bluuebunny/crossref_metadata_2025 huggingface dataset:
Summertime ozone at Mount Washington: Meteorological controls at the highest peak in the northeast
Authors: Fischer Emily V. , Talbot Robert W. , Dibb Jack E. , Moody Jennie L. , Murray Georgia L.
Published: December 2004

This study examined the synoptic and regional‐scale meteorological controls on summertime O3 at Mount Washington, the highest peak (1910 m) in the northeastern United States. Analysis of air mass transport to Mount Washington was conducted for the summers of 1998–2003 using backward trajectories. Distinct patterns in air mass history were revealed using this approach that helped explain extreme variations in O3 mixing ratios. Most enhanced (≥90th percentile) and depleted (≤10th percentile) O3 events were short‐lived and spread out over the summer months. Enhanced O3 events at Mount Washington were generally associated with westerly transport, while depleted events corresponded to northwesterly transport. Periods of O3 greater than 80 ppbv during nighttime periods coincided with westerly (71%) and southwesterly (29%) transport. Periods of elevated O3 commonly occurred during regional warm sector flow or on the western edge of a surface anticyclone. Our analysis also identified a stratospheric contribution to a small percentage (∼5%) of extreme O3 events at the site, but more evidence is required to establish the significance of the contribution to background O3 levels in this region.
El Niño–Southern Oscillation–induced variability in terrestrial carbon cycling
Authors: Hashimoto Hirofumi , Nemani Ramakrishna R. , White Michael A. , Jolly William M. , Piper Steve C. , Keeling Charles D. , Myneni Ranga B. , Running Steven W.
Published: December 2004

We examined the response of terrestrial carbon fluxes to climate variability induced by the El Niño–Southern Oscillation (ENSO). We estimated global net primary production (NPP) from 1982 to 1999 using a light use efficiency model driven by satellite‐derived canopy parameters from the Advanced Very High Resolution Radiometer and climate data from the National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis project. We estimated a summed heterotrophic respiration and fire carbon flux as the residual between NPP and the terrestrial net carbon flux inferred from an atmospheric inversion model, excluding the impacts of land use change. We propose that for global applications this approach may be more robust than traditional, biophysically based approaches of simulating heterotrophic respiration. NPP interannual variability was significantly related to ENSO, particularly at lower latitudes (22.5°N–22.5°S) but was weakly related to global temperature. Global heterotrophic respiration and fire carbon fluxes were strongly correlated with global temperature (7.9 pgC/°C). Our results confirm the dependence of global heterotrophic respiration and fire carbon fluxes on interannual temperature variability and strongly suggest that ENSO‐mediated NPP variability influences the atmospheric CO2 growth rate.
Evolution of passive margin escarpments: What can we learn from low‐temperature thermochronology?
Authors: Braun Jean , van der Beek Peter
Published: December 2004

Recent studies integrating geomorphology, thermochronology, cosmogenic erosion rate estimates, and numerical modeling suggest that escarpment evolution may take place following two dramatically different modes: (1) parallel retreat from the escarpment's original position at the continent‐ocean boundary to its present‐day inland position and (2) formation‐in‐place by progressive downwearing of a plateau initially located between the coast and a preexisting inland drainage divide. Using a three‐dimensional finite element model to solve the heat transfer equation, we show that the mode of migration of a passive margin escarpment can be constrained by low‐temperature (apatite (U‐Th)/He) thermochronology. We first couple the heat equation solver to a surface processes model that predicts the two different escarpment evolution modes from only slightly different initial conditions. We predict (U‐Th)/He age distributions that are markedly different for the two scenarios. We perform a thorough investigation of the model behavior to determine under which circumstances thermochronological data can be used to constrain passive margin escarpment dynamics. These conditions include (a) a tall escarpment, (b) a high geothermal gradient, and/or (c) a low flexural rigidity of the lithosphere. We demonstrate that to determine the rate and mode of escarpment migration from low‐temperature thermochronology, one needs to collect samples along transects perpendicular as well as parallel to the escarpment. Tightest constraints on escarpment development are provided by (in ascending order) the minimum (U‐Th)/He age encountered seaward of the escarpment, the location of where the minimum age is found, the slope of the age‐distance relationship (in a direction perpendicular to the coast), and the slope of the age‐elevation relationship (from a transect parallel to the escarpment). We finally demonstrate that there are situations where thermochronological data sets do not provide constraints on the mode of escarpment migration, such as along the escarpment of southeastern Australia, where migration has possibly been very rapid. Using the Neighborhood Algorithm method, we are, however, able to extract from an existing apatite (U‐Th)/He data set very useful constraints on the evolution of the southeastern Australian escarpment, including the duration of the migration event (<15 Myr), the local geothermal gradient (32°–40°C km−1), and the effective elastic thickness of the underlying lithosphere (6–8 km).
Amino acid geochronology of individual foraminifer (Pulleniatina obliquiloculata) tests, north Queensland margin, Australia: A new approach to correlating and dating Quaternary tropical marine sediment cores
Authors: Hearty Paul J. , O'Leary Michael J. , Kaufman Darrell S. , Page Michael C. , Bright Jordon
Published: December 2004

In this study, we demonstrate the utility of amino acid geochronology based on single‐foraminiferal tests in Quaternary sediment cores from the Queensland margin, Australia. The large planktonic foraminifer Pulleniatina obliquiloculata is ubiquitous in shelf, slope, and basin sediments of north Queensland as well as pantropical oceans. Fossil tests are resistant to dissolution, and retain substantial concentrations of amino acids (2–4 nmol mg−1 of shell) over hundreds of thousands of years. Amino acid D and L isomers of aspartic acid (Asp) and glutamic acid (Glu) were separated using reverse phase chromatography, which is sensitive enough to analyze individual foraminifera tests. In all, 462 Pulleniatina tests from 80 horizons in 11 cores exhibit a systematic increase in D/L ratios down core. D/L ratios were determined in 32 samples whose ages are known from AMS 14C analyses. In all cases, the Asp and Glu D/L ratios are concordant with 14C age. D/L ratios of equal‐age samples are slightly lower for cores taken from deeper water sites, reflecting the sensitivity of the rate of racemization to bottom water temperature. Beyond the range of 14C dating, previously identified marine oxygen‐isotope stage boundaries provide approximate ages of the sediments up to about 500,000 years. For this longer time frame, D/L ratios also vary systematically with isotope‐correlated ages. The rate of racemization for Glu and Asp was modeled using power functions. These equations can be used to estimate ages of samples from the Queensland margin extending back at least 500,000 years. This analytical approach provides new opportunities for geochronological control necessary to understand fundamental sedimentary processes affecting a wide range of marine environments.
A quasi‐analytical boundary condition for three‐dimensional finite difference electromagnetic modeling
Authors: Mehanee Salah , Zhdanov Michael
Published: December 2004

Numerical modeling of the quasi‐static electromagnetic (EM) field in the frequency domain in a three‐dimensional (3‐D) inhomogeneous medium is a very challenging problem in computational physics. We present a new approach to the finite difference (FD) solution of this problem. The FD discretization of the EM field equation is based on the balance method. To compute the boundary values of the anomalous electric field we solve for, we suggest using the fast and accurate quasi‐analytical (QA) approximation, which is a special form of the extended Born approximation. We call this new condition a quasi‐analytical boundary condition (QA BC). This approach helps to reduce the size of the modeling domain without losing the accuracy of calculation. As a result, a larger number of grid cells can be used to describe the anomalous conductivity distribution within the modeling domain. The developed numerical technique allows application of a very fine discretization to the area with anomalous conductivity only because there is no need to move the boundaries too far from the inhomogeneous region, as required by the traditional Dirichlet or Neumann conditions for anomalous field with boundary values equal to zero. Therefore this approach increases the efficiency of FD modeling of the EM field in a medium with complex structure. We apply the QA BC and the traditional FD (with large grid and zero BC) methods to complicated models with high resistivity contrast. The numerical modeling demonstrates that the QA BC results in 5 times matrix size reduction and 2–3 times decrease in computational time.
Evaluation of a two‐stage evaporation approximation for contrasting vegetation cover
Authors: Boulet G. , Chehbouni A. , Braud I. , Duchemin B. , Lakhal A.
Published: December 2004

For a regional assessment of water needs and consumption in semiarid agricultural zones, one needs robust and simple tools that provide space‐time estimates of evaporation losses. Most operational evaporation estimates rely on semiempirical relationships that are not generally applicable. Several authors have proposed physically based simple expressions to model the “energy‐limited” (stage‐one) and the “supply‐limited” (stage‐two) evaporation rates during a dry down. They use the time compression approximation (TCA) to relate stage‐one and stage‐two drying. Two asymptotic approximations of the TCA corresponding to the diffusion‐dominated and the drainage‐dominated flows have been proposed in the literature. In this study a full analytical solution of the TCA is presented. The derived “supply‐limited” evaporation rate is evaluated for a wide range of soil conditions and vegetation cover against a physically based complex soil‐vegetation‐atmosphere transfer model, the Simple Soil‐Plant‐Atmosphere Transfer scheme (SiSPAT). SiSPAT solves the differential equations of water flow in a vertical soil column and computes estimates of soil evaporation and transpiration. SiSPAT is used to evaluate the performance of the full solution as well as the two existing asymptotic approximations for the case of sparse to dense vegetation in a semiarid environment. The full analytical solution gives accurate predictions of first‐ to second‐stage evaporation time series for the bare soil and vegetated cover conditions with a leaf area index of 3 or higher. The results of the full solution are closer to the evaporation rate time series simulated by SISPAT than the asymptotic approximations.
Stability‐oriented programs for regulating water withdrawals in riparian regions
Authors: An Hyunhee , Eheart J. Wayland , Braatz Richard D.
Published: December 2004

Under permit programs stemming from regulated riparian systems of water withdrawal control, significant quantities of water cannot be withdrawn from the stream without a withdrawal‐constraining permit. There are two versions of such a permit system, one of which fixes the allowable withdrawal, the other of which allows withdrawals to vary directly with streamflows. However, both tie allowable withdrawal to streamflow at some level, the former simply shutting off all withdrawals when the streamflow breaches a low flow standard. Simple logic and the simulation of such systems with hydrologic models predict, in cases where the indexing gauge is downstream of the withdrawal point, the possibility of unstable feedback, leading to severe variability of both streamflow and allowable withdrawal. In this paper we characterize the streamflow variability with three indices, namely, flow crossing, flow reversal, and standard deviation, and compare the difference in those indices to represent the degree of the streamflow variability under the fixed flow and fractional flow withdrawal permit programs. Techniques based on control theory are proposed for modifying the fractional flow withdrawal program to reduce the streamflow variability. It is concluded that regulatory programs modified by inclusion of a first‐order filter are able to reduce streamflow variability without significant sacrifice in net benefit or low flow frequency.
Co‐existent cutaneous cryptococcosis of the forearm and cutaneous alternariosis of the leg in patient with metastatic thymoma
Authors: Courville P. , Favennec L. , Viacroze C. , Barrel A. , Young P. , Abboud P. , Thomine E. , Metayer J. , Nouvet G.
Published: December 2004

Background:  Cryptococcosis and alternariosis are rare opportunistic infections often observed in immunocompromised patients. Because Cryptococcus and Alternaria are ubiquitous fungi found in soil, the presence of fungi in the dermis has to be observed on histological examination to confirm a real cutaneous, invasive, infection.

Patient:  We report the first case of concomitant cutaneous cryptococcosis and cutaneous alternariosis, in an immunocompromised patient treated for a metastatic thymoma.

Conclusion:  This observation underlines the fact that the possible co‐existence of several rare infections in immunocompromised patients should take into consideration pathogen identification in order to adapt the therapy to individual patient requirements.
Dermatofibroma with sclerotic areas resembling a sclerotic fibroma of the skin
Authors: Sohn In‐Bum , Hwang Sang Min , Lee Seung Hun , Choi Eung Ho , Ahn Sung Ku
Published: December 2004

Background:  Dermatofibromas are common benign tumors that occur as single or multiple nodules on the extremities in adults. Sclerotic fibroma of the skin (SFS) is a benign tumor characterized histopathologically by a well‐demarcated, non‐encapsulated dermal nodule composed of hypocellular, sclerotic collagen bundles with prominent clefts. The pathogenesis of these two conditions is still in dispute.

Methods:  We present a case of dermatofibroma with sclerotic areas resembling a sclerotic fibroma of the skin and a review of the literature.

Results:  The tumor showed a well‐demarcated dermal, fibrocollagenous tumor with three different histopathological features. One‐fourth of the lesion was consistent with dermatofibroma. Another area adjacent to dermatofibroma revealed hyalinized eosinophilic collagen bundles arranged in the characteristic interwoven pattern with prominent clefts, as is described in sclerotic fibroma of the skin. One‐half of the lesion between the dermatofibroma and sclerotic fibroma showed transitional changes from dermatofibroma to sclerotic fibroma.

Conclusion:  According to these findings, the possibility that sclerotic fibroma is an ancient or degenerated stage of dermatofibroma cannot be completely ruled out, but some authors still consider that dermatofibroma and sclerotic fibroma of the skin are completely different neoplasms.
Effect of selective logging on tree and understory regeneration in miombo woodland in western Tanzania
Authors: Schwartz M. W. , Caro T. M.
Published: December 2004

Tree regeneration and understory response to selective cutting of Pterocarpus angolensis DC, and Sterculia quinqueloba Sim, was measured outside Katavi National Park, Tanzania. Contrary to expectations, a selective harvest had no effect on tree recruitment for either species in this miombo woodland. In unlogged plots along transects taken at increasing distance from a main road, the stand densities of young trees declined away from the road. Since anthropogenic activity along the road results in a high fire frequency but low native ungulate densities, the increased rate of tree regeneration near the road may result from either reduced grazing and browsing pressure by native ungulates, or reduced fire intensity and severity along roads. These effects appear to mask any possible effect of selective harvest on tree recruitment. Currently, there is no evidence of compensatory recruitment of trees of any species into the canopy to replace logged trees and this will lead to a gradual thinning in overstory stand density.
Cenozoic stratigraphy and subsidence history of the South China Sea margin in the Taiwan region
Authors: Lin A. T. , Watts A. B. , Hesselbo S. P.
Published: December 2004

Seismic reflection profiles and well data are used to determine the Cenozoic stratigraphic and tectonic development of the northern margin of the South China Sea. In the Taiwan region, this margin evolved from a Palaeogene rift to a latest Miocene–Recent foreland basin. This evolution is related to the opening of the South China Sea and its subsequent partial closure by the Taiwan orogeny.

Seismic data, together with the subsidence analysis of deep wells, show that during rifting (∼58–37 Ma), lithospheric extension occurred simultaneously in discrete rift belts. These belts form a >200 km wide rift zone and are associated with a stretching factor,β, in the range ∼1.4–1.6. By ∼37 Ma, the focus of rifting shifted to the present‐day continent–ocean boundary off southern Taiwan, which led to continental rupture and initial seafloor spreading of the South China Sea at ∼30 Ma. Intense rifting during the rift–drift transition (∼37–30 Ma) may have induced a transient, small‐scale mantle convection beneath the rift. The coeval crustal uplift (Oligocene uplift) of the previously rifted margin, which led to erosion and development of the breakup unconformity, was most likely caused by the induced convection.

Oligocene uplift was followed by rapid, early post‐breakup subsidence (∼30–18 Ma) possibly as the inferred induced convection abated following initial seafloor spreading. Rapid subsidence of the inner margin is interpreted as thermally controlled subsidence, whereas rapid subsidence in the outer shelf of the outer margin was accompanied by fault activity during the interval ∼30–21 Ma. This extension in the outer margin (β∼1.5) is manifested in the Tainan Basin, which formed on top of the deeply eroded Mesozoic basement. During the interval ∼21–12.5 Ma, the entire margin experienced broad thermal subsidence. It was not until ∼12.5 Ma that rifting resumed, being especially active in the Tainan Basin (β∼1.1). Rifting ceased at ∼6.5 Ma due to the orogeny caused by the overthrusting of the Luzon volcanic arc.

The Taiwan orogeny created a foreland basin by loading and flexing the underlying rifted margin. The foreland flexure inherited the mechanical and thermal properties of the underlying rifted margin, thereby dividing the basin into north and south segments. The north segment developed on a lithosphere where the major rift/thermal event occurred ∼58–30 Ma, and this segment shows minor normal faulting related to lithospheric flexure. In contrast, the south segment developed on a lithosphere, which experienced two more recent rift/thermal events during ∼30–21 and ∼12.5–6.5 Ma. The basal foreland surface of the south segment is highly faulted, especially along the previous northern rifted flank, thereby creating a deeper foreland flexure that trends obliquely to the strike of the orogen.
Recent tectonics in the Turkana Rift (North Kenya): an integrated approach from drainage network, satellite imagery and reflection seismic analyses
Authors: Vétel W. , Le Gall B. , Johnson T. C.
Published: December 2004

The Turkana rifted zone in northern Kenya is a long‐lived and polyphased rift system where the lack of well‐marked rift morphology makes it difficult to identify the zone of active deformation. A high‐density river network is exceptionally well developed over the study area and shows evidence of drainage anomalies that suggest recent fault‐induced movements at various scales. Correlation of surface drainage anomalies with Landsat remote sensing and deep seismic reflection data permits to characterize the deep geometry of the inferred fault structures. Seismic stratigraphy further allows distinction between the inherited (Oligocene–Pliocene) and the newly formed (<3.7 Ma) origin of the recent deformation. Evidence for neotectonics are observed (1) along a large‐scale transverse (EW) fault rooted at depth along a steep basement discontinuity (Turkwell), (2) along a rift‐parallel (NS) fault zone probably emplaced during the Pliocene–Pleistocene and currently bounding the Napedet volcanic plateau to the west and (3) over a round‐shaped uplifted zone caused by positive inversion tectonics (Kalabata). The major contribution of this work is the recognition of a broad (80 km wide) zone of recent/active extensional deformation in the Turkana Rift in contrast with the narrow (20 km wide) N10°E‐trending axial trough forming the Suguta valley to the south, and the Chew Bahir faulted basin to the north. These along‐strike variations in structural style are partly controlled by the occurrence of rejuvenated Oligocene–Miocene rift faults and long‐lived transverse discontinuities in the Turkana Rift area. More generally, this study has implications for the use of river drainage network about recent/active extensional domains with subdued topography and slow deformation rate.
Expansion of cytotoxic effectors with lytic activity against autologous blasts from acute myeloid leukaemia patients in complete haematological remission
Authors: Torelli Giovanni F. , Guarini Anna , Palmieri Gabriella , Breccia Massimo , Vitale Antonella , Santoni Angela , Foa Robin
Published: December 2004

Summary. New therapeutic approaches are needed to improve the cure rates in acute myeloid leukaemia (AML). The present study was designed to investigate whether: (1) cytotoxic lymphocytes could be expanded from AML patients in complete remission; (2) their signal transduction machinery was preserved; (3) these cells were capable of producing cytokines involved in the cytolytic process; and (4) these cells showed cytotoxic activity against allogeneic and autologous blasts. By co‐culturing blood mononuclear cells with feeder cells, we obtained an average 5·3‐fold increase in the total cell number and a 35‐fold increase in natural killer (NK) cells. Expression of the ζ chain and of tyrosine kinases of the Src and Syk‐ZAP families involved in the triggering of NK functions was analysed on expanded cells. The results demonstrated a signal transduction apparatus preserved and quantitatively similar to that of normal donors. After phorbol myristate acetate and ionomicin stimulation, the ability of expanded cells to produce interferon γ and tumour necrosis factor α was documented. Patients' expanded cells showed a cytotoxic activity against target lines and allogeneic blasts which was similar to that of normal donors. Purification experiments indicated that the NK cell fraction was responsible for most of the lytic effect. More significantly, these cells also exerted a lytic effect against autologous blasts that could be further enhanced following incubation with low‐dose interleukin 2. These findings document the possibility of expanding cytotoxic effectors with preserved signal transduction machinery and autologous killing capacity from AML patients in remission, and suggest a new potential immunotherapeutic strategy for the management of early disease recurrence or of residual disease.
Infliximab chimaeric anti‐tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes
Authors: Stasi Roberto , Amadori Sergio
Published: December 2004

Summary. Tumour necrosis factor alpha (TNF‐α) is believed to play a major role in apoptotic death of bone marrow cells in myelodysplastic syndromes (MDS). We explored the efficacy and safety profile of infliximab chimaeric anti‐TNF‐α monoclonal antibody treatment in two MDS patients. They both had low‐/intermediate‐risk MDS, isolated anaemia and elevated circulating levels of TNF‐α. Infliximab produced no adverse side‐effects and resulted in sustained erythroid responses, one major and one minor. Laboratory studies indicated a remarkable decrease in the percentage of apoptotic stem cells in the bone marrow. This preliminary report indicates that infliximab may have an application as MDS therapy and warrants further investigation.
Secondary acute myeloid leukaemia with monosomy 7 in identical adult twins
Authors: Seipelt Gernot , Germing Ulrich , Koschmieder Steffen , Böhme Angelika , Aul Carlo , Hoelzer Dieter
Published: December 2004

Summary. We report the development of secondary acute myeloid leukaemia (AML) with monosomy 7 in identical twins, both at the age of 52 years. In the first twin, induction therapy resulted in complete remission (CR). At relapse 9 months later monosomy 7 was found. The patient died of sepsis 11 months after diagnosis. The other twin presented with leucopenia and thrombocytopenia and refractory anaemia (RA) was diagnosed. During follow‐up, fluorescence in situ hybridization analysis demonstrated a monosomy 7 in 11% of the cells. Twenty‐eight months following diagnosis the patient progressed to RA with excess blasts in transformation and induction chemotherapy was initiated without achieving CR. Three months later an allogeneic stem cell transplantation from a niece was performed, resulting in CR of the secondary AML.
Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results
Authors: Harrison Christine J. , Mazzullo Helen , Cheung Kan L. , Gerrard Gareth , Jalali G. Reza , Mehta Atul , Osier David G. , Orchard Kim H.
Published: December 2004

Summary. The cytogenetic picture in multiple myeloma (MM) is highly complex, from which non‐random numerical and structural chromosomal changes have been identified. Specifically, translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and either monosomy or deletions of chromosome 13 have been reported in a significant number of patients from both cytogenetic and interphase fluorescence in situ hybridization (FISH) studies. Importantly, these abnormalities of chromosome 13 have recently been associated with a poor prognosis. In view of the highly complex nature of the karyotypes in MM patients, interphase FISH results may be difficult to interpret. In this study, cytogenetics and/or interphase FISH were carried out on bone marrow samples or purified plasma cells from 37 MM patients. Abnormal karyotypes, characterized by multiplex FISH (M‐FISH) were found in 11 patients, all of which were highly complex. Interphase FISH revealed translocations involving the IGH locus in 16 (43%) patients. The IGH/cyclin D1 (CCND1) gene fusion characteristic of the translocation, t(11;14)(q13;q32), was seen in 12 (32%) of these patients and other rearrangements of IGH in four (11%) patients. Fourteen patients had additional copies of chromosome 11. Twenty patients (54%) had 13q14 deletions, 10 of whom also had t(11;14) or another IGH translocation. By comparing cytogenetic and FISH results, this study has revealed that significant chromosomal abnormalities might be hidden within highly complex karyotypes. Therefore, extreme caution is required in the interpretation of interphase FISH results in MM, particularly in relation to certain abnormalities, such as 13q14 deletions, which have an impact on prognosis.
Leukaemic pulmonary infiltrates in adult acute myeloid leukaemia: a high‐resolution computerized tomography study
Authors: Potenza Leonardo , Luppi Mario , Morselli Monica , Tonelli Stefania , D'Apollo Nicola , Facchini Luca , Torricelli Pietro , Tazzioli Giovanni , Saviola Alessia , Bresciani Paola , Longo Giuseppe , Torelli Giuseppe
Published: December 2004

Summary. Leukaemic infiltration of the lungs may occur in acute myeloid leukaemia (AML). Pulmonary infiltrates are usually microscopic and invariably associated with hyperleucocytosis. Four AML patients with respiratory symptoms and low leucocyte counts underwent standard chest radiography, bronchoscopy with bronchoalveolar lavage and high‐resolution computerized tomography (HRCT) of the lungs. HRCT scans showed pulmonary infiltrates with alveolar, interstitial, mixed and peribronchial/perivascular patterns in all patients, including one with negative standard radiographic findings. Infectious agents were excluded. Histology of the lung biopsy/autopsy specimens showed leukaemic infiltrates. Pulmonary leukaemia may be the cause of pulmonary infiltrates, even in non‐hyperleucocytosic AML patients with low blast counts.
Resistance to spontaneous apoptosis in acute myeloid leukaemia blasts is associated with p‐glycoprotein expression and function, but not with the presence of FLT3 internal tandem duplications
Authors: Pallis Monica , Turzanski Julie , Grundy Martin , Seedhouse Claire , Russell Nigel
Published: December 2004

Summary. The ability of acute myeloid leukaemia (AML) blasts to survive in culture has been associated with poor patient response to chemotherapy. Other biological factors predicting an adverse outcome include p‐glycoprotein (pgp) expression, which is associated with a reduced remission rate, and the presence of fms‐like tyrosine kinase 3 gene (FLT3) internal tandem duplications (ITDs), predictive of a high rate of leukaemic relapse. Our previous work has indicated a drug efflux‐independent role for pgp in apoptosis resistance. We measured spontaneous in vitro apoptosis in 58 primary AML samples to establish its relationship with functional and phenotypic pgp and with FLT3 ITDs. Cells were incubated for 48 h in a suspension culture, and the remaining viable cells were counted by flow cytometry. Median survival was 38% of baseline values. Resistance to spontaneous apoptosis was strongly associated with pgp (MRK‐16 antibody) expression (P = 0·001) and with pgp functional activity (P < 0·001). FLT3 ITDs, found in 20 cases, were inversely associated with functional pgp activity: thus, the median pgp modulation ratio was 2·0 in FLT3 wild‐type cases and 1·38 in ITD cases (P = 0·018). Also, the presence of FLT3 ITDs was not associated with in vitro apoptosis resistance. In conclusion, we have found that the presence of FLT3 ITDs is not related to AML blast survival in vitro, and is inversely associated with pgp activity, whereas pgp expression and activity are associated with resistance to spontaneous apoptosis. These results may help to explain the differing adverse effects of pgp (on remission induction) and FLT3 ITDs (on relapse) in AML.
Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B‐cell non‐Hodgkin's lymphoma or multiple myeloma
Authors: Lincz Lisa F. , Scorgie Fiona E. , Kerridge Ian , Potts Rachelle , Spencer Andrew , Enno Arno
Published: December 2004

Summary. Lymphoproliferative diseases are characterized by chromosomal aberrations, and susceptibility may depend on inherited activity of enzymes required for DNA synthesis and methylation. We analysed genetic polymorphisms for methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in Caucasians with non‐Hodgkin's lymphoma (NHL; n = 151), multiple myeloma (MM; n = 90) and 299 control subjects. The MS 2756 AG/GG genotypes were significantly under‐represented in NHL (26·2%) vs control subjects (37·2%; P = 0·02), and conferred a 2·4‐fold lower risk of follicular (odds ratio = 0·41, 95% confidence interval: 0·19–0·88, p = 0·02) but not diffuse large B‐cell lymphoma. MM patients showed no significant difference in the polymorphisms compared with control subjects.
Disparate expression of the PTEN gene: a novel finding in B‐cell chronic lymphocytic leukaemia (B‐CLL)
Authors: Leupin Nicolas , Cenni Bruno , Novak Urban , Hügli Barbary , Graber Hans U. , Tobler Andreas , Fey Martin F.
Published: December 2004

Summary. One fifth of B‐cell chronic lymphocytic leukaemia (B‐CLL) patients exhibit loss of heterozygosity (LOH) at 10q23.3, the site of the tumour suppressor PTEN. Microsatellite markers mapped complete LOH to 10q23.3 in 2/41 B‐CLL (5%) and allelic imbalances in 6/41 (15%). No PTEN gene mutations were found. PTEN protein expression was not detected in 11 B‐CLL (28%), and was reduced in eight patients (20%). LOH or allelic imbalances at 10q23.3 were fairly frequent in B‐CLL, but did not encompass the PTEN gene. Nevertheless, PTEN protein may be absent in B‐CLL with a normal PTEN genotype, suggesting a role of this phosphatase in the molecular pathology of B‐CLL.
Increased platelet Fc receptor expression as a potential contributing cause of platelet hypersensitivity to collagen in diabetes mellitus
Authors: Calverley David C. , Hacker Michele R. , Loda Kimberly A. , Brass Elizabeth , Buchanan Thomas A. , Tsao‐Wei Denice D. , Groshen Susan
Published: December 2004

Summary. Recent clinical and laboratory observations support a potential role for the platelet FcγRIIA receptor (FcR) in collagen‐mediated platelet activation associated with arterial thrombosis. Stable age‐ and sex‐independent variation in receptor expression exists. Flow cytometry showed that 100 diabetes patients had increased mean platelet FcR expression levels compared with 201 non‐diabetes patients (P < 0·001). Aggregation studies following FcR cross‐linking supported a receptor role in increased activation of diabetes platelets after collagen stimulation (P = 0·018). Immunoprecipitation of collagen‐stimulated and FcR‐crosslinked platelets demonstrated enhanced levels of tyrosine‐phosphorylated Syk in diabetic platelets. Increased platelet FcR‐mediated sensitivity to collagen may contribute to cardiovascular morbidity and mortality in diabetes.
Constitutional sequence variation in the Fanconi anaemia group C (FANCC) gene in childhood acute myeloid leukaemia
Authors: Barber Lisa M. , McGrath Helen E. N. , Meyer Stefan , Will Andrew M. , Birch Jillian M. , Eden Osborn B. , Taylor G. Malcolm
Published: December 2004

Summary. The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino‐acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4·09, P = 0·047; 95% confidence interval 1·08–15·54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.
Chronic but not acute graft‐versus‐host disease improves outcome in multiple myeloma patients after non‐myeloablative allogeneic transplantation
Authors: Pérez‐Simón José A. , Martino Rodrigo , Alegre Adrián , Tomás José F. , De Leon Angel , Caballero Dolores , Sureda Ana , Sierra Jordi , San Miguel Jesús F.
Published: December 2004

Summary. The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan‐based non‐myeloablative allogeneic transplant (NMT) was evaluated. Event‐free survival (EFS) at 24 months was 33%, being significantly higher for patients who developed chronic graft‐versus‐host disease (cGVHD) when compared with those who did not [51%vs 0% respectively, P = 0·02; hazard rate = 3·16 (95% confidence interval = 1·09–9·15, P = 0·03)] as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43%vs 0% respectively, P = 0·02). Overall survival (OS) at 24 months was 60%[72%vs 42% for patients who did and did not develop cGVHD respectively (P = 0·1); 63%vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (P = 0·013)]. At a median follow‐up of 366 d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant‐related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, P = 0·04). The present study suggests that graft‐versus‐myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.
Erythropoietin improves cardiac contractility in post‐hypoxic mice
Authors: Sterin‐Borda Leonor , Barceló Ana C. , Bozzini Carlos E.
Published: December 2004

Summary. Mice myocardia, in which plasma erythropoietin (EPO) concentrations were modified in response to different experimental conditions, were studied to evaluate contractility (dF/dt). CF1 mice were randomly separated into four main groups: group I, normocythaemic normoxic; group II‐a, normocythaemic intermittently exposed to hypobaria for 72 h; group II‐b, normocythaemic intermittently exposed to hypobaria for 3 weeks; group III, hypertransfused polycythaemic exposed to 72 h hypobaria; and group IV, hypertransfused polycythaemic maintained in normobaric air. Plasma EPO, contractile studies and binding assays were performed. The dF/dt was significantly higher in group II‐a than in group I and group II‐b; but in groups III and IV, the dF/dt was reduced. The toxic action of ouabain was reduced and delayed in its onset, accompanied by increased numbers of 3H‐ouabain binding sites in group II‐a. Contractility was positively correlated with plasma EPO (pEPO) in the different groups. Treating group I with recombinant human (rHu)‐EPO enhanced contractility while treating group II‐a with a monoclonal anti‐EPO decreased the dF/dt. The inhibition of enzymatic pathway(s) known to participate in the cytokines signal transduction, decreased the basal dF/dt values on atria from group II‐a and on group I atria treated with rHu‐EPO. The results demonstrated: (1) a cardiac non‐haematopoietic effect of EPO; (2) that mice in which the pEPO concentration increased showed improvement in contractility and in the therapeutic action of ouabain; and (3) it is possible that EPO may act as a cardioprotective agent by modulating the cardiac Na+–K+ pump.
Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients
Authors: Mourad Fadi H. , Hoffbrand A. Victor , Sheikh‐Taha Marwan , Koussa Susane , Khoriaty Adlette I. , Taher Ali
Published: December 2004

Summary. Desferrioxamine (DFX) alone (40–50 mg/kg/d s.c. over 8–12 h, five times weekly) was compared with combined DFX twice weekly and deferiprone (75 mg/kg/d) over 12 months in previously poorly chelated thalassaemia patients. Serum ferritin fell from 5506 ± 635 µg/l (mean ± SEM) to 3998 ± 604 µg/l (P < 0·001; n = 14) in the DFX group and from 4153 ± 517 µg/l to 2805 ± 327 µg/l in the combined group (P < 0·01; n = 11). Deferiprone plus DFX produced a greater mean urine iron excretion (1·01 mg/kg/24 h) than iron intake from blood transfusion in each patient. Main side‐effects were skin reactions (DFX alone), nausea and arthralgia (combined therapy). As chelation therapy, the combined protocol was as effective as DFX five times weekly.
Anti‐tumour activity of interferon‐alpha in multiple myeloma: role of interleukin 6 and tumor cell differentiation
Authors: Matsui William , Huff Carol Ann , Vala Milada , Barber James , Smith B. Douglas , Jones Richard J.
Published: December 2004

Summary. Interferon‐alpha (IFN‐α) is a pleotropic cytokine that has clinical activity against a wide variety of malignancies, including multiple myeloma (MM). In vitro, IFN‐α has diverse effects on both normal and malignant cells, however, the exact mechanisms responsible for its clinical anti‐tumour activity remain unclear. We found that IFN‐α inhibited MM cell proliferation in association with cell cycle arrest at G1 and limited the clonogenic growth of both MM cell lines and primary patient specimens. At the doses tested, IFN‐α was not cytotoxic, but induced terminal plasma cell differentiation resulting in the loss of clonogenicity. These activities were markedly enhanced by the major MM growth factor interleukin 6 (IL‐6). Moreover, IL‐6 was required for this process, as neutralizing antibodies against IL‐6 inhibited the effects of IFN‐α. IL‐6 also induced MM cell terminal differentiation when combined with a second, unrelated, antiproliferative agent bryostatin‐1, suggesting that its differentiating activities are preferentially enhanced in the presence of agents that inhibit cell cycling. These results suggest that the differentiating activities of IFN‐α may play a role in its clinical antimyeloma activity and provide the rationale for clinical differentiation therapy in MM.
Allogeneic bone marrow transplantation for severe post‐splenectomy thrombophilic state in leaky red cell membrane haemolytic anaemia of the stomatocytosis class
Authors: Bergheim Jann , Ernst Peter , Brinch Lorentz , Gore D. M. , Chetty M. C. , Stewart G. W.
Published: December 2004

Summary. The tendency for thrombosis to occur if haemolysis persists after splenectomy is especially marked in ‘hereditary stomatocytosis’, in which the red cell membrane ‘leaks’ Na and K. A 21‐year‐old woman, who was splenectomized in childhood for a congenital haemolytic state, presented with major pulmonary embolism that recurred despite anticoagulation. Tests showed a significant cation leak with a ‘shallow‐slope’ abnormality in temperature dependence. Allogeneic bone marrow transplantation caused the thrombophilic state to cease and subsequently anticoagulation was stopped without recurrence of thromboembolism. However, she died 9 months after transplantation: iron overload, intensified by the transfusion demands of the transplant, was a major factor.
Cytomegalovirus infection following unrelated cord blood transplantation for adult patients: a single institute experience in Japan
Authors: Tomonari Akira , Iseki Tohru , Ooi Jun , Takahashi Satoshi , Shindo Motohiro , Ishii Koji , Nagamura Fumitaka , Uchimaru Kaoru , Tani Kenzaburo , Tojo Arinobu , Asano Shigetaka
Published: December 2004

Summary. Cytomegalovirus (CMV) infection in 28 adult patients after cord blood transplantation (CBT) from unrelated donors was compared with that after bone marrow transplantation from HLA (human leucocyte antigen)‐matched related (R‐BMT) and unrelated (U‐BMT) donors. Positive CMV antigenaemia was seen in 19 (79%) of 24 CMV‐seropositive patients at a median of 42 d (range 29–85 d) after CBT, but in zero of four CMV‐seronegative patients. This did not differ significantly from values observed after R‐BMT and U‐BMT (66%, P = 0·22, and 60%, P = 0·15 respectively). Based on the antigenaemia results, 16 patients (67%) received pre‐emptive ganciclovir therapy from a median of 47 d (range 36–67 d) after CBT. This proportion was higher than that observed after R‐BMT (28%, P = 0·0048), but did not differ from that after U‐BMT (50%, P = 0·21). In addition, the probability of requiring more than two courses of ganciclovir therapy after CBT (21%) was higher than after R‐BMT and U‐BMT (0%, P = 0·015 and 0·039 respectively). One patient (5%) developed CMV disease after U‐BMT, whereas no patients developed CMV disease after CBT or R‐BMT. The CMV serostatus, use of a steroid and HLA disparity affected the probability of requiring ganciclovir therapy after CBT (P = 0·024, 0·032 and 0·017 respectively). These results suggest that recovery of CMV‐specific immunity after CBT is delayed when compared with BMT.
Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B‐cell chronic lymphocytic leukaemia
Authors: Dewald Gordon W. , Brockman Stephanie R. , Paternoster Sarah F. , Bone Nancy D. , O'Fallon Judith R. , Allmer Cristine , James Charles D. , Jelinek Diane F. , Tschumper Renee C. , Hanson Curtis A. , Pruthi Rajiv K. , Witzig Thomas E. , Call Timothy G. , Kay Neil E.
Published: December 2004

Summary. Fluorescence in situ hybridization (FISH) was used to detect 6q–, 11q–, +12, 13q–, 17p– and translocations involving 14q32 in interphase nuclei from blood and/or bone marrow from 113 patients with B‐cell chronic lymphocytic leukaemia (B‐CLL). A total of 87 patients (77%) had a FISH anomaly: 13q– × 1 was most frequent (64%) followed by 13q– × 2 (28%), +12 (25%), 11q– (15%), 17p– (8%) and 6q– (0%). FISH results for blood and bone marrow cells in 38 patients were similar. Purified CD5+/CD19+ cells from blood were studied in eight patients and results indicate that in some patients not all B cells have FISH anomalies. We used a defined set of hierarchical FISH risk categories to compare FISH results by stable versus progressive disease, age, sex, Rai stage, CD38+ expression and IgVH mutational status. Significant differences in FISH risk distributions were associated with Rai stage, disease status and CD38+, but not by age, sex or IgVH mutational status. To look for baseline factors associated with high‐risk disease, multivariate analysis of age, sex, Rai stage, CD38+ and disease status versus FISH risk category was performed. Importantly, only CD38+ was significantly associated with high‐risk FISH categories (+12, 11q– and 17p–) after adjustment for the effects of other variables.
Development of a liquid culture system for megakaryocyte terminal differentiation: fibrinogen promotes megakaryocytopoiesis but not thrombopoiesis
Authors: Sato Takahiro , Ono Minoru , Fujita Hiroshi , Tanaka Nobuhito , Tomiyama Junji , Sakamoto Yujiro , Takano Yoshiro , Murota Sei‐itsu , Morita Ikuo
Published: December 2004

Summary. Megakaryocyte differentiation is composed of three distinct stages: formation of erythromegakaryocytic progenitor cells, maturation of megakaryocytes and production of platelets. We have developed a liquid culture system for megakaryocyte terminal differentiation from haematopoietic stem cells into proplatelets. In this system, CD34+ cells isolated from human cord blood, differentiated to CD41+ cells, were classified either as propidium iodide (PI)+ cells (large) or PI– cells (small) by fluorescence‐activated cell sorting analysis on the late‐stage CD41+ cells. Transmission electron microscopy showed that the cultured small cells were morphologically identical to platelets isolated from normal peripheral blood. Moreover, the number of differentiated cells that were CD42b‐positive attained an approximately 60‐fold expansion over that of the primary CD34+ cells in this culture system. Furthermore, gene expression of megakaryocytopoietic transcriptional factors, GATA‐1 and NF‐E2, and several megakaryocytic markers such as glycoprotein (GP)IIb and thromboxane synthase was observed in the individual differentiation stage. Treatment with fibrinogen, a ligand of GPIIb/IIIa, increased the number of CD41+/PI+ cells, but treatment in the late stage suppressed CD41+/PI– cell formation, suggesting that fibrinogen promotes megakaryocytopoiesis, but not thrombopoiesis. We conclude that this liquid culture system using human CD34+ cells may be used to mimic the physiological development from haematopoietic stem cells into megakaryocytes, as well as promote subsequent thrombopoiesis.