bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of the Intensity Parameter of the Germ‐Grain Quermass‐Interaction Model when the Number of Germs is not Observed
Authors: Dereudre David , Lavancier Frédéric , Helisová Kateřina Staňková 
Published: February 2014

ABSTRACTThe Quermass‐interaction model allows to generalize the classical germ‐grain Boolean model in adding a morphological interaction between the grains. It enables to model random structures with specific morphologies, which are unlikely to be generated from a Boolean model. The Quermass‐interaction model depends in particular on an intensity parameter, which is impossible to estimate from classical likelihood or pseudo‐likelihood approaches because the number of points is not observable from a germ‐grain set. In this paper, we present a procedure based on the Takacs–Fiksel method, which is able to estimate all parameters of the Quermass‐interaction model, including the intensity. An intensive simulation study is conducted to assess the efficiency of the procedure and to provide practical recommendations. It also illustrates that the estimation of the intensity parameter is crucial in order to identify the model. The Quermass‐interaction model is finally fitted by our method to P. Diggle's heather data set.
Suicidal Ideation and Behavior in Adolescents Aged 12–16 Years: A 17‐Year Follow‐Up
Authors: Joffe Benjamin I. , Van Lieshout Ryan J. , Duncan Laura , Boyle Michael H. 
Published: February 2014

The prevalence of suicidal ideation/behavior in 1983 or 1987 and its association with future mental health in 2001 were evaluated in a provincially representative sample of Canadian adolescents (n = 1,248) aged 12 to 16 years. Approximately 13.3% (95% CI = 11.5–15.3) of adolescents self‐reported suicidal ideation/behavior. Adolescent agreement with parent (κ = .07) and teacher (κ = .05) reports at baseline was low because adults identified so few subjects. In adulthood, the associations between adolescent self‐reports of suicidal behavior/ideation and major depression and other mental health indicators were explained by respondent sex and adolescent emotional problems reported in 1983/1987. Adolescents with suicidal behavior/ideation often are not recognized by their parents and teachers and may be at risk for persistent psychiatric problems attributable to coexisting mental health problems early‐on.
Antisense gene inhibition by phosphorothioate antisense oligonucleotide in Arabidopsis pollen tubes
Authors: Mizuta Yoko , Higashiyama Tetsuya 
Published: February 2014

SummarySexual reproduction is an essential biological event for proliferation of plants. The pollen tube (PT) that contained male gametes elongates and penetrates into the pistils for successful fertilization. However, the molecular mechanisms of plant fertilization remain largely unknown. Here, we report a transient inhibition of gene function using phosphorothioate antisense oligodeoxynucleotides (AS‐ODNs) without cytofectin, which is a simple way to study gene function in Arabidopsis thaliana PTs. The PTs treated with AS‐ODNs against both ANX1 and ANX2 showed short, knotted, and ruptured morphology in vitro/semi‐in vitro, whereas normal PT growth was shown in its sense control in vitro/semi‐in vitro. PT growth was impaired in a manner dependent on the dose of AS‐ODNs against both ANX1 and ANX2 above 10 μm. The treatment with AS‐ODNs against ROP1 and CalS5 resulted in waving PTs and in short PTs with a few callose plugs, respectively. The expression levels of the target genes in PTs treated with their AS‐ODNs were lower than or similar to those in the sense control, indicating that the inhibition was directly or indirectly related to the expression of each mRNA. The AS‐ODN against fluorescent protein (sGFP) led to reduced sGFP expression, suggesting that the AS‐ODN suppressed protein expression. This method will enable the identification of reproductively important genes in Arabidopsis PTs.
GABAergic and glycinergic inputs modulate rhythmogenic mechanisms in the lamprey respiratory network
Authors: Cinelli Elenia , Mutolo Donatella , Robertson Brita , Grillner Sten , Contini Massimo , Pantaleo Tito , Bongianni Fulvia 
Published: February 2014

Key points
In this study we investigated the role of GABA and glycine receptors within the respiratory central pattern generator, i.e. the paratrigeminal respiratory group (pTRG), and the vagal motoneuron region of the lamprey.
Only GABA‐mediated inhibition modulates the pTRG both during apnoea induced by blockade of glutamatergic transmission and under basal conditions.
Both GABA‐ and glycine‐mediated inhibition within the vagal region are involved in the regulation of respiratory frequency via ascending excitatory projections to the pTRG.
Projecting neurons are retrogradely labelled from the pTRG, and intense GABA immunoreactivity is present within the pTRG and the vagal motoneuron region.
Inhibitory mechanisms, which appear to be evolutionarily conserved, regulate network excitability and may provide an important contribution to rhythmic activities, such as respiration and locomotion.
AbstractWe have previously shown that GABA and glycine modulate respiratory activity in the in vitro brainstem preparations of the lamprey and that blockade of GABAA and glycine receptors restores the respiratory rhythm during apnoea caused by blockade of ionotropic glutamate receptors. However, the neural substrates involved in these effects are unknown. To address this issue, the role of GABAA, GABAB and glycine receptors within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator, and the vagal motoneuron region was investigated both during apnoea induced by blockade of glutamatergic transmission and under basal conditions through microinjections of specific antagonists. The removal of GABAergic, but not glycinergic transmission within the pTRG, causes the resumption of rhythmic respiratory activity during apnoea, and reveals the presence of a modulatory control of the pTRG under basal conditions. A blockade of GABAA and glycine receptors within the vagal region strongly increases the respiratory frequency through disinhibition of neurons projecting to the pTRG from the vagal region. These neurons were retrogradely labelled (neurobiotin) from the pTRG. Intense GABA immunoreactivity is observed both within the pTRG and the vagal area, which corroborates present findings. The results confirm the pTRG as a primary site of respiratory rhythm generation, and suggest that inhibition modulates the activity of rhythm‐generating neurons, without any direct role in burst formation and termination mechanisms.
Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy
Authors: Benaim Gustavo , Casanova Paola , Hernandez-Rodriguez Vanessa , Mujica-Gonzalez Sheira , Parra-Gimenez Nereida , Plaza-Rojas Lourdes , Concepcion Juan Luis , Liu Yi-Liang , Oldfield Eric , Paniz-Mondolfi Alberto , Suarez Alirica I. 
Published: February 2014

ABSTRACT

Dronedarone and amiodarone are cationic lipophilic benzofurans used to treat cardiac arrhythmias. They also have activity against the parasitic protozoan
Trypanosoma cruzi
, the causative agent of Chagas' disease. They function by disrupting intracellular Ca
2+
homeostasis of the parasite and by inhibiting membrane sterol (ergosterol) biosynthesis. Amiodarone also has activity against
Leishmania mexicana
, suggesting that dronedarone might likewise be active against this organism. This might be of therapeutic interest, since dronedarone is thought to have fewer side effects in humans than does amiodarone. We show here that dronedarone effectively inhibits the growth of
L. mexicana
promastigotes in culture and, more importantly, has excellent activity against amastigotes inside infected macrophages (the clinically relevant form) without affecting the host cell, with the 50% inhibitory concentrations against amastigotes being 3 orders of magnitude lower than those obtained previously with
T. cruzi
amastigotes (0.65 nM versus 0.75 μM). As with amiodarone, dronedarone affects intracellular Ca
2+
homeostasis in the parasite, inducing an elevation of intracellular Ca
2+
levels. This is achieved by rapidly collapsing the mitochondrial membrane potential and inducing an alkalinization of acidocalcisomes at a rate that is faster than that observed with amiodarone. We also show that dronedarone inhibits parasite oxidosqualene cyclase, a key enzyme in ergosterol biosynthesis known to be vital for survival. Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases.
Fungicidal Mechanisms of Cathelicidins LL-37 and CATH-2 Revealed by Live-Cell Imaging
Authors: Ordonez Soledad R. , Amarullah Ilham H. , Wubbolts Richard W. , Veldhuizen Edwin J. A. , Haagsman Henk P. 
Published: February 2014

ABSTRACT

Antifungal mechanisms of action of two cathelicidins, chicken CATH-2 and human LL-37, were studied and compared with the mode of action of the salivary peptide histatin 5 (Hst5).
Candida albicans
was used as a model organism for fungal pathogens. Analysis by live-cell imaging showed that the peptides kill
C. albicans
rapidly. CATH-2 is the most active peptide and kills
C. albicans
within 5 min. Both cathelicidins induce cell membrane permeabilization and simultaneous vacuolar expansion. Minimal fungicidal concentrations (MFC) are in the same order of magnitude for all three peptides, but the mechanisms of antifungal activity are very different. The activity of cathelicidins is independent of the energy status of the fungal cell, unlike Hst5 activity. Live-cell imaging using fluorescently labeled peptides showed that both CATH-2 and LL-37 quickly localize to the
C. albicans
cell membrane, while Hst5 was mainly directed to the fungal vacuole. Small amounts of cathelicidins internalize at sub-MFCs, suggesting that intracellular activities of the peptide could contribute to the antifungal activity. Analysis by flow cytometry indicated that CATH-2 significantly decreases
C. albicans
cell size. Finally, electron microscopy showed that CATH-2 affects the integrity of the cell membrane and nuclear envelope. It is concluded that the general mechanisms of action of both cathelicidins are partially similar (but very different from that of Hst5). CATH-2 has unique features and possesses antifungal potential superior to that of LL-37.
Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients
Authors: Valade Elodie , Tréluyer Jean-Marc , Bouazza Naïm , Ghosn Jade , Foissac Frantz , Benaboud Sihem , Fauchet Floris , Viard Jean-Paul , Urien Saïk , Hirt Déborah 
Published: February 2014

ABSTRACT

The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CL
CR
), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC
0-24
) was 12.5 mg · h/liter for patients with normal renal function (CL
CR
, >80 ml/min), 14.7 mg · h/liter for patients with mild renal impairment (CL
CR
, 79 to 50 ml/min), and 17.9 mg · h/liter for patients with moderate renal impairment (CL
CR
, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC
0-48
, 17.2 mg · h/liter) than for patients with normal renal function (median AUC
0-48
, 25.6 mg · h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.
Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam
Authors: Wooley Myra , Miller Benjamin , Krishna Gopal , Hershberger Ellie , Chandorkar Gurudatt 
Published: February 2014

ABSTRACT

Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a β-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC
0-∞
) for ceftolozane and tazobactam increased 1.4- and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC
0-∞
increased 2.5- and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC
0-∞
for ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC
0-∞
before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups.
Isavuconazole Therapy Protects Immunosuppressed Mice from Mucormycosis
Authors: Luo Guanpingsheng , Gebremariam Teclegiorgis , Lee Hongkyu , Edwards John E. , Kovanda Laura , Ibrahim Ashraf S. 
Published: February 2014

ABSTRACT

We studied the
in vitro
and
in vivo
efficacies of the investigational drug isavuconazole against mucormycosis due to
Rhizopus delemar
. Isavuconazole was effective, with MIC and minimal fungicidal concentration (MFC) values ranging between 0.125 and 1.00 μg/ml. A high dose of isavuconazole prolonged the survival time and lowered the tissue fungal burden of cyclophosphamide/cortisone acetate-treated mice infected with
R. delemar
and was as effective as a high-dose liposomal amphotericin B treatment. These results support the further development of this azole against mucormycosis.
CYP2B6
18492T→C Polymorphism Compromises Efavirenz Concentration in Coinfected HIV and Tuberculosis Patients Carrying
CYP2B6
Haplotype *1/*1
Authors: Manosuthi Weerawat , Sukasem Chonlaphat , Thongyen Supeda , Nilkamhang Samruay , Manosuthi Sukanya , Sungkanuparph Somnuek 
Published: February 2014

ABSTRACT

Data regarding the effect of the
CYP2B6
18492T→C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIV-infected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within
CYP2B6
were genotyped. Seven SNPs, including 64C→T, 499C→G, 516G→T, 785A→G, 1375A→G, 1459C→T, and 21563C→T, were included for
CYP2B6
haplotype determination. The
CYP2B6
18492T→C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean ± standard deviation (SD)], 56 ± 10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the
CYP2B6
18492T→C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (±SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8 ± 1.6, 1.7 ± 0.9, and 1.4 ± 0.5 mg/liter, respectively (
P
= 0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4 ± 0.8, 1.7 ± 0.8, and 1.2 ± 0.4 mg/liter, respectively (
P
= 0.003). A low efavirenz concentration was independently associated with 18492T→C (β = −0.937,
P
= 0.004) and high body weight (β = −0.032,
P
= 0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (
P
= 0.254). In summary, the
CYP2B6
18492T→C polymorphism compromises efavirenz concentrations in patients who carry
CYP2B6
haplotype *1/*1 and are coinfected with HIV and tuberculosis.
Comparison of Local Features from Two Spanish Hospitals Reveals Common and Specific Traits at Multiple Levels of the Molecular Epidemiology of Metallo-β-Lactamase-Producing Pseudomonas spp
Authors: Viedma Esther , Estepa Vanesa , Juan Carlos , Castillo-Vera Jane , Rojo-Bezares Beatriz , Seral Cristina , Castillo Francisco Javier , Sáenz Yolanda , Torres Carmen , Chaves Fernando , Oliver Antonio 
Published: February 2014

ABSTRACT

Twenty-seven well-characterized metallo-β-lactamase (MBL)-producing
Pseudomonas
strains from two distantly located hospitals were analyzed. The results revealed specific features defining the multilevel epidemiology of strains from each hospital in terms of species, clonality, predominance of high-risk clones, composition/diversity of integrons, and linkages of Tn
402
-related structures. Therefore, despite the global trends driving the epidemiology of MBL-producing
Pseudomonas
spp., the presence of local features has to be considered in order to understand this threat and implement proper control strategies.
Novel Regimens Identified in Mice for Treatment of Latent Tuberculosis Infection in Contacts of Patients with Multidrug-Resistant Tuberculosis
Authors: Lanoix Jean-Philippe , Betoudji Fabrice , Nuermberger Eric 
Published: February 2014

ABSTRACT

Preventing the development of tuberculosis (TB) in contacts of patients with multidrug-resistant TB (MDR-TB) by the treatment of latent TB infection (LTBI) is highly desirable. However, few safe, well tolerated, and effective drugs are available to treat MDR-LTBI and the published guidance is limited. Fortunately, six new chemical entities from four classes developed to treat TB have entered clinical trials in the past decade. We tested three of these drugs alone and in combination in an experimental paucibacillary LTBI chemotherapy model using BALB/c and C3HeB/FeJ mice immunized with a recombinant strain of
Mycobacterium bovis
bacillus Calmette-Guérin (rBCG30) and then challenged with a low-dose aerosol of
M. tuberculosis
H37Rv. The regimens tested contained bedaquiline (TMC), PA-824 (Pa), sutezolid (PNU), and/or one of two fluoroquinolones. Control mice received rifampin (RIF) or isoniazid (INH). In BALB/c mice, TMC-containing regimens and the Pa-PNU combination were the most active test regimens and were at least as effective as RIF. Pa, PNU, and levofloxacin had activity comparable to that of INH. Virtually identical results were observed in C3HeB/FeJ mice. This study confirms the potent activity of TMC observed previously in BALB/c mice and highlights Pa alone or in combination with either PNU or a fluoroquinolone as a regimen worthy of evaluation in future clinical trials of MDR-LTBI. Given their closer pathological representation of human TB lesions, C3HeB/FeJ mice may become a preferred model for the experimental chemotherapy of LTBI. Future studies should evaluate additional clinically relevant LTBI regimens in this strain including relapse as an endpoint.
Variation in Potency and Spectrum of Tigecycline Activity against Bacterial Strains from U.S. Medical Centers since Its Approval for Clinical Use (2006 to 2012)
Authors: Sader Helio S. , Farrell David J. , Flamm Robert K. , Jones Ronald N. 
Published: February 2014

ABSTRACT

Tigecycline was initially approved by the U.S. Food and Drug Administration (FDA) in June 2005. We assessed the evolution of tigecycline
in vitro
activities since the initial approval of tigecycline for clinical use by analyzing the results of 7 years (2006 to 2012) of data from the SENTRY Antimicrobial Surveillance Program in the United States. We also analyzed trends over time for key resistance phenotypes. The analyses included 68,608 unique clinical isolates collected from 29 medical centers and tested for susceptibility using reference broth microdilution methods. Tigecycline was highly active against Gram-positive organisms, with MIC
50
and MIC
90
values of 0.12 and 0.25 μg/ml for
Staphylococcus aureus
(28,278 strains; >99.9% susceptible), 0.06 to 0.12 and 0.12 to 0.25 μg/ml for enterococci (99.3 to 99.6% susceptible), and ≤0.03 and ≤0.03 to 0.06 μg/ml for streptococci (99.9 to 100.0% susceptible), respectively. When tested against 20,457
Enterobacteriaceae
strains, tigecycline MIC
50
and MIC
90
values were 0.25 and 1 μg/ml, respectively (98.3% susceptible using U.S. FDA breakpoints). No trend toward increasing tigecycline resistance (nonsusceptibility) was observed for any species or group during the study period. The prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR)
Enterobacteriaceae
increased from 4.4 and 0.5%, in 2006 to 8.5 and 1.5% in 2012, respectively. During the same period, the prevalence of
Escherichia coli
and
Klebsiella
spp. with an extended-spectrum β-lactamase (ESBL) phenotype increased from 5.8 and 9.1% to 11.1 and 20.4%, respectively, whereas rates of meropenem-nonsusceptible
Klebsiella pneumoniae
escalated from 2.2% in 2006 to 10.8% in 2012. The results of this investigation show that tigecycline generally retained potent activities against clinically important organisms isolated in U.S. institutions, including MDR organism subsets of Gram-positive and Gram-negative pathogens.