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Biomedical subjects

L Kunkel

Publications and source records attributed to L Kunkel.

34 records · Page 2Linked to original sources
PubMed1997

Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal haemoglobinuria.

Seven patients with paroxysmal nocturnal haemoglobinuria (PNH) were treated with antithymocyte globulin (ATG). Each patient received ATG (20 mg/kg/d) for 8 d and prednisone to prevent or control serum sickness. Three patients experienced a sustained improvement in at least one peripheral blood cytopenia, including one patient who had a complete trilineage response. Several pretreatment clinical features appeared to be associated with response to ATG. All responding patients had hypoproliferative features including depressed platelet counts (< 30 x 10(9)/l), and a minor degree of chronic haemolysis as indicated by relatively low reticulocyte counts (< 100 x 10(9)/l), lactate dehydrogenase (< 1000 U/l) and total bilirubin (< 17 mumol/l) levels. Responding patients continued to have chronic low-grade haemolysis after their response to immunosuppression that was similar to that observed prior to treatment. The non-responding patients had a classic haemolytic form of PNH characterized by elevated reticulocyte counts (> 100 x 10(9)/l), lactate dehydrogenase (> 2000 U/l) and total bilirubin (> 17 mumol/l) levels. The impaired haemopoiesis that occurs in hypoproliferative PNH may respond to ATG treatment, but the haemolytic component of the disease, and hence the PNH clone, is not altered by immunosuppressive therapy.

Adult↗
PubMed1997

Whole-body FDG-PET imaging for staging of Hodgkin's disease and lymphoma.

UNLABELLED: Accurate staging of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) is important for treatment management. In this study, the utility of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) whole-body PET was evaluated as an imaging modality for initial staging or restaging of 7 HD and 11 NHL patients. METHODS: Whole-body PET-based staging results were compared to the patient's clinical stage based on conventional staging studies, which included combinations of CT of the chest, abdomen and pelvis, MRI scans, gallium scans, lymphangiograms, staging laparatomies and bone scans. RESULTS: Accurate staging was performed in 17 of 18 patients using a whole-body PET-based staging algorithm compared to the conventional staging algorithm in 15 of 18 patients. In 5 of 18 patients, whole-body PET-based staging showed additional lesions not detected by conventional staging modalities, whereas conventional staging demonstrated additional lesions in 4 of 18 patients not detected by whole-body PET. The total cost of conventional staging was $66,292 for 16 CT chest scans, 16 CT abdominal/pelvis scans, three limited MRI scans, four bone scans, five gallium scans, two laparotomies and one lymphangiogram. In contrast, scans cost $36,250 for 18 whole-body PET studies and additional selected correlative studies: one plain film radiograph, one limited CT, one bone marrow scan, one upper GI and one endoscopy. CONCLUSION: A whole-body FDG-PET-based staging algorithm may be an accurate and cost-effective method for staging or restaging HD and NHL.

Adolescent↗
PubMed1996

Expression and cytokine regulation of glucocorticoid receptors in Kaposi's sarcoma.

Development of Kaposi's sarcoma (KS) after glucocorticoid therapy has been observed in a variety of clinical states including human immunodeficiency virus-1 infection and recent in vitro studies provided evidence for a direct stimulation effect of glucocorticoid hormones on KS cell proliferation. The importance of glucocorticoids in KS pathogenesis is further highlighted by the finding that glucocorticoids synergize with cytokines to promote acquired immune deficiency syndrome (AIDS)-associated KS (AIDS-KS) growth. Furthermore, cytokine effects were abrogated by the glucocorticoid antagonist RU-486. As glucocorticoid action is mediated through activation of their intracellular cognate receptors, we hypothesized that enhanced responsiveness of AIDS-KS cells to glucocorticoids may be due to elevated glucocorticoid receptor (GR) content. Indeed, high expression of GRs in AIDS-KS tumor biopsies was detected both at the level of mRNA and protein. Quantitative measurements of GRs in these specimens by a sensitive immunoassay showed that GR content was significantly elevated in the tumor tissue (4663 fmol/mg protein) compared with the uninvolved skin of the same patients (2777 fmol/mg protein), both of which were markedly above the normal skin of healthy donors (893 fmol/mg protein). Immunocytochemical analysis confirmed the presence of GRs in the cytoplasm and the nucleus of KS cells. Interestingly, four major KS cytokines, namely interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and oncostatin M, all of which are known autocrine growth factors for AIDS-KS cells, significantly increased the expression of functional GRs in cultured AIDS-KS cells. The latter result may explain, at least in part, the synergistic effect of glucocorticoid and oncostatin M on AIDS-KS cell proliferation. Thus, the high levels of GR expression in AIDS-KS and the up-regulation of GRs by KS-growth-promoting factors may confer enhanced and sustained sensitivity to the stimulatory effects of glucocorticoids. The data presented also provide molecular bases for therapeutic interventions targeting GRs in this disease.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Allogeneic bone marrow transplantation for Hodgkin's and non-Hodgkin's lymphoma.

We studied 23 consecutive patients, median age 34 years, with relapsed or resistant aggressive lymphoma who underwent allogeneic BMT at the UCLA Medical Center Bone Marrow Transplantation Unit from 1 November 1984 to 30 March 1993. All patients were < 50 years of age and had sibling donors who were matched at the HLA-A, B and DR loci. Nine patients had Hodgkin's disease (HD) and 14 had non-Hodgkin's lymphoma (NHL); three of these had low grade histology and 11 had intermediate or high grade lymphoma histology. After a median follow-up of 34 months, eight patients are alive, seven without recurrent lymphoma. Five patients had early deaths. The disease-free survival for the entire group is 26% with an overall survival of 29%. There was no difference in survival rate on the basis of disease or histology. Comparing preparative regimens containing TBI to those without there was no difference in survival rate (P = 0.35). Neither age nor sex was a significant determinant of outcome (P = 0.63 and 0.36, respectively). Disease status at the time of transplantation proved to be the important determinant of outcome. Patients transplanted with chemotherapy sensitive disease (n = 9), defined as a partial or complete response to salvage chemotherapy, had a survival rate of 42%, which was significantly better than those who had refractory disease at transplantation (n = 14), who had a survival rate of 21% (P = 0.006). However, this small, but significant fraction of patients with refractory disease was curable. Thus, our data demonstrate that allogeneic bone marrow transplantation is an effective means of treatment for relapsed or aggressive Hodgkin's and non-Hodgkin's lymphoma.

Adolescent↗
PubMed1990

Immune hemolytic anemia associated with biclonal cold autoagglutinins.

A 65-year-old man with bladder outlet obstruction due to prostatic hypertrophy was incidentally discovered to have cold-antibody autoimmune hemolytic anemia (cold-aggluthinin syndrome; CAS) due to autoanti-I (titer 1,024 at 4 degrees C and 64 at 30 degrees C), and a biclonal gammopathy. Immunofixation electrophoresis of serum and a red blood cell eluate revealed the patient's autoantibody to be biclonal IgM kappa and IgA kappa. No underlying cause could be determined to explain the development of either the biclonal gammopathy or the CAS. To our knowledge, this is the first reported case of CAS associated with a biclonal gammopathy and biclonal cold autoagglutinins of the IgM kappa, IgA kappa type.

Aged↗
PubMed1987

Molecular heterogeneity of translocations associated with muscular dystrophy.

Individual translocation chromosomes from six girls suffering from Duchenne or Becker muscular dystrophy (DMD or BMD) have been isolated in human-mouse somatic cell hybrids. DNA prepared from these hybrids was probed with sequences physically close to the locus; these include a junction fragment from the site of the X:21 translocation (pXJ1) and subclones from the pERT 87 (DXS164) region which are absent in a minority of male DMD patients. Both sets of sequences mapped within the area defined by the translocation breakpoints, confirming their close proximity to the DMD and BMD loci. Furthermore, the X chromosome breakpoints of the translocations can be divided into three categories depending upon their position in relation to the sequences recognised by pXJ1 and pERT 87. The genomic target disrupted by the translocations examined here is a minimum of 176 kb.

Chromosome Mapping↗
PubMed1986

Mapping of the X-linked agammaglobulinemia locus by use of restriction fragment-length polymorphism.

A molecular linkage analysis in 11 families with X-linked agammaglobulinemia (XLA) localized the XLA gene to the proximal part of the long arm of the human X chromosome. Significant linkage was detected between XLA and loci defined by two polymorphic DNA probes called 19-2 for the DXS3 locus and S21 for the DXS17 locus. Both localize to the region Xq21.3-Xq22. Most likely recombination distances (theta) and associated logarithm of the odds (lod) scores for the XLA-DXS3 and XLA-DXS17 pairs were theta = 0.04 morgans (lod, 3.65) and theta = 0 (lod, 2.17), respectively. Tight linkage between XLA and the locus DXS43 defined by the X short arm probe D2 (localized to Xp22-Xp21) was strongly excluded and we obtained no evidence for significant linkage between XLA and any other X short arm probe. The probe pair 19-2 and S21 should be informative for molecular linkage-based analysis of XLA segregation in the majority of families afflicted with this disorder.

Agammaglobulinemia↗
PubMed1985

Genetic linkage relationships of seven DNA probes with Duchenne and Becker muscular dystrophy.

The inheritance of seven restriction fragment length polymorphisms detected by DNA probes has been studied in families with Duchenne and Becker muscular dystrophies (DMD and BMD). The probes used have all been mapped to the short arm of the X-chromosome, four being distal and three proximal to the disease loci located within the Xp21 region. Linkage analysis of the DNA polymorphisms in relation to the two disorders showed similar genetic distances. Data obtained from DMD and BMD families have been combined to give more precise values for the different recombination fractions. Combined use of these polymorphic DNA markers will be of practical value in the genetic counselling of women at risk for Duchenne and Becker muscular dystrophy.

Alleles↗
PubMed1985

Accurate and superaccurate gene mapping.

Highly accurate gene mapping techniques need to be developed to clone disease genes with unknown defective products. The classical pedigree method and methods based on cytologically observable chromosome aberrations share definite limits in resolution. We quantify the limits in resolution for the pedigree method. We also discuss a technique for gene localization that exploits the possible presence of minute depletions overlapping the disease locus. One can search for such submicroscopic deletions by aiming random probes at them. We show quantitatively that relatively few probes may suffice to hit a target deletion. Choosing which probes to aim should be guided by pedigree studies and by close examination of relevant cytologically observable translocations and deletions.

Chromosome Deletion↗
PubMed1985

Staphylococcal Protein A column: correlation of mitogenicity of perfused plasma with clinical response.

Eleven patients with advanced breast cancer and four with astrocytoma were treated with plasma perfused over columns containing staphylococcal Protein A (SPA). Doses of 5 to 20 mg of SPA were bound to collodion charcoal particles, and this treatment resulted in partial remissions in one patient with astrocytoma and in two patients with breast cancer. Remission duration was 6 wk to 6 mo. Resolution of lymphadenopathy and a decrease in carcinoembryonic antigen were noted in an additional two breast cancer patients. Systemic reactions to infused plasma consisted of fever, chills, and rigors. In brain cancer patients, increased intracranial pressure was also noted. A mitogenic substance was generated in plasma of 11 patients after it was perfused over the SPA charcoal matrix. The mitogenic material induced lymphoproliferation comparable to concanavalin A and required the presence of SPA on the collodion charcoal but was not due to leakage of SPA from the column during plasma perfusion. Of considerable significance was that only patients whose column perfused plasma contained this mitogenic activity exhibited systemic reactions, and five of these patients obtained antitumor responses. This striking correlation implies that the mitogenic factor is an active component of SPA therapy. The ability to demonstrate mitogenicity in column perfused plasma might also be useful for selecting patients amenable to SPA therapy. These findings attest to the therapeutic value of this mode of treatment and provide an initial definition of a mediator of SPA antitumor activity.

Adult↗
PubMed1984

A strategy to reveal high-frequency RFLPs along the human X chromosome.

Fifteen human X-chromosome-specific DNA fragments, localized to particular regions of that chromosome, were used to search for restriction fragment length polymorphisms. A screening panel prepared by digesting DNA from only two females and one male with 24 restriction enzymes was sufficient to reveal two-allele polymorphisms among one-third of the probes tested. These polymorphisms, as theoretically anticipated, showed minor allele frequencies above 20%, as a rule. Such high-frequency polymorphism allowed identifying females, from pedigrees segregating three X-linked diseases, who were multiply heterozygous for polymorphic loci spread throughout the X chromosome. In addition, two of the 24 enzymes tested with these X-specific probes, Msp I and Taq I, generate fragment sizes in DNA-blotting experiments that, on average, are significantly larger than expected from nearest neighbor predicted recognition site frequencies.

Alleles↗
PubMed1983

Cytologic and molecular analysis of 46,XXq- cells to identify a DNA segment that might serve as a probe for a putative human X chromosome inactivation center.

Cloned human X chromosome-specific DNA segments, derived from a recombinant phage library enriched for the human X and previously localized to different regions of the X, were used as probes in Southern blots to confirm the nature of a deletion of the long arm of the X chromosome as del(X)(q13) in a patient with some features of Turner's syndrome and suspected from cytologic studies to have a 46,XXq- karyotype. Two dimensional scanning densitometry of autoradiograms of the Southern blots was used to quantitate hybridization of the 32P-labeled probes, reinforcing visual analysis and permitting distinction between sequences present at one or two copies per diploid genome. Once thus characterized, DNA from the patient's cells was used in quantitatively analyzed Southern blots to refine the location of an additional DNA segment, previously mapped to somewhere in the proximal part of the long arm of the X chromosome, to the juxtacentromeric region of Xq, which has been hypothesized to be critical for X-inactivation. Cloned DNA probes such as that localized to the juxtacentromeric region of Xq should be useful for evaluating this hypothesis.

Absorptiometry, Photon↗