PubMed Health⌕ Search

Biomedical subjects

L Davidson

Publications and source records attributed to L Davidson.

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

Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha.

Phosphoinositide 3-kinase (PI3K) activation has been implicated in many cellular responses, including fibroblast growth, transformation, survival, and chemotaxis. Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in lymphocyte function is not clear. The mouse gene encoding the PI3K adapter subunit p85alpha and its splice variants p55alpha and p50alpha was disrupted. Most p85alpha-p55alpha-p50alpha-/- mice die within days after birth. Lymphocyte development and function was studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation and decreased survival after incubation with interleukin-4. In contrast, T cell development and proliferation was normal. This phenotype is similar to defects observed in mice lacking the tyrosine kinase Btk.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Activated Ras signals developmental progression of recombinase-activating gene (RAG)-deficient pro-B lymphocytes.

To elucidate the intracellular pathways that mediate early B cell development, we directed expression of activated Ras to the B cell lineage in the context of the recombination-activating gene 1 (RAG1)-deficient background (referred to as Ras-RAG). Similar to the effects of an immunoglobulin (Ig) mu heavy chain (HC) transgene, activated Ras caused progression of RAG1-deficient progenitor (pro)-B cells to cells that shared many characteristics with precursor (pre)-B cells, including downregulation of surface CD43 expression plus expression of lambda5, RAG2, and germline kappa locus transcripts. However, these Ras-RAG pre-B cells also upregulated surface markers characteristic of more mature B cell stages and populated peripheral lymphoid tissues, with an overall phenotype reminiscent of B lineage cells generated in a RAG- deficient background as a result of expression of an Ig mu HC together with a Bcl-2 transgene. Taken together, these findings suggest that activated Ras signaling in pro-B cells induces developmental progression by activating both differentiation and survival signals.

Animals↗
PubMed1999

On the road to collaborative treatment planning: consumer and provider perspectives.

Although consumers have made significant gains in having their voices heard in several areas within mental health, they have made less progress in being able to collaborate with their own treaters in setting treatment goals. On the basis of several years of groundwork by staff at the Connecticut Mental Health Center (CMHC), the Patient Care Committee conducted a needs assessment of providers and consumers to assess both groups' current involvement, interest in, and attitudes toward collaborative treatment planning. The results indicate that providers tend to place much of the responsibility for the difficulties in implementing collaborative treatment planning on consumers. Also, providers tend to underestimate consumers' interest in participating in this process. Implications of these findings for the development of an agency-wide training to enhance the collaborative nature of treatment planning are discussed.

Adult↗
PubMed1999

Developmental regulation of TCR delta locus accessibility and expression by the TCR delta enhancer.

We have used gene-targeted mutation to assess the role of the T cell receptor delta (TCR delta) enhancer (E delta) in alphabeta and gammadelta T cell development. Mice lacking E delta exhibited no defects in alphabeta T cell development but had a severe reduction in thymic and peripheral gammadelta T cells and decreased VDJ delta rearrangements. Simultaneous deletion of both E delta and the TCR alpha enhancer (E alpha) demonstrated that residual TCR delta rearrangements were not driven by E alpha, implicating additional elements in TCR delta locus accessibility. Surprisingly, while deletion of E delta severely impaired germline TCR delta expression in double-negative thymocytes, absence of E delta did not affect expression of mature delta transcripts in gammadelta T cells. We conclude that E delta has an important role in TCR delta locus regulation at early, but not late, stages of gammadelta T cell development.

Animals↗
PubMed1999

Immature thymocytes employ distinct signaling pathways for allelic exclusion versus differentiation and expansion.

T cell receptor (TCR) beta chain allelic exclusion occurs at the thymocyte CD4- 8- (double-negative, or DN) to CD4+ 8+ (double-positive, or DP) transition, concurrently with differentiation and cellular expansion, and is imposed by a negative feedback loop in which a product of the first rearranged TCRbeta allele arrests further recombination in the TCRbeta locus. All of the major events associated with the development of DP cells can be induced by the introduction of TCRbeta or activated Lck transgenes. Here, we present evidence that the signaling pathways that promote thymocyte differentiation and expansion of RAG-deficient DN cells but not those that suppress rearrangements of endogenous TCRbeta genes in normal DN cells are engaged by activated Ras. We propose that TCRbeta allelic exclusion is mediated by effector pathways downstream of Lck but independent of Ras.

Alleles↗
PubMed1999

RAG2:GFP knockin mice reveal novel aspects of RAG2 expression in primary and peripheral lymphoid tissues.

We generated mice in which a functional RAG2:GFP fusion gene is knocked in to the endogenous RAG2 locus. In bone marrow and thymus, RAG2:GFP expression occurs in appropriate stages of developing B and T cells as well as in immature bone marrow IgM+ B cells. RAG2:GFP also is expressed in IgD+ B cells following cross-linking of IgM on immature IgM+ IgD+ B cells generated in vitro. RAG2:GFP expression is undetectable in most immature splenic B cells; however, in young RAG2:GFP mice, there are substantial numbers of splenic RAG2:GFP+ cells that mostly resemble pre-B cells. The latter population decreases in size with age but reappears following immunization of older RAG2:GFP mice. We discuss the implications of these findings for current models of receptor assembly and diversification.

Animals↗
PubMed1999

Symptom assessment in schizophrenic prodromal states.

Individuals who develop schizophrenia often suffer long standing deficits. All too often available treatments remain palliative and do not improve the long-term course of illness. The neurobiological deficits associated with the onset of schizophrenia may be most active and damaging in the early stages of this life long illness, a fact which has shifted the focus of research and clinical work toward the early or prodromal stages of this disorder. Results from limited studies suggest that early intervention may lead to a better prognosis. Early interventions that could delay or prevent the onset of psychotic illnesses have obvious public health implications and rely on being able to identify true prodromal patients. The Structured Interview for Prodromal Symptoms and the Scale of Prodromal Symptoms are assessment instruments developed for operationally defining diagnosis and for quantitatively rating symptom severity for patients prodromal for psychosis.

Antipsychotic Agents↗
PubMed1999

Therapeutic agents of assertive community treatment.

The goal of this study was to learn how assertive community treatment (ACT) contributes to the improvement of those with serious mental illness in order to contribute to the growing clinical literature regarding the therapeutic agents of ACT teams. Methods included reviewing the case records of three ACT clients who have improved significantly, as well as interviewing the clients themselves and their clinicians. The results indicated that there was significant agreement among the case records, the clients, and their clinicians in identifying the most useful aspects of assertive community treatment. Primary among these factors were the persistence demonstrated by ACT clinicians in engaging their clients, the trust that clients developed in their clinicians, and as a result, the process by which their clinicians became "guides" to the world of psychiatric and social services that further facilitated their clients' community adjustment. In closing, we consider implications from these findings both for staff development for ACT team members, and for suggestions toward the development of a model of recovery from serious mental illness.

Adult↗
PubMed1999

Measurement of abdominal fat by magnetic resonance imaging, dual-energy X-ray absorptiometry and anthropometry in non-obese men and women.

OBJECTIVE: To investigate whether the dual-energy X-ray absorptiometry (DEXA) was a better predictor of abdominal fat, measured by magnetic resonance imaging (MRI) at the level of L2-L3, than anthropometric measurements in non-obese men and non-obese women. DESIGN: Observational, cross sectional study. SUBJECTS: 34 healthy subjects (17 men and 17 women) aged 20-53 y with a body mass index (BMI) < 30 kg/m2. MEASUREMENTS: Fat distribution parameters including waist circumference and waist-to-hip ratio (WHR); intra abdominal fat (IAF) by MRI; and central abdominal fat (CAF) by DEXA. RESULTS: Measurement of IAF by MRI, was highly correlated to the CAF measured by DEXA. In men, both waist circumference and WHR had similar correlation to IAF as DEXA. In women, waist circumference was less well correlated with IAF than DEXA, and the WHR had a weaker non significant correlation with IAF. CONCLUSIONS: In non-obese men; DEXA, waist circumference and WHR can predict IAF equally well, while in non-obese women, DEXA is superior to waist circumference and much better than WHR.

Abdomen↗
PubMed1999

Clinicians' and clients' perspectives on the impact of assertive community treatment.

OBJECTIVE: Clients in an assertive community treatment program and their clinicians were asked to rate clients' current difficulties in 13 quality-of-life areas to determine whether improvement in any area predicted reductions in hospitalization and incarceration. METHODS: A peer counselor interviewed 45 clients about psychiatric symptoms, substance use and abuse, medical issues, medication compliance, primary supports, social supports, vocational and occupational issues, housing, daily living skills, economic issues and entitlements, legal involvement, behavioral issues, and treatment involvement. The clients' clinicians rated the clients in these same areas. Ratings of clients' difficulties in these areas at program entry were based on combined ratings made at intake and after a review of clients' charts. Data on hospitalization and incarceration were obtained from medical and police records. Logistic regression analyses were used to seek predictors of declines in admissions to hospitals and jails (referred to as institutional admissions). RESULTS: Institutional admissions decreased after program entry; decreases were larger among clients admitted in recent years. Clients improved significantly in all 13 quality-of-life areas based on comparisons of both clinicians' and clients' ratings and baseline ratings; however, clients rated themselves as having less difficulty than their clinicians thought they had in the areas of substance abuse, medication compliance, primary supports, social supports, daily living skills, and treatment involvement. Based on clinicians' ratings, improvement in substance abuse issues predicted declines in institutionalized admissions. Based on clients' ratings, improvement in social support and economic issues predicted declines. CONCLUSIONS: These findings emphasize the importance of clients' perspectives in treatment planning and suggest that clinicians may overlook the smaller incremental steps toward improvement that are valued by clients.

Activities of Daily Living↗
PubMed1999

Approaches to enhance expression after adenovirus-mediated gene transfer to the carotid artery.

The goal of this study was to enhance transgene expression after adenoviral-mediated gene transfer to the carotid artery. We used an adenoviral vector with a transgene that expresses beta-galactosidase, driven by the human cytomegalovirus (CMV) promoter/enhancer. The CMV promoter drives constitutive expression, and response elements within the enhancer allow inducible expression through binding of active transcription factors, such as cAMP response element binding protein (CREB) and nuclear factor kappa B (NFkappaB). Rings of rabbit carotid artery were incubated ex vivo with a replication-deficient adenovirus that expresses beta-galactosidase (AdCMV-betagal). Virus was removed from the medium, and forskolin or phorbol-12-myristate-13-acetate (PMA), which can induce activation of CREB or NFkappaB, respectively, were added to the medium. Pyrrolidine dithiocarbamate (PDTC) was used to inhibit activation of NFkappaB. Following incubation for 24 hours, beta-galactosidase activity was assessed by chemiluminescent reporter assay. Forskolin and PMA enhanced transgene expression in the carotid artery. Activity increased from 56+/-13 mU/mg protein (mean+/-SE) in rings of carotid treated with virus alone (10(9) pfu) to 159+/-23 mU/mg protein (P<0.05) in rings treated with forskolin, and to 189+/-40 mU/mg protein (P<0.05) in rings treated with PMA. Phorbol didecanoate, an inactive phorbol, did not affect expression of beta-galactosidase. After pre-incubation with PDTC prior to PMA, expression of beta-galactosidase was less than in rings incubated with PMA alone (29+/-11, P<0.05). Histochemical staining of carotid artery for beta-galactosidase demonstrated enhanced endothelial expression following administration of PMA. These findings suggest that expression after gene transfer to the carotid artery using an adenoviral vector with the CMV promoter/enhancer may be enhanced by PMA and forskolin, perhaps by activation of transcription factors.

Activating Transcription Factor 1↗
PubMed1999

School age prostitution: an issue for children's nurses?

Creating supportive environments for street working children requires children's nurses to be knowledgeable. Strengthening community action requires awareness of existing groups who currently work with child prostitutes. Nurses need to develop counselling skills to enable child prostitutes to make healthy choices. Building healthy public policies challenges nurses to mediate with politicians regarding policies which may adversely affect children. A health service, re-oriented to improve the care of school age prostitutes, necessitates collaboration with health, community and charity workers.

Adolescent↗
PubMed1998

A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis.

XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins and point to the general stage of neuronal development in which these proteins are necessary.

Animals↗
PubMed1998

Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV.

The DNA-end-joining reactions used for repair of double-strand breaks in DNA and for V(D)J recombination, the process by which immunoglobulin and T-cell antigen-receptor genes are assembled from multiple gene segments, use common factors. These factors include components of DNA-dependent protein kinase (DNA-PK), namely DNA-PKcs and the Ku heterodimer, Ku70-Ku80, and XRCC4. The precise function of XRCC4 is unknown, but it interacts with DNA ligase IV. Ligase IV is one of the three known mammalian DNA ligases; however, the in vivo functions of these ligases have not been determined unequivocally. Here we show that inactivation of the ligase IV gene in mice leads to late embryonic lethality. Lymphopoiesis in these mice is blocked and V(D)J joining does not occur. Ligase IV-deficient embryonic fibroblasts also show marked sensitivity to ionizing radiation, growth defects and premature senescence. All of these phenotypic characteristics, except embryonic lethality, resemble those associated with Ku70 and Ku80 deficiencies, indicating that they may result from an impaired end-joining process that involves both Ku subunits and ligase IV. However, Ku-deficient mice are viable, so ligase IV must also be required for processes and/or in cell types in which Ku is dispensable.

Animals↗
PubMed1998

Class switching in B cells lacking 3' immunoglobulin heavy chain enhancers.

The 40-kb region downstream of the most 3' immunoglobulin (Ig) heavy chain constant region gene (Calpha) contains a series of transcriptional enhancers speculated to play a role in Ig heavy chain class switch recombination (CSR). To elucidate the function of this putative CSR regulatory region, we generated mice with germline mutations in which one or the other of the two most 5' enhancers in this cluster (respectively referred to as HS3a and HS1,2) were replaced either with a pgk-neor cassette (referred to as HS3aN and HS1,2N mutations) or with a loxP sequence (referred to as HS3aDelta and HS1,2Delta, respectively). B cells homozygous for the HS3aN or HS1,2N mutations had severe defects in CSR to several isotypes. The phenotypic similarity of the two insertion mutations, both of which were cis-acting, suggested that inhibition might result from pgk-neor cassette gene insertion rather than enhancer deletion. Accordingly, CSR returned to normal in B cells homozygous for the HS3aDelta or HS1,2Delta mutations. In addition, induced expression of the specifically targeted pgk-neor genes was regulated similarly to that of germline CH genes. Our findings implicate a 3' CSR regulatory locus that appears remarkably similar in organization and function to the beta-globin gene 5' LCR and which we propose may regulate differential CSR via a promoter competition mechanism.

Animals↗
PubMed1998

The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow.

The TEL (translocation-Ets-leukemia or ETV6) locus, which encodes an Ets family transcription factor, is frequently rearranged in human leukemias of myeloid or lymphoid origins. By gene targeting in mice, we previously showed that TEL-/- mice are embryonic lethal because of a yolk sac angiogenic defect. TEL also appears essential for the survival of selected neural and mesenchymal populations within the embryo proper. Here, we have generated mouse chimeras with TEL-/- ES cells to examine a possible requirement in adult hematopoiesis. Although not required for the intrinsic proliferation and/or differentiation of adult-type hematopoietic lineages in the yolk sac and fetal liver, TEL function is essential for the establishment of hematopoiesis of all lineages in the bone marrow. This defect is manifest within the first week of postnatal life. Our data pinpoint a critical role for TEL in the normal transition of hematopoietic activity from fetal liver to bone marrow. This might reflect an inability of TEL-/- hematopoietic stem cells or progenitors to migrate or home to the bone marrow or, more likely, the failure of these cells to respond appropriately and/or survive within the bone marrow microenvironment. These data establish TEL as the first transcription factor required specifically for hematopoiesis within the bone marrow, as opposed to other sites of hematopoietic activity during development.

Animals↗