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Biomedical subjects

J W Knowles

Publications and source records attributed to J W Knowles.

17 recordsLinked to original sources
PubMed2002

Ventricular expression of natriuretic peptides in Npr1(-/-) mice with cardiac hypertrophy and fibrosis.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and volume, and exert their biological actions via the natriuretic peptide receptor-A gene (Npr1). Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure. This study examined the relationships between ANP and BNP gene expression, immunoreactivity and fibrosis in cardiac tissue, circulating ANP levels, and ANP and BNP mRNA during embryogenesis in Npr1(-/-) mice. Disruption of the Npr1 signaling pathway resulted in augmented ANP and BNP gene and ANP protein expression in the cardiac ventricles, most pronounced for ANP mRNA in females [414 +/- 57 in Npr1(-/-) ng/mg and 124 +/- 25 ng/mg in wild-type (WT) by Taqman assay, P < 0.001]. This increased expression was highly correlated to the degree of cardiac hypertrophy and was localized to the left ventricle (LV) inner free wall and to areas of ventricular fibrosis. In contrast, plasma ANP was significantly greater than WT in male but not female Npr1(-/-) mice. Increased ANP and BNP gene expression was observed in Npr1(-/-) embryos from 16 days of gestation. Our study suggests that cardiac ventricular expression of ANP and BNP is more closely associated with local hypertrophy and fibrosis than either systemic blood pressure or circulating ANP levels.

Animals↗
PubMed2001

Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert their physiological actions by binding to natriuretic peptide receptor A (NPRA), a receptor guanylate cyclase (rGC) that synthesizes cGMP in response to both ligands. The family of rGCs is rapidly expanding, and it is plausible that there might be additional, as yet undiscovered, rGCs whose function is to provide alternative signalling pathways for one or both of these peptides, particularly given the low affinity of NPRA for BNP. We have investigated this hypothesis, using a genetically modified (knockout) mouse in which the gene encoding NPRA has been disrupted. Enzyme assays and NPRA-specific Western blots performed on tissues from wild-type mice demonstrate that ANP-activated cGMP synthesis provides a good index of NPRA protein expression, which ranges from maximal in adrenal gland, lung, kidney, and testis to minimal in heart and colon. In contrast, immunoreactive NPRA is not detectable in tissues isolated from NPRA knockout animals and ANP- and BNP-stimulatable GC activities are markedly reduced in all mutant tissues. However, testis and adrenal gland retain statistically significant, high-affinity responses to BNP. This residual response to BNP cannot be accounted for by natriuretic peptide receptor B, or any other known mammalian rGC, suggesting the presence of a novel receptor in these tissues that prefers BNP over ANP.

Adrenal Glands↗
PubMed2001

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice.

Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control.

Animals↗
PubMed2000

Genetic modifiers of atherosclerosis in mice.

Atherosclerosis is a complex, multifactorial disease with both genetic and environmental determinants. Experimental investigation of the effects of these determinants on the development and progression of atherosclerosis has been greatly facilitated by the use of targeted mouse models of the disease, particularly those resulting from the absence of functional genes for apolipoprotein E or the low density lipoprotein receptor (LDLR). This review focuses on the influence on atherosclerosis of combining apoE or LDLR deficiencies with factors affecting atherogenesis, including (1) inflammatory processes, (2) glucose metabolism, (3) blood pressure, and (4) coagulation and fibrinolysis. We also discuss the general problem of using the mouse to test the effects on atherogenesis of human polymorphic variations and future ways of enhancing the usefulness of these mouse models.

Animals↗
PubMed2000

Enhanced atherosclerosis and kidney dysfunction in eNOS(-/-)Apoe(-/-) mice are ameliorated by enalapril treatment.

Hypertension and atherosclerosis are each important causes of morbidity and mortality in the developed world. We have investigated the interaction between these conditions by breeding mice that are atherosclerotic due to lack of apolipoprotein (apo) E with mice that are hypertensive due to lack of endothelial nitric oxide synthase (eNOS). The doubly deficient mice (nnee) have higher blood pressure (BP) and increased atherosclerotic lesion size but no change in plasma lipoprotein profiles compared with normotensive but atherosclerotic (NNee) mice. The nnee mice also develop kidney damage, evidenced by increased plasma creatinine, decreased kidney weight/body weight ratio, and glomerular lipid deposition and calcification. Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosis, and kidney dysfunction in nnee mice. In striking contrast, a genetic lack of inducible NOS, which does not affect BP, has no effect on the development of atherosclerotic lesions in Apoe(-/-) mice. We also observed a positive relationship between BP and size of atherosclerotic lesions These results suggest that the atherogenic effects of eNOS deficiency can be partially explained by an increase in BP and reemphasize the importance of controlling hypertension in preventing atherosclerosis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Low salt intake down-regulates the guanylin signaling pathway in rat distal colon.

BACKGROUND & AIMS: Guanylin, an endogenous gastrointestinal peptide, causes the translocation of NaCl from interstitial fluid to the intestinal lumen. The aim of this study was to examine whether changes in dietary salt intake lead to compensatory changes in expression of the guanylin signaling pathway. METHODS: Rats received low-, normal-, or high-sodium diets for 1 week. Colonic guanylin expression was evaluated by Western and Northern blotting, rates of guanylin secretion by measuring biologically active guanylin released into the medium from colon explants, and expression of the guanylin receptor (C-type guanylate cyclase) by Northern blotting and bioassay. RESULTS: By every criterion, the low-salt diet reduced expression of guanylin to 30%-40% of the level found in control animals. Guanylin receptor expression was also decreased, although less dramatically and with a lower statistical significance. For both guanylin and guanylin receptor, the high-salt diet had no significant effect on expression. CONCLUSIONS: The data support the hypothesis that the guanylin pathway is down-regulated as an adaptive response to salt restriction.

Animals↗
PubMed1982

Oral hygiene and maintenance of periodontal support.

The role of personal plaque control in periodontal maintenance care was studied in 78 patients who had undergone periodontal therapy and were on 3-month recall for prophylaxis over 8 years. Variations in pocket depth and attachment levels were related to individuals with plaque scores above and below the median. The results also were analyzed by comparing the 25% of the sample having the lowest plaque scores with the 25% having the highest scores over 7 years of maintenance care. Students t test was used. It was found that personal oral hygiene as expressed in plaque scores was not critical for maintenance of post-treatment pocket depth and attachment levels in patients with professional tooth cleaning every 3 months. The initial post-treatment reductions in pocket depth and variations in attachment levels were more favorable in patients with good than with poor oral hygiene, but, these differences were not significant after 3 to 4 years of maintenance care.

Dental Plaque↗
PubMed1980

Tooth mobility and periodontal therapy.

Data collected as part of an 8-year longitudinal study on periodontal therapy involving 82 patients and 1974 teeth were analyzed to determine if tooth mobility influenced the result of treatment. For each patient, pocket depth, attachment level and tooth mobility were scored clinically at the initial appointment, and once a year for 8 years following periodontal therapy. The treatment consisted of scaling, oral hygiene instruction, occlusal adjustment, periodontal surgery (curettage, modified Widman or pocket elimination), followed by recall prophylaxes every 3 months. Tooth mobility data on a scale of 0--3 were related to changes in attachment levels for three grades of severity of periodontal disease, based on initial pocket depth (1--3 mm, 4--6 mm, and 7 + mm). Mean patient attachment changes were calculated from teeth in the same severity category for each patient. The data were analyzed by one-way analysis of variance and Scheffe's multiple comparison procedure to test the hypothesis of equal effects of tooth mobility on the results of the treatment for the three severity groups over 8 years. The results indicate that there is a statistically significant relationship between original tooth mobility and the change in level of attachment following treatment. Pockets of clinically mobile teeth do not respond as well to periodontal treatment as do those of firm teeth exhibiting the same initial disease severity.

Humans↗
PubMed1980

Results of periodontal therapy related to tooth type.

Certain teeth or groups of teeth are prone to develop more severe periodontal destruction than other teeth in the same individuals. A test was made to assess if these same teeth or groups of teeth also respond less favorably to periodontal therapy than other teeth. Data from a longitudinal study of periodontal therapy for 78 patients over 8 years were analyzed with regard to effect of tooth types on treatment results. The response to periodontal treatment was only marginally related to tooth type with the most favorable responses in the maxillary and mandibular anterior teeth and the least favorable responses in the maxillary molars and bicuspids. Although a number of these differences were significant statistically, the actual values were too small to be of appreciable clinical significance. The overall prognosis for treatment of periodontal pockets apparently is good for all tooth types and this observation applies to moderate as well as to deep pockets.

Bicuspid↗
PubMed1977

Short term results of three modalities of periodontal treatment.

Short term data were obtained from 74 patients who recieved comprehensive periodontal treatment using a split mouth approach to test three variables; subgingival curettage, pocket elimination surgery, and modified Widman flap procedure. The patients initially had an average interproximal loss of attachment of 3.2 mm and an average interproximal pocket depth of 3.9 mm. Evaluation of the data indicate that after 4 to 6 weeks: 1. All three surgical procedures reduce pocket depths. In order of effectiveness they are: pocket elimination surgery, modified Widman flap, and subgingival curettage. 2. Pocket elimination surgery reduces pockets more than subgingival curettage on the buccal, lingual and interproximal, and more than the modified Widman flap on the lingual. The modified Widman flap procedure reduces pockets more interproximally than subgingival curettage. 3. Subgingival curettage results in a gain of attachment interproximally, and on the lingual side, while the modified Widman flap resulted in a gain of attachment interproximally only. 4 Pocket elimination surgery resulted in a loss of attachment buccally. 5 Subgingival curettage results in a more favorable postoperative attachment level on all surfaces than did pocket elimination surgery.

Adult↗
PubMed1975

Radiographs in clinical periodontal trials.

Fifty-eight patients were selected from an ongoing study of periodontal therapy at The University of Michigan. Pre-and post-treatment series of full mouth radiographs obtained by conventional paralleling long cone technique were available. Mesial and distal radiographic bone height was scored using the technique developed by Björn et al. A total of 1416 teeth were scored from the itial radiographs, and subsequently at one, two, three, and four years after the treatment. Radiographic bone height scores were compared with level of attachment and pocket depth scores for the same teeth at the same time. Statistical significance and correlation coefficients were derived using computer analysis of the data. The data were analyzed using three different data groupings: individual teeth, patient means, and half-mouth treatment methods. High positive correlations were found between initial measurements of radiographic bone height and attachment level as well as pocket depth. The correlations between changes in measurements of radiographic bone height and attachment level after treatment were markedly lower but are statistically significant. A highly significant correlation between radiographic bone heights and measurements of attachment level also appeared in follow-up data one to four years after treatment. The method of data grouping resulted in different correlation coefficients. Highest correlations were found if the data were pooled for patients. Lowest correlations were found if the data for individual teeth were analyzed. When the data were combined to produce patient scores, sample variation is reduced and correlations increase in magnitude. The generally high correlations between radiographic bone height and attachment level scores before and after treatment tend to confirm the fact that radiographic assessment of alveolar bone height using the method of Björn et al. can provide fairly accurate assessment of interproximal periodontal support.

Alveolar Process↗
PubMed1975

Results following three modalities of periodontal therapy.

Three methods for treatment of periodontal pockets (subgingival curettage, modified Widman flap surgery, and pocket elimination) were applied as a clinical trial to 82 patients. Follow up results over one to five years after the initial treatment are reported. The variations in attachment levels and pocket depth were analyzed statistically as related to methods of treatment and yearly time intervals following the initial treatment. The most favorable results regarding gain or maintenance of attachment levels and reduction of pocket depth were observed interproximally. Subgingival curettage provided the greatest gain in attachment level up to three years postoperatively, but after four to five years there was no significant difference in results following the three methods. The most significant loss of attachment and return of pocket depth occurred on the buccal aspects of the teeth, and the results were not significantly different for the three methods except at the first year of follow up when the attachment level was maintained best after curettage.

Adult↗