Biomedical subjects
Publications and source records attributed to M Abedi.
The marrow hematopoietic stem cell is currently being redefined as to all aspects of its phenotype and its total differentiation capacity. This redefinition now includes its plasticity as to production of nonhematopoietic and hematopoietic cell types, the determinants of its in vivo engraftment potential and its expression of stem cell functional characteristics.
Long-term multilineage allochimerism can be obtained in H2-mismatched B6.SJL to BALB/c transplants with host irradiation of 100 cGy, donor spleen cell pre-exposure and costimulator blockade with anti-CD40 ligand (CD40L) antibody. We evaluated this allochimerism approach in murine marrow transplants with different degrees of major histocompatibility complexe (MHC) mismatching; these include: (1) H2-mismatched transplant H2Kk to H2Kb, (2) full haplo-identical transplant H2Kbd to H2Kbk, (3) a partial haplo-identical transplant H2Kd to H2Kbd and (4) an MHC class II mismatch. Levels of chimerism increased up to 12 weeks and then stayed relatively stable up to 1 year after transplant. At 18 weeks post-transplant, the H2-mismatched, haplo-identical, partial haplo-identical and class II-mismatch transplants evidenced 17.9+/-4.4, 40.7+/-0.9, 25.1+/-4.19 and 33.7+/-3.5% donor chimerism, respectively. Dropping the anti-CD40 antibody treatment and spleen cells or changing the schedule of antibody to one injection, in haplo-identical or full-mismatched transplants resulted in no donor-derived chimerism. On the other hand, these still resulted in minor chimerism in class II-mismatched transplants. Lineage analysis of peripheral blood at 6 and 12 months post-transplant demonstrated a significant shift toward increased chimeric lymphocytes and decreased chimeric granulocytes in the full H2 as compared with haplo-identical or class II transplants. Transplantation with anti-CD40L antibody eliminated both graft-versus-leukemia and graft-versus-host disease (GVHD) and delayed lymphocyte infusion did not rescue animals from fatal leukemia. In conclusion, under the conditions of our tolerization regimen, a haplo transplant gives higher engraftment levels than a full H2 mismatch, and despite lower engraftment levels, a class II-mismatched transplant can be successfully accomplished with only 100 cGy and no CD40L blockade.
On the basis of our studies of the fluctuation of the hematopoietic stem cell phenotype with cell cycle trnsit, we hypothesize that the ability of marrow stem cells to convert to nonhematopoietic cells will also vary at different points in the cell cycle. The new biology of stem cells has an impact on many fields including developmental biology and stem cell biology and the clinical potential is enormous.
BACKGROUND: Transcriptional transactivation is a process with remarkable tolerance for sequence diversity and structural geometry. In studies of the features that constitute transactivating functions, acidity has remained one of the most common characteristics observed among native activation domains and activator peptides. RESULTS: We performed a deliberate search of random peptide libraries for peptides capable of conferring transcriptional transactivation on the lexA DNA binding domain. Two libraries, one composed of C-terminal fusions, the other of peptide insertions within the green fluorescent protein structure, were used. We show that (i) peptide sequences other than C-terminal fusions can confer transactivation; (ii) though acidic activator peptides are more common, charge neutral and basic peptides can function as activators; and (iii) peptides as short as 11 amino acids behave in a modular fashion. CONCLUSIONS: These results support the recruitment model of transcriptional activation and, combined with other studies, suggest the possibility of using activator peptides in a variety of applications, including drug development work.
High levels of chimerism in syngeneic BALB/c transplants were reported when hosts were exposed to 1 Gy (100 cGy) whole body irradiation (WBI) and infused with 40 x 10(6) marrow cells. The recovery of host stem cells and alterations of enhanced host engraftability at varying times after 1 Gy WBI have now been evaluated in this study. Male BALB/c marrow (40 x 10(6) cells) was infused into female BALB/c hosts immediately or at 6, 12, and 24 weeks after 1 Gy WBI of host female BALB/c mice; engraftment percentages 8 weeks after cell injection at week 0, 6, 12, or 24 were 68% +/- 12%, 45% +/- 15%, 51% +/- 12%, or 20% +/- 8%, respectively. Eight-week engraftment levels in nonirradiated hosts average 7.7%. Conversely, engraftable stem cells measured at 8 weeks postengraftment in 1 Gy--exposed hosts were reduced to 8.6% +/- 3% of nonirradiated mice at time 0, 35% +/- 12% 6 weeks later, 49% +/- 10% at 3 months, and 21% +/- 7% at 6 months. Engraftment was still increased and stem cell decreased 1 year after 1 Gy. Furthermore, the primary cells transplanted into 1 Gy hosts can be serially transplanted, and the predominant effect of 1 Gy is directly on engrafting stem cells and not through accessory cells. These data show that transplantation in 1 Gy mice may be delayed until recovery of hematopoiesis, suggesting strategies in allogeneic transplantation to avoid the adverse effects of cytokine storm. The incomplete recovery of engraftable stem cells out to 12 months indicates that stem cell expansion, especially in patients previously treated with radiomimetic drugs, may not be feasible. (Blood. 2001;98:1246-1251)
The donor stem cell phenotype and host microenvironment determine the outcome of a stem cell transplant. In a series of transplant studies in syngeneic male to female or congenic Ly5.1/Ly5.2 models in which hosts have received no or minimal irradiation (100 cGy), evidence overwhelmingly supports the concept that syngeneic engraftment is determined by stem cell competition. These approaches can be extended to H-2 mismatched allogeneic mouse combination when antigen pre-exposure and CD40-CD40 ligand antibody blockage are employed. A human trial in patients with resistant neoplasia infusing pheresed blood with 10(8) CD3 cells/kg showed that tumor responses and complete chimerism occur with very low levels of CD34+ cells/kg and that the extent of previous treatment is a critical factor in determining chimerism. A major feature of transplants is the phenotype of the donor stem cell. This phenotype shows dramatic reversible plasticity involving differentiation, adhesion protein expression, and engraftment with cytokine-induced cell-cycle transit. Homing is probably also plastic. Marked fluctuations in engraftment capacity are also seen at different points in marrow circadian rhythm.
OBJECTIVE: To describe the frequency, clinical, and laboratory features of patients diagnosed with multiple sclerosis (MS) or MS-like illnesses (MSL) among a large, prospectively followed cohort of anti-phospholipid antibody (aPL)-positive patients. METHODS: Between 1990 and 1995 patients referred to a university-affiliated rheumatology clinic were prospectively evaluated for aPL based on questionnaires designed to detect aPL-related symptoms and/or a family history of aPL-related illnesses. Magnetic resonance imaging (MRI) was performed when significant neurological features were present. A subgroup of all patients diagnosed with MS or MSL was identified and their clinical, laboratory, and imaging findings were reviewed. RESULTS: Of 322 patients evaluated for aPL-related symptoms or events, 189 (59%) were positive for at least one class of aPL. Twenty-six of 322 patients (8%) carried a diagnosis of MS or MSL, either at the initial evaluation or during the study period. Twenty-three of the 26 individuals (88%) tested positive for aPL, while the remaining 3 (11%) tested repeatedly negative. Eighteen of the 23 patients (78%) had either more than one class of aPL or had multiple positive titers. IgM aCL was noted in 18 of the 23 patients (78%). Oligoclonal bands were noted in five patients. Antinuclear antibodies (ANA) and low complement levels were frequently observed. Blinded MRI readings showed lesions consistent with MS in the majority of cases. Clinically, 7 patients had transverse myelitis (TM), while optic neuritis (ON) was present in 8 patients. Most patients had either occult symptoms of rheumatic disease or contributory family histories. None had a defined underlying connective-tissue disease. CONCLUSION: A substantial number of aPL-positive patients have a concurrent diagnosis of MS or MSL, frequently presenting with elevated IgM aCL, optic neuritis, and transverse myelitis. The anti-phospholipid syndrome (APS) should be strongly considered as an alternative diagnosis to MS in these patients.
Using fluoroscopic guidance, polyethylene biliary stents are replaced endoscopically or percutaneously when bile duct stenosis recurs. To improve the sensitivity of conventional biliary cytology, we examined cells recovered from removed stents. Biliary stents removed endoscopically from each of 11 patients were rinsed with saline; next, the rinse was centrifuged and the sediment smeared and Papanicolaou stained. Three patients with choledocholithiasis had biliary stent replacement cytology (BSRC) to exclude a neoplastic etiology. Eight patients with clinicoradiologic evidence of hepatobiliary or pancreatic carcinoma had BSRCs performed for pathologic documentation of carcinoma. BSRC from six of eight patients with clinicoradiologically malignant biliary strictures contained malignant cells, predominantly in loose clusters, but also singly (sensitivity 75%, specificity 100%; positive predictive value 75%, negative predicative value 60%). Reparative epithelial atypia was also present in all cases. BSRC from two patients with clinicoradiological evidence of carcinoma of the biliary region and from three with choledocholithiasis contained only bile pigment, leukocytes, and benign epithelial cells. The sampling of cells which have accumulated on, or in biliary stents, improves the sensitivity of biliary cytology. This is most applicable when 1) a patient is inoperable, 2) tissue biopsy is neither feasible nor diagnostic, 3) prior brush, suction, percutaneous, or endoscopic needle aspiration cytology is inconclusive, and 4) permanent metal stent is needed.
Watermelon stomach (WMS) is an uncommon cause of chronic gastrointestinal blood loss, which once suspected can often be easily diagnosed and endoscopically managed in most cases. The current review intends to heighten the gastroenterologist's awareness of this condition to avoid costly delays in its diagnosis. The characteristic endoscopic appearance of WMS and the other variants of gastric vascular ectasia (GVE) are described. The conditions often associated with WMS are reviewed, including the recently described occurrence of WMS in bone marrow transplant patients presenting with acute upper gastrointestinal hemorrhage. We have clearly differentiated GVE from portal hypertensive gastropathy. The biopsy findings, although usually not required for diagnosis, are discussed. The theories of pathogenesis of WMS are presented and their relation to the observed phenomena is explored. Finally, the management of GVE, which essentially involves endoscopic application of thermal ablation methods, and the newer developments in the field, such as argon plasma coagulation, are discussed.
The full-length genes for the heavy (H) and light (L) chains of ferritin isolated from a rat liver cDNA library were amplified using polymerase chain reaction. Each was inserted at the unique BglII site downstream of the p10 promoter of the baculovirus transfer vector pAcUW21. The genes were transferred separately to infectious Autographa californica nuclear polyhedrosis virus (AcNPV) expression vectors after in vivo homologous recombination. Ferritin homopolymers of either H or L chain were expressed up to approximately 1.5 mg per 100 ml of infected cultures (2.0 x 10(6) cells/ml) of Spodoptera frugiperda, Sf-21, 4 days postinfection. Both recombinant H chain ferritin (rH-Ft) and recombinant L chain ferritin (rL-Ft) assembled as multi-subunit complexes with predicted electrophoretic mobility. Neither rH-Ft nor rL-Ft homopolymers had ferroxidase activity in 50 mM NaCl, as we have reported previously for native ferritin [D. DeSilva, D. M. Miller, D.W. Reif, and S.D. Aust (1992) Arch. Biochem. Biophys. 293,409-415]. When ceruloplasmin, a copper-containing protein, was used as a ferroxidase, rH-Ft loaded iron at rates comparable those obtained with native rat liver apoferritin, but rL-Ft failed to load any iron. The initial rate of Fe(II) oxidation catalyzed by ceruloplasmin was increased in the presence of rH-Ft or rat liver ferritin but not in the presence of rL-Ft. A maximum of about 2500 atoms of iron were incorporated into both rH-Ft and rat liver ferritin. These results demonstrate that both rat liver rH-Ft and rL-Ft homopolymer can be properly produced by the baculovirus expression system and ceruloplasmin can only load iron into H chain ferritin. The physiological significance of these results is discussed.
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Celiac plexus neurolysis is an established technique for relieving pain in cancers of the upper abdomen. This article reviews the novel technique of endoscopic ultrasound (EUS)-guided neurolytic celiac plexus block. This recently described procedure is a therapeutic extension of curvilinear array endosonographic fine needle aspiration. The indications, patient preparation, and technical aspects of the procedure are described in detail. The potential complications are mentioned and the results of the published studies are reviewed. We believe that where the expertise is available, this procedure can be integrated into the diagnostic EUS of patients with inoperable upper abdominal malignancy. As such, this would be the safest and most cost-effective approach for celiac plexus neurolysis in these patients. The role of EUS-guided celiac plexus block in patients with chronic pancreatitis may be emerging and needs further study.