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Biomedical subjects

S Kinsey

Publications and source records attributed to S Kinsey.

At least 19 recordsLinked to original sources
PubMed2006

Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study.

The United Kingdom Childhood Cancer Study was designed to examine the relation between childhood cancer and preceding exposure to infectious diseases. The authors analyzed the relation between diagnosis (1991-1996) of acute lymphoblastic leukemia (ALL) at ages 2-5 years and clinically diagnosed infections in infancy. Almost all study children (96% of both cases and controls) were taken to a general practitioner for a non-immunization-associated visit at least once before their first birthday. Children diagnosed with ALL had significantly more clinically diagnosed infectious episodes in infancy than did controls; the average number of episodes was 3.6 (95% confidence interval (CI): 3.3, 3.9) versus 3.1 (95% CI: 2.9, 3.2). This case-control difference was most apparent in the neonatal period (< or =1 month); 18% of controls and 24% of ALL cases were diagnosed with at least one infection (odds ratio = 1.4, 95% CI: 1.1, 1.9; p < 0.05). Cases who had more than one neonatal infectious episode tended to be diagnosed with ALL at a comparatively young age; the mean age at ALL diagnosis was 37.7 months for cases with two or more episodes versus 45.3 months for cases with only one episode or none (p < 0.01). These findings support the hypothesis that a dysregulated immune response to infection in the first few months of life promotes transition to overt ALL later in childhood.

Age of Onset↗
PubMed2006

The measurement of whole blood pre-treatment cyclosporine A: metabolite ratios predicts the onset of renal dysfunction in recipients of allogeneic stem cell transplantation.

BACKGROUND: In the context of post-transplant immunosuppression, cyclosporine A (CSA) is dose adjusted in accordance with whole blood drug monitoring. While currently available immunoassay systems primarily target the parent drug, cross-reactivity results in the detection of the major circulating CSA metabolites, though their contribution to both immunosuppression and toxicity remain unclear. This study examines the relationship of CSA metabolites to hepatic and renal dysfunction and the incidence of graft-versus-host disease (GvHD) through parallel assaying of parent drug and drug/metabolites expressed as a metabolite ratio (Cp:mR). METHOD: Sequential pre-treatment (trough) whole blood samples (n=527) were collected from 31 allo-stem cell transplantation (SCT) recipients. Both parent drug and drug/metabolite levels were determined using the Abbott fluorescence polarization immunoassay. RESULTS: The average mean Cp:mR was significantly higher in patients with hepatic (P=0.004) and renal dysfunction (P=0.004) than in those without. Significantly higher Cp:mR were also found in patients with grades II-IV GvHD (P=0.001) than were observed in patients who did not experience significant GvHD. When measured prospectively, an increasing Cp:mR predated the rise in serum creatinine concentration by a median of two weeks. CONCLUSIONS: This study demonstrates a clinically useful CSA metabolite ratio that shows association with hepatic and renal dysfunction and with GvHD. The measure can be used to predict those patients on CSA therapy who are likely to develop renal dysfunction.

Adolescent↗
PubMed2005

American fresh frozen plasma for neonates and children.

From the spring of 2004 the United Kingdom Blood Services have been importing fresh frozen plasma from United States donors for all neonates and children born after 1 January 1996. The decision to mandate the use of American plasma in this age group was taken by the Department of Health in 2002 as part of its precautionary approach to the risk of transfusion transmitted variant Creutzfeldt-Jakob disease. In this article we explain the background to this decision and explore some of the implications it raises for clinical practice.

Blood Component Transfusion↗
PubMed2003

Oral glutamine in paediatric oncology patients: a dose finding study.

OBJECTIVE: The purpose of this study was to determine the most appropriate dose of oral glutamine to use in a further clinical study in paediatric oncology patients. DESIGN: This was a phase I, pharmokinetic study. SETTING: The study was carried out at The Yorkshire Regional Centre for Paediatric Oncology and Haematology, St James's University Hospital, Leeds, UK. SUBJECTS: Thirteen patients undergoing treatment for paediatric malignancy participated in this study. All 13 completed the study. INTERVENTIONS: The most appropriate dose was determined by patient acceptability and by plasma glutamine and ammonia levels measured at timed intervals after ingestion of a single glutamine dose. RESULTS: Doses of 0.35, 0.5 and 0.65 g/kg were well tolerated with no untoward plasma glutamine and ammonia levels. One patient was recruited to a higher dose of 0.75 g/kg, but the plasma glutamine and ammonia levels peaked at 2601 and 155 micro mol/l, respectively. The ammonia level was greater than the acceptable upper limit. It was difficult to disperse the glutamine adequately at this dose, resulting in the suspension being found to be unpalatable and therefore no further patients were recruited at this dose. CONCLUSION: It was concluded that 0.65 g/kg is a safe dose of glutamine to use in a clinical study in paediatric oncology patients.

Administration, Oral↗
PubMed2002

The adaptation of soleus and edl in a rat model of distraction osteogenesis: IGF-1 and fibrosis.

The distraction rate of 0.5 mm/day produces good osteogenesis in small rodents; however, the effects of this distraction rate on muscle are not well documented. We evaluated the soleus and the extensor digitorum longus (EDL) after two weeks of lengthening distraction osteogenesis (DO) at 0.5 mm/day in skeletally mature rats. We found a modest but significant local increase of insulin like growth factor-1 (IGF-1) in the EDL, however, muscle growth indicated by developmental forms of myosin heavy chain (MHC) was not detected by mRNA (RT-PCR). To the contrary. the data suggested a decrease in cross-sectional area of the muscle fibers as well as a decrease in mRNA for slow MHC. Immunolabeling of fibronectin in cryosections of the EDL indicated fibrosis of the perimuscular connective tissue while assessment of the passive joint motion did not suggest a lack of excursion on the part of the dorsal flexors. While the literature suggests that IGF-1 facilitates muscle growth especially in young animals, excess of IGF-1 in muscle from adults may exacerbate DO-induced fibrosis.

Adaptation, Physiological↗
PubMed2001

Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI).

In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment-related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Down's syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.

Antineoplastic Agents↗
PubMed2001

Paediatric transfusion.

Paediatric transfusion encompasses a wide range of clinical circumstances including the consideration of maternal antibodies, the changing nature of the transfusion recipient with respect to growth and development, and the management of inherited conditions which if optimally treated in early life may have problems which are delayed or less severe in adult life. Whilst the transfusion of adults and children has much in common, a child cannot be considered as a scaled down adult; there are many important differences. Developmental changes are most marked in the neonate and, together with the fact that their antibodies are maternally derived, this population provide some of the most striking challenges. The increased use of intra uterine transfusion adds an extra dimension here. A particular paediatric concern is the long-term consequences of transfusion. It is to be hoped that paediatric transfusion recipients will live long enough that any potential problems will manifest themselves, thus the aim must be to minimize transfusion risks.

Blood Cells↗
PubMed2000

Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials. UK Medical Research Council's Working Party on Childhood Leukaemia.

Treatment of children with acute lymphoblastic leukaemia (ALL) aims to cure all patients with as little toxicity as possible and, if possible, to restrict further intensification of chemotherapy to patients with an increased risk of relapse. However in Medical Research Council (MRC) trial UKALL X two short myeloablative blocks of intensification therapy given at weeks 5 and 20 were of benefit to children in all risk groups. The successor trials, MRC UKALL XI and MRC ALL97, tested whether further intensification would continue to benefit all patients by randomising them to receive, or not, an extended third intensification block at week 35. After a median follow-up of 4 years (range 5 months to 8 years), 5 year projected event-free survival was superior at 68% for the 894 patients allocated a third intensification compared with 60% for the 887 patients who did not receive one (odds ratio 0.75, 95% CI 0.63-0.90, 2P = 0.002). This difference was almost entirely due to a reduced incidence of bone marrow relapses in the third intensification arm (140 of 891 in the third intensification arm vs. 171 of 883 in the no third intensification, 2P = 0.02). Subgroup analysis suggests benefit of the third intensification for all risk categories. Overall survival to date is no different in the two arms, indicating that a greater proportion of those not receiving a third intensification arm and subsequently relapsing can be salvaged. These results indicate that there is benefit of additional intensification for all risk subgroups of childhood ALL.

Adolescent↗
PubMed1999

Visceral chemical nociception in mice lacking mu-opioid receptors: effects of morphine, SNC80 and U-50,488.

Writhing responses to intraperitoneal acetic acid administration and their modulation by mu-, kappa- and delta-opioid receptor agonists were compared in wild-type and mu-opioid receptor knockout mice. Unpretreated homozygous knockout mice displayed less writhing than wild-type mice. U-50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl]-benze neacetamide]) reduced writhing responses in wild-type and knockouts. Morphine and SNC80 [(+)-4-[9-alpha-R)-alpha-(2S,5RO-4-allyl-2,5-dimethyl-1-piperaziny l)-3-methoxybenzyl]-N,N-diethylbenzamide] were effective in wild-type mice but ineffective in knockouts. Mu-opioid receptors appear to play important roles in responses to this visceral nociceptive stimulus and its modulation by mu- and delta-opioid receptor agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping.

Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.

Adolescent↗
PubMed1998

No heroin or morphine 6beta-glucuronide analgesia in mu-opioid receptor knockout mice.

Recent reports suggest that heroin and its metabolite morphine 6beta-glucuronide can produce analgesia independent of the morphine-preferring mu-opioid receptor. We have tested heroin and morphine 6beta-glucuronide analgesia in wild-type, homozygous and heterozygous mu-opioid receptor knockout mice. Homozygotes display no heroin or morphine 6beta-glucuronide analgesia. Heterozygous mice with one mu-opioid receptor gene copy reveal reduced heroin and morphine 6beta-glucuronide analgesia. The mu-opioid receptor-dependence of heroin and morphine 6beta-glucuronide fails to support a requirement for a heroin-specific opiate receptor subtype.

Analgesia↗
PubMed1998

Proton Diffusion and T1 Relaxation in Polyacrylamide Gels: A Unified Approach Using Volume Averaging.

The structure of polyacrylamide gels was studied using proton spin-lattice relaxation and PFG diffusion methods. Polyacrylamide gels, with total polymer concentrations ranging from 0.25 to 0.35 g/ml and crosslinker concentrations from 0 to 10% by weight, were studied. The data showed no effect of the crosslinker concentration on the diffusion of water molecules. The Ogston-Morris and Mackie-Meares models fit the general trends observed for water diffusion in gels. The diffusion coefficients from the volume averaging method also fit the data, and this theory was able to account for the effects of water-gel interactions that are not accounted for in the other two theories. The averaging theory also did not require the physically unrealistic assumption, required in the other two theories, that the acrylamide fibers are of similar size to water molecules. Contrary to the diffusion data, T1 relaxation measurements showed a significant effect of crosslinker concentration on the relaxation of water in gels. The model developed using the Bloch equations and the volume averaging method described the effects of water adsorption on the gel medium on both the diffusion coefficients and the relaxation measurements. In the proposed model the gel medium was assumed to consist of three phases (i.e., bulk water, uncrosslinked acrylamide fibers, and a bisacrylamide crosslinker phase). The effects of the crosslinker concentration were accounted for by introducing the proton partition coefficient, Keq, between the bulk water and crosslinker phase. The derived relaxation equations were successful in fitting the experimental data. The partition coefficient, Keq, decreased significantly as the crosslinker concentration increased from 5 to 10% by weight. This trend is consistent with the idea that bisacrylamide tends to form hydrophobic regions with increasing crosslinker concentration. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Residual disease detection using fluorescent polymerase chain reaction at 20 weeks of therapy predicts clinical outcome in childhood acute lymphoblastic leukemia.

PURPOSE: Ninety-five percent of children with acute lymphoblastic leukemia (ALL) will achieve a remission, but approximately 25% will relapse. Identifying these patients is difficult, as patients with adverse prognostic features at presentation are rare and the majority are standard risk. Analysis of minimal residual disease (MRD) may be able to determine those at risk of relapse, but the best method by which this can be accomplished has yet to be defined. The object of this study was to determine the predictive value of residual disease detection in a group of standard-risk patients with precursor-B ALL at a fixed point in therapy (week 20) using a simple fluorescent consensus immunoglobulin H (IgH) heavy chain polymerase chain reaction (PCR). PATIENTS AND METHODS: Forty-two patients who presented with precursor-B ALL with standard-risk clinical features and treated according to either the Medical Research Council (MRC) UKALL X or XI protocols were assessed using a combination of both fluorescent consensus framework I and framework III Ig heavy-chain PCR. The results of the PCR were analyzed on an ABI 373 gene sequencer with genescan software (Applied Biosystems, Foster City, CA). Clonal rearrangements detected at presentation were looked for at week 20. RESULTS: Of 42 patients, 35 had a clonal population detectable at presentation; of these, seven had more than two clonal rearrangements; this latter group showed a similar disease-free survival (DFS) to the group as a whole. Thirty of 35 patients were analyzed before their second course of intensification therapy at week 20. At this point, nine of 30 had a detectable clonal rearrangement, eight (89%) of whom have since relapsed with a median DFS of 27.5 months. Of the rest of the group (n=21), in whom no clonal rearrangement was detectable, only six (21%) have relapsed. CONCLUSION: Fluorescent IgH PCR at week 20 provides a sensitive and specific means to predict ultimate relapse (57% and 89%, respectively) and is a simple yet promising technique for the identification of patients at risk of poor outcome.

Adolescent↗
PubMed1996

1H- and 31P-nuclear magnetic resonance studies of l-lactate transport in isolated muscle fibers from the spiny lobster Panulirus argus

Proton (1H) and phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy were used to investigate the mode of transport of l-lactate across the plasma membranes of the abdominal extensor muscles of the spiny lobster Panulirus argus. Individual fibers or bundles of 2&shy;3 fibers were superfused in a dual-tuned (1H, 31P) microsolenoid NMR probe. 1H-NMR spectra were diffusion-weighted, which eliminated the signal contribution of the fast-flowing extracellular lactate but retained that of intracellular lactate. Well-resolved intracellular lactate signals could be acquired at 15 s intervals, permitting estimation of initial velocities (Vi) of influx and efflux during loading/unloading of muscle fibers. 31P-NMR spectra were acquired to assess cellular energy status and intracellular pH. Transport results showed that Vi values for influx and efflux were a linear function of total lactate concentration, displaying no saturation effects. The rate of lactate influx was enhanced by increasing the concentration of the free acid by altering the superfusate pH. Vi values for influx and efflux of d- and l-lactate were identical. Finally, traditional inhibitors of monocarboxylate and/or anion transport had no effect on influx/efflux of lactate from these cells. The above results strongly suggest that the primary mode of lactate transport is by passive diffusion. These cells appear to lack a monocarboxylate transporter, which may be related to the apparent absence of organ-specific compartmentation of lactate metabolism in crustaceans.

Journal Article↗
PubMed1993

Assessment of graft status following allogeneic bone marrow transplantation for haematological disorders in children using locus-specific minisatellite probes.

We have examined peripheral blood or bone marrow DNA following allogeneic bone marrow transplantation (BMT) in children suffering from a variety of haematological disorders. Using either locus-specific minisatellite probes separately or in combination with a Y specific probe for sex-mismatched transplants, complete haematological chimaerism, autologous reconstitution, or mixed chimaeric states have been defined immediately post-BMT. We have also been able to identify emerging autologous cells or relapse prior to morphological diagnosis. Forty-two children, mean age 6.4 years (range 9 months to 15 years), received an allogeneic BMT for: acute lymphoblastic leukaemia (ALL), n = 17; acute myeloid leukaemia (AML), n = 5; biphenotypic leukaemia, n = 1; myelodysplastic syndrome (MDS), n = 5; chronic granulocytic leukaemia (CGL), n = 1; severe aplastic anaemia (SAA), n = 7; familial erythrophagocytic lymphohistiocytosis (FEL), n = 2; beta thalassaemia major (beta thal), n = 1; and juvenile chronic myeloid leukaemia (JCML), n = 3. Immediately post-transplant, 78% had achieved complete haematological chimaerism, 12% had failed to engraft (DNA analysis confirmed autologous reconstitution) and 10% had mixed chimaerism. SAA was the underlying disease in two of the chimaeric cases, the third case having had a matched unrelated donor (MUD) BMT for MDS. In 3/4 cases which subsequently relapsed, DNA analysis showed re-emergence of autologous cells (indicative of relapse), prior to their morphological identification. We conclude that DNA analysis using minisatellite probes to assess graft status provides a useful contribution to patient management following allogeneic BMT.

Bone Marrow Transplantation↗