bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells
Authors: Muzaffar Saima , Shukla Nilima , Srivastava Amit , Angelini Gianni D , Jeremy Jamie Y 
Published: June 2005

Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O2•−) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO). Since NO inhibits NADPH oxidase expression through a cyclic GMP‐mediated mechanism, sildenafil, a type V phosphodiesterase inhibitor, may be therapeutically effective in ARDS through an augmentation of NO‐mediated inhibition of NADPH oxidase. Therefore, the effect of sildenafil citrate and NO‐donating sildenafil (NCX 911) on O2•− formation and gp91phox (active catalytic subunit of NADPH oxidase) expression was investigated in cultured porcine pulmonary artery endothelial cells (PAECs).
PAECs were incubated with 10 nM TXA2 analogue, 9,11‐dideoxy‐9α,11α‐methanoepoxy‐prostaglandin F2α (U46619) (±sildenafil or NCX 911), for 16 h and O2•− formation measured spectrophometrically and gp91phox using Western blotting. The role of the NO‐cGMP axis was studied using morpholinosydnonimine hydrochloride (SIN‐1), the diethylamine/NO complex (DETA‐NONOate), the guanylyl cyclase inhibitor, 1H‐{1,2,4}oxadiazolo{4,3‐a}quinoxalin‐1‐one (ODQ), and the protein kinase G inhibitor, 8‐bromoguanosine‐3′,5′‐cyclic monophosphorothioate, Rp‐isomer (Rp‐8‐Br‐cGMPS). NO release was studied using a fluorescence assay and O2•−–NO interactions by measuring nitrites.
After a 16‐h incubation with 10 nM U46619, both NCX 911 and sildenafil elicited a concentration‐dependent inhibition of O2•− formation and gp91phox expression, NCX 911 being more potent (IC50; 0.26 nM) than sildenafil citrate (IC50; 1.85 nM). These inhibitory effects were reversed by 1 μM ODQ and 10 μM Rp‐8‐Br‐cGMPS. NCX 911 stimulated the formation of cGMP in PAECs and generated NO in a cell‐free system to a greater degree than sildenafil citrate. The inhibitory effect of sildenafil was augmented by 1 μM SIN‐1 and blocked partially by the eNOS inhibitor 10 μM N5‐(1‐iminoethyl)‐ornithine (L‐NIO). Acutely, sildenafil and NCX 911 also inhibited O2•− formation, again blocked by 1 μM ODQ. NCX 911 reacted with O2•− generated by xanthine oxidase, an effect that was inhibited by superoxide dismutase (500 U ml−1).
Since O2•− formation plays contributory role in ARDS, both sildenafil citrate and NCX 911 may be indicated for treating ARDS through suppression of NADPH oxidase expression and therefore of O2•− formation and preservation of NO bioavailability.

British Journal of Pharmacology (2005) 146, 109–117. doi:10.1038/sj.bjp.0706305
Evaluation of benzyltetrahydroisoquinolines as ligands for neuronal nicotinic acetylcholine receptors
Authors: Exley Richard , Iturriaga‐Vásquez Patricio , Lukas Ronald J , Sher Emanuele , Cassels Bruce K , Bermudez Isabel 
Published: June 2005

Effects of derivatives of coclaurine (C), which mimic the ‘eastern’ or the nonquaternary halves of the alkaloids tetrandrine or d‐tubocurarine, respectively, both of which are inhibitors of nicotinic acetylcholine receptors (nACh), were examined on recombinant, human α7, α4β2 and α4β4 nACh receptors expressed in Xenopus oocytes and clonal cell lines using two‐electrode voltage clamping and radioligand binding techniques.
In this limited series, Cs have higher affinity and are most potent at α4 subunit‐containing‐nACh receptors and least potent at homomeric α7 receptors, and this trend is very marked for the N‐unsubstituted C and its O,O′‐bisbenzyl derivative.
7‐O‐Benzyl‐N‐methylcoclaurine (BBCM) and its 12‐O‐methyl derivative showed the highest affinities and potencies at all three receptor subtypes, and this suggests that lipophilicity at C7 and/or C12 increases potency.
Laudanosine and armepavine (A) were noncompetitive and voltage‐dependent inhibitors of α7, α4β2 or α4β4 receptors, but the bulkier C7‐benzylated 7BNMC (7‐O‐benzyl‐N‐methylcoclaurine) and 7B12MNMC (7‐O‐benzyl‐N,12‐O‐dimethyl coclaurine) were voltage‐independent, noncompetitive inhibitors of nACh receptors. Voltage‐dependence was also lost on going from A to its N‐ethyl analogue.
These studies suggest that C derivatives may be useful tools for studies characterising the antagonist and ion channel sites on human α7, α4β2 or α4β4 nACh receptors and for revealing structure–function relationships for nACh receptor antagonists.

British Journal of Pharmacology (2005) 146, 15–24. doi:10.1038/sj.bjp.0706307
Prospective gene expression analysis accurately subtypes acute leukaemia in children and establishes a commonality between hyperdiploidy and t(12;21) in acute lymphoblastic leukaemia
Authors: van Delft Frederik W. , Bellotti Tony , Luo Zhiyuan , Jones Louise K. , Patel Naina , Yiannikouris Olga , Hill Alex S. , Hubank Mike , Kempski Helena , Fletcher Danielle , Chaplin Tracy , Foot Nicola , Young Bryan D. , Hann Ian M. , Gammerman Alex , Saha Vaskar 
Published: June 2005

SummaryWe have prospectively analysed and correlated the gene expression profiles of children presenting with acute leukaemia to the Royal London and Great Ormond Street Hospitals with morphological diagnosis, immunophenotype and karyotype. Total RNA extracted from freshly sorted blast cells was obtained from 84 lymphoblastic [acute lymphoblastic leukaemia (ALL)], 20 myeloid [acute myeloid leukaemia (AML)] and three unclassified acute leukaemias and hybridised to the high density Affymetrix U133A oligonucleotide array. Analysis of variance and significance analysis of microarrays was used to identify discriminatory genes. A novel 50‐gene set accurately identified all patients with ALL and AML and predicted for a diagnosis of AML in three patients with unclassified acute leukaemia. A unique gene set was derived for each of eight subtypes of acute leukaemia within our data set. A common profile for children with ALL with an ETV6–RUNX1 fusion, amplification or deletion of ETV6, amplification of RUNX1 or hyperdiploidy with an additional chromosome 21 was identified. This suggests that these rearrangements share a commonality in biological pathways that maintains the leukaemic state. The gene TERF2 was most highly expressed in this group of patients. Our analyses demonstrate that not only is microarray analysis the single most effective tool for the diagnosis of acute leukaemias of childhood but it has the ability to identify unique biological pathways. To further evaluate its prognostic value it needs to be incorporated into the routine diagnostic analysis for large‐scale clinical trials in childhood acute leukaemias.
FLT3 inhibition in t(4;11)+ adult acute lymphoid leukaemia
Authors: Torelli Giovanni F. , Guarini Anna , Porzia Alessandra , Chiaretti Sabina , Tatarelli Caterina , Diverio Daniela , Maggio Roberta , Vitale Antonella , Ritz Jerome , Foa Robin 
Published: June 2005

SummaryThe present study was designed to investigate, in t(4;11)+ adult lymphoid leukaemia (ALL) blast cells, the pathogenetic role of the FLT3 protein, its level of mRNA and protein expression, the degree of constitutive phosphorylation, the possible presence of mutations of the sequence, the capacity of signal transduction and the potential therapeutic role of specific inhibitors. We evaluated nine adult ALL patients carrying this translocation. The increasedFLT3mRNA levels, determined by oligonucleotide microarray analysis, was in agreement with the increased protein expression evaluated by Western blot. The protein was constitutively phosphorylated in all cases analysed. Polymerase chain reaction detected no internal tandem duplication or point mutations. The signal transduction apparatus, after stimulation with the specific ligand, was preserved. We then investigated the effect of specific FLT3 inhibition on signal transduction and survival. The PKC412 inhibitor specifically inhibited ligand‐induced phosphorylation; the same inhibitor reduced the survival of leukaemic cells when compared with untreated cells. These data indicate that the FLT3 protein might play a role in this subgroup of ALL with a particularly poor prognosis. Specific inhibition of the kinase receptor must be hypothesised as an innovative therapeutic tool for t(4;11)+ ALL patients.
Severe and prolonged myeloid haematopoietic toxicity with myelodysplastic features following alemtuzumab therapy in patients with peripheral T‐cell lymphoproliferative disorders
Authors: Gibbs Simon D. J. , Westerman David A. , McCormack Christopher , Seymour John F. , Miles Prince H. 
Published: June 2005

SummaryAlemtuzumab is effective therapy for B‐ and T‐cell lymphoproliferative disorders (LPD) but is associated with prolonged lymphopenia. Myeloid haematological toxicities are less well described, especially in T‐cell disorders, and are usually transient. We report myeloid toxicities in a phase II trial of alemtuzumab for T‐cell LPD. Five of 11 patients treated developed severe neutropenia and thrombocytopenia. Three cases had prolonged cytopenias (32–88+ weeks), including two with severe marrow hypoplasia. We observed three incidences of trilineage morphological myelodysplasia, two with new clonal cytogenetic abnormalities. Alemtuzumab can be associated with prolonged severe multilineage cytopenias, marrow hypoplasia and myelodysplasia in T‐cell LPD.
Outcome after first relapse in childhood acute lymphoblastic leukaemia – lessons from the United Kingdom R2 trial
Authors: Roy Anindita , Cargill Anna , Love S. , Moorman Anthony V. , Stoneham Sara , Lim Anita , Darbyshire Phil J. , Lancaster Donna , Hann Ian , Eden Tim , Saha Vaskar 
Published: June 2005

SummaryA retrospective analysis of children with first relapse of acute lymphoblastic leukaemia (ALL), treated on the UKALL R2 protocol at four different hospitals, between June 1995 and December 2002 was performed. Of the 150 children 139 (93%) achieved a second complete remission. The overall survival (OS) and event‐free survival (EFS) for the whole group was 56% and 47% respectively. The duration of first complete remission and immunophenotype, but not sites of relapse, were predictive for survival. Using the Berlin–Frankfürt–Münster risk stratification for relapsed ALL, the OS and EFS for standard, intermediate (IR) and high risk (HR) groups were 92% and 92%, 64% and 51%, and 14% and 15%, respectively; P < 0·0001 for both OS and EFS. In the IR group, those with a very early isolated central nervous system relapse also had a significantly worse outcome (P = 0·0001). Given the poor outcome of a second relapse, clear strategies are required to identify those in the IR group who will most benefit from stem cell transplantation (SCT). A higher proportion (16%) of induction failures in the HR group suggest the need for novel agents during this phase of treatment, but SCT was associated with a lower relapse rate and better outcome than those treated with chemotherapy alone.
Engraftment of NOD/SCID/γcnull mice with multilineage neoplastic cells from patients with juvenile myelomonocytic leukaemia
Authors: Nakamura Yoichi , Ito Masafumi , Yamamoto Tomoko , Yan Xu Y. , Yagasaki Hiroshi , Kamachi Yoshiro , Kudo Kazuko , Kojima Seiji 
Published: June 2005

SummarySeveral lines of evidence indicate the clonal nature of juvenile myelomonocytic leukaemia (JMML), involving myeloid, erythroid, megakaryocyte and B‐lymphoid lineages. However, it is unclear whether the T‐lymphocyte lineage is involved. We demonstrated that cells from six patients with JMML repopulated in non‐obese diabetic/severe combined immunodeficient/γcnull mice and differentiated into granulocytes, monocytes, erythrocytes, B lymphocytes, T lymphocytes and natural killer cells. The percentage of human CD45 antigen‐positive cells ranged from 41% to 73% in the murine bone marrow 12 weeks after transplantation. To examine the involvement of lymphocyte subpopulations, we purified human CD3+, CD19+ and CD56+ cells from murine bone marrow cells transplanted from a patient with monosomy 7. Fluorescence in situ hybridization (FISH) showed the clonal marker in 96–100% of purified CD3+, CD19+ and CD56+ subpopulations. These findings support the concept that JMML originates in transplantable multilineage haematopoietic stem cells. This novel murine xenotransplant model should be useful for investigating the nature of stem cells and testing new therapies for patients with JMML.
Large B‐cell lymphoma with Hodgkin's features
Authors: García J F , Mollejo M , Fraga M , Forteza J , Muniesa J A , Pérez‐Guillermo M , Pérez‐Seoane C , Rivera T , Ortega P , Piris M A 
Published: June 2005

Aims : To describe the features of a series of nine cases of diffuse large B‐cell lymphoma (DLBCL) showing morphological and immunophenotypic features that are intermediate with Hodgkin's lymphoma (HL).Methods and results : Most cases (6/9) presented as mediastinal tumours affecting young males, while the other three cases arose in extramediastinal locations. Histopathologically, tumours showed diffuse large cell areas in a polymorphous background, with pleomorphic cytology and the common presence of Hodgkin's and Reed–Sternberg cells. Immunophenotypically, tumours shared features of DLBCL and classical HL, with expression of CD30, CD15 (6/9), and a full B‐cell profile including CD45RB, CD20, CD79a and OCT2. Epstein–Barr virus–latent membrane protein expression was found in 2/9 cases. The majority of tumours had immunohistochemical features consistent with activation of the NF‐κB pathway, including nuclear location of the c‐REL/p65 subunit, overexpression of phosphorylated IκBα, and overexpression of NF‐κB targets. Finally, 2/9 cases showed 3q27 (BCL6) rearrangement, and 1/9 had p53 gene mutations, both of which are rarely detected in classical HL.Conclusions : These findings suggest that DLBCLs with HL features constitute a distinctive subgroup of aggressive lymphomas whose neoplastic growth and peculiar characteristics could be facilitated by a particular microenvironment found in the mediastinum.
IL‐6, its receptors and its relationship with bcl‐2 and bax proteins in infiltrating and in situ human breast carcinoma
Authors: Garcia‐Tuñón I , Ricote M , Ruiz A , Fraile B , Paniagua R , Royuela M 
Published: June 2005

Aims : To characterize the expression pattern of IL‐6 and its receptors (IL‐6Rα and gp130), to relate this pattern to bcl‐2 and bax expression and to elucidate the effects on the proliferation/apoptosis equilibrium in benign conditions and in situ and infiltrating breast cancer.Methods and results : The immunoexpression of IL‐6 and its receptors (IL‐6Rα and gp130), and their relationship with bcl‐2 and bax proteins, were studied in in situ and infiltrating tumours and in benign breast lesions by means of Western blotting and immunohistochemistry. The percentages of samples positive for IL‐6, bcl‐2 and bax and their immunoreaction densities were higher in in situ carcinomas and infiltrating tumours than in benign lesions; although in in situ lesions were not so high as in infiltrating tumours, except for bax, whose immunoexpression was as weak as in benign conditions, resulting in a bcl‐2/bax ratio higher than in infiltrating tumours.Conclusions : The high expression of IL‐6 and its receptors in tumours might be related to the enhanced cell proliferation occurring in breast cancer. IL‐6 could act by increasing bcl‐2 expression and thus altering the proliferation/apoptosis balance toward neoplastic cell proliferation. The increased bax immunoreactivity observed only in infiltrating tumours, which was not so high as the increase in bcl‐2 immunoreactivity, might be interpreted as an attempt to hinder cell proliferation.
An outbreak of Pichia ohmeri infection in the paediatric intensive care unit: case reports and review of the literature
Authors: Otag Feza , Kuyucu Necdet , Erturan Zayre , Sen Sebahat , Emekdas Gurol , Sugita Takashi 
Published: June 2005

SummarySince the first report in 1998, 10 cases of Pichia ohmeri infection have been reported in the literature. Here we present two new cases of P. ohmeri infection in the paediatric age group. The first case was an 8‐month‐old male infant, who was admitted with fever, convulsions and altered consciousness. Conservative therapy was started with a presumptive diagnosis of encephalitis. The patient failed to respond to the given treatments and died on the 21st day of hospitalisation. The second case was a 10‐year‐old male with B‐cell acute lymphoblastic leukaemia. He was hospitalised with neutropenic fever. He was discharged after 3 weeks of therapy. In both cases P. ohmeri was identified in blood samples. Growing evidence indicates that P. ohmeri should be added to the lengthening list of opportunistic fungal pathogens that can cause infection in all ages, including infants, and particularly in those who are immunocompromised.
In vitro susceptibility of 15 strains of zygomycetes to nine antifungal agents as determined by the NCCLS M38‐A microdilution method
Authors: Singh Jagpal , Rimek Dagmar , Kappe Reinhard 
Published: June 2005

SummaryThe in vitro susceptibility of 15 strains of six genera of zygomycetes including Rhizopus oryzae (Rhizopus arrhizus), Rhizopus stolonifer, Mucor circinelloides (three), Absidia corymbifera (three), Rhizomucor pusillus (three), Cunninghamella bertholletiae (two), and Syncephalastrum racemosum (two) to nine antifungal agents were determined by the NCCLS M38‐A broth microdilution method. Geometric means of the minimal inhibitory concentrations (MIC) were: amphotericin B 0.07 mg l−1 (range 0.03–0.5 mg l−1), nystatin 0.83 mg l−1 (range 0.25–4 mg l−1), itraconazole 0.59 mg l−1 (range 0.03 to >8 mg l−1), voriconazole 6.50 mg l−1 (range 2 to >8 mg l−1), ciclopiroxolamine 1.59 mg l−1 (range 0.5–4 mg l−1), and amorolfine 9.19 mg l−1 (range 1 to >16 mg l−1). All strains were resistant to 5‐flucytosine, fluconazole (MIC >64 mg l−1) and caspofungin (MIC >16 mg l−1).
Candidaemia in an Irish tertiary referral hospital: epidemiology and prognostic factors
Authors: Boo T. W. , O'Reilly B. , O'Leary J. , Cryan B. 
Published: June 2005

SummaryThere were two parts to this study. Part 1 evaluated the epidemiology of Candida bloodstream isolates within the Southern Health Board (SHB) of Ireland from 1992 to 2003 by retrospective surveillance of all such isolates of patients reported from SHB hospitals to our laboratory database during that period. Part 2 reviewed candidaemia cases occurring in Cork University Hospital (CUH) from 1999 to 2003 using surveillance of all positive blood culture isolates in CUH microbiology laboratory during the 5‐year period. In part 1, 250 Candida bloodstream isolates were reported in the SHB over 12 years. There was a pattern of decreasing percentage of C. albicans with time. Whereas in part 2, 63 cases of candidaemia were identified in CUH from 1999 to 2003. Candida albicans constituted 50% of all isolates, while C. parapsilosis and C. glabrata accounted for 21.2% and 18.2% respectively. Average annual incidence rate was 0.48 episodes/1000 admissions and 0.70 episodes/10 000 patient‐days. Vascular catheters were the commonest source of candidaemia (61.9%) followed by the urinary tract (12.7%). Risk factors included exposure to multiple antibiotics (75%); central vascular catheterization (73%); multiple colonization sites (71%); severe gastrointestinal (GI) dysfunction (54%) and acute renal failure (43%). Crude 7‐day and 30‐day mortality rates were 20.6% and 39.7% respectively. Logistic regression multivariate analysis identified the following to be independent predictors for mortality: age ≥65 years [odds ratio (OR) 7.2, P = 0.013]; severe GI dysfunction (OR 10.6, P = 0.01); acute renal failure (OR 7.6, P = 0.022); recent/concurrent bacteraemia (OR 5.2, P = 0.042); endotracheal intubation (OR 7.7, P = 0.014); while major surgery was associated with a better prognosis (OR 0.05, P = 0.002). Appropriate antifungal treatment was also found to be associated with survival (Fisher's exact test, P < 0.001). The epidemiology of Candida bloodstream isolates within our health board had changed over the years. Incidence and mortality of candidaemia were relatively high in our hospital. Dysfunction of major organ systems and recent bacteraemia were found to predict mortality.
Dermatophytoses in forestry workers and farmers
Authors: Sahin Idris , Kaya Demet , Parlak Ali Haydar , Oksuz Sukru , Behcet Mustafa 
Published: June 2005

SummaryTo assess the frequency of superficial mycoses in forestry workers and farmers in the rural region of Duzce, a total of 467 residents of the rural region were examined for dermatomycosis infection. Of these, 349 were forestry workers and 118 farmers. All specimens collected were analysed by direct microscopy and culture. Tinea pedis et manus was found in 23 (19.4%), and onycomycosis in 21 (17.7%) farmers. Tinea pedis et manus was found in 50 (14.3%), and onycomycosis in 28 (8%) forestry workers. One tinea corporis, two tinea inguinalis and two erosio interdigitalis cases were determined in the farmer group but no cases of tinea corporis, tinea inguinalis, or erosio interdigitalis were found in the forestry group. In total, five tinea versicolor cases were found in the two groups on clinical examination but no agent positivity was yielded in mycological cultures. The most frequently isolated agent in the two groups was Trichophyton rubrum. The frequencies of superficial mycosis and onychomycosis were found to be higher in the farmer group than in the forestry group, although similar aetiological agents were isolated in both groups. The farmers had greater rates of contact with pathogenic fungi present in soil as well as from infected farm animals than the foresters; furthermore, animal husbandry, and the wearing of rubber shoes and nylon socks were more frequent in the farmer group. These results suggest that habits such as the wearing of rubber shoes and nylon socks, and the practice of animal husbandry may be the most important factors in determining the frequency of superficial mycoses and aetiological agents in forestry workers and farmers. To our knowledge, there is no previous report about dermatophytoses in forestry workers.
THE VIETNAMESE REFUGEES AT OUR DOORSTEP: POLITICAL AMBIGUITY AND SUCCESSFUL IMPROVISATION
Authors: Moos Felix , Morrison C.S. 
Published: June 2005

In the spring of 1975, the United States was faced not only with military defeat in Vietnam, but also with the challenge of processing, caring for and eventually resettling more than 130,000 persons fleeing Vietnam.This paper presents a case study of the operation‐“New Life” which evacuated these refugees and cared for them on Guam until they could be resettled. The account focuses on the logistic problems and pragmatic solutions reached in a situation where there existed a wide gap between public policy and i t s application. This discussion is especially instructive in light of the growing national and international problem of refugee relocation.