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Biomedical subjects

Jerry Stein

Publications and source records attributed to Jerry Stein.

15 recordsLinked to original sources
PubMed2006

Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation.

Wolman disease is a rapidly fatal lysosomal storage disease caused by the complete absence of lysosomal acid lipase activity. We report the cure of an infant with Wolman disease following transplantation of unrelated HLA-mismatched umbilical cord blood-derived stem cells. Umbilical cord blood was chosen as the stem-cell source because of its immediate availability and reduced tendency to cause graft-versus-host disease. The transplantation resulted in restoration of normal acid lipase levels before the onset of permanent end-organ damage. Four years after transplantation, the patient is thriving and has normal levels of acid lipase in peripheral blood cells. To our knowledge, this is the first report of a successful unrelated cord blood transplant in a patient with Wolman disease. Umbilical cord stem cells transplantation can restore acid lipase levels in Wolman disease, and if performed early, can cure the disease.

Brain↗
PubMed2006

Does physiological beta cell turnover initiate autoimmune diabetes in the regional lymph nodes?

The initial immune process that triggers autoimmune beta cell destruction in type 1 diabetes is not fully understood. In early infancy there is an increased beta cell turnover. Recurrent exposure of tissue-specific antigens could lead to primary sensitization of immune cells in the draining lymph nodes of the pancreas. An initial immune injury to the beta cells can be inflicted by several cell types, primarily macrophages and T cells. Subsequently, infiltrating macrophages transfer antigens exposed by apoptotic beta cells to the draining lymph nodes, where antigen presenting cells process and amplify a secondary immune reaction. Antigen presenting cells evolve as dual players in the activation and suppression of the autoimmune reaction in the draining lymph nodes. We propose a scenario where destructive insulitis is caused by recurrent exposure of specific antigens due to the physiological turnover of beta cells. This sensitization initiates the evolution of reactive clones that remain silent in the regional lymph nodes, where they succeed to evade regulatory clonal deletion.

Animals↗
PubMed2006

The dual role of Fas-ligand as an injury effector and defense strategy in diabetes and islet transplantation.

The exact process that leads to the eruption of autoimmune reactions against beta cells and the evolution of diabetes is not fully understood. Macrophages and T cells may launch an initial immune reaction against the pancreatic islets of Langerhans, provoking inflammation and destructive insulitis. The information on the molecular mechanisms of the emergence of beta cell injury is controversial and points to possibly important roles for the perforin-granzyme, Fas-Fas-ligand (FasL) and tumor-necrosis-factor-mediated apoptotic pathways. FasL has several unique features that make it a potentially ideal immunomodulatory tool. Most important, FasL is selectively toxic to cytotoxic T cells and less harmful to regulatory T cells. This review discusses the intrinsic sensitivity of beta cells to FasL-mediated apoptosis, the conditions that underlie this beta cell sensitivity, and the feasibility of using FasL to arrest autoimmunity and prevent islet allograft rejection. In both the autoimmune and transplant settings, it is imperative to progress from the administration of nonspecific immunosuppressive therapy to the concept of beta-cell-specific immunomodulation. FasL evolves as a prime candidate for antigen-specific immunomodulation.

Animals↗
PubMed2006

The tale of early hematopoietic cell seeding in the bone marrow niche.

Since introduction of the notion of a "niche" that hosts engraftment and activity of hematopoietic cells, there is a massive effort to discover its structure and decipher its function. Our understanding of the niche is continuously changing with reinterpretation of traditional concepts and apprehension of new insights into the biology of hematopoietic cell homing, seeding, and engraftment. Here we discuss some of the early events in hematopoietic stem cell seeding and engraftment and propose a perspective based on visualization of labeled bone marrow cells in real time in vivo. Primary seeding of hematopoietic cells in the bone marrow niches evolves as a complex and dynamic process; however, it follows discrete topological and chronological patterns. Initial seeding occurs on the endosteal surface of the marrow, which includes heterogeneous niches for primary seeding. Several days after transplantation the endosteal niches become more restrictive, hosting primarily mitotically quiescent cells, and gradual centripetal migration is accompanied by engagement in proliferation and differentiation. The hematopoietic niches evolve as heterogeneous three-dimensional microenvironments that are continuously changing over time.

Animals↗
PubMed2006

Prolonged course of familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis is usually diagnosed in the first 2 years of life and, if untreated, is rapidly fatal. We describe a 10-year-old boy with a 9-year history of prolonged fever and progressive hepatosplenomegaly who was diagnosed as having hemophagocytic lymphohistiocytosis 2, being homozygote to a previously described mutation in the PRF1 gene, and cured by the HLH-2004 protocol and allogenic bone marrow transplantation. This unique case emphasizes the heterogeneity of this disease and the diversity of its clinical presentations.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Catheter-associated bloodstream infections in pediatric hematology-oncology patients: factors associated with catheter removal and recurrence.

The aims of this study were to analyze the factors associated with antibiotic failure leading to tunneled central venous catheter (CVC) removal during catheter-associated bloodstream infections (CABSIs) and with recurrence and reinfection in children with cancer. All cases of CABSI in patients attending the Department of Pediatric Hematology-Oncology between November 2000 and November 2003 were reviewed. A total of 207 episodes of CABSI, including multiple episodes involving the same catheter, were identified in 146 of 410 tunneled CVCs (167 Hickman, 243 implantable ports). The most common organism isolated was coagulase-negative Staphylococcus (CONS). The CVC was removed in 96 (46%) episodes. Hypotension, persistent bacteremia, previous stem cell transplantation, multiple CABSIs in the same CVC, exit-site infection, inappropriate empiric antibiotic therapy, and Candida infection were all significantly associated with increased risk of catheter removal (P < 0.05, odds ratios 7.81, 1.14, 2.22, 1.93, 3.04, 2.04 and 24.53, respectively). There were 12 episodes of recurrent infection, all except 1 caused by CONS (odds ratio 20.5, P = 0.006). Inappropriate empiric therapy, especially in implantable ports, was the only mutable risk factor for antibiotic failure. Because CONS was the predominant isolate in these devices, adding glycopeptides to the empiric therapy for suspected implantable-port CABSI might decrease the removal rate. This issue should be explored in future controlled trials.

Adolescent↗
PubMed2005

Corneal staining and subjective symptoms with multipurpose solutions as a function of time.

PURPOSE: Short-term changes in corneal staining and ocular symptoms were assessed at defined intervals to evaluate combinations of three soft lenses and four multipurpose solutions. METHODS: A series of pilot studies were conducted over 11 months using a double-masked, randomized, crossover design. Asymptomatic, adapted, daily-wear soft lens users wore group II or IV soft hydrophilic or silicone hydrogel lenses for a maximum period each day. Before wear, new lenses were soaked overnight in one of four multipurpose solutions: Alcon OPTI-FREE Express MPDS, Bausch & Lomb ReNu MultiPlus Multipurpose Solution, CIBA Vision SOLO-Care PLUS Multipurpose Solution, or AMO Complete MoisturePLUS. Subjects rated comfort and ocular symptoms. Corneal staining type and area were evaluated at baseline and after lens removal. RESULTS: Significantly increased extent of corneal staining, defined as the proportion of corneal zones showing staining of grade 1 or more severe, was observed at 1 and 2 hours when subjects wore group II lenses soaked in the polyhexamethylene biguanide-based systems. Significantly increased extent of staining was observed at 2 hours when subjects used silicone hydrogel lenses soaked in regimen 4. When subjects used regimen 1 and wore group II lenses, only a minimal staining response was observed at 1 and 2 hours of wear. Significant symptoms were not correlated with extent of staining. CONCLUSIONS: This study design is a promising tool that can discriminate between the performance of different soft lens and multipurpose solution combinations rapidly using small patient samples. With some lens-care product combinations, corneal appearance may vary according to the time of day the patient is examined.

Biguanides↗
PubMed2005

Critical early events in hematopoietic cell seeding and engraftment.

Durable hematopoietic stem cell engraftment requires efficient homing to and seeding in the recipient bone marrow. Dissection of cellular and molecular mechanisms by retrospective analysis of functional engraftment studies imposes severe limitations on the understanding of the early stages of this process. We have established an experimental approach for in vivo functional imaging of labeled cells at the level of recipient bone marrow in real time. The adhesive interaction of hematopoietic cells with the bone marrow stroma evolves as the most important early event. Adhesion to the marrow, rather than the vascular endothelium, determines the efficiency of both homing and seeding, and is absolutely essential to maintain cell viability in the marrow. Seeding and engraftment may be improved either by bypassing homing or by localized transplant of a large number of cells in a relatively small marrow space. There is functional redundancy in the molecular pathways that mediate the cell-stroma interaction, such that blockage of a single pathway has only minor effect on homing and seeding. We hypothesize that successfully seeding-engrafting cells undergo extensive phenotypic changes as a consequence of interaction with the stroma, without engaging in rapid proliferation. Surprisingly, Fas-ligand appears to promote hematopoietic cell engraftment by immunomodulatory and trophic effects.

Animals↗
PubMed2005

Hematopoietic chimerism monitoring based on STRs: quantitative platform performance on sequential samples.

Hematopoietic stem cell transplantation (HSCT) creates a donor-recipient cellular chimerism in the patient, which is quantitatively assayed from peripheral blood based on STR-DNA. Since chimerism values often vary across a patient's samples, it is important to determine to what extent this variability reflects technical aspects of platform performance. This issue is systematically assessed in the current study for the first time. Using the SGM Plus multiplex PCR kit and ABI platform, the longitudinal performance of STR markers was quantitatively evaluated in two chimeric models with true values, and in patient samples (n >500 marker loci). Computation of percent chimerism for each marker, and mean (sample) percent chimerism, standard deviation, and coefficient of variance was performed by our ChimerTrack utility. In chimeric models with known values, individual markers exhibited an accuracy (observed/true) of 88-98%; replication precision was 92-100% true, with a mean error of 2%. Fragment size calling was greater than 99% accurate and precise. Patient results were comparable for markers, relaive to sample means. One source of technical variability in chimerism estimation was allelic differential amplification efficiency. The latter was influenced by signal amplitude, dye label, marker size, and allelic size interval. It can be concluded that long-term chimeric tracking is routinely feasible using this platform in conjunction with ChimerTrack software. Importantly, mean percent chimerism, for any sample, should closely approximate the true chimeric status, with a technical accuracy of 98%. Guidelines are presented for selecting an optimized marker profile.

Alleles↗
PubMed2004

Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report from a referral centre in Israel.

The incidence of cytogenetic abnormalities in childhood de novo acute myeloid leukaemia (AML) and its prognostic significance was assessed in an Israeli paediatric referral centre. Cytogenetic analysis was successful in 86 of 97 children (< 20 years of age) diagnosed between 1988 and 2002 with de novo AML. Fluorescence in situ hybridization analysis detected new information in 11 of them, leading to reassignment in cytogenetic group classification. The incidence of the various cytogenetic subgroups was as follows: normal - 9%; t(11q23) - 22%; t(8;21) - 13%; t(15;17) - 8%; inv(16) - 3.4%; abn(3q) - 4.6%; 7/7q-(sole or main) - 5.8%; del(9q)(sole) and +21(sole) - 4.6% each; t(8;16) - 2.3%; t(6;9), t(1;22), +8(sole) - 1.1% each; and miscellaneous - 18%. The overall survival (OS) and event-free survival (EFS) (4 years) for 94 patients treated with the modified Berlin-Frankfürt-Münster (BFM) AML protocols (non-irradiated) were 59.9% (SE = 5%) and 55.7% (SE = 5%), respectively, and for the favourable t(8;21), t(15;17) and inv(16), OS was 60% (SE = 15%), 83% (SE = 15%) and 100% respectively. For the normal group it was 62% (SE = 17%), miscellaneous 64% (SE = 12%), t(11q23) 44.6% (SE = 11%) and of the -7/7q-, del(9q)(sole) or t(6;9), none had survived at 4 years. The incidence of cytogenetic subgroups in the Israeli childhood AML population and their outcome were similar to other recently reported paediatric series. Cytogenetic abnormalities still carry clinical relevance for treatment stratification in the context of modern chemotherapy.

Acute Disease↗
PubMed2003

der(11)t(11;17): a distinct cytogenetic pathway of advanced stage neuroblastoma (NBL) - detected by spectral karyotyping (SKY).

Conventional cytogenetic, molecular cytogenic and genetic methods disclosed a broad spectrum of genetic abnormalities leading to gain and loss of chromosomal segments in advanced stage neuroblastoma (NBL). Specific correlation between the genetic findings could delineate distinct genetic pathways, of which the biology and prognostic significance is as yet undetermined. Using spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) on metaphases from 16 patients with advanced stage NBL, it was possible to explore the whole spectrum of rearrangement within complex karyotypes and to detect hidden recurrent translocations. All translocations were unbalanced. The most prevalent recurrent unbalanced translocations resulted in 17q gain in 12 patients (75%), 11q loss in nine patients (56%), and 1p deletion/imbalance in eight patients (50%). The most frequent recurrent translocation was der(11)t(11;17) in six patients. Three cytogenetic pathways could be delineated. The first, with six patients, was characterized by the unbalanced translocation der(11)t(11;17), detected only by SKY, resulting in the concomitant 17q gain and 11q loss. No MYCN amplification or 1p deletion (except one patient with 1p imbalance) were found, while 3p deletion, and complex karyotypes were common. The second subgroup, with four patients, had 17q gain and 1p deletion, and in two patients 11q loss, that was apparent only by FISH. 1p deletion occurred through der(1)t(1;17) or del(1p). The third subgroup of four patients was characterized by MYCN amplification with 17q gain and 1p deletion, very rarely with 11q loss (one patient) through a translocation with a non-17q partner. The SKY subclassifications were in accordance with the findings reported by molecular genetic techniques, and may indicate that distinct oncogenes and suppressor genes are involved in the der(11)t(11;17) pathway of advanced stage NBL.

Chromosome Aberrations↗
PubMed2002

Distinct cytogenetic pathways of advanced-stage neuroblastoma tumors, detected by spectral karyotyping.

Molecular studies of advanced-stage neuroblastoma (NBL) have revealed a marked genetic heterogeneity. In addition to MYCN amplification and chromosome 1 short-arm deletions/translocations detected by conventional cytogenetics, application of fluorescence in situ hybridization has disclosed a high prevalence of 17q gain, whereas allelotyping and comparative genomic hybridization techniques also have revealed loss of 11q and of other chromosomal material. Using the recently developed technique of spectral karyotyping (SKY), we sought to refine the cytogenetic information, identify hidden recurrent structural chromosomal abnormalities, and compare them to the molecular findings. Thirteen samples of metaphase spreads from 11 patients with advanced-stage NBL were analyzed by SKY. Most of them were found to have complex karyotypes (more than three changes per metaphase) and complex unbalanced rearrangements. Recurrent aberrations leading to 17q gain, deletion of 1p, MYCN amplification, and loss of 11q appeared in 7, 4, 4, and 5 patients, respectively, in simple and complex karyotypes. Chromosome 3 changes and gain of 1q and 7q appeared in 6, 5, and 4 patients, respectively, in complex karyotypes only, reflecting later changes. A strikingly high prevalence of the unbalanced translocation der(11)t(11;17), leading to concomitant 11q loss and 17q gain in 4 patients, delineated a distinct cytogenetic group, none having 1p deletion and/or MYCN amplification. der(11)t(11;17) was associated with complex karyotypes with changes in chromosomes 3 and 7q. The 17q translocations with partners other than 11q were associated with 1p deletion and/or MYCN amplification. The distinct cytogenetic subgroups identified by SKY confirm and extend the recent molecular observations, and suggest that different genes may interact in the der(11)t(11;17) pathway of NBL development and progression.

Adolescent↗
PubMed2002

Acquired trisomy 21 and distinct clonal evolution in acute megakaryoblastic leukaemia in young monozygotic twins.

An intrauterine origin of childhood acute lymphoblastic leukaemia (ALL) was proven by the identical clonotypic gene rearrangement in the concordant leukaemias of monozygotic twins, arising from a single clonogenic progeny. The monozygotic twins, presented at the age of 22 months with acute megakaryoblastic leukaemia (AML-M7) in one and myelodysplasia transformed to AML-M7 in the other. Leukaemic cells in both twins carried trisomy 21 and additional different clonal evolution changes of del(20q) in the first twin and trisomy 8 in the second. AML-M7 of late infancy with trisomy 21 may be included in the leukaemias of intrauterine origin, possibly a result of genotoxic insult.

Cytogenetic Analysis↗