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S Sheldon

Publications and source records attributed to S Sheldon.

At least 19 recordsLinked to original sources
PubMed2004

Should selecting saviour siblings be banned?

By using tissue typing in conjunction with preimplantation genetic diagnosis doctors are able to pick a human embryo for implantation which, if all goes well, will become a "saviour sibling", a brother or sister capable of donating life-saving tissue to an existing child. This paper addresses the question of whether this form of selection should be banned and concludes that it should not. Three main prohibitionist arguments are considered and found wanting: (a) the claim that saviour siblings would be treated as commodities; (b) a slippery slope argument, which suggests that this practice will lead to the creation of so-called "designer babies"; and (c) a child welfare argument, according to which saviour siblings will be physically and/or psychologically harmed.

Child↗
PubMed2003

Detection of juvenile sleep deprivation by stochastic optimization of pupillographic records.

OBJECTIVE: To address the challenging problem of measuring juvenile sleep deprivation, we test the hypothesis that a pupillographic method found successful for adult narcoleptics might also discriminate between sleep deprived juveniles acting as their own controls. METHODS: A linear, nonstationary model relating pupillary diameter and a random photic stimulus are estimated by recursive regressions from pupillographic records of 8 juveniles of median age 7 years acting as their own rested controls. The estimated pupillary impulse response noise functions are stochastically optimized using the Kullback divergence measure to maximally separate the sleep deprived records from the control records. RESULTS: Both the average and covariance statistics of the estimated pupillary noise functions exhibit statistically significant differences between sleep deprived and rested subjects. The main result is that sleep deprivation decreases pupillary noise variance; a finding consistent with a previous study of adult narcoleptics. Further, it was found that virtually the same stochastic parameters were optimal for the juvenile sleep deprived data and for the previous adult narcoleptic study. CONCLUSIONS: Although our results are preliminary, the consistent reduction of pupillary noise appears to justify a comprehensive clinical trial across a broad range of age classes. In addition, the finding that the same parameters stochastically optimize both juvenile and adult recordings suggests the procedure holds promise as a clinical test which could produce sleep deprivation measures simultaneous with data collection.

Algorithms↗
PubMed2001

CHARGE association with choanal atresia and inner ear hypoplasia in a child with a de novo chromosome translocation t(2;7)(p14;q21.11).

A 3-year-old boy was diagnosed with CHARGE association on the basis of bilateral choanal atresia, absence of the semicircular canals, hypoplastic cochleae, genital hypoplasia, growth and developmental delays, cranial nerve dysfunction, and facial anomalies. Ophthalmologic and cardiac evaluations were normal. He was found to have an apparently balanced t(2;7)(p14;q21.11) chromosomal translocation. Parental karyotypes were normal. Although there is evidence suggesting a genetic basis for CHARGE association, individuals with chromosomal abnormalities and CHARGE are rare. In the described patient, the presence of characteristic CHARGE features suggests that the t(2;7)(p14;q21.11) translocation breakpoints may cause a deletion or disruption of genes within the involved regions that are involved in the generation of the CHARGE association phenotype.

Abnormalities, Multiple↗
PubMed2001

A comparison of enzyme-linked immunoabsorbent assays and flow cytometry techniques for the detection of HLA specific antibodies.

LATM, Quikscreen (QS), and B-Screen (QSB) are ELISA-based tests for the detection of HLA specific antibodies. FlowPRA beads are microparticles coated with HLA antigens for the detection of HLA specific antibodies by flow cytometry. The aim of this study was to evaluate the sensitivity and specificity of the LATM, QS, QSB, and FlowPRA screening tests. One hundred sixty-three sera from renal transplant patients were tested using LATM, FlowPRA, QS, and QSB. Discrepant results were further investigated using complement dependent cytotoxicity, QuikID, and PRA-STAT. When QS was compared with LATMI and FlowPRAI for the detection of HLA class I specific antibodies the overall concordance was 82.8% with no particular specificity missed by any one test. Comparing QSB with LATMII and FlowPRAII, for the detection of HLA class II specific antibodies, there was 90.7% concordance. Although the overall concordance was better for class II specific antibodies, QSB failed to detect antibodies to HLA-DQ in a number of samples from different patients. Of the methods tested, flow cytometry using FlowPRA beads appeared to be the most sensitive and specific, missing the least number of specificities. However, the ELISA methods offer the advantage of being more suitable for testing large numbers of samples in a more time- and cost-effective manner.

Antibody Specificity↗
PubMed2000

A multicenter investigation with D-FISH BCR/ABL1 probes.

Twenty-eight laboratories evaluated a new fluorescence in situ hybridization (FISH) strategy for chronic myeloid leukemia. In a three-part study, bcr/abl1 D-FISH probes were used to study bone marrow specimens. First, laboratories familiarized themselves with the strategy by applying it to known normal and abnormal specimens. Then, collectively the laboratories studied 20 normal and 20 abnormal specimens blindly and measured workload. Finally, each laboratory and two experts studied six serial dilutions with 98-0% abnormal nuclei. Using the reported normal cutoff of < 1% abnormal nuclei, participants reported no false-negative cases and 15 false-positive cases (1-6.6% abnormal nuclei). Results provided by participants for serial dilutions approximated the expected percentages of abnormal nuclei, but those from the experts exhibited greater precision. The clinical sensitivity, precision, nomenclature, workload, recommendations for training, and quality assurance in methods using D-FISH in clinical practice are discussed.

Bone Marrow↗
PubMed1999

The influence of histocompatibility on graft rejection and graft survival within a single center population of heart transplant recipients.

BACKGROUND: We report a consecutive single center series of 261 patients who received first orthotopic heart transplants from 1986 to 1997. The 1- and 5-year graft survivals were 78 and 68%. The influence of histocompatibility was investigated by comparing graft survival and numbers of treated rejection episodes with HLA-A, -B, and -DR mismatches over different time periods. FINDINGS: Recipients with six mismatches for HLA-A+-B+-DR combined (13.4%) had reduced survival at 7 years (47%) when compared with other recipients (64%). In the first year of transplant, recipients with four HLA-A+-B mismatches had significantly reduced actuarial graft survival (P=0.03) with the greatest influence apparent at 6 months [0-3 mismatches (n=193) 85% versus 4 mismatches (n=68) 69%; P=0.005, OR=2.1]. For 182 recipients with functioning hearts at 1 year, the number of rejection episodes treated within this time was strongly influenced by HLA-DR mismatch [0 DR mismatch (n=15) mean 1.2 rejection episodes versus 1 DR mismatch (n=76) mean 2.7 rejection episodes versus 2 DR mismatches (n=91) mean 3.8 rejection episodes: P=0.0002]. Of these 182 transplants, recipients who had more than four treated rejection episodes during the first year had a significantly reduced 7- year survival [<5 rejection episodes (n=133) 85% versus more than four rejection episodes (n=49) 66%; P=0.02, OR=3.4], as did those with two HLA-DR mismatches [0+1 mismatch (n=91) 87% versus 2 mismatches (n=91) 70%; P<0.05, OR=2.4]. INTERPRETATION: We show that graft loss in the first 6 months of transplant is significantly influenced by four HLA-A+-B mismatches. HLA-DR mismatch significantly increases the number of rejection episodes within the first year, without influencing graft survival. After 12 months both >4 rejection episodes in the first year and two HLA-DR mismatches are markers for late graft loss. We postulate that immunological graft loss in the first 6 months is dominated by the direct allorecognition pathway driven by HLA-DR mismatch. This mechanism is later lost or suppressed. Our data highlight HLA-DR mismatch as a marker for late graft loss and we show an advantage to avoiding transplanting hearts with six HLA-A+-B+-DR mismatches and to minimizing HLA-DR mismatches whenever possible.

Adolescent↗
PubMed1999

Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation.

BACKGROUND: Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-beta has been implicated in the pathogenesis of fibrosis. METHODS: We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-beta polyclonal antibodies. OB and interstitial fibrosis were diagnosed and graded in all biopsies. Other potential histologic and clinical risk factors for OB were analysed. RESULTS: Procedures were heart and lung (n = 32), bilateral sequential lung (n = 18), and single lung transplantation (n = 41). The incidence of OB in this group was 28.5%. In all patients with OB, TGF-beta was immunolocalized in the airways and lung parenchyma. TGF-beta expression was greater in OB patients (median score 8, range 5-12) in comparison to patients without OB (median score 4, range 1-13), p < .0001. Positive TGF-beta staining preceded the histologic confirmation of OB by 6 to 18 months. The development of OB was associated with two HLA mismatches at the A locus (p = .02); recurrent acute rejection episodes (p < .0005); lymphocytic bronchiolitis (p = .0001); and tissue eosinophilia, regardless of the rejection grade (p < .0001). CONCLUSIONS: Increased expression of TGF-beta is a risk factor for the development of OB. Other risk factors are recurrent acute rejection, lymphocytic bronchiolitis, tissue eosinophilia, and two mismatches at the HLA-A locus. This suggests that the pathogenesis of progressive small airway fibrosis characteristic of OB may be inflammatory damage, followed by an aberrant repair process due to excessive TGF-beta production following allograft injury. Hence, modulation of TGF-beta levels or function by antagonists may represent an important approach to control OB.

Adult↗
PubMed1999

Chromosomal aneuploidy in leukemic blast crisis: a potential source of error in interpretation of bone marrow engraftment analysis by VNTR amplification.

BACKGROUND: Polymerase chain reaction (PCR) amplification of polymorphic microsatellite or minisatellite DNA markers has proven to be a fast, sensitive, and specific technique in post-transplantation monitoring of bone marrow engraftment, as well as early detection of residual disease and relapse. Deletion or amplification of chromosomal segments carrying marker loci, as can occur in leukemia and other hematologic malignancies, may result in loss or increased dosage of marker alleles. Examination of these marker alleles by PCR therefore may give aberrant results, which might lead to misinterpretation of bone marrow transplantation (BMT) engraftment studies. METHODS AND RESULTS: We report a case of chronic myelogenous leukemia treated by BMT. PCR amplification of the minisatellite at the apoB locus on chromosome 2 was used to monitor the donor bone marrow engraftment. The patient experienced relapse in blast crisis with a near-haploid karyotype with loss of recipient-specific apoB allele causing an aberrant PCR result for bone marrow engraftment that mimicked full donor engraftment. CONCLUSIONS: Loss or gain of polymorphic DNA markers because of chromosomal losses or gains in some hematologic malignancies may affect the interpretation of bone marrow engraftment studies by PCR. When choosing polymorphic markers for such studies, it is important to avoid those that will be affected by expected chromosomal alteration, if possible. In addition, any abberant post-transplantation typing should prompt further investigation to rule out the possibility of chromosomal aberration. Review of all pertinent laboratory studies is important to avoid misinterpretation of results from a single test for engraftment analysis.

Adult↗
PubMed1998

Cytogenetic abnormalities and therapy-related myelodysplastic syndromes in rheumatic disease.

OBJECTIVE: To describe the myelodysplastic syndromes (MDS) and cytogenetic abnormalities that occur in patients who have been treated with alkylating drugs for their rheumatic disease. METHODS: Patients with rheumatic disease who developed MDS after current or previous treatment with alkylating drugs were selected for evaluation by chart review and cytogenetic studies. RESULTS: Eight patients with rheumatic disease (mean age 56.9 years) developed MDS over the study period. Seven had received oral cyclophosphamide and 1 chlorambucil as their main immunosuppressive drug. The mean total cumulative dose of cyclophosphamide or chlorambucil was 118 gm and 6.5 gm, respectively, over a period of 2-10 years. The cytogenetic abnormalities included a deletion of all or part of chromosome 7 in 5 patients, while 4 had a deletion of part of the long arm of chromosome 5. Six of the patients have since died. CONCLUSION: Large cumulative doses of cyclophosphamide and chlorambucil were associated with the development of MDS, the occurrence of abnormalities of chromosome 5 and/or chromosome 7 deletions, and a poor prognosis.

Adult↗
PubMed1998

Chromosomes in autism and related pervasive developmental disorders: a cytogenetic study.

Few studies have examined the occurrence of chromosome abnormalities in a large sample of patients with autism and related pervasive developmental disorders (PDDs). In the present report, the authors examined a consecutive series of 92 children with PDDs (DSM-III-R; 75 males and 17 females). A cytogenetic examination, including growth in folate deficient medium, was performed in all cases. Three patients (3.2%) (two females and one male) showed chromosome abnormalities: deletion of the long arm of chromosome 8; tetrasomy of chromosome 15; and XYY syndrome. Only the subject who had tetrasomy 15 met the criteria for autistic disorder, while the other were diagnosed as suffering from a PDD not otherwise specified (PDDNOS). Another patient showed an abnormal fragile site at Xq27 in three out of 100 cells. However, subsequent molecular studies did not confirm the presence of fragile-X syndrome. These results suggest that chromosome abnormalities are uncommon in traditional autism and may be relatively more common in people with PDDNOS.

Adolescent↗
PubMed1998

Follicular large cell lymphoma with immunoblastic features in a child with Wiskott-Aldrich syndrome: an unusual immunodeficiency-related neoplasm not associated with Epstein-Barr virus.

Patients with Wiskott-Aldrich syndrome, a severe inherited immunodeficiency disorder, have a markedly increased risk of developing non-Hodgkin's lymphoma compared with the general population. These are uniformly diffuse aggressive B-cell neoplasms that resemble those seen in AIDS and the posttransplantation setting and also may be associated with Epstein-Barr virus. We report what to our knowledge is the first case of follicular lymphoma in a 14-year-old child with Wiskott-Aldrich syndrome. The neoplasm was composed predominantly of large cells with immunoblastic features, and it possessed light chain-restricted surface immunoglobulin, clonal immunoglobulin gene rearrangements, and a t(14;18). The tumor lacked Epstein-Barr virus sequences by in situ hybridization and Southern blot terminal repeat analysis. Interestingly, however, the tumor contained c-myc gene rearrangement.

Blotting, Southern↗
PubMed1998

Familial Mondini dysplasia.

OBJECTIVES/HYPOTHESIS: To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. STUDY DESIGN: Correlative clinical genetic analysis of a single kindred. METHODS: Clinical history, physical examination, audiologic analysis, computed tomography of the temporal bones, and cytogenetic analysis. RESULTS: The male proband, three affected sisters, and an affected brother are offspring of unaffected parents. The mother and an unaffected brother have audiologic findings suggestive of heterozygous carrier status for a recessive hearing loss gene. CONCLUSIONS: Pedigree analysis indicates autosomal recessive inheritance in this family. The observed inheritance and clinical, audiologic, and radiologic findings are different from those previously described for another family with nonsyndromic Mondini dysplasia. The phenotype in this study family therefore represents a distinct subtype, indicating clinical and genetic heterogeneity of this disorder. This information should facilitate future molecular linkage analyses and genetic counselling of patients with inner ear malformations.

Adult↗
PubMed1998

Inflammatory myofibroblastic tumor: cytogenetic evidence supporting clonal origin.

The inflammatory myofibroblastic tumor (IMT) is a distinctive but controversial lesion, usually occurring during childhood, composed of fascicles of bland myofibroblastic cells admixed with a prominent inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils. Often affecting the lung and associated with constitutional symptoms, this lesion has been variously termed plasma cell granuloma, inflammatory pseudotumor, inflammatory myofibrohistiocytic proliferation, and inflammatory fibrosarcoma to reflect divergent views concerning its pathogenesis and level of malignancy. Cytogenetic analysis of an intra-abdominal myxoid hamartoma, a probable variant of this lesion, and a pulmonary IMT demonstrated clonal chromosomal abnormalities, lending support to the view that the IMT might be a neoplasm. There have been few cases studied to date, however, and the extent of cytogenetic anomalies in IMTs is not known. Karyotype analyses were performed on IMTs showing typical histologic features from three children. In addition, one case was studied by fluorescence in situ hybridization. Seventeen of 20 metaphase cells examined from a pulmonary IMT in a 5.5-year-old girl had an abnormal 47,XX+r(ring) karyotype. Fluorescence in situ hybridization studies demonstrated that the ring chromosome contained sequences of chromosome 8. Of 40 metaphase cells studied from a mesenteric IMT in an 8-month-old boy, 12 showed clonal aberrations, characterized as 43,XY,add(1)(p36),add(2)(p24),-6,der(14,22)(q10;q10),-19. Each of 20 metaphase cells examined from a retroperitoneal IMT in a 14-year-old girl contained complex clonal and nonclonal aberrations, characterized as 46-47,X,-X,add(2)(p22),add(2)(q13),+add(2)(q13),+5,-6,+i(7)(p10),add(8)( p11.2),+del(9)(p13),add(11)(p11.2)add(11)(q25),-13,-16,-18,add(19)(q13.1 ),add(19)(q13.1),+20,-21,-22,+mar1,+1-2mars. The presence of clonal chromosomal aberrations in all of the three tumors indicates that the IMT is a neoplastic proliferation.

Adolescent↗
PubMed1997

XY sex reversal and gonadal dysgenesis due to 9p24 monosomy.

We describe a case of XY sex reversal, gonadal dysgenesis, and gonadoblastoma in a patient with a deletion of 9p24 due to a familial translocation. The rearranged chromosome 9 was inherited from the father; the patient's karyotype was 46,XY,der(9)t(8;9) (p21;p24)pat. A review shows that 6 additional patients with 46,XY sex reversal associated with monosomy of the distal short arm of chromosome 9 have been observed. The observation that all 7 patients with sex reversal share a deletion of the distal short arm of chromosome 9 is consistent with the hypothesis that the region 9p24 contains a gene or genes necessary for male sex determination. This present case narrows the chromosome interval containing a critical sex determination gene to the relatively small region 9p24. A molecular analysis of this region will provide a means to identify a gene involved in male sex determination.

Chromosomes, Human, Pair 9↗
PubMed1997

Cytokine gene polymorphism and heart transplant rejection.

BACKGROUND: Allograft rejection is mediated by cytokines. As polymorphism in cytokine genes can result in interindividual differences in cytokine production, we hypothesize that some patients may have an increased risk of rejection. METHODS: We have related polymorphisms that influence cytokine production in the tumor necrosis factor (TNF)-A and interleukin (IL)-10 genes to early graft rejection in 115 heart transplant recipients. RESULTS: Certain combinations of TNF-A and IL-10 gene polymorphisms are associated with rejection. Five of 19 patients who had high levels of rejection typed as high TNF-alpha/low IL-10 producers compared with 4 of 96 patients with lower levels of rejection (P<0.005). CONCLUSIONS: We have identified a particular cytokine genotype that may confer susceptibility to increased levels of early rejection. Patients with a worse prognosis may be able to be identified pretransplant by DNA analysis of TNF-A, IL-10, and other gene polymorphisms.

Cytokines↗