bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene transfer strategies in tissue engineering
Authors: Bleiziffer Oliver , Eriksson Elof , Yao Feng , Horch Raymund E. , Kneser Ulrich 
Published: May 2007

Introduction
Methods of gene delivery
Gene delivery from scaffolds for tissue engineering
Gene therapy applications in tissue engineering
Outlook

AbstractAiming for regeneration of severed or lost parts of the body, the combined application of gene therapy and tissue engineering has received much attention by regenerative medicine. Techniques of molecular biology can enhance the regenerative potential of a biomaterial by co‐delivery of therapeutic genes, and several different strategies have been used to achieve that goal. Possibilities for application are many‐fold and have been investigated to regenerate tissues such as skin, cartilage, bone, nerve, liver, pancreas and blood vessels. This review discusses advantages and problems encountered with the different gene delivery strategies as far as they relate to tissue engineering, analyses the positive aspects of polymeric gene delivery from matrices and discusses advances and future challenges of gene transfer strategies in selected tissues.
E2F1 death pathways as targets for cancer therapy
Authors: Pützer B. M. 
Published: May 2007

Introduction
Molecular mechanisms of E2F1 induced apoptosis
E2F1 sensitizes tumor cells to DNA damage
E2F1 guided death pathways in cancer
E2F1 apoptosis and new therapeutic strategies

AbstractDefects in apoptotic programs contribute to a number of human diseases, ranging from neurodegenerative disorders to malignancy, and treatment failure. The genetic basis for apoptosis implies that cell death can be disrupted by mutations, raising the intriguing possibility that cell numbers can be regulated by factors that influence cell survival. It is well documented that the E2F1 transcription factor is a key regulator of apoptotic programs. E2F1‐induced cell death occurs via multiple pathways, some of which involve the tumour suppressor p53, and autonomous of p53. This has led to the opinion that E2F1 functions as a tumour surveillance factor, detecting aberrant proliferation and engaging apoptotic pathways to protect the organism from developing tumours. Frequently, novel players are discovered that expand the interpretation of apoptosis control by E2F1. This information will help to produce new strategies to exploit E2F1‐induced apoptosis for therapeutic benefit.
The extracellular matrix and blood vessel formation: not just a scaffold
Authors: Rhodes John M. , Simons Michael 
Published: May 2007

Introduction
ECM: composition and structure
Evaluation of ECM molecules and their modulators in vessel formation
ECM signalling in vessel formation: what next?

AbstractThe extracellular matrix plays a number of important roles, among them providing structural support and information to cellular structures such as blood vessels imbedded within it. As more complex organisms have evolved, the matrix ability to direct signalling towards the vasculature and remodel in response to signalling from the vasculature has assumed progressively greater importance. This review will focus on the molecules of the extracellular matrix, specifically relating to vessel formation and their ability to signal to the surrounding cells to initiate or terminate processes involved in blood vessel formation.
Cataract surgery anaesthesia: is topical anaesthesia really better than retrobulbar?
Authors: Gombos Katalin , Jakubovits Edit , Kolos Agoston , Salacz György , Németh Janos 
Published: May 2007

Abstract.Purpose:  To compare the effectiveness for the patient of retrobulbar anaesthesia (RBA) and topical anaesthesia (TA) in cataract surgery by phacoemulsification.Methods:  We performed a prospective, randomized study on 115 patients operated at our clinic using the two anaesthesia techniques. The RBA group comprised 57 patients (20 women, 37 men; age 72 ± 10 years); the TA group comprised 58 patients (20 women, 38 men; age 74 ± 10 years). Measured parameters were: blood pressure; heart rate; blood oxygen saturation level; serum adrenaline, noradrenaline and cortisol levels; white blood cell count; indicated pain during the procedure, and pain as reported by the patient afterwards. Two psychological tests were used: the State−Trait Anxiety Inventory (STAI), and the patient‐selected face‐scale test. Statistical analysis was performed using Student's t‐test and the chi‐square test. Results were also analysed using a logistic regression model.Results:  Both types of anaesthesia were adequate for the surgical procedure. In the RBA group fewer patients experienced pain during surgery (p < 0.01) and fewer recalled any perioperative discomfort. With RBA the objective parameters were more stable than with TA, and systolic blood pressure was significantly lower (p = 0.01). The logistic model was able to predict perioperative pain with 93% certainty. Pain sensitivity was higher in younger patients and in patients with higher initial cortisol and noradrenaline serum levels.Conclusions:  Both methods of anaesthesia are appropriate, but phacoemulsification with TA is more painful than with RBA. In hypertonic patients and younger patients who are more susceptible to pain, TA should be avoided or used in combination with individualized sedation.
Differentially Expressed Proteins in Derivatives of
Candida albicans
Displaying a Stable Histatin 3-Resistant Phenotype
Authors: Fitzgerald-Hughes Deirdre H. , Coleman David C. , Connell Brian C. O’ 
Published: May 2007

ABSTRACT

Histatin-resistant derivatives of
Candida albicans
strain 132A, generated by successive exposure to increasing concentrations of histatin 3, were previously reported to be similar to the parent strain in their histatin binding, internalization, oxygen consumption, ATP efflux, and histatin degradation. Proteomic analysis of further histatin-resistant secondary derivatives of this series revealed that 59 proteins were differentially expressed compared to the parental strain. Of these 59 proteins, 3 were absent in histatin-resistant secondary derivatives and 11 were absent in the parent strain. Of the proteins absent in the histatin-resistant derivatives, the most notable was elongation factor 2, a target for the natural antifungal sordarin. Of the proteins absent in the parent strain but present in histatin-resistant derivatives, those identified included isocitrate lyase (Icl1p), fructose biphosphate aldolase (Fba1p), pyruvate decarboxylase (Pdc2p), and ketol-acid reductoisomerase (Ilv5p). The present secondary derivatives showed significantly decreased rates of oxygen consumption and histatin 3-mediated ATP release compared to the parent strain and also showed stability of the histatin-resistant phenotype. A significant (twofold) decrease in transcript levels of the potassium transporter encoded by
TRK1
, a critical mediator of histatin killing, was found in only one of the secondary histatin-resistant derivatives compared to the parent strain. The sequential exposure of
C. albicans
to histatin 3 described here resulted in the induction or selection of a phenotype with impaired metabolic function. The results support an important role for metabolic pathways in the histatin resistance mechanism and suggest that there may be several intracellular targets for histatin 3 in
C. albicans
.
Mass Spectrometry-Based Systems Approach for Identification of Inhibitors ofPlasmodium falciparumFatty Acid Synthase
Authors: Sharma Shilpi , Sharma Shailendra Kumar , Modak Rahul , Karmodiya Krishanpal , Surolia Namita , Surolia Avadhesha 
Published: May 2007

ABSTRACTThe emergence of strains ofPlasmodium falciparumresistant to the commonly used antimalarials warrants the development of new antimalarial agents. The discovery of type II fatty acid synthase (FAS) inPlasmodiumdistinct from the FAS in its human host (type I FAS) opened up new avenues for the development of novel antimalarials. The process of fatty acid synthesis takes place by iterative elongation of butyryl-acyl carrier protein (butyryl-ACP) by two carbon units, with the successive action of four enzymes constituting the elongation module of FAS until the desired acyl length is obtained. The study of the fatty acid synthesis machinery of the parasite inside the red blood cell culture has always been a challenging task. Here, we report the in vitro reconstitution of the elongation module of the FAS of malaria parasite involving all four enzymes, FabB/F (β-ketoacyl-ACP synthase), FabG (β-ketoacyl-ACP reductase), FabZ (β-ketoacyl-ACP dehydratase), and FabI (enoyl-ACP reductase), and its analysis by matrix-assisted laser desorption-time of flight mass spectrometry (MALDI-TOF MS). That this in vitro systems approach completely mimics the in vivo machinery is confirmed by the distribution of acyl products. Using known inhibitors of the enzymes of the elongation module, cerulenin, triclosan, NAS-21/91, and (−)-catechin gallate, we demonstrate that accumulation of intermediates resulting from the inhibition of any of the enzymes can be unambiguously followed by MALDI-TOF MS. Thus, this work not only offers a powerful tool for easier and faster throughput screening of inhibitors but also allows for the study of the biochemical properties of the FAS pathway of the malaria parasite.
Comparative Antimalarial Activities of Six Pairs of 1,2,4,5-Tetraoxanes (Peroxide Dimers) and 1,2,4,5,7,8-Hexaoxonanes (Peroxide Trimers)
Authors: Dong Yuxiang , Creek Darren , Chollet Jacques , Matile Hugues , Charman Susan A. , Wittlin Sergio , Wood James K. , Vennerstrom Jonathan L. 
Published: May 2007

ABSTRACT

Six tetraoxanes had 50% inhibitory concentrations in the range of 10 to 100 ng/ml against
Plasmodium falciparum
, whereas the corresponding hexaoxonanes had minimal antimalarial activity. The lack of iron-mediated reactivity of the hexaoxonanes may explain their low activity compared to the tetraoxanes, the latter of which are able to undergo iron(II)-mediated activation.
Use of Population Pharmacokinetic Modeling and Monte Carlo Simulation To Describe the Pharmacodynamic Profile of Cefditoren in Plasma and Epithelial Lining Fluid
Authors: Lodise Thomas P. , Kinzig-Schippers Martina , Drusano George L. , Loos Ulrich , Vogel Friedrich , Bulitta Jürgen , Hinder Markus , Sörgel Fritz 
Published: May 2007

ABSTRACTCefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistantStreptococcus pneumoniae. This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive γ). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was <80% for a MIC of >0.06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was <80% for MIC of >0.06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of >0.06 mg/liter, which includes mostS. pneumoniaeisolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.
Inhibition of Isolated
Mycobacterium tuberculosis
Fatty Acid Synthase I by Pyrazinamide Analogs
Authors: Ngo Silvana C. , Zimhony Oren , Chung Woo Jin , Sayahi Halimah , Jacobs William R. , Welch John T. 
Published: May 2007

ABSTRACT

An analog of pyrazinamide (PZA), 5-chloropyrazinamide (5-Cl-PZA), has previously been shown to inhibit mycobacterial fatty acid synthase I (FASI). FASI has been purified from a recombinant strain of
M. smegmatis
(
M. smegmatis Δfas1 attB
::
M. tuberculosis fas1
). Following purification, FASI activity and inhibition were assessed spectrophotometrically by monitoring NADPH oxidation. The observed inhibition was both concentration and structure dependent, being affected by both substitution at the 5 position of the pyrazine nucleus and the nature of the ester or
N
-alkyl group. Under the conditions studied, both 5-Cl-PZA and PZA exhibited concentration and substrate dependence consistent with competitive inhibition of FASI with

K
i

s of 55 to 59 μM and 2,567 to 2,627 μM, respectively. The results were validated utilizing a radiolabeled fatty acid synthesis assay. This assay showed that FASI was inhibited by PZA and pyrazinoic acid as well as by a series of PZA analogs.
Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys
Authors: Asif Ghazia , Hurwitz Selwyn J. , Obikhod Aleksandr , Delinsky David , Narayanasamy Janarthanan , Chu Chung K. , McClure Harold M. , Schinazi Raymond F. 
Published: May 2007

ABSTRACTβ-d-Dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h−1; fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.
Exogenous Heat-KilledEscherichia coliImproves Alveolar Macrophage Activity and ReducesPneumocystis cariniiLung Burden in Infant Mice
Authors: Empey Kerry M. , Hollifield Melissa , Garvy Beth A. 
Published: May 2007

ABSTRACTPneumocystis cariniiis an opportunistic fungal pathogen that causes life-threatening pneumonia in immunocompromised individuals. Infants appear to be particularly susceptible toPneumocystispulmonary infections. We have previously demonstrated that there is approximately a 3-week delay in the clearance ofPneumocystisorganisms from pup mouse lungs compared to that in adults. We have further shown that there is approximately a 1-week delay in alveolar macrophage activation in pups versus adult mice. Alveolar macrophages are the primary effector cells responsible for the killing and clearance ofPneumocystis, suggesting that pup alveolar macrophages may be involved in the delayed clearance of this organism. Alveolar macrophages cultured in vitro withPneumocystisalone demonstrate little to no activation, as indicated by a lack of cytokine production. However, when cultured with lipopolysaccharide (LPS) or zymosan, cytokine production was markedly increased, suggesting that pup alveolar macrophages are specifically unresponsive toPneumocystisorganisms rather than being intrinsically unable to become activated. Furthermore, pup mice treated with aerosolized, heat-killedEscherichia coliin vivo were able to clearPneumocystismore efficiently than were control mice. Together, these data suggest that while pup alveolar macrophages are unresponsive toP. cariniif. sp.murisorganisms, they are capable of activation by heat-killedE. coliin vivo, as well as LPS and zymosan in vitro. The lack of response of pup mice toP. cariniif. sp.murismay reflect protective mechanisms specific to the developing pup lung, but ultimately it results in insufficient clearance ofPneumocystisorganisms.
In the Absence of CD154, Administration of Interleukin-12 Restores Th1 Responses but Not Protective Immunity toSchistosoma mansoni
Authors: Hewitson James P. , Hamblin Paul A. , Mountford Adrian P. 
Published: May 2007

ABSTRACTThe cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154−/−mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154−/−mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154−/−mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154−/−mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154−/−mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c+cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154−/−mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.
Modulation of Autoimmunity by Treatment of an Infectious Disease
Authors: Hyland Kenneth V. , Leon Juan S. , Daniels Melvin D. , Giafis Nick , Woods LaKitta M. , Bahk Thomas J. , Wang Kegiang , Engman David M. 
Published: May 2007

ABSTRACTChagas’ heart disease (CHD), caused by the parasiteTrypanosoma cruzi, is the most common form of myocarditis in Central America and South America. Some humans and experimental animals develop both humoral and cell-mediated cardiac-specific autoimmunity during infection. Benznidazole, a trypanocidal drug, is effective at reducing parasite load and decreasing the severity of myocarditis in acutely infected patients. We hypothesized that the magnitude of autoimmunity that develops followingT. cruziinfection is directly proportional to the amount of damage caused by the parasite. To test this hypothesis, we used benznidazole to reduce the number of parasites in an experimental model of CHD and determined whether this treatment altered the autoimmune response. Infection of A/J mice with the Brazil strain ofT. cruzileads to the development of severe inflammation, fibrosis, necrosis, and parasitosis in the heart accompanied by vigorous cardiac myosin-specific delayed-type hypersensitivity (DTH) and antibody production at 21 days postinfection. Mice succumbed to infection within a month if left untreated. Treatment of infected mice with benznidazole eliminated mortality and decreased disease severity. Treatment also reduced cardiac myosin-specific DTH and antibody production. Reinfection of treated mice with a heart-derived, virulent strain ofT. cruzior immunization with myosin led to the redevelopment of myosin-specific autoimmune responses and inflammation. These results provide a direct link between the levels ofT. cruziand the presence of autoimmunity and suggest that elimination of the parasite may result in the reduction or elimination of autoimmunity in the chronic phase of infection.
Neural Cell Adhesion Molecule, a New Cytoadhesion Receptor forPlasmodium falciparum-Infected Erythrocytes Capable of Aggregation
Authors: Pouvelle Bruno , Matarazzo Valéry , Jurzynski Christophe , Nemeth Johannes , Ramharter Michael , Rougon Geneviève , Gysin Jürg 
Published: May 2007

ABSTRACTThe cytoadhesion ofPlasmodium falciparum-infected erythrocytes (IEs) to the endothelial cells lining the microvasculature, clogging the microvessels of various organs, is a key event in the pathogenesis of certain severe forms of malaria, such as cerebral malaria and pulmonary edema. Studies aiming to identify possible correlations between the severity of clinical cases and the presence of particular cytoadhesion phenotypes have been largely unsuccessful. One of the possible reasons for this failure is that some of the key receptors and/or mechanisms involved have yet to be identified. By combining IE selection, cell transfection, and adhesion inhibition assays, we identified a new cytoadhesion receptor, neural cell adhesion molecule (NCAM). NCAM is a member of the immunoglobulin superfamily and has nonpolysialylated and polysialylated isoforms, the latter being rare in adults. The nonpolysialylated form is present on the surfaces of endothelial cells in the microvessels of various organs in which IE sequestration occurs. We found that multiphenotypic IEs interacted with nonpolysialylated NCAM and with another, as yet unidentified receptor. These IEs also displayed cytoadhesion in flow conditions, presenting the unique ability to form adherent macroaggregates composed of hundreds of IEs. These features may act as virulence factors, increasing the capacity of IEs to clog microvessels via receptor synergy and macroaggregate formation, thereby facilitating the pathogenesis of severe forms of malaria.
Amended Description of the Genes for Synthesis ofActinomyces naeslundiiT14V Type 1 Fimbriae and Associated Adhesin
Authors: Chen Ping , Cisar John O. , Hess Sonja , Ho Jenny T. C. , Leung Kai P. 
Published: May 2007

ABSTRACTThe type 1 fimbriae ofActinomyces naeslundiiT14V mediate adhesion of this gram-positive species to the tooth surface. The present findings show that the locus for type 1 fimbria production in this strain includes three genes,fimQfor a minor fimbrial subunit that appears to be an adhesin,fimPfor the major structural subunit, andsrtC1for a type 1 fimbria-specific sortase involved in the assembly of these structures.
Diagnosis and treatment of swellings in the hand
Authors: Hasham Saiidy , Burke Frank D 
Published: May 2007

Abstract
Patients commonly present to their general practitioner with swellings of the hand. These include a variety of diagnoses with certain lesions (for example, ganglion) being more common than others. Some may even be familiar as they are often site specific. For those that are not routinely seen, or for those that look suspicious, referral to a hand surgeon is usually customary. This article aims to provide general practitioners with clear and concise information and terms of reference on the common hand swellings that they may encounter.