bluuebunny/crossref_metadata_2025 huggingface dataset:
Engraftment and dissemination of T lymphocytes from primary haemophagocytic lymphohistiocytosis in scid mice
Authors: Yoshida Nobuyuki , Ishii Eiichi , Oshima Koichi , Yanai Fumio , Ogawa Atushi , Kataoka Satoshi , Sako Masahiro , Park Yong Dong , Koide Kayoko , Imayoshi Miyoko , Zaitsu Masafumi , Muraoka Kenji , Hamasaki Yuhei , Imashuku Shinsaku , Yasukawa Masaki
Published: December 2004

Summary. Although primary haemophagocytic lymphohistiocytosis (HLH) is a genetic disorder of T lymphocytes, it remains unclear why T lymphocytes of primary HLH patients preferentially infiltrate the central nervous system and peripheral blood, in addition to the reticuloendothelial systems. We engrafted Herpesvirus saimiri (HVS)‐immortalized T‐lymphocyte lines established from primary HLH patients into severe combined immunodeficient (scid) mice and examined their capacity to infiltrate mouse organs. A diffuse infiltration of human T lymphocytes was detected in each organ of scid mice treated with 1 × 106 T lymphocytes from all four primary HLH patients assessed, whereas no infiltration of T lymphocytes from healthy individuals was observed in any organ. The infiltration of T lymphocytes was mainly observed in the lung, brain and peripheral blood, in association with haemophagocytosis. These cells were positive for HLA‐DR, CD3 and either CD8 or CD4, but negative for CD68. Certain markers of proliferation and apoptotic activities were highly positive in these cells. There was no difference between the infiltration pattern of T lymphocytes of primary HLH patients with a perforin deficiency and those without. By Southern blot analysis, T lymphocytes infiltrating mouse organs were observed to be polyclonal. These findings suggest that our murine model implementing HVS‐immortalized human T lymphocytes is suitable to clarify the pathogenesis of primary HLH.
The use of recombinant factor VIIa in children with inherited platelet function disorders
Authors: Almeida Antonio M. , Khair Kate , Hann Ian , Liesner Ri
Published: December 2004

Summary. Inherited deficiencies of platelet surface glycoproteins such as Glanzmann's thrombasthenia (GT) or Bernard–Soulier syndrome (BSS) can lead to a severe bleeding diathesis. In the past, bleeding episodes in these patients have often required platelet transfusion to secure haemostasis but recently a number of patient reports have suggested that recombinant factor VIIa (rVIIa) may also be effective. We have used rVIIa on 33 occasions in seven children with inherited platelet function disorders over a 2‐year period: five had GT, one had BSS and one had storage pool disease with a severe phenotype. Bleeding ceased with rVIIa alone in 10 of 28 acute bleeding episodes, but recurred in two of these. The two features that predicted response to rVIIa were the severity of the bleeding and the delay from the onset of bleeding to treatment. Five episodes of planned surgical intervention were treated successfully with rVIIa. Eighteen out of the 28 acute episodes and none of the planned surgical episodes required blood product support. We have found variable efficacy of rVIIa for acute bleeding episodes in this small series of children with inherited platelet function defects but larger studies are warranted, particularly as rVIIa is a relatively low‐risk treatment approach for these disorders.
Cardiac morbidity in advanced chronic myelogenous leukaemia patients treated by successive allogeneic stem cell transplantation with busulphan/cyclophosphamide conditioning after imatinib mesylate administration
Authors: Sohn Sang Kyun , Kim Jong Gwang , Kim Dong Hwan , Lee Kyu Bo
Published: December 2004

Summary. Imatinib mesylate is useful for facilitating allogeneic stem cell transplantation (allo‐SCT) in advanced‐phase chronic myelogenous leukaemia (AP‐CML) patients. However, although the side‐effects of imatinib are usually minor, cardiac morbidity can develop as a latent adverse effect post SCT when a myeloablative SCT is given to patients taking imatinib. Two AP‐CML patients who were treated with imatinib manifested severe cardiac dysfunction after an allo‐SCT, whereas cardiac morbidity was not observed in 45 other patients who had not received imatinib. It would appear that exposure to imatinib may have an adverse impact on the heart in AP‐CML patients who receive an allo‐SCT conditioned with busulphan/cyclophosphamide.
Thrombopoietin increases platelet adhesion under flow and decreases rolling
Authors: Van Os Erim , Wu Ya‐Ping , Pouwels Jos G. , Ijsseldijk Martin J. W. , Sixma Jan J. , Akkerman Jan Willem N. , De Groot Philip G. , Van Willigen Gijsbert
Published: December 2004

Summary. Thrombopoietin (TPO) is known to sensitize platelets to other agonists at 20 ng/ml, and above 100 ng/ml it is an independent activator of aggregation and secretion. In studies with a perfusion chamber, TPO, between 0·01 ng/ml and 1 ng/ml, increased platelet adhesion to surface‐coated fibrinogen, fibronectin and von Willebrand Factor (VWF) but not to a collagen‐coated surface. Increased adhesion was observed at shear rates of 300/s and 800/s in perfusions with whole blood as well as in suspensions of platelets and red blood cells reconstituted in plasma. The by the cyclooxygenase inhibitor, indomethacin, and the thromboxane A2‐receptor blocker, SQ30741, abolished the stimulation by TPO. The effect of TPO was mimicked by a very low concentration (10 nmol/l) of the thromboxane TxA2 analogue, U46619. Real‐time studies of platelet adhesion to a VWF‐coated surface at a shear of 1000/s showed that about 20% of the platelets were in a rolling phase before they became firmly attached. TPO (1 ng/ml) pretreatment reduced this number to < 5%, an effect again abolished by indomethacin. Thus, TPO potentiates the direct and firm attachment of platelets to surface‐coated ligands for αIIbβ3, possibly by increasing the ligand affinity of the integrin.
Influence of antithymocyte globulin dose on outcome in cytomegalovirus‐seropositive recipients of partially T cell‐depleted stem cell grafts from matched‐unrelated donors
Authors: Meijer Ellen , Dekker Adriaan W. , Verdonck Leo F.
Published: December 2004

Summary. The adverse impact of positive‐recipient Cytomegalovirus (CMV) serostatus on the outcome of matched‐unrelated donor (MUD) grafts has been stressed. We evaluated whether CMV‐seropositive MUD recipients transplanted after 1999 still showed inferior outcome compared with CMV‐seronegative recipients. Two important changes in transplantation procedure were introduced in 1999: (1) reduction of antithymocyte globulin dose, (2) introduction of sequence‐based typing of HLA‐DRB1. Thirty‐six patients received partial T cell‐depleted grafts before 1999, and 44 after 1999. CMV‐seropositive patients transplanted before 1999 showed a highly significant inferior outcome compared with seronegative recipients. In contrast, no difference in outcome was observed between the two groups of patients transplanted after 1999.
Role of Gαq and phospholipase C‐β2 in human platelets activation by thrombin receptors PAR1 and PAR4: studies in human platelets deficient in Gαq and phospholipase C‐β2
Authors: Vaidyula Vijender R. , Rao A. Koneti
Published: December 2004

Summary. Thrombin responses in human platelets are mediated by the protease‐activated receptors (PAR), PAR1 and PAR4. The signalling pathways mediating PAR activation have not been fully delineated for human platelets. We assessed cytoplasmic Ca2+ mobilization in response to activation with thrombin and PAR1 (SFLLRN) and PAR4 (GYPGKF) peptides in two patients whose platelets were deficient in two major signalling proteins, Gαq or phospholipase (PLC)‐β2. In normal platelets, thrombin induced a biphasic Ca2+ response with a rapid rise to a peak followed by a sustained elevation in Ca2+. The peak Ca2+ rise was impaired in both patients at lower thrombin concentrations. At higher concentrations, it was decreased in PLC‐β2‐deficient platelets; the sustained Ca2+ elevation observed in normal and Gαq‐deficient platelets was reduced in PLC‐β2‐deficient platelets. The response to SFLLRN was decreased in both patients at lower concentrations. The peak Ca2+ in response to GYPGKF was reduced in both patients; the sustained Ca2+ increase was markedly decreased in PLC‐β2‐deficient platelets. These studies provide evidence that, in human platelets, both Gαq and PLC‐β2 play a major role in responses to PAR1 and PAR4 activation, and that PLC‐β2 is required for the sustained Ca2+ rise upon thrombin activation.
Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan
Authors: Ueda Ikuyo , Morimoto Akira , Inaba Tohru , Yagi Tomohito , Hibi Shigeyoshi , Sugimoto Tohru , Sako Masahiro , Yanai Fumio , Fukushima Takashi , Nakayama Masahiko , Ishii Eiichi , Imashuku Shinsaku
Published: December 2004

Summary. Perforin gene (PRF1) mutations appear to occur in about 30% of patients with haemophagocytic lymphohistiocytosis (HLH). We tested perforin expression and gene mutations in 14 HLH patients and six patients with Epstein–Barr virus‐associated HLH (EBV‐HLH) in Japan. Five of the 14 HLH patients had perforin abnormalities. The presence of PRF1 genetic abnormality correlated well with the lack of perforin expression as determined by flow cytometry. Sequencing showed that four patients had a compound heterozygous mutation while the fifth patient had a homozygous mutation. Three of the mutations we detected were novel. In contrast, none of the six EBV‐HLH patients showed perforin abnormalities. Our data, combined with the PRF1 mutations in three previously reported Japanese patients, suggest that the 1090–1091delCT and 207delC mutations of the perforin gene are frequently present in Japanese HLH patients (62·5% and 37·5% respectively). Examination of the geographical origins of the ancestors in the perforin‐mutant HLH patients revealed that they mostly came from the Western part of Japan, suggesting that the present‐day cases may largely derive from a common ancestor.
Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning
Authors: Einsele Hermann , Schäfer Hans‐Jörg , Hebart Holger , Bader Peter , Meisner Christoph , Plasswilm Ludwig , Liebisch Peter , Bamberg Michael , Faul Christoph , Kanz Lothar
Published: December 2004

Summary. Allogeneic stem cell transplantation (allo‐SCT) after reduced‐intensity conditioning was evaluated in 22 patients (median age 53, range 36–66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)‐identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA‐mismatched unrelated donor]. Graft‐versus‐host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant‐related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2–19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8–36 months) post allografting. Estimated 2 year overall and event‐free survival was, respectively, 25·5% and 22·0% for the whole patient group, and 62·5% and 57·1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0·0182) and absence of cGVHD (P = 0·069) were associated with shorter event‐free survival. Thus long‐term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.
Ex vivo stimulation of cytomegalovirus (CMV)‐specific T cells using CMV pp65‐modified dendritic cells as stimulators
Authors: Carlsson Björn , Cheng Wing‐Shing , Tötterman Thomas H. , Essand Magnus
Published: December 2004

Summary. Cytomegalovirus (CMV) infection is a dangerous complication in immunosuppressed individuals such as allogeneic stem cell transplant patients. CMV disease can be prevented by the early post‐transplant transfer of donor‐derived, CMV‐directed, T cells. Fast and cost efficient methods to generate CMV‐specific T cells are, therefore, warranted. The current study utilized peptide‐pulsed and adenovirus‐transduced dendritic cells (DC) to generate CMV‐restricted T cells. After one stimulation with CMV pp65495−503 peptide‐pulsed DC and three re‐stimulations with peptide‐pulsed monocytes, virtually all T cells were CD8+, expressed the relevant T cell receptor and exhibited high peptide‐specific lytic activity. After only one stimulation, pp65495−503‐restricted T cells could be sorted to a purity of higher than 95% and expanded up to 1000‐fold in 2 weeks. This technique may prove useful for the rapid generation of large quantities of specific cytolytic T lymphocytes (CTL) for cell therapy. DC transduced with an adenoviral vector encoding the full‐length pp65 protein (Adpp65) were able to simultaneously expand CTL against multiple epitopes of pp65. In addition, they activated CMV‐specific CD4+ T‐helper cells. This approach would stimulate multiple‐epitope populations of pp65‐specific T cells and could be made available to patients of any human leucocyte antigen (HLA) haplotype. DC transduced with adenoviral vectors to express full‐length antigens may prove to be potent vaccines against viral pathogens and cancer.
Significant and persistent loss of bone mineral density in the femoral neck after haematopoietic stem cell transplantation: long‐term follow‐up of a prospective study
Authors: Gandhi Maher K. , Lekamwasam Sarath , Inman Ingrid , Kaptoge Stephen , Sizer Lorraine , Love Shirley , Bearcroft Philip W. , Milligan Thomas P. , Price Christopher P. , Marcus Robert E. , Compston Juliet E.
Published: December 2004

Summary. Reduced bone mineral density (BMD) has been reported following allogeneic stem cell transplantation (alloSCT) but the effects of autologous SCT (autoSCT) are less well characterized. We performed a prospective study of BMD changes and its determinants in 44 SCT recipients (38 auto and six allo; 30 peripheral blood SCT and 14 bone marrow transplantation). Serial measurements of BMD at the lumbar spine and femoral neck were performed at baseline and at 3, 6, 12 and 24 months, and spinal radiographs were performed at baseline and 12 months. Mean baseline BMD values at the femoral neck and spine were within normal limits. At 3 months, there was a significant decline of BMD at the femoral neck (P = 0·011) and a non‐significant trend towards reduction at the spine. BMD loss persisted for up to 2 years at the femoral neck (P = 0·005), but values returned to baseline at the spine. Reflecting the rapid initial decline in BMD, bone‐specific alkaline phosphatase (a serum marker of bone formation) showed a significant initial decline at 1 month but had recovered to pretransplant levels by 3 months. No new fractures were detected at 1 year post transplant. Sex, diagnosis, use of total body irradiation, stem cell source and type of graft (auto versus allo) did not significantly predict BMD change over the first 12 months. In conclusion, significant and persistent bone loss at the femoral neck was demonstrated in this group of patients following stem cell transplantation. The implications of these findings for future fracture risk require further study.
Selective internalization of monoclonal antibodies by B‐cell chronic lymphocytic leukaemia cells
Authors: Sieber Thomas , Schoeler Dagmar , Ringel Frauke , Pascu Maria , Schriever Folke
Published: December 2004

Summary. B‐cell chronic lymphocytic leukaemia (B‐CLL) cannot be cured by conventional chemotherapy, therefore, toxin‐linked therapeutic monoclonal antibodies (mAbs) are increasingly examined for their potential to improve clinical outcome. The current study aimed to identify mAbs that were internalized by the B‐CLL cells of 14 patients, using both flow cytometry and confocal laser scanning microscopy. Anti‐CD5, CD22 and CD40 mAbs were effectively taken up by B‐CLL cells, whereas mAbs against CD19, CD20, CD23 and CD45 were not. This study may form a basis for further research to identify antibodies that may serve as carriers for toxins to treat B‐CLL.
Aurora2/BTAK/STK15 is involved in cell cycle checkpoint and cell survival of aggressive non‐Hodgkin's lymphoma
Authors: Hamada Makoto , Yakushijin Yoshihiro , Ohtsuka Masaki , Kakimoto Miki , Yasukawa Masaki , Fujita Shigeru
Published: December 2004

Summary. Non‐Hodgkin's lymphoma (NHL) has a wide biological heterogeneity and shows extremely variable responses to therapeutic measures. However, markers that indicate disease activity and determine treatment strategies for this malignancy are little recognized. Using the differential display method, we have identified Aurora2/BTAK/STK15, a centrosome‐associated serine/threonine kinase, whose overexpression leads to centrosome amplification, chromosomal instability and transformation of mammalian solid tumours. Northern analysis with mRNA from a single tumour cell suspension of NHL confirmed that Aurora2/BTAK/STK15 was highly expressed in histologically aggressive types. To elucidate the function of Aurora2/BTAK/STK15 in NHL, Aurora2/BTAK/STK15 sense or antisense genes were transfected to B‐cell lymphoma cell lines to generate overexpressed or under‐regulated tumour cells. Aurora2/BTAK/STK15 antisense transfectant was barely established compared with a sense or vector‐only transfectant. Two clones were finally established that exhibited a low proliferation rate and significantly increased G1 arrest compared with vector‐only transfectants. Moreover, antisense oligo treatment in vitro showed that restriction of cell growth appeared in proportion to antisense oligo concentration. These results suggest that Aurora2/BTAK/STK15 is an effective candidate to indicate not only disease activity but also tumorigenesis of non‐Hodgkin's lymphoma. Retardation of tumour cell growth resulting from the restriction of this gene's functions may be a novel therapeutic approach for non‐Hodgkin's lymphoma.
The Fya, Fy6 and Fy3 epitopes of the Duffy blood group system recognized by new monoclonal antibodies: identification of a linear Fy3 epitope
Authors: Wasniowska Kazimiera , Lisowska Elwira , Halverson Gregory R. , Chaudhuri Asok , Reid Marion E.
Published: December 2004

Four new anti‐Duffy murine monoclonal antibodies (MAbs): two anti‐Fy6 (MIMA‐107 and MIMA‐108), one anti‐Fya (MIMA‐19) and one anti‐Fy3 (MIMA‐29) were characterized. Identification of epitopes by means of synthetic peptides (Pepscan) showed that the anti‐Fy6 reacted most strongly with peptides containing the sequence 19QLDFEDV25 of the Duffy glycoprotein, and less strongly with peptides containing LDFEDV (MIMA‐107) or LDF only (MIMA‐108). The anti‐Fya recognized epitope 38DGDYGA43 containing the Gly42 residue, which defines the Fya blood group antigen. MIMA‐29 is the first anti‐Fy3 reactive with a linear epitope 281ALDLL285 located in the fourth extracellular domain (ECD4, loop 3) of the Duffy glycoprotein. The four new antibodies extend the list of six anti‐Fy MAbs formerly characterized by Pepscan analysis that allow some general conclusions. Fine specificities of various anti‐Fya, or anti‐Fy6 are not identical, but all of them recognize linear epitopes located around, respectively, Gly42 or between two potential N‐glycosylation sites at Asn16 and Asn27. Anti‐Fy3 recognize either a linear epitope located in ECD4, or a conformational epitope that includes amino acid residues of ECD4 and of other ECDs.
Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk‐stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172)
Authors: Hill Frank G. H. , Richards Sue , Gibson Brenda , Hann Ian , Lilleyman John , Kinsey Sally , Mitchell Christopher , Harrison Christine J. , Eden Osborn B. ,   the UK Medical Research Council Working Party on Childhood Leukaemia
Published: December 2004

Concern about late adverse effects of cranial radiotherapy (XRT) has led to alternative approaches to eliminate leukaemia from the central nervous system (CNS) in childhood acute lymphoblastic leukaemia (ALL). The Medical Research Council UKALL XI trial recruited 2090 children with ALL between 1990 and 1997. Median follow‐up is 7 years 9 months; event‐free survival (EFS) and overall survival were 63·1% and 84·6%, respectively, at 5 years and 59·8% and 79·4% at 10 years. The isolated CNS relapse rate was 7·0% at 10 years. Patients were randomized for CNS‐directed therapy within white blood cell (WBC) groups. For WBC <50 × 109/l, high‐dose intravenous methotrexate (HDMTX) (6–8 g/m2) with intrathecal methotrexate (ITMTX) was compared with ITMTX alone, and was significantly better at preventing isolated and combined CNS relapse, but non‐CNS relapses were similar. There was no significant difference in EFS at 10 years, 64·1% [95% confidence interval (CI) 60·4–67·8] with HDMTX plus ITMTX, and 63·0% (95% CI 59·5–66·5) with ITMTX alone. For WBC ≥50 × 109/l, HDMTX with ITMTX was compared with XRT and a short course of ITMTX. CNS relapses were significantly fewer with XRT, but there was a non‐significant increase in non‐CNS relapses. EFS was not significantly different, being 55·2% (95% CI 47·8–62·6) at 10 years with XRT and 52·1% (95% CI 44·8–59·4) with HDMTX plus ITMTX.
Asymmetric multiplex‐polymerase chain reaction – a high throughput method for detection and sequencing genomic fusion sites in t(4;11)
Authors: Metzler M. , Brehm U. , Langer T. , Viehmann S. , Borkhardt A. , Stanulla M. , Schrappe M. , Harbott J. , Beck J. D. , Rascher W. , Repp R.
Published: December 2004

Chromosomal translocations are a characteristic feature of leukaemia and other malignant diseases. As clonal markers, they can be applied to identify and quantify the number of malignant cells by polymerase chain reaction (PCR) methods. The translocation t(4;11) is present in >60% of infant leukaemia. In order to facilitate the sequencing of chromosomal breakpoints, we developed an optimized set of 30 PCR primers and a new approach, designated as asymmetric multiplex PCR (am‐PCR). Due to the high number of primers, small breakpoint‐spanning DNA fragments are obtained in one nested multiplex PCR reaction. All PCR products contain an identical binding site for the initiation of direct sequencing. By using am‐PCR, the translocation t(4;11) was examined in bone marrow and blood samples from children with acute leukaemia. Compared with previously described methods for the determination of genomic breakpoints, am‐PCR may be advantageous with regard to its simplicity and rapidity. Breakpoint‐spanning sequences were also evaluated with regard to their applicability as unique clonal markers to design primers and probes for minimal residual disease quantification by real‐time PCR. This approach can easily be adapted to other chromosomal translocations in malignant diseases for the detection and analysis of clone‐specific DNA markers.
Transplantation of a combination of CD133+ and CD34+ selected progenitor cells from alternative donors
Authors: Lang Peter , Bader Peter , Schumm Michael , Feuchtinger Tobias , Einsele Hermann , Führer Monika , Weinstock Christof , Handgretinger Rupert , Kuci Selim , Martin David , Niethammer Dietrich , Greil Johann
Published: December 2004

Positive selected haematopoietic stem cells are increasingly used for allogeneic transplantation with the CD34 antigen employed in most separation techniques. However, the recently described pentaspan molecule CD133 appears to be a marker of more primitive haematopoietic progenitors. Here we report our experience with a new CD133‐based selection method in 10 paediatric patients with matched unrelated (n = 2) or mismatched‐related donors (n = 8). These patients received a combination of stem cells (median = 29·3 × 106/kg), selected with either anti‐CD34 or anti‐CD133 coated microbeads. The proportion of CD133+ selected cells was gradually increased from patient to patient from 10% to 100%. Comparison of CD133+ and CD34+ separation procedures revealed similar purity and recovery of target populations but a lower depletion of T cells by CD133+ selection (3·7 log vs. 4·1 log, P < 0·001). Both separation procedures produced >90% CD34+/CD133+ double positive target cells. Engraftment occurred in all patients (sustained primary, n = 8; after reconditioning, n = 2). No primary acute graft versus host disease (GvHD) ≥ grade II or chronic GvHD was observed. The patients showed a rapid platelet recovery (median time to independence from substitution = 13·5 d), whereas T cell regeneration was variable. Five patients are alive with a median follow‐up of 10 months. Our data demonstrates the feasibility of CD133+ selection for transplantation from alternative donors and encourages further trials with total CD133+ separated grafts.
Mismatch between trainees' subspecialist interest and advertised jobs; worrying implications for upper gastrointestinal trainees
Authors: Cameron I C , Johnson A G
Published: December 2004

Aims

The aim of this study was first to assess the primary subspecialist interests of general surgical specialist registrars who were accredited and still looking for a consultant position, or who were within 3 years of their CCST (certificate of completion of surgical training). These interests were then compared with subspecialist interests declared in consultant vacancies advertised in the British Medical Journal over the preceding 16 months.

Methods

All trainees in general surgery holding a national training number in six regions (Mersey, North West, Trent, Yorkshire, Northern, West Midlands) were identified, and those accredited or within 3 years of their CCST (n = 136) were telephoned to ascertain their primary subspecialist interest, whether they had a higher degree and what their desired consultant job would be. The consultant vacancies advertised in the British Medical Journal between 3 January 1998 and 8 May 1999 were assessed according to the required subspecialist interest.

Results

Upper gastrointestinal surgery is the second most popular subspecialty (n = 37; 27 per cent of trainees) after colorectal surgery (n = 40; 29 per cent of trainees). However, there were fewer consultant vacancies in upper gastrointestinal surgery (31 of 226; 14 per cent of jobs) than in any of the other three main subspecialist areas of general surgery (colorectal, vascular and breast/endocrine). The ratio of percentage of jobs to percentage of trainees was lowest in upper gastrointestinal surgery (0·50), compared with colorectal (0·77), vascular (0·89) and breast/endocrine (2·23) surgery.

Conclusions

Upper gastrointestinal surgery appears to be the most competitive of the general surgical subspecialties at present, having by far the lowest ratio of jobs to trainees. In addition, 87 per cent of upper gastrointestinal trainees have or are completing a higher degree, and 43 per cent expressed a desire to work in a teaching hospital.
Current practice in the management of acute cholecystitis
Authors: Cameron I C , Chadwick C , Phillips J , Johnson A G
Published: December 2004

Aims

Several recent papers have advocated emergency cholecystectomy for patients with acute cholecystitis, stating that it is safe, cost effective and leads to less time off work. This study was designed to assess current practice in the management of acute cholecystitis in the UK.

Methods

A postal questionnaire was sent to 357 consultant surgeons who were thought to be involved in a general surgical on-call rota, to ascertain their current management of patients with acute cholecystitis. Replies were received from 250 consultants (70 per cent) of whom 242 (68 per cent) were involved in a general surgical take. Sixteen of these consultants, however, handed their patients with acute cholecystitis on to a different team the following day for further management.

Results

Twenty-seven consultants (12 per cent) routinely treat their patients by emergency cholecystectomy whenever possible, with 24 stating that they would do this within 72 h. Limiting factors to this practice were stated to be availability of surgical staff (15), theatre space (nine) and radiological investigations (four). The remaining consultants (n = 199) routinely manage their patients conservatively initially and providing they settle, either (1) book directly for cholecystectomy (n = 94, 47 per cent), (2) reassess as an outpatient (n = 65, 33 per cent), (3) either of above (n = 21; 11 per cent) or (4) refer on to a colleague (n = 19, 10 per cent). The commonest indications for acute cholecystectomy stated by consultants whose initial treatment policy is conservative are spreading peritonitis due to bile leak (93 per cent), empyema (89 per cent), unexpected space on a theatre list (28 per cent) and failure of an acute episode to settle (21 per cent). The laparoscopic method is the commonest for both elective and emergency cholecystectomy, but the percentage of consultants using an open method rises dramatically from 9 per cent in the elective situation to 48 per cent for emergency cholecystectomy.

Conclusions

Despite evidence to support the increased use of emergency cholecystectomy, this practice is routinely carried out by only 12 per cent of consultants. However, of the consultants who treat their patients conservatively, 28 per cent are prepared to undertake emergency cholecystectomy if an unexpected space appears on the theatre list.
Thromboembolic events after carotid endarterectomy are not prevented by aspirin, but are due to the platelet response to adenosine 5′-diphosphate
Authors: Hayes P D , Box H , Tull S , Gaunt M E , Bell P R F , Goodall A H , Naylor A R
Published: December 2004

Background

Aspirin therapy fails to prevent a number of postprocedural thrombotic events, yet it still remains the standard antiplatelet regimen in most vascular surgical centres. After carotid endarterectomy (CEA), thrombosis of the endarterectomized vessel is preceded by increasing numbers of microemboli that can be detected with transcranial Doppler (TCD). The number and rate of emboli is highly predictive of thrombotic stroke. It was hypothesized that a preoperative test of platelet function might identify the mechanism(s) underlying post-CEA thrombosis.

Methods

Blood was taken from 120 patients using a standardized phlebotomy technique. Platelet fibrinogen binding was measured by whole blood flow cytometry, in unstimulated samples, and in response to adenosine 5′-diphosphate (ADP) (10−5−10−7 mol l−1) and thrombin (0·02–0·16 units ml−1). Platelet aggregation was measured using ADP (4–20 × 10−7 mol l−1). The ability of aspirin to inhibit platelets was assessed by the aggregation induced by arachidonic acid. For the first 3 h after operation, the number of emboli occurring was quantified using TCD.

Results

Of the 120 patients studied, 110 were monitored by TCD. These were divided into patients with more than 25 postoperative emboli (n = 22) and those with fewer than 25 emboli (n = 88). The degree of platelet inhibition induced by aspirin was not significantly different between the two groups (P = 0·89). However, platelets from the group with high rates of embolization bound 58 per cent more fibrinogen on flow cytometry in response to stimulation with a physiological dose of ADP (10−7 mol l−1) (P = 0·006). Aggregation of platelets from this group was also increased in response to ADP (35 per cent) relative to the group with few emboli (P = 0·001). ADP also induced more rapid aggregation in the patients with more than 25 emboli (P = 0·04). There was no difference in the activity of resting platelets (P = 0·4) or platelets stimulated by thrombin (P = 0·43), between the two groups of patients.

Conclusion

These data suggest that it is the platelet response to ADP which is important in arterial thrombotic complications rather than products of the cyclo-oxygenase pathway. This observation could have significant therapeutic implications for other vascular or interventional procedures in which the endothelium is disrupted.
Abdominal tuberculosis in children
Authors: Tireli G A , Özbey H , Salman T
Published: December 2004

Background

Abdominal tuberculosis (AT) is a rare cause of abdominal infection in children. Surgical intervention is rarely indicated, other than for obtaining a specimen for histopathological diagnosis or for the treatment of complications.

Methods

The medical records of 13 patients who were operated on with the diagnosis of AT, between 1983 and 1999, were reviewed retrospectively.

Results

The median age was 7 years (range 6 months to 10 years). The clinical signs and symptoms were as follows: abdominal pain (eight patients), loss of weight (seven), abdominal mass (six), vomiting (four) and night fever (four). Twelve patients were operated on, while diagnostic laparoscopy was perfomed in one. Patients operated on with the diagnosis of acute abdomen were diagnosed immediately at laparotomy. Surgery was limited to sampling of peritoneum and/or lymph node biopsy and ascites. The reason for surgical intervention was intestinal obstruction (eight), abdominal mass or ascites (six), psoas abscess (one) and intussusception (one). In all patients the diagnosis was confirmed by either histopathological or microbiological examination. In eight patients the AT was defined as intestinal and mesenteric type, in three patients it was localized to the peritoneum and in two the disease was diffuse. All patients were treated with INH, rifampicin and streptomycin–pyrazinamide combination. Two patients, one with a faecal fistula and one with malnutrition, came from another hospital. All patients survived and were treated successfully except the patient with a faecal fistula.

Conclusion

The diagnosis of AT is difficult before presentation with complications of intra-abdominal infection. In patients with suspected AT, aggressive surgery should be avoided and surgical intervention should be limited to tissue and/or fluid sampling.
Bacterial lipoprotein induces endotoxin-independent tolerance to the systemic inflammatory response syndrome in vivo and in vitro
Authors: Doyle M , Wang J H , Redmond H P
Published: December 2004

Background

Sublethal doses of endotoxin (lipopolysaccharide; LPS) induce tolerance in vivo and in vitro, and protect against the lethal effects of a further LPS challenge. Tolerance is characterized by diminished production of tumour necrosis factor (TNF) α. Bacterial lipoprotein (BLP), another bacterial wall component, might induce tolerance against its own lethal effects as well as those of endotoxin.

Methods

Ninety male MF-1 mice (mean(s.d.) weight 18(2) g) were randomized into three groups (n = 30 per group). Mice in group 1 received a single BLP-tolerant dose (10 mg kg−1) by intraperitoneal injection, whereas mice in group 2 received a second BLP-tolerant dose (10 mg kg−1) after 24 h. Following induction of tolerance, all mice were challenged with high doses of LPS 45 mg kg−1, BLP 45 mg kg−1 or a combination of LPS 30 mg kg−1 plus BLP 30 mg kg−1. Mice in group 3 were treated with a high dose of the above agents only. Mortality was assessed at 24 and 48 h. Macrophages were isolated from mice and pretreated in vitro with culture medium alone or culture medium containing LPS 10 ng ml−1 or BLP 10 ng ml−1 for 24 h. The cells were then stimulated with high doses (100–1000 ng ml−1) of LPS, BLP or LPS plus BLP for 6 h. The cell culture supernatants were collected and TNF-α levels were determined using enzyme-linked immunosorbent assay.

Results

BLP-induced tolerance significantly improved survival compared with that of mice without tolerance (P < 0·05). In vitro, pretreatment of murine macrophages with BLP significantly attenuated LPS, BLP and LPS plus BLP stimulation-induced TNF-α production.

Conclusion

BLP mimics LPS in the development of the systemic inflammatory response syndrome. Furthermore, BLP is capable of inducing tolerance, both in vivo and in vitro, which subsequently prevents BLP- and LPS plus BLP-induced death.
Association between intraplaque haemorrhage in the carotid atherosclerotic lesion, the degree of internal carotid artery stenosis and timing of ischaemic neurological events
Authors: Mofidi R , Crotty T , Fulton G F , Powell T , MacErlaine D , Sheehan S J , Mehigan D , Keaveny T V
Published: December 2004

Background

Expansion of carotid atherosclerotic plaques as a result of intraplaque haemorrhage has been implicated in the development of ischaemic neurological events. The relationship between the quantity of haemorrhage in the dominant atherosclerotic lesion, the degree of internal carotid artery (ICA) stenosis and the chronology of patients' symptoms was examined.

Methods

Consecutive patients undergoing carotid endarterectomy were included. The nature and timing of symptoms were recorded. Aortic arch injection digital subtraction angiography was performed before operation. Carotid endarterectomy specimens were serially sectioned and examined histologically. The amount of intraplaque haemorrhage was measured with digital image analysis. The influence of timing of symptoms on the quantity of intraplaque haemorrhage was compared with Kaplan–Meier analysis. Correlation between degree of ICA stenosis and quantity of intraplaque haemorrhage was assessed by means of regression analysis.

Results

Seventy-four patients (20 asymptomatic, 54 symptomatic) were included. The median latency of symptoms was 28 (1–600) days. Intraplaque haemorrhage was common: 54 (73 per cent) of 74 patients. Mean(s.e.m.) cumulative symptom-free survival before operation for patients with no intraplaque haemorrhage was 0·71(0·11), compared with 0·58(0·11) in those exhibiting haemorrhage in less than 50 per cent of the plaque area, and 0·20(0·07) in lesions with over 50 per cent (P = 0·002). A close correlation was observed between the degree of ICA stenosis and haemorrhagic content of the dominant atherosclerotic lesion (r2 = 0·433, P < 0·001).

Conclusion

These results confirm the association between intraplaque haemorrhage and the degree of ICA stenosis. They further demonstrate an association between the size of haemorrhage and timing of neurological events, suggesting a causative role for intraplaque haemorrhage in the development of ischaemic neurological events.
Cytoreduction including total gastrectomy for pseudomyxoma peritonei
Authors: Sugarbaker P H
Published: December 2004

Background

Cytoreductive surgery supplemented by perioperative intraperitoneal chemotherapy is a therapeutic option for selected patients with pseudomyxoma peritonei syndrome. In some patients, the stomach and/or its vascular supply are so covered by mucinous tumour that total gastrectomy is required for complete resection.

Methods

Forty-five patients underwent total gastrectomy with a temporary diverting jejunostomy as part of the surgical treatment of pseudomyxoma peritonei syndrome of appendiceal origin. Heated intraoperative intraperitoneal chemotherapy with mitomycin was used in all patients, and 36 had early postoperative intraperitoneal 5-fluorouracil. To date, 39 patients have had second-look surgery and stoma closure; 37 had additional perioperative intraperitoneal chemotherapy. A prospective database was maintained on all patients.

Results

The median age was 47 (range 33–66) years. Median interval from diagnosis of pseudomyxoma peritonei to definitive cytoreductive surgery was 23 (range 0–140) months. Six patients presented with intestinal obstruction. The need for gastrectomy was predicted before operation by abdominal computed tomography. Mean operative time was 13 (range 9–17) h. Mean intraoperative requirement for packed red blood cells was 3·0 units, and that for fresh frozen plasma was 9·9 units. Six peritonectomy procedures, including total gastrectomy, were required for complete cytoreduction. All except seven patients were maintained on parenteral nutrition before second-look surgery for jejunostomy closure. All but two patients have resumed oral nutrition with discontinuation of parenteral feeding. There was one postoperative death and one late death. Thirty-seven patients are alive and disease-free, 0–56 months after initiation of treatment.

Conclusion

Total gastrectomy with a temporary diverting jejunostomy may be used to facilitate complete cytoreduction in patients with advanced pseudomyxoma peritonei syndrome.
Effects of experimental lower-limb ischaemia–reperfusion injury on the mesenteric microcirculation
Authors: Wehrens X H T , Rouwet E V , oude Egbrink M G A , Slaaf D W , Ramsay G
Published: December 2004

Background

Ischaemia–reperfusion (I-R) of the leg is associated with functional and structural changes in the intestine. This study assessed whether acute hind-limb I-R in rats induced a reduction in perfusion and/or signs of an inflammatory response in the intestine.

Methods

Rats were subjected to 2 h of unilateral hind-limb ischaemia followed by 2 h of reperfusion (I-R group, n = 9) or to a sham procedure (control group, n = 9). Mesenteric microvascular diameters, red blood cell velocity, blood flow and leucocyte–vessel wall interactions during reperfusion were measured using intravital microscopy.

Results

Blood pressure and heart rate decreased from 30 min of reperfusion onwards in the I-R group compared with controls. From 15 min after the start of reperfusion, mesenteric arteriolar and venular red blood cell velocity and blood flow decreased by 40–50 per cent. Microvascular diameters and leucocyte–vessel wall interactions did not change.

Conclusion

Restoration of blood flow to an acutely ischaemic hind limb led to a significant decline in the splanchnic microcirculatory blood flow. There were, however, no signs of an early inflammatory response in the gut.
Significance of immunohistochemical nodal micrometastasis as a prognostic indicator in potentially curable oesophageal carcinoma
Authors: Komukai S , Nishimaki T , Suzuki T , Kanda T , Kuwabara S , Hatakeyama K
Published: December 2004

Background

The number of positive lymph nodes is an important prognostic predictor in patients with oesophageal cancer. However, the significance of nodal micrometastasis in patients with overt nodal metastasis is unknown. The aim of this study was to clarify the clinical implications of nodal micrometastasis in patients undergoing curative oesophagectomy for oesophageal cancer.

Methods

Cervical, mediastinal and abdominal lymph nodes systematically removed from 104 patients with oesophageal cancer were examined immunohistochemically to detect cells that stained positively for cytokeratins with the monoclonal antibody cocktail AE1/AE3. The postoperative course and survival rates were compared among patients with and without micrometastases, after numerical classification of overt metastatic nodes (none, between one and four, five or more).

Results

Univariate analysis showed T stage, nodal micrometastasis and number of overt nodal metastases to be significant prognostic factors after oesophagectomy. Multivariate analysis revealed nodal micrometastasis and number of overt nodal metastases to be independent prognostic factors. The presence of micrometastases had a significant adverse effect on postoperative survival in patients with no overt metastasis and in patients with one to four overt metastatic nodes, but no such impact in patients with five or more overt metastatic nodes.

Conclusion

Assessment of nodal status by both histological examination for overt metastases and immunohistochemical examination for micrometastases is useful in stratifying patients undergoing curative oesophagectomy.
Litigation for pneumothorax as a complication of fine-needle aspiration of the breast
Authors: Bates T , Davidson T , Mansel R E
Published: December 2004

Background

Pneumothorax is a rare but recognized complication of diagnostic needle aspiration of the breast. Two recent court cases alleging negligence have reached opposing opinions on very similar findings.

Methods

A Medline literature search was carried out.

Results

The reported incidence of pneumothorax after diagnostic aspiration of the breast in seven series varied between three in 100 and one in 10 000, but the weight of evidence tended towards the latter rate. Two studies reported that the complication is more common in the hands of trainees. It is not always possible to maintain the aspirating needle parallel or tangential to the chest wall. Pleural puncture may be more common than is apparent, and is most common in the tail of the breast in a thin woman.

Conclusion

It is important that breast clinicians are aware of the risk of pneumothorax but, provided proper care has been taken, this complication is not the result of a negligent act.
Extensive surgery for carcinoma of the gallbladder
Authors: Kondo S , Nimura Y , Hayakawa N , Kamiya J , Nagino M , Uesaka K
Published: December 2004

Background

The purpose of this study was to clarify the efficacy of, and define the indications for, extensive surgery for gallbladder carcinoma.

Methods

Between 1979 and 1994, 116 patients with gallbladder carcinoma underwent operation. Radical resection was performed in 80 patients.

Results

In 68 patients with stage III or IV disease, extensive resection including extended right hepatectomy (n = 40), pancreaticoduodenectomy (n = 23) and/or portal vein resection (n = 23) was employed to achieve complete tumour excision. The hospital mortality rate was 18 per cent. The postoperative 3- and 5-year survival rates were 44 and 33 per cent respectively in the patients with stage III disease (n = 9), and 24 and 17 per cent respectively in patients with stage IV (M0) disease (n = 29). In contrast, the postoperative survival rate for the 30 patients with stage IV (M1) disease (7 per cent at 3 years and 3 per cent at 5 years) was worse than that for patients with stage III and stage IV (M0) disease (P = 0·009 and P = 0·062 respectively).

Conclusion

Radical resection should be undertaken for stage III and stage IV (M0) gallbladder cancer. Although portal vein resection and/or pancreaticoduodenectomy did not contribute to long-term survival, better survival was obtained than that for the unresected patients.
Immediate bromodeoxyuridine labelling of unseparated human bone marrow cells ex vivo is superior to labelling after routine laboratory processing
Authors: Jensen P. Ø. , Mortensen B. T. , Christensen I. J. , Larsen J. K.
Published: December 2004

It is important to evaluate the proliferation of bone marrow cells in several disease conditions and during treatment of patients with for example cytokines. Labelling with bromodeoxyuridine (BrdUrd), immunocytochemical staining with anti‐BrdUrd antibody and analysis by flow cytometry provides a reliable and reproducible technique for estimation of the fraction of cells that incorporated BrdUrd into DNA during S‐phase. We have compared immediate BrdUrd labelling of unseparated bone marrow cells with the previously used labelling in the laboratory after routine separation of the mononuclear cells. Bone marrow aspirates from seven lymphoma patients without bone marrow involvement were studied with these two methods. We found higher BrdUrd labelling indices (LI) in the mononuclear cells, when cells were labelled immediately. A large variation in LI was found between patients. Our results suggest that ex vivo BrdUrd labelling of bone marrow cells should be performed immediately after aspiration and before separation, because these data are closer to values reported from in vivo labelling with BrdUrd.