bluuebunny/crossref_metadata_2025 huggingface dataset:
Compared genomics of the strand switch region of Leishmania chromosome 1 reveal a novel genus-specific gene and conserved structural features and sequence motifs
Authors: Puechberty Jacques , Blaineau Christine , Meghamla Sabrina , Crobu Lucien , Pagès Michel , Bastien Patrick
Published: February 2007

Background

Trypanosomatids exhibit a unique gene organization into large directional gene clusters (DGCs) in opposite directions. The transcription "strand switch region" (SSR) separating the two large DGCs that constitute chromosome 1 of Leishmania major has been the subject of several studies and speculations. Thus, it has been suspected of being the single replication origin of the chromosome, the transcription initiation site for both DGCs or even a centromere. Here, we have used an inter-species compared genomics approach on this locus in order to try to identify conserved features or motifs indicative of a putative function.

Results

We isolated, and compared the structure and nucleotide sequence of, this SSR in 15 widely divergent species of Leishmania and Sauroleishmania. As regards its intrachromosomal position, size and AT content, the general structure of this SSR appears extremely stable among species, which is another demonstration of the remarkable structural stability of these genomes at the evolutionary level. Sequence alignments showed several interesting features. Overall, only 30% of nucleotide positions were conserved in the SSR among the 15 species, versus 74% and 62% in the 5' parts of the adjacent XPP and PAXP genes, respectively. However, nucleotide divergences were not distributed homogeneously along this sequence. Thus, a central fragment of approximately 440 bp exhibited 54% of identity among the 15 species. This fragment actually represents a new Leishmania-specific CDS of unknown function which had been overlooked since the annotation of this chromosome. The encoded protein comprises two trans-membrane domains and is classified in the "structural protein" GO category. We cloned this novel gene and expressed it as a recombinant green fluorescent protein-fused version, which showed its localisation to the endoplasmic reticulum. The whole of these data shorten the actual SSR to an 887-bp segment as compared with the original 1.6 kb. In the rest of the SSR, the percentage of identity was much lower, around 22%. Interestingly, the 72-bp fragment where the putatively single transcription initiation site of chromosome 1 was identified is located in a low-conservation portion of the SSR and is itself highly polymorphic amongst species. Nevertheless, it is highly C-rich and presents a unique poly(C) tract in the same position in all species.

Conclusion

This inter-specific comparative study, the first of its kind, (a) allowed to reveal a novel genus-specific gene and (b) identified a conserved poly(C) tract in the otherwise highly polymorphic region containing the putative transcription initiation site. This allows hypothesising an intervention of poly(C)-binding proteins known elsewhere to be involved in transcriptional control.
Aerosolized amikacin for treatment of pulmonary Mycobacterium aviuminfections: an observational case series
Authors: Davis Kala K , Kao Peter N , Jacobs Susan S , Ruoss Stephen J
Published: February 2007

Background

Current systemic therapy for nontuberculous mycobacterial pulmonary infection is limited by poor clinical response rates, drug toxicities and side effects. The addition of aerosolized amikacin to standard oral therapy for nontuberculous mycobacterial pulmonary infection may improve treatment efficacy without producing systemic toxicity. This study was undertaken to assess the safety, tolerability and preliminary clinical benefits of the addition of aerosolized amikacin to a standard macrolide-based oral treatment regimen.

Case Presentations

Six HIV-negative patients with Mycobacterium avium intracellulare pulmonary infections who had failed standard therapy were administered aerosolized amikacin at 15 mg/kg daily in addition to standard multi-drug macrolide-based oral therapy. Patients were monitored clinically and serial sputum cultures were obtained to assess response to therapy. Symptomatic improvement with radiographic stabilization and eradication of mycobacterium from sputum were considered markers of success.

Of the six patients treated with daily aerosolized amikacin, five responded to therapy. All of the responders achieved symptomatic improvement and four were sputum culture negative after 6 months of therapy. Two patients became re-infected with Mycobacterium avium intracellulare after 7 and 21 months of treatment. One of the responders who was initially diagnosed with Mycobacterium avium intracellulare became sputum culture positive for Mycobacterium chelonae resistant to amikacin after being on intermittent therapy for 4 years. One patient had progressive respiratory failure and died despite additional therapy. There was no evidence of nephrotoxicity or ototoxicity associated with therapy.

Conclusion

Aerosolized delivery of amikacin is a promising adjunct to standard therapy for pulmonary nontuberculous mycobacterial infections. Larger prospective trials are needed to define its optimal role in therapy of this disease.
Low back pain education and short term quality of life: a randomized trial
Authors: Tavafian Sedigheh Sadat , Jamshidi Ahmadreza , Mohammad Kazem , Montazeri Ali
Published: February 2007

Background

Different interventions can reduce the burden of the chronic low back pain. One example is the use of a 'Back School Programme'. This is a brief therapy that uses a health education method to empower participants through a procedure of assessment, education and skill development. This study aimed to evaluate to what extent the programme could improve quality of life in those who suffer from the condition.

Methods

This was a randomized controlled trial. One-hundred and two female patients with low back pain (n = 102) were randomly allocated into two groups, matched in terms of age, weight, education, socioeconomic status, occupation and some aspects of risk behavior. Group 1 (back school group, n = 50) but not group 2 (clinic group, n = 52) received the 'Back School Programme'. Then quality of life using the Short Form Health Survey (SF-36) was assessed at two time points: at baseline and at three months follow-up. The findings were compared both within and between two groups.

Results

The 'Back School Programme' was effective in improving patients' quality of life; significant differences were found on all eight subscales of the SF-36 for group 1. In the clinic group (group 2), improvement was observed on three scales (bodily pain, vitality and mental health) but these improvements were less than in group 1. The mean improvement over all eight subscales of the SF-36 was significantly better for the 'Back School Programme' group.

Conclusion

The 'Back School Programme' is an effective intervention and might improve the quality of life over a period of 3 months in patients who experience chronic low back pain.
Phantom investigation of 3D motion-dependent volume aliasing during CT simulation for radiation therapy planning
Authors: Tanyi James A , Fuss Martin , Varchena Vladimir , Lancaster Jack L , Salter Bill J
Published: February 2007

Purpose

To quantify volumetric and positional aliasing during non-gated fast- and slow-scan acquisition CT in the presence of 3D target motion.

Methods

Single-slice fast, single-slice slow, and multi-slice fast scan helical CTs were acquired of dynamic spherical targets (1 and 3.15 cm in diameter), embedded in an anthropomorphic phantom. 3D target motions typical of clinically observed tumor motion parameters were investigated. Motion excursions included ± 5, ± 10, and ± 15 mm displacements in the S-I direction synchronized with constant displacements of ± 5 and ± 2 mm in the A-P and lateral directions, respectively. For each target, scan technique, and motion excursion, eight different initial motion-to-scan phase relationships were investigated.

Results

An anticipated general trend of target volume overestimation was observed. The mean percentage overestimation of the true physical target volume typically increased with target motion amplitude and decreasing target diameter. Slow-scan percentage overestimations were larger, and better approximated the time-averaged motion envelope, as opposed to fast-scans. Motion induced centroid misrepresentation was greater in the S-I direction for fast-scan techniques, and transaxial direction for the slow-scan technique. Overestimation is fairly uniform for slice widths < 5 mm, beyond which there is gross overestimation.

Conclusion

Non-gated CT imaging of targets describing clinically relevant, 3D motion results in aliased overestimation of the target volume and misrepresentation of centroid location, with little or no correlation between the physical target geometry and the CT-generated target geometry. Slow-scan techniques are a practical method for characterizing time-averaged target position. Fast-scan techniques provide a more reliable, albeit still distorted, target margin.
Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip
Authors: Machold Robert P , Kittell Deborah Jones , Fishell Gordon J
Published: February 2007

Background

During the embryonic development of the cerebellum, neurons are produced from progenitor cells located along a ventricular zone within dorsal rhombomere 1 that extends caudally to the roof plate of the fourth ventricle. The apposition of the caudal neuroepithelium and roof plate results in a unique inductive region termed the cerebellar rhombic lip, which gives rise to granule cell precursors and other glutamatergic neuronal lineages. Recently, we and others have shown that, at early embryonic stages prior to the emergence of granule cell precursors (E12), waves of neurogenesis in the cerebellar rhombic lip produce specific hindbrain nuclei followed by deep cerebellar neurons. How the induction of rhombic lip-derived neurons from cerebellar progenitors is regulated during this phase of cerebellar development to produce these temporally discrete neuronal populations while maintaining a progenitor pool for subsequent neurogenesis is not known.

Results

Employing both gain- and loss-of-function methods, we find that Notch1 signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch1, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch1 activity prevents the induction of Math1 by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression.

Conclusion

Our results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development.
Modulation of Adiponectin and Leptin during Refeeding of Female Anorexia Nervosa Patients
Authors: Modan-Moses Dalit , Stein Daniel , Pariente Clara , Yaroslavsky Amit , Ram Anka , Faigin Michal , Loewenthal Ron , Yissachar Eleanor , Hemi Rina , Kanety Hannah
Published: February 2007

Context: Several studies assessed adiponectin levels in anorexia nervosa (AN) patients, however, data regarding the dynamics of changes in adiponectin levels during refeeding of these patients is limited and contradicting.

Objective: Our objective was to assess adiponectin levels and the distribution of its different isoforms in AN patients before and after long-term refeeding, and to relate them to alterations in body mass index, leptin, insulin sensitivity, and additional endocrine parameters.

Design, Setting, and Participants: We conducted a longitudinal controlled study of 38 female adolescent malnourished AN inpatients, with 13 young, lean, healthy women serving as controls. Blood samples were obtained upon admission and thereafter at 1, 3, and 5 months (at target weight).

Main Outcome Measures: Changes in body mass index, leptin, adiponectin, insulin sensitivity, and adiponectin multimeric forms were measured.

Results: At admission, leptin levels of AN patients were significantly lower, whereas insulin sensitivity (assessed by homeostasis model assessment-insulin resistance), adiponectin levels, and the ratio of high molecular weight (HMW) adiponectin to total adiponectin were significantly higher compared with controls. During weight recovery, leptin levels and homeostasis model assessment-insulin resistance increased significantly, whereas adiponectin and HMW adiponectin/total adiponectin ratio decreased significantly, to levels similar to controls. An initial increase in adiponectin levels was observed after 1 month of refeeding. There was no correlation between adiponectin and either T4 or cortisol levels.

Conclusions: Our study demonstrates hyperadiponectinemia, increased adiponectin HMW isoform, and increased insulin sensitivity in adolescent AN female patients and reversal of these findings with weight rehabilitation. We hypothesize that increased adiponectin levels may have a protective role in maintaining energy homeostasis during extreme malnourishment.
The Diagnosis of Partial Growth Hormone Deficiency in Adults with a Putative Insult to the Hypothalamo-Pituitary Axis
Authors: Murray Robert D. , Bidlingmaier Martin , Strasburger Christian J. , Shalet Stephen M.
Published: February 2007

Context: Similar to patients with severe GH deficiency (GHD), those with a more moderate impairment of GH secretion [GH insufficiency (GHI)] have abnormal body composition, dyslipidemia, and insulin resistance. Given the inherent problems in the diagnosis of severe GHD, the situation is likely to be even more difficult in individuals with GHI.

Objective: The objective of the study was to examine the utility of GH stimulation tests and GH-dependent proteins in the diagnosis of GHI.

Design: The study was a cross-sectional, case-controlled study.

Patients: The study included 31 patients with GHD, 23 with GHI [peak GH 3–7 μg/liter (9–21 mU/liter)], and 30 age- and sex-matched controls.

Main Outcome Measures: Demographic and biochemical markers of GH status were measured.

Results: Nineteen of the patients with GHI (83%) had no additional anterior pituitary hormone deficits. Ten GHI patients showed discordant GH status based on the two GH stimulation tests performed. GH status was defined by the highest peak GH value achieved; in four this was to the insulin tolerance test (ITT), four the arginine test, and two the GHRH-arginine test. In five of the six patients in whom GH status was not defined by the ITT, peak GH levels to the ITT were in the range 2.4–2.9 μg/liter. IGF-I values for the GHI adults were significantly lower than the control subjects (121 ± 48 vs. 162 ± 75 μg/liter; P < 0.05); however, only six (26%) had values below the 10th percentile of levels seen in the control group. IGF binding protein-3 and acid labile subunit levels of the GHI adults were not significantly different from the controls.

Conclusion: The diagnosis of GHI in an individual is extremely difficult because the patients rarely exhibit additional pituitary hormone deficits, and levels of GH-dependent proteins are normal in the majority. Diagnosis relies heavily on GH stimulation tests and requires two tests in all patients to define GHI; obesity when present is potentially a major confounder.
Recent developments in superporous hydrogels
Authors: Omidian Hossein , Park Kinam , Rocca Jose G
Published: February 2007

Superporous hydrogels (SPHs) were originally developed as a novel drug delivery system to retain drugs in the gastric medium. These systems should instantly swell in the stomach and maintain their integrity in the harsh stomach environment, while releasing the pharmaceutical active ingredient. For years, the synthetic features and properties of these SPH materials have been modified and improved to meet the requirements for gastric retention applications. Furthermore, an instant swelling hydrogel has also shown potential application for peroral intestinal peptide and protein absorption. This review discusses the formulation, characterization, properties and applications of these polymers.
Gene therapy used for tissue engineering applications
Authors: Heyde Mieke , Partridge Kris A , Oreffo Richard O C , Howdle Steven M , Shakesheff Kevin M , Garnett Martin C
Published: February 2007

This review highlights the advances at the interface between tissue engineering and gene therapy. There are a large number of reports on gene therapy in tissue engineering, and these cover a huge range of different engineered tissues, different vectors, scaffolds and methodology. The review considers separately in-vitro and in-vivo gene transfer methods. The in-vivo gene transfer method is described first, using either viral or non-viral vectors to repair various tissues with and without the use of scaffolds. The use of a scaffold can overcome some of the challenges associated with delivery by direct injection. The ex-vivo method is described in the second half of the review. Attempts have been made to use this therapy for bone, cartilage, wound, urothelial, nerve tissue regeneration and for treating diabetes using viral or non-viral vectors. Again porous polymers can be used as scaffolds for cell transplantation. There are as yet few comparisons between these many different variables to show which is the best for any particular application. With few exceptions, all of the results were positive in showing some gene expression and some consequent effect on tissue growth and remodelling. Some of the principal advantages and disadvantages of various methods are discussed.
Formulation, preparation and evaluation of flunarizine-loaded lipid microspheres
Authors: Wang Yan Jiao , Wang Juan , Zhang Hong Yao , He Hai Bing , Tang Xing
Published: February 2007

The aim of this study was to investigate the feasibility of preparing flunarizine-loaded lipid microspheres. Lipid microspheres (LMs) are excellent drug carriers for drug delivery systems (DDS) and are relatively stable and easily mass-produced. They have no particular adverse effects. LMs have been widely studied as drug carriers for water-soluble drugs, lipid-soluble drugs and inadequately soluble (in water or in lipid) drugs, in that they have a lipid layer, a water layer and an emulsifier layer. Flunarizine (FZ), a poorly water-soluble drug, was incorporated in lipid microspheres to reduce side effects by avoiding the use of supplementary agents, compared with solution injection. After investigation, the final formulation was as follows: 10% oil phase (long-chain triglyceride (LCT); medium-chain fatty acid (MCT) = 50:50); 1.2% egg lecithin; 0.2% Tween-80; 2.5% glycerin; 0.3% dl-α-tocopherol; 0.02% EDTA; 0.03% sodium oleate; 0.1% FZ and double-distilled water to give a total volume of 100 mL. Homogenization was the main method of preparation and the best conditions were a temperature of 40°C, a pressure of 700–800 bar and a suitable cycle frequency of about 10. The particle size distribution, zeta-potential and entrapment efficacy were found to be 198.7 ± 54.0 nm, −26.4mV and 96.2%, respectively. Its concentration in the preparation was 1.0mg mL−1. The lipid microspheres were stable during storage at 4°C, 25°C and 37°C for 3 months. Pharmacokinetic studies were performed in rats using a dose of 1.0 mg kg−1. The pharmacokinetic parameters were as follows: AUC0-t 6.13 μg h mL−1, t½ 5.32 h and Ke 0.16 Lh−1. The preparation data fitted a two-compartment model estimated by using 3p87 analysis software. From the observed data, FZ encapsulated in LMs did not significantly alter the pharmacokinetic characteristic compared with the FZ solution injection and did not produce a delayed release effect, when it was released in-vivo in rats. However, the availability of the drug was increased. These results suggested that this LM system is a promising option for the preparation of the liquid form of FZ for intravenous administration.
Compression coated systems for colonic delivery of 5-fluorouracil
Authors: Sinha V R , Singh Asmita , Singh Sanjay , Bhinge J R
Published: February 2007

Compression coating is one of the approaches for delaying the release of drugs. The aim of this study was to develop colon-specific compression coated systems of 5-fluorouracil (5-FU) for the treatment of colorectal cancer using xanthan gum, boswellia gum and hydroxypropyl methylcellulose (HPMC) as the coating materials. Core tablets containing 50 mg of 5-FU were prepared by direct compression. The coating of the core tablets was done using different coat weights (230, 250, 275 and 300 mg) and different ratios (1:2, 2:1, 1:3, 1:7 and 3:4) of boswellia gum and xanthan gum and different ratios (1:1, 1:2, 2:1, and 2:3) of boswellia gum and HPMC. In-vitro release studies were carried out using simulated gastric and intestinal fluids, with and without rat caecal contents. Among the different ratios used for coating with boswellia:xanthan gum combination, ratio 1:3 gave the best release profile with the lowest coating weights of 230 mg (7.47 ± 1.56% in initial 5 h). Further increase in the coat weights to 250, 275 and 300 mg led to drug release of 5.63 ± 0.53%, 5.09 ± 1.56% and 4.57 ± 0.88%, respectively, in the initial 5 h and 96.90 ± 0.66%, 85.05 ± 1.01% and 80.22 ± 0.35%, respectively, in 24h. When coating was carried out using different ratios of the combination boswellia gum and HPMC, the ratio 2:3 gave the best results among the initial trial batches (7.80 ± 0.57% in 5 h). Increasing the coat weights to 250, 275 and 300 mg led to drug release of 6.5 ± 0.27%, 3.70 ± 2.3% and 2.99 ± 0.72%, respectively, in the initial 5h and 96.90 ± 0.66%, 85.05 ± 1.01% and 80.22 ± 0.35%, respectively, in 24h. In-vitro studies were further carried out in the presence of 2% w/v rat caecal contents, which led to complete release of the drug from the tablets. Therefore, this study lays a basis for use of compression coating of 5-FU as a tool for delaying the release of the drug, which ensures better clinical management of the disease.
Hypromellose films for the delivery of growth factors for wound healing
Authors: Braund Rhiannon , Tucker Ian G , Medlicott Natalie J
Published: February 2007

Hypromellose was investigated as a carrier for extending topical growth factor delivery to wounds. Films of hypromellose (E4M, K4M and E10M) containing a model protein horseradish peroxidase (1 % w/w HRP, MW 40 000) were cast from aqueous solutions and dried at 37°C. In-vitro release was determined using Franz-type diffusion cells and films were mounted directly into the Franz cell or cast onto a wound dressing (Melolin) backing. There was an initial burst release then an extended release over 5 h. The Melolin backing significantly reduced the burst but not the extended release rates (P < 0.05). Release of HRP was also determined from 7% w/v hypromellose gels and was significantly lower for E10M than E4M, suggesting that, once hydrated, the E10M hypromellose provides the greatest resistance to HRP release. The release profile of basic fibroblast growth factor from Melolin-backed films made from E4M hypromellose was not significantly different at any time point to that of HRP release from the same formulation. Hypromellose may be incorporated into a wound dressing such as Melolin to provide a prolonged release of an incorporated protein active.
Characterisation of blends of paracetamol and citric acid
Authors: Hoppu Pekka , Jouppila Kirsi , Rantanen Jukka , Schantz Staffan , Juppo Anne M
Published: February 2007

The purpose of this study was to characterise physically stable amorphous blends that were sticky (low glass transition temperature) in ambient conditions. The effects of composition, melting time and melting temperature were evaluated with respect to physical and chemical property. Citric acid anhydrate and paracetamol were melt-quenched as binary mixtures and as pure materials. Bulk samples were characterised by differential scanning calorimetry, X-ray powder diffractometry, and Raman and Fourier transform infrared spectroscopy. The composition and the sample exposure to moisture affected significantly the physical stability of samples. The extreme melting conditions, coupled with long exposure to heat and a high melting temperature, lowered the overall crystallisation rate. Paracetamol had a stronger tendency to crystallise from the blends than did citric acid. The 50:50% (w/w) blend was physically stable for at least 27 weeks in dry conditions and was partly crystalline after 4 weeks of storage at a relative humidity of 43%. The result of the physical stability of blends is discussed in terms of hydrogen bonding interaction between paracetamol and citric acid and in relation to degradation products formed in a mixing state.
Investigation of low levels of plasma valproic acid concentration following simultaneous administration of sodium valproate and rizatriptan benzoate
Authors: Hokama Nobuo , Hobara Norio , Kameya Hiromasa , Ohshiro Susumu , Hobara Narumi , Sakanashi Matao
Published: February 2007

Drug interaction between rizatriptan benzoate, an anti-migraine agent, and sodium valproate (VPA-Na), an anticonvulsant, was studied in rats. When rizatriptan benzoate was administered orally immediately after VPA-Na oral administration, the pharmacokinetic parameters, such as plasma valproic acid (VPA) and area under the plasma concentration-time curve up to 3 h (AUC0–3), were significantly decreased compared with those in the control group. However, when rizatriptan benzoate was administered intraperitoneally immediately after VPA-Na orally, these parameters were not changed. In addition, when benzoic acid was administered orally immediately after VPA-Na orally, these were significantly lower compared with the control values. Therefore, it might be possible that VPA transport by monocarboxylate transporter was competitively inhibited by rizatriptan benzoate and thus absorption of VPA was decreased.
Pharmacokinetics and distribution of clioquinol in golden hamsters
Authors: Bondiolotti Gianpietro , Sala Mariaelvina , Pollera Claudia , Gervasoni Marco , Puricelli Maria , Ponti Wilma , Bareggi Silvio R
Published: February 2007

Clioquinol (5-chloro-7-iodo-8-quinolinol) is a zinc and copper chelator that can dissolve amyloid deposits and may be beneficial in Alzheimer's disease. Prion diseases are also degenerative CNS disorders characterised by amyloid deposits. The pharmacokinetics and tissue distribution of drugs active against prions may clarify their targets of action. We describe the harmacokinetics of clioquinol in hamster plasma, spleen and brain after single and repeated oral or intraperitoneal administration (50 mg kg−1), as well as after administration with the diet. A single intraperitoneal administration led to peak plasma clioquinol concentrations after 15 min (Tmax), followed by a decay with an apparent half-life of 2.20 ± 1.1 h. After oral administration, Tmax was reached after 30 min and was followed by a similar process of decay; the AUC0-last was 16% that recorded after intraperitoneal administration. The Cmax and AUC values in spleen after a single administration were about 65% (i.p.) and 25% (p.o.) those observed in blood; those in liver were 35% (p.o.) those observed in blood and those in brain were 20% (i.p.) and 10% (p.o.) those observed in plasma. After repeated oral doses, the plasma, brain and spleen concentrations were similar to those observed at the same times after a single dose. One hour after intraperitoneal dosing, clioquinol was also found in the ventricular CSF. Clioquinol was also given with the diet; its morning and afternoon concentrations were similar, and matched those after oral administration. No toxicity was found after chronic administration. Our results indicate that clioquinol, after oral administration with the diet, reaches concentrations in brain and peripheral tissues (particularly spleen) that can be considered effective in preventing prion accumulation, but are at least ten times lower than those likely to cause toxicity.
Intestinal efflux transport kinetics of green tea catechins in Caco-2 monolayer model
Authors: Chan K Y , Zhang Li , Zuo Zhong
Published: February 2007

The bioavailability of green tea catechins (GTCs), including epigallocatechin gallate (EGCG), epigal-locatechin (EGC), epicatechin gallate (ECG) and epicatechin (EC) is low in both animals and humans. The contribution of intestinal efflux to this low bioavailability has been suggested by previous studies. The objective of the present study was to investigate the kinetics of efflux transport of the four major GTCs in Caco-2 cell lines, to provide comparison on the efflux transport between each GTC. The basal-to-apical transport of each GTC at concentrations ranging from 15 to 265 μM was examined using the Caco-2 cell monolayer model. Transported amount of GTC was measured by high-performance liquid chromatography with electrochemical detection. Kinetic parameters, Vmax, Km and Vmax/Km were determined and compared among the four studied GTCs. The extent of basal-to-apical transport was, in descending order, EC > EGC > ECG ≅ EGCG. Kinetic studies indicated that active and saturable efflux transport of EC took place in Caco-2 cells, with a Km of 131 μM, a Vmax of 0.0249 nmol min cm−2 and an intrinsic clearance (Vmax/Km) of 0.19 μL min cm−2. No saturation could be observed for the efflux transport of EGC, ECG and EGCG even at concentrations up to about 200 μM, which may be due to their low affinity towards the transporters at the concentration range studied. In conclusion, the extent of efflux transport of GTCs in Caco-2 cells was, in descending order, EC > EGC > ECG ≅ EGCG, which may reflect the order of elimination occurring in the intestine. The kinetic studies showed the importance of efflux transporters in basal-to-apical transport of EC and suggests their role in the limited oral bioavailability of EC.
Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-α in rats
Authors: Reguiga Makrem Ben , Bonhomme-Faivre Laurence , Farinotti Robert
Published: February 2007

Interferon-α (IFN-α) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-α (rhIFN-α) on oral and intravenous pharmacokinetics of a P-gp substrate, docetaxel (DTX; Taxotere) were investigated in a rat model. The bioavailability and distribution in different organs were also studied. Sprague-Dawley rats were subcutaneously pre-treated with either rhIFN-α for 8 days (4MIUkg−1, once daily) or with pegylated-IFN-α (ViraferonPeg; 60 μg kg−1, Days 1, 4 and 7). The rats were then distributed into subgroups (n = 5–6) according to the pre-treatment type, and received one dose of [14C]DTX (20 mg kg−1) either orally or intravenously. Pharmacokinetics studies were then performed over 240 min, at the end of which tissues (intestine, liver, kidneys, lung, heart and brain) were immediately removed for radioactivity quantitation. Non-pegylated and pegylated IFN-αboth increased DTX oral bioavailability parameters: Cmax (17.0 ± 4.0 μgL−1 (P < 0.02) and 18 ± 5.5 μg L−1 (P < 0.05), respectively, vs 7.4 ± 2.5 μ g L−1 for the control) and AUC (0.036 ± 0.010 μg h mL−1 (P < 0.01) and 0.033 ± 0.009 μgh mL−1(P < 0.01), respectively, versus 0.012 ± 0.004 μghmL−1 for the control). IFN-α also delayed DTX absorption from 60 min in controls to about 95 min and 80 min in non-pegylated and pegylated treated animals, respectively. However, IFN-αdid not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [14C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-α modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.
Measurements of oxidative stress status and antioxidant activity in chronic leukaemia patients
Authors: Al-Gayyar Mohammed M H , Eissa Laila A , Rabie Ahmed M , El-Gayar Amal M
Published: February 2007

There is an interactive relationship between leukaemia and oxidative stress. Leukaemic cells produce larger amounts of reactive oxygen species (ROS) than non-leukaemic cells as they are under a continual state of oxidative siege. So, this study was performed on 20 patients with chronic leukaemia from the Oncology Centre, Mansoura University. We measured leucocytic H2O2 concentrations and lipid peroxidation as serum malondialdehyde (MDA) concentration, serum total antioxidant activity, plasma ascorbic acid and dehydroascorbic acid concentrations, blood reduced glutathione concentration, haemolysate G6PD activity, blood catalase activity, serum superoxide dismutase (SOD) activity and serum anti-dsDNA concentration. We found that chronic leukaemia patients showed a significant increase (P < 0.05) in leucocytic H2O2, serum MDA concentration and total anti-oxidant activity either before or after treatment as compared with control group. Also, there was a significant increase in the other parameters (glutathione, catalase and SOD) either before or after treatment, but we found a significant decrease in ascorbic acid concentration and G6PD activity. There was a significant increase in anti-dsDNA concentration either before or after treatment. It can be concluded that leukaemic patients produce larger amounts of ROS than non-leukaemic patients. Also, the increase in antioxidant activity in leukaemic patients is not high enough to counteract the harmful effects of free radicals. This scenario becomes worse after administration of chemotherapy.
Physico-chemical alterations of urine in experimental hyperoxaluria: a biochemical approach with fucoidan
Authors: Veena Coothan Kandaswamy , Josephine Anthony , Preetha Sreenivasan P , Varalakshmi Palaninathan
Published: February 2007

Urinary supersaturation-induced crystal formation has been attributed as one of the key factor for the pathogenesis/progression of lithogenesis. This study was aimed at investigating whether fucoidan, a naturally occurring sulfated glycosaminoglycan, could ameliorate the biochemical changes in urine induced by stone formation. Two groups of male albino Wistar rats (120 ± 20 g) received 0.75% ethylene glycol (EG) for 28 days to induce hyperoxaluria, and one of them received sulfated polysaccharides (fucoidan from Fucus vesiculosus, 5 mg kg−1, S.C.), commencing from the 8thday of the experimental period. One group was maintained as normal control group and another group served as drug control, which received sulfated polysaccharides. The urine collected from all the groups was analysed for changes in pH, volume, oxalate, calcium, phosphorus, uric acid, magnesium, citric acid and glycosaminoglycans. Urinary crystals were analysed with a light microscope. Renal tissues were studied under polarized light for deposition of crystals and also analysed for their oxalate and calcium content. The changes in extracellular matrix on crystal deposition were also evaluated. The urinary pH and volume were altered in rats treated with EG along with an increase in weight of the kidney. Further, administration of EG to rats increased the supersaturation of urine by escalating the levels of the stone-forming constituents, such as oxalate, calcium, phosphorus and uric acid, which was completely restored by fucoidan treatment. The decrease in the inhibitors, like citrate, magnesium and glycosaminoglycans, in urine was prevented by the co-treatment with fucoidan. In hyperoxaluric rats, there was an increased excretion of calcium oxalate monohydrate crystals in urine along with crystal deposition in renal tissues; this was prevented by fucoidan treatment. Fucoidan administration reversed even the tissue levels of calcium and oxalate. The increased accumulation of collagen and expression of transforming growth factor-β1 in hyperoxaluria was normalized on fucoidan administration. These results suggest that the physico-chemical alterations in urine produced during hyperoxaluria can be reversed by fucoidan administration.
β-Blocking activity of PP-34, a newly synthesized aryloxypropanolamine derivative, and its cardioprotective effect against ischaemia/reperfusion injury in laboratory animals
Authors: Bhatt Lokesh K , Nandakumar K , Bodhankar S L , Bansal Jyotika , Piplani Poonam
Published: February 2007

β-Adrenoceptor antagonists are widely used in cardiovascular medicine. However, the main side effect of these drugs is due to antagonism of β2-adrenoceptors in the airways, resulting in broncho-spasm. Therefore, more cardioselective β-blockers have been developed to offer a lower side effect profile. We have studied a new aryloxypropanolamine derivative (PP-34) with more cardioselectivity and efficacy against ischaemia/reperfusion injury in rats. Oxalate salts of 1-(tert-butylamino)-3-(5-tert-butylaminomethyl-2-methoxyphenoxy) propan-2-ol (PP-34) is a novel β-adrenoceptor antagonist. In-vitro studies in rat isolated right atria, guinea-pig trachea and rat distal colon preparations were carried out to investigate the potency of PP-34 towards different β-adrenoceptor subtypes. pA2/pKB values of PP-34 for β1, β2, and β3 adrenoceptor were 7.89 ± 0.15, 6.13 ± 0.09 and 6.30 ± 0.19, respectively. The β1/β2 selectivity ratio calculated was in the order of PP-34 > atenolol > propranolol. Pre-ischaemic administration (20 min before coronary occlusion) of PP-34 (0.3 or 1 mg kg−1) showed cardioprotective effects against ischaemia/reperfusion injury in rats and significantly reduced arrhythmias, infarct area and necrosis induced by ischaemia/reperfusion injury. The efficacy of PP-34 was found to be greater then atenolol. In conclusion, PP-34 is a cardioselective β-adrenoceptor antagonist, possessing potent anti-arrhythmic and cardioprotective effects against ischaemia/reperfusion injury in rats.
Improvement of hyperglycaemia and metabolic syndromes in type 2 diabetic KKAy mice by oral treatment with [meso-tetrakis(4-sulfonatophenyl) porphyrinato]oxovanadium(IV)(4-) complex
Authors: Saha Tapan Kumar , Yoshikawa Yutaka , Sakurai Hiromu
Published: February 2007

Recently, we reported that [meso-tetrakis(4-sulfonatophenyl)porphyrinato]oxovanadium(IV)(4-), VO(tpps), shows in-vitro insulin-mimetic and in-vivo anti-diabetic activity in streptozotocin (STZ)-induced type 1 diabetic mice. This result prompted us to examine its ability in type 2 diabetic model KKAy mice with insulin resistance. We studied the in-vivo anti-diabetic activity of VO(tpps), compared with that of vanadium(IV) oxide sulfate, VS, as control. Both compounds were orally administered at doses of 5–10 mg (0.1-0.2 mmol) V/kg body weight to the KKAy mice for 28 days. VO(tpps) normalized the hyperglycaemia within 15 days, while VS lowered the blood glucose concentration only by a small degree. In addition, metabolic syndromes characterized by insulin and leptin resistance were significantly improved in VO(tpps)-treated KKAy mice compared with those treated with VS. The improvement in diabetes was validated by oral glucose tolerance test and decrease in HbA1c concentration. Based on these observations, VO(tpps) is proposed to be an orally active oxovanadium(IV)-porphyrin complex for treating not only type 2 diabetes but also metabolic syndromes in animals.
Antioxidant effect of 2-hydroxy-4-methoxy benzoic acid on ethanol-induced hepatotoxicity in rats
Authors: Saravanan Nadana , Rajasankar Srinivasagam , Nalini Namasivayam
Published: February 2007

Alcoholic liver disease (ALD) is one of the most common diseases in society. A large number of studies are in progress to identify natural substances that are effective in reducing the severity of ALD. 2-Hydroxy-4-methoxy benzoic acid (HMBA), the active principle of Hemidesmus indicus, an indigenous Ayurvedic medicinal plant in India, is expected to significantly inhibit the development of liver injury in ethanol administration. It is expected to reduce the severity of liver damage in terms of body weight, hepatic marker enzymes, oxidative stress, antioxidant status and histological changes in ethanol-induced hepatotoxic rats. Hepatotoxicity was induced by administering 20% ethanol (5 g kg−1 daily) for 60 days to male Wistar rats, which resulted in significantly decreased body weight and an increase in liver-body weight ratio. The liver marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, γ-glutamyl transpeptidase and lactate dehydrogenase were elevated. In addition, the levels of plasma, erythrocyte and hepatic thiobarbituric acid reactive substances, hydroperoxides and conjugated dienes were also elevated in ethanol-fed rats as compared with those of the experimental control rats. Decreased activity of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C and α-tocopherol was also observed on alcohol administration as compared with experimental control rats. HMBA was co-administered at a dose of 200 μgkg−1 daily for the last 30 days of the experiment to rats with alcohol-induced liver injury, which significantly increased body weight, significantly decreased the liver-body weight ratio, transaminases, alkaline phosphatase, γ-glutamyl transpeptidase and lactate dehydrogenase, significantly decreased the levels of lipid peroxidative markers, significantly elevated the activity of enzymic and non-enzymic antioxidants in plasma, erythrocytes and liver and also increased levels of plasma and liver vitamin C and α-tocopherol at the end of the experimental period as compared with untreated ethanol-administered rats. The histological changes were also in correlation with the biochemical findings. The results suggest that HMBA administration may afford protection against ethanol-induced liver injury in rats.
Protective effect of a phenolic-rich fraction from Schisandra chinensis against H2O2-induced apoptosis in SH-SY5Y cells
Authors: Jung Chang Hwa , Hong Myung Hee , Kim Ji Hye , Lee Ji Yun , Ko Seong Gyu , Cho Kiho , Seog Ho Moon
Published: February 2007

We have investigated the neuroprotective effects of a phenolic-rich fraction (PRF) on the hydrogen peroxide (H2O2)-induced apoptosis of cultured SH-SY5Y cells. The PRF was obtained from the 80% ethanol extract of the fruits of Schisandra chinensis by Sepabeads SP-850 column chromatography. Cell viability assays revealed that pretreating SH-SY5Y cells with PRF (10–200 μgmL−1) resulted in significant dose-dependent protection against H2O2-induced cell death. The protective effect of PRF against H2O2-induced apoptosis was assessed by flow cytometric analysis of DNA contents using propidium iodide (PI) staining. Pre-incubation of cells with PRF at different concentrations for 24 h partially protected apoptosis by H2O2 (150 μM). Moreover, cells treated with PRF reduced H2O2-induced caspase-3 activation and poly (ADP-ribose) polymerase cleavage and exerted an apparent suppressive effect on oxidative stress induced by reactive oxygen species (ROS). We concluded that PRF may be useful in the treatment and prevention of neurodegenerative diseases associated with elevated ROS levels.
Effect of Baccharis dracunculifolia D.C (Asteraceae) extracts and its isolated compounds on macrophage activation
Authors: Missima Fabiane , Filho Ademar A da Silva , Nunes Gladston A , Bueno Paula C Pires , De Sousa João Paulo B , Bastos Jairo K , Sforcin Jose M
Published: February 2007

Baccharis dracunculifolia D.C. (Asteraceae), a shrub which grows wild in Brazil, is the main botanical source of Brazilian green propolis. Since Brazilian propolis shows an immunomodulatory activity, the goal of this work was to evaluate the action of B. dracunculifolia extracts and some of its isolated compounds on reactive oxygen intermediate (H2O2) production by macrophages obtained from male BALB/c mice. The results showed that the leaf (Bd-L) (25, 50, and 100 μg mL−1), leaf rinse (Bd-LR) (25 μg mL−1), and the root (Bd-R) (25 μg mL−1) extracts enhanced H2O2 release by macrophages. A phytochemical study of the root and leaves of B. dracunculifolia was carried out. The chromatographic fractionation of Bd-R, using several techniques, afforded the isolation of baccharis oxide (1), friedelanol (2), viscidone (11), 11-hydroxy-10,11-dihydro-euparin (12), and 6-hydroxy-tremetona (13), while Bd-LR gave the following isolated compounds: baccharis oxide (1), friedelanol (2), isosakuranetin (3), aromadendrin-4′-methyl ether (4), dihydrocumaric acid (5), baccharin (6), hautriwaic acid lactone (7), hautriwaic acid acetate (8), drupanin (9), and cumaric acid (10). Among the isolated compounds, baccharis oxide (1) and friedelanol (2) increased H2O2 production at a concentration of 100μM. This is the first time that the presence of compounds 7, 8, 12, and 13 in B. dracunculifolia has been reported. Based on these results it is suggested that the crude extracts and some isolated compounds from B. dracunculifolia display an immunomodulatory action.
Rtnl1 is enriched in a specialized germline ER that associates with ribonucleoprotein granule components
Authors: Röper Katja
Published: February 2007

During oogenesis in Drosophila an organelle called the fusome plays a crucial role in germline cyst development and oocyte selection. The fusome consists of cytoskeletal proteins and intracellular membranes and, whereas many cytoskeletal components have been characterized, the nature and function of the membrane component is poorly understood. I have found the reticulon-like 1 (Rtnl1) protein, a membrane protein resident in the endoplasmic reticulum (ER), to be highly enriched in the fusome. In other Drosophila tissues Rtnl1 marks a subset of ER membranes often derived from smooth ER. During oogenesis, Rtnl1-containing membranes are recruited to the fusome by the cytoskeletal components and become concentrated into the forming oocyte. On the central part of the fusome, which is contained within the future oocyte and also at later stages in the growing oocyte and the nurse cells, Rtnl1-containing membranes colocalize with components of ribonucleoprotein complexes that store translationally repressed mRNAs. As the ER is actively transported into the oocyte, this colocalization suggests a role for the Rtnl1-containing subdomain in anchoring the ribonucleoprotein complexes within and/or transporting them into the oocyte.
Effects of exhaust gas recirculation on combustion and emissions of a homogeneous charge compression ignition engine fuelled with primary reference fuels
Authors: Yao M , Zhang B , Zheng Z , Chen Z , Xing Y
Published: February 2007

The effects of exhaust gas recirculation (EGR) of primary reference fuel on combustion and emissions of a homogeneous charge compression ignition (HCCI) engine are investigated. The results show that EGR delays the ignition timing, slows down the combustion reaction rate, reduces the pressure in cylinder, and extends the HCCI operation region. The maximum indicated thermal efficiency of fuels with different octane numbers appears in the region of high EGR rate and large fuel: air equivalence ratio. In the region of high EGR rate, hydrocarbon emissions rise up sharply as the EGR rate increases. Carbon monoxide emissions increase with the increase in EGR rate. Nitrogen oxides emissions increase abruptly as knocking combustion occurs.