bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory and Bactericidal Activities of Daptomycin, Vancomycin, and Teicoplanin against Methicillin-Resistant
Staphylococcus aureus
Isolates Collected from 1985 to 2007
Authors: Traczewski Maria M. , Katz Bradley D. , Steenbergen Judith N. , Brown Steven D.
Published: February 2009

The inhibitory and bactericidal activities of daptomycin, vancomycin, and teicoplanin against a collection of 479 methicillin-resistant
Staphylococcus aureus
isolates were assessed. The isolates were collected from U.S. and European hospitals from 1985 to 2007 and were primarily from blood and abscess cultures. The MICs and minimum bactericidal concentrations (MBCs) of the three agents were determined, and the MBC/MIC ratios were calculated to determine the presence or absence of tolerance. Tolerance was defined as an MBC/MIC ratio of ≥32 or an MBC/MIC ratio of ≥16 when the MBC was greater than or equal to the breakpoint for resistance. Tolerance to vancomycin and teicoplanin was observed in 6.1% and 18.8% of the strains, respectively. Tolerance to daptomycin was not observed.
Tolevamer Is Not Efficacious in the Neutralization of Cytotoxin in a Human Gut Model of
Clostridium difficile
Infection
Authors: Baines Simon D. , Freeman Jane , Wilcox Mark H.
Published: February 2009

The efficacy of tolevamer, a nonantimicrobial styrene derivative toxin-binding agent, in treating simulated
Clostridium difficile
infection in an in vitro human gut model was investigated. Tolevamer reduced neither the duration nor magnitude of cytotoxin activity by
C. difficile
, reflecting poor efficacy observed in recent phase III clinical trials.
Contribution of Oxidative Damage to Antimicrobial Lethality
Authors: Wang Xiuhong , Zhao Xilin
Published: February 2009

A potential pathway linking hydroxyl radicals to antimicrobial lethality was examined by using mutational and chemical perturbations of
Escherichia coli
. Deficiencies of
sodA
or
sodB
had no effect on norfloxacin lethality; however, the absence of both genes together reduced lethal activity, consistent with rapid conversion of excessive superoxide to hydrogen peroxide contributing to quinolone lethality. Norfloxacin was more lethal with a mutant deficient in
katG
than with its isogenic parent, suggesting that detoxification of peroxide to water normally reduces quinolone lethality. An iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) reduced the lethal activity of norfloxacin, indicating that norfloxacin-stimulated accumulation of peroxide affects lethal activity via hydroxyl radicals generated through the Fenton reaction. Ampicillin and kanamycin, antibacterials unrelated to fluoroquinolones, displayed behavior similar to that of norfloxacin except that these two agents showed hyperlethality with an
ahpC
(alkyl hydroperoxide reductase) mutant rather than with a
katG
mutant. Collectively, these data are consistent with antimicrobial stress increasing the production of superoxide, which then undergoes dismutation to peroxide, from which a highly toxic hydroxyl radical is generated. Hydroxyl radicals then enhance antimicrobial lethality, as suggested by earlier work. Such findings indicate that oxidative stress networks may provide targets for antimicrobial potentiation.
Model-Based Approach To Characterize Efavirenz Autoinduction and Concurrent Enzyme Induction with Carbamazepine
Authors: Zhu Min , Kaul Sanjeev , Nandy Partha , Grasela Dennis M. , Pfister Marc
Published: February 2009

Characterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.
Lack of a Clinically Important Effect of Moderate Hepatic Insufficiency and Severe Renal Insufficiency on Raltegravir Pharmacokinetics
Authors: Iwamoto Marian , Hanley William D. , Petry Amelia S. , Friedman Evan J. , Kost James T. , Breidinger Sheila A. , Lasseter Kenneth C. , Robson Richard , Lunde Norman M. , Wenning Larissa A. , Stone Julie A. , Wagner John A.
Published: February 2009

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor with potent activity in vitro and in vivo. Raltegravir is primarily cleared by hepatic metabolism via glucuronidation (via UDP glucuronosyltransferase 1A1), with a minor component of elimination occurring via the renal pathway. Since the potential exists for raltegravir to be administered to patients with hepatic or renal insufficiency, two studies were conducted to evaluate the influence of moderate hepatic insufficiency (assessed by using the Child-Pugh criteria) and severe renal insufficiency (creatinine clearance, <30 ml/min/1.73 m2) on the pharmacokinetics of raltegravir. Study I evaluated the pharmacokinetics of 400 mg raltegravir in eight patients with moderate hepatic insufficiency and eight healthy, matched control subjects. Study II evaluated the pharmacokinetics of 400 mg raltegravir in 10 patients with severe renal insufficiency and 10 healthy, matched control subjects. All participants received a single 400-mg dose of raltegravir in the fasted state. In study I, the geometric mean ratios (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% confidence intervals (CIs) for the area under the concentration-time curve from time zero to infinity (AUC0-∞), the maximum concentration of drug in plasma (Cmax), and the concentration at 12 h (C12) were 0.86 (90% CI, 0.41, 1.77), 0.63 (90% CI, 0.23, 1.70), and 1.26 (90% CI, 0.65, 2.43), respectively. In study II, the GMRs (mean value for the group with renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC0-∞,Cmax, andC12were 0.85 (90% CI, 0.49, 1.49), 0.68 (90% CI, 0.35, 1.32), and 1.28 (90% CI, 0.79, 2.06), respectively. Raltegravir was generally well tolerated by patients with moderate hepatic or severe renal insufficiency, and there was no clinically important effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of raltegravir. No adjustment in the dose of raltegravir is required for patients with mild or moderate hepatic or renal insufficiency.
Pharmacokinetics of LB80331 and LB80317 following Oral Administration of LB80380, a New Antiviral Agent for Chronic Hepatitis B (CHB), in Healthy Adult Subjects, CHB Patients, and Mice
Authors: Yuen Man-Fung , Lee Sung-Hack , Kang Hyang-Mi , Kim Chung Ryeol , Kim John , Ngai Vincent , Lai Ching-Lung
Published: February 2009

LB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (Tmax) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the meanTmaxof LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption.
Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity against Flaviviruses
Authors: Chang Jinhong , Wang Lijuan , Ma Dongling , Qu Xiaowang , Guo Haitao , Xu Xiaodong , Mason Peter M. , Bourne Nigel , Moriarty Robert , Gu Baohua , Guo Ju-Tao , Block Timothy M.
Published: February 2009

Imino sugars, such as
N
-butyl-deoxynojirimycin and
N
-nonyl-deoxynojirimycin (NNDNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II in the endoplasmic reticulum and exhibit antiviral activities against many types of enveloped viruses. Although these molecules have broad-spectrum antiviral activity, their development has been limited by a lack of efficacy and/or selectivity. We have previously reported that a DNJ derivative with a hydroxylated cyclohexyl side chain, called OSL-95II, has an antiviral efficacy similar to that of NNDNJ but significantly less toxicity. Building upon this observation, a family of imino sugar derivatives containing an oxygenated side chain and terminally restricted ring structures were synthesized and shown to have low cytotoxicity and superior antiviral activity against members of the
Flaviviridae
family, including bovine viral diarrhea virus, dengue virus (DENV), and West Nile virus. Of particular interest is that several of these novel imino sugar derivatives, such as PBDNJ0801, PBDNJ0803, and PBDNJ0804, potently inhibit DENV infection in vitro, with 90% effective concentration values at submicromolar concentrations and selectivity indices greater than 800. Therefore, these compounds represent the best in their class and may offer realistic candidates for the development of antiviral therapeutics against human DENV infections.
Effects of Double and Triple Combinations of Antifungal Drugs in a Murine Model of Disseminated Infection by
Scedosporium prolificans
Authors: Rodríguez M. Mar , Calvo Enrique , Serena Carolina , Mariné Marçal , Pastor F. Javier , Guarro Josep
Published: February 2009

We have evaluated the efficacies of micafungin, amphotericin B, and voriconazole, alone and in double and triple combinations, in a murine model of systemic infection by
Scedosporium prolificans
. Micafungin combined with voriconazole or amphotericin B was the most effective, these being the only treatments able to prolong survival and to reduce the fungal load in the kidneys and brain. Triple combinations of these drugs did not improve the results obtained with double combinations.
Single-Dose Escalation and Multiple-Dose Safety, Tolerability, and Pharmacokinetics of IDX899, a Candidate Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Subjects
Authors: Zhou Xiao-Jian , Pietropaolo Keith , Damphousse David , Belanger Bruce , Chen Jie , Sullivan-Bólyai John , Mayers Douglas
Published: February 2009

IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50- to 400-mg doses) and then fed (≥200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (
t
1/2
) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean
t
1/2
of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 μg/ml (range, 0.2 to 2.5 μg/ml) and 2.1 μg/ml (range, 0.5 to 4.5 μg/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.
Antianaerobic Activity of Sulopenem Compared to Six Other Agents
Authors: Ednie Lois M. , Appelbaum Peter C.
Published: February 2009

Agar dilution MIC methodology was used to compare the activity of sulopenem with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes. Overall, MIC
50
/
90
values were as follows: sulopenem, 0.25/1.0 μg/ml; amoxicillin/clavulanate, 0.5/2.0 μg/ml; ampicillin/sulbactam, 0.5/4.0 μg/ml; piperacillin/tazobactam, 0.25/8.0 μg/ml; imipenem, 0.06/1.0 μg/ml; clindamycin, 0.25/16.0 μg/ml; and metronidazole, 1.0/4.0 μg/ml.
Susceptibility of Human Immunodeficiency Virus Type 1 to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag Spacer Peptide 1
Authors: Van Baelen Kurt , Salzwedel Karl , Rondelez Evelien , Van Eygen Veerle , De Vos Stephanie , Verheyen Ann , Steegen Kim , Verlinden Yvan , Allaway Graham P. , Stuyver Lieven J.
Published: February 2009

In this study, we evaluated baseline susceptibility to bevirimat (BVM), the first in a new class of antiretroviral agents, maturation inhibitors. We evaluated susceptibility to BVM by complete
gag
genotypic and phenotypic testing of 20 patient-derived human immunodeficiency virus type 1 isolates and 20 site-directed mutants. We found that reduced BVM susceptibility was associated with naturally occurring polymorphisms at positions 6, 7, and 8 in Gag spacer peptide 1.
Reduced Efficacy of Intermittent Preventive Treatment of Malaria in Malnourished Children
Authors: Danquah Ina , Dietz Ekkehart , Zanger Philipp , Reither Klaus , Ziniel Peter , Bienzle Ulrich , Mockenhaupt Frank P.
Published: February 2009

Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], −7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%;
P
= 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.
The RNA Chaperone Hfq Is Involved in Stress Response and Virulence in
Neisseria meningitidis
and Is a Pleiotropic Regulator of Protein Expression
Authors: Fantappiè Laura , Metruccio Matteo M. E. , Seib Kate L. , Oriente Francesca , Cartocci Elena , Ferlicca Francesca , Giuliani Marzia M. , Scarlato Vincenzo , Delany Isabel
Published: February 2009

The well-conserved protein Hfq has emerged as the key modulator of riboregulation in bacteria. This protein is thought to function as an RNA chaperone and to facilitate base pairing between small regulatory RNA (sRNA) and mRNA targets, and many sRNAs are dependent on the Hfq protein for their regulatory functions. To address the possible role of Hfq in riboregulated circuits in
Neisseria meningitidis
, we generated an Hfq mutant of the MC58 strain, and the knockout mutant has pleiotropic phenotypes; it has a general growth phenotype in vitro in culture media, and it is sensitive to a wide range of stresses, including those that it may encounter in the host. Furthermore, the expression profile of a vast number of proteins is clearly altered in the mutant, and we have identified 27 proteins by proteomics. All of the phenotypes tested to date are also restored by complementation of Hfq expression in the mutant strain. Importantly, in ex vivo and in vivo models of infection the Hfq mutant is attenuated. These data indicate that Hfq plays a key role in stress response and virulence, and we propose a major role for Hfq in regulation of gene expression. Moreover, this study suggests that in meningococcus there is a large Hfq-mediated sRNA network which so far is largely unexplored.
A Baculovirus Dual Expression System-Based Malaria Vaccine Induces Strong Protection againstPlasmodium bergheiSporozoite Challenge in Mice
Authors: Yoshida Shigeto , Kawasaki Masanori , Hariguchi Norimitsu , Hirota Kuniko , Matsumoto Makoto
Published: February 2009

We have previously shown that a recombinant baculovirus that displaysPlasmodium bergheicircumsporozoite protein (PbCSP), a homolog of the leading human malaria vaccine candidate, on the viral envelope protected 60% of mice againstP. bergheiinfection. Here, we describe a second-generation baculovirus vaccine based on the “baculovirus dual expression system,” which drives PbCSP expression by a dual promoter that consists of tandemly arranged baculovirus-derived polyhedrin and mammal-derived cytomegalovirus promoters. The baculovirus-based PbCSP vaccine not only displayed PbCSP on the viral envelope but also expressed PbCSP upon transduction of mammalian cells. Immunization with the baculovirus-based PbCSP vaccine elicited high PbCSP-specific antibody titers (predominantly immunoglobulin G1 [IgG1] and IgG2a) and PbCSP-specific CD8+T-cell responses without extraneous immunological adjuvants in mice, indicating that there was induction of both Th1 and Th2 responses (a mixed Th1/Th2 response). Importantly, upon intramuscular inoculation, the baculovirus-based PbCSP vaccine conferred complete protection against sporozoite challenge. Thus, the baculovirus-based PbCSP vaccine induced strong protective immune responses against preerythrocytic parasites. These results introduce a novel concept for the baculovirus dual expression system that functions as both a subunit vaccine and a DNA vaccine and offer a promising new alternative to current human vaccine delivery platforms.
Analysis of Immunity to Febrile Malaria in Children That Distinguishes Immunity from Lack of Exposure
Authors: Bejon Philip , Warimwe George , Mackintosh Claire L. , Mackinnon Margaret J. , Kinyanjui Sam M. , Musyoki Jennifer N. , Bull Peter C. , Marsh Kevin
Published: February 2009

In studies of immunity to malaria, the absence of febrile malaria is commonly considered evidence of “protection.” However, apparent “protection” may be due to a lack of exposure to infective mosquito bites or due to immunity. We studied a cohort that was given curative antimalarials before monitoring began and documented newly acquired asymptomatic parasitemia and febrile malaria episodes during 3 months of surveillance. With increasing age, there was a shift away from febrile malaria to acquiring asymptomatic parasitemia, with no change in the overall incidence of infection. Antibodies to the infected red cell surface were associated with acquiring asymptomatic infection rather than febrile malaria or remaining uninfected. Bed net use was associated with remaining uninfected rather than acquiring asymptomatic infection or febrile malaria. These observations suggest that most uninfected children were unexposed rather than “immune.” Had they been immune, we would have expected the proportion of uninfected children to rise with age and that the uninfected children would have been distinguished from children with febrile malaria by the protective antibody response. We show that removing the less exposed children from conventional analyses clarifies the effects of immunity, transmission intensity, bed nets, and age. Observational studies and vaccine trials will have increased power if they differentiate between unexposed and immune children.
Cholera Toxin andEscherichia coliHeat-Labile Enterotoxin, but Not Their Nontoxic Counterparts, Improve the Antigen-Presenting Cell Function of Human B Lymphocytes
Authors: Negri Donatella R. M. , Pinto Dora , Vendetti Silvia , Patrizio Mario , Sanchez Massimo , Riccomi Antonella , Ruggiero Paolo , Del Giudice Giuseppe , De Magistris Maria Teresa
Published: February 2009

B lymphocytes play an important role in the immune response induced by mucosal adjuvants. In this study we investigated the in vitro antigen-presenting cell (APC) properties of human B cells upon treatment with cholera toxin (CT) andEscherichia coliheat-labile enterotoxin (LT) and nontoxic counterparts of these toxins, such as the B subunit of CT (CT-B) and the mutant of LT lacking ADP ribosyltransferase activity (LTK63). Furthermore, forskolin (FSK), a direct activator of adenylate cyclase, and cyclic AMP (cAMP) analogues were used to investigate the role of the increase in intracellular cAMP caused by the A subunit of CT and LT. B lymphocytes were cultured with adjuvants and polyclonal stimuli necessary for activation of B cells in the absence of CD4 T cells. Data indicated that treatment with CT, LT, FSK, or cAMP analogues, but not treatment with CT-B or LTK63, upregulated surface activation markers on B cells, such as CD86 and HLA-DR, and induced inhibition of the proliferation of B cells at early time points, while it increased cell death in long-term cultures. Importantly, B cells treated with CT, LT, or FSK were able to induce pronounced proliferation of both CD4+and CD8+allogeneic T cells compared with untreated B cells and B cells treated with CT-B and LTK63. Finally, only treatment with toxins or FSK induced antigen-specific T-cell proliferation inMycobacterium tuberculosispurified protein derivative or tetanus toxoid responder donors. Taken together, these results indicated that the in vitro effects of CT and LT on human B cells are mediated by cAMP.
A prospective study on gait-related intrinsic risk factors for lower leg overuse injuries
Authors: Hesar N Ghani Zadeh , Van Ginckel A , Cools A , Peersman W , Roosen P , De Clercq D , Witvrouw E
Published: February 2009

Objective:

To determine prospectively gait-related risk factors for lower leg overuse injury (LLOI).

Design:

A prospective cohort study.

Setting:

Male and female recruits from a start-to-run (STR) programme during a 10-week training period.

Participants:

131 healthy subjects (20 men and 111 women), without a history of any lower leg complaint, participated in the study.

Interventions:

Before the start of the 10-week STR programme, plantar force measurements during running were performed. During STR, lower leg injuries were diagnosed and registered by a sports physician.

Main Outcome Measures:

Plantar force measurements during running were performed using a footscan pressure plate.

Results:

During the STR, 27 subjects (five men and 22 women) developed a LLOI. Logistic regression analysis revealed that subjects who developed a LLOI had a significantly more laterally directed force distribution at first metatarsal contact and forefoot flat, a more laterally directed force displacement in the forefoot contact phase, foot flat phase and at heel-off. These subjects also had a delayed change of the centre of force (COF) at forefoot flat, a higher force and loading underneath the lateral border of the foot, and a significantly higher directed force displacement of the COF at forefoot flat.

Conclusions:

These findings suggest that a less pronated heel strike and a more laterally directed roll-off can be considered as risk factors for LLOI. Clinically, the results of this study can be considered important in identifying individuals at risk of LLOI.
Prospective study on shoulder symptoms among kitchen workers in relation to self-perceived and observed work load
Authors: Pehkonen I , Miranda H , Haukka E , Luukkonen R , Takala E-P , Ketola R , Leino-Arjas P , Riihimäki H , Viikari-Juntura E
Published: February 2009

Objectives:

To study the occurrence of shoulder symptoms among professional kitchen workers, and whether reduction in self-perceived and observed physical work load decreases future symptoms.

Methods:

In this prospective study conducted in 2002–2005 in municipal kitchens in Finland, changes during a 1-year follow-up in the physical strenuousness of work tasks were self-assessed by 376 female workers (substudy I). Changes in exposure to manual lifting and awkward upper arm posture during the follow-up were also observed by experts in 69 kitchens with 183 workers (substudy II). Information on shoulder symptoms was collected with questionnaires at baseline and at follow-up. The risk of shoulder symptoms at follow-up related to changes in exposure was estimated with logistic regression.

Results:

The 3-month prevalence of shoulder pain was 34% at baseline and 41% at follow-up. Reduction during follow-up in work tasks perceived as the most strenuous physically (ie, receiving and storing raw food) led to a significantly reduced risk of future shoulder pain with an adjusted odds ratio (OR) of 0.41 (95% CI 0.17 to 0.98) and trouble caused by the pain with an OR of 0.34 (0.14 to 0.83). The observed reduction in lifting was also associated with a lower risk for future shoulder symptoms.

Conclusions:

Reduction in lifting showed beneficial protective effects on the shoulder. Although more risk factor and intervention studies are needed to estimate the health impacts of kitchen work, special attention should be paid to work tasks that include lifting when assessing risk and designing preventive measures.
Detection of intergenomic chromosome rearrangements in irradiatedTriticum aestivum –Aegilops biuncialisamphiploids by multicolour genomic in situ hybridization
Authors: Molnár István , Benavente Elena , Molnár-Láng Márta
Published: February 2009

The frequency and pattern of irradiation-induced intergenomic chromosome rearrangements were analysed in the mutagenized (M0) and the first selfed (M1) generations of Triticum aestivum  L. – Aegilops biuncialis Vis. amphiploids (2n = 70, AABBDDUbUbMbMb) by multicolour genomic in situ hybridization (mcGISH). mcGISH allowed the simultaneous discrimination of individual Ae. biuncialis genomes and wheat chromosomes. Dicentric chromosomes, fragments, and terminal translocations were most frequently induced by γ-irradiation, but centric fusions and internal exchanges were also more abundant in the treated plants than in control amphiploids. Rearrangements involving the Ubgenome (Ub-type aberrations) were more frequent than those involving the Mbgenome (Mb-type aberrations). This irradiation sensitivity of the Ubchromosomes was attributed to their centromeric or near-centromeric regions, since Ub-type centric fusions were significantly more abundant than Mb-type centric fusions at all irradiation doses. Dicentrics completely disappeared, but centric fusions and translocations were well transmitted from M0to M1. Identification of specific chromosomes involved in some rearrangements was attempted by sequential fluorescence in situ hybridization with a mix of repeated DNA probes and GISH on the same slide. The irradiated amphiploids formed fewer seeds than untreated plants, but normal levels of fertility were recovered in their offspring. The irradiation-induced wheat – Ae. biuncialis intergenomic translocations will facilitate the successful introgression of drought tolerance and other alien traits into bread wheat.
Genome-wide analysis of rice (Oryza sativa L. subsp. japonica) TATA box and Y Patch promoter elements
Authors: Civáň P. , Švec M.
Published: February 2009

The TATA box is one of the best characterized transcription factor binding sites. However, it is not a ubiquitous element of core promoters, and other sequence motifs such as Y Patches seem to play a major role in plants. Here, we present a first genome-wide computational analysis of the TATA box and Y Patch distribution in rice ( Oryza sativa L. subsp. japonica) promoter sequences. Utilizing a probabilistic sequence model, we ascertain that only ~19% of rice genes possess the TATA box, but ~50% contain one or more Y Patches in their core promoters. By computational processing of identified elements, we generated extended TATA box and Y Patch nucleotide frequency matrices capable of predicting these motifs in plants with a high degree of confidence.
Mutation scanning and genotyping by high-resolution DNA melting analysis in olive germplasm
Authors: Muleo Rosario , Colao Maria Chiara , Miano Dario , Cirilli Marco , Intrieri Maria C. , Baldoni Luciana , Rugini Eddo
Published: February 2009

The application of high-resolution melting (HRM) analysis of DNA is reported for scanning and genotyping Olea europaea germplasm. To test the sensitivity of the method, a functional gene marker, phytochrome A (phyA), was used, since this gene is correlated with important traits for the ecology of the species. We have designed a set of oligos able to produce amplicons of 307 bp to scan for the presence of single polymorphic mutations in a specific phyA fragment encompassing the chromophore attachment site (Cys323). The presence of mutations for substitution, either homozygous or heterozygous, was easily detected by melting curve analysis in a high-resolution melter. It has been established that the sensitivity of the HRM analysis can be significantly improved designing specific primers very close to the mutation sites. All SNPs found were confirmed by sequence analyses and ARMS-PCR. The method has also been confirmed to be very powerful for the visualization of microsatellite (SSR) length polymorphisms. HRM analysis has a very high reproducibility and sensitivity for detecting SNPs and SSRs, allowing olive cultivar genotyping and resulting in an informative, easy, and low-cost method able to greatly reduce the operating time.
A comparison of Doppler, tissue Doppler imaging, and strain rate imaging in the assessment of postexercise left ventricular function
Authors: Shave Rob , George Keith , Whyte Greg , Middleton Natalie , Hart Emma , Artis Nigel , Oxborough David
Published: February 2009

Left ventricular (LV) function is characterized by contraction in the longitudinal, radial, and circumferential planes. Previous studies of postexercise changes in LV function have assessed global indices of LV function. The purpose of this study was to use 2-dimensional (2D) strain analysis to examine LV function following marathon running in the circumferential, radial, and longitudinal planes, and to compare these data with other global and regional indices of function. Fifteen (mean ± SD: age, 32 ± 7 years; stature, 1.76 ± 0.08 m; body mass, 77.8 ± 8.2 kg) competitors in the London Marathon were echocardiographically assessed pre- and postrace. 2D strain (ejection fraction (EF), Doppler (early (E) and late (A) trans-mitral filling), tissue Doppler imaging (TDI) (systolic (S′) and early diastolic (E′) wall-motion velocities); TDI-derived longitudinal strain (εTDI), and systolic and diastolic strain rate (SRTDI); and 2D-derived peak circumferential, radial, and longitudinal strain (ε2D), and systolic and diastolic strain rate (SR2D) were examined. Differences pre- and postrace completion were assessed using paired t tests, with alpha set at 0.01. All participants completed the marathon in a mean time of 213 ± 41 min. A varied response was observed for measures of LV systolic and diastolic function following completion of the marathon (mean ± SD): EF, 63 ± 6 vs. 63 ± 7% (p > 0.01); E:A, 1.70 ± 0.37 vs. 1.17 ± 0.37; E′:A′, 2.36 ± 0.79 vs. 1.60 ± 0.57 (p < 0.01); mean longitudinal εTDI, 19.1 ± 5.1 vs. 17.5 ± 4.2% (p < 0.01); mean longitudinal diastolic SRTDI, 1.81 ± 0.54 vs. 1.58 ± 0.51·s–1 (p < 0.01); mean longitudinal systolic SR2D, 0.73 ± 0.21 vs. 0.97 ± 0.22·s–1 (p < 0.01); mean longitudinal diastolic SR2D, 0.94 ± 0.34 vs. 1.01 ± 0.23·s–1 (p > 0.01); mean radial systolic SR2D, 1.20 ± 0.15 vs. 1.45 ± 0.32·s–1 (p < 0.01); mean radial diastolic SR2D, 1.19 ± 0.25 vs. 1.29 ± 0.41·s–1 (p > 0.01); mean circumferential systolic SR2D, –1.09 ± 0.16 vs. –1.24 ± 0.18·s–1 (p < 0.01); and mean circumferential diastolic SR2D, –1.27 ± 0.28 vs. –1.22 ± 0.31·s–1 (p > 0.01). Marathon running promotes a varied echocardiographic response, with some functional parameters showing no change, some increasing, and some decreasing postexercise. This varied response likely reflects the complexities of cardiac function and highlights the need to adopt a multimodality approach when assessing cardiac function following exercise.
Direct quantitation of omega-3 fatty acid intake of Canadian residents of a long-term care facility
Authors: Fratesi Jennifer A. , Hogg Ryan C. , Young-Newton Genevieve S. , Patterson Ashley C. , Charkhzarin Payman , Block Thomas Karin , Sharratt Michael T. , Stark Ken D.
Published: February 2009

An increased dietary intake of n-3 highly unsaturated fatty acids (HUFA; ≥20 carbons, ≥3 carbon–carbon double bonds), particularly eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), is associated with the decreased risk and incidence of several morbidities afflicting the elderly, including cognitive decline, dementia, rheumatoid arthritis, and macular degeneration. In this study, the dietary intake and blood levels of fatty acids were directly determined in residents of a retirement home or assisted living phase of a continuum of care facility for Canadian seniors. Finger-tip-prick blood samples, 3-day food duplicates, and 3-day food records were collected. The fatty acid composition of food duplicates and blood was determined by gas chromatography. Fifteen participants (7 male, 8 female; 87.1 ± 4.8 years of age) completed the protocol. The daily intake of EPA and DHA combined, determined directly, was 70 mg (95% CI, 41–119) or 0.036% of total energy (95% CI, 0.022–0.058). In finger-tip-prick blood, the percent of n-3 HUFA in total HUFA of whole blood, a biomarker of n-3 polyunsaturated fatty acid status, was 28.8 ± 5.2%. Correlations between daily n-3 HUFA intake and n-3 HUFA in blood were not significant (r = 0.14; n = 15), but became significant after the removal of 2 participants who appeared to consume fish irregularly (r = 0.59; n = 13). The n-3 HUFA intake and corresponding n-3 HUFA blood levels of Canadian long-term care residents are lower than levels estimated to prevent several morbidities associated with aging.
Metabolic profile and quality of life in class I sarcopenic overweight and obese postmenopausal women: a MONET study
Authors: Messier Virginie , Karelis Antony D. , Lavoie Marie-Eve , Brochu Martin , Faraj May , Strychar Irene , Rabasa-Lhoret Remi
Published: February 2009

Sarcopenia is believed to be associated with disability and metabolic complications. The objective of this study was to examine the metabolic and quality-of-life profile of sarcopenic overweight and obese postmenopausal women. In this cross-sectional study of 136 healthy overweight and obese postmenopausal women, 9 class I sarcopenic women were identified. Class I sarcopenia was defined as an appendicular lean body mass index (ALBMI) ≤ 6.44 kg·m–2 (appendicular lean body mass/height). Outcome measures were body composition (dual energy X-ray absorptiometry and computed tomography), blood lipids, inflammation markers, blood pressure, insulin sensitivity (homeostasis model assessment and hyperinsulinemic-euglycemic clamp), cardiorespiratory fitness, and quality of life (Medical Outcomes Study General Health Survey questionnaire). By design, class I sarcopenic women (n = 9) had a significantly lower ALBMI and appendicular lean body mass than nonsarcopenic women (n = 127). In addition, class I sarcopenic women tended to have lower levels of insulin resistance (p = 0.070) and fasting glucose (p = 0.054). However, no difference between the groups was observed for quality of life. This study showed that, in our sample of class I sarcopenic overweight and obese postmenopausal women, subjects did not present an unfavourable metabolic or quality-of-life profile, compared with nonsarcopenic overweight and obese postmenopausal women.
Regulatory noncoding RNAs atHoxlociThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.
Authors: Brock Hugh W. , Hodgson Jacob W. , Petruk Svetlana , Mazo Alexander
Published: February 2009

There is growing awareness of the importance of noncoding (nc)RNAs in the regulation of gene expression during pattern formation in development. Spatial regulation of Hox gene expression in development controls positional identity along the antero–posterior axis. In this review, we will focus on the role of short ncRNAs that repress Hox genes in Drosophila and mammals by RNA interference (RNAi), on long ncRNAs that may repress a Hox in cis in Drosophila by transcriptional interference, and on a novel long ncRNA that functions in trans to regulate Hox genes mammals.
Actin dynamics and functions in the interphase nucleus: moving toward an understanding of nuclear polymeric actinThis paper is one of a selection of papers published in this Special Issue, entitled 29th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.
Authors: Gieni Randall S. , Hendzel Michael J.
Published: February 2009

Actin exists as a dynamic equilibrium of monomers and polymers within the nucleus of living cells. It is utilized by the cell for many aspects of gene regulation, including mRNA processing, chromatin remodelling, and global gene expression. Polymeric actin is now specifically linked to transcription by RNA polymerase I, II, and III. An active process, requiring both actin polymers and myosin, appears to drive RNA polymerase I transcription, and is also implicated in long-range chromatin movement. This type of mechanism brings activated genes from separate chromosomal territories together, and then participates in their compartmentalization near nuclear speckles. Nuclear speckle formation requires polymeric actin, and factors promoting polymerization, such as profilin and PIP2, are concentrated there. A review of the literature shows that a functional population of G-actin cycles between the cytoplasm and the nucleoplasm. Its nuclear concentration is dependent on the cytoplasmic G-actin pool, as well as on the activity of import and export mechanisms and the availability of interactions that sequester it within the nucleus. The N-WASP-Arp2/3 actin polymer-nucleating mechanism functions in the nucleus, and its mediators, including NCK, PIP2, and Rac1, can be found in the nucleoplasm, where they likely influence the kinetics of polymer formation. The actin polymer species produced are tightly regulated, and may take on conformations not easily recognized by phalloidin. Many of the factors that cleave F-actin in the cytoplasm are present at high levels in the nucleoplasm, and are also likely to affect actin dynamics there. The absolute and relative G-actin content in the nucleoplasm and the cytoplasm of a cell contains information about the homeostatic state of that cell. We propose that the cycling of G-actin between the nucleus and cytoplasm represents a signal transduction mechanism that can function through both extremes of global cellular G-actin content. MAL signalling within the serum response factor pathway, when G-actin levels are low, represents a well-studied example of actin functioning in signal transduction. The translocation of NCK into the nucleus, along with G-actin, during dissolution of the cytoskeleton in response to DNA damage represents another instance of a unique signalling mechanism operating when G-actin levels are high.
Regulation of gene expression and cellular proliferation by histone H2A.ZThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.
Authors: Svotelis Amy , Gévry Nicolas , Gaudreau Luc
Published: February 2009

The mammalian genome is organized into a structure of DNA and proteins known as chromatin. In general, chromatin presents a barrier to gene expression that is regulated by several pathways, namely by the incorporation of histone variants into the nucleosome. In yeast, H2A.Z is an H2A histone variant that is incorporated into nucleosomes as an H2A.Z/H2B dimer by the Swr1 complex and by the SRCAP and p400/Tip60 complexes in mammalian cells. H2A.Z has been associated with the poising of genes for transcriptional activation in the yeast model system, and is essential for development in higher eukaryotes. Recent studies in our laboratory have demonstrated a p400-dependent deposition of H2A.Z at the promoter of p21WAF1/CIP1, a consequence that prevents the activation of the gene by p53, thereby inhibiting p53-dependent replicative senescence, a form of cell-cycle arrest crucial in the prevention of carcinogenic transformation of cells. Moreover, H2A.Z is overexpressed in several different types of cancers, and its overexpression has been associated functionally with the proliferation state of cells. Therefore, we suggest that H2A.Z is an important regulator of gene expression, and its deregulation may lead to the increased proliferation of mammalian cells.
Connection between histone H2A variants and chromatin remodeling complexesThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.
Authors: Altaf Mohammed , Auger Andréanne , Covic Marcela , Côté Jacques
Published: February 2009

The organization of the eukaryotic genome into chromatin makes it inaccessible to the factors required for gene transcription and DNA replication, recombination, and repair. In addition to histone-modifying enzymes and ATP-dependent chromatin remodeling complexes, which play key roles in regulating many nuclear processes by altering the chromatin structure, cells have developed a mechanism of modulating chromatin structure by incorporating histone variants. These variants are incorporated into specific regions of the genome throughout the cell cycle. H2A.Z, which is an evolutionarily conserved H2A variant, performs several seemingly unrelated and even contrary functions. Another H2A variant, H2A.X, plays a very important role in the cellular response to DNA damage. This review summarizes the recent developments in our understanding of the role of H2A.Z and H2A.X in the regulation of chromatin structure and function, focusing on their functional links with chromatin modifying and remodeling complexes.
Future emissions from Canadian boreal forest fires
Authors: Amiro B.D. , Cantin A. , Flannigan M.D. , de Groot W.J.
Published: February 2009

New estimates of greenhouse gas emissions from Canadian forest fires were calculated based on a revised model for fuel consumption, using both the fire fuel load and the Drought Code of the Canadian Forest Fire Weather Index System. This model was applied to future climate scenarios of 2×CO2 and 3×CO2 environments using the Canadian Global Climate Model. Total forest floor fuel consumption for six boreal ecozones was estimated at 60, 80, and 117 Tg dry biomass for the 1×CO2, 2×CO2, and 3×CO2 scenarios, respectively. These ecozones cover the boreal and taiga regions and account for about 86% of the total fire consumption for Canada. Almost all of the increase in fuel consumption for future climates is caused by an increase in the area burned. The effect of more severe fuel consumption density (kilograms of fuel consumed per square metre) is relatively small, ranging from 0% to 18%, depending on the ecozone. The emissions of greenhouse gases from all Canadian fires are estimated to increase from about 162 Tg·year–1 of CO2 equivalent in the 1×CO2 scenario to 313 Tg·year–1 of CO2 equivalent in the 3×CO2 scenario, including contributions from CO2, CH4, and N2O.
A robust optimization approach protected harvest scheduling decisions against uncertainty
Authors: Palma Cristian D. , Nelson John D.
Published: February 2009

Harvest scheduling decisions are made in an uncertain environment, and current modeling techniques that consider uncertainty impose severe difficulties when solving real problems. In this paper we describe a robust optimization methodology that explicitly considers randomness in most of the model coefficients while keeping the model computationally tractable. We apply the method to schedule harvest decisions when both timber yield and demand of two products are uncertain. Since uncertain coefficients must be independent, uniform, and symmetrically distributed, we only address uncertainty attributable to estimate errors of forecast models. The methodology was applied to a 245 090 ha forest in British Columbia, Canada. We compared the change in harvest decisions and objective function when robust solutions are implemented relative to deterministic solutions. Although probability bounds can be used to a priori define the probability of constraint violations, they produce conservative solutions. We therefore tested the rates of constraint violations by simulation. While traditional deterministic decisions were always infeasible when uncertain data were simulated, robust decisions were much less sensitive to uncertainty and were, to a large extent, protected against the occurrence of infeasibilities. In exchange, reasonable reductions in the objective function were observed.