bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of Rho/Rho‐associated coiled coil‐forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase‐dependent manner
Authors: Xue Feng , Takahara Terumi , Yata Yutaka , Xia Qiang , Nonome Kazunobu , Shinno Eiji , Kanayama Masami , Takahara Shiro , Sugiyama Toshiro 
Published: May 2008

Aim:  There is growing evidence that the Rho/Rho‐associated coiled coil‐forming kinase (ROCK) signaling pathway is upregulated in tumors and plays a key role in cancer invasion and metastasis. Our aim was to test the anticancer effects of Rho/ROCK inhibitor, Y‐27632, including possible mechanisms in a highly‐metastasizing hepatocellular carcinoma (HCC) mouse model on its secretion of matrix metalloproteinase (MMP) and tumor progression.Methods:  Following orthotopic implantation of CBO140C12 HCC tumor fragments into the liver of mice, the mice were randomly assigned to a Y‐27632‐treated group or control group. After treatment for 4 weeks, specimens were obtained to evaluate tumor size, metastases, and immunohistochemical findings. In vitro, we examined the effects of Y‐27632 and RhoC siRNA on MMP‐2 and ‐9 expressions, invasiveness, and apoptosis in cultured tumor cells.Results:  Both RhoA and RhoC were upregulated in HCC‐bearing livers, and Y‐27632 significantly inhibited not only tumor growth and intrahepatic metastasis (P < 0.05), but also tumoral MMP‐9 expression. Moreover, Y‐27632 treatment resulted in large necrotic areas in tumors. In vitro, Y‐27632 and RhoC siRNA reduced MMP‐2 and ‐9 expressions, as well as the chemotactic migration of tumor cells dose‐dependently, and increased apoptosis eight times.Conclusion:  Y‐27632 suppresses progression and limits the intrahepatic metastasis of established HCC. This could be linked to the decreased MMP expression and induction of apoptosis in tumor cells. Rho signaling may prove to be a productive target in anticancer therapy.
Abstinence in patients with alcoholic liver cirrhosis: A follow‐up study
Authors: Kalaitzakis Evangelos , Wallskog Jesper , Björnsson Einar 
Published: May 2008

Aim:  To investigate the proportion of patients with alcoholic cirrhosis who abstained from alcohol after contact with a hepatology unit, the predictors for abstinence, and the role of clinical and psychosocial factors in short‐term mortality in these patients.Methods:  Eighty‐seven consecutive patients with alcoholic cirrhosis from a transplant center were included. Data on cirrhosis severity and complications, as well as on abstinence and psychosocial factors were collected. Patients were followed up for 19 (12–25) months. Data on abstinence during follow up, alcohol abuse treatment, psychiatric contact, severity of cirrhosis, mortality, and liver transplantation were analyzed.Results:  Prior to inclusion, 53/87 (61%) patients had abstained from alcohol for 24 months (interquartile range: 18–33). Twenty percent had a history of other substance abuse, 47% had undergone alcohol abuse treatment, and 21% had a previous psychiatric diagnosis. Forty‐eight percent lived with a partner, 23% worked/studied, and 53% were pensioners. During follow up, 26% died, 20% received a liver transplant, 55% abstained from alcohol, 47% received alcohol abuse treatment, and 33% had psychiatric contact. In a multivariate analysis, abstinence during follow up was found to be related to abstinence upon inclusion in the study, to the model for end‐stage liver disease (MELD) score at follow up, and to no abuse treatment in a detoxification unit, whereas mortality was related to index MELD and alcohol abuse treatment during follow up. Neither abstinence nor mortality was related to psychosocial factors.Conclusion:  More than half of patients with alcoholic cirrhosis were found to abstain from alcohol during follow up, which was related to prior documentation of abstinence and cirrhosis severity. Cirrhosis severity (expressed as the MELD) and alcohol abuse treatment during follow up were related to short‐term mortality.
Characterization of the Carbapenem-Hydrolyzing Oxacillinase Oxa-58 in an
Acinetobacter
Genospecies 3 Clinical Isolate
Authors: Marti Sara , Sánchez-Céspedes Javier , Blasco M. Dolores , Ruiz Marc , Espinal Paula , Alba Verónica , Fernández-Cuenca Felipe , Pascual Alvaro , Vila Jordi 
Published: May 2008

ABSTRACT

Based on imipenem resistance in an
Acinetobacter
genospecies 3 clinical isolate, we were able to identify, for the first time in this genomic species, a plasmid-encoded
bla
OXA-58
gene that was 100% homologous to the same gene in
Acinetobacter baumannii
.
Alteration of GyrA Amino Acid Required for Ciprofloxacin Resistance in
Klebsiella pneumoniae
Isolates in China
Authors: Fu Yingmei , Guo Lishuang , Xu Yan , Zhang Wenli , Gu Jiaao , Xu Jianfeng , Chen Xiaobei , Zhao Yuehui , Ma Jiayu , Liu Xinghan , Zhang Fengmin 
Published: May 2008

ABSTRACT

Resistance to ciprofloxacin was detected in 111 (48.1%) isolates of
Klebsiella pneumoniae
from China. GyrA alterations were identified in the ciprofloxacin-resistant and ciprofloxacin-susceptible isolates. The results, including previously published data, indicate that the single substitution Ser83→Ile and three types of double mutations at Ser83 and Asp87 were required for ciprofloxacin resistance (
P
< 0.05).
Comparative Study of the Susceptibilities of Major Epidemic Clones of Methicillin-Resistant
Staphylococcus aureus
to Oxacillin and to the New Broad-Spectrum Cephalosporin Ceftobiprole
Authors: Chung Marilyn , Antignac Aude , Kim Choonkeun , Tomasz Alexander 
Published: May 2008

ABSTRACT

Multidrug-resistant strains of
Staphylococcus aureus
continue to increase in frequency worldwide, both in hospitals and in the community, raising serious problems for the chemotherapy of staphylococcal disease. Ceftobiprole (BPR; BAL9141), the active constituent of the prodrug ceftobiprole medocaril (BAL5788), is a new cephalosporin which was already shown to have powerful activity against a number of bacterial pathogens, including
S. aureus
. In an effort to test possible limits to the antibacterial spectrum and efficacy of BPR, we examined the susceptibilities of the relatively few pandemic methicillin-resistant
S. aureus
(MRSA) clones that are responsible for the great majority of cases of staphylococcal disease worldwide. We also included in the tests the highly oxacillin-resistant subpopulations that are present with low frequencies in the cultures of these clones. Such subpopulations may represent a natural reservoir from which MRSA strains with decreased susceptibility to BPR may emerge in the future. We also tested the efficacy of BPR against MRSA strains with reduced susceptibility to vancomycin and against MRSA strains carrying the enterococcal vancomycin resistance gene complex. BPR was shown to be uniformly effective against all these resistant MRSA strains, and the mechanism of superb antimicrobial activity correlated with the strikingly increased affinity of the cephalosporin against penicillin-binding protein 2A, the protein product of the antibiotic resistance determinant
mecA
.
Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis
Authors: Rustomjee R. , Diacon A. H. , Allen J. , Venter A. , Reddy C. , Patientia R. F. , Mthiyane T. C. P. , De Marez T. , van Heeswijk R. , Kerstens R. , Koul A. , De Beule K. , Donald P. R. , McNeeley D. F. 
Published: May 2008

ABSTRACT

Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log
10
decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log
10
CFU counts (± standard deviation) from baseline to day 7 were 0.04 ± 0.46 for 25 mg TMC207 (
n
= 14), 0.26 ± 0.64 for 100 mg TMC207 (
n
= 14), 0.77 ± 0.58 for 400 mg TMC207 (
n
= 14), 1.88 ± 0.74 for INH (
n
= 11), and 1.70 ± 0.71 for RIF (
n
= 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.
Role of Cj1211 in Natural Transformation and Transfer of Antibiotic Resistance Determinants inCampylobacter jejuni
Authors: Jeon Byeonghwa , Muraoka Wayne , Sahin Orhan , Zhang Qijing 
Published: May 2008

ABSTRACTCampylobacter jejuni, an important food-borne human pathogen, is increasingly resistant to antimicrobials. Natural transformation is considered to be a main mechanism for mediating the transfer of genetic materials encoding antibiotic resistance determinants inC. jejuni, but direct evidence for this notion is still lacking. In this study, we determined the role of Cj1211 in natural transformation and in the development of antibiotic resistance inC. jejuni. Insertional mutagenesis of Cj1211, aHelicobacter pyloriComH3 homolog, abolished natural transformation inC. jejuni. In vitro coculture ofC. jejunistrains carrying either kanamycin or tetracycline resistance markers demonstrated the development of progenies that were resistant to both antibiotics, indicating that the horizontal transfer of antibiotic resistance determinants actively occurs in mixedCampylobacterpopulations. A mutation of Cj1211 or the addition of DNase I in culture media completely inhibited the formation of progenies that were resistant to both antibiotics, indicating that the horizontal transfer of the resistance determinants is mediated by natural transformation. Interestingly, the mutation of Cj1211 also reduced the frequency of emergence of spontaneous mutants that were resistant to fluoroquinolone (FQ) and streptomycin but did not affect the outcome of FQ resistance development under FQ treatment, suggesting that natural transformation does not play a major role in the emergence of FQ-resistantCampylobacterstrains during treatment with FQ antimicrobials. These results define Cj1211 as a competence factor inCampylobacter, prove the role of natural transformation in the horizontal transfer of antibiotic resistance determinants inCampylobacter, and provide new insights into the mechanism underlying the development of FQ-resistantCampylobacterstrains.
Inhibition of Cell-to-Cell Transmission of Human T-Cell Lymphotropic Virus Type 1 In Vitro by Carbohydrate-Binding Agents
Authors: Balestrieri Emanuela , Ascolani Arianna , Igarashi Yasuhiro , Oki Toshikazu , Mastino Antonio , Balzarini Jan , Macchi Beatrice 
Published: May 2008

ABSTRACT

Peripheral blood mononuclear cells (PBMCs) from healthy individuals can be infected by human T-lymphotropic virus type 1 (HTLV-1) upon cocultivation of the PBMCs with irradiated HTLV-1-transformed human MT-2 cells. This model system closely mimics HTLV-1 transmission through cell-to-cell contact. Carbohydrate-binding agents (CBAs) such as the α(1,3)/α(1,6)mannose-specific
Hippeastrum hybrid
agglutinin and the GlcNAc-specific
Urtica dioica
agglutinin, and also the small, nonpeptidic α(1,2)-mannose-specific antibiotic pradimicin A, were able to efficiently prevent cell-to-cell HTLV-1 transmission at nontoxic concentrations, as evidenced by the lack of appearance of virus-specific mRNA and of the viral protein Tax in the acceptor cells. Consistently, antivirally active doses of CBAs fully prevented HTLV-1-induced stimulation of PBMC growth. The inhibitory effects of CBAs on HTLV-1 transmission were also evident when HTLV-1-infected C5MJ cells were used in place of MT-2 cells as a virus donor cell line. The anti-HTLV-1 properties of the CBAs highlight the importance of the envelope glycans in events underlying HTLV-1 passage from cell to cell and indicate that CBAs should be further investigated for their potential to prevent HTLV-1 infection, including mother-to-child virus transmission by cell-to-cell contact through breast milk feeding.
Hookworm-Induced Persistent Changes to the Immunological Environment of the Lung
Authors: Reece Joshua J. , Siracusa Mark C. , Southard Teresa L. , Brayton Cory F. , Urban Joseph F. , Scott Alan L. 
Published: May 2008

ABSTRACTA number of important helminth parasites of humans have incorporated short-term residence in the lungs as an obligate phase of their life cycles. The significance of this transient pulmonary exposure to the infection and immunity is not clear. Employing a rodent model of infection with hookworm (Nippostrongylus brasiliensis), we characterized the long-term changes in the immunological status of the lungs induced by parasite infection. At 36 days after infection, alterations included a sustained increase in the transcription of both Th2 and Th1 cytokines as well as a significant increase in the number and frequency of alveolar macrophages displaying an alternatively activated phenotype. WhileN. brasiliensisdid not induce alternate activation of lung macrophages in STAT6−/−animals, the parasite did induce a robust Th17 response in the pulmonary environment, suggesting that STAT6 signaling plays a role in modulating Th17 immunity and pathology in the lungs. In the context of the cellular and molecular changes induced byN. brasiliensisinfection, there was a significant reduction in overall airway responsiveness and lung inflammation in response to allergen. In addition, theN. brasiliensis-altered pulmonary environment showed dramatic alterations in the nature and number of genes that were up- and downregulated in the lung in response to allergen challenge. The results demonstrate that even a transient exposure to a helminth parasite can effect significant and protracted changes in the immunological environment of the lung and that these complex molecular and cellular changes are likely to play a role in modulating a subsequent allergen-induced inflammatory response.
Native Outer Membrane Proteins Protect Mice against Pulmonary Challenge with Virulent Type AFrancisella tularensis
Authors: Huntley Jason F. , Conley Patrick G. , Rasko David A. , Hagman Kayla E. , Apicella Michael A. , Norgard Michael V. 
Published: May 2008

ABSTRACTFrancisella tularensisis a gram-negative intracellular bacterium and the causative agent of the zoonotic disease tularemia.F. tularensisis a category A select agent and thus a potential agent of bioterrorism. Whereas anF. tularensislive, attenuated vaccine strain (LVS) is the basis of an investigational vaccine, this vaccine is not licensed for human use because of efficacy and safety concerns. In the present study, we immunized mice with isolated native outer membrane proteins (OMPs), ethanol-inactivated LVS (iLVS), or purified LVS lipopolysaccharide (LPS) and assessed the ability of each vaccine preparation to protect mice against pulmonary challenge with the virulent type AF. tularensisstrain SchuS4. Antibody isotyping indicated that both Th1 and Th2 antibody responses were generated in mice after immunization with OMPs or iLVS, whereas LPS immunization resulted in only immunoglobulin A production. In survival studies, OMP immunization provided the greatest level of protection (50% survival at 20 days after infection with SchuS4), and there were associated 3-log reductions in the spleen and liver bacterial burdens (compared to nonvaccinated mice). Cytokine quantitation for the sera of SchuS4-challenged mice indicated that OMP and iLVS immunizations induced high levels of tumor necrosis factor alpha and interleukin-2 (IL-2) production, whereas only OMP immunization induced high levels of IL-10 production. By comparison, high levels of proinflammatory cytokines, including RANTES, granulocyte colony-stimulating factor, IL-6, IL-1α, IL-12p40, and KC, in nonvaccinated mice indicated that these cytokines may facilitate disease progression. Taken together, the results of this study demonstrate the potential utility of an OMP subunit (acellular) vaccine for protecting mammals against type AF. tularensis.
Distinct Isoforms of Phospholipase A2Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils
Authors: Mumy Karen L. , Bien Jeffrey D. , Pazos Michael A. , Gronert Karsten , Hurley Bryan P. , McCormick Beth A. 
Published: May 2008

ABSTRACTSalmonellaspp. andShigellaspp. are responsible for millions of cases of enteric disease each year worldwide. While these pathogens have evolved distinct strategies for interacting with the human intestinal epithelium, they both induce significant proinflammatory responses that result in massive transepithelial migration of neutrophils across the intestinal mucosa. It has previously been shown withSalmonella entericaserotype Typhimurium that the process of neutrophil transmigration is mediated in part by the secretion of hepoxilin A3(HXA3; 8-hydroxy-11,12-epoxy-eicosatetraenoic acid), a potent neutrophil chemoattractant, from the apical surface of infected model intestinal epithelium. This study confirms that HXA3is also secreted in response to infection byShigella flexneri, that it is produced by a pathway involving 12/15-lipoxygenase (12/15-LOX), and thatS. entericaserovar Typhimurium andS. flexnerishare certain elements in the mechanism(s) that underlies the otherwise separate signal transduction pathways that are engaged to induce polymorphonuclear leukocyte (PMN) transepithelial migration (protein kinase C and extracellular signal-regulated kinases 1 and 2, respectively). PMN transepithelial migration in response to infection withS. flexneriwas dependent on 12/15-LOX activity, the enzyme responsible for the initial metabolism of arachidonic acid to HXA3. Probing further into this pathway, we also found thatS. entericaserovar Typhimurium andS. flexneriactivate different subtypes of phospholipase A2, a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. Thus, althoughS. entericaserovar Typhimurium andS. flexneriutilize different mechanisms for triggering the induction of PMN transepithelial migration, we found that their reliance on 12/15-LOX is conserved, suggesting that enteric pathogens may ultimately stimulate similar pathways for the synthesis and release of HXA3.
The prevalence and effects of adult attention-deficit/hyperactivity disorder (ADHD) on the performance of workers: results from the WHO World Mental Health Survey Initiative
Authors: de Graaf R , Kessler R C , Fayyad J , ten Have M , Alonso J , Angermeyer M , Borges G , Demyttenaere K , Gasquet I , de Girolamo G , Haro J M , Jin R , Karam E G , Ormel J , Posada-Villa J 
Published: May 2008

Objectives:To estimate the prevalence and workplace consequences of adult attention-deficit/hyperactivity disorder (ADHD).Methods:An ADHD screen was administered to 18–44-year-old respondents in 10 national surveys in the WHO World Mental Health (WMH) Survey Initiative (n = 7075 in paid or self-employment; response rate 45.9–87.7% across countries). Blinded clinical reappraisal interviews were administered in the USA to calibrate the screen. Days out of role were measured using the WHO Disability Assessment Schedule (WHO-DAS). Questions were also asked about ADHD treatment.Results:An average of 3.5% of workers in the 10 countries were estimated to meet DSM-IV criteria for adult ADHD (inter-quartile range: 1.3–4.9%). ADHD was more common among males than females and less common among professionals than other workers. ADHD was associated with a statistically significant 22.1 annual days of excess lost role performance compared to otherwise similar respondents without ADHD. No difference in the magnitude of this effect was found by occupation, education, age, gender or partner status. This effect was most pronounced in Colombia, Italy, Lebanon and the USA. Although only a small minority of workers with ADHD ever received treatment for this condition, higher proportions were treated for comorbid mental/substance disorders.Conclusions:ADHD is a relatively common condition among working people in the countries studied and is associated with high work impairment in these countries. This impairment, in conjunction with the low treatment rate and the availability of cost-effective therapies, suggests that ADHD would be a good candidate for targeted workplace screening and treatment programs.
Chemoprevention and screening in primary sclerosing cholangitis
Authors: Kitiyakara T , Chapman R W 
Published: May 2008

Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that causes fibrosis of the biliary tree. Life expectancy of patients is reduced by liver failure and a high incidence of malignancy. It is closely associated with inflammatory bowel disease, particularly ulcerative colitis, which coexists in approximately three-quarters of northern European patients. Cancers include cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, pancreatic cancer and colorectal cancer. Ursodeoxycholic acid appears to reduce the incidence of colorectal neoplasia in patients with PSC, and there is some suggestion that it may also reduce the incidence of cholangiocarcinoma. A chemoprotective benefit of 5-aminosalicylates has not been confirmed in patients with PSC with associated inflammatory bowel disease. There is no accepted screening programme for cholangiocarcinoma, but methods for detecting early disease using biochemical markers, scanning using positron emission tomography or MRI, and endoscopic procedures such as endosonography and endoscopic retrograde cholangiopancreatography are discussed. A combination of techniques is often used in an attempt to diagnose early cholangiocarcinoma. Cholecystectomy should be performed for gallbladder polyps, as many are malignant, and ultrasonography and α-fetoprotein testing are suggested for screening for hepatocellular carcinoma. Colorectal carcinoma screening should be performed after the diagnosis of PSC, and surveillance colonoscopy should be performed annually if there is concomitant colitis.
Stroke in pregnancy and the puerperium
Authors: Treadwell S D , Thanvi B , Robinson T G 
Published: May 2008

Abstract
Stroke is a recognised complication of pregnancy, contributing to more than 12% of all maternal deaths. Estimated incidence rates vary considerably from 4.3 to 210 strokes per 100 000 deliveries. Atherosclerosis is rare in young adults, and so other causes of stroke become increasingly likely. Aetiological factors important in pregnancy include hypercoagulability due to maternal physiological changes, pre-eclampsia and eclampsia, cerebral venous thrombosis, paradoxical embolism, postpartum cerebral angiopathy and peripartum cardiomyopathy. Management of patients with pregnancy-related stroke should generally proceed as for non-pregnant patients, although there are a number of important areas specific to pregnancy which will be considered here.