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Biomedical subjects

J M Davidson

Publications and source records attributed to J M Davidson.

At least 73 records · Page 4Linked to original sources
PubMed1993

Modulation of transforming growth factor-beta 1 stimulated elastin and collagen production and proliferation in porcine vascular smooth muscle cells and skin fibroblasts by basic fibroblast growth factor, transforming growth factor-alpha, and insulin-like growth factor-I.

During tissue repair and development, matrix accumulation is modulated as multiple signals impinge on target cells. We have investigated the effects of combinations of the mitogenic cytokines, basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGF-alpha), and insulin-like growth factor-1 (IGF-1) with transforming growth factor-beta 1 (TGF-beta 1) with respect to the production of two matrix components, elastin and type I collagen. Using specific enzyme-linked immunoassays for detection of secreted precursors in both vascular smooth muscle cells and skin fibroblasts from the domestic pig, production of these two fibrous proteins was shown to be strongly stimulated by TGF-beta 1. In the smooth muscle cell, both bFGF and TGF-alpha were potent antagonists of TGF-beta 1-mediated matrix production, whereas IGF-1 was only weakly additive with respect to elastin production. Antagonism was also evident to a lesser extent in skin fibroblasts. Reduced responsiveness to TGF-beta 1 did not appear to be due to a switch to a proliferative state, since TGF-beta 1 itself acted as a mitogen in confluent SMC, and TGF-alpha was only a weak mitogen in confluent fibroblast cultures. Although a predominant effect of TGF-beta is matrix accumulation, these findings suggest that this property will be significantly modified by the cytokine context.

Animals↗
PubMed1993

Sub ablation effects of the KTP laser on wound healing.

The KTP laser (wavelength 532 nm) was used in a sub ablative format to determine the effect of low energy density irradiation on the normal healing by primary intention of scalpel skin incisions in rats. Two longitudinal lased strips were created by a 1 cm diameter defocused beam on the shaved, cleaned dorsal epidermis of 32 Sprague-Dawley rates; one strip was produced with a 2.0 W beam (54 J, or 18 J/cm2 total dose), and the other with a 3.5 W beam (94.5 J or 31.5 J/cm2, total dose). Scalpel incisions were made longitudinally within the irradiated zones, using contra lateral scalpel incisions on unirradiated skin as controls. Tensiometric analysis of wound strength was performed at 3, 7, 14, and 23 days following surgery. The data from fresh tissue tensiometry indicate that KTP laser irradiation of skin incisions results in a lower tensile strength for the wound at 7 and 14 days. The decrease in tensile strength is proportional to the total energy density of the exposure. At day 3 and 23, the tensile strength of the wound was independent of the sub ablative laser exposure. The results are in general agreement with studies of the healing process of laser incisions and may help us to understand the details of the healing process from laser incisions.

Animals↗
PubMed1993

Effects of antihypertensive drugs atenolol and nifedipine on sexual function in older men: a placebo-controlled, crossover study.

Investigated the adverse sexual effects of two antihypertensive drugs, atenolol and slow-release nifedipine, in a placebo-controlled, randomized, crossover study. Subjects were 16 older men (mean age = 66.6 years, SEM = 1.4) with mild to moderate hypertension. Subjects completed daily self-reports on 13 measures of sexuality: frequency of desire, coitus, noncoital partner sex, masturbation, morning erections, spontaneous erections, orgasms in coitus and masturbation, firmness of morning, masturbatory and coital erections, and subjective pleasure in coitus and masturbation. Except for a significant decrease in masturbatory erectile firmness with nifedipine therapy, variables did not differ between the two drug treatments or between either drug and placebo. Although the sample was relatively small, small differences between treatment means suggest that these antihypertensive agents are fairly benign relative to sexual function in men.

Aged↗
PubMed1993

Aging and sexual function in men.

Sexual function, and in particular erectile capacity, declines with age in men. The present study attempted to identify possible sensory/neural and autonomic factors related to this decline. Data on self-reported sexual activity and functioning, as well as erectile response to visual erotic stimulation, were gathered from 39 healthy, sexually functional men ranging in age from 21 to 82. In addition, four parameters of putative significance to sexual functioning were measured: penile electrical and vibrotactile thresholds, pudendal somatosensory evoked potentials, penile autonomic response to ischemia, and blood testosterone. Results indicated significant age-related decreases in self-reported frequency of sexual activity and in erectile response to erotica. Furthermore, penile sensitivity, response to penile ischemia, and somatosensory evoked potentials showed age-related changes. In contrast, self-reported erectile capacity, ratings of overall sex life, and levels of testosterone did not change over age groups. These findings suggest that decreasing erectile capacity in aging men may be related to decreasing sensory/neural and autonomic functioning, but they also indicate that factors other than the frequency of and potency for sexual response are important to the overall rating of sex life.

Adult↗
PubMed1993

Neutrophil elastase inhibitors, SC-37698 and SC-39026, reduce endotoxin-induced lung dysfunction in awake sheep.

Neutrophils have been implicated as important cellular mediators of the pulmonary dysfunction observed following endotoxemia in chronically instrumented awake sheep. Several areas of research suggest that neutrophil-derived proteases may be mediators of this dysfunction. We hypothesized that neutrophil elastase inhibitors would attenuate the effects of endotoxemia in sheep. To test this hypothesis, we studied the effects of two putative neutrophil elastase inhibitors, SC-37698 and SC-39026 (Searle, Skokie, IL), on endotoxin-induced lung dysfunction in awake sheep. Sheep were given intravenous neutrophil elastase inhibitor alone (20 mg/kg/h for 6 h), intravenous endotoxin (E. coli endotoxin, 0.5 microgram/kg over 20 min) 1 h after beginning the 6-h infusion of elastase inhibitor, or endotoxin 1 h after beginning a 6-h infusion of elastase inhibitor vehicle. SC-37698 attenuated the increase in lung lymph flow and lung lymph protein clearance, the alterations in lung mechanics, and the fall in white blood count. Qualitatively similar effects were seen with SC-39026. These data suggest the need for further research examining the role of protease-antiprotease interactions and the potential utility of neutrophil elastase inhibitors in acute lung injury like that observed in the adult respiratory distress syndrome (ARDS) in the human.

Analysis of Variance↗
PubMed1993

Extracellular matrix modifications in rat tissues of different ages. Correlations between elastin and collagen type I mRNA expression and lysyl-oxidase activity.

We used a rat model to correlate age, matrix gene expression and lysyl oxidase activity in three connective tissues, skin, aorta and lung. By in situ hybridization, we showed that intense collagen type I and elastin mRNA expression were limited to a brief postnatal period. Although there were some organ-specific differences, the mRNA abundance for these two scleroproteins drastically diminished with time. Thus, the majority of mesenchymal cells in young (60 days) and old (720 days) animals, appeared to be in a quiescent state, consistent with the slow turnover of these two scleroproteins. We also measured the activity of lysyl oxidase, an enzyme which plays a crucial role in the formation of crosslinks in both procollagen and tropoelastin molecules. In all the organs investigated, we observed a tissue-dependent pattern of activity. Moreover in this study we focused on the importance of gene matrix expression in evaluating lysyl oxidase activity of aging tissues.

Aging↗
PubMed1992

Hormones and sexual behavior in relationship to aging in male rats.

To determine if the age-related decline in male sex behavior is correlated with hormonal factors, a longitudinal study was conducted. Sexually experienced males were given mating tests every 2 months from 7 through 27 months of age. To study possible relationships between changes in behavior and alterations in hormone levels, blood samples were taken before and after these bimonthly tests. At 23 months, cross-sectional studies were also conducted comparing results to those obtained in 5-month-old males. Significant changes in mating behavior first appeared at 11 months; mount latency, intromission latency, ejaculation latency, postejaculatory interval, and intercopulatory interval were increased. Similarly, detectable decreases in testosterone (T) also occurred at this age. A significant decline in luteinizing hormone (LH) was not seen until 19 months. Correlational analyses revealed small (r less than or equal to -0.29) but significant negative correlations between T and parameters of mating behavior with age. When each age was examined separately, no significant correlations appeared. Plasma T was not predictive of behavioral performance. At 23 months, cross-sectional studies revealed deficits in mounting and penile reflex behavior but ejaculatory reflex capacity was unimpaired. At 28 months, males were decapitated. Only T levels showed a significant effect of age; estradiol, prolactin, and LH were unaffected when compared to 5-month-old males. The data suggest that although there are small and significant negative correlations between circulating testosterone and parameters of mating behavior with advancing age, it is unlikely that the observed decline in testosterone is the primary cause of the age-induced behavioral deficits. It is likely that the major causal factor(s) involves non-hormone-dependent changes within the CNS.

Aging↗
PubMed1992

Buschke-Ollendorff syndrome associated with elevated elastin production by affected skin fibroblasts in culture.

Buschke-Ollendorff syndrome (BOS; McKusick 16670) is an autosomal dominant connective-tissue disorder characterized by uneven osseous formation in bone (osteopoikilosis) and fibrous skin papules (dermatofibrosis lenticularis disseminata). We describe two patients in whom BOS occurred in an autosomal dominant inheritance pattern. The connective tissue of the skin lesions showed both collagen and elastin abnormalities by electron microscopy. Cultured fibroblasts from both patients produced 2-8 times more tropoelastin than normal skin fibroblasts in the presence of 10% calf serum. Involved skin fibroblasts of one patient produced up to eight times normal levels, whereas apparently uninvolved skin was also elevated more than threefold. In a second patient, whose involvement was nearly complete, elastin production was high in involved areas and less so in completely involved skin. Transforming growth factor-beta 1 (TGF beta 1), a powerful stimulus for elastin production, brought about similar relative increases in normal and BOS strains. Basic fibroblast growth factor, an antagonist of TGF beta 1-stimulated elastin production, was able to reduce elastin production in basal and TGF beta 1 stimulated BOS strains. Elastin mRNA levels were elevated in all patient strains, suggesting that Buschke-Ollendorff syndrome may result, at least in part, from abnormal regulation of extracellular matrix metabolism that leads to increased steady-state levels of elastin mRNA and elastin accumulation in the dermis.

Blotting, Southern↗
PubMed1992

Comparison of elastin peptide concentrations in body fluids from healthy volunteers, smokers, and patients with chronic obstructive pulmonary disease.

Proteolysis of elastic fibers is central to the development of emphysema, and a simple, noninvasive assay of elastin degradation would be useful in diagnosis and in therapeutic monitoring. We have adapted an indirect enzyme-linked immunosorbent assay (ELISA) to determine plasma, urine, and bronchoalveolar lavage fluid (BALF) elastin peptide concentrations in nonsmokers, healthy smokers, and patients with chronic obstructive pulmonary disease (COPD). Plasma elastin peptide concentrations were significantly higher in subjects with COPD (66.8 +/- 5.8 ng/ml, n = 10) compared with nonsmokers (23.4 +/- 4.6 ng/ml, n = 12), and healthy smokers had intermediate values (36.0 +/- 6.8, n = 6), p less than 0.05. Urine values (both unadjusted and normalized to urine creatinine concentration) were approximately 10-fold higher than plasma in all subject groups, and the relative differences among groups were the same as for plasma with values of 910.8 +/- 105.6, 358.1 +/- 101.2, and 281.0 +/- 67.8 ng/ml for subjects with COPD (n = 10), healthy smokers (n = 6), and healthy nonsmokers (n = 12), respectively. Poor recovery of BALF in COPD subjects reduced differences in the BALF elastin peptide concentrations among subjects groups, although the healthy smokers and COPD subjects tended to have higher amounts. Assuming some dilution due to lavage technique, elastin peptide concentrations were estimated to be substantially higher in epithelial lining fluid than in plasma, suggesting lung as a significant source of elastin peptides in COPD. This is the first application of elastin peptide measurement to human urine or BALF, and we conclude that this assay in urine is useful in characterizing elastin turnover in patients with or at risk for emphysema.

Adult↗
PubMed1992

Semidry electrophoretic transfer of RNA to membranes.

We describe a method using a semi-dry gel electro-blotter to transfer RNA from standard agarose-formaldehyde denaturing gels in less than 30 min. The method requires equilibrating the gel in a low ionic strength buffer. The transfer is done under high-current and low-voltage conditions. This method maintains the overall sharpness of the bands on the final autoradiogram while shortening the time required for Northern transfer by approximately 12 hours.

Animals↗
PubMed1991

Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia.

We have studied the consequences of introducing human recombinant transforming growth factor beta 1 (hrTGF-beta 1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-beta is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 microgram of hrTGF-beta 1 into rat knee joints, extensive recruitment of polymorphonuclear leukocytes (PMNs) was observed. Cytochemistry and high resolution histological techniques were used to quantitate the influx of PMNs, which peaked 6 h post-injection. In a Boyden chamber assay, hrTGF-beta 1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-beta 1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-beta in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-beta 1 was secreted during phorbol myristate acetate-stimulated degranulation in vitro. Acid/ethanol extracts of human PMNs assayed by ELISA contained an average of 355 ng of TGF/beta 1 per 10(9) cells potentially available for secretion during degranulation of PMNs. [3H]Thymidine incorporation in vivo and autoradiography of tissue sections revealed that widespread cell proliferation was triggered by TGF-beta 1 injection. Synovial lining cells and cells located deep within the subsynovial connective tissue were identified as sources of at least some of the new cells that contribute to TGF-beta 1-induced hyperplasia. Our results demonstrate that TGF-beta is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-beta present in synovial effusions.

Animals↗
PubMed1991

Testosterone therapy is associated with reduced tactile sensitivity in human males.

Responses to vibrotactile stimuli were examined in men as a function of chronic exposure to either exogenous or endogenous androgens. Psychophysical techniques were used to evaluate thresholds to stimulus detection and perceived stimulus intensities in response to mild vibration applied to either the finger or the penis. Normal men were compared to the following groups: (a) untreated hypogonadal men, (b) androgen-replaced hypogonadal men, or (c) infertile men with androgen levels in the low normal range. Among the four groups, untreated hypogonadal men perceived vibrotactile stimuli as most intense and were slightly more sensitive to touch than were men with higher levels of androgen. Chronic treatment with testosterone enanthate was associated with a decline in the perceived intensity of vibrotactile stimuli in hypogonadal men. The lowest levels of sensitivity to tactile stimuli were observed in the infertile men.

Adult↗
PubMed1991

Hyaluronate derivatives and their application to wound healing: preliminary observations.

Hyaluronic acid and its derivatives show promise as biomaterials in wound healing applications. Studies of cutaneous wound repair were carried out in two animal models to compare the biological effects of hyaluronic acid and hyaluronic acid ethyl ester, a new semisynthetic derivative. The two compounds were tested in partial-thickness excisional wounds in 40-kg pigs and full-thickness excisional wounds in the rabbit ear as 0.2% (w/w) formulations in a neutral Na alginate vehicle. All compounds were administered daily under an occlusive, polyurethane dressing. Neither hyaluronic acid nor the hyaluronic acid ethyl ester showed toxic or inflammatory influences over the observation period of about 2 weeks. Morphometric analysis of porcine wounds revealed small differences among treatment groups which may have been masked by the effect of the vehicle. The rabbit ear model data suggested a very slight inhibition of wound closure. Biochemical analysis of ear wounds showed this injury model to be a sensitive system for evaluation of vulnerary agents. The hyaluronate-treated wounds tended to accumulate collagen more slowly, which may reflect the capacity of these compounds to modify the scarring process. Given the ability to fabricate hyaluronate esters into films and fibers, these data suggest that such biomaterials will not, by themselves, exert a negative influence on the repair process and may improve healing, either alone or in combination with other soluble agents.

Animals↗
PubMed1991

A reliable method for northern blot analysis using synthetic oligonucleotide probes.

We have developed a method for using short (30-42 base pair) synthetic oligonucleotide DNA probes in Northern blot assays. The method involves labeling the probes to high specific activity, very stringent hybridization and wash conditions, and the presence of several inhibitors of nonspecific binding in the hybridization buffer. We have tested this method with several probes obtained from local and commercial sources. The results with every probe used were high signal-to-noise ratios in an exposure time range of 30 min to 7 days.

Animals↗
PubMed1991

Sequence of structural changes and elastin peptide release during vascular remodelling in sheep with chronic pulmonary hypertension induced by air embolization.

The progression of structural changes in the pulmonary arterial bed were followed in a model of chronic pulmonary hypertension. Chronically instrumented awake sheep received continuous air embolization for 0 (controls), 1, 4, 8, or 12 days (n = 5-6/group). After the period of embolization, the lungs were removed, the pulmonary arteries were distended with barium-gelatin, and the lungs were fixed via the airways with formal-saline. Quantitative techniques were applied to sections from random blocks from the lungs of each animal. One day of embolization resulted in granulocyte sequestration in the lung interstitium and in small vessels; additionally, intraalveolar and perivascular edema was present. By 4 days, increased medial thickness, appearance of muscle in smaller arteries than normal (e.g., muscular arteries at alveolar duct level: control = 1.2 +/- 1.2%; day 4 = 22.7 +/- 7.7) and reduction in number of barium-filled intraacinar arteries was found. The arterial changes progressed in severity to day 8 and were similar at day 12. Since arterial remodelling involves increased elastin deposition, the concentration of elastin peptides was measured in lung lymph. Increased flux of elastin peptides was apparent from day 2 of embolization and continued to increase to a level 20 x baseline by day 12 (baseline 351 +/- 86 micrograms/15 min; day 12 = 6338 +/- 2999). Comparison of the onset of the structural changes with previous findings shows that the arterial remodelling parallels the onset of sustained pulmonary hypertension. The increase in lung-lymph elastin peptides by day 2 provides evidence that vascular remodelling is initiated before day 4 of embolization. The early sequestration of granulocytes and appearance of edema suggest that these may be part of the trigger to the development of the structural changes.

Angiography↗
PubMed1991

Human elastin gene: new evidence for localization to the long arm of chromosome 7.

In this study we have utilized human elastin cDNAs in molecular hybridizations to establish the chromosomal location of the human elastin gene. First, in situ hybridizations were performed with metaphase chromosomes from phytohemagglutinin-stimulated human peripheral blood lymphocytes. In three separate experiments using two different regions of human elastin cDNAs, the distribution of grains was found to be concentrated on the long arm of chromosome 7 within the [q11.1-21.1] region, and the peak number of grains coincided with the locus 7q11.2. Second, hybridizations with a panel of human-rodent cell hybrids showed concordance with human chromosome 7. Third, PCR analyses with elastin-specific primers of DNA from a hybrid cell line containing chromosome 7 as the only human chromosome yielded a product of the expected size, while DNA containing human chromosome 2, but not chromosome 7, did not result in a product. The results indicate that the human elastin gene is located in the proximal region of the long arm of chromosome 7. The precise localization of the elastin gene in the human genome is useful in establishing genetic linkage between inheritance of an allele with a mutated elastin gene and a heritable disorder.

Alleles↗
PubMed1991

Opposing effects of ascorbate on collagen and elastin deposition in the neonatal rat aorta.

Ascorbic acid plays an important role in connective tissue metabolism, where, among other effects, it acts as a reducing factor in the reactions catalyzed by prolyl and lysyl hydroxylases. In vitro, ascorbic acid has been shown to have a positive influence on collagen synthesis at pre- and/or post-translational levels and a negative effect on elastin production. In the present work, the effects of vitamin C on extracellular matrix deposition have been studied in vivo. Stereological analysis on electron micrographs showed, compared to age-matched controls, a 50 to 60% increase of collagen deposition in the media and in the adventitia of the aorta of rats treated for 30 days from the 18th day of life with 10% ascorbate in their drinking water. By contrast, elastin volume density was significantly reduced by the treatment at all ages examined. These morphological data were supported by in situ hybridization observations showing enhanced collagen type I mRNA and reduced elastin mRNA expression upon treatment. Although vitamin C did not inhibit lysyl oxidase activity in vivo, being only slightly higher than in controls, enzyme activity was significantly reduced, when high doses of ascorbate were added in vitro. Lysyl oxidase activity may be a function of enhanced collagen metabolism rather than a direct effect of the vitamin on the enzyme activity. These data indicate that ascorbate exerts opposite effects on the deposition of two major components of the extracellular matrix in vivo, at least during periods of rapid growth.

Animals↗