Factors associated with the reporting of Down syndrome as the underlying cause of death on US death certificates.

BACKGROUND: Efforts aimed at preventing premature mortality for people with Down syndrome are hindered by the practice of reporting disability as the underlying cause of death. Prior research suggests this form of diagnostic overshadowing may be the result of increased uncertainty surrounding the death. METHODS: This study uses bivariable analysis and multivariable logistic regression models to investigate associations between sociodemographic characteristics, comorbidities, and death context and processing characteristics with the reporting of Down syndrome as the underlying cause of death in 2005-2017 US Multiple Cause of Death data files. RESULTS: The reporting of Down syndrome as the underlying cause of death was associated with characteristics indicative of an increased amount of uncertainty surrounding the death. Results also suggest other mechanisms may inform inaccurate reporting, such as racial bias, and the continued conflation of disability and health. CONCLUSIONS: Medical personnel certifying death certificates should strive for accuracy when reporting the causes of death. To ensure this outcome, even in the midst of increased uncertainty, Down syndrome should not be reported as the underlying cause of death unless the decedent was diagnosed with Alzheimer's disease or unspecified dementia. Future research should further explore the possibility that increased death certification errors for adults with Down syndrome, or other developmental disabilities, are associated with racial bias.

Proliferation in vivo of T lymphocytes reactive to histocompatibility alloantigens: a correction.

Rat lymphocytes in mixed cultures can reutilize tritiated thymidine from labeled granulocytes. Shortly after thymidine injections in vivo, major effects on the frequency of labeled lymphocyte mitoses in peripheral blood cultures are introduced by 10-20% polymorph contamination, even though transfer of label via supernates is not demonstrable. Cold thymidine in the cultures prevents reutilization, and has permitted reevaluation of several previous conclusions concerning the life history of lymphocytes reactive to major histocompatibility alloantigens (HARC). Rather than being predominantly recently divided cells, HARC do not appear to have an age distribution, in blood or lymph, significantly different from the general recirculating lymphocyte population. However, the ability of immunization across strong allogeneic differences to increase markedly the proportion of young HARC among the specifically responsive population has been confirmed.

Locus of the alpha-chain of the T-cell receptor is split by chromosome translocation in T-cell leukemias.

Mouse lymphoma cells were hybridized with two human acute T-cell leukemias with a t(11;14) (p13;q11) translocation and the segregated hybrids were examined for the presence of the DNA segments coding for the constant (C) and the variable (V) regions of the alpha chain (C alpha and V alpha) of the T-cell receptor. The C alpha segment was translocated to the involved chromosome 11 (11p+) while the V alpha segment remained on the involved chromosome 14 (14q-). The data indicate that the locus for the alpha chain of the T-cell receptor is split by the chromosomal breakpoint between the V alpha and the C alpha gene segments, and that the V alpha segments are proximal to the C alpha segment within chromosome band 14q11.2.

Deregulation of c-myc by translocation of the alpha-locus of the T-cell receptor in T-cell leukemias.

Two human T-cell leukemias carrying a t(8;14)(q24;q11) chromosome translocation were studied for rearrangements and expression of the c-myc oncogene. For one leukemia, rearrangement was detected in a region immediately distal (3') to the c-myc locus; no rearrangements of c-myc were observed in the second case (DeF). However, studies with hybrids between human and mouse leukemic T cells indicated that in the leukemic cells of DeF, the breakpoint in chromosome 14 occurred between genes for the variable (V alpha) and the constant (C alpha) regions for the alpha chain of the T-cell receptor. The C alpha locus had translocated to a region more than 38 kilobases 3' to the involved c-myc oncogene. Since human c-myc transcripts were expressed only in hybrids carrying the 8q+ chromosome but not in hybrids containing the normal chromosome 8, it is concluded that the translocation of the C alpha locus 3' to the c-myc oncogene can result in its transcriptional deregulation.

Karyotypic differences between primary cultures and cell lines from tumors with the human T-cell leukemia virus.

Chromosome abnormalities were studied in primary cultures and in established T-cell lines from patients with human T-cell leukemia virus (HTLV)-positive leukemia or lymphoma. The present findings, and data from other laboratories, indicated that primary cultures of the HTLV-positive neoplastic cells nearly always showed a chromosomally abnormal clone, whereas most established cell lines had an apparently normal karyotype. These differences included circumstances in which the same blood specimen was used for both types of culture or in which separate specimens were obtained within a short time span. These observations indicated that many cell lines from HTLV-positive leukemia or lymphoma may be derived from nonneoplastic T-cells that were transformed in vitro by the leukemia virus; human T-cells newly infected with HTLV were suggested to have an in vitro growth advantage over the HTLV-infected tumor cells.

Molecular characterization of a t(11;14)(q23;q32) chromosome translocation in a B-cell lymphoma.

We have analyzed the molecular features of a t(11;14)(q23;q32) chromosome translocation of a cell line established from a B-cell lymphoma. Somatic hybrid cells carrying the 11q- and/or 14q+ chromosome(s) were produced in order to map the breakpoints. Southern blot analyses of DNAs from these hybrid cell lines together with various probes from the IGH locus on chromosome 14 and the ETS-1 and CD3 genes on chromosome 11 showed that the breakpoints of the translocation occurred between the constant regions of the C phi gamma and C gamma 2 genes on chromosome 14 and between the CD3 and ETS-1 genes on chromosome 11. The t(11;14)(q23;q32) translocation does not seem to involve the same mechanism that is responsible for translocations occurring at the immunoglobulin heavy chain joining segment (JH).

Transition to tetraploidy in 1,25-dihydroxyvitamin D3-resistant HL60 cells is preceded by reduced growth factor dependence and constitutive up-regulation of Sp1 and AP-1 transcription factors.

Increased ploidy is an ominous event in the progression of human malignancies. It is usually associated with an increased growth rate of the neoplastic cells and a generally more autonomous and aggressive biological behavior. However, it has not been established whether the more rapid growth rate and growth factor independence are consequences of the polyploid, karyotypically increasingly aberrant nature of these cells or whether the accelerated, more autonomous growth contributes to polyploidization. In this study, we have examined a recently described (H. J. Wajchman et al., Exp. Cell Res., 224: 312-322, 1996) series of sublines of HL60 cells with increasing resistance to the monocytic differentiation-inducing steroid hormone 1,25-dihydroxyvitamin D3 (1,25D3) and found that growth factor independence, shown by reduced requirement for serum supplementation of the medium and the ability to grow at low seeding densities, precedes polyploidization of these cultures. The growth factor independence was found to be accompanied by constitutive changes in the DNA binding pattern of the ubiquitous transcription factor Sp1, characteristic of an exposure to 1,25D3. Similar changes in the pattern of AP-1 binding were also observed in the 1,25D3-resistant HL60 sublines, but the intensity of the DNA binding by AP-1 was increased only in sublines with resistance to 1,25D3 but still near-diploid. The data suggest that the culture of HL60 cells in the presence of 1,25D3 results in constitutive up-regulation of growth-related machinery that reduces the need for growth factors and cytokines and demonstrate that this increased growth potential precedes polyploidization of the culture populations.

Clonal characteristics of cutaneous T cell lymphomas: cytogenetic evidence from blood, lymph nodes, and skin.

Chromosome studies were done on mitogen-stimulated lymphocytes from one or more tissues (blood, lymph nodes, skin lesions) in 15 patients with mycosis fungoides or Sézary syndrome. A cytogenetically abnormal clone was found in 10 individuals, including 6 with data from several tissues. In 4 cases the same aberrant clone was identified in a skin lesion as well as in blood and/or lymph node. The abnormal chromosome patterns ranged from hypodiploid to hypertetraploid, and there was no evidence of unrelated karyotypically-altered lines at different sites. A 6q- chromosome, previously reported in acute lymphocytic leukemia, was found in 2 patients. The results support the concept that cutaneous T cell lymphomas (CTCL) are clonal disorders, presumably unifocal in origin, with the skin lesions populated by cells from the same neoplastic clone that involves lymph nodes and blood.

Long-term integration and neuronal differentiation of human embryonal carcinoma cells (NTera-2) transplanted into the caudoputamen of nude mice.

NTera-2 (NT2) cells are a human embryonal carcinoma (EC) cell line derived from a teratocarcinoma that differentiate exclusively into postmitotic neurons in vitro following retinoic acid (RA) treatment. Like other EC cell lines, NT2 cells rapidly form lethal tumors following transplantation into peripheral sites or many regions of the brain. However, when grafts are confined to the caudoputamen (CP), the NT2 cells differentiate into postmitotic neuronlike cells and do not form lethal tumors. To examine the long-term fate of such grafts, we studied NT2 cell transplants in the CP of nude mice that survived for > 1 year. NT2 cells in these grafts acquired molecular markers of fully mature neurons including the low, middle, and high molecular weight neurofilament proteins, microtubule-associated protein 2, tau, and synaptophysin. Furthermore, neuronlike cells in long-term CP grafts formed synaptic structures, and their processes became myelinated, whereas tyrosine hydroxylase (TH)-positive neuronlike cells in the grafts increased with progressively longer postimplantation survival times. Soluble extracts of the adult mouse CP augmented TH expression in RA-treated NT2 cells in vitro. These data suggest that the adult mouse CP is a source of factor(s) that inhibits tumor formation and induce a catecholaminergic neuronal phenotype in these human NT2 cells in vivo and in vitro. Identification of these factors could accelerate efforts to elucidate mechanisms that regulate progenitor cell fate and the commitment of neurons to specific neurotransmitter phenotypes.

Hepatosplenic and subcutaneous panniculitis-like gamma/delta T cell lymphomas are derived from different Vdelta subsets of gamma/delta T lymphocytes.

Gamma/delta T cell lymphomas (gamma/delta TCL) represent rare, often aggressive types of T cell malignancy that are clinically and pathologically diverse. Most gamma/delta TCL occur as a hepatosplenic or subcutaneous type. To date, analysis of the T cell receptor delta (TCRS) gene repertoire of hepatosplenic gamma/delta TCL (gamma/delta HSTCL) and subcutaneous panniculitis-like gamma/delta TCL (gamma/delta SPTCL) has been reported only in a limited number of cases. In this study we analyzed 11 gamma/delta HSTCL and 4 gamma/delta SPTCL by polymerase chain reaction and immunostaining to determine their usage of the Vdelta subtypes (Vdelta1-6). It is noteworthy that 10 of 11 gamma/delta HSTCL expressed the Vdelta1 gene. The remaining case also expressed T cell receptor delta (TCRS) as determined by flow cytometry and TCRdelta rearrangement in Southern blot. However, the Vdelta gene expressed by this lymphoma could not be determined, which suggests usage of an as yet unidentified Vdelta gene. In striking contrast to the gamma/delta HSTCL, all 4 gamma/delta SPTCL expressed the Vdelta2 gene. Our data demonstrate that gamma/delta HSTCL are preferentially derived from the Vdelta1 subset of gamma/delta T lymphocytes, whereas gamma/delta SPTCL are preferentially derived from the Vdelta2 subset. The pattern of Vdelta gene expression in HSTCL and SPTCL corresponds to the respective, predominant gamma/delta T cell subsets normally found in the spleen and skin. This finding suggests that gamma/delta TCL are derived from normal gamma/delta T lymphocytes which reside in the affected tissues. Furthermore, the selective, lymphoma type-specific Vdelta gene segment usage may provide a molecular tool to distinguish better among various types of gamma/delta TCL lymphoma particularly in the clinically advanced, widely disseminated cases.

Ph-negative T cells in a patient with chronic myelogenous leukemia for twenty-eight years.

The frequency of metaphases without a Philadelphia chromosome was determined in mitogen-stimulated cultures of peripheral blood mononuclear cells (PBMC) and purified T lymphocytes (93% CD2-positive) from a patient with chronic myelogenous leukemia (CML) for 28 years. The PBMC cultures contained few Ph-negative cells (8%), but they constituted 92% of the metaphases in T cell cultures, indicating few if any Ph-positive T cells in the patient's circulation. The results demonstrate that T cells derived from the leukemic clone may fail to replace the non-neoplastic population even when CML arises in childhood and the patient survives for many years. This raises questions concerning the normal role of the bone marrow as a source of T cells after infancy, and also whether Ph-positive lymphocytes may be at a disadvantage for growth.

Evidence for early hematopoietic progenitor cell involvement in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) represents a subtype of acute myeloid leukemia with characteristic morphologic, molecular, and immunophenotypic features. Previous immunophenotypic analyses have shown that leukemic cells in APL typically express the myeloid markers CD33 and CD13 but lack expression of the early hematopoietic progenitor cell antigens CD34 and HLA-DR. We analyzed selected immunophenotypic features of APL by flow cytometry and showed that 7 (41%) of 17 cases contained significant subsets of CD34+ leukemic cells: CD34+ myeloid cells predominated in 2 APL cases. By using a fluorescence-activated cell sorter-fluorescence in situ hybridization approach, we confirmed that the CD34+ cells harbored the t(15;17) translocation characteristic of APL. By using the same experimental approach, CD34+ populations were stratified into primitive CD34+ CD38- and committed CD34+ CD38+ progenitor cell subpopulations; cells in both subsets contained the t(15;17) translocation. The knowledge that APL may be partly or largely CD34+ is important for proper diagnosis. Furthermore, identification of the t(15;17) translocation in CD34+ CD38- blasts indicates that, in at least some cases, the leukemogenic mutation in APL occurs within primitive hematopoietic progenitor cells.

Hepatosplenic gamma-delta T-cell lymphoma as a late-onset posttransplant lymphoproliferative disorder in renal transplant recipients.

We report 2 cases of renal transplant recipients in whom hepatosplenic gamma-delta T-cell lymphoma (gamma-delta HSTCL) developed 5 and 10 years after transplantation. Both patients had marked hepatosplenomegaly, B symptoms (weight loss, fever, and night sweats), and abnormal peripheral blood findings, including anemia in both, thrombocytopenia and leukoerythroblastic changes in 1, and leukocytosis in the other. Markedly atypical lymphoid infiltrate of intermediate to large cells was observed in the spleen, liver, and bone marrow. The malignant cells showed typical immunophenotype of gamma-delta T cells (CD2+, CD3+, CD4-, CD8-, CD7+, gamma-delta T-cell receptor-positive, and alpha-beta T-cell receptor-negative) with clonal T-cell receptor gene rearrangement and were of the V-delta-1 subset. In addition, the cells contained a cytolytic granule-associated protein, TIA-1, and Fas ligand, indicating cytotoxic T-cell differentiation. The malignant T cells in both cases were of host tissue origin. Both cases were negative for Epstein-Barr virus genome using Southern blot analysis. The patients did not respond to reduction of immunosuppression. Despite initial response to chemotherapy, both patients died within 6 months of diagnosis. Our findings indicate that gamma-delta HSTCL can occur as a late complication in transplant recipients.

A 2p;11q chromosome translocation in dysmyelopoietic preleukemia.

Three patients with dysmyelopoietic preleukemia had a marrow clone with translocation t(2;11)(p21;q23) as the only chromosome change. In one patient, the cytogenetically altered cells disappeared following treatment with 13-cis-retinoic acid. Although these patients did not constitute a homogeneous clinical subgroup, the 2p;11q translocation should probably be added to the short list of nonrandom karyotypic alterations involving 11q23 that have been described in various hematopoietic disorders.

Preleukemia and leukemia with 12p- and 19q+ chromosome alterations following Alkeran therapy.

Among 20 patients with acute nonlymphocytic leukemia or dysmyelopoietic preleukemia secondary to Alkeran therapy for another tumor, four had a del(12)(p11-p12) and four had a translocation to 19q13 among multiple karyotypic alterations in their neoplastic hematopoetic clones. It is suggested that these two cytogenetic abnormalities may occur nonrandomly in such hemic disorders and may play a limited role in their pathogenesis.

Two adult siblings with thrombocytopenia and a familial 13;14 translocation.

A woman with thrombocytopenia that progressed to aplastic anemia, and her brother, who had persistent thrombocytopenia, both had a constitutional t(13;14) translocation. Six other family members, in three generations, had the same translocation, but no hematologic disorder. There was evidence suggestive of increased chromosomal fragility in lymphocyte cultures from two members of the kindred, but not in the two patients. The findings support a postulated association between the t(13;14) and hematologic disorders, but whether the mechanism involves an inherited defect in chromosomal stability is unproved.

The most common chromosome change in 86 chronic B cell or T cell tumors: a 14q32 translocation.

Among 46 patients with chronic lymphocytic leukemia (CLL) (40 B cell, 6 T cell) and 40 patients with cutaneous T cell lymphoma (CTCL), a chromosomally abnormal neoplastic clone was identified in 43 cases. A translocation involving 14q32 was present in nine cases (five B-CLL, two T-CLL, two CTCL). The donor chromosomal site was 11q13 in four patients and 1q12, 4q25-27, 17q21-22, 18q21, and 22q11 in one case each. The next most frequent abnormalities were rearrangements involving 6q21-23 (four cases), and trisomy 12 (four cases, all B-CLL). In one CTCL patient, the t(11;14) translocation was present in one of three apparently unrelated T cell clones. Recent studies indicate that the selective advantage conferred by the 14q+ chromosome in B cell neoplasms appears to result from an oncogene being brought adjacent to a rearranged and transcriptionally active immunoglobulin heavy chain locus. The present findings suggest that similar mechanisms may operate in certain T cell neoplasms, although the activating gene is not necessarily the same.

Marrow fibrosis associated with a Philadelphia chromosome.

Three patients had marked marrow fibrosis and an apparent Philadelphia (Ph) chromosome. Hematologic, cytogenetic, and molecular studies demonstrated the heterogeneity of such cases, including the first example of clinically typical myelofibrosis (MF) associated with a bcr gene rearrangement characteristic of chronic myelogenous leukemia (CML).

Chromosome studies in preleukemic states. IV. Myeloproliferative versus cytopenic disorders.

The prognostic value of marrow chromosome studies was examined in 112 "preleukemic" patients followed for at least one year or until death. Based on recent definitions, 49 patients were classified as myeloproliferative disorders (MPD) (polycythemia vera, myelofibrosis, undifferentiated myeloproliferative disorder, essential thrombocythemia), and 58 as cytopenic states (refractory anemia, pancytopenia). In each group, approximately one-third had a chromosomally-abnormal clone. For MPD, this had little predictive value, but in the cytopenias, 77% with a cytogenetic abnormality developed leukemia versus 39% without. Twelve cytopenic patients had multiple alterations involving more than 2 chromosomes and 11 died within 6 months, 9 with leukemia. Such patients may warrant consideration for aggressive chemotherapy before the appearance of clinical leukemia. Banding studies did not reveal any specific chromosome abnormalities consistently associated with these various preleukemic disorders, or with progression to leukemia, but nonrandom alterations were noted involving chromosomes 1, 5, 7-9, and 20 in the MPD group, and chromosomes 6 and 16 in the cytopenic patients. Correlation of these data with other reports indicates that certain cytogenetic abnormalities involving specific segments of the human genome confer a selective growth advantage on hemic clones which may present clinically as either preleukemia or leukemia.