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Biomedical subjects

R A Brown

Publications and source records attributed to R A Brown.

At least 91 records · Page 5Linked to original sources
PubMed1999

Augmentation of the inotropic response to insulin in diabetic rat hearts.

Insulin participates in the modulation of myocardial function, but its inotropic action in diabetes mellitus is not fully clear. In the present study, we examined contractile responses to insulin in left-ventricular papillary muscles and ventricular myocytes isolated from hearts of normal or short-term (5-7 days) streptozotocin-induced (65 mg/kg) diabetic rats. Mechanical properties of papillary muscles and ventricular myocytes were evaluated using a force transducer and an edge-detector, respectively. Contractile properties of papillary muscles or cardiac myocytes, electrically stimulated at 0.5 Hz, were analyzed in terms of peak tension development (PTD) or peak twitch amplitude (PTA), time-to-peak contraction (TPT) and time-to-90% relaxation (RT90). Intracellular Ca2+ transients were measured as fura-2 fluorescence intensity change (deltaFFI). Insulin (1-500 nM) had no effect on PTD in normal myocardium, whereas it produced a positive inotropic response in preparations from diabetic animals, with a maximal increase of 11%. Insulin did not modify TPT or RT90 in either group. Further studies revealed that insulin enhanced cell shortening in diabetic but not normal myocytes, with a maximal increase of 21%. Consistent with its action on the mechanical properties of papillary muscles and cardiac myocytes, insulin also induced a dose-dependent increase in the intracellular Ca2+ transient in diabetic but not normal myocytes. Collectively, these data suggest that the myocardial contractile response to insulin may be altered in diabetes.

Animals↗
PubMed1999

Stabilization of fibronectin mats with micromolar concentrations of copper.

Fibronectin, a large extracellular matrix cell adhesion glycoprotein has diverse functions in wound repair including organization of matrix deposition and promotion of angiogenesis. We have previously shown that purified plasma fibronectin can be made into three-dimensional, fibrous materials, termed fibronectin mats (Fn-mat). The aim of this study was to examine means of increasing the stability of Fn-mats using a novel treatment with micromolar concentrations of copper ions which may be used to improve wound healing/nerve repair. Cytotoxicity of incorporated copper was determined using rat Schwann cells, rat tendon fibroblasts and human dermal fibroblasts. Dissolution of protein from the Fn-mat showed that treatment with the lowest concentration of copper used (1 microM) increased the stability of mats by 3-4 times at room temperature relative to control mats and twofold at 37 degrees C. Copper mediated increase in stability was dose dependent. Orientation of the Fn-fibres (within mats), monitored by scanning electron microscopy was retained with 1 microM copper but disappeared with higher concentrations. Schwann cells grew in culture with mats stabilized by 1 microM copper treatment without reduction in cell number but growth was inhibited at 10-200 microM Cu. All types of fibroblasts were unaffected by copper treatment upto 200 microM. Fn-mats can be successfully stabilized by this technique producing longer survival in vitro. The differential effects of copper on these cell types suggests that CuFn-mats may be used to select the type of cells which colonize these materials.

Animals↗
PubMed1999

Immune reconstitution following allogeneic peripheral blood stem cell transplants.

Growth factor-mobilized peripheral blood stem cells (PBSCs) engraft rapidly in myeloablated recipients compared to conventional BM, but this procedure also mobilizes mature lymphocytes and monocytes which can impact immune reconstitution and GVHD. Hence, we serially evaluated immune reconstitution and cytokine expression in PBSCT recipients in the first year. Engraftment of neutrophils and monocytes stabilized early but NK cells, B cells and CD4+ T cell numbers were significantly (P < 0.05) low with persistently reversed CD4:CD8 ratios. NK function remained low throughout the first year. The quantitative decrease in CD4+ T cells resulted in significantly decreased proliferation in response to mitogens and alloHLA antigens. Yet, a qualitative analysis of T cell function measured by Ca++ influx after T cell activation with antiCD3 as well as T-dependent polyclonal Ig secretion by mitogen-stimulated B cells was preserved even early post transplant. TNF alpha mRNA was detected in almost all recipients in the first year. IL-10 mRNA was detected in 77%, IL-2 in 22% and IFN gamma in 44% of recipients in the first 6 months. Only 30% expressed IL-10 in the second 6 months post transplant while expression of IL-2 and IFN gamma was detected in 38% and 46% respectively. Thirty-seven percent of PBSCT recipients developed grades II-IV acute GVHD but 72% went on to develop chronic extensive GVHD at a median of 120 days. Sixty-two percent developed CMV viremia and 5.4% developed overt CMV disease in the first year post PBSCT. Lymphocyte engraftment is quantitatively delayed but CD4 functions are preserved while NK numbers and function are compromised post PBSCT. IL-10 expression decreases after the first 6 months post transplant while TNF alpha is continually expressed. The balance between quantitative lymphocyte reconstitution and qualitative lymphocyte functions as well as changes in lymphokine patterns may influence infection and GVHD and thus the clinical outcome post PBSCT.

Adolescent↗
PubMed1999

Level of current and past adolescent cigarette smoking as predictors of future substance use disorders in young adulthood.

AIMS: This study examined the impact of adolescent cigarette smoking (life-time use, recency, frequency and age of onset) on the occurrence of substance use disorders during young adulthood. DESIGN: Participants were assessed while in high school (T1), approximately 1 year later (T2) and then after they had turned 24 years of age (T3). SETTING: Adolescents were randomly selected at T1 from nine senior high schools in western Oregon. PARTICIPANTS: A subset (n = 684) of 1709 adolescents who had been assessed regarding cigarette smoking during high school were evaluated for alcohol, cannabis and other drug abuse/dependence up to age 24. MEASUREMENTS: Semi-structured interviews provided information regarding life-time use of cigarettes and chewing tobacco, age of smoking onset, frequency and quantity of cigarette smoking and quit efforts in adolescence. Diagnoses of substance abuse and dependence in young adulthood were made as per DSM-IV. FINDINGS: Life-time smoking among older adolescents significantly increased the probability of future alcohol, cannabis, hard drug and multiple drug use disorders during young adulthood. Having been a former smoker did not reduce the risk of future substance use disorder, although having maintained smoking cessation for more than 12 months was associated with significantly lower rates of future alcohol use disorder. Daily smoking was associated with increased risk of future cannabis, hard drug and multiple drug use disorders. Among daily smokers, earlier smoking onset age predicted future substance use disorders. CONCLUSIONS: The results extend knowledge about relationships between cigarette smoking during adolescence and the development of substance use disorders during young adulthood, illustrating additional risks associated with early cigarette smoking. Future research is needed to examine potential causal associations.

Adolescent↗
PubMed1999

Influence of age on inotropic response to insulin and insulin-like growth factor I in spontaneously hypertensive rats: role of nitric oxide.

Insulin-like growth factor-1 (IGF-1) and insulin stimulate cardiac growth and contractility. Recent evidence suggests a relationship between essential hypertension, left ventricular hypertrophy, and circulating IGF-1 levels. Advanced age alters cardiac function in a manner similar to hypertension. The aim of this investigation was to evaluate the effects of IGF-1 and insulin on the force generating capacity of cardiac muscle in hypertension and the influence of age on this response. Contractile responses to IGF-1 and insulin were examined using papillary muscles from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at 10 and 25 weeks of age. Muscles were electrically stimulated at 0.5 Hz, and contractile properties, including peak tension development (PTD), time-to-peak tension, time-to-90% relaxation, and the maximal velocities of contraction and relaxation, were evaluated. PTD was similar in WKY and SHR myocardium at both age groups. At 10 weeks of age, IGF-1 (1-500 ng/ml) caused a dose-dependent increase in PTD in WKY but not SHR myocardium, whereas insulin (1-500 nM) had no effect on PTD in either group. At 25 weeks of age, the positive inotropic effect of IGF-1 was attenuated in the WKY group, and IGF-1 exerted no inotropic action in the SHR group. Pretreatment with the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME, 100 microM), did not alter the IGF-1-induced positive inotropic response in 10-week-old WKY myocardium, whereas it unmasked a positive inotropic action in muscles from age-matched SHR animals. At 25 weeks of age, L-NAME abolished IGF-1-induced a positive inotropic response in WKY myocardium, and did not unmask an IGF-induced inotropic response in SHR myocardium. Our results suggest that alterations in nitric oxide modulation of IGF-1-induced contraction may underlie resistance to this inotropic peptide with advancing age, and/or hypertension.

Aging↗
PubMed1999

Nerve growth factor enhances peripheral nerve regeneration in non-human primates.

Fibronectin mat implants impregnated with NGF have been successfully used in rat nerve regeneration model. The aim of this study was to assess their action in a primate model. Mats were implanted into a 5 mm gap in a peripheral nerve in Macaca fascicularis monkeys, either alone (Fn) or in the presence of nerve growth factor (Fn + NGF). Four months postoperatively, the regenerated nerve was analysed by light microscopy, and target skin reinnervation was assessed by quantification of cutaneous nerve terminals immunostained with protein gene product (PGP) antibodies. The diameter of the regenerated nerve was similar in Fn + NGF grafts and nerve autografts, but significantly larger for plain Fn grafts with evidence of more connective tissue surrounding the axons. Myelinated fibres counts showed similarities in normal control nerve, nerve autograft and Fn + NGF graft groups. However, in nerve grafted with plain Fn mats the regenerating fibres were lower in number and showed a wider variability in diameter and myelination, resulting in a significantly smaller G-ratio (axonal diameter/myelinated fibre diameter). The amount of cutaneous reinnervation was lowest in Fn graft group, while comparable amounts of skin reinnervation were observed in the Fn + NGF and autograft groups. These results suggest that Fn-mats are a suitable conduit to promote peripheral nerve regeneration also in primate, and supplying NGF locally at the lesion site can further enhance nerve regrowth.

Animals↗
PubMed1999

Influence of age on contractile response to insulin-like growth factor 1 in ventricular myocytes from spontaneously hypertensive rats.

Evidence suggests a pathophysiological role of insulin-like growth factor 1 (IGF-1) in hypertension. Cardiac function is altered with advanced age, similar to hypertension. Accordingly, the effects of IGF-1 on cardiac myocyte shortening and intracellular Ca(2+) were evaluated in hypertension at different ages. Ventricular myocytes were isolated from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), aged 12 and 36 weeks. Mechanical and intracellular Ca(2+) properties were examined by edge-detection and fluorescence microscopy. At 12 weeks, IGF-1 (1 to 500 ng/mL) increased peak twitch amplitude (PTA) and FFI changes (DeltaFFI) in a dose-dependent manner in WKY myocytes, with maximal increases of 27.5% and 35.2%, respectively. However, IGF-1 failed to exert any action on PTA and DeltaFFI in the age-matched SHR myocytes. Interestingly, at 36 weeks, IGF-1 failed to exert any response in WKY myocytes but depressed both PTA and DeltaFFI in a dose-dependent manner in SHR myocytes, with maximal inhibitions of 40.5% and 16.1%, respectively. Myocytes from SHR or 36-week WKY were less sensitive to norepinephrine (1 micromol/L) and KCl (30 mmol/L). Pretreatment with nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/L) did not alter the IGF-1-induced response in 12-week WKY myocytes but unmasked a positive action in 12-week SHR and 36-week WKY myocytes. L-NAME also significantly attenuated IGF-1-induced depression in 36-week SHR myocytes. In addition, the Ca(2+) channel opener Bay K8644 (1 micromol/L) abolished IGF-1-induced cardiac depression in 36-week SHR myocytes. Collectively, these results suggest that the IGF-1-induced cardiac contractile response was reduced with advanced age as well as with hypertension. Alterations in nitric oxide and intracellular Ca(2+) modulation may underlie, in part, the resistance to IGF-1 in hypertension and advanced age.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Long-term follow-up of high-risk allogeneic peripheral-blood stem-cell transplant recipients: graft-versus-host disease and transplant-related mortality.

PURPOSE: To determine the risks of graft-versus-host disease (GVHD) and transplant-related mortality after allogeneic peripheral-blood stem-cell (PBSC) transplantation. PATIENTS AND METHODS: Between December 1994 and July 1996, 50 consecutive patients with high-risk hematologic malignancies in first remission or relapse received high-dose therapy followed by transplantation of granulocyte colony-stimulating factor-mobilized, allogeneic PBSCs collected from HLA-identical siblings. GVHD prophylaxis included cyclosporine and corticosteroids. RESULTS: As of April 1, 1998, 18 patients (36%+/-13%) survived with a median follow-up period of 767 days (range, 602 to 1,127 days). The actuarial probability of grades 2-4 acute GVHD was 0.37+/-0.14 (95% confidence interval). Of 36 assessable patients, 26 (72%+/-15%) developed chronic GVHD. The actuarial probability of chronic GVHD 2 years after transplantation was 0.87+/-0.15. Of 14 progression-free survivors, 11 (79%+/-22%) have active, chronic GVHD. All 11 patients require ongoing immunosuppression, and nearly two thirds have extensive disease. Thirteen patients died as a result of transplant-related mortality (26%+/-12%), six (12%) before and seven (14%) after day +100. CONCLUSION: We observed a high risk of chronic GVHD after allogeneic PBSC transplantation, which compromised the performance status of most long-term survivors and resulted in a relatively high risk of late transplant-related mortality. Approximately 75% of transplant-related deaths were associated with GVHD; thus, reduction in transplant-related mortality after allogeneic PBSC transplantation will require more effective strategies for the prophylaxis and/or treatment of GVHD.

Adolescent↗
PubMed1999

Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: a phase II study from the North American Marrow Transplant Group.

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hodgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkin's disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (300-600 mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related toxicity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkin's disease, producing long-term, durable remissions.

Adolescent↗
PubMed1999

Assessing attitudes and behaviors of high-risk adolescents: an evaluation of the self-report method.

This study evaluated the self-report method in the assessment of attitudes and behaviors. Forty-two problem youth from diverse ethnic and socioeconomic backgrounds were surveyed. In addition, their parents were surveyed and school and police data were collected. Five self-report factors were compared against parental report factors and police and school records. Significant relationships were found only for self-report factors that contained more positively oriented items. Self-report factors that contained items inquiring directly into high-risk behaviors were not significantly associated with parental report factors or school and police data. The implications of these findings are discussed.

Adolescent↗
PubMed1999

Acetaldehyde depresses myocardial contraction and cardiac myocyte shortening in spontaneously hypertensive rats: role of intracellular Ca2+.

Acetaldehyde (ACA), the major metabolite of ethanol, exerts both stimulatory and depressive actions on myocardial tissue. We have recently shown that ACA depresses myocardial contraction, cardiac myocyte shortening and intracellular Ca2+ transients in normal rat heart. The purpose of the present study was to determine the influence of hypertension on ACA-induced myocardial actions. Mechanical properties of left ventricular papillary muscles and ventricular myocytes isolated from both 25-week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were evaluated using force-transducer and video edge-detection, respectively. Papillary muscles and cardiac myocytes were electrically stimulated to contract at 0.5 Hz. Contractile properties analyzed include: peak tension development (PTD), peak twitch amplitude (PTA), time-to-PTD/PTA (TPT/TPS), time-to-90% relaxation/relengthening (RT90/TR90) and maximal velocities of contraction/shortening and relaxation/relengthening (+/-VT/+/-dL/dt). Intracellular Ca2+ transients were measured as fura-2 fluorescence intensity (FFI) changes. ACA (1-30 mM) depressed PTD without affecting other mechanical indices in both WKY and SHR myocardium, with maximal inhibition of 64 and 69%, respectively. SHR myocytes exhibited increased cell dimension, baseline PTA and resting intracellular Ca2+ levels, compared to WKY counterparts. ACA (0.03-30 mM) depressed PTA without affecting TPT, TR90 and +/-dL/dt. The maximal inhibitions were 31 and 36% in WKY and SHR groups, respectively. Interestingly, ACA exerted a biphasic effect on FFI, displaying potentiation at lower doses (<3 mM) and inhibition at higher doses (>3 mM). The maximal increase in FFI changes were 19 and 22% at 0.3 mM and the maximal decreases were 37 and 29% at 30 mM ACA, in WKY and SHR myocytes, respectively. Neither resting intracellular Ca2+ levels (FFI) nor fluorescence decay time (FDT) were affected by ACA. The increase in FFI was attenuated by propranolol (1 microM), whereas the decrease in FFI was reversed by BayK 8644 (1 microM). These results suggest that hypertension does not appear to alter ACA-induced myocardial depression. The mechanism underlying ACA-induced myocardial actions may involve increased beta-adrenergic activity at low doses and reduced Ca2+ entry and/or release at high doses.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Neonatal Soave endorectal pull-through for Hirschsprung's disease.

In October 1994 we changed our management of neonatal Hirschsprung's disease from a staged procedure after initial colostomy to a neonatal single-stage Soave endorectal pull-through (SERPT) without a colostomy. We report on our experience with the first 12 neonatal SERPTs, comparing them retrospectively with a consecutive series of 12 patients managed with initial colostomy, followed by a SERPT months later. A neonatal SERPT proved to be an easier and quicker procedure than the same procedure in the older child. Patients could be discharged earlier and fewer complications were encountered; in addition a colostomy was avoided. The cosmetic result and parental acceptance were excellent. At the same time the cost was less than half compared with the staged group. At this stage of follow-up functional results are comparable with previous staged pull-through procedures.

Anastomosis, Surgical↗
PubMed1999

Naltrexone's effect on cue-elicited craving among alcoholics in treatment.

BACKGROUND: Advancing knowledge of biobehavioral effects of interventions can result in improved treatments. Thus, a standardized laboratory cue reactivity assessment has been developed and validated to assess the cognitive and psychophysiological responses to a simulated high-risk situation: alcohol cues. The present study investigates the effects of a pharmacotherapy (naltrexone) on a laboratory-based, cue-elicited urge to drink among abstinent alcoholics in treatment. METHODS: Alcohol-dependent subjects were randomized to 12 weeks of naltrexone or placebo after completing a partial hospital program. After approximately 1 week on medication, all received cue reactivity assessment. RESULTS: Significantly fewer patients taking naltrexone reported any urge to drink during alcohol exposure than did those on placebo. Those with any urges reported no decrement in level of the urges. Mean arterial pressure decreased significantly for those on placebo, but not for those on naltrexone, whereas cue-elicited decreases in heart rate were not affected by the medication. CONCLUSIONS: The results have implications for models of relapse and naltrexone's effects. Cue reactivity methodology has utility for investigating hypothesized mediators of therapeutic effects of pharmacotherapies as well as behavioral treatments.

Adult↗
PubMed1998

cDNA cloning of a third human C2-domain-containing class II phosphoinositide 3-kinase, PI3K-C2gamma, and chromosomal assignment of this gene (PIK3C2G) to 12p12.

Phosphoinositide (PI) 3-kinases have been shown to have critical roles in signaling pathways that regulate proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. We have previously used reverse-transcription polymerase chain reaction methods to identify novel PI 3-kinase isoforms in normal human breast and in lymph nodes containing metastatic breast cancer. Here we report the cDNA cloning of a Class II PI 3-kinase found in normal breast tissue. This gene (PIK3C2G) encodes the third distinct protein of the human Class II PI 3-kinase family, PI3K-C2gamma. PIK3C2G was mapped to chromosome 12 at 12p12 by fluorescence in situ hybridization.

Amino Acid Sequence↗
PubMed1998

Effect of precise mechanical loading on fibroblast populated collagen lattices: morphological changes.

The contraction of a collagen lattice by resident fibroblasts causes strains to be developed within that lattice. These strains can be increased or decreased by altering the aspect ratio (ratio of length/width/thickness) of the fibroblast populated collagen lattice, as the cross-sectional area resisting the strain is changed and by the application of an external load. The fibroblasts align themselves with the direction of the maximum principle strain; in effect, these cells are "hiding" from the perceived strain. The direction of the maximum principle strain can be predetermined by the use of a computational finite element analysis. Using the tensioning-Culture Force Monitor to apply pre-determined loading patterns of known repeatable magnitudes, as calculated by the finite element analysis, we have succeeded in aligning fibroblasts into a deliberate predicted orientation. This study has shown that the resident fibroblast population will respond to changes in strain resulting from the most subtle of mechanical loads. This may be an important mechanism in development and repair of connective tissue.

Biomechanical Phenomena↗
PubMed1998

Tensional homeostasis in dermal fibroblasts: mechanical responses to mechanical loading in three-dimensional substrates.

Many soft connective tissues are under endogenous tension, and their resident cells generate considerable contractile forces on the extracellular matrix. The present work was aimed to determine quantitatively how fibroblasts, grown within three-dimensional collagen lattices, respond mechanically to precisely defined tensional loads. Forces generated in response to changes in applied load were measured using a tensional culture force monitor. In a number of variant systems, resident cells consistently reacted to modify the endogenous matrix tension in the opposite direction to externally applied loads. That is, increased external loading was followed immediately by a reduction in cell-mediated contraction whilst decreased external loading elicited increased contraction. Responses were cell-mediated and not a result of material properties of the matrices. This is the first detailed characterisation of a tensional homeostatic response in cells. The maintained force, after 8 h in culture, was typically around 40-60 dynes/million cells). Maintenance of an active tensional homeostasis has widespread implications for cells in culture and for whole tissue function.

Cells, Cultured↗
PubMed1998

Biomechanical characterization of tissues in Dupuytren's disease.

The aim of this study was to characterize mechanical properties of tissues of Dupuytren's disease and to attempt to identify changes due to cellular activity. Tensile tests confirmed the heterogeneity of Dupuytren's disease tissue with distinct stress-strain curves for the three tissue types normally present, namely, cord, transition zone and nodule. The tensile strength for cord tissue was nearly twice that of nodule tissue, but the latter was nearly twice as stretchable as cord. In contrast, the transition tissue had the tensile strength of cord with the stretchability of nodule. It was found that tensile loading stimulated a cellular response as demonstrated by an increase in the creep strain rate of the tissue at 37 degrees C compared with that at 4 degrees C using Dupuytren's tissue in an in vitro culture test. The creep strain rate for nodule at 37 degrees C was more than seven times that for cord at a nominal creep stress of 0.75 MPa.

Biomechanical Phenomena↗