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Biomedical subjects

D D Ma

Publications and source records attributed to D D Ma.

At least 19 recordsLinked to original sources
PubMed2001

Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia.

Patterns of failure were studied in two consecutive randomized trials of intensified induction therapy carried out by the Australian Leukaemia Study Group (ALSG) between 1984 and 1991 to determine the impact of dose intensification. Patients received standard dose cytarabine and daunorubicin (7-3), 7-3 plus etoposide (7-3-7) or 7-3 plus high-dose cytarabine (HIDAC-3-7) chemotherapy. Patients with FAB M3 morphology were excluded. Time to failure (TTF) was defined as the time from randomization to induction death or removal from study for non-responders, or to relapse or death in complete response (CR) for complete responders. An estimated 86% of 470 de novo patients with acute myeloid leukaemia failed within 10 years of randomization, as a result of death in induction in 17% of the randomized patients, failure to achieve CR in a further 17%, relapse in 44% and death in CR in 8% of patients. An estimated 66% of patients failed as a result of refractory disease or relapse within that period (disease-related failures). Multifactor analysis identified age and peripheral blast count as the most significant pretreatment factors associated with overall TTF. These factors, together with cytogenetics, were significantly associated with disease-related failures. High-dose cytarabine in induction significantly decreased the disease-related failure rate as did allogeneic transplantation in first CR. The impact of high-dose cytarabine did not depend on the cytogenetic risk group.

Acute Disease↗
PubMed2001

Increased incidence of venous thrombosis in patients with shortened activated partial thromboplastin times and low ratios for activated protein C resistance.

A cohort of 69 hospital patients with shortened activated partial thromboplastin time (APTT) were prospectively identified and were further investigated for resistance to activated protein C (APC). This was quantified by APTT-based and Russel viper venom time (RVVT)-based methods. The prevalence of objectively confirmed venous thromboembolism (VTE) in this cohort was 19% (13/69). Of these 69 patients, 28 also had low APC resistance ratios and the incidence of VTE among these patients (group 1) was 36% (10/28). This was significantly higher (P=0.003) than that in the remaining 41 patients (group 2) with shortened APTT and normal APC resistance (7%, 3/41). DNA analysis confirmed 13 of the group 1 patients were FV Leiden positive. The incidence of VTE in the FV Leiden group (group 1a, n=13) was 38% (5/13) and in the group whose abnormal resistance to APC was independent of FV Leiden (group 1b, n=15) was 33% (5/15). These results suggest that a shortened APTT, coexisting with a low APC resistance ratio, regardless of FV Leiden carriership status, is a marker for VTE. Increased resistance to the anticoagulant activity of APC is multifactorial as reflected by evidence of abnormal resistance differing in the two assays.

Activated Protein C Resistance↗
PubMed2000

Synthetic oligonucleotides as therapeutics: the coming of age.

Synthetic oligonucleotides (ODNs) are short nucleic acid chains that can act in a sequence specific manner to control gene expression. Significant progress has been made in the development of synthetic ODN therapeutics since the first demonstration of gene inhibition by antisense ODNs in a cell culture system two decades ago. This new class of therapeutic agents can potentially target any abnormally expressed genes in a broad range of diseases from viral infections to psychoneurological disorders. A number of "first" generation synthetic ODNs have entered into human clinical trials in the last few years. The eminent approval of the first ODN for the treatment of cytomaglovirus retinitis by the FDA in USA will provide much excitement that this new class of compounds holds great promise as a therapeutic "magic bullet". However, many obstacles still exist in the development of this technology. In this review, the current status of synthetic ODN chemistry, drug delivery methods, mechanisms of ODN action, potential clinical applications and its limitations in a wide range of human disorders will be described.

Animals↗
PubMed1999

Self-reported depressive symptoms among Chinese adolescents.

Previous reports on the prevalence and features of depression among adolescents have been inconsistent. The purpose of the current study was to estimate the prevalence of depression among Chinese adolescents with a standardized instrument. A total of 2462 students, aged 13-22, were sampled from the Shandong province of China. The Zung Self-Rating Depression Scale (SDS) was administered to the subjects in their classrooms. It was shown that the mean SDS score was 44.8 (SD 9.9) and it decreased significantly from the age of 18 upward (F = 31.73, df = 9, P < 0.01). No significant difference was found between males and females (t = 0.70, P > 0.05). Taking 55 as a cut-off score, the prevalence rate of depression was 16.9% (95% CI = 15.4-18.4%). Logistic regression showed that increasing age appeared to decrease the risk for depression. Most of the individual items differed between ages, except for weight loss and constipation. Principal components factor analysis revealed that the characteristics of adolescent depression were depressive/anxious mood, psychomotor retardation, loss of self-esteem, somatic symptoms and decreased appetite and libido. Although the study was based on a large sample using an established instrument, the sample was not from a general adolescent population and case ascertainment was not by clinical diagnosis.

Adolescent↗
PubMed1999

Acral keratotic graft versus host disease simulating warts.

A 55-year-old man experienced persistent oral graft versus host disease after receiving an HLA-matched allogeneic stem cell peripheral blood transplant for chronic myeloid leukaemia. Twelve months post-transplant, multiple keratotic lesions resembling warts developed on his fingers, on his palms and on the soles of his feet. Skin biopsy showed a lichenoid reaction under a hyperplastic and hyperkeratotic epidermis lacking signs of papillomavirus infection. The lesions partially regressed when the patient's oral prednisone was increased. This instance of acral keratotic lesions may represent an unusual expression of chronic graft versus host disease; however, the the hydroxychloroquine which had been used for 8 months to control the patient's oral graft versus host disease cannot be excluded as a cofactor.

Bone Marrow Transplantation↗
PubMed1998

Non-malignant bone marrow necrosis: a report of two cases.

We present two cases of bone marrow necrosis not associated with malignancy, infection or sickle cell disease. The first case, a 28 year old woman with the antiphospholipid syndrome and a factor V Leiden abnormality, suffered an illness characterised by multiple organ thromboses, anemia and refractory thrombocytopenia. She had documented bone marrow necrosis of the posterior iliac spine and numerous hot spots on bone scanning suggestive of widespread marrow necrosis. This patient also suffered hepatic infarcts and a miscarriage and may represent an explanation for the previously described "catastrophic antiphospholipid syndrome". The second patient developed widespread bone pain over a three week period, underwent a cholecystectomy and suffered major post-operative complications including a delayed transfusion reaction and disseminated intravascular coagulation. Pancytopenia developed and bone marrow trephines from numerous foci revealed widespread bone marrow necrosis. The only predisposing factor to account for this presentation was that the patient had been sniffing glue for two months prior to the illness, as the foci of necrosis had healed on repeat marrow examination eight weeks later when the patient had abstained from glue sniffing. This case may represent a reversible, toxic cause of bone marrow necrosis.

Adult↗
PubMed1997

A comparison between two activated protein C resistance methods as routine diagnostic tests for factor V Leiden mutation.

The most common commercially available test measuring activated protein C (APC) resistance relies on the the anticoagulant response to added APC in an activated partial thromboplastin time (APTT) based method. Another method is a Russell Viper venom time (RVVT) based system. To improve the specificity for factor V Leiden of the APTT based method, pre-dilution of test plasma in FV-deficient plasma has recently been recommended. In this study we tested the relative suitabilities of the APTT-based system, the RVVT-based system and their corresponding assays modified by pre-dilution in FV-deficient plasma, for screening asymptomatic subjects, a group of thrombophilic patients (in particular those with low APC ratios), patients on oral anticoagulants, and patients with lupus anticoagulant (LAC). We found the RVVT-based assay to be superior to the APTT-based method in the separation of normals from those with FV Leiden mutation both in asymptomatic subjects and in the thrombophilic patient group. Both modified assays demonstrated a sensitivity and specificity of 100% for FV Leiden, as verified by genotyping in asymptomatic subjects, thrombophilic patients and patients on oral anticoagulants, with the modified RVVT-based assay giving better separation between normals and FV Leiden. Inhibition of phospholipid-dependent coagulation by LAC antibodies rendered the APTT-based system less suitable than the phospholipid-rich RVVT-based one, and as nine of the 20 LAC-positive patients were on warfarin, we showed only the modified RVVT assay to be a reliable predictor of factor V Leiden in this patient group.

Adult↗
PubMed1996

The influence of flow cytometric gating strategy on the standardization of CD34+ cell quantitation: an Australian multicenter study. Australasian BMT Scientists Study Group.

The Australian Multi-centre study on CD34+ cell quantitation by flow cytometry documented, first, the extent of variation of CD34+ cell enumeration and, second, the influence of flow cytometric gating on CD34+ cell measurement. A PBSC harvest analyzed by 20 participating centers showed results ranging from 0.64% to 2.80%, with a median of 1.54% CD34+ cells. Of 20 centers, 9 obtained results within +/-10% of the median (the criteria for reproducibility suggested by the ISHAGE Guidelines). The flow cytometric gating strategy was identified as one of the major variables among the methods used. In stage 2, list mode data from two samples were analyzed by 24 Australian and overseas centers, including the authors of three published guidelines. Significantly different CD34+ results were obtained when different gating strategies were used (p < 0.006). When all the centers used the same gating strategy, the measurement of CD34+ cells fell within a narrow range, with 0-7% of results outside +/-10% of the median. However, when different gating strategies were used, the results were more widely scattered, with 17% of centers outside +/-10% of the median. This study demonstrated the potential impact of flow cytometric gating strategy on the reproducibility of CD34+ cell enumeration.

Australia↗
PubMed1996

Evolution of bone marrow fibrosis and stromal antigenic expression in chronic myeloid leukemia on alpha interferon and Ara-C therapy.

We conducted a retrospective study to assess the changes in bone marrow (BM) stromal antigenic profile and fibrosis in chronic myeloid leukemia (CML) under combined interferon-alpha (IFN) and Ara-c therapy. Bone marrow biopsies were taken before therapy and twice (at 4 and 15 months) during therapy in 10 CML patients and compared with non-CML samples. Collagen and reticulin fibrosis was assessed by histochemical methods and phenotypic changes were studied by immunohistochemistry (APAAP) with antibodies directed against endothelial cell antigens, cell adhesion molecules, and HLA-DR. It was found that: (1) BM endothelial cells in patient and in control specimens showed a specific pattern of antigen expression: high expression of FVIII and CD34 (except on sinusoids for the latter), variable expression of UEA I, and no expression of HLA-DR and E-selectin. (2) Compared to non-CML controls, CML specimens at diagnosis showed an increased reticulin fibrosis and a decreased expression of CD61 on megakaryocytes and of CD31 on vessels and hemopoietic cells. (3) Treatment did not influence BM fibrosis, the vascular content of the BM, or the expression of the antigens tested except an increase in the number of CD34+ sinusoids (5/10 patients), an increase in the number of HLA-DR+, and a decrease in the number of CD34+ hemopoietic cells (6/10). (4) On therapy, difficulty in aspiration and/or reduced BM fragment numbers were noted in 8 of 10 patients whose bone marrow was still normocellular or slightly hypercellular. In conclusion, CML samples at diagnosis showed increased fibrosis and decreased CD31 and CD61 expression compared to controls. During the period of observation, combined therapy did not modify BM fibrosis; however, an increase in CD34+ sinusoids and a decrease in CD34+ hemopoietic cells were noted.

Adult↗
PubMed1996

[Research progress on the glia cell line-derived neurotrophic factor].

Glia cell line-derived neurotrophic factor (GDNF) is a novel type of neurotrophic factor cloned in 1993. Recent research revealed that it may have potential application in the treatment of Parkinson's disease and motor neuron diseases. This short review summarized the character of the protein, gene structure, tissue distribution, and its physiological functions and pathological implications.

Animals↗
PubMed1995

Interferon response in chronic myeloid leukaemia correlates with ABL/BCR expression: a preliminary study.

alpha-Interferon (IFN) has been used to induce cytogenetic remission in chronic myeloid leukaemia (CML), but there are few indicators to predict IFN response. The role of the chimaeric BCR/ABL gene in the malignant process is undisputed. There are, however, conflicting views as to whether the breakpoint site within the BCR gene, and the type of mRNA produced determine disease prognosis and progression. The function and clinical significance of the newly discovered ABL/BCR mRNA has not been investigated for a correlation with CML prognosis or response to therapy. We have used a two-step reverse transcriptase polymerase chain reaction (RT-PCR) to detect the transcripts of the chimaeric genes BCR/ABL, ABL/BCR, as well as the normal ABL and BCR genes in 24 CML patients treated with IFN. Because of the variable expression of the four transcripts at presentation, a correlation between gene expression, prognosis and clinical progression was examined. No correlation between prognosis and gene expression was seen. Also, no correlation was found between expression of BCR, ABL or BCR/ABL mRNA and response to treatment with IFN. However, 7/10 ABL/BCR mRNA positive patients achieved a major cytogenetic response to IFN; but of the 13 ABL/BCR mRNA negative patients, only two achieved a major cytogenetic response (P = 0.013). Further studies are required to confirm these findings.

Adolescent↗
PubMed1995

Activated protein c resistance (APC) and inherited factor V (FV) mis-sense mutation in patients with venous and arterial thrombosis in a haematology clinic.

BACKGROUND: Inherited factor V (FV) mis-sense point mutation has recently been identified as a major cause of familial venous thrombosis. The incidence of this congenital haemostatic disorder in Australia is unknown. AIM: To examine the incidence of this congenital defect in patients with thrombosis attending a haematology clinic. METHODS: Individuals investigated or treated for venous and arterial thrombosis over a four month period, as well as those who were on anticoagulant for valvular replacement or arrhythmia were studied for the presence of FV mis-sense point mutation, FV Q506 (G to A at nucleotide position 1691) by a polymerase chain reaction based test, and activated protein C (APC) resistance using an APTT based coagulation assay. RESULTS: Forty-five patients with venous thromboembolism (VTE), 20 patients with coronary artery disease and 25 patients with valvular replacement or arrhythmia who were on anticoagulant were examined. The frequency of FV mis-sense point mutation in these three groups was 26.7%, 15% and 4% respectively. In this study, patients with FV Q506 were of a younger age and had a higher incidence of extensive thrombosis or recurrence as compared to those with the normal factor V gene. This mutation was found in a diverse group of people (four of the 12 patients were of non-European origin). Nearly 50% of these patients had other risk factors for VTE. The number of patients with a family history of VTE was similar for those with the FV mutation and the normal FV. CONCLUSION: This study confirms the high incidence of FV Q506 mutation in patients with VTE reported overseas. Several clinical features, i.e. young age of onset of VTE, high recurrence rate, diverse ethnic background and importance of associated risk factors are highlighted. The findings in this study also raise the possibility that this mutation may be a risk factor for arterial thrombosis. Large studies are required to substantiate these findings.

Adult↗
PubMed1995

Long-term culture of autologous transplanted bone marrow for acute myeloid leukaemia: evidence for an in vitro haemopoietic defect and lack of correlation with the speed of engraftment.

Haematological recovery after autologous bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) is often delayed and available laboratory assays cannot accurately predict speed of engraftment. By using the long-term bone marrow culture (LTBMC) method, we attempted to define the haemopoietic defect underlying this slow engraftment, and assessed the usefulness of LTBMC in predicting engraftment. Cryopreserved bone marrow (BM) harvested from three different groups (AML autografts, n = 18; autografts for non-leukaemic diseases, n = 23; normal donors. n = 10) were cultured and their growth was compared and correlated with the speed of engraftment. In the AML autografts, non-adherent and adherent progenitor production was significantly reduced compared with normal BM during the whole culture period (P < 0.01). None of the LTBMC parameters was found to correlate with engraftment after autologous BMT. The non-leukaemic autografts showed progenitor production intermediate between normal and AML autografts. Their progenitor content at the end of the culture period (reflecting the stem cell pool) was not statistically different from normal BM. In this group, most of the progenitor cell contents, during LTBMC correlated with neutrophil (rs = -0.618 to -0.879, P < 0.01) and platelet (rs = -0.479 to -0.707, P < 0.02) recovery. The conclusion drawn from these results is that AML autografts are defective in their ability to sustain in vitro haemopoiesis, but this in vivo defect does not correlate with the slow haemopoietic recovery after autologous BMT. In contrast, LTBMC of autografts for non-leukaemic diseases, whose defect affects the stem cell pool to a lesser extent than BM in AML correlates with the speed of engraftment.

Acute Disease↗
PubMed1994

Daunorubicin pharmacokinetics and the correlation with P-glycoprotein and response in patients with acute leukaemia.

The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Targeted photochemical modification of HIV-derived oligoribonucleotides by antisense oligodeoxynucleotides linked to porphyrins.

Antisense oligodeoxynucleotides directed against a 24-mer RNA derived from the long terminal repeat (LTR) region of HIV were linked to proto- and methylpyrroporphyrin and their zinc derivatives. The oligonucleotide-porphyrin conjugates were tested for their ability to induce photodamage on the target RNA. Upon hybridization followed by irradiation at 405 nm, the photochemical reaction led to photocross-linking of the antisense derivative to the RNA substrate. The protoporphyrin exhibited a much higher cross-linking yield than the methylpyrroporphyrin while the Zn-porphyrin derivatives were found to be less efficient than their corresponding nonmetallated congeners. The specificity of the photocross-linking reaction between the porphyrin-oligomer and its target RNA was demonstrated by the following evidence: (1) hybrid formation was required for photocross-linking to occur, (2) the sites of cross-linking on the target RNA were identified at G residues located in close proximity to the porphyrin photoactive center in the hybrid and (3) addition of bulk calf liver RNA did not affect the photocross-linking efficiency.

Base Sequence↗