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PubMed1990

Plasma concentrations of remoxipride and the gastrointestinal transit of 111In-marked extended-release coated spheres.

To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in 111In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules within the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again extended distribution of the microcapsules. A mean Cmax of 2.7 microM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 mumol.L-1.hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation.

Administration, Oral↗

PubMed1996

In vitro-in vivo relationship of oral extended-release dosage forms.

PURPOSE: A method to establish the in vitro-in vivo relationship of oral extended-release products is proposed. METHODS: The approach utilizes incremental amounts of drug released and absorbed within defined time intervals, to construct a chi2 distributed variable for testing in vitro-in vivo similarity. RESULTS: A case study is used to demonstrate that the similarities between incremental values of in vivo absorbed and in vivo dissolved fractions are distinguishable for different dissolution profiles despite naturally significant linear correlations between cumulative in vivo absorbed and in vitro dissolved fractions (with different dissolution tests) of an oral extended-release product. CONCLUSIONS: The method enables investigators to compare different in vitro dissolution profiles of an oral extended-release product to find an optimized dissolution profile to be the surrogate of the in vivo release process of the product.

Absorption↗

PubMed2003

Dry powder coating of pellets with micronized Eudragit RS for extended drug release.

PURPOSE: To develop a novel powder coating technology for extended-release pellets based on the acrylic polymer, Eudragit RS. METHODS: A mixture of micronized Eudragit RS plus talc and a liquid feed (plasticizer plus binder solution) were sprayed separately onto propranolol hydrochloride-loaded pellets in a fluidized bed coater. The coated pellets were heat-cured under different conditions (40 degrees C to 60 degrees C, 2 h to 24 h). The coalescence (film formation) of the polymer particles was studied via the determination of the glass transition and the minimum polymer-softening temperatures (MST). The coated pellets were characterized with respect to their morphologic, release, and stability properties. RESULTS: The optimum plasticizer type and concentration and process temperatures could be identified by the determination of the MST. High concentrations of plasticizer (40% based on the polymer) and a thermal treatment were necessary to achieve complete film formation and extended drug release. Curing the pellets resulted in release profiles, which did not change during storage for 3 years. The coated pellets had a smooth, continuous surface and a dense film structure after curing. CONCLUSIONS: This novel coating technique avoids the use of organic polymer solutions or latex dispersions, has short processing times, and results in stable extended-release profiles.

Acrylic Resins↗

PubMed1998

Children's understanding of extended identity.

As adults, we appreciate that judgments of us may reflect our associations with other people. This article examines the development of "extended identity" (G.R. Semin & K. Papadopoulou, 1989) in children between 5 and 11 years. In Experiment 1, children were presented with hypothetical scenarios in which they imagined a close associate had committed a rule violation in a highly public context. Only the older children judged that they would be evaluated negatively through their association with the wrongdoer and that they themselves would feel embarrassment. Given the late appearance of extended identity, Experiment 2 addressed contexts in which the child was responsible for a younger child, so that accountability for the other was explicitly demanded. In such contexts, an appreciation of extended identity appeared earlier than it did in Experiment 1, in which no responsibility for the other was involved.

Child↗

PubMed2005

How does attention select and track spatially extended objects? New effects of attentional concentration and amplification.

Real-world situations involve attending to spatially extended objects, often under conditions of motion and high processing load. The present experiments investigated such processing by requiring observers to attentionally track a number of long, moving lines. Concurrently, observers responded to sporadic probes as a measure of the distribution of attention across the lines. The results revealed that attention is concentrated at the centers of lines during tracking, despite their uniformity, and that this center advantage grew as the lines became longer: Not only did observers get worse near the endpoints, but they became better at the lines' centers, as if attention became more concentrated as the objects became more extended. These results begin to show how attention is flexibly allocated in online visual processing to extended dynamic objects.

Attention↗

PubMed2001

Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans.

In Caenorhabditis elegans, mutations that reduce the activity of an insulin-like receptor (daf-2) or a phosphatidylinositol-3-OH kinase (age-1) favour entry into the dauer state during larval development and extend lifespan in adults. Downregulation of this pathway activates a forkhead transcription factor (daf-16), which may regulate targets that promote dauer formation in larvae and stress resistance and longevity in adults. In yeast, the SIR2 gene determines the lifespan of mother cells, and adding an extra copy of SIR2 extends lifespan. Sir2 mediates chromatin silencing through a histone deacetylase activity that depends on NAD (nicotinamide adenine dinucleotide) as a cofactor. We have surveyed the lifespan of C. elegans strains containing duplications of chromosomal regions. Here we report that a duplication containing sir-2.1-the C. elegans gene most homologous to yeast SIR2-confers a lifespan that is extended by up to 50%. Genetic analysis indicates that the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway. Our findings suggest that Sir2 proteins may couple longevity to nutrient availability in many eukaryotic organisms.

Animals↗

PubMed1990

HLA extended haplotypes in steroid-sensitive nephrotic syndrome of childhood.

Idiopathic nephrotic syndrome has been postulated to have an immunopathogenic basis. To determine whether steroid-sensitive nephrotic syndrome is associated with greater than expected frequencies of specific extended haplotypes of the major histocompatibility complex, we studied genetic markers (Class I, II, III HLA alleles and glyoxalase I) in 173 subjects in 42 families of patients with nephrotic syndrome of childhood. The single allele, DQW2, was found in 72% of steroid sensitive patients compared with only 35% of the controls (P = 0.003). In half of 32 steroid sensitive, but not 10 steroid resistant, patients, one or both of two specific extended haplotypes (alleles that segregate together) were identified. The first, [HLA-A1, B8, DR3, DRW52, SCO1], occurred in 11 of 64 haplotypes, or 17%, compared to 5% of controls (P = 0.017). The other, [HLA-B44, DR7, DRW53, FC31], occurred in 10 of 64 haplotypes, 16% compared to 3.8% of controls (P = 0.014). Five patients had both haplotypes. Patients with these specific extended haplotypes had a greater frequency of relapses than did those with other haplotypes. These data provide additional support for the hypothesis that steroid-sensitive nephrotic syndrome has an immunogenetic basis.

Blotting, Southern↗

PubMed2002

Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration.

Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.

Adenosine Triphosphate↗

PubMed2006

A magnetic reconnection X-line extending more than 390 Earth radii in the solar wind.

Magnetic reconnection in a current sheet converts magnetic energy into particle energy, a process that is important in many laboratory, space and astrophysical contexts. It is not known at present whether reconnection is fundamentally a process that can occur over an extended region in space or whether it is patchy and unpredictable in nature. Frequent reports of small-scale flux ropes and flow channels associated with reconnection in the Earth's magnetosphere raise the possibility that reconnection is intrinsically patchy, with each reconnection X-line (the line along which oppositely directed magnetic field lines reconnect) extending at most a few Earth radii (R(E)), even though the associated current sheets span many tens or hundreds of R(E). Here we report three-spacecraft observations of accelerated flow associated with reconnection in a current sheet embedded in the solar wind flow, where the reconnection X-line extended at least 390R(E) (or 2.5 x 10(6) km). Observations of this and 27 similar events imply that reconnection is fundamentally a large-scale process. Patchy reconnection observed in the Earth's magnetosphere is therefore likely to be a geophysical effect associated with fluctuating boundary conditions, rather than a fundamental property of reconnection. Our observations also reveal, surprisingly, that reconnection can operate in a quasi-steady-state manner even when undriven by the external flow.

Journal Article↗

PubMed2005

High-energy-density extended CO solid.

Covalently bonded extended phases of molecular solids made of first- and second-row elements at high pressures are a new class of materials with advanced optical, mechanical and energetic properties. The existence of such extended solids has recently been demonstrated using diamond anvil cells in several systems, including nitrogen, carbon dioxide and carbon monoxide. However, the microscopic quantities produced at the formidable high-pressure/temperature conditions have limited the characterization of their predicted novel properties, including high-energy content. In this paper, we present experimental evidence that these extended low-Z solids are indeed high-energy-density materials, by milligram-scale high-pressure synthesis, recovery and characterization of polymeric CO (p-CO). Our spectroscopic data reveal that p-CO is a random polymer made of lactonic entities and conjugated C=C with an energy content rivalling or exceeding that of HMX (cyclo-tetramethylene tetranitramine, a commonly used conventional high explosive). Solid p-CO explosively decomposes to CO(2) and glassy carbon, and thus might be used as an advanced energetic material.

Carbon↗

PubMed2005

Decreased motivation following cocaine self-administration under extended access conditions: effects of sex and ovarian hormones.

We have previously shown that following extended access to cocaine, females, but not males, show marked increases in motivation to obtain cocaine, and we have hypothesized that such changes may contribute to long-term compulsive aspects of addiction that result in a persistent vulnerability to relapse. Here, we investigate the effects of extended cocaine access on short-term motivational changes in both male and female rats. An additional goal was to determine whether estrogen modulates motivation to self-administer cocaine in female rats following extended access to cocaine. A discrete trial procedure was used that allowed rats 24-h access to cocaine infusions (1.5 mg/kg) that were available in discrete trials (four, 10-min trials/h) for 7 consecutive days. Motivation to obtain cocaine was assessed by responding under a progressive ratio schedule, and preference for sucrose (1%) vs water was assessed using a two-bottle, 24-h test. Each was assessed prior to and immediately following discrete trial cocaine self-administration. Results showed that following discrete trial cocaine self-administration, both males and females showed a decrease in preference for sucrose, but only females showed a reduction in levels of responding for cocaine under the progressive ratio schedule, suggesting a sex difference in motivation that was specific to cocaine. Subsequent studies with ovariectomized rats showed that estrogen replacement blocked the decrease in motivation to obtain cocaine infusions. Together, these findings suggest that there is a dissociation between sex and the short- vs long-term alteration in motivation to use cocaine. The mechanisms that may underlie these observed sex differences, including the role of estrogen, are discussed.

Animals↗

PubMed2004

Plications of extended ultra-violet circular dichroism spectroscopy in biology and medicine.

Deep ultra-violet circular dichroism is fast becoming an important technique in structural biology. The exponential increase in the number of protein structures deposited in the Protein Data Bank together with programs that extract protein secondary structure from atomic coordinates and the advancement of the software to analyse circular dichroic spectra, have revolutionised the technique. In addition, the extended short wavelength data afforded by synchrotron radiation is set to have a major impact on the development of the area. We have selected three diverse areas of research and development in the biomedical sciences to illustrate the ubiquity of the technique for future applications in the area of biomedical research. For example, the high flux of synchrotron radiation has provided a gold standard for the assay of the lipoprotein HDL in serum which has been proven to reverse the effects of coronary heart disease. In a second example, the high flux of synchrotron radiation enables the recording of millisecond data during the conformational changes in proteins over their spectrum, mapping out changes to protein secondary structure and thus providing absolute structural measurements in the millisecond time regime. In the third example, subtle conformational changes are interpreted from the extended CD spectra on protein drug binding, distinguishing between induced binding effects and the conformational changes in the target protein. The strengths and weaknesses of extended ultra-violet circular dichroism using synchrotron radiation are discussed using these examples as a template.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Characterization of an insulin from the three-toed amphiuma (Amphibia: Urodela) with an N-terminally extended A-chain and high receptor-binding affinity.

Insulin was isolated from an extract of the pancreas of a urodele, the three-toed amphiuma (Amphiuma tridactylum), and its primary structure established as Ala-Arg-Gly-Ile-Val-Glu-Gln-Cys-Cys-His10-Asn-Thr-Cys- Ser-Leu-Asn-Gln-Leu-Glu-Asn20-Tyr-Cys-Asn for the A-chain and Ile-Thr-Asn-Gln-Tyr-Leu-Cys-Gly-Ser-His10-Leu-Val-Glu-Ala- Leu-Tyr-Leu-Val-Cys-Gly20-Asp-Arg-Gly-Phe-Phe-Tyr-Ser-Pro-Lys for the B-chain. The N-terminus of the A-chain is extended by two amino acids (Ala-Arg) relative to all other known insulins suggesting an anomalous pathway of post-translational processing in the region of the C-peptide/A-chain junction of proinsulin. In common with chicken and Xenopus insulins, which contain a HisA8, amphiuma insulin was more potent (approx. 5-fold) than porcine insulin in inhibiting the binding of [125I-TyrA14]insulin to the soluble human insulin receptor from transfected 293EBNA cells (an adenovirus-transformed human kidney cell line). This result is consistent with previous data showing that insulin analogues extended at GlyA1 by uncharged groups have reduced binding affinity whereas high affinity is preserved in analogues extended by basic amino acid residues.

Amino Acid Sequence↗

PubMed1995

Specific language impairment as a period of extended optional infinitive.

English-speaking children with specific language impairment (SLI) are known to have particular difficulty with the acquisition of grammatical morphemes that carry tense and agreement features, such as the past tense -ed and third-person singular present -s. In this study, an Extended Optional Infinitive (EOI) account of SLI is evaluated. In this account, -ed, -s, BE, and DO are regarded as finiteness markers. This model predicts that finiteness markers are omitted for an extended period of time for nonimpaired children, and that this period will be extended for a longer time in children with SLI. At the same time, it predicts that if finiteness markers are present, they will be used correctly. These predictions are tested in this study. Subjects were 18 5-year-old children with SLI with expressive and receptive language deficits and two comparison groups of children developing language normally: 22 CA-equivalent (5N) and 20 younger, MLU-equivalent children (3N). It was found that the children with SLI used nonfinite forms of lexical verbs, or omitted BE and DO, more frequently than children in the 5N and 3N groups. At the same time, like the normally developing children, when the children with SLI marked finiteness, they did so appropriately. Most strikingly, the SLI group was highly accurate in marking agreement on BE and DO forms. The findings are discussed in terms of the predictions of the EOI model, in comparison to other models of the grammatical limitations of children with SLI.

Child↗

PubMed1996

Extended multidrug resistance in haemopoietic cells.

The development of drug resistance was studied in a series of haemopoietic cells to determine its relationship to cell lineage. Treatment of the U937 monocytic cell line with epirubicin (15 ng/ml) or vinblastine (8 ng/ml) induced drug-resistant sublines with cross-resistance to epirubicin (8- and 16-fold respectively), vinblastine (5- and 20-fold), paclitaxel (15- and 42-fold) and etoposide (19- and 13-fold). However, sublines were also 3-5-fold resistant to the alkylating agent chlorambucil, cis-platinum and methotrexate, demonstrating an extended multidrug resistance (MDR) phenotype. These cells over-expressed P-glycoprotein, but decreased drug accumulation was not restored in the presence of verapamil, suggesting that the P-glycoprotein was not functional. Similar drug treatment of the HL60 promyelocytic cell line also produced sublines exhibiting an extended MDR phenotype. The KG1a and the HEL cell lines expressed functional P-glycoprotein and were resistant to the drug concentrations used for treatment. Multidrug resistance as mediated by P-glycoprotein cannot explain the resistance of CML patients to chemotherapy, especially in blast crisis. The induction of an extended MDR phenotype specifically in myeloid cells in response to drug treatment may explain the resistance observed in the treatment of CMI.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Beneficial effects of arterialization of the portal vein on extended hepatectomy.

BACKGROUND: Extended hepatectomy may result in postoperative liver failure. The aim of this study was to evaluate the effects of arterialization of the portal vein on oxygen supply, hepatic energy metabolism and liver regeneration after extended hepatectomy. METHODS: Portal haemodynamics were evaluated 0 or 10 days after arterialization of the portal vein in three experimental groups: 85 per cent partial hepatectomy, 85 per cent partial hepatectomy 10 days after arterialization of the portal vein and 85 per cent partial hepatectomy 10 days after ligation of the hepatic artery. Survival rates, weight of the regenerating liver, levels of adenine nucleotides and hepatic energy charge were assessed. RESULTS: Arterialization of the portal vein caused a significant increase in partial pressure of oxygen and oxygen saturation. Portal blood flow 10 days after arterialization was significantly increased. Survival rate and weight of the regenerating liver in the group with arterialization of the portal vein were significantly higher than those in the other two groups. The group with arterialization of the portal vein showed the highest levels of adenosine 5'-triphosphate. CONCLUSION: The increase in portal blood flow and oxygen supply produced by arterialization of the portal vein has beneficial effects on hepatic energy metabolism and liver regeneration, and leads to improved survival after experimental extended hepatectomy.

Animals↗

PubMed2003

A new extended haplotype Cw0602-B57-DRB10701-DQA10201-DQB10201 associated with psoriasis in the Croatian population.

In this study, we have analysed the distribution of HLA class II alleles and the extended haplotype HLA-Cw-B-DRB1-DQA1-DQB1 in Croatian patients with type I and type II psoriasis by hybridization with specific oligonucleotide probes. Type I psoriasis showed a significant association with the DRB1*0701 [P < 0.00001; relative risk (RR) = 5.83], DQA1*0201 (P < 0.00001; RR = 6.12), DQB1*0201 (P = 0.0006; RR = 3.29) and DQB1*0303 alleles (P = 0.0008; RR = 7.51). A negative correlation with type I disease was observed for the DQA1*0102 allele (P = 0.002; RR = 0.26). Type II psoriasis did not show any association with any class II alleles. The extended haplotype HLA-Cw*0602-B57-DRB1*0701-DQA1*0201-DQB1*0201 was present at a significantly higher frequency in type I patients (P < 0.00001; RR = 7.72). However, this haplotype was not detected at all in patients with type II psoriasis. In conclusion, the extended haplotype HLA-Cw*0602-B57-DRB1*0701-DQA1*0201-DQB1*0201 is a risk haplotype for type I disease in the Croatian population. This particular haplotype has not been reported previously in association with psoriasis in any other ethnic groups.

Alleles↗

PubMed1996

High-resolution physical mapping in Arabidopsis thaliana and tomato by fluorescence in situ hybridization to extended DNA fibres.

A technique to detect DNA sequences on extended DNA fibres (EDF) prepared from interphase nuclei from tomato (Lycopersicon esculentum) and Arabidopsis thaliana leaves by fluorescence in situ hybridization (FISH) is described. Three nuclear lysis procedures have been tested for their ability to decondense chromatin and to generate highly extended intact DNA fibres on microscopic slides. DNA probes of various sizes have been used in FISH experiments to EDFs to establish the resolution and sensitivity of the technique. The fluorescent signals of a 5S rDNA probe hybridized to tomato EDFs revealed continuous strings of about 200 microns, that corresponded to a molecular size of about 660 kb. In A. thaliana, a contig of three cosmids spanning a genomic region with a total length of about 89 kb was analysed. By means of multicolour hybridization the physical positions of the cosmids were visualized as red and green fluorescence strings with overlapping regions in yellow. Comparison of the length of the fluorescent signals with the molecular data revealed a stretching degree of the DNA fibres at 3.27 kb microns-1, which is close to the Watson-Crick DNA length estimate of 2.9 kb microns-1. Other experiments on small size molecular probes with both lambda clones (13.5-17 kb insert sizes) and plasmids (4.2 and 5 kb) in a contig of A. thaliana, and the 5S rDNA region in tomato showed close agreement with molecular data. The lower limit of the detection, which was established in a hybridization experiment with two DNA probes from the 45S ribosomal gene on extended fibres of tomato, was about 0.7 kb. Consistent patterns of alternating fluorescent red and green spots were obtained reflecting the tandemly repeated arrangement of the 18S and 25S ribosomal sequences. On the basis of the microscopic distance between these hybridization spots the size of the ribosomal unit was estimated at 8.2 kb. This implies a drastic improvement of high-resolution physical mapping of DNA sequences by FISH on plant DNA.

Arabidopsis↗