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Data analysis is carried out for four detector stacks composed of passive Lexan polycarbonate detectors exposed in space by the Ultra Heavy Cosmic Ray Experiment on board NASA’s Long Duration Exposure Facility. Scanning and analysis of the 0.21 m2detector area resulted in the finding of 72 ultra heavy (68 ≤ Z ≤ 96) cosmic ray nuclei. About 15% of the cosmic ray nuclei show charge fragmentation within the detector stack of 5.6 g × cm–2. A detailed analysis of these fragmented cosmic ray nuclei is presented, including a discussion within the context of “physical anomalons”. This last term, describing a sub-set of all anomalon phenomena, is defined in the text.

The aluminum industry generates large quantities of red mud during the beneficiation of bauxite ore. The red mud is disposed of as a waste in dry or wet form. Given the issues with its disposal due to the large volume and high alkalinity, many research groups and industries have examined the use of red mud for different applications. The use of red mud as a pre-catalyst for the cracking of hydrocarbon leads to hydrogen formation and carbon deposition. Our earlier studies have shown its activity for reaction with methane and the formation of magnetic materials containing iron, iron carbide, and nanocarbon species. In this study, two aspects were studied: one was methane cracking over red mud, modified red mud, and waste from a nailwork factory site and the other was the application of different hydrocarbons, including nitrogen-containing precursors over red mud. Preliminary characterization of the resulting carbon deposits was performed. The activity for methane cracking increased when the red mud was activated and reduced before the reaction. Nitrogen-containing reactants led to the formation of nitrogen-doped carbon nanotubes. The nitrogen amount and morphology varied with the precursor used and the reaction temperature. This is an attractive application with potential for further modification of the carbon deposits for other catalytic and electrochemical applications.

Adenosine, an important signaling molecule in asthma, produces bronchoconstriction in asthmatics. Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating A1 adenosine receptors (ARs). Effects of L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxyethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione] a water-soluble, small molecule A1 AR antagonist were investigated on early and late phase allergic responses (EAR and LAR) in a hyper-responsive rabbit model of asthma. Rabbits were made allergic by intraperitoneal injections of house dust mite [HDM; 312 allergen units (AU)] extract within 24 h of their birth. Booster HDM injections were given weekly for 1 month, biweekly for 4 months, and continued monthly thereafter. Hyperresponsiveness was monitored by measuring lung dynamic compliance (Cdyn), after histamine or adenosine aerosol challenge in allergic rabbits. Hyper-responsive rabbits were subjected to aerosol of HDM (2500 AU), 1 h after intragastric administration of L-97-1 (10 mg/kg) solution or an equivalent volume of saline. Cdyn was significantly higher after treatment with L-97-1 compared with untreated controls (p < 0.05 n = 5). Histamine PC30 was significantly higher (p < 0.05; n = 5) after L-97-1 at 24 h compared with histamine PC30 at 24 h after HDM. Adenosine PC30 was significantly higher at 15 min and 6 h after L-97-1 compared with control (p < 0.05; n = 5). L-97-1 showed strong affinity for human A1 ARs in radioligand binding studies and no inhibition toward human phosphodiesterase II, III, IV, and V enzymes. These data suggest that L-97-1 produces a significant reduction of histamine or adenosine-induced hyper-responsiveness and HDM-induced EAR and LAR in allergic rabbits by blocking A1 ARs and may be beneficial as an oral therapy for human asthma.

Ezetimibe is a novel selective inhibitor of intestinal cholesterol absorption, which has been shown to significantly decrease low‐density lipoprotein cholesterol (LDL‐C). In this article, the relationship between plasma ezetimibe concentrations and lowering of LDL‐C is determined using Emaxand regression models. Data from two phase II doubleblind placebo‐controlled studies (n = 232 and 177) were used in which daily doses of ezetimibe ranging from 0.25 to 10 mg were administered for 12 weeks. Ezetimibe concentrations correlated significantly with percentage change in LDL‐C from baseline (%LDL‐C). Reductions in %LDL‐C of 10%, 15%, and 20% were achieved with concentrations in the ranges 0 to 2, 2 to 15, and ® 15 ng/ml, respectively, as compared with placebo. To achieve ® 15% reduction in LDL‐C, patients need to maintain trough concentrations ® 15 ng/ml, taking plasma concentrations as a surrogate for concentrations at the enterocyte. Based on the doses administered, the 10 mg dose had the highest likelihood of sustaining such concentrations, confirming that a daily 10 mg dose of ezetimibe is an optimal therapeutic dose in the treatment of hypercholesterolemia.

Growth of Nb3Sn layers in multifilamentary composites has been investigated and their superconducting critical temperatures are measured using both resistive and inductive techniques. The growth parameters are discussed in the light of the analytical models of Reddi et al. Results show that for the composites studied, the rate controlling step for Nb3Sn growth is diffusion of tin through grain boundaries of Nb3Sn with the time exponent n determined by both the initial grain size and grain growth. Tc measurements show that for composites with a higher filament number, the width of superconducting transition is broader with no significant change in the onset Tc.

To present a method of quantifying variability in the outcome of a refractive surgical procedure using the SD of the difference between achieved and expected refractive changes. We used this method to determine whether the refractive outcome of radial keratotomy in a first eye is predictive of outcome in the second eye.

SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the “link” model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid Emax PD model. For the 300 mg BID dose, PD parameters were: maximum effect (Emax), 8.1mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC50), 0.87 µg·ml-1; and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple Emax PD model. PD parameters obtained over the dose range were: Emax, 10.3 mmHg; Eo, 2.0 mmHg; and EC50, 0.7 µg·ml-1. These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 µg·ml-1.

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.

A C Josephson effect is now used by several countries as the reference standard for the unit of d.c. voltage. This paper describes the work done at the National Physical Laboratory (NPL), New Delhi in the realization of the unit of volt based on the a.c Josephson effect. A voltage standard at 1 mV level using a Nb-Nb point contact junction has been established and the as-maintained volt based on a bank of standard cells has been intercompared against it using a 1:1000 voltage divider. The experimental set-up used in this comparison and the results of recent measurements are described. The overall uncertainty in assigning the value of emf to a standard cell is about 1 ppm. The as-maintained volt has been found to agree with the Josephson voltage within overall uncertainty.

Attempts were made to obtain intergeneric hybrids between Diplotaxis siifolia, a wild species, and cultivars of Brassica (B. campestris, B. juncea, and B. napus). The crosses showed unilateral incompatibility. When the wild species was used as female parent, pollen germination and pollen tube growth were normal, but hybrid seeds aborted due to post-fertilization barriers. Reciprocal crosses (cultivars as female parent) showed strong pre-fertilization barriers; although pollen grains showed germination, pollen tubes failed to enter the stigma. Hybrids were realized in two of the crosses, D. siifolia x B. juncea and D. siifolia x B. napus, through ovary culture. The hybrids were multiplied in vitro by multiplication of axillary shoots, or somatic embryogenesis. Detailed studies were carried out on the hybrid D. siifolia x B. juncea. F1 hybrids had shrivelled anthers and were pollen sterile. Amphiploids of this hybrid showed 60% pollen fertility and produced seeds upon self-pollination as well as backcross pollination with the pollen of B. juncea.

Human T-cell leukemia virus type I (HTLV-I) gives rise to a neurologic disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the pathogenesis of the disease is unknown, the presence of a remarkably high frequency of Tax-specific, cytotoxic CD8 T cells may suggest a role of these cells in the development of HAM/TSP. Antigen-mediated signaling in a CD8 T-cell clone specific for the Tax(11-19) peptide of HTLV-I was studied using analog peptides substituted in their T-cell receptor contact residues defined by x-ray crystallographic data of the Tax(11-19) peptide in the groove of HLA-A2. CD8 T-cell stimulation with the wild-type peptide antigen led to activation of p56lck kinase activity, interleukin 2 secretion, cytotoxicity, and clonal expansion. A Tax analog peptide with an alanine substitution of the T-cell receptor contact residue tyrosine-15 induced T-cell-mediated cytolysis without activation of interleukin 2 secretion or proliferation. Induction of p56lck kinase activity correlated with T-cell-mediated cytotoxicity, whereas interleukin 2 secretion correlated with [3H]thymidine incorporation and proliferation. Moreover, Tax peptide analogs that activated the tyrosine kinase activity of p56lck could induce unresponsiveness to secondary stimulation with the wild-type peptide. These observations show that a single amino acid substitution in a T-cell receptor contact residue of Tax can differentially signal CD8 T cells and further demonstrate that primary activation has functional consequences for the secondary response of at least some Tax-specific CD8 T cells to HTLV-I-infected target cells.

The effect of the agonist sarafotoxin 6c (S6c), selective for endothelin (ET) receptor subtype B (ETB), on cytosolic free Ca2+ concentrations ([Ca2+]i) was determined by fura-2 methodology using aortic smooth muscle cells (ASMC) isolated from spontaneously hypertensive rats (SHR) and two normotensive strains, Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. The basal [Ca2+]i was significantly higher in the ASMC of SHR (139 +/- 8 nM) than WKY (107 +/- 7 nM) and SD (102 +/- 4 nM) rats. S6c produced concentration-dependent elevations in [Ca2+]i in the ASMC of WKY and SHR, whereas it did not evoke significant increases in the [Ca2+]i levels in the ASMC of SD rats. The peak [Ca2+]i levels observed with maximal concentrations of S6c (500 nM) was higher (P< 0.01) in the SHR (346 +/- 36 nM) than the WKY group (148 +/- 19 nM). The natural nonselective agonist, ET-1, evoked maximal [Ca2+]i in the ASMC of SHR, WKY, and SD rats of 635 +/- 43, 304 +/- 19, and 289 +/- 24 nM, respectively. Depletion of extracellular Ca2+ concentration led to the reduction of the peak [Ca2+]i response to ET-1 by 60 and 40% in the WKY and SHR cells, respectively, whereas the response to S6c remained unaffected. The ETA-selective antagonist, BQ-123 (1 microM), did not affect the [Ca2+]i response to S6c, whereas it attenuated the response to ET-1 by 90 and 70% in the WKY and SHR cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Laminar fluid flow through small tubes and capillaries having frequent changes in cross‐section plays an important role in a number of processes. In the present study the effect of the wave parameters of ¼‐in. and ⅜‐in. nominal diameter rigid, periodically convergent‐divergent (wavy) tubes on the laminar flow‐characteristics was investigated. The value of friction factor increases with decreasing wavelength‐to‐diameter ratios (< 0.5) by as much as 120% of the uniform tube value (wave amplitude‐to‐diameter ratios were in the range 0.13‐0.25). The value of the critical Reynolds number of transition to turbulence decreases with decreasing wavelength‐to‐diameter ratio. For steady, fully developed laminar flow through deep flat channels with wavy sides, the value of friction factor increases with increasing depth‐to‐mean width ratio and obeys the relationship f = m/NRe, where m is a constant. L'écoulement laminaire d'un fluide, dans des tubes petits et capillaires dont la section transversale est soumise à des changements fréquents, joue un rôle important dans un certain nombre de procédés. On a étudié dans le présent travail l'effet, sur les propriétés d'écoulement laminaire, des paramètres d'ondes de tubes (onduleux) rigides de diamètres nominaux de ¼″ et ⅜″ qui étaient périodiquement convergents et digergents. La valeur du coefficient de frottement a augmenté à mesure que les rapports entre la longueur d'on et le diamètre décroissait et cette augmentation a atteint 120% de la valeur du tube uniforme (les rapports entre l'amplitude des vagues et le diamètre ont été dans l'échelle de 0.13 à 0.25). La valeur du nombre critique de Reynolds pour le passage à la turbulence a diminué lorsque le rapport entre la longueur d'onde et le diamètre a décru. Dans le cas d'un écoulement laminaire stable et en plein fonctionnement dans des canaux profonds et plats et dont les côtés étaient onduleux, la valeur du facteur de frottement a augmenté avec le rapport entre la profondeur et la largeur moyenne conformément à la relation f = m/NRe, où m est une constante.

The pharmacokinetics of isepamicin following administration of a 1-g dose were evaluated for 18 healthy male volunteers between the ages of 26 and 38. In a randomized crossover fashion, each volunteer received doses of isepamicin by a 30-min intravenous infusion and as an intramuscular injection. Blood samples were collected at specified times after dosing and assayed for isepamicin by a validated radioimmunoassay method. The individual plasma concentration-time curves were analyzed by noncompartmental methods. In general, the pharmacokinetics after intravenous infusion and intramuscular injection were similar. As expected, the maximum concentration of isepamicin in serum following intramuscular injection (37.2 microg/ml) was lower than the observed concentration at the end of infusion (66.7 microg/ml). The areas under the concentration-time curves from 0 h to infinity following intramuscular and intravenous administration were 164.8 and 154.5 microg x hr/ml, respectively, indicating complete absorption following intramuscular administration. The respective mean terminal-phase half-life (t1/2) values were 2.6 and 3.6 h. Although t1/2 was slightly longer following intravenous infusion, the small difference in the observed t1/2 values was not considered to be clinically significant. Total body clearances following intramuscular injection and intravenous infusion were 1.3 and 1.4 ml/min/kg, respectively, which were similar to renal serum creatinine clearances in healthy volunteers (> 1.14 ml/min/kg). The drug was safe and well tolerated. The results of the present study clearly show complete absorption of isepamicin following intramuscular administration. The similarity in the pharmacokinetics after intravenous infusion and intramuscular dosing would permit interchangeable administration of isepamicin by either route without compromising clinical efficacy.

Twelve healthy adult male volunteers received 1 g (base equivalent) of 14C-isepamicin (131 microCi) as an intravenous bolus over 5 min. The areas under the plasma concentration-time curves at infinity for isepamicin (196 micrograms*h/ml) and total radioactivity (164 micrograms*h/ml) were similar, indicating no biotransformation of isepamicin. The disappearance of isepamicin from plasma followed a triexponential decline, with half-lives of 0.17, 2.12, and 34 h for the alpha, beta, and gamma phases, respectively. However, the contribution of the gamma phase to the total area under the concentration-time curve was only 2.6%. There were no detectable metabolites in plasma and urine, confirming that isepamicin was not biotransformed. The cumulative levels of isepamicin and total radioactivity excretion in urine from 0 to 120 h were 97.3 and 92.1% of the dose, respectively, indicating that the drug was excreted mainly as unchanged isepamicin in urine.

L (SCH 66336), a tricyclic farnesyl protein transferase inhibitor, is being developed for the treatment of various cancers. Three Phase 1 studies with different oral dosing schedules were conducted to explore the safety and to characterize the PK of L. 79 patients received 25-400 mg L, twice daily with food (continuously, 7 days on/21-day cycle, and 14 days on/28-day cycle). Plasma and urine samples were collected and L concentrations were determined by LC-MS/MS. The single and multiple dose PK were determined using model-independent methods. The PK characteristics are: L is absorbed and eliminated slowly after oral administration with food. Mean Cmax occurs between 2.5 and 8 hr; mean t1/2 ranges from 3 to 10 hr.L accumulates in plasma after twice daily dosing. The accumulation factor ranged from 3 to 5, which is greater than predicted by the elimination t1/2.Plasma concentrations increase in a greater than dose-proportional manner.Elimination t1/2 appears to increase and clearance appears to decrease as dose increases and following multiple- vs. single-dose administration.Steady state is attained by Day 7.Urinary recovery of L is less than 0.1% of the dose.These results indicate dose-dependent PK and support the twice daily dosing of L in ongoing clinical trials.Clinical Pharmacology & Therapeutics (2004) 75, P59–P59; doi: 10.1016/j.clpt.2003.11.226

L (SCH 66336), a tricyclic farnesyl protein transferase inhibitor, is being developed for the treatment of various cancers. A single-dose study in healthy volunteers was conducted to evaluate the effects of age and gender on L pharmacokinetics (PK). Subjects, stratified by age and gender into 4 groups (young male, young female, elderly male, and elderly female), received 100 mg L orally in the morning. Plasma samples were collected and L concentrations were determined by LC-MS/MS. Mean (%CV) PK parameters and statistical results are: (see Table 1)Following single-dose administration, age and gender had a significant effect on the AUC(I) of L, but with considerable overlap of the data. The AUC(I) value was 59% higher in elderly vs. young subjects, and was 44% higher in females vs. males. Age and gender had less of an effect on Cmax as compared to AUC. Clinical relevance of this age and gender effect following multiple-dose to patients will be further assessed in clinical trials.Clinical Pharmacology & Therapeutics (2004) 75, P59–P59; doi: 10.1016/j.clpt.2003.11.225