Biomedical subjects
M Feldman
Publications and source records attributed to M Feldman.
A comparison of every-third-day versus daily low-dose aspirin therapy on serum thromboxane concentrations in healthy men and women.
Aspirin's antithrombotic effect is mediated predominately by inhibition of platelet cyclooxygenase-1, leading to a decline in serum thromboxane A2 concentrations. We performed a placebo-controlled, randomized, double-blind trial to determine whether aspirin could be given at 3-day intervals and still achieve potent serum thromboxane inhibition. One hundred nine healthy men and women with no recent exposure to aspirin and no contraindications to its use participated. Subjects received 325 mg, 81 mg, or 40 mg of plain aspirin every third day, with placebo on other days; 81 mg of aspirin every day; or placebo every day. Serum concentrations of thromboxane B2 (the metabolite of thromboxane A2) were measured at 3-day intervals during a 31-day treatment period, as well as 4, 7, and 14 days after treatment ended. Serum thromboxane B2 concentrations were nearly identical during treatment with 325 mg of aspirin every third day or 81 mg of aspirin per day (86% inhibition [84%, 89%] and 85% inhibition [73%, 96%], respectively). An aspirin dose of 81 mg every third day was nearly as potent (74% inhibition [70%, 79%]), whereas 40 mg of aspirin every third day achieved only 50% inhibition (40%, 60%). Every-third-day low-dose aspirin regimens (325 and 81 mg) deserve comparison with daily low-dose aspirin regimens in controlled clinical trials because the former regimens could prove to have equal efficacy with reduced toxicity.
Genotypic variation in tetraploid wheat affecting homoeologous pairing in hybrids with Aegilops peregrina.
The Ph1 gene has long been considered the main factor responsible for the diploid-like meiotic behavior of polyploid wheat. This dominant gene, located on the long arm of chromosome 5B (5BL), suppresses pairing of homoeologous chromosomes in polyploid wheat and in their hybrids with related species. Here we report on the discovery of genotypic variation among tetraploid wheats in the control of homoeologous pairing. Compared with the level of homoeologous pairing in hybrids between Aegilops peregrina and the bread wheat cultivar Chinese Spring (CS), significantly higher levels of homoeologous pairing were obtained in hybrids between Ae. peregrina and CS substitution lines in which chromosome 5B of CS was replaced by either 5B of Triticum turgidum ssp. dicoccoides line 09 (TTD09) or 5G of Triticum timopheevii ssp. timopheevii line 01 (TIMO1). Similarly, a higher level of homoeologous pairing was found in the hybrid between Ae. peregrina and a substitution line of CS in which chromosome arm 5BL of line TTD140 substituted for 5BL of CS. It appears that the observed effect on the level of pairing is exerted by chromosome arm 5BL of T turgidum ssp. dicoccoides, most probably by an allele of Ph1. Searching for variation in the control of homoeologous pairing among lines of wild tetraploid wheat, either T turgidum ssp. dicoccoides or T timopheevii ssp. armeniacum, showed that hybrids between Ae. peregrina and lines of these two wild wheats exhibited three different levels of homoeologous pairing: low, low intermediate, and high intermediate. The low-intermediate and high-intermediate genotypes may possess weak alleles of Ph1. The three different T turgidum ssp. dicoccoides pairing genotypes were collected from different geographical regions in Israel, indicating that this trait may have an adaptive value. The availability of allelic variation at the Ph1 locus may facilitate the mapping, tagging, and eventually the isolation of this important gene.
A new lectin in red kidney beans called PvFRIL stimulates proliferation of NIH 3T3 cells expressing the Flt3 receptor.
A new legume lectin has been identified by its ability to specifically stimulate proliferation of NIH 3T3 fibroblasts expressing the Flt3 tyrosine kinase receptor. The lectin was isolated from conditioned medium harvested from human peripheral blood mononuclear cells activated to secrete cytokines by a crude red kidney bean extract containing phytohemagglutinin (PHA). Untransfected 3T3 cells and 3T3 cells transfected with the related Fms tyrosine kinase receptor do not respond to this lectin, which we called PvFRIL (Phaseolus vulgaris Flt3 receptor-interacting lectin). When tested on cord blood mononuclear cells enriched for Flt3-expressing progenitors, purified PvFRIL fractions maintained a small population of cells that continued to express CD34 after 2 weeks in suspension cultures containing IL3. These cultures did not show the effects of IL3's strong induction of proliferation and differentiation (high cell number and exhausted medium); instead, low cell number at the end of the culture period resulted in persistence of cells in the context of cell death. These observations led to the hypothesis that PvFRIL acts in a dominant manner to preserve progenitor viability and prevent proliferation and differentiation.
Clinical aspects of genetic variability in Helicobacter pylori.
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Novel breast-tumor-associated MUC1-derived peptides: characterization in Db-/- x beta2 microglobulin (beta2m) null mice transgenic for a chimeric HLA-A2.1/Db-beta2 microglobulin single chain.
The MUC1 protein was found to be up-regulated in a spectrum of malignant tumors. T-cell responses to the MUC1 extracellular tandem repeat array (TRA) were observed in murine models as well as in breast-carcinoma patients. In the present study, we evaluated the anti-tumor potential of HLA-A2.1-motif-selected peptides from non-TRA domains of the molecule. Peptide immunogenicity was examined in the Db-/- x beta2 microglobulin (beta2m) null mice transgenic for a modified HLA-A2.1/Db-beta2 microglobulin single chain (HHD mice). Our results show the existence of 3 novel HLA-A2.1-restricted MUC1-derived cytotoxic T-lymphocyte (CTL) epitopes. These peptides are processed and presented by the HHD-transfected breast-tumor cell line MDA-MB-157. Moreover, CTL induced by these 3 peptides show higher lysis of target cells pulsed with breast-carcinoma-derived peptides than of targets pulsed with normal breast-tissue-derived peptides. These data suggest an important role for non-TRA MUC1-derived peptides as inducers of a MHC-restricted CTL reaction to a breast-carcinoma cell line and patient-derived tumor extracts.
Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity?
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Induction of antitumor immunity by proteasome-inhibited syngeneic fibroblasts pulsed with a modified TAA peptide.
CTLs specific for tumor antigens play a major role in immunity against cancer. Improved binding affinity of putative TAA peptides could enhance the in vivo immunogenicity of these self-altered self- tumor antigens. We examined here the efficacy of tumor vaccines composed of an altered peptide ligand of MUT-1, designated MUT-D, which exhibited significantly higher class-I allele K(b) binding affinity than its native counterpart MUT-1. The peptide was loaded on antigen presenting cells composed of the C57BL/6-syngeneic fibroblast cell line BLK.CL4. These cells were treated with proteasome inhibitor in order to shut off the degradation of proteins and the subsequent loading of endogenous peptides onto MHC class-I molecules, thus allowing for the pulsing of these cells with the modified peptide MUT-D. Proteasome-inhibited and modified peptide-loaded fibroblasts induced a peptide-specific CTL that significantly delayed primary tumor progression and protected the pre-immunized mice against the development of lung metastasis following the surgical removal of the primary tumor. Genetic modification of the fibroblasts to express the immunostimulatory cytokine IL-2 did not improve the APC function of the modified cells, nor did it result in augmentation of the potency of the vaccine. Our results suggest that the proteasome-inhibited fibroblasts pulsed with modified, high binder tumor-associated antigen peptide are good antigen-presenting cells and represent an effective form of tumor vaccine.
RFLP-based analysis of three RbcS subfamilies in diploid and polyploid species of wheat.
The RbcS multigene family of hexaploid (bread) wheat, Triticum aestivum (genome BBAADD), which encodes the small subunit of Rubisco, comprises at least 22 genes. Based on their 3' non-coding sequences, these genes have been classified into four subfamilies (SFs), of which three (SF-2, SF-3 and SF-4) are located on chromosomes of homoeologous group 2 and one (SF-1) on homoeologous group 5. In the present study we hybridized three RbcS subfamily-specific probes (for SF-1, SF-2 and SF-3) to total DNA digested with four restriction enzymes and analyzed the RFLP patterns of these subfamilies in eight diploid species of Aegilops and Triticum, and in two tetraploid and one hexaploid species of wheat (the diploid species are the putative progenitors of the polyploid wheats). The three subfamilies varied in their level of polymorphism, with SF-2 being the most polymorphic in all species. In the diploids, the order of polymorphism was SF-2 > SF-3 > SF-1, and in the polyploids SF-2 > SF-1 > SF-3. The RbcS genes of the conserved SF-1 were previously reported to have the highest expression levels in all the wheat tissues studied, indicating a negative correlation between polymorphism and gene expression. Among the diploids, the species with the D and the S genomes were the most polymorphic and the A-genome species were the least polymorphic. The polyploids were less polymorphic than the diploids. Within the polyploids, the A genome was somewhat more polymorphic than the B genome, while the D genome was the most conserved. Among the diploid species with the A genome, the RFLP pattern of T. urartu was closer to that of the A genome of the common wheat cultivar Chinese Spring (CS) than to that of T. monococcum. The pattern in Ae. tauschii was similar to that of the D genome of CS. Only partial resemblance was found between the RFLP patterns of the species with the S genome and the B genome of CS.
The plant lectin FRIL supports prolonged in vitro maintenance of quiescent human cord blood CD34(+)CD38(-/low)/SCID repopulating stem cells.
Ex vivo maintenance of human stem cells is crucial for many clinical applications. Current culture methods rely on optimized combinations of cytokines. Although these conditions provide some level of stem cell support, they primarily induce proliferation and differentiation, resulting in reduced repopulation capacity. The recently identified legume lectin FRIL has been shown to preserve human cord blood progenitors up to a month in suspension culture without medium changes. To test whether FRIL also preserves human SCID repopulating stem cells (SRC), we cultured human CD34(+) cord blood cells in medium containing FRIL, with or without subsequent exposure to cytokines, and tested their repopulating potential. We report that FRIL maintains SRC between 6 and 13 days in culture. Incubation of CD34(+) cells with FRIL results in significantly lower numbers of cycling cells compared with cytokine-stimulated cells. CD34(+) cells first cultured with FRIL for 6 days and subsequently exposed to cytokines for an additional 4 days generated significantly more mononuclear and progenitor cells and higher levels of engraftment in NOD/SCID mice compared with CD34(+) cells cultured with FRIL alone. Similar results were obtained with CD34(+)CD38(-/low) cells, including expansion of SRC that were cultured in FRIL followed by cytokine stimulation. Moreover, CD34(+) cells precultured with FRIL successfully engrafted primary and more importantly secondary recipients with lymphoid and myeloid cells, providing further support that FRIL maintains SRC for prolonged periods.FRIL's ability to preserve quiescent primitive cells in a reversible manner may significantly expand the time and range of ex vivo manipulations of human stem cells for clinical applications.
IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis.
Growth hormone (GH) is essential for rodent mammary gland development during puberty. It binds to GH receptors in the stromal compartment of the mammary gland and stimulates IGF-I mRNA expression. These findings lead to the hypothesis that GH acts through locally produced IGF-I, which in turn, causes development of terminal end buds (TEBs), the structures that lead the process of mammary gland development during puberty. Subsequent studies have in large measure proven this hypothesis. They include the observations that mammary development was grossly impaired in female mice deficient in IGF-I (IGF-I(-/-) knockout mice), and treatment of these mice with IGF-I plus estradiol (E2) restored pubertal mammary development while treatment with GH + E2 did not. Thus, the full phenotypic action of GH in mammary gland development is mediated by IGF-I. We have demonstrated one effect of GH on the mammary gland that does not appear to be mediated by the action of IGF-I. GH increased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammary fat pad cells, but IGF-I did not. In addition to the critical role of the GH/IGF-I axis during pubertal mammary development, other data suggest that IGF-I might also be of importance during pregnancy and lactation. In summary, the earliest phase of pubertal mammary development (formation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormones have been shown to stimulate formation of TEBs unless GH or IGF-I is present. GH-induced IGF-I is of major importance in ductal morphogenesis, and may, in fact, be necessary for later stages of mammary development, as well.
Consensus conference on second opinions in diagnostic anatomic pathology. Who, What, and When.
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Allograft dermal implant (AlloDerm) in a previously irradiated field.
OBJECTIVE: To evaluate the integration of AlloDerm (LifeCell Corp., The Woodlands, TX) in a field exposed to external-beam radiation (EBR) by analyzing graft thickness, fibroblast recellularization, and neovascularization. STUDY DESIGN: Randomized control. METHODS: Thirty-six male Sprague-Dawley rats (n = 36) were randomly assigned to four groups. One hind leg of each rat was exposed to 20 Gy of EBR; the other limb served as the nonirradiated control. Two weeks after irradiation, AlloDerm was implanted into both hind legs. Grafts were harvested at 3, 4, 6, and 14 weeks after implantation and underwent histological analyses. RESULTS: There was no statistically significant difference in graft thickness, fibroblast count, or neovascularization between the grafts placed in the irradiated bed and the controls (n = 33, P = .332, P = .336, and P = .057, respectively). However, at week 3, fibroblast counts in the graft placed in the field exposed to EBR were significantly lower than those of controls (P = .019), although at week 14 the counts in the experimental limb were higher than those of the controls (P = .002). Graft thickness (P = .001) and fibroblast count (P < .004) were lower at week 14 than at earlier time periods for both the experimental and control grafts. CONCLUSIONS: In the rat model, graft thickness and neovascularization of the AlloDerm dermal implant do not appear to be adversely affected by a field that has received EBR. Fibroblast ingrowth may be hindered in the early postimplantation period but appears to normalize in the long term. Furthermore, overall graft thickness and fibroblast counts decrease over time, regardless of irradiation status.
Pseudomonas aeruginosa cell-to-cell signaling is required for virulence in a model of acute pulmonary infection.
Cell-to-cell signaling controls many virulence genes in Pseudomonas aeruginosa. We tested the virulence of las and rhl quorum-sensing mutants in neonatal mice. A lasI rhlI double mutant was nearly avirulent, and the respective single mutant strains were reduced in virulence compared with the wild-type strain. Quorum sensing plays a role in P. aeruginosa pneumonia in neonatal mice.
Simplifying physicians' response to domestic violence.
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Time course inhibition of gastric and platelet COX activity by acetylsalicylic acid in humans.
Aspirin causes peptic ulcers predominately by reducing gastric mucosal cyclooxygenase (COX) activity and prostaglandin synthesis. Because aspirin circulates for only a few hours, we hypothesized that aspirin's inhibitory effect on gastric COX activity must be prolonged. We performed a placebo-controlled experiment in healthy humans to determine the duration of inhibition of aspirin on gastric mucosal COX activity (PGE(2) and PGF(2alpha) synthesis rates). Recovery of gastric COX activity after stopping aspirin was slow and linear. Seventy-two hours after 325-mg aspirin, gastric COX activity was still reduced by 57% (P < 0.001). Duration of inhibition of gastric COX activity was estimated to be 7-8 days after 325-mg aspirin and 5 days after 81-mg aspirin. Recovery of gastric prostaglandin synthesis after 325-mg but not after 81-mg aspirin occurred at slower rates in subjects with Helicobacter pylori-associated gastritis than in those with normal histology. In conclusion, aspirin inhibits gastric COX activity for much longer than predicted from its pharmacokinetic profile, explaining why aspirin at widely spaced intervals is ulcerogenic.
Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine.
Familial dysalbuminemic hyperthyroxinemia (FDH), is the most common cause of inherited increase in serum total T4 (TT4) in the Caucasian population. It is caused by a mutation (R218H) in the human serum albumin (HSA) gene, resulting in 10-fold higher affinity for T4 and, in heterozygous affected subjects, a TT4 level 2-fold higher than that in subjects expressing the wild-type HSA only. We now report FDH in a Swiss family, caused by HSA R218P, previously reported in subjects of Japanese origin. In this form of FDH, serum TT4 levels are 14- to 20-fold the normal mean, confirmed by measurements in serum extracts. TrT3 and TT3, concentrations are 7- and 2-fold above the mean, respectively. Thus, to maintain a normal free T4 level, the calculated affinity constant (Ka) of HSA R218P should be about 16-fold higher than that of HSA R218H. Surprisingly, the Ka values measured at saturation were similar: 5.4 x 10(6) and 6.4 x 10(6) mol/L(-1) for HSA R218H, respectively. To determine how subjects with HSA R218P and R218P maintain a euthyroid state despite the markedly high serum TT4, the concentration of dialyzable T4 was measured at increasing amounts of TT4. At a TT4 level equivalent to that found in the subjects with HSA R218P, the absolute FT4 concentrations were 40, 432, and 1970 pmol/L for sera expressing HSAs R218P, R218H, and wild type, respectively. Thus, the affinity of HSA R218P for T4 must be higher than that of R218H to produce an 11-fold difference in FT4 at the same concentration ofTT4 This difference was obliterated at saturating concentrations of TT4 used for the determination of Ka values by the method of Scatchard.