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1.
Unfallchirurgie (Heidelb) ; 126(11): 880-885, 2023 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-36048176

RESUMO

BACKGROUND: Missed Monteggia lesions results in chronic luxation and deficits in the range of motion. The overall therapeutic goal is a quick and stable anatomical repositioning of the lesion. The prognosis of Monteggia lesions in comparison to its equivalents is better, especially with early diagnosis. OBJECTIVE: Comparison of the types of lesion, treatment modalities, hospitalization, immobilization, movement deficits, perioperative complications and outcome. MATERIAL AND METHODS: Retrospective study of 62 patients treated with acute Monteggia lesions and its equivalents during the period of 2009-2020. RESULTS: 2 patients were treated with cast immobilization only, 11 with repositioning under general anesthesia, 39 with intramedullary nailing and 10 with screw osteosynthesis. The average observation period was 4.1 months. Patients with cast immobilization needed only a short hospitalization (2 days), patients with repositioning or osteosynthesis had longer hospitalization (3.4 or 4.3 days, respectively). Deficits of the range of motion did not appear in simple cast immobilization or intramedullary nailing without reduction; however, patients with closed reduction or screw osteosynthesis showed some degree of deficits (9% and 40%, respectively). Monteggia lesions needed shorter hospitalization than their equivalents (3.7 vs. 4.5 days) and had less deficits in the range of motion (7% vs. 21%). CONCLUSION: Most patients were treated with osteosynthesis (79%). Patients with Monteggia lesions had a better outcome than patients with equivalent lesions.


Assuntos
Fixação Intramedular de Fraturas , Fratura de Monteggia , Humanos , Criança , Fratura de Monteggia/cirurgia , Estudos Retrospectivos , Fixação Interna de Fraturas/métodos , Prognóstico
2.
Z Orthop Unfall ; 151(4): 401-6, 2013 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-23963987

RESUMO

BACKGROUND: One of the biggest health insurance companies in Germany (AOK, Allgemeine Ortskrankenkasse) has published new results focussing on process quality of total knee replacement in 2010. These results were published in the online portal "Weiße Liste", which is based on health insurance routine data. The German Association of Orthopeadic Surgery questions the credibility of the rating system of the "Weiße Liste". To prove the system an interdisciplinary task force was created. MATERIAL AND METHODS: The task force identified patient-specific parameters, which influence the outcome of total knee replacement based on the literature and expert opinions. Out of 907 orthopaedic departments, 4 above average and four below average were identified. The AOK was asked to provide 80 data sets for each department. These anonymised data sets could be converted into patient-specific data sets in the identified departments. Statistical analysis was performed to answer the question of whether there are differences between the below and the above average groups. RESULTS: 625 cases could be investigated. We found an increased rate of postoperative complications in the below average group. There are differences between both groups in terms of factors influencing the procedure. In the below average group an increased rate of patients with one or more comorbidities and a preoperative extension lag of over 10° was found. The above average group has a higher rate of operations before the knee replacement. CONCLUSION: The results need to be proven on a larger scale. Further, prospective investigations are planned.


Assuntos
Artroplastia do Joelho/estatística & dados numéricos , Artroplastia do Joelho/normas , Interpretação Estatística de Dados , Medicina Baseada em Evidências , Pesquisas sobre Atenção à Saúde/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Garantia da Qualidade dos Cuidados de Saúde/estatística & dados numéricos , Alemanha/epidemiologia , Complicações Pós-Operatórias/diagnóstico , Garantia da Qualidade dos Cuidados de Saúde/métodos , Garantia da Qualidade dos Cuidados de Saúde/normas
3.
Biotechnol Bioeng ; 95(5): 883-92, 2006 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-16937404

RESUMO

Lipase-catalyzed kinetic resolution of racemates is a popular method for synthesis of chiral synthons. Most of these resolutions are reversible equilibrium limited reactions. For the first time, an extensive kinetic model is proposed for kinetic resolution reactions, which takes into account the full reversibility of the reaction, substrate inhibition by an acyl donor and an acyl acceptor as well as alternative substrate inhibition by each enantiomer. For this purpose, the reversible enantioselective transesterification of (R/S)-1-methoxy-2-propanol with ethyl acetate catalyzed by Candida antarctica lipase B (CAL-B) is investigated. The detailed model presented here is valid for a wide range of substrate and product concentrations. Following model discrimination and the application of Haldane equations to reduce the degree of freedom in parameter estimation, the 11 free parameters are successfully identified. All parameters are fitted to the complete data set simultaneously. Six types of independent initial rate studies provide a solid data basis for the model. The effect of changes in substrate and product concentration on reaction kinetics is discussed. The developed model is used for simulations to study the behavior of reaction kinetics in a fixed bed reactor. The typical plot of enantiomeric excess versus conversion of substrate and product is evaluated at various initial substrate mixtures. The model is validated by comparison with experimental results obtained with a fixed bed reactor, which is part of a fully automated state-of-the-art miniplant.


Assuntos
Lipase/metabolismo , Modelos Químicos , Propilenoglicóis/isolamento & purificação , Enzimas Imobilizadas/química , Cinética , Estereoisomerismo
4.
Phys Rev Lett ; 90(22): 222002, 2003 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-12857309

RESUMO

We report on geometric scaling in inclusive eA scattering data from the NMC and E665 experiments. This scaling and nuclear shadowing follows the pattern expected from nonlinear perturbative QCD for zero impact parameter at sufficiently small x(bj) and is compatible with geometric scaling in ep.

5.
Phys Rev Lett ; 90(9): 092001, 2003 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-12689214

RESUMO

Exclusive proton-antiproton annihilation into two photons at large s ( approximately 10 GeV2) and /t/,/u/ approximately s can be described by a generalized parton picture analogous to the "soft mechanism" in wide-angle real Compton scattering. The two photons are emitted in the annihilation of a single fast quark and antiquark. The matrix element describing the transition of the pp system to a qq pair can be related to the timelike proton elastic form factors as well as to the quark/antiquark distributions measured in inclusive deep-inelastic scattering. The reaction could be studied with the proposed 1.5-15 GeV high-luminosity antiproton storage ring (HESR) at GSI.

6.
J Synchrotron Radiat ; 10(Pt 3): 233-5, 2003 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-12714753

RESUMO

The sagittal deviation of a Laue-diffracted X-ray beam caused by the inclination of an exit crystal surface with respect to an entrance crystal surface has been studied both theoretically and experimentally. The use of this effect for sagittal focusing of X-ray synchrotron radiation diffracted by a Laue crystal is suggested. The focusing is based on the refraction effect due to the parabolic profile of an exit or/and entrance surface. The crystal is not bent. In order to achieve a reasonable focusing distance, the crystal should be cut asymmetrically. The experiment was performed at beamline BM5 at the ESRF.

7.
Anal Chem ; 75(6): 1536-41, 2003 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-12659219

RESUMO

Cryogenic cooling of the NMR radio frequency coils and electronics to give greatly enhanced sensitivity is arguably the most significant recent advance in NMR spectroscopy. Here we report the first cryogenic probe built in flow configuration and demonstrate the application to LC-NMR-MS studies. This probe provides superior sensitivity over conventional noncryogenic flow NMR probes, allowing the use of 100 microL of untreated urine (40% less material than previous studies that required preconcentration) and yet revealing drug metabolites hitherto undetected by LC-NMR-MS at 500 MHz. Besides the known sulfate and glucuronide metabolites, previously undetected metabolites of acetaminophen were directly observable in a 15-min on-flow experiment. Simultaneous MS data also provided knowledge on the NMR-silent functional moieties. Further, stop-flow LC-NMR-MS experiments were conducted for greater signal-to-noise ratios on minor metabolites. The cryoflow probe enables the NMR analysis of lower concentrations of metabolites than was previously possible for untreated biofluids. This strategy is generally applicable for samples containing mass-limited analytes, such as those from drug metabolism studies, biomarker and toxicity profiling, impurity analysis, and natural product analysis.


Assuntos
Acetaminofen/metabolismo , Acetaminofen/urina , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Acetaminofen/administração & dosagem , Adulto , Temperatura Baixa , Feminino , Glucuronídeos/urina , Humanos , Espectroscopia de Ressonância Magnética/instrumentação , Espectrometria de Massas/instrumentação , Sulfatos/urina
8.
Insect Biochem Mol Biol ; 33(1): 29-39, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12459198

RESUMO

Variants of U1 small nuclear RNAs (snRNAs) have been previously detected in a permanent cell line (BmN) of the silk moth Bombyx mori. In this study, the existence of U1 snRNA isoforms in the silk gland (SG) of the organism is investigated. The polyploidy (approximately 200,000X the 2N somatic value) state of the B. mori silk gland cells represents a unique system to explore the potential presence and differential expression of multiple U1 variants in a normal tissue. B. mori U1-specific RT-PCR libraries from the silk gland were generated and five U1 isoforms were isolated and characterized. Nucleotide differences, structural alterations, as well as protein and RNA interaction sites were examined in these variants and compared to the previously reported isoforms from the transformed BmN cell line. In all these SG U1 variants, variant sites and inter-species differences are located in moderately conserved regions. Substitutional or compensatory changes were found in the double stranded areas and clustered in moderately conserved regions. Some of the changes generate stronger base pairing. Calculated free energy (DeltaG) values for the entire U1 snRNA secondary structures and for the individual stem/loops (I, II, III and IV) domains of the isoforms were generated and compared to determine their structural stability. Using phylogenetic analysis, an evolutionary parallelism is observed between the polymorphic sites in B. mori and variant locations found among animal and plant species.


Assuntos
Bombyx/genética , RNA Nuclear Pequeno/genética , Animais , Sequência de Bases , Primers do DNA , Evolução Molecular , Conformação de Ácido Nucleico , Filogenia , RNA Nuclear Pequeno/química , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie
9.
Insect Mol Biol ; 11(1): 105-14, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11841508

RESUMO

Eight U2 snRNA variants were isolated from several Bombyx mori U2-specific RT-PCR libraries. U2 sequences and secondary structures were generated and examined in terms of potential RNA and protein interactions. Analysis indicated that nucleotide changes occurred in both stem/loop and single-stranded areas. Changes in the double stranded areas were either compensatory, single substitutions (e.g. C <--> U) or prevented the double-stranded formation of one or two base pairs. The polymorphisms were clustered in moderately conserved regions. Some of the changes observed generated stronger base pairing. Inter-species conserved protein or RNA-binding sites were relatively unaffected. No polymorphic sites were found in known functional sequences. Bombyx mori and Drosophila melanogaster U2 sequences are 95% and 70% similar at the 5'- and the 3'-ends of the molecule, respectively. Phylogenetic analysis of the U2 sequences demonstrates remarkable conservation across species.


Assuntos
Bombyx/genética , RNA Nuclear Pequeno/análise , Animais , Sequência de Bases , Transferência de Energia , Biblioteca Gênica , Variação Genética , Humanos , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Filogenia , RNA Nuclear Pequeno/classificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico
10.
J Synchrotron Radiat ; 8(Pt 6): 1203-6, 2001 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11679773

RESUMO

The possibility of concentrating a synchrotron X-ray beam using diffraction by a single crystal with a properly designed transverse groove on its surface, suggested earlier, has been studied experimentally. Here, the first experimental demonstration of this effect is reported, performed on beamline BM5 at the ESRF. The experimental result confirms the theoretical model.

11.
J Synchrotron Radiat ; 8(Pt 6): 1207-13, 2001 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11679774

RESUMO

A very simple method of sagittal focusing of X-ray synchrotron radiation is presented. A special ray-tracing program which utilizes the diffraction-refraction effect is developed. It is demonstrated both by ray-tracing simulations and by an experiment whereby a reasonably good sagittal concentration of 8 keV synchrotron radiation may be achieved by diffraction on the walls of a cylindrical hole drilled into an Si crystal. The holes were drilled parallel to the (111) planes and their diameter, 1 mm, was chosen so that the focusing distance fits the geometrical arrangement of beamline BM5 at the ESRF. Two such crystals have been used in a dispersive and non-dispersive arrangement. The better result was achieved using the dispersive arrangement. The intensity at the centre of the focus is increased by five times with respect to unfocused radiation. Excellent agreement exists between the ray-tracing simulations and experimental results.

12.
Psychol Sci ; 12(3): 230-7, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11437306

RESUMO

This study investigated predictions of the life-span theory of selection, optimization, and compensation, focusing on different patterns of task priority during dual-task performance in younger and older adults. Cognitive (memorizing) and sensorimotor (walking a narrow track) performance were measured singly, concurrently, and when task difficulty was manipulated. Use of external aids was measured to provide another index of task priority. Before dual-task testing, participants received extensive training with each component task and external aid. Age differences in dual-task costs were greater in memory performance than walking, suggesting that older adults prioritized walking over memory. Further, when given a choice of compensatory external aids to use, older adults optimized walking, whereas younger adults optimized memory performance. The results have broad implications for systemic theories of cognitive and sensorimotor aging, and the costs and benefits of assistive devices and environmental support for older populations.


Assuntos
Envelhecimento/psicologia , Atenção/fisiologia , Cognição , Memória , Desempenho Psicomotor/fisiologia , Caminhada/psicologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Tecnologia Assistiva/psicologia , Testes de Associação de Palavras
13.
Leukemia ; 15(1): 69-73, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11243402

RESUMO

The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine (F-ara-A) and hydroxyurea (HU) enhanced ara-CTP levels in two human myeloid (HL-60, CMK) and two lymphoblastic leukemia cell lines (MOLT-4, BLIN-1) and also in blasts from 28 children with acute leukemia (AML: 14, ALL: 14). Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.


Assuntos
Antineoplásicos/farmacologia , Arabinofuranosilcitosina Trifosfato/metabolismo , Hidroxiureia/farmacologia , Leucemia/metabolismo , Vidarabina/análogos & derivados , Vidarabina/farmacologia , Adulto , Células HL-60 , Humanos
14.
Z Exp Psychol ; 48(1): 57-73, 2001.
Artigo em Alemão | MEDLINE | ID: mdl-11219186

RESUMO

This study examines whether setting priorities in personal life-investment is reflected in a heightened sensitivity towards thematically related stimuli. Two groups of adults (N = 47; M = 30 years; 53% female) were compared: (1) participants with a parallel goal structure (n = 12) who feel equally committed to the work and the family domain, both in the present and in the future, and (b) participants with a sequential goal structure (n = 24), who currently feel more involved in the work domain, but expect to be more engaged in the family domain in the future. Five tasks were used to assess preference, all of them simultaneously presenting work- and family-related stimuli. As hypothesized, individuals with a sequential goal structure showed a stronger preference for work-related stimuli than individuals with a parallel structure. There were clear differences in word detection, in the elaboration of work-related statements, and in the choice between work-related and family-related reading material. Results are discussed primarily in reference to models of action-regulation.


Assuntos
Atenção , Comportamento de Escolha , Objetivos , Individualidade , Adulto , Família/psicologia , Feminino , Humanos , Satisfação no Emprego , Masculino , Rememoração Mental , Motivação , Tempo de Reação , Semântica , Aprendizagem Verbal
15.
AIHAJ ; 61(2): 290-4, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10782202

RESUMO

A one-year Back Injury Prevention Program was initiated at a 440-bed acute care hospital in 1996 in response to concerns over high incidence and severity of back injuries among nursing staff and others. The program included an ergonomic evaluation of patient handling, pilot testing and purchase of new equipment, a train-the-trainer program, and training of 374 nurses and other patient handling staff (approximately one-half of the nursing staff). An impact evaluation, measured by comparing self-reported knowledge, work practices, and back pain among a subset of trainees and controls revealed an increase in knowledge of risk factors, a marginal increase in the use of mechanical devices to transfer patients, and a significant decrease in repositioning of patients in bed among trained versus control subjects (p = .017). Over the course of the program, the number of back injuries was 30% below the average of the prior 3 years, with the number of reported injuries in the final quarter (immediately following the training program) approximately one-seventh of the three prior quarters. It is concluded that back injury training may increase knowledge of risk factors and controls and may impact behaviors over which individuals have control (e.g., how often they move patients). However, training effectiveness is limited when engineering controls such as patient transfer devices are unavailable.


Assuntos
Lesões nas Costas/prevenção & controle , Ergonomia/métodos , Doenças Profissionais/prevenção & controle , Recursos Humanos em Hospital/educação , Humanos , Capacitação em Serviço , Remoção , Avaliação de Resultados em Cuidados de Saúde , Transferência de Pacientes , Projetos Piloto , Avaliação de Programas e Projetos de Saúde
16.
J Synchrotron Radiat ; 7(Pt 2): 53-60, 2000 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16609174

RESUMO

In the period of the late-1980s, before the construction of multi-GeV third-generation storage rings with their intense insertion-device sources, the perceived number one problem for X-ray instrumentation was proper cooling of the first optical element in the beamline. This article, first given as an acceptance speech for the Compton Award ceremony at the Advanced Photon Source, presents a somewhat historical and anecdotal overview of how cryogenically cooled monochromator optics have been developed to provide a monochromator cooling solution adequate for today's power levels. A series of workshops and international collaborations were the key components for the progress and final success of this development.

17.
Ann Oncol ; 10(3): 335-8, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10355579

RESUMO

BACKGROUND: Accumulation of the cytosine arabinoside (ara-C) metabolite ara-C-triphosphate (ara-CTP) in leukemic blast cells is considered to be the main determinant of ara-C cytotoxicity in vitro and in vivo. Retinoids such as all-trans-retinoic acid (ATRA) have been shown to increase the sensitivity of acute myelogenous leukemic (AML) blast cells to ara-C. To investigate the mechanism of this sensitisation, the hypothesis was tested that ATRA augments cellular ara-CTP levels in human-derived myelogenous leukemia HL-60 cells. MATERIALS AND METHODS: The effect of ATRA and 13-cis-retinoic acid on ara-CTP accumulation and ara-C-induced apoptosis was studied. Ara-CTP levels were measured by high-performance liquid chromatography (HPLC), cytotoxicity by the tetrazolium (MTT) assay, and apoptosis by occurrence of DNA fragmentation (gel electrophoresis), cell shrinkage and DNA loss (flow cytometry). RESULTS: Pretreatment of HL-60 cells with ATRA (0.01-1 microM) caused a significant decrease in intracellular ara-CTP levels; e.g., incubation for 72 hours with ATRA 1 microM prior to one hour ara-C 10 microM reduced ara-CTP levels to 41% +/- 4% of control. Similar results were obtained after preincubation with 13-cis-retinoic acid. In spite of decreased ara-CTP levels, the cytotoxicity of the combination was supraadditive and ATRA augmented ara-C-induced apoptosis. CONCLUSION: At therapeutically relevant concentrations ATRA increased ara-C cytotoxicity and ara-C induced apoptosis but this augmentation is not the corollary of elevated ara-CTP levels. The feasibility of ara-C treatment optimisation via strategies other than those involving elevation of ara-CTP levels should be investigated further.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Arabinofuranosilcitosina Trifosfato/metabolismo , Citarabina/administração & dosagem , Células HL-60/efeitos dos fármacos , Tretinoína/administração & dosagem , Análise de Variância , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/análise , Apoptose/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Eletroforese em Gel de Ágar , Citometria de Fluxo , Células HL-60/citologia , Células HL-60/metabolismo , Humanos , Tretinoína/análise , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo
18.
J Gerontol B Psychol Sci Soc Sci ; 54(1): P55-67, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9934396

RESUMO

Spontaneous self-definition was investigated in a heterogeneous sample of N = 516 participants of the Berlin Aging Study, aged between 70 and 103 years. The content of the self-definition revealed that old and very old persons view themselves as active and present-oriented. The self-definition also reflected an inward orientation, and central themes of life-review, health, and family. Participants generated more positive than negative evaluations in their self-definition, but the ratio of positive to negative evaluations was less favorable for the oldest old (> or = 85 years) than that of persons aged 70 to 84 years. Older individuals with more health-related constraints reported fewer and less rich self-defining domains (i.e., a less multifaceted self-definition). Positive emotional well-being was associated with naming more and richer self-defining domains. Multifacetness, however, did not buffer against the negative effect of low functional capacity on subjective well-being.


Assuntos
Idoso/psicologia , Autoimagem , Idoso de 80 Anos ou mais , Atitude Frente a Saúde , Humanos , Saúde Mental
19.
Exp Aging Res ; 25(1): 95-107, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-11370112

RESUMO

Open-ended tasks such as the "Who am I?" (Bugental & Zelen, 1950) or the Twenty Statement Test (Kuhn & McPartland, 1954) have facevalidity with regard to assessing content and dimensions of self-definition. Examined in the present study were questions about short-term temporal stability. Theory suggests that measures of the self may better reflect intraindividual variability than personality tests. Free-response and card-sort versions of the "Who am I?" were completed twice over an 8-week period by a volunteer sample of older persons (N = 104; age range: 69-92 years, M = 79). Low temporal stability of self-definition was found on an intraindividual level and on the level of interindividual differences. Measures of personality showed high stability. Although the "Who am I?" may not be the best instrument for assessing the content aspects of self-definition that are stable over time and across situations, it may provide a measure of situation-related variability.


Assuntos
Envelhecimento/psicologia , Autoimagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Testes de Personalidade , Fatores de Tempo
20.
Eur J Cancer ; 34(6): 895-901, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9797704

RESUMO

The ribonucleotide reductase inhibitors hydroxyurea (HU), arabinosyl-2-fluoroadenine (F-Ara-A) and 2-chlorodeoxyadenosine (2-CdA) and the antisignalling drugs all-trans retinoic acid (ATRA), staurosporine and quercetin have been reported to enhance the cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C). We tested the hypothesis that the ara-C-sensitising potency of the antisignalling agents is equipotent with that of the ribonucleotide inhibitors. The cytotoxicity, determined by the 3-(4,5 dimethylthiazol-2-yl-)5 diphenyltetrazolium bromide (MTT) assay, of combinations of ara-C with the agents named above was compared in the leukaemia cell lines HL-60, ara-C-resistant HL-60 (HL-60/ara-C) and U937. Furthermore, a range of protein tyrosine kinase inhibitors, genistein, CGP 52411, tyrphostin A48 and nordihydroguaiaretic acid (NDGA), for which ara-C-sensitisation has hitherto not been described, were included in the study. All three cell types acquired increased sensitivity to ara-C when co-incubated with HU or ATRA, but their ara-C sensitivity was not affected by quercetin or genistein. 2-CdA, CGP 52411, tyrphostin A48, staurosporine and NDGA were active as sensitisers against ara-C in HL-60 cells, CGP 52411 and tyrphostin A48 also in HL-60/ara-C cells, and 2-CdA, staurosporine and NDGA also in U937 cells. F-Ara-A increased ara-C toxicity in HL-60/ara-C and U937 cells. To address the mechanism of the observed sensitisation, the influence of agents with ara-C-sensitising properties on ara-C-induced apoptosis was investigated in HL-60 cells as measured by cell shrinkage, DNA loss and DNA fragmentation. HU, ATRA, tyrphostin A48 and NDGA augmented apoptosis induced by ara-C as assessed by all three indicators. CGP 52411 decreased the effect of ara-C on apoptotic indicators after incubation for 4 h, but not after 12 h. The results suggest that ATRA, CGP 52411, tyrphostin A48, staurosporine and NDGA may be suitable alternatives to the clinically applied ribonucleotide reductase inhibitors as modifiers of ara-C cytotoxicity in the treatment of acute myeloid leukaemia.


Assuntos
Leucemia/tratamento farmacológico , Ribonucleotídeo Redutases/antagonistas & inibidores , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Citarabina/farmacologia , Células HL-60/efeitos dos fármacos , Humanos
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