Search PubMed⌕ Search

Biomedical subjects

M L Watson

Publications and source records attributed to M L Watson.

At least 55 records · Page 3Linked to original sources
PubMed1993

A study of genetic linkage heterogeneity in 35 adult-onset polycystic kidney disease families.

A genetic heterogeneity analysis of 35 kindreds with adult-onset polycystic kidney disease (ADPKD) was carried out using the D16S85, D16S84, D16S125 and D16S94 loci that are closely linked to the PKD1 locus on chromosome 16. The results show that the likelihood of two ADPKD loci is 2,514.9 times greater than for a single locus (P < 0.0001). The maximum likelihood lod score is 27.38 under heterogeneity with PKD1 lying 4.9 cM proximal to D16S85 (in males). At least 3% of kindreds are unlinked to PKD1, since the 95% confidence limits of alpha, the proportion of families linked to PKD1, are 0.54-0.97. Only 2 out of 35 kindreds (5.7%) show statistically significant evidence of non-linkage to PKD1, with conditional probabilities of 0.987 and 0.993 that the disease locus is unlinked. This confirms the existence of a small subgroup of ADPKD kindreds that are unlinked to PKD1 and provides a firm basis for genetic counselling of this population on the basis of DNA probes.

Adult↗
PubMed1993

Single-strand conformational polymorphism (SSCP) mapping of the mouse genome: integration of the SSCP, microsatellite, and gene maps of mouse chromosome 1.

Interspersed repetitive sequence (IRS) PCR and repetitive element-to-bubble (IRS-bubble) PCR have been utilized to rapidly generate large numbers of mouse-specific, chromosome 1-enriched STSs from mouse-hamster somatic cell hybrids. Single-strand conformational polymorphism (SSCP) has been used to localize 39 new repetitive element-linked STSs to the mouse map: 22 to Chr 1, 10 to Chr. 15, 2 each to Chrs 12 and 14, and three to Chr 7. In addition, we have integrated the SSCP, single-strand length polymorphism, and restriction fragment length polymorphism maps of mouse Chr. 1, resulting in a high-density map of the chromosome, containing over 100 loci, all typed on a single interspecific backcross.

Animals↗
PubMed1993

Cytokines contribute to airway dysfunction in antigen-challenged guinea pigs: inhibition of airway hyperreactivity, pulmonary eosinophil accumulation, and tumor necrosis factor generation by pretreatment with an interleukin-1 receptor antagonist.

The role of pro-inflammatory cytokines in an animal model of allergic lung disease was examined by use of an interleukin-1 receptor antagonist (IL-1ra) and a specific bioassay for tumor necrosis factor (TNF). Ovalbumin-sensitized guinea pigs exhibit a marked bronchial hyperreactivity (assessed by airway responsiveness to intravenous histamine) and pulmonary eosinophil accumulation (assessed by bronchoalveolar lavage) 24 h after challenge with aerosolized antigen. Exposure of animals to an aerosol of IL-1ra (50 micrograms over 30 min) immediately before antigen challenge resulted in a marked protection against bronchial hyperreactivity and pulmonary eosinophil accumulation compared with IL-1ra vehicle-pretreated animals. Additionally, we report for the first time generation of TNF bioactivity in the bronchoalveolar lavage of antigen-challenged animals, which was significantly reduced in animals exposed to aerosolized IL-1ra before challenge. These studies point to a key role for the cytokines IL-1 and possibly TNF in the pulmonary changes observed during allergic airway disease.

Aerosols↗
PubMed1993

Eosinophil accumulation induced by human interleukin-8 in the guinea-pig in vivo.

Interleukin-8 (IL-8) is a neutrophil chemoattractant cytokine. Initially IL-8 appeared to exhibit specificity for neutrophils over other cells of the immune system. However, several recent studies have shown that this mediator can also activate other leucocyte types in vitro. In this study we have used an in vivo model of local [111In]leucocyte accumulation in the guinea-pig and an in vitro assay of leucocyte activation (changes in cytosolic-free Ca2+) to investigate the eosinophil chemoattractant activity of IL-8. The intradermal injection of recombinant human (rh)IL-8 induced a dose-dependent accumulation of intravenously administered [111In]eosinophils into the skin sites over 4 hr. Time-course experiments revealed that this cell infiltration was delayed in onset, occurring between 1 and 2 hr after injection of IL-8. The delay may indicate that IL-8 operates via an indirect mechanism. In contrast, eosinophil accumulation induced by the complement fragment C5a occurred within the first hour following injection. Other human cytokines, IL-1, IL-3, IL-5, tumour necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), were not eosinophil chemoattractants in this in vivo test system. Direct activation of eosinophils by IL-8 was demonstrated in vitro by a transient elevation in cytoplasmic-free Ca2+ levels where it was less potent than either rhC5a or leukotriene B4 (LTB4). Experiments using [111In]neutrophils in vivo indicated that rhIL-8 and rhC5a were similar in potency in inducing local neutrophil infiltration into guinea-pig skin. The demonstration of the eosinophil chemoattractant activity of IL-8 in vivo raises the possibility that this cytokine, or a structurally related molecule, contributes towards eosinophil infiltration in a number of inflammatory conditions such as asthma, helminthic infections and adult respiratory distress syndrome.

Animals↗
PubMed1992

Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci.

In MRL mice, the mostly recessive lpr mutation results in both the accumulation of CD4-, CD8-, CD3+ T cells in lymphoid tissue and many features of generalized autoimmune disease, including immune complex glomerulonephritis. To positionally clone the lpr mutation and analyze the effects of background genes, backcross offspring were examined from the cross: (MRL/MpJ-lpr x CAST/Ei)F1 x MRL/MpJ-lpr. The lpr gene was found to be closely linked to a mouse chromosome 19 marker defined by a variation of a Fas gene restriction fragment. Our results identified differences in RNA expression and differences in the genomic organization of the Fas gene between normal and lpr mice, and confirm the recent report that a mutation in the Fas apoptosis gene is the lpr mutation. However, our results also indicate that the Fas gene is expressed in spleen cells from normal mice, and spleen and lymph node cells from mice with a second mutation at the lpr locus (lprcg). Together these results suggest that altered Fas transcription results in the failure of lymphocytes to undergo programmed cell death and may lead to an altered immune cell repertoire. This mechanism may explain certain central and peripheral defects in tolerance that are present in autoimmune disease. The current study also demonstrates the profound effect of background genes on the degree of nephritis, lymphadenopathy, and anti-DNA antibody production. Of major note, our studies suggest the identification of chromosomal positions for genes that modify nephritis. Analysis of the backcross mice for markers covering most of the mouse genome suggests that over 50% of the variance in renal disease is attributable to quantitative trait loci on mouse chromosomes 7 and 12. Moreover, this study provides a model for dissecting the complex genetic interactions that result in manifestations of autoimmune disease.

Animals↗
PubMed1992

A linkage map of mouse chromosome 1 using an interspecific cross segregating for the gld autoimmunity mutation.

An interspecific backcross was used to define a high resolution linkage map of mouse Chromosome (Chr) 1 and to analyze the segregation of the generalized lymphoproliferative disease (gld) mutation. Mice homozygous for gld have multiple features of autoimmune disease. Analysis of up to 428 progeny from the backcross [(C3H/HeJ-gld x Mus spretus)F1 x C3H/HeJ-gld] established a map that spans 77.6 cM and includes 56 markers distributed over 34 ordered genetic loci. The gld mutation was mapped to a less than 1 cM segment on distal mouse Chr 1 using 357 gld phenotype-positive backcross mice. A second backcross, between the laboratory strains C57BL/6J and SWR/J, was examined to compare recombination frequency between selected markers on mouse Chr 1. Significant differences in crossover frequency were demonstrated between the interspecific backcross and the inbred laboratory cross for the entire interval studied. Sex difference in meiotic crossover frequency was also significant in the laboratory mouse cross. Two linkage groups known to be conserved between segments of mouse Chr 1 and the long arm of human Chrs 1 and 2 where further defined and a new conserved linkage group was identified that includes markers of distal mouse Chr 1 and human Chr 1, bands q32 to q42.

Animals↗
PubMed1992

A linkage map of mouse chromosome 19: definition of comparative mapping relationships with human chromosomes 10 and 11 including the MEN1 locus.

A linkage map of mouse Chromosome (Chr) 19 was constructed using an interspecific cross and markers defined by restriction fragment length variants. The map includes 20 markers, 9 of which had not been mapped previously in the mouse. The data further defined the relationship between genes on mouse Chr 19 and those on the long arm of human Chr 10 and the pericentric region of the long arm of human Chr 11. The comparative mapping analysis suggests that the proximal segment of mouse Chr 19 may contain the MEN1 locus and that the current study has identified additional genes that may be useful for positional cloning of this putative tumor suppressor gene.

Animals↗
PubMed1992

Effects of angiotensin converting enzyme inhibition in adult polycystic kidney disease.

The pathogenesis of hypertension in autosomal-dominant polycystic kidney disease (ADPKD) is unclear, but increased activity of the renin-angiotension system may contribute. The renal and systemic hemodynamic response to lisinopril, an angiotension converting enzyme (ACE) inhibitor, in patients with ADPKD without renal failure was compared with the response in matched unaffected family members. Mean blood pressure and renal vascular resistance decreased in the affected group after lisinopril, with no significant change in the unaffected group. Glomerular filtration rate (GFR) was unchanged and therefore filtration fraction fell significantly. Changes in urinary excretion of 6-keto-PGF1 alpha and kallikrein suggested that increased renal synthesis of PGI2 or activation of the renal kallikrein-kinin system were not likely to be responsible for the hemodynamic effects. The acute decrease in renal vascular resistance without change in GFR suggests that ACE inhibition may have a particular value in the treatment of hypertension associated with ADPKD which should be assessed by further long-term studies.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Construction of a physical map on mouse and human chromosome 1: comparison of 13 Mb of mouse and 11 Mb of human DNA.

Long range restriction site maps of 13 Mb of mouse chromosome 1 and 11 Mb of human chromosome 1 were constructed using a framework provided by a detailed mouse genetic map. Where an unambiguous gene order could be determined in both species (14 genes), the human and mouse orders were identical. In addition, the distances between markers in the mouse and human were similar except for one region of the conserved linkage group where we could detect a larger distance in the mouse compared to the human. These data support the use of comparative mapping in physical map construction and further suggest the value of using mouse genetics to help define human disease loci.

Animals↗
PubMed1992

Multipoint mapping of adult onset polycystic kidney disease (PKD1) on chromosome 16.

Analysis of genetic linkage data in 33 adult onset polycystic kidney (ADPKD) families was carried out using probes for the D16S85, D16S84, and D16S94 loci. The data set of 33 families shows no evidence of genetic heterogeneity since one unlinked family was previously excluded. Two point linkage analysis showed maximum likelihood values of the recombination fraction of 0.07 for ADPKD and D16S85 (lod score 18.78), 0.02 for ADPKD and D16S84 (lod score 7.55), and 0.00 for ADPKD and D16S94 (lod score 6.73). Multipoint analysis showed a maximum likelihood order of tel-D16S85-0.06-D16S84-0.02-(PKD1, D16S94)-cen with a multipoint lod score of 32.16. Analysis of rare recombinants lying close to PKD1 gave results consistent with this order.

Chromosome Mapping↗
PubMed1991

Histamine, leukotriene D4 and platelet-activating factor in guinea pig passive cutaneous anaphylaxis.

The involvement of histamine, leukotriene D4 (LTD4) and platelet-activating factor (PAF) in cutaneous anaphylaxis was investigated in a guinea pig model. When given alone, the H1 receptor antagonist chlorpheniramine, the LTD4/E4 antagonist LY171883 and the PAF antagonist WEB2086 were unable to inhibit increased microvascular plasma protein leakage in passive cutaneous anaphylaxis (PCA) reactions, as monitored by the extravasation of intravenously injected 125I-albumin. Furthermore the H2 receptor antagonist cimetidine and the serotonin antagonist methysergide were unable to reduce PCA responses when given alone or in combination with chlorpheniramine. In marked contrast, combinations of antagonists were able to reduce plasma leakage significantly. A combination of chlorpheniramine, LY171883 and WEB2086 virtually abolished plasma leakage during the PCA response, but did not influence the plasma protein leakage induced by intradermal injection of bradykinin. These results demonstrate that these allergic reactions involve several mediators and that the inability of an individual mediator antagonist to reduce responses does not necessarily rule out a role for that mediator.

Acetophenones↗
PubMed1991

Mouse platelet-derived growth factor receptor alpha gene is deleted in W19H and patch mutations on chromosome 5.

The mouse W19H mutation is an x-ray-induced deletion of more than 2 centimorgans on chromosome 5 encompassing the white spotting mutation W (encoded by the Kit protooncogene), patch (Ph), and recessive lethal (l) loci. The platelet-derived growth factor receptor alpha gene (PDGFRA) like Kit encodes a transmembrane receptor tyrosine kinase. By using mouse-Chinese hamster somatic cell hybrids and haplotype analysis in interspecific backcross mice, mouse Pdgfra was mapped to chromosome 5 in tight linkage with Kit. Hybridization of a PDGFRA probe to DNAs from W19H/ + heterozygous mice and patch heterozygous mice, and their wild-type littermates, demonstrated deletion of Pdgfra. Pulsed-field gel electrophoresis indicated that Kit and Pdgfra are linked on a 630-kilobase Mlu I DNA fragment. Thus the W19H deletion removes at least two receptor tyrosine kinases and the results suggest Pdgfra as a candidate for the Ph locus.

Animals↗
PubMed1991

Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease.

We studied young adults with autosomal dominant polycystic kidney disease (ADPKD) to determine the characteristics that precede renal impairment. Nineteen affected (A) and 20 unaffected (U) offspring from families with ADPKD showed no significant differences in basal glomerular filtration rate (A: mean 97, SD 19; U: 100, SD 23 ml/min/1.73 m2) or renal functional reserve, but effective renal plasma flow was significantly lower in affected offspring (A: 532, SD 86; U: 605, SD 118 ml/min/1.73 m2, P less than 0.01). Plasma renin activity [A: median 26 (95% CI: 15 to 37); U: 14 (11 to 27) microU/ml, P less than 0.05, one-tailed test] and aldosterone [A: 2.5 (2.0 to 3.0), U: 1.0 (1.5 to 2.0) micrograms/100 ml, P less than 0.04, one-tailed test] were increased in affected offspring despite the higher systolic blood pressure (A: mean 123, SD 5; U: 115, SD 3 mm Hg, P less than 0.02) and significant expansion of total exchangeable sodium (A: 40.8, SD 2.3; U: 38.0, SD 3.5 mmol/kg, P less than 0.01). The ouabain-sensitive component of red cell sodium efflux was less in affected offspring (A: 0.258; SD 0.040; U: 0.288, SD 0.042 hr-1, P less than 0.04) and in both groups was correlated inversely with total exchangeable sodium. Echocardiography revealed no difference in left ventricular mass index nor prevalence of mitral valve prolapse. Potential cyst growth factors such as the glucocorticoids and somatomedin C were similar in both affected and unaffected groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗