracene—phenanthrene mixtures with varying resolutions and concentration ratios are analyzed. In the third experiment 3-methyl chrysene is quantified in six-component mixtures of polyeyclic aromatic hydrocarbons by GRAFA and ITTFA.

The authors have grown 997 nm vertical-cavity surface-emitting lasers with an offset between the wavelength of the cavity mode and the quantum well gain peak to improve high temperature operation, and with higher aluminum-content barriers around the active region to improve the carrier confinement. They fabricated lasers of 8-15 and 20- mu m diameters. The 8- mu m-diameter devices exhibited CW operation up to 140 degrees C with little change in threshold current from 15 degrees C to 100 degrees C, and the 20- mu m-diameter devices showed CW output power of 11 mW at 25 degrees C without significant heat sinking. >

Many studies relate the ecological fate of a contaminant to its chemical structure, but few combine quantitative structure-activity relationships with environmental properties that may modulate those effects, so the modulating role of such properties remains unquantified. This study determines the effects of variations in suspended biomass, dissolved and colloidal organic carbon, and pH on the time course of 2, 2[prime], 4, 4[prime], 5, 5[prime]-hexachlorobiphenyl uptake by laboratory cultures of Selenastrum capricornutum Printz. Variations in pH had no effect, but uptake increased with biomass and decreased at higher levels of organic carbon, measured as absorbance at 440 nm (Abs, per meter). Coefficients for these effects combined with existing relations based on simple first-order molecular connectivity ([chi]) or capacity ratio (K[prime]) yielded semi-empirical equations to predict the instantaneous rate of uptake and bioconcentration factor (BCF) of organic contaminants: log rate = [minus]3.30 + 0.32[chi] + 1.1 log biomass [minus] 0.42 log Abs; log BCF = 4.11 + 0.86 log K[prime] [minus] 0.87 log biomass [minus] 0.22 log Abs. These equations, entirely based on pure laboratory cultures, were assessed by comparing predicted uptake with the time courses of polychlorinated biphenyl (PCB) uptake by plankton in water from 11 Quebec lakes and proved tomore » be more effective than predictions based on contaminant properties alone.« less

Weak interactions of neurotransmitters and the lipid matrix in the synaptic membrane have been hypothesized to play a role in synaptic transmission of nerve signals, particularly with respect to receptor desensitization (Cantor, R. S. Biochemistry 2003, 42, 11891). The strength of such interactions, however, was not measured, and this is an obvious impediment for further evaluation and understanding of a possible role for desensitization. We have used dialysis equilibrium to directly measure the net affinity of selected neurotransmitters for lipid membranes and analyzed this affinity data with respect to calorimetric measurements and molecular dynamics simulations. We studied an anionic (glutamate), a cationic (acetylcholine), and two zwitterionic (gamma-aminobutyric acid and glycine) neurotransmitters, and membranes of pure dimyristoyl phosphatidylcholine (DMPC), DMPC doped with 10% anionic lipid (dimyristoyl phosphatidylglycerol, DMPG, or dimyristoyl phosphatidylserine, DMPS), or 1:1 mixtures of dipalmitoyl phosphatidylcholine (DPPC) and dilauroyl phosphatidylcholine (DLPC). The results showed a remarkable variability among the investigated systems. For example, the chloride salt of acetylcholine interacts unfavorably with DMPC and is thus preferentially excluded from the membrane's hydration layer. Conversely, the zwitterionic neurotransmitters are attracted to membranes with 10% anionic lipid and their local concentration at the interface is 5-10 times larger than in the aqueous bulk. The simulations suggest that this attraction mainly relies on electrostatic interactions of the amino group of the neurotransmitter and the lipid phosphate. We conclude that moderate attraction to lipid membranes occurs for some polar neurotransmitters and hence that one premise for a theory of bilayer-mediated modulation of nerve transmission seems to be fulfilled. However, the strong variability in interaction strengths also shows that this attraction is not an inherent property of all neurotransmitters.

Photodiode (PD) is a key component in optical transmission and optical measurement systems. In this paper, we present the design and fabrication of traveling-wave edge-coupled Unitraveling Carrier (UTC) PD. The fabricated UTC PD with 40μm×5μm waveguide shows 3dB bandwidth 13GHZ and 32GHz under 0 biases and -1V respectively. In parallel, PIN PD was also fabricated for comparison and only shows 4GHz and 18GHz under same bias conditions. This indicates the UTC PD is superior to the PIN PD for higher speed operation, especially in application of system without power supply.

The scope and limitations of the enzymatic resolution of α,α-disubstituted α-amino acid amides by an amino acid amidase from Mycobacterium neoaurum and of the corresponding ethyl esteis with Pig liver estetase (PLE) have been studied. Moderate enantiomeric excesses were obtained with PLE, with only a narrow substrate specificity. Mycobacterium neoaurum on the contrary yields a broad range of S-α,α-disubstituted α-amino acids 1 and the corresponding R-amides 2.

Angiogenesis is one of the major processes controlling growth and metastasis of tumors. Angiogenesis inhibitors have been targeted for the treatment of various cancers for more than 2 decades. We have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues. Our lead compound, SR16388, is a potent antiangiogenic agent with binding affinity to estrogen receptor-α (ER-α) and -β (ER-β) at the nanomolar range. This compound inhibited the proliferation of human microvascular endothelial cells (HMVEC) and various types of human cancer cells in vitro. SR16388 inhibited embryonic angiogenesis as measured in the chick chorioallantoic membrane (CAM) assay. The blood vessel density in the CAM was greatly reduced after the embryos were treated with 3 μg/CAM of SR16388 for 24 h. SR16388 at a dose of 2 μM prevented tube formation in Matrigel after HMVEC cells were treated for 8 h. In a modified Boyden chamber assay, SR16388 inhibited the migration of HMVECs by 80% at 500 nM. Using a novel in vivo Fibrin Z-chamber model, we demonstrated that SR16388 at a single daily oral dose of 3 mg/kg for 12 days significantly inhibited the granulation tissue (GT) thickness and the microvessel density of the GT as compared to control. More importantly, SR16388 down-regulated the pro-angiogenic transcription factors, hypoxia inducible factor 1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) in non-small cell lung cancer (NSCLC) cells. Together, these effects of SR16388 can lead to the reduction of vascularization and tumor growth in vivo.

Silicon nanowire Schottky junction solar cells have been fabricated using n-type silicon nanowire arrays and a spin-coated conductive polymer (PEDOT). The polymer Schottky junction cells show superior surface passivation and open-circuit voltages compared to standard diffused junction cells with native oxide surfaces. External quantum efficiencies up to 88% were measured for these silicon nanowire/PEDOT solar cells further demonstrating excellent surface passivation. This process avoids high temperature processes which allows for low-cost substrates to be used.

Fibronectins, involved in cell-matrix interactions and cell attachment, are glycoproteins which show a remarkable heterogeneity, due to alternative splicing. The type III-related domains, ED-A and ED-B, are present in cellular fibronectin in a variety of ratios whereas they are absent in circulating plasma fibronectin. Fibronectin synthesis by hepatocytes which are accepted as suppliers of plasma fibronectin was studied in primary cultures during a 6-day culture period. Using site-specific antibodies we demonstrate that rat hepatocytes are also able to synthesize and secrete fibronectin bearing the ED-A domain from Day 3 on after inoculation. By immunocytological characterization of the hepatocyte monolayer with antibodies directed against desmin, laminin, collagen IV, alpha-SM-actin, or ED-1 or factor VIII-related antigen, contaminating mesenchymal hepatic cell-types as a source for cellular fibronectin production could be ruled out. Dexamethasone treatment caused enhanced fibronectin synthesis and cellular fibronectin was already detectable at Day 1 after plating. Elevation of cellular fibronectin synthesis after prolonged culture-terms and by dexamethasone could also be demonstrated on mRNA steady-state level, using ED-A cDNA as a probe in hybridization analysis. Dot blot hybridisation proved a prominent response of cellular fibronectin mRNA level to dexamethasone at Day 1 when dexamethasone treatment resulted in an increased contribution of ED-A-positive fibronectin transcripts to total fibronectin mRNA level.

Between August 1983 and December 1988, 47 patients with metastatic testicular tumours (44 non-seminomatous, three seminomas) were treated with two to six courses of bleomycin, etoposide, cisplatin and vincristine (BEPV). Five stage I tumours were included, three because of raised tumour markers following orchidectomy, one with vascular invasion of spermatic cord vessels and the other with both these features. Forty-four patients (93.6%) are alive and disease free 12–75 months (median 39 months) after completion of BEPV. Further treatment was necessary in 12 of the survivors. Eight had residual disease excised, one of whom received radiotherapy, one additional chemotherapy and one both radiotherapy and chemotherapy. Of the remaining four, two had radiotherapy and two second line chemotherapy. Thirty-one non-seminomatous and the three seminoma patients had small volume disease and all are in complete remission. Ten of the 13 patients with bulky disease are alive. It is concluded that BEPV is a well-tolerated, effective, first line therapy for patients with metastatic testicular tumour.

To determine nonscorbutic effects of moderate vitamin C deficiency we measured immune function and oxidative damage in eight healthy men (25-43 y) who consumed 5-250 mg/d of ascorbic acid over 92 d on a metabolic unit. During ascorbic acid intakes of 5, 10, or 20 mg/d, subjects attained a state of moderate ascorbic acid deficiency as ascorbic acid concentrations in plasma, leucocytes, semen, and buccal cells dropped to less than 50% of baseline with no scorbutic symptoms observed. No changes in cell proliferation, erythrocyte antioxidant enzymes, and DNA strand breaks were observed; however, blood levels of glutathione and NAD(P) decreased during ascorbic acid deficiency, as did delayed hypersensitivity responsiveness. Concentrations of the oxidatively modified DNA base, 8-hydroxydeoxyguanosine in sperm DNA and fecapentaenes, ubiquitous fecal mutagens, were increased during ascorbic acid depletion. Moderate vitamin C deficiency, in the absence of scurvy, results in alteration of antioxidant chemistries and may permit increased oxidative damage.

Methods of sampling lake phosphorus and chlorophyll concentrations were assessed by comparing mean values for 16 lake basins in southern Quebec. Integrating tube and discrete-depth samples were analyzed to yield six different subsurface, depth-integrated, and volume-weighted average values representing epilimnetic, euphotic, and trophogenic zones. The different protocols were found to be similarly precise. Epilimnetic samples yield low values, while trophogenic samples yield high ones; however, the differences in protocol accounted for less than 50%. Analysis of variance associated most of the uncertainty in these estimates with lake and sampling date and showed that sampling site rarely had a significant effect. Year had only a minor effect, but interannual variation is probably underestimated, since these data represent only two years. These patterns suggest that representative sampling for a given lake requires only a single sample per visit but several visits within a season. Since chlorophyll varied more spatially than phosphorus, sampling protocol affects its estimates to a greater extent. Phosphorus–chlorophyll regressions based on data collected in different ways were very similar, so differences in protocol and sampling depth seem unlikely to contribute to the high uncertainty in existing phosphorus response models.

(1991). Short-term sorption of chlorinated benzenes by concentrated seston. SIL Proceedings, 1922-2010: Vol. 24, No. 4, pp. 2302-2306.

Systematic variations in methods for the storage, digestion and measurement of lake water samples for phosphorus determinations show that these methods are very robust. Frozen samples can be kept for at least one year without any detectable change in total phosphorus, [TP], but the concentrations of P subfractions may change. Variations in the amount of oxidant (0.05 to 0.8 g potassium persulphate/40 ml sample), in the duration (10–90 min), or pressure (100 vs 200 k Pa) of oxidation, and in the amount of sample lost in autoclaving had no effect on estimated [TP]. The exact composition of acid molybdate “mixed reagent” also proved not to be critical, for when each of the components was varied in turn, similar results were obtained with 5 to 10 g ammonium molybdate, 2.5 to 20 g ascorbic acid, 0.025 to 0.4 g potassium antimony tartrate and 55 to 100 ml sulphuric acid per liter of mixed reagent. No significant difference was obtained by varying the amount of mixed reagent from 1 to 7.5 ml/40 ml sampl...

In a previous paper (1) the effects of particle inertia on the diffusional deposition of Brownian particles onto a surface in viscous, axisymmetric stagnation-point flow were investigated using the method of Brownian dynamics. Following Fernandez de la Mora and Rosner (2), under the conditions of large Schmidt numbers and small Stokes numbers (less than the critical Stokes number), an approximate analytical solution is obtained here that also includes an arbitrary external force acting on the particles. This solution is shown to be in excellent agreement with the results from Brownian dynamics simulations. An important characteristic of these solutions is inertial particle concentration “enrichment” outside the diffusion boundary layer near the adsorbing surface at subcritical Stokes numbers. In general, it is shown that attractive external particle forces only slightly reduce the amount of this enrichment. On the other hand, in the absence of inertia, attractive external particle forces increase the surface flux of particles beyond that for solely diffusional deposition. The combination of inertial particle concentration enrichment and an attractive external particle force leads to a synergistic-type increase in the surface flux of particles beyond that for solely diffusional deposition. Finally, Robinson's theorem (6) is extended to formally prove these results for inviscid-type flows.

The problems of the gas dynamic interactions of two spherical particles and a single spherical particle with a plane wall are reviewed here. The resistance and mobility functions that describe the relationship between the forces and torques acting on the spheres with their translational and angular velocities are summarized for continuum and near-continuum (small Knudsen number) flows. For intermediate and large Knudsen number (free-molecule) flows, these functions are only known in their asymptotic limit of infinitely large interparticle or particle-wall separation distances (isolated particles). Potentially useful analytical and computational methods to treat these regimes are also reviewed.

The volatile anesthetic isoflurane poses a number of experimental challenges in the laboratory. Due to its rapid evaporation, the open conditions of most in vitro electrophysiological recording systems make the determination of actual isoflurane concentrations a challenge. Since the absolute anesthetic concentration in solution is directly related to efficacy, concentration measurements are important to allow comparisons between laboratory and clinical studies. In this study we quantify the sources of isoflurane loss during experimentation and describe a method for the measurement of isoflurane concentrations using gas chromatography and mass spectrometry simultaneous to in vitro electrophysiological measurements. Serial samples of perfused bath solution allowed correlation of isoflurane concentrations with ongoing biological effects. Saturated physiological solutions contained 13.4 +/- 0.2 mM isoflurane and were diluted to desired "nominal" concentrations for experiments. The perfusion system established stable isoflurane concentrations within the bath by 2 minutes. However, bath isoflurane concentrations varied substantially and unpredictably between experiments. The magnitudes of such discrepancies in isoflurane concentrations spanned clinically important levels. Our studies suggest that, despite countermeasures, solution handling significantly impacted the isoflurane content in the tissue bath. The magnitude of these discrepancies appears to necessitate systematic direct measurement of bath isoflurane concentrations during most in vitro conditions.

Cranial nerve visceral afferents enter the brain stem to synapse on neurons within the solitary tract nucleus (NTS). The broad heterogeneity of both visceral afferents and NTS neurons makes understanding afferent synaptic transmission particularly challenging. To study a specific subgroup of second-order neurons in medial NTS, we anterogradely labeled arterial baroreceptor afferents of the aortic depressor nerve (ADN) with lipophilic fluorescent tracer (i.e., ADN+) and measured synaptic responses to solitary tract (ST) activation recorded from dye-identified neurons in medial NTS in horizontal brain stem slices. Every ADN+ NTS neuron received constant-latency ST-evoked excitatory postsynaptic currents (EPSCs) (jitter

Molecular dynamics simulations of phospholipid membranes reveals striking correlations between equilibrium fluctuations of volume and energy on the nanosecond time‐scale. Volume‐energy correlations have previously been observed experimentally at the phase transition between the Lα phase and the Lβ phase, but not in the fluid Lα phase. The correlations are investigated in four membranes, with correlation coefficients ranging between 0.81 and 0.89. An experimentally single parameter test is proposed.

By raising the temperature of a surface above that of the ambient fluid, a temperature gradient that results in a thermophoretic force that repels particles from the surface is created. It has been recommended that this effect be used to reduce the contamination of product surfaces during manufacturing. It has been shown that even modest levels of electrostatic interactions between particles and surfaces can overwhelm the thermophoretic repulsion available by raising the temperature of the surface 10% above that of the ambient fluid. We present an analysis for axisymmetric, viscous stagnation-point flow, extending the work of Friedlander et al. (1988, J. Colloid Interface Sci.125, 351), and show the temperature differences that must be achieved to succeed in preventing particle deposition due to diffusion, gravitation, and electrostatic attraction. Simple algebraic relationships are established that allow for a ready determination of the temperature differences needed to suppress particle diffusional deposition onto surfaces under the action of uniform external forces, such as gravitational and coulombic forces, and a spatially dependent external force, which for this study we have chosen to be the electrostatic image force. These relationships are further verified through approximate analytical and “exact” numerical solutions also given here. Various results of practical interest are discussed. For example, for a flow intensity of 6.67 s−1 in air, an electric field as small as 100 V/cm makes it unlikely that particles with a minimal charge distribution (Boltzmann) will be kept from deposition on a surface by raising the surface temperature 10 or 20% above the ambient temperature. This emphasizes the importance of reducing the electric charge levels of product surfaces during manufacturing.

Exposure of cells of the K-562 erythroleukemia cell line to 4-hydroperoxycyclophosphamide (4-HC), an analog of activated cyclophosphamide, causes a concentration-dependent inhibition of in vitro colony formation by these cells. For investigation of the role of glutathione (GSH) in the metabolism of 4-HC, GSH levels of K-562 cells were modulated by exposing the cells to buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, and/or to GSH ethyl esters. Both the mono- and diethyl esters of GSH were synthesized in our laboratories and their identities were determined by chromatographic methods and fast-atom-bombardment mass spectrometry. An HPLC method including electrochemical detection used for thiol determination was applied for the measurement of GSH esters. Incubation of the cells with BSO depleted GSH levels to approximately 11% of control values and potentiated the cytotoxicity of 4-HC. By contrast, exposure to GSH esters approximately doubled GSH levels and protected the cells against the toxicity of 4-HC. Moreover, when cellular GSH levels were first depleted by BSO exposure and then replenished by incubation with GSH esters, the BSO-associated potentiation of 4-HC cytotoxicity was abolished. The work described herein extends the application of an HPLC method used for thiol determination to the measurement of GSH ethyl esters. In addition, it established that GSH acts as a competitive protecting agent against the in vitro toxicity of 4-HC in the K-562 cell line.

Submicron (≤1μm) particle contamination can produce unacceptably low yields in the manufacture of integrated circuits. Calculations were made to predict deposition velocities of 0·01-lOμm particles, incorporating gravitational, dlffusional, and electrostatic effects. The results were summarized in equations that correlate non-dimensional deposition (Sherwood number) with convective-diffusion (Peclet number) and with electrostatics (Boltzmann and Fuchs charge distributions). These equations were used In conjunction with particle size distributions to predict particle deposition. In a companion paper |25| the predictions were shown to compare well with limited experimental data. To reduce deposition product surfaces should not be electrically charged and, where possible, these surfaces should be at higher temperatures than the ambient gas. For quality control purposes, the deposition flux predictions could serve to link the specifications of gas cleanliness with the specifications of surface cleanl...

A series of 9 alpha-halo-12 beta-hydroxy and 12 beta-acyloxy analogues of betamethasone 17,21-dipropionate were synthesized and tested for topical antiinflammatory potency in the croton oil ear assay. The compounds were assayed for systemic absorption in the contralateral ear assay, in which it was found that 12 beta-hydroxy analogues 9, 13, and 15 were all absorbed but the corresponding 12 beta-esters 11a-e, 14, and 16 were not. On repeated high-dose applications to the mouse ear, there was no evidence of systemic absorption of any 12 beta-propionate ester as gauged by thymus weights (thymic involution) and plasma cortisol levels (adrenal suppression). Results of limited SAR studies showed that topical antiinflammatory activity and systemic absorption were not greatly influenced by the 9 alpha-halogen but were largely dependent on the polarity and size of the 12 substituent. While the optimal compounds 14 and 16 were less topically active than the controls beta- and beclomethasone dipropionate, unlike the controls, they displayed no systemic effects, even after repeated high-dose applications. Surprisingly, propionate 14 was devoid of atrophogenic activity.

Cellular fibronectin (Fn) bearing an alternatively spliced extra type III structural repeat (ED1) is normally present at low concentrations in blood plasma. The source of this material remains uncertain. In this study, primary cultures of human umbilical vein endothelial cells (HUVEC) labeled with 35S-methionine were observed to synthesize Fn monomers both with and without this segment. Monomers isolated from cell lysates with antibodies to the ED1 sequence comigrated in nonreduced sodium dodecyl sulfate polyacrylamide gel electrophoresis with the slower (designated M1), but not the faster (designated M2), of two major monomeric populations that were recognized by antibodies raised to plasma-derived Fn. The differences between M1 and M2 were not due to glycosylation, since they were also observed between species of Fn monomer purified from cells grown in the presence of tunicamycin. M1 and M2 were both observed to incorporate with a similar rate into dimeric Fn, indicating that Fn monomers with and without the ED1 site can dimerize with similar efficiency. Analysis of reduced samples of Fn isolated from cells with anti-ED1 antibodies indicated the presence of both M1-M1 and M1-M2 dimers. In addition to being incorporated into extracellular matrix, ED1 + Fn was observed to be secreted in soluble form into the medium, potentially reflecting intravascular release of this protein by endothelial cells in vivo.

Contains fulltext : 51504.pdf ( ) (Open Access) BACKGROUND: Glutathione is a tripeptide composed of glutamate, cysteine and glycine, accomplishing a broad range of vital functions. Synthesis of glutathione and cysteine is performed mainly in the liver, whereas most other tissues are supplied with these thiols via sinusoidal efflux into the blood. Since canalicular efflux also occurs, thiols may be present in human bile. However, thiol composition of human gallbladder bile is largely unknown, which makes it difficult to speculate on the exact function of thiols in bile. In this study we report on the levels of non-protein bound thiols in gallbladder bile of patients with various gastrointestinal disorders. METHODS: Gallbladder bile was obtained after cholecystectomy from 30 patients who were operated for pancreatic cancer, duodenal cancer, chronic pancreatitis or cholecystolithiasis. Bile was analysed for non-protein bound total- and oxidised glutathione and related thiols, by high performance liquid chromatography. RESULTS: A more than 100-fold inter-individual variation in non-protein bound thiol levels was found in human gallbladder bile of patients with a variety of gastrointestinal disorders. Bile did contain high amounts of cysteine, whereas much lower levels of glutathione, cysteinylglycine and homocysteine were detected. Most thiols were present in their oxidised forms. CONCLUSION: Thiols are present in considerable amounts in human gallbladder bile of patients with various gastrointestinal disorders, levels of cysteine being much higher than those of glutathione and other thiols. Most thiols were in their oxidised forms, which may indicate the presence of considerable chemical- or oxidative stress in the patients studied here.

Endocrine therapy is the ideal treatment choice for estrogen receptor alpha (ERalpha)-positive breast cancer patients. Principal used therapies target either the ERalpha e.g. by selective ERalpha modulators (SERMs) such as tamoxifen or target estrogen biosynthesis with aromatase inhibitors. Steroid sulfatase (STS) plays a crucial role in formation of compounds with estrogenic properties, converting inactive sulfate-conjugated steroids to active non-conjugated forms. Steroid sulfates are considered as a reservoir for active steroids due to their prolonged half-life and increased concentration in plasma. STS is present in several tissues including the breast, and the STS the mRNA level and enzyme activity is significantly increased in ERalpha-positive breast tumors. Inhibition of STS is therefore a new approach for decreasing estrogenic steroids that stimulate breast cancer. The novel dual-acting compound SR 16157 is designed as a sulfamate-containing STS inhibitor that releases a tissue-selective SERM SR 16137. Use of a dual-target STS inhibitor and SERM represents a new strategy in the treatment of hormone-dependent breast cancer. In this study, we tested the potential of SR 16157 and SR 16137 on STS activity, cell growth and ERalpha function in MCF-7 breast cancer cells. We confirmed that the dual-target compound SR 16157 exerts STS inhibition and antiestrogenic effects. SR 16157 was a highly effective growth inhibitor, being 10 times more potent than the antiestrogens SR 16137 and tamoxifen. Relative to tamoxifen, SR 16137 displays profoundly improved ERalpha binding affinity and antiestrogenic effects on expression of estrogen-regulated genes. Thus, the dual-target SR 16157 is possibly a promising new treatment alternative, superior to tamoxifen.

In this study, the simultaneous roles of transport, diffusion, and surface kinetic uptake of liposome (Lip-FD), adenoviral (AD-Cy2), and liposome-adenoviral complex (lip-FD-Ad) particles by a non-small cell human lung cancer (A549) were examined through a coupling of in vitro experimental and mathematical modeling techniques. Experimentally, quantitative fluorescence spectroscopy was used to monitor time dependent particle uptake rates including low temperature (5 degrees C) conditions where endocytosis could be inhibited. Mathematically, analytic solutions to the Brownian particle diffusion equation with Langmuir type boundary conditions for the adsoprtion, desorption, and endocytosis process, were obtained for both unsteady and steady-state (no endocytosis) conditions. By direct comparisons of experimental data to model solutions, the adsorption constants, desorption constants, and number of cell surface receptor sites were determined for all particle types considered. It was found that the particle adsorption and desorption constants were of the same order of magnitude compared to earlier studies (Singh, M., T. Ghose, G. Faulkner, and M. Mezei. Cancer Res. 49:3976-3984, 1990.) using different cell lines, particle types, and methodologies. Also in agreement with previous studies using differing cell lines and methodologies (Miller, C. R., B. Boundurant, S. D. McLeon, K. A. McGovern, and D. F. O'Brien. Biochemistry 37:12875-12883, 1998; Perry, D. G., and W. J. Martin II. J. Immunol. Methods 181:269-285, 1995; Muller, W. J., K. Zen, A. B. Fisher, and H. Shuman. Am. J. Physiol. L11-L19, 1995), the number of cell surface receptor sites was predicted to be several orders of magnitude higher for liposome and liposome-viral complex than for viral particles alone, suggesting a nonspecific or nonrestrictive binding pattern for liposomes and liposome complexes and a specific or restrictive binding pattern for viral particles. The surface kinetic constants obtained here for the A549 cells may be useful in physiological modeling or pharmacokinetic applications of chemical or genetic carrying particles in the treatment of lung cancer and other lung diseases. Furthermore, the methodologies given here are straightforward and can be applied to other particle-cell uptake systems.

We have previously reported that intraceliac infusion of leptin induces a reduction of meal size that depends on intact vagal afferents. This effect of leptin is enhanced in the presence of cholecystokinin (CCK). The mechanisms by which leptin and CCK activate vagal afferent neurons are not known. In the present study, we have begun to address this question by using patch-clamp electrophysiological techniques to examine the mechanisms by which leptin and CCK activate cultured vagal afferents from adult rat nodose ganglia. We found that leptin depolarized 41 (60%) of 68 neurons. The magnitude of membrane depolarization was dependent on leptin concentration and occurred in both capsaicin-sensitive and capsaicin-insensitive neurons. We also found that a majority (16 of 22; 73%) of nodose neurons activated by leptin were also sensitive to CCK. CCK-induced depolarization was primarily associated with the increase of an inward current (11 of 12), whereas leptin induced multiple changes in background conductances through a decrease in an outward current (7 of 13), an increase in an inward current (3 of 13), or both (3 of 13). However, further isolation of background currents by recording in solutions that contained only sodium or only potassium revealed that both leptin and CCK were capable of increasing a sodium-dependent conductance or inhibiting a potassium-dependent conductance. Our results support the hypothesis that vagal afferents are a point of convergence and integration of leptin and CCK signaling for control of food intake and suggest multiple ionic mechanisms by which leptin and CCK activate vagal afferent neurons.

Experiments are reported on convective boiling of water in a system of parallel micro-channels with a constant wall heat flux and highly sub-cooled inlet flow. The test section comprises a nickel plate containing ∼388 micro-channels along the center-plane with a mean hydraulic diameter of 145 μm with and a mean separation of 35 μm. The data set spans wall heat fluxes from 94 to 152 kW/m2, 8 < G < 24 kg/m2-s, and 2 < Re < 40. These parameters produce Weber, capillary and boiling numbers one to two orders of magnitude below those of the current published database. Overall heat transfer coefficients in flow boiling are estimated in the range 65 to 325 kW/m2-K. The present experiments more nearly emulate conditions for practical micro-channel heat exchangers compared to those of reported studies using artificially induced two-phase flows and either one or several micro-channels.

100 Gb/s transmitters and receivers are realized through the monolithic integration of over 50 discrete functions onto a single InP chip. The modules are capable of simultaneously transmitting and receiving 10 DWDM wavelengths at >10 Gb/s.

An edge-coupled high-speed photodiode based on strained InGaAs quantum wells for detection at 2000nm is demonstrated. The fabricated device shows a leakage current as low as 120nA at −3V bias voltage and a responsivity of around 0.3A/W at 2000nm. The high-speed butterfly packaging of the device is presented which shows a 3dB bandwidth of more than 10GHz. The device shows similar high-speed performance at 1550nm.

Ranolazine is a clinically approved anti-anginal drug with potential antiarrhythmic, antiepileptic, and analgesic applications. The therapeutic effects of ranolazine are dependent on its ability to preferentially inhibit persistent currents in a variety of voltage-gated sodium channels. Extracellular acidosis, as occurs during ischemic events, may alter the interaction between ranolazine and the channel. In this study, we performed whole-cell patch clamp experiments with extracellular solution titrated to pH 7.4 or pH 6.0 using HEK cells expressing NaV1.5 and CHO cells expressing NaV1.2. We found that ranolazine modulates these sodium channels with onset/recovery kinetics and voltage-dependence resembling slow inactivation. In this way, ranolazine increases use-dependent inactivation of the channel and decreases window currents. At pH 6.0, ranolazine interaction with the sodium channel is slowed approximately 4-5 fold in both NaV1.2 and NaV1.5. Despite the slowed kinetics, ranolazine remains effective at steady-state during acidic conditions. At low extracellular pH ranolazine rescues the voltage-dependence of slow inactivation at a therapeutically relevant concentration (10µM). Our results suggest that, at pH 6.0, ranolazine compensates for proton-induced impaired slow inactivation and remains effective at reducing persistent currents.

The alternatively spliced and highly conserved EIIIA domain of fibronectin (FN) is included in most FN of the extracellular matrix in embryos. In adults, both extracellular matrix and plasma FN essentially lack EIIIA. In diverse inflammatory situations however, EIIIA is specifically included by regulated RNA splicing. In atherosclerotic lesions, FN, including the EIIIA domain (EIIIA-FN), is abundant, whereas FN in the flanking vessel wall lacks EIIIA. Lesional EIIIA-FN is localized with endothelial cells and macrophage foam cells. To directly test the function of EIIIA-FN, we generated EIIIA-null (EIIIA–/–) mice that lack the EIIIA exon and crossed them with apolipoprotein E (ApoE)–null (ApoE–/–) mice that develop arterial wall lesions. Compared with ApoE–/– controls, EIIIA–/–ApoE–/– mice had significantly smaller lesions throughout the aortic tree. EIIIA-FN was increased in ApoE–/– plasma, and total plasma cholesterol was reduced in EIIIA–/–ApoE–/– mice, specifically in large lipoprotein particles, suggesting a functional role for plasma EIIIA-FN. To assess a role for macrophage EIIIA-FN in the vessel wall, we conducted in vitro foam cell assays. EIIIA–/–ApoE–/– macrophages accumulated significantly less intracellular lipid than control ApoE–/– cells. These results provide genetic evidence that suggests roles for EIIIA-FN in plasma lipoprotein metabolism and in foam cell formation.

New techniques have emerged for the detection of bacteria in blood, because the blood culture as gold standard is slow and insufficiently sensitive when the patient has previously received antibiotics or in the presence of fastidious organisms. DNA-based techniques, hybridisation probes, and PCR-based detection or protein-based detection by mass spectroscopy are aimed at rapid identification of bacteria and provide results within 2 h after the first signal of growth in conventional blood cultures. Also, detection of microorganisms directly in blood by pathogen-specific or broad-range PCR assays (eubacterial or panfungal) shows promising results. Interpretation is complex, however, because of detection of DNA rather than living pathogens, the risk of interfering contamination, the presence of background DNA in blood, and the lack of a gold standard. As these techniques are emerging, clinical value and cost-effectiveness have to be assessed. Nevertheless, molecular assays are expected eventually to replace the current conventional microbiological techniques for detection of bloodstream infections.

Electron beam deposition (EBD) is a maskless technique suitable for the fabrication of nanometer scale structures. Metals can be deposited from an organometallic gas, but simultaneous carbon deposition typically yields grossly impure (∼25% metal) deposits. We have found that the metal content of the deposited solid is dramatically improved by performing the whole EBD process in a reactive gaseous environment containing a source of oxygen (O2 or H2O) in addition to the organometallic gas. With simple procedures we prepared Au deposits showing significantly diminished C content (up to 50% metal) as the partial pressure of O2 (or H2O) is increased in the gas.

Vertical cavity surface-emitting lasers originally designed for room temperature operation are operated at 77 K. At this temperature, the gain peak and the cavity mode do not overlap. However, due to joule heating, at high biasing levels they come back into alignment and high single-mode output powers and large modulation bandwidths are observed. >

The study uses data from the National Family Health Survey-II, a nationally representative survey from India of 92,486 households, to investigate the association between household tobacco and alcohol use, and child health. The study findings show that children from households that use tobacco or alcohol were less likely to be immunized, more likely to have acute respiratory tract infection, more likely to be malnourished, and more likely to die before first birthday, even after controlling for other socio-economic and demographic characteristics. Policies and programs for child survival may also need to incorporate strategies to control household tobacco and alcohol use in addition to other ongoing interventions.

(R,S)-Mevalonolactone-2-13C reactant: 4.40 g (0.050 mol) of 4-hydroxy-2-butanone catalyst: 13.9 g (0.060 mol) of freshly prepared silver oxide reactant: 12.0 g (0.070 mol) of benzyl bromide intermediate: 4-benzyloxy-2-butanone reactant: 0.439 g (0.00720 mol) of acetic acid-2-13C intermediate: 0.519 g (0.00217 mol) of 5-benzyloxy-3-hydroxy-3-methylpentanoic acid-2-13C product: mevalonolactone-2-13C Keywords: addition, to CO; alkylation, O-alkylation; annulation, heterocyclic-[6]; cleavage, dealkylation; cyclization, reductive cyclization; reduction, miscellaneous; acetic acid-2-13c, drying of; assay methods, for butyllithium, with 2-butanol, menthol, 2-pentanol, or 2-propanol, 1,10-phenanthroline indicator; assay methods, for butyllithium, with diphenylacetic acid; diisopropylamine; silver oxide, preparation; tetrahydrofuran; toluene; benzyl bromide; hydrogenation catalysts; tetrahydrofuran, purification; apparatus, for catalytic hydrogenation

Ranolazine is an anti-anginal drug previously shown to block persistent currents of the cardiac voltage gated sodium channel, NaV1.5. The effects of ranolazine, however, have not yet been described in all sodium channel isoforms. We studied the effects of ranolazine on the neuronal sodium channel isoform, NaV1.2, and its modulation by extracellular protons. Ionic currents were measured from Chinese Hamster Ovary (CHO) cells expressing the α-subunit of NaV1.2, using whole cell patch clamp techniques. Voltage protocols were run with extracellular solutions of pH 7.4 and pH 6.0 before and after the addition of ranolazine. The addition of 100 μM ranolazine at pH 7.4 led to a significant decrease in late sodium current, faster rate of open state fast inactivation, and slower recovery from inactivation. Similar trends were seen in preliminary experiments at 10 μM and 30 μM ranolazine. In addition, we observed a tonic block of peak current and an increase in total use-dependent block. Many of these effects were different at low pH. Low pH led to a significant depolarizing shift of the conductance curve, and slowed the onset of fast inactivation. Adding ranolazine at pH 6.0 significantly decreased the rate of fast inactivation recovery, and increased the total use-dependent block and rate of open state inactivation. Although directions of the effects were unchanged, the magnitude of these effects was significantly different between the two pH values. Our results suggest that ranolazine stabilizes fast inactivation at both pH 7.4, and pH 6.0. It is possible that ranolazine and protons may compete for a common binding site or indirectly interact leading to decreased ranolazine efficacy at low pH. (Supported by a research grant from Gilead Sciences, Inc. and an NSERC Discovery Grant to PCR, and an NSERC URSA to CHP.)

High-yield, reliable electrically pumped index-guided vertical cavity lasers with diameters less than 4 microns have been fabricated using low resistance, alloyed, ring contact metallization. Existing metallization schemes used for bottom emitting vertical cavity lasers (VCLs) tend to be highly resistive, since the top metallization layer serves the dual purpose of mirror and electrical contact. This results in acceptable performance for large diameter devices, but poor performance for smaller devices that operate at higher current densities. Low resistance alloyed ring contacts have been developed for small bottom emitting VCLs that maintain the required optical properties while dramatically improving the electrical properties. >

Contacts have been made to p- and n-type layers on opposite sides of the active region within the cavity of an InGaAs vertical cavity surface emitting laser. The two concentric ring contacts allow all electrical connections on and emission from the top surface of a semi-insulating GaAs substrate. The design includes a novel current leveling layer to minimize current crowding effects. A high external quantum efficiency of 46% has been measured with maximum output powers up to 6 mW for a 15 /spl mu/m diameter device and threshold currents of 0.72 mA for a 7 /spl mu/m diameter laser. >

Modifications to the epitaxial growth of vertical-cavity surface-emitting laser (VCSEL) material have recently led to improved characteristics. By offsetting the quantum-well gain peak from the cavity mode, and implementing lower barrier p-type Al/sub 0.67/Ga/sub 0.33/As/GaAs DBR mirrors with parabolic interface gradings, better high-temperature operation and lower voltages have been achieved. These effects combine to yield a peak wall plug efficiency of 17.3% for room temperature, CW operation. >

Background: Barrett's Esophagus (BE) is a precancerous lesion in which the normal squamous epithelium of the esophagus undergoes columnar metaplasia as a result of protracted duodeno-esophageal reflux. Bile acid (BA) both conjugated and unconjugated at an acidic pH, forms the chief component of reflux and has the ability to affect cellular processes by virtue of its anionic detergent action or acting as a signaling molecule. Previously, our group had shown that the esophageal squamous epithelium loses the expression of genes involved in squamous differentiation following exposure to a cocktail containing conjugated and unconjugated BA at pH5. In this study, we aimed determining which BA component, whether conjugated or unconjugated, predominantly contributed to the down-regulation of squamous differentiation. Methods: Human telomerase-immortalized primary esophageal squamous cells (EPC1) were grown on polyester transwells and treated separately with conjugated or unconjugated BA at both pH7.4 and pH5, in 15 min pulses three times a day for six days. Trans-epithelial Electrical Resistance (TEER) was measured daily, and at the end of the treatment cells were harvested for mRNA and protein. Results: Unconjugated BA at pH5 reduced the expression of genes involved in squamous differentiation as well as the TEER in the EPC1 in transwells culture, whereas conjugated BA did not have any significant effect. Moreover, unconjugated BA at pH5 induced the expression of FGF-19, a transcription target of BA nuclear receptor FXR. Conclusions: Unconjugated BA at pH5 is unionized and can penetrate through cell membrane to enter EPC1 cells. On the other hand, EPC1 cell membrane is impermeable to conjugated BA due to the absence of apical BA transporters. Since the anionic detergent properties of BA increases with conjugation and ionization, these results implicate a possible intracellular signaling mechanism of action of BA to reduce the squamous differentiation in primary esophageal cells, as opposed to detergent action. Long term gastric acid suppression therapy might be putting patients at risk to BA induced altered cellular differentiation, as the therapy is known to increase bacterial deconjugation of BA.

Brugada Syndrome (BrS) is an inherited cardiac arrhythmia implicated in SIDS and sudden death in young men. BrS is caused by loss-of-function mutations in the cardiac voltage-gated sodium channel NaV1.5. The decrease in sodium current can lead to electrical abnormalities in the ventricular action potential that can degenerate into ventricular tachycardia. The ECG phenotype and electrical abnormalities associated with BrS are not always present and are often unmasked clinically with sodium channel blockers. Paradoxically, BrS associated arrhythmias manifest during and after exercise as well as in sleeping infants. We hypothesize that one trigger for arrhythmias in BrS may be extracellular acidosis, which can occur during both exercise and sleep apnea. We used whole-cell patch clamp to characterize 3 BrS mutants, R376H, R1193Q, and E1784K, at pH 7.4 and pH 6.0. At pH 7.4 all mutants have reduced current compared to WT channels and there are changes in channel activation and fast inactivation. At pH 6.0, E1784K showed the largest proton-dependent effect with a 20 mV depolarizing shift in the midpoint voltage of activation compared to the 12 mV shift in WT. All 3 mutants showed decreased function at pH 6.0 although the magnitude of the shifts was not always different from WT. Overall, extracellular acidosis would be expected to challenge already decreased sodium currents, particularly in the E1784K mutant. Therefore, acidosis may be one of the triggers for arrhythmia in BrS patients.