Biomedical subjects

J M Davidson

Publications and source records attributed to J M Davidson.

At least 55 records · Page 3Linked to original sources

PubMed1996

The effects of keratinocyte growth factor on healing of tympanic membrane perforations.

Tympanic membrane (TM) perforations heal by reepithelialization and fibrous layer proliferation. The rat TM model may be used to study growth factors that promote epithelialization and fibroblast proliferation, such as epidermal growth factor (EGF) and fibroblast growth factor (FGF). The authors previously evaluated the effects of FGF on tympanic membrane perforations and showed an enhanced rate of wound healing with preservation of normal structure and function. The same model was used to test keratinocyte growth factor (KGF, also called FGF-7). This growth factor has been shown to stimulate the migration and proliferation of keratinocytes. This is the first study investigating KGF in the tympanic membrane perforation model. Our results show that in contrast to FGF and EGF, KGF does not enhance the rate of wound healing, but rather results in a more organized wound repair process.

Animals↗

PubMed1996

Thermal injury patterns and tensile strength of canine oral mucosa after carbon dioxide laser incisions.

The amount of collateral damage in laser surgery is affected by the precision of the beam delivery. To test a new control system, the authors of this study produced surgical incisions in the canine oral mucosa and then documented histologic and tensile strength changes during the wound healing process. The incisions were made by three different methods: scalpel, manually controlled carbon dioxide (CO2) laser, and computer-controlled C02 laser. Both types of laser incisions took longer to heal than the scalpel incisions. The laser incisions were accompanied by a zone of thermal damage lateral to the incision. With the computer-controlled laser incision, the area of thermal damage was reduced, the laser-induced delay in wound healing was less, and tensile strength was relatively greater. The data indicate that surgical performance is improved by critical beam control.

Animals↗

PubMed1996

Cutis laxa acquisita associated with multiple myeloma: a case report and review of the literature.

Cutis laxa acquisita is a rare disorder that affects collagen and elastin metabolism. The cause is unknown. Characteristic features include sagging and laxity of the skin, as well as involvement of the lungs, heart, gastrointestinal system, and urogenital tract. Three cases of cutis laxa acquisita have been reported in association with multiple myeloma. Due to the rarity of these disorders, a linkage has been postulated. The clinical and histologic data from the fourth case of cutis laxa acquisita associated with multiple myeloma were compared to the three other cases previously reported in the literature. The relationship between acquired cutis laxa and multiple myeloma is unclear, with only one case revealing possible immune-mediated elastin destruction via IgG immunoglobulin bound to dermal elastin fibers on immunofluoresence examination. No pattern in the clinical courses of the disorder can be seen on review of the four cases with coincident disease. We hypothesize that cutis laxa acquisita represents a paraneoplastic process of multiple myeloma, given the rarity of these diseases. Further investigation is necessary to determine the underlying linkage between these disorders. We suggest that serum and urine protein electrophoresis results be obtained in patients presenting with cutis laxa acquisita to screen for multiple myeloma given this association.

Antineoplastic Agents↗

PubMed1996

Connective tissue in skin biopsies from patients suffering systemic sclerosis.

Little information is available on elastin during systemic sclerosis since biochemical and morphological data have primarily focused on collagen and glycosaminoglycan alterations of connective tissues in this pathological process. We performed ultrastructural, morphometric, biochemical and in situ hybridisation analyses on skin biopsies from patients affected by scleroderma and from site and age-matched control subjects. Affected skin revealed alterations in the distribution and organisation of collagen bundles and fibrils together with zonal increase of the microfibrillar component. Elastic fibres were significantly more numerous than in control skin, were more frequently vacuolated and characterised by electron-dense inclusions; moreover, morphometric analysis provided evidence for a significant increase of the percentage of both collagen bundles and elastin fibres in the measured tissue, compared to normal skin. Biochemical analysis seemed to confirm the increased elastin content per unit of dried weight tissue in sclerodermic skin. Differences observed among patients were only partially associated with disease duration and/or to severity of clinical manifestations. The abnormal amount of elastic fibres observed in skin biopsies from patients, and data from in situ hybridisation suggest the presence of a deregulation of the whole extracellular matrix that might be related to the role of cytokines such as TGF-beta, which has already been suggested to be involved in systemic sclerosis and in enhanced collagen and elastin production.

Adult↗

PubMed1995

Regulation of elastin synthesis in pathological states.

Elastin is rapidly deposited during late gestation in resilient tissues such as the arteries, lungs and skin owing to increased concentration of its mRNA. Pathological states can arise from congenital insufficiency or disorganization of elastin (cutis laxa). Other elastin deficiencies may be due to excess elastolysis or gene dosage effects. In the former, high turnover rates can be assessed by measurements of elastin degradation products in urine. Excess elastin accumulation by skin fibroblasts is characteristic of genetic diseases such as Buschke-Ollendorff syndrome, Hutchinson-Gilford progeria and keloid. Elastin expression is modulated by peptide growth factors, steroid hormones and phorbol esters, among which transforming growth factor beta (TGF-beta) is an especially potent up-regulator, acting largely through stabilization of mRNA. Recent evidence indicates cutis laxa fibroblasts that express little or no elastin have normal transcriptional activity but abnormal rates of elastin mRNA degradation. This defect is substantially reversed by TGF-beta through mRNA stabilization. Current studies explore the hypothesis that stability determinants lie within the 3' untranslated region of elastin mRNA. Post-transcriptional control of elastin expression appears to be a major regulatory mechanism.

Animals↗

PubMed1995

Regional mitogenic response of the meniscus to platelet-derived growth factor (PDGF-AB).

Since meniscal healing is region-specific, we studied the regional (peripheral compared with central) response of meniscal explants to human, recombinant platelet-derived growth factor-AB. Meniscal explants from the hindlimbs of both knees of mature sheep were sectioned and were cultured with variable doses of human, recombinant platelet-derived growth factor-AB, and incorporation of [3H]-thymidine was measured. The mitogenic response was measured at different times in culture (48 or 96 hours) and by location (lateral or medial). In the absence of the growth factor, the peripheral third of both menisci incorporated 10-fold more [3H]-thymidine on a weight basis than did the central two-thirds. Cellularity was equivalent in the two regions. Doses of less than 100 ng/ml of growth factor produced either no stimulation or a variable response. A dose of 100 ng/ml resulted in consistent, significant (p < 0.05) stimulation in all groups in the peripheral region, and a dose of 200 ng/ml provided more than a 2.5-fold increase. Multiple-factor analysis of variance demonstrated that there were no significant differences between experiments, times in culture, or menisci. The central region did not respond to stimulation with the growth factor at any of the doses tested. These data suggest that regional differences (peripheral compared with central) in responsiveness to human, recombinant platelet-derived growth factor-AB may reflect a different level of signal transduction machinery for growth factor receptors and distinct fibrobchondrocyte populations. These findings are consistent with the variable healing capacity of the meniscal regions in vivo and suggest a pharmacological means to promote the repair of the peripheral meniscal region.

Animals↗

PubMed1995

The inhibitory effects of propranolol on genital reflexes in male rats.

We have previously reported that propranolol adversely affects sexual behavior in male rats. To elucidate whether the effects of propranolol might involve decrements in ability, we examined two components of sexual function ex copula--ejaculatory reflex capacity and erectile reflexes. In the first study, we examined the effects of various doses of (+/-)-propranolol (1.25-10 mg/kg) administered subcutaneously. Marked inhibition was observed, evidenced by increases in the latency to ex copula ejaculation and to initial erection and decrements in the number of seminal emissions and in the number of erectile reflexes. Analyses of dose-response relationships indicated that the degree of inhibition increased with increasing dose. In the second study, we evaluated the stereo-selectivity of the responses. Both (+)- and (-)-propranolol (1.25 mg/kg) significantly inhibited ejaculatory reflex potential, and although (+)- and (-)-propranolol significantly inhibited erectile reflexes, (-)-propranolol had a greater effect. The data are interpreted to indicate that a) propranolol-induced sexual dysfunction involves both motivational and ability aspects; and b) propranolol-induced inhibition of genital reflexes may be due, at least in part, to mechanisms other than beta-adrenoceptor blockade.

Adrenergic beta-Antagonists↗

PubMed1995

Glucocorticoid regulation of elastin synthesis in human fibroblasts: down-regulation in fibroblasts from normal dermis but not from keloids.

Keloids arise as benign connective tissue masses at sites of injury in genetically predisposed individuals. In addition to excessive collagen accumulation, there is biochemical and histologic evidence of elastic tissue. Previous studies showed that glucocorticoid regulation of collagen synthesis differs in fibroblasts from normal adult dermis and keloids. To define further the abnormal regulation of matrix synthesis in keloid fibroblasts, we examined glucocorticoid regulation of elastin synthesis. The basal level of elastin synthesis was significantly higher in keloid than in normal cells, and hydrocortisone reduced synthesis of elastin and elastin mRNA in normal but not in keloid fibroblasts. We had shown previously that fibroblasts from fetal dermis resembled keloid fibroblasts in glucocorticoid regulation of growth and collagen synthesis. In this study, glucocorticoids failed to down-regulate elastin synthesis in fetal cells that had not differentiated to produce normal levels of elastin, whereas fetal cells with normal elastin production exhibited glucocorticoid down-regulation. Abnormal regulation in keloid cells was independent of cell density and was confined to fibroblasts cultured from the keloid nodule. These findings reinforce the conclusion that a matrix-regulatory pathway is deranged in these focal lesions. Coordinate down-regulation of collagen and elastin by hydrocortisone in normal adult dermal fibroblasts and the failure of hydrocortisone to down-regulate synthesis of either protein in keloid cells support the existence of common elements in the regulatory pathways of these two matrix proteins.

Adult↗

PubMed1995

Secretory leukoprotease inhibitor attenuates lung injury induced by continuous air embolization into sheep.

Continuous air embolization (CAE) into the pulmonary arterial circulation of sheep results in functional and structural changes of chronic pulmonary hypertension. Release of elastin peptides into lung lymph during CAE and attenuation of CAE-induced pulmonary hypertension by neutrophil depletion suggest that neutrophil elastase may contribute to these changes. To investigate this notion, we treated awake sheep with a potent neutrophil elastase inhibitor, recombinant secretory leukoprotease inhibitor (SLPI) (100 mg/day by aerosol), during 12 days of CAE (CAE+SLPI; n = 7). Controls included sheep receiving CAE + vehicle (VEH) (n = 6), VEH alone (n = 3), and SLPI alone (n = 3). SLPI significantly attenuated the CAE-induced increases in lung lymph flow (day 8; 2.3 +/- 0.5 vs. 5.6 +/- 1.7 ml/15 min), protein clearance (day 8; 1.36 +/- 0.32 vs. 3.08 +/- 0.84 ml/15 min), and elastin peptide concentration (day 8; 243 +/- 41 vs. 398 +/- 44 ng/ml). SLPI delayed the onset of sustained pulmonary hypertension from day 8 to day 12. Both CAE groups showed similar structural changes in the pulmonary arteries. SLPI was well tolerated in control sheep and did not affect hemodynamics or structure. We conclude that serine proteases may contribute to the early initiation of chronic pulmonary hypertension but do not play a striking role in its eventual development.

Aerosols↗

PubMed1995

Transforming growth factor-beta reverses a posttranscriptional defect in elastin synthesis in a cutis laxa skin fibroblast strain.

Skin fibroblasts from two cases of autosomal recessive cutis laxa (CL), having insignificant elastin production and mRNA levels, were challenged with transforming growth factor beta-1 (TGF-beta 1). Elastin production was brought from undetectable values to amounts typical of normal human skin fibroblasts in a dose-dependent fashion. Basic fibroblast growth factor (100 ng/ml) alone or in combination with TGF-beta 1 reduced elastin production and mRNA expression in CL skin fibroblasts more extensively than in normal cells. In situ hybridization showed that these effects were at the transcript level. One of the CL strains was examined in detail. Transcription rates for elastin were similar in normal and CL and unchanged by TGF-beta 1 or TGF-beta 2 (10 ng/ml), while in CL elastin mRNA half-life was increased > 10-fold by TGF-beta 2 and reduced 6-fold after TGF-beta 2 withdrawal, as compared with a control strain. Cycloheximide partially reversed elastin mRNA instability. These data are consistent with a defect in elastin mRNA stability that requires synthesis of labile factors or intact translational machinery, resulting in an extremely low steady state level of mRNA present in this strain of CL. Furthermore, TGF-beta can relieve elastin mRNA instability in at least one CL strain and elastin production defects in both CL strains.

Cells, Cultured↗

PubMed1995

A tissue-culture model for the study of canine vocal fold fibroblasts.

A tissue-culture model has been developed for the study of fibroblasts from the canine vocal fold. Laryngeal tissue (lamina propria) obtained from euthanized dogs is rinsed, cut into 1-mm3 pieces, and incubated in 5% carbon dioxide at 37 degrees C. A confluent monolayer is established within several days. Detectable levels of elastin in the tissue culture supernatant are measured by an indirect enzyme-linked immunosorbent assay. Various external agents have been shown to affect elastin production. The effects of KTP laser irradiation, hydrocortisone (1.3 mumol/L), transforming growth factor-beta (10 ng/mL), and human leukocyte elastase have been measured. Thus the canine vocal fold fibroblast tissue culture is established as a model for further investigations to improve wound healing and to understand the wound-healing process following laryngeal microsurgery.

Animals↗

PubMed1995

Proliferative responses to platelet-derived growth factor in young and old rat patellar tendon.

Musculoskeletal soft tissue repair is often a slow process that may be complicated by aging, thus we investigated the mitogenic response of young and old rat patellar tendon (PT) explants to platelet-derived growth factor-AB (PDGF-AB). Bilateral PT explants from young (4 months) and old (29 or 36 months) rats of two strains (Fisher 344 and Fisher-Brown-Norway) were cultured for 72 h in platelet-poor horse serum in the presence or absence of 100 ng/ml recombinant human PDGF-AB. The explants were radiolabelled with [3H]-TdR for the final 24 h in culture. Tendon cellularity and DNA synthesis data were analyzed by multiple factor ANOVA (age, strain, and side), Mann-Whitney t-test (cellularity and DNA synthesis), and a sign test (proliferative response to PDGF). Tendon cellularity declined significantly with age in both strains (p < 0.05), while both young and old patellar tendon fibroblasts in both strains had a significant (> 100%) increase in DNA synthesis with the addition of PDGF (p < 0.05). Although there was a trend to lower proliferative responses in older tendons, the differences were not significant. Autoradiographic analysis of labeling indices in F344 tendons showed a diminished responsiveness to PDGF (p < 0.04, ANOVA). Strain and side response on a per cell or tissue weight basis were not significant factors. Under appropriate experimental conditions, these two animal models of aging showed declines in responses to high levels of PDGF, suggesting that the PT reflects an age-dependent diminished capacity for wound repair.

Aging↗

PubMed1994

Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity.

To determine the psychophysiological correlates of hormonal response during sexual activity, systolic blood pressure (SBP), anal electromyography (EMG), and anal photoplethysmography (APG) were monitored continuously throughout testing in 13 women and 10 men. Each subject completed two or more tests of self-stimulation to 5 min beyond orgasm. Blood samples were obtained continuously for measurement of oxytocin (OT) levels. In both men and women, very high positive correlations were observed between the percentage change in levels from baseline through orgasm of: OT and SBP; OT and EMG intensity prior to and during orgasm; APG and EMG. The number of anal contractions and duration of orgasm were also highly correlated. Two patterns of orgasm were defined by the presence or absence of a quiescent period between orgasmic contractions. EMG and APG amplitudes correlated with the pattern of orgasm. Subjective orgasm intensity correlated significantly with increased levels of OT in multiorgasmic women only. The positive correlations between measures are consistent with a possible functional role for OT in human sexual response.

Adult↗

PubMed1994

Phenotypic stability and variation in cells of the porcine aorta: collagen and elastin production.

The extracellular matrix of the developing vasculature varies in composition as a function of time and position. Cellular models of vascular biology and pathology depend on the assumption that stable phenotypic characteristics of vascular cells can be propagated through several generations of in vitro cultivation. We show that the positional and developmental heterogeneity of matrix phenotypes in the porcine aorta are expressed by explanted vascular smooth muscle cell (SMC) and adventitial cell populations for a limited number of passages. Elastin was expressed most highly by thoracic SMC while interstitial collagen production was usually maximal in abdominal segments. Parallel gradients of collagen types I, III and V, detected by specific ELISA assays, were expressed in early-passage SMC. Adventitial cell populations from the abdominal aorta of the neonatal pig accumulated significant levels of collagen, while these fibroblasts produced less than 10% of the elastin made by SMC. All cell populations expressed alpha-smooth muscle actin in vitro. Gradients of collagen and elastin expression were evident for no more than three passages, and direct outgrowth of cells without limited digestion of the matrix further reduced phenotypic stability. Variation and decline of the elastin phenotype could be due to hypermethylation of regulatory sequences in the elastin gene or trans-acting factors, but elastin production was dose-dependently stimulated to a similar extent (100%; 10 microM 5-azacytidine) in all segmental SMC populations at early (p1) and late (p3) passage. These data indicated that faithful reflection of in vivo SMC behavior was limited to a few population doublings, at least under standard culture conditions. Modification of the cellular environment by reducing serum factors, changing matrix, or adding mechanical stimulation may increase phenotypic stability.

Aging↗

PubMed1994

Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS.

(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a nucleotide analogue with potent in vitro and in vivo activity against a broad range of herpesviruses, including acyclovir-resistant herpes simplex virus (HSV). A patient with severe acyclovir-resistant perineal HSV infection received intravenous HPMPC at 5 mg/kg/week, with concomitant oral probenecid and prehydration, and had 95% healing after four infusions. The patient developed a hypersensitivity reaction to probenecid and discontinued HPMPC after the fourth infusion. Recurrence of the perineal lesions 2 weeks later prompted initiation of an oral desensitization program to probenecid and enabled the patient to resume therapy. The lesions again responded to infusions of HPMPC, but the drug was discontinued before complete healing because of transient nephrotoxicity (proteinuria, 2+; creatinine, 1.7 mg/dL). HPMPC is a potent antiviral agent that holds promise as a potential treatment for acyclovir-resistant HSV infection.

AIDS-Related Opportunistic Infections↗

PubMed1994

Elastin production and degradation in cutis laxa acquisita.

A case of cutis laxa acquisita was studied with the aim of defining the molecular defects involved and comparing them with those of an inherited form of cutis laxa. In the acquisita form of cutis laxa ultrastructural and biochemical observations confirmed a dramatic reduction of dermal elastin, whereas collagen content was normal. Elastin mRNA expression as well as tropoelastin production by dermal fibroblasts, in vitro, were normal compared with control cells, as revealed by in situ hybridization and enzyme-linked immunosorbent assay, respectively. Lysyl oxidase activity, measured on cultured fibroblasts, was reduced to 60% compared with age-matched control subjects. Unlike control skin fibroblasts or fibroblasts from inherited cutis laxa, the affected skin cells from cutis laxa acquisita predominantly expressed an elastolytic activity identified as cathepsin G. Patient serum also has reduced elastase inhibitory capacity and reduced levels of alpha 1-antiproteinase inhibitor (alpha 1-antitrypsin). Although cutis laxa acquisita is a heterogeneous group of disorders, findings in this patient were consistent with excessive loss of cutaneous elastin due to the combined effects of several factors, such as low lysyl oxidase activity together with high levels of cathepsin G and reduction of circulating proteinase inhibitor(s).

Adult↗

PubMed1994

Evaluation of basic fibroblast growth factor in tympanic membrane repair.

Basic fibroblast growth factor (bFGF) has been shown to enhance speed of wound repair at a number of anatomic sites. This study presents an evaluation of bFGF in a model of acute tympanic membrane (TM) perforation in order to assess rate of healing as well as structural and functional outcome. Perforations were created in the tympanic membranes of rats, then allowed to heal in the presence of topically applied bFGF with the opposite ear serving as a control. The growth factor was applied in repeated doses beginning 2 days after creation of the TM defect. The treated ears healed faster by an average of 4.0 days. The healed tympanic membranes were assessed using tympanometry and light microscopy. Structurally and functionally, the healed tympanic membranes were similar to the controls. The observed results indicate that bFGF promotes accelerated healing and restoration of normal architecture in acute TM defects.

Acoustic Impedance Tests↗

PubMed1993

Familial co-segregation of the elastin phenotype in skin fibroblasts from Hutchinson-Gilford progeria.

Elastin and type IV collagen production are markedly elevated in fibroblasts derived from the skin of patients with Hutchinson-Gilford progeria (HGP). Fibroblasts from three affected children and their parents were compared to normal human skin fibroblasts with respect to elastin production as a function of different concentrations of calf serum and the cytokines, transforming growth factor-beta and basic fibroblast growth factor (TGF-beta 1, bFGF). In cultured fibroblasts from the parents of probands that were very high elastin producers (> 10(5) molecular equivalents/cell per h), at least one parent (mother) presented the same phenotype. Overproduction of elastin in culture could have been due to increased sensitivity of HGP strains to stimuli present in serum; however, relative stimulation of elastin production by calf serum in cell strains from HGP elastin over-producers was less than half the control strain. In most of the cultures examined, the responsiveness of elastin production to TGF-beta 1 was almost absent when compared to the response of normal fibroblasts. HGP strains with high elastin production modified conditioned medium to enhance elastin production in normal cells. These results suggest the presence, in HGP skin fibroblasts, of inheritance of high elastin production that is associated with accelerated aging.

Adolescent↗