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Biomedical subjects

J M Adams

Publications and source records attributed to J M Adams.

At least 55 records · Page 3Linked to original sources
PubMed1999

Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.

Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells and succumbed to autoimmune kidney disease. Lymphocytes were refractory to apoptotic stimuli such as cytokine deprivation, calcium ion flux, and microtubule perturbation but not to others. Thus, Bim is required for hematopoietic homeostasis and as a barrier to autoimmunity. Moreover, particular death stimuli appear to activate apoptosis through distinct BH3-only proteins.

Animals↗
PubMed1999

Transgenic models of lymphoid neoplasia and development of a pan-hematopoietic vector.

The pathways to lymphoid neoplasia have been explored in a number of transgenic models. Because B lymphoid malignancies often involve translocation of an oncogene (e.g. myc, bcl-2, cyclin D1) to an immunoglobulin locus, resulting in its deregulated expression, the consequences of oncogene overexpression in lymphocytes can be evaluated with transgenes driven by an immunoglobulin regulatory element, such as an enhancer from the IgH locus. Mice bearing such transgenes have provided insight into the preneoplastic state, including alterations in the control of cellular proliferation, differentiation or apoptosis. They have also allowed studies on oncogene cooperation in vivo and the modulating effect of genetic background. Briefly reviewed here are the models studied in the authors' laboratories. Mice bearing myc and bcl-2 transgenes have received most attention but others studied include abl, ras, cyclin D1 and bmi-1 oncogenes. Also discussed is a new transgenic vector that should facilitate transgenic approaches to non-lymphoid leukemias. The vector bears elements from the promoter region of the vav gene, which is expressed almost exclusively in hematopoietic cells. It has proven capable of driving transgene expression throughout the hematopoietic compartment, including progenitor cells and their precursors. This novel vector should aid studies on many aspects of hematopoiesis, including the modeling of leukemogenesis.

Animals↗
PubMed1999

Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment.

To develop a method for targeting expression of genes to the full hematopoietic system, we have used transgenic mice to explore the transcriptional regulation of the vav gene, which is expressed throughout this compartment but rarely outside it. Previously, we showed that a cluster of elements surrounding its promoter could drive hematopoietic-specific expression of a bacterial lacZ reporter gene, but the expression was confined to lymphocytes and was sporadically silenced. Those limitations are ascribed here to the prokaryotic reporter gene. With a human CD4 (hCD4) cell surface reporter, the vav promoter elements drove expression efficiently and stably in virtually all nucleated cells of adult hematopoietic tissues but not notably in nonhematopoietic cell types. In multiple lines, hCD4 appeared on most, if not all, B and T lymphocytes, granulocytes, monocytes, megakaryocytes, eosinophils, and nucleated erythroid cells. Moreover, high levels appeared on both lineage-committed progenitors and the more primitive preprogenitors. In the fetus, expression was evident in erythroid cells of the definitive but not the primitive type. These results indicate that a prokaryotic sequence can inactivate a transcription unit and that the vav promoter region constitutes a potent transgenic vector for the entire definitive hematopoietic compartment.

Animals↗
PubMed1999

Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1.

The Bcl-2 family of proteins regulates apoptosis, the cell death program triggered by activation of certain proteases (caspases). An attractive model for how Bcl-2 and its closest relatives prevent caspase activation is that they bind to and inactivate an adaptor protein required for procaspase processing. That model has been supported by reports that mammalian prosurvival Bcl-2 relatives bind the adaptor Apaf-1, which activates procaspase-9. However, the in vivo association studies reported here with both overexpressed and endogenous Apaf-1 challenge this notion. Apaf-1 could be immunoprecipitated together with procaspase-9, and the Apaf-1 caspase-recruitment domain was necessary and sufficient for their interaction. Apaf-1 did not bind, however, to any of the six known mammalian prosurvival family members (Bcl-2, Bcl-x(L), Bcl-w, A1, Mcl-1, or Boo), or their viral homologs adenovirus E1B 19K and Epstein-Barr virus BHRF-1. Endogenous Apaf-1 also failed to coimmunoprecipitate with endogenous Bcl-2 or Bcl-x(L), or with two proapoptotic relatives (Bax and Bim). Moreover, apoptotic stimuli did not induce Apaf-1 to bind to these family members. Thus, the prosurvival Bcl-2 homologs do not appear to act by sequestering Apaf-1 and probably instead constrain its activity indirectly.

Apoptosis↗
PubMed1999

Insights from Bcl-2 and Myc: malignancy involves abrogation of apoptosis as well as sustained proliferation.

The chromosome translocations typifying Burkitt's lymphoma and follicular lymphoma deregulate very different oncogenes, myc and bcl-2. Transgenic mouse models have illuminated how each contributes to lymphomagenesis. Constitutive myc expression provokes sustained cell proliferation and retards differentiation. However, the resulting expansion in cell number is self-limiting, because the cells remain dependent on cytokines and undergo apoptosis when these become limiting. In contrast, bcl-2 is the prototype of a new class of oncogene that enhances cell survival but does not promote proliferation. Coexpression of these genes leads to the rapid transformation of lymphocytes, probably because each can counter an antioncogenic aspect of the other. Several close homologues of Bcl-2 also enhance cell survival and are thus potential oncogenes; each is essential for maintenance of particular major organs. More distant Bcl-2 relatives instead promote apoptosis and can be regarded as tumor suppressors. For many but not all apoptic signals, the balance between these competing activities determines cell survival. Learning how to adjust the apoptotic threshold in cancer cells should promote development of more effective therapeutic strategies.

Animals↗
PubMed1999

Retroviral transduction of enriched hematopoietic stem cells allows lifelong Bcl-2 expression in multiple lineages but does not perturb hematopoiesis.

Transduction of hematopoietic stem cells with a novel retrovirus has allowed long-term expression of human Bcl-2 in multiple hematopoietic lineages. Thy-1.2lo Sca-1+ H-2Khi stem cells enriched from the bone marrow of 5-fluorouracil-treated (Ly5-2) mice were infected with the bcl-2 retrovirus and injected into (Ly5-1) irradiated recipients. Analysis at 5 months indicated that reconstitution of hematopoiesis occurred predominantly from donor-derived (Ly5-2+) stem cells and that, in half the mice (18 of 35), most blood cells derived from virally transduced stem cells. The level of Bcl-2 expression achieved with the retroviral vector approached that of a well-characterized transgenic vector and could be sustained for life in several blood cell lineages. In the 25 mice assessed at 10 months, human Bcl-2 was readily detectable in 62+/-22% of Ly5-2+ peripheral blood leukocytes. More detailed analysis of a cohort killed between 14 and 20 months established that human Bcl-2 protein could be detected in B and T lymphocytes, granulocytes, macrophages, and some immature erythroid cells. Furthermore, hematopoietic stem cells from the bone marrow of these mice maintained Bcl-2 expression in hematopoietic tissues of secondary recipients for at least another 19 months. These data provide clear evidence for efficient infection of primitive hematopoietic stem cells and for maintenance of proviral expression for over 2.5 years, the lifespan of mice. The level of exogenous Bcl-2 was sufficient to enhance survival of B and T lymphoid cells, granulocytes, and myeloid colony-forming cells cultured under suboptimal conditions, but hematopoiesis in the mice was not notably perturbed.

Animals↗
PubMed1999

Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members.

Certain Bcl-2 family members promote cell survival, whereas others promote apoptosis. To explore further how heterodimerization of opposing members affects survival activity, we have compared the abilities of the anti-apoptotic Bcl-w and A1 to bind to the pro-apoptotic Bax, Bak, Bad and Bik and to protect cells from their cytotoxic action. Bcl-w co-immunoprecipitated from cell lysates with Bax, Bak, Bad and Bik, but A1 bound only Bak and Bik. Mutation of A1 at a highly conserved glycine within the BH1 domain prevented binding, but the comparable Bcl-w mutant still bound Bak, Bad and Bik, indicating that the glycine is not essential for all heterodimerization. Bcl-w and A1 protected against apoptosis induced by over-expression of Bax or Bad but not that induced by Bak or Bik. With several gene pairs, binding and protection were discordant. The results may reflect critical threshold affinities but also suggest that certain pro-apoptotic proteins may also contribute to apoptosis by a mechanism independent of binding pro-survival proteins.

Animals↗
PubMed1999

Interference with gene expression induces rapid apoptosis in p53-null T lymphoma cells.

Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of gene expression. With either actinomycin D or cycloheximide, apoptosis commenced within 2 h, as indicated by loss of membrane integrity, degradation of certain proteins (including the phosphatase calcineurin) and DNA fragmentation. These effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in place in these cells but held in check by an unknown labile protein, which probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or p38 MAP kinases in some cells, neither was implicated here. However, disruption of phosphoinositide 3-kinase signaling may be involved, because the cells were also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells to inhibitors of gene expression suggests that such inhibitors might prove useful in the cytotoxic therapy of certain tumors.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Inhibin A and inhibin B responses to gonadotropin withdrawal depends on stage of follicle development.

Previous studies demonstrate that inhibin A and B are differentially secreted across the menstrual cycle. To test the hypothesis that the responses of inhibin A and inhibin B to partial gonadotropin withdrawal are influenced by the stage of follicular development, a maximally suppressive dose of the Nal-Glu GnRH antagonist (150 microg/kg) was administered to normal cycling women during the midfollicular (MFP; n = 8), late follicular (LFP; n = 6), and midluteal phase (MLP; n = 5) to assess ovarian responsiveness over a broad range of developmental stages. Administration of the GnRH antagonist resulted in a significant decrease in LH (75 +/- 5%, 63 +/- 3%, and 84 +/- 7%; P < 0.05) and FSH (23 +/- 9%, 32 +/- 5%, and 39 +/- 6%; P < 0.04) during the MFP, LFP, and MLP, respectively. During the MFP, partial withdrawal of gonadotropins resulted in disappearance of the dominant follicle on ultrasound accompanied by a decrease in estradiol (E2; 64.9 +/- 11.4 to 23.9 +/- 3.3 pg/mL; P < 0.02) and inhibin B levels (121.6 +/- 14.8 to 28.4 +/- 4.8 pg/mL; P < 0.002) from baseline to near the limit of detection. Inhibin A was near the limit of detection in this cycle stage (0.8 +/- 0.1 IU/mL). When gonadotropins were withdrawn during the LFP, the size of the dominant follicle remained stationary in four of five subjects, and inhibin B (84.1 +/- 14.1 to 22.2 +/- 3.4 pg/mL; 71 +/- 5%; P < 0.02), inhibin A (4.4 +/- 1.1 to 1.3 +/- 0.5 IU/mL; 71 +/- 7%; P < 0.02), and E2 (236.8 +/- 48.2 to 95.6 +/- 39.0 pg/mL; 61 +/- 12%; P < 0.02) decreased similarly. Time to ovulation was shorter in association with higher inhibin A (r = -0.67; P < 0.02) and E2 (r = -0.79; P < 0.003), but there was no relation to inhibin B. During the MLP, decreased gonadotropin levels resulted in the disappearance of corpus luteum function with a significant decrease in inhibin A (9.0 +/- 0.4 to 0.7 +/- 0.1 IU/mL; 92 +/- 1%; P < 0.0001) in combination with decreased E2 (150.4 +/- 22.9 to 23.8 +/- 4.2 pg/mL; 83 +/- 3%; P < 0.005) and progesterone (12.6 +/- 2.6 to 0.9 +/- 0.2 ng/mL; 92 +/- 2%; P < 0.01). Administration of a GnRH antagonist at precise stages of the menstrual cycle provides further evidence that differential regulation of inhibin A and inhibin B is critically dependent on the stage of follicular development. Inhibin B secretion is exquisitely sensitive to gonadotropin withdrawal during the MFP when inhibin A has not yet risen. Inhibin A and inhibin B decrease equally after GnRH antagonist administration during the LFP. However, before antagonist administration, the positive correlation between estradiol and inhibin A and time to ovulation and the lack of such a correlation with inhibin B suggest that the source of inhibin B secretion is different from that of inhibin A and E2. The decrease in inhibin A secretion after antagonist administration during the luteal phase confirms gonadotropin-dependent secretion of dimeric inhibin A by the corpus luteum.

Adult↗
PubMed1999

Selecting a clinical system.

For more than three decades, health care information systems have built upon the administrative and financial information needs of the health care delivery organization. Industry analysts project that administrative and financial information systems will continue to be important to health care, but post-Y2K resources increasingly will fall on the purchase, installation and support of clinical documentation and reporting tools. This manuscript provides a brief overview of the electronic medical record (EMR), and identifies and explains the need for EMRs in health care. This article also provides strategies for medical group managers and information systems managers to successfully select and negotiate a contract for an electronic medical record.

Clinical Medicine↗
PubMed1998

Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant.

Proteins of the Bcl-2 family are important regulators of apoptosis in many tissues of the embryo and adult. The recently isolated bcl-w gene encodes a pro-survival member of the Bcl-2 family, which is widely expressed. To explore its physiological role, we have inactivated the bcl-w gene in the mouse by homologous recombination. Mice that lack Bcl-w were viable, healthy, and normal in appearance. Most tissues exhibited typical histology, and hematopoiesis was unaffected, presumably due to redundant function with other pro-survival family members. Although female reproductive function was normal, the males were infertile. The testes developed normally, and the initial, prepubertal wave of spermatogenesis was largely unaffected. The seminiferous tubules of adult males, however, were disorganized, contained numerous apoptotic cells, and produced no mature sperm. Both Sertoli cells and germ cells of all types were reduced in number, the most mature germ cells being the most severely depleted. The bcl-w-/- mouse provides a unique model of failed spermatogenesis in the adult that may be relevant to some cases of human male sterility.

Animals↗
PubMed1998

The Bcl-2 protein family: arbiters of cell survival.

Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer.

Animals↗
PubMed1998

The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4.

Bcl-2 and close homologues such as Bcl-xL promote cell survival, while other relatives such as Bax antagonize this function. Since only the pro-survival family members possess a conserved N-terminal region denoted BH4, we have explored the role of this amphipathic helix for their survival function and for interactions with several agonists of apoptosis, including Bax and CED-4, an essential regulator in the nematode Caenorhabditis elegans. BH4 of Bcl-2 could be replaced by that of Bcl-x without perturbing function but not by a somewhat similar region near the N-terminus of Bax. Bcl-2 cell survival activity was reduced by substitutions in two of ten conserved BH4 residues. Deletion of BH4 rendered Bcl-2 (and Bcl-xL) inactive but did not impair either Bcl-2 homodimerization or ability to bind to Bax or five other pro-apoptotic relatives (Bak, Bad, Bik, Bid or Bim). Hence, association with these death agonists is not sufficient to promote cell survival. Significantly, however, Bcl-xL lacking BH4 lost the ability both to bind CED-4 and antagonize its pro-apoptotic activity. These results favour the hypothesis that the BH4 domain of pro-survival Bcl-2 family members allows them to sequester CED-4 relatives and thereby prevent apoptosis.

Amino Acid Sequence↗
PubMed1998

Bim: a novel member of the Bcl-2 family that promotes apoptosis.

Certain members of the Bcl-2 family inhibit apoptosis while others facilitate this physiological process of cell death. An expression screen for proteins that bind to Bcl-2 yielded a small novel protein, denoted Bim, whose only similarity to any known protein is the short (nine amino acid) BH3 motif shared by most Bcl-2 homologues. Bim provokes apoptosis, and the BH3 region is required for Bcl-2 binding and for most of its cytotoxicity. Like Bcl-2, Bim possesses a hydrophobic C-terminus and localizes to intracytoplasmic membranes. Three Bim isoforms, probably generated by alternative splicing, all induce apoptosis, the shortest being the most potent. Wild-type Bcl-2 associates with Bim in vivo and modulates its death function, whereas Bcl-2 mutants that lack survival function do neither. Significantly, Bcl-xL and Bcl-w, the two closest homologues of Bcl-2, also bind to Bim and inhibit its activity, but more distant viral homologues, adenovirus E1B19K and Epstein-Barr virus BHRF-1, can do neither. Hence, Bim appears to act as a 'death ligand' which can only neutralize certain members of the pro-survival Bcl-2 sub-family.

Amino Acid Sequence↗
PubMed1998

Transcriptional regulation of vav, a gene expressed throughout the hematopoietic compartment.

The vav gene is expressed in all hematopoietic but few other cell types. To explore its unusual compartment-wide regulation, we cloned the murine gene, sequenced its promoter region, identified DNase I hypersensitive (HS) sites in the chromatin, and tested their promoter activity with a beta-galactosidase (beta-gal) reporter gene in cell lines and transgenic mice. Whereas fibroblasts had no HS sites, a myeloid and an erythroid cell line contained five, located 0.2 kb (HS1), 1.9 kb (HS2), and 3.6 kb (HS3) upstream from the transcription start and 0.6 kb (HS4) and 10 kb (HS5) downstream. A vav DNA fragment including HS1 promoted beta-gal expression in a myeloid but not a fibroblast line. Expression in leukocytes of transgenic mice also required HS2 and HS5. Only hematopoietic organs contained beta-gal, but virtually all beta-gal+ cells were B or T lymphocytes. Expression was always variegated (mosaic), and the proportion of beta-gal+ cells declined with lymphoid maturation and animal age. Thus, these vav regulatory elements promoted hematopoietic-specific expression in vivo, at least in lymphocytes, but the transgene was sporadically silenced. Maintaining pan-hematopoietic expression may require additional vav elements or an alternative reporter.

3T3 Cells↗
PubMed1998

Previous infection with Helicobacter pylori is the primary determinant of spontaneous gastric hypoacidity in human immunodeficiency virus-infected outpatients.

To investigate the incidence and demographics of gastric hypoacidity among persons infected with human immunodeficiency virus (HIV), 146 asymptomatic subjects were evaluated with use of a radiotelemetry device (Heidelberg capsule). Gastric hypoacidity (minimum gastric pH of > or = 3) occurred in 24 subjects (17%). Demographic characteristics, CD4 cell counts, and Helicobacter pylori serological status were evaluated for an association with gastric pH. Subjects with hypoacidity were more likely to have positive H. pylori serology than were subjects without hypoacidity (15 of 24 vs. 23 of 74, respectively; P = .004). Multivariate analysis indicated that a positive H. pylori serology was the most significant predictor of hypoacidity, accounting for an increase in gastric pH of 39%. A history of injection drug use, heterosexual transmission of HIV, and male gender were also associated with an elevated gastric pH. CD4 cell counts did not contribute to predictions of gastric pH. A history of H. pylori infection is relatively common in HIV-positive black and Hispanic populations and is a predictor of gastric pH.

AIDS-Related Opportunistic Infections↗