bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Defects 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?

The 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

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.
Prevention of Osteoporosis: The Calcium Controversy
Authors: Johnston Joan Evelyn
Published: May 2007

The continuing scientific controversy regarding the use of calcium supplements for the prevention of osteoporosis during menopause presents a challenge to the nurse practitioner. There is little doubt that estrogen prevents bone loss following menopause, but there is a growing doubt among many researchers whether calcium supplementation beyond 800 mg/ per day produces any benefit at all in preventing postmenopausal osteoporosis. Yet, the medical consensus in this country continues to recommend 1500 mg of calcium per day for menopausal women. The practitioner's clinical questions relate to the effectiveness, cost, and compliance of calcium prescription. An alternate recommendation and protocol are presented here.
Report of the National Survey of the American Academy of Nurse Practitioners, Part II: Pharmacologic Management Practices
Authors: PhD Jan Towers
Published: May 2007

Nurse practitioners provide pharmacologic management to their patients throughout the country. This report focuses on the results of the Academy's national survey regarding pharmacological management practices by nurse practioners according to locale and specialty. Included is data regarding methods for handling prescriptive medications, types of drugs prescribed or recommended, and interactions with pharmacists.
The Effects of Polydextrose and Xylitol on Microbial Community and Activity in a 4‐Stage Colon Simulator
Authors: Mäkeläinen H.S. , Mäkivuokko H.A. , Salminen S.J. , Rautonen N.E. , Ouwehand A.C.
Published: May 2007

ABSTRACT:  This study focused on the effects of candidate prebiotics polydextrose (PDX) and xylitol on the microbial community and its metabolic activity in a colon simulator. A semicontinuous, anaerobic culture system was used with 4 vessels mimicking the conditions in the human large intestine from proximal to distal colon. Bacterial inocula for the independent simulations were obtained from fecal samples of different donors. Synthetic medium, mimicking the contents of the small intestine, containing either 2% of the prebiotic candidate or no added carbohydrates as a control, was fed to the system. After 48 h of simulation samples were collected and analyzed. A sustained degradation of polydextrose throughout the colon model and a more rapid degradation of xylitol were observed. The fermentation of both compounds was characterized by a significantly increased production of short‐chain fatty acids (SCFA). Polydextrose increased the concentrations of all SCFA, especially acetate and propionate, and xylitol especially the concentration of butyrate. Branched‐chain fatty acids (BCFA) levels decreased significantly as a result of polydextrose and xylitol supplementation, whereas biogenic amine levels remained mostly unchanged. Thus, a beneficial shift in the metabolic patterns of the colon microbes was measured with both of the tested products. These in vitro studies provide evidence to the prebiotic characteristics of polydextrose; also, further beneficial properties of xylitol were demonstrated in the colon model.
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

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

The 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

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

Cefditoren 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

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

β-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

Pneumocystis 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

The 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

Chagas’ 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

The 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

The 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

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.
Age-related macular degeneration and recent developments: new hope for old eyes?
Authors: Morris Brid , Imrie Fraser , Armbrecht Ana-Maria , Dhillon Baljean
Published: May 2007

Age-related macular degeneration (AMD) is the commonest cause of blindness in the population over 60 years of age and accounts for over 50% of those registered blind in the UK. The incidence is increasing and as older generations live longer a growing number of patients will be affected in the future. Affected patients lose central vision, important in all aspects of everyday life. This review outlines risk factors for AMD, clinical features, treatment and management strategies for patients, families and physicians caring for those with AMD. Recent trials are included along with practical clinical advice. While there is no curative treatment at present, intervention can reduce the risk of developing AMD and limit disease progression if it occurs. These modalities are discussed here. As new discoveries in the field of genetics and novel therapies emerge, a brighter future seems certain for the ageing population.
Effects of comorbidity and hospital care on 6-month mortality in patients with elevated cardiac troponin T
Authors: Wong P , Ramsewak A , Murray S , Robinson A , Robinson D , Rodrigues E
Published: May 2007

Objective

To examine the effects of comorbidity and hospital care on mortality in patients with elevated cardiac troponin T.

Design

Observational study.

Setting

A large university hospital with on-site diagnostic cardiac catheter laboratory.

Patients

All hospitalised patients with elevated cardiac troponin T level (⩾0.01 μg/l) over an 8-week period.

Main outcome measures

6-month all-cause mortality.

Results

Among 313 patients with elevated cardiac troponin T, 195 had acute coronary syndrome and 118 had other conditions. Multivariate analysis showed that among patients with acute coronary syndrome, increasing comorbidity score (odds ratio (OR) 1.23 per point increase, 95% confidence interval (CI) 1.00 to 1.51; p = 0.048), age (OR 1.08 per year, 95% CI 1.04 to 1.13; p<0.001), raised troponin T level (OR 2.22 per 10-fold increase, 95% CI 1.27 to 3.89; p = 0.005), and ST depression (OR 3.12, 95% CI 1.38 to 7.03; p = 0.006) were independent adverse predictors, while cardiologist care (OR 0.22, 95% CI 0.09 to 0.51; p<0.001) was associated with a better survival. Increasing troponin T level (OR 3.33 per 10-fold increase, 95% CI 1.24 to 8.91; p = 0.017) was found to predict a worse prognosis among patients without acute coronary syndrome, and cardiologist care did not affect outcome in this group. Among hospital survivors with acute coronary syndrome, increasing comorbidity score, age and a lack of cardiologist care were independently associated with lesser use of effective medications.

Conclusions

Comorbidity was associated with a higher 6-month mortality in patients having acute coronary syndrome, and lesser use of effective medicines among hospital survivors. Cardiologist care was associated with better 6-month survival in patients with acute coronary syndrome, but not in those without acute coronary syndrome.
Maimonides: an early but accurate view on the treatment of haemorrhoids
Authors: Magrill Dan , Sekaran Prabhu
Published: May 2007

Moses Maimonides was not only one of the most influential religious figures of the middle ages, but also a pioneer in a wide variety of medical practices. A brief history of his life, and what is known about his medical education, is given here. His paper on haemorrhoids is summarised, as well as a review of the current understanding of the pathogenesis, prevention and treatment of this common condition. The comparison of Maimonides' writings to modern understanding of not only the prevention and treatment of haemorrhoids, but also his approach to the patient as a whole in terms of pre- and postoperative care, demonstrate how ahead of his time this great philosopher was.
Left ventricle diastolic function in the patients after coronary arteries bypass graft combined with left ventricle aneurismectomy according to tissue doppler imaging: one year follow-up
Authors: Dolzhenko Maryna N , Rudenko S A , Potashev S V , Simagina T V , Nosenko N N , Kravchenko T G
Published: May 2007

Aim

To evaluate left ventricle (LV) diastolic function dynamics in patients after acute myocardial infarction (AMI) after combined operation of coronary artery bypass graft with LV aneurismectomy (CABG + AE) according to the results of tissue Doppler imaging (TDI).

Methods

Forty patients after AMI underwent Doppler echocardiography (EchoCG) with TDI and M-mode colour-flow imaging before and in 3 and 12 months after CABG + AE. Mitral annulus (MA) TDI with velocity indices was performed in 4 segments of LV.

Results

Conventional transmitral diastolic Doppler indices before and after CABG + AE remained unchanged. TDI showed significant improvement of LV systolic (systolic movement velocity S: 6.1±0.8, 7.4±1.2 and 6.9±1.3 cm/sec. before and in 3 and 12 months after the operation, respectively, p<0.01) and diastolic function after the operation (MA early diastolic movement velocity (e’): 7.3 ± 2.1, 8.4 ± 1.5 and 8.9 ± 1.8 cm/s.; ratio of transmitral early-flow velocity (E) to MA early-diastolic movement velocity (E/e’): 18.4 ± 2.2, 12.3 ± 1.8 and 11.5 ± 2.3; ratio of E diastolic flow propagation velocity (Vp) 3.1 ± 0.45, 2.2 ± 0.38 and 1.8 ± 0.16 before and in 3 and 12 months after the operation, respectively, p<0.01).

Conclusions

Results of the study demonstrate significant improvement of LV diastolic function in the patient after CABG + AE according to TDI, regardless of transmitral flow pattern. TDI is more sensitive and preload independent method of LV myocardial function evaluation.
Synergistic effect of triptolide combined with 5-fluorouracil on colon carcinoma
Authors: Tang Xiao-yan , Zhu You-qing , Tao Wen-hui , Wei Bai , Lin Xiao-ling
Published: May 2007

Aim

To investigate the inhibitive effects of triptolide (TPL) combined with 5-fluorouracil (5-FU) on colon carcinoma HT-29 cells in vitro and in vivo and their side effects.

Methods

HT-29 cells were cultured with RPMI 1640 medium. The single or combined effects of TPL and 5-FU on HT-29 cells were examined by MTT assay, flow cytometry. The combined effects were evaluated by the median-effect principle. The model of tumour xenografts was established in nude mice. TPL 0.25 mg/kg/day and 5-FU 12 mg/kg/day, either in combination or on their own, were injected into mice and the inhibitive effects and side effects were observed.

Results

TPL and 5-FU either combined or alone inhibited significantly the proliferation of HT-29 cells and induced obvious apoptosis. Mean (SD) growth inhibition rate reached 94.92 (2.76)% and the apoptic rate at 48 h reached 41.71 (1.38)%. The combined effects were synergistic (CI<1) at lower concentrations. TPL or 5-FU alone inhibited significantly the growth of tumour xenografts and the inhibition rates were 78.53% and 84.16%; the drugs combined had more significant effect, the tumour inhibition rate reaching 96.78%. During the course of chemotherapy, no obvious side effect was observed.

Conclusion

The combined effects of TPL and 5-FU on the growth of colon carcinoma in vitro and in vivo were superior to the effects when the agents were used individually. TPL combined with 5-FU had synergistic effects at lower concentrations and promoted apoptosis, but did not increase the side effects of chemotherapy.
Influence of curcumin, capsaicin, and piperine on the rat liver drug-metabolizing enzyme system in vivo and in vitro
Authors: Suresh D. , Srinivasan K.
Published: May 2007

The effect of dietary supplementation of spice-active principles, curcumin (0.2%), capsaicin (0.015%), and piperine (0.02%) on the activities of the liver drug-metabolizing enzyme system was examined. All the 3 dietary spice principles significantly stimulated the activity of aryl hydroxylase. A synergistic action of dietary curcumin and capsaicin with respect to stimulating the activity of aryl hydroxylase was also evidenced when fed in combination. The activity of N-demethylase essentially remained unaffected by dietary curcumin, capsaicin, or their combination, but was significantly lowered as a result of piperine feeding. Uridine dinucleotide phosphate (UDP)-glucuronyl transferase activity was decreased by dietary piperine and the combination of curcumin and capsaicin. NADPH-cytochrome c reductase activity was significantly decreased by dietary piperine. The levels of hepatic microsomal cytochrome P450and cytochrome b5were not influenced by any of the dietary spice-active principles. These spice-active principles were also examined for their possible in vitro influence on the components of the hepatic drug-metabolizing enzyme system in rat liver microsomal preparation. Piperine significantly decreased the activity of liver microsomal aryl hydroxylase activity when included in the assay medium at 1 × 10−6 mol/L, 1 × 10−5 mol/L, and 1 × 10−4 mol/L level. Lowered activity of N-demethylase was observed in presence of capsaicin or piperine at 1 × 10−6mol/L in the assay medium. Hepatic microsomal glucuronyl transferase activity was significantly decreased in vitro by addition of capsaicin or piperine. Capsaicin and piperine brought about significant decrease in liver microsomal cytochrome P450when included at 1 × 10−6 mol/L and 1 × 10−5 mol/L, the effect being much higher in the case of piperine. The results suggested that whereas the 3 spice principles have considerable similarity in structure, piperine is exceptional in its influence on the liver drug-metabolizing enzyme system. The study also indicated that a combination of curcumin and capsaicin does not produce any significant additive effect on the liver drug-metabolizing enzyme system.
Prevention of occupational asthma in OntarioThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.
Authors: Tarlo Susan M.
Published: May 2007

Occupational asthma continues to be one of the most common occupational lung diseases in industrialized areas. Primary and secondary preventive measures have been well described, but there are relatively few studies to support the effectiveness of such measures, although the benefits of tertiary measures such as early recognition and removal from further exposure to a causative sensitizing agent are well recognized. In Ontario, a combined approach of preventive measures has shown effectiveness in allergy and asthma from occupational exposure to natural rubber latex. In addition, a program to reduce exposure to diisocyanates and introduce medical surveillance was associated with earlier diagnosis and fewer cases in a compensation population. However there remain barriers to the early diagnosis of occupational asthma in Ontario, especially in workers of lower education and lower income. In addition, there is recognized need for further physician education to allow early suspicion and diagnosis of occupational asthma.
Locomotor and peripheral effects of sibutramine modulated by 5-HT2receptors
Authors: Frassetto Silvana Soriano , Della Santa Rubio Ângela , Lopes Janaína Jardim , Pereira Patrícia , Brum Clarice , Khazzaka Márcia , Vinagre Anapaula Sommer
Published: May 2007

Sibutramine has been described as an anti-obesity drug with the ability to inhibit serotonin (5-HT), noradrenaline, and dopamine re-uptake, but without affinity to histamine and muscarinic receptors. On the other hand, cyproheptadine antagonizes serotonin 5-HT2A, 5-HT2B, and 5-HT2C, histamine H1, and muscarinic (M) receptors. There are many reports concerning the influence of sibutramine on central serotoninergic pathways. In this study, we suggest that peripheral pathways may also be involved in the serotoninergic effects of sibutramine. In vivo experiments were undertaken to investigate the serotoninergic effects of sibutramine on body mass, the glycogen concentration in the diaphragm of rats, and locomotor behaviour. Rats were submitted to oral treatment with sibutramine, cyproheptadine, or sibutramine applied in combination with cyproheptadine, for a period of 2 months to investigate the 5-HT2effects of sibutramine on these parameters. As the results demonstrated, the lower increase in body mass and the increased glycogen levels in the diaphragm muscle of rats treated with sibutramine seem to be modulated by 5-HT2receptors, since these effects were completely antagonized by cyproheptadine in the group treated with the 2 drugs co-applied. Furthermore, the behavioural results also suggest that mechanisms modulated by 5-HT2receptors are involved in the increase of locomotion in the rats treated with sibutramine, since the effect did not occur in the rats treated with sibutramine co-applied with the 5-HT2receptor antagonist, cyproheptadine. The results suggest that sibutramine modifies energy-related parameters such as body mass, diaphragm glycogen, and locomotor behaviour in rats via 5-HT2serotoninergic pathways.
Systemic inflammation and mortality in chronic obstructive pulmonary diseaseThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.
Authors: Sin Don D. , Man S.F. Paul
Published: May 2007

Cardiovascular diseases and cancer (especially lung cancer) are leading causes of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Some have implicated systemic inflammation, which is commonly observed in COPD, as the potential mechanistic bridge between COPD and these disorders. This concept has been supported by animal studies especially in rabbits, which have clearly demonstrated the effect of local lung inflammation on systemic inflammation and on the progression of atherosclerosis and by cross-sectional population-based studies, which have shown a significant relationship between systemic inflammation, as measured by circulating C-reactive protein (CRP) and the risk of cardiovascular diseases in COPD patients. These data have been further extended by a recent study that has elucidated the temporal nature of the relationship between systemic inflammation and the risk of cardiovascular events and cancer in COPD patients. This study showed that baseline CRP levels predicted the incidence of cardiovascular events and cancer-specific mortality over 7 to 8 years of follow-up. CRP levels also predicted all-cause mortality. Collectively, these data indicate that systemic inflammation may play an important role in mediating the extra-pulmonary complications of COPD. Systemic inflammation may contribute substantially to the overall morbidity and mortality of COPD patients.
Phospholipid-mediated signaling systems as novel targets for treatment of heart diseaseThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.
Authors: Tappia Paramjit S.
Published: May 2007

The phospholipases associated with the cardiac sarcolemmal (SL) membrane hydrolyze specific membrane phospholipids to generate important lipid signaling molecules, which are known to influence normal cardiac function. However, impairment of the phospholipases and their related signaling events may be contributory factors in altering cardiac function of the diseased myocardium. The identification of the changes in such signaling systems as well as understanding the contribution of phospholipid-signaling pathways to the pathophysiology of heart disease are rapidly emerging areas of research in this field. In this paper, I provide an overview of the role of phospholipid-mediated signal transduction processes in cardiac hypertrophy and congestive heart failure, diabetic cardiomyopathy, as well as in ischemia–reperfusion. From the cumulative evidence presented, it is suggested that phospholipid-mediated signal transduction processes could serve as novel targets for the treatment of the different types of heart disease.
Mechanisms of cardiodepression by an Na+–H+exchange inhibitor methyl-N-isobutyl amiloride (MIA) on the heart: lack of beneficial effects in ischemia–reperfusion injuryThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.
Authors: Saini Harjot K. , Elimban Vijayan , Ozcelikay A. Tanju , Dhalla Naranjan S.
Published: May 2007

Although Na+–H+exchange (NHE) inhibitors such as methyl-N-isobutyl amiloride (MIA) are known to depress the cardiac function, the mechanisms of their negative inotropic effect are not completely understood. In this study, isolated rat hearts were perfused with MIA to study its action on cardiac performance, whereas isolated subcellular organelles such as sarcolemma, myofibrils, sarcoplasmic reticulum, and mitochondria were treated with MIA to determine its effect on their function. The effect of MIA on intracellular Ca2+mobilization was examined in fura-2-AM-loaded cardiomyocytes. MIA was observed to depress cardiac function in a concentration-dependent manner in HCO3–-free buffer. On the other hand, MIA had an initial positive inotropic effect followed by a negative inotropic effect in HCO3–-containing buffer. MIA increased the basal concentration of intracellular Ca2+([Ca2+]i) and augmented the KCl-mediated increase in [Ca2+]i. MIA did not show any direct effect on myofibrils, sarcolemma, and sarcoplasmic reticulum ATPase activities; however, this agent was found to decrease the intracellular pH, which reduced the myofibrils Ca2+-stimulated ATPase activity. MIA also increased Ca2+uptake by mitochondria without having any direct effect on sarcoplasmic reticulum Ca2+uptake. In addition, MIA did not protect the hearts subjected to mild Ca2+paradox as well as ischemia–reperfusion-mediated injury. These results suggest that the increase in [Ca2+]iin cardiomyocytes may be responsible for the initial positive inotropic effect of MIA, but its negative inotropic action may be due to mitochondrial Ca2+overloading as well as indirect depression of myofibrillar Ca2+ATPase activity. Thus the accumulation of [H+]ias well as occurrence of intracellular and mitochondrial Ca2+overload may explain the lack of beneficial effects of MIA in preventing the ischemia–reperfusion-induced myocardial injury.
Neuropeptide Y (NPY) and NPY receptors in the cardiovascular system: implication in the regulation of intracellular calciumThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.
Authors: Jacques Danielle , Abdel-Samad Dima
Published: May 2007

The 3-dimensional confocal microscopy technique has allowed us to identify the presence of yet another cardioactive factor and its receptor, namely neuropeptide Y (NPY) and its Y1receptor, at the level of vascular smooth muscle cells and heart cells including endocardial endothelial cells (EECs). Using this technique, we also demonstrated that NPY is able to induce an increase in both cytosolic and nuclear calcium in all these cell types. Furthermore, besides being expressed at the level of EECs, NPY is also released from these cells following a sustained increase of intracellular Ca2+. This suggests the ability of NPY to contribute to the regulation of the excitation–secretion coupling of EECs and the excitation–contraction coupling of cardiomyocytes and vascular smooth muscle cells.
Who will be active? Predicting exercise stage transitions after hospitalization for coronary artery diseaseThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.
Authors: Reid Robert D. , Tulloch Heather , Kocourek Jana , Morrin Louise I. , Beaton Louise J. , Papadakis Sophia , Blanchard Chris M. , Riley Dana L. , Pipe Andrew L.
Published: May 2007

We describe transitions between exercise stages of change in people with coronary artery disease (CAD) over a 6-month period following a CAD-related hospitalization and evaluate constructs from Protection Motivation Theory, Theory of Planned Behavior, Social Cognitive Theory, the Ecological Model, and participation in cardiac rehabilitation as correlates of stage transition. Seven hundred eighty-two adults hospitalized with CAD were recruited and administered a baseline survey including assessments of theory-based constructs and exercise stage of change. Mailed surveys were used to gather information concerning exercise stage of change and participation in cardiac rehabilitation 6 months later. Progression from pre-action stages between baseline and 6 month follow-up was associated with greater perceived efficacy of exercise to reduce risk of future disease, fewer barriers to exercise, more access to home exercise equipment, and participation in cardiac rehabilitation. Regression from already active stages between baseline and 6 month follow-up was associated with increased perceived susceptibility to a future CAD-related event, fewer intentions to exercise, lower self-efficacy, and more barriers to exercise.
Down-regulation of calponin destabilizes actin cytoskeletal structure in A7r5 cells
Authors: Dykes Ava C. , Wright Gary L.
Published: May 2007

The effects of changes in the expression levels of h1 calponin (CaP) on actin cytoskeletal organization were studied in control and phorbol-ester-treated A7r5 smooth muscle cells. Protein association and expression in control and stimulated A7r5 smooth muscle cells were evaluated by Western blotting, laser scanning confocal microscopy (LSCM), and fluorescence resonance energy transfer (FRET) microscopy in cells treated with either 2 × 10−6mol/L TGF-β1 or 2 × 10−5mol/L PDGF-BB to alter h1 calponin expression. Single immunostained samples showed that CaP and α-actin, localized in fibers in unstimulated control A7r5 smooth muscle cells, were translocated to podosomes following treatment with phorbol-12,13-dibutyrate (PDBu). Confocal colocalization imaging and FRET analysis both indicated substantial association of CaP with α-actin in stress fibers of control cells and in podosomes of PDBu-treated cells. PKCα, which showed evidence of only slight association with CaP in control cells, exhibited markedly increased (293%) association in PDBu-contracted cells. Platelet-derived growth factor (PDGF)-BB down-regulated CaP to non-detectable levels, whereas transforming growth factor (TGF)-β1 up-regulated (424%) the expression of CaP without affecting the levels of α-actin or PKCα. PDGF-BB resulted in a significant loss in α-actin stress fibers (–47%) and reduced podosome formation (–69%). By comparison, TGF-β1 had no effect on stress fibers in control cells but also reduced (–70%) podosome formation. The results suggest that CaP could play a major role in the stabilization of actin stress fibers in resting cells and may contribute to podosome formation in PDBu-treated cells.