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Biomedical subjects

R Skinner

Publications and source records attributed to R Skinner.

At least 19 recordsLinked to original sources
PubMed2004

Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England.

AIMS: To determine the incidence and outcome of congenital leukaemia. METHODS: Retrospective population based study of putative leukaemia arising during the first 3 months of life over an 18 year period within the Northern Health Region of England. RESULTS: Nine infants with putative leukaemia were identified. Five had acute leukaemia and four had transient myeloproliferative disorder (TMD). Trisomy 21, either as Down's syndrome or perhaps restricted to proliferating marrow cells, was present in all four infants with TMD. The incidence of congenital acute leukaemia was 8.6/10(6) live births/year, but would be less than half this value if only patients presenting within 4 weeks of birth were counted. Remission was induced in three of the five patients with acute leukaemia. One patient, who presented at birth, remains well five years after diagnosis. All four patients with TMD survive. CONCLUSIONS: Congenital leukaemia is very rare but is not inevitably fatal. Finding trisomy 21 in spontaneously dividing blood or bone marrow cells of an infant with putative acute leukaemia, particularly within 3 months of birth, should encourage a cautious clinical approach and suggests that the diagnosis might be TMD.

Acute Disease↗
PubMed2004

Analysis of expressed sequence tag loci on wheat chromosome group 4.

A total of 1918 loci, detected by the hybridization of 938 expressed sequence tag unigenes (ESTs) from 26 Triticeae cDNA libraries, were mapped to wheat (Triticum aestivum L.) homoeologous group 4 chromosomes using a set of deletion, ditelosomic, and nulli-tetrasomic lines. The 1918 EST loci were not distributed uniformly among the three group 4 chromosomes; 41, 28, and 31% mapped to chromosomes 4A, 4B, and 4D, respectively. This pattern is in contrast to the cumulative results of EST mapping in all homoeologous groups, as reported elsewhere, that found the highest proportion of loci mapped to the B genome. Sixty-five percent of these 1918 loci mapped to the long arms of homoeologous group 4 chromosomes, while 35% mapped to the short arms. The distal regions of chromosome arms showed higher numbers of loci than the proximal regions, with the exception of 4DL. This study confirmed the complex structure of chromosome 4A that contains two reciprocal translocations and two inversions, previously identified. An additional inversion in the centromeric region of 4A was revealed. A consensus map for homoeologous group 4 was developed from 119 ESTs unique to group 4. Forty-nine percent of these ESTs were found to be homoeologous to sequences on rice chromosome 3, 12% had matches with sequences on other rice chromosomes, and 39% had no matches with rice sequences at all. Limited homology (only 26 of the 119 consensus ESTs) was found between wheat ESTs on homoeologous group 4 and the Arabidopsis genome. Forty-two percent of the homoeologous group 4 ESTs could be classified into functional categories on the basis of blastX searches against all protein databases.

Chromosome Mapping↗
PubMed2003

Chronic ifosfamide nephrotoxicity in children.

Nephrotoxicity is a frequent complication of treatment with ifosfamide in children. Although renal damage may be acute and reversible, chronic toxicity may develop with potentially serious consequences. Chronic nephrotoxicity due to ifosfamide may lead to a wide variety of subclinical and clinical manifestations. Proximal tubular dysfunction is the commonest presentation, and may lead to a Fanconi syndrome, including hypophosphataemic rickets and proximal renal tubular acidosis. Glomerular impairment is also common, whilst distal tubular impairment has been described but is relatively rare. Although full reversibility has been described occasionally, there is no information about the very long-term outcome of chronic ifosfamide nephrotoxicity. We studied a cohort of 12 children 1 and 10 years after completion of ifosfamide treatment. There was no statistically significant change in either glomerular or tubular toxicity in the group as a whole over this time period. However, marked improvements were seen in some aspects of toxicity in some patients, and deterioration was observed in others. We concluded that considerable nephrotoxicity is still present 10 years after completion of ifosfamide treatment, but that the outcome varies between individual patients. Although several risk factors for the development of chronic nephrotoxicity have been described, total ifosfamide dose, patient age at treatment, previous or concurrent cisplatin treatment, and unilateral nephrectomy are the most important. Nevertheless, it remains difficult to predict the occurrence of this toxicity with confidence. The pathogenesis of ifosfamide nephrotoxicity is poorly understood. There is an urgent need for the development and clinical investigation of nephroprotective strategies.

Antineoplastic Agents, Alkylating↗
PubMed2003

Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment.

Hepatic veno-occlusive disease (HVOD) following bone marrow transplantation is potentially fatal. Criteria for diagnosis and starting treatment are mainly based on adult studies. Recombinant tissue plasminogen activator (rtPA) has been used with variable success. rtPA and heparin were given to 12 children (nine with immunodeficiency, two malignancy, one thalassaemia) with moderate to severe HVOD. Of the 12, 10 responded with a fall in bilirubin concentration; eight survived with complete resolution of HVOD. Four of the five patients with associated multiorgan failure (MOF) died despite rtPA treatment. One child suffered significant, and one minor, bleeding during rtPA treatment. A scoring system for quantifying the severity of HVOD in children is proposed, incorporating the criteria used to diagnose HVOD, risk factors for its development and also parameters reflective of the patient's general condition. This will facilitate early diagnosis and management of those cases which, if not treated promptly, are likely to deteriorate with an adverse outcome. Our experience suggests rtPA and heparin are an effective treatment for HVOD in children, with relatively little toxicity provided therapy is started before MOF develops.

Bilirubin↗
PubMed2002

Nephrotoxicity in survivors of Wilms' tumours in the North of England.

One aspect of concern for survivors of Wilms' tumour has been the late outcome in terms of renal function. Previous studies have documented low glomerular filtration rate and high blood pressure in some patients. Furthermore, disorders in tubular function (especially urinary concentration defects) have been suggested but not confirmed in small studies. The aim of this study was to determine the prevalence and nature of subclinical and overt glomerular, proximal and distal renal tubular toxicity in a population based cohort of survivors of Wilms' tumour. Forty patients (24 female) with a median age of 4.3 years (3 months-11.8 years) at diagnosis were studied. Median follow-up was 8.8 (range 0.06-27.5) years. Glomerular filtration rate was measured by (51)Cr-EDTA plasma clearance, proximal tubular function by electrolyte fractional excretions, urine excretion of low molecular weight proteins (retinol-binding protein) and renal tubular enzymes (alanine aminopeptidase; N-acetylglucosaminidase) and distal tubular function by the osmolality of the first two urines of the day on 3 consecutive days. Renal size (ultrasound) and blood pressure were also measured. Mean (range) glomerular filtration rate was 100 (61-150) ml min(-1) 1.73 m(-2). Nine were below the reference range for healthy individuals with two kidneys. Most serum electrolyte concentrations (sodium, potassium, chloride, calcium, magnesium and phosphate) fell within the normal range for age, as did the fractional excretions. The values that fell outside the normal range were only marginally abnormal. Subclinical measures of tubular toxicity (retinal-binding protein, alanine aminopeptidase, N-acetylglucosaminidase) were abnormal in only four patients. Thirty-seven patients achieved maximal urine osmolalities > or =800 mOsm kg(-1), but three failed to achieve this value even after DDAVP administration. Two patients had evidence of increased urinary albumin excretion. Compensatory renal hypertrophy was seen in all but two patients, but blood pressure was within normal limits in all patients. Current and past treatment for Wilms' tumour does not have any clinically important nephrotoxic effect in the majority of patients. This finding will enable paediatric oncologists to reassure patients and parents that treatment for Wilms' tumour rarely causes long-term renal impairment.

Age Factors↗
PubMed2002

Cytokine fingerprinting of chemical allergens: species comparisons and statistical analyses.

The cellular and molecular mechanisms that result in the induction of chemical respiratory sensitization are unclear, although there is evidence for the development of T helper (Th) 2 type responses and, in some cases, the production of IgE. We have compared cytokine secretion patterns stimulated by topical exposure of BALB/c strain mice or Brown Norway (BN) strain rats to the reference respiratory allergen trimellitic anhydride (TMA), or to the reference contact allergen 2,4-dinitrochlorobenzene (DNCB). Under conditions where TMA and DNCB provoke similar levels of immune activation [increases in lymph node cell (LNC) cellularity and proliferation] divergent cytokine expression patterns are elicited. TMA-activated LNC isolated from BALB/c mice or BN rats elaborated high levels of the Th2-type cytokines interleukin (IL)-10 and IL-13, but relatively little of the Th1-type cytokines IL-12 or interferon gamma. For LNC derived from both species there was a requirement for restimulation in vitro with the mitogen concanavalin A for IL-4 production. Generally, DNCB-stimulated LNC displayed the converse type 1 cytokine phenotype. The cytokine secretion profiles of LNC isolated from BN rats were considerably more variable than those observed for LNC from BALB/c mice. Statistically significant differences (P<0.01) between DNCB- and TMA-activated LNC were recorded for all cytokines in BALB/c strain mice. For the BN rat, differences reached statistical significance (P<0.01) only for the expression of IL-4 and IL-13. These data demonstrate that the intrinsic ability of DNCB and TMA to promote preferential Th1- and Th2-type responses, respectively, is species-independent and provide further evidence that chemical respiratory allergens are associated with polarized Th2-type responses. For the prospective assessment of chemical respiratory allergens as a function of induced cytokine secretion profiles, however, these data suggest that the use of the BALB/c strain mouse will provide the more robust method.

Allergens↗
PubMed2002

A prospective randomised trial of two treatments for wound seroma after breast surgery.

AIMS: Seroma formation is a recognised complication of breast surgery causing wound pain and discomfort. It was hypothesised that daily aspiration of symptomatic seromas that formed after breast surgery would encourage flap adherence to the chest wall, thereby allowing swifter resolution of seroma. METHODS: Thirty-six patients undergoing mastectomy and/or axillary clearance who formed seroma post operatively, were randomised into two groups either having daily aspiration of seroma or aspiration as required by patient symptoms. RESULTS: The daily aspiration required significantly more attendances for aspiration (P<0.005) and the time from surgery to final aspiration was not reduced. CONCLUSION: Daily aspiration of symptomatic seroma did not result in swifter resolution.

Aged↗
PubMed2001

The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians.

Currently there are no brief, self-administered instruments for measuring the degree to which an adult with normal intelligence has the traits associated with the autistic spectrum. In this paper, we report on a new instrument to assess this: the Autism-Spectrum Quotient (AQ). Individuals score in the range 0-50. Four groups of subjects were assessed: Group 1: 58 adults with Asperger syndrome (AS) or high-functioning autism (HFA); Group 2: 174 randomly selected controls. Group 3: 840 students in Cambridge University; and Group 4: 16 winners of the UK Mathematics Olympiad. The adults with AS/HFA had a mean AQ score of 35.8 (SD = 6.5), significantly higher than Group 2 controls (M = 16.4, SD = 6.3). 80% of the adults with AS/HFA scored 32+, versus 2% of controls. Among the controls, men scored slightly but significantly higher than women. No women scored extremely highly (AQ score 34+) whereas 4% of men did so. Twice as many men (40%) as women (21%) scored at intermediate levels (AQ score 20+). Among the AS/HFA group, male and female scores did not differ significantly. The students in Cambridge University did not differ from the randomly selected control group, but scientists (including mathematicians) scored significantly higher than both humanities and social sciences students, confirming an earlier study that autistic conditions are associated with scientific skills. Within the sciences, mathematicians scored highest. This was replicated in Group 4, the Mathematics Olympiad winners scoring significantly higher than the male Cambridge humanities students. 6% of the student sample scored 32+ on the AQ. On interview, 11 out of 11 of these met three or more DSM-IV criteria for AS/HFA, and all were studying sciences/mathematics, and 7 of the 11 met threshold on these criteria. Test-retest and interrater reliability of the AQ was good. The AQ is thus a valuable instrument for rapidly quantifying where any given individual is situated on the continuum from autism to normality. Its potential for screening for autism spectrum conditions in adults of normal intelligence remains to be fully explored.

Adult↗
PubMed2001

Adolescent hepatitis B immunisation--should it be the law?

Universal hepatitis B immunisation of young adolescents was included in the Australian Standard Vaccination Schedule in 1998. However, rates of immunisation among adolescents world-wide have often been inadequate. Australia's experience in this area is no exception, particularly in States where school-based delivery is not carried out. Legislation for pre-school immunisation certification currently exists in several States and this legislation is distinctly different from the compulsory or mandatory immunisation that exists in several other developed countries. There have been demonstrable gains in uptake as a result of mandatory immunisation requirements in the United States and there is evidence to suggest that immunisation certification in Australia has also been beneficial. However, it is important to recognise that both certification and mandatory immunisation legislation have inherent difficulties. In this paper, we argue that legislation for high school immunisation certification, as part of a multi-faceted vaccine delivery strategy tailored to adolescents, is required to achieve the uptake that will lead to interruption of transmission of the hepatitis B virus in Australia. Not only will it substantially reduce incident cases of hepatitis B for the next decade, it will also provide a framework for the successful introduction of future adolescent vaccine initiatives in Australia.

Adolescent↗
PubMed2001

Dietary practices, attitudes, and physiological status of collegiate freshman football players.

The purpose of this study was to determine the dietary practices, attitudes, and physiological status of freshman collegiate football players. Thirty-one freshman football players at a National Collegiate Athletic Association division I school completed a self-administered nutrition screening questionnaire designed to determine their dietary practices and attitudes. Fasting blood samples were collected and height and weight were measured. The mean age of these athletes was 18 years. These players reported eating 3.6 times per day and on the average eating out 4.8 times per week. Fast food was the most common choice when eating out (55%). Of these athletes, 42% reported the use of dietary supplements, the most popular one being creatine (36%). Although more than 90% of the athletes recognized the importance of maintaining proper hydration status, greater than 50% believed that protein supplements were necessary for muscle growth and development, protein was the primary source of energy for muscle, and vitamin and mineral supplements increased energy levels. The plasma lipid profiles of the majority (76%) of the athletes were within normal ranges. The data suggest that these athletes may require education about healthy dietary practices and on the proper use of dietary supplements. This is not only important to help improve performance but to also promote healthy dietary practices in the long term.

Adolescent↗
PubMed2000

Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparin.

Antithrombin, uniquely among plasma serpins acting as proteinase inhibitors in the control of the blood coagulation cascade, circulates in a relatively inactive form. Its activation by heparin, and specifically by a pentasaccharide core of heparin, has been shown to involve release of the peptide loop containing the reactive centre from partial insertion in the A sheet of the molecule. Here we compare the structures of the circulating inactive form of antithrombin with the activated structure in complex with heparin pentasaccharide. We show that the rearrangement of the reactive centre loop that occurs upon activation is part of a widespread conformational change involving a realignment of the two major domains of the molecule. We also examine natural mutants that possess high affinity for heparin pentasaccharide, and relate the kinetics of their interaction with heparin pentasaccharide to the structural transitions occuring in the activation process.

Amino Acid Sequence↗
PubMed2000

T-cell frequency analysis does not predict the incidence of graft-versus-host disease in HLA-matched sibling bone marrow transplantation.

BACKGROUND: Graft-versus-host disease (GVHD) is a major and sometimes fatal complication of allogeneic bone marrow transplantation (BMT). The prediction of GVHD remains an important issue in preventing morbidity and mortality after allogeneic BMT. In the past 10 years, there has been great interest in using the frequency analysis of alloreactive helper and cytotoxic T lymphocyte precursors (HTLp and CTLp) to detect recipient-specific alloreactivity and thus predict GVHD in HLA-matched related and unrelated BMT. However, the results remain controversial. The intention of the present study was to investigate whether alloreactive HTLp and CTLp frequencies measured in donor peripheral blood before BMT would be a useful predictor for the occurrence of acute GVHD after HLA-matched sibling BMT. METHOD: A combined limiting dilution assay was used to determine alloreactive HTLp and CTLp frequencies for 42 HLA-matched sibling patient/donor pairs. The pretransplantation host-reactive HTLp and CTLp frequencies were then correlated with post-transplantation clinical outcomes of acute GVHD. The association between HTLp/CTLp frequencies and the incidence of acute GVHD was determined using the Fisher's exact test. RESULTS: The mean values of HTLp and CTLp frequencies for this cohort of HLA-matched sibling patient/donor pairs were 1:321,322 (range 1:71,000 to 1:1000,000) and 1:195,260 (range 1:3,717 to 1:1000,000), respectively. Acute GVHD (> or =II) was observed in one of four patients with high (>1:100,000) HTLp frequencies and 20 of 36 patients with low (<1:100,000) HTLp frequencies. Similarly, 6 of 10 patients with high (>1: 100,000) CTLp frequencies and 14 of 29 patients with low (<1:100,000) CTLp frequencies developed acute GVHD (> or =II). The overall correlation between hostreactive HTLp/CTLp frequencies and the incidence of acute GVHD in this cohort of patients was 42.5% and 53.9%, respectively. There was no significant difference in the incidence of acute GVHD between the patients with either high or low host-reactive HTLp/ CTLp frequencies (P=0.331 and 0.716, respectively). The data were also analyzed separately for the adult patient group based on GVHD prophylaxis with either cyclosporine alone or the combination of cyclosporine and methotrexate. Within these two prophylaxis groups, neither HTLp nor CTLp frequencies correlated with acute GVHD. CONCLUSION: Host-reactive HTLp and CTLp frequency analysis did not provide informative prediction for the occurrence of acute GVHD after HLA-matched sibling BMT.

Acute Disease↗
PubMed2000

Conformational changes in serpins: I. The native and cleaved conformations of alpha(1)-antitrypsin.

The serpins (SERine Proteinase INhibitors) are a family of proteins with important physiological roles, including but not limited to the inhibition of chymotrypsin-like serine proteinases. The inhibitory mechan- ism involves a large conformational change known as the S-->R (stressed-->relaxed) transition. The largest structural differences occur in a region around the scissile bond called the reactive centre loop: In the native (S) state, the reactive centre is exposed, and is free to interact with proteinases. In inhibitory serpins, in the cleaved (R) state the reactive centre loop forms an additional strand within the beta-sheet. The latent state is an uncleaved state in which the intact reactive centre loop is integrated into the A sheet as in the cleaved form, to give an alternative R state. The serpin structures illustrate detailed control of conformation within a single protein. Serpins are also an unusual family of proteins in which homologues have native states with different folding topologies. Determination of the structures of inhibitory serpins in multiple conformational states permits a detailed analysis of the mechanism of the S-->R transition, and of the way in which a single sequence can form two stabilised states of different topology. Here we compare the conformations of alpha(1)-antitrypsin in native and cleaved states. Many protein conformational changes involve relative motions of large rigid subunits. We determine the rigid subunits of alpha(1)-antitrypsin and analyse the changes in their relative position and orientation. Knowing that the conformational change is initiated by cleavage at the reactive centre, we describe a mechanism of the S-->R transition as a logical sequence of mechanical effects, even though the transition likely proceeds in a concerted manner.

Amino Acid Sequence↗
PubMed2000

Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation.

Severe congenital neutropenia (CN) (Kostmann syndrome) is a hematologic disorder characterized by a maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage of development. This arrest results in severe neutropenia leading to absolute neutrophil counts (ANC) below 0.2 x 10(9)/L associated with severe bacterial infections from early infancy. Data on over 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) beginning in 1994 indicate that more than 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (r-HuG-CSF) treatment with an ANC greater than 1. 0 x 10(9)/L. For patients who are refractory to r-HuG-CSF treatment and continue to have severe and often life-threatening bacterial infections, hematopoietic stem cell transplantation is the only currently available treatment. We report on a total of 11 patients with CN reported to the SCNIR who underwent transplantation for reasons other than malignant transformation between 1976 and 1998. Of these patients, 8 were nonresponders or showed only partial response to r-HuG-CSF treatment with ongoing infections. Results from these patients suggest that transplantation of stem cells from an HLA-identical sibling is beneficial for patients refractory to r-HuG-CSF. (Blood. 2000;95:1195-1198)

Adolescent↗
PubMed2000

Conformational changes in serpins: I. The native and cleaved conformations of alpha(1)-antitrypsin.

The serpins (SERine Proteinase INhibitors) are a family of proteins with important physiological roles, including but not limited to the inhibition of chymotrypsin-like serine proteinases. The inhibitory mechan- ism involves a large conformational change known as the S-->R (stressed-->relaxed) transition. The largest structural differences occur in a region around the scissile bond called the reactive centre loop: In the native (S) state, the reactive centre is exposed, and is free to interact with proteinases. In inhibitory serpins, in the cleaved (R) state the reactive centre loop forms an additional strand within the beta-sheet. The latent state is an uncleaved state in which the intact reactive centre loop is integrated into the A sheet as in the cleaved form, to give an alternative R state. The serpin structures illustrate detailed control of conformation within a single protein. Serpins are also an unusual family of proteins in which homologues have native states with different folding topologies. Determination of the structures of inhibitory serpins in multiple conformational states permits a detailed analysis of the mechanism of the S-->R transition, and of the way in which a single sequence can form two stabilised states of different topology. Here we compare the conformations of alpha(1)-antitrypsin in native and cleaved states. Many protein conformational changes involve relative motions of large rigid subunits. We determine the rigid subunits of alpha(1)-antitrypsin and analyse the changes in their relative position and orientation. Knowing that the conformational change is initiated by cleavage at the reactive centre, we describe a mechanism of the S-->R transition as a logical sequence of mechanical effects, even though the transition likely proceeds in a concerted manner.

Amino Acid Sequence↗
PubMed2000

Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors: a study on behalf of the European Group for Blood and Marrow Transplantation.

Allogeneic stem cell transplantation is the only treatment that can restore a normal hematopoiesis in Fanconi anemia (FA). In this retrospective multicenter study, we analyzed the results of this approach using HLA-matched unrelated bone marrow donors, and tried to identify covariates predicting the outcome of the transplant. From January 1985 to June 1998, 69 FA patients were transplanted with unrelated HLA-matched donors. Patients' characteristics before and after transplant were provided by the European group blood and marrow transplant registry and were analyzed in collaboration with the European Fanconi Anemia Registry. The 3-year probability of survival was 33%. Extensive malformations, a positive recipient cytomegalovirus serology, the use of androgens before transplant, and female donors were associated with a worse outcome. Primary graft failures were observed more frequently when female donors were used, mainly because the grafts contained lower nucleated cell doses per kilogram of recipient body weight compared with grafts coming from male donors. The probability of grade III-IV acute graft-versus-host disease (GVHD) was 34%. Elevated serum alanine/aspartate transaminases before transplantation; limb, urogenital tract, or nephrologic malformations; and non-T-cell-depleted grafts were predictors of severe acute GVHD. This study shows the dramatic impact of preexisting congenital malformations on the outcome of FA patients transplanted with HLA-matched unrelated donors. If the use of T-cell depletion has led to a dramatic reduction of acute GVHD incidence, no significant outcome improvement was observed with this approach, mainly because of an increased risk of graft failure. (Blood. 2000;95:422-429)

Adolescent↗