Biomedical subjects

D Pearson

Publications and source records attributed to D Pearson.

At least 19 recordsLinked to original sources

PubMed2006

Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936.

Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig/TCR rearrangement patterns as well as t(14;18) and t(11;14) translocations of 369 B-cell malignancies belonging to five WHO-defined entities using the standardized BIOMED-2 multiplex PCR tubes accompanied by international pathology panel review. B-cell clonality was detected by combined use of the IGH and IGK multiplex PCR assays in all 260 definitive cases of B-cell chronic lymphocytic leukemia (n=56), mantle cell lymphoma (n=54), marginal zone lymphoma (n=41) and follicular lymphoma (n=109). Two of 109 cases of diffuse large B-cell lymphoma showed no detectable clonal marker. The use of these techniques to assign cell lineage should be treated with caution as additional clonal TCR gene rearrangements were frequently detected in all disease categories. Our study indicates that the BIOMED-2 multiplex PCR assays provide a powerful strategy for clonality assessment in B-cell malignancies resulting in high Ig clonality detection rates particularly when IGH and IGK strategies are combined.

Chromosomes, Human, Pair 11↗

PubMed2006

Polymerase chain reaction-based clonality testing in tissue samples with reactive lymphoproliferations: usefulness and pitfalls. A report of the BIOMED-2 Concerted Action BMH4-CT98-3936.

Lymphoproliferations are generally diagnosed via histomorphology and immunohistochemistry. Although mostly conclusive, occasionally the differential diagnosis between reactive lesions and malignant lymphomas is difficult. In such cases molecular clonality studies of immunoglobulin (Ig)/T-cell receptor (TCR) rearrangements can be useful. Here we address the issue of clonality assessment in 106 histologically defined reactive lesions, using the standardized BIOMED-2 Ig/TCR multiplex polymerase chain reaction (PCR) heteroduplex and GeneScan assays. Samples were reviewed nationally, except 10% random cases and cases with clonal results selected for additional international panel review. In total 75% (79/106) only showed polyclonal Ig/TCR targets (type I), whereas another 15% (16/106) represent probably polyclonal cases, with weak Ig/TCR (oligo)clonality in an otherwise polyclonal background (type II). Interestingly, in 10% (11/106) clear monoclonal Ig/TCR products were observed (types III/IV), which prompted further pathological review. Clonal cases included two missed lymphomas in national review and nine cases that could be explained as diagnostically difficult cases or probable lymphomas upon additional review. Our data show that the BIOMED-2 Ig/TCR multiplex PCR assays are very helpful in confirming the polyclonal character in the vast majority of reactive lesions. However, clonality detection in a minority should lead to detailed pathological review, including close interaction between pathologist and molecular biologist.

Biopsy↗

PubMed2006

RIZ1 repression is associated with insulin-like growth factor-1 signaling activation in chronic myeloid leukemia cell lines.

RIZ1 is a histone methyltransferase whose expression and activity are reduced in many cancers. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located and with decreased RIZ1 expression. Forced RIZ1 expression in model CML blast crisis (BC) cell lines decreases proliferation, increases apoptosis and enhances differentiation. We characterized molecular mechanisms that may contribute to potential CML tumor suppressor properties of RIZ1. Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays. RIZ1 was shown to associate with promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation using chromatin immunoprecipitation assays. IGF-1-blocking antibody was used to demonstrate the importance of autocrine IGF-1 signaling in CML-BC cell line viability. Forced RIZ1 expression in CML-BC cell lines decreases IGF-1 receptor activation and activation of downstream signaling components extracellular signal-regulated kinase 1/2 and AKT. These results highlight the therapeutic potential of inhibiting IGF-1 pathway in the acute phase of CML.

DNA-Binding Proteins↗

PubMed2005

Endoscopy waiting times and impact of the two week wait scheme on diagnosis and outcome of upper gastrointestinal cancer.

The NHS has introduced the two week wait scheme to detect upper gastrointestinal cancers at an early stage and improve survival rates The aim of this study was to assess the impact of this scheme and changes in endoscopy waiting times on tumour stage and resection rates over a four year period. Data were analysed prospectively for all patients diagnosed with oesophagogastric cancer between September 1998 and September 2002 and from those referred under the two week wait scheme since its introduction in 2000. Of those tumours diagnosed by this scheme (15%) only 5% were early disease (stage 1 or 2). Patients with early cancer, mainly diagnosed by routine gastroscopy, do not present with symptoms meeting the two week wait criteria. An increase in the resection rates for early disease will most probably be seen with a reduction in routine endoscopy waiting times.

Ambulatory Care↗

PubMed2004

Recovery of pregnancy mediated bone loss during lactation.

It is uncertain whether bone is routinely mobilised during pregnancy to provide calcium for the fetus and whether this is of a magnitude to cause osteoporosis. We have made sequential measurements of lumbar spine and hip bone mineral density (BMD) in 60 normal women before conception and then during the subsequent pregnancy out to one year after delivery. During pregnancy there was a significant fall in the BMD at the spine (1.53%), total hip (1.15%), and trochanter (3.90%) but not at the femoral neck. After delivery the women who breast-fed (n=34) showed a significant fall in BMD at all measurement sites (P<0.001) with the greatest change at the spine (4.7 +/- 3.1%) with 38% of women showing a change >5%. The women who bottle fed (n=10) increased or maintained BMD at all sites with the mixed feeders (n=16) showing an intermediate response. There was no consistent relationship between the change during pregnancy and lactation but 47% of the breast-feeders lost >5% at either the lumbar spine or trochanter. There was a good correlation between the change in BMD at these two sites (r=0.48, P<0.001). At 1 year after delivery all but 7 women had returned to within 5% of the preconceptual value at the spine and trochanter but the recovery at the total hip was less complete. Several women became transiently osteoporotic (T score below -2.5) at either spine or hip during reproduction of whom three started pregnancy with a normal BMD.

Adult↗

PubMed2003

Long-term effects of BIBN-99, a selective muscarinic M2 receptor antagonist, on improving spatial memory performance in aged cognitively impaired rats.

Aged Long-Evans rats were screened for spatial memory deficits using the Morris water maze task. Rats found to have impaired performance on the task (aged-impaired, AI) were then treated with a selective muscarinic M2 receptor antagonist, 5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (BIBN-99; 0.5 mg/kg, s.c.), for 3 successive days while receiving additional water maze training. BIBN-99 significantly improved performance in the task during the 3 days of drug treatment. Treatment was then ceased for the remainder of the study and rats were tested again in the water maze on days 10, 17, and 24. Compared to vehicle-treated rats, enhanced performance was observed in the AI rats that had previously been treated with BIBN-99. These results indicate that BIBN-99 enhances spatial learning in AI animals and that enhanced (or long-term) memory persists in the absence of the drug. In a second experiment, a 2-month delay was imposed in between the original water maze screening and the drug treatment regime. Again, BIBN-99 significantly improved performance in AI rats. This latter study suggests that reference memory does not decay, even in an AI animal that had displayed poor learning following original water maze screening. Together, these studies help provide further insight into possible mechanism(s) of reference memory and its potential clinical usefulness.

Aging↗

PubMed2003

The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer's disease.

Several recent epidemiological studies have proposed that cholesterol-lowering drug Statin may provide protection against Alzheimer's disease (AD). Probucol is a non-Statin cholesterol-lowering drug and a potent inducer of apolipoprotein E (apoE) production in peripheral circulation. A recent clinical study using Probucol in elderly AD subjects revealed a concomitant stabilisation of cognitive symptoms and significant increases in apoE levels in the cerebral spinal fluid in these patients. To gain insight into the mechanisms underlying these effects, we treated a cohort of aged male rats (26-month-old) with oral dose of Probucol for 30 days. Specifically, we examined the effects of Probucol on apoE production and its receptors (low density lipoprotein receptor [LDLr] and low density lipoprotein receptor-related protein [LRP]), astroglial marker of cell damage (glial fibrillary acidic protein [GFAP]), markers of neuronal synaptic plasticity and integrity (synaptosomal associated protein of 25 kDa [SNAP-25] and synaptophysin) as well as cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCoAr]) in the hippocampus. We report that Probucol induces the production of apoE and one of its main receptors, LRP, increases HMGCoAr (rate-limiting enzyme in cholesterol synthesis), substantially attenuates age-related increases in glial activation, and induces production of synaptic marker SNAP-25, a molecule commonly associated with synaptogenesis and dendritic remodeling. These findings suggest that Probucol could promote neural and synaptic plasticity to counteract the synaptic deterioration associated with brain aging through an apoE/LRP-mediated system. Consistent with the beneficial effects of other cholesterol-lowering drugs such as the Statin, Probucol could also offers additional benefits based on apoE neurobiology.

Aging↗

PubMed2003

Longitudinal changes in bone mineral density during normal pregnancy.

Pregnancy is a common physiological event that could affect peak bone mass and the risk of developing osteoporosis later in life. There have been few longitudinal studies over a complete reproductive cycle of any size to show whether bone mineral density (BMD) changes. We have measured BMD by dual-energy X-ray absorptiometry in 46 normal women before conception and then again immediately after delivery and compared them with 30 control women who failed to conceive. Fifteen women were osteopenic in preconceptual BMD, but there was no difference between those who did or did not become pregnant. During pregnancy there was a small and statistically nonsignificant decline in BMD at all sites. The decrease at the trochanteric region was 4.2%, while losses at other sites were about 1%. The decline at the trochanter exceeded the least significant change between two measurements (5.04%) in 17 women (40.5%) with significant changes within individuals being much less common at the other measurement sites. The nonpregnant controls showed small increases in BMD of 0.3%-1.9% but no woman lost more than the least significant change. At the trochanter there was a significant difference (P = 0.013) between those who did and did not become pregnant. There was a good correlation between changes in BMD at all sites and no significant difference in the slope of these correlations between the pregnant and control groups. Correlations with lumbar spine were total hip, r = 0.46, P = 0.0001; femoral neck, r = 0.49, P = 0.0005; and trochanter, r = 0.66, P < 0.0001.

Absorptiometry, Photon↗

PubMed2003

Benchmarking beam alignment for a clinical helical tomotherapy device.

A clinical helical tomotherapy treatment machine has been installed at the University of Wisconsin Comprehensive Cancer Center. Beam alignment has been finalized and accepted by UW staff. Helical tomotherapy will soon be clinically available to other sites. Clinical physicists who expect to work with this machine will need to be familiar with its unique dosimetric characteristics, and those related to the geometrical beam configuration and its verification are described here. A series of alignment tests and the results are presented. Helical tomotherapy utilizes an array of post-patient xenon-filled megavoltage radiation detectors. These detectors have proved capable of performing some alignment verification tests. That is particularly advantageous because those tests can then be automated and easily performed on an ongoing basis.

Benchmarking↗

PubMed2002

The genome sequence of Schizosaccharomyces pombe.

We have sequenced and annotated the genome of fission yeast (Schizosaccharomyces pombe), which contains the smallest number of protein-coding genes yet recorded for a eukaryote: 4,824. The centromeres are between 35 and 110 kilobases (kb) and contain related repeats including a highly conserved 1.8-kb element. Regions upstream of genes are longer than in budding yeast (Saccharomyces cerevisiae), possibly reflecting more-extended control regions. Some 43% of the genes contain introns, of which there are 4,730. Fifty genes have significant similarity with human disease genes; half of these are cancer related. We identify highly conserved genes important for eukaryotic cell organization including those required for the cytoskeleton, compartmentation, cell-cycle control, proteolysis, protein phosphorylation and RNA splicing. These genes may have originated with the appearance of eukaryotic life. Few similarly conserved genes that are important for multicellular organization were identified, suggesting that the transition from prokaryotes to eukaryotes required more new genes than did the transition from unicellular to multicellular organization.

Base Sequence↗

PubMed2002

A comparison of phantoms for cross-calibration of lumbar spine DXA.

The aim of this project was to compare three phantoms used for cross-calibration of dual-energy X-ray absorptiometers with an in vivo cross-calibration. The phantoms used were the Bona Fide Phantom (BFP), the European Spine Phantom (ESP) and the GE Lunar Aluminum Spine Phantom (ASP). The cross calibration was for L2-L4 lumbar spine bone mineral density (BMD) on a GE Lunar DPX-L and Hologic QDR 2000. The in vivo cross-calibration was obtained using 72 subjects (61 female, 11 male; mean age 49 years, range 14-84 years). The phantoms were measured 10 times without repositioning on both instruments. A further, long-term cross-calibration was obtained with the BFP over a 9 month period. The true linear relationship between the two instruments was calculated used a standardized principal components method. The mean residuals were calculated between each phantom cross-calibration line and the in vivo data to obtain a measure of the goodness of fit between the phantom cross-calibration and the in vivo data. There was no significant difference between the in vitro and in vivo cross-calibrations. The long-term BFP cross-calibration gave an in vitro cross-calibration that is closest to the in vivo cross-calibration in this group of subjects. When calculating Hologic QDR BMD from results on the GE Lunar DPX-L, the ASP underestimates Hologic QDR 2000 BMD by 4% at high BMD and overestimates by 4% at low BMD. The ESP cross-calibration overestimates Hologic QDR2000 BMD by 1% at high BMD and 4% at low BMD. The BFP performs best, overestimating Hologic QDR2000 BMD by between 1.2% and 1.8%, whilst the difference between the long-term BFP cross-calibration and the in vivo data is less than 1% over the range of BMD covered.

Absorptiometry, Photon↗

PubMed2001

Observation of the ideal Josephson effect in superfluid 4He.

Superfluids and superconductors are the only states of condensed matter that can be described by a single wavefunction, with a coherent quantum phase Phi. The mass flow in a superfluid can be described by classical hydrodynamics for small flow velocity, but above a critical velocity, quantized vortices are created and the classical picture breaks down. This can be observed for a superfluid flowing through a microscopic aperture when the mass flow is measured as a function of the phase difference across the aperture; the curve resembles a hysteretic sawtooth where each jump corresponds to the creation of a vortex. When the aperture is made small enough, the system can enter the so-called 'ideal' Josephson regime, where the superfluid mass flow becomes a continuous function of the phase difference. This regime has been detected in superfluid 3He, but was hitherto believed to be unobservable, owing to fluctuations, in 4He. Here we report the observation of the ideal Josephson effect in 4He. We study the flow of 4He through an array of micro-apertures and observe a transition to the ideal Josephson regime as the temperature is increased towards the superfluid transition temperature, Tlambda.

Journal Article↗

PubMed2001

Amyloid beta peptide levels and its effects on hippocampal acetylcholine release in aged, cognitively-impaired and -unimpaired rats.

Excessive extracellular deposition of amyloid beta (Abeta) peptide in neuritic plaques and degeneration of forebrain cholinergic neurones, which innervate the hippocampus and the neocortex, are the invariant characteristic features of Alzheimer's disease (AD). Studies of the pathological changes that characterize AD, together with several other lines of evidence, indicate that Abeta accumulation in vivo may initiate and/or contribute to the process of neurodegeneration observed in the AD brain. However, the underlying mechanisms by which Abeta peptide influences/causes degeneration of the basal forebrain cholinergic neurones in AD brains remain obscure. We reported earlier that nM concentrations of Abeta-related peptides, under acute conditions, can potently inhibit K+-evoked endogenous acetylcholine (ACh) release from the hippocampus and the cortex but not from striatum in young adult rats (J. Neurosci. 16 (1996) 1034). In the present study, to determine whether the effects of Abeta peptides alter with normal aging and/or cognitive state, we have measured Abeta1-40 levels and the effects of exogenous Abeta1-40 on hippocampal ACh release in young adult as well as aged cognitively-unimpaired (AU) and -impaired (AI) rats. Endogenous levels of Abeta(1-40) in the hippocampus are significantly increased in aged rats. Additionally, 10 nM Abeta1-40 potently inhibited endogenous ACh release from the hippocampus of the three groups of rats, but the time-course of the effects clearly indicate that the cholinergic neurones of AI rats are more sensitive to Abeta peptides than either AU or young adult rats. These results, together with earlier reports, suggest that the processing of the precursor protein of Abeta peptide alters with normal aging and the response of the cholinergic neurones to the peptide possibly varies with the cognitive status of the animals.

Acetylcholine↗

PubMed2001

Medical history for tomorrow--preserving the record of today.

This paper addresses the need to recognize the importance, and the challenges, of preserving the hugely expanding record of medicine today for historians of the future. We are faced not only with an increase in traditional publishing formats, but also with the rapid growth in electronic communications. Two celebrated medical cases, one from the late seventeenth century and one from the late twentieth, are used to illustrate the differences and the difficulties. The need for active and effective professional collaboration is stressed; libraries should work together to address these issues.

Archives↗

PubMed2001

Prevalence of imaginary companions in a normal child population.

Approximately 1800 children between the ages of 5 and 12 years were randomly selected and asked whether they had present or past experiences of imaginary companions. It was found that 829 (46.2%) children reported experiences of imaginary companions. These findings were unexpected as previous studies had suggested that imaginary companions are generally experienced by fewer, much younger children. There were no significant differences in creativity scores between children who reported imaginary companions compared with those who did not. Imaginary companions were reported by more girls than boys, and were not restricted to very young children.

Child↗

PubMed2001

Can parents accurately perceive hyperactivity in their child?

In all, 1872 children were recruited as part of a larger study concerning food additives and behaviours in preschool children. This figure represented 70% of the whole population of 3 1/4 -year-old children resident on the Isle of Wight, UK. Parents completed an assessment concerning their perceptions of their child's behaviour. The results of this assessment were compared with scores on two validated parental questionnaires, the Weiss Werry Peters (WWP) hyperactivity scale and the Emotionality, Activity and Sociability Temperament Questionnaire (EAS), which were used to assess hyperactivity. The accuracy of parents in perceiving hyperactivity in their children was found to be around 50% if the child was hyperactive, and 89% if the child was not hyperactive. The implications of these findings for services are discussed. Frequencies of potential risk groups for future Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder were also suggested.

Child Behavior↗

PubMed2001

Developing a general practice library: a collaborative project between a GP and librarian.

The authors report on a self-completed questionnaire study from a North Yorkshire based general practice regarding the information needs of its clinicians. The work was carried out with a particular focus on the practice library, and the findings identified that a new approach to maintaining and developing the library was needed. The literature regarding the information needs of primary care clinicians and the role of practice libraries is considered, and compared to those of the clinicians at the practice. Discussion follows on how a collaborative project was set up between the practice and a librarian based at the local NHS Trust library in order to improve the existing practice library. Difficulties encountered and issues unique to the project are explored, including training implications presented by the implementation of electronic resources. Marketing activities implemented are discussed, how the library will operate in its new capacity, and how ongoing support and maintenance of the library will be carried out. It is concluded that although scepticism still exists regarding librarian involvement in practice libraries, collaboration between clinicians and librarians is an effective approach to the successful development and maintenance of a practice library, and recommendations are therefore made for similar collaborative work.

Adult↗

PubMed2001

Induction of stable long-term mixed hematopoietic chimerism following nonmyeloablative conditioning with T cell-depleting antibodies, cyclophosphamide, and thymic irradiation leads to donor-specific in vitro and in vivo tolerance.

BACKGROUND: Successful transplantation of solid organs relies on long-term immunosuppression for the prevention of graft rejection. Donor-specific tolerance without the need for continuous immunosuppression can be observed after allogeneic BMT. However, its routine use for tolerance induction has been precluded so far by the high conditioning-related toxicity of standard BMT regimens. Our laboratory has recently established a cyclophosphamide (CTX) plus thymic irradiation (TI)-based nonmyeloablative conditioning protocol for the treatment of hematologic malignancies. We have recently described the successful clinical application of this approach for the induction of donor-specific tolerance in a patient receiving a living-related kidney transplant, which resulted in graft acceptance without long-term immunosuppression. The aim of this study was to evaluate the induction and maintenance of host-versus-graft tolerance following this CTX-plus-TI-based regimen in a mouse model. METHODS: Induction of mixed hematopoietic chimerism and development of donor-specific tolerance following the CTX-based nonmyeloablative conditioning regimen (200 mg/kg CTX, in vivo T-cell depletion [anti-CD4 monoclonal antibody (MoAb) GK1.5 and anti-CD8 MoAb 2.43], and 7 Gy TI) was studied in the fully major histocompatibility complex (MHC)-mismatched B10.A (H2a)-->B6 (H2b) strain combination. RESULTS: The conditioning regimen allowed allogeneic bone marrow engraftment and persistent (>30 weeks) mixed lymphohematopoietic chimerism in almost all recipients. TI was essential to allow engraftment and development of tolerance, which was evident in all lasting chimeras. Compared to animals receiving a similar TBI-based conditioning regimen, overall levels of chimerism were significantly lower in the CTX-plus-TI-conditioned animals. However, donor-specific tolerance in vitro and in vivo was evident in CTX-plus-TI-conditioned chimeras. Tolerance was associated with the presence of donor-type MHC class II+ cells in the thymus and deletion of donor-reactive cells, as determined by Mtv-8 and Mtv-9 superantigen-mediated deletion of Vbeta11+ and Vbeta5/1.2+ T cells. CONCLUSION: Engraftment, long-term chimerism, and induction of donor-specific tolerance can be achieved using a nonmyeloablative CTX-based conditioning regimen in fully MHC-mismatched BMT recipients without the induction of GVHD.

Animals↗