bluuebunny/crossref_metadata_2025 huggingface dataset:
Life history adaptations and stress tolerance of four domestic species of Drosophila
Authors: KOJIMA Kazuya , KIMURA Masahito T.
Published: September 2003

Life history traits and stress tolerance were studied in four domestic species of Drosophila–D. melanogaster, D. simulans, D. auraria and D. immigrans– to understand how they adapt to their environments. In all species, larval weight approximately doubled in 1 day. The relative egg weight (egg weight : pupal weight) was smaller and the larval period was longer in D. immigrans than in the other three species. The pupal period was the longest in D. auraria. However, the adaptive significance of these differences in larval and pupal periods was not clear. The pupal case was generally thicker in the larger species, probably to support the larger pupal body. The start of oviposition was earliest and reproductive effort was greatest in female D. simulans, followed by female D. melanogaster. In contrast, starvation tolerance and the increase in bodyweight after eclosion was greater in D. immigrans and D. auraria than in the other two species. Pupal desiccation tolerance was greatest in D. melanogaster and lowest in D. auraria, and the less tolerant species seemed to select more humid sites for pupation. Adult tolerance to desiccation was greatest in D. melanogaster and lowest in D. simulans. In contrast, adult cold tolerance was greater in D. auraria and adult heat tolerance was lower in D. immigrans than in the other species. These differences in life history traits and stress tolerance represent the Drosophila species differential adaptations, and are assumed to allow coexistence of the species.
Population change and immature mortality process of Luehdorfia japonica (Lepidoptera: Papilionidae) feeding on an unusual host plant, Asarum caulescens Maxim. (Aristolochiaceae)
Authors: MATSUMOTO Kazuma
Published: September 2003

A population of the butterfly Luehdorfia japonica dependent on a small stand of an unusual host plant, Asarum caulescens, was found and observed for 5 years. The plant was growing in patchy clumps in a forest and in an adjoining clearing, but the number of leaves in the clearing decreased during the 5 year study period. Butterflies laid eggs mostly in or near the clearing, and the number of eggs steadily decreased year by year, along with the decrease in the number of leaves. The survival rate of the larvae was similar to that of the same species feeding on the usual host plant, Asarum takaoi, in an adjacent habitat. It is considered that A. caulescens is rarely a host of L. japonica because the plant grows in shady conditions and the butterfly prefers a host plant growing in a sunny locations for oviposition.
Chronosequential change in a butterfly community after clear‐cutting of deciduous forests in a cool temperate region of central Japan
Authors: INOUE Takenari
Published: September 2003

Transect counts of butterflies were conducted in the northern part of Ibaraki, central Japan, from 1997 to 2001 at 11 census sites, composed of successive stages of deciduous forest development: grassland (one site, early abandoned stage); cutover land (one site, 1–5 years after clear‐cutting); secondary forests (very young (two sites, 6–9 years), middle (two sites, 16–22 years) and old (two sites, 47–51 years)) and old‐growth natural forests (three sites, ≥124 years old). A total of 86 species and 8858 individual butterflies were recorded by 29 sets (406 times) of transect counts. The species richness (number of species), abundance (number of individuals) and diversity indices (Shannon–Wiener H′ and Simpson's 1–λ) of butterflies were high in the early stages (grassland, cutover land and very young secondary forests) of secondary succession. Typical natural forest species increased with the progress of succession, and the old secondary forests and old‐growth natural forests had similar species composition. In contrast, most of the typical natural grassland species were recorded only in the grassland site. In the cutover land site, the number of individuals of grassland species considerably decreased from the first to the second year; furthermore, only one typical natural grassland species was recorded. Thus, the suitable stage for grassland butterfly species lasts for only 1–2 years after clear‐cutting. Old secondary forests (approximately>50 years old) would be able to give refuge to the forest butterfly species, including typical natural forest species. Based on the results, a practical, forestry‐based plan to conserve butterfly diversity was proposed.
Two new species of the cryptic chrysidid parasitoid subfamily Loboscelidiinae: The second species in Rhadinoscelidia and the first Loboscelidia for the Indonesian fauna
Authors: KOJIMA Jun‐ichi , UBAIDILLAH Rosichon
Published: September 2003

Two new species in the cryptic chrysidid wasp subfamily Loboscelidiinae are described based on males from Gunung Halimun National Park, West Java, Indonesia. One is the second species in Rhadinoscelidia Kimsey, and the other, belonging in Loboscelidia Westwood, is the first species of the genus for the Indonesian fauna.
Colorectal cancer chemotherapy
Authors: Gill S. , Thomas R. R. , Goldberg R. M.
Published: September 2003

Colorectal cancer is a leading cause of cancer death world‐wide. There have been important advances in the chemotherapeutic management of colorectal cancer as a result of a deliberate collaborative process of well‐designed clinical trials. From the earlier standard of 5‐fluorouracil‐based therapy alone, the recent availability of newer agents, including capecitabine, irinotecan and oxaliplatin, has significantly expanded the options available for the management of patients with advanced colorectal cancer, with consequent improvements in survival. For patients with resected, high‐risk, localized disease, adjuvant systemic chemotherapy improves survival. The identification of new chemotherapy regimens, the use of predictive testing and the integration of novel targeted therapies with cytotoxic chemotherapies are areas of active clinical investigation. A review of the chemotherapeutic management of colorectal cancer is presented.
Oral esomeprazole vs. intravenous pantoprazole: a comparison of the effect on intragastric pH in healthy subjects
Authors: Armstrong D. , Bair D. , James C. , Tanser L. , Escobedo S. , Nevin K.
Published: September 2003

Background: Intravenous (IV) proton‐pump inhibitor therapy is used in patients who cannot take oral medications or require greater acid suppression. Oral esomeprazole produces greater acid suppression than oral pantoprazole; however, no comparative data exist for oral esomeprazole and IV pantoprazole.

Aim: To compare acid suppression (time with pH > 3.0, 4.0, 5.0 and 6.0) produced by standard doses of oral esomeprazole and IV pantoprazole in healthy subjects.

Methods: A randomized, two‐way crossover study in 30 subjects receiving oral esomeprazole (40 mg o.d.) or IV pantoprazole (40 mg o.d.) for 5 days followed by a 2‐week washout period before the second 5‐day drug administration period using the crossover drug regimen.

Results: Oral esomeprazole produced greater acid suppression than IV pantoprazole on day 1 [pH > 3.0 (56.9%, 35.8%;P < 0.001), pH > 4.0 (43.4%, 25.0%;P < 0.001) and pH > 5.0 (28.7%, 15.6%;P < 0.001)] and on day 5 [pH > 3.0 (70.4%, 45.9%;P < 0.001), pH > 4.0 (59.2%, 33.9%;P < 0.001), pH > 5.0 (45.5%, 23.9%;P < 0.001) and pH > 6.0 (19.6%, 12.6%;P = 0.045)]. The adverse event profiles indicated both treatments to be safe and well tolerated.

Conclusions: In healthy subjects, esomeprazole, 40 mg o.d. dispersed in water, produces greater acid suppression than pantoprazole 40 mg IV o.d. after 1 and 5 days of medication.
Peginterferon vs. standard interferon in the treatment of chronic hepatitis C
Authors: Zaman A. , Fennerty M. B. , Keeffe E. B.
Published: September 2003

Background : Randomized controlled trials over the last decade have demonstrated incremental improvement in the treatment efficacy of chronic hepatitis C with combination interferon and ribavirin therapy when compared with interferon monotherapy.

Aim : To perform a systematic review of clinical trials directly comparing interferon formulations to test the hypothesis that a true difference in terms of efficacy exists between standard interferon (with and without ribavirin) and peginterferon (with and without ribavirin).

Methods : A search of the on‐line bibliographic databases MEDLINE and PUBMED was performed independently by two authors to identify all relevant articles. In addition, the reference sections of all relevant articles were manually searched to identify any missed articles. Quality was assessed using the Jadad scale, which is an accepted scale specific for randomized controlled trials. A priori, it was decided to include only articles with a Jadad score of three or higher in the final analysis. Data were abstracted on to pre‐determined abstraction sheets. The inclusion of articles, the data abstracted and the methodological score differences were adjudicated by consensus with agreement of the authors performing the search.

Results : Seven citations of randomized controlled trials, comparing at least two different interferon formulations and evaluating the sustained virological response as a primary end‐point, were identified. These relevant articles were abstracted, and five of the seven were found to have a Jadad score of three or higher and comprised the final set of citations reviewed. The studies consistently demonstrated that peginterferon monotherapy was superior to standard interferon, even in patients with advanced fibrosis. With regard to combination interferon therapy, only two high‐quality articles compared peginterferon plus ribavirin with standard interferon plus ribavirin. Both studies demonstrated that the overall sustained virological response was statistically better with peginterferon plus ribavirin.

Conclusions : On the basis of this systematic review, peginterferon‐based regimens are superior to standard interferon‐based regimens for the treatment of chronic hepatitis C.
Inulin is an ideal substrate for a hydrogen breath test to measure the orocaecal transit time
Authors: Geboes K. P. , Luypaerts A. , Rutgeerts P. , Verbeke K.
Published: September 2003

Background : A better substrate is needed for a hydrogen breath test to measure the orocaecal transit time. The currently used substrate, lactulose, accelerates the orocaecal transit time by increasing the osmolality of the gut contents. The recently developed lactose 13C‐ureide breath test is reliable, but a hydrogen breath test is preferred, as it allows the simultaneous investigation of the digestion and absorption of nutrients by means of 13C‐labelled compounds.

Methods : The usefulness of different types of inulin as a substrate for a hydrogen breath test was studied. Raftilin HP (> 99% inulin with a degree of polymerization of between 5 and 60 and < 0.5% glucose, fructose and sucrose) was further evaluated and compared with lactulose with regard to its effects on gastric emptying and the digestion of protein and lipids.

Results : A good correlation was found between the orocaecal transit times using Raftilin HP (338 min; interquartile range, 300–383 min) and lactose 13C‐ureide (353 min; interquartile range, 285–375 min) (r = 0.85; P < 0.001). The administration of 5 or 10 g Raftilin HP had no influence on the orocaecal transit time, whereas lactulose significantly shortened the orocaecal transit time. Neither inulin nor lactulose had a significant influence on gastric emptying or protein or lipid assimilation.

Conclusion : Raftilin HP is an ideal substrate for a hydrogen breath test to measure the orocaecal transit time.
Cyclo‐oxygenase‐2 over‐expression in sporadic colorectal carcinoma without lymph node involvement
Authors: Buecher B. , Heymann M.‐F. , Lièvre A. , Nguyen J.‐M. , Wilson K. , Bézieau S. , Mosnier J.‐F. , Galmiche J.‐P. , Blottière H. M.
Published: September 2003

Background : Cyclo‐oxygenase‐2 over‐expression has been reported in most advanced human colorectal cancers.

Aims : To assess the prevalence of cyclo‐oxygenase‐2 over‐expression in non‐advanced colorectal cancers, to investigate the correlation between cyclo‐oxygenase‐2 status and tumour clinicopathological features and molecular phenotype, and to determine the impact of cyclo‐oxygenase‐2 status on long‐term clinical outcome.

Methods : Sixty‐one patients who had undergone surgery for colorectal cancer without lymph node involvement were evaluated retrospectively. Cyclo‐oxygenase‐2 expression was determined by immunohistochemistry. The tumour replication error phenotype was assessed by amplification of the two microsatellites, BAT‐25 and BAT‐26.

Results : Thirty‐six tumours were classified as cyclo‐oxygenase‐2 positive and 25 as cyclo‐oxygenase‐2 negative. No correlation was found between cyclo‐oxygenase‐2 over‐expression and clinicopathological features or molecular phenotype. Cyclo‐oxygenase‐2 over‐expression was an independent predictor of a poor prognosis. Indeed, the relative risk of tumour recurrence or death for patients with cyclo‐oxygenase‐2‐positive tumours was 2.13 times that of patients with cyclo‐oxygenase‐2‐negative tumours (P = 0.008; 95% confidence interval, 1.22–3.73). This difference remained significant when post‐operative deaths were censored in the multivariate analysis (P = 0.014).

Conclusion : Cyclo‐oxygenase‐2 over‐expression is not associated with tumour phenotype, but is indicative of a poorer clinical outcome in patients with non‐advanced colorectal carcinoma.
The economic impact of irritable bowel syndrome
Authors: Inadomi J. M. , Fennerty M. B. , Bjorkman D.
Published: September 2003

Background: Although little mortality is associated with irritable bowel syndrome, curative therapy does not exist and thus the economic impact of this disorder may be considerable.

Methods: A systematic review of the literature was performed. Studies were included if their focus was irritable bowel syndrome, and direct and/or productivity (indirect) costs were reported. Two investigators abstracted the data independently.

Results: One hundred and seventy‐four studies were retrieved by the search; 11 fulfilled all criteria for entry into the review. The mean direct costs of irritable bowel syndrome management were reported to be UK£90, Canadian$259 and US$619 per patient annually, with total annual direct costs related to irritable bowel syndrome of £45.6 million (UK) and $1.35 billion (USA). Direct resource consumption of all health care for irritable bowel syndrome patients ranged from US$742 to US$3166. Productivity costs ranged from US$335 to US$748, with total annual costs of $205 million estimated in the USA. Annual expenditure for all health care, in addition to expenditure limited to gastrointestinal disorders, was significantly higher in irritable bowel syndrome patients than in control populations.

Conclusions: Despite the lack of significant mortality, irritable bowel syndrome is associated with high direct and productivity costs. Irritable bowel syndrome patients consume more gastrointestinal‐related and more total health care resources than non‐irritable bowel syndrome controls, and sustain significantly greater productivity losses.
The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups
Authors: Oosterveld Margriet , Wittebol Shulamiet H. , Lemmens Wim A. J. G. , Kiemeney Bart A. L. M. , Çatik Ashuman , Muus Petra , Schattenberg Anton V. M. B. , De Witte Theo J. M.
Published: September 2003

Summary. The present study applied the International Prognostic Scoring System (IPSS) to 306 consecutive myelodysplastic syndrome (MDS) patients diagnosed between August 1977 and September 2000 at the University Medical Centre Nijmegen. The aim was to investigate whether the IPSS could be used as a prognostic tool in MDS patients aged less than 61 years who were treated with acute myeloid leukaemia (AML)‐like chemotherapy with or without transplantation, and whether the scoring system discriminated between the subgroups of patients who benefit from intensive treatment strategies. The patients were retrospectively assigned to the IPSS risk categories and compared with the IPSS workshop patients. Eighty‐three of 159 patients aged < 61 years, classified as intermediate 1, intermediate 2 and high risk according to the IPSS, received intensive treatment consisting of chemotherapy only (n = 30), chemotherapy followed by either autologous stem cell transplantation (n = 7) or allogeneic stem cell transplantation (n = 46). After intensive treatment, the median survival was 2·6 years for the intermediate 1 risk group (n = 33), 3·4 years for the intermediate 2 risk group (n = 27) and 0·9 years for the high‐risk group (n = 23). We conclude that the IPSS is an improved scoring system for patients receiving supportive care. Nevertheless, the scoring system does not seem to be the best method for predicting outcome after intensive antileukaemic treatment. In particular, intermediate 2 risk patients may benefit from intensive treatment.
Long‐term outcomes of allogeneic stem cell transplant recipients after calcineurin inhibitor‐induced neurotoxicity
Authors: Chohan Rizwana , Vij Ravi , Adkins Douglas , Blum William , Brown Randy , Tomasson Michael , Devine Steven , Graubert Timothy , Goodnough Lawrence T. , DiPersio John F. , Khoury Hanna
Published: September 2003

Summary. Calcineurin inhibitor‐induced central nervous system toxicities are uncommon and often resolve after discontinuation of the offending drug. The long‐term outcome of these patients is, however, unknown. Resolution of symptoms occurred in 70% of 30 allografted recipients who developed calcineurin inhibitor‐induced neurotoxicity. When patients were rechallenged with the same or a different calcineurin inhibitor, symptoms recurred in 41%, leading to permanent discontinuation of the drug. De novo or progressive acute graft‐versus‐host disease (GVHD) was observed in 54% of patients at a median of 7 d (range 1–70 d) after initial onset of neurotoxicity. The prognosis was grim, with 24 (80%) of these patients dying a median 33 d after the onset of neurotoxicity (range 2–594 d). GVHD and/or infection occurred in 54% and were the most common primary causes of death. We conclude that calcineurin inhibitor‐induced neurotoxicity is frequently reversible but associated with a poor prognosis.
Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia
Authors: Garg Mamta , Moore Helen , Tobal Khalid , Liu Yin John A.
Published: September 2003

Summary. We have developed a sensitive, competitive, nested reverse transcription polymerase chain reaction (RT‐PCR) titration assay that quantifies the number of Wilm's tumour (WT1) gene transcripts in bone marrow (BM) and peripheral blood (PB), coupled with a competitive RT‐PCR protocol for the ABL gene as control. We studied BM/PB samples from 107 acute myeloid leukaemia (AML) patients and 22 acute lymphoblastic leukaemia (ALL) patients at presentation and detected the WT1 gene in > 90% of patients by a qualitative assay. Quantitative analysis of WT1 transcript at presentation in 66 patients (52 AML, 14 ALL) correlated significantly with remission rate, disease‐free survival (DFS) and overall survival (OS) (P = 0·003). WT1 levels were normalized to 105ABL transcripts. Within good and standard cytogenetic risk groups, high WT1 levels correlated with poorer outcome. Serial quantification was performed in 35 patients (28 AML, seven ALL); those with less than 103 copies of WT1 after induction and second consolidation chemotherapy had significantly better DFS and OS. Fourteen patients have relapsed with a median complete remission duration of 12 (range 4–49) months. We detected a rise in WT1 levels in nine out of 14 patients, 2–4 months before the onset of haematological relapse, whereas in the remaining five patients, WT1 levels remained persistently high during the disease course. WT1 levels were lower in PB than in BM, but mirrored changes in the BM samples and were equally informative. We suggest that WT1 is a useful molecular target to monitor minimal residual disease in acute leukaemia, especially in cases without a specific fusion gene.
Pure red cell aplasia associated with expansion of CD3+ CD8+ granular lymphocytes expressing cytotoxicity against HLA‐E+ cells
Authors: Mori Kiyoshi L. , Furukawa Hisae , Hayashi Keiko , Sugimoto Kei‐ji J. , Oshimi Kazuo
Published: September 2003

Summary. T‐cell granular lymphocyte‐proliferative disorder (T‐GLPD) is characterized by the proliferation of cytotoxic T lymphocytes, and is often associated with pure red cell aplasia (PRCA). The mechanism involved in the development of PRCA in T‐GLPD is unknown. Peripheral blood mononuclear cells were isolated from 20 patients with T‐GLPD. Ten patients had associated PRCA. Granular lymphocytes (GLs) of T‐GLPD are positive for CD94, but not NKG2A. To clarify the functional role of CD94 in T‐GLPD, we performed a cytotoxicity assay against the trophoblast cell line, BeWo, which is known to express human leucocyte antigen (HLA)‐E, a natural ligand of CD94, and is deficient in other HLA class I and class II antigens. GLs isolated from T‐GLPD with PRCA patients killed BeWo cells more significantly than GLs from T‐GLPD without PRCA patients. Furthermore, GLs from T‐GLPD with PRCA were significantly stimulated by a monoclonal antibody against CD94, whereas those of T‐GLPD without PRCA were not. Taken together, HLA‐E, a ligand of CD94, was suggested to stimulate CD94+ cells to kill HLA‐E+ cells in T‐GLPD with PRCA. GLs of T‐GLPD with PRCA have a potential positive activity against HLA‐E+ cells, whereas GLs from T‐GLPD without PRCA do not. CD94 may play a key role in the pathogenesis of PRCA in T‐GLPD.
Bernard–Soulier syndrome due to the homozygous Asn‐45Ser mutation in GPIX: an unexpected, frequent finding in Germany
Authors: Sachs Ulrich J. H. , Kroll Hartmut , Matzdorff Axel C. , Berghöfer Heike , Löpez José A. , Santoso Sentot
Published: September 2003

Summary. Bernard–Soulier syndrome (BSS) is a rare inherited disorder with giant platelets, thrombocytopenia and a prolonged bleeding time. These abnormalities are caused by genetic defects of the glycoprotein (GP) Ib‐IX complex that constitutes the von Willebrand factor receptor on the platelet surface. Here, we describe four unrelated German patients with low platelet counts and mild bleeding tendency. Three patients had been diagnosed with immune thrombocytopenia (ITP) and were treated with steroids without response. Another patient presented with easy bruising. Peripheral blood smears showed giant platelets. Ristocetin‐induced platelet aggregation was almost absent, and quantitative flow cytometry and Western blotting disclosed a greatly reduced surface expression of GPIb‐IX. Unexpectedly, sequencing the entire coding regions of GPIbα, GPIbβ and GPIX revealed that all four unrelated patients were homozygous for an A to G mutation in position 1826 of the GPIX gene, constituting a Asn‐45Ser change. This mutation has been described before and now represents by far the most often identified molecular defect causing BSS in Caucasians. Because BSS patients are likely to be misdiagnosed with ITP, treatment‐resistant ITP patients should be re‐evaluated thoroughly. Asn‐45Ser genotyping may be a helpful tool for differential diagnosis.
Tandem high‐dose therapy (HDT) for multiple myeloma: recombinant human erythropoietin therapy given between first and second HDT allows second peripheral blood stem cell transplantation without red blood cell transfusion
Authors: Baron Frédéric , Frère Pascale , Fillet Georges , Beguin Yves
Published: September 2003

Summary. We evaluated the ability of recombinant human erythropoietin (rHuEpo) therapy, given before high‐dose therapy (HDT), to allow autologous peripheral blood stem cell transplantation (PBSCT) without red blood cell (RBC) transfusions. Eleven multiple myeloma patients underwent tandem HDT and autologous PBSC, receiving 500 U/kg/week rHuEpo from d 30 after initial transplant. Haemoglobin levels were 9·5 ± 1·1 g/dl and 12·5 ± 0·9 g/dl at the first and second transplant respectively (P < 0·001). RBC transfusions were required for 10/11 patients for the first transplant versus 1/11 for the second (P < 0·001). To conclude, a short course of rHuEpo therapy before HDT facilitates the performance of an autologous transplant without RBC transfusions.
Molecular, ultrastructural and functional characterization of a Spanish family with Hermansky–Pudlak syndrome: role of insC974 in platelet function and clinical relevance
Authors: González‐Conejero Rocio , Rivera José , Escolar Ginés , Zuazu‐Jausoro Isabel , Vicente Vicente , Corral Javier
Published: September 2003

Summary. Hermansky–Pudlak syndrome (HPS) is a rare autosomal recessive disorder, which is genetically heterogeneous. In humans, mutations associated with this syndrome have been identified that affect four genes, most of them located in the HPS‐1 gene. We evaluated the clinical, molecular, platelet ultrastructure and platelet function data obtained from one Spanish HPS patient and his relatives. The proband was compound heterozygous for a de novo nonsense mutation (Arg‐131Stop), which has not been described previously, and for a common frameshift mutation (insC974). These two mutations were also identified by reverse transcription polymerase chain reaction (RT‐PCR) in half the RNA, supporting the premise that they have minor effects on either transcription or RNA stability. The patient had an almost complete absence of platelet‐dense granules. Accordingly, his platelets showed a small aggregatory response, reduced CD63 surface expression after platelet activation and minor serotonin uptake. Interestingly, despite the absence of clinical symptoms, two relatives carrying only one HPS‐1 mutation (insC974) presented a decreased content of platelet‐dense granules and showed significant reductions in platelet aggregation, expression of CD63 after platelet activation and serotonin uptake. Data show that the presence of a single mutation affecting one allele of the HPS‐1 gene might have relevance in the organogenesis of platelet‐dense granules, affecting platelet function. However, these functional defects were not of a great enough magnitude to have clinical significance and, thus, these subjects were clinically asymptomatic.
Hypoxic response of iron absorption is not affected by the Hfe gene knock‐out in mice
Authors: Laftah Abas H. , Simpson Robert J. , Beaumont Nick , Bahram Seiamak , Schümann Klaus , Srai S. Kaila S.
Published: September 2003

Summary. The effect of Hfe (haemochromatosis) gene deletion on the hypoxic response of iron absorption was investigated. Hfe knock‐out mice were exposed to 0·5 atmospheres hypoxia for 3 d before in vivo iron absorption was measured. Both wild‐type and Hfe knock‐out mice had similar (two‐ to threefold) increases in iron absorption in response to hypoxia. We conclude that the Hfe gene product is not required for mice to increase iron absorption rates in response to hypoxia. The data further support the hypothesis that at least two independent mechanisms for the regulation of iron absorption exist, only one of which requires Hfe.
Serum levels of macrophage inflammatory protein‐1 alpha (MIP‐1α) correlate with the extent of bone disease and survival in patients with multiple myeloma
Authors: Terpos Evangelos , Politou Marianna , Szydlo Richard , Goldman John M. , Apperley Jane F. , Rahemtulla Amin
Published: September 2003

Summary. The role of serum macrophage inflammatory protein‐1 alpha (MIP‐1α) in bone disease and survival was evaluated in 85 newly diagnosed multiple myeloma (MM) patients. MIP‐1α was elevated in MM patients and correlated with the extent of bone disease, bone resorption markers and levels of soluble receptor activator of nuclear factor‐κB (RANK) ligand. MIP‐1α was also associated with survival; the 3‐year probability of survival was 85% and 44% for MIP‐1α levels below and above 48 pg/ml respectively (P = 0·021). This suggests that MIP‐1α contributes to the pathogenesis of bone disease in MM and possibly in tumour growth, as reflected by its impact on survival.
Cytogenetic abnormalities in paroxysmal nocturnal haemoglobinuria usually occur in haematopoietic cells that are glycosylphosphatidylinositol‐anchored protein (GPI‐AP) positive
Authors: Sloand Elaine M. , Fuhrer Monika , Keyvanfar Keyvan , Mainwaring Lori , Maciejewski Jaroslaw , Wang Yu , Johnson Sarah , Barrett A. John , Young Neal S.
Published: September 2003

Summary. Some patients with paroxysmal nocturnal haemoglobinuria (PNH) have bone marrow findings characteristic of myelodysplastic syndrome. We studied nine PNH patients to determine whether these karyotypic abnormalities were more likely to occur in glycosylphosphatidylinositol‐anchored protein (GPI‐AP)‐negative cells. Abnormal chromosome patterns were evident only in the GPI‐AP‐positive populations of the PNH clone in 8 of 9 cases studied. Purified GPI‐AP‐negative CD34 cells gave rise only to cells of normal karyotype, whereas the progeny of the GPI‐AP‐positive CD34 cells showed the karyotypic abnormality. These findings suggest that environmental factors, but not genetic instability of the GPI‐AP‐deficient clone, foster development or survival of haematopoietic cells with chromosomal abnormalities.
A novel deletion causing (εγδβ)° thalassaemia in a Chilean family
Authors: Game Laurence , Bergounioux Jean , Close James Paul , Marzouka B. Esperenza , Thein Swee Lay
Published: September 2003

Summary. We describe a novel deletion causing (εγδβ)° thalassaemia segregating in three generations of a Chilean family of Spanish descent. Heterozygotes for the deletion were all affected by neonatal haemolytic anaemia. The deletion of 152,569 bp extends from 77 kb upstream of the ε gene to 31 kb downstream of the β gene, and includes the entire β‐globin gene cluster and two upstream olfactory receptor genes. Comparison of the sequences of the deletion junction with those of the flanking normal DNA suggests that the deletion results from a non‐homologous recombination event. The insertion of 16 ‘orphan’ nucleotides in the deletion junction creates a perfect inverted repeat of 12 nucleotides, forming a 12‐bp stem with a four‐nucleotide loop that could have contributed to the illegitimate recombination. The 3′ breakpoint is located within an L1 family repeat that contains a perfect 160‐bp palindrome, and is in close proximity to the 3′ breakpoints of five other deletions in the β cluster – Indian (HPFH‐3), Italian (HPFH‐4) and Vietnamese GγAγ (δβ)° HPFH, German and Belgian Gγ (Αγδβ)° thalassaemia.
Quiescent CD34+ early erythroid progenitors are resistant to several erythropoietic ‘inhibitory’ cytokines; role of FLIP
Authors: Ratajczak Janina , Kucia Magdalena , Reca Ryan , Zhang Jin , Machalinski Bogdan , Ratajczak Mariusz Z.
Published: September 2003

Summary. In this study, quiescent bone marrow‐derived CD34+ erythroid burst‐forming units (BFU‐E) were found to be resistant to the inhibitory effects of tumour necrosis factor (TNF)‐α and ‐β as well as interferon (IFN)‐α, ‐β and ‐γ, in contrast to those stimulated by a combination of erytrhropoietin (Epo) plus kit ligand (KL). Unexpectedly, we found that TNF‐α also inhibited the apoptosis of quiescent normal human CD34+ BFU‐E cells. Accordingly, TNF‐α added to CD34+ cells cultured for 2 d in serum‐free medium protected clonogeneic BFU‐E from undergoing serum deprivation‐mediated apoptosis. Furthermore, the prosurvival effect of TNF‐α in quiescent CD34+ cells was consistent with its ability to induce phosphorylation of mitogen‐activated protein kinase (MAPK) p42/44. However, when added to CD34+ cells that were stimulated by Epo + KL, TNF‐α induced apoptosis and inhibited proliferation of BFU‐E. To explain this intriguing differential sensitivity between unstimulated CD34+ cells versus those stimulated by Epo + KL, we examined the expression of apoptosis‐regulating genes (FLIP, BCL‐2, BCL‐XL, BAD and BAX) in these cells. Of all the genes tested, FLIP became rapidly downregulated in CD34+ cells 24 h after stimulation with Epo + KL, suggesting that it may protect quiescent CD34+ BFU‐E progenitors residing in the bone marrow from the inhibitory effects of inflammatory cytokines. Thus, we hypothesize that cycling cells may become more sensitive to proapoptotic stimuli (e.g. chemotherapy, inhibitory cytokines) than quiescent ones because of the downregulation of protective FLIP.
The type 1 CD10/neutral endopeptidase 24.11 promoter: functional characterization of the 5′‐untranslated region
Authors: Sezaki Nobuo , Ishimaru Fumihiko , Tabayashi Takayuki , Kataoka Itaru , Nakase Koichi , Fujii Keiko , Kozuka Teruhiko , Nakayama Hiroyuki , Harada Mine , Tanimoto Mitsune
Published: September 2003

Summary. The cell surface zinc metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) is expressed on normal and malignant lymphoid progenitors, granulocytes and a variety of epithelial cells. Because CD10/NEP functions as part of a regulatory loop that controls local concentrations of peptide substrates and associated peptide‐mediated signal transduction, its role in each tissue is different depending on the availability of substrate. To characterize further how this widely distributed molecule is regulated differentially in each tissue, we analysed the major type 2 CD10/NEP promoter and found three functionally important transcription factor binding sites, one of which was identical to CCAAT‐binding transcription factor/nuclear transcription factor Y. In this report, we analyse the type 1 CD10/NEP promoter and found a functionally important transcription factor binding site in the 5′‐untranslated region. The results of the competition and supershift experiments demonstrated that the functionally important transcription factor was identical to Sp1. Our results suggest that ubiquitously expressed Sp1 may play an important role in differentiation stage‐specific regulation of CD10/NEP expression in lymphoid lineage.
Veno‐occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia
Authors: Stoneham Sara , Lennard Lynne , Coen Pietro , Lilleyman John , Saha Vaskar
Published: September 2003

Summary. The case records of 99 consecutive children with acute lymphoblastic leukaemia who received either 6‐thioguanine (6‐TG) or 6‐mercaptopurine (6‐MP) as maintenance therapy for at least 1 year were reviewed for hepatic veno‐occlusive disease (VOD). Overall, 12% of those on 6‐TG developed VOD (all boys). Isolated persistent thrombocytopenia appeared to be the earliest indicator of incipient VOD. Multivariate analysis identified male sex and 6‐TG as risk factors. In all cases, VOD was mild and reversible on withdrawing 6‐TG or replacing it with 6‐MP. The data implicate a sex‐linked polymorphic variation in xenobiotic pathways of thiopurine metabolism in the pathogenesis of VOD.
Phenotype, function and chimaerism of monocyte‐derived blood dendritic cells after allogeneic haematopoietic stem cell transplantation
Authors: Nachbaur David , Kircher Brigitte , Eisendle Klaus , Lätzer Karla , Haun Margot , Gastl Günther
Published: September 2003

Summary. Dendritic cells (DCs) are essential for initiating T‐cell responses against either host‐ or leukaemia‐specific antigens. We analysed phenotype, allostimulatory capacity and chimaerism of monocyte‐derived DCs (moDCs) serially in 28 patients receiving allogeneic stem cell grafts after conventional myeloablative (n = 14) or reduced‐intensity conditioning (RIC, n = 14). Although the recovery of phenotype and function of moDCs after myeloablative stem cell transplantation (SCT) was prompt, there was a trend to a lower expression of co‐stimulatory molecules and major histocompatibility antigen class II antigens on mature moDCs in patients who had received RIC transplants. Similarly, the allostimulatory capacity of mature moDCs after RIC transplants was reduced for up to 6 months. Six out of 14 (43%) RIC transplant patients showed a pattern of mixed chimaerism within the first 3 months after transplant. RIC transplant patients with a mixed donor DC chimaerism had a significantly higher risk of relapse (75% versus 35% for patients with full donor DC chimaerism, P = 0·03) but a lower incidence of acute graft‐versus‐host disease (25% versus 56% for patients with full donor DC chimaerism, P = 0·157). These data, although preliminary, provide evidence that DC function is impaired after RIC transplants and that DC chimaerism may have an impact on graft‐versus‐host and graft‐versus‐leukaemia reactions.
Is attention deficit hyperactivity disorder over‐represented among HIV‐seronegative boys with haemophilia? Preliminary results from our centre
Authors: Wodrich D. L. , Recht M. , Gradowski M. , Wagner L.
Published: September 2003

Summary.  Haemophilia care providers report anecdotally that many boys under their care bear the diagnosis of attention deficit hyperactivity disorder (ADHD). This study investigated the hypothesis that ADHD is over‐represented among boys with haemophilia. All the boys with haemophilia, aged 5–14 years, who receive their comprehensive care at our centre were solicited to participate in this study. Of the 78 eligible boys, 34 (44%) were successfully contacted and agreed to participate. All participants were HIV‐negative on both serological and PCR‐based assays. The presence of ADHD symptoms was established via a parent‐ and teacher‐completed standardized rating instrument. On the parent‐rating scale, 26% of the participants exceeded the cut‐off for inattentive ADHD, 18% for hyperactive/impulsive ADHD, and 18% for combined. On the teacher rating scale, 4% of the participants exceeded the cut‐off for inattentive ADHD, but no participants were rated as having extreme hyperactive/impulsive or combined ADHD symptoms. Retrospectively, 29% of the participants had previously been diagnosed with ADHD, all treated with stimulant medications. Of note, 38% of our participants were enrolled in special education programmes. All of the above were more common in boys with haemophilia compared with national controls. A chart review of non‐participating patients from the same clinic suggested that sampling bias is unlikely to account for these differences. These results provide the first empirical evidence that ADHD may be over‐represented among boys with haemophilia.
Central venous catheter‐related thrombosis presenting as superior vena cava syndrome in a haemophilic patient with inhibitors
Authors: Carcao M. D. , Connolly B. L. , Chait P. , Stain A. M. , Acebes M. , Massicotte P. , Blanchette V. S.
Published: September 2003

Summary.  We report the case of a 10.5‐year‐old boy with severe haemophilia A (SHA) and inhibitors who presented with superior vena cava (SVC) obstruction while on immune tolerance induction (ITI) with daily recombinant factor VIII (rFVIII) and factor eight bypassing activity (FEIBA) (75 U kg−1) twice a week. The boy had a right‐sided implanted central venous catheter. Imaging revealed a large occlusive thrombus in the SVC with all upper venous system drainage occurring through the azygos and collateral veins. Despite initial success with local thrombolytic therapy using recombinant tissue plasminogen activator, the thrombus persisted. Mechanical thrombolysis and angioplasty resulted in the successful removal of the thrombus and resolution of the SVC syndrome. Unfractionated heparin was used to prevent thrombus reformation/propagation. A work‐up did not reveal any underlying genetic prothrombotic risk factors.

The occurrence of such a profoundly symptomatic thromboembolism (TE) in a boy with SHA with inhibitors is unusual. A combination of risk factors, including the ongoing infusion of high doses of FVIII in the context of a disappearance of inhibitors together with the infusion of clotting factors known to be potentially thrombogenic, may place haemophilic patients on ITI (immune tolerance induction) at risk for this rare, life‐threatening complication. The appropriate management of TEs in such a setting is unknown.
Surveillance of infectious complications associated with central venous access devices in children with haemophilia
Authors: Tarantino M. D. , Lail A. , Donfield S. M. , Lynn H. , Peddle L. , Hunsberger S. , Shapiro A. D.
Published: September 2003

Purpose : To analyse the risk factors for infection associated with central venous access device (CVAD) use in children with haemophilia.

Methods : Risk factors for CVAD infection among patients with congenital haemophilia who had had a CVAD implanted at a single institution were evaluated utilizing the following variables: age at CVAD placement, age at end of study, number of days with a CVAD, percentage of lifetime with a CVAD, and history of inhibitor.

Results : Fifty‐nine patients had a total of 97 936 (median 1768 days per patient) CVAD days in the study period. The median age at CVAD placement was 2.7 years (range 0–14.0). Twenty‐six (44%) patients reported CVAD infections during the study period from January 1993 to October 2000. Twenty‐four patients had their CVAD replaced, 17 (71%) of whom reported having infections and seven (29%) of whom had a history of inhibitor. The strongest predictor for having any infections was inhibitor status (P = 0.16), although none of the risk factors had statistically significant effects.

Among the 26 patients reporting infections, 42% had more than one CVAD‐related infection. Seven patients had multiple infections involving the same organism. The mean rate of infection was 0.45 per 1000 catheter days, with a 95% confidence interval of 0.33–0.60. Those with a history of inhibitor had an infection rate of 0.66 compared with 0.38 per 1000 catheter days (P = 0.09) for those without a history of inhibitor. Patients who were older (greater than the median age of 2.7) at CVAD placement had a lower rate of infection (0.29 vs. 0.65, P < 0.01) compared with those ≤2.7 years. Adjustment for inhibitor status had little impact on these results.

For the group as a whole, the median time to first infection was 1977 days from CVAD placement. Patients who were older at CVAD placement or study exit had lower relative hazards of infection (P = 0.05 and P = 0.09 respectively), while those who had inhibitors had a higher but not statistically significant relative hazard of 1.88 (P = 0.13).

Conclusions : These data reveal that while considerable numbers of patients develop CVAD‐related infection, the interval between catheter placement and infection can be quite long. In addition, the earlier in life a CVAD is placed, the higher the risk of infectious complications, as evidenced by the tendency towards a higher infection rate. Measures to prevent CVAD‐related infection might be focused on very young patients who appear to be at higher risk.
Acquired factor VIII inhibitor in a non‐haemophilic boy
Authors: Klukowska A. , Łaguna P. , Obitko‐Płudowska A. , Niedzielska K. , Malinowska I. , Rokicka‐Milewska R.
Published: September 2003

Summary.  We describe the case of a previously healthy 8‐year‐old non‐haemophilic boy who developed a factor VIII inhibitor of unknown origin. The symptoms of this disease were haemorrhages in the muscles of the right thigh, numerous bruises and a large haematoma of the right crus with subsequent tissue necrosis. Activated and non‐activated prothrombin complex concentrates were administered in the therapy of the haemorrhages. To eliminate factor VIII inhibitor, the patient was treated first with prednisone, then immunoglobulin G and finally with a combination of prednisone and cycylophosphamide, without any effect. A total spontaneous remission was observed after 15 months from the beginning of the disease.
Radionuclide synovectomy and chronic haemophilic synovitis in Asians: a retrospective study
Authors: Chew E. M. D. , Tien S. L. , Sundram F. X. , Ho Y. K. L. , Howe T. S.
Published: September 2003

Summary.  Radionuclide synovectomy has been identified as the procedure of choice in treating chronic haemophilic synovitis among Caucasian populations. Its effectiveness among East Asians has not been studied. A retrospective study was carried out on 12 Asian haemophiliacs who underwent 12 radionuclide synovectomies. The average follow‐up was 30.7 months (range 6–55) for primary procedures. 32P chromic phosphate and 188Re–tin colloid were injected into target joints according to protocol. There was a significant 80% decrease in the median frequency of haemarthrosis from 1.4 per month (range 0.2–7.0) to 0.25 per month (range 0.0–1.8) (P < 0.05). Half of the patients had excellent results by 1 year of synovectomy. The median factor usage for target joint haemarthrosis postsynovectomy was 792 units per month (range 0–3209) reduced significantly from a presynovectomy level of 1452 units per month (range 306–7125) (P < 0.05). Patients also reported a reduction in joint pain scores, and an improvement in joint mobility and quality of life. The majority of patients were satisfied with the overall outcome of radionuclide synovectomy. Radionuclide synovectomy appears to be effective in reducing the incidence of target joint haemarthrosis and quantity of factor usage for such bleeds among Asians with haemophilic synovitis.
Type I coagulation factor V deficiency caused by compound heterozygous mutation of F5 gene
Authors: Fu Q. , Wu W. , Ding Q. , Hu Y. , Wang X. , Wang H. , Wang Z.
Published: September 2003

A 16‐year‐old Chinese female with prolonged bleeding after surgery has been studied. Routine clotting tests revealed a prolonged activated partial thromboplastin time (APTT; 126.6 s) and prothrombin time (PT; 42.8 s). The coagulation factors activities were normal except for factor V, which was only 0.3% of normal. DNA analysis of the FV gene revealed five nucleotide substitutions in exons, including two silent mutations (G327A and A5112G), one polymorphism (G1628A), a G1348T missense mutation and 4887∼8delG. These abnormalities were associated with her FV deficiency, perhaps by causing a Gly392Cys substitution in FV amino acid sequence or by introducing a premature stop codon at amino acid position 1390. This is the third case in which FV deficiency is caused by compound heterozygous mutation of F5 gene, and is the first report from a Chinese family.
Transjugular liver biopsy is safe and diagnostic for patients with congenital bleeding disorders and hepatitis C infection
Authors: DiMichele D. M. , Mirani G. , Wilfredo Canchis P. , Trost D. W. , Talal A. H.
Published: September 2003

Summary.  The prevalence of chronic hepatitis C virus (HCV) infection among patients with severe congenital bleeding disorders is as high as 98%. Advances in HCV treatment currently result in sustained virological response rates of ≥50%. Recent recommendations have reaffirmed that liver biopsy, which provides a direct histological assessment of liver inflammation and fibrosis, is still important for accurate diagnosis and therapeutic decision making. Percutaneous liver biopsy is a simple, standardized procedure that can be performed rapidly and relatively inexpensively, and has been safely performed in patients with congenital coagulopathies. However, the safety and efficacy of the transjugular approach (transjugular liver biopsy, TJLB), recommended for patients with acquired coagulopathies, has only been minimally studied in the congenital bleeding diathesis population.

We now report our institutional experience with TJLB in 13 such adult patients (mean age 33 years) with severe/mild haemophilia A/B (10); von Willebrand disease (1); factor V deficiency (1) and factor XIII deficiency (1). Data were collected by retrospective chart review and the TJLB was performed according to institutional protocol as described. Haemostasis prophylaxis was given for 1–5 days. Patients were hospitalized for ≤48 h and all tolerated the procedure without bleeding. Three patients experienced self‐limited abdominal discomfort; one episode was accompanied by transient transaminaemia. Diagnostic specimens were obtained from all patients and were instrumental in the therapeutic decision‐making process. We suggest that with a co‐ordinated multidisciplinary approach to care, TJLB is a safe, effective and potentially cost‐effective alternative to the percutaneous approach in the congenital bleeding disorders population.