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L Davidson

Publications and source records attributed to L Davidson.

At least 91 records · Page 5Linked to original sources
PubMed1996

Gene-targeted deletion and replacement mutations of the T-cell receptor beta-chain enhancer: the role of enhancer elements in controlling V(D)J recombination accessibility.

To assess the role of transcriptional enhancers in regulating accessibility of the T-cell receptor beta-chain (TCRbeta) locus, we generated embryonic stem cell lines in which a single allelic copy of the endogenous TCRbeta enhancer (Ebeta) was either deleted or replaced with the immunoglobulin heavy-chain intronic enhancer. We assayed the effects of these mutations on activation of the TCRbeta locus in normal T- and B-lineage cells by RAG-2 (recombination-activating gene 2)-deficient blastocyst complementation. We found that Ebeta is required for rearrangement and germ-line transcription of the TCRbeta locus in T-lineage cells. In the absence of Ebeta, the heavy-chain intronic enhancer partially supported joining region beta-chain rearrangement in T- but not in B-lineage cells. However, ability of the heavy-chain intronic enhancer to induce rearrangements was blocked by linkage to an expressed neomycin-resistance gene (neo(r)). These results demonstrate a critical role for Ebeta in promoting accessibility of the TCRbeta locus and suggest that additional negative elements may cooperate to further modulate this process.

Alleles↗
PubMed1996

Activated Ras signals differentiation and expansion of CD4+8+ thymocytes.

We describe a novel approach to assay the ability of particular gene products to signal transitions in lymphocyte differentiation in vivo. The method involves transfection of test expression constructs into RAG-1-deficient embryonic stem cells, which are subsequently assayed by the RAG-2-deficient blastocyst complementation approach. We have used this method to demonstrate that expression of activated Ras in CD4-8- (double negative, DN) prothymocytes in vivo induces their differentiation into small CD4+8+ (double positive, DP) cortical thymocytes with accompanying expansion to normal thymocyte numbers. However, activated Ras expression in DP cells does not cause proliferation or maturation to CD4+8- or CD4-8+ (single positive) thymocytes. Therefore, signaling through Ras is sufficient for promoting differentiation of DN to DP cells, but further differentiation requires the activity of additional signaling pathways.

Animals↗
PubMed1996

Function of the pre-T-cell receptor alpha chain in T-cell development and allelic exclusion at the T-cell receptor beta locus.

The pre-T-cell receptor, composed of the T-cell receptor (TCR) beta chain (TCRbeta), pre-Talpha (pTalpha) chain, and CD3 molecules, has been postulated to be a transducer of signals during the early stages of T-cell development. To examine the function of the transmembrane pTalpha chain during tbymocyte development, we generated pTalpha-/- embryonic stem cells and assayed their ability to differentiate into lymphoid cells in vivo after injection into recombination-activating gene (RAG)-2-deficient blastocysts. Thymocytes representing all stages of T-cell differentiation were detected in the thymus of pTalpha-/- chimeric mice, indicating that thymocyte development can occur without pTalpha. However, greatly reduced thymocyte numbers and substantially increased percentages of both CD4-CD8- thymocytes and TCRgammadelta+ thymocytes suggest that pTalpha plays a critical role in thymocyte expansion. To investigate the role of the pTalpha chain in allelic exclusion at the TCRbeta locus, a functionally rearranged TCRbeta minigene was introduced into pTalpha-/- and pTalpha+/- embryonic stem cells, which were subsequently assayed by RAG-2-deficient blastocyst complementation. In the absence of pTalpha, expression of the transgenic TCRbeta inhibited rearrangement of the endogenous TCRbeta locus to an extent similar to that seen in normal TCRbeta transgenic mice, suggesting that pTalpha may not be required for signaling allelic exclusion at the TCRbeta locus.

Alleles↗
PubMed1996

Descriptive epidemiology of injury in the south east: identifying priorities for action.

OBJECTIVE: To demonstrate the significance of injury in relation to other health problems, to describe the pattern of injury in one region of England, and to identify priorities for further epidemiological and prevention work. DESIGN: Cases were identified retrospectively from secondary data sources, namely using routinely collected data on deaths (OPCS anonymized death registrations for the period 1988-1991) and hospital in-patients (South Thames (East) RHA files of in-patient episodes). Denominator data for rates were obtained from the 1991 mid-year population estimates from the OPCS. SETTING: The cohort was defined as those resident in South Thames (East) during the study period, namely Kent, East Sussex, and South East London. The study period was 1988-1991 calendar years inclusive for the fatalities: and was the financial year from 1 April 1991-31 March 1992 for injury resulting in hospital admission. MAIN RESULTS: Injuries were found to be the fifth leading cause of death, the third leading cause of potential years of life lost (PYLL), and the third most common cause of hospital bed utilisation. Injury rates varied dramatically with age, and sex. The highest injury death and hospitalization rates were amongst elderly people. The leading causes of injury death were motor vehicle traffic crashes (25%), and suicide (23%), and falls (15%); for injury hospitalizations they were falls (60% of bed-days), and motor-vehicle traffic crashes (13% of bed-days). The most common places identified for the occurrence of injury death were road, home and residential institutions. Those injuries that accounted for most admissions to hospital were fractures (59% of bed-days). CONCLUSIONS: A number of areas have been identified as regional priorities. These are motor vehicle traffic crashes involving pedestrians (especially children under 15 and those aged 65 and over), car occupants and motor cyclists (especially young adult males); falls (especially those aged 65 and over); those occurring in residential institutions (especially for elderly people); fire and flames (affecting children under 15); suicide/self harm (all ages 15 and above); and homicide/assault (in males aged 15-34).

Adolescent↗
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

'Identities ascertained': British ophthalmology in the first half of the nineteenth century.

The paper takes its cue from the work on specialization and American ophthalmology by George Rosen (1944). Where Rosen's account was inspired by sociology, this paper gives a non-teleological account of medical specialization through a cultural history of ophthalmology. The cultural nature of the ophthalmic epidemics motivated practitioners to study the eye in earnest. These practitioners had to surmount obstacles intrinsic to the medical culture: the division between physicians and surgeons, hostility to specialisms, and the association with quackery. Practitioners justified their interests through the management of history, the association with philanthropy, and the construction of a father-figure. New interest in the eye was partly legitimated by the use of existing discourses, both philosophical and religious, that offered practitioners motivating languages to describe their practice. Specialization was effected through varying combinations of elements: emotional and intellectual investment in the eye, the advocacy of further research, and the explicit prosecution of specialties. The process depended upon generalist enthusiasm for the eye, and specialists' championing of generalist medicine. Specialization is a continual cultural process in a constant balancing act with the generalist tendency in medicine.

History, 19th Century↗
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↗