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Biomedical subjects

K A Lawson

Publications and source records attributed to K A Lawson.

At least 19 recordsLinked to original sources
PubMed2001

Otx2 is required for visceral endoderm movement and for the restriction of posterior signals in the epiblast of the mouse embryo.

Genetic and embryological experiments have demonstrated an essential role for the visceral endoderm in the formation of the forebrain; however, the precise molecular and cellular mechanisms of this requirement are poorly understood. We have performed lineage tracing in combination with molecular marker studies to follow morphogenetic movements and cell fates before and during gastrulation in embryos mutant for the homeobox gene Otx2. Our results show, first, that Otx2 is not required for proliferation of the visceral endoderm, but is essential for anteriorly directed morphogenetic movement. Second, molecules that are normally expressed in the anterior visceral endoderm, such as Lefty1 and Mdkk1, are not expressed in Otx2 mutants. These secreted proteins have been reported to antagonise, respectively, the activities of Nodal and Wnt signals, which have a role in regulating primitive streak formation. The visceral endoderm defects of the Otx2 mutants are associated with abnormal expression of primitive streak markers in the epiblast, suggesting that anterior epiblast cells acquire primitive streak characteristics. Taken together, our data support a model whereby Otx2 functions in the anterior visceral endoderm to influence the ability of the adjacent epiblast cells to differentiate into anterior neurectoderm, indirectly, by preventing them from coming under the influence of posterior signals that regulate primitive streak formation.

Animals↗
PubMed2000

Requirement of Bmp8b for the generation of primordial germ cells in the mouse.

In the mouse embryo, the generation of primordial germ cells (PGCs) from the epiblast requires a bone morphogenetic protein-4 (BMP4) signal from the adjacent extraembryonic ectoderm. In this study, we report that Bmp8b, a member of the Gbb-60A class of the BMP superfamily, is expressed in the extraembryonic ectoderm in pregastrula and gastrula stage mouse embryos and is required for PGC generation. A mutation in Bmp8b on a mixed genetic background results in the absence of PGCs in 43% null mutant embryos and severe reduction in PGC number in the remainder. The heterozygotes are unaffected. On a largely C57BL/6 background, Bmp8b null mutants completely lack PGCs, and Bmp8b heterozygotes have a reduced number of PGCs. In addition, Bmp8b homozygous null embryos on both genetic backgrounds have a short allantois, and this organ is missing in some more severe mutants. Since Bmp4 heterozygote embryos have reduced numbers of PGCs, we used a genetic approach to generate double-mutant embryos to study interactions of Bmp8b and Bmp4. Embryos that are double heterozygotes for the Bmp8b and Bmp4 mutations have similar defects in PGC number as Bmp4 heterozygotes, indicating that the effects of the two BMPs are not additive. These findings suggest that BMP4 and BMP8B function as heterodimers and homodimers in PGC specification in the mouse.

Animals↗
PubMed2000

Asthma: an analysis of high-cost patients.

OBJECTIVE: To examine characteristics of asthma patients who accounted for 80 percent of national expenditures in 1994 dollars. STUDY DESIGN: Data were extracted from a comprehensive data source, the 1987 National Medical Expenditure Survey (NMES) of approximately 35,000 individuals. PATIENTS AND METHODS: Persons of interest were identified using any occurrence of the ICD-9 code 493 or subcategories. Population weighting factors were used to estimate the population in the United States who sought care for the treatment of asthma. Two groups were identified: a high-cost group, which accounted for 80 percent of the direct medical expenditures, and a low-cost group, which represented 20 percent of expenditures. All analyses were performed using SUDAAN software, which takes into account the complex sampling design used in NMES. RESULTS: Individuals who rated their health as poor or fair were more likely to be in the high-cost group, as compared with those who rated their health as good or excellent (p < .0009). Persons who reported having Medicare, other government, or private insurance were more likely to be in the high-cost group as compared to those with Medicaid and self-pay (p = .01). A person was more likely to be in the high-cost group if he or she used four or more different medications to treat asthma (p < .0001). CONCLUSIONS: Persons with asthma are more likely to have greater medical expenditures if they use four or more medications and have deteriorated health status. Managed care organizations and public programs may find these characteristics useful in targeting asthma prevention and management programs.

Anti-Asthmatic Agents↗
PubMed1999

Bmp4 is required for the generation of primordial germ cells in the mouse embryo.

In many organisms the allocation of primordial germ cells (PGCs) is determined by the inheritance of maternal factors deposited in the egg. However, in mammals, inductive cell interactions are required around gastrulation to establish the germ line. Here, we show that Bmp4 homozygous null embryos contain no PGCs. They also lack an allantois, an extraembryonic mesodermal tissue derived, like the PGCs, from precursors in the proximal epiblast. Heterozygotes have fewer PGCs than normal, due to a reduction in the size of the founding population and not to an effect on its subsequent expansion. Analysis of beta-galactosidase activity in Bmp4(lacZneo) embryos reveals that prior to gastrulation, Bmp4 is expressed in the extraembryonic ectoderm. Later, Bmp4 is expressed in the extraembryonic mesoderm, but not in PGCs. Chimera analysis indicates that it is the Bmp4 expression in the extraembryonic ectoderm that regulates the formation of allantois and primordial germ cell precursors, and the size of the founding population of PGCs. The initiation of the germ line in the mouse therefore depends on a secreted signal from the previously segregated, extraembryonic, trophectoderm lineage.

Allantois↗
PubMed1999

Ectopic expression of the transforming growth factor beta type II receptor disrupts mesoderm organisation during mouse gastrulation.

Transforming growth factor beta (TGFbeta) regulates the cell cycle and extracellular matrix (ECM) deposition of many cells in vitro. We have analysed chimaeric mouse embryos generated from embryonic stem cells with abnormal receptor expression to study the effect of TGFbeta on these processes in vivo and the consequences for normal development. The binding receptor for TGFbeta, TbetaRII, is first detected in the embryo proper around day 8.5 in the heart. Ectopic expression of TbetaRII from the blastocyst stage onward resulted in an embryonic lethal around 9.5 dpc. Analysis of earlier stages revealed that the primitive streak of TbetaRII chimaeras failed to elongate. Furthermore, although cells passed through the streak and initially formed mesoderm, they tended to accumulate within the streak. These defects temporally and spatially paralleled the expression of the TGFbeta type I receptor, which is first expressed in the node and primitive streak. We present evidence that classical TGFbeta-induced growth inhibition was probably the cause of insufficient mesoderm being available for paraxial and axial structures. The results demonstrate that (1) TGFbeta mRNA and protein detected previously in early postimplantation embryos is present as a biologically active ligand; and (2) assuming that ectopic expression of TbetaRII results in no other changes in ES cells, the absence of TbetaRII is the principle reason why the embryo proper is unresponsive to TGFbeta ligand until after gastrulation.

Animals↗
PubMed1999

Procedure costs and outcomes associated with pharmacologic management of peripheral arterial disease in the Department of Defense.

This study was undertaken to determine if differences existed between pharmacologic treatments of peripheral arterial disease (PAD) with respect to PAD-related costs and health care outcomes in the United States Department of Defense health care system. We performed a retrospective review of hospital and prescription data to explore the effects of at least 90 days of aspirin, pentoxifylline, papaverine, or dipyridamole on 4 PAD-related outcomes: number of PAD-related invasive procedures (INV), number of PAD-related examination procedures (EXM), number of PAD-related hospitalization days (HDAYS), and cost of PAD-related procedures (COST) during 5 years. A covariate representing the number of PAD-related hospitalizations before the study period was used to attempt to control for severity of disease state. General linear models were used in the analyses. A statistically significant difference was seen between treatment groups for a linear combination of INV, EXM, HDAYS, and COST when controlling for past PAD-related hospitalizations (P < 0.014). A statistically significant relationship existed between treatment groups and INV (P < 0.041). The pentoxifylline treatment group had a statistically significant higher covariate-adjusted mean INV compared with the aspirin treatment group (P < 0.043). Also, PAD-related past hospitalizations were significantly related to EXM (P < 0.006). Our results appear to support the use of aspirin as a preventive treatment in PAD compared with pentoxifylline or dipyridamole.

Adult↗
PubMed1999

Developmental bioinformatics: linking genetic data to virtual embryos.

This paper discusses current efforts to produce databases of gene expression for the major model embryos used in developmental biology. The efforts to build these resources were motivated by the need for immediate internet access to all types of research data, and the production of these databases is a major and new challenge for bioinformatics. Thus far bioinformatics has mainly been concerned with textually oriented resources and data, much of it concerned with gene and protein sequences. Because the genetic basis of developmental biology is integrated with developmental anatomy, these databases require the use of images to link molecular data with spatial information. In order to standardise database formats, digital atlases of some model systems are being produced that include integrated anatomical descriptions and these are being linked to appropriate genetic data. Integrating such image-based, searchable data into databases makes new demands on the field of bioinformatics and we consider here the imaging modalities that are used to obtain information and we discuss in particular the production of 3D images from serial sections. Next, we consider how to integrate textual and spatial descriptions of gene expression and the key tool needed to make this possible, i.e. anatomical nomenclature. A short review of internet resources on developmental biology is also given and future prospects for the development of these databases are discussed.

Animals↗
PubMed1999

Fate mapping the mouse embryo.

The use of clonal analysis to obtain a fate map of the epiblast of the mouse embryo and to investigate cell distribution during gastrulation and early neurulation is described in a personal reminiscence. A revised fate map of the epiblast at 6.5 days gestation is provided, and the development of 3-dimensional, quantitative image analysis techniques outlined.

Animals↗
PubMed1998

The Polycomb-group gene eed is required for normal morphogenetic movements during gastrulation in the mouse embryo.

We have characterized an induced mutation, called embryonic ectoderm development or eed, that disrupts A-P patterning of the mouse embryo during gastrulation. Positional cloning of this gene revealed it to be the highly conserved homologue of the Drosophila gene extra sex combs, which is required for maintenance of long-term transcriptional repression of homeotic gene expression. Mouse embryos homozygous for loss-of-function alleles of eed initiate gastrulation but display abnormal mesoderm production. Very little embryonic mesoderm is produced; in contrast, extraembryonic mesoderm is relatively abundant. These observations, along with mRNA in situ hybridization analyses, suggested a defect in the anterior primitive streak, from which much of the embryonic mesoderm of the wild-type embryo is derived. To analyse this defect, we initiated clonal analysis of the pre-streak epiblast in eed mutant embryos, using the lineage tracer horseradish peroxidase (HRP). The results of these studies indicate that epiblast cells ingress through the anterior streak, but the newly formed mesoderm does not migrate anteriorly and is mislocalized to the extraembryonic compartment. Abnormal localization of mesoderm to the extraembryonic region did not appear to be due to a restriction and alteration of distal epiblast cell fate, since the majority of clones produced from regions fated to ingress through the anterior streak were mixed, displaying descendants in both embryonic and extraembryonic derivatives. eed mutant embryos also fail to display proper epiblast expansion, particularly with respect to the A-P axis. Based on patterns of clonal spread and calculated clone doubling times for the epiblast, this does not appear to be due to decreased epiblast growth. Rather, epiblast, which is normally fated to make a substantial contribution to the axial midline, appears to make mesoderm preferentially. The data are discussed in terms of global morphogenetic movements in the mouse gastrula and a disruption of signalling activity in the anterior primitive streak.

Animals↗
PubMed1997

A cost of illness study of allergic rhinitis in the United States.

BACKGROUND: Allergic rhinitis is a common condition, but the burden of this condition on the national economy is not well understood. OBJECTIVE: The purpose of this study was to estimate the national direct and indirect costs of allergic rhinitis. METHODS: Data from the National Medical Expenditure Survey were used to provide estimates of resource utilization, medical expenditures, and lost productivity. With the complex survey design, variance estimates were used to construct confidence intervals for cost estimates of resource utilization and lost productivity. RESULTS: It is estimated that approximately 39 million persons in the United States experienced allergic rhinitis in 1987. However, only 12.3% (4.8 million) sought medical treatment for allergic rhinitis. The total estimated cost of the condition, in 1994 dollars, was $1.23 billion (95% confidence interval, $846 million to $1.62 billion). Direct medical expenses accounted for 94% of total costs. Allergic rhinitis results in approximately 811,000 missed workdays, 824,000 missed school days, and 4,230,000 reduced activity days. CONCLUSION: Allergic rhinitis clearly creates a burden in terms of the number of persons affected, total expenditures, and lost productivity. It also appears that a relatively large proportion of persons with allergic rhinitis were not seeking medical treatment.

Adolescent↗
PubMed1997

A national estimate of the economic costs of asthma.

This cost of illness analysis examines national cost and resource utilization by persons with asthma using a single, comprehensive data source, the 1987 National Medical Expenditure Survey. Direct medical expenditures included payments for ambulatory care visits, hospital outpatient services, hospital inpatient stays, emergency department visits, physician and facility payments, and prescribed medicines. Indirect medical costs included costs resulting from missed work or school and days with restricted activity at work. Point estimates and 95% confidence intervals (CI) were calculated and inflated to 1994 dollars. The total estimated cost was $5.8 billion (95% CI, $3.6 to $8 billion). The estimated direct expenditures were $5.1 billion (95% CI, $3.3 to $7.0 billion), and indirect expenditures were valued at $673 million (95% CI, $271 to $1,076 million). Hospitalization accounted for more than half of all expenditures. More than 80% of resources were used by 20% of the population (defined as 'high-cost patients'). The estimated annual per patient cost for those high-cost patients was $2,584, in contrast with $140 for the rest of the sample. Findings from this study indicate that future asthma research and intervention efforts directed at hospitalizations and high-cost patients could help to decrease health care resource use and provide cost savings.

Absenteeism↗
PubMed1997

An analysis of predictors of prescription drug costs among Medicaid nursing home residents in Texas.

A study was conducted to examine the relations among patient-specific demographic characteristics, previous prescription costs and utilization, and subsequent prescription costs for a population of 55,677 Medicaid nursing home residents in Texas. Patient-specific factors, based on previous patient utilization and cost levels, exist within the Texas Medicaid nursing home population that may serve as predictors of subsequent prescription costs. Although some statistically significant relations exist between prescription costs and patient demographic factors such as age, sex, and location, these demographic factors are of little or no practical value in prediction of prescription costs for subsequent periods of time.

Aged↗
PubMed1996

Relationship between hospital pharmacists' job satisfaction and involvement in clinical activities.

Job satisfaction among hospital pharmacists employed by a national hospital pharmacy management company was measured by using a mail questionnaire. A previously validated survey that measured pharmacists' job satisfaction was adapted for use in this study. Additional questions determined the pharmacist's clinical pharmacy training and participation in clinical pharmacy services. Questionnaires were mailed to all full-time hospital pharmacists employed by the pharmacy management company. Of the 606 mailed, deliverable questionnaires, 354 usable responses were returned, for a response rate of 58.4%. The respondent hospital pharmacists' level of job satisfaction showed a positive association with clinical pharmacy involvement. Of the nine items in the questionnaire that measured the pharmacists' involvement in clinical pharmacy services, seven items showed a positive relationship between involvement in that clinical activity and job satisfaction. Mean job satisfaction increased as the percentage of time spent performing clinical pharmacy activities increased. Job satisfaction decreased as time spent performing distributive functions increased. The percentage of time hospital pharmacists were engaged in clinical activities was significantly associated with job satisfaction.

Adult↗
PubMed1994

Clonal analysis of the origin of primordial germ cells in the mouse.

Qualitative and quantitative clonal analysis has been used to answer three basic questions about the establishment of the germ cell lineage in the mouse. Where do primordial germ cells originate? What is the size of the founding population at the time of lineage restriction? When and where does lineage restriction occur? Single epiblast cells of 6.0 dpc and 6.5 dpc mouse embryos were injected with a short-term lineage label (lysinated rhodamine dextran, LRDX) and their descendants traced after 40 h embryo culture at neural plate and early somite stages, respectively. An objective matching technique was used to detect the lineage marker in primordial germ cells identified by their characteristic alkaline phosphatase staining. Precursors of the primordial germ cells were found in the proximal epiblast close to the extraembryonic ectoderm in both pregastrulation and early-streak stage embryos. They form part of the presumptive extraembryonic mesoderm and are not lineage restricted while in the epiblast. Quantitative analysis gives a best fit to a model of a founding population of 45 at the time of lineage restriction. The data indicate that the generation time lengthens at the time of allocation. Calculation of clonal histories gives a best fit of 16 h generation time after allocation compared with < 7 h before allocation, with lineage restriction occurring at the early midstreak stage, presumably in the region posterior to the streak in which primordial germ cells are first identifiable. Therefore primordial germ cells are probably allocated early during gastrulation in a group of > 40 cells already segregated in the extraembryonic mesoderm.

Animals↗
PubMed1993

Psychiatric norms for the Rey 15-item Visual Memory Test.

The 15-item Visual Memory Test was proposed by Rey in 1964 as a measure of malingering of visual memory. Among psychiatric patients the task has a significant cognitive component, with IQ accounting for 37% of the variance in scores (r = .60). Any interpretation of scores on this task should be ability-based. Such ability-based norms are provided in this study of psychiatric patients (N = 300). Use of a single cut-off score to indicate malingering or any other interpretation is inappropriate given the psychometric properties of the task. In the assessment of immediate visual memory the task has some utility, which is greatly enhanced with the use of ability-based norms.

Adult↗
PubMed1992

Clonal analysis of cell fate during gastrulation and early neurulation in the mouse.

The foundation of the germ layers and the extraembryonic mesoderm from the epiblast between 6.5 and 7.5 days post coitum (p.c.) is accompanied by substantial cell proliferation. It is followed during the next 24 hours by the organization of major systems of the embryo such as the central nervous system, somites, heart and vascular system. Injection in situ of a short-term lineage label (horse radish peroxidase) into single epiblast cells at 6.7 days p.c. and analysis of the descendant clones in cultured embryos have been used to trace these processes and led to the following conclusions: (1) There is extensive but not indiscriminate cell mixing at the onset of gastrulation; epiblast cells spread towards the primitive streak and descendants are there progressively incorporated into mesoderm. (2) The fate map of the mouse epiblast at the early primitive streak stage is topologically similar to those of other vertebrates. (3) Germ layers and the extraembryonic mesoderm are not clonally distinct before gastrulation, the region of overlapping boundaries in the fate map being occupied by cells that will have descendants in more than one layer. (4) Cranial neurectoderm is mainly derived from axial epiblast immediately anterior to the primitive streak of the early streak stage embryo, clonal descendants being spread rostrocaudally in the developing neural tube. Contribution to the putative floor plate is made by progenitors some of which also contribute to notochord and mesoderm.

Animals↗