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Biomedical subjects

J A Holmes

Publications and source records attributed to J A Holmes.

At least 37 records · Page 2Linked to original sources
PubMed1994

The effect of MDR-1 gene expression on outcome in acute myeloblastic leukaemia.

Resistance to cytotoxic agents may be encountered during the treatment of acute myeloblastic leukaemia (AML). P-glycoprotein encoded by the MDR-1 gene has been implicated as a potential drug resistance mechanism in leukaemic cells. In recent years, many data have been accrued concerning the expression of P-glycoprotein in leukaemia, and several studies have been published which have related MDR status to outcome in AML. Conclusions as to the effect of P-glycoprotein expression on prognosis in AML have varied widely. The studies are not immediately comparable, since they differ in methodology, treatment regimens, demographic profile and, perhaps most importantly, criteria for positivity of MDR status. The technique of statistical overview (meta-analysis) can be used to pool observational studies. Application of this statistical method to existing studies suggests an estimated relative risk of 0.68 for P-glycoprotein expression with respect to complete remission in AML. Further large studies are required to determine fully the role of P-glycoprotein in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Chronic granulocytic leukaemia presenting with an extramedullary T lymphoblastic crisis.

A 33-year-old man presented with hepatosplenomegaly and lymphadenopathy. Bone marrow findings were consistent with Philadelphia-positive accelerated-phase chronic granulocytic leukaemia (CGL). Lymph node histology and immunhistochemistry were diagnostic of T lymphoblastic lymphoma. Molecular studies on lymph node DNA identified rearrangement within the major breakpoint cluster region (M-bcr), indicating a common clonal origin of CGL and the T lymphoblastic lymphoma. We report the second case where extramedullary T lymphoblastic crisis was the presenting feature of CGL.

Adult↗
PubMed1994

Topoisomerase II alpha expression in acute myeloid leukaemia and its relationship to clinical outcome.

The treatment of acute myeloid leukaemia (AML) is often complicated by resistance to chemotherapeutic drugs. Many of the most effective drugs used to treat haematological malignancies target the nuclear enzyme topoisomerase II. Resistance to these drugs in vitro has been associated with quantitative and qualitative changes in the enzyme. In this study, we have investigated topoisomerase II mRNA expression in leukaemic blasts from 23 AML patients. Expression levels ranged from 1-47% relative to the haemopoietic cell line HL60 in 16 evaluable patients. Thirteen of 16 patients achieved complete remission (CR). We have therefore chosen ease of entry into CR as the most sensitive clinical correlate. Decreased topoisomerase II mRNA expression in vitro results in drug resistance. The clinical relevance of reduced expression is not known. All cases of AML and de novo AML have been studied separately. We are unable to identify a correlation between topoisomerase II mRNA levels and ease of entry into CR in either of these groups. Taking these findings into account, group size calculations have been undertaken and indicate that a multi-centre study of this question is warranted.

Adolescent↗
PubMed1993

Linkage group XIX of Chlamydomonas reinhardtii has a linear map.

Linkage group XIX (or the UNI linkage group) of Chlamydomonas reinhardtii has been reported to show a circular meiotic recombination map. A circular map predicts the existence of strong chiasma and chromatid interference, which would lead to an excess number of two-strand double crossovers during meiosis. We have tested this prediction in multipoint crosses. Our results are consistent with a linear linkage group that shows positive chiasma interference and no chromatid interference. Chiasma interference occurs both within arms and across the centromere. Of the original loci that contributed to the circular map, we find that two map to other linkage groups and a third cannot be retested because the mutant strain that defined it has been lost. A second reported unusual property for linkage group XIX was the increase in meiotic recombination with increases in temperature during a period that precedes the onset of meiosis. Although we observed changes in recombination frequencies in some intervals on linkage group XIX in crosses to CC-1952, and in strains heterozygous for the mutation ger1 at 16 degrees, we also show that our strains do not exhibit the previously observed patterns of temperature-sensitive recombination for two different pairs of loci on linkage group XIX. We conclude that linkage group XIX has a linear genetic map that is not significantly different from other Chlamydomonas linkage groups.

Animals↗
PubMed1993

Topoisomerase II expression in normal haemopoietic cells and chronic lymphocytic leukaemia: drug sensitivity or resistance?

Chronic lymphocytic leukaemia (CLL) is a progressive disease, commonly treated in its early stage with alkylating agents. A multi-agent regimen which includes anthracyclines is used to treat advanced disease. Despite chemotherapy, the disease remains incurable. There is now considerable evidence to suggest that anthracyclines exert their effect via the nuclear enzyme topoisomerase II and that alterations in amount or activity of this enzyme may mediate drug resistance. We have investigated topoisomerase II mRNA expression in 34 CLL patients and in haemopoietic cells from 10 normal donors. Expression was found to be low but detectable in all patients and normals. Such low levels may contribute to the toxicity of alkylating agents, but could severely limit the effect of anthracyclines.

Antineoplastic Agents↗
PubMed1992

Erector spinae activation and movement dynamics about the lumbar spine in lordotic and kyphotic squat-lifting.

Activation of the erector spinae during squat lifts depends on the initial posture of the lumbar spine. The authors assessed erector spinae activation by electromyography during squat lifts from lordotic and kyphotic postures, measured kinematics of the lifts from digitized video images, and inferred torques from the kinematics, using a two-dimensional model of a human lifting in the sagittal plane, with a joint at L3. Lifts from the lordotic initial posture had peak electromyographic signals early in the lift, whereas lifts from kyphotic initial posture had an initial "flexor relaxation," and peak activity in the middle of the lift. Lumbar flexion was much greater in lifts from kyphotic initial position. Torques required about L3 were similar between the two postures, though somewhat larger initially in lifts from kyphosis. The largest torques were therefore sustained by flexed lumbar spines, during periods of little or no erector spinae activity, in lifts made from kyphotic initial position. A sizable portion of the early torque is inertial, and therefore strongly dependent on movement time. Movements with a 30-lb load in the hands were similar, in kinematics and electromyography, to unloaded lifts, though longer in duration. The clinical implications of the differences in activation with posture, the practical implications of the inertial component of torque, and the need for consideration of lumbar posture in future modeling of squat lifting are discussed.

Adult↗
PubMed1991

Leukaemia mortality among relatives of cystic fibrosis patients.

A total of 219 families of patients with cystic fibrosis living in Wales were studied for the occurrence of other diseases and for cause of death, and the findings in relation to leukaemia are reported. There were eight deaths due to leukaemia, five of the myeloid type, in first and second degree relatives; this is significantly more than the expected on the basis of national age specific mortality rates. In comparison, mortality among siblings, parents, aunts and uncles, and grandparents from all causes was within the expected. Screening the five patients with myeloid leukaemia for the delta F508 mutation showed that four were carriers of this mutation. It is concluded that carriers of the delta F508 mutation may have an increased risk of developing acute myeloid leukaemia. This could happen through the direct effect of the cystic fibrosis gene itself, or through its influence on another gene, such as the met oncogene, or gene(s) involved in granulocyte function on the long arm of chromosome 7.

Adult↗
PubMed1990

Differential effects of avoidant and attentional coping strategies on adaptation to chronic and recent-onset pain.

Examined the effectiveness of attentional and avoidant coping strategies for somatic, behavioral, and psychological adaptation to clinical pain. Subjects were 30 chronic and 30 recent-onset pain patients who used either attentional or avoidant coping strategies in response to their pain. Based on a review of the coping literature, it was hypothesized that subjects with recent-onset pain would demonstrate greater adaptation (lower anxiety, depression, lower pain severity and somatization ratings, and higher levels of social activity) when employing avoidant rather than attentional strategies. Chronic pain subjects using attentional strategies were predicted to demonstrate greater adaptation than chronic pain subjects using avoidant strategies. The results supported this "time x strategy" hypothesis. Implications for pain treatment programs are discussed, and suggestions are made for matching pain duration with patient coping style.

Adaptation, Psychological↗
PubMed1990

Is the mdr 1 gene relevant in chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is a progressive disease in which chemotherapy may result in temporary suppression of the peripheral blood lymphocyte count, but cure is not usually possible. Drug resistance mechanisms and the multidrug resistant (MDR) phenotype may be relevant to the therapeutic response. We have studied 34 patients with CLL (seven untreated, 27 treated), screening both DNA and RNA with the mdr 1 gene probe. In pure lymphocyte populations from 10 normal subjects, low levels of mdr 1 RNA expression were found. Eighteen CLL patients (four untreated, 14 treated) had levels of mdr 1 RNA expression above the normal range. No evidence of mdr 1 gene amplification could be found in these patients. Sequential estimations of RNA levels in three patients suggest that malignant lymphocytes in CLL can increase mdr 1 expression in response to chemotherapy and return to basal levels on withdrawal of the treatment. Such data raise important questions about the type of timing of cytotoxic therapy in CLL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Ocular complications of bone marrow transplantation.

Thirty-four patients who had undergone bone marrow transplantation (BMT) were examined; 83.3% of those who received single shot and none of those who received fractionated total body irradiation (TBI) developed cataracts. The use of steroids to treat chronic Graft Versus Host Disease (GVHD) produced more severe cataracts in those who had allogeneic transplants after single shot TBI, but follow-up has not been long enough to assess their effect following fractionated TBI. Keratoconjunctivitis sicca (KCS) was seen in 81.8% of patients with chronic GVHD and in 33.3% of patients after autologous BMT.

Adolescent↗
PubMed1989

Cellular asymmetry in Chlamydomonas reinhardtii.

Although largely bilaterally symmetric, the two sides of the unicellular alga Chlamydomonas reinhardtii can be distinguished by the location of the single eyespot. When viewed from the anterior end, the eyespot is always closer to one flagellum than the other, and located at an angle of approximately 45 degrees clockwise of the flagellar plane. This location correlates with the position of one of four acetylated microtubule bundles connected to the flagellar apparatus. Each basal body is attached to two of these microtubule rootlets. The rootlet that positions the eyespot is always attached to the same basal body, which is the daughter of the parental/daughter basal body pair. At mitosis, the replicated basal body pairs segregate in a precise orientation that maintains the asymmetry of the cell and results in mitotic poles that have an invariant handedness. The fusion of gametic cells during mating is also asymmetric. As a result of asymmetric, but different, locations of the plus and minus mating structures, mating preferentially results in quadriflagellate dikaryons with parallel flagellar pairs and both eyespots on the same side of the cell. This asymmetric fusion, as well as all the other asymmetries described, may be necessary for the proper phototactic behavior of these cells. The invariant handedness of the spindle pole, eyespot position, and mating structure position appears to be based on the inherent asymmetry of the basal body pair, providing an example of how an intracellular pattern can be determined and maintained.

Chlamydomonas↗
PubMed1989

Autoantibody analysis in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) bears clinical similarities to connective tissue diseases which are characterized by a spectrum of autoantibody formation. A wide range of autoantibody analyses in 19 allogeneic and 16 autologous bone marrow transplant (BMT) patients has determined that the most commonly detected antibody is IgM anti-cytoplasmic factor (ACF) occurring in 37% and 20% of allogeneic and autologous group respectively and of a type not normally seen in connective tissue disease. The antigen is as yet unidentified. These results suggest that autoantibody formation post-BMT is unrelated to the graft-versus-host process. Ophthalmic examination revealed evidence of a Sjögren-like syndrome in 20% autologous and 47% allogeneic patients, suggesting that the development of dry eyes post-BMT is not uniquely a feature of cGVHD.

Adult↗