Biomedical subjects

S Fruchtman

Publications and source records attributed to S Fruchtman.

At least 19 recordsLinked to original sources

PubMed2003

Collection of autologous PBSC in patients with polycythemia vera.

BACKGROUND: Allogeneic stem-cell transplantation (SCT) can eradicate myelofibrosis (MF), but is limited by donor availability and toxicity. We previously reported normalization of counts and resolution of MF after ablative, syngeneic SCT in spent phase polycythemia vera (PV). Hence, GvL is not required to eradicate MF. Autologous SCT may advance treatment for spent phase PV by restoring effective hematopoiesis. The influence of organomegaly, myelosuppression and MF on PBSC collection has not been studied in the setting of PV. METHODS: Sixteen patients with PV underwent PBSC collection. Mobilization was with filgrastim alone, with a target cell content of 2.5 x 10(6) CD34(+)/kg. All myelosuppression was discontinued 2 weeks prior to collection. RESULTS: Median ages at diagnosis and collection were 47 and 57 years, respectively. Organomegaly, MF and use of myelosuppressive therapies were present in 10 (63%), 4 (25%) and 7 (44%) patients. Median total nucleated cells (TNC) and CD34(+) counts were 8.3 x 10(8)/kg and 4.98 x 10(8)/kg. MF had an adverse effect on TNC (p=0.05) but not on the CD34(+) content. Time from diagnosis and the use of myelosuppresion had no influence on TNC and CD34(+) contents. Four patients had CD34(+) contents <2.5 x 10(6)/kg. Complete blood count (CBC) parameters were not predictive of CD34(+) content. DISCUSSION: Autologous PBSC collection is feasible in PV several years after diagnosis. Organomegaly and MF are not absolute contraindications for collection. Discontinuing myelosuppresion for 2 weeks before mobilization appears sufficient to collect adequate numbers of CD34(+) progenitors.

Adult↗

PubMed2001

Insulin-like growth factor-I augments prolactin and inhibits growth hormone release through distinct as well as overlapping cellular signaling pathways.

We recently discovered a new role for insulin-like growth factor-I (IGF-I) as a specific and direct stimulator of prolactin (PRL) release in addition to its recognized function as an inhibitor of growth hormone (GH) release and synthesis. Little is known of the mechanisms that transduce the actions of IGF-I on PRL and GH release in vertebrates. The present study was undertaken to determine the cellular pathways that mediate the disparate actions of IGF-I on PRL and GH release in hybrid striped bass (Morone saxatilis X M. chrysops). When regulating cellular function, IGF-I may activate two primary pathways, phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase (MAPK). The specific MAPK inhibitor, PD98059, blocked IGF-I-evoked PRL release as well as GH release inhibition over an 18-20-h incubation. LY294002, a specific PI 3-K inhibitor, overcame IGF-I's inhibition of GH release but was ineffective in blocking PRL release stimulated by IGF-I. These studies suggest IGF-I disparately alters PRL and GH by activating distinct as well as overlapping signaling pathways central for mediating actions of growth factors on secretory activity as well as cell proliferation. These results further support a role for IGF-I as a physiological regulator of PRL and GH.

Animals↗

PubMed2001

Cortisol suppresses prolactin release through a non-genomic mechanism involving interactions with the plasma membrane.

In the classical theory of steroid hormone action, steroids diffuse through the membrane and alter transcription of specific genes resulting in synthesis of proteins important for modulating cell function. Most often, steroids work solely through the genome to exert their physiological actions in a process that normally takes hours or days to occur. In tilapia (Oreochromis mossambicus), cortisol inhibits prolactin (PRL) release within 10-20 min in vitro. This action is accompanied by similarly rapid reductions in cellular Ca(2+) and cAMP levels, second messengers known to transduce the membrane effects of peptide hormones. We further examined whether cortisol might inhibit PRL release through a non-genomic, membrane-associated mechanism using the protein synthesis inhibitor, cycloheximide, and a membrane impermeant form of cortisol, cortisol-21 hemisuccinate BSA (HEF/BSA). Cycloheximide (2 and 10 microg/ml) was ineffective in overcoming PRL release induced by hyposmotic medium or that inhibited by cortisol over 4 h static incubations. These dosages reduced protein synthesis as measured by amino acid incorporation in pituitaries by 75 and 99%, respectively. During 4-h incubation, HEF/BSA and HEF significantly reduced PRL release in a dose-dependent fashion. These studies suggest that cortisol inhibits PRL release through a plasma membrane-associated, protein-synthesis independent (non-genomic) pathway.

Animals↗

PubMed2001

Human leukocyte antigens (HLA)-Cw as prognostic indicators in autologous transplantation for lymphoma.

The human leukocyte antigens (HLA) function as transplantation antigens and as markers in disease association. Disparity at the HLA A, B, Cw, and DR loci in allogeneic stem cell transplants results in an increased incidence of graft-versus-host disease, graft rejection, and decreased survival. HLA class I loci A, B, and Cw also function as ligands for natural killer (NK) cell receptors in an interaction that predominantly inhibits cytolysis of target antigens. This HLA-NK cell inhibitory function is required for protection against auto-aggression, and is of unclear significance in other clinical settings. Furthermore, the prevention of auto-aggression is HLA molecule specific as demonstrated by the association of specific HLA types with autoimmune diseases. It is not known whether the HLA molecules might serve as markers for outcome in autologous transplants. We investigated an association of HLA class I molecules and early transplant outcome in a cohort of patients who underwent autologous transplantation for the treatment of lymphoma. In this retrospective study, HLA class I molecules were analyzed to determine whether they affect transplant outcome. HLA typing was performed by microlymphocytotoxicity assays. Factors such as age, sex, disease type, lactate dehydrogenase (LDH), cell dose, type of graft, and transfusion events were reviewed. Outcome was defined as death (or survival) at 6 months from the date of transplant. HLA-Cw8 was significantly associated with poor outcome (odds ratio = 18 and 9.3, p = 0.01 and 0.02 in homozygous and all patients, respectively). The HLA-A and B locus molecules were not associated with outcome. Age, sex, elevated LDH, and cell dose were not associated with outcome. A blood progenitor cell dose of greater than 6 x 10(8) nucleated cells/kg was favorably associated with outcome (p = 0.08). The number of transfusions received was not associated with outcome. In the multivariate analysis of HLAs and factors associated with outcome, HLA-Cw8 emerged as an independent risk factor for poor outcome (p = 0.03) following autologous transplantation in lymphoma patients. The association of HLA-Cw molecules with outcome in this study group indicates a need for further investigation of the HLA-mediated interactions that affect antitumor cytotoxicity, cytokine release, and regimen related toxicity.

Adult↗

PubMed2000

Comparison of four echocardiographic techniques for measuring left ventricular ejection fraction.

Accurate quantitative measurement of left ventricular (LV) ejection fraction (EF) by 2-dimensional echocardiography is limited by subjective visual endocardial border detection. Both harmonic and precision contrast microbubbles provide better delineation of endocardial borders than fundamental imaging. The aim of this study was to correlate 2-dimensional echocardiographic quantification of LVEF measured by 4 currently available techniques with radionuclide angiography. A total of 50 patients who underwent radionuclide (EF) measurement (47 of 50 had technically difficult echocardiograms by fundamental imaging) underwent echocardiography by 4 methods: fundamental alone, fundamental with contrast, harmonic alone, and harmonic with contrast. Three echocardiologists measured the biplane 2-dimensional echocardiographic LVEF independently and were blinded to radionuclide angiography. The correlation of echocardiographic EF with radionuclide EF improved incrementally with each method. However, contrast with harmonic imaging provided the closest correlation (r = 0.95, 0.96, and 0.95 as assessed by the 3 independent analysts.

Adult↗

PubMed2000

Purification, characterization, and bioassay of prolactin and growth hormone from temperate basses, genus Morone.

Prolactin (PRL) and two variants of growth hormone (GH), purified from pituitaries of striped bass (Morone saxatilis) and its hybrid with white bass (M. saxatilis x M. chrysops) by gel filtration chromatography under alkaline conditions followed by reversed-phase high pressure liquid chromatography, appear similar between species. Both the minor (GH I) and the major (GH II) forms of purified GH appeared as single bands (M(r) approximately 23,000) after sodium dodecyl sulfate-polyacrylamide gel electrophoresis, as did the purified PRL (M(r) approximately 24,000). The molecular weights of GH II and PRL determined by MALDI TOF mass spectroscopy were 21.2 and 21.3 kDa, respectively. In Western blotting experiments, an antiserum against tilapia (Oreochromis mossambicus) 24K PRL specifically recognized Morone PRL, while an antiserum against tilapia GH specifically recognized Morone GH I and II. Chemical identities of the putative PRL and GH I were further confirmed by N-terminal peptide sequencing, while internal sequence analysis was performed on GH II because it was blocked at its N-terminus. Over a stretch of 29 amino acids, Morone PRL was found to be 76% identical to tilapia 24K PRL, 72% identical to tilapia 20K PRL, 72% identical to chum salmon (Oncorhynchus keta) PRL I, and 69% identical to eel (Anguilla japonica) PRL I. Alignment of the hybrid striped bass GH sequences with those of several other advanced marine teleosts indicated 75-85% sequence identity for GH I (40 amino acids) and 95-98% identity for GH II (45 amino acids). Biological activity of striped bass GH II was confirmed using a heterologous in vitro assay of insulin-like growth factor I mRNA production by coho salmon (On. kisutch) hepatocytes. An in vivo bioassay, involving hypophysectomy of hybrid striped bass and treatment of the fish maintained in fresh water with homologous PRL, confirmed that the purified striped bass PRL was also bioactive.

Amino Acid Sequence↗

PubMed2000

Long-term follow-up after allogeneic granulocyte colony-stimulating factor--primed bone marrow transplantation.

Granulocyte colony-stimulating factor (G-CSF) priming increases the number of progenitor cells in harvested bone marrow (BM) and has been used for allogeneic transplantation. Primed bone marrow (pBM) seems to offer faster engraftment than steady-state BM, but the stability of such engraftment has been questioned. The incidence of graft-versus-host disease (GVHD) and disease relapse after pBM, compared with such incidence after BM or peripheral blood progenitor allotransplantation, has not been established. We studied the long-term outcome (median follow-up, 24 months) of sibling matched allografting with G-CSF pBM. Seventeen patients received pBM from matched sibling donors primed with G-CSF 10 microg/kg per day for 2 days before BM harvest. Conditioning consisted of total body irradiation and cyclophosphamide (CY); busulfan and CY; or total lymphoid irradiation, CY, and antithymocyte globulin. All infused grafts contained > or = 3.5 to 4 x 10(8) mononuclear cells per kilogram. Ten of 17 patients received methotrexate as part of their GVHD prophylaxis. International Bone Marrow Transplant Registry definitions for engraftment were used. Control subjects consisted of 112 consecutive patients who received allogeneic transplantation at our institution with steady-state BM; control subjects for length of hospitalization consisted of the subset of patients who underwent transplantation during 1996. Neutrophil engraftment occurred a median of 7 days earlier in primed bone marrow transplantation (pBMT) patients when compared with steady-state BMT patients; this shortened hospitalization by a median of 11 days. The peritransplant mortality rate was 18% in pBMT patients and 25% in BMT patients (not significant). The rate of GVHD of grade > II and the rate of relapse were almost identical in pBMT and BMT patients (GVHD: 18% and 19%, respectively; relapse: 14% and 13%, respectively). There were 4 transplant-related deaths within the first 100 days; 1 patient died of disease relapse on day 470. Twelve patients remained alive on days 430 through 1522 after BMT. Results showed that pBM allografts resulted in more rapid engraftment and shorter hospitalization. All patients maintained stable donor engraftment. In this cohort of patients, G-CSF pBMT resulted in rates of GVHD, disease relapse, and peritransplant mortality that were similar to those produced by conventional BMT.

Adolescent↗

PubMed2000

An immunological syndrome featuring transverse myelitis, Evans syndrome and pulmonary infiltrates after unrelated bone marrow transplant in a patient with severe aplastic anemia.

A patient with severe aplastic anemia underwent a matched unrelated bone marrow transplant, following which he developed a complex autoimmune syndrome. This featured transverse myelitis, immune mediated Coombs positive hemolytic anemia and immune thrombocytopenia (Evans syndrome), pulmonary infiltrates, eosinophilia, muscle pains and cramps and lichenoid dermatitis all of which may represent manifestations of graft-versus-host disease as they showed response to immunosuppression. Thus, although immune-mediated cytopenias after an allogeneic bone marrow transplant are rare, they should be considered as a possible cause of cytopenia in post-transplant patients.

Adult↗

PubMed2000

Insulin-like growth factor I disparately regulates prolactin and growth hormone synthesis and secretion: studies using the teleost pituitary model.

Although insulin-like growth factor I (IGF-I)'s inhibition of GH release is well documented, little is known of its control of GH synthesis at the posttranscriptional level. The manner by which IGF-I alters PRL synthesis and secretion is also unclear. This study was undertaken to examine the role IGF-I plays in regulating in vitro PRL and GH synthesis and release using the teleost pituitary model system. This model allows for isolation of nearly homogenous populations of distinct pituitary cell types that can be cultured in a completely defined, hormone-free medium. Tissues containing PRL cells and those consisting of GH cells were dissected from pituitaries of hybrid striped bass and exposed to varying concentrations of IGF-I, IGF-II, and insulin for 18-20 h. Exposure to graded doses of IGF-I markedly stimulated fractional, total, and newly synthesized PRL release in a dose-dependent fashion (ED50 for fractional release, 35 ng/ml or 4.6 nM; P < 0.0001). IGF-II and insulin also increased PRL release, but only at 10-fold higher concentrations than the lowest effective IGF-I dose. The total PRL content in the incubations and PRL synthesis, as measured by [35S]methionine incorporation, were not altered by IGF-I. By contrast, IGF-I potently reduced GH release (ED50, 29 ng/ml or 3.8 nM; P < 0.0001) and synthesis. Both 100 and 1000 ng/ml IGF-I decreased newly synthesized GH and total GH content (P < 0.001). Insulin and IGF-II mimicked IGF's action in attenuating GH release, but only at 10- to 11-fold higher concentrations. Taken together, these findings clearly indicate that IGF-I disparately regulates PRL and GH synthesis and secretion. We show that the effects of IGF-I on pituitary hormone release occur in a variety of species, suggesting that its actions are well conserved. The inhibition of GH release and synthesis by IGF-I probably reflects a negative feedback loop for maintaining tight control over GH cell function. These findings further indicate that IGF-I is a potent and specific secretagogue of PRL release in vertebrates.

Animals↗

PubMed1999

Transmission of factor VII deficiency through liver transplantation.

The liver is the primary site of synthesis for the majority of coagulation factors. There are published accounts of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia and factor XI deficiency. In this article, we report what we believe to be the first observation, of transmission of factor VII deficiency, a rare, autosomal recessive coagulation disorder, from an affected liver donor to a naive liver recipient. At 300 days after transplantation, the recipient remains with an isolated prolongation of the prothrombin time and a below-normal level of factor VII, and has had no bleeding complications.

Adult↗

PubMed1999

Comparative analysis of HLA-B 8101 by serology, isoelectric focusing, and sequence-based typing.

We describe a bone marrow donor evaluation on a twenty-four-year-old patient from Honduras, Central America. The patient's phenotype included a HLA-B7v, with serologic reactivity to HLA- B7, 8101, and 48, and was consistent with, HLA-B*8101. One-dimensional isoelectric focusing (IEF) identified HLA-B 7.1, a low frequency isotype that has previously been associated with the HLA-B7 variant, B*0705. To further classify this allele, sequence based typing (SBT) was performed, confirming HLA-B*8101 sequence homology. The diagnostic evaluation of this case illustrates the correlation of sequenced based typing and isoelectric focusing in defining HLA Class I antigen characteristics and the use of IEF in screening for rare and novel alleles.

HLA-B Antigens↗

PubMed1999

Allogeneic bone marrow transplantation for advanced Waldenstrom's macroglobulinemia.

Waldenstrom's disease is a lymphoproliferative disorder that is typically treated with plasmapheresis and/or alkylating agents. In young patients, other lymphoproliferative disorders have been treated with allogeneic transplantation. Two patients with aggressive Waldenstrom's disease, who progressed in spite of multi-agent chemotherapy and autologous stem cell transplantation, in one case, underwent allogeneic transplantation from their HLA-identical donors. Both remain alive with event-free survivals of more than 3, and more than 9 years, respectively. Allogeneic transplantation should be considered for young patients with Waldenstrom's disease.

Adult↗

PubMed1999

Identification of novel chromosomal rearrangements in acute myelogenous leukemia involving loci on chromosome 2p23, 15q22 and 17q21.

Chromosomal translocations are frequently linked to multiple hematological malignancies. The study of the resulting abnormal gene products has led to fundamental advances in the understanding of cancer biology. This is the first report of t(2;15)(p23;q22) and t(2;17)(p23;q21) translocations in human malignancy. Patient 1, a 73-year-old male, was diagnosed with myeloblastic (FAB M1 sub-type) AML. Cytogenetic analysis showed a 47,XY,t(2;15)(p23;q22),+13 karyotype. Fluorescent in situ hybridization (FISH) showed that the PML gene was transferred intact to the short arm of chromosome 2 while the ALK gene on chromosome 2p23 was passively transferred to the long arm of chromosome 15. Patient 2 was a 60-year-old male diagnosed with monocytic (FAB M4-type) AML. Cytogenetic analysis showed 46,XY,t(2;17)(p23;q21) karyotype. FISH analysis showed that neither RARalpha nor ALK were disrupted by the translocation. None of the coding region of the three genes studied were translocated in these patients. This raises the possibilities that other neighboring genes could be involved or that noncoding regulatory sequences of the studied genes could be put in contact and deregulate expression of other genes. Alternatively, displacement of ALK, RARalpha and PML to novel positions could lead to loss of their normal regulation

Acute Disease↗

PubMed1997

Interphase FISH analysis of sex-mismatched BMT utilizing dual color XY probes.

Interphase FISH analysis, utilizing dual color XY probes, was performed on 27 patients following allogeneic sex-mismatched bone marrow transplantation and on 31 controls. Of the 123 167 examined interphase nuclei, 63 318 were from 19 of the 21 patients (54 specimens) who engrafted, 31 827 from five of the six patients (29 specimens) who relapsed (four) or failed to engraft (one) and 24 703 from the 31 control specimens. In patients who engrafted, the mean percentage of host cells was 0.26% between day 29 and 5 years following BMT. Microchimerism of 0.7% or less than 1-5 years following BMT was not predictive of relapse. Interphase FISH analysis predicted relapse or failure of engraftment in five of the six evaluable patients. In three of five patients both conventional cytogenetics and interphase FISH of bone marrow cells provided important information regarding engraftment status and degree of chimerism.

Bone Marrow Transplantation↗

PubMed1997

A pilot study of allogeneic bone marrow transplantation using related donors stimulated with G-CSF.

Growth factor administration to donors prior to bone marrow (BM) harvesting results in an enrichment of the graft for myeloid precursors. In animals, growth factor-primed BM has a higher repopulating ability than untreated BM. Ten patients received an HLA-identical sibling, allogeneic transplant using granulocyte colony-stimulating factor (G-CSF)-stimulated BM. Stimulation consisted of G-CSF at 10 microg/kg/day for 2 days prior to harvest. Patients were transplanted for various benign and malignant hematological conditions. The GVHD prophylaxis consisted of cyclosporine, methotrexate and/or prednisone. Compared to untreated historical control BM, stimulated BM infusions contained similar number of nucleated cells (mean +/- s.d.: 3.5 +/- 1.5 vs 4.0 +/- 0.9 x 10(8)/kg), CD34+ cells (mean +/- s.d.: 7.5 +/- 3.0 vs 9.4 +/- 6.7 x 10(6)/kg), and CD3+ cells (mean +/- s.d.: 129 +/- 30 vs 190 +/- 59 x 10(6)/kg) but higher numbers of granulocyte-macrophage colony-forming units (mean +/- s.d.: 20 +/- 12 vs 96 +/- 34 x 10(4)/kg). Patients receiving stimulated BM had prompt and stable engraftment of white cells and platelets. On average they attained an ANC of > or = 1 x 10(9)/l 9 days earlier and a platelet count of > or = 20 x 10(9)/l 6 days earlier than historical controls receiving unstimulated HLA-identical sibling BM. Hospitalization was shortened by a mean of 10 days and transfusion requirements were modest. None of the patients developed severe GVHD or disease relapse. Two patients died of severe VOD post-BMT and thus were unevaluable for platelet engraftment. A third patient died of TTP on day 76 post-BMT. Seven patients are alive and well 49-585 days post-BMT. Stimulated BM may provide a valuable alternative to allogeneic BM and PBSC transplants. Ideal stimulation regimens need to be investigated.

Adolescent↗

PubMed1997

Evidence for the embryonic origin of partial chromosome 7 deletion in monozygotic twins with juvenile chronic myelogenous leukemia.

During donor evaluation for allogeneic bone marrow transplantation (BMT) of a 28-month-old child with juvenile chronic myelogeneous leukemia (JCML) with 46,XY,-7,+mar karyotype, the potential donor twin brother was found to be thrombocytopenic. Subsequent genotype analysis determined monozygosity with 98% probability. Bone marrow analysis of the twin brother revealed the same 46,XY,-7,+mar karyotype and a diagnosis of JCML was made. Metaphase FISH studies documented that mar chromosome in both twins contains the pericentromeric region of chromosome 7 and thus both twins had a partial monosomy of chromosome 7. A possible embryonic origin of del(7) is proposed.

Antineoplastic Agents↗

PubMed1997

Disparate lympho-erythroid donor to recipient chimaerism in a beta(0)-thalassaemia bone marrow transplant recipient with red cell indices indicative of apparent full engraftment.

A 4-year-old girl with transfusion-dependent beta(0)-thalassaemia received an HLA-identical bone marrow transplant (BMT) from her beta(0)-thalassaemia trait sister. Prior to BMT, chromosomal analysis revealed the recipient to have 46,XX,9qh+, a polymorphic variant of the heterochromatin region of chromosome 9, which her donor did not have. Within 1 month post-BMT, 89% of nucleated bone marrow cells were of donor origin. One year later, donor engraftment had decreased to 44% and 34% in nucleated bone marrow cells and blood lymphocytes, respectively. By 2 years, donor lymphocyte engraftment fell to 5%, raising concern of possible graft rejection. To examine erythroid chimaerism, globin synthesis by individual erythroid progenitor cell derived colonies (BFU-E) was analysed. On days 1000 and 1130 post-BMT, 79% and 77% of colonies, respectively, synthesized beta-globin and therefore were of donor origin.

Bone Marrow Transplantation↗

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↗