bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of cyclooxygenase‐1 and ‐2 modulates angiogenic responses to engagement of αvβ3
Authors: Murphy Joseph F. , Steele Christopher , Belton Orina , Fitzgerald Desmond J.
Published: December 2004

Summary. Prostaglandins and cyclooxygenase (COX) have been implicated in the angiogenesis that occurs around tumours, but how they are induced is unclear. Prostaglandin formation is regulated by the availability of arachidonic acid and/or COX activity that in turn are controlled by activation of G‐protein‐coupled receptors or kinase receptors. Adhesion receptors provide another potential level of control as they transduce a variety of ‘outside‐in’ signals implicated in inflammation. We examined whether engagement of the vitronectin receptor (αvβ3) modulated prostacyclin (PGI2) formation in human umbilical vein endothelial cells (EC). Engagement of EC αvβ3 by vitronectin (versus fibronectin or gelatin) or by monoclonal antibodies (mAbs) LM609 and LIBS6, enhanced PGI2 generation and also induced expression of both COX‐1 and ‐2 isoforms. αvβ3 engagement also led to vascular endothelial cell growth factor (VEGF) generation and EC proliferation that was attenuated by inhibition of both COX‐1 and COX‐2. COX‐1 inhibition also prevented new vessel formation in an in vitro model of angiogenesis that is αvβ3 dependent. Inhibition of angiogenesis by the COX‐1 inhibitor was partially reversed by removal of the inhibitor or by addition of the stable analogue of PGI2, iloprost. These findings strongly indicate that αvβ3‐mediated angiogenesis is partly due to induction of both isoforms of COX.
Anaplastic large cell lymphoma in Japanese children: retrospective analysis of 34 patients diagnosed at the National Research Institute for Child Health and Development
Authors: Mori Tetsuya , Kiyokawa Nobutaka , Shimada Hiroyuki , Miyauchi Jun , Fujimoto Junichiro
Published: December 2004

Summary. This report presents a retrospective study of 34 Japanese children diagnosed at a single laboratory as having anaplastic large cell lymphoma (ALCL). Most of the pathological features of the Japanese ALCL children observed, such as anaplastic lymphoma kinase protein expression, in addition to most of the clinical characteristics and the outcomes of the patients, are very similar to those reported by European groups. To our knowledge, this is the first report describing the details of the clinicopathological features of Japanese ALCL patients. A further International study, including Japanese patients, might contribute to the establishment of an optimal treatment for paediatric ALCL.
Treatment with short‐term, high‐dose cyclosporin A in children with refractory chronic idiopathic thrombocytopenic purpura
Authors: Perrotta Silverio , Amendola Giovanni , Locatelli Franco , Conte Maria Luisa , Rossi Francesca , D'Urzo Giovanna , Nobili Bruno
Published: December 2004

Summary. We report on 14 children (seven boys, seven girls) with chronic idiopathic thrombocytopenic purpura (ITP) refractory to multiple treatments, who were given a short‐term therapy (range between 6 and 10 weeks) with high doses of cyclosporin A (CyA) (median, 10 mg/kg/d). Six patients experienced adverse events and one developed severe systemic mycosis during therapy. A complete response (CR) was observed in four patients and a partial response (PR) in three patients. Only the four CR patients, who were all girls, had a sustained response. These data suggest that CyA may be effective in some children with chronic symptomatic ITP.
Decreased levels of von Willebrand factor‐cleaving protease in coronary heart disease and thrombotic thrombocytopenic purpura: study of a simplified method for assaying the enzyme activity based on ristocetin‐induced platelet aggregation
Authors: Yoo Gina , Blombäck Margareta , Schenck‐Gustafsson Karin , He Shu
Published: December 2004

Summary. The haemostatic activity of von Willebrand Factor (VWF) is dependent on VWF multimer stability. Fragments, arising from the proteolytic cleavage of the multimers by VWF‐cleaving protease, are ineffective in initiating platelet aggregation. We designed a simple method to determine the protease activity, which was expressed as the reduction in the level of ristocetin‐induced platelet aggregation between the inactive enzyme and the enzyme when activated by the addition of calcium. Samples from senior women (n = 14) with chronic coronary heart disease (CHD), age‐matched control subjects (n = 15) and young healthy individuals (n = 13), as well as patients with either thrombotic thrombocytopenic purpura (TTP) (n = 2) or von Willebrand disease type 2A (VWD‐2A) (n = 2), were examined. The lower protease activity observed in the CHD group, compared with the control subjects, indicated that the increased levels of VWF found in CHD relate to impaired enzyme function. The assessment of TTP patients reconfirmed the reduced protease activity previously observed in this disorder. In VWD‐2A, normal enzyme function was observed, suggesting that there is an increased sensitivity of the mutated VWF protein to the protease, rather than an increase in the activity or quantity of the enzyme involved in pathogenesis. In summary, the present simplified method efficiently determines VWF protease activity and is suitable for use in laboratories where platelet aggregation analyses can be performed.
Macrophage depletion following liposomal‐encapsulated clodronate (LIP‐CLOD) injection enhances megakaryocytopoietic and thrombopoietic activities in mice
Authors: Alves‐Rosa Fernanda , Vermeulen Mónica , Cabrera Juana , Stanganelli Carmen , Capozzo Alejandra , Narbaitz Marina , Van Rooijen Nico , Palermo Marina , Isturiz Martín A.
Published: December 2004

Summary. Megakaryocytopoiesis is the cellular process by which stem cells progress through commitment, proliferation and differentiation, leading to the production of platelets. In the mouse, this process is accomplished within the bone marrow (BM) and spleen microenvironment and is carried out by regulatory molecules and accessory cells, including macrophages, fibroblasts and endothelial‐like cells. Previously, we demonstrated that specific macrophage depletion, using liposomal‐encapsulated clodronate (LIP‐CLOD), induced a rapid recovery of the platelet count in a mouse model of immune thrombocytopenia. We now show that LIP‐CLOD treatment also provoked enhancement of both megakaryocytopoiesis and thrombocytopoiesis. In fact, a dose‐dependent increase in the number of BM and spleen megakaryocytes was detected after treatment and this pattern correlated inversely to the macrophage count detected in these organs. Furthermore, the mice treated with the higher dose of LIP‐CLOD showed signs of enhanced thrombopoiesis as they had an increased frequency of reticulated platelets and an improvement in the total platelet count 2 d later. In addition, the in vitro cytokine‐induced megakaryocytopoiesis in BM and spleen cell cultures was significantly augmented in the presence of LIP‐CLOD. Taken together, these results suggest that BM and spleen microenvironmental macrophages could be involved in the regulation of megakaryocyte and platelet production.
CD27 is heterogeneously expressed in multiple myeloma: low CD27 expression in patients with high‐risk disease
Authors: Guikema Jeroen E. J. , Hovenga Sjoerd , Vellenga Edo , Conradie Jelle J. , Abdulahad Wayel H. , Bekkema Roelof , Smit Jan W. , Zhan Fenghuang , Shaughnessy John , Bos Nicolaas A.
Published: December 2004

Summary. Expression of CD27 on malignant plasma cells (PC) (CD138+CD38++) was analysed in a cross‐sectional study of bone marrow (BM) samples from multiple myeloma (MM) patients (n = 28), monoclonal gammopathy of undetermined significance (MGUS) patients (n = 6) and BM PC from healthy donors (n = 4). MM PC expressed CD27 with a variable, lower intensity pattern compared with the consistent high expression in MGUS and healthy donors. MM patients in complete clinical remission displayed a higher percentage of CD27+ PC compared with patients at diagnosis, relapse or in partial remission. In MM, loss of CD27 correlated with loss of CD19 (R2 = 0·4, P < 0·0001). Human MM cell lines (n = 9) did not express CD27 whereas de novo plasma cell leukaemia (PCL) (n = 3) had a high expression. Re‐analysis of a cDNA microarray data set, generated from newly diagnosed MM patients (n = 74), demonstrated that the MM subgroup with the highest prevalence of poor prognostic factors had the lowest CD27 mRNA expression. Fluorescence‐activated cell sorting and allele‐specific oligonucleotide polymerase chain reaction showed that both CD27+ and CD27– PC subpopulations in MM can belong to the clonal disorder. In conclusion, CD27 is heterogeneously expressed on MM PC and loss of CD27 expression might have prognostic value in MM.
Long‐term complete haematological and molecular remission after allogeneic bone marrow transplantation in a patient with a stem cell myeloproliferative disorder associated with t(8;13)(p12;q12)
Authors: Suzan Florence , Guasch Géraldine , Terre Christine , Garcia Isabel , Bastie Jean‐Noël , Maarek Odile , Ribaud Patricia , Gluckman Eliane , Daniel Marie‐Thérèse , Pébusque Marie‐Josèphe , Castaigne Sylvie
Published: December 2004

Summary. A rare atypical myeloproliferative disorder (aMPD) associated with chromosomal translocations involving the short arm of chromosome 8, region p11–p12 has been described. In most patients, the cytogenetic abnormality is a t(8;13)(p12;q12) that fuses fibroblast growth factor receptor 1, the 8p12 key gene, to FIM/ZNF198 gene. Prognosis is poor with frequent evolution to acute myeloid leukaemia within 1 year of diagnosis. We report a new patient with aMPD with a t(8;13) translocation. Complete haematological, cytogenetic and molecular remission was demonstrated 39 months after allogeneic bone marrow transplantation. This is the first report to demonstrate a molecular remission in this disorder.
Position paper on the therapeutic use of rituximab in CD20‐positive diffuse large B‐cell non‐Hodgkin's lymphoma
Authors: Pettengell Ruth , Linch David
Published: December 2004

Summary. The available data on rituximab in combination with chemotherapy confirm that the addition of an independently active biological agent to full‐dose standard chemotherapy results in higher rates of complete response, lower rates of relapse, prolonged survival, little additional toxicity and no compromise of the dose intensity of standard chemotherapy regardless of age and risk group. Given the strength of these data, the British Committee for Standards in Haematology believes that rituximab should be available for prescription by UK haematologists and oncologists according to its licensed indication in patients with diffuse large B‐cell lymphoma until further data are available to confirm or refute these results. We consider that the use of rituximab with chemotherapy in aggressive lymphoma is cost‐effective and that failure to support its introduction will be strongly in conflict with professional and patient opinion.
Intraocular relapse of childhood acute lymphoblastic leukaemia
Authors: Somervaille Tim C. P. , Hann Ian M. , Harrison Georgina , Eden Tim O.B. , Gibson Brenda E. , Hill Frank G. , Mitchell Chris , Kinsey Sally E. , Vora Ajay J. , Lilleyman John S. ,   on behalf of the MRC childhood leukaemia working party
Published: December 2004

Summary. Relapse of childhood acute lymphoblastic leukaemia (ALL) involving the eye is a rare but challenging problem. Twenty cases occurred in patients treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia XI and ALL97 trials between 1991 and 2001, representing 2·2% of ALL relapses. Seventeen occurred as a first relapse, either in isolation or combined with relapse at another site, and three occurred as a second relapse. All patients with intraocular disease at first relapse were treated with both chemotherapy and radiotherapy, but the doses and protocols used varied. Eleven of these 17 patients are alive and in complete remission with a median follow up of 4 years 2 months from relapse. All 11 children that were treated with a full chemotherapy relapse protocol, together with local radiotherapy have survived. Patients treated with chemotherapy of shorter duration and intensity, despite radiotherapy and/or bone marrow transplantation, did poorly with only one survivor, currently in chronic relapse. Consequently, we suggest that children with eye relapse of ALL be treated with an intensive relapse chemotherapy protocol with local ocular radiotherapy, whether the relapse occurs in isolation or in combination with relapse at another site.
Hyaluronan, a major non‐protein glycosaminoglycan component of the extracellular matrix in human bone marrow, mediates dexamethasone resistance in multiple myeloma
Authors: Vincent Thierry , Molina Laurence , Espert Lucile , Mechti Nadir
Published: December 2004

Summary. Originating from a post‐switch memory B cell or plasma cell compartment in peripheral lymphoid tissues, malignant multiple myeloma (MM) cells accumulate in the bone marrow of patients with MM. In this favourable microenvironment, their growth and survival are dependent upon both soluble factors and physical cell‐to‐cell and cell‐to‐extracellular‐matrix contacts. In this study, hyaluronan (HA), a major non‐protein glycosaminoglycan component of the extracellular matrix in mammalian bone marrow, acted as a survival factor against dexamethasone (Dex)‐induced apoptosis in MM cell lines. These effects were mediated through an interleukin 6 (IL‐6) autocrine pathway, involving signal transducers and activators of transcription‐3 phosphorylation on IL‐6‐dependent XG‐1 and XG‐6 cell lines. HA promoted accumulation of IL‐6 in the culture medium without affecting IL‐6 gene expression, suggesting that HA protects, stabilizes and concentrates IL‐6 close to its site of secretion, thus favouring its autocrine activity. In contrast, in the IL‐6‐independent RPMI8226 cell line, HA survival effect was mediated through a gp80‐IL‐6 receptor‐independent pathway, resulting in the upregulation of Bcl‐2 anti‐apoptotic protein expression and nuclear factor‐κB activation. Taken together, these data suggest that HA antagonizes Dex‐induced apoptosis of MM cells by favouring the autocrine activity of different cytokines or growth factors. As HA is a major component of the bone marrow extracellular matrix, these findings support the idea that HA could play a major role in the survival of MM cells in vivo, and could explain why MM cells accumulate in the bone marrow of patients with MM and escape conventional chemotherapy.
Mediators of inflammation correlate with microalbuminuria in patients with non‐Hodgkin's lymphoma
Authors: Pedersen Lars Møller , Sørensen Peter Grundtvig
Published: December 2004

Summary. Recent studies have demonstrated a high frequency of minor glomerular leakage of albumin in cancer patients. Pathogenic mechanisms of increased urinary albumin excretion (UAE) in malignancies remain to be clarified. We have attempted to identify whether microalbuminuria in lymphoma patients is associated with inflammatory mediators and the acute‐phase response. UAE, urinary excretion of β2‐microglobulin and IgG, and serum levels of interleukin 6 (IL‐6), tumour necrosis factor alpha (TNF‐alpha) and C‐reactive protein (CRP) were determined in 113 patients with newly diagnosed non‐Hodgkin's lymphoma. We demonstrated a high frequency of microalbuminuria (≥ 20 μg/min) and UAE correlated strongly with serum levels of CRP, IL‐6 and TNF‐alpha. UAE, CRP, IL‐6 and TNF‐alpha were significantly higher in patients with advanced disease stage, B symptoms and in high‐risk patients according to the International Prognostic Index. Urinary excretion of β2‐microglobulin was unaffected in patients with increased UAE. However, UAE was significantly correlated with urinary excretion of IgG, suggesting an altered size selectivity of the glomerular filtration barrier. This is the first study that shows a direct correlation between microalbuminuria and proinflammatory cytokines in malignancies, indicating a pathogenic relationship between inflammation and glomerular leakage of albumin. Future efforts should focus on the pathophysiological cause–effect mechanisms and larger studies are needed to confirm the clinical significance of UAE.
Monoclonal gammopathy of undetermined significance in atomic bomb survivors: incidence and transformation to multiple myeloma
Authors: Neriishi Kazuo , Nakashima Eiji , Suzuki Gen
Published: December 2004

Summary. Among 6737 atomic bomb survivors who did not have monoclonal gammopathy at the first examination, 112 developed monoclonal gammopathy of undetermined significance (MGUS) between 1985 and 2001. The crude incidence rate was 164 per 100 000 person‐years in the overall study population, with a sharp increase in incidence after age 60 years. The incidence was not significantly associated with radiation dose (P = 0·91), although the incidence at less than 80 years of age showed a marginally significant association (P = 0·05). Among 75 patients with MGUS detected in 1985, 50 patients (67%) had died by 2001, 16 (21%) of these deaths were due to multiple myeloma (MM). MM mortality among MGUS patients was 2284 per 100 000 person‐years while the rate in the total population was 14·6 per 100 000 person‐years. The risk of MM mortality was greater in the older generation. The transformation from MGUS to MM was faster in exposed persons than in non‐exposed persons, but this was not statistically significant.
Survival implications of molecular heterogeneity in variant Philadelphia‐positive chronic myeloid leukaemia
Authors: Reid Alistair G. , Huntly Brian J. P. , Grace Colin , Green Anthony R. , Nacheva Elisabeth P.
Published: December 2004

Summary. The BCR‐ABL fusion in chronic myeloid leukaemia (CML) is generated by the Philadelphia (Ph) translocation t(9;22) or, in 10% of patients, variants thereof (vPh). Deletion encompassing the reciprocal product (ABL‐BCR) from the derivative chromosome 9 [der(9)] occurs in 15% of all patients, but with greater frequency in vPh patients. Reports of physical separation of ABL‐BCR in non‐deleted patients, as well as evolution from classical to variant Ph, introduce further heterogeneity to the vPh subgroup and raise the possibility that such translocations may herald disease progression. Survival analyses, however, have thus far yielded contradictory results. We assessed the frequency of der(9) deletions, ABL‐BCR abrogation, cytogenetic evolution and cryptic rearrangement in a large cohort of 54 patients with vPh CML. Deletions encompassing ABL‐BCR were detected in 37% of patients, consistent with a model in which a greater number of chromosome breaks increases the risk of genomic loss. The components of ABL‐BCR were physically separated in a further 52% of patients while fused in the remaining 11%. Evolution from classical to vPh was demonstrated in three patients. The difference in survival, as indicated by Kaplan–Meier analysis, was marked between classical and vPh patients (105 vs 60 months respectively; P = 0·0002). Importantly, this difference disappeared when patients with deletions were removed from the analysis. Our study showed that, despite the existence of several levels of genomic heterogeneity in variant Ph‐positive CML, der(9) deletion status is the key prognostic factor.
Eighteen unrelated patients with factor XI deficiency, four novel mutations and a 100% detection rate by denaturing high‐performance liquid chromatography
Authors: Mitchell Michael , Harrington Purvee , Cutler Jacqueline , Rangarajan Savita , Savidge Geoffrey , Alhaq Anwar
Published: December 2004

Summary.  Factor XI (FXI) deficiency is an autosomal bleeding disorder of variable severity. Inheritance is not completely recessive as heterozygotes may display a distinct, if mild, bleeding tendency. Eighteen unrelated FXI‐deficient patients were screened blind by fluorescent single‐stranded conformation polymorphism (F‐SSCP) analysis and denaturing high‐performance liquid chromatography (dHPLC). Mutations were detected in 14 of the 18 patients (∼78%) by F‐SSCP and in all 18 patients by dHPLC. Dideoxy sequencing confirmed the mutations in all 18 patients: eight of the mutations being novel (four of which were in previously reported patients). This showed dHPLC to be a highly sensitive, reliable technique for mutation screening in heterogeneous disorders.
In vitro aspirin resistance detected by PFA‐100TM closure time: pivotal role of plasma von Willebrand factor
Authors: Chakroun Tahar , Gerotziafas Grigoris , Robert Françoise , Lecrubier Chantal , Samama Meyer Michel , Hatmi Mohamed , Elalamy Ismail
Published: December 2004

The in vitro closure time (CT), determined by the Platelet Function Analyzer (PFA‐100TM), is used to monitor patients treated with aspirin. A relatively high percentage of in vitro aspirin resistance was reported despite an adequate inhibition of platelet response to arachidonic acid and we investigated whether high plasma levels of von Willebrand factor ristocetin cofactor activity (vWF:RCo) may contribute to this profile. Platelet aggregation test, CT [collagen adrenaline (CEPI‐CT) and collagen adenosine 5′‐diphosphate (ADP) (CADP‐CT)], and vWF:RCo levels were evaluated in 55 consecutive patients receiving aspirin (75–250 mg/d) versus 32 untreated control subjects. All the aspirin‐treated patients showed platelet aggregation responses that reflected the aspirin intake. However, CT data analysis enabled aspirin good‐responder (GR) and aspirin bad‐responder (BR) patients to be identified. All GR group subjects (n = 27), had a CEPI‐CT and a CADP‐CT longer than 300 s and 96 s respectively. The BR group (n = 28) had CEPI‐CT values below 200 s and all CADP‐CT were in the normal range (77 ± 19 s). Interestingly, the BR plasma vWF:RCo levels were significantly higher (159 ± 43%) than those of the GR group (121 ± 34%) (P < 0·01), which were similar to control values (114 ± 31%). A negative correlation between vWF:RCo and CT values was established. We demonstrate that in vitro aspirin‐resistance, revealed by PFA‐100TM CT prolongation failure, is correlated to increased plasmatic vWF:RCo levels, reinforcing its particular importance in PFA‐100TM cartridges performance.
Fludarabine, cytosine arabinoside, granulocyte‐colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes
Authors: Virchis Andres , Koh Mickey , Rankin Peter , Mehta Atul , Potter Michael , Victor Hoffbrand A. , Grant Prentice H.
Published: December 2004

The combination of fludarabine (FDR), high dose cytarabine and granulocyte colony stimulating factor (FLAG) with or without idarubicin (Ida) was used in the treatment of poor risk acute leukaemia or myelodysplastic syndrome (MDS) in a single centre experience. A total of 105 patients were treated over a 4‐year period with 59% achieving a complete remission (CR); no statistical difference observed between FLAG and FLAG‐Ida. For patients responding to FLAG ± Ida, the median event‐free survival (EFS) was 11 months and 23% at 5 years. Such patients proceeded either to further chemotherapy or a haematopoietic stem cell transplant (HSCT). The median EFS (13 months vs. 8 months) and projected 5‐year survival (37% vs. 13%) of patients undergoing HSCT was significantly better than those who did not (P = 0.021). In all, 14 of 72 patients remain alive in continuing CR (median duration 43 months) with 10 of 31 having had a HSCT vs. four of 41 that did not (P = 0·033). Both regimens were well tolerated, with the majority of patients experiencing grade 1 or less non‐haematological toxicity (mainly nausea and vomiting). The median time to neutrophil and platelet recovery was 28 and 31 d, respectively. No significant differences were seen with the addition of ida. There was a 17% incidence of treatment‐related deaths, of which 39% was caused by invasive aspergillus infection. The results show that FLAG ± Ida is an effective and well‐tolerated remission induction regimen for poor risk leukaemia and MDS.
Eosin‐5‐maleimide binding to band 3 and Rh‐related proteins forms the basis of a screening test for hereditary spherocytosis
Authors: King May‐Jean , Smythe Jonathan S. , Mushens Rosey
Published: December 2004

Flow cytometric analysis of eosin‐5‐maleimide (EMA) binding to red cells is a screening test for the diagnosis of hereditary spherocytosis (HS). The present study used chemical modifications to determine the integral membrane proteins that react with EMA. The predominant interaction of EMA, contributing c. 80% of fluorescence, was with the ɛ‐NH2 group of lysine in band 3 protein, as previously reported. The remainder of the EMA fluorescence was attributable to labelling of accessible sulfhydryl groups on intact red cells. This reaction was heat labile. Three molecules containing sulfhydryl groups were shown to be associated with the Rh blood group protein complex by sodium dodecyl sulphate polyacrylamide gel electrophoresis. These were CD47 and the Rh‐associated glycoprotein, both in the Mr 40–60 kD region, and the Rh blood group proteins in the 30–32 kD region. Immunoprecipitation, using specific monoclonal antibodies and antibody binding studies by flow cytometry, showed that the relative content of these three membrane proteins was lower in HS than normal red cells. Thus, the high predictive value of the EMA binding test for HS reflects changes in the relative amounts of the Rh‐related integral membrane proteins as well as band 3 in HS red cells.
Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis
Authors: Steward C. G. , Pellier I. , Mahajan A. , Ashworth M. T. , Stuart A. G. , Fasth A. , Lang D. , Fischer A. , Friedrich W. , Schulz A. S. ,   the Working Party on Inborn Errors of the European Blood and Marrow Transplantation Group
Published: December 2004

This report describes eight infants who developed acute severe pulmonary arterial hypertension (PAH) at days −2 to +89 after allogeneic stem cell transplantation (SCT) for malignant infantile osteopetrosis (MIOP). They were taken from a total of 28 children (frequency 29%) transplanted for this disease at three institutions between 1996 and 2002. Typical presentations were acute dyspnoea, hypoxia and brady/tachycardia usually in the absence of fever, crepitations or other evidence of infection. Six patients (75%) required assisted ventilation and five (62%) died. There was clinical or pathological evidence of veno‐occlusive disease (VOD) in three children, but absence of VOD in the remaining five suggests that a separate disease process may be responsible for the PAH. Responses to nitric oxide (NO), defibrotide (DF), nicardipine and steroids in varying combinations were disappointing. Three children showed sustained improvement after administration of epoprostenol (EP, prostacyclin) in conjunction with NO and/or DF and remain well and free of PAH 25, 31 and 32 months post‐transplant. PAH must therefore be excluded in any child who becomes acutely breathless after SCT for osteopetrosis.
Prevention of lumbar artery endoleaks following endovascular abdominal aortic aneurysm repair with the selective use of absorbable gelatin sponge
Authors: Walker S R , Macierewicz J , Hopkinson B R
Published: December 2004

Background

The aim of endovascular repair of an abdominal aortic aneurysm is to exclude the aneurysm from the systemic circulation in order to prevent aneurysm expansion and rupture. Lumbar artery (LA) endoleaks have been associated with continued expansion of the aneurysm sac and occur with a reported incidence of approximately 10 per cent. The aim of this study was to reduce the incidence of LA or inferior mesenteric artery (IMA) endoleaks.

Methods

Following deployment of an aortic uni-iliac graft an aneurysmograph was performed by injecting contrast into the aneurysm sac to look for patent aortic side branches. Patients with no visible side branches had an occluder deployed in the contralateral iliac artery. Patients with patent side branches had an absorbable gelatin sponge inserted into the aneurysm sac before occluder deployment. Patients had contrast-enhanced spiral computed tomography (CT) during follow-up at 1 week, and 3, 6 and 12 months.

Results

Fifty-four patients were studied. Eleven were excluded (two perioperative deaths, seven top endoleaks and two occluder endoleaks). Median follow-up was 2 (range 11–7) months. Of the 17 patients in whom patent vessels were demonstrated on an aneurysmograph, one had a patent IMA only, three had a patent LA and IMA, and the remainder had a patent LA. No patient within the study has had a LA or IMA endoleak identified at follow-up CT.

Conclusion

An intraoperative aneurysmograph can help select patients for aneurysm sac packing with gelatin sponge and has been successful in the short term in preventing LA and IMA endoleaks.
Benign anastomotic stricture following transthoracic subtotal oesophagectomy and stapled oesophago-gastrostomy: risk factors and management
Authors: Dresner S M , Lamb P J , Wayman J , Hayes N , Griffin S M
Published: December 2004

Aims

Benign anastomotic stricture (BAS) is a common cause of dysphagia following oesophagectomy. The aim of this study was to assess the incidence of BAS, identify risk factors for its development and evaluate the results of postoperative endoscopic dilatation.

Methods

A consecutive series of 234 patients undergoing oesophagectomy with a stapled intrathoracic oesophagogastric anastomosis (Autosuture CEEA gun) between April 1990 and April 1999 were studied. BAS was defined as dysphagia with anastomotic narrowing (XQ200 endoscope) and no suspicion of recurrence. Statistical analysis was by the χ2 and Mann–Whitney U tests.

Results

The postoperative mortality rate was 5 per cent (12 of 234) and the anastomotic leak rate 3 per cent (six of 234). One-third of patients (70 of 222) who survived surgery re-presented with dysphagia; 5 per cent (11 of 222) were found to have proven local recurrence and 27 per cent (59 of 222) BAS. The median time to development of BAS was 92 (range 24–210) days. BAS formation was significantly related to the size of the staple gun employed: 21 mm, 80 per cent (eight of ten); 25 mm, 32 per cent (25 of 78); 28 mm, 23 per cent (19 of 81); 31 mm, 19 per cent (seven of 37) and 34 mm, 0 per cent (none of five) (χ2 = 18·3, 4 d.f., P < 0·01). All patients underwent radiographically controlled endoscopic dilatation with no complications. Recurrent BAS occurred in over half of these patients (32 of 59), who had a median of 2 (range 2–17) recurrences all resolving within 532 (mean interval 68) days. Recurrent BAS formation was also significantly related to the size of the staple gun employed (χ2 = 11·6, 4 d.f., P < 0·05). Following the introduction of the Autosuture ‘tilt-top’ device in July 1995 the median size of gun used rose from 25 to 28 mm with an overall decrease in the incidence of BAS from 33 to 21 per cent (χ2 = 4·0, 1 d.f., P < 0·05). All patients with anastomotic leaks survived and none subsequently developed BAS. Similarly, no association was found between the development of BAS and the anastomotic site (measured from incisors), tumour subtype, resection margin length, sex, age or preoperative cardiorespiratory status.

Conclusions

Staple gun size is an important risk factor for BAS formation and ‘tilt-top’ devices enable the use of a larger head with a subsequently lower incidence of BAS. Endoscopic dilatation is an effective treatment for BAS which rarely recurs and always resolves within 18 months.
Effect of stockings on calf muscle oxygenation in patients with venous insufficiency
Authors: Agu O , Seifalian A , Hamilton G , Baker D M
Published: December 2004

Background

The mechanism of action of stockings in symptom relief and treatment of venous insufficiency is still inadequately understood. Near-infrared spectroscopy (NIRS) provides continuous non-invasive monitoring of changes in tissue oxygen reserves and availability, by monitoring oxyhaemoglobin (HbO2), deoxyhaemoglobin (HbD) and cytochrome oxidase (CtO2). This study investigated the effect of stockings on calf muscle oxygenation during exercise using NIRS in patients with venous insufficiency.

Methods

Ten patients (mean(s.e.m.) age 56(5) years, seven women) with venous insufficiency participated in the study. Patients rested in a supine posture for 20 min. NIRS probes were attached to the calf at interoptodes spacing of 4 cm and initialized to zero. Calf oxygenation was continuously monitored during standing followed by a 5-min slow walk at 1·6 km h−1 with and without stockings chosen at random. A 30-min rest in the supine position was allowed between stockings. Pulse rate and peripheral oxygen saturation were monitored continuously by a pulse oximeter.

Results

Mean HbO2 concentration, HbD and mitochondrial oxygenation (CtO2) increased significantly with stockings during exercise.

Conclusion

Graduated compression stockings may achieve beneficial effects by improving calf muscle oxygenation during exercise in patients with venous insufficiency.
Carotid artery plaque morphology is related to time since last neurological event
Authors: Senaratne J W B , Handa A , Hands L J , Collin J , Morris P J , Green F R
Published: December 2004

Background

Conflicting conclusions have been drawn regarding the relationship of plaque morphology and symptomatology of carotid atherosclerosis. Previous papers have examined the nature of symptoms and the degree of stenosis. This study determined whether plaque morphology was related to symptomatology with regard to the nature, timing and amount of symptoms, and the degree of stenosis.

Methods

In 60 consecutive carotid endarterectomies the symptoms (transient ischaemic attack (TIA), cerebrovascular accident (CVA), amaurosis fugax (AF), other), time between last neurological event and surgery, number of episodes and the degree of stenosis were recorded prospectively. The plaques removed at surgery were examined immediately and by histology. The macroscopic appearance was recorded as stable (fibrous or fatty plaque with or without calcification) or unstable (plaques with ulceration, rupture or thrombosis). Microscopic grading as either stable or unstable was done using the criteria of a consensus document (Circulation 1995).

Results

There were more CVAs (11 of 34 versus four of 26), and fewer TIAs (17 of 34 versus 16 of 26) and instances of AF (six of 34 versus six of 26) when the plaque was deemed unstable, but this was not statistically significant. Twenty of 34 patients with an unstable plaque had an event in the 6 weeks preceding surgery compared with one of 26 with a stable plaque (P < 0·001). Unstable plaques were associated with more events (12 of 34 patients had more than three events compared with one of 26 with a stable plaque; P = 0·012). Degree of stenosis was not related to plaque morphology. In a logistic regression model, the only predictive factor for finding an unstable plaque at surgery was the timing of the last neurological event (P < 0·001).

Conclusion

The importance of time since the last neurological event in predicting plaque instability is shown. This factor may help to clarify future studies attempting to determine plaque morphology before operation by ultrasonography.
Mortality rate of elective abdominal aortic aneurysm repair is lower in screened men
Authors:   Gloucestershire Vascular Group, Irvine C D , Whyman M R , Poskitt K R , Heather B P , Earnshaw J J
Published: December 2004

Background

It is expected that the main benefit of abdominal aortic aneurysm (AAA) screening will be derived from differences in the mortality rate between elective and ruptured AAA repair. There may also be differences in elective AAA mortality rate between screened and non-screened patients, and the aim of this study was to compare mortality rates for these two groups using standard statistical analysis, Physiological and Operative Severity Score for enUmeration of Mortality and morbidity (POSSUM) and P-POSSUM scoring.

Methods

Patients undergoing elective AAA repair were either from a current screening programme to detect men over 65 years with AAA (screened) or were referred from other sources (non-screened). All patients were scored using the POSSUM scoring system. Mortality data were studied. Agreement between observed and expected deaths for POSSUM and P-POSSUM for screened and non-screened patients was determined.

Results

Some 276 elective AAA repairs were performed with an overall mortality rate of 6·9 per cent (see Table below). The mortality rate of 2·7 per cent for 111 screened patients was significantly less than that of 9·7 per cent for 165 non-screened patients (Pearson χ2 = 5·06, P = 0·02). Actual versus predicted death ratio for all elective patients was 0·93 for POSSUM and 2·38 for P-POSSUM.

Conclusion

Screened patients have a lower mortality rate than non-screened patients for AAA repair. POSSUM scoring provides the best prediction of death in this elective AAA group.
Lower extremity arterial injury: results of 550 cases and review of risk factors associated with limb loss
Authors: Hafez H , Woolgar J , Robbs J
Published: December 2004

Background

The authors' experience of lower limb arterial injury (LLAI) management was analysed and risk factors associated with limb loss were identified.

Methods

Between 1987 and 1997, data on 550 patients with 646 LLAIs were analysed retrospectively.

Results

The mechanism of LLAI was gunshot wounds in 46 per cent, blunt trauma in 19 per cent, stabbing in 12 per cent and shotgun in 9 per cent. The most frequently injured vessel was the superficial femoral artery (37 per cent) followed by the popliteal (31 per cent), crural (11 per cent), common femoral (9 per cent) and profunda (59 per cent) arteries. In 3 per cent of patients there was a combined injury on either side of the knee. Associated injuries included bony injury in 35 per cent, nerve injury in 8 per cent and remote injuries affecting the head, chest or abdomen in 4 per cent. Surgery was carried out in 96 per cent of patients with a limb salvage rate of 84 per cent and a survival rate of 98 per cent. Despite a rising trend in LLAI, total and delayed amputation rates remained stable. On stepwise logistic regression analysis, significant (P < 0·01) independent risk factors for amputation were blocked graft (odds ratio (OR) 16·7), combined above- and below-knee injury (OR 4·4), tense compartment at presentation (OR 4·2), arterial transection (OR 2·8) and associated compound fractures (OR 2·7). Factors such as simple fractures, venous injury/ligation and the use of synthetic grafts were not associated with increased risk of limb loss.

Conclusion

LLAI carries a high amputation rate. Stab injuries are the least likely to lead to amputation whereas injuries associated with severe soft tissue damage, such as high-velocity firearm injuries and blunt trauma with compound fractures, are the most likely to do so. The most significant independent risk factor for limb loss was failed revascularization.
Patch angioplasty reduces morbidity and restenosis following carotid endarterectomy
Authors: Ray S A , Lockhart S J , Dourado R , Irvine A , Burnand K G
Published: December 2004

Background

The role of patch angioplasty in the prevention of stroke and restenosis following carotid endarterectomy remains controversial, partly because of confounding variables such as surgical expertise and selective shunting.

Methods

A consecutive series of 177 carotid endarterectomies performed on 168 patients by, or under the supervision of, one surgeon between December 1992 and July 1999 with routine shunt insertion and completion arteriography was studied. Until April 1997 arteriotomies were closed primarily, with patch angioplasty reserved for small vessels or patients found to have occlusion of the internal carotid artery at operation. After April 1997 Dacron patch closure was performed routinely. All patients had duplex ultrasonography 3 months following endarterectomy.

Results

The indication for surgery and patient characteristics were similar in those who had primary closure and those with patch angioplasty. The postoperative morbidity and incidence of restenosis is shown in the Table.

One of two patients found at surgery to have a recently occluded internal carotid artery had a stroke. The only patient with patch angioplasty and postoperative reocclusion had the lupus anticoagulant and reported amaurosis. Two wound infections overlying Dacron patches resolved with antibiotics and there were no episodes of patch disruption.

Conclusion

This study provides further evidence that patch angioplasty following carotid endarterectomy may reduce postoperative morbidity and early restenosis.
Risk factors for delayed healing and long-term recurrence in chronic venous leg ulcers
Authors:   Gloucestershire Vascular Group, Barwell J R , Taylor M , Ghauri A S K , Bronder C , Phillips L , Poskitt K R , Whyman M R
Published: December 2004

Background

This study aimed to identify risk factors for delayed healing and increased recurrence of chronic venous leg ulcers.

Methods

Some 669 patients with chronic leg ulcers were assessed at a one-stop clinic over the 4 years to July 1999. Possible risk factors and venous reflux patterns, assessed with colour duplex, were recorded prospectively for each patient. Some 633 legs with an ankle: brachial pressure index greater than 0·85 were treated with weekly four-layer bandaging until healed, followed by class 2 compression stockings and regular follow-up. Patients with isolated superficial venous reflux were offered surgery.

Results

Cox regression analyses of possible risk factors are summarized in the Table below.

Conclusion

Age, ulcer chronicity and reflux in the popliteal vein are independent risk factors for delayed ulcer healing. Delayed ulcer healing and rheumatoid arthritis are independent risk factors for ulcer recurrence. Legs with surgically corrected superficial venous reflux are relatively protected from ulcer recurrence.
Bacterial lipoprotein delays neutrophil apoptosis via a CD14-independent pathway
Authors: Power C , Wang J H , Blankson S , Kirwan W O , Redmond H P
Published: December 2004

Background

Lipopolysaccharide (LPS) is considered the most potent exogenous mediator of the systemic inflammatory response syndrome (SIRS) which results, in part, from delayed neutrophil (PMN) apoptosis. The effects of another ubiquitous bacterial component, bacterial lipoprotein (BLP), the most abundant protein in the cell wall of all bacteria, on PMN apoptosis are unknown. The potential role of BLP in the regulation of PMN apoptosis was investigated and these effects were compared with those of LPS.

Methods

PMNs from healthy volunteers were isolated and exposed to identical concentrations of LPS and BLP in the presence or absence of recombinant antihuman CD14 monoclonal antibody. PMN apoptosis was assessed 6 hourly using Annexin V–propidium iodide staining and confirmed on cell morphology. PNM activation was assessed flow cytometrically using expression of functional markers CD11b and CD18.

Results

BLP significantly delayed PMN apoptosis and upregulated PMN adhesion receptor expression compared with control values. The effects seen were markedly similar to those of LPS.

Conclusion

BLP is capable of upregulating PMN adhesion receptor expression and delaying PMN apoptosis in a time- and dose-dependent manner independent of CD14. The potency, and the effects mediated by, BLP are very similar to those of LPS. This identifies BLP as a putative mediator of SIRS and demands that due attention be paid to other bacterial products in the investigation and treatment of septic states.
Requirement for fungal prophylaxis in high-risk surgical patients: a randomized trial
Authors: Emparan C , Diaz-Aguirregoitia J , Iturburu I , Perdigo L F
Published: December 2004

Background

In previous studies the authors have selected patients and surgical procedures with a high risk of fungal infection. Whether these patients and procedures require fungal prophylaxis was studied.

Methods

From June to December 1999, 850 surgical patients from two university hospitals were enrolled in a prospective open randomized study. Fifty were selected according to demographics (age, sex, co-morbidity) and surgical procedures (defined by GDRs and ICD9-CM) as at high risk of fungal infection according to a previously defined algorithm (presented to the Surgical Infection Society of Europe 1999). In these 50 patients the CD lymphocyte population was recollected, and urine, blood, sputum and wound (if infected) cultures were performed. Then, 25 were treated with nystatin wash and swallow, and the others with placebo. Fungal infection and fungal colonization were defined and used as the endpoint of the study.

Results

Patients not selected for the study did not develop fungal infection. Of the high-risk patients, 20 presented with fungal colonization (12 urine, seven wound and five bloodstream cultures) and 12 presented with subsequent fungal infections. Of these 20 colonized patients, only those with nystatin prophylaxis did not require fungal treatment, whereas controls required treatment. CD4 lymphocyte recount (below 300) was uniformly decreased in all patients with fungal infection.

Conclusion

Immunodepressed patients at high risk with concomitant fungal colonization develop fungal infections 2–5 days after high-risk surgical procedures. Nystatin prophylaxis in such patients may reduce the degree and severity of fungal infection. If fungal colonization is present and the CD4 lymphocyte count is below 300, fungal treatment might be advisable.
Antivascular endothelial growth factor therapy prevents peritoneal adhesion formation without adversely affecting wound strength or anastomotic integrity
Authors: Sookhai S , Wang J , Austin K , Maguire D , Blankson S , Kirwan W O , Redmond H P
Published: December 2004

Background

Postoperative intra-abdominal adhesion formation remains a significant cause of complications in surgical patients. To date, no agent has been shown consistently to block adhesion formation; preliminary evidence has shown that intra-abdominal adhesion formation is angiogenesis dependent. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis and promotes vascular leakage. This study determined whether a specific VEGF monoclonal antibody (mAb) could prevent postoperative adhesion formation without affecting wound and anastomotic integrity.

Methods

After developing a standardized peritoneal injury which resulted in a reproducible adhesion model, 40 CD-1 mice were randomized and treated intraperitoneally with either VEGF mAb (n = 20) or immunoglobulin (Ig) G isotype control mAb (n = 20) at the time of abdominal closure. Animals (n = 10 per group) were killed on postoperative day 14, and the development of intra-abdominal adhesions was determined and graded blindly using well established criteria. Animals (n = 10 per group) were also killed 10 days after operation, and laparotomy wounds and gastrointestinal anastomoses were assessed by tensiometry. Statistical analyses were performed using the Mann–Whitney and Fisher's exact tests.

Results

Treatment with VEGF mAb resulted in a significantly lower incidence of adhesion formation compared with control animals (P < 0·001). Furthermore, intergroup analysis for the presence of marked adhesions (grade 2 or 3) demonstrated that mice treated with VEGF mAb had a significantly lower incidence of advanced adhesions compared with controls (10 versus 90 per cent). Laparotomy wound and gastrointestinal anastomotic strength were similar between groups.

Conclusion

This study demonstrates that the formation of postoperative intra-abdominal adhesions is attenuated following the administration of VEGF mAb without adversely affecting wound strength or anastomotic integrity.