Clotrimazole Binds to Heme and Enhances Heme-dependent Hemolysis: Proposed Antimalarial Mechanism of Clotrimazole

The Journal of Biological Chemistry. Feb, 2002  |  Pubmed ID: 11707446

Two recent studies have demonstrated that clotrimazole, a potent antifungal agent, inhibits the growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum, in vitro. We explored the mechanism of antimalarial activity of clotrimazole in relation to hemoglobin catabolism in the malaria parasite. Because free heme produced from hemoglobin catabolism is highly toxic to the malaria parasite, the parasite protects itself by polymerizing heme into insoluble nontoxic hemozoin or by decomposing heme coupled to reduced glutathione. We have shown that clotrimazole has a high binding affinity for heme in aqueous 40% dimethyl sulfoxide solution (association equilibrium constant: K(a) = 6.54 x 10(8) m(-2)). Even in water, clotrimazole formed a stable and soluble complex with heme and suppressed its aggregation. The results of optical absorption spectroscopy and electron spin resonance spectroscopy revealed that the heme-clotrimazole complex assumes a ferric low spin state (S = 1/2), having two nitrogenous ligands derived from the imidazole moieties of two clotrimazole molecules. Furthermore, we found that the formation of heme-clotrimazole complexes protects heme from degradation by reduced glutathione, and the complex damages the cell membrane more than free heme. The results described herein indicate that the antimalarial activity of clotrimazole might be due to a disturbance of hemoglobin catabolism in the malaria parasite.

Effect of Antifungal Azoles on the Heme Detoxification System of Malarial Parasite

Journal of Biochemistry. Mar, 2002  |  Pubmed ID: 11872173

The antimalarial activities of some antifungal azole agents (ketoconazole, miconazole, and clotrimazole) have been known for several years, however, their antimalarial mechanism remains equivocal. Our recent study showed that clotrimazole has a relative high affinity for heme, inhibits reduced glutathione-dependent heme catabolism, and enhances heme-induced hemolysis. In the present study, we have found that clotrimazole can remove heme from histidine rich peptide-heme complex, which initiates heme-polymerization in malaria. In addition, we show that two other azoles (ketoconazole and miconazole) behave similarly to clotrimazole in binding to heme: they bind to heme with similar affinities, remove heme from the histidine rich peptide-heme complex and from the reduced glutathione-heme complex to form stable heme-azole complexes with two nitrogenous ligands derived from the imidazole moieties of two azole molecules. We have also revealed that clotrimazole and miconazole have stronger promoting activities for heme-induced hemolysis than ketoconazole, implying that the stronger antimalarial activities of clotrimazole and miconazole might arise from their stronger ability to promote heme-induced hemolysis of clotrimazole and clotrimazole than that of ketoconazole. These results also suggest that ketoconazole and miconazole, like clotrimazole, might possess an antimalarial mechanism relating to their inhibition of heme polymerization and the degradation of reduced glutathione-dependent heme.

The Structure of Haplotype Blocks in the Human Genome

Science (New York, N.Y.). Jun, 2002  |  Pubmed ID: 12029063

Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.

Spectrum of Disease in U.S. Veteran Patients with Hepatitis C

The American Journal of Gastroenterology. Jul, 2002  |  Pubmed ID: 12135041

Hepatitis C virus (HCV) infection is more prevalent in U.S. veterans attending Veterans Affairs Medical Centers than in the general population. The purpose of this study was to examine the risk factors, psychiatric and substance abuse conditions, and severity of liver disease in veterans with HCV.

Potentiation of Amphetamine-induced Changes in Dopamine and 5-HT by a 5-HT(6) Receptor Antagonist

Brain Research Bulletin. Feb, 2003  |  Pubmed ID: 12576149

Although recent data has shown that 5-HT(6) receptor antagonists' can enhance basal cholinergic and glutamatergic neurotransmission in the cortex and hippocampus, the distribution of this receptor within terminal regions of the dopaminergic system suggests a possible role for this receptor in the modulation of dopamine (DA). Therefore, the role of the 5-HT(6) receptor was examined in the rat striatum in the presence and absence of the DA transport inhibitor/releaser, amphetamine. Amphetamine (0.3mg/kg s.c.) induced a selective increase in extracellular DA reaching a maximum of 311.3+/-73.5% of preinjection levels. Administration of SB-271046 (1 and 10mg/kg s.c.) followed by amphetamine produced an augmentation of amphetamine-induced changes in both DA and 5-hydroxytryptamine (5-HT), reaching maximum levels of 510.1+/-110.5% and 271+/-93.4% of preinjection values, respectively. Similarly, local infusion of amphetamine (100 nM) resulted in an increase in striatal DA levels reaching a maximum of 365.7+/-73.3% of preinfusion values. However, combination treatment with SB-271046 (1mg/kg s.c.) and amphetamine produced no augmentation of amphetamine-induced increases in extracellular levels of DA or in any other neurotransmitter measured. Taken together these data indicate that the 5-HT(6) receptor is not playing a role in the tonic modulation of NA, DA, 5-HT or glutamate neurotransmission in the striatum. However, when dopaminergic neurotransmission is enhanced the 5-HT(6) receptor appears to have a modulatory influence on not only DA but also 5-HT systems. This is the first direct neurochemical evidence that the 5-HT(6) receptor may have modulatory influences on both DA and 5-HT systems in the rat striatum.

Neutralization of Toxic Heme by Plasmodium Falciparum Histidine-rich Protein 2

Journal of Biochemistry. May, 2003  |  Pubmed ID: 12801923

Plasmodium falciparum histidine-rich protein 2 (PfHRP2) has been suggested to be an initiator of the polymerization of heme, which is produced as by-product on the digestion of hemoglobin, and a promoter of the H(2)O(2)-induced degradation of heme in food vacuoles of the malarial parasite. In this work, we have designed PfHRP2 model peptides, R18 and R27 (18 and 27 residues, respectively), and used them for optical and electron spin resonance spectroscopic measurements to confirm that the axial ligands of the heme-PfHRP2 complex are the nitrogenous donors derived from the imidazole moieties of histidine residues of PfHRP2. In addition, we revealed that the affinities of R18 and R27 for heme (K(d) = 2.21 x 10(-6) M and 0.71 x 10(-6) M, respectively) might be as high as that of PfHRP2 (K(d) = 0.94 x 10(-6) M). The R27 peptide can remove heme from membrane-intercalated heme and inhibit heme-induced hemolysis. Therefore, we suggest another function of PfHRP2: it may play an important role in the neutralization of toxic heme in the parasite cytoplasm and infected erythrocytes by removing heme from heme-bound membranes or reducing heme-induced hemolysis.

Adapting a Substance Abuse Court Diversion Model for Felony Offenders with Co-occurring Disorders: Initial Implementation

The Psychiatric Quarterly. 2003  |  Pubmed ID: 14686460

Treatment Alternatives for Dually Diagnosed (TADD) was developed to address the need for criminal justice diversion of seriously mentally ill substance-using felons and persistent misdemeanants. The population served by the TADD program and key elements of the program are described, including identification, screening and assessment, specialized court processing and judicial oversight, case management monitoring, joint case conferencing between community and monitoring staff, enforcement, and key stakeholder collaboration. One hundred and thirteen clients diverted by the TADD program were followed for six months. A description is provided of these clients, the community services accessed, as well as the monitoring of clients drug use. During six months of program involvement 87% remained connected to the diversion team, 80% remained in community treatment and the majority took advantage of the rich service environment created through TADD's case management linkage services. The majority of these clients tested drug-free during this six-month period.

Recurrent Ibuprofen-induced Aseptic Meningitis

The Annals of Pharmacotherapy. Mar, 2004  |  Pubmed ID: 14742833

To report a case of recurrent aseptic meningitis temporally associated with the use of ibuprofen.

Enhancement of Heme-induced Membrane Damage by the Anti-malarial Clotrimazole: the Role of Colloid-osmotic Forces

Biological & Pharmaceutical Bulletin. Mar, 2004  |  Pubmed ID: 14993803

Two recent studies have demonstrated that clotrimazole, a well-known potential antifungal agent, inhibits the in vitro growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum. In a previous study, we suggested that clotrimazole acts as an anti-malarial agent by inhibiting heme catabolism in the malaria parasite and by enhancing heme-induced membrane damage. In this paper, we examined the mechanism of action by measuring hemolysis as an indicator of membrane damage. Our results showed that clotrimazole does not promote the binding of heme to membranes, and that the enhancement of heme-induced hemolysis by clotrimazole is not caused by lipid peroxidation or by oxidation of thiol groups in membrane proteins. Instead, clotrimazole inhibits glutathione-dependent heme degradation, resulting in an enhancement of heme-induced hemolysis. We also found that clotrimazole increases the susceptibility of erythrocytes to hypotonic lysis in the presence of heme and that sucrose could inhibit hemolysis induced by heme-clotrimazole complexes. Thus, it appears that the enhancement of heme-induced hemolysis by clotrimazole in our experiments is due to a colloid osmotic hemolysis mechanism. The hydrophobicity and the large molecular size of the heme-clotrimazole complex might be key factors for induction of hemolysis.

One-step Concentration of Malarial Parasite-infected Red Blood Cells and Removal of Contaminating White Blood Cells

Malaria Journal. Mar, 2004  |  Pubmed ID: 15025790

Isolation of a concentrated, living preparation of malarial parasite-infected red blood cells (PRBCs) that have low contamination of white blood cells (WBCs) facilitates research on the molecular, biochemical and immunological aspects of malarial parasites. This is currently carried out by a two-step method, including the concentration of PRBCs using density gradient centrifugation through Percoll or Nycodenz, followed by the removal of host WBCs using a cellulose powder column or a commercially available filtration unit. These two-step methods can help isolate sufficient PRBCs, but they are laborious. In this study, a simplified one-step procedure that takes advantage of the difference between diamagnetic low-spin oxyhaemoglobin and paramagnetic haemozoin (haem polymer) was described. The paramagnetic polymer is deposited in the food vacuoles of the parasite, allowing the use of magnetic separation to efficiently and rapidly concentrate PRBCs while removing contaminating host WBCs.

Excitotoxic Calcium Overload in a Subpopulation of Mitochondria Triggers Delayed Death in Hippocampal Neurons

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jun, 2004  |  Pubmed ID: 15201334

In neurons, excitotoxic stimulation induces mitochondrial calcium overload and the release of pro-apoptotic proteins, which triggers delayed cell death. The precise mechanisms of apoptogen release, however, remain controversial. To characterize the linkage between mitochondrial calcium load and cell vulnerability, and to test the hypothesis that only a subpopulation of mitochondria damaged by calcium overload releases apoptogens, we have measured directly the concentrations of total Ca (free plus bound) in individual mitochondria and monitored in parallel structural changes and the subcellular localization of pro-apoptotic cytochrome c after NMDA overstimulation in cultured hippocampal neurons. Beyond transient elevation of cytosolic calcium and perturbation of Na+/K+ homeostasis, NMDA stimulation induced dramatic, but mainly reversible, changes in mitochondria, including strong calcium elevation, membrane potential depolarization, and variable swelling. Elevation of matrix Ca in the approximately one-third of mitochondria that were strongly swollen, as well as the absence of swelling when Ca2+ entry was abolished, indicate an essential role for Ca overload. Shortly after NMDA exposure, cytochrome c, normally localized to mitochondria, became diffusely distributed in the cytoplasm, coincident with the appearance of severely swollen mitochondria with ruptured outer membranes; under these conditions, cytochrome c was retained in intact mitochondria, implying that it was released mainly from damaged mitochondria. Consistent with the role of mitochondrial Ca overload, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone decreased Ca accumulation, prevented cytochrome c release, and was neuroprotective. These results support a mechanism in which delayed excitotoxic death involves apoptogen release from a subpopulation of calcium-overloaded mitochondria, whereas other, undamaged mitochondria maintain normal function.

Effectiveness of a Burn Prevention Campaign for Older Adults

The Journal of Burn Care & Rehabilitation. Sep-Oct, 2004  |  Pubmed ID: 15353939

Older adults are involved in one fifth of burn injury admissions in the Province of Ontario Canada. Most burn injuries in this population occur at home while cooking, bathing, or smoking. The purpose of this study was to evaluate the effectiveness of an educational campaign to improve burn prevention knowledge in older adults of a major metropolitan city. Changes in participants' burn prevention knowledge were determined using standardized precampaign and postcampaign (4-6 weeks) surveys. Of 209 older adult participants, 126 (60.3%) completed the precampaign and postcampaign surveys. There was a significant increase (P <.05) in burn prevention knowledge postintervention. Age, education level, and living conditions did not influence the change in burn prevention knowledge. This burn prevention campaign for older adults was effective in improving burn prevention knowledge, but it remains unclear as to whether this will ultimately result in a change in burn prevention behavior.

Assessment of Therapeutic Response in Patients with Metastatic Bone Disease

The Lancet Oncology. Oct, 2004  |  Pubmed ID: 15465464

Metastatic bone disease is common in cancer patients and causes substantial disease-related morbidity and mortality. However, several effective treatments are available for the management of these patients. Bisphosphonates, which inhibit osteoclast-mediated resorption of bone matrix, are especially important because they decrease the incidence of skeletal-related events in many tumour types and can complement antineoplastic therapies. At present, assessment of treatment for bone metastases is hindered by a lack of effective, rapid methods to measure disease response. We discuss the difficulties of current measures of response assessment and describe the development of new radiological and biochemical markers of bone metastases. Assays that detect type I collagen telopeptides as markers of bone resorption seem to be most promising at present.

Dexamethasone for the Treatment of Tuberculous Meningitis in Adolescents and Adults

The New England Journal of Medicine. Oct, 2004  |  Pubmed ID: 15496623

Tuberculous meningitis kills or disables more than half of those affected with the disease. Previous studies have been too small to determine whether adjunctive treatment with corticosteroids can reduce the risk of disability or death among adults with tuberculous meningitis, and the effect of coinfection with the human immunodeficiency virus (HIV) is unclear.

Identification of Progressive Cervical Epithelial Cell Abnormalities Using DNA Image Cytometry

Cancer. Dec, 2004  |  Pubmed ID: 15526273

The objectives of the current study were to compare the capabilities of conventional cervical cytology and of DNA image cytometry (DNA-ICM) in the prediction of progressive or regressive behavior in atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL), and atypical glandular cells (AGC).

[Surgical Treatment of Malignant Sinonasal Tumors with Orbital Extension: 20 Patients]

Annales D'oto-laryngologie Et De Chirurgie Cervico Faciale : Bulletin De La Société D'oto-laryngologie Des Hôpitaux De Paris. Feb, 2005  |  Pubmed ID: 15851943

The purpose of this work was to assess changes in surgical treatment of malignant sinonasal tumors with orbital extension, with or without orbital exenteration, on the basis of clinical, radiological and preoperative data.

An Improved Colorimetric Method for Quantitation of Heme Using Tetramethylbenzidine As Substrate

Analytical Biochemistry. Sep, 2005  |  Pubmed ID: 16091279

Treatment of Fulminant Liver Failure by Transplantation of Microencapsulated Primary or Immortalized Xenogeneic Hepatocytes

Xenotransplantation. Nov, 2005  |  Pubmed ID: 16202069

The aim of this study was to evaluate in vitro and in vivo functions of isolated hepatocytes after immortalization, cryopreservation, encapsulation and xenotransplantation into mice with fulminant liver failure (FLF).

Leukocyte Activation by Malarial Pigment

Parasitology International. Mar, 2006  |  Pubmed ID: 16316776

Malarial pigment, a unique hemozoin crystal composed of unit cells of heme dimers, is present in large amounts in circulating monocytes and neutrophils and can persist unchanged in macrophages for several months. In the present study, we investigated the effect of hemozoin not only on macrophages, but also on neutrophils. We used beta-hematin (BH), a chemically synthetic crystal structurally identical to hemozoin, for these studies. In vitro, BH up-regulated the expression of tumor necrosis factor-alpha in whole blood and in isolated peritoneal macrophages, indicating that hemozoin is able to stimulate monocytes. BH stimulated murine peritoneal neutrophils to express macrophage inflammatory protein-2 (MIP-2), a homologue of human interleukin-8 that is used as a marker of neutrophil activation. Injecting BH into the peritoneal cavity resulted in a dose-dependent migration of neutrophils and a high level of myeloperoxidase activity of peritoneal cells. Finally, BH directly induced neutrophil chemotaxis in vitro. Taken together, these results suggest that the malarial pigment hemozoin can activate leukocytes and may participate in the pathology of severe malaria.

Inhibition Assay of Beta-hematin Formation Initiated by Lecithin for Screening New Antimalarial Drugs

Analytical Biochemistry. Feb, 2006  |  Pubmed ID: 16376288

Measurement of heme crystallization provides a tool for screening new antimalarial drugs. Current assays for heme crystallization have employed initiators such as thermo, histidine-rich proteins, and lipids extracted from parasites and infected plasma. These initiators are unnatural or require laborious steps to prepare. In this study, we used a commercially available lipid, lecithin, a kind of phospholipid containing about 50% unsaturated fatty acids, as an initiator for heme crystal (beta-hematin) formation. We demonstrated that the inhibition of lecithin-based beta-hematin formation by antimalarial drugs is highly correlated with the preformed beta-hematin-based method. In addition, the lecithin-based assay is sensitive and convenient for large-scale screening of new novel antimalarials. We also indicated that dimethyl sulfoxide is an ideal solvent for preparation of heme stock solution, which is stable and can be used for 1 month.

A Metallocene-pyrrolidinopyridine Nucleophilic Catalyst for Asymmetric Synthesis

Organic Letters. Feb, 2006  |  Pubmed ID: 16468763

[reaction: see text] A highly active chiral 4-aminopyridine nucleophilic catalyst, available in three steps from (S,S)-hexane-2,5-diol, was applied to the asymmetric Steglich rearrangement of O-aceylated azlactones (1 mol % loading, up to 76% ee).

A Simple and Rapid Colorimetric Method to Measure Hemozoin Crystal Growth in Vitro

Analytical Biochemistry. Jul, 2006  |  Pubmed ID: 16729953

WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A Novel 5-hydroxytryptamine 2C Receptor-selective Agonist with Preclinical Antipsychotic-like Activity

The Journal of Pharmacology and Experimental Therapeutics. Jan, 2007  |  Pubmed ID: 17038512

Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D2 receptor antagonism, the 5-HT2C-selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7-30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3-3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity. WAY-163909 (1.7-17 mg/kg i.p.) reversed MK-801 (5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)- and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding, WAY-163909 (0.3-3 mg/kg i.p.; 1-17 mg/kg p.o.) reduced avoidance responding, an effect blocked by the 5-HT(2B/2C) receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole]. WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1-10 mg/kg i.p.). Thus, the profile of the 5-HT2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.

Simple Colorimetric Inhibition Assay of Heme Crystallization for High-throughput Screening of Antimalarial Compounds

Antimicrobial Agents and Chemotherapy. Jan, 2007  |  Pubmed ID: 17088494

Current assays for screening new antimalarials need initiators of beta-hematin formation that require laborious preparation, special devices, and substrates. In this study, based on reduction of heme absorption in beta-hematin formation, we developed a simple colorimetric assay using Tween 20 as an initiator and a microplate reader for high-throughput screening of inhibitors of beta-hematin formation.

Alcohols Induce Beta-hematin Formation Via the Dissociation of Aggregated Heme and Reduction in Interfacial Tension of the Solution

Acta Tropica. Feb, 2007  |  Pubmed ID: 17274939

The formation of the malarial pigment, a unique hemozoin crystal with unit cells comprised of heme dimers, has been proposed as an ideal target for antimalarial screening. The mechanism of beta-hematin formation (a synthetic crystal structurally identical to hemozoin) has been suggested that a hydrophobic interaction is needed to solubilize heme, but this hypothesis needs further evidence. Direct study of the process of hemozoin formation in the malarial food vacuole has not been performed, due to complicated groups of lipids and proteins. To overcome this difficulty and to explore the environmental conditions for beta-hematin formation, we systematically studied beta-hematin formation induced by a series of small normal alcohols (methanol, ethanol, n-propanol, and n-butanol), which are structurally similar. For the first time, the ability of beta-hematin inducer could be evaluated by its concentration that is required to enhance heme crystallization by 50% (EC(50) values). These values provide a rapid and convenient tool for comparing the ability of initiators in beta-hematin formation. Our results showed that the ability of alcohols to induce beta-hematin formation in the order: n-butanol>n-propanol>ethanol>methanol. The induction of beta-hematin formation by alcohols is related with their degree of hydrophobicity and ability to solubilize heme, suggesting that the dissociation of aggregated heme by alcohols is a major factor in beta-hematin formation. In addition, alcohols can reduce the surface tension of a solution, thus lowering the energy barrier for creating critical nuclei.

Rhenium and Technetium Complexes with N,N-dialkyl-N'-benzoylthioureas

Inorganic Chemistry. Jun, 2007  |  Pubmed ID: 17487967

N,N-Dialkyl-N'-benzoylthioureas, HR(1)R(2)btu, react under single deprotonation and form air-stable chelate complexes with common rhenium or technetium complexes such as (NBu(4))[MOCl(4)] (M = Re, Tc) or [ReOCl(3)(PPh(3))(2)]. Compositions and molecular structures of the products are strongly dependent on the precursors used and the reaction conditions applied. Reactions with [ReOCl(3)(PPh(3))(2)] in CH(2)Cl(2) give complexes of the general formula [ReOCl(2)(R(1)R(2)btu)(PPh(3))] (3), with the benzoyl oxygen atom of the chelating benzoylthiourea being trans to the oxo ligand, and/or Re(III) complexes of the composition [ReCl(2)(R(1)R(2)btu)(PPh(3))(2)] (4) with the PPh(3) ligands in trans positions to each other. In polar solvents such as MeOH, EtOH or acetone, corresponding reactions without addition of a supporting base only result in intractable brown solutions, from which no crystalline complexes could be isolated. The addition of NEt(3), however, allows the isolation of the bis-chelates [ReOCl(R(1)R(2)btu)(2)] (1) in good yields. In this type of complex, one of the chelating R(1)R(2)btu- ligands coordinates equatorially, while the second occupies the position trans to the oxo ligand with its oxygen atom. The latter compounds can also be prepared from (NBu(4))[ReOCl(4)] in MeOH when no base is added, while the addition of NEt(3) results in the formation of [ReO(OMe)(R(1)R(2)btu)(2)] (5) complexes with the methoxo ligand trans to O(2-). Compounds of the type 5 can alternatively be prepared by heating 1 in MeOH with addition of NEt(3). A reversible conversion of 5 into oxo-bridged dimers of the composition [{ReO(R(1)R(1)btu)(2)}(2)O] (6) is observed in water-containing solvents. Starting from (NBu(4))[TcOCl(4)], a series of technetium complexes of the type [TcOCl(R(1)R(2)btu)(2)] (2) could be prepared. The structures of such compounds are similar to those of the rhenium analogues 1. Reduction of 2 with PPh(3) in CH(2)Cl(2) gives Tc(III) complexes of the composition [TcCl(R(1)R(2)btu)(2)(PPh(3))] (7) having the chloro and PPh(3) ligands in cis positions. When this reaction is performed in the presence of excess chelating ligand, the Tc(III) tris-chelates [Tc(R(1)R(2)btu)(3)] (8) are formed.

Activation of the Extrinsic Caspase Pathway in Cultured Cortical Neurons Requires P53-mediated Down-regulation of the X-linked Inhibitor of Apoptosis Protein to Induce Apoptosis

Journal of Neurochemistry. Aug, 2007  |  Pubmed ID: 17488272

Cultured cortical neurons exposed to the Human Immunodeficiency Virus gp120 coat protein undergo apoptosis involving activation of both caspase-8 and caspase-9. Additionally, gp120-mediated neuronal apoptosis requires the pro-apoptotic transcription factor p53. As caspase-8-induced apoptosis does not typically require p53, we examined the possibility of a novel role for p53 in caspase-8 activation initiated by gp120. We observed that gp120 treatment of cultured cortical neurons induced caspase-8 activity and Bid cleavage independently of p53, but induction of caspase-3 enzymatic activity required p53 expression. These findings suggested the possibility that p53 down-regulates a caspase-3 inhibitor. We observed high-level expression of the caspase-3/9 inhibitor X-linked inhibitor of apoptosis protein (XIAP) in cultured cortical neurons. Adenoviral expression of p53 or induction of endogenous p53 by camptothecin treatment reduced XIAP protein in neurons. Infection with a p53 expressing adenovirus increased expression of the mRNA for Omi/HtrA2, a protease that cleaves and inactivates XIAP. These findings suggest that p53 regulates neuronal apoptosis, in part, by suppressing the anti-apoptotic protein XIAP via transcriptional activation of Omi/HtrA2.

2-tert-butyl-8-quinolinamines Exhibit Potent Blood Schizontocidal Antimalarial Activity Via Inhibition of Heme Crystallization

Antimicrobial Agents and Chemotherapy. Aug, 2007  |  Pubmed ID: 17562796

We have recently reported that the attachment of a bulky metabolically stable tert-butyl group at the C-2 position of a quinoline ring in primaquine results in a tremendous improvement in the blood schizontocidal antimalarial activity of 8-quinolinamine. Because free heme released from hemoglobin catabolism in a malarial parasite is highly toxic, the parasite protects itself mainly by crystallization of heme into insoluble nontoxic hemozoin. We now demonstrate the ability of 2-tert-butylprimaquine to inhibit in vitro beta-hematin formation, to form a complex with heme with a stoichiometry of 1:1, and to enhance heme-induced hemolysis. The results described herein indicate that a major improvement in the blood-schizontocidal antimalarial activity of 2-tert-butylprimaquine might be due to a disturbance of heme catabolism pathway in the malarial parasite.

Accelerated Telomere Erosion is Associated with a Declining Immune Function of Caregivers of Alzheimer's Disease Patients

Journal of Immunology (Baltimore, Md. : 1950). Sep, 2007  |  Pubmed ID: 17785865

Caregivers of Alzheimer's disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation-induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-alpha and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.

A Second Generation Human Haplotype Map of over 3.1 Million SNPs

Nature. Oct, 2007  |  Pubmed ID: 17943122

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

Genome-wide Detection and Characterization of Positive Selection in Human Populations

Nature. Oct, 2007  |  Pubmed ID: 17943131

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

The Glial Response to CNS HIV Infection Includes P53 Activation and Increased Expression of P53 Target Genes

Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology. Dec, 2007  |  Pubmed ID: 18040854

HIV-associated dementia (HAD) is a chronic neuroinflammatory disease that remains an important clinical problem without available rational treatment. As HIV does not infect neurons, the pathogenesis of HAD is thought to be secondary to the impact of infected leukocytes, including parenchymal microglia, which can secrete inflammatory mediators and viral products that alter the function of surrounding uninfected cells. We previously reported that the transcription factor p53 accumulates in neurons, microglia, and astrocytes of HAD patients. We have also shown that microglia from p53-deficient mice fail to induce neurotoxicity in response to the HIV coat protein gp120 in a coculture system, supporting the hypothesis that p53 plays a pathogenic role in the chronic neuroinflammatory component of HIV-associated neurodegeneration. We analyzed the extent and cell type specificity of p53 accumulation in subcortical white matter of ten AIDS patients that had previously been shown to demonstrate white matter p53 accumulation. To determine if p53 activation functioned to alter gene expression in HAD, cortical tissue sections were also immunolabeled for the p53 target genes Bax and p21(WAF1). These studies reveal that microglia, astrocytes, and oligodendrocytes all demonstrate p53 activation in response to HIV infection. We observed immunoreactivity for both Bax and p21(WAF1) in neurons and glia from patients demonstrating elevated p53 immunoreactivity. Our findings demonstrate that widespread increased p53 expression is present in HAD. Activation of p53 mediated pathways in the glia of HAD patients may contribute to the neuroinflammatory processes that promote neurodegeneration by inhibiting glial proliferation and/or promoting glial cell dysfunction.

Significant Prevalence of Histologic Disease in Patients with Chronic Hepatitis B and Mildly Elevated Serum Alanine Aminotransferase Levels

Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association. May, 2008  |  Pubmed ID: 18455697

Serum ALT remains the most accessible test available to clinicians for monitoring chronic hepatitis B virus infection, but appropriate action when ALT levels are only mildly elevated is ambiguous in standard guidelines.

Low Proportion of Barrett's Esophagus in Asian Americans

The American Journal of Gastroenterology. Jul, 2008  |  Pubmed ID: 18557711

To determine the proportion of Barrett's esophagus (BE) in Asians versus non-Asians and the predictors of BE in patients with upper gastrointestinal (GI) symptoms.

Effects of Amino Acids on Malarial Heme Crystallization

Biological & Pharmaceutical Bulletin. Aug, 2008  |  Pubmed ID: 18670076

To gain insight into the mechanism of malarial hemozoin formation and to explore various biological groups for screening novel antimalarial drugs, we examined the effects of amino acids on the formation of beta-hematin (BH), which is a synthetic heme crystal structurally identical to hemozoin, in vitro. Our results showed that BH formation was significantly inhibited by basic amino acids (arginine, lysine, and histidine), probably due to the abilities of these amino acids to complex with heme. The results suggest an involvement in the improvement of the blood-schizonticidal activity of 8-quinolinamine when conjugated with basic amino acids. In addition, cysteine also inhibited BH formation, possibly due to its ability to reduce heme iron or decompose heme in acidic conditions. In contrast, BH formation was enhanced by amino acids with high hydrophobicity values (leucine, isoleucine, valine, methionine, and phenylalanine), with the exception of tryptophan at high temperature but was not affected in Tween-induced BH formation under normal physiological conditions. The present results can lead to further research on the development of new antimalarials by conjugating these amino acids, especially basic amino acids, with other substances, or by forming complex or small peptides that could have special effects on BH formation.

Comparison of Vaginal and Sublingual Misoprostol for Second Trimester Abortion: Randomized Controlled Equivalence Trial

Human Reproduction (Oxford, England). Jan, 2009  |  Pubmed ID: 18794161

To identify an effective misoprostol-only regimen for the termination of second trimester pregnancy, we compared sublingual and vaginal administration of multiple doses of misoprostol in a randomized, placebo-controlled equivalence trial.

Prevalence of Colorectal Neoplasms in Asian Americans

Digestive Diseases and Sciences. Jan, 2009  |  Pubmed ID: 18975084

To determine the yield of colonoscopy in a predominantly Asian American gastroenterology practice in California from 8/2003 to 2/2005.

Age- and Fatigue-related Markers of Human Faces: an Eye-tracking Study

Ophthalmology. Feb, 2009  |  Pubmed ID: 19084276

To investigate the facial cues that are used when making judgments about how old or tired a face appears.

Providing Counseling on Alcohol Use for Patients with Liver Disease: Another Missed Opportunity

Patient Education and Counseling. Feb, 2009  |  Pubmed ID: 19108979

Acute Hepatitis in a Patient Given Propofol During Colonoscopy

Southern Medical Journal. Mar, 2009  |  Pubmed ID: 19204630

Vitamin D Screening by Gastroenterologists in Patients with Inflammatory Bowel Disease

The American Journal of Gastroenterology. Mar, 2009  |  Pubmed ID: 19262531

Addition Reactions of Sulfonylimidates with Imines Catalyzed by Alkaline Earth Metals

Angewandte Chemie (International Ed. in English). 2009  |  Pubmed ID: 19343744

Corticosteroid Side Effects and Counseling in Patients with Inflammatory Bowel Disease

Journal of Clinical Gastroenterology. Aug, 2009  |  Pubmed ID: 19384243

Adaptive Cellular Memetic Algorithms

Evolutionary Computation. 2009  |  Pubmed ID: 19413489

A cellular genetic algorithm (CGA) is a decentralized form of GA where individuals in a population are usually arranged in a 2D grid and interactions among individuals are restricted to a set neighborhood. In this paper, we extend the notion of cellularity to memetic algorithms (MA), a configuration termed cellular memetic algorithm (CMA). In addition, we propose adaptive mechanisms that tailor the amount of exploration versus exploitation of local solutions carried out by the CMA. We systematically benchmark this adaptive mechanism and provide evidence that the resulting adaptive CMA outperforms other methods both in the quality of solutions obtained and the number of function evaluations for a range of continuous optimization problems.

Rate of Red Blood Cell Destruction Varies in Different Strains of Mice Infected with Plasmodium Berghei-ANKA After Chronic Exposure

Malaria Journal. 2009  |  Pubmed ID: 19416511

Severe malaria anaemia in the semi-immune individuals in the holo-endemic area has been observed to occur at low parasite density with individual variation in the responses. Thus the following has been thought to be involved: auto-immune-mediated mechanisms of uninfected red blood cell destruction, and host genetic factors to explain the differences in individual responses under the same malaria transmission. In this study, the extent of red blood cell (RBC) destruction in different strains of semi-immune mice model at relatively low parasitaemia was studied.

Evaluation of Bifenthrin Applications in Tires to Prevent Aedes Mosquito Breeding

Journal of the American Mosquito Control Association. Mar, 2009  |  Pubmed ID: 19432071

The efficacy of maximum label rates of bifenthrin applications to dry tires to prevent Aedes mosquito breeding was investigated by field colonization and bioassay trials in shaded and unshaded locations. Aedes notoscriptus and Culex quinquefasciatus larvae were the most abundant species present in the field colonization trial. Colonization and survival of Ae. notoscriptus larvae to the late instar occurred significantly earlier in treated tires in shaded compared with unshaded locations (P = 0.002). Bifenthrin applications in shaded tires only prevented early instar survival for approximately 2.6 wk. Aedes notoscriptus late instars did not appear in the treated unshaded tires. Culex quinquefasciatus colonized treated tires from the 2nd wk in both shaded and unshaded treatments. In the bioassay, water from bifenthrin-treated tires, through extrapolation, was found to kill approximately 100% of late instar Ae. notoscriptus for only approximately 2.0-2.2 wk in shaded and unshaded tires. Under conditions optimal for Aedes breeding, such as shaded locations, high ambient temperatures, high relative humidity, and high amounts of leaf/organic matter accumulations, bifenthrin may not be effective as a larval control measure in tires for greater than 2.0-2.6 wk.

Prevalence and Risk Factors Associated with Reversed Robin Hood Syndrome in Acute Ischemic Stroke

Stroke; a Journal of Cerebral Circulation. Aug, 2009  |  Pubmed ID: 19461025

Early deterioration can occur after acute stroke for a variety of reasons. We describe a hemodynamic steal and associated neurological deterioration, the reversed Robin Hood syndrome (RRHS). We aimed to investigate the frequency and factors associated with RRHS.

Inhibition of Sphingosine-1-phosphate Lyase for the Treatment of Autoimmune Disorders

Journal of Medicinal Chemistry. Jul, 2009  |  Pubmed ID: 19489538

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

Histological Disease in Asian-Americans with Chronic Hepatitis B, High Hepatitis B Virus DNA, and Normal Alanine Aminotransferase Levels

The American Journal of Gastroenterology. Sep, 2009  |  Pubmed ID: 19491836

At present there is no clear consensus on how patients with chronic hepatitis B (CHB), high serum hepatitis B virus (HBV) DNA, and normal alanine aminotransferase (NLALT) levels should be managed. This study hypothesizes that a significant proportion of such patients may have histological disease.

Renal Dysfunction in Chronic Hepatitis B Patients Treated with Adefovir Dipivoxil

Hepatology (Baltimore, Md.). Sep, 2009  |  Pubmed ID: 19517525

Renal dysfunction has been reported in patients treated with adefovir dipivoxil (ADV); however, its incidence and clinical importance may be underappreciated given the lack of long-term follow-up and data outside of a clinical trial setting. Our goal was to examine the severity and incidence of renal dysfunction in a real-life setting for patients treated with ADV and whose baseline estimated glomerular filtration rate (eGFR) was >50 mL/minute. We performed a cohort study of 290 chronic hepatitis B patients: 145 patients treated with 10 mg ADV and 145 patients unexposed to ADV at two community clinics, who were matched for age (+/-10 years), sex, and baseline eGFR. The exposed and unexposed populations were well-matched with a similar mean age (46-47 years), proportion of male patients (76.5%), baseline serum creatinine (0.97-0.99 mg/dL), and baseline creatinine clearance (85.0-85.4 mL/minute). The incidence density for renal dysfunction defined by treatment termination and/or development of eGFR < or =50 mL/minute was five cases per 100 patient-years in the exposed group compared with 1.36 cases per 100 patient-years in the unexposed group (P = 0.02). The relative risk of exposed to unexposed was 3.68 (95% confidence interval 1.1-19.3). On Cox proportional hazard analysis also inclusive of sex, ADV was a significant predictor of significant renal dysfunction (hazard ratio [HR] 3.94, P = 0.03). There were also significant trends for age >50 years (HR 3.49, P = 0.087), mild renal impairment at baseline (HR 4.49, P = 0.073), and hypertension and/or diabetes mellitus (HR 2.36, P = 0.074). Conclusion: ADV is an independent predictor for significant deterioration of renal function. Patients on ADV should be monitored, especially patients who are older, have baseline renal insufficiency, or have hypertension and/or diabetes mellitus.

Prevalence of Hepatitis B Virus Genotype B in Vietnamese Patients with Chronic Hepatitis B

Hepatology International. Jul, 2009  |  Pubmed ID: 19669244

PURPOSE: Hepatitis B virus (HBV) genotypes can affect treatment response to interferon-based therapy and disease outcomes in patients with chronic hepatitis B (CHB). Little data exist to characterize HBV genotypes in Vietnamese, one of the largest minority groups in the United States and also one with one of the highest CHB and liver cancer disease burdens. The goal of this study was to compare the distribution of HBV genotypes in Vietnamese and Chinese patients. METHODS: We performed a cross-sectional study of 567 consecutive patients of Vietnamese (n = 478) or Chinese (n = 89) descent, with HBV genotype mutation analysis performed between 7/2,005 and 6/2,008 at a community gastroenterology clinic and a university-affiliated liver clinic in the United States. RESULTS: There were no significant differences between the Vietnamese and Chinese groups in mean age (45 and 44 years), gender (58% and 61% male), HBeAg status (64% and 65% negative), median alanine aminotransferase (33 and 41 U/L), and log(10) HBV DNA (4.9 and 5.0 log(10) IU/ml), or the prevalence of precore/basic core promoter mutations (72% and 71%), respectively. Vietnamese patients had a much higher prevalence of HBV genotype B and a lower prevalence of genotype C than Chinese patients: 74% and 25% vs. 55% and 43% (P = 0.001). CONCLUSIONS: Chinese patients with CHB often carry either B or C genotype. Vietnamese patients with CHB mostly have HBV genotype B. Additional studies are needed to further characterize the clinical significance of HBV genotype in the natural history and treatment outcomes of CHB in Vietnamese patients.

Beijing Genotype of Mycobacterium Tuberculosis is Significantly Associated with High-level Fluoroquinolone Resistance in Vietnam

Antimicrobial Agents and Chemotherapy. Nov, 2009  |  Pubmed ID: 19721073

Consecutive fluoroquinolone (FQ)-resistant isolates (n = 109) identified at the Pham Ngoc Thach Hospital for Tuberculosis, Ho Chi Minh City, Vietnam, were sequenced in the quinolone resistance-determining regions of the gyrA and gyrB genes and typed by large sequence polymorphism typing and spoligotyping to identify the Beijing genotype of Mycobacterium tuberculosis. Beijing genotype prevalence was compared with 109 consecutive isolates from newly presenting patients with pulmonary tuberculosis from the hospital outpatient department. Overall, 82.6% (n = 90/109) of isolates had mutations in gyrAB. Nine novel mutations were identified in gyrB (S486F, N538T, T539P, D500A, D500H, D500N, G509A, E540V, and E540D). The influence of these novel gyrB mutations on FQ resistance is not proven. The Beijing genotype was significantly associated with FQ resistance (odds ratio [OR], 2.39 [95% confidence interval {CI}, 1.34 to 4.25]; P = 0.003). Furthermore, Beijing genotype FQ-resistant isolates were significantly more likely than FQ-resistant isolates of other genotypes to have gyrA mutations (OR, 7.75 [95% CI, 2.84 to 21.15]; P = 0.0001) and high-level (>8 microg/ml) FQ resistance (OR, 11.0 [95% CI, 2.6 to 47.0]; P = 0.001). The underlying mechanism of the association of the Beijing genotype with high-level FQ resistance in this setting remains to be determined. The association of the Beijing genotype with relatively high-level FQ resistance conferred by specific gyrA mutations reported here is of grave concern given the epidemic spread of the Beijing genotype and the current hopes for shorter first-line treatment regimens based on FQs.

Randomized Controlled Study Investigating Viral Suppression and Serological Response Following Pre-S1/pre-S2/S Vaccine Therapy Combined with Lamivudine Treatment in HBeAg-positive Patients with Chronic Hepatitis B

Antimicrobial Agents and Chemotherapy. Dec, 2009  |  Pubmed ID: 19770281

The aim of the current study was to evaluate viral suppression following combined treatment with an S/pre-S1/pre-S2 vaccine and lamivudine in patients with chronic hepatitis B. We established a randomized, controlled clinical trial to compare the responses of three different treatment groups: those receiving vaccine monotherapy, lamivudine monotherapy, or combination treatment. Viral response was evaluated via hepatitis B virus (HBV) DNA suppression using different levels of classification. Seroconversion was evaluated via HBeAg loss, HBeAg seroconversion, HBsAg loss, and anti-HBs response. We found that the group receiving combination treatment demonstrated a significant increase in viral suppression over that for the lamivudine or vaccine monotherapy group, although the HBeAg seroconversion rate was not different. This enhanced suppression effect in the combination group was reversed after the discontinuation of vaccine treatment, suggesting that booster doses are required for a sustained viral response. Anti-HBs was detected in 55/120 vaccine recipients, but only 3 patients demonstrated HBsAg loss, indicating that the vaccine-induced anti-HBs was unable to completely neutralize HBsAg in the serum. At the study end point, anti-HBs responders showed significantly higher HBeAg seroconversion rates, greater suppression of HBV DNA levels, and a lower median reduction in HBV DNA levels than those of anti-HBs nonresponders. Our results suggest that combined treatment with the vaccine and lamivudine was significantly more effective than lamivudine monotherapy in the short term and was especially successful in producing viral suppression and an enhanced anti-HBs antibody response.

Visual Impairment in the Absence of Dystroglycan

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2009  |  Pubmed ID: 19846701

Ocular involvement in muscular dystrophy ranges from structural defects to abnormal electroretinograms. While the mechanisms underlying the abnormal retinal physiology in patients are not understood, it is thought that alpha-dystroglycan extracellular interactions are critical for normal visual function. Here we show that beta-dystroglycan anchors dystrophin and the inward rectifying K(+) channel Kir4.1 at glial endfeet and that disruption of dystrophin and potassium channel clustering in dystroglycan mutant mice is associated with an attenuation of the electroretinogram b-wave. Glial-specific inactivation of dystroglycan or deletion of the cytoplasmic domain of beta-dystroglycan was sufficient to attenuate the electroretinogram b-wave. Unexpectedly, deletion of the beta-dystroglycan cytoplasmic domain did not disrupt the laminar structure of the retina. In contrast to the role of alpha-dystroglycan extracellular interactions during early development of the CNS, beta-dystroglycan intracellular interactions are important for visual function but not the laminar development of the retina.

Adherence to Screening for Hepatocellular Carcinoma Among Patients with Cirrhosis or Chronic Hepatitis B in a Community Setting

Digestive Diseases and Sciences. Dec, 2009  |  Pubmed ID: 19876735

Screening for hepatocellular carcinoma (HCC) has been shown to improve survival via earlier cancer detection. Although HCC screening is considered standard of care in the USA, little is known of the adherence to this practice, especially in a community setting.

Frequency of Alcohol and Smoking Cessation Counseling in Hepatitis C Patients Among Internists and Gastroenterologists

World Journal of Gastroenterology : WJG. Dec, 2009  |  Pubmed ID: 20014469

Given the overwhelming evidence that both alcohol consumption and smoking accelerate the progression of hepatitis C virus (HCV)-induced liver disease, we evaluated the frequency of alcohol and smoking counseling of patients with HCV-induced liver disease by their primary care internists and gastroenterologists. One hundred and twenty-three medical records of consecutive patients with HCV-induced liver disease referred by an internist to a gastroenterologist for its management were reviewed. Patient gender, race, history of and counseling against alcohol and tobacco use by a physician and a gastroenterologist were obtained. A database was created using Microsoft Excel. There were 105 African-Americans, 12 Caucasians and six patients of other races/ethnicities. Forty-six (37%) patients were daily tobacco users and 34 (28%) patients were daily alcohol consumers. There was a statistically significant difference in the frequencies of alcohol (P = 0.0002) and smoking cessation (P = 0.0022) between gastroenterologists and internists. This study reveals that internists and gastroenterologists, alike, inadequately counsel patients with hepatitis C about tobacco and alcohol use.

An Effectiveness Trial of Multiple Micronutrient Supplementation During Pregnancy in Vietnam: Impact on Birthweight and on Stunting in Children at Around 2 Years of Age

Food and Nutrition Bulletin. Dec, 2009  |  Pubmed ID: 20120792

Multiple micronutrient deficiencies during pregnancy in Vietnam may contribute to poor fetal growth and stunting, which are major determinants of the health and development offuture generations.

An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV

The New England Journal of Medicine. Feb, 2010  |  Pubmed ID: 20181972

Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy. No internationally accepted, evidence-based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common.

Epidemiology Training Needs Assessment in Vietnam

Medical Education. May, 2010  |  Pubmed ID: 20519002

Rif1 Provides a New DNA-binding Interface for the Bloom Syndrome Complex to Maintain Normal Replication

The EMBO Journal. Sep, 2010  |  Pubmed ID: 20711169

BLM, the helicase defective in Bloom syndrome, is part of a multiprotein complex that protects genome stability. Here, we show that Rif1 is a novel component of the BLM complex and works with BLM to promote recovery of stalled replication forks. First, Rif1 physically interacts with the BLM complex through a conserved C-terminal domain, and the stability of Rif1 depends on the presence of the BLM complex. Second, Rif1 and BLM are recruited with similar kinetics to stalled replication forks, and the Rif1 recruitment is delayed in BLM-deficient cells. Third, genetic analyses in vertebrate DT40 cells suggest that BLM and Rif1 work in a common pathway to resist replication stress and promote recovery of stalled forks. Importantly, vertebrate Rif1 contains a DNA-binding domain that resembles the αCTD domain of bacterial RNA polymerase α; and this domain preferentially binds fork and Holliday junction (HJ) DNA in vitro and is required for Rif1 to resist replication stress in vivo. Our data suggest that Rif1 provides a new DNA-binding interface for the BLM complex to restart stalled replication forks.

Integrating Common and Rare Genetic Variation in Diverse Human Populations

Nature. Sep, 2010  |  Pubmed ID: 20811451

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of

Risk Factors, Genotype 6 Prevalence, and Clinical Characteristics of Chronic Hepatitis C in Southeast Asian Americans

Hepatology International. 2010  |  Pubmed ID: 20827411

Although infection with hepatitis C virus (HCV) affects 32 million individuals from Southeast Asia, little is known about the mode of HCV acquisition and the epidemiology of chronic hepatitis C (CHC) in these individuals. Our goal was to examine risk factors for HCV acquisition, prevalence, and clinical characteristics of HCV genotype 6 compared with genotypes 1 and 2/3 in Southeast Asian (SEA) patients.

Similar Treatment Response to Peginterferon and Ribavirin in Asian and Caucasian Patients with Chronic Hepatitis C

The American Journal of Gastroenterology. May, 2010  |  Pubmed ID: 19904247

Previous studies have found ethnicity to be an important predictor of outcomes of treatment with peginterferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C. Although the expected sustained virological response (SVR) rates of Hispanics and African Americans are lower than those of Caucasians, SVR rates in Asians appear to be more favorable. However, in some of these studies, hepatitis C virus (HCV) genotype was identified by INNO-LiPA assay, which can mistype the easier-to-treat HCV genotype 6 as genotype 1. Our goal was to compare SVR rates among Caucasian and Asian-American patients with genotype 1 and 2/3 infection whose HCV genotypes were accurately classified by core sequencing testing.

Neutralization of Toxic Haem by Porphyromonas Gingivalis Haemoglobin Receptor

Journal of Biochemistry. Mar, 2010  |  Pubmed ID: 19861401

Free haem is known to be toxic to organs, tissues and cells. It enhances permeability by binding to a cell membrane, which leads to cell death, and damages lipids, proteins and DNA through the generation of reactive oxygen species. Lysine- and arginine-specific gingipains (Kgp and RgpA/B) are major proteinases that play an important role in the pathogenicity of a black-pigmented periodontopathogen named Porphyromonas gingivalis. One of the adhesin domains of gingipain, HbR could bind haem as an iron nutrient source for P. gingivalis. Using erythrocyte and its membrane as a model, results from the present study demonstrate that recombinant HbR expressed in Escherichia coli could inhibit haem-induced haemolysis, probably through removing haem from the haem-membrane complex and lowering free haem toxicity by mediating dimerization of haem molecules. The ability to protect a cell membrane from haem toxicity is a new function for HbR.

IL-21 Preferentially Enhances IL-15-mediated Homeostatic Proliferation of Human CD28+ CD8 Memory T Cells Throughout the Adult Age Span

Journal of Leukocyte Biology. Jan, 2010  |  Pubmed ID: 19797296

An age-related decline in human immune response is marked by the accumulation of CD28(-) CD8 T cells, which is attributed to repeated antigenic stimulation and to homeostatic proliferation mediated by cytokines such as IL-15. However, the identity of the cytokines that are responsible for the maintenance of CD28 expression is less known. Here, we report the role of IL-21 in the regulation of IL-15-mediated growth and CD28 expression of CD8 memory T cells of young and old donors. We showed that IL-21 drives more IL-15-stimulated cells to enter cell division and to undergo apoptosis. Furthermore, IL-21 preferentially enhanced IL-15-induced proliferation of CD28(+) CD8 memory T cells over their CD28(-) counterparts, as CD28(+) cells expressed higher levels of IL-15R and IL-21R and greater pSTAT5 upon IL-15 and IL-21 stimulation. In addition, IL-21 reduced IL-15-induced CD28 down-regulation in CD8 memory T cells. Finally, the ability of proliferation and survival in response to homeostatic cytokines IL-15 and IL-21 of CD28(+) CD8 memory T cells was well-maintained with age. Together, these findings suggest that IL-21 enhances IL-15-mediated proliferation of CD8 memory T cells, particularly CD28(+) memory T cells, and also serves as an antagonist to the IL-15-induced increase of CD28(-) CD8 T cells.

Passive Optical Separation and Enrichment of Cells by Size Difference

Biomicrofluidics. 2010  |  Pubmed ID: 21264058

A size-selective cell sorting microfluidic device that utilizes optical force is developed. The device consists of a three-dimensional polydimethylsiloxane microstructure comprised of two crossed microchannels in a three-dimensional configuration. A line shaped focused laser beam is used for automatic size-selective cell sorting in a continuous flow environment. As yeast cells in an aqueous medium are fed continuously into a lower channel, the line shaped focused laser beam is applied (perpendicular to the direction of flow) at the junction of the two crossed channels. The scattering force of the laser beam was employed to push cells matching specific criteria upward from one channel to another. The force depends on the size of the cells, the laser power, and the fluid flow speed. The variation in size of yeast cells causes them to follow different routes at the intersection. For flow speeds below 30 μm∕s, all yeast cells larger than 3 μm were removed from the main stream. As a result, a high purity sample of small cells can be collected at the outlet of bottom channel.

The Frequency of Osteoporosis Screening in Men with Inflammatory Bowel Disease

American Journal of Men's Health. Mar, 2010  |  Pubmed ID: 19477762

Osteoporosis is underdiagnosed in men, and osteoporosis-related fractures carry high morbidity and mortality. Recent recommendations on osteoporosis screening in men from the American College of Physicians state that screening and risk factor assessment need to occur earlier in men at high risk. Men with inflammatory bowel disease are at high risk for osteoporosis and fragility fractures due to corticosteroid use, malabsorption from intestinal resection, potential vitamin D deficiency, and fluctuations in weight. This study examines the rate of corticosteroid use, vitamin D screening, and bone mineral density screening of men with inflammatory bowel disease in a gastroenterology practice. The vast majority of men with inflammatory bowel disease are at high risk for osteoporosis. Screening and risk factor assessment should be emphasized.

Distinct Functions of Glial and Neuronal Dystroglycan in the Developing and Adult Mouse Brain

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2010  |  Pubmed ID: 20980614

Cobblestone (type II) lissencephaly and mental retardation are characteristic features of a subset of congenital muscular dystrophies that include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type congenital muscular dystrophy. Although the majority of clinical cases are genetically undefined, several causative genes have been identified that encode known or putative glycosyltransferases in the biosynthetic pathway of dystroglycan. Here we test the effects of brain-specific deletion of dystroglycan, and show distinct functions for neuronal and glial dystroglycan. Deletion of dystroglycan in the whole brain produced glial/neuronal heterotopia resembling the cerebral cortex malformation in cobblestone lissencephaly. In wild-type mice, dystroglycan stabilizes the basement membrane of the glia limitans, thereby supporting the cortical infrastructure necessary for neuronal migration. This function depends on extracellular dystroglycan interactions, since the cerebral cortex developed normally in transgenic mice that lack the dystroglycan intracellular domain. Also, forebrain histogenesis was preserved in mice with neuron-specific deletion of dystroglycan, but hippocampal long-term potentiation was blunted, as is also the case in the Largemyd mouse, in which dystroglycan glycosylation is disrupted. Our findings provide genetic evidence that neuronal dystroglycan plays a role in synaptic plasticity and that glial dystroglycan is involved in forebrain development. Differences in dystroglycan glycosylation in distinct cell types of the CNS may contribute to the diversity of dystroglycan function in the CNS, as well as to the broad clinical spectrum of type II lissencephalies.

Randomized Controlled Trial of Pegylated Interferon-alfa 2a and Ribavirin in Treatment-naive Chronic Hepatitis C Genotype 6

Hepatology (Baltimore, Md.). Nov, 2010  |  Pubmed ID: 21038410

Hepatitis C virus (HCV) genotype is an important criteria in determining duration of therapy and predictor of sustained virologic response (SVR) to pegylated interferon (PEG IFN) and ribavirin (RBV) therapy. Optimal duration of therapy for patients with HCV genotype 6 is not known. We conducted a multicenter, open-label randomized controlled trial of patients with HCV genotype 6 at five gastroenterology clinics in the western U.S. Patients were stratified by viral load and histologic stage and assigned to receive PEG IFN-α2a 180 μg subcutaneously weekly and weight-based oral RBV 800 to 1,200 mg daily for 24 or 48 weeks. Primary outcome measurement was SVR rate by intention-to-treat analysis. From February 2005 to October 2007 a total of 60 patients (age 51 ± 10 years, 47% male, log HCVRNA 6.3 ± 1.1 IU/mL) were enrolled: 27 patients to 24 weeks and 33 patients to 48 weeks of therapy. In the 24-week and 48-week groups, 96% and 97% achieved early virologic response (P = 0.90); 89% versus 94% achieved end of therapy virologic response (P = 0.48). SVR was achieved in 70% versus 79% of patients assigned to 24 weeks versus 48 weeks (P = 0.45). Rapid virologic response (RVR) was a significant predictor of SVR in the 48-week group and trending towards significance in the 24-week group: 82% and 83% of those with RVR achieved SVR versus 33% and 29% for the 24-week and 48-week groups, respectively (P = 0.07 and P = 0.02). CONCLUSION: There was no significant difference in SVR rates in patients with HCV genotype 6 treated with PEG IFN-α2a and RBV for 24 versus 48 weeks.

Cancer and Age Related Colonic Crypt Deficiencies in Cytochrome C Oxidase I

World Journal of Gastrointestinal Oncology. Dec, 2010  |  Pubmed ID: 21191537

To investigate whether deficiency of expression of cytochrome c oxidase I (CcOI) in colonic crypts is associated with colon cancer.

Cerebrospinal Fluid Lactate Concentration to Distinguish Bacterial from Aseptic Meningitis: a Systemic Review and Meta-analysis

Critical Care (London, England). 2010  |  Pubmed ID: 21194480

Making a differential diagnosis between bacterial meningitis and aseptic meningitis is a critical clinical problem. The utility of a cerebrospinal fluid (CSF) lactate assay for this purpose has been debated and is not yet routinely clinically performed. To adequately evaluate this assay, a systematic review and meta-analysis of studies of the CSF lactate concentration as a marker for both bacterial meningitis and aseptic meningitis was performed.

Presenilin 2 is the Predominant γ-secretase in Microglia and Modulates Cytokine Release

PloS One. 2010  |  Pubmed ID: 21206757

Presenilin 1 (PS1) and Presenilin 2 (PS2) are the enzymatic component of the γ-secretase complex that cleaves amyloid precursor protein (APP) to release amyloid beta (Aβ) peptide. PS deficiency in mice results in neuroinflammation and neurodegeneration in the absence of accumulated Aβ. We hypothesize that PS influences neuroinflammation through its γ-secretase action in CNS innate immune cells. We exposed primary murine microglia to a pharmacological γ-secretase inhibitor which resulted in exaggerated release of TNFα and IL-6 in response to lipopolysaccharide. To determine if this response was mediated by PS1, PS2 or both we used shRNA to knockdown each PS in a murine microglia cell line. Knockdown of PS1 did not lead to decreased γ-secretase activity while PS2 knockdown caused markedly decreased γ-secretase activity. Augmented proinflammatory cytokine release was observed after knockdown of PS2 but not PS1. Proinflammatory stimuli increased microglial PS2 gene transcription and protein in vitro. This is the first demonstration that PS2 regulates CNS innate immunity. Taken together, our findings suggest that PS2 is the predominant γ-secretase in microglia and modulates release of proinflammatory cytokines. We propose PS2 may participate in a negative feedback loop regulating inflammatory behavior in microglia.

The Impella Recover 2.5 and TandemHeart Ventricular Assist Devices Are Safe and Associated with Equivalent Clinical Outcomes in Patients Undergoing High-risk Percutaneous Coronary Intervention

Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. Jan, 2011  |  Pubmed ID: 21234916

OBJECTIVES:: To compare the practical use, safety and clinical outcomes associated with the TandemHeart (TH) versus Impella Recover 2.5 (IR2.5) devices when used for circulatory support during high-risk percutaneous coronary intervention (PCI). BACKGROUND:: Small studies and registries suggest safety and efficacy for the TH and IR2.5 percutaneous-left ventricular assist devices (P-LVADs). However, these P-LVADs differ markedly in their insertion, operation and manner of circulatory augmentation. To date, no study has compared these devices. METHODS:: We identified 68 patients (49 males, 19 females; age 71.1±12.1 years) from our single-center database that underwent 'high-risk' PCI with P-LVAD support from 04/2005-06/2010 (32 with TH, 36 with IR2.5). Relevant data were extracted and imputed for analysis. RESULTS:: Baseline demographics were similar, including low LVEF (overall mean 31.0±13.7%) and elevated STS mortality risk score (4.2±3.7%). Angiographic characteristics were also similar, with a mean of 2.4±1.0 lesions treated per patient, and 29% undergoing left main PCI. PCI success rates were 99% in both groups, with similar in-hospital outcomes and a combined 7% major vascular access site complication rate. A single episode of left atrial perforation occurred during TH use. No patient required emergent CABG and no in-hospital deaths occurred. The 30 day MACE rate (death, myocardial infarction, target lesion revascularization) was 5.8%. There were no differences between the IR2.5 and TH groups with respect to short- or long-term clinical outcomes. CONCLUSIONS:: The IR2.5 and TH assist devices are safe, equally effective, and associated with acceptable short- and long-term clinical outcomes in patients undergoing 'high-risk' PCI. © 2011 Wiley-Liss, Inc.

Carcinogenicity of Deoxycholate, a Secondary Bile Acid

Archives of Toxicology. Aug, 2011  |  Pubmed ID: 21267546

High dietary fat causes increased bile acid secretion into the gastrointestinal tract and is associated with colon cancer. Since the bile acid deoxycholic acid (DOC) is suggested to be important in colon cancer etiology, this study investigated whether DOC, at a high physiologic level, could be a colon carcinogen. Addition of 0.2% DOC for 8-10 months to the diet of 18 wild-type mice induced colonic tumors in 17 mice, including 10 with cancers. Addition of the antioxidant chlorogenic acid at 0.007% to the DOC-supplemented diet significantly reduced tumor formation. These results indicate that a high fat diet in humans, associated with increased risk of colon cancer, may have its carcinogenic potential mediated through the action of bile acids, and that some dietary anti-oxidants may ameliorate this carcinogenicity.

Medication Nonadherence with Long-term Management of Patients with Hepatitis B E Antigen-negative Chronic Hepatitis B

Digestive Diseases and Sciences. Aug, 2011  |  Pubmed ID: 21327918

Antiviral treatment responses for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are well-defined by data from registration trials but may differ from patients seen in community settings where medical adherence is usually not as strictly monitored. The goal of this study was to examine the long-term outcomes of HBeAg-negative patients in a community clinical setting.

Insertion of an Alkene into an Ester: Intramolecular Oxyacylation Reaction of Alkenes Through Acyl C-O Bond Activation

Angewandte Chemie (International Ed. in English). Feb, 2011  |  Pubmed ID: 21328662

Heterologous Expression of Endo-1,4-beta-xylanaseC from Phanerochaete Chrysosporium in Pichia Pastoris

Journal of Bioscience and Bioengineering. Jun, 2011  |  Pubmed ID: 21393056

The cDNA of endo-1,4-β-xylanaseC, isolated from Phanerochaete chrysosporium, was expressed in Pichia pastoris, under the control of the alcohol oxidase I promoter. Using either the intrinsic leader peptide of xylanaseC or the α-factor signal peptide of Saccharomyces cerevisiae, xylanaseC is efficiently secreted into the medium, at a maximum concentration of 2500 U·l(-1).

Whole Body Shaking Due to Intracranial Blood Flow Steal

Journal of the Neurological Sciences. Jun, 2011  |  Pubmed ID: 21429522

Unilateral limb shaking has been described as brief, repetitive jerking movements of arm and leg, resembling seizures and attributed to transient cerebral ischemia. We report a patient with numerous episodes of whole body shaking in the setting of bilateral carotid occlusions as well as vertebral stenoocclusive disease. These episodes of whole body shaking occurred in the presence of bilateral intracranial blood flow steal phenomenon. After angioplasty of the vertebral artery and initiation of aggressive medical therapy and non-invasive ventilatory correction, intracranial blood flow improved and whole body shaking episodes were resolved during 6-months follow-up.

Occurrence and Formation Potential of N-nitrosodimethylamine in Ground Water and River Water in Tokyo

Water Research. May, 2011  |  Pubmed ID: 21514620

N-nitrosodimethylamine (NDMA), a disinfection byproduct of water and wastewater treatment processes, is a potent carcinogen. We investigated its occurrence and the potential for its formation by chlorination (NDMA-FP Cl2) and by chloramination (NDMA-FP NH2Cl) in ground water and river water in Tokyo. To characterize NDMA precursors, we revealed their molecular weight distributions in ground water and river water. We collected 23 ground water and 18 river water samples and analyzed NDMA by liquid chromatography-tandem mass spectrometry. NDMA-FP Cl2 was evaluated by chlorinating water samples with free chlorine for 24 h at pH 7.0 while residual free chlorine was kept at 1.0-2.0 mg Cl(2)/L. NDMA-FP NH2Cl was evaluated by dosing water samples with monochloramine at 140 mg Cl(2)/L for 10 days at pH 6.8. NDMA precursors and dissolved organic carbon (DOC) were fractionated by filtration through 30-, 3-, and 0.5 kDa membranes. NDMA concentrations were <0.5-5.2 ng/L (median: 0.9 ng/L) in ground water and <0.5-3.4 ng/L (2.2 ng/L) in river water. NDMA concentrations in ground water were slightly lower than or comparable to those in river water. Concentrations of NDMA-FP Cl2 were not much higher than concentrations of NDMA except in samples containing high concentrations of NH(3) and NDMA precursors. The increased NDMA was possibly caused by reactions between NDMA precursors and monochloramine unintentionally formed by the reaction between free chlorine and NH(3) in the samples. NDMA precursors ranged from 4 to 84 ng-NDMA eq./L in ground water and from 11 to 185 ng-NDMA eq./L in river water. Those in ground water were significantly lower than those in river water, suggesting that NDMA precursors were biodegraded, adsorbed, or volatilized during infiltration. The molecular weight of NDMA precursors in river water was dominant in the <0.5 kDa fraction, followed by 0.5-3 kDa. However, their distribution was inconsistent in ground water: one was dominant in the <0.5 kDa fraction, and the other in 0.5-3 kDa. Molecular weight distributions of NDMA precursors were very different from those of DOC. This is the first study to reveal the widespread occurrence and characterization of NDMA precursors in ground water.

Association of HLA and Post-schistosomal Hepatic Disorder: a Systematic Review and Meta-analysis

Parasitology International. Dec, 2011  |  Pubmed ID: 21664486

Several human genetic variants, HLA antigens and alleles are reportedly linked to post-schistosomal hepatic disorder (PSHD), but the results from these reports are highly inconclusive. In order to estimate overall associations between human genetic variants, HLA antigens, HLA alleles and PSHD, we systematically reviewed and performed a meta-analysis of relevant studies in both post-schistosomal hepatic disorder and post-schistosomal non-hepatic disorder patients. PubMed, Scopus, Google Scholar, The HuGE Published Literature database, Cochrane Library, and manual search of reference lists of articles published before July 2009 were used to retrieve relevant studies. Two reviewers independently selected articles and extracted data on study characteristics and data regarding the association between genetic variants, HLA antigens, HLA alleles and PSHD in the form of 2×2 tables. A meta-analysis using fixed-effects or random-effects models to pooled odds ratios (OR) with corresponding 95% confidence intervals were calculated only if more than one study had investigated particular variation. We found 17 articles that met our eligibility criteria. Schistosoma mansoni and Schistosoma japonicum were reported as the species causing PSHD. Since human genetic variants were only investigated in one study, these markers were not assessed by meta-analysis. Thus, only HLA-genes (a total of 66 HLA markers) were conducted in the meta-analysis. Our meta-analysis showed that human leucocyte antigens HLA-DQB1*0201 (OR=2.64, P=0.018), DQB1*0303 (OR=1.93, P=0.008), and DRB1*0901 (OR=2.14, P=0.002) alleles and HLA-A1 (OR=5.10, P=0.001), A2 (OR=2.17, P=0.005), B5 (OR=4.63, P=0.001), B8 (OR=2.99, P=0.02), and B12 (OR=5.49, P=0.005) serotypes enhanced susceptibility to PSHD, whereas HLA-DQA1*0501 (OR=0.29, P≤0.001) and DQB1*0301 (OR=0.58, P=0.007) were protective factors against the disease. We further suggested that the DRB1*0901-DQB1*0201, DRB1*0901-DQB1*0303 and A1-B8 haplotypes enhanced susceptibility to PSHD, whereas DQA1*0501-DQB1*0301 linkage decreased the risk of PSHD. The result improved our understanding of the association between the HLA loci and PSHD with regard to pathogenic or protective T-cells and provided novel evidence that HLA alleles may influence disease severity.

High Rate of Complete Viral Suppression with Combination Therapy in Patients with Chronic Hepatitis B and Prior Treatment Failure

Journal of Clinical Gastroenterology. Nov-Dec, 2011  |  Pubmed ID: 21778896

Combination therapy for chronic hepatitis B virus (HBV) infection is recommended for patients with antiviral resistance (AVR) or partial response (PR) to earlier antiviral therapy; however, data on outcomes are limited.

Automated Segmentation of Blood-flow Regions in Large Thoracic Arteries Using 3D-cine PC-MRI Measurements

International Journal of Computer Assisted Radiology and Surgery. Jul, 2011  |  Pubmed ID: 21779767

PURPOSE: Quantitative analysis of vascular blood flow, acquired by phase-contrast MRI, requires accurate segmentation of the vessel lumen. In clinical practice, 2D-cine velocity-encoded slices are inspected, and the lumen is segmented manually. However, segmentation of time-resolved volumetric blood-flow measurements is a tedious and time-consuming task requiring automation. METHODS: Automated segmentation of large thoracic arteries, based solely on the 3D-cine phase-contrast MRI (PC-MRI) blood-flow data, was done. An active surface model, which is fast and topologically stable, was used. The active surface model requires an initial surface, approximating the desired segmentation. A method to generate this surface was developed based on a voxel-wise temporal maximum of blood-flow velocities. The active surface model balances forces, based on the surface structure and image features derived from the blood-flow data. The segmentation results were validated using volunteer studies, including time-resolved 3D and 2D blood-flow data. The segmented surface was intersected with a velocity-encoded PC-MRI slice, resulting in a cross-sectional contour of the lumen. These cross-sections were compared to reference contours that were manually delineated on high-resolution 2D-cine slices. RESULTS: The automated approach closely approximates the manual blood-flow segmentations, with error distances on the order of the voxel size. The initial surface provides a close approximation of the desired luminal geometry. This improves the convergence time of the active surface and facilitates parametrization. CONCLUSIONS: An active surface approach for vessel lumen segmentation was developed, suitable for quantitative analysis of 3D-cine PC-MRI blood-flow data. As opposed to prior thresholding and level-set approaches, the active surface model is topologically stable. A method to generate an initial approximate surface was developed, and various features that influence the segmentation model were evaluated. The active surface segmentation results were shown to closely approximate manual segmentations.

Development of Interdigitated Arrays Coated with Functional Polyaniline/MWCNT for Electrochemical Biodetection: Application for Human Papilloma Virus

Talanta. Sep, 2011  |  Pubmed ID: 21807222

In this study, polyaniline-multiwalled carbon nanotube film (PANi-MWCNT) has been polymerized on interdigitated platinum electrode arrays (IDA), fabricated by MEMS technology for the detection of human papillomavirus (HPV) infection, using immobilized peptide aptamers as affinity capture reagent. Label-free, electrochemical detection of the specific immune reaction between antigen peptide aptamer HPV-16-L1 (with a molecular weight of 1825 Da), the most common genotype in cytological normal women worldwide, and its specific antibody of HPV-16 (which is much bigger with molecular weight of ca. 150 kDa) on multifunctional PANi-MWCNT based arrays was reported. The most significant advantage of this technique consists of reagentless and multiple detection of antigen-antibody complex formation on well conducting IDA interface of PANi-MWCNT, without intermediate steps or any labeling reagents, as normally required in the previous works.

Improving Nitrogen Removal in Two Modified Decentralized Wastewater Systems

Water Environment Research : a Research Publication of the Water Environment Federation. Aug, 2011  |  Pubmed ID: 21905409

Efficient nutrient removal in decentralized wastewater treatment systems is a challenging task. To improve the removal of organic matter and nitrogen from wastewater, two types of bioreactors using membrane-aerated biofilm reactor (MABR) and microbial fuel cell (MFC) techniques were evaluated. During more than 250 days of continuous-flow reactor operation, both reactors showed consistently high chemical oxygen demand removal (>86%). At an influent ammonium-nitrogen (NH4(+)-N) concentration of 30 mg N/L, the average effluent NH4(+)-N concentrations were 6.2 and 0.5 mg N/L for the MABR and MFC reactor, respectively, while the effluent nitrate-nitrogen (NO3(-)-N) concentrations were 5.4 mg/ L in the MABR and 19.2 mg/L in the MFC-based reactor. The overall total inorganic nitrogen removal efficiencies were 64% and 36% for the MABR and MFC reactor, respectively. At the measured dissolved oxygen concentrations of 5.2 and 0.23 mg/L in the aerobic/anoxic zone of the MFC and MABR, respectively, a specific oxygen uptake rate of 0.1 g O2/g VSS-d, resulting from ammonia oxidation, was detected in the settled sludge of the MFC, while no nitrifying activity of the sludge from the MABR was detected. Molecular microbial analysis demonstrated a link between the bacterial community structure and nitrifying activity. The relatively high abundance of Nitrosomonas europaea was associated with its detectable nitrification activity in the settled sludge of the MFC. The results suggest that MABR and MFC techniques have the potential to improve organic and nitrogen removal in decentralized wastewater systems.

Modified Interdigitated Arrays by Novel Poly(1,8-diaminonaphthalene)/carbon Nanotubes Composite for Selective Detection of Mercury(II)

Talanta. Oct, 2011  |  Pubmed ID: 21962666

This study describes a novel type of interdigitated arrays (IDA), microfabricated by electropolymerizing structured Poly(1,8-diaminonaphthalene)/functionalized multi-walled carbon nanotubes (PDAN/CNT) thin film onto a silicon chip for square wave voltammetry (SWV) multi-element heavy metal ion detection. The structure of PDAN/CNT was characterized by Raman, FE-SEM and AFM techniques. Analysed experiments reveal that the uptake of Hg(2+) by PDAN/CNT is quite specific and it can be used advantageously for electrochemical sensing of Hg(2+) thanks to original feature of (Hg(2+)/Hg(2)(2+)) redox potential with the respect to that of PDAN/CNT. As-developed IDA type electrode can extend its utility in other sensing applications.

Elevated Levels of Cell-free Circulating DNA in Patients with Acute Dengue Virus Infection

PloS One. 2011  |  Pubmed ID: 22016795

Apoptosis is thought to play a role in the pathogenesis of severe dengue and the release of cell-free DNA into the circulatory system in several medical conditions. Therefore, we investigated circulating DNA as a potential biomarker for severe dengue.

Social Contexts of Risk Behaviors for HIV Among Male, Unskilled, Unregistered Laborers in Urban Vietnam

Qualitative Health Research. Nov, 2011  |  Pubmed ID: 22068045

In Vietnam there has been relatively little success in controlling the HIV epidemic, in part because the subpopulations most exposed to the virus are often difficult to engage in prevention research and programs. In this qualitative study we explored social contexts shaping HIV risk behaviors among Vietnamese men involved in unskilled, unregistered, and low-income labor in urban settings. Based on self-disclosed behaviors, it is clear that these men were at high risk of sexually transmitted infection (STI). Evidence emerged from the interview data highlighting equivalent influences of individual psychological factors, social integration, social barriers, and accessibility regarding drug use and sexual risk behavior. Psychological influences such as tedium, distress, fatalism and revenge, and the strong effects of collective decision making and fear of social isolation appeared important for these men living on the economic and social margins of this rapidly urbanizing society. The study findings suggest directions for research and culturally appropriate HIV preventive education and services for these men.

Centromedian Thalamic Nuclei Deep Brain Stimulation in Refractory Status Epilepticus

Brain Stimulation. Oct, 2011  |  Pubmed ID: 22078068

BACKGROUND: Refractory status epilepticus (RSE) is associated with high mortality. We report a potential treatment alternative. HYPOTHESIS: Deep brain stimulation (DBS) of the centromedian thalamic nuclei (CMN) can be effective in the treatment of RSE. METHODS: Report of the evolution of RSE after DBS of the CMN in a 27-year-old man. RESULTS: In the course of an encephalopathy of unknown origin, and after a cardiac arrest, the patient developed RSE with myoclonic jerks and generalized tonic-clonic seizures. The EEG showed continuous generalized periodic epileptiform discharges (GPEDS). Five weeks after RSE onset, bilateral DBS of the CMN was started. This treatment was immediately followed by disappearance of tonic-clonic seizures and GPEDS, suggesting a resolution of RSE. The patient continued having multifocal myoclonic jerks, probably subcortical in origin, which resolved after 4 weeks. The patient remained clinically stable for 2 months in a persistent vegetative state. CONCLUSIONS: The remission of RSE, the abolition of GPEDS, and the patient survival suggest that DBS of the CMN may be efficacious in the treatment of refractory, generalized status epilepticus.

Propensity Score Matching in Estimating the Effect of Managerial Education on Academic Planning Behavior. Study Design: a Cross-sectional Study

BMC Medical Education. 2011  |  Pubmed ID: 22151539

ABSTRACT:

Maspin is a Deoxycholate-inducible, Anti-apoptotic Stress-response Protein Differentially Expressed During Colon Carcinogenesis

Clinical and Experimental Gastroenterology. 2011  |  Pubmed ID: 22162927

Increased maspin expression in the colon is related to colon cancer risk and patient survival. Maspin is induced by the hydrophobic bile acid, deoxycholate (DOC), which is an endogenous carcinogen and inducer of oxidative stress and DNA damage in the colon. Persistent exposure of colon epithelial cells, in vitro, to high physiologic levels of DOC results in increased constitutive levels of maspin protein expression associated with the development of apoptosis resistance. When an apoptosis-resistant colon epithelial cell line (HCT-116RC) developed in the authors' laboratory was treated with a maspin-specific siRNA probe, there was a statistically significant increase in apoptosis compared to treatment with an siRNA control probe. These results indicate, for the first time, that maspin is an anti-apoptotic protein in the colon. Immunohistochemical evaluation of maspin expression in human colonic epithelial cells during sporadic colon carcinogenesis (131 human tissues evaluated) indicated a statistically significant increase in maspin protein expression beginning at the polyp stage of carcinogenesis. There was no statistically significant difference in maspin expression between hyperplastic/adenomatous polyps and colonic adenocarcinomas. The absence of "field defects" in the non-neoplastic colonic mucosa of patients with colonic neoplasia indicates that maspin may drive the growth of tumors, in part, through its anti-apoptotic function.

Dexamethasone and Long-term Outcome of Tuberculous Meningitis in Vietnamese Adults and Adolescents

PloS One. 2011  |  Pubmed ID: 22174748

Dexamethasone has been shown to reduce mortality in patients with tuberculous meningitis but the long-term outcome of the disease is unknown.

Histopathological Studies in Two Strains of Semi-immune Mice Infected with Plasmodium Berghei ANKA After Chronic Exposure

Parasitology Research. Apr, 2011  |  Pubmed ID: 20978790

To mimic a human malaria infection in the endemic condition, two strains of mice (Balb/c and CBA) were infected and treated several times to generate so-called semi-immune status. As previously reported, neither mice (Balb/c and CBA) strain showed cerebral malaria, even in the susceptible C57BL/6 (B6). The significant difference between the mice strains in our previous study was the rate of destruction of uninfected red blood cells (uRBCs) at infection. After the established repeated cycles of infection and treatment and the final challenge with 10(4) Plasmodium berghei ANKA until minimum Hb, Balb/c and CBA mice were sacrificed. The spleen, liver, brain, kidney, lung, heart, and muscle were removed, stained with hematoxylin-eosin and analyzed with light microscopy. Previous observation suggested that Balb/c destroyed uRBC at much higher rate than the other strains although the parasitemia was very low. Pathological investigation carried out in this study revealed that this destruction was mainly contributed by the uRBCs as no parasite sequestration was observed in any of the organs. However, malaria pigment deposition was observed in spleen and liver of all the semi-immune mice strains. This histopathological study in the severe malaria anemia model, which is difficult to conduct in humans, will be helpful in taking into account different responses to malaria infection when designing therapeutic interventions and vaccine studies.

A Novel, High-sensitivity and Drug-tolerant Sandwich Immunoassay for the Quantitative Measurement of Circulating Proteins

Bioanalysis. Feb, 2012  |  Pubmed ID: 22303828

Background: Accurate measurement of a total protein target (free plus bound) is essential to optimize dose selection for monoclonal antibody drugs. Herein, we describe a novel sandwich immunoassay format in which the biotherapeutic antibody itself serves as the primary detection antibody. A signal is then generated through the addition of a labeled secondary antibody that recognizes the biotherapeutic antibody. The secondary antibody is conjugated with ruthenium to facilitate electrochemiluminescent analysis. Results: Data are presented from the analysis of two protein biomarkers having disparate size and structure; a 4.5 kDa peptide and a 60 kDa protein. In both cases, validated, highly specific assays were developed and shown to be tolerant to elevated levels of the therapeutic monoclonal antibody in question. Conclusion: Our novel format allows drug-tolerant measurement of soluble protein biomarkers targeted by monoclonal antibodies when only two independent epitopes for antibody binding are available and one is recognized by the therapeutic antibody.