bluuebunny/crossref_metadata_2025 huggingface dataset:
Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis
Authors: Cerboni Cristina , Zingoni Alessandra , Cippitelli Marco , Piccoli Mario , Frati Luigi , Santoni Angela
Published: April 2007

Recent evidence indicates that natural killer (NK) cells can negatively regulate T-cell responses, but the mechanisms behind this phenomenon as a consequence of NK–T-cell interactions are poorly understood. We studied the interaction between the NKG2D receptor and its ligands (NKG2DLs), and asked whether T cells expressed NKG2DLs in response to superantigen, alloantigen, or a specific antigenic peptide, and if this rendered them susceptible to NK lysis. As evaluated by FACS, the major histocompatibility complex (MHC) class I chain-related protein A (MICA) was the ligand expressed earlier on both CD4+ and CD8+ T cells in 90% of the donors tested, while UL16-binding protein-1 (ULBP)1, ULBP2, and ULBP3 were induced at later times in 55%–75% of the donors. By carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, we observed that NKG2DLs were expressed mainly on T cells that had gone through at least one division. Real-time reverse-transcription polymerase chain reaction confirmed the expression of all NKG2DLs, except ULBP4. In addition, T-cell activation stimulated phosphorylation of ataxia-telangiectasia mutated (ATM), a kinase required for NKG2DLs expression after DNA damage, and ATM/Rad3-related kinase (ATR) inhibitors blocked MICA induction on T cells with a mechanism involving NF-κB. Finally, we demonstrated that activated T cells became susceptible to autologous NK lysis via NKG2D/NKG2DLs interaction and granule exocytosis, suggesting that NK lysis of T lymphocytes via NKG2D may be an additional mechanism to limit T-cell responses.
Sickle cell trait and the risk of venous thromboembolism among blacks
Authors: Austin Harland , Key Nigel S. , Benson Jane M. , Lally Cathy , Dowling Nicole F. , Whitsett Carolyn , Hooper W. Craig
Published: April 2007

People with sickle cell disease have a chronically activated coagulation system and display hemostatic perturbations, but it is unknown whether they experience an increased risk of venous thromboembolism. We conducted a case–control study of venous thromboembolism that included 515 hospitalized black patients and 555 black controls obtained from medical clinics. All subjects were assayed for hemoglobin S and hemoglobin C genotypes. The prevalence of the S allele was 0.070 and 0.032 for case patients and controls, respectively (P < .001). The odds that a patient had sickle cell trait were approximately twice that of a control, indicating that the risk of venous thromboembolism is increased approximately 2-fold among blacks with sickle cell trait compared with those with the wild-type genotype (odds ratio = 1.8 with 95% confidence interval, 1.2-2.9). The odds ratio for pulmonary embolism and sickle cell trait was higher, 3.9 (2.2-6.9). The prevalence of sickle cell disease was also increased among case patients compared with controls. We conclude that sickle cell trait is a risk factor for venous thromboembolism and that the proportion of venous thromboembolism among blacks attributable to the mutation is approximately 7%.
Service innovation: assertive outreach teams for adults with learning disability
Authors: Prakash Jamuna , Andrews Tim , Porter Ian
Published: April 2007

Assertive community treatment (ACT) was developed in the early 1970s as a means of coordinating the care of people with severe mental illness in the community. A Cochrane review of the effectiveness of ACT for the general adult population found that people receiving ACT were more likely to engage with services, and were less likely to be admitted to hospital (Marshall & Lockwood, 2000). The National Service Framework for Mental Health (Department of Health, 1999) and the NHS Plan (Department of Health, 2000) called for a total of 220 assertive outreach teams by April 2003.
Patient feedback on services: a questionnaire survey approach
Authors: Kumar Palanivelu S. , McBride Andrew
Published: April 2007

Aims and Method

The aims of the project were to develop a simple, low-cost patient satisfaction questionnaire with face validity and to obtain patient feedback on a range of service areas in a community addiction team. A questionnaire was designed and revised after feedback from multidisciplinary team members and a pilot sample. The questionnaire was distributed until 100 correctly completed forms were received.

Results

The survey took approximately 30 h of authors' time from commencement to completion and costs were minimal. The majority of the 12 areas evaluated were rated by patients as good or very good. Overall quality of care was rated as good or very good by 88% of participants. There was no enthusiasm in this sample for more active participation in service development.

Clinical Implications

All National Health Service staff and services are now enjoined to engage with service users and carers for the purposes of evaluation and development. Simple, affordable methods for obtaining such information about community services can contribute to this process.
Local clinical attachment scheme in psychiatry
Authors: White Oliver , Malik Amit , Bagalkote Hemant
Published: April 2007

Clinical attachments are an essential step in the process by which international medical graduates (IMGs) secure training posts in the UK. Although the British Medical Association (BMA) provides general guidelines for clinical attachments, the current system lacks a structured process regarding selection, defined length of posts, predetermined contents of training and detailed guidance for consultants supervising clinical attachments in psychiatry. This article outlines the experience in Nottingham of developing a formalised clinical attachment scheme and includes the lessons learnt and difficulties faced during the process. Also presented are the results of feedback surveys from consultants and IMGs who have partaken in the new formalised scheme.
Bilateral Adrenal Infiltration in Erdheim-Chester Disease. Report of Seven Cases and Literature Review
Authors: Haroche Julien , Amoura Zahir , Touraine Philippe , Seilhean Danielle , Graef Claire , Birmelé Béatrice , Wechsler Bertrand , Cluzel Philippe , Grenier Philippe A. , Piette Jean-Charles
Published: April 2007

Context: Erdheim-Chester disease (ECD) is a rare non-Langerhans form of histiocytosis characterized by xanthomatous tissue infiltration with CD68+ CD1a− foamy histiocytes. Endocrine problems, such as diabetes insipidus and hypogonadotropic hypogonadism, frequently occur in ECD, but bilateral adrenal infiltration has rarely been reported in this disease.

Objective: The aim of the study was to describe adrenal and periadrenal infiltration in ECD.

Patients: A total of 22 patients with ECD undergoing systematic computed tomography to search for signs of adrenal enlargement participated in the study.

Results: Of the 22 patients with ECD, seven (31.8%) displayed adrenal infiltration on computed tomography. In one case, autopsy confirmed that the adrenal enlargement was due to foamy histiocyte infiltration in the adrenal glands. Possible adrenal insufficiency was assessed in five of the seven patients. One developed signs of adrenal insufficiency, which was confirmed by adrenocorticotropin stimulation tests. Adrenal involvement was reported in only 15 of the 240 ECD cases published up to May 2006. This frequency is significantly lower than that in our series (P = 0.0008; Fisher’s exact test).

Conclusion: Physicians should be aware of ECD as a possible cause of morphological changes in adrenal size and infiltration.
Evidence of Prolonged Orocecal Transit Time and Small Intestinal Bacterial Overgrowth in Acromegalic Patients
Authors: Resmini Eugenia , Parodi Andrea , Savarino Vincenzo , Greco Alfredo , Rebora Alberto , Minuto Francesco , Ferone Diego
Published: April 2007

Context: Gastrointestinal abnormalities in acromegaly include dolichomegacolon, slow colonic transit, and increased prevalence of colonic polyps. Conversely, no data are available on the small intestine.

Objective: The aim of the study was to investigate the orocecal transit time (OCTT) and the presence of small intestinal bacterial overgrowth (SIBO).

Patients: A total of 41 acromegalic patients and 30 sex- and age-matched control subjects entered the study. Acromegalic patients were classified according to the medical treatment with somatostatin analogs as “treated” (n = 22) and “untreated” (n = 19), whereas according to the disease control, as “controlled” (n = 17), “uncontrolled” (n = 10), and “partially controlled” (n = 14). Patients and controls completed a questionnaire and underwent a standardized 10-g lactulose hydrogen breath test to determine the OCTT and presence of SIBO. SIBO-positive patients underwent eradication with rifaximine.

Results: An increased prevalence of SIBO (18 of 41 vs. 1 of 30; P < 0.0001) and a significantly delayed OCTT (169.53 ± 8.15 vs. 107.25 ± 6.56 min; P < 0.0001) were evidenced in patients compared with controls. No significant statistical differences were found between “treated” or “untreated” patients positive for SIBO or between “controlled,” “partially controlled,” and “uncontrolled” patients. OCTT was significantly delayed in “treated” vs. “untreated” patients (183.21 ± 9.01 and 158.89 ± 6.38, respectively; P = 0.02) and in patients compared with controls (105.75 ± 6.34; P < 0.0001). Rifaximine eradicated SIBO in more than 50% of patients who underwent treatment.

Conclusions: These data demonstrate for the first time that SIBO occurs more frequently in acromegalic patients, however, it can be successfully treated by a specific antibiotic. Medical therapy with somatostatin analogs does not affect SIBO prevalence. OCTT resulted significantly prolonged in both “treated” and “untreated” patients, suggesting that acromegaly determines per se an impairment of the intestinal motility. Indeed, disease control seems irrelevant on the delayed OCTT, suggesting that this alteration might be an irreversible complication of acromegaly, probably related to an autonomic intestinal disorder, as we have previously demonstrated at the cardiac level.
Transforming Growth Factor β Is a Critical Regulator of Adult Human Islet Plasticity
Authors: Hanley Stephen , Rosenberg Lawrence
Published: April 2007

Tissue plasticity is well documented in the context of pancreatic regeneration and carcinogenesis, with recent reports implicating dedifferentiated islet cells both as endocrine progenitors and as the cell(s) of origin in pancreatic adenocarcinoma. Accordingly, it is noteworthy that accumulating evidence suggests that TGFβ signaling is essential to pancreatic endocrine development and maintenance, whereas its loss is associated with the progression to pancreatic adenocarcinoma. The aim of this study was to examine the role of TGFβ in an in vitro model of islet morphogenetic plasticity. Human islets were embedded in a collagen gel and cultured under conditions that induced transformation into duct-like epithelial structures (DLS). Addition of TGFβ caused a dose-dependent decrease in DLS formation. Although it was demonstrated that collagen-embedded islets secrete low levels of TGFβ, antibody-mediated neutralization of this endogenously released TGFβ improved DLS formation rates, suggesting local TGFβ concentrations may in fact be higher. Time course studies indicated that TGFβ signaling was associated with an increase in ERK and p38 MAPK phosphorylation, although inhibitor-based studies were consistent with an islet endocrine-stabilizing effect mediated by p38 alone. Localization of TGFβ signaling molecules suggested that the action of TGFβ is directly on the β-cell to inhibit apoptosis and thus stabilize endocrine phenotype.
pH-Sensitive liposomes-principle and application in cancer therapy
Authors: Karanth H , Murthy R S R
Published: April 2007

The purpose of this review is to provide an insight into the different aspects of pH-sensitive liposomes. The review consists of 6 parts: the first introduces different types of medications made in liposomal drug delivery to overcome several drawbacks; the second elaborates the development of pH-sensitive liposomes; the third explains diverse mechanisms associated with the endocytosis and the cytosolic delivery of the drugs through pH-sensitive liposomes; the fourth describes the role and importance of pH-sensitive lipid dioleoylphosphatidylethanolamine (DOPE) and research carried on it; the fifth explains successful strategies used so far using the mechanism of pH sensitivity for fusogenic activity; the final part is a compilation of research that has played a significant role in emphasizing the success of pH-sensitive liposomes as an efficient drug delivery system in the treatment of malignant tumours. pH-Sensitive liposomes have been extensively studied in recent years as an amicable alternative to conventional liposomes in effectively targeting and accumulating anti-cancer drugs in tumours. This research suggests that pH-sensitive liposomes are more efficient in delivering anti-cancer drugs than conventional and long-circulating liposomes due to their fusogenic property. Research focused on the clinical and therapeutic side of pH-sensitive liposomes would enable their commercial utility in cancer treatment.
Synthesis and evaluation of ampicillin-conjugated gum arabic microspheres for sustained release
Authors: Nishi K K , Antony M , Jayakrishnan A
Published: April 2007

Ampicillin was conjugated to periodate-oxidized gum arabic (GA), a branched polysaccharide, to form the imino conjugate of the drug and the polysaccharide. The water-soluble conjugate was dispersed by sonication in a mixture of toluene and liquid paraffin in the presence of a non-ionic surfactant as droplet stabilizer and fabricated into microspheres by heat denaturation at 80°C to obtain spheres less than 2 μm in diameter. These microspheres did not undergo dissolution in water on prolonged incubation. In-vitro release of ampicillin into phosphate buffer from the microspheres was slow and sustained with a cumulative release between 10 and 25% of the drug content in 10 days depending on the degree of oxidation of GA and the drug payload. Release into simulated gastric fluid was faster due to faster hydrolysis of the drug-GA bond in the acid medium, but when the medium was changed to intestinal fluid, the release was slowed down. Ampicillin released was functionally active and inhibited the growth of S. aureus and E. coli in cultures, although not as actively as free ampicillin. The microspheres underwent slow biodegradation on prolonged incubation in aqueous media. These studies show that ampicillin conjugated with oxidized GA and fabricated into microspheres possesses sustained-release characteristics for prolonged periods.
Pharmacokinetic modelling of pentoxifylline and lisofylline after oral and intravenous administration in mice
Authors: Wyska Elzbieta , Szymura-Oleksiak Joanna , Pȩkala Elżbieta , Obruśnik Anna
Published: April 2007

The aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(-)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis-Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration-time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis-Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration-time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans.
Transport and metabolism of MitoQ10, a mitochondria-targeted antioxidant, in Caco-2 cell monolayers
Authors: Li Yan , Fawcett J Paul , Zhang Hu , Tucker Ian G
Published: April 2007

Mitoquinone (MitoQ10 mesylate) is a mitochondria-targeted antioxidant formulated for oral administration in the treatment of neurodegenerative diseases. We have investigated the absorption and metabolism of MitoQ10 in Caco-2 cell monolayers. The intracellular accumulation of MitoQ10 was 18–41% of the total amount of MitoQ10 added. Some of the intracellular MitoQ10 was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Transport of MitoQ10 was polarized with the apparent permeability (Papp) from basolateral (BL) to apical (AP) (PappBL→AP) being >2.5-fold the Papp from apical to basolateral (PappAP→BL). In the presence of 4% bovine serum albumin on the basolateral side, the PappAP→BL value increased 7-fold compared with control. The PappBL→AP value decreased by 26, 31 and 61% in the presence of verapamil 100 μM, ciclosporin 10 and 30 μM, respectively, whereas the PappAP→BL value increased 71% in the presence of ciclosporin 30 μM. Apical efflux of mitoquinol sulfate and mitoquinol glucuronide conjugates was significantly decreased by ciclosporin 30 μM and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 μM, respectively. These results suggested that the bioavailability of MitoQ10 may be limited by intracellular metabolism and the action of P-glycoprotein and BCRP. However, the dramatic increase in absorptive Papp in the presence of bovine serum albumin on the receiver side suggests these barrier functions may be less significant in-vivo.
Site-specific bidirectional efflux of 2,4-dinitrophenyl-S-glutathione, a substrate of multidrug resistance-associated proteins, in rat intestine and Caco-2 cells
Authors: Yokooji Tomoharu , Murakami Teruo , Yumoto Ryoko , Nagai Junya , Takano Mikihisa
Published: April 2007

The site-specific function of multidrug-resistance-associated proteins (MRPs), especially MRP2 and MRP3, was examined in rat intestine and human colon adenocarcinoma (Caco-2) cells. The MRP function was evaluated pharmacokinetically by measuring the efflux transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG), an MRP substrate, after application of 1-chloro-2,4-dinitrobenzene (CDNB), a precursor of DNP-SG. The expression of rat and human MRP2 and MRP3 was analysed by Western blotting. The rat jejunum exhibited a higher apical MRP2 and a lower basolateral MRP3 expression than ileum. In accordance with the expression level, DNP-SG efflux to the mucosal surface was significantly greater in jejunum, while serosal efflux was greater in ileum. Site-specific bidirectional efflux of DNP-SG was also observed in in-vivo studies, in which portal and femoral plasma levels and biliary excretion rate of DNP-SG were significantly higher when CDNB was administered to ileum. Caco-2 cells also showed a bidirectional efflux of DNP-SG. Probenecid, an MRP inhibitor, significantly suppressed the mucosal efflux in jejunum and serosal efflux in ileum. In contrast, probenecid significantly suppressed both apical and basolateral efflux of DNP-SG in Caco-2 cells, though the inhibition was of small magnitude. In conclusion, the efflux of DNP-SG from enterocytes mediated by MRPs exhibited a significant regional difference in rat intestine, indicating possible variability in intestinal bioavailabilities of MRP substrates, depending on their absorption sites along the intestine.
Protective action of 9-hydroxypinoresinol against oxidative damage in brain of mice challenged with kainic acid
Authors: Cui Hui Song , Sok Dai-Eun , Min Byung Sun , Kim Mee Ree
Published: April 2007

The neuroprotective effect of 9-hydroxypinoresinol was examined in mice challenged with kainic acid (KA), a potent central nervous system excitotoxin. For this purpose, mice were administered intraperitoneally with 9-hydroxypinoresinol before KA injection. A remarkable neuroprotective effect was observed with a single dose of 9-hydroxypinoresinol (30 mg kg−1) 24 h before KA challenge. Furthermore, 9-hydroxypinoresinol (20 mg kg−1) administered for 3 days before KA challenge reduced the mortality (60%) induced by KA to zero, and alleviated behavioural signs of KA neurotoxicity. Additionally, pretreatment with 9-hydroxypinoresinol (20 mg kg−1) prevented the decrease in the levels of total glutathione (GSH) and thiobarbituric acid reactive substances (P <0.05). GSH peroxidase activity in brain tissue was restored to control levels, although GSH reductase activity and GSH S-transferase activity were not affected. Such a protective action was also observed even with a lower dose (10 mg kg−1) of 9-hydroxypinoresinol administered for 3 days, albeit to a lesser extent. From the results, it is proposed that 9-hydroxypinoresinol exerts a potent neuroprotective effect mainly by preventing oxidative stress in brain tissue of mice challenged with KA.
Amides fromPiper nigrumL. with dissimilar effects on melanocyte proliferation in-vitro
Authors: Lin Zhixiu , Liao Yonghong , Venkatasamy Radhakrishnan , Hider Robert C , Soumyanath Amala
Published: April 2007

Melanocyte proliferation stimulants are of interest as potential treatments for the depigmentary skin disorder, vitiligo. Piper nigrum L. (Piperaceae) fruit (black pepper) water extract and its main alkaloid, piperine (1), promote melanocyte proliferation in-vitro. A crude chloroform extract of P. nigrum containing piperine was more stimulatory than an equivalent concentration of the pure compound, suggesting the presence of other active components. Piperine (1), guineensine (2), pipericide (3), N-feruloyltyramine (4) and N-isobutyl-2E, 4E-dodecadienamide (5) were isolated from the chloroform extract. Their activity was compared with piperine and with commercial piperlongumine (6) and safrole (7), and synthetically prepared piperettine (8), piperlonguminine (9) and 1-(3, 4-methylenedioxyphenyl)-decane (10). Compounds 6–10 either occur in P. nigrum or are structurally related. Compounds 1, 2, 3, 8 and 9 stimulated melanocyte proliferation, whereas 4, 5, 6, 7 and 10 did not. Comparison of structures suggests that the methylenedioxyphenyl function is essential for melanocyte stimulatory activity. Only those compounds also possessing an amide group were active, although the amino component of the amide group and chain linking it to the methylenedioxyphenyl group can vary. P. nigrum, therefore, contains several amides with the ability to stimulate melanocyte proliferation. This finding supports the traditional use of P. nigrum extracts in vitiligo and provides new lead compounds for drug development for this disease.
Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase
Authors: McNally Virginia A , Rajabi Mehdi , Gbaj Abdul , Stratford Ian J , Edwards Philip N , Douglas Kenneth T , Bryce Richard A , Jaffar Mohammed , Freeman Sally
Published: April 2007

A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low μM range. The absence of a methylene bridge between the uracil and the imidazolyl sub-units (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding.
Hypothermic effects of hops are antagonized with the competitive melatonin receptor antagonist luzindole in mice
Authors: Butterweck Veronika , Brattstroem Axel , Grundmann Oliver , Koetter Uwe
Published: April 2007

Hops (Humulus lupulus, Cannabinaceae) has been used in traditional European medicine as a mild sedative for the treatment of anxiety, nervousness, and insomnia. However, there has been little information available about the underlying sleep inducing mechanism of hops. We have investigated the effects of a hops extract on the rectal body temperature in mice. Hops extract (250 mg kg−1) significantly decreased body temperature in male BL6/C57J mice (ΔT −0.75 ± 0.07°C) 2 h after oral administration. The effects of the plant extract were comparable with melatonin (50 mg kg−1; ΔT −0.66 ± 0.06°C; 2 h after i.p. injection). The hypothermic effects of melatonin and hops extract were antagonized with the competitive melatonin receptor antagonist luzindole. Thus, our data suggests that the hypothermic-and therefore the sleep-inducing-effects of hops extract are possibly mediated through activation of melatonin receptors.
Antioxidant and anticancer activity of 3‘-formyl-4’, 6‘-dihydroxy-2’-methoxy-5‘-methylchalcone and (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone
Authors: Ye Chun-Lin , Liu Yu , Wei Dong-Zhi
Published: April 2007

Two new flavonoids - 3′-formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) and (2S)-8-formyl-5-hydroxy-7-methoxy-6-methylflavanone (FMF) - isolated from the buds of Cleistocalyx operculatus, were investigated for their antioxidant and anticancer activity. Total antioxidant activity and reducing ability were measured. 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and superoxide anion radical scavenging assays were carried out to evaluate the antioxidant potential of the two compounds. The antioxidant activity of the two compounds increased in a concentration-dependent manner. FMC and FMF at a concentration of 500 μM inhibited lipid peroxidation by 64.3 ± 2.5% and 60.3 ± 2.3%, respectively, an antioxidant activity approximately similar to that of 500 μM α-tocopherol (66.3 ± 2.5%). Similarly, the effect of FMC and FMF on reducing power increased in a concentration-dependent manner. In DPPH radical scavenging assays, the IC50 values of FMC and FMF were 50.2 ± 2.8 μM and 75.8 ± 2.5 μM, respectively. Moreover, FMC and FMF scavenged the superoxide generated by the phenazine methosulfate (PMS)/reduced β-nicotinamide adenine dinucleotide (NADH) nitroblue tetrazolium (NBT) system, with IC50 values of 56.3 ± 2.3 μM and 317.5 ± 2.9 μM, respectively. The anticancer activity of the two compounds were determined in five human cancer cell lines, SMMC-7721 (liver cancer), 8898 (pancreatic cancer), K562 (chronic leukaemia), HeLa (tumour of cervix uteri) and 95-D (high metastic lung carcinoma). FMC and FMF showed broad-spectrum anticancer activity against all the human cancer cell lines tested. The results obtained in the current study indicate that the two flavonoids could be a potential source of natural antioxidant and anticancer agents. To our knowledge, this is the first report on bioactivity of FMC and FMF.
Suppression of the NF-kB signalling pathway by ergolide, sesquiterpene lactone, in HeLa cells
Authors: Chun Jae Kwang , Seo Dong-Wan , Ahn Seong Hoon , Park Jae Hyun , You Jueng-Soo , Lee Chang-Hee , Lee Jae Cheol , Kim Yong Kee , Han Jeung-Whan
Published: April 2007

We have previously reported that ergolide, a sesquiterpene lactone isolated from Inula britannica, suppresses inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression by inhibiting nuclear factor-kB (NF-kB) in RAW 264.7 macrophages. In this study, we show that ergolide suppresses the DNA binding activity of NF-kB and nuclear translocation of NF-kB p65 subunit, leading to the inhibition of NF-kB-dependent gene transcription in 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated HeLa cells. We also show that ergolide decreases the degradation and phosphorylation of IkB, an inhibitory protein of NF-kB, and this effect is accompanied by a simultaneous reduction of IkB kinase (IKK) activity. However, ergolide does not inhibit in-vitro IKK activity directly, suggesting the possible involvement of upstream IKK kinases in the regulation of NF-kB activation. Furthermore, ergolide-mediated protein kinase Cα (PKCα) inhibition is involved in reduction of NF-kB inhibition, as demonstrated by the observation that dominant negative PKCα, but not p44/42 MAPK and p38 MAPK, inhibits TPA-stimulated reporter gene expression. Taken together, our results suggest that ergolide suppresses NF-kB activation through the inhibition of PKCα-IKK activity, providing insight for PKCα as a molecular target for anti-inflammatory drugs.
Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content
Authors: Modarai M , Gertsch J , Suter A , Heinrich M , Kortenkamp A
Published: April 2007

Echinacea preparations are one of the best selling herbal medicinal products with a well established therapeutic use in the prophylaxis of upper respiratory tract infections. Their consumption is increasing, but information about their ability to inhibit cytochrome P450 enzymes (CYP) is fragmentary. The picture is further complicated by a lack of phytochemical characterization of previously tested preparations. Due to its well characterized immunomodulatory activity, the standardized Swiss registered Echinacea purpurea (L.) Moench Echinaforce extract was selected for detailed study. With the single baculovirus-expressed CYP isoforms 1A2, 2C19, 2D9 and 3A4, inhibitory actions were measured by monitoring fluorescent metabolites derived from enzyme substrates (supersome assay). The Echinaforce extract induced mild inhibition of all these isoforms, with CYP 3A4 being the most, and CYP 2D6 the least sensitive enzyme. To assess whether CYP inhibition might be a general feature of Echinacea preparations, an additional nine commercially available preparations were screened using CYP 3A4. All tested preparations were able to inhibit CYP 3A4, but inhibitory potencies (expressed as median inhibitory concentration, IC50) varied by a factor of 150. The alkylamides are thought to be responsible for the immunomodulatory activity of Echinacea, and so the concentration of 2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and total alkylamide content were determined in all preparations, and the latter was found to be associated with their CYP 3A4 inhibitory potency. The chemically pure alkylamides dodeca-2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and dodeca-2E,4E-dieonoic acid isobutylamide (2) showed inhibitory activity on CYP 2C19, 2D6 and 3A4. However, unlike the Echinaforce extract, the alkylamides did not induce CYP 1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in-vitro.
Anti-diabetic effect of an α-glucan from fruit body of maitake (Grifola frondosa) on KK-Ay mice
Authors: Hong Lei , Xun Ma , Wutong Wu
Published: April 2007

We have evaluated the anti-diabetic effect of a α-glucan (MT-α-glucan) from the fruit body of maitake mushrooms (Grifola frondosa) on KK-Ay mice (a kind of genetical type 2 diabetes animal model). The effects of MT-α-glucan (450 or 150 mg kg−1) on diabetic mice were investigated by observing the changes in body weight, the level of fasting plasma glucose, glycosylated serum protein (GSP), hepatic glycogen, serum insulin, triglycerides, cholesterol, free fatty acid, liver superoxide dismutase (SOD), glutathione peroxidase (GSHpx), reduced glutathione (GSH) and malondialdehyde (MDA). Moreover, the binding capacity of insulin receptors on liver crude plasma membranes was assayed and histopathological changes in the pancreas were observed. Treatment with MT-α-glucan significantly decreased the body weight, level of fasting plasma glucose, GSP, serum insulin, triglycerides, cholesterol, free fatty acid and MDA content in livers. Treatment with MT-α-glucan significantly increased the content of hepatic glycogen, GSH and the activity of SOD and GSHpx. Moreover, the insulin binding capacity to liver crude plasma membranes increased and histopatho-logical changes in the pancreas were ameliorated in the treatment group. These data suggest that MT-α-glucan has an anti-diabetic effect on KK-Ay mice, which might be related to its effect on insulin receptors (i.e., increasing insulin sensitivity and ameliorating insulin resistance of peripheral target tissues).
Yin-Chen-Hao-Tang ameliorates obstruction-induced hepatic apoptosis in rats
Authors: Lee Tzung-Yan , Chang Hen-Hong , Wu Mei-Yao , Lin Han-Chieh
Published: April 2007

The accumulation of hydrophobic bile acids in the liver is considered to play a pivotal role in the induction of apoptosis of hepatocytes during cholestasis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. Yin-Chen-Hao-Tang (YCHT) decoctions have been recognised as a hepatoprotective agent for jaundice and various types of liver diseases. We used an experimental rat model of bile-duct ligation (BDL) to test whether YCHT plays a regulatory role in the pathogenesis of hepatic apoptosis. BDL-plus-YCHT groups received 250 or 500 mg kg−1 YCHT by gavage once daily for 27 days. YCHT significantly ameliorated the portal hypertensive state and serum TNF-α compared with the vehicle-treated control group. In BDL-plus-YCHT-treated rats, hepatic glutathione contents were significantly higher than than in BDL-only rats. BDL caused a prominent liver apoptosis that was supported by an increase in Bax and cytochrome c protein and increased expression of Bax and Bcl-2 messenger RNA. The normalising effect of YCHT on expression of Bax and Bcl-2 mRNA was dependent on the dose of YCHT, 500 mg kg−1 having the greater effect on both Bax and Bcl-2 of mRNA levels. Additionally, YCHT treatment down-regulated both hepatic caspase-3 and −8 activities of BDL rats. This study demonstrates the anti-apoptotic properties of YCHT and suggests a potential application of YCHT in the clinical management of hepatic disease resulting from biliary obstruction.
Anti-inflammatory and antinociceptive properties of blueberry extract(Vaccinium corymbosum)
Authors: Torri Eliane , Lemos Marivane , Caliari Vinícius , Kassuya Cândida A L , Bastos Jairo K , Andrade Sérgio F
Published: April 2007

Blueberries are among the edible fruits that are recognized best for their potential health benefits. The crude extract from Vaccinium corymbosum was assessed in anti-inflammatory and antinociceptive models. The crude hydroalcoholic extract was administered orally at doses of 100, 200 or 300 mg kg−1 for all the assays. In the carrageenan test, the crude extract reduced rat paw oedema by 9.8, 28.5 and 65.9%, respectively. For the histamine assay, the reductions of oedema were 70.1, 71.7 and 81.9%, respectively. In the myeloperoxidase (MPO) assay, 300 mg kg−1 crude extract produced a significant inhibition of the MPO activity, at 6 h and 24 h after injection of carrageenan, by 42.8 and 46.2%, respectively. With the granulomatous tissue assay dexamethasone displayed significant activity, whereas the blueberry extract was inactive. For the abdominal constriction test, inhibitions of 49.0, 54.5, 53.5%, respectively, were observed for the crude extract, and 61.4% for indometacin. In the formalin test, the crude extract (200 and 300 mg kg−1) and indometacin inhibited only the second phase by 36.2, 35.3 and 45.8%, respectively. Considering that the crude extract of blueberry displayed antinociceptive and anti-inflammatory activity, its consumption may be helpful for the treatment of inflammatory disorders.
Iron (III) chelation and antioxidant properties of myo-inositol phosphorylated polymeric microspheres
Authors: Iemma Francesca , Cirillo Giuseppe , Puoci Francesco , Trombino Sonia , Castiglione Mariarosaria , Picci Nevio
Published: April 2007

New chelating and antioxidant polymeric microspheres were synthesized through precipitation polymerization of 4-O-(4-vinylbenzyl)-myo-inositol 1,3,5-orthoformate with ethylene glycol dimethacrylate and subsequent exhaustive phosphorylation of the myo-inositol groups with phosphoric acid. Three different microspheres using different molar ratios of the two co-monomers were prepared. The antioxidant properties of these polymers were evaluated in rat liver microsomal membranes. This study showed that the macromolecular systems are very effective at inhibiting iron-dependent lipid peroxidation of the membranes. This antioxidant effect is due to the chelating properties of polyphosphorylated inositol residues in the polymeric devices toward ferric ions. The amount of polyphosphorylated inositol in the microspheres was found to play a crucial role in determining the chelating efficiency of the polymers: the polymer with the greatest amount of polyphosphorylated inositol was the most powerful antioxidant polymer.
Baccharis dracunculifolia, the main botanical source of Brazilian green propolis, displays antiulcer activity
Authors: Lemos Marivane , De Barros Muriel Primon , Sousa João Paulo Barreto , Filho Ademar Alves da Silva , Bastos Jairo Kenupp , De Andrade Sérgio Faloni
Published: April 2007

Baccharis dracunculifolia is the most important botanical source of Southeastern Brazilian propolis, known as green propolis for its colour. In a previous study, we described the gastric protective effect of the hydroalcoholic extract of Brazilian green propolis. We therefore wanted to investigate the possibility of using B. dracunculifolia extract for antiulcer treatment. This study was undertaken to evaluate the anti-ulcerogenic property of hydroalcoholic extract of B. dracunculifolia aerial parts. The HPLC analysis of the chemical composition of B. dracunculifolia extract used in this study revealed the presence mainly of cinnamic acid derivates and flavonoids. Doses of 50, 250 and 500 mg/kg of B. dracunculifolia crude extract and positive controls (omeprazole or cimetidine) significantly diminished the lesion index, the total lesion area and the percentage of lesion compared with negative control groups. The percentage of ulcer inhibition was significantly higher in groups treated with B. dracunculifolia, cimetidine or omeprazole, with all protocols used, compared with negative control groups. Regarding the model of gastric secretion, reductions in the volume of gastric juice and total acidity were observed, as well as an increase in the gastric pH. These results were similar to results from studies carried out with green propolis extract. Although more investigations are required, our results suggest that B. dracunculifolia has potential to be used as a phytotherapic preparation for the treatment of gastric ulcer.
Stuck in reverse: loss of LC1 inTrypanosoma bruceidisrupts outer dynein arms and leads to reverse flagellar beat and backward movement
Authors: Baron Desiree M. , Kabututu Zakayi P. , Hill Kent L.
Published: April 2007

Axonemal dyneins are multisubunit molecular motors that provide the driving force for flagellar motility. Dynein light chain 1 (LC1) has been well studied in Chlamydomonas reinhardtii and is unique among all dynein components as the only protein known to bind directly to the catalytic motor domain of the dynein heavy chain. However, the role of LC1 in dynein assembly and/or function is unknown because no mutants have previously been available. We identified an LC1 homologue (TbLC1) in Trypanosoma brucei and have investigated its role in trypanosome flagellar motility using epitope tagging and RNAi studies. TbLC1 is localized along the length of the flagellum and partitions between the axoneme and soluble fractions following detergent and salt extraction. RNAi silencing of TbLC1 gene expression results in the complete loss of the dominant tip-to-base beat that is a hallmark of trypanosome flagellar motility and the concomitant emergence of a sustained reverse beat that propagates base-to-tip and drives cell movement in reverse. Ultrastructure analysis revealed that outer arm dyneins are disrupted in TbLC1 mutants. Therefore LC1 is required for stable dynein assembly and forward motility in T. brucei. Our work provides the first functional analysis of LC1 in any organism. Together with the recent findings in T. brucei DNAI1 mutants [Branche et al. (2006). Conserved and specific functions of axoneme components in trypanosome motility. J. Cell Sci. 119, 3443-3455], our data indicate functionally specialized roles for outer arm dyneins in T. brucei and C. reinhardtii. Understanding these differences will provide a more robust description of the fundamental mechanisms underlying flagellar motility and will aid efforts to exploit the trypanosome flagellum as a drug target.
Minimizing maintenance cost involving flow-time and tardiness penalty with unequal release dates
Authors: Adjallah K. H. , Adzakpa K. P.
Published: April 2007

This paper proposes important and useful results relating to the minimization of the sum of the flow time and the tardiness of tasks or jobs with unequal release dates (occurrence date), with application to maintenance planning and scheduling. First, the policy of real-time maintenance is defined for minimizing the cost of tardiness and critical states. The required local optimality rule (flow time and tardiness rule) is proved, in order to minimize the sum or the linear combination of the tasks' flow time and tardiness costs. This rule has served to design a scheduling algorithm, with O( n3) complexity when it is applied to schedule a set of n tasks on one processor. To evaluate its performance, the results are compared with a lower bound that is provided in a numerical case study. Using this algorithm in combination with the tasks' urgency criterion, a real-time algorithm is developed to schedule the tasks on a parallel processors. This latter algorithm is finally applied to schedule and assign preventive maintenance tasks to processors in the case of a distributed system. Its efficiency enables, as shown in the numerical example, the cost of preventive maintenance tasks expressed as the sum of the tasks' tardiness and flow time to be minimized. This corresponds to the costs of critical states and of tardiness of preventive maintenance.
A Preliminary Investigation of the Relationship between Athletes' Self-Talk and Coaches' Behaviour and Statements
Authors: Zourbanos Nikos , Hatzigeorgiadis Antonis , Theodorakis Yannis
Published: April 2007

The aim of the present study was to explore the relationship between coaches' behaviour and statements, and athletes' self-talk. Two hundred and forty three athletes (106 females and 137 males) representing a variety of sports participated in the study. Participants completed the Athletes' Positive and Negative Self-Talk Scale, which assesses frequency of positive and negative self-talk; the Coaches' Positive and Negative Statements Scale, which assesses frequency of coaches' positive and negative statements; and the Coaching Behaviour Questionnaire, which assesses two dimensions of coaches' behaviour, supportiveness and negative activation. Structural equation modeling with latent factors was used to test the hypothesized relationships. The results showed that coaches' positive statements were found to mediate the relationship between coaches' supportiveness and athletes' positive self-talk. Similarly, negative statements made by the coach were found to mediate the relationship between coaches' negative activation and athletes' negative self-talk Overall, these preliminary findings suggest the importance of both coaching behaviour and statements in relation to their athletes' self-talk.
The Role of Selegiline in the Treatment of Negative Symptoms Associated with Schizophrenia
Authors: Fohey Krista D , Hieber Robin , Nelson Leigh Anne
Published: April 2007

Objective:

To evaluate the role of selegiline in the treatment of negative symptoms associated with schizophrenia.

Data Sources:

MEDLINE (1966–January 2007) and PsychINFO (1967–January 2007) were searched, using the terms schizophrenia, negative symptoms, and selegiline. A bibliographic search was conducted, as well.

Study Selection and Data Extraction:

All English-language articles identified from the search were evaluated. All primary literature was included in the review.

Data Synthesis:

Based on its dopamine-enhancing property, selegiline has been studied as augmentation to antipsychotic therapy for the treatment of negative symptoms associated with schizophrenia. The efficacy of low-dose oral selegiline for the treatment of negative symptoms has been evaluated in 1 case report, 2 open-label trials, and 2 controlled trials. The case report and both open-label trials report improvement of negative symptoms associated with low-dose oral selegiline. In 1 of the controlled trials, selegiline showed no difference in effect from that of placebo. These data are limited by small sample sizes. The largest controlled trial demonstrated a statistically significant difference between selegiline and placebo; however, the clinical significance is questionable, given that patients treated with selegiline were still experiencing marked negative symptoms at study completion. No comparative studies evaluating low-dose oral selegiline versus other augmentative treatment options for negative symptoms associated with schizophrenia exist at this time.

Conclusions:

Given the limitations of current literature, low-dose oral selegiline cannot be recommended for treatment of negative symptoms associated with schizophrenia. Additional controlled trials are needed to better delineate whether there is a role for selegiline in decreasing the burden of negative symptoms associated with schizophrenia.
St. Paul's Shipwreck and Early Christianity in Malta
Authors: Buhagiar Mario
Published: April 2007

Small islands have a need for a myth of national identity. The small Central Mediterranean archipelago of Malta, geographically located on the respective peripheries of Muslim North Africa and Christian Europe, has since the Late Middle Ages used the claim to be the site of the shipwreck of the apostle Paul in A.D. 60 (Acts 28) as a key argument for a Latin European identity. The fact that the islands had emerged from a traumatic Muslim experience made it psychologically imperative for them to trace their Christian roots to apostolic times. This study examines the validity of their claims and discusses the earliest known evidence for a Pauline tradition.
The American College of Louvain
Authors: Codd Kevin A
Published: April 2007

The American College of the Immaculate Conception in Louvain (Leuven), Belgium, has been preparing young men for service as priests to the Church in North America for one hundred and fifty years. Conceived in 1857 by Martin J. Spalding, Bishop of Louisville, and by Peter Paul Lefevere, Bishop of Detroit, the seminary in its early decades took advantage of a flourishing of missionary interest and vocations in Europe to provide much needed clergy to the Church in North America. It also provided to American seminarians the opportunity to study philosophy and theology in the famed Catholic University of Louvain in preparation for priestly ministry. It has served as an intellectual, spiritual, and pastoral cradle for many of America's missionaries, pastors, and educators, and continues to do so to the present.