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Biomedical subjects

E Lawrence

Publications and source records attributed to E Lawrence.

At least 19 recordsLinked to original sources

The enhancement of traditional behavioral couples therapy: consideration of individual factors and dyadic development.

There has been little effort by behavior therapists to develop couple interventions that view marriage from a content-relevant or developmental perspective. Consequently, we have delineated ways in which a perspective of intimate relationships including individual factors and dyadic development might guide the enhancement of traditional behavioral couples therapy (TBCT) with novel and improved techniques that will ultimately allows us to reach a wider range of distressed couples than our current interventions allows. Specifically, we examined the potential benefits to intervention that could occur by considering the impact of individual factors on relationship quality, using the literature on attachment patterns as an example. Further, we have discussed the potential gains to couple interventions that could occur by considering the impact of dyadic development on relationship satisfaction. We first addressed gradual changes in marriage, using intimacy as an example. Next we examined "stage of marriage" issues, using child behavior problems as an example. Finally, we considered whether or not a problem was chronic. Throughout, we have proposed utilizing TBCT as a starting point, and considering ways to enhance TBCT specifically, as it is the marital therapy for which we have the most information and empirical support.

Behavior Therapy

Practical approach to electron beam dosimetry at extended SSD.

This paper presents a practical approach to clinical dosimetry for electron beams at extended source-to-surface distance (SSD). Characteristics of electron beams from a Siemens MD-2 accelerator are presented at a nominal SSD of 100 cm and an extended SSD of 115 cm. Relative output factors are measured at both 100 and 115 cm SSDs for a range of square field sizes for each beam energy. The change of output with SSD does not follow the inverse square law, if the nominal SSD is used. This deviation is larger for lower beam energy and smaller field sizes. An effective SSD, SSDeff, has been determined at dmax for each beam energy as a function of field size. A comprehensive approach to treatment time calculations is proposed.

Electrons

Polymorphonuclear leukocytes released from the bone marrow preferentially sequester in lung microvessels.

OBJECTIVE: A hallmark of the systemic response to an inflammatory stimulus is the release of polymorphonuclear leukocytes (PMNs) from the bone marrow. This study was designed to measure the release of PMNs from the bone marrow and to determine their sequestration in the lung after an intravenous injection of either endotoxin (n = 5) or saline (n = 5). METHODS AND RESULTS: The thymidine analogue 5'-bromo-2-deoxyuridine (BrdU) was used to pulse label dividing PMNs in the bone marrow of rabbits (n = 13), and immunohistochemistry and morphometry were used to detect the release of BrdU-labeled PMNs into the circulation and to determine their sequestration in the lung. Endotoxin treatment caused a drop in the circulating PMN counts (3.3 +/- 0.08 at baseline to 0.12 +/- 0.02 x 10(9)/L at 1 hour after endotoxin), which was followed by a neutrophilia at 8 hours (6.3 +/- 1.1 x 10(9)/L, P < 0.01), an increase in circulating band cells (0.12 +/- 0.01 at baseline to 2.18 +/- 0.4 x 1(9)/L at 8 hours, p < 0.001), and an increase in the percentage of BrdU-labeled PMNs (0.01% +/- 0.004% at baseline to 26.1% +/- 3.2% at 8 hours, p < 0.001). Endotoxemia caused an arteriovenous difference in BrdU-labeled PMNs across the lung (35.9% +/- 2.9% versus 26.1% +/- 3.1%, mixed venous versus arterial, p < 0.02). Morphometric studies showed that endotoxin caused sequestration of PMNs in the lung (2.2 +/- 0.4 versus 1.0 +/- 0.2 x 10(10), endotoxin versus saline, p < 0.03) with preferential retention of BrdU-labeled PMNs (0.79 +/- 0.21 versus 0.039 +/- 0.016 x 10(10), endotoxin versus saline, p < 0.05). The percentage of BrdU-labeled PMNs in the alveolocapillary walls was higher than in circulating blood (64.01% +/- 4.3% versus 26.1% +/- 3.2%, p < 0.01) in the endotoxin group. In vitro filtration of cells through 5-mm pore size filters showed that circulating BrdU-labeled PMNs, 8 hours after endotoxin, were preferentially retained in the filters (p < 0.01). CONCLUSIONS: We conclude that endotoxemia stimulates the bone marrow to release mature and immature PMNs. Compared to PMNs released from the bone marrow during normal turnover, these PMNs are less deformable and preferentially sequester in the lung microvessels.

Animals

Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated adenomatous polyposis coli.

Mutation of Pla2g2a, a secretory phospholipase A(2) gene, dramatically increases the number of intestinal polyps that develop in the multiple intestinal neoplasia (Min) mouse, a murine model for adenomatous polyposis coli in humans. We tested the hypothesis that mutation of the human homologue(s) of this gene might be responsible for the more severe phenotype (hundreds of polyps) seen in a subset of individuals with attenuated adenomatous polyposis coli (AAPC). DNA sequence analysis demonstrated that alterations of PLA2G2A, as well as related genes PLA2G2C and PLA2G5, were evenly distributed between three classes of AAPC subjects: those with small, intermediate, and large numbers of adenomatous colonic polyps. Among 67 additional unrelated AAPC subjects, a stop mutation in PLA2G2C did not correlate with an increased burden of adenomatous polyps. Therefore, mutation of the human homologue(s) of murine Pla2g2a does not appear to be responsible for phenotypic variation among subjects with AAPC.

Adenomatous Polyposis Coli

Polymorphonuclear leukocyte (PMN) migration in streptococcal pneumonia: comparison of older PMN with those recently released from the marrow.

In acute bacterial pneumonia, polymorphonuclear leukocytes (PMN) sequester in the lung and migrate into the alveolar airspaces. These local events are accompanied by a systemic response that includes release of PMN from the bone marrow into the circulation. The present study was designed to compare the sequestration and migration of these newly released PMN with those already in the circulation in a model of acute streptococcal pneumonia in rabbits. PMN were labeled in the mitotic pool in the marrow by administration of 5'-bromo-2'-deoxyuridine (BrdU 100 mg/kg) and the labeled cells were detected in blood and tissues by immunohistochemistry. The proportion of BrdU-labeled PMN (PMN BrdU) that sequestered and migrated in the lung tissue infected with Streptococcus pneumoniae and the uninfected lung was measured using morphometric techniques. The results show an increase in the proportion of PMN BrdU (6.0 +/- 1.0% to 17.3 +/- 3.8%, P<0.05) in the circulation 5 h following the induction of a pneumonia and the PMN expressed a higher concentration of L-selectin (9.3 +/- 0.7 to 14.9 +/- 0.8 MFI, P<0.05). The proportion of PMN BrdU in the control tissue was not different from the proportion in the systemic circulation (11.4 +/- 1.6%). The PMN BrdU increased in the pneumonic site at 5 h (19.9 +/- 3.4%, P<0.05) and 8 h (26.6 +/- 1.5%, P<0.05) after treatment. Only 2.8 +/- 0.3% and 2.8 +/- 0.6% of the PMN that migrated into the airspace at 5 and 8 h were PMN BrdU. We conclude that PMN released into the circulation as part of the systemic response to a local streptococcal pneumonia sequester normally but may be slow to migrate into the airspaces at the inflammatory site.

Animals

Luteinizing hormone-releasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys.

Several investigators have demonstrated that LHRH agonists (LHRHa) inhibit ovarian follicular depletion induced by chemotherapeutic agents in rodents. It is not clear whether or not the same effects occur in primates. Six adult female rhesus monkeys underwent unilateral ovariectomy and were divided into two groups that received monthly injections of either Lupron depot (LHRHa) or placebo vehicle. Both groups received cyclophosphamide (CTX) injections. Weekly blood samples were assayed for FSH, estradiol and progesterone. Mean serum FSH levels significantly increased in the CTX group and significantly decreased in the LHRHa+CTX group. At the end of treatment, the remaining ovary was removed and serially sectioned, and ovarian follicle number and size were analyzed. CTX resulted in a significant reduction of nonprimordial follicles < 50 microns in diameter. The rate of loss of primordial follicles was expressed as a percentage of the original follicle count. During the treatment period, 64.6 +/- 2.8% of the total primordial follicles were lost in the CTX group compared to only 28.9 +/- 9.1% in the LHRHa+CTX group (p < 0.05). The percentage rate of decline per day was 0.120 +/- 0.012 for the CTX group compared to 0.057 +/- 0.019 (p < 0.05) for the LHRHa+CTX group. The findings indicate that LHRHa can protect the ovary against CTX-induced damage in rhesus monkeys.

Animals

Evidence for ETA and ETB receptors in rat skin and an investigation of their function in the cutaneous microvasculature.

1. The relative contribution of ETA and ETB receptors in the response of rat skin to endothelins was investigated by use of the selective ETB agonist IRL-1620 and the selective ETA antagonist BQ-123. 2. Binding data suggest the presence of ETA and ETB receptors as preincubation with [Ala3,11,18Nle7]-endothelin-1 reduced ET-1 binding by approximately 40%. 3. Intradermal injection of endothelin-1 (ET-1, 1-10 pmol/site) and ET-3 (3-100 pmol/site) induced a dose-dependent decrease in local blood flow assessed by 133Xe clearance at test sites in rat skin. 4. The endothelin analogue [Ala3,11,18Nle7]-ET-1 (30-1000 pmol/site) induced significant vasoconstriction (P < 0.05) at the highest doses used and the selective ETB receptor agonist, IRL-1620 [Suc[Glu9,Ala11,15] endothelin (8-21)], (0.01-100 pmol/site) acted in a potent manner to induce a significant (P < 0.01) dose-dependent decrease in 133Xe clearance. 5. Co-injection with the selective ETA receptor antagonist, BQ-123 (1 nmol/site), completely abolished the vasoconstriction to ET-1 and partially to ET-3, but had no effect on IRL-1620-induced vasoconstriction. In addition, IRL-1620 responses were not altered at sites treated with submaximal doses of a nitric oxide synthase inhibitor or a prostaglandin synthase inhibitor. 6. ET-1 and IRL-1620 (100 fmol-1 pmol/site) did not induce oedema formation as measured by [125I]-albumin accumulation in the presence or absence of the vasodilator, calcitonin gene-related peptide (CGRP). ET-1 (1-3 pmol/site) inhibited substance P-induced oedema formation and this effect,suggested to be secondary to a vasoconstrictor effect, was significantly reversed by BQ-123 (1 nmol/site).7. The findings in this study indicate that there are ETA and ETB receptors in rat skin and agents which activate either receptor act to mediate a decrease in cutaneous blood flow, but have no effect on increased microvascular permeability.

Animals

A strategy for constructing high-resolution genetic maps of the human genome: a genetic map of chromosome 17p, ordered with meiotic breakpoint-mapping panels.

Genetic linkage analyses with genotypic data obtained from four CEPH reference families initially assigned 24 new PCR-based markers to chromosome 17 and located the markers at specific intervals of an existing genetic map of chromosome 17p. Each marker was additionally genotyped with an ordered set of obligate, phase-known recombinant chromosomes. The breakpoint-mapping panels for each family consisted of two parents, one sib with a nonrecombinant chromosome, and one or more sibs with obligate recombinant chromosomes. The relative order of markers was determined by sorting segregation patterns of new markers and ordered anchor markers and by minimizing double-recombination events. Consistency of segregation patterns with multiple flanking loci constituted support for order. A genetic map of chromosome 17p was completed with 39 markers in 23 clusters, with an average space of 3 cM between clusters. The collection of informative genotypes was highly efficient, requiring fivefold fewer genotypes than would be collected with all the CEPH families. Given the availability of large numbers of highly informative PCR-based markers, meiotic breakpoint mapping should facilitate construction of a human genomic map with 1-cM resolution.

Base Sequence

Effect of BQ-123 and Ro 47-0203 (bosentan) on endothelin-induced vasoconstriction in the rat skin.

The effectiveness of intradermal (i.d.) BQ-123 (cyclo[D-Asp-Pro-D-Val-Leu-D-Trp]) and i.d. Ro 47-0203 (bosentan, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4 - yl]-benzene-sulfonamide) has been evaluated on local microvascular responses to endothelin-1 and endothelin-3, measured by a multiple site 133Xe clearance technique in rat skin in vivo. Intradermal injection of endothelin-1 (0.3 pmol/site) and endothelin-3 (10 pmol/site) induced a similar (approximately 50-60%) decrease in basal blood flow in rat skin. BQ-123 (3-1000 pmol/site), a selective endothelin ETA receptor antagonist, caused a significant dose-dependent decrease in the vasoconstriction induced by endothelin-1 (P < 0.05) but was less effective on vasoconstriction induced by endothelin-3. Bosentan (3-1000 pmol/site), a new non-peptide mixed antagonist of endothelin ETA and endothelin ETB receptors, significantly reduced the vasoconstriction induced by endothelin-1 but was less effective than BQ-123. BQ-123 and bosentan were similarly effective as antagonists of endothelin-3. BQ-123 and bosentan had no effect on basal blood flow and no inhibitory activity on vasoconstriction induced by vasopressin (0.03 pmol/site) or phenylephrine (300 pmol/site). These findings indicate that BQ-123 and bosentan are effective and selective inhibitors of the vasoconstriction induced by endothelins in the rat skin microvasculature.

Animals

Physical and genetic mapping of human chromosome 3 loci containing microsatellite repeats.

One hundred and six microsatellite repeat-containing loci, including 59 CA-containing repeats from the CEPH/Genethon collection, were regionally assigned on human chromosome 3 using a somatic cell hybrid mapping panel, diving the chromosome into 14 intervals. The others were dinucleotide and tetranucleotide repeat-containing loci newly developed for human chromosome 3, of which 26 were also localized by means of genetic linkage analysis against selected CEPH microsatellites. The regional assignment of these two marker sets in a common mapping panel facilitates their integration. Incorporation of these highly polymorphic loci into the developing physical and genetic maps should provide useful information for studies of various diseases involving chromosome 3.

Base Sequence

Genetic mapping of the BRCA1 region on chromosome 17q21.

Chromosome 17q21 harbors a gene (BRCA1) associated with a hereditary form of breast cancer. As a step toward identification of this gene itself we developed a number of simple-sequence-repeat (SSR) markers for chromosome 17 and constructed a high-resolution genetic map of a 40-cM region around 17q21. As part of this effort we captured genotypes from five of the markers by using an ABI sequencing instrument and stored them in a locally developed database, as a step toward automated genotyping. In addition, YACs that physically link some of the SSR markers were identified. The results provided by this study should facilitate physical mapping of the BRCA1 region and isolation of the BRCA1 gene.

Base Sequence

A radiation hybrid map of the BRCA1 region.

A locus on chromosome 17q, designated "BRCA1," has been identified as a predisposition gene for breast cancer. A panel of chromosome 17-specific radiation-reduced somatic cell hybrid clones has been assembled for high-resolution mapping of chromosome 17. A series of 35 markers, known to span the BRCA1 locus, were tested against this hybrid panel by PCR assays. Statistical analysis of these data yields a BRCA1 radiation hybrid map at a density sufficient to initiate YAC cloning and pulsed-field gel electrophoretic mapping of the candidate region. In addition, many of the markers reveal genetic polymorphisms and may be tested in breast cancer families and in loss-of-heterozygosity studies of sporadic breast cancers to better define the BRCA1 gene candidate region.

Animals

Big endothelin-1 and big endothelin-3 are constrictor agents in the microvasculature: evidence for the local phosphoramidon-sensitive conversion of big endothelin-1.

The effect of local administration of big endothelin-1 (1-38, big ET-1) has been investigated on blood flow in the skin of anaesthetised rats, measured by 133Xe clearance. The local effects of big ET-1 and big endothelin-3 (1-41, big ET-3) have also been determined on microvessel diameter by intravital microscopy of the cheek pouch of anaesthetised hamsters. Big ET-1 (i.d.) caused a dose-dependent decrease in skin blood flow and was 10 times less potent than endothelin-1 (ET-1). Phosphoramidon (30 nmol/site i.d.) did not effect blood flow but when coinjected selectively attenuated the effect of big ET-1 (1 and 3 pmol/site, P < 0.05). In the cheek pouch big ET-1 (100 pmol) induced an intense and long-lasting arteriolar constriction. Phosphoramidon (100 nmol) abolished constriction to big ET-1 (100 pmol) but not to ET-1 (10 pmol). The modest constriction induced by big ET-3 (300 pmol) was not inhibited by phosphoramidon (100 nmol). Results suggest that a phosphoramidon-sensitive endothelin-converting enzyme situated close to microvascular vessels is important in the conversion of big ET-1. The mechanism for activity of big ET-3 in the microcirculation is unclear.

Animals

Polymorphic SSR (simple-sequence-repeat) markers for chromosome 20.

Chromosome 20-specific simple-sequence-repeat (SSR) markers were developed from a flow-sorted phage library (LL20NS01), subcloned in Bluescript, and screened with a tetranucleotide repeat, (AAAG)6, to identify potentially polymorphic loci. Of 100 clones sequenced, 39 were selected to construct primers. Of these 39, 22 were polymorphic. Reference to the CEPH linkage database (version 5) permitted genetic mapping of 16 of the new markers to specific regions of chromosome 20. Ten of the SSRs showed heterozygosity indices (above 70%) that would qualify them as potential index markers.

Base Sequence

Isolation of 1001 new markers from human chromosome 11, excluding the region of 11p13-p15.5, and their sublocalization by a new series of radiation-reduced somatic cell hybrids.

The determination of the physical map of human chromosome 11 will require more clones than are currently available. We have isolated an additional 1001 new markers in a bacteriophage vector from a somatic cell hybrid cell line that contains most of chromosome 11, except the middle of the short arm. These markers were localized to five different regions, 11p15-pter, 11p12-cen, 11q11-q14, 11q14-q23, and 11q23-qter, by a panel of previously characterized somatic cell hybrids. The region 11q11-14 harbors genes that have been shown to be important in breast cancer, B-cell lymphomas, centrocytic lymphomas, asthma, and multiple endocrine neoplasia, type 1 (MEN1). To determine the positions of the recombinant clones located there, we developed a new series of radiation-reduced somatic cell hybrids. These hybrids, together with those previously characterized, allowed us to map the 11q11-q14 markers into 11 separate segregation groups.

Asthma