bluuebunny/crossref_metadata_2025_split huggingface dataset:
2-
tert
-Butyl-8-Quinolinamines Exhibit Potent Blood Schizontocidal Antimalarial Activity via Inhibition of Heme Crystallization
Authors: Huy Nguyen Tien , Mizunuma Keisuke , Kaur Kirandeep , Nhien Nguyen Thanh Thuy , Jain Meenakshi , Uyen Dinh Thanh , Harada Shigeharu , Jain Rahul , Kamei Kaeko 
Published: June 2007

ABSTRACT

We have recently reported that the attachment of a bulky metabolically stable
tert
-butyl group at the C-2 position of a quinoline ring in primaquine results in a tremendous improvement in the blood schizontocidal antimalarial activity of 8-quinolinamine. Because free heme released from hemoglobin catabolism in a malarial parasite is highly toxic, the parasite protects itself mainly by crystallization of heme into insoluble nontoxic hemozoin. We now demonstrate the ability of 2-
tert
-butylprimaquine to inhibit in vitro beta-hematin formation, to form a complex with heme with a stoichiometry of 1:1, and to enhance heme-induced hemolysis. The results described herein indicate that a major improvement in the blood-schizontocidal antimalarial activity of 2-
tert
-butylprimaquine might be due to a disturbance of heme catabolism pathway in the malarial parasite.
Retapamulin Inhibition of Translation and 50S Ribosomal Subunit Formation in
Staphylococcus aureus
Cells
Authors: Champney W. Scott , Rodgers Ward K. 
Published: June 2007

ABSTRACT

Retapamulin inhibited protein biosynthesis and cell viability in methicillin-sensitive and methicillin-resistant
Staphylococcus aureus
organisms. A specific inhibitory effect on 50S ribosomal subunit formation was also found. Pulse-chase labeling experiments confirmed the specific inhibition of 50S subunit biogenesis. Turnover of 23S rRNA was found, with no effect on 16S rRNA amounts.
Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats
Authors: Li Qigui , Kozar Michael P. , Shearer Todd W. , Xie Lisa H. , Lin Ai J. , Smith Kirsten S. , Si Yuanzheng , Anova Lalaine , Zhang Jing , Milhous Wilbur K. , Skillman Donald R. 
Published: June 2007

ABSTRACT
Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng·h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng·h/ml) and one-half (1,381 ng·h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.
Dexamethasone as Adjuvant Therapy to Moxifloxacin Attenuates Valve Destruction in Experimental Aortic Valve Endocarditis Due to
Staphylococcus aureus
Authors: Skiadas Ioannis , Pefanis Angelos , Papalois Apostolos , Kyroudi Aspasia , Triantafyllidi Helen , Tsaganos Thomas , Giamarellou Helen 
Published: June 2007

ABSTRACT

Although the beneficial effects of dexamethasone have frequently been investigated in various serious-infection settings, insufficient data on valve histology and cardiac function for infective endocarditis are available. The efficacy of moxifloxacin for the treatment of experimental aortic valve endocarditis due to methicillin-susceptible
Staphylococcus aureus
and the long-term effects of dexamethasone were evaluated in the current study. Sixty-eight rabbits were randomly assigned to four groups: A, B, C, and D. Group A consisted of 18 animals and functioned as a control group. Groups B and C consisted of 11 and 23 subjects, respectively, which received moxifloxacin for 5 days in a human-like pharmacokinetic simulation. Group D consisted of 16 animals that were administered moxifloxacin plus dexamethasone (0.25 mg/kg of body weight twice a day intravenously). The group B animals were sacrificed a day after the completion of treatment, and group C and D animals were sacrificed after 12 days in order to monitor any possible relapse and allow microbiological, histopathological, and echocardiographic evaluation of the long-term effects of glucocorticoids. No differences in survival, sterilization rates, or inflammatory infiltration and calcification of valve tissue were observed among the treated groups. However, the degrees of valve damage and collagenization were significantly worse, the fibroblast content was higher, and fractional shortening of the left ventricle fluctuated significantly in group C compared to group D (all groups,
P
< 0.05). We concluded that dexamethasone treatment for experimental
S. aureus
endocarditis attenuates valve destruction and preserves overall cardiac function without impeding the efficacy of moxifloxacin.
Yersinia enterocolitica
Infection of Mice Reveals Clonal Invasion and Abscess Formation
Authors: Oellerich Mark F. , Jacobi Christoph A. , Freund Sandra , Niedung Katy , Bach Alexandra , Heesemann Jürgen , Trülzsch Konrad 
Published: June 2007

ABSTRACT

Yersinia enterocolitica
is a common cause of food-borne gastrointestinal disease leading to self-limiting diarrhea and mesenteric lymphadenitis. Occasionally, focal abscess formation in the livers and spleens of certain predisposed patients (those with iron overload states such as hemochromatosis) is observed. In the mouse oral infection model, yersiniae produce a similar disease involving the replication of yersiniae in the small intestine, the invasion of Peyer's patches, and dissemination to the liver and spleen. In these tissues and organs, yersiniae are known to replicate predominately extracellularly and to form microcolonies. By infecting mice orally with a mixture of equal amounts of green- and red-fluorescing yersiniae (yersiniae expressing green or red fluorescent protein), we were able to show for the first time that yersiniae produce exclusively monoclonal microcolonies in Peyer's patches, the liver, and the spleen, indicating that a single bacterium is sufficient to induce microcolony and microabscess formation in vivo. Furthermore, we present evidence for the clonal invasion of Peyer's patches from the small intestine. The finding that only very few yersiniae are required to establish microcolonies in Peyer's patches is due to both
Yersinia
-specific and host-specific factors. We demonstrate that yersiniae growing in the small intestinal lumen show strongly reduced levels of invasin, the most important factor for the early invasion of Peyer's patches. Furthermore, we show that the host severely restricts sequential microcolony formation in previously infected Peyer's patches.
Factor H Binding to PspC ofStreptococcus pneumoniaeIncreases Adherence to Human Cell Lines In Vitro and Enhances Invasion of Mouse Lungs In Vivo
Authors: Quin Lisa R. , Onwubiko Chinwendu , Moore Quincy C. , Mills Megumi Fujioka , McDaniel Larry S. , Carmicle Stephanie 
Published: June 2007

ABSTRACTPneumococcal surface protein C (PspC) binds to both human secretory immunoglobulin A (sIgA) and complement factor H (FH). FH, a regulator of the alternative pathway of complement, can also mediate adherence of different host cells. Since PspC contributes to adherence and invasion of host cells, we hypothesized that the interaction of PspC with FH may also mediate adherence of pneumococci to human cells. In this study, we investigated FH- and sIgA-mediated pneumococcal adherence to human cell lines in vitro. Adherence assays demonstrated that preincubation ofStreptococcus pneumoniaeD39 with FH increased adherence to human umbilical vein endothelial cells (HUVEC) 5-fold and to lung epithelial cells (SK-MES-1) 18-fold, relative to that of D39 without FH on the surface. The presence of sIgA enhanced adherence to SK-MES-1 6-fold and to pharyngeal epithelial cells (Detroit 562) 14-fold. Furthermore, sIgA had an additive effect on adherence to HUVEC; specifically, preincubation of D39 with both FH and sIgA led to a 21-fold increase in adherence. Finally, using a mouse model, we examined the significance of the FH-PspC interaction in pneumococcal nasal colonization and lung invasion. Mice intranasally infected with D39 preincubated with FH had increased bacteremia and lung invasion, but they had similar levels of nasopharyngeal colonization compared to that of mice challenged with D39 without FH.
Role of the Omp25/Omp31 Family in Outer Membrane Properties and Virulence ofBrucella ovis
Authors: Caro-Hernández Paola , Fernández-Lago Luis , de Miguel María-Jesús , Martín-Martín Ana I. , Cloeckaert Axel , Grilló María-Jesús , Vizcaíno Nieves 
Published: June 2007

ABSTRACTThe genes coding for the five outer membrane proteins (OMPs) of the Omp25/Omp31 family expected to be located in the outer membrane (OM) of rough virulentBrucella ovisPA were inactivated to evaluate their role in virulence and OM properties. The OM properties of the mutant strains and of the mutants complemented with the corresponding wild-type genes were analyzed, in comparison with the parental strain and roughB. abortusRB51, in several tests: (i) binding of anti-Omp25 and anti-Omp31 monoclonal antibodies, (ii) autoagglutination of bacterial suspensions, and (iii) assessment of susceptibility to polymyxin B, sodium deoxycholate, hydrogen peroxide, and nonimmune ram serum. A tight balance of the members of the Omp25/Omp31 family was seen to be essential for the stability of theB. ovisOM, and important differences between the OMs ofB. ovisPA andB. abortusRB51 rough strains were observed. Regarding virulence, the absence of Omp25d and Omp22 from the OM ofB. ovisPA led to a drastic reduction in spleen colonization in mice. While the greater susceptibility of the Δomp22mutant to nonimmune serum and its difficulty in surviving in the stationary phase might be on the basis of its dramatic attenuation, no defects in the OM able to explain the attenuation of the Δomp25dmutant were found, especially considering that the fully virulent Δomp25cmutant displayed more important OM defects. Accordingly, Omp25d, and perhaps Omp22, could be directly involved in the penetration and/or survival ofB. ovisinside host cells. This aspect, together with the role of Omp25d and Omp22 in the virulence both ofB. ovisin rams and of otherBrucellaspecies, should be thoroughly evaluated in future studies.
Increasing the Interaction of
Borrelia burgdorferi
with Decorin Significantly Reduces the 50 Percent Infectious Dose and Severely Impairs Dissemination
Authors: Xu Qilong , Seemanaplli Sunita V. , McShan Kristy , Liang Fang Ting 
Published: June 2007

ABSTRACT

Tight regulation of surface antigenic expression is crucial for the pathogenic strategy of the Lyme disease spirochete,
Borrelia burgdorferi
. Here, we report the influence of increasing expression of decorin-binding protein A (DbpA), one of the most investigated spirochetal surface adhesins, on the 50% infectious dose (ID
50
), dissemination, tissue colonization, pathogenicity, and persistence of
B. burgdorferi
in the murine host. Our in vitro assays showed that increasing DbpA expression dramatically increased the interaction of
B. burgdorferi
with decorin and sensitivity to growth inhibition/killing by anti-DbpA antibodies; however, this increased interaction did not affect spirochetal growth and replication in the presence of decorin. Increasing DbpA expression significantly reduced ID
50
values and severely impaired dissemination in severe combined immunodeficiency (SCID) and immunocompetent mice. During infection of SCID mice,
B. burgdorferi
with increased DbpA expression was able to effectively colonize heart and skin tissues, but not joint tissues, completely abrogating arthritis virulence. Although increasing DbpA expression did not affect spirochetal persistence in the skin, it diminished the ability of
B. burgdorferi
to persist in the heart and joint tissues during chronic infection of immunocompetent mice. Taken together, the study highlights the importance of controlling surface antigen expression in the infectivity, dissemination, tissue colonization, pathogenicity, and persistence of
B. burgdorferi
during mammalian infection.
Development and Application of an Oral Challenge Mouse Model for StudyingClostridium perfringensType D Infection
Authors: Fernandez-Miyakawa Mariano E. , Sayeed Sameera , Fisher Derek J. , Poon Rachael , Adams Vicki , Rood Julian I. , McClane Bruce A. , Saputo Julian , Uzal Francisco A. 
Published: June 2007

ABSTRACTClostridium perfringenstype D isolates cause enterotoxemia in sheep, goats, and probably cattle. While the major disease signs and lesions of type D animal disease are usually attributed to epsilon toxin, a class B select agent, these bacteria typically produce several lethal toxins. Understanding of disease pathogenesis and development of improved vaccines are hindered by the lack of a small-animal model mimicking natural disease caused by type D isolates. Addressing this need, we developed an oral challenge mouse model ofC. perfringenstype D enterotoxemia. When BALB/c mice with a sealed anus were inoculated by intragastric gavage with type D isolates, 7 of 10 type D isolates were lethal, as defined by spontaneous death or severe clinical signs necessitating euthanasia. The lethalities of the seven type D isolates varied between 14 and 100%. Clinical signs in the lethally challenged mice included seizures, convulsions, hyperexcitability, and/or depression. Mild intestinal gas distention and brain edema were observed at necropsy in a few mice, while histology showed multifocal acute tubular necrosis of the kidney and edema in the lungs of most challenged mice that developed a clinical response. When the lethality of type D isolates in this model was compared with in vitro toxin production, only a limited correlation was observed. However, mice could be protected against lethality by intravenous passive immunization with an epsilon toxin antibody prior to oral challenge. This study provides an economical new model for studying the pathogenesis ofC. perfringenstype D infections.
Borrelia gariniiInduces CXCL13 Production in Human Monocytes through Toll-Like Receptor 2
Authors: Rupprecht Tobias A. , Kirschning Carsten J. , Popp Bernadette , Kastenbauer Stefan , Fingerle Volker , Pfister Hans-Walter , Koedel Uwe 
Published: June 2007

ABSTRACTRecent studies have suggested an important role for the B-cell-attracting chemokine CXCL13 in the B-cell-dominated cerebrospinal fluid (CSF) infiltrate in patients with neuroborreliosis (NB). High levels of CXCL13 were present in the CSF of NB patients. It has not been clear, however, whether high CSF CXCL13 titers are specific for NB or are a characteristic of other spirochetal diseases as well. Furthermore, the mechanisms leading to the observed CXCL13 expression have not been identified yet. Here we describe similarly elevated CSF CXCL13 levels in patients with neurosyphilis, while pneumococcal meningitis patient CSF do not have high CXCL13 levels. In parallel, challenge of human monocytes in vitro with two of the spirochetal causative organisms,Borrelia garinii(theBorreliaspecies most frequently found in NB patients) andTreponema pallidum, but not challenge with pneumococci, induced CXCL13 release. This finding implies that a common spirochetal motif is a CXCL13 inducer. Accordingly, we found that the lipid moietyN-palmitoyl-S-(bis[palmitoyloxy]propyl)cystein (Pam3C) (three palmitoyl residues bound to N-terminal cysteine) of the spirochetal lipoproteins is critical for the CXCL13 induction in monocytes. As the Pam3C motif is known to signal via Toll-like receptor 2 (TLR2) and an anti-TLR2 monoclonal antibody blocked CXCL13 production of human monocytes incubated withB. garinii, this suggests that TLR2 is a major mediator ofBorrelia-induced secretion of CXCL13 from human monocytes.
Conserved Regions fromNeisseria gonorrhoeaePilin Are Immunosilent and Not Immunosuppressive
Authors: Hansen Johanna K. , Demick Karen P. , Mansfield John M. , Forest Katrina T. 
Published: June 2007

ABSTRACTPilE is the primary subunit of type IV pili fromNeisseria gonorrhoeaeand contains a surface-exposed hypervariable region thought to be one feature of pili that has prevented development of a pilin-based vaccine. We have created a three-dimensional structure-based antigen by replacing the hypervariable region of PilE with an aspartate-glutamine linker chosen from the sequence ofPseudomonas aeruginosaPilA. We then characterized murine immune responses to this novel protein to determine if conserved PilE regions could serve as a vaccine candidate. The control PilE protein elicited strong T-cell-dependent B-cell responses that are specific to epitopes in both the hypervariable deletion and control proteins. In contrast, the hypervariable deletion protein was unable to elicit an immune response in mice, suggesting that in the absence of the hypervariable region, the conserved regions of PilE alone are not sufficient for antibody production. Further analysis of these PilE proteins with suppressor cell assays showed that neither suppresses T- or B-cell responses, and flow cytometry experiments suggested that they do not exert suppressor effects by activating T regulatory cells. Our results show that in the murine model, the hypervariable region of PilE is required to activate immune responses to pilin, whereas the conserved regions are unusually nonimmunogenic. In addition, we show that both hypervariable and conserved regions of pilin are not suppressive, suggesting that PilE does not cause the decrease in T-cell populations observed during gonococcal cervicitis.
Severe spinal injuries in alpine skiing and snowboarding: a 6-year review of a tertiary trauma centre for the Bernese Alps ski resorts, Switzerland
Authors: Franz T , Hasler R M , Benneker L , Zimmermann H , Siebenrock K A , Exadaktylos A K 
Published: June 2007

Objective:To analyse the epidemiological data, injury pattern, clinical features and mechanisms of severe spinal injuries related to alpine skiing and snowboarding.Study design:A six-year review of all adult patients with severe spinal injuries sustained from alpine skiing or snowboarding.Setting:Tertiary trauma centre in Bern, Switzerland.Patients and methods:All adult patients (over 16 years of age) admitted to a tertiary trauma centre from 1 July 2000, through 30 June 2006, were reviewed using a computerised database. From these records, a total of 728 patients injured from snow sports were identified. Severe spinal injuries (defined as spinal fractures, subluxations, dislocations or concomitant spinal cord injuries) were found in 73 patients (17 female, 56 male). The clinical features of these patients were reviewed with respect to epidemiological factors, mechanism of injury, fracture pattern, and neurological status.Results:The majority of severe spinal injuries (n = 63) were related to skiing. Fatal central-nervous injuries and transient or persistent neurological symptoms occurred in 28 patients (23 skiers, 5 snowboarders). None of the snowboarders suffered from persistent neurological sequelae. Snowboarders with severe spinal injuries (n = 10) were all male (p<0.05), and were significantly younger than skiers (p<0.001). The most commonly affected site was the lumbar spine. However, 39 patients (53.4%) suffered from injury pattern at two or more levels.Conclusions:With advances in technology and slope maintenance, skiers and snowboarders progress to higher skill levels and faster speeds more rapidly than ever before. Great efforts have been focused on reducing extremity injuries in snow sports, but until recently very little attention has been given to spinal injury prevention on the slopes. Suggestions for injury prevention include the use of spine protectors, participation on appropriate runs for ability level, proper fit and adjustment of equipment, and taking lessons with the goal of increasing ability and learning hill etiquette.
Out of the smokescreen II: will an advertisement targeting the tobacco industry affect young people’s perception of smoking in movies and their intention to smoke?
Authors: Edwards Christine , Oakes Wendy , Bull Diane 
Published: June 2007

Objective:To evaluate the effect of an antismoking advertisement on young people’s perceptions of smoking in movies and their intention to smoke.Subjects/setting:3091 cinema patrons aged 12–24 years in three Australian states; 18.6% of the sample (n = 575) were current smokers.Design/intervention:Quasi-experimental study of patrons, surveyed after having viewed a movie. The control group was surveyed in week 1, and the intervention group in weeks 2 and 3. Before seeing the movie in weeks 2 and 3, a 30 s antismoking advertisement was shown, shot in the style of a movie trailer that warned patrons not to be sucked in by the smoking in the movie they were about to see.Outcomes:Attitude of current smokers and non-smokers to smoking in the movies; intention of current smokers and non-smokers to smoke in 12 months.Results:Among non-smokers, 47.8% of the intervention subjects thought that the smoking in the viewed movie was not OK compared with 43.8% of the control subjects (p = 0.04). However, there was no significant difference among smokers in the intervention (16.5%) and control (14.5%) groups (p = 0.4). A higher percentage of smokers in the intervention group indicated that they were likely to be smoking in 12 months time (38.6%) than smokers in the control group (25.6%; p<0.001). For non-smokers, there was no significant difference in smoking intentions between groups, with 1.2% of intervention subjects and 1.6% of controls saying that they would probably be smoking in 12 months time (p = 0.54).Conclusions:This real-world study suggests that placing an antismoking advertisement before movies containing smoking scenes can help to immunise non-smokers against the influences of film stars’ smoking. Caution must be exercised in the type of advertisement screened as some types of advertising may reinforce smokers’ intentions to smoke.