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Biomedical subjects

L Davidson

Publications and source records attributed to L Davidson.

At least 73 records · Page 4Linked to original sources
PubMed1996

Deletion of the Ig kappa light chain intronic enhancer/matrix attachment region impairs but does not abolish V kappa J kappa rearrangement.

Roles of the kappa intronic enhancer (iE kappa) and its associated matrix attachment region (MAR) during B cell development were examined using mutant embryonic stem (ES) cell lines in which the entire region on both chromosomes was replaced with either a recombined LoxP site (E kappa ND) or the PGK-neomycin resistance (PGK-neo(r)) gene (E kappa NI). B cells derived from E kappa ND ES cells had greatly impaired V kappa J kappa rearrangement, normal levels of kappa expression, and kappa:lambda ratios of 1:1 instead of the usual 10:1. Furthermore, lambda-producing hybridomas derived from E kappa ND cells displayed little kappa rearrangement. Thus, the MAR and iE kappa are quantitatively significant for kappa rearrangement but not necessary. In addition, little V kappa J kappa rearrangement could be detected in B cells derived from E kappa NI ES cells, demonstrating that an inserted PGK-neo(r) gene dominantly suppresses V kappa J kappa rearrangement.

Animals↗
PubMed1996

The Ig(kappa) enhancer influences the ratio of Ig(kappa) versus Ig(lambda) B lymphocytes.

We generated mice harboring germline mutations in which the enhancer element located 9 kb 3' of the immunoglobulin kappa light chain gene (3'E kappa) was replaced either by a single loxP site (3'E kappa delta) or by a neomycin resistance gene (3'E kappa N). Mice homozygous for the 3'E(kappa delta) mutation had substantially reduced numbers of kappa-expressing B cells and increased numbers of lambda-expressing B cells accompanied by decreased kappa versus lambda gene rearrangement. In these mutant mice, kappa expression was reduced in resting B cells, but was normal in activated B cells. The homozygous 3'E(kappa)N mutation resulted in a similar but more pronounced phenotype. Both mutations acted in cis. These studies show that the 3'E(kappa) is critical for establishing the normal kappa/lambda ratio, but is not absolutely essential for kappa gene rearrangement or, surprisingly, for normal kappa expression in activated B cells. These studies also imply the existence of additional regulatory elements that have overlapping function with the 3'E(kappa) element.

Animals↗
PubMed1996

Day hospital/crisis respite care versus inpatient care, Part I: Clinical outcomes.

OBJECTIVE: The authors investigated the clinical feasibility and the outcome for patients of a program designed as an alternative to acute hospitalization. METHOD: This was a random-design study comparing a conventional inpatient program for urban, poor, severely ill voluntary patients who usually require hospitalization to an alternative experimental program consisting of a day hospital linked to a crisis residence. Patients were assessed with standardized measures of symptoms, functioning, social adjustment, quality of life, and satisfaction with clinical services upon admission to the study, at discharge from the index admission, and at follow-ups 2, 5, and 10 months after discharge. RESULTS: One hundred ninety-seven patients were enrolled in the 2-year research program and followed for 10 months. Of the voluntary patients who would have been admitted to the hospital, 83% were appropriate for the experimental program. The clinical, functional, social adjustment, quality of life, and satisfaction outcome measures were not statistically different for the patients in the two treatment conditions; however, there was a slightly more positive effect of the experimental program on measures of symptoms, overall functioning, and social functioning. CONCLUSIONS: The experimental condition, a combined day hospital/crisis respite community residence, seems to have had the same treatment effectiveness as acute hospital care for urban, poor, acutely ill voluntary patients with severe mental illness.

Community Mental Health Services↗
PubMed1996

Differences in social environment between inpatient and day hospital-crisis respite settings.

OBJECTIVE: The study compared the social environment of a conventional psychiatric inpatient setting with that of a combined acute day hospital and crisis respite program that functions as an alternative to hospitalization for patients judged appropriate for acute inpatient admission. METHODS: As part of a randomized controlled study comparing the clinical effectiveness and cost-effectiveness of the two settings, the quality of the social environment in the two settings was assessed using the Multiphasic Environmental Assessment Procedure, an empirical measure of established reliability and validity that is based on objective ratings and perceptions of staff members and patients. RESULTS: Compared with the inpatient setting, the day hospital-crisis respite program had higher expectations for patients' functioning, a lower tolerance for deviance, and more flexibility in patients' choice of activities. The day hospital-crisis respite program also had a more attractive physical environment, and respondents rated its social milieu as more cohesive, less conflictual, and more comfortable. This setting also promoted higher levels of patient functioning and activity and more utilization of health services, assistance with daily living skills, and social and recreational resources and encouraged fuller integration of patients in the community. CONCLUSIONS: The social environment of the community-based day hospital-crisis respite program embodied several principles of community support systems, including provision of treatment in a less restrictive setting, avoiding disruption of patients' ongoing involvement in the community, promoting activities in the community, offering patients respect and opportunities for self-determination, and enhancing their dignity.

Activities of Daily Living↗
PubMed1996

Examination of p53 alterations and cytokeratin expression in sputa collected from patients prior to histological diagnosis of squamous cell carcinoma.

Mutations in the p53 gene are detected in greater than 50% of squamous cell carcinomas of the lung and to a lesser extent in adenocarcinomas. The p53 protein is also overexpressed in a relatively high percentage of preinvasive lesions of the bronchial epithelium. However, unlike tumor tissue, immunoreactivity does not necessarily imply that cells in preinvasive lesions carry a mutant p53 allele. In some cases, overexpression may result from a cellular checkpoint reaction to a toxic or mutagenic substance such as exposure to tobacco smoke. In any case, p53 overexpression in preinvasive lesions may serve as a biomarker for high risk assessment of lung cancer and other tumors in the aerodigestive tract. A study was designed to retrospectively analyze p53 overexpression in cells from sputum samples collected prior to histological tumor diagnosis. The rationale was based on the observation that both preinvasive and tumor cells from the bronchial epithelium are exfoliated into the airways and can be detected based on morphology in sputa. Two sets of cases were chosen: 1) patients whose first primary tumor was a squamous cell carcinoma containing a mutant p53 allele with overexpression observed in most of the tumor cells; and 2) patients whose squamous cell tumor did not contain a mutant p53 allele. Cells which stained positive for p53 expression were observed in sputum samples collected from all six patients whose tumors were positive for a mutant p53 allele. Also p53 positive cells were detected on sputum slides for two of the five cases where the tumor DNA did not contain a mutation and/or tumor cells which overexpress p53 were not detected in tissue sections. Although cells which stained positive for p53 were present in sputum from patients whose tumors contained a missense mutation, the presence of p53 overexpression was not specific for tumors which contain an altered p53 allele since overexpression was detected in sputum cells from patients whose tumor DNA did not contain a p53 mutation and/or tumor cells which stained positive for p53 were not observed in tissue sections. However, the p53 positive cells in sputa collected from the latter group of patients could have been exfoliated from other lesions which contained a mutant p53 allele. The accumulation of p53 in some sputum cells was concomitant with expression of simple epithelial type cytokeratins (CK) 8 and 18 or at least one of the other cytokeratins detected by a broad spectrum (PAN) CK antibody mixture. These data imply that most of the sputum cells which overexpress p53 are epithelial cells. Moreover, our results are consistent, at least in part, with other observations that cells which overexpress p53 in dyplasias and hyperplasias express CK 8, 18. We will continue to explore the possibility that expression of cytokeratins 8, 18 and/or other cytokeratins in conjunction with p53 overexpression and/or morphological criteria could define a new class of atypical cells which are predisposed to cancer development.

Alleles↗
PubMed1995

Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene.

The Ets-1 proto-oncogene is a member of a transcription factor family characterized by homology to the v-ets oncogene. In adult mice, Ets-1 is expressed predominantly in lymphoid cells where it has been implicated in regulating transcription of lymphocyte-specific genes. Following T-cell activation, the specific DNA binding activity of Ets-1 is inactivated by transient phosphorylation, suggesting a function in the transition from the resting to activated state. Ets-1 has also been suggested to cooperate with the AP-1 transcription factor complex to mediate cellular growth factor responses. Here we show, by using RAG-2-deficient blastocyst complementation, that Ets-1 deficiency has dramatic, but different, effects on development and function of T- and B-lineage cells. Ets-1-deficient T cells were present in reduced numbers and were highly susceptible to cell death in vitro. In contrast, Ets-1-deficient B cells were present in normal numbers but a large proportion were IgM plasma cells. Our data demonstrate that Ets-1 is essential for maintenance of the normal pool of resting T- and B-lineage cells.

Animals↗
PubMed1995

Bclx regulates the survival of double-positive thymocytes.

The bclx gene has been shown to regulate programmed cell death in vitro. We now show that Bclx expression increases dramatically when T cells differentiate from CD4- CD8- (double negative) thymocytes to CD4+ CD8+ [double positive (DP)] thymocytes. In contrast single-positive (SP) thymocytes express negligible amounts of Bclx protein. This expression pattern contrasts with that of Bcl2, which is present in double-negative thymocytes, down-regulated in DP thymocytes, and reinduced upon maturation to SP thymocytes. Elimination of Bclx by gene targeting dramatically shortens the survival of DP thymocytes but not the survival of SP thymocytes or peripheral SP T cells. These data suggest that the induction of Bclx during thymic maturation plays a critical role in regulating the length of time DP thymocytes survive in the absence of selection.

Animals↗
PubMed1995

Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene.

The product of the vav proto-oncogene, p95vav or Vav, is tyrosine phosphorylated upon stimulation of T and B cells by antigen and other receptors, and contains motifs associated with signal transduction. To determine its role in vivo, we used vav-gene-targeted embryonic stem cells and RAG-2-/- blastocyst complementation. The vav(-/-)-RAG-2-/- chimaeras displayed thymic atrophy with reduced numbers of peripheral T cells. Whereas the total number of B cells was normal, the subset of peritoneal B-1 (CD5+) cells was missing. The vav-/- T and B cells were hyporeactive when stimulated through antigen receptors, but vav-/- T cells proliferated on exposure to phorbol ester and calcium ionophore, whereas B cells responded normally to bacterial mitogen, lipopolysaccharide or the CD40 ligand. Thus, we have established here a functional role for vav in the control of T- and B-cell development and activation.

Animals↗
PubMed1995

Defective B cell development and function in Btk-deficient mice.

Mutations in the Bruton's tyrosine kinase (Btk) gene have been linked to severe early B cell developmental blocks in human X-linked agammaglobulinemia (XLA), and to milder B cell activation deficiencies in murine X-linked immune deficiency (Xid). To elucidate unequivocally potential Btk functions in mice, we generated mutations in embryonic stem cells, which eliminated the ability to encode Btk pleckstrin homology or kinase domains, and assayed their effects by RAG2-deficient blastocyst complementation or introduction into the germline. Both mutations block expression of Btk protein and lead to reduced numbers of mature conventional B cells, severe B1 cell deficiency, serum IgM and IgG3 deficiency, and defective responses in vitro to various B cell activators and in vivo to immunization with thymus-independent type II antigens. These results prove that lack of Btk function results in an Xid phenotype and further suggest a differential requirement for Btk during the early stages of murine versus human B lymphocyte development.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1995

Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.

Interleukin-2 receptor alpha chain (IL-2R alpha) expression occurs at specific stages of early T and B lymphocyte development and is induced upon activation of mature lymphocytes. Young mice that lack IL-2R alpha have phenotypically normal development of T and B cells. However, as adults, these mice develop massive enlargement of peripheral lymphoid organs associated with polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo. Older IL-2R alpha-deficient mice also develop autoimmune disorders, including hemolytic anemia and inflammatory bowel disease. Thus, IL-2R alpha is essential for regulation of both the size and content of the peripheral lymphoid compartment, probably by influencing the balance between clonal expansion and cell death following lymphocyte activation.

Animals↗
PubMed1995

Effective treatment for acute alkali injury to the esophagus using weak-acid neutralization therapy: an ex-vivo study.

OBJECTIVE: 1) To evaluate whether neutralization therapy with weak acid is effective in reducing observed histopathologic esophageal tissue injury secondary to liquid alkali, 2) to quantify the temperature change of the neutralizing agent, and 3) to determine the effect of interval to therapy on injury severity. METHODS: Harvested Sprague-Dawley rat esophagi were catheterized and placed in an oxygenated saline bath (37 degrees C) for 60 minutes and then fixed in 10% formalin. Nine groups (n = 10) were perfused with 50% sodium hydroxide (NaOH). Six of the groups were treated by neutralization with cooled orange juice (OJ) or cola that was maintained between 2 degrees C and 4 degrees C. This was performed at 0, 5, or 30 minutes after injury. In addition, two positive control groups were exposed to OJ or cola at time 0 and were not exposed to strong alkali. A third control group was exposed to strong alkali but was not administered any subsequent treatment. The temperature of the neutralizing agent was recorded prior to instillation and after exiting the esophagus. Blinded pathologic scoring of 0 (no injury) to 3 (severe) was recorded performed for six histopathologic categories: epithelial cell viability, cornified epithelial cell differentiation, granular cell differentiation, epithelial cell nuclei, muscle cells, and muscle cell nuclei. Comparisons were made among treatment times using the Kruskal-Wallis test and linear trend analysis. RESULTS: For each histopathologic category and each treatment mode, the Kruskal-Wallis test showed significant differences between the groups (p < 0.002) over time. Trend analyses showed more severe injury with delayed neutralization therapy (p < 0.05) for each treatment mode and histopathologic category. CONCLUSION: Early neutralization therapy with OJ or cola reduces acute esophageal alkali injury. Additional in-vivo study is needed before neutralization therapy is adopted for clinical use.

Acids↗
PubMed1995

Histopathologic evaluation of the therapeutic efficacy of water and milk dilution for esophageal acid injury.

OBJECTIVE: To determine whether acid-induced injury to the esophagus is decreased by early dilutional therapy with water or milk. METHODS: A controlled in-vitro animal model for acid injury to the esophagus was carried out using esophagi harvested from 70 Sprague-Dawley rats of both sexes and weighing 250-350 g. One control and six experimental groups each containing ten esophagi were instilled with 1 mL of 0.5 normal solution of hydrogen chloride (N HCl). Dilution with water or milk was performed at 0, 5, or 30 minutes postinjury in the experimental groups. No dilution was performed with the control group. Specimens were maintained in an oxygenated saline bath for a 60-minute experimental period and then fixed in 10% formalin for histologic evaluation. Injury severity was rated by blinded histopathologic examination using scores of 0 (no injury), 1 (minor), 2 (moderate), and 3 (severe) for the histopathologic categories: cornified epithelial cells (CEs), granular cells (GCs), granular cell nuclei (GNs), and basal cells (BCs). Red blood cells were scored as positive or negative for lysis. RESULTS: The controls showed the most severe outcomes. Significant differences in injury occurred for all time periods and histopathologic categories, except for the GN/water and BC/milk histopathologic category/treatment groups. However, a linear trend analysis was significant for all histopathologic categories except BC. These analyses support decreased injury in the earlier treated groups. Injury severity was highest in the most superficial cell layer (CE). CONCLUSIONS: Emergency therapy with water or milk reduces acute acid injury to the esophagus. Earlier treatment is associated with decreased injury severity. This research supports the use of dilutional therapy with water or milk for acute acid injury to the esophagus.

Acids↗
PubMed1994

CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation.

To study the role of B-cell antigen CD40 in immune responses, mouse embryonic stem (ES) cells in which both copies of the gene encoding CD40 had been disrupted by homologous recombination were injected in RAG-2 (recombination-activating gene-2)-deficient blastocysts to generate chimeras in which all mature lymphocytes are derived from the CD40-deficient ES cells. T- and B-cell number and phenotype were normal in the CD40-/- chimeras. However, B cells failed to proliferate and undergo isotype switching in vitro in response to soluble CD40 ligand (sCD40L) with interleukin 4 (IL-4) but responded normally to lipopolysaccharide (LPS) with IL-4. CD40-/- chimeras completely failed to mount an antigen-specific antibody response or to develop germinal centers following immunization with the T cell-dependent (TD) antigen keyhole limpet hemocyanin. In contrast, CD40-/- mutant mice responded normally to the T cell-independent (TI) antigens, 2,4,6-trinitrophenyl (TNP)-LPS and TNP-Ficoll. The most noticeable alteration in the serum immunoglobulin levels of young (6-8 weeks old) CD40-/- animals was absence of IgE and severe decrease of IgG1 and IgG2a. These results confirm the essential role of CD40- CD40L interactions in the antibody response to TD antigens and in isotype switching.

Animals↗
PubMed1994

The influence of exercise on the energy requirements of adult males in the UK.

Energy expenditure was measured over 10 d using the doubly-labelled water (DLW) and activity diary methods in summer and winter in subjects with 'light' occupations but leisure activities which ranged from 'non-active' to 'very active'. The basal metabolic rate (BMR) and the energy cost of activities were determined by indirect calorimetry. The Department of Health (1991) predicted BMR for the group (6.89 (SD 0.30) MJ/d; n 18) was not significantly different from the measured value (7.17 (SD 0.70) MJ/d; n 18). The range of DLW-derived expenditure values within the group was BMR x 1.41 to 2.41. The largest seasonal change within individuals was BMR x 0.5. The energy expenditure of the group as a whole was lower in winter (BMR x 1.88; SD 0.33; n 9) than summer (BMR x 2.01; SD 0.30; n 9) though the difference was not statistically significant. The average summer and winter DLW-derived expenditure was BMR x 1.96 (SD 0.31; n 17). The activity diary estimate of expenditure was BMR x 1.79 (SD 0.32; n 17). In a subset of the group who were representative of the most active 26% of all adult males in the UK, the DLW-derived expenditure was BMR x 2.08 (SD 0.24; n 11). This is higher than the highest Department of Health (1991) estimate of BMR x 1.6 for individuals in light occupations. The measured energy costs of low-intensity activities were similar to those presented in the Department of Health (1991) report but the value determined for running (BMR x 13.08; SD 2.4; n 6) was higher than the highest value in the report (BMR x 6 to 8). The results indicate that the recent Department of Health (1991) reference values for energy may underestimate the expenditure of a significant proportion of the UK population largely because the energy costs of activity used in the report to calculate expenditure do not accurately reflect those achieved during active leisure in individuals who take regular exercise.

Adult↗
PubMed1994

Sequence of ornithine decarboxylase from Lactobacillus sp. strain 30a.

A gene encoding biodegradative ornithine decarboxylase from Lactobacillus sp. strain 30a was isolated from a genomic DNA library and sequenced. Primer extension analysis revealed two transcription initiation sites. The deduced amino acid sequence is compared with the amino acid sequences of five previously reported bacterial decarboxylases, and conserved pyridoxal phosphate motif residues are identified.

Amino Acid Sequence↗
PubMed1994

Defining managed care in public-sector psychiatry.

Although managed care is an established force in the private sector, there is growing interest and experimentation with this concept in the public sector. This interest has been generated by the increased demand for services, the shrinking resource base due to cutbacks in state budgets, and the fragmentation of care that has accompanied the shift from a centralized, hospital-based model to a decentralized, community-based model for treating individuals with serious mental illness. But despite this interest, no consensus exists about the form or functions of managed care in the public arena. Simply importing private-sector versions of managed care is inadequate given the substantial differences in the patient population and service delivery mechanisms. The authors present a functional analysis of managed care in the public sector. Drawing on their conceptualization of managed care, they outline a functional approach to evaluating the strengths and weaknesses of treatment systems, innovations such as privatization and capitation, and recent health care reform proposals.

Community Mental Health Services↗