bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycogen debranching enzyme association with β-subunit regulates AMP-activated protein kinase activity
Authors: Sakoda Hideyuki , Fujishiro Midori , Fujio Junko , Shojima Nobuhiro , Ogihara Takehide , Kushiyama Akifumi , Fukushima Yasushi , Anai Motonobu , Ono Hiraku , Kikuchi Masatoshi , Horike Nanao , Viana Amelia Y. I. , Uchijima Yasunobu , Kurihara Hiroki , Asano Tomoichiro
Published: May 2005

AMP-activated protein kinase (AMPK) regulates both glycogen and lipid metabolism functioning as an intracellular energy sensor. In this study, we identified a 160-kDa protein in mouse skeletal muscle lysate by using a glutathione- S-transferase (GST)-AMPK fusion protein pull-down assay. Mass spectrometry and a Mascot search revealed this protein to be a glycogen debranching enzyme (GDE). The association between AMPK and GDE was observed not only in the overexpression system but also endogenously. Next, we showed the β1-subunit of AMPK to be responsible for the association with GDE. Furthermore, experiments using deletion mutants of the β1-subunit of AMPK revealed amino acids 68–123 of the β1-subunit to be sufficient for GDE binding. W100G and K128Q, both β1-subunit mutants, are reportedly incapable of binding to glycogen, but both bound GDE, indicating that the association between AMPK and GDE does not involve glycogen. Rather, the AMPK-GDE association is likely to be direct. Overexpression of amino acids 68–123 of the β1-subunit inhibited the association between endogenous AMPK and GDE. Although GDE activity was unaffected, basal phosphorylation and kinase activity of AMPK, as well as phosphorylation of acetyl-CoA carboxylase, were significantly increased. Thus it is likely that the AMPK-GDE association is a novel mechanism regulating AMPK activity and the resultant fatty acid oxidation and glucose uptake.
Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects
Authors: Chaikomin Reawika , Doran Selena , Jones Karen L. , Feinle-Bisset Christine , O'Donovan Deirdre , Rayner Christopher K. , Horowitz Michael
Published: May 2005

The rate of gastric emptying of glucose-containing liquids is a major determinant of postprandial glycemia. The latter is also dependent on stimulation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Although overall emptying of glucose approximates 1–3 kcal/min, the “early phase” of gastric emptying is usually more rapid. We have evaluated the hypothesis that increased stimulation of incretin hormones and insulin by a more rapid initial rate of small intestinal glucose delivery would reduce the overall glycemic response to a standardized enteral glucose load. Twelve healthy subjects were studied on two separate days in which they received an intraduodenal (id) glucose infusion for 120 min. On one day, the infusion rate was variable, being more rapid (6 kcal/min) between t = 0 and 10 min and slower (0.55 kcal/min) between t = 10 and 120 min, whereas on the other day the rate was constant (1 kcal/min) from t = 0–120 min, i.e., on both days 120 kcal were given. Between t = 0 and 75 min, plasma insulin, GIP, and GLP-1 were higher with the variable infusion. Despite the increase in insulin and incretin hormones, blood glucose levels were also higher. Between t = 75 and 180 min, blood glucose and plasma insulin were lower with the variable infusion. There was no difference in the area under the curve 0–180 min for blood glucose. We conclude that stimulation of incretin hormone and insulin release by a more rapid initial rate of id glucose delivery does not lead to an overall reduction in glycemia in healthy subjects.
Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex
Authors: Elbatarny Hisham S. , Maurice Donald H.
Published: May 2005

An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation is a major cause of acute coronary events and leptin was shown previously to facilitate ADP-induced platelet aggregation, we chose to define the signaling events involved in leptin-mediated platelet activation. Using pharmacological, biochemical, and cell biological approaches, we show that leptin-induced platelet activation required activation of a signaling cascade that included the long form of the leptin receptor, three kinases [Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt)], the insulin receptor substrate-1 (IRS-1), and the major human platelet cAMP phosphodiesterase phosphodiesterase 3A (PDE3A). Moreover, we identify a role for an intraplatelet LEPR/JAK2/IRS-1/PI3K/PKB/PDE3A molecular complex that allows for the selective leptin-mediated activation of platelets. Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease.
Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria
Authors: Bevilacqua Lisa , Ramsey Jon J. , Hagopian Kevork , Weindruch Richard , Harper Mary-Ellen
Published: May 2005

Calorie restriction (CR) without malnutrition increases life span and delays the onset of a variety of diseases in a wide range of animal species. However, the mechanisms responsible for the retardation of aging with CR are poorly understood. We proposed that CR may act, in part, by inducing a hypometabolic state characterized by decreased reactive oxygen species (ROS) production and mitochondrial proton leak. Here, we examine the effects of long-term CR on whole animal energetics as well as muscle mitochondrial energetics, ROS production, and ROS damage. CR was initiated in male FBNF1rats at 6 mo of age and continued for 12 or 18 mo. Mean whole body V̇o2was 34.6 ( P < 0.01) and 35.6% ( P < 0.001) lower in CR rats than in controls after 12 and 18 mo of CR, respectively. Body mass-adjusted V̇o2was 11.1 and 29.5% lower (both P < 0.05) in CR rats than in controls after 12 and 18 mo of CR. Muscle mitochondrial leak-dependent (State 4) respiration was decreased after 12 mo compared with controls; however, after 18 mo of CR, there were slight but not statistically significant differences. Proton leak kinetics were affected by 12 mo of CR such that leak-dependent respiration was lower in CR mitochondria only at protonmotive force values exceeding 170 mV. Mitochondrial H2O2production and oxidative damage were decreased by CR at both time points and increased with age. Muscle UCP3 protein content increased with long-term CR, consistent with a role in protection from ROS but inconsistent with the observed decrease or no change in proton leak.
Oleylethanolamide impairs glucose tolerance and inhibits insulin-stimulated glucose uptake in rat adipocytes through p38 and JNK MAPK pathways
Authors: González-Yanes Carmen , Serrano Antonia , Bermúdez-Silva Francisco Javier , Hernández-Dominguez María , Páez-Ochoa María Angeles , de Fonseca Fernando Rodríguez , Sánchez-Margalet Víctor
Published: May 2005

Oleylethanolamide (OEA) is a lipid mediator that inhibits food intake and body weight gain and also exhibits hypolipemiant actions. OEA exerts its anorectic effects peripherally through the stimulation of C-fibers. OEA is synthesized in the intestine in response to feeding, increasing its levels in portal blood after the meal. Moreover, OEA is produced by adipose tissue, and a lipolytic effect has been found. In this work, we have examined the effect of OEA on glucose metabolism in rats in vivo and in isolated adipocytes. In vivo studies showed that acute administration (30 min and 6 h) of OEA produced glucose intolerance without decreasing insulin levels. Ex vivo, we found that 10 min of preincubation with OEA inhibited 30% insulin-stimulated glucose uptake in isolated adipocytes. Maximal effect was achieved at 1 μM OEA. The related compounds palmitylethanolamide and oleic acid had no effect, suggesting a specific mechanism. Insulin-stimulated GLUT4 translocation was not affected, but OEA promoted Ser/Thr phosphorylation of GLUT4, which may impair transport activity. This phosphorylation may be partly mediated by p38 and JNK kinases, since specific inhibitors (SB-203580 and SP-600125) partly reverted the inhibitory effect of OEA on insulin-stimulated glucose uptake. These results suggest that the lipid mediator OEA inhibits insulin action in the adipocyte, impairing glucose uptake via p38 and JNK kinases, and these effects may at least in part explain the glucose intolerance produced in rats in vivo. These effects of OEA may contribute to the anorectic effects induced by this mediator, and they might be also relevant for insulin resistance in adipose tissue.
Vasopressin increases urea permeability in the initial IMCD from diabetic rats
Authors: Pech Vladimir , Klein Janet D. , Kozlowski Shelley D. , Wall Susan M. , Sands Jeff M.
Published: May 2005

In normal rats, vasopressin and hyperosmolality enhance urea permeability ( Purea) in the terminal, but not in the initial inner medullary collecting duct (IMCD), a process thought to occur through the UT-A1 urea transporter. In the terminal IMCD, UT-A1 is detected as 97- and 117-kDa glycoproteins. However, in the initial IMCD, only the 97-kDa form is detected. During streptozotocin-induced diabetes mellitus, UT-A1 protein abundance is increased, and the 117-kDa UT-A1 glycoprotein appears in the initial IMCD. We hypothesize that the 117-kDa glycoprotein mediates the vasopressin- and osmolality-induced changes in Purea. Thus, in the present study, we measured Pureain in vitro perfused initial IMCDs from diabetic rats by imposing a 5 mM bath-to-lumen urea gradient without any osmotic gradient. Basal Pureawas similar in control vs. diabetic rats (3 ± 1 vs. 5 ± 1 × 10−5cm/s, n = 4, P = not significant). Vasopressin (10 nM) significantly increased Pureato 16 ± 5 × 10−5cm/s ( n = 4, P < 0.05) in diabetic but not in control rats. Forskolin (10 μM, adenylyl cyclase activator) also significantly increased Pureain diabetic rats. In contrast, increasing osmolality to 690 mosmol/kgH2O did not change Pureain diabetic rats. We conclude that initial IMCDs from diabetic rats have vasopressin- and forskolin-, but not hyperosmolality-stimulated Purea. The appearance of vasopressin-stimulated Pureain initial IMCDs correlates with an increase in UT-A1 protein abundance and the appearance of the 117-kDa UT-A1 glycoprotein in this region during diabetes. This suggests that the 117-kDa UT-A1 glycoprotein is necessary for vasopressin-stimulated urea transport.
Trajectory Interpretation by Supplementary Eye Field Neurons During Ocular Baseball
Authors: Kim Yong-Guk , Badler Jeremy B. , Heinen Stephen J.
Published: May 2005

Good performance in the sport of baseball shows that humans can determine the trajectory of a moving object and act on it under the constraint of a rule. We report here on neuronal activity in the supplementary eye field (SEF) of monkeys performing an eye movement task inspired by baseball. In “ocular baseball,” a pursuit eye movement to a target is executed or withheld based on the target’s trajectory. We found that a subset of neurons in the SEF interpreted the trajectory according to the task rule. Other neurons specified at a later time the command to pursue the target with the eyes. The results suggest that the SEF can interpret sensory signals about target motion in the context of a rule to guide voluntary eye movement initiation.
Development of Structures and Transport Functions in the Mouse Placenta
Authors: Watson Erica D. , Cross James C.
Published: May 2005

The placenta is essential for sustaining the growth of the fetus during gestation, and defects in its function result in fetal growth restriction or, if more severe, fetal death. Several molecular pathways have been identified that are essential for development of the placenta, and mouse mutants offer new insights into the cell biology of placental development and physiology of nutrient transport.
Gene expression profiling and phenotype analyses ofS. cerevisiaein response to changing copper reveals six genes with new roles in copper and iron metabolism
Authors: van Bakel Harm , Strengman Eric , Wijmenga Cisca , Holstege Frank C. P.
Published: May 2005

Exhaustive microarray time course analyses of Saccharomyces cerevisiae during copper starvation and copper excess reveal new aspects of metal-induced gene regulation. Aside from identifying targets of established copper- and iron-responsive transcription factors, we find that genes encoding mitochondrial proteins are downregulated and that copper-independent iron transport genes are preferentially upregulated, both during prolonged copper deprivation. The experiments also suggest the presence of a small regulatory iron pool that links copper and iron responses. One hundred twenty-eight genes with putative roles in metal metabolism were further investigated by several systematic phenotype screens. Of the novel phenotypes uncovered, hsp12-Δ and arn1-Δ display increased sensitivity to copper, cyc1-Δ and crr1-Δ show resistance to high copper, vma13-Δ exhibits increased sensitivity to iron deprivation, and pep12-Δ results in reduced growth in high copper and low iron. Besides revealing new components of eukaryotic metal trafficking pathways, the results underscore the previously determined intimate links between iron and copper metabolism and mitochondrial and vacuolar function in metal trafficking. The analyses further suggest that copper starvation can specifically lead to downregulation of respiratory function to preserve iron and copper for other cellular processes.
Colour Discrimination in the Black-Tufted-Ear Marmoset (Callithrix penicillata): Ecological Implications
Authors: Pessoa Daniel M.A. , Cunha Juliana F. , Tomaz Carlos , Pessoa Valdir F.
Published: May 2005

The dietary diversity of marmosets is substantial, which may reflect differences in their colour vision. This study examined the colour discrimination ability of a gummivore/insectivore callitrichid, Callithrix penicillata, which inhabits the Brazilian cerrado (bush savanna). A series of ecologically relevant tasks, involving a behavioural paradigm of discrimination learning in semi-natural conditions and the usage of ecologically relevant stimuli, was executed. Three marmosets, 2 males and a female, behaved like human dichromats, showing an impaired performance when orange and green stimuli had to be discriminated. In contrast, 2 females resembled human trichromats, discriminating those kinds of pairs. Our data suggest that Callithrix penicillata presents a polymorphic trichromacy, with dichromatic males and dichromatic or trichromatic females.
Primate Population Densities in Three Nutrient-Poor Amazonian Terra Firme Forests of South-Eastern Colombia
Authors: Palacios Erwin , Peres Carlos A.
Published: May 2005

We censused primate populations at three non-hunted ‘terra firme’ forests of south-eastern Colombian Amazonia. The aggregate biomass densities of diurnal primates at all sites were amongst the lowest recorded for any non-hunted forest in western Amazonia and elsewhere in the Neotropics. Densities of red howler monkeys were low, as is typical in Amazonian terra firme forests far removed from white-water rivers, and densities of woolly monkeys were 1.5–3.5 times lower than those estimated for this species in central-western Brazilian Amazonia. Densities of small to mid-sized primates except for brown capuchins (Cebus apella) and white-faced capuchins (Cebus albifrons) were similar to those of other oligotrophic Amazonian forest sites. Our results are in agreement with other studies showing that terra firme forests of lowland Amazonia typically sustain a low biomass density of primates and other mid-sized to large vertebrates. Large reserves are therefore required to assure the viability of primate populations in oligotrophic systems. Given the escalating negative impacts of human habitat disturbance and hunting in Colombian Amazonia, we urge that a baseline sampling protocol to quantify the abundance and distribution of the harvest-sensitive vertebrate fauna be established within protected areas and the large indigenous reserves so that conservation efforts can be defined and implemented.
New Fossil Platyrrhine from Argentina
Authors: Tejedor Marcelo F.
Published: May 2005

A new fossil primate was found in the Pinturas Formation, south-western Patagonia, at the type locality of the rare Soriacebus ameghinorum. It is a mandibular fragment with two molars that strongly resemble those of S. ameghinorum in their high and closed trigonid, distal expansion of the talonid, small hypoconulid, buccal expansion of the enamel and similar cusp development. But the type of S. ameghinorum differs by having mesiodistally longer trigonids, long premetacristids and more oblique distal trigonid walls, with the metaconid more lingually placed and the postmetacristid distolingually oriented and with the talonid being buccolingually smaller than the trigonid with a more restricted basin. M2 is slightly smaller than in the new specimen, and the buccal enamel is less flared. Although it is difficult to determine if this new specimen represents an individual variation of S. ameghinorum or a new species of Soriacebus, its morphology appears to be less derived than that of the type mandible, and it is, therefore, of systematic significance.
A Comparative Study of Adult Facial Morphology and Its Ontogeny in the Fossil Macaque Macaca majori from Capo Figari, Sardinia, Italy
Authors: Rook Lorenzo , O’Higgins Paul
Published: May 2005

This study examines the morphology of the face in the fossil macaque Macaca majori from Capo Figari (north-eastern Sardinia, Italy) in a comparative ontogenetic context. Thus, a fairly complete face from an adult representative of this fossil species is compared with 3 extant macaque species: Macaca sylvanus (of which species it is questioned whether it is a subspecies, M. sylvanus majori), Macaca mulatta and Macaca fascicularis. Additional incomplete subadult and adult specimens are also examined in order to compare their facial ontogeny with that of the same living species. The comparisons are based on facial landmark data and are undertaken using geometric morphometric methods. These studies indicate that the adult facial morphology and ontogeny of face size and shape in M. majori share much in common with extant macaque species. However, the adult M. majori face displays some unique morphological features, in particular with regard to lateral flaring and relative size of the zygomatic roots. From the study of a limited sample of fossils there is an indication that this flaring arises during postnatal growth, and in consequence the ontogeny of the face of this fossil species may be different from that of M. sylvanus and the other macaque species included in this analysis. From these studies, we conclude that M. majori shows differences in adult facial morphology and possibly in ontogeny from M. sylvanus compatible with a specific rather than subspecific distinction.
Diclofenac-Na Gel Is Effective in Reducing the Pain and Inflammation Associated with Exposure to Ultraviolet Light – Results of Two Clinical Studies
Authors: Kienzler J.L. , Magnette J. , Queille-Roussel C. , Sanchez-Ponton A. , Ortonne J.P.
Published: May 2005

The potential of a diclofenac-Na EmulgelTM (diclofenac gel) to alleviate the pain and associated symptoms caused by sunburn has been evaluated versus vehicle. Sunburn was induced on the buttock skin of healthy adult male subjects by irradiation with UVA + UVB rays. Investigational products were applied 6 and 10 h after irradiation, and efficacy was assessed on the basis of spontaneous and provoked pain, erythema, oedema, skin colour and temperature. The minimal efficacious concentration evaluated in an extension (0.1 vs. 0.25% diclofenac gel) of a previous concentration-finding study (1, 0.5 and 0.25% diclofenac gel) was 0.1% and was efficacious in alleviating pain (spontaneous and provoked) as well as reducing erythema, oedema and skin temperature. In a single- versus 2-application comparison study, a single application of 0.1% gel was sufficient to alleviate the pain and accompanying symptoms of sunburn with an onset of action 2 h after application. A second application of gel 4 h after the first maintained the analgesia and reduction of other symptoms for a period of up to 48 h after irradiation.
Efficacy of an Aluminum Oxide Scrub Cream in the Treatment of Xerotic Skin of the Elderly
Authors: Andersen F. , Andersen K.H. , Kligman A.M.
Published: May 2005

Abrasive agents used as exfoliants in acne and xerotic skin conditions have been criticized for being double-edged swords that might create more skin damage than benefit due to exaggerated use. Paradoxically, it has been demonstrated that scrub creams may induce beneficial changes in human skin similar to treatment with topical tretinoin. In the present study, the efficacy of an aluminum-oxide-based scrub cream in combination with an α-hydroxy acid formulation was compared to the α-hydroxy acid formulation alone in 12 elderly female volunteers with itchy, xerotic leg skin. Following a 2-week washout period, the midportions of the lower lateral legs were treated with the combined treatment on one leg and with the α-hydroxy acid formulation on the other for 3 weeks. Clinical scoring, self-assessment as well as objective measurements of transepidermal water loss (TEWL) and hydration were performed at baseline and 3 days after the last treatment. In 3 volunteers, punch biopsies were obtained at the same time points. Both treatment strategies improved xerosis and pruritus, the combined treatment was statistically more effective. Hydration was not affected by the treatments, whereas TEWL was significantly reduced by both treatments, more so with the α-hydroxy acid formulation, indicating an improvement in barrier function. The clinical and instrumental findings were supported by histological findings following the combined treatment showing thickening of the epidermis and partial correction of epidermal atypia indicating increased epidermal proliferation. It appears that the combination treatment used in a controlled fashion has the potential for reversing some of the changes induced by photoaging. The changes induced are most likely due to unspecific mechanical stimulation of epidermal proliferation in combination with increased exfoliation.
Susceptibilities of Neisseria gonorrhoeae and Ureaplasma urealyticum Isolates from Male Patients with Urethritis to Several Antibiotics Including Telithromycin
Authors: Aydın Derya , Küçükbasmacı Ömer , Gönüllü Nevriye , Aktaş Zerrin
Published: May 2005

Background: The minimal inhibitory concentrations (MICs) of erythromycin, azithromycin, clarithromycin, telithromycin, tetracycline, doxycycline, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, gemifloxacin and moxifloxacin against 78 Neisseria gonorrhoeae and 31 Ureaplasma urealyticum strains, which were isolated from patients with urethritis in Istanbul, were determined and compared. Additionally, the activities of penicillin and ceftriaxone against N. gonorrhoeae strains were explored. Methods: MICs were determined by agar and broth dilution methods for N. gonorrhoeae and U. urealyticum, respectively. Results: The susceptibility rates for penicillin and tetracycline in N. gonorrhoeae strains were 35.9 and 24.3%, respectively. All gonococcal strains were susceptible to ceftriaxone, with very low MICs (MIC90 0.008 µg/ml). Telithromycin was highly active against N. gonorrhoeae and U. urealyticum strains (MIC90 0.25 µg/ml for both). Ciprofloxacin was the most active quinolone against N. gonorrhoeae (MIC90 0.008 µg/ml) while quinolone resistance was detected in a single strain (1.3%). Conclusions: Tetracycline and penicillin should not be the option in empirical treatment of N. gonorrhoeae infections due to the very low susceptibility rates. Ceftriaxone continues to be the first choice antibiotic in the treatment of gonococcal urethritis.
The Irinotecan/5-Fluorouracil Combination Induces Apoptosis and Enhances Manganese Superoxide Dismutase Activity in HT-29 Human Colon Carcinoma Cells
Authors: Grivicich Ivana , Regner Andréa , da Rocha Adriana B. , Kayser Guilherme B. , Schunemann Daniel P. , Grass Luciano B. , Alves Pedro A.G. , Henriques João A.P. , Schwartsmann Gilberto
Published: May 2005

Background: We examined whether induction of apoptosis and Mn-superoxide dismutase (Mn-SOD) and Cu,Zn-superoxide dismutase (Cu,Zn-SOD) activities were involved in the greater cytotoxicity of the irinotecan (CPT-11)/5-fluorouracil (5-FU) combination for human colon cancer cells when compared to both drugs alone. Methods: HT-29 and SNU-C4 human colon carcinoma cell lines were treated with 5-FU and CPT-11, then apoptosis was evaluated by flow cytometry and SOD activities were determined by polyacrylamide gel electrophoresis. Results: Enhanced apoptosis of HT-29 cells was observed with all treatments containing 5-FU in SNU-C4 cells; however, in HT-29 cells, apoptosis was enhanced only with the CPT-11/5-FU combination. In the SNU-C4 cell line, none of the treatments exerted a significant effect on Cu,Zn-SOD or Mn-SOD activity. However, in HT-29 cells, the CPT-11/5-FU combination enhanced Mn-SOD activity when compared to cells treated with CPT-11 alone. Nevertheless, the combined treatment did not interfere with Cu,Zn-SOD activity. Conclusion: Treatment with the CPT-11/5-FU combination may promote in HT-29 cell apoptosis by enhancing Mn-SOD activity.
Tapering and Discontinuation of Glucocorticoid Prophylaxis during Prolonged Weekly to Biweekly Paclitaxel Administration
Authors: Braverman Albert S. , Rao Sujatha , Salvatti Mary Ellen , Adamson Barbara , McManus Margaret , Pierre Shirley
Published: May 2005

Background: Taxanes cause hypersensitivity reactions, averted by premedication with H1 blockers and high glucocorticoid (GC) doses. Prolonged weekly taxane administration may lead to GC toxicity. Purpose: To determine whether patients not hypersensitive to initial paclitaxel (PTX) infusion after high-dose GC premedication will tolerate subsequent, prolonged PTX treatment without GC prophylaxis. Patients and Methods: In 115/122 breast cancer patients not hypersensitive to initial PTX treatment, 20 mg dexamethasone (DXM) doses were tapered by 2.0 mg/week, reaching 0 in those receiving 9 or more courses. After 4 PTX courses, diphenhydramine was administered orally, rather than intravenously. Results: PTX was administered 143 times after 2.0–5.0 mg of DXM and 357 times without DXM. A total of 46 patients received 1–40 PTX courses without DXM. None of these 115 patients experienced hypersensitivity reactions. Conclusion: Patients unreactive to their first PTX infusions, after high-dose and tapering GC premedication, may not require GC prophylaxis for subsequent PTX therapy.
A Phase II Study of Docetaxel and Infusional Cisplatin in Advanced Non-Small-Cell Lung Cancer
Authors: Mori Kiyoshi , Kamiyama Yukari , Kondo Tetsuro , Kano Yasuhiko , Kodama Tetsuro
Published: May 2005

Background: To evaluate the efficacy and safety of combination chemotherapy of cisplatin (5-day continuous infusion) and docetaxel for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Materials and Methods: Eligible patients had an ECOG performance status of 0–2 with measurable NSCLC. Patients received continuous infusion cisplatin 20 mg/m2/day on 5 days and bolus docetaxel 60 mg/m2/day (day 1; PiD therapy) at a 4-week interval. Results: Forty-three patients were enrolled. The mean number of cycles administered per patient was 2, and ranged from 1 to 4. The response rate was 49% (95% confidence interval, 33.9–63.8%). The median survival time was 47 weeks and the 1-year survival rate was 47%. The major toxic effects were grade 3 or 4, neutropenia (88%), leukopenia (81%), thrombocytopenia (14%) and anemia (42%). There were no treatment-related deaths. Conclusion: PiD therapy was a well-tolerated and active regimen for patients with advanced NSCLC. The major toxicity was neutropenia.
A Phase I Study of Prolonged Ambulatory Infusion of Ifosfamide with Oral Mesna
Authors: Olver Ian , Keefe Dorothy , Myers Melinda , Caruso Diana
Published: May 2005

Background: Oral mesna allows investigation of ifosfamide as a prolonged ambulatory infusion for dose-intense out-patient use. Methods: Cohorts of 3 patients received escalating doses of ifosfamide from 200 to 1,000 mg/m2/day as continuous ambulatory infusion with oral mesna at 30% of the ifosfamide dose every 6 h commencing 2 h prior to ifosfamide infusion as uroprotection on a 14-day schedule with cycles repeated every 28 days. Results: Fifteen patients received a median of three cycles.Dose-limiting toxicities with cycle 1 were lethargy and hepatotoxicity at 1,000 mg/m2/14 days. Transient transaminase elevation was seen at all dose levels. The other grade 3 toxicities were single episodes of anaemia, granulocytopenia, nausea and hypotension. The best response was stable disease in a patient with thyroid cancer. Conclusion: Ambulatory infusion of 600 mg/m2 ifosfamide with 180 mg/m2 oral mesna was considered suitable for phase II trials and delivers dose-intense out-patient therapy without urotoxicity.
Bacteremia in Patients with Hematological Malignancies
Authors: Wang Fu-Der , Lin Mei-Lin , Liu Cheng-Yi
Published: May 2005

Background: An appropriate regimen in the empirical therapy of neutropenic fever episodes must be individualized at each institution. Hospitals have different patterns of microbial isolates and antibiotic resistance that must be taken into account. The aim of this study was to investigate isolates of bacteremia and their antibiotic susceptibility in patients with hematological malignancies. Methods: All positive blood cultures at a medical center in Taiwan between 1999 and 2002 from patients with hematological malignancies were evaluated. Eleven kinds of antibiotics were tested for antimicrobial activities. The risk factors for mortality were evaluated. Results: Three hundred seventy-one episodes of bacteremia in 266 patients with hematological malignancies were recorded. Gram-negative bacilli (GNB) were still predominant and accounted for 78.2% of isolates, followed by gram-positive cocci for 20.8% of isolates, and anaerobes for 1% of isolates. Escherichia coli was the most common isolated organism accounting for 27.5% of GNB isolates. Other isolates included Klebsiella pneumoniae (19.3%), Pseudomonas aeruginosa (11%), and Enterobacter cloacae (10.1%). The most isolated microorganisms were susceptible to cefoperazone/sulbactam, piperacillin/tazobactam, cefepime or imipenem. Age, GNB microorganism and inadequate empirical antibiotics were risk factors. Conclusions: We suggest that cefoperazone/sulbactam, piperacillin/tazobactam, cefepime or imipenem is an ideal empirical therapy.
Binding Properties of Dipropyltryptamine at the Human 5-HT1a Receptor
Authors: Thiagaraj Harish V. , Russo Ethan B. , Burnett Andrea , Goldstein Eric , Thompson Charles M. , Parker Keith K.
Published: May 2005

Dipropyltryptamine (DPT) is a synthetic indolealkylamine first characterized in the 1960s. Largely forgotten since the discovery of multiple serotonin receptor subtypes, some of the properties of DPT at the cloned human 5-HT1a receptor are described here. When [3H]8-OH-DPAT is bound to the receptor, DPT inhibits the interaction with an IC50 of 0.1 µmol/l. This interaction is shown to be competitive when double-reciprocal plots of the DPT/agonist interaction are analyzed. DPT’s effects in the signal transduction system are complex. While DPT alone (0.1–1,000 µmol/l) activates Gi when both cAMP and γ-S-GTP incorporation are measured, in the presence of 5-HT (0.1–10 µmol/l), DPT blocks the agonist effect. In combination, the findings suggest that DPT is a moderate affinity partial agonist at the human 5-HT1a receptor. These results provide evidence that DPT has potential as a versatile experimental tool at 5-HT1a receptors.
Impact of Tuberculosis on Serum Leptin Levels in Patients with HIV Infection
Authors: Prabha C. , Karthic S. , Das Sulochana D. , Swaminathan Soumya , Subramaniam Sudha , Sukumar B.
Published: May 2005

Aim: Tuberculosis (TB) and human immunodeficiency virus (HIV) are classical wasting diseases accompanied by immunosuppression. As leptin is involved in the weight regulation and cellular immunity, we investigated the role of leptin levels in the co-infection of HIV and TB (HIV-TB). Methods: The study group consists of the patients with asymptomatic HIV infection (n = 20), patients with HIV-TB co-infection (n = 20) and healthy control subjects (n = 20). Serum leptin levels and the concentrations of IFN-γ, TNF-α, IL-12 and IL-4 cytokines were measured by ELISA before the start of the treatment. CD4+ T-cell counts were determined in patients with HIV and HIV-TB by flow cytometry. Body mass index (BMI) of the study subjects was calculated. Results: Serum leptin levels and BMI were significantly lower in the patients with HIV-TB than control and HIV subjects. Multivariate regression analysis showed that serum leptin concentration was significantly dependent on BMI and sex but not on age and the disease groups. The leptin levels did not correlate either with CD4+ T-cell counts or with any of the serum cytokines in HIV and HIV-TB patients. Conclusion: Thus our finding suggests that the leptin concentrations were strongly associated with BMI and gender but not with the disease state or with the circulating cytokine levels.
Economic Burdens and Quality of Life of Family Caregivers of Cancer Patients
Authors: Yun Young Ho , Rhee Young Sun , Kang Im Ok , Lee Jung Suk , Bang Soo Mee , Lee Won Sup , Kim Jun Suk , Kim Si Young , Shin Sang Won , Hong Young Seon
Published: May 2005

Objectives: We conducted this study to identify factors influencing the burdens cancer brings to a patient’s family and to evaluate the association between the burdens and the caregiver’s quality of life (QOL). Methods: Participants were drawn from the primary family caregivers of cancer patients at 6 university hospitals and the National Cancer Center in Korea. Of the 738 eligible caregivers, 704 (95.4%) completed the questionnaire packets (Family Impact Questions and Caregiver’s QOL-Cancer). Results: Caregivers, who were poor (OR, 2.11; 95% CI, 1.44–3.10), whose health status was poor (OR, 1.87; 95% CI, 1.29–2.70), who were married (OR, 1.75; 95% CI, 1.12–2.72), who provided care for a long time (OR, 2.29; 95% CI, 1.59–3.28), who cared for patients with poor performance status (OR, 1.35; 95% CI, 1.00–1.82), and who paid high medical expenses (OR, 1.70; 95% CI, 1.21–2.40), were more likely to lose their family savings. In multiple regression analysis, most burden variables – including requiring caregiving assistance, major life change, inability to function normally, loss of savings, loss of income, and altered educational plans – were associated with caregiver QOL. Loss of family income, which was related to economic issues, was most strongly associated with it (16.0%). Conclusions: Our study suggests that to improve caregiver QOL, we should give priority to decreasing the economic burden that cancer places on patient’s family.
Bedside Estimation of the Glomerular Filtration Rate in Hospitalized Elderly Patients
Authors: Burkhardt Heinrich , Hahn Thomas , Gretz Norbert , Gladisch Rainer
Published: May 2005

Aims: To evaluate the quality of bedside estimation of glomerular filtration rate (GFR) in hospitalized elderly patients. Methods: We evaluated common estimators of GFR in 29 women and 32 men aged 60 and older hospitalized in a geriatric ward: creatinine clearance (CCR), the Cockcroft-Gault formula (CG), the modification of diet in renal disease formula (MDRD), Baracskay formula (BAR), and a newly developed formula derived recently by us (GCM). Inulin clearance (CINU) was used to assess GFR. Exclusion criteria were mental illness and urinary incontinence. Results: According to Bland and Altman accuracy and precision of all estimators were low and there was an underestimation of actual GFR: CCR 38.9 ml/min; CG 39.7 ml/min; MDRD 19.8 ml/min; BAR 34.0 ml/min, and GCM: 24.7 ml/min. The accuracy and precision of all methods were even lower in patients with a GFR of >90 ml/min and in patients with diabetes. In receiver-operating characteristics (ROC analysis) all formulas were superior to serum creatinine and overall MDRD disclosed the best results in detecting both a GFR of <90 ml/min and <60 ml/min. Conclusions: In general, estimation errors are large in an acute care setting. However, formula estimation is clearly superior to serum creatinine and CCR. MDRD gave the best results but may be replaced by the more simple CG and GCM formulas, whereas BAR was inferior.
Fabry Disease in Patients with End-Stage Renal Failure: The Potential Benefits of Screening
Authors: Bekri Soumeya , Enica Adrian , Ghafari Thomas , Plaza Gisèle , Champenois Isabelle , Choukroun Gabriel , Unwin Robert , Jaeger Philippe
Published: May 2005

Background/Aims: α-Galactosidase A (α-GLA) deficiency (Fabry disease) is an X-linked lysosomal storage disorder. The associated visceral complications are progressive and multiorgan; renal involvement is common, usually leading to end-stage renal failure (ESRF). The reported benefits of specific enzyme replacement therapy (ERT) indicate the importance of screening for Fabry disease in high-risk populations, as this approach should make it possible to identify other family members with little or no clinical features of the disease, and for them to be considered for early preventive treatment. Methods: We screened for Fabry disease in 106 patients on hemodialysis in our hospital-based hemodialysis unit. We did this by measuring α-GLA enzyme activity in blood leukocytes taken from each patient and we then carried out gene analysis when indicated. Results: We were able to discover 1 patient with low residual α-GLA activity (a prevalence of 0.94%). α-GLA gene analysis identified a point mutation within the coding region producing a N215S amino acid substitution in the protein. Among the relatives of this index case, molecular testing found 7 family members with the same N215S α-GLA mutation. Of these, 3 had reduced α-GLA activity and clinical features of Fabry disease, and for which ERT was subsequently given. Conclusion: Screening for Fabry disease is simple and although the yield is small, it is potentially significant and of possible benefit to the relatives of affected cases in this ‘at-risk’ ESRF population, many of who do not have a clear renal diagnosis.
The N- and L-Type Calcium Channel Blocker Cilnidipine Suppresses Renal Injury in Dahl Rats Fed a High-Sucrose Diet, an Experimental Model of Metabolic Syndrome
Authors: Konda Tomoyuki , Enomoto Azusa , Matsushita Junko , Takahara Akira , Moriyama Toshiki
Published: May 2005

Background/Aims: The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress progressive renal disease in a variety of experimental models, but the characteristic effects of N-type calcium channel blocking action on renal injury have not been examined in detail. Therefore, we investigated the beneficial effects of cilnidipine on renal injury in Dahl salt-sensitive (Dahl S) rats fed a high-sucrose diet (HSD), which mimics metabolic syndrome, and compared them with the effects of an L-type CCB, amlodipine. Methods: Male Dahl S rats were divided into groups with similar blood pressure at 8 weeks of age and fed an HSD. They received vehicle, cilnidipine or amlodipine for 27 weeks. At 35 weeks of age, urine and blood samples were collected for physiological analysis, and the kidneys were removed for histopathological evaluation. Results: Cilnidipine reduced albuminuria, glomerular hypertrophy, glomerular expression of ICAM-1, ED-1-positive cell infiltration and interstitial fibrosis compared with vehicle-treated rats. In contrast, amlodipine had no effect on these parameters. Urinary norepinephrine excretion, renal expression of renin mRNA and renal tissue levels of angiotensin II were increased only in the amlodipine-treated group. Conclusion: Cilnidipine provided superior protection against renal damage compared with amlodipine in Dahl S rats given an HSD. The different effects between these two drugs may be partly explained by their different actions on the renal sympathetic nerve activity and the renin-angiotensin system through the N-type calcium channel blocking action.
Lipopolysaccharide-Induced Cytokine and Chemokine Expression in Human Carotid Lesions
Authors: Jatta Ken , Wågsäter Dick , Norgren Lars , Stenberg Björn , Sirsjö Allan
Published: May 2005

The release of cytokines and chemokines from activated immune-competent cells plays a crucial role in determining the pathology of the atherogenic progress. We investigated the effect of bacterial lipopolysaccharide (LPS) on cytokine/chemokine expression in carotid lesions and normal renal arteries. The lesions or renal arteries were incubated for 6 h at 37°C in serum-free media treated with or without LPS. After LPS treatment, increased protein levels of IL-1β, IL-6, IL-8, IL-10, TNF-α and MCP-1 were observed in the culture medium from the lesions measured with cytometric bead array. We were able to detect the induction of IL-1β, IL-6, IL-8, IL-10, TNF-α and MCP-1 mRNA in the lesions after stimulation with LPS using real-time PCR. In renal arteries, LPS also induces mRNA expression of all chemokines and cytokines investigated with the exception of IL-6. However, LPS induces significantly higher levels of TNF-α, IL-1β and IL-10 mRNA in lesions compared to renal arteries. The results suggest that infectious agents are capable of enhancing the production of cytokines/chemokines in an already ongoing inflammatory process such as in atherosclerosis, and that low levels of circulating LPS may affect the levels of pro-inflammatory cytokines much more in atherosclerotic vessels than in normal vessels and may contribute to the development of the atherosclerotic lesion.
Combined Systemic Chronotherapy and Hepatic Artery Infusion for the Treatment of Metastatic Colorectal Cancer Confined to the Liver
Authors: Shimonov Mordechai , Hayat Henry , Chaitchik Samario , Brener Joseph , Schachter Pinhas , Czerniak Abraham
Published: May 2005

Background: The optimal treatment of patients with metastatic colorectal cancer is still a clinical challenge. We describe the use of combined hepatic arterial infusion (HAI) of irinotecan (CPT-11) in conjunction with systemic chronotherapy infusion of 5-fluorouracil (5FU), folinic acid and carboplatin in patients with colorectal liver metastases. Methods: Twenty-three patients with colorectal cancer and isolated liver metastases were enrolled in this trial. Intraoperative insertion of an intra-arterial catheter into the hepatic artery was accomplished during the colon operation (in cases of synchronous tumor) or as a separate procedure in colorectal cancer patients with newly diagnosed liver metastases. A systemic double-lumen double-chamber port was inserted via the subclavian vein as a separate procedure. The treatment plan included irinotecan given by intra-arterial infusion at 150 mg/m2 for 1 h. After 2 weeks of rest chronomodulated 5FU (700 mg/m2; peak delivery rate at 04:00 h), leucovorin (175 mg/m2; peak delivery rate at 04:00 h) and carboplatin (40 mg/m2; peak delivery rate at 16:00 h) for 4 days was followed by 10 days’ rest and then given again. After 10 days’ rest another HAI was introduced using the same method. Each cycle of therapy included 2 HAI courses and 2 chronotherapy courses in between. After 2 complete cycles, patients were evaluated for their response with weekly accessed toxicity recording. Results: Seven women, 8 men, median age 61 years (range 46–72). Eight patients had synchronous colon and hepatic disease and 7 patients had metachronous disease. Ten patients had previously been treated with 5FU and leucovorin while 5 patients were chemonaive. The mean number of cycles were 11.6 per patient (range 8–19). Partial response was achieved in 6 patients (40%) and was followed by laparoscopic radiofrequency ablation in 5 patients (33%). Disease stabilization was observed in 2 patients (13%) and disease progression in 7 patients (47%) mainly after previous chemotherapy failure. Side effects were infrequent and mild including grade 2 GIT complaints (5 patients), RUQ pain during HAI (9 patients) and grade 2 hematological complaints in 2 patients. Conclusion: A combined chemotherapy protocol (HAI and chronotherapy) with irinotecan (CPT-11) together with chronomodulated infusion of 5FU, folinic acid and carboplatin can be used in metastatic colorectal patients with a high efficacy rate and minor side effects especially in pretreated patients.
Factor VIII efficient and specific non-covalent binding to PEGylated liposomes enables prolongation of its circulation time and haemostatic efficacy
Authors: Carmel-Goren Lea , Barenholz Yechezkel , Dayan Inbal , Ostropolets Savely , Slepoy Igal , Gvirtzer Nira , Fukson Vladimir , Spira Jack , Baru Moshe
Published: May 2005

Haemophilia A is a bleeding disorder caused by the lack of factor VIII (FVIII). We report the prolongation of exogenous FVIII circulation time and haemostatic efficacy by its formulation with PEGylated liposomes (PEGLip). FVIII binds non-covalently but with high affinity in a specific mode with the external surface of PEGLip neither losing its activity nor its binding to von Willebrand Factor. Experiments in haemophilic and non-haemophilic mice indicate that the circulation time and clotting efficacy of PEGLip-formulated exogenous FVIII (PEGLip-FVIII) are significantly enhanced over those of free FVIII. The data support the feasibility of using PEGLip-FVIII to extend the duration of haemostatic efficacy in the treatment of haemophilia A.
Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers
Authors: Maris Nico , de Vos Alex , Bresser Paul , van der Zee Jaring , Meijers Joost , Lijnen Roger , Levi Marcel , Jansen Henk , van der Poll Tom
Published: May 2005

Pneumonia is frequently associated with changes in coagulation and fibrinolysis in the bronchoalveolar space. To determine the effect of lipopolysaccharide (LPS) on the hemostatic balance in the human lung, six healthy subjects inhaled nebulized LPS or saline in a randomized cross-over study and bronchoalveolar lavage fluid was obtained six hours thereafter. LPS induced soluble tissue factor and thrombin-antithrombin complexes and inhibited plasminogen activator activity in BALF. Additionally plasminogen activator inhibitor type 1 production was upregulated after LPS inhalation. LPS also elicited local activation of neutrophils (release of elastase, myeloperoxidase and bactericidal/permeability increasing protein) and secretion of interleukin (IL)-6 and IL-8. Inhalation of LPS by healthy humans reproduces major features of the procoagulant response to inflammatory and infectious lung diseases and may be used as a novel model to evaluate pathogenetic mechanisms and new interventions.