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Biomedical subjects

C D Mitchell

Publications and source records attributed to C D Mitchell.

At least 19 recordsLinked to original sources
PubMed1992

Mycobacterium tuberculosis in children with human immunodeficiency virus type 1 infection.

A retrospective study was conducted at the Childrens Hospital Center at Jackson Memorial Hospital in Miami, FL, to evaluate the natural history of Mycobacterium tuberculosis infection in nine children with vertically acquired human immunodeficiency virus type 1 infection. The patients' ages ranged from 6 months to 7 years (median age, 42 months). Common presenting symptoms included prolonged fever, cough and anorexia. Only one patient had a positive tuberculin test. Five patients evidenced only pulmonary disease, three patients had pulmonary and extrapulmonary disease and one patient developed extrapulmonary tuberculosis (mastoiditis) and pulmonary interstitial disease that could not be attributed to mycobacterial infection because of lack of information. Organisms isolated before January, 1989, were susceptible to isoniazid and rifampin whereas isolates from three patients cultured after that time were resistant to multiple antituberculosis drugs. The median survival time after M. tuberculosis diagnosis for all children was 20 months. Our study suggests that children with human immunodeficiency virus type 1 infection who have tuberculosis have an increased risk for extrapulmonary disease. A high index of suspicion for the diagnosis of M. tuberculosis should be maintained in human immunodeficiency virus type 1-infected children with prolonged fever and respiratory symptoms. In areas of high endemicity of multidrug-resistant organisms, therapy with a broader panel of drugs may need to be instituted until susceptibility testing becomes available.

AIDS-Related Opportunistic Infections↗
PubMed1991

Molecular analysis of chromosome region 11p13 in patients with Drash syndrome.

The association of nephropathy, Wilms' tumour and genital abnormalities is known as Drash syndrome. Two of these features are also seen in the WAGR (Wilms' tumour, aniridia, genito-urinary abnormalities, mental retardation) complex, known to be associated with deletions of chromosome region 11p13. We have carried out karyotypic and molecular studies in 10 Drash patients, 5 males and 5 females. All the males had a 46XY karyotype as did 3/5 of the phenotypic females, the other two having a 46XX karyotype. One of the 46XX females also had a deletion of region 11p13-p12, the only detectable autosomal chromosome abnormality in any of the patients studied. Lymphoblastoid cell lines were prepared from 6 of the Drash patients and were used in dosage studies using a variety of DNA probes from the 11p13 region. There was no evidence of microdeletions in any patient with a normal karyotype. Because of the 46XY karyotype in phenotypic females, selected X and Y chromosome loci were analysed and all found to be normal. Although Drash syndrome is likely to be of genetic origin, there are no readily detected deletions within the 11p13 region.

Cell Line↗
PubMed1991

Recessive oncogenes, antioncogenes and tumour suppression.

Oncogenesis results from an accumulation of genetic mutations in a single cell. Mutations may result in the cell acquiring new functions or losing specific functions required for normal growth control. Evidence for the latter may be adduced from the results of fusing tumour and normal cells to form somatic cell hybrids, and from studies of allele loss in a number of human tumours. The locations the critical genes have been discerned in some cancer predisposition syndromes either by observations of consistent cytogenetic abnormalities, or by genetic linkage studies, or both. Genes whose inactivation is important in the genesis of retinoblastoma, Wilms' tumour and colorectal cancer have been identified and cloned. Their normal functions include control of transcription and cell-cell interactions. In the case of retinoblastoma, the interaction between the normal gene product and that of the transforming genes of a number of oncogenic DNA viruses has been delineated. Identification of 'tumour suppressor' genes has not only improved understanding of the process of oncogenesis, but may also aid in the presymptomatic detection of mutant gene carriers.

Animals↗
PubMed1991

Propagation and properties of Kaposi's sarcoma-derived cell lines obtained from patients with AIDS: similarity of cultured cells to smooth muscle cells.

Cells derived from Kaposi's sarcoma (KS) were propagated in vitro using conditions which resulted in elimination of contaminating fibroblasts and the emergence of homogeneous cell populations which morphologically resembled smooth muscle cells and had neoplastic characteristics. In long-term culture, they differentiated into large ribbon-like cells with longitudinal fibrillarity of their cytoplasm. These fibrils stained red by Masson trichrome staining, and were reactive with antibodies to desmin. Dense bodies typical of myoblasts were observed in some cells by electron microscopy. The cells did not form capillary structures like endothelial cells, they lacked Weible-Palade bodies, and did not express the blood-clotting Factor VIII-related antigen or receptors for the lectin Ulex europaeus agglutinin I. They did express four other antigens, however, in common with endothelial cells. The cells did not form tumors in athymic nude mice; however, they formed colonies in soft agar, manifested tumor-like growth on muscle organ cultures, and were invasive in an artificial basement membrane invasion assay. The results indicate that a component of KS is closely related to leiomyoblasts and and has neoplastic properties.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Molecular definition in a somatic cell hybrid of a specific 2:13 translocation breakpoint in childhood rhabdomyosarcoma.

A consistent, balanced, reciprocal chromosomal translocation t(2:13) (q35:q14) has been identified in alveolar rhabdomyosarcoma. Somatic cell hybrids have been constructed between rhabdomyosarcoma cell lines carrying the (2:13) translocation and mouse 3T3 cells. One hybrid cell line was shown to have retained the derivative (13:2) chromosome, but segregated the normal chromosome 13 and the derivative (2:13) chromosome. Using available DNA probes from human chromosome 13 we find that the loci for retinoblastoma, esterase D, p7D2, pG24E6.8 and pG14E1.9 lie distally to the 13q14 breakpoint, whereas those for p7F12, pHU10 and pG2E3.1 all lie proximally. Thus we have defined a region of 13q14 of approximately 28mB which contains the breakpoint associated with this rearrangement.

Animals↗
PubMed1990

Application of intragenic DNA probes in prenatal screening for retinoblastoma gene carriers in the United Kingdom.

Restriction fragment length polymorphisms (RFLPs) in 55 families affected by retinoblastoma have been studied using recombinant DNA probes derived from within the retinoblastoma predisposition gene. Only six families were uninformative for any of the DNA polymorphisms. The remaining 49 families can be offered prenatal screening. No obligate recombinations between any of the polymorphic loci and the retinoblastoma phenotype were observed. Four previously unknown cases of non-penetrance were identified. Prenatal testing for the inheritance of mutant alleles was performed in two cases and perinatal screening in two additional cases. One fetus inherited the normal allele from the affected parent and is therefore not at risk of retinoblastoma; the second fetus inherited the mutant allele and will require frequent screening for early detection of retinoblastoma. Both perinatal tests showed the absence of the mutant allele.

DNA Probes↗
PubMed1989

Survival in children with perinatally acquired human immunodeficiency virus type 1 infection.

We describe our experience at Jackson Memorial Hospital in Miami, Florida, with 172 children who were given diagnoses of perinatally acquired infection with human immunodeficiency virus type 1 (HIV-1). The 146 mothers of the children acquired HIV-1 through heterosexual contact (69 percent), intravenous drug use (30 percent), or blood transfusion (1 percent). The children presented with symptomatic disease at a median age of eight months; only 21 percent presented after the age of two years. The most common first manifestations of disease were lymphoid interstitial pneumonia (in 17 percent), encephalopathy (in 12 percent), recurrent bacterial infections (in 10 percent), and candida esophagitis (in 8 percent), for which the median survival times from diagnosis were 72, 11, 50, and 12 months, respectively. Nine percent of the children had Pneumocystis carinii pneumonia at a median age of five months and had a median survival of only one month. The median survival for all 172 children was 38 months from the time of diagnosis. Mortality was highest in the first year of life (17 percent), and by proportional-hazard analysis the probability of long-term survival is low. In multivariate analyses, early age at diagnosis and the first identifiable pattern of clinical disease were found to be independently related to survival. We conclude that children with perinatally acquired HIV-1 infection have a very poor prognosis and that most become symptomatic before one year of age. Early diagnosis is important, since there is only a short interval in which to initiate prophylactic or antiviral treatment before progressive disease begins.

Acquired Immunodeficiency Syndrome↗
PubMed1989

A somatic cell hybrid mapping panel for regional assignment of human chromosome 13 DNA sequences.

We have constructed somatic cell hybrids containing different overlapping deletions involving human chromosome 13. Cytogenetic characterisation of the breakpoints allowed division of the chromosome into six distinct regions. Molecular characterisation of these hybrids allowed regional assignment of anonymous DNA sequences, cDNAs, and isoenzyme variants and these hybrids should prove valuable in the analysis and isolation of genes and disease loci on chromosome 13.

Animals↗
PubMed1989

Predisposition to retinoblastoma due to a translocation within the 4.7R locus.

A candidate for the retinoblastoma (Rb) predisposition gene, known as 4.7R, has recently been cloned. Authentication of this gene depends on abnormalities detected in either the genomic sequence or transcription products (or both) in Rb tumours and cell lines. We report a constitutional chromosome translocation, with a breakpoint lying within the putative retinoblastoma gene, from a patient with retinoblastoma; there is an associated small intragenic deletion. This structural rearrangement, which confers susceptibility to tumour formation, provides strong evidence that the 4.7R cDNA represents the Rb gene.

Adolescent↗
PubMed1988

Invasive activity and chemotactic response to growth factors by Kaposi's sarcoma cells.

Kaposi's sarcoma (KS) is a relatively low grade neoplasm, classically occurring in the skin of elderly men. A more virulent and invasive form of Kaposi's sarcoma has been described in patients with acquired immune deficiency syndrome (AIDS). The origin and identification of the tumor cells in these lesions is controversial. Here we have studied the behavior of cells derived from KS lesions in an in vitro assay which measures the ability of cells to invade through a reconstituted basement membrane. In agreement with previous work, KS cells obtained under selective culture conditions were invasive showing activity comparable to that of malignant tumor cells. Normal fibroblasts, smooth muscle cells, and endothelial cells did not demonstrate invasive behavior under the same experimental conditions. To characterize further the nature of the KS cells we tested the chemotactic response of cells from the most invasive line to a variety of growth factors and compared their response to those of fibroblasts, smooth muscle, and endothelial cells. These studies suggest that normal cells respond to a unique repertoire of chemotactic factors. The chemotactic response of the KS cells most closely resembled that of smooth muscle cells and was quite distinct from endothelial cells. These results indicate that the KS-derived cultures contain invasive cells with a smooth muscle cell-like phenotype.

Biopsy↗
PubMed1988

Molecular evidence that the esterase-D gene lies proximal to the retinoblastoma susceptibility locus in chromosome region 13q14.

Somatic cell hybrids have been created between transformed mouse 3T3 cells and fibroblasts from a retinoblastoma patient with normal red-cell esterase-D (ESD) levels and a constitutional deletion of chromosome region 13q14-q31. In one subclone, which has retained the deletion chromosome but not the homologous normal copy, we have demonstrated the presence of the human ESD gene sequence. The breakpoint in this patient therefore must have occurred between the ESD gene and the retinoblastoma (Rb) predisposition locus. We have also been able to demonstrate that the ESD gene lies proximally to be the Rb gene in region 13q14. The recently isolated 4.7R cDNA gene sequence was absent from the deletion-containing hybrid, a finding consistent with the hypothesis that this sequence represents the Rb gene itself.

Animals↗
PubMed1988

Management of infections in the neutropenic child with cancer.

The last two decades have witnessed significant improvements in the management of infectious complications in the neutropenic child with cancer. Protected environments and the use of white blood cell transfusions have been found to have a limited clinical role. The development of new classes of pencillins, the monobactam aztreonam, and the third generation cephalosporins have expanded the therapeutic armamentarium available for treating gram-negative infections including Pseudomonas aeruginosa. The re-emergence of gram-positive organisms as common pathogens in these patients has prompted the reintroduction of vancomycin into general clinical use. Increased incidence of gram-positive infections also led to the development of agents containing the beta-lactamase inhibitor clavulanic acid. Attempts at prevention of bacterial infections in the neutropenic patient have been partially successful. Recent studies in adults suggest that the quinolone group of antibiotics may be the ideal agents for this purpose. Finally, the availability of recombinant human hematopoietic colony-stimulating factors may represent a significant advance in efforts to prevent infections. Early studies in animals and in humans suggest that these cell growth factors are effective in correcting neutropenia.

Agranulocytosis↗
PubMed1987

PDGF induces c-myc mRNA expression in MG-63 human osteosarcoma cells but does not stimulate cell replication.

The platelet-derived growth factor (PDGF) modulated growth response of the MG-63 human osteosarcoma cell line, which neither expresses c-sis mRNA nor secretes a PDGF analogue, was characterized. Scatchard analysis demonstrated that the MG-63 cells have 23,000 receptors per cell with a Kd of 5 X 10(-11) M. The receptor became phosphorylated, in a PDGF concentration-dependent manner, when 32P-orthophosphate-labeled cells were treated with PDGF for 3 h at 4 degrees C. The phosphorylated receptor was identified by autoradiography and gel electrophoresis after isolation of the 32P-labeled receptor using a solid-phase monoclonal antibody directed against phosphotyrosine. Binding of the receptor to the antibody was inhibited by 5 mM phenyl phosphate, further suggesting that PDGF stimulated tyrosine-specific receptor autophosphorylation. In addition, treatment of MG-63 cells with PDGF for 3 h at 37 degrees C induced a 7.5-fold increase in c-myc mRNA accumulation as analyzed on Northern gels. However, MG-63 cells grew equally well in either serum-(which contains PDGF) or plasma-(which does not) supplemented medium. Furthermore, PDGF did not stimulate DNA synthesis in growth arrested MG-63 cells, nor did it potentiate DNA synthesis modulated by somatomedin C. Thus MG-63 cells are a naturally occurring cell variant in which PDGF stimulates c-myc expression but does not modulate mitogenesis.

Animals↗
PubMed1987

IV melphalan in children.

Forty children with multiply relapsed cancers received iv melphalan at three doses: 30 mg/m2, 45 mg/m2, and 60 mg/m2. The hematologic toxicity was severe and protracted at all dose levels, whether or not the bone marrow was involved with tumor. Of 39 evaluable patients, 37 had grade 3 or 4 hematologic toxicity. Nonhematologic toxic effects were infrequent and not severe. Two complete responses (Hodgkin's disease, rhabdomyosarcoma), eight partial responses, and 30 failures were seen. There appeared to be a very narrow margin between efficacy and toxicity. Further study of melphalan in pediatric tumors may be warranted in special circumstances: in higher doses (greater than 100 mg/m2) as cytoreduction therapy for specific cancers with marrow rescue, or as part of combination therapy in certain cancers (eg, lymphoma, sarcoma), possibly at doses of 20 to 30 mg/m2 every 4 weeks.

Child↗
PubMed1986

Varicella-zoster-specific immune responses in acute herpes zoster during a placebo-controlled trial of oral acyclovir therapy.

During a placebo-controlled trial of oral acyclovir therapy for acute zoster in immunocompetent patients, we examined the blastogenic response of peripheral blood mononuclear cells and antibody titers in both placebo and acyclovir recipients to determine whether the drug affected the cell-mediated or humoral immune responses. Proliferative responses to mitogens and two dilutions of varicella-zoster virus antigen were not inhibited when fresh peripheral blood mononuclear cells were simultaneously tested in autologous sera collected before and on day 7 of a 10-day course of 2 g/day of oral acyclovir (plasma drug levels averaged 4.6 microM). Using cryopreserved cells from study days 0, 3, 7, 14, and 30, thawed and tested simultaneously, there was no significant difference at the p less than or equal to 0.05 level between the net proliferative responses at each time point for the two groups. On day 14, however, the proliferative response of the acyclovir group was approximately 50% lower than that of the placebo group. Geometric mean antibody titer rises to varicella-zoster virus were also lower among drug recipients but not significantly so. Although this dose of acyclovir did not have a statistically significant effect on lymphocyte proliferative responses to varicella-zoster virus antigen or antibody titers, the lower values in drug recipients may be a reflection of the ability of acyclovir to terminate viral replication, thus reducing the patient's antigenic burden.

Acyclovir↗
PubMed1986

Clinical, haematological, and radiological features in T-cell lymphoblastic malignancy in childhood.

T-cell lymphoblastic malignancy in childhood includes both T-cell acute lymphoblastic leukemia (T-ALL) and non-Hodgkin's lymphoblastic lymphoma (T-NHL). There is considerable overlap between these disorders, which probably represent two ends of the same disease spectrum. To determine whether there are radiological differences between T-ALL and T-NHL we reviewed the clinical, haematological and radiological features of 58 children seen in one centre over a 9-year period. Splenomegaly and adenopathy were significantly more common in T-ALL than in T-NHL. Patients with T-ALL were usually anaemic and thrombocytopenic, with elevated white blood cell counts; patients with T-NHL had normal blood counts. The radiological abnormalities seen were mediastinal enlargement, pleural effusions, and tracheal compression. All patients with T-NHL had abnormal chest radiographs, whereas 10 of 39 patients with T-ALL had normal chest radiographs. When only abnormal radiographs were compared, however, there were no differences in the degree of mediastinal widening or in the size of pleural effusions. Tracheal compression was more common in T-NHL and was always most marked in the intrathoracic airway and in an antero-posterior direction. We conclude that there is little difference in the radiological abnormalities seen in T-ALL and T-NHL, which further supports the theory that they represent points along a common spectrum of disease. As airway compression is primarily intrathoracic and in an antero-posterior direction, adequate radiological evaluation should include a lateral chest radiograph.

Adolescent↗