bluuebunny/crossref_metadata_2025_split huggingface dataset:
Priapism Associated with Lumbar Stenosis in a Dog
Authors: Payan‐Carreira R , Colaço B , Rocha C , Albuquerque C , Luis M , Abreu H , Pires MA 
Published: April 2013

ContentsPriapism, a persistent long‐lasting involuntary erection of the penis, is uncommon in dogs. In this report, the case of a 13‐year‐old malePointer, referred to our services due to persistent exposition of the penis, is described. This condition was consecutive to an intermittent priapism situation lasting for several days, which has been initially attributed to the inflammation and haematoma associated with a perianal bite. The owners became unable to retract the penis into the prepuce. At presentation, the dog was anorectic for 48 h, intolerant to manipulation, and showed poor body condition and unsteady locomotion. During physical evaluation, a marked engorgement of the local vessels in the prepuce and penis was found. An abdominalX‐ray was asked under the suspicion of a neurogenic origin for the clinical situation, which showed evidences of spondylosis. After discussion of the clinical condition, the owners asked for euthanasia. The necropsy confirmed the engorgement of the regional vessels deriving from the pudendal arteries and blood accumulation within all the cavernous spaces, accompanied by congestion and thrombosis within the erectile structures of the penis. No significant changes were observed in the pelvic organs that could be at the origin of priapism. The lumbar‐sacral spinal regions were carefully inspected and evidenced signs ofL7‐S1 stenosis due to spondylosis. The case presented herein is a rare situation of priapism of neurogenic origin in a dog. Necropsy findings suggest that it was consecutive to cauda equina compression due to lumbar spinal stenosis.
Heterogeneity in Parent‐reported Social Skill Development in Early Elementary School Children
Authors: Lamont Andrea , Van Horn M. Lee 
Published: April 2013

AbstractDespite known risks associated with aberrant social skill development, there has been a relative dearth of literature on typical developmental changes in social skills over time. In this study, we examine systematic changes in social skills from kindergarten (typical age of 5–6 years) to third grade (typical age of 8–9 years), and focus on systematic heterogeneity across these developmental trajectories. Data came from the National Head Start—Public School Early Childhood Transition Demonstration Project (N = 6964). Mixture models provide evidence for multiple classes of individuals representing heterogeneity in the development of social skills. Classes were defined as a majority class (whose trajectories remained relatively stable over time), an increasing class (whose trajectories increased at a faster rate than the majority class), and a decreasing class (whose trajectories decreased at a faster rate than the majority class). Developmental trends accounted for a substantial proportion of the variance in social skill components. Implications and limitations of the study are discussed.
Identification and Characterization of a Novel HIV-1 Nucleotide-Competing Reverse Transcriptase Inhibitor Series
Authors: Rajotte D. , Tremblay S. , Pelletier A. , Salois P. , Bourgon L. , Coulombe R. , Mason S. , Lamorte L. , Sturino C. F. , Bethell R. 
Published: April 2013

ABSTRACT

Several groups have recently reported on the identification of nucleotide-competing reverse transcriptase inhibitors (NcRTIs), a new class of RT inhibitors. NcRTIs reversibly inhibit binding of the incoming nucleotide to the RT active site but do not act as chain terminators, unlike the nucleos(t)ide reverse transcriptase inhibitor (NRTI) class. We identified a novel benzo[4,5]furo[3,2,
d
]pyrimidin-2-one NcRTI chemical series. Structure-activity relationship evaluation of this series with both RT and viral replication assays led to the identification of compound A, a new NcRTI. Compound A inhibited HIV-1 RT in a primer extension assay (50% inhibitory concentration, 2.6 nM) but had no measurable activity against human DNA polymerase γ at 10 μM. It potently inhibited HIV-1 replication
in vitro
(50% effective concentration, 1.5 nM). The antiviral potency of compound A was unaffected by the presence of nonnucleotide RT inhibitor (NNRTI) mutations tested (L100I, K103N/Y181C, V106A, or Y188L). Notably, viruses encoding K65R were hypersusceptible to inhibition by compound A. Compound A also retained full activity against viruses encoding M184V.
In vitro
selection for resistant virus to compound A led to the selection of a single substitution within RT: W153L. A recombinant virus encoding the RT W153L was highly resistant to compound A (fold change, 160). W153 is a highly conserved residue in HIV RT and has not been previously associated with drug resistance. In summary, a novel NcRTI series with optimized antiviral activity, minimal cross-resistance to existing RT inhibitor classes, and a distinct resistance profile has been discovered. These results further establish NcRTIs as an emerging class of antiretroviral agents.
Kinetic and Structural Analysis for Potent Antifolate Inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and Human Dihydrofolate Reductases and Their Active-Site Variants
Authors: Cody Vivian , Pace Jim , Queener Sherry F. , Adair Ona O. , Gangjee Aleem 
Published: April 2013

ABSTRACT

A major concern of immunocompromised patients, in particular those with AIDS, is susceptibility to infection caused by opportunistic pathogens such as
Pneumocystis jirovecii
, which is a leading cause of pneumonia in immunocompromised patients. We report the first kinetic and structural data for 2,4-diamino-6-[(2′,5′-dichloro anilino)methyl]pyrido[2,3-
d
]pyrimidine (OAAG324), a potent inhibitor of dihydrofolate reductase (DHFR) from
P. jirovecii
(pjDHFR), and also for trimethoprim (TMP) and methotrexate (MTX) with pjDHFR,
Pneumocystis carinii
DHFR (pcDHFR), and human DHFR (hDHFR). OAAG324 shows a 9.0-fold selectivity for pjDHFR (

K
i

, 2.7 nM) compared to its selectivity for hDHFR (

K
i

, 24.4 nM), whereas there is only a 2.3-fold selectivity for pcDHFR (

K
i

, 6.3 nM). In order to understand the determinants of inhibitory potency, active-site mutations of pj-, pc-, and hDHFR were explored to make these enzymes more like each other. The most unexpected observations were that the variant pcDHFR forms with K37Q and K37Q/F69N mutations, which made the enzyme more like the human form, also made these enzymes more sensitive to the inhibitory activity of OAAG324, with

K
i

values of 0.26 and 0.71 nM, respectively. A similar gain in sensitivity was also observed for the hDHFR N64F variant, which showed a lower

K
i

value (0.58 nM) than native hDHFR, pcDHFR, or pjDHFR. Structural data are reported for complexes of OAAG324 with hDHFR and its Q35K and Q35S/N64F variants and for the complex of the K37S/F69N variant of pcDHFR with TMP. These results provide useful insight into the role of these residues in the optimization of highly selective inhibitors of DHFR against the opportunistic pathogen
P. jirovecii
.
Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors
Authors: Alhajlan Mai , Alhariri Moayad , Omri Abdelwahab 
Published: April 2013

ABSTRACT

We investigated the efficacy and safety of liposomal clarithromycin formulations with different surface charges against clinical isolates of
Pseudomonas aeruginosa
from the lungs of cystic fibrosis (CF) patients. The liposomal clarithromycin formulations were prepared by the dehydration-rehydration method, and their sizes were measured using the dynamic-light-scattering technique. Encapsulation efficiency was determined by microbiological assay, and the stabilities of the formulations in biological fluid were evaluated for a period of 48 h. The MICs and minimum bactericidal concentrations (MBCs) of free and liposomal formulations were determined with
P. aeruginosa
strains isolated from CF patients. Liposomal clarithromycin activity against biofilm-forming
P. aeruginosa
was compared to that of free antibiotic using the Calgary Biofilm Device (CBD). The effects of subinhibitory concentrations of free and liposomal clarithromycin on bacterial virulence factors and motility on agar were investigated on clinical isolates of
P. aeruginosa
. The cytotoxicities of the liposome preparations and free drug were evaluated on a pulmonary epithelial cell line (A549). The average diameter of the formulations was >222 nm, with encapsulation efficiencies ranging from 5.7% to 30.4%. The liposomes retained more than 70% of their drug content during the 48-h time period. The highly resistant strains of
P. aeruginosa
became susceptible to liposome-encapsulated clarithromycin (MIC, 256 mg/liter versus 8 mg/liter;
P
< 0.001). Liposomal clarithromycin reduced the bacterial growth within the biofilm by 3 to 4 log units (
P
< 0.001), significantly attenuated virulence factor production, and reduced bacterial twitching, swarming, and swimming motilities. The clarithromycin-entrapped liposomes were less cytotoxic than the free drug (
P
< 0.001). These data indicate that our novel formulations could be a useful strategy to enhance the efficacy of clarithromycin against resistant
P. aeruginosa
strains that commonly affect individuals with cystic fibrosis.
Comparative Activities of Telavancin Combined with Nafcillin, Imipenem, and Gentamicin against Staphylococcus aureus
Authors: Leonard Steven N. , Supple Megan E. , Gandhi Ronak G. , Patel Meghna D. 
Published: April 2013

ABSTRACT

Beta-lactams enhance the killing activity of vancomycin. Due to structural and mechanistic similarities between vancomycin and telavancin, we investigated the activity of telavancin combined with nafcillin and imipenem compared to the known synergistic combination of telavancin and gentamicin. Thirty strains of
Staphylococcus aureus
, 10 methicillin-susceptible
S. aureus
(MSSA), 10 methicillin-resistant
S. aureus
(MRSA), and 10 heterogeneously vancomycin-intermediate
S. aureus
(hVISA), were tested for synergy by time-kill methodology. Six strains (2 each of MSSA, MRSA, and hVISA) were further evaluated in an
in vitro
pharmacokinetic/pharmacodynamic (PK/PD) model with simulated regimens of 10 mg/kg of body weight of telavancin once daily alone and combined with 2 g nafcillin every 4 h, 500 mg imipenem every 6 h, or 5 mg/kg gentamicin once daily over 72 h. In the synergy test, 67% of strains displayed synergy with the combination of telavancin and gentamicin, 70% with telavancin and nafcillin, and 63% with telavancin and imipenem. In the PK/PD model, the activities of all three combinations against MRSA and hVISA were superior to all individual drugs alone (
P
≤ 0.002) and were similar to each other (
P
≥ 0.187). The activities of all three combinations against MSSA were generally similar to each other except for one strain where the combination of telavancin and imipenem was superior to all other regimens (
P
≤ 0.011). The activity of the combination of telavancin and beta-lactam agents was similar to that of telavancin and gentamicin against
S. aureus
, including resistant strains. Because beta-lactam combinations are less likely to be nephrotoxic than telavancin plus gentamicin, these beta-lactam combinations may have clinical utility.
Safety and Tolerability of Luliconazole Solution 10-Percent in Patients with Moderate to Severe Distal Subungual Onychomycosis
Authors: Jones T. , Tavakkol A. 
Published: April 2013

ABSTRACTThe study objective was to evaluate the safety, tolerability, systemic exposure, and pharmacokinetics (PK) of 10% luliconazole solution (luliconazole) when topically applied once daily to all 10 toenails and periungual areas in patients with moderate to severe distal subungual onychomycosis. In this single-center, open-label study, 24 patients applied 20 mg/ml of luliconazole (twice the clinical dose) for 29 days with a 7-day follow-up. Complete PK profiles were determined on days 1, 8, 15, and 29. Safety/tolerability assessments included application site reactions, adverse events, vital signs, clinical laboratory findings, and electrocardiograms. Mean luliconazole plasma concentrations remained around the lower limit of quantitation (0.05 ng/ml) and were comparable on days 8, 15, and 29 (range, 0.063 to 0.090 ng/ml), suggesting steady state occurred by day 8. Every patient had undetectable plasma luliconazole levels for at least 11% of the time points, and 12 of the 24 patients had undetectable levels for at least 70% of the time points. The maximum plasma concentration of luliconazole (Cmax) observed in any patient was 0.314 ng/ml and the maximum area under the concentration-time curve from 0 to 24 h (AUC0–24) was 4.34 ng · h/ml. Five patients (21%) had measureable luliconazole levels in the plasma 7 days after the last dose. The median concentration of luliconazole in the nail at this time point was 34.65 mg/g (from 42 of 48 collected toenail samples). There was one mild incidence of skin erythema on day 5 that resolved on day 8, there were no reports of drug-induced systemic side effects, and there was no evidence of QT prolongation. Luliconazole, when applied once daily to all 10 fungus-infected toenails for 29 days, is generally safe and well tolerated and results in significant accumulation of drug in the nail. Systemic exposure is very low, with no evidence of drug accumulation.
Candida albicans-Staphylococcus aureus Polymicrobial Peritonitis Modulates Host Innate Immunity
Authors: Peters Brian M. , Noverr Mairi C. 
Published: April 2013

ABSTRACTDespite advances in medical device fabrication and antimicrobial treatment therapies, fungal-bacterial polymicrobial peritonitis remains a serious complication for surgery patients, those on peritoneal dialysis, and the critically ill. Using a murine model of peritonitis, we have demonstrated that monomicrobial infection withCandida albicansorStaphylococcus aureusis nonlethal. However, coinfection with these same doses leads to a 40% mortality rate and increased microbial burden in the spleen and kidney by day 1 postinfection. Using a multiplex enzyme-linked immunosorbent assay, we have also identified a unique subset of innate proinflammatory cytokines (interleukin-6, granulocyte colony-stimulating factor, keratinocyte chemoattractant, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α) that are significantly increased during polymicrobial versus monomicrobial peritonitis, leading to increased inflammatory infiltrate into the peritoneum and target organs. Treatment of coinfected mice with the cyclooxygenase (COX) inhibitor indomethacin reduces the infectious burden, proinflammatory cytokine production, and inflammatory infiltrate while simultaneously preventing any mortality. Further experiments demonstrated that the immunomodulatory eicosanoid prostaglandin E2(PGE2) is synergistically increased during coinfection compared to monomicrobial infection; indomethacin treatment also decreased elevated PGE2levels. Furthermore, addition of exogenous PGE2into the peritoneal cavity during infection overrode the protection provided by indomethacin and restored the increased mortality and microbial burden. Importantly, these studies highlight the ability of fungal-bacterial coinfection to modulate innate inflammatory events with devastating consequences to the host.
Intranasal Prophylaxis with CpG Oligodeoxynucleotide Can Protect against Yersinia pestis Infection
Authors: Hickey Anthony J. , Lin Jr-Shiuan , Kummer Lawrence W. , Szaba Frank M. , Duso Debra K. , Tighe Michael , Parent Michelle A. , Smiley Stephen T. 
Published: April 2013

ABSTRACTImmunomodulatory agents potentially represent a new class of broad-spectrum antimicrobials. Here, we demonstrate that prophylaxis with immunomodulatory cytosine-phosphate-guanidine (CpG) oligodeoxynucleotide (ODN), a toll-like receptor 9 (TLR9) agonist, confers protection againstYersinia pestis, the etiologic agent of plague. The data establish that intranasal administration of CpG ODN 1 day prior to lethal pulmonary exposure toY. pestisstrain KIM D27 significantly improves survival of C57BL/6 mice and reduces bacterial growth in hepatic tissue, despite paradoxically increasing bacterial growth in the lung. All of these CpG ODN-mediated impacts, including the increased pulmonary burden, are TLR9 dependent, as they are not observed in TLR9-deficient mice. The capacity of prophylactic intranasal CpG ODN to enhance survival does not require adaptive immunity, as it is evident in mice lacking B and/or T cells; however, the presence of T cells improves long-term survival. The prophylactic regimen also improves survival and reduces hepatic bacterial burden in mice challenged intraperitoneally with KIM D27, indicating that intranasal delivery of CpG ODN has systemic impacts. Indeed, intranasal prophylaxis with CpG ODN provides significant protection against subcutaneous challenge withY. pestisstrain CO92 even though it fails to protect mice from intranasal challenge with that fully virulent strain.
Toll-Like Receptor 5-Dependent Immunogenicity and Protective Efficacy of a Recombinant Fusion Protein Vaccine Containing the Nontoxic Domains of Clostridium difficile Toxins A and B and Salmonella enterica Serovar Typhimurium Flagellin in a Mouse Model of Clostridium difficile Disease
Authors: Ghose Chandrabali , Verhagen Janneke M. , Chen Xinhua , Yu Jian , Huang Yaoxing , Chenesseau Olivia , Kelly Ciarán P. , Ho David D. 
Published: April 2013

ABSTRACT

Clostridium difficile
is a spore-forming bacillus that produces toxin-mediated enteric disease.
C. difficile
expresses two major virulence factors, toxin A (TcdA) and toxin B (TcdB). Human and animal studies demonstrate a clear association between humoral immunity to these toxins and protection against
C. difficile
infection (CDI). The receptor binding-domains (RBDs) of TcdA and TcdB are known to be immunogenic. Here, we tested the immunoadjuvant properties of
Salmonella enterica
serovar Typhimurium flagellin (FliC) subunit D1 as an innate immune agonist expressed as a recombinant fusion vaccine targeting the RBDs of TcdA and TcdB in mice. Intraperitoneally immunized mice developed prominent anti-TcdA and anti-TcdB immunoglobulin G in serum. The protective efficacy of the recombinant vaccines, with or without an adjuvant, was tested in a mouse model of CDI that closely represents the human disease. Following intraperitoneal immunization equivalent to two doses of toxoid A and toxoid B vaccine adjuvanted with alum and oral challenge with
C. difficile
VPI 10463, C57BL/6 mice were able to mount a protective immune response that prevented diarrhea and death compared to mice immunzed with alum alone. These results are significantly different from those for control mice (
P
< 0.001). These results provide evidence that a recombinant protein-based vaccine targeting the RBDs of the
C. difficile
toxins adjuvanted with
S
. Typhimurium flagellin can induce rapid, high-level protection in a mouse model of CDI when challenged with the homologous strain from which the vaccine antigens were derived and warrant further preclinical testing against clinically relevant
C. difficile
strains in the mouse and hamster models of CDI.
Toxoplasma gondii Rhoptry 16 Kinase Promotes Host Resistance to Oral Infection and Intestinal Inflammation Only in the Context of the Dense Granule Protein GRA15
Authors: Jensen Kirk D. C. , Hu Kenneth , Whitmarsh Ryan J. , Hassan Musa A. , Julien Lindsay , Lu Diana , Chen Lieping , Hunter Christopher A. , Saeij Jeroen P. J. 
Published: April 2013

ABSTRACTToxoplasma gondiitransmission between intermediate hosts is dependent on the ingestion of walled cysts formed during the chronic phase of infection. Immediately following consumption, the parasite must ensure survival of the host by preventing adverse inflammatory responses and/or by limiting its own replication. Since theToxoplasmasecreted effectors rhoptry 16 kinase (ROP16) and dense granule 15 (GRA15) activate the JAK-STAT3/6 and NF-κB signaling pathways, respectively, we explored whether a particular combination of these effectors impacted intestinal inflammation and parasite survivalin vivo. Here we report that expression of the STAT-activating version of ROP16 in the type II strain (strain II+ROP16I) promotes host resistance to oral infection only in the context of endogenous GRA15 expression. Protection was characterized by a lower intestinal parasite burden and dampened inflammation. Host resistance to the II+ROP16Istrain occurred independently of STAT6 and the T cell coinhibitory receptors B7-DC and B7-H1, two receptors that are upregulated by ROP16. In addition, coexpression of ROP16 and GRA15 enhanced parasite susceptibility within tumor necrosis factor alpha/gamma interferon-stimulated macrophages in a STAT3/6-independent manner. Transcriptional profiling of infected STAT3- and STAT6-deficient macrophages and parasitized Peyer's patches from mice orally challenged with strain II+ROP16Isuggested that ROP16 activated STAT5 to modulate host gene expression. Consistent with this supposition, the ROP16 kinase induced the sustained phosphorylation and nuclear localization of STAT5 inToxoplasma-infected cells. In summary, only the combined expression of both GRA15 and ROP16 promoted host resistance to acute oral infection, andToxoplasmamay possibly target the STAT5 signaling pathway to generate protective immunity in the gut.
Is flirting with clients taboo?
Authors: McCulloch Steven 
Published: April 2013

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved. In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘Is flirting with clients taboo?’, is presented and discussed by Steven McCulloch. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘Rodents’ rights: patients or pet food?', which was published in the March issue of In Practice, appears on page 223.The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas.