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Biomedical subjects

R Hong

Publications and source records attributed to R Hong.

At least 37 records · Page 2Linked to original sources
PubMed1998

The DiGeorge anomaly (CATCH 22, DiGeorge/velocardiofacial syndrome).

The DiGeorge anomaly (DGA), originally considered a clinical paradigm for isolated thymus deficiency, has now been redefined as a member of a group of disorders that share in common a chromosome deletion, which results in monosomy 22q11 (CATCH-22 or DiGeorge/velocardiofacial [VCFS] syndrome). In addition to the thymus defect, conotruncal heart anomalies, dysmorphism, hypoparathyroidism, and cleft palate are prominent features. Despite the emphasis on thymus involvement in DGA, a clinically significant thymus defect is found only in a small percentage of these patients. The basic embryological fault in these disorders is an inadequate development of the facial neural crest tissues, resulting in defective organogenesis of pharyngeal pouch derivatives. Although first described by an endocrinologist, this experiment of nature has become a major subject of investigation for geneticists and immunologists. Elucidation of the etiology and attempts to effectively treat the diverse clinical problems continue to challenge and stimulate many disciplines of medicine both in the laboratory and at the bedside.

Chromosome Deletion↗
PubMed1997

Three functional luciferase domains in a single polypeptide chain.

We report a unique case of a gene containing three homologous and contiguous repeat sequences, each of which, after excision, cloning, and expression in Escherichia coli, is shown to code for a peptide catalyzing the same reaction as the native protein, Gonyaulax polyedra luciferase (Mr = 137). This enzyme, which catalyzes the light-emitting oxidation of a linear tetrapyrrole (dinoflagellate luciferin), exhibits no sequence similarities to other luciferases in databases. Sequence analysis also reveals an unusual evolutionary feature of this gene: synonymous substitutions are strongly constrained in the central regions of each of the repeated coding sequences.

Amino Acid Sequence↗
PubMed1997

An adenosine deaminase (ADA) allele contains two newly identified deleterious mutations (Y97C and L106V) that interact to abolish enzyme activity.

Genetic deficiency of the purine salvage enzyme adenosine deaminase (ADA) results in varying degrees of immunodeficiency, ranging from neonatal onset Severe Combined Immunodeficiency (SCID) to an adult onset immunodeficiency disorder. Multiple different mutations have now been identified in these immunodeficient patients. Additional mutations, initially identified in healthy individuals, abolish ADA in erythrocytes but retain 10-80% of activity in non-erythroid cells ('partial deficiency mutations'). In general, severity of disease correlates inversely with the amount of residual ADA expressed by the mutant enzymes and directly with the accumulation of the toxic metabolites deoxyATP and deoxyadenosine. We report two newly identified mutations (Y97C and L106V), both carried on the same allele of an immunodeficient patient who was diagnosed prenatally and successfully transplanted with haploidentical bone marrow. Based on the ability of mutant cDNAs to express ADA in vitro , the L106V mutation resulted in activity similar to 'partial' mutations (30% of normal) while the Y97C mutation resulted in detectable but markedly reduced activity (1.5% of normal). However, the presence of both mutations on the same allele virtually abolished detectable enzyme activity. Analysis of the crystallographic structure of ADA to understand the marked deleterious effect of the Y97C mutation suggested a previously unappreciated role of salt bridges in the catalytic mechanism of ADA. The patient was also heteroallelic for a previously described deletion of the promoter and exon 1. Testing of additional patients in whom we had not identified a mutation on the second allele revealed presence of this deletion in three of four patients tested. This deletion is therefore relatively common, accounting for 10% of almost 100 chromosomes studied by this and other laboratories, but is easily missed by currently used methods of mutation detection. Lastly, the finding of two mutations on the same allele that interact to reduce residual enzyme function emphasizes hazards in evaluating potential genotype-phenotype correlations in individuals analyzed only for the presence of single specific mutations.

Adenosine Deaminase↗
PubMed1997

[The change of trace elements content in hair during the period of gestation].

Study on trace elements content change in hair during the period of gestation for 52 lying-in women was performed. The quantitative results for 7 elements have been obtained and the change tendencies for other 7 elements without standard value have been observed on the basis of a self comparison method for each individual.

Female↗
PubMed1997

Retrospective study of empyema cases in National Pediatric Hospital, Cambodia.

Majority of empyema cases admitted into the National Pediatric Hospital (NPH), Cambodia were of bacterial origin (EB: 95%), the rest were caused by tuberculosis bacilli (ETB: 5%). The morbidity of overall empyema, empyema of bacterial origin and empyema of TB origin between boys and girls was the same, even though boys were more likely to be exposed than girls. The mean age of patients with ETB was significantly greater than those of EB, 84.7 +/- 46 months versus 52.5 +/- 37 months. Since NPH is located in Phnom Penh, most of our cases were from Kandal, Phnom Penh, and provinces nearby. On average all of the patients stayed in the hospital for 23.26 +/- 14.9 days (rank 1-91 days), and the mean duration of hospitalization of the ETB patients was significantly longer than that of EB patients, 32 +/- 19 days versus 22 +/- 14 days respectirely. The yearly incidence of empyema cases in 1990-1993 had the trend of slightly increased frequency during March to May. The overall EB case fatality rate was 3%, contributed to by delayed referral of cases.

Adolescent↗
PubMed1996

Organ culture for thymus transplantation.

A method is presented for organ culture of postnatal thymus. Such tissue has been used for transplantation for nearly 20 years, but lasting benefit has been observed only in patients with the DiGeorge anomaly. Transplantation in other diseases has produced little or no results. Recently, improved methods for preparing the tissue as well as modifications of the culture media show marked improvement in quality and quantity of tissue suitable for transplant. In addition, using recently available monoclonal antibodies, preservation of vital stromal components can be monitored. The availability of reasonable amounts of high quality thymus tissue for transplantation may stimulate interest in further clinical trials where thymus transplantation may augment or restore T cell immunity.

DiGeorge Syndrome↗
PubMed1996

B-cell proliferation and differentiation in common variable immunodeficiency patients produced by an antisense oligomer to the rev gene of HIV-1.

The immunostimulatory activity of a phosphorothioate oligodeoxynucleotide (27 mer) that is antisense to the rev gene of HIV-1 was studied on normal human lymphocytes and on cells from patients with common variable immunodeficiency (CVI). For peripheral blood mononuclear cells from nine normal individuals, the proliferation index (16.8 +/- 12.5) after anti-rev oligomer exposure was proportional to the percentage of peripheral B-cells (r = 0.76, P = 0.02). In five experiments, enriched B- or T-cell populations had proliferation indices of 47.2 +/- 32.9 and 2.4 +/- 1.9, respectively. The addition of T-cells to anti-rev oligomer treated B-cells had no effect (proliferation index = 47.5 +/- 38.1). After anti-rev oligomer stimulation, autoradiography, and counterstaining for B- and T-cell markers, all detectable [3H]thymidine uptake was by CD19-positive cells. Eight of the 14 CVI patients had a proliferation index and secreted levels of IgM and IgG comparable to cells from normal individuals. In contrast to normal cells, the direct correlation between proliferation of peripheral blood mononuclear cells and the percentage of peripheral B-cells was weak in samples from 13 CVI patients (r = 0.4, P = 0.2). These findings indicate that peripheral blood B-cells from about half of CVI patients proliferate and produce immunoglobulin after exposure to anti-rev oligomer. These data demonstrate that under the appropriate circumstances, B-cells of some CVI patients can proliferate and differentiate normally.

B-Lymphocytes↗
PubMed1996

Amplification of antibody production by phosphorothioate oligodeoxynucleotides.

A phosphorothioate oligodeoxynucleotide that is complementary (antisense) to the initiation region of the rev gene of HIV-1 causes hypergammaglobulinemia and splenomegaly in mice, and it induces B cell proliferation and differentiation in mouse spleen mononuclear cells (SMNCs) and human peripheral blood mononuclear cells in vitro. The current studies were performed to investigate the specificity of these immunomodulatory effects. Both the sense and antisense rev oligomers stimulated tritiated thymidine incorporation and secretion of immunoglobulin M (IgM) and immunoglobulin G (IgG) by mouse SMNCs in a concentration-dependent fashion, but the antisense oligomer produced greater immune effects. Studies comparing phosphorothioate oligomers (anti-rev, c-myc, and c-myb) either methylated or unmethylated at CpG dinucleotides showed that methylation effectively abrogated the proliferative effect and tended to reduce the immunoglobulin secretory activity, but the latter was not statistically significant except in the case of IgG in anti-rev oligomer-treated cultures. Mice were injected with the sense or antisense rev oligomers singly or in combination. The animals then were immunized with tetanus toxoid and received a booster 21 days later. Oligodeoxynucleotide-treated mice had significantly higher levels of IgM antibodies on days 28 and 35 and of IgG antibodies on days 14 and 35 as compared with mice that were immunized but received vehicle alone. There was no evidence for additive, synergistic, or antagonistic interactions of the sense and antisense rev oligomers. These results indicate that the unmethylated anti-rev oligomer is the most potent of the phosphorothioate oligomers tested at activating lymphocyte proliferation and differentiation and that a single intravenous injection of this oligodeoxynucleotide augments antibody production to a specific antigen as long as 35 days later.

Animals↗
PubMed1994

Severe combined immunodeficiency, interleukin-2 (IL-2), and the IL-2 receptor: experiments of nature continue to point the way.

The recent discovery of molecular defects in three forms of X-linked immunodeficiency has quickly transformed the study of immunodeficiency into one of the most exciting in basic and clinical immunology. The identification of defects in the IL-2R gamma chain in the etiology of X-linked SCID has suggested a heretofore unanticipated functional role of the gamma chain in immunologic development. While new and novel cytokines and cytokine receptors continue to be identified, it has become clear that our knowledge of IL-2, one of the best understood cytokine/receptor systems, is far from complete. Clarifying the molecular interactions between IL-2 and its receptor complex will improve the sophistication with which these interactions are manipulated in the clinic for the treatment of autoimmune disorders and allograft rejection, treatment of lymphoid malignancies, and cytokine-based therapies for immunotherapeutic treatment of nonlymphoid cancers. Recent gene therapy approaches to the treatment of children with the ADA-deficient form of SCID offers yet another exciting path for investigation. The use of retrovirally infected cord blood hematopoietic progenitor cells in attempts to reconstitute the immune system of ADA-deficient SCID children with ADA-producing cells raises the possibility of similarly "correcting" the defect in X-linked SCID. Such approaches almost certainly loom on the near horizon for other diseases. However, in view of the complexity and potentially pleiomorphic nature of defects in the IL-2R gamma chain, both in terms of their identification and correction, gene therapy for treatment of X-linked SCID will require a thorough understanding of the molecular nature of the respective defects. Effective therapy will require precise knowledge of the defects, in terms of their influence on the ligand, receptor, and signaling apparatus, as well as their potential effects on cells of multiple lineages. However, these caveats aside, the potential for understanding and correcting a disease that robs infants at so early an age of the potential for a normal life will continue to make these exciting and extraordinarily rewarding pursuits.

Humans↗
PubMed1994

Treatment of neuroblastoma patients with antiganglioside GD2 antibody plus interleukin-2 induces antibody-dependent cellular cytotoxicity against neuroblastoma detected in vitro.

Therapy of neuroblastoma patients with interleukin (IL)-2 activates effector cells capable of lysing tumor cells in vitro. When tumor cells are pretreated with certain monoclonal antibodies (MoAb), these in vivo activated effectors show augmented tumor lysis via antibody-dependent cellular cytotoxicity (ADCC). This study presents immunological analyses of serial blood samples from two refractory neuroblastoma patients who received combined in vivo therapy with murine anti-ganglioside GD2 monoclonal antibody 14.G2a and IL-2. These studies were designed to determine whether conditions that induce ADCC in vitro can be generated in vivo by combined therapy with IL-2 and MoAb. As shown previously, administration of IL-2 dramatically augments the ability of peripheral blood mononuclear cells (PBMC) to mediate ADCC. In addition, we demonstrate here that sera, obtained 1 h after infusion of 14.G2a, provides an effective source of functional antibody for ADCC mediated by PBMC from healthy donors. Finally, effective ADCC-mediated killing of neuroblastoma target cells was also achieved in vitro following IL-2 plus 14.G2a treatment when patients' effector cells were combined with patients' serum, as the source of 14.G2a antibody. These results indicate that this combination of IL-2 and 14.G2a generates conditions within the peripheral blood of pediatric neuroblastoma patients that enable their own lymphocytes to mediate antibody-dependent cellular cytotoxicity sufficient to effectively kill neuroblastoma cells in vitro.

Antibodies, Monoclonal↗
PubMed1993

Simultaneous demonstration of the Philadelphia chromosome in T, B, and myeloid cells.

A patient presented with lymphoblastic lymphoma in lymph-nodes and chronic myelogenous leukemia (CML) in narrow and peripheral blood. All marrow and unstimulated peripheral blood cells contained the Philadelphia chromosome[t(9:22)]. Lymphoma cells were analyzed by flow cytometry and were identified as T cells (CD2+CD5+CD7+CD34+). All fresh lymphoma cells contained the t(9:22) translocation. Cultures of purified peripheral blood T and B cells and specifically stimulated NK cells revealed that 59% of the B cells, 10% of the NK cells, and none of the normal T cells contained the translocation. The lack of translocation in normal peripheral T cells is attributed to their long lifespan. No rearrangement of immunoglobulin or T cell receptor beta or gamma genes was found in either the leukemia or lymphoma cells. Analysis of the DNA from cryopreserved lymphoma biopsy showed clonal rearrangement within the common breakpoint cluster region of the bcr gene identical to the bcr rearrangement in DNA from leukemia blood cells. The data support the concept that T and B cells originate in the patient's totipotent stem cell from which the CML is also derived.

Antigens, CD↗
PubMed1993

Bone marrow transplantation.

BMT has been successfully utilized in clinical medicine for nearly 25 years. Successful accomplishment of BMT has severely taxed the research and clinical capabilities of medical scientists, but the attainment of a cure for fatal disease has amply justified the efforts expended. The major problems still to be solved include better conditioning regimens, better control of GVHD, and enlargement of donor pools. The control of problems created by this therapy demands a thorough understanding of the immune system. As this knowledge increases, useful manipulation of immunity to control the hundreds of other diseases caused by aberrant immune processes should become possible. Soon, genetically engineered marrow transplants should be possible.

Acute Disease↗
PubMed1992

Antilymphoma activity of human gamma delta T-cells in mice with severe combined immune deficiency.

Human Burkitt lymphoma (Daudi) cells grow as disseminated tumors in mice with severe combined immune deficiency (SCID) after either i.v. or i.p. injection. These cells are lysed in vitro by human V gamma 9/V delta 2 T-cells that recognize the groEL homologue on the Daudi cell surface. We report that both Daudi cell-stimulated peripheral blood mononuclear cells (Daudi-PBMC) containing 41-95% of V gamma 9/V delta 2 T-cells and V gamma 9/V delta 2 T-cell clones prolong the survival of SCID mice given inoculations of a lethal dose of Daudi cells. Groups of 6-8-week-old SCID mice were given inoculations i.v. or i.p. of 10(5) Daudi cells followed (through different injection sites) by: (a) 10(7) Daudi-PBMC; or (b) 10(7) unstimulated PBMC; or (c) 0.9% saline solution. All animals in groups (b) and (c) died of disseminated lymphoma, and their survival was significantly shorter than that of mice in group (a) (P < 0.001 for both i.v. and i.p. routes). Significant antitumor effects were also detected when Daudi-PBMC were injected 4 days before or 4 days after Daudi cells (P < 0.05). In vivo depletion of murine natural killer cells by anti-asialo GM-1 rabbit antiserum did not affect survival, suggesting that these cells did not contribute to lymphoma killing. Daudi-PBMC did not exert in vivo antitumor activity against the control Raji lymphoma. Mice receiving i.p. injections of Daudi cells followed by cytotoxic V gamma 9/V delta 2 T-cell clones also survived significantly longer (P < 0.05 for 3 different clones) than animals given Daudi cells alone or Daudi cells followed by noncytotoxic gamma delta T-cell clones. Our results indicate that this model system can be used for studies of human antilymphoma T-cell responses in vivo.

Animals↗
PubMed1992

Prognostic significance of programmed ventricular stimulation in patients surviving complicated acute myocardial infarction: a prospective study.

In survivors of complicated myocardial infarction, the inducibility of sustained ventricular tachycardia may help identify a subset that is at increased risk for subsequent sudden cardiac death or spontaneous sustained ventricular tachycardia. We performed prehospital discharge programmed ventricular stimulation in 86 survivors of acute myocardial infarction complicated by heart failure, angina pectoris, or nonsustained ventricular tachycardia. These patients also underwent cardiac catheterization with coronary angiography and 24-hour ambulatory ECG recording. Programmed ventricular stimulation induced sustained ventricular tachycardia in 19 patients (22%) and ventricular fibrillation in six (7%) and did not induce these arrhythmias in 61 patients (71%). During an average follow-up of 18 +/- 13 months, 11 patients had arrhythmic events (seven sudden death and four nonfatal spontaneous sustained ventricular tachycardia) and 10 patients had nonsudden cardiac death. The total cardiac mortality rate was 20%. Arrhythmic events occurred in 32% of the 19 patients with inducible sustained ventricular tachycardia compared with 7% of the remaining 67 patients (p less than 0.003). By multivariate analysis the occurrence of arrhythmic events was independently predicted by both inducible sustained ventricular tachycardia and Killip class III or IV heart failure. The risk of arrhythmic events was 4.4% in the absence of both variables versus 38.4% (p less than 0.001) when both variables were present. The total cardiac mortality rate was best predicted by low left ventricular ejection fraction (less than 30%). Thus programmed ventricular stimulation is useful in risk stratification of survivors of complicated acute myocardial infarction. The prognostic utility appears to be particularly high in patients with infarction complicated by Killip class III or IV heart failure.

Arrhythmias, Cardiac↗