bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling landscape evolution on geological time scales: a new method based on irregular spatial discretization
Authors: Braun Jean , Sambridge Malcolm
Published: November 2003

We present simulations of large‐scale landscape evolution on tectonic time scales obtained from a new numerical model which allows for arbitrary spatial discretization. The new method makes use of efficient algorithms from the field of computational geometry to compute the set of natural neighbours of any irregular distribution of points in a plane. The natural neighbours are used to solve geomorphic equations that include erosion/deposition by channelled flow and diffusion. The algorithm has great geometrical flexibility, which makes it possible to solve problems involving complex boundaries, radially symmetrical uplift functions and horizontal tectonic transport across strike‐slip faults. The algorithm is also ideally suited for problems which require large variations in spatial discretization and/or self‐adaptive meshing. We present a number of examples to illustrate the power of the new approach and its advantages over more ‘classical’ models based on regular (rectangular) discretization. We also demonstrate that the synthetic river networks and landscapes generated by the model obey the laws of network composition and have scaling properties similar to those of natural landscapes. Finally we explain how orographically controlled precipitation and flexural isostasy may be easily incorporated in the model without sacrificing efficiency.
New palaeogeographic and lake‐level reconstructions of Lake Tanganyika: implications for tectonic, climatic and biological evolution in a rift lake
Authors: Cohen A. S. , Lezzar K.‐E. , Tiercelin J.‐J. , Soreghan M.
Published: November 2003

Palaeogeographic and lake‐level reconstructions provide powerful tools for evaluating competing scenarios of biotic, climatic and geological evolution within a lake basin. Here we present new reconstructions for the northern Lake Tanganyika subbasins, based on reflection seismic, core and outcrop data. Reflection seismic radiocarbon method (RSRM) age estimates provide a chronological model for these reconstructions, against which yet to be obtained age dates based on core samples can be compared. A complex history of hydrological connections and changes in shoreline configuration in northern Lake Tanganyika has resulted from a combination of volcanic doming, border fault evolution and climatically induced lake‐level fluctuations. The stratigraphic expression of lake‐level highstands and lowstands in Lake Tanganyika is predictable and cyclic (referred to here as Capart Cycles), but in a pattern that differs profoundly from the classic Van Houten cycles of some Newark Supergroup rift basins. This difference results from the extraordinary topographic relief of the Western Rift lakes, coupled with the rapidity of large‐scale lake‐level fluctuations. Major unconformity surfaces associated with Lake Tanganyika lowstands may have corresponded with high‐latitude glacial maxima throughout much of the mid‐ to late Pleistocene.

Rocky shorelines along the eastern side of the present‐day Ubwari Peninsula (Zaire) appear to have had a much more continuous existence as littoral rock habitats than similar areas along the north‐western coastline of the lake (adjacent to the Uvira Border Fault System), which in turn are older than the rocky shorelines of the north‐east coast of Burundi. This model of palaeogeographic history will be of great help to biologists trying to clarify the evolution of endemic invertebrates and fish in the northern basin of Lake Tanganyika.
Quantitative analysis of Miocene to Recent forearc basin evolution along the Colombian convergent margin
Authors: Mountney Nigel P. , Westbrook Graham K.
Published: November 2003

The Colombian accretionary complex forms the active convergent margin of the North Andes block of South America beneath which the east Panama Basin of the Nazca plate is subducted at a rate of 50–64 km Myr−1. Multichannel seismic reflection data, collected as part of RRS Charles Darwin cruise CD40, image a series of well‐developed forearc basins along the length of the margin, bounded on their oceanward side by an active accretionary complex and on their landward side by oceanward‐dipping continental basement. Sedimentary sequences within the forearc basins indicate successive landward migration of the basin depocentre as the structural high bounding its oceanward edge is forced upward and landward by continued growth of the accretionary complex. Uplift beneath the oceanward side of the basins has resulted in progressive landward rotation of the older sedimentary sequences. Prominent seismic reflectors across the basins show a complex onlap–offlap relationship between successive sequences that reflects the interplay between tectonic uplift, sediment supply, differential sediment compaction and basement subsidence due to loading. A numerical model has been devised to investigate how Miocene to Recent forearc basin stratigraphy is controlled by progressive growth of the accretionary complex resulting in elevation of the outer‐arc high and landward motion of the rear of the complex up the seaward‐dipping backstop formed by the leading edge of the continental lithosphere. The effects of sediment accretion are modelled by treating the accretionary complex as a doubly vergent, noncohesive Coulomb wedge, where forces exerted by the proto‐ and retro‐wedges must be balanced for the system to be in equilibrium. The model generates synthetic basin‐fill architecture over a series of steps, each of which represents the deposition of individual sedimentary sequences and their subsequent deformation due to wedge growth. The model accounts for differential sediment compaction and the flexural response of the underlying lithosphere to changes in load distribution over time. Forearc basin evolution is simulated for various rates of sediment supply to the forearc and accretionary complex growth until the synthetic basin‐fill geometry matches the observed geometry. The model enables either the rate of accretionary wedge growth or the rate of sediment supply to the forearc basin to be established. The technique is generally applicable to those convergent margins with forearc basins that have developed between an actively accreting wedge and a seaward‐dipping backstop. Other examples include Peru, S. Chile, Sumatra and Barbados.
Insufficiency of compaction disequilibrium as the sole cause of high pore fluid pressures in pre‐Cenozoic sediments
Authors: Kooi Henk
Published: November 2003

The method of indirect demonstration is used to investigate if compaction disequilibrium can account for high overpressures that occur in Mesozoic and older basin formations. First the equations governing compaction disequilibrium are analysed for the factors controlling overpressure levels. Then limiting values of these control parameters are sought which favour high fluid pressures. The analysis shows why ‘close‐to‐lithostatic fluid pressures’ in pre‐Cenozoic basin units are difficult to attain by compaction disequilibrium alone. Subsequently, the limiting favourable conditions are used in a series of generic numerical model experiments. The experiments serve as templates to construct the upper bounds of overpressures due to sediment loading for most geological settings including those where shale seals have developed. Two regional examples are studied in some detail. It is shown that observed overpressures in Mesozoic strata on the Scotian Shelf can be explained by compaction disequilibrium, but require the limiting values assigned to the properties of shale. For the Central North Sea Graben these limiting conditions are not sufficient, providing evidence for an active role of other pressure‐generating mechanisms.
Tectonic and thermal evolution of Queen Charlotte Basin: lithospheric deformation and subsidence models
Authors: Dehler S. A. , Keen C. E. , Rohr K. M. M.
Published: November 2003

A two‐layer lithospheric stretching model that includes the effects of decompression melting was used to estimate the deformation and thermal evolution of the Queen Charlotte Basin, British Columbia. The basin contains up to 6 km of Tertiary fill and is postulated to have been formed during a transtensional stage of Cenozoic plate motion between the Pacific and North American plates. Several models of basin formation have been proposed to explain the sediment distribution, contemporaneous volcanism and high present‐day heat flow.

We used bathymetry, Tertiary sediment thickness and crustal thickness to calculate the amount of stretching in the crust and lower lithosphere, and the volume of melt generated during advection of mantle rocks. A second set of calculations traced the thermal evolution of the sediments and lithosphere, and we show maps of estimated present‐day heat flow and sediment maturity. This study differs significantly from previous work in the use of gridded data that provide coverage over a large region and permit lateral variations in lithospheric deformation and thermal properties to be clearly defined, a difficult quest in studies based on single‐point or profile data. In addition, the use of crustal thickness, derived from a regional interpretation of gravity data and constrained by seismic refraction results, as an input allows reliable estimates of extension to be made despite recent deformation of sedimentary strata in Hecate Strait.

We present results for a model which used a prerift crustal thickness of ≈34 km and a short rifting period from 25 to 20 Ma. This model infers that significant thinning occurred beneath south‐western Hecate Strait and southern Queen Charlotte Sound, and several kilometres of igneous crust were added at these sites, without requiring elevated asthenospheric temperatures prior to extension. Net lithospheric extension is surprisingly uniform within the basin and averages 76%, or ≈50 km, across the margin. This amount is consistent with other estimates of extension and may provide information useful in refining models of plate motion along this margin.
On the power law size distribution of turbidite beds
Authors: Malinverno Alberto
Published: November 2003

A number of studies have shown that cumulative distributions of turbidite bed thicknesses (as observed in boreholes or outcrops) follow a power law in the sense that the number of beds whose measured thickness is greater than η is proportional to η−β. The purpose of this paper is to investigate the relationship between the distribution of measured thicknesses of turbidite sand beds and the distribution of bed volumes. The distribution of sand bed volumes has practical implications to model hydrocarbon reservoirs in 3D and quantifies how the total amount of sand within a turbidite sequence is distributed among beds of different sizes. If the cumulative distribution of bed volumes v is proportional to v−c the few largest beds account for more and more of the total volume of sand and the sequence becomes more and more ‘punctuated’ as the exponent c decreases below 1. The relationship between the exponents of the distribution of measured bed thicknesses (β)and of bed volumes (c) can be investigated by assuming that the turbidite beds are disc‐like bodies distributed in the 3D space of a basin, and that their thicknesses are sampled on a vertical line that does not in general intersect all the beds. The relationship between β and c can be shown to depend on how bed length scales with bed thickness (as noted by other authors) and on how the beds are distributed in the 3D space of the basin (which is a new result). The main conclusion is that it is not generally possible to make inferences on the distribution of turbidite bed volumes knowing only the distribution of bed thicknesses. On the other hand, if some independent information is available on the geometrical characteristics of the turbidite deposit, the observations of bed thicknesses can be converted to bed volumes, thus providing general information on the 3D characteristics of the sequence.
Headless submarine canyons and fluid flow on the toe of the Cascadia accretionary complex
Authors: Orange Daniel L. , McAdoo Brian G. , Casey Moore J. , Tobin Harold , Screaton Elizabeth , Chezar Hank , Lee Homa , Reid Mark , Vail Rick
Published: November 2003

Headless submarine canyons with steep headwalls and shallowly sloping floors occur on both the second and third landward vergent anticlines on the toe of the Cascadia accretionary complex off central Oregon (45 °N, 125° 30′W). In September 1993, we carried out a series of nine deep tow camera sled runs and nine ALVIN dives to examine the relationship between fluid venting, structure and canyon formation. We studied four canyons on the second and third landward vergent anticlines, as well as the apparently unfailed intercanyon regions along strike. All evidence of fluid expulsion is associated with the canyons; we found no evidence of fluid flow between canyons. Even though all fluid seeps are related to canyons, we did not find seeps in all canyons, and the location of the seeps within the canyons differed.

On the landward facing limb of the second landward vergent anticline a robust cold seep community occurs at the canyon’s inflection point. This seep is characterized by chemosynthetic vent clams, tube worms and extensive authigenic carbonate. Fluids for this seep may utilize high‐permeability flow paths either parallel to bedding within the second thrust ridge or along the underlying thrust fault before leaking into the overriding section. Two seaward facing canyons on the third anticlinal ridge have vent clam communities near the canyon mouths at approximately the intersection between the anticlinal ridge and the adjacent forearc basin. No seeps were found along strike at the intersection of the slope basin and anticlinal ridge. We infer that the lack of seepage along strike and the presence of seeps in canyons may be related to fluid flow below the forearc basin/slope unconformity (overpressured by the impinging thrust fault to the west?) directed toward canyons at the surface.
Regular spacing of drainage outlets from linear fault blocks
Authors: Talling Peter J. , Stewart Michael D. , Stark Colin P. , Gupta Sanjeev , Vincent Stephen J.
Published: November 2003

Outlets of river basins located on fault blocks often show a regular spacing. This regularity is most pronounced for fault blocks with linear ridge crests and a constant half‐width, measured perpendicular to the ridge crest. The ratio of the half‐width of the fault block and the outlet spacing is used in this study to characterize the average shape (or spacing ratio) of 31 sets of drainage basins. These fault‐block spacing ratios are compared with similar data from small‐scale flume experiments and large‐scale mountain belts. Fault‐block spacing ratios are much more variable than those measured for mountain belts. Differences between fault‐block spacing ratios are attributed to variability in factors influencing the initial spacing of channel heads and subsequent rates of channel incision during the early stages of channel network growth (e.g. initial slope and uplift rate, precipitation, runoff efficiency and substrate erodibility). Widening or narrowing of fault blocks during ongoing faulting will also make spacing ratios more variable. It is enigmatic that some of these factors do not produce similar variability in mountain belt spacing ratios. Flume experiments in which drainage networks were grown on static topography show a strong correlation between spacing ratios and surface gradient. Spacing ratios on fault blocks are unaffected by variations in present‐day gradients. Drainage basins on the Wheeler Ridge anticline in central California, which have formed on surfaces progressively uplifted by thrust faulting during the last 14 kyr, demonstrate that outlet spacing is likely to be determined during the early stages of drainage growth. This dependency on initial conditions may explain the lack of correlation between spacing ratios of fault blocks and slopes measured at the present day.

Spacing ratios determine the location of sediment supply points to adjacent areas of deposition, and hence strongly influence the spatial scale of lateral facies variations in the proximal parts of sedimentary basins. Spacing ratios may be used to estimate this length scale in ancient sedimentary basins if the width of adjacent topography is known. Spacing ratio variability makes these estimates much less precise for fault blocks than for mountain belts.
Intermediate‐dose busulphan before autografting for advanced‐phase chronic myeloid leukaemia
Authors: Rule Simon A. J. , Savage David G. , O'Brien Stephen G. , Orchard Kim , McDonald Christine , Davidson John , Matthey Francis , Reilly John T. , Bardhan G. , Miller Elizabeth , Cranfield Tanya , Apperley Jane F. , Goldman John M.
Published: November 2003

Between June 1994 and October 1995 we performed 11 autografts in nine patients with advanced‐ phase chronic myeloid leukaemia (CML) using an attenuated cytoreductive regimen consisting of busulphan 8 mg/kg given in divided doses over 4 d. Five patients were restored to chronic phase. Four patients survived >50 weeks and one remains well at 79 weeks. Toxicity was generally mild. Four procedures were managed entirely in the out‐patient clinic. Therefore autografting after this ‘intermediate’ dose busulphan provides good palliation for patients with advanced CML with relatively little toxicity. Attenuated autografting should offer major advantages in terms of quality of life and cost for patients with advanced‐phase CML.
Combined negative and positive selection of mobilized CD34+ blood cells
Authors: Di Nicola Massimo , Bregni Marco , Siena Salvatore , Adelchi Ruffini Pier , Milanesi Marco , Ravagnani Fernando , Massimo Gianni A.
Published: November 2003

We tested four negative and two positive selection methods for separation of CD34+ cells from mobilized blood cells, and analysed fold‐enrichment, purity and recovery of CD34+ cells after selection procedures. The elimination of mature CD34− cells was achieved by adhesion to nylon‐wool fibre (5.9 ± 1.0 mean fold‐enrichment and 65.2 ± 2.3 mean recovery of CD34+ cells). Standard or modified Ficoll‐Hypaque and Percoll density gradients, as well as phagocytosis with magnetic beads, were less effective in eliminating CD34− cells, both purity and fold‐enrichment of CD34+ cells being lower than those obtained with separation by nylon‐wool. Both positive selection methods tested, Ceprate and MiniMacs System, generated highly purified CD34+ cell populations ranging from 80% to 90%. The recovery of CD34+ cells was optimal with MiniMacs (77.9±3.6) and low with Ceprate (28.8±2.8). Based on these results, in two large‐scale experiments we combined nylon‐wool fibre and MiniMacs System in a two‐step separation procedure obtaining a 36.9±2.6 mean fold‐enrichment and a 50.5±0.3 mean recovery of CD34+ cells. In this way we achieved optimal enrichment and recovery of CD34+ cells, with a substantial saving of cost compared to either selection method alone.
Chronic neutrophil leukaemia in adolescence and young adulthood
Authors: Hasle Henrik , Olesen Gitte , Kerndrup GITTE , Philip Preben , Jacobsen Niels
Published: November 2003

Chronic neutrophil leukaemia (CNL) is a rare myeloproliferative disorder predominantly reported in elderly patients. We present a 15‐year‐old girl and a 25‐year‐old male with CNL. Clonal cytogenetic abnormalities were detected in both patients. One showed trisomy 21 evolving into tetrasomy 21. The second patient showed a unique chromosome aberration during blast crisis: t(2;2)(q32;p24). Both patients were successfully treated with allogeneic bone marrow transplantation (BMT). CNL should also be considered as a differential diagnosis in adolescence and young adulthood. BMT represents a potentially curative treatment option in such patients.
Detection of bcl‐2 rearrangement in HIV‐related follicular lymphoid hyperplasia
Authors: Molina Thierry J. , Devez Francis , Bigorgne Claude , Le Tourneau Agnès , Joulin Virginie , Audouin Josée , Diebold Jacques
Published: November 2003

Rearrangement of the bcl‐2 gene at the MBR (major breakpoint region) locus with the immunoglobulin heavy‐chain joining region has been reported in a high proportion of follicular lymphomas. This rearrangement has also been reported in very few normal B cells of the blood, tonsils, follicular lymphoid hyperplasia (FLH) of the lymph nodes. HIV infection is often associated at the onset of the disease with FLH, but the presence of rearranged bcl‐2 B cells in these lymph nodes has not been described. In using a standard PCR assay with Southern blot or a semi‐nested PCR on 48 cases of FLH, we demonstrated that there were a few bcl‐2 rearranged B cells in HIV FLH, at almost the same level as that in non‐HIV‐related FLH. The usual absence of bcl‐2 rearrangement in the HIV‐associated B‐cell lymphomas suggests that the bcl‐2 oncogene in the rearranged B cells of FLH is not cooperating with other oncogenes during HIV lymphomagenesis.
Down‐regulation of bcl‐2 in AML blasts by all‐trans retinoic acid and its relationship to CD34 antigen expression
Authors: Bradbury D. A. , Aldington S. , Zhu Y‐M , Russell N. H.
Published: November 2003

High levels of expression of the bcl‐2 oncoprotein in acute myeloblastic leukaemia (AML) cells have been associated with low complete remission rates and poor survival. The sensitivity of AML blasts to drugs such as Ara‐C can be increased by the down‐regulation of bcl‐2 expression by antisense oligonucleotides. All‐trans retinoic acid (ATRA) has been reported to increase the sensitivity of AML cell lines to Ara‐C and to induce differentiation in the HL60 promyelocytic cell line, with both effects being accompanied by a decrease in bcl‐2 expression. Using flow cytometry and a monoclonal antibody to bcl‐2, we have investigated the effects of ATRA (1 μM) on bcl‐2 expression in the blast cells of 25 AML patients and the K562 cell line after incubation for 72 or 24 h, respectively. Using Kolmogorov‐Smirnov statistical analysis where a D value of > 0.12 was statistically significant, we found that in 8/25 AML samples and the K562 cells there was a significant decrease in bcl‐2 protein expression after incubation with ATRA (D value range 0.14–0.44). The mean peak fluorescence (MPF) values for the bcl‐2 levels of the ATRA responders (n = 8) was reduced to 35.5 ± 6.9 following incubation with ATRA compared to 47.6 ± 8.2 (mean ± SEM) for control samples incubated in the absence of ATRA (P = 0.014). There was no significant difference between the baseline bcl‐2 molecules of equivalent soluble fluorochrome (MESF) levels in the ATRA responders (48.9 ± 5.7, n = 8) and the non‐responders (41.3 ± 3.9, n = 17) (mean ± SEM) (P = 0.28). The down‐ regulation of bcl‐2 expression by ATRA was particularly associated with CD34‐negative AML and of the eight AML patients’ cells that responded to ATRA by down‐regulating bcl‐2, seven were CD34 negative (P<0.05). Our data suggest that the addition of ATRA to combination chemotherapy would increase the chemosensitivity of some patients with AML, particularly CD34‐negative AML, due to down‐regulation of bcl‐2 expression.
Gene expression in somatic cell hybrids derived from embryonic mice transgenic for human globin genes
Authors: Stanworth S. J. , Roberts N. A. , Sharpe J. A. , Wood W. G.
Published: November 2003

Somatic cell hybrids have been used previously to investigate the developmental regulation of globin gene expression. When a chromosome containing an active human fetal γ gene is transferred to mouse erythroleukaemia (MEL) cells by cell fusion, there is persistent expression of this gene through multiple hybrid‐cell divisions despite the ‘adult’trans‐acting factor environment of the MEL cell. We analysed hybrids formed between embryonic erythroblasts and MEL cells to determine whether the embryonic globin genes would be similarly regulated. Surprisingly, there was no detectable expression of either the endogenous (ε, βh1) or the transgenic (human ε) embryonic β‐like genes in a large number of hybrid pools and clones, even though these genes were expressed in the donor cells at the time of fusion. In contrast, the human γ gene, which is also expressed as an embryonic gene in transgenic mice, continued to be expressed in these hybrids. This lack of embryonic gene expression in hybrids also applied to the α gene cluster; no mouse or human ζ mRNA was detectable in embryonic cell hybrids from mice transgenic for the human α globin genes. Hybrids generated from embryonic non‐erythroid cells resulted in expression that was largely restricted to the adult β gene. It has previously been suggested that epigenetic modifications to the β‐globin gene cluster during normal development are responsible for the perpetuation of γ and β gene expression in this hybrid cell system. The results presented here suggest that no such stable modifications occur around the embryonic genes and therefore that the regulatory mechanisms determining embryonic globin gene transcription differ from those responsible for the expression of γ and β genes in this system.
Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia
Authors: Coyle Luke A. , Papaioannou Maria , Yaxley John C. , Chim James S. , Attard M. , Hoffbrand A. Victor , Foroni Letizia
Published: November 2003

Immunoglobulin heavy chain gene (IgH gene) rearrangements are found in the majority of cases of B‐lineage acute lymphoblastic leukaemia (ALL). We have examined bone marrow samples taken at presentation or relapse from 109 patients (79 adults and 30 children) and have performed sequence analysis of the complementarity determining region 3 (CDR3) on 65 alleles from 54 patients. We aimed to define immunoglobulin heavy chain (IgH) variable segment family use and investigate biological and structural features of the B cell in adult and childhood ALL. Using the FR1 fingerprinting method, a rearranged band was identified in 70 (89%) of 79 adult ALL and in 29 (97%) of 30 childhood ALL. This study found no preferential use or selection of IgH VH genes and no statistically significant structural differences between normal and leukaemic B cells in either adult and childhood ALL. An equal proportion of amplifiable cases of adult and childhood ALL uses more than one VH family gene (24/70, 34%, and 8/29, 27.5%, respectively). There were no significant differences in the structure or size of the CDR3 region and the variable (V) or joining (J) segment use in ALL patients compared to normal B cells. We observed that the N2 region was shorter than N1 in children whereas the opposite was observed in adults (not statistically significant). The J4 segment was a more common rearrangement in children than in adults, and in both groups J4 was more frequently associated with multiple D segment VDJ rearrangements. An increase in VH6 use in leukaemic alleles compared to normal B lymphocytes (2%) was observed but it was not statistically significant in our group of patients. Amongst children and adults, in‐frame CDR3 junctions occurred in 78% and 64% of rearranged alleles, respectively, compared to 75% of in‐frame sequences reported by others to occur among normal B cells.
A randomized study of VAD therapy with either concurrent or maintenance interferon in patients with newly diagnosed multiple myeloma
Authors: Abrahamson G. M. , Bird J. M. , Newland A. C. , Gaminara E. , Giles Chrissie , Joyner M. , Kelsey S. M. , Lewis D. , McCarthy D. M. , Roques A. W. , Tew C. J. , Treacy M. , Van DePette J. , Samson Diana
Published: November 2003

This randomized study was designed to determine whether response to VAD chemotherapy could be prolonged by using rh α‐2b‐interferon (IFN) at a dose of 3 mU three times per week, either concurrently with VAD (VIC) or as maintenance after completion of VAD (VIF). Maintenance IFN was given for 9 months in order for the duration of IFN therapy to be similar in both groups. 72 patients were randomized between December 1988 and August 1993. The majority of patients had poor prognostic features. The objective response rate was similar in each arm, 78% in VIF and 77% in VIC. Of the 56 responders, 33 have relapsed, three died in remission, and 18 proceeded to high‐dose therapy, withdrew for other reasons or were lost to follow‐up and were censored from analysis at the relevant time point. Only two patients remain in remission (both in partial remission). Median PFS was 15 months for both VIF and VIC, compared with 16.5 months for a historic control group treated with VAD alone (n.s.), The estimated median survival in VIF was 43 months and in VIC 22 months, compared with 45 months in the historic controls (n.s.). These findings indicate that neither maintenance nor concurrent IFN prolongs response to VAD.
Umbilical vein endothelial cells are an important source of c‐kit and stem cell factor which regulate the proliferation of haemopoietic progenitor cells
Authors: Yamaguchi Hideto , Ishii Eiichi , Saito Shigeru , Tashiro Katsuya , Fujita Ichiro , Yoshidomi Seiko , Ohtubo Masamichi , Akazawa Kouhei , Miyazaki Sumio
Published: November 2003

The expression and production of c‐kit and its ligand, stem cell factor (SCF), in cord blood and neonates were studied. Serum SCF levels were significantly higher in cord blood, neonates aged 1–30 d, and in 4‐month‐old infants than in the maternal serum (P < 0.01). SCF levels decreased in children from 7 months to 15 years of age (P < 0.01). The serum soluble c‐kit levels were significantly higher in cord (P < 0.01) and neonatal blood (P < 0.05) than in the maternal blood. SCF and c‐kit levels in placental tissue homogenates and the culture media of decidual cells and trophoblasts were low. To determine the sites of high SCF and c‐kit production in cord blood and in early neonates, SCF and c‐kit mRNA expression was analysed in various tissues by polymerase chain reaction. High SCF mRNA expression was observed in human umbilical vein endothelial cells (HUVEC). Moderate c‐kit mRNA expression was detected in HUVEC, the bone marrow, and cord blood. These findings suggest that endothelial cells mainly produce the SCF in cord blood and in early neonates. To confirm the role of endothelial cells in haemopoiesis, colony‐forming assays were performed in the presence of HUVEC culture media, which induced the formation of high numbers of granulocyte and erythroid colonies in cord blood. IL‐3, IL‐6 and SCF levels were elevated in the media. Our findings suggest that endothelial cells have an important role in the maintenance and proliferation of progenitor cells in neonatal blood via the interaction of c‐kit and SCF with other factors. The ex vivo expansion of cord progenitor cells in the presence of endothelial cells needs to be investigated further.
Epistaxis in anticoagulated patients: educating an at‐risk population
Authors: Lavy Jeremy
Published: November 2003

Epistaxis is a common problem amongst anticoagulated patients. Application of first‐aid principles can control the majority of bleeds. In our sample of 60 patients attending the anticoagulant clinic, 40% were unable to think of a single measure that would be helpful in controlling a nose bleed. 6 weeks after being given first‐aid advice the proportion of patients able to recall at least three first‐aid principles had improved from 8% to 50%. First‐aid education in this respect was well received and there was a good recall rate. Provision of advice verbally backed up by a printed sheet gave best rates of recall.
High response rates with short infusional 2‐chlorodeoxyadenosine in de novo and relapsed low‐grade lymphoma
Authors: Morton J. , Taylor K. , Bunce I. , Eliadis P. , Rentoul A. , Moore D. , Kelly C. , Wright S. , Bashford J. , Rodwell R. , Rooney K. , Mulligan S. , Firkin F. , Dodds A. , Parkin J. , Lowenthal R. , Kimber R. , Frost T. , Grigg A. , Goldstein D. , Stone J. , Lee N.
Published: November 2003

Thirty‐five patients (eight de novo, 27 relapsed disease) with low‐grade non‐Hodgkin's lymphoma (diffuse small lymphocytic, follicular small cleaved cell, follicular mixed cell, and lymphoplasmacytoid) were treated with 2‐chlorodeoxyadenosine (2CdA) at a daily dose of 0.14 mg/kg for 5 d (2 h infusion) for an average of three cycles. Minor treatment delays, generally due to haematological toxicities, occurred in nine of 105 cycles. Major toxicities were lymphopenia, neutropenia and thrombocytopenia. Opportunistic infections occurred in seven patients.  Overall response rate was 69% (five complete, 19 partial) reaching 88% for de novo patients (two complete, five partial). Elevated β2‐microglobulin level was negatively predictive of response (P = 0.0014). Eight of 24 responders relapsed, with a median follow‐up of 13 months.  2CdA administered as an intermittent infusion shows considerable single‐agent activity in low‐grade lymphomas achieving high response rates of prolonged duration. Consideration of schedules where 2CdA is alternatively administered with combination chemotherapy appears warranted.
Characterization of platelet‐reactive antibodies in children with varicella‐associated acute immune thrombocytopenic purpura (ITP)
Authors: Wright J. Fraser , Blanchette Victor S. , Wang Hong , Arya Naveen , Petric Martin , Semple John W. , Chia Wah‐Kiam , Freedman John
Published: November 2003

Biochemical analyses were performed on blood samples obtained from two children (P1, P2) who presented with acute immune thrombocytopenic purpura (ITP) following a recent varicella zoster virus (VZV) infection. Patient sera had antibodies that were reactive with normal blood‐group O platelets as measured by flow‐cytometric assay. Western blot analysis of electrophoretically separated normal blood‐group O platelets under reducing and non‐reducing conditions demonstrated that these sera were reactive with platelet antigens of ∼50 and ∼110 kD, respectively. These 50/110 kD antigens were not reactive with seven sera from acute ITP patients whose illness was not preceded by VZV infection, with serum from a patient with a prior history of VZV and no thrombocytopenia, nor with normal healthy control sera. VZV antibodies (IgG and IgM), isolated from patient sera by affinity chromatography using immobilized purified VZV glycoproteins, were found to bind to gel‐filtered autologous platelets and with normal blood‐group O platelets, as analysed by flow cytometry. No binding was observed using antibodies similarly prepared from healthy volunteer sera. To investigate their ability to sensitize platelets to complement activation, affinity‐purified VZV antibodies were incubated with platelets and then with purified complement components C1 and 125I‐labelled C4. Platelets reacted with VZV‐specific antibodies from the two patients and showed increases of 2.3–2.4‐fold of platelet‐surface deposition of 125I‐C4b, compared to controls. These data provide evidence that virus‐specific antibodies occurring in children with varicella‐associated acute ITP cross‐react with normal platelet antigens, and may contribute to platelet clearance.
Immunologic quantification of fibrin deposition in thrombi formed in flowing native human blood
Authors: ØRvim Una , Barstad R. Marius , Stormorken Helge , Brosstad Frank , Sakariassen Kjell S.
Published: November 2003

We describe a new method for quantification of fibrin in thrombi formed in native human blood at venous and arterial shear conditions in a parallel‐plate perfusion chamber device. Thrombi consisting of various proportions of fibrin and platelets were digested by plasmin. Fibrin deposition (μg/cm2) was calculated from the measured D‐dimer levels.

Fibrin deposition in thrombi formed on a tissue factor (TF)‐rich surface increased with increasing shear rate from 37 μg/cm2 at 100/s to 77 μg/cm2 at 2600/s (significant at 95%, ANOVA). The plasma levels of thrombin–antithrombin III complexes (TAT) increased in concert. In contrast, fibrin deposition in thrombi formed on collagen fibrils and the corresponding TAT plasma levels were independent of the shear rate and much lower than those elicited by the TF‐rich surface (significant at 95%, ANOVA). The intra‐individual variation in fibrin deposition was on average 10%, whereas the inter‐individual differences were >500%. Such a large inter‐individual difference has not been detected by morphometry which usually is employed in similar studies.

The present method is more accurate and less time‐consuming than the morphometric approach. The novel method measures fibrin on the surface and in and around the thrombi, thus total deposited fibrin. In contrast, the morphometry approach quantifies surface coverage with fibrin only, thus being semiquantitative at best.
Blood smears and prenatal diagnosis
Authors: Forestier FranÇois , Hohlfeld Patrick , Vial Yvan , Olin Valérie , Andreux Jean‐Paul , Tissot Jean‐Daniel
Published: November 2003

Fetal blood sampling is a widely used technique for both diagnostic and therapeutic purposes. However, despite the fact that examination of blood smears is a critical step in the study of a large variety of disorders, the place of fetal blood smears analysis has been overshadowed by more sophisticated diagnostic tools such as those offered by molecular biology. Nevertheless, as highlighted by four cases presented in this paper, the role of fetal blood smears examination must be re‐emphasized. The recognition of abnormal cytological findings limits the number of possible aetiologies, thus elegantly contributing to the diagnosis without multiplying unnecessary test techniques.
The kinetics of HLA class I elution and the relevance for the use of HLA‐eluted platelet transfusions
Authors: Novotny V. M. J. , Doxiadis I. N. N. , Van Doorn R. , Brand A.
Published: November 2003

HLA‐eluted platelet transfusions may be feasible for transfusion in HLA‐alloimmunized refractory patients, but the reduction in HLA expression after elution is variable. Using different anti‐HLA antibodies directed against the HLA class I complex, the heavy chain, β2‐microglobulin (β2M) and the intracytoplasmatic part of the heavy chain, we investigated factors which influenced the HLA reduction by flow cytometry. Reduction of HLA expression by acid treatment resulted in an almost complete removal of HLA class I molecules from the site of the intracytoplasmatic part of the heavy chain. Re‐expression of HLA heavy chain, β2M and some of the trimolecular complex (comprised by β2M, heavy chain and peptide) occurred within 4 h. This was presumably the result of adsorption from the supernatant (eluate or plasma). After immediate removal of the eluate and incubation in plasma‐free supernatant no re‐expression of HLA occurred after a 4 h interval.
A role for paclitaxel in the combination chemotherapy of acute myeloblastic leukaemia: preclinical cell culture studies
Authors: Curtis J. E. , Minkin S. , Minden M. D. , McCulloch E. A.
Published: November 2003

Paclitaxel dose responses in culture have been investigated alone and in association with cytosine arabinoside (ARA‐C) and all‐trans retinoic acid (ATRA), with the objective of identifying a role for paclitaxel in the treatment of acute myeloblastic leukaemia (AML). Initial studies were done to determine if paclitaxel dose responses of AML blast cell precursors were altered by regulatory compounds known to modify the dose responses of ARA‐C. In contrast to ARA‐C, paclitaxel dose responses were independent of cell culture method, the growth factors G‐CSF and GM‐CSF, and the ligands all‐trans retinoic acid (ATRA) and hydrocortisone. Most blast cell populations were sensitive to paclitaxel; compared with normal marrow progenitors the dose responses were markedly heterogenous with some more, and others less, sensitive. Remission marrow progenitor paclitaxel responses resembled those of AML blasts in heterogeneity. The cell culture model tested the effect of paclitaxel and ATRA on the ARA‐C dose responses of OCI/AML‐5: paclitaxel exposure was either before or after ARA‐C to test for an effect of schedule; ATRA was added to the MEC cultures after paclitaxel and ARA‐C. Repeat experiments were done to test three dose levels each of paclitaxel and ATRA. When paclitaxel was given after ARA‐C, synergism was found for all but one of the dose combinations tested; only three examples of synergy were seen when paclitaxel preceded ARA‐C. The studies justify trials combining ARA‐C, paclitaxel and ATRA using a schedule suggested by the cell culture findings.
Transfer of p16inka/CDKN2 gene in leukaemic cell lines inhibits cell proliferation
Authors: Quesnel Bruno , Preudhomme Claude , Lepelley Pascale , Hetuin Dominique , Vanrumbeke Michael , Bauters Francis , Velu Thierry , Fenaux Pierre
Published: November 2003

The gene encoding for p16ink4a, a negative regulator of transition between G1 and S phase, is homozygously deleted in a large proportion of acute lymphoblastic leukaemias (ALL). Transfer of p16ink4a gene in several solid tumour cell lines with functional pRb and lacking both p16ink4a alleles has resulted in a dramatic reduction of cell proliferation, and the aim of this work was to confirm this effect in leukaemic (especially ALL) cell lines. We tested the proliferation in liquid medium and in soft agar after transfer of p16ink4a gene by a retroviral vector in leukaemic cell lines with homozygous p16ink4a gene deletion (K562, CEM, Jurkat cell lines) or with p16ink4a gene hemizygous deletion and a point mutation inactivating the remaining allele (HL60 cell line). The viral titre obtained after transfection of PA317 amphotropic packaging cell line, which has a p16ink4a gene homozygous deletion, was low, suggesting that p16ink4a gene expression could impair viral production of retroviral packaging cell lines derived from the NIH3T3 cell line.

After retroviral transfer of p16ink4a in cell lines and G418 selection in liquid medium, a strong cell proliferation inhibition was observed for K562, CEM and Jurkat, but no inhibition was seen for HL60. A strong growth reduction in soft agar was also observed with p16ink4a‐transduced CEM, Jurkat and K562 cells, with a moderate growth reduction in the HL60 cell line. The growth inhibition in liquid culture, of K562 and Jurkat cell lines, was confirmed by electroporation transfer of the p16ink4a gene.

Our findings show that p16ink4a gene transfer has a growth‐inhibitory effect in leukaemic cell lines with p16ink4a gene homozygous deletion. These data suggest that p16 could be a suitable gene for gene therapy in ALL.
Abnormalities of membrane protein composition in patients with autoimmune haemolytic anaemia
Authors: De Angelis V. , De Matteis M. C. , Cozzi M. R. , Fiorin F. , Pradella P. , Steffan A. , Vettore L.
Published: November 2003

Acquired abnormalities of red cell membrane protein composition in 37 patients with a positive direct antiglobulin test have been studied: 17 patients had true autoimmune haemolytic anaemia and 20 were HIV‐infected subjects with a positive direct antiglobulin test but without signs of haemolysis. The study was carried out by performing sodium dodecyl sulphate polyacrylamide gel electrophoresis of ghost proteins followed by densitometric evaluation of the areas under the peaks, normalized by the total (α + β) spectrin content. Results show a significant decrease of bands 3, 4.1 and 4.2 over spectrin in patients with autoimmune haemolysis as compared to controls; at least in a small subset of patients, different specificities recognized by autoantibodies do not seem to account for these abnormalities which are reproducible independently from the molecular size of bands immunoprecipitated by autoantibodies. A similar decrease of protein 4.2 but not of band 3 staining intensity is also noticeable in HIV patients with a positive direct antiglobulin test. These results are consistent with the hypothesis that, following interactions between autoantibodies and autoantigens, modifications occur on membrane proteins resembling a variety of quantitative defects described in inherited haemolytic anaemias, and mainly the ‘vertical interaction defects’ of hereditary spherocytosis. Moreover, the decrease of band 3 staining intensity seems to represent a feature of patients with immune mediated haemolysis and not only with autoantibody binding.
In‐vitro clonogenicity of mobilized peripheral blood CD34‐expressing cells: inverse correlation to both relative and absolute numbers of CD34‐expressing cells
Authors: SERKE STEFAN , Watts Mike , KNUDSEN LENEN MELDGAARD , KREISSIG CARLA , SCHNEIDER ULRIKE , SCHWELLA NIMROD , LINCH DAVID , JOHNSEN HANS E.
Published: November 2003

The determination of CD34‐expressing cells by multiparameter flow cytometry is now widely used to estimate the reconstitution potential of cells harvested by cytapheresis for peripheral blood stem cell and progenitor cell transplantation. There is a correlation between the number of CD34‐expressing cells collected and committed progenitor cells (CFU‐GM and BFU‐E) capable of forming colonies in vitro, but there is considerable variation in the proportion of CD34‐expressing cells capable of clonogenic growth. The data in this study of 782 cytapheresis samples indicates that there is a negative correlation between the clonogenicity of the CD34‐expressing cells and the absolute number or the proportion of CD34‐expressing cells within the harvest. In 116 samples the proportion of CD34‐expressing cells co‐expressing the CD45‐RA‐antigen (a  subset of CD34‐expressing cells which includes virtually all clonogenic cells in terms of CFU‐GM) was determined, but this did not help to identify the clonogenicity of a given sample. These findings may have clinical relevance, particularly when mobilization is judged to be relatively poor or when a good harvest is to be divided for multiple high‐dose procedures.
Iron deprivation increases erythropoietin production in vitro, in normal subjects and patients with malignancy
Authors: Kling Pamela J. , Dragsten Paul R. , Roberts Robin A. , Dos Santos Betty , Brooks Donald J. , Hedlund Bo E. , Taetle Raymond
Published: November 2003

Although tissue hypoxia is the major stimulus for erythropoietin (EPO) production, serum EPO (sEPO) levels at any given Hb in iron‐deficiency anaemia are relatively higher than in other anaemias. Iron chelators stimulate erythropoiesis in anaemia of chronic disease via unknown mechanisms. A recent study suggested that deferoxamine (DFO) regulates steady‐state EPO RNA. Here we report that altered intracellular iron balance regulates EPO production both in vitro and in two unique clinical trials. In vitro, both iron chelation with DFO and blockade of Tf‐mediated iron uptake with anti‐Tf receptor antibody 42/6, stimulated EPO production in serum‐deprived hepatoma cells. Conversely, iron repletion by haemin, inhibited EPO production in these cells. In clinical studies, sEPO levels rose in adult volunteers treated with DFO coupled to hydroxyethyl starch (HES‐DFO) and in patients with advanced malignancy treated with anti‐Tf receptor antibody 42/6, in a time‐ and dose‐dependent manner. These studies indicate intracellular iron balance regulates EPO production in humans.
A myeloproliferative disorder with eosinophilia associated with a unique translocation (3;5)
Authors: Shanske Alan L. , Kalman Andrea , Grunwald Hans
Published: November 2003

An association between eosinophilia and a structural chromosome abnormality has been noted in patients with acute non‐lymphoblastic leukaemia (ANLL) and a deletion of the long arm of chromosome 16. There have been a number of other associations of specific chromosome abnormalities with neoplastic diseases involving the eosinophilic lineage; these include chromosome 12 short arm rearrangements, trisomy 8, t(8;21), t(5;14) and t(5;12). We report a patient with a myeloproliferative disorder characterized by chronic eosinophilic leukaemia complicated by autoimmune haemolytic anaemia and a previously unreported translocation (3;5)(p13;q13), and discuss the possible contribution of the RASA gene, localized to 5q13.3, to the development of the malignant phenotype.