bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults
Authors: Bhalodi Amira A. , Papasavas Pavlos K. , Tishler Darren S. , Nicolau David P. , Kuti Joseph L. 
Published: December 2012

ABSTRACT

The pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m
2
receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (±standard deviation) age, height, and weight were 42.2 ± 12.2 years, 64.8 ± 3.5 in, and 109.5 ± 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ± 1.9 liters/h), which could be inhibited to 85.5% ± 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ± 9.6 liters), and the intercompartment transfer constants (
K
12
and
K
21
) of 8.04 ± 6.22 and 7.99 ± 5.46 h
−1
, respectively. The areas under the curve for the 12-h dosing interval (AUCτ) were similar between moderately obese and morbidly obese groups: 130.3 ± 60.1 versus 109.2 ± 25.5 μg · h/ml (
P
= 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (
r
2
= 0.524), adjusted body weight (
r
2
= 0.587), lean body weight (
r
2
= 0.495), and ideal body weight (
r
2
= 0.398), but not with BMI (
r
2
= 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUCτ values similar to those seen in nonobese participants.
Comparison of Six Generic Vancomycin Products for Treatment of Methicillin-Resistant Staphylococcus aureus Experimental Endocarditis in Rabbits
Authors: Tattevin P. , Saleh-Mghir A. , Davido B. , Ghout I. , Massias L. , Garcia de la Maria C. , Miró J. M. , Perronne C. , Laurent F. , Crémieux A. C. 
Published: December 2012

ABSTRACT

Concerns have recently emerged about the potency and the quality of generic vancomycin (VAN) products approved for use in humans, based on experiments in a neutropenic mouse thigh infection model. However, other animal models may be more appropriate to decipher the bactericidal activities of VAN generics
in vivo
and to predict their efficacy in humans. We aimed to compare the bactericidal activities of six generic VAN products currently used in France (Mylan and Sandoz), Spain (Hospira), Switzerland (Teva), and the United States (Akorn-Strides and American Pharmaceutical Products [APP]) in a rabbit model of aortic valve endocarditis induced by 8 × 10
7
CFU of methicillin-resistant
Staphylococcus aureus
(MRSA) strain COL (VAN MIC, 1.5 μg/ml).
In vitro
, there were no significant differences in the time-kill curve studies performed with the six generic VAN products. Ten rabbits in each group were treated with intravenous (i.v.) VAN, 60 mg/kg of body weight twice a day (b.i.d.) for 4 days. Mean peak serum VAN levels, measured 45 min after the last injection, ranged from 35.5 (APP) to 45.9 μg/ml (Teva). Mean trough serum VAN levels, measured 12 h after the last injection, ranged from 2.3 (Hospira) to 9.2 (APP) μg/ml. All generic VAN products were superior to controls (no treatment) in terms of residual organisms in vegetations (
P
< 0.02 for each comparison) and in the spleen (
P
< 0.005 for each comparison). Pairwise comparisons of generic VAN products found no significant differences. In conclusion, a stringent MRSA endocarditis model found no significant differences in the bactericidal activities of six generic VAN products currently used in Europe and America.
In Vitro
and
In Vivo
Activities of 2-Aminopyrazines and 2-Aminopyridines in Experimental Models of Human African Trypanosomiasis
Authors: Vodnala Suman K. , Lundbäck Thomas , Sjöberg Birger , Svensson Richard , Rottenberg Martin E. , Hammarström Lars G. J. 
Published: December 2012

ABSTRACT

New drugs for the treatment of human African trypanosomiasis are urgently needed. A number of 2-aminopyrazines/2-aminopyridines were identified as promising leads following a focused screen of 5,500 compounds for
Trypanosoma brucei
subsp.
brucei
viability. Described compounds are trypanotoxic in the submicromolar range and show comparably low cytotoxicity on representative mammalian cell lines. Specifically, 6-([6-fluoro-3,4-dihydro-2
H
-1-benzopyran-4-yl)]oxy)-
N
-(piperidin-4-yl)pyrazin-2-amine (CBK201352) is trypanotoxic for
T. brucei
subsp.
brucei
,
T. brucei
subsp.
gambiense
, and
T. brucei
subsp.
rhodesiense
and is nontoxic to mammalian cell lines, and
in vitro
preclinical assays predict promising pharmacokinetic parameters. Mice inoculated intraperitoneally (i.p.) with 25 mg/kg CBK201352 twice daily for 10 days, starting on the day of infection with
T. brucei
subsp.
brucei
, show complete clearance of parasites for more than 90 days. Thus, CBK201352 and related analogs are promising leads for the development of novel treatments for human African trypanosomiasis.
Randomized, Open-Label Trial of Primaquine against Vivax Malaria Relapse in Indonesia
Authors: Sutanto Inge , Tjahjono Bagus , Basri Hasan , Taylor W. Robert , Putri Fauziah A. , Meilia Rizka A. , Setiabudy Rianto , Nurleila Siti , Ekawati Lenny L. , Elyazar Iqbal , Farrar Jeremy , Sudoyo Herawati , Baird J. Kevin 
Published: December 2012

ABSTRACT

Radical cure of
Plasmodium vivax
infection applies blood schizontocidal therapy against the acute attack and hypnozoitocidal therapy against later relapse. Chloroquine and primaquine have been used for 60 years in this manner. Resistance to chloroquine by the parasite now requires partnering other blood schizontocides with primaquine. However, the safety and efficacy of primaquine against relapse when combined with other drugs have not been demonstrated. This randomized, open-label, and relapse-controlled trial estimated the efficacy of primaquine against relapse when administered with quinine or dihydroartemisinin-piperaquine for treatment of the acute infection. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute
P. vivax
malaria were eligible for study. One hundred sixteen enrolled subjects were randomized to these treatments: artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or dihydroartemisinin (120 mg) plus piperaquine (960 mg) daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered dihydroartemisinin-piperaquine plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for dihydroartemisinin-piperaquine plus primaquine. Antirelapse therapy with primaquine begun a month after treatment of the acute attack with dihydroartemisinin-piperaquine proved safe and highly efficacious against relapse by
P. vivax
acquired in Papua, Indonesia.
Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment
Authors: Moise Pamela A. , Amodio-Groton Maria , Rashid Mohamad , Lamp Kenneth C. , Hoffman-Roberts Holly L. , Sakoulas George , Yoon Min J. , Schweitzer Suzanne , Rastogi Anjay 
Published: December 2012

ABSTRACT

Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and
Staphylococcus aureus
bacteremia treatment failure. In light of recent data demonstrating the successful use of β-lactam plus daptomycin in very difficult cases of
S. aureus
bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant β-lactams. We identified 106 patients who received daptomycin for
S. aureus
bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a β-lactam (87% versus 78%;
P
= 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%;
P
= 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with
S. aureus
bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.
Role of the NK Cell-Activating Receptor CRACC in Periodontitis
Authors: Krämer Benjamin , Kebschull Moritz , Nowak Michael , Demmer Ryan T. , Haupt Manuela , Körner Christian , Perner Sven , Jepsen Søren , Nattermann Jacob , Papapanou Panos N. 
Published: December 2012

ABSTRACT

Periodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cell-activating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation
in vivo
. We delineate how
Aggregatibacter actinomycetemcomitans
, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae from
Porphyromonas gingivalis
, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis.
Schistosome Egg Antigens Elicit a Proinflammatory Response by Trophoblast Cells of the Human Placenta
Authors: McDonald Emily A. , Kurtis Jonathan D. , Acosta Luz , Gundogan Fusun , Sharma Surendra , Pond-Tor Sunthorn , Wu Hai-wei , Friedman Jennifer F. 
Published: December 2012

ABSTRACT

Schistosomiasis affects nearly 40 million women of reproductive age. Many of these women are infected while pregnant and lactating. Several studies have demonstrated transplacental trafficking of schistosome antigens; however, little is known regarding how these antigens affect the developing fetus and placenta. To evaluate the impact of schistosomiasis on trophoblasts of the human placenta, we isolated primary trophoblast cells from healthy placentas delivered at term. These trophoblasts were placed in culture and treated with
Schistosoma japonicum
soluble egg antigens (SEA) or plasma from
S. japonicum
-infected pregnant women. Outcomes measured included cytokine production and activation of signal transduction pathways. Treatment of primary human trophoblast cells with SEA resulted in upregulation of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8 and the chemokine macrophage inflammatory protein 1α (MIP-1α). Cytokine production in response to SEA was dose dependent and reminiscent of production in response to other proinflammatory stimuli, such as Toll-like receptor 2 (TLR2) and TLR4 agonists. In addition, the signaling pathways extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal protein kinase (JNK), p38, and NF-κB were all activated by SEA in primary trophoblasts. These effects appeared to be mediated through both carbohydrate and protein epitopes of SEA. Finally, primary trophoblasts cocultured with plasma from
S. japonicum
-infected pregnant women produced increased levels of IL-8 compared to trophoblasts cocultured with plasma from uninfected pregnant women. We report here a direct impact of SEA on primary human trophoblast cells, which are critical for many aspects of a healthy pregnancy. Our data indicate that schistosome antigens can activate proinflammatory responses in trophoblasts, which might compromise maternal-fetal health in pregnancies complicated by schistosomiasis.
Republished: Bacterial proteases in IBD and IBS
Authors: Steck Natalie , Mueller Kerstin , Schemann Michael , Haller Dirk 
Published: December 2012

Abstract
Proteases play a decisive role in health and disease. They fulfil diverse functions and have been associated with the pathology of gastrointestinal disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). The current knowledge focuses on host-derived proteases including matrix metalloproteinases, various serine proteases and cathepsins. The possible contribution of bacterial proteases has been largely ignored in the pathogenesis of IBD and IBS, although there is increasing evidence, especially demonstrated for proteases from pathogenic bacteria. The underlying mechanisms extend to proteases from commensal bacteria which may be relevant for disease susceptibility. The intestinal microbiota and its proteolytic capacity exhibit the potential to contribute to the pathogenesis of IBD and IBS. This review highlights the relevance of host- and bacteria-derived proteases and their signalling mechanisms.
Autocrine Motility Factor Promotes HER2 Cleavage and Signaling in Breast Cancer Cells
Authors: Kho Dhong Hyo , Nangia-Makker Pratima , Balan Vitaly , Hogan Victor , Tait Larry , Wang Yi , Raz Avraham 
Published: December 2012

Abstract
Trastuzumab (Herceptin) is an effective targeted therapy in HER2-overexpressing human breast carcinoma. However, many HER2-positive patients initially or eventually become resistant to this treatment, so elucidating mechanisms of trastuzumab resistance that emerge in breast carcinoma cells is clinically important. Here, we show that autocrine motility factor (AMF) binds to HER2 and induces cleavage to the ectodomain-deleted and constitutively active form p95HER2. Mechanistic investigations indicated that interaction of AMF with HER2 triggers HER2 phosphorylation and metalloprotease-mediated ectodomain shedding, activating phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase signaling and ablating the ability of trastuzumab to inhibit breast carcinoma cell growth. Furthermore, we found that HER2 expression and AMF secretion were inversely related in breast carcinoma cells. On the basis of this evidence that AMF may contribute to HER2-mediated breast cancer progression, our findings suggest that AMF–HER2 interaction might be a novel target for therapeutic management of patients with breast cancer, whose disease is resistant to trastuzumab. Cancer Res; 73(4); 1411–9. ©2012 AACR.
Contrasting Hypoxic Effects on Breast Cancer Stem Cell Hierarchy Is Dependent on ER-α Status
Authors: Harrison Hannah , Rogerson Lynsey , Gregson Hannah J. , Brennan Keith R. , Clarke Robert B. , Landberg Göran 
Published: December 2012

Abstract
Tumor hypoxia is often linked to decreased survival in patients with breast cancer and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia-induced angiogenesis. Antiangiogenic therapies show some therapeutic potential with increased disease-free survival, but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting from increased tumor hypoxia. We studied the effects of hypoxia on CSC activity, using in vitro mammosphere and holoclone assays as well as in vivo limiting dilution experiments, in 13 patient-derived samples and four cell lines. There was a HIF-1α–dependent CSC increase in ER-α–positive cancers following hypoxic exposure, which was blocked by inhibition of estrogen and Notch signaling. A contrasting decrease in CSC was seen in ER-α–negative cancers. We next developed a xenograft model of cell lines and patient-derived samples to assess the hypoxic CSC response. Varying sizes of xenografts were collected and analyzed for HIF1-α expression and CSC. The same ER-α–dependent contrasting hypoxic-CSC response was seen validating the initial observation. These data suggest that ER-α–positive and negative breast cancer subtypes respond differently to hypoxia and, as a consequence, antiangiogenic therapies will not be suitable for both subgroups. Cancer Res; 73(4); 1420–33. ©2012 AACR.
New Strategies in Prostate Cancer: Translating Genomics into the Clinic
Authors: Beltran Himisha , Rubin Mark A. 
Published: December 2012

Abstract
With the rapidly developing use of next-generation sequencing technologies, there has been a surge in our knowledge of the genomic landscape of prostate cancer and a movement toward developing a molecular subclassification system for the disease. With this new understanding comes great clinical potential, both for the development of biomarkers as well as new therapeutic targets. Herein, we highlight the potential clinical use of recent discoveries and how they fit into our current paradigm. We describe the challenges that lie ahead as we move from genomic sequencing toward routine clinical practice and adopt precision cancer care for patients with prostate cancer. Clin Cancer Res; 19(3); 517–23. ©2012 AACR.
MUC1 Vaccine for Individuals with Advanced Adenoma of the Colon: A Cancer Immunoprevention Feasibility Study
Authors: Kimura Takashi , McKolanis John R. , Dzubinski Lynda A. , Islam Kazi , Potter Douglas M. , Salazar Andres M. , Schoen Robert E. , Finn Olivera J. 
Published: December 2012

AbstractCancer vaccines based on human tumor-associated antigens (TAA) have been tested in patients with advanced or recurrent cancer, in combination with or following standard therapy. Their immunogenicity and therapeutic efficacy has been difficult to properly evaluate in that setting characterized by multiple highly suppressive effects of the tumor and the standard therapy on the patient's immune system. In animal models of human cancer, vaccines administered in the prophylactic setting are most immunogenic and effectively prevent cancer development and progression. We report results of a clinical study that show that in patients without cancer but with a history of premalignant lesions (advanced colonic adenomas, precursors to colon cancer), a vaccine based on the TAA MUC1 was highly immunogenic in 17 of 39 (43.6%) of vaccinated individuals, eliciting high levels of anti-MUC1 immunoglobulin G (IgG) and long-lasting immune memory. Lack of response in 22 of 39 individuals was correlated with high levels of circulating myeloid-derived suppressor cells (MDSC) prevaccination. Vaccine-elicited MUC1-specific immune response and immune memory were not associated with significant toxicity. Our study shows that vaccines based on human TAAs are immunogenic and safe and capable of eliciting long-term memory that is important for cancer prevention. We also show that in the premalignant setting, immunosuppressive environment (e.g., high levels of MDSC) might already exist in some individuals, suggesting an even earlier premalignant stage or preselection of nonimmunosuppressed patients for prophylactic vaccination. Cancer Prev Res; 6(1); 18–26. ©2012 AACR.
Virtual Lesion of Angular Gyrus Disrupts the Relationship between Visuoproprioceptive Weighting and Realignment
Authors: Block Hannah , Bastian Amy , Celnik Pablo 
Published: December 2012

Abstract
Posterior parietal cortex is thought to be involved in multisensory processes such as sensory weighting (how much different modalities are represented in sensory integration) and realignment (recalibrating the estimates given by unisensory inputs relative to each other, e.g., when viewing the hand through prisms). Sensory weighting and realignment are biologically independent but can be correlated such that the lowest-weighted modality realigns most. This is important for movement precision because it results in the brain's estimate of hand position favoring the more reliable (higher-weighted) modality. It is unknown if this interaction is an emergent property of separate neural pathways for weighting and realignment or if it is actively mediated by a common substrate. We applied disruptive TMS to the angular gyrus near the intraparietal sulcus (PGa) before participants performed a task with misaligned visual and proprioceptive information about hand position. Visuoproprioceptive weighting and realignment were unaffected. However, the relationship between weighting and realignment, found in control conditions, was absent after TMS in the angular gyrus location. This suggests that a specific region in the angular gyrus actively mediates the interaction between visuoproprioceptive weighting and realignment and may thus play a role in the decreased movement precision associated with posterior parietal lesions.