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Background In preclinical models, high doses of specific emulsifiers induce intestinal inflammation. How these findings translate to Crohn’s disease (CD) is unclear, but the effects of dietary emulsifiers in the context of our food supply are needed before safe evaluation in a CD population. Aims To develop novel trial healthy diets matched for all dietary components, except emulsifiers; and to evaluate their suitability for study in patients with CD by defining, in healthy subjects, tolerance, blinding and adherence to the diets and their impact on intestinal permeability with and without stress. Methods In a pilot single-blinded, cross-over, randomised study, healthy subjects were fed for 4 weeks with ≥3-week washout between diets. Acute stress was induced via 100 mg intravenous corticotrophin-releasing hormone (CRH) on day 28 of each diet. Intestinal permeability was analysed directly with urinary lactulose to rhamnose ratio (LRR) before and at 2 weeks; fasting serum biomarkers reflecting barrier function (intestinal fatty acid binding protein, lipopolysaccharide binding protein [LBP], soluble CD14 and syndecan-1) were measured before and during each diet. All markers were also measured 2 h post CRH. Tolerance was assessed by gastrointestinal symptoms daily using a 100-mm visual analogue scale. Success of blinding was assessed by direct questioning and adherence (defined >95% consumption of only food provided) with food diaries. Results 18 of 20 participants enrolled [median age: 34 IQR 23-46 y; 75% female] finished both diets. The diets were well tolerated with minimal overall symptoms (low: mean 9.9 (SD 8.3) vs high: 9.5 [5.5] mm). Adherence was excellent (>95%). Blinding was reasonable with 30% of participants either not knowing or choosing a high emulsifier diet as the therapeutic diet. In the unstressed state (Fig 1), LRR reduced on the HIGH diet compared to baseline (p=0.016), but no difference between diets was seen. LPB concentrations were lower in the HIGH than LOW diet (p=0.039). Under acute stress (Fig 2), LRR increased by 49% during the HIGH diet (p=0.034), but fell by 41% during the LOW diet (p=0.027). The paired CRH-induced LRR was reduced on LOW vs HIGH diet in acute stress (p=0.043). No difference in concentrations of other biomarkers were seen between diets. Conclusion Novel low and high emulsifier trial diets were well tolerated, achieved good adherence and reasonable blinding. Paradoxically, intestinal permeability reduced with the HIGH diet in the unstressed state, but the LOW diet protected from stress-induced increase in permeability. These diets are suitable to evaluate the effects of emulsifiers on intestinal permeability and inflammation in patients with CD.

Standard treatment for higher risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and low blast acute myeloid leukemia (AML) is azacitidine. In single arm studies, the addition of lenalidomide had been suggested to improve outcomes. The ALLG MDS4 phase II clinical trial randomized such patients to standard azacitidine or combination azacitidine (75mg/m2/d days 1 to 5) with lenalidomide (10mg days 1 to 21 of 28-day cycle from cycle 3) to assess clinical benefit (alive without progressive disease) at 12 months. A total of 160 patients were enrolled; median age 70.7 years (range 42.5-87.2), 31.3% female with 14% CMML, 12% AML and 74% MDS. Adverse events were similar in both arms. There was excellent delivery of protocol therapy (median aza cycles 11 both arms) with few dose reductions, delays or early cessations. At median follow up 33.1 months (range 0.7-59.5), the rate of clinical benefit at 12 months was 65% AZA arm and 54% LEN AZA arm (p=0.2). There was no difference in clinical benefit between each arm according to WHO diagnostic subgroup (MDS, AML or CMML) or IPSS-R. ORR was 57% in AZA arm and 69% in LEN AZA (p=0.14). There was no difference in progression free or overall survival between the arms (each p > 0.12). Although the combination of lenalidomide and azacitidine was tolerable, there was no improvement in clinical benefit, response rates or overall survival in higher risk MDS, CMML or low blast AML patients compared to treatment with azacitidine alone. This trial was registered at www.anzctr.org.au as ACTRN12610000271000. Funding: This study was supported by Celgene with grant funding for study conduct, Snowdome Foundation and the Victorian Epigenetic Group for funding support for molecular studies. Conflict of Interest Disclosure: MK, DH, JFS received research funding from Celgene MK and JFS are advisory board members for Celgene JFS is a member of speakers bureau for Celgene MH is an advisory board member for Takeda, Roche, MSD, Gilead, Janssen WS receives honoraria from Amgen and Novartis The remaining authors declare no conflict of interest; IC, KT, DZant, MW, MD, RE, SJ, TG, DZann, PB, WB. Ethics Approval Statement: Study design and treatment ALLG MDS4 was an open-label, multi-centre study conducted across 30 Australian sites. The study was reviewed and approved by the Human Research Ethics Committees of each centre and conducted according to the Declaration of Helsinki. All patients provided written informed consent prior to participation.

Background: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration. Patients and methods: We studied the efficacy and tolerability of combination therapy with interferon-alpha-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-alpha-2b (5 MU/m(2)/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for I year. Results: The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon alpha-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle. Conclusions: Interferon-alpha-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-alpha-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Background One of the drawbacks of the currently available vectors for gene therapy is the lack of selectivity in gene delivery. We have therefore investigated a strategy to generate immunoliposomes to target non-viral vectors to cell surface receptors on endothelium. Materials and methods We have developed a novel method of coupling antibodies (Abs) to liposomes complexed to DNA, using mild heat treatment to aggregate the immunoglobulin G (IgG). The interaction of plasmid DNA, liposomes and Abs was measured using a gel retardation assay and a resonant mirror biosensor. The size of the transfection complex was determined by light scattering, and the binding and internalization of the complex to cells was followed using flow cytometry. The transfection ability was tested on cell lines and primary cells in vitro and human corneal or vascular tissues ex vivo. Results The interaction of antibodies with liposomes is relatively stable (t1/2 ≅ 45 min). The size of the liposome, Ab and DNA complex was found to be around 500 nm in 4% BSA. The addition of anti-transferrin receptor Abs increased the internalization of the liposome-DNA complex into cells. Abs against both transferrin receptor and E-selectin were shown to augment transfection efficiency of liposomes to cell expressing the appropriate antigens. They are also shown to be efficient in mediating gene delivery to corneal and vascular tissues ex vivo. Conclusions We have shown that our novel vector is capable of in vitro and ex vivo gene delivery to cells and human tissues including cornea, artery and vein. In particular, an Ab against E-selectin was effective at selectively delivering genes to activated endothelial cells expressing the adhesion molecule. Such a strategy will have applications for targeting these tissues prior to transplantation or autologous grafting, and, in the longer term, may allow in vivo targeting of gene therapy to inflammatory sites. Copyright © 2002 John Wiley & Sons, Ltd.

OBJECTIVETo investigate the risk of outlet strut fracture (OSF) in Björk-Shiley convexo concave (BSCC) valves in relation to patients' clinical and valve characteristics.DESIGNA cohort of 2977 patients with 3325 valves with a follow up of 18 years.SETTING38 cardiac implantation centres in the UK.RESULTS56 OSF events were reported with 43 occurring in mitral and 13 in aortic valves. The overall OSF rate was 0.17%/year. No dominant clinical factor of risk was found, but multiple regression analysis identified age, body surface area, valve size, shop order fracture rate, and manufacturing period as risk factors for OSF. A 4% (95% confidence interval (CI) 2% to 6%) decrease in the risk of OSF was observed for each advancing year of age and a fivefold (95% CI 2 to 13) increase in risk for a 0.5 m2 increase in body surface area. The association between the risk of OSF and valve size was not constant over time. Excess risks among 31 mm and 33 mm sizes (mainly mitral valves) decreased over time while that for 23 mm (almost all aortic valves) increased. The risk of OSF increased by 40% (95% CI 20% to 50%) for a unit increase in the fracture rate of other valves in the same batch. For valves manufactured during 1981 to 1984 the risk of OSF was 4 (95% CI 2 to 12) times greater than for valves manufactured before 1981.CONCLUSIONSThe OSF rates for 60° BSCC valves observed in the UK are the highest among all monitored populations. The changing patterns of mitral and aortic valve OSF rates over time observed in this study have not been identified previously and highlight the need for continued monitoring of patients with the BSCC valve.

Purpose: Objectives of this study were to obtain data from Eastern Cooperative Oncology Group (ECOG) oncologists regarding their views on quality of life (QOL) information; perform psychometric testing on the MD-QOL questionnaire, develop a model to describe oncologists' willingness to use QOL information and propose data-based interventions to facilitate use of QOL information in clinical decision-making. Methods: A self-administered questionnaire, MD-QOL, designed to assess physician perspective on QOL information was mailed to a random sample of 500 oncologists, members of ECOG; 271 responded. Results: Oncologists' attitude, current behaviour, knowledge of QOL data, and reported willingness to use QOL can be measured using MD-QOL. The attitude, behaviour and willingness scales have high internal consistency. Physician attitude and behaviour account for 59% of the variance in the willingness to use QOL information. Demographic variables influencing physician responses were their primary income source and exposure to trials with a QOL component. Conclusions: This report of ECOG oncologists' views on QOL information suggests a model to describe relationship between physician willingness to use QOL information on the basis of their attitude and behaviour. Data-based interventions are proposed to influence the key variables and thus facilitate the incorporation of QOL data in clinical practice.

Essential thrombocythaemia (ET) is a clonal stem cell disorder that frequently presents as an incidental finding of elevated platelet counts. Diagnosis depends on exclusion of other myeloproliferative disorders and reactive thrombocytosis. Patients with platelet counts above 1000 x 10(9)/L should receive platelet-lowering therapy, even if asymptomatic. Definitive recommendations cannot yet be made for asymptomatic patients with lower platelet counts. ET can be treated with alkylating agents, radioactive phosphorus or hydroxyurea, but there is evidence that these agents increase transformation to acute leukaemia. Interferon alfa-2a and anagrelide are useful treatment agents, particularly in younger patients.

Background: Essential thrombocythaemia (ET) has an associated risk of thrombotic and haemorrhagic complications, which can be minimised by control of the platelet count. Anagrelide selectively lowers the platelet count, however, there is little Australasian experience with its use and scant data on symptom control. Aims: To evaluate the efficacy of anagrelide for platelet reduction and symptom control in a broad cohort of patients with well-defined ET, and to determine the safety and tolerability in such a population. Methods: Seventeen patients with ET and a platelet count >600×10 9 /L were prospectively enrolled. The evaluable four males and 12 females with a median age of 58 years (range 14-79) included ten patients (63%) previously treated with two or more agents and 12 patients (75%) who had failed other therapies. The median follow-up was seven months (range 15 days to 36 months). Results: Anagrelide, in an average dose of 1.9 mg/day, reduced the platelet count from a mean of 728×10 9 /L (95% CI 611-845×10 9 /L) to 412×10 9 /L (95% CI 319-504×10 9 /L) (p

Background The management of patients with concomitant coronary and carotid artery discase remains a controversial subject. The aim of this review was to develop a rational plan for the management of such patients based on a review of the literature. Method and results A retrospective review was carricd out of relevant papers derived from the Medline database from 1964 to 1996. Conclusion The management of paticnts with concomitant coronary and carotid artery disease has not yet been put to the test in a properly designed and randomized multicentre trial. It is suggestcd that, until the results of such a trial are available, the rational approach to combined symptomatic disease is combined carotid endarterectomy and coronary artery bypass grafting (CABG). Combined surgery is also appropriate for patients with symptomatic carotid artery disease and significant but asymptomatie cardiac disease. At present there is inadequate evidence to promote carotid endarterectomy for asymptomatic disease in combination with CABG.

Savannah River National Laboratory (SRNL) analyzed solvent samples from Modular Caustic-Side Solvent Extraction Unit (MCU) in support of continuing operations. A quarterly analysis of the solvent is required to maintain solvent composition within specifications. Analytical results of the analyses of Solvent Hold Tank (SHT) samples MCU-13-814, MCU-13-815, MCU-13-816, MCU-13-817, MCU-13-818 and MCU-13-819 received May 28, 2013 are reported. The results show that the solvent at MCU does not require an Isopar® L addition, but it will require addition of trioctylamine despite of the 272 g of TOA that was added to the solvent on June 5, 2013 based on the solvent containing a TOA level of 45% of nominal. A new TOA analysis method (HCl titration) has been used and its output was statistically similar to the results from the SVOA-TOA method. This method provides an independent method for measuring TOA and TiDG in MCU-NG solvent. An impurity containing a tert-butyl group was detected in the solvent and further analytical analysis is needed to identify it. SRNL recommends determining the impact of this impurity on the mass transfer ability of the solvent. SRNL also analyzed the SHT sample for {sup 137}Cs content and determined the measured value is above themore » results observed from the January 2013.« less

There is an implicit assumption that physicians incorporate quality of life (QOL) information in clinical decision-making. However, very limited data exists on how physicians view QOL information and how they actually use it. To explore this issue, an in-depth study was conducted using a semi-structured interview guide, with 60 oncologists in Canada and the USA. While the majority of respondents perceived QOL as important they reported a tendency to use it informally and not in all situations. Key findings include the belief expressed by 88% of respondents that the term QOL could be defined, although they differed in their definitions. Although 85% stated that QOL can be formally measured, only a third perceived that the current instruments provide valid and reliable data. Respondents noted a number of significant benefits and drawbacks of using QOL data in their clinical practice that had not been previously noted in the literature. For example, its use as an endpoint in clinical trials was generally perceived to enhance both physician and patient participation. A drawback noted was that including QOL might adversely affect the decision-making process. These findings have been used to develop a self-administered questionnaire (MD-QOL) which will test the generalizability of these findings.

Myelodysplasia or myelodysplastic syndromes represent a heterogeneous group of bone marrow disorders characterized by dysmaturation, cytopenias, and a propensity for leukemic transformation. Although universally adopted, the French-American-British classification still has several limitations and an inability to categorize all patients. Refinements in morphologic and histologic interpretation in addition to the use of scoring systems may improve diagnostic and prognostic capability. Cytogenetics and molecular genetic abnormalities are providing clues to the fundamental pathogenesis of myelodysplastic syndromes. However, the lesions responsible for initiation or disease progression are as yet unresolved. Although chemotherapy and allogeneic transplantation may be used in selected patients, the mainstay of therapy remains supportive care, with differentiating therapy being largely disappointing so far and the role of hematopoietic growth factors remaining unresolved.

Advances in medical technology have made insulin pumps an attractive treatment option for patients with type 1 diabetes and in particular for children and young people. Previous studies have accounted the experiences and views of children/young people and their parents for the use of the injection therapy, but very few have focused on the use of insulin pumps. The objective of this review was to identify studies that explore the experiences of children/young people and their parents on the transition from injections to insulin pump therapy, in the context of their social life.A systematic literature search was conducted, and six studies meeting the inclusion and exclusion criteria were identified. Views and perspectives from the studies identified mainly focused on: introduction to the pump; reasons for the transition to pump therapy; advantages and disadvantages of this treatment option; and impact on quality of life (QoL). Parents and/or children reported that they learned about pump therapy either formally from a healthcare professional or informally from a friend or the internet. Many reasons were identified for the transition, the most important being the pursuit of stable and controlled blood sugar levels and the desire for a more flexible lifestyle. Participants highlighted the advantages of insulin pumps in terms of improved diabetes control. Moreover, there was a positive impact on the QoL, as insulin pumps provided children greater flexibility in lifestyles especially with regards to meals and socialization. In contrast, psychosocial issues such as pump visibility and physical restrictions were highlighted as disadvantages. Issues such as day-to-day management were also discussed.Exploring children/young people's perspectives on the use of pump therapy for managing their diabetes, and parental reflections in caring for those children is important as it provides evidence informing policy for the wider implementation of this technology in the management of diabetes in children. However, the review revealed that there is a scarcity of data in this area and that further research is needed.

Capillary heel prick plasma elastase alpha 1-proteinase inhibitor (E alpha 1-PI) measured by an immunoassay (using commercially available reagents) was examined as an early indicator of neonatal sepsis. Fifty five infants were studied within 24 hours of birth; 60 (including 10 studied on the first day of life) were examined between two and 30 days after birth. Reference ranges for the neonatal period were developed. Raised E alpha 1-PI concentrations (range 440-2600 micrograms/l) were found at the outset of each of the 24 infectious episodes including five with concomitant neutropenia. On the first day of life, obstetric and neonatal complications were also associated with high concentrations (range 190-2400 micrograms/ml). In infants who survived infection, E alpha 1-PI normalised with antibiotic treatment. It is concluded that capillary heel prick plasma is suitable for E alpha 1-PI testing and raised concentrations provide a sensitive but non-specific index of infection in the first 24 hours after birth. Sequential testing may provide early warning of infectious complications and serve as a guide to the cessation of antibiotic treatment.

Summary Infections due to Gram-positive bacteria, especially coagulase-negative staphylococci. have been increasing in immunocompromised patients during the last 5 years because of an increased use of Hickman catheters and oral gut decontamination with quinolones. Teicoplanin. a new glycopeptide antibiotic. has a long plasma half-life which allows once-a-day bolus administration, making it a‘user friendly’agent. A randomized comparative evaluation of teicoplanin plus aztreonam versus gentamicin plus piperacillin in leukaemic patients with a clinical diagnosis of septicaemia was undertaken. The objectives of this study were (1) to evaluate the efficacy and safety of teicoplanin and aztreonam in comparison to a 'standard antibiotic’regimen and (2) to assess the local and systemic tolerance of these drugs. Results of the study in more than 70 patients to date are presented, and the role of anti-Gram-positive antibiotics in the management of severe sepsis in immunocompromised patients is discussed.

Coronary artery bypass graft surgery is associated with an unacceptably high incidence of neurological and neuropsychological complications (Breur et al., 1981; Smith, 1988). The main cause of cerebral dysfunction following this type of surgery is probably cerebral microembolism (Dutton et al., 1974; Taylor, 1986). The eye is an outgrowth of the brain and therefore is uniquely suitable for the study of cerebral microcirculation. Retinal fluorescein angiography has been employed during this surgical procedure to demonstrate the changes which occur in the cerebral microcirculation during operation.

Increased anthropogenic mercury (Hg) deposition since pre-industrial times, and subsequent transformation of inorganic Hg to methylmercury (MeHg) in aquatic environments, has created areas in North America where Hg poses a relatively high risk to wildlife, especially long-lived, piscivorous species. From 1995 to 2001, we opportunistically collected 577 eggs abandoned by Common Loons from eight states. Egg-Hg concentrations ranged from 0.07 to 4.42 microg/g (ww) or 0.10 to 19.40 microg/g (dw). Mercury was higher in eastern than in western North America. Female blood-Hg concentrations strongly correlated with those of eggs from the same territory even though the mean intraclutch Hg difference was 25%. In New England, egg volume declined significantly as egg-Hg concentrations increased. Fertility was not related to egg-Hg concentrations. Based on existing literature and this study's findings, egg-Hg risk levels were established and applied to our US data set and an existing Canadian data set. Regionally, we found the greatest risk levels in northeastern North America. With few exceptions, loon eggs are suitable indicators of methylmercury availability on lakes with territorial pairs.

Plasma histamine concentrations in samples obtained simultaneously from the extracorporeal circuit and the cardiotomy suction line were measured in two groups of patients undergoing cardiopulmonary bypass (CPB). In Group A patients, the technique for myocardial protection involved the use of intra-aortic instilled cardioplegic solution and extracorporeal cooling. Plasma histamine concentrations in the cardiotomy suction effluent (CSE) (median: 1.20 ng/ml; range: 0.31–8.42) were significantly higher than those in the extracorporeal circuit (ECC) (median: 0.53 ng/ml; range: 0.17–1.52) (p

Interferon tau (IFNtau) is the signal for maternal recognition of pregnancy in ruminants. The positive effects of IFNtau on IFN-stimulated gene (ISG) expression are mediated by ISG factor 3 (ISGF3), which is composed of signal transducer and activator of transcription (Stat) 1, Stat 2, and IFN regulatory factor-9 (IRF-9), and by gamma-activated factor (GAF), which is a Stat 1 homodimer. Induction of ISGs, such as ISG17 and 2',5'-oligoadenylate synthetase, by IFNtau during pregnancy is limited to the endometrial stroma (S) and glandular epithelium (GE) of the ovine uterus. The IRF-2, a potent transcriptional repressor of ISG expression, is expressed in the luminal epithelium (LE). This study determined effects of the estrous cycle, pregnancy, and IFNtau on expression of Stat 1, Stat 2, IRF-9, IRF-1, and IRF-2 genes in the ovine endometrium. In cyclic ewes, Stat 1, Stat 2, IRF-1, and IRF-9 mRNA and protein were detected at low levels in the S and GE. During pregnancy, expression of these genes increased only in the S and GE. Expression of IRF-2 was detected only in the LE and superficial GE (sGE) of both cyclic and pregnant ewes. In cyclic ewes, intrauterine administration of IFNtau stimulated Stat 1, Stat 2, IRF-9, and IRF-1 expression in the endometrium. Ovine IRF-2 repressed transcriptional activity driven by IFN-stimulated response elements that bind ISGF3, but not by gamma-activation sequences that bind GAF. These results suggest that IRF-2 in the LE and sGE restricts IFNtau induction of ISGs to the S and GE. In the S and GE, IFNtau hyperactivation of ISG expression likely involves formation and actions of the transcription factors ISGF3 and, perhaps, IRF-1.

To investigate the relationship between admission plasma glucose and 30-day mortality after primary isolated coronary artery bypass grafting (CABG) in nondiabetic patients.All nondiabetic patients with admission plasma glucose measurement undergoing primary isolated CABG from 1993 to 1997 were included in this study.In 878 consecutive patients (155 women), overall mortality was 3.4% (95% CI 2.3-4.8). The mortality rate in women (n = 11; 7.1%, 3.6-12.3) was higher than in men (n = 19; 2.6%, 1.6-4.1) (P = 0.01). There was a positive correlation between plasma glucose and 30-day mortality among women only (P = 0.0001). There was a higher mortality rate in the upper two glucose quartiles (11.7%, 5.5-21.0) compared with the lower two quartiles (2.6%, 3.0-8.9) in the female patients (P = 0.03); a plasma glucose of 6.0 mmol/l separated high- and low-mortality groups. Furthermore, women in the upper two glucose quartiles had a fourfold higher mortality rate than men in the similar quartiles (P = 0.002). Among men, there was no difference in mortality rate across glucose quartiles. In a multivariate analysis, admission plasma glucose, history of thyroid disease, left ventricular ejection fraction0.35, operation bypass time, and perioperative myocardial infarction were independently associated with mortality.Women with admission plasma glucoseor =6.0 mmol/l and men across the whole range of glucose values had similar mortality rates after CABG. The surplus female mortality was found only in subjects with plasma glucose6 mmol/l. Further studies are needed to appraise the possible influence of glucose status on outcome from CABG in nondiabetic subjects.

Objectives of this study were to obtain data from Eastern Cooperative Oncology Group (ECOG) oncologists regarding their views on quality of life (QOL) information; perform psychometric testing on the MD-QOL questionnaire, develop a model to describe oncologists' willingness to use QOL information and propose data-based interventions to facilitate use of QOL information in clinical decision-making.A self-administered questionnaire, MD-QOL, designed to assess physician perspective on QOL information was mailed to a random sample of 500 oncologists, members of ECOG; 271 responded.Oncologists' attitude, current behaviour, knowledge of QOL data, and reported willingness to use QOL can be measured using MD-QOL. The attitude, behaviour and willingness scales have high internal consistency. Physician attitude and behaviour account for 59% of the variance in the willingness to use QOL information. Demographic variables influencing physician responses were their primary income source and exposure to trials with a QOL component.This report of ECOG oncologists' views on QOL information suggests a model to describe relationship between physician willingness to use QOL information on the basis of their attitude and behaviour. Data-based interventions are proposed to influence the key variables and thus facilitate the incorporation of QOL data in clinical practice.

Endometrial glands secrete molecules hypothesized to support conceptus growth and development. In sheep, endometrial gland morphogenesis occurs postnatally and can be epigenetically ablated by neonatal progestin exposure. The resulting stable adult uterine gland knockout (UGKO) phenotype was used here to test the hypothesis that endometrial glands are required for successful pregnancy. Mature UGKO ewes were bred repeatedly to fertile rams, but no pregnancies were detected by ultrasound on Day 25. Day 7 blastocysts from normal superovulated ewes were then transferred synchronously into Day 7 control or UGKO ewes. Ultrasonography on Days 25-65 postmating indicated that pregnancy was established in control, but not in UGKO ewes. To examine early uterine-embryo interactions, four control and eight UGKO ewes were bred to fertile rams. On Day 14, their uteri were flushed. The uterus of each control ewe contained two filamentous conceptuses of normal length. Uteri from four UGKO ewes contained no conceptus. Uteri of three UGKO ewes contained a single severely growth-retarded tubular conceptus, whereas the remaining ewe contained a single filamentous conceptus. Histological analyses of these uteri revealed that endometrial gland density was directly related to conceptus survival and developmental state. Day 14 UGKO uteri that were devoid of endometrial glands did not support normal conceptus development and contained either no conceptuses or growth-retarded tubular conceptuses. The Day 14 UGKO uterus with moderate gland development contained a filamentous conceptus. Collectively, these results demonstrate that endometrial glands and, by inference, their secretions are required for periimplantation conceptus survival and development.

Approximately 82,000 Björk-Shiley convexo-concave (BSCC) 60 degree prosthetic heart valves were implanted in patients worldwide between 1979 and 1986. Outlet strut fractures (OSF) of some of the valves were first reported shortly after their introduction. Here, the determinants of OSF are examined, and the between-country variation and long-term risk are assessed.Cohorts of patients in the UK, Netherlands and USA with 15,770 BSCC 60 degree heart valves were followed up to 18 years for the occurrence of OSF.Crude rates of OSF were highest in the UK (0.18% per year), intermediate in the Netherlands (0.13%), and lowest in the USA (0.06%), although risk factor adjustment reduced the inter-country differences. Furthermore, in the UK and Netherlands, OSF rates (particularly for mitral valves) declined with time since implantation, and between-country differences were considerably diminished 10 or more years post implantation. The risk of OSF decreased steadily with advancing patient age. Fracture rates were lower among women than men, and also varied significantly with valve size and position and OSF status of other valves in the same shoporder.This long-term follow up of BSCC 60 degree heart valve patients indicates that risk factors for valve fracture are generally similar in the UK, Netherlands and USA. It also identifies a strong association between fracture risk and age, newly reveals gender-related differences, and shows that the risk of valve fracture persisted, albeit at a reduced rate, into the 1990s.

In sheep, uterine development begins during fetal life but is only completed postnatally with proliferation and branching morphogenetic differentiation of the endometrial glandular epithelium (G) from the luminal epithelium (L) between birth or Postnatal Day (PND) 0 and PND 56. In other epithelial-mesenchymal organs, fibroblast growth factor (FGF)-7 and FGF-10, hepatocyte growth factor (HGF), and insulin-like growth factor (IGF)-I and IGF-II play essential roles in ductal branching morphogenesis. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization analyses were used to study temporal and spatial alterations in expression of mRNAs for growth factors (FGF-7, FGF-10, HGF, IGF-I, IGF-II) and their respective receptors (FGF receptor or FGFR2IIIb, c-met, and IGF-IR) in the developing neonatal ovine uterus. The RT-PCR analyses indicated that expression of FGF-10, HGF, IGF-I, and IGF-II mRNAs increased in the neonatal uterus between PND 1 and 56. In situ hybridization analyses indicated that FGFR2IIIb and c-met mRNAs were expressed solely in uterine L and developing G, whereas IGF-IR was expressed in all uterine cell types, with highest levels in L and developing G. Both IGF-I and IGF-II mRNAs were expressed in the endometrial stroma and myometrium, with IGF-I predominantly in the intercaruncular endometrial stroma. The highest levels of IGF-I and IGF-II mRNA expression were detected in the intercaruncular endometrial stroma surrounding the nascent and proliferating glands. Immunohistochemistry revealed that phosphorylated extracellular regulated kinases-1 and -2 were most abundantly expressed in the nascent and proliferating glands of the developing neonatal uterine wall. These results implicate FGF-7, FGF-10, HGF, IGF-I, IGF-II, and their epithelial receptors in epithelial-mesenchymal interactions regulating endometrial gland morphogenesis in the neonatal sheep uterus.

Effects of age on uterine histoarchitecture, cell proliferation, and hormone receptor expression were determined for neonatal ewe lambs from birth (Postnatal Day [PND] 0) to PND 56. Uteri were histologically evaluated and proliferating cell nuclear antigen (PCNA), estrogen receptor alpha (ER-alpha), progesterone receptor (PR), and prolactin receptor (PRL-R) expression were characterized by in situ hybridization (ISH), immunohistochemistry, or both. The most striking feature of neonatal uterine development was the genesis and development of glands in the intercaruncular areas of endometrium. After birth, endometrial glandular epithelium (GE) budded and differentiated into the underlying stroma from the luminal epithelium (LE) between PNDs 1 and 7. Between PNDs 14 and 56, extensive coiling and branching morphogenesis of nascent endometrial glands occurred. By PND 56, the uterine wall appeared to be histoarchitecturally mature. At birth, nuclear PCNA protein was strongly detected in LE. Between PNDs 7 and 56, high levels of PCNA, ER-alpha, and PR gene expression were detected in both nascent and developing GE. Higher levels of PCNA and ER-alpha expression were detected in GE at the tips of developing glands as well as in the surrounding stroma. Progesterone was below detectable limits in serum. Serum estradiol-17beta levels were high on PND 1, increased from PNDs 14 to 28, and declined from PND 42 to PND 56. Serum PRL levels increased from PNDs 1 to 14 and declined thereafter. Using ISH and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, expression of mRNAs for short and long forms of the ovine PRL-R were first detected in nascent GE on PND 7 and increased between PNDs 7 and 56 in proliferating and differentiating GE. These results indicate that 1) uterine gland genesis is initiated between PNDs 1 and 7 after birth and is essentially completed by PND 56; 2) neonatal uterine morphogenesis involves temporal and spatial alterations in cell proliferation and ER-alpha, PR, and PRL-R gene expression; 3) PRL-R expression is a unique marker of GE differentiation and proliferation; and 4) serum estradiol-17beta and PRL levels increase during the onset of GE tubular branching morphogenesis. Results support the hypothesis that neonatal ovine uterine development involves epithelial PRL-R and ER-alpha activation to stimulate and maintain endometrial gland genesis and branching morphogenesis.

Investigation of the protein product of the oestrogen-regulated gene LIV-1, implicated in metastatic breast cancer, has revealed 10 protein sequences of unknown function that belong to a new family with potential to control intracellular Zn2+ homeostasis. Sequence alignment highlights the similarity in transmembrane domains and extramembrane charged residues, indicating potential ion-transport ability. This family has a novel highly conserved motif of 66 residues, including a transmembrane domain and a catalytic zinc-binding sequence of zinc metalloproteases, containing conserved (indicated in bold type) proline and glutamine residues, HEXPHEXGD. These proteins contain more plentiful histidine-rich repeats than zinc transporters, suggesting an ability to bind or transport zinc across membranes. I propose that these 11 proteins form a new family with the potential to control intracellular Zn2+ homeostasis.

In many species, endometrial gland adenogenesis occurs neonatally in an ovary- and steroid-independent manner. Chronic exposure of the developing neonatal ovine uterus to norgestomet (NOR) from birth permanently ablates endometrial gland morphogenesis or adenogenesis, creating an adult ovine uterine gland knockout (UGKO) phenotype. This study was conducted to determine the mechanism(s) whereby NOR inhibits adenogenesis in the neonatal ewe. Ewe lambs received no implant or a NOR implant at birth and on postnatal day (PND) 14, and they were necropsied on PND28. Histological analyses of the tracts indicated NOR exposure specifically inhibited endometrial adenogenesis, but no histoarchitectural differences were observed in the oviduct, cervix, or vagina. No effect of NOR treatment was detected on proliferating cell nuclear antigen (PCNA) expression in the endometrial luminal epithelium (LE), stroma, or myometrium. In control (CX) ewes, estrogen receptor alpha (ER-alpha) and progesterone receptor (PR) mRNA and protein were expressed strongly in nascent and proliferating glandular epithelium (GE) but were undetected in epithelium of NOR uteri. Expression of c-met and fibroblast growth factor receptor 2IIIb (FGFR2IIIb) mRNA was detected in the LE and GE of CX uteri. In NOR uteri, c-met was expressed in the LE similar to CX uteri, but FGFR2IIIb mRNA levels were lower than in the LE of CX uteri. Uterine hepatocyte growth factor (HGF), the ligand for c-met, and FGFR2IIIb mRNA expression was substantially lower in NOR ewes, but expression of FGF-7 and FGF-10 mRNAs, ligands for FGFR2IIIb, was unaffected. These results indicate that NOR disrupts endometrial adenogenesis by ablating epithelial ER-alpha expression and altering expression of paracrine growth factors and/or receptors involved in epitheliomesenchymal interactions. Likewise, these mechanisms are proposed to be important regulators of normal uterine gland morphogenesis in the neonate.

The purpose of this study was to use ex vivo testing techniques to determine the magnetic resonance imaging (MRI) safety aspects for 32 different heart valve prostheses that had not been evaluated previously in association with the 1.5-T MR environment. Ex vivo testing was performed using previously described techniques for the evaluation of magnetic field interactions (deflection angle and torque), heating [gel-filled phantom and fluoroptic thermometry; 15 minutes of MRI at a specific absorption rate (SAR) of 1.1 W/kg], and artifacts (using gradient echo and T1-weighted spin-echo pulse sequences). Thirteen heart valve prostheses displayed interactions with the magnetic field. However, these magnetic field interactions were considered relatively minor. Heating wasor =0.8 degrees C for these implants. Artifacts varied from mild to severe depending on the amount and type of metal used to make the particular heart valve prosthesis. For these 32 different heart valve prostheses, the relative lack of substantial magnetic field interactions and negligible heating indicate that MR procedures may be conducted safely in individuals with these implants using MR systems with static magnetic fields of 1.5 T or less.

The influence of peptide structure on immunogenicity has been investigated by constructing a series of cowpea mosaic virus (CPMV) chimaeras expressing the 14 amino acid NIm-1A epitope from human rhinovirus 14 (HRV-14) at different positions on the capsid surface. Biochemical and crystallographic analysis of a CPMV/HRV chimaera expressing the NIm-1A epitope inserted into the betaC'-betaC" loop of the S protein revealed that, although the inserted peptide was free at its C-terminus, it adopted a conformation distinct from that previously found when a similarly cleaved peptide was expressed in the betaB-betaC loop of the S protein. Adjustment of the site of insertion within the betaB-betaC loop resulted in the isolation of a chimaera in which cleavage at the C-terminus of the epitope was much reduced. Crystallographic analysis confirmed that in this case the epitope was presented as a closed loop. Polyclonal antisera raised against the CPMV/ HRV chimaera presenting the NIm-1A epitope as a closed loop had a significantly enhanced ability to bind to intact HRV-14 particles compared with antisera raised against chimaeras presenting the same sequence as peptides with free C-termini. These results demonstrate that the mode of presentation of an epitope on a heterologous carrier can dramatically affect its immunological properties.

Osteopontin (OPN) is an acidic phosphorylated glycoprotein component of the extracellular matrix that binds to integrins at the cell surface to promote cell-cell attachment and cell spreading. This matrix constituent is a ligand that could potentially bind integrins on trophectoderm and endometrium to facilitate superficial implantation and placentation. OPN mRNA increases in the endometrial glandular epithelium (GE) of early-pregnant ewes, and OPN protein is secreted into the uterine lumen. Therefore, progesterone and/or interferon-tau (IFNtau) may regulate OPN expression in the uterine GE. Cyclic ewes were ovariectomized and fitted with intrauterine (i. u.) catheters on Day 5 and treated daily with steroids (i.m.) and protein (i.u.) as follows: 1) progesterone (P, Days 5-24) and control serum proteins (CX, Days 11-24); 2) P and ZK 136.317 (ZK; progesterone receptor [PR] antagonist, Days 11-24) and CX proteins; 3) P and recombinant ovine IFNtau (roIFNtau, Days 11-24); or 4) P and ZK and roIFNtau. All ewes were hysterectomized on Day 25. Progesterone induced the expression of endometrial OPN mRNA in the GE and increased secretion of a 45-kDa OPN protein from endometrial explants maintained in culture for 24 h. Administration of ZK ablated progesterone effects. Intrauterine infusion of roIFNtau did not affect OPN gene expression or secretion in any of the steroid treatments. Interestingly, OPN mRNA-positive GE cells lacked detectable PR expression, although PR were detected in the stroma. Results indicate that progesterone regulates OPN expression in GE through a complex mechanism that includes PR down-regulation, and we suggest the possible involvement of a progesterone-induced stromal cell-derived growth factor(s) that acts as a progestamedin.

Disulfide bonds between the side chains of cysteine residues are the only common crosslinks in proteins. Bovine pancreatic ribonuclease A (RNase A) is a 124-residue enzyme that contains four interweaving disulfide bonds (Cys26-Cys84, Cys40-Cys95, Cys58-Cys110, and Cys65-Cys72) and catalyzes the cleavage of RNA. The contribution of each disulfide bond to the conformational stability and catalytic activity of RNase A has been determined by using variants in which each cystine is replaced independently with a pair of alanine residues. Thermal unfolding experiments monitored by ultraviolet spectroscopy and differential scanning calorimetry reveal that wild-type RNase A and each disulfide variant unfold in a two-state process and that each disulfide bond contributes substantially to conformational stability. The two terminal disulfide bonds in the amino-acid sequence (Cys26-Cys84 and Cys58-Cys110) enhance stability more than do the two embedded ones (Cys40-Cys95 and Cys65-Cys72). Removing either one of the terminal disulfide bonds liberates a similar number of residues and has a similar effect on conformational stability, decreasing the midpoint of the thermal transition by almost 40 degrees C. The disulfide variants catalyze the cleavage of poly(cytidylic acid) with values of kcat/Km that are 2- to 40-fold less than that of wild-type RNase A. The two embedded disulfide bonds, which are least important to conformational stability, are most important to catalytic activity. These embedded disulfide bonds likely contribute to the proper alignment of residues (such as Lys41 and Lys66) that are necessary for efficient catalysis of RNA cleavage.

Approximately 150,000 heart valves are implanted annually world-wide, of which 4% are implanted in the UK. We present a comprehensive profile of the trends in valve replacement (VR) surgery in the UK since 1986 based on data from the UK Heart Valve Registry (UKHVR).The UKHVR is a computerized database collecting prospective data on VR surgery in all UK cardiac units. All patients are tracked by national agencies who register all deaths of UK residents. Thus, the Registry receives a copy of each patient's death certificate and enters the date, place and certified cause(s) of death on the database.Between January 1st 1986 and December 31st 1997, a total of 58,195 patients underwent first-time VR surgery and received 63,649 valves. Mean age at operation in 1986 was 58.7 years (range: 18-87 years) and this rose to 64.7 years (range: 18-94 years) in 1997. In 1986, 12% (n = 578) of patients who underwent VR surgery were aged70 years compared with 36% (n = 5125) in 1997. There was a 4% decrease in double VR surgery and a 15% reduction in mitral VR between 1986 and 1997. The majority of patients received a mechanical valve; within this group the number of bileaflet valve implants increased significantly since 1986. There has been a reversal in the downward trend in pericardial valves implanted since 1993. Follow up was 96.1% complete, with a total of 342,993 patient-years. Mortality (30-day) fell from 6.9% in 1986 to 3.8% in 1995, but increased to 6.7% in the two years to 1997. Actuarial survival at 1, 5 and 10 years was 89.5%, 78.5% and 61.8%, respectively; confidence intervals of 0.5% reflect the enormity of the database and quality of the data.UKHVR data can provide comprehensive year-by-year and trend analyses in a database in excess of 63,000 valves. Changes in patient demographics, choice of implanted valve and the pattern of heart valve disease are evident within the UK over the past 11 years.

Studies were conducted to determine effects of intrauterine administration of recombinant ovine interferon tau (IFNtau), placental lactogen (PL), and growth hormone (GH) on endometrial function. In the first study, administration of IFNtau to cyclic ewes for one period (Days 11-15) resulted in an interestrous interval (IEI) of approximately 30 days, whereas administration for two periods (Days 11-15 and Days 21-25) extended the IEI to greater than 50 days. Administration of IFNtau from Days 11 to 15 and of PL or GH from Days 21 to 25 failed to extend the IEI more than for IFNtau alone. In the second study, effects of IFNtau, PL, and GH on endometrial differentiation and function were determined in ovariectomized ewes receiving ovarian steroid replacement therapy. Endometrial expression of mRNAs for estrogen receptor (ER), progesterone receptor (PR), and oxytocin receptor (OTR) were not affected by PL or GH treatment; however, uterine milk protein mRNA levels and stratum spongiosum gland density were increased by both PL and GH treatments. Collectively, results indicated that 1) PL and GH do not regulate endometrial PR, ER, and OTR expression or affect corpus luteum life span; 2) down-regulation of epithelial PR expression is requisite for progesterone induction of secretory gene expression in uterine glandular epithelium; 3) effects of PL and GH on endometrial function require IFNtau; and 4) PL and GH regulate endometrial gland proliferation and perhaps differentiated function.

To determine the safety and efficacy of the combination of idarubicin, cytarabine and etoposide ("ICE") for induction and consolidation treatment of acute myeloid leukemia (AML), and of dose-intensification of cytarabine in this setting, 54 previously untreated patients in three cohorts were studied by sequential dose escalation of cytarabine, in combination with standard doses of idarubicin and etoposide. Cytarabine was given to Cohort 1 at the conventional dosage of 100 mg/m2 per day by continuous infusion for 7 days in induction and 5 days in consolidation; to Cohort 2 at high-dose (HiDAC) (3 g/m2 intravenously twice daily on days 1, 3, 5 and 7) during induction with conventional dosage during consolidation; to Cohort 3 HiDAC was given for both induction and consolidation. In addition, Cohort 3 patients received lenograstim (Granocyte; rHuG-CSF) after both induction and consolidation courses. We found that there was no significant difference between the three cohorts in hematological toxicity in induction, but that HiDAC was associated with a greater incidence of gastro-intestinal toxicities. There was no difference in induction mortality between the three cohorts, which was 11% overall. Consolidation with HiDAC led to a significant increase in hematological toxicity. Overall, the complete remission (CR) rate was 80% with no significant difference between the three regimens. The estimated disease free survival at 3 years was 28%, 67% and 54% respectively for Cohorts 1, 2 and 3 with an estimated overall survival of 38%, 63% and 47%. We conclude that cytarabine dosage can be escalated safely in combination with idarubicin and etoposide in both induction and consolidation. The combination is effective for induction treatment of AML and its side-effects appear similar to those of standard regimens. Whether its use offers long-term benefits compared with standard regimens is the subject of ongoing controlled randomized studies.

Cardiac surgery is the first of any therapeutic discipline to attempt to establish a major international registry on a patient-by-patient basis. Being the first necessarily imposes a challenge since no rules or guidelines exist. Possibilities and boundaries must be identified.The EACTS database committee established ECSUR (The European Cardiac SUrgical Registry) with the aim of collecting patient-by-patient information from centres across Europe. It was decided to collect patient data in three areas; adult cardiac surgery, paediatric cardiac surgery and thoracic surgery. Currently, these three areas are in different stages of development, with multinational data collection now having already commenced in adult cardiac surgery.After just over a year of data collection ECSUR has now received data from 98 centres in 30 countries, encompassing approximately 100,000 patients. Three national cardiac surgical registries currently send their data to ECSUR, and agreement has been reached with three other countries for prospective data sharing during 1999.This paper describes how ECSUR was established, the on-going status of the project, and how the project has now developed a global perspective through a joint European and US initiative to undertake international dataset unification for surgeons worldwide, by the definition of core adult cardiac, paediatric cardiac and thoracic surgical datasets.

Several conflicting theories have been proposed to explain the development of oedema. Pulse reverse osmosis (PRO) suggests that oedema occurs when the mean pulse capillary pressure exceeds the osmotic gradient between the plasma and the interstitial fluid. In order to test this concept mean arterial blood pressures and colloid osmotic pressures were taken in a group of healthy volunteers, a group of patients with bilateral ankle oedema and a group of treated hypertensives. Patients with oedema were found to have colloid osmotic pressures (COP's) which were significantly less than those of the healthy volunteers (p0.001) and the treated hypertensives (p0.001). The results support the oedema mechanism proposed by PRO and indicate that the relationship between blood pressure and COP may be a useful biochemical marker of oedema and its treatment. Further study is required to numerically quantify this relationship.

To collect information from a group of Canadian oncologists about their perspectives on quality of life (QOL) and QOL information.A self-administered questionnaire (MD-QOL) containing 75 items with a 4-point Likert categorical response scale was administered by mail using Dillman survey methodology to all staff oncologists at a single institution.A large Canadian cancer care centre (Princess Margaret Hospital, Toronto).Oncologists' knowledge, attitude, current behaviour and intended willingness to use QOL information.Of 67 eligible respondents 54 replied (80% response rate). In all, 74% felt that QOL can be quantified, and 95% felt that it gives information distinct from performance status measures. A total of 87% felt that published QOL data are useful for individual patient care, but 69% indicated that, at present, they would be more likely to base their recommendations on personal experience rather than on published literature. Of the respondents, 57% felt that decisions were made more difficult when QOL issues are considered.The surveyed oncologists support the relevance and importance of QOL information. Data from this study were used to develop a predictive model to assess oncologists' willingness to use QOL information; the model is being tested in other studies.

Coronary artery bypass surgery classically is undertaken with hypothermic cardiopulmonary bypass (CPB). There is a high incidence of neuropsychological defects after cardiac surgery, which may be related to cerebral ischaemia during the rewarming period. In this study, phosphorus-31 magnetic resonance spectroscopy (31P MRS) was used to identify changes in cerebral 31P MR spectra in patients before and immediately after hypothermic CPB. Four neurologically normal patients undergoing coronary artery bypass surgery were studied. Localised cerebral 31P MRS (TR 5000 ms) was performed at 1.5 Tesla on each patient the day before and within an hour of completion of surgery. Peak areas for phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and beta ATP (betaATP) were measured. Metabolite peak area ratios and relative percentages of each 31P MR resonance with respect to the total 31P MR signal were calculated. In the post-operative MR spectra, each patient displayed a marked reduction in Pi/betaATP and increase in PCr/Pi ratios. Spectral changes in percentage metabolite signals following surgery varied both in magnitude and pattern between patients. In two patients there was an increased postoperative percentage PME and percentage PCr with a decrease in percentage betaATP. The converse was found in the other two patients, but all four subjects displayed a markedly decreased percentage Pi after CPB. These metabolite changes probably reflect rebound phosphorylation in the immediate postoperative period and suggest increased metabolic activity in the hyperaemic brain on rewarming from hypothermic CPB.

To assess the 30-day mortality, long-term survival and freedom from reoperation following surgery for prosthetic endocarditis (PVE).A retrospective analysis of data from the UK Heart Valve Registry of 322 patients who had undergone single mechanical/bioprosthetic valve replacement for PVE between 1 January 1986 and 31 December 1996. The mean age was 54.9 +/- 12.8 years and 213 (66.1%) were males. There were 170 aortic and 152 mitral valve implantations. Eighty-five (26%) of the infected valves were bioprosthetic and 237 (74%) were mechanical. Of the new prostheses implanted 53 (17%) were bioprosthetic and 269 (83%) were mechanical. Of those with infected bioprostheses, 50 (15.2%) had mechanical valves at redo surgery, whilst 219 (68.3%) of infected mechanical prostheses were re-replaced by mechanical prostheses. The follow-up was 98% complete with a total of 1084.9 patient years.The 30-day mortality was 63 (19.9%; 95%CI 15.9-24.7%). There were 85 late deaths. One, 5 and 10 year survival rates were 67.1% (61.6-72.0%), 55.0% (49.0-60.7%) and 37.6% (27.9-47.2%), respectively. Age was the only significant determinant of 30-day mortality (P = 0.04). Age (P = 0.001) and explanting of infected bioprosthesis and replacement by mechanical valve (P = 0.04) determined long-term survival (P = 0.001). The incidence of re-reoperation was 9.9%. Freedom from reoperation for PVE was 88.4, 87.3 and 87.3% at 1, 5 and 10 years, respectively. Explanting of bioprosthesis and replacement by mechanical valve (P0.001) and reoperation within 60 days of native valve replacement (P = 0.02) were determinants of reoperation for PVE. Freedom from death or reoperation was 61.1, 50.6 and 34.2% at 1, 5 and 10 years, respectively. Age (P = 0.003), explanting of bioprosthesis and replacement by mechanical valve (P = 0.002) and the period between prosthetic re-replacement (P = 0.04) determined freedom from death or reoperation.Operation for PVE carries a high 30-day mortality and reduced long-term survival. There is no evidence that type of prosthesis used for re-reoperation determines survival or freedom from re-reoperation.

A series of permeability thresholds to Ca2+ metabolites and macromolecules, occurring at different times when cells are attacked by complement, has been established by imaging HeLa cells transiently expressing a recombinant cytosolic fusion protein of firefly luciferase and aequorin (luciferase-aequorin) to measure changes in ATP and cytosolic free Ca2+. Nuclear fluorescence of propidium was used as a measure of permeability to small molecules, and luciferase activity imaged to assess lysis. The rise in cytosolic free Ca2+ observed after C9 attack preceded by at least 60 s both the increase in propidium fluorescence, measured in single cells, and the decrease in ATP monitored by luciferase light emission. These effects were dependent on the concentration of C9. At concentrations of C9 up to 4 micrograms/ml no loss of luciferase-aequorin protein was detected at the end of the experiment. Thus the membrane integrity of the cells remained intact, even though the cells were permeable to propidium. These results confirmed our earlier observations that propidium permeability in cells attacked by complement was not a reliable measure of cell death. They also show that it is vital to take account of cellular heterogeneity if the mechanisms by which cells respond to membrane pore former attack are to be correctly interpreted.

Because of its ability to depict intravascular, intramural, and extramural pathology, non-invasive imaging is well suited to assessing life-threatening hemoptysis that may complicate Behcet disease. We made exclusive use of CT angiography supplemented by MR to identify pulmonary thromboembolism, mediastinal lymphadenopathy, and bilateral pulmonary artery aneurysms with signs of previous unilateral rupture. Two-dimensional reformatted CT images provided surgeons with a road map of upstream and downstream vascular relationships prior to aneurysm resection. Imaging findings were confirmed by surgery and pathology. Non-invasive imaging proved to be a useful alternative to standard catheter arteriography in the preoperative assessment of hemoptysis in this patient with Behcet disease.

The management of patients with concomitant coronary and carotid artery disease remains a controversial subject. The aim of this review was to develop a rational plan for the management of such patients based on a review of the literature.A retrospective review was carried out of relevant papers derived from the Medline database from 1964 to 1996.The management of patients with concomitant coronary and carotid artery disease has not yet been put to the test in a properly designed and randomized multicentre trial. It is suggested that, until the results of such a trial are available, the rational approach to combined symptomatic disease is combined carotid endarterectomy and coronary artery bypass grafting (CABG). Combined surgery is also appropriate for patients with symptomatic carotid artery disease and significant but asymptomatic cardiac disease. At present there is inadequate evidence to promote carotid endarterectomy for asymptomatic disease in combination with CABG.