bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term follow-up of patients treated with glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-controlled, MRI-monitored trial
Authors: Rovaris M. , Comi G. , Rocca MA , Valsasina P. , Ladkani D. , Pieri E. , Weiss S. , Shifroni G. , Wolinsky JS , Filippi M. , European/Canadian Glatiramer Acetate Study Group
Published: February 2007

Glatiramer acetate (GA) is effective in reducing clinical and magnetic resonance imaging (MRI) activity in relapsing-remitting multiple sclerosis (RRMS). Serial long-term MRI data are lacking for large cohorts of GA-treated patients. The European/Canadian GA study consisted of two consecutive phases, each lasting nine months. The first treatment phase was randomized, double-blind and placebo-controlled. The second was an open-label, active treatment phase with daily administration of 20 mg GA subcutaneously for all patients. For the long-term follow-up (LTFU), dual echo, pre- and postgadolinium T1-weighted brain MRI scans were obtained with the same acquisition scheme as for the original trial and a neurological assessment was performed. Lesion volumes, normalized brain volumes and percentage brain volume changes (PBVC) were measured. One hundred and forty-two (63.4%) of the 224 patients who completed the two phases of the European/Canadian study underwent the LTFU after a mean period of 5.8 years (range: 5.3-6.4); 73 were treated with GA from study initiation. MRI measures at LTFU did not significantly differ between patients originally assigned to placebo and those who were always treated with GA, but the proportion of patients who did not require walking aids at LTFU was lower in the latter group (P=0.034). PBVC between baseline and LTFU was significantly correlated with lesion load at study entry. An earlier initiation of GA treatment in patients with active RRMS might, at least partially, have a favourable impact on long-term disease evolution. Multiple Sclerosis 2007; 13: 502-508. http://msj.sagepub.com
`Fighting for everything': service experiences of people severely affected by multiple sclerosis
Authors: Edmonds P. , Vivat B. , Burman R. , Silber E. , Higginson I.J.
Published: February 2007

Background No previous research exists specifically exploring the needs of those people severely affected by multiple sclerosis (MS).

Methods Semi-structured interviews were conducted with people identified by the referring health or social care professional as being severely affected by their MS and informal carers, in order to explore their perceptions of their illness and care. The data were analysed for themes using the constant comparative approach.

Results The data relate to 32 people severely affected by MS, who identified several broad themes, relating to loss and change, and provision of services and care. In relation to service provision, people with MS (PwMS) and their carers identified two, interlinked themes - a lack of continuity and co-ordination of care, and a lack of information about services, aids and adaptations, welfare benefits and end-of-life issues. A further theme was identified, which underpinned and linked the two other themes, that of `fighting for everything' - a sense that people had to struggle for their needs to be met.

Conclusion There is a need to develop models of care in order to better meet patients and carers needs for information, co-ordination, and to reduce the feeling of struggling to receive services. Multiple Sclerosis 2007; 13: 660-667. http://msj.sagepub.com
Are ex vivo neutralising antibodies against IFN-β always detrimental to therapeutic efficacy in multiple sclerosis?
Authors: Sorensen PS , Koch-Henriksen N. , Bendtzen K.
Published: February 2007

Neutralising antibodies (NAbs) against interferon (IFN)-β reduce the treatment effect in multiple sclerosis (MS). However, data from pivotal trials of IFN-β in MS suggest that NAb-positive patients may have a reduced relapse rate during the first six to 12 months of therapy. We collected clinical data and plasma samples for NAb measurements prospectively, every six months, in 468 patients treated with the same IFN-β preparation for at least 24 months. NAbs were measured blindly with a cytopathic effect (CPE) assay. During treatment months 0-6, patients who became NAb-positive had significantly fewer relapses compared to patients who maintained the NAb-negative status, whereas the opposite was observed after month 6. This is in accordance with observations in randomised studies of the three different IFN-β preparations, showing that patients who become NAb-positive have lower relapse rates during the first six or 12 months of therapy. We hypothesise that low affinity NAbs, present early after the start of IFN-β therapy, though neutralising in vitro in sensitive assays increase the half-life of IFN-β in vivo and, thereby, enhance the therapeutic effect. With affinity maturation, NAbs effectively prevent IFN-β binding to its receptors also in vivo and, hence, abolish the treatment effect. Multiple Sclerosis 2007; 13: 616-621. http://msj.sagepub.com
Explanation and Intergroup Emotion: Social Explanations as a Foundation of Prejudice-Related Compunction
Authors: Gill Michael J. , Andreychik Michael R.
Published: February 2007

Two studies examined whether social explanations—causal frameworks used to make sense of a group’s status and behavior—are associated with prejudice-related compunction. In Study 1, based on Devine, Monteith, Zuwerink, & Elliott, (1991), participants who endorsed external explanations (e.g. low socioeconomic status of Blacks stems from historical maltreatment) showed a particularly strong tendency to experience compunction in response to prejudice-related discrepancies. Study 2 involved a novel paradigm. Participants were induced to admit that they would discriminate against Black males. Conceptually replicating Study 1, endorsement of external explanations was positively associated with compunction in response to this imagined discrimination. Across both studies, there was also evidence that the effects of external explanations are not explicable in terms of internal motivation to avoid prejudice, global prejudice, or global positive evaluation of African Americans. Discussion centers on the importance of explanations in shaping intergroup emotions and how the concept of explanation links the intergroup emotion literature to other emotion literatures.
Aid in the Aftermath of Hurricane Katrina: Inferences of Secondary Emotions and Intergroup Helping
Authors: Cuddy Amy J. C. , Rock Mindi S. , Norton Michael I.
Published: February 2007

This research examines inferences about the emotional states of ingroup and outgroup victims after a natural disaster, and whether these inferences predict intergroup helping. Two weeks after Hurricane Katrina struck the southern United States, White and non-White participants were asked to infer the emotional states of an individualized Black or White victim, and were asked to report their intentions to help such victims. Overall, participants believed that an outgroup victim experienced fewer secondary, ‘uniquely human’ emotions (e.g. anguish, mourning, remorse) than an ingroup victim. The extent to which participants did infer secondary emotions about outgroup victims, however, predicted their helping intentions; in other words, those participants who did not dehumanize outgroup victims were the individuals most likely to report intentions to volunteer for hurricane relief efforts. This investigation extends prior research by: (1) demonstrating infraglobalhumanization of individualized outgroup members (as opposed to aggregated outgroups); (2) examining infrahumanization via inferred emotional states (as opposed to attributions of emotions as stereotypic traits); and (3) identifying a relationship between infra-humanization of outgroup members and reduced intergroup helping.
The Impact of Intergroup Emotions on Forgiveness in Northern Ireland
Authors: Tam Tania , Hewstone Miles , Cairns Ed , Tausch Nicole , Maio Greg , Kenworthy Jared
Published: February 2007

Although prejudice researchers have mainly focused their attention on changing attitudes toward outgroups, other outcome variables may also be important. In post-conflict reconciliation, intergroup forgiveness may play a crucial role in helping groups in conflict put the atrocities of the past behind them (Cairns, Tam, Hewstone, & Niens, 2005). Two studies showed that both the specific intergroup emotion of anger and infrahumanization (the attribution of more human emotions to the ingroup than to the outgroup) predicted decreased intergroup forgiveness in Northern Ireland. Results further revealed intergroup contact as a potential means of reducing anger toward the outgroup and improving attitudes toward them. This research integrated prior interpersonal theory with intergroup literature to examine the concept of intergroup forgiveness and its predictors. Results are discussed in terms of their implications for reconciliation in conflict societies.
Student perceptions of active learning in a large cross-disciplinary classroom
Authors: Machemer Patricia L. , Crawford Pat
Published: February 2007

This investigation reports on a study that assesses how students value active, cooperative, and traditional learning activities within a single large cross-disciplinary class. The study surveyed students' perceived value of a range of teaching techniques (from traditional to cooperative) utilized within a general education class. Students rated the various techniques on an ordinal scale and the values were statistically compared using a mean difference (paired sample) test. The study was replicated four times over four semesters, where class size ranged from 125 to 180.The study found that students valued lectures and being active. From the students' perspective, however, working with others (cooperative learning) diminishes the value significantly. Any activity, be it active, cooperative or traditional, that directly relates to improving exam performance was the most valued of all.
Assessing multiple choice question (MCQ) tests - a mathematical perspective
Authors: Scharf Eric M. , Baldwin Lynne P.
Published: February 2007

The reasoning behind popular methods for analysing the raw data generated by multiple choice question (MCQ) tests is not always appreciated, occasionally with disastrous results.This article discusses and analyses three options for processing the raw data produced by MCQ tests. The article shows that one extreme option is not to penalize a student for wrong answers or for missing out questions, and the other extreme option is actually to penalize both aspects.The intermediate option of focusing on the number of questions actually attempted while penalizing wrong answers can be regarded as the fairest. In this case blind guessing will on average not help the student, although partial knowledge will lessen the negative impact on the final overall score. There are still many interesting challenges in designing techniques for MCQ tests.
Peer, professor and self-evaluation of class participation
Authors: Ryan Gina J. , Marshall Leisa L. , Porter Kalen , Jia Haomiao
Published: February 2007

The purpose of this project was to determine the validity of peer and self-evaluations of class participation compared to professors' class participation grades. Students (N = 96) evaluated themselves and their classmates on class participation on a four-point scale and students were required to assign grades in a normalized distribution. Relative to faculty evaluations, the bias and precision of the peer grades were 0.48 points and 36.3 per cent (p < 0.05) and self-evaluations scores were -0.48 and 77.5 per cent (p < 0.05).There was no correlation between a student's grade point average and his/her opinion of this process (R = 0.02). Students did not like peer assessment using forced distribution of grades.
To love your country as your mother
Authors: Wingo Ajume
Published: February 2007

The practical power of appeals to patriotism implies that patriotism in one form or another is here to stay. As such, arguments for the repudiation of patriotism cannot avoid seeming a bit utopian or ethereal. Practically speaking, we cannot repudiate patriotism and still have effective functioning states. To that end, political philosophers should concern themselves with finding legitimate uses of the potent tool that is patriotism. This article is one part of this project, and in it I consider one small but critical aspect of patriotism: specifically, the legitimate uses of patriotic capital - who should use it and when? Can one be a patriot - a state requiring at least some degree of chauvinism or parochialism - and a good liberal democrat at the same time? My answer is a categorical yes.
Should we teach homosexuality as a controversial issue?
Authors: Hand Michael
Published: February 2007

Philosophers of education disagree on how the question of the moral status of homosexual acts should be tackled in the classroom. Some argue that the question should be taught as a controversial issue, that we should present rival moral positions as even-handedly as possible; others maintain that we should actively promote the view that homosexual acts are morally legitimate or unproblematic. Here I attempt to resolve this disagreement. In the first part of the article I defend the use of Robert Dearden's epistemic criterion for identifying the questions that should be taught as controversial issues. In the second part I argue that the question of the moral status of homosexual acts does not satisfy this criterion because moral objections to homosexuality are rationally indefensible. I conclude that we ought to affirm the moral legitimacy of homosexual acts in the moral education of children and young people.
Individual choice and unequal participation in higher education
Authors: Voigt Kristin
Published: February 2007

Does the unequal participation of non-traditional students in higher education indicate social injustice, even if it can be traced back to individuals' choices? Drawing on luck egalitarian approaches,this article suggests that an answer to this question must take into account the effects of unequal brute luck on educational choices.I use a framework based on expected utility theory to analyse qualitative studies on educational choice.This reveals a variety of mechanisms through which differences in background conditions make non-traditional students less likely to apply to university and/or particular institutions; the unequal participation of nontraditional students in higher education remains a problem of social justice.
Fit for the task’: equipment sizes and the transmission of military lore, sixth to tenth centuries
Authors: Dawson Timothy
Published: February 2007

The interpretation of the measurements given in Byzantine military manuals from the sixth to the tenth centuries has been a problematic matter. If the main conclusions of currently accepted scholarship are applied, an appearance is created of equipment much too large to be usable. When the measurements are compared to equipment which practical experience and comparable history show to be functional, it can be seen that as the middle Byzantine period progressed units of measurement were devalued. The sources also reveal the processes whereby military lore was transmitted, including accidental corruption and deliberate revision.
Antique nation? ‘Hellenes’ on the eve of Greek independence and in twelfth-century Byzantium
Authors: Beaton Roderick
Published: February 2007

The Hellenic nation, as constituted in the early nineteenth century, is a recent construct; its name and the traditions to which it lays claim are ancient. In the context of modern debates about the antiquity of nations, and particularly the work of Anthony D. Smith, this paper sets out to make a comparative examination of the contexts and semantic field(s) in which the term ‘Hellene’ came to be revived by Greek-speakers, as a term of communal self-designation, at two widely separated turning-points in their history. All Greek quoted in the main text is also given in my own translation.
The first naturalist novel in Greek: evidence from a close reading of Xenopoulos’ Nikolas Sigalos
Authors: Borghart Pieter
Published: February 2007

This article argues that Xenopoulos’ first extended novel, Nikolas Sigalos (1890), deserves to be analysed in greater detail than has been the case to date. The basis for this claim is two-fold: against the background of a nuanced vision of the nature of naturalism, Nikolas Sigalos proves to be a genuine offspring of this European literary movement, featuring remarkable similarities with the poetics of Emile Zola, whereas a profound critical analysis using the same literary model points to a number of structural shortcomings which exemplify the author’s subsequent negative stance towards his first-fruits. The methodology for conducting the proper textual analysis consists of such narratological concepts as story-line, description, semantic content, narrator and focalization.
Is Whole Breast Ultrasound (WBUS) Preferable to Target Scanning in Symptomatic Breast Disease?: BMUS Pump Priming Research Grant 2002: Final report
Authors: Dixon Anne Marie , De Pledge Sheila , Hampshaw Ann , Robertshaw Alina
Published: February 2007

Aim to estimate the potential clinical utility of ipsilateral whole breast ultrasound (WBUS) in women attending a symptomatic clinic with focal abnormality. Method Between February 2003 and January 2004 all women attending the rapid access symptomatic breast clinic at a large UK DGH with signs and symptoms of focal breast abnormality were invited to participate in a prospective cohort study to evaluate the role of ipsilateral WBUS in identifying synchronous abnormality elsewhere in the breast. Ultrasound examinations were performed and reported by one of three qualified and experienced non-medical sonographers. Diagnostic outcomes were corroborated by tissue diagnosis or follow-up of no less than 12 months duration. Results Six-hundred-and-eleven women were recruited to the study. Six-hundred-and-seventy-two breasts were scanned. Mean duration of follow-up was 26 9 months (range 21–30 months). Overall prevalence of malignancy in the sample of women was 6 4%; sensitivity and specificity of WBUS were 89 7% and 97 8%, respectively. Index lesion pathology was present in 238 (35 4%) breasts. Incidental abnormality was identified elsewhere in the breast in 153 (22 8%) breasts. Of the synchronous lesions identified, 14 (9 2%) were malignant. Twelve (85 7%) of a total of 15 malignancies present elsewhere in the breast occurred in women with a malignant presenting abnormality. Two malignancies (one index, one incidental) were not detected at the WBUS examination. There was no statistically significant difference in interval rescan rate (21 7%) or malignancy positive predictive rate for biopsy (43%) between index and incidental lesions. Conclusion WBUS will reveal synchronous incidental abnormality in approximately one in five women referred to a ‘one-stop’ clinic with a focal lump, localized pain or focal area of nodularity. These additional abnormalities generate diagnostic follow up and/or interventional examinations in the same manner as presenting abnormalities. The majority of incidental abnormalities are benign, incidental malignancy being associated with increased patient age, presenting palpable lump and index malignancy. The case for performing WBUS in symptomatic women with no, or benign index abnormality is unsubstantiated.
Effects of bone marrow-derived cells on monocrotaline- and hypoxia-induced pulmonary hypertension in mice
Authors: Raoul William , Wagner-Ballon Orianne , Saber Guitanouch , Hulin Anne , Marcos Elisabeth , Giraudier Stéphane , Vainchenker William , Adnot Serge , Eddahibi Saadia , Maitre Bernard
Published: February 2007

Background

Bone marrow -derived cells (BMDCs) can either limit or contribute to the process of pulmonary vascular remodeling. Whether the difference in their effects depends on the mechanism of pulmonary hypertension (PH) remains unknown.

Objectives

We investigated the effect of BMDCs on PH induced in mice by either monocrotaline or exposure to chronic hypoxia.

Methods

Intravenous administration of the active monocrotaline metabolite (monocrotaline pyrrole, MCTp) to C57BL/6 mice induced PH within 15 days, due to remodeling of small distal vessels. Three days after the MCTp injection, the mice were injected with BMDCs harvested from femurs and tibias of donor mice treated with 5-fluorouracil (3.5 mg IP/animal) to deplete mature cells and to allow proliferation of progenitor cells.

Results

BMDCs significantly attenuated PH as assessed by reductions in right ventricular systolic pressure (20 ± 1 mmHg vs. 27 ± 1 mmHg, P ≤ 0.01), right ventricle weight/left ventricle+septum weight ratio (0.29 ± 0.02 vs. 0.36 ± 0.01, P ≤ 0.03), and percentage of muscularized vessels (26.4% vs. 33.5%, P ≤ 0.05), compared to control animals treated with irradiated BMDCs. Tracking cells from constitutive GFP-expressing male donor mice with anti-GFP antibodies or chromosome Y level measurement by quantitative real-time PCR showed BMDCs in the lung. In contrast, chronically hypoxic mice subjected to the same procedure failed to show improvement in PH.

Conclusion

These results show that BMDCs limit pulmonary vascular remodeling induced by vascular injury but not by hypoxia.
Gabexate in the prophylaxis of post-ERCP pancreatitis: a meta-analysis of randomized controlled trials
Authors: Zheng Minghua , Chen Yongping , Yang Xinjun , Li Ji , Zhang Youcai , Zeng Qiqiang
Published: February 2007

Background

Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography and the benefit of its pharmacological treatment is unclear. Although prophylactic use of gabexate for the reduction of pancreatic injury after ERCP has been evaluated, the discrepancy about gabexate's beneficial effect on pancreatic injury still exists. This study aimed to evaluate the effectiveness and safety of gabexate in the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP).

Methods

We employed the method recommended by the Cochrane Collaboration to perform a meta-analysis of randomized controlled trials (RCTs) of gabexate in the prevention of post-ERCP pancreatitis (PEP) including three RCTs conducted in Italy and one in China.

Results

All of the four RCTs were of high quality. When the RCTs were analyzed, odds ratios (OR) for gabexate mesilate were 0.67 [95% CI (0.31~1.47), p = 0.32] for PEP, 3.78 [95% CI (0.62~22.98), p = 0.15] for severe PEP, 0.68 [95% CI (0.19~2.43), p = 0.56] for the case-fatality of PEP, 0.88 [95% CI (0.72~1.07), p = 0.20] for post-ERCP hyperamylasemia, 0.69 [95% CI (0.39~1.21), p = 0.19] for post-ERCP abdominal pain, thus indicating no beneficial effects of gabexate on acute pancreatitis, the death rate of PEP, hyperamylasemia and abdominal pain. No evidence of publication bias was found.

Conclusion

Gabexate mesilate can not prevent the pancreatic injury after ERCP. It is not recommended for the use of gabexate mesilate in the prophylaxis of PEP.
Functional analysis of splicing mutations in exon 7 of NF1gene
Authors: Bottillo Irene , De Luca Alessandro , Schirinzi Annalisa , Guida Valentina , Torrente Isabella , Calvieri Stefano , Gervasini Cristina , Larizza Lidia , Pizzuti Antonio , Dallapiccola Bruno
Published: February 2007

Background

Neurofibromatosis type 1 is one of the most common autosomal dominant disorders, affecting about 1:3,500 individuals. NF1 exon 7 displays weakly defined exon-intron boundaries, and is particularly prone to missplicing.

Methods

In this study we investigated the expression of exon 7 transcripts using bioinformatic identification of splicing regulatory sequences, and functional minigene analysis of four sequence changes [c.910C>T (R304X), c.945G>A/c.946C>A (Q315Q/L316M), c.1005T>C (N335N)] identified in exon 7 of three different NF1 patients.

Results

Our results detected the presence of three exonic splicing enhancers (ESEs) and one putative exonic splicing silencer (ESS) element. The wild type minigene assay resulted in three alternative isoforms, including a transcript lacking NF1 exon 7 (NF1ΔE7). Both the wild type and the mutated constructs shared NF1ΔE7 in addition to the complete messenger, but displayed a different ratio between the two transcripts. In the presence of R304X and Q315Q/L316M mutations, the relative proportion between the different isoforms is shifted toward the expression of NF1ΔE7, while in the presence of N335N variant, the NF1ΔE7 expression is abolished.

Conclusion

In conclusion, it appears mandatory to investigate the role of each nucleotide change within the NF1 coding sequence, since a significant proportion of NF1 exon 7 mutations affects pre-mRNA splicing, by disrupting exonic splicing motifs and modifying the delicate balance between aberrantly and correctly spliced transcripts.
Vitamin D status in mothers and their newborns in Iran
Authors: Maghbooli Zhila , Hossein-Nezhad Arash , Shafaei Ali Reza , Karimi Farzaneh , Madani Farzaneh Sadat , Larijani Bagher
Published: February 2007

Background

Adequate vitamin D concentrations during pregnancy are necessary to neonatal calcium homeostasis, bone maturation and mineralization. The aim of study is to evaluate serum vitamin D concentrations in mothers and their newborns and effect of vitamin D deficiency on pregnancy outcomes.

Methods

552 pregnant women were recruited from Tehran University educating hospitals in the winter of 2002. Maternal and cord blood samples were taken at delivery. The serum was assayed for 25-hydroxyvitamin D3, calcium, phosphorus and parathyroid hormone.

Results

The prevalence of vitamin D deficiency in maternal and cord blood samples were 66.8% and 93.3%, respectively (<35 nmol/l). There was significant correlation between maternal and cord blood serum concentrations of vitamin D. In mothers with vitamin D deficiency, cord blood vitamin D concentrations was lower than those from normal mothers (P = .001). Also, a significant direct correlation was seen between maternal vitamin D intake and weight gain during pregnancy.

Conclusion

Consideration to adequate calcium and vitamin D intake during pregnancy is essential. Furthermore, we think it is necessary to reconsider the recommendation for vitamin D supplementation for women during pregnancy.
Hyperoxia retards growth and induces apoptosis and loss of glands and blood vessels in DMBA-induced rat mammary tumors
Authors: Raa Anette , Stansberg Christine , Steen Vidar M , Bjerkvig Rolf , Reed Rolf K , Stuhr Linda EB
Published: February 2007

Background

This study investigated the effects of hyperoxic treatment on growth, angiogenesis, apoptosis, general morphology and gene expression in DMBA-induced rat mammary tumors.

Methods

One group of animals was exposed to normobaric hyperoxia (1 bar, pO2= 1.0 bar) and another group was exposed to hyperbaric hyperoxia (1.5 bar, pO2= 1.5 bar). A third group was treated with the commonly used chemotherapeutic drug 5- Fluorouracil (5-FU), whereas animals housed under normal atmosphere (1 bar, pO2= 0.2 bar) served as controls. All treatments were performed on day 1, 4, 7 and 10 for 90 min. Tumor growth was calculated from caliper measurements. Biological effects of the treatment, was determined by assessment of vascular morphology (immunostaining for von Willebrandt factor) and apoptosis (TUNEL staining). Detailed gene expression profiles were obtained and verified by quantitative rtPCR.

Results

Tumor growth was significantly reduced (~57–66 %) after hyperoxic treatment compared to control and even more than 5-FU (~36 %). Light microscopic observations of the tumor tissue showed large empty spaces within the tissue after hyperoxic treatment, probably due to loss of glands as indicated by a strong down-regulation of glandular secretory proteins. A significant reduction in mean vascular density (30–50%) was found after hyperoxic treatment. Furthermore, increased apoptosis (18–21%) was found after hyperoxic treatment.

Conclusion

Thus, by increasing the pO2in mammary tumor tissue using normobaric and moderate hyperbaric oxygen therapy, a significant retardation in tumor growth is achieved, by loss of glands, reduction in vascular density and enhanced cell death. Hyperbaric oxygen should therefore be further evaluated as a tumor treatment.
Characterization of antibodies in single-chain format against the E7 oncoprotein of the Human papillomavirus type 16 and their improvement by mutagenesis
Authors: Donà Maria Gabriella , Giorgi Colomba , Accardi Luisa
Published: February 2007

Background

Human papillomaviruses (HPV) are the etiological agents of cervical cancer. The viral E7 protein plays a crucial role in viral oncogenesis. Many strategies have been explored to block the E7 oncoprotein activity. The single-chain variable antibody fragments (scFvs) are valuable tools in cancer immunotherapy and can be used as "intracellular antibodies" to knock out specific protein functions. For both in vivo and in vitro employment, the scFv intrinsic solubility and stability are important to achieve long-lasting effects. Here we report the characterization in terms of reactivity, solubility and thermal stability of three anti-HPV16 E7 scFvs. We have also analysed the scFv43 sequence with the aim of improving stability and then activity of the antibody, previously shown to have antiproliferative activity when expressed in HPV16-positive cells.

Methods

The three anti-HPV16 E7 scFv 32, 43 51 were selected from the ETH-2 "phage-display" library. Thermal stability was evaluated with ELISA by determining the residual activity of each purified scFv against the recombinant HPV16 E7, after incubation in the presence of human seroalbumine for different time-intervals at different temperatures. Sequence analysis of the scFvs was performed with BLAST and CLUSTALL programs. The scFv43 aminoacid changes were reverted back to the consensus sequence from the immunoglobuline database by site-directed mutagenesis. ScFv solubility was evaluated with Western blotting by determining their relative amounts in the soluble and insoluble fractions of both prokaryotic and eukaryotic systems.

Results

ScFv51 was the most thermally stable scFv considered. Sequence analysis of the most reactive scFv43 has evidenced 2 amino acid changes possibly involved in molecule stability, in the VH and VL CDR3 regions respectively. By mutagenesis, two novel scFv43-derived scFvs were obtained, scFv43 M1 and M2. ScFv43 M2 showed to have improved thermal stability and solubility in comparison with the parental scFv43.

Conclusion

The characterization of 5 specific anti-HPV16 E7 scFvs shows features important for their activityin vivo. ScFv43 M2 shows higher thermal stability with respect to the parental scFv43, and scFv51 shows high stability and solubility. These properties make the 2 scFvs the best candidates to be tested for anti-E7 activityin vivo.
Caspase-dependent proteolytic cleavage of STAT3α in ES cells, in mammary glands undergoing forced involution and in breast cancer cell lines
Authors: Matthews James R , Watson Susan MR , Tevendale Maxine CL , Watson Christine J , Clarke Alan R
Published: February 2007

Background

The STAT (Signal Transducers and Activators of Transcription) transcription factor family mediates cellular responses to a wide range of cytokines. Activated STATs (particularly STAT3) are found in a range of cancers. Further, STAT3 has anti-apoptotic functions in a range of tumour cell lines. After observing a proteolytic cleavage in STAT3α close to a potential apoptotic caspase protease cleavage site we investigated whether STAT3α might be a caspase substrate.

Methods

STAT3α status was investigatedin vitroin several cell systems:- HM-1 murine embryonic stem (ES) cells following various interventions; IOUD2 murine ES cells following induction to differentiate along neural or adipocyte lineages; and in a number of breast cancer cell lines. STAT3α status was also analysedin vivoin wild type murine mammary glands undergoing controlled, forced involution.

Results

Immunoblotting for STAT3α in HM-1 ES cell extracts detected amino and carboxy terminal species of approximately 48 kDa and 43 kDa respectively – which could be diminished dose-dependently by cell treatment with the nitric oxide (NO) donor drug sodium nitroprusside (SNP). UV irradiation of HM-1 ES cells triggered the STAT3α cleavage (close to a potential caspase protease cleavage site). Interestingly, the pan-caspase inhibitor z-Val-Ala-DL-Asp-fluoromethylketone (z-VAD-FMK) and the JAK2 tyrosine kinase inhibitor AG490 both inhibited cleavage dose-dependently, and cleavage was significantly lower in a heterozygousJAK2knockout ES cell clone. STAT3α cleavage also occurredin vivoin normal murine mammary glands undergoing forced involution, coinciding with a pulse of phosphorylation of residue Y705 on full-length STAT3α. Cleavage also occurred during IOUD2 ES cell differentiation (most strikingly along the neural lineage) and in several human breast cancer cell lines, correlating strongly with Y705 phosphorylation.

Conclusion

This study documents a proteolytic cleavage of STAT3α into 48 kDa amino and 43 kDa carboxyl terminal fragments in a range of cell types. STAT3α cleavage occurs close to a potential caspase site, and can be inhibited dose-dependently by SNP, AG490 and z-VAD-FMK. The cleavage seems to be caspase-dependent and requires the phosphorylation of STAT3α at the Y705 residue. This highly regulated STAT3α cleavage may play an important role in modulating STAT3 transcriptional activity.
General practice cooperatives: long waiting times for home visits due to long distances?
Authors: Giesen Paul , van Lin Nieke , Mokkink Henk , van den Bosch Wil , Grol Richard
Published: February 2007

Background

The introduction of large-scale out-of-hours GP cooperatives has led to questions about increased distances between the GP cooperatives and the homes of patients and the increasing waiting times for home visits in urgent cases. We studied the relationship between the patient's waiting time for a home visit and the distance to the GP cooperative. Further, we investigated if other factors (traffic intensity, home visit intensity, time of day, and degree of urgency) influenced waiting times.

Methods

Cross-sectional study at four GP cooperatives. We used variance analysis to calculate waiting times for various categories of traffic intensity, home visit intensity, time of day, and degree of urgency. We used multiple logistic regression analysis to calculate to what degree these factors affected the ability to meet targets in urgent cases.

Results

The average waiting time for 5827 consultations was 30.5 min. Traffic intensity, home visit intensity, time of day and urgency of the complaint all seemed to affect waiting times significantly. A total of 88.7% of all patients were seen within 1 hour. In the case of life-threatening complaints (U1), 68.8% of the patients were seen within 15 min, and 95.6% of those with acute complaints (U2) were seen within 1 hour. For patients with life-threatening complaints (U1) the percentage of visits that met the time target of 15 minuts decreased from 86.5% (less than 2.5 km) to 16.7% (equals or more than 20 km).

Discussion and conclusion

Although home visits waiting times increase with increasing distance from the GP cooperative, it appears that traffic intensity, home visit intensity, and urgency also influence waiting times. For patients with life-threatening complaints waiting times increase sharply with the distance.
Public-private delivery of insecticide-treated nets: a voucher scheme in Volta Region, Ghana
Authors: Kweku Margaret , Webster Jayne , Taylor Ian , Burns Susan , Dedzo McDamien
Published: February 2007

Background

Coverage of vulnerable groups with insecticide-treated nets (ITNs) in Ghana, as in the majority of countries of sub-Saharan Africa is currently low. A voucher scheme was introduced in Volta Region as a possible sustainable delivery system for increasing this coverage through scale-up to other regions. Successful scale-up of public health interventions depends upon optimal delivery processes but operational research for delivery processes in large-scale implementation has been inadequate.

Methods

A simple tool was developed to monitor numbers of vouchers given to each health facility, numbers issued to pregnant women by the health staff, and numbers redeemed by the distributors back to the management agent. Three rounds of interviews were undertaken with health facility staff, retailers and pregnant women who had attended antenatal clinic (ANC).

Results

During the one year pilot 25,926 vouchers were issued to eligible women from clinics, which equates to 50.7% of the 51,658 ANC registrants during this time period. Of the vouchers issued 66.7% were redeemed by distributors back to the management agent. Initially, non-issuing of vouchers to pregnant women was mainly due to eligibility criteria imposed by the midwives; later in the year it was due to decisions of the pregnant women, and supply constraints. These in turn were heavily influenced by factors external to the programme: current household ownership of nets, competing ITN delivery strategies, and competition for the limited number of ITNs available in the country from major urban areas of other regions.

Conclusion

Both issuing and redemption of vouchers should be monitored as factors assumed to influence voucher redemption had an influence on issuing, and vice versa. More evidence is needed on how specific contextual factors influence the success of voucher schemes and other models of delivery of ITNs. Such an evidence base will facilitate optimal strategic decision making so that the delivery model with the best probability of success within a given context is implemented. Rigorous monitoring has an important role to play in the successful scaling-up of delivery of effective public health interventions.
Thank you reviewers- CytoJournal 2007
Authors: Shidham Vinod B , Atkinson Barbara F
Published: February 2007

Significant efforts, time, and resources are devoted for peer-reviewing numerous CytoJournal manuscripts. The Editorial Board of CytoJournal shares a significant proportion of this activity. Additional peers are requested to join periodically as ‘academic editors’ and reviewers to review CytoJournal manuscripts. We thank all the reviewers and academic editors for their time and efforts for completing the peer-review of CytoJournal manuscripts during 2006. The continued success of this important academic exercise depends on their continued enthusiasm to support with their highest standards. We also thank all the contributing authors for selecting CytoJournal and supporting open access initiative, which allows retention of the copyrights to their corresponding academic accomplishments.
Interrupted coding sequences in Mycobacterium smegmatis: authentic mutations or sequencing errors?
Authors: Deshayes Caroline , Perrodou Emmanuel , Gallien Sebastien , Euphrasie Daniel , Schaeffer Christine , Van-Dorsselaer Alain , Poch Olivier , Lecompte Odile , Reyrat Jean-Marc
Published: February 2007

Background

In silico analysis has shown that all bacterial genomes contain a low percentage of ORFs with undetected frameshifts and in-frame stop codons. These interrupted coding sequences (ICDSs) may really be present in the organism or may result from misannotation based on sequencing errors. The reality or otherwise of these sequences has major implications for all subsequent functional characterization steps, including module prediction, comparative genomics and high-throughput proteomic projects.

Results

We show here, using Mycobacterium smegmatis as a model species, that a significant proportion of these ICDSs result from sequencing errors. We used a resequencing procedure and mass spectrometry analysis to determine the nature of a number of ICDSs in this organism. We found that 28 of the 73 ICDSs investigated correspond to sequencing errors.

Conclusion

The correction of these errors results in modification of the predicted amino acid sequences of the corresponding proteins and changes in annotation. We suggest that each bacterial ICDS should be investigated individually, to determine its true status and to ensure that the genome sequence is appropriate for comparative genomics analyses.
Comparison of the Effects of Hypothermia at 33°C or 35°C after Cardiac Arrest in Rats
Authors: Logue Eric S. , McMichael Melissa J. , Callaway Clifton W.
Published: February 2007

Objectives:
Hypothermia of 32°C–34°C induced after resuscitation from cardiac arrest improves neurologic recovery, but the optimal depth of cooling is unknown. Using a rat model, the authors tested the hypothesis that cooling to 35°C between hours 1 and 24 after resuscitation would improve neurologic outcome as much as cooling to 33°C.

Methods:
Halothane‐anesthetized rats (n= 38) underwent 8 minutes of asphyxial cardiac arrest and resuscitation. Cranial temperature was maintained at 37°C before, during, and after arrest. Between one and 24 hours after resuscitation, cranial temperature was maintained at 33°C, 35°C, or 37°C using computer‐controlled cooling fans and heating lamps. Neurologic scores were measured daily, and rats were killed at 14 days for histologic analysis. Neurons per high‐powered field were counted in the CA1 region of the anterior hippocampus using neuronal nuclear antigen staining.

Results:
After 14 days, 12 of 12 rats (100%) cooled to 33°C, 11 of 12 rats (92%) cooled to 35°C, and ten of 14 rats (71%) cooled to 37°C survived, with hazard of death greater in the rats cooled to 37°C than in the combined hypothermia groups. Neurologic scores were worse in the rats cooled to 37°C than in the hypothermia groups on days 1, 2, and 3. Numbers of surviving neurons were similar between the groups cooled to 33°C and 35°C and were higher than in the group cooled to 37°C.

Conclusions:
These data illustrate that hypothermia of 35°C or 33°C over the first day of recovery improves neurologic scores and neuronal survival after cardiac arrest in rats. The benefit of induced hypothermia of 35°C appears to be similar to the benefit of 33°C.
Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: O'Brien Susan , Moore Joseph O. , Boyd Thomas E. , Larratt Loree M. , Skotnicki Aleksander , Koziner Benjamin , Chanan-Khan Asher A. , Seymour John F. , Bociek R. Gregory , Pavletic Steve , Rai Kanti R.
Published: February 2007

Purpose

Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL.

Patients and Methods

Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR).

Results

Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups.

Conclusion

The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.
Post-natal development of the electromotor system in a pulse gymnotid electric fish
Authors: Pereira Ana Carolina , Rodríguez-Cattaneo Alejo , Castelló María E. , Caputi Angel A.
Published: February 2007

Some fish emit electric fields generated by the coordinated activation of electric organs. Such discharges are used for exploring the environment and for communication. This article deals with the development of the electric organ and its discharge in Gymnotus, a pulse genus in which brief discharges are separated by regular silent intervals. It is focused on the anatomo-functional study of fish sized between 10 and 300 mm from the species of Gymnotus, in which electrogenic mechanisms are best known. It was shown that: (1) electroreception and electromotor control is present from early larval stages; (2) there is a single electric organ from larval to adult stages; (3) pacemaker rhythmicity becomes similar to that of the adult when the body length becomes greater than 45 mm and (4) there is a consistent developmental profile of the electric organ discharge in which waveform components are added according to a programmed sequence. The analysis of these data allowed us to identify three main periods in post-natal development of electrogenesis: (1) before fish reach 55 mm in length, when maturation of neural structures is the main factor determining a characteristic sequence of changes observed in the discharge timing and waveform; (2) between 55 and 100 mm in length, when peripheral maturation of the effector cells and changes in post-effector mechanisms due to the fish's growth determine minor changes in waveform and the increase in amplitude of the discharge and (3) beyond 100 mm in length, when homothetic growth of the fish body explains the continuous increase in electric power of the discharge.