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Biomedical subjects

H Messner

Publications and source records attributed to H Messner.

At least 37 records · Page 2Linked to original sources
PubMed1997

A new syndrome of familial aplastic anemia and chronic liver disease.

This report describes a new familial syndrome characterized by a combination of bone marrow failure and chronic liver disease. This disorder appears to be genetic in origin with an autosomal dominant inheritance and was characterized by hyperactivity of the immune system with increased activated cytotoxic T lymphocytes in peripheral blood and bone marrow and the presence of gamma-interferon messenger RNA in bone marrow of several cases.

Adolescent↗
PubMed1996

Preclinical assessment of human hematopoietic progenitor cell transduction in long-term marrow cultures.

Long-term marrow cultures (LTMCs) were established from 27 human marrows. Hematopoietic cells were subjected to multiple rounds of exposure to retroviral vectors during 3 weeks of culture. Seven different retroviral vectors were evaluated. LTMCs were assessed for viability, replication-competent retrovirus, progenitors capable of proliferating in immune-deficient mice, and gene transfer. The average number of adherent cells and committed granulocyte-macrophage progenitors (CFU-GM) recovered from LTMCs was 28% and 11% of the input totals, respectively. There was no evidence by marker rescue assay or polymerase chain reaction (PCR) of replication-competent virus production during LTMC. No toxicity to cellular proliferation due to the transduction procedure was observed. The adherent layers of LTMCs exposed to retroviral vectors were positive for proviral DNA by PCR and by Southern blot analysis. Fifty-three percent of 1,427 individual CFU-GM from transduced LTMC adherent layers were positive for vector-derived DNA. For neocontaining vectors, the average G418 resistance was 28% of 1,393 LTMC-derived CFU-GM. Forty percent of 187 tissues from 30 immune-deficient mice injected with human LTMC cells were positive for human DNA 4-5 weeks after adoptive transfer. These studies indicate that multiple exposures of human LTMCs to retroviral vectors result in consistent and reproducible LTMC viability and gene transfer into committed progenitors. Our results further support the use of transduced LTMC cells in clinical trials of hematopoietic stem cell gene transfer.

Animals↗
PubMed1996

Human hematopoiesis in SCID mice implanted with human adult cancellous bone.

The persistence of hematopoietic cells from human adult cancellous bone fragments implanted subcutaneously into CB-17 scid/scid mice was studied. Recipient mice received either no pretreatment (control group) or pretreatment with 3 Gy total-body irradiation and anti-asialo GM1 sera (ASGM1; pretreated group) before implantation. Pretreated severe combined immunodeficient (SCID) mice implanted with human bone were subsequently given ASGM1 every 7 days for the duration of the experiments. At 12 weeks postimplantation, flow cytometry of cells from pretreated and control animal tissues detected human CD45+ cells in the mouse spleen (mean, 7.8% and 3.4% positive cells, pretreated and control animals, respectively), bone marrow (BM; mean, 16.5% and 4.8% positive cells, respectively), and blood (mean, 5.5% and < 2% positive cells, respectively), and in the implanted human bone (73% and 8.9% positive cells, respectively). At 12 weeks, pretreated mice had human granulocyte-macrophage colony-forming cells (GM-CFC) and burst-forming units-erythrocyte (BFU-E) in the implanted human bone in the murine BM and in some of the spleens. The spleens also had extensive infiltration of human B cells and macrophages. Mean serum levels of human IgG in pretreated animals were 14 micrograms/mL during weeks 6 to 12, compared with trace levels (< 1 microgram/mL) in control mice. Bone from patients with acute myeloblastic leukemia (AML) was also implanted in pretreated SCID mice, and retrieved at 8 weeks for analysis. Comparison of preimplantation and implanted samples showed that the original histology was maintained, and massive infiltration of human CD68+ cells was observed in the mice spleens and BM. Implantation of AML bone in SCID mice facilitates analysis of in situ AML cell interaction with stromal cells in the leukemic state, and therapies against AML can be tested in this system, especially the selective killing of AML cells in the presence of other BM cells. Furthermore, this model requires no exogenous administration of cytokines to maintain human hematopoiesis with both normal or AML bone. Because the structure and function of both normal and diseased human adult bone is maintained, this animal model should facilitate investigation of both normal human hematopoiesis and hematopoietic malignancies.

Acute Disease↗
PubMed1996

Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis.

Progress in understanding the abnormal regulation of hematopoiesis in chronic myelogenous leukemia (CML) would be facilitated if neoplastic cells, at all stages of the disease, could be studied in an animal model. In this report, we show that irradiated severe combined immunodeficient (SCID) mice can be transplanted with both normal (Philadelphia chromosome [Ph]-negative) and neoplastic (Ph+) cells from CML patients with either chronic or blast phase disease. Mice transplanted with peripheral blood (PB) or bone marrow (BM) cells from 9 of 12 chronic phase CML patients were well engrafted with human cells including multilineage colony-forming progenitors and CD34+ cells for at least 90 days posttransplantation. Repeated posttransplant injections of cytokines did not enhance the number of engrafted human cells. Interestingly, approximately 70% of the human progenitors found in the engrafted SCID BM were Ph-, suggesting that the growth of primitive normal cells is favored in this in vivo transplant model. A similar number of normal cells were found in mice transplanted with either PB or BM cells, suggesting that elevated numbers of primitive normal cells are present in CML PB. When cells from patients with CML in either myeloid or lymphoid blast crisis were transplanted into SCID mice, the BM of these mice was more rapidly repopulated and to a higher level than that observed with transplants of chronic phase cells. Moreover, all human colony-forming progenitors present in the BM of mice transplanted with blast crisis cells were Ph+, and the majority of cells showed the same morphological features of the blast crisis cells originally transplanted. These experiments provide a starting point for the creation of an animal model of CML and establish the feasibility of using this model for the future characterization of transplantable CML stem cells during disease progression.

Animals↗
PubMed1996

Detection of donor cell derived acute myelogenous leukaemia in a patient transplanted for chronic myelogenous leukaemia using fluorescence in situ hybridization.

The recurrence of leukaemia following allogeneic bone marrow transplantation appears to develop rarely in donor cells. However, the standard method for assigning the origin of recurrence, metaphase analysis, can be unreliable. We have applied the technique of fluorescence in situ hybridization (FISH) directly on archival Wright stained bone marrow slides obtained from a patient who developed acute myelogenous leukaemia (AML) following allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia (CML). Using a chromosome-specific DNA probe we linked a chromosomal aberration, previously detected by conventional metaphase analysis, directly to morphologically identifiable blast cells. In this way we were able to assess cell-lineage involvement of the secondary leukaemia and assign a donor origin.

Adult↗
PubMed1994

Effects of combined antigrowth factor receptor treatment on in vitro growth of multiple myeloma.

BACKGROUND: Although passive serotherapy for cancer with monoclonal antibodies is an attractive concept, it has unfortunately had limited efficacy in clinical trials. An alternative approach to passive serotherapy is targeting cell surface growth factor receptors with monoclonal antibodies. With some limitations, anti-growth factor receptor antibodies can limit cell growth by blocking stimulatory or trophic growth factor receptors and by marshaling in vivo antitumor immune responses. PURPOSE: The purpose of our study was to determine the extent to which anti-interleukin-6 (IL-6) and anti-transferrin (Tf) receptor antibodies, when used individually or combined, could limit myeloma cell growth. METHODS: The four myeloma cell lines studied varied in IL-6 responses from factor independence (myeloma cell lines 8226 and U266) to strict factor dependence (OCI-My4 myeloma cells and human acute myelogenous leukemia [AML] cell line UCSD/AML1). IL-6 RNA was detected using reverse transcriptase-polymerase chain reaction. IL-6 protein was detected in U266 supernatant by growth stimulation of UCSD/AML1 cells and by enzyme-linked immunosorbent assay. For cell growth assays, cell lines were plated with various concentrations of IL-6 and anti-receptor antibodies and [3H]thymidine uptake determined after 3 days. Cells were grown in varying concentrations of IgG1 monoclonal anti-Tf receptor antibodies E2.3 and A27.15 or antibodies PM1, AUK 146-15, AUK 64-7, or AUK 12-20 to the human IL-6 receptor-alpha protein. Tf and IL-6 receptors were detected by immunofluorescence staining. RESULTS: Using short-term proliferation assays, anti-Tf receptors and anti-IL-6 antibodies caused dose-dependent growth inhibition of varying degrees, and, in one of three cell lines, a combination of anti-Tf and anti-IL-6 antibodies showed supra-additive growth inhibition. IL-6-independent cells were inhibited by anti-Tf receptor antibodies, while IL-6-dependent cells were resistant to these antibodies but sensitive to anti-IL-6 receptor. Factor-dependent myeloma cells exposed to either anti-Tf or anti-IL-6 receptor antibodies for 48 hours lost colony-forming capability. A combination of anti-Tf and anti-IL-6 antibodies increased elimination of colony-forming cells at 24 hours. CONCLUSIONS: Anti-receptor antibodies have distinct patterns of myeloma cell growth inhibition and inhibit in vitro growth of factor-dependent myeloma cells. Combinations of anti-growth factor receptor antibodies also increase toxicity for IL-6-dependent myeloma colony-forming units.

Antibodies, Monoclonal↗
PubMed1994

Secondary malignancies after bone marrow transplantation in adults.

PURPOSE: The records of 557 consecutive adult recipients of allogeneic-related and -unrelated and syngeneic bone marrow transplants (BMTs) were reviewed to determine the incidence of secondary cancers. PATIENTS AND METHODS: Four hundred fifty-six patients were transplanted for acute lymphocytic leukemia (ALL; n = 79), acute myelogenous leukemia (AML; n = 182), and chronic myelogenous leukemia (CML; n = 195); 42 patients were transplanted for aplastic anemia (AA) and 59 for a variety of other hematologic and nonhematologic disorders, malignant and nonmalignant. Conditioning regimens included high-dose chemotherapy with or without total-body irradiation (TBI). Statistical analyses determined the cumulative incidence of developing a secondary cancer and elucidated the associated risk factors. Complete records (1 to 24 years of follow-up) on all patients were available. RESULTS: Nine patients developed 10 secondary cancers for a cumulative actuarial risk of 12% (95% confidence interval [CI], 4.3 to 23.0) 11 years after transplant. The age-adjusted incidence of secondary cancer was 4.2 times higher than that of primary cancer in the general population. Eight of the 10 were epithelial in origin and three were cutaneous. TBI and acute graft-versus-host disease (GVHD) with a severity > or = grade II were associated with the development of any secondary cancer. On the other hand, chronic GVHD was a risk factor only for the development of secondary skin neoplasms. CONCLUSION: Adult recipients of BMT face a significant risk of developing a secondary malignancy. Their risk is similar to that of other patients with hematologic malignancies who are treated with chemoradiotherapy only. Epithelial tumors, rather than the more commonly reported Epstein-Barr virus (EBV)-associated lymphomas, were most common. The fact that we did not routinely use T-cell-depleted marrow grafts nor anti-T-cell immunoglobulin for the treatment of acute GVHD may explain this variance.

Adolescent↗
PubMed1994

Pneumatosis intestinalis with free air mimicking intestinal perforation in a bone marrow transplant patient.

A case of pneumatosis intestinalis with perforation is reported in a patient after bone marrow allograft for chronic myeloid leukemia. Risk factors included the transplant, prolonged immunosuppression and neutropenia, graft-versus-host disease, extended use of corticosteroids, infection and lower gastrointestinal endoscopic biopsy. The literature is reviewed and a management plan for patients presenting with this complication is discussed.

Adult↗
PubMed1993

Undifferentiated (embryonal) sarcoma of the liver in childhood. Successful combined-modality therapy in four patients.

BACKGROUND: Undifferentiated (embryonal) sarcoma of the liver is a rare, highly malignant, mesenchymal tumor presenting predominantly in late childhood. Four girls, ages 6-13 years, who were treated with combined-modality regimens are reported. METHODS: In the first and second patients, hemihepatectomy resulted in complete removal of the tumor, and multiple-agent chemotherapy was administered postoperatively. In the third patient, only partial resection could be accomplished initially. By synchronous radiation therapy and chemotherapy, the tumor decreased to an extent that it could be resected completely and was totally devitalized on histologic examination. Postoperative chemotherapy was discontinued after 8 weeks. In the fourth patient, the tumor was not resectable at diagnostic biopsy. Polychemotherapy led to a significant reduction of the tumor size, and resection with clear margins could be performed subsequently. Because histologic necrosis amounted to about 95%, postoperative chemotherapy was also discontinued after 6 weeks. RESULTS: All four patients remain well without evidence of tumor recurrence after 79, 41, 36, and 22 months from diagnosis. CONCLUSIONS: The authors suggest that a multimodal therapeutic regimen should be used in patients with undifferentiated hepatic sarcoma.

Adolescent↗
PubMed1993

Influence of dietary taurine on vitamin D absorption.

To evaluate the influence of dietary taurine supplementation on vitamin D absorption, we studied three groups of infants: 21 (11 preterm) were fed a taurine-free formula, 21 (10 preterm) were fed a taurine-supplemented formula (50 mg/100 g of powder) and 20 (9 preterm) were fed human, not heat-treated milk. Taurine, total bile acids, glyco-(GBA) and tauro-(TBA) conjugated bile acids, 25-hydroxyvitamin D3 (25OHD3) and 1,25-dihydroxyvitamin D3 (1,25OH2D3) were determined in all infants at birth in blood cord and at one and three months of life. In preterm infants fed a taurine-free formula, we found lower plasma taurine levels than in infants of other groups at one and three months of life. In these infants, GBA predominated, with a G/T ratio of 1.1 and 1.4 at one and three months of life, whereas in all other infants TBA predominated with a G/T ratio always < 1. Also, 25OHD3 and 1,25OH2D3 levels were significantly lower in preterm infants fed a taurine-free formula than in infants fed a taurine-enriched formula or human milk. Term infants fed a taurine-free formula did not show differences in the parameters studied in comparison to infants of other groups. Low taurine dietary intake appears to compromise vitamin D absorption in preterm infants, and therefore taurine supplementation of preterm infant formulas should be encouraged.

Bile Acids and Salts↗
PubMed1993

Cyclosporine as possible prophylaxis for obstructive airways disease after allogeneic bone marrow transplantation.

The objective of this study was to evaluate the impact of cyclosporine (cyclosporin A; CyA) prophylaxis for graft-versus-host disease (GVHD) on the development of obstructive airways disease (OAD) after allogeneic bone marrow transplantation (BMT) in leukemic patients. Patients with normal pulmonary function tests (PFTs) prior to BMT were followed with serial PFTs for the development of OAD. Follow-up PFTs were performed at 3, 6, 9, and 12 months, and thereafter at consecutive yearly intervals. Obstructive airways disease was defined as FEV1 less than 80 percent, ratio of FEV1 over the forced vital capacity (FEV1/FVC) less than 80 percent of predicted, maximal midexpiratory flow rate at 50 percent vital capacity less than 65 percent of predicted, or residual volume greater than 120 percent of predicted. In the period prior to CyA prophylaxis for GVHD development (March 1983 to September 1986), 17 (39 percent) of the 44 patients undergoing BMT developed OAD, compared with 2 (4 percent) of 45 in the post-CyA period (September 1986 to March 1990) (chi 2 = 17; p < 0.00005). Age, sex, type of leukemia, severity of GVHD, histocompatibility status, presence of acute GVHD, and sex mismatch between donor and recipient were not associated with development of OAD. Although chronic GVHD was associated with OAD in univariate analysis, a multivariate logistic regression analysis showed that the only significant independent predictor for OAD was the use of CyA. We conclude that CyA is protective against the development of OAD after BMT in leukemic patients.

Adolescent↗
PubMed1992

Long-term sequelae after recovery from cytomegalovirus pneumonia in allogeneic bone marrow transplant recipients.

The clinical course of cytomegalovirus (CMV) pneumonia in seven consecutive bone marrow transplant (BMT) recipients during a 24-month period was studied. Retrospective analysis of clinical data on the recipients with CMV pneumonia during the illness and prospective follow-up of those who recovered from the pneumonia was performed. Those who had CMV as the sole pathogen and with lymphocytosis in the BAL or the peripheral blood during the illness recovered from the pneumonia. On the contrary, those who had mixed bacterial or fungal infection with peripheral lymphopenia died. Persistent lymphocytosis in the BAL and the peripheral blood, in the absence of CMV infection, was observed in the survivors. Two subsequently developed restrictive lung disease and two had relapse of their primary malignancy. These data suggest that CMV pneumonia in BMT patients is associated with significant long-term sequelae. The phenomenon of persistent lymphocytosis in the BAL and the peripheral blood, in the absence of CMV infection, supports Grundy's hypothesis that CMV pneumonia in BMT recipients is an immunopathologic condition.

Bone Marrow Transplantation↗
PubMed1991

Point mutation in the cytoplasmic domain of the neutrophil p22-phox cytochrome b subunit is associated with a nonfunctional NADPH oxidase and chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a congenital disorder in which phagocytes cannot generate superoxide (O2-) and other microbial oxidants due to mutations in any one of four components of the O2(-)-generating complex, NADPH oxidase. We report here a female CGD patient in whom a missense mutation in one of these components, the p22-phox subunit of the neutrophil membrane cytochrome b [where phox indicates phagocyte oxidase (used to designate protein components of the phagocyte NADPH oxidase)] results in a nonfunctional oxidase and failure of neutrophils to produce O2- in response to phorbol 12-myristrate 13-acetate. Cytochrome b in the patient's neutrophils was normal in appearance and abundance as determined by visible spectroscopy and by immunoblots of the gp91 and p22 subunits. However, the neutrophil plasma membranes were devoid of activity in the cell-free oxidase activation system, whereas the cytosol functioned normally. We postulated that the patient was homozygous for a mutation in p22 that results in the synthesis of normal levels of a nonfunctional cytochrome b. A single-base substitution (C----A) was found in the patient's mononuclear cell p22-phox cDNA that predicts a nonconservative Pro----Gln substitution at residue 156. The same mutation was also identified in all clones sequenced from patient genomic DNA, demonstrating homozygosity for the mutant allele. An antipeptide antibody against p22 residues 153-164 was found to bind only to permeabilized neutrophils, indicating that the mutation occurs in a cytoplasmic domain. These studies establish that this domain of p22-phox is cytoplasmic and that mutations in this region can have profound effects on cytochrome b function.

Adult↗
PubMed1991

Sodium lithium countertransport is acutely influenced by heparin-induced extracorporal LDL precipitation.

Sodium lithium countertransport may be a genetic marker for arterial hypertension and for the risk of diabetic nephropathy in type 1 diabetic patients. Since various factors seem to influence the transport velocity including serum lipid alterations, erythrocytes of seven patients with severe hyperlipoproteinaemia who were chronically and intermittently treated with LDL apheresis were examined before and immediately after therapy. The LDL apheresis reduced sodium lithium countertransport significantly (0.383 vs 0.269, P less than 0.02). Therefore, we conclude that serum lipid composition must be considered when interpreting sodium lithium countertransport velocity.

Adult↗
PubMed1991

Unrelated bone marrow transplantation in Canada, the national experience.

The Canadian Unrelated Bone Marrow Donor Registry (UBMDR) of the Canadian Red Cross Society (CRCS) Blood Transfusion Service (BTS) was officially funded as of April 1, 1989 for an initial three year period with a mandate to recruit 50,000 unrelated bone marrow donors and conduct the search activities for unrelated bone marrow donors worldwide on behalf of Canadian patients (1). All provinces of Canada agreed to fund the Registry and it was unanimously adopted to locate the Canadian National Coordinating Centre (CNCC) of the Registry in Vancouver. Since February of 1988, 64 unrelated bone marrow transplants have been carried out in Canada. Over half of the unrelated donors have come from other countries. Canada has established working relationships with the United States, the United Kingdom and France. Recruitment of unrelated bone marrow donors is now established in twelve Canadian cities with more to follow. It is anticipated that the size of the registries world wide will continue to increase, that their ethnic makeup will become diversified and that the indications for unrelated bone marrow transplantation will broaden in the years to come.

Bone Marrow Transplantation↗
PubMed1990

[Diabetic nephropathy. Pathogenetic, diagnostic and therapeutic concepts].

Today the clinical picture of diabetes mellitus is often determined by its late complications. Diabetic nephropathy appears in about 40% of all diabetic patients with type 1 (insulin-dependent) diabetes mellitus within a period of 10-15 years. Early diagnosis is crucial for the prognosis as appropriate therapy may delay or even arrest the reduction of filtration fraction and terminal renal failure. Most important for the early diagnosis is the measurement of albumin and protein excretion.

Diabetes Mellitus, Type 1↗