Zaprinast raises glucose utilisation in SHR skeletal muscle.
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Animals↗
Biomedical subjects
M E Young
Publications and source records attributed to M E Young.
Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR--an activator of AMP-activated protein kinase.
We determined whether the cell permeable molecule AICAR, whose metabolite activates AMP-activated protein kinase (AMPK) in cells, affected glycogen metabolism in rat soleus muscle preparations in vitro. The basal and insulin-stimulated rates of radiochemical lactate formation, net lactate release and glycogen synthesis were determined. AICAR stimulated net lactate release (but not radiochemical lactate formation) only at a basal concentration of insulin. An increased rate of glycogenolysis was the likely cause of increased net lactate release as glycogen phosphorylase activity was significantly increased by AICAR. AICAR-stimulated net lactate release and phosphorylase activity were potently inhibited by insulin.
AMP-Activated Protein Kinases↗
Sexual functioning among women with physical disabilities.
OBJECTIVE: Three a priori hypotheses were tested: (1) There are significant differences in sociosexual behaviors of women with physical disabilities compared with women without disabilities; (2) the sexual functioning of women with disabilities is significantly related to age at onset of disability; (3) psychological factors explain more of the variance in the sexual functioning of women with physical disabilities than do disability, social and environmental factors. DESIGN: Case-comparison study using written survey. SETTING: General community. PARTICIPANTS: The questionnaire was mailed to 1,150 women with physical disabilities who were recruited as volunteers or through independent living centers. Each woman gave a second copy of the questionnaire to an able-bodied female friend, which comprised the comparison group. The response rate was 45%, with 475 cases and 425 comparisons eligible to participate. The most common disability type was spinal cord injury (24%), followed by polio (18%), muscular dystrophy (11%), cerebral palsy (11%), multiple sclerosis (10%), joint disorders (7%), and skeletal abnormalities (5%). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Sexual-functioning, consisting of four factors: (1) sexual desire, (2) sexual activity, (3) sexual response, (4) sexual satisfaction. RESULTS: Highly significant differences were found in level of sexual activity (p = .000001), response (p = .000009), and satisfaction (p=.000001) between women with and without disabilities. No significant differences were found between groups on sexual desire. Severity of disability was not significantly related to level of sexual activity. CONCLUSIONS: Psychological and social factors exert a strong impact on the sexual functioning of women with physical disabilities. Further investigations is needed of the effect of social environment on development of self-esteem and sexual self-image, and how these influences affect levels of sexual functioning in women with physical disabilities.
Adolescent↗
Glycogen phosphorylase may be activated by AMP-kinase in skeletal muscle.
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Adenylate Kinase↗
Effects of treatment of spontaneously hypertensive rats with the angiotensin-converting enzyme inhibitor trandolapril and the calcium antagonist verapamil on the sensitivity of glucose metabolism to insulin in rat soleus muscle in vitro.
We measured the sensitivity of glucose metabolism to insulin in soleus muscle preparations isolated from spontaneously hypertensive (SH) rats and normotensive age-matched Wistar-Kyoto (WKY) rats. SH rats were treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (1 mg/kg) and/or a second antihypertensive drug, the calcium antagonist verapamil, alone (100 mg/kg) or as combination therapy (50 mg/kg). Treatment of SH rats with trandolapril or trandolapril in combination with verapamil for 6 weeks normalized the blood pressure. The estimated concentration of insulin required for half-maximal stimulation of glycogen synthesis (i.e., EC50 values) was approximately 500 microU/ml for muscles from both WKY and SH rats. This value is five times higher than the value obtained from soleus muscle preparations isolated from insulin-sensitive Wistar rats. This indicates that glycogen synthesis is insensitive to insulin in SH and WKY rat soleus muscle. Treatment of SH rats with trandolapril with or without verapamil improved the sensitivity of glycogen synthesis to insulin in soleus muscle. Further experiments investigated whether acute exposure (1 h) of insulin-sensitive skeletal muscle with either trandolaprilat (the active metabolite of trandolapril) or bradykinin (levels of which may be raised by ACE inhibition) could affect the insulin-stimulated rate of glucose metabolism. These results show that both trandolaprilat and bradykinin caused a small but significant increase in the rates of glucose metabolism. In conclusion, 1) SH and WKY rat skeletal muscle was insulin resistant, 2) chronic treatment of SH rats with trandolapril with or without verapamil normalized blood pressure and improved the response of glycogen metabolism to insulin, and 3) bradykinin and trandolaprilat acutely caused a small but significant increase in the rate of glycogen synthesis to a submaximal physiological concentration of insulin.
Angiotensin-Converting Enzyme Inhibitors↗
Alcohol and marijuana use in a community-based sample of persons with spinal cord injury.
The prevalence of self-reported alcohol and marijuana use, along with alcohol abuse as measured by the Short Michigan Alcoholism Screening Test, was assessed for a community-based sample (n = 123) of persons with spinal cord injury (SCI). Correlates of alcohol and marijuana use and alcohol abuse also were examined, including demographic variables, measures of impairment, disability, and handicap, SCI medical complications, and measures of subjective assessment such as health rating, health maintenance behaviors, depression, life satisfaction, perceived stress, pain, and social support. Prevalence of alcohol use (59%) and marijuana use (16%) in persons with SCI was less than that of comparison groups in the general population. However, prevalence of alcohol abuse (21%) exceeded that of general population studies. Participants who abused alcohol shared the following criteria: (1) perceived their overall health as worse than those who did not abuse alcohol; (2) were more depressed; and (3) experienced more stress in their lives than those who did not abuse alcohol. Participants who used marijuana were younger at the time of the study and were younger at injury. They were also more depressed and more stressed. The indications of alcohol abuse in one in five persons with SCI living in the community mandates that screening, treatment, and referrals be part of any rehabilitation treatment program.
Adult↗
Socialization to the culture of a rehabilitation hospital: an ethnographic study.
OBJECTIVES: Most previous research on rehabilitation of patients after spinal cord injuries has dealt with the attainment of outcomes valued by staff members or with the prediction of successful outcomes based on sociodemographic characteristics of patients. This study examined the rehabilitation process from the insider's perspective of an individual patient to determine his view of important adaptive problems and to examine how these problems were addressed. METHODS: Ethnographic methods were used for fine-grained documentation of the experiences of one 30-year-old man with spinal cord injury. Daily interview were conducted with this patient during his 116 days of inpatient rehabilitation. An interdisciplinary research team analyzed the data with the constant comparative method to identify a number of recurring themes. RESULTS: Findings indicate that in addition to learning how to function in the local world of the rehabilitation hospital, the patient also learned a new identify as a person with a long-term disability. DISCUSSION: A central theme was the patient's ongoing attempt to figure out how his future was related to his life before the injury and how he could use previous competencies in adapting to disability. Staff members seemed so intent on teaching the patient new skills that they often discounted the significance of his past experience and failed to engage in helping the patient connect his future life story to his past.
Activities of Daily Living↗
Activation of the protein kinase a signal transduction pathway by granulocyte-macrophage colony-stimulating factor or by genetic manipulation reduces cytoskeletal organization in Lewis lung carcinoma variants.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) that is produced by metastatic Lewis lung carcinoma (LLC-LN7) cells functions as an autocrine stimulator of tumor-cell motility through protein kinase A (PKA) signal transduction. This GM-CSF-mediated enhancement of LLC-LN7 cell motility coincides with a reduction in the level of polymerized F-actin. In contrast, non-metastatic LLC-C8 tumor cells, which have a diminished level of PKA signaling, do not produce GM-CSF and do not respond to exogenous GM-CSF, since they remain non-motile and retain a high content of filamentous actin. The capacity of PKA to regulate the cytoskeletal organization of tumor cells was further studied with the use of LLC variants that had been stably transfected to over-express the C alpha subunit of PKA (CEV cells) or to express a mutant cAMP-resistant PKA RI alpha subunit resulting in a defective PKA (REV cells). When compared with wild-type metastatic LLC-LN7 cells, in which the F-actin staining was too diffuse to be clearly visualized microscopically, the PKA-defective REV-LN7 transfectants had an increased level of F-actin. In comparison with the wild-type non-metastatic LLC-C8 cells, which had a high content of F-actin, the CEV-C8 transfectants that over-expressed PKA activity had a reduced level of F-actin. The reduced polymerization of actin in these CEV-C8 transfectants was accompanied by reduced levels of the intermediate filament protein vimentin and a shift in the distribution both of F-actin and of vimentin to the periphery of the cells. These results show reduced cytoskeletal organization in metastatic LLC-LN7 cells as compared with that of non-metastatic LLC-C8 cells, and indicate that elevation of PKA activity, either by autologous GM-CSF or by genetic manipulation, diminishes cytoskeletal organization.
Animals↗
Granulocyte-macrophage colony-stimulating factor stimulates the metastatic properties of Lewis lung carcinoma cells through a protein kinase A signal-transduction pathway.
Expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) by metastatic Lewis lung carcinoma cells (LLC-LN7) was previously shown to contribute to the maintenance of phenotypic characteristics associated with an increased capacity to metastasize. In the present study, pre-incubation of LLC-LN7 cells with neutralizing anti-GM-CSF antibodies diminished the capacity of the tumor cells to form experimental metastases after i.v. inoculation, while pre-incubation with recombinant GM-CSF (rGM-CSF) increased formation of metastases. In the presence of rGM-CSF, the LLC-LN7 cells exhibited an increased capacity to migrate, invade through a reconstituted basement membrane, and adhere to lung tissue. Studies to identify the signal transduction pathway through which GM-CSF enhanced the in vitro metastatic properties of the LLC-LN7 tumor cells implicated protein kinase A (PKA). Signaling through PKA was suggested by the demonstration that the stimulation of tumor-cell motility by GM-CSF was blocked in the presence of the adenylate cyclase inhibitor nicotinic acid, or the PKA inhibitors A3 or KT5720. In addition, the role of PKA as a signaling mechanism for GM-CSF was assessed by using REV-LN7 cells, which are LLC-LN7 cells that have been stably transfected with an expression vector encoding a mutant PKA RI alpha subunit and which, in turn, express a cAMP-resistant PKA. Adherence and invasion by the PKA-defective REV-LN7 cells were not stimulated by rGM-CSF, contrasting with the stimulation observed for wild-type LLC-LN7 cells. These data suggest that rGM-CSF can further enhance the in vitro metastatic characteristics of LLC-LN7 tumor cells and that this is dependent on signal transduction through PKA.
Animals↗
Assistive technology and the newly disabled adult: adaptation to wheelchair use.
A naturalistic, ethnographic, phenomenological study of adaptation to wheelchair use was conducted with one key informant, a 30-year-old white man with acquired paraplegia who was undergoing acute rehabilitation. Primary staff members served as additional informants. It was found that adaptation to wheelchair use had both pragmatic and emotional components. The latter appeared in alternating phases of resistance and neutrality or detente. Therapist and patient had conflicting goals relative to wheelchair use, which occasioned considerable friction. The patient's initial attitudes regarding wheelchairs were prejudicial, which hampered his ability to see the chair as a useful tool for mobility and independence. Successful pragmatic adaptation hinged in part on emotional acceptance of the wheelchair.
Activities of Daily Living↗
Stimulation of splenic T-lymphocyte function by endogenous serotonin and by low-dose exogenous serotonin.
The modulatory effects of endogenous serotonin on splenic T-cell activity were investigated using two distinct approaches. The first approach showed that pretreatment of mice with p-cholorphenylalanine (PCPA) to deplete intracellular stores of serotonin reduced the capacity of their splenic T cells to proliferate and to express interleukin-2 receptor (IL-2R) in response to concanavalin A (Con A). These responses could be restored by the addition of serotonin to the spleen cell cultures. In contrast, PCPA treatment did not effect stimulation of spleen cells to produce IL-2. The second approach showed that T-cell proliferation to Con A as well as to IL-2 was diminished by the presence of antagonists to the serotonin-2 receptor (5-HT2R). The effects of low doses (100 ng/ml) of exogenously added serotonin on functions of normal spleen cells were also examined. At this low dose, serotonin stimulated splenic T-cell proliferation in response to IL-2, and enhanced both proliferation and IL-2 production in response to a suboptimal concentration of Con A. These results show autologous serotonin to be required for T-cell activation and that the activation of suboptimally stimulated T cells can be augmented with low doses of exogenously added serotonin. These data also suggest that the positive regulation of T-cell function by serotonin is mediated through 5-HT2R.
Animals↗
Depressive symptomatology in persons with spinal cord injury who reside in the community.
Depressive symptomatology was studied in a community-based sample of 100 men and 40 women with spinal cord injury. The mean for the Center for Epidemiologic Studies Depression Scale was higher than that reported previously for the general population, and the mean for women was higher than that for men. Findings from the Mobility dimension of the Craig Handicap Assessment and Reporting Technique (CHART) suggested that differences between men and women in degree of mobility within home and community partly mediate the gender difference in depressive symptomatology. Other CHART dimensions, Social Integration and Occupation, were inversely related with depression scores, although these dimensions did not differentiate men and women. A statistically significant relationship was not obtained between depression and disability, assessed by a self-report version of the Functional Independence Measure, or between depression and impairment, reflected by the ASIA Total Motor Index Score. Depression was not related with the presence of either pressure ulcers or presumptive evidence of urinary tract infection.
Adult↗
Stimulation of the metastatic properties of Lewis-lung-carcinoma cells by autologous granulocyte-macrophage colony-stimulating factor.
Using both polymerase-chain-reaction analysis and the soft-agar colony-forming unit assay, granulocyte-macrophage colony-stimulating factor (GM-CSF) was shown to be expressed by cloned metastatic Lewis-lung-carcinoma (LLC-LN7) cells but not by non-metastatic LLC-C8 cells. Furthermore, the metastatic LLC-LN7 cells were shown to respond both to autologous GM-CSF and to exogenous recombinant GM-CSF (rGM-CSF). In the presence of neutralizing anti-GM-CSF antibodies, the metastatic LLC cells became less able to migrate or to adhere and invade through a reconstituted basement membrane. Moreover, the addition of rGM-CSF further enhanced the capacity of the metastatic LLC cells to adhere to the reconstituted basement membrane. This stimulation of metastatic properties of the LLC cells by either autologous or exogenous GM-CSF was associated with enhanced endogenous protein phosphorylation. Two proteins of approximately Mr 45,000 and Mr 64,000 were the dominant target proteins to be phosphorylated by the presence of GM-CSF. These results suggest that autologous GM-CSF may function as an autocrine stimulator of the metastatic properties of metastatic LLC cells.
Cell Movement↗
Tumor-derived cytokines induce bone marrow suppressor cells that mediate immunosuppression through transforming growth factor beta.
Normal bone marrow cells become immunosuppressive when cultured with supernatants of metastatic Lewis lung carcinoma (LLC-LN7) cells. The suppressor-inducing activities in the LLC-LN7 supernatants are interleukin-3 and granulocyte/macrophage-colony-stimulating factor. In the present study, the mechanisms by which these induced suppressor cells (LLCsup-BM) mediate their immunosuppression were investigated. The suppression by LLCsup-BM of splenic concanavalin CA blastogenesis was not dependent on cell contact since immunosuppression occurred regardless of whether the LLCsup-BM were separated from the responder spleen cells by a permeable membrane or if the LLCsup-BM were cocultured with the spleen cells. Culture supernatants of LLCsup-BM also inhibited T cell blastogenesis, being more suppressive than were supernatants of control bone marrow cells, which had been precultured with medium. The suppression by the soluble inhibitors elaborated from the LLCsup-BM was not restricted to the inhibition of T cell function as the supernatants also inhibited the natural killer activity of normal spleen cells. Studies to determine the identity of the suppressive activity produced by the LLCsup-BM showed increased levels of transforming growth factor beta (TGF beta) in their supernatants. Immunosuppressive bone marrow and spleen cells obtained from mice bearing metastatic LLC-LN7 tumors also secreted more TGF beta than did the cells obtained from normal mice. When anti-TGF beta antibodies were added to the LLCsup-BM supernatants, the suppressive activity was diminished. These results suggest that the LLCsup-BM mediate at least part of their immunosuppression through production of TGF beta.
Animals↗
Sexual activities, concerns and interests of men with spinal cord injury.
A representative sample of 79 men with spinal cord injury, drawn from a sampling frame of 661 women and men who reside in the community, was studied in terms of sexual activity, concerns and interests. Participants responded to a questionnaire and rating scales and were physically examined to establish their neurologic status. With respect to eleven other areas of life, sex life ranked the lowest in terms of satisfaction and fifth in terms of importance. Of the sample, 67% reported having had a physical relationship (not necessarily including intercourse) in the past 12 months. Areas of sexual activity about which respondents were most concerned were not satisfying a partner, getting or giving a sexual disease, urinary accidents, and not getting enough personal satisfaction. From among seven topics related to sexuality, the three in which there was greatest interest were methods and techniques to achieve sexual satisfaction, helping a partner cope emotionally with limitations on sexual activity and ability to have children.
Adult↗
Regulation of murine T-lymphocyte function by spleen cell-derived and exogenous serotonin.
The modulatory effects of serotonin on T-cell activity were investigated. T-cell blastogenesis of normal spleen cells was slightly stimulated by the addition of low doses (1 and 10 ng/ml) of the inducer of serotonin release, fenfluramine. In contrast to the stimulatory effects of low doses of fenfluramine, high doses of fenfluramine (1 and 10 ug/ml) or of exogenously added serotonin (> or = 0.1 ug/ml) inhibited T-cell activation. Both the stimulation by low dose fenfluramine and the inhibition by high dose fenfluramine were accentuated by pretreating mice with tryptophan to heighten intracellular stores of serotonin and then inducing serotonin release. Pretreatment of mice with the serotonin inhibitor p-chlorophenylalanine (PCPA) abolished the fenfluramine inhibition of T-cell activation indicating that the fenfluramine inhibitory effect was mediated via endogenous spleen cell-derived serotonin. However, the PCPA treatment diminished T-cell activation. These results suggest that endogenous serotonin causes a biphasic dose-response effect on T-cell activity with serotonin being required for optimal T-cell function, low doses being immune stimulatory and higher doses being suppressive.
Adjuvants, Immunologic↗
Activation of protein kinase A increases the in vitro invasion, migration, and adherence to reconstituted basement membrane by Lewis lung carcinoma tumor cells.
Prostaglandin E2 (PGE2) stimulated in vitro invasion, migration, and adherence to reconstituted basement membrane by metastatic Lewis lung carcinoma (LLC) clones, but this stimulation was blocked by protein kinase A (PKA) inhibitors and by expression of a transfected mutant RI alpha which blocks PKA activation. In vitro migration and adherence of metastatic LLC transfectants was heightened by expression of a transfected C alpha gene and further heightened by Zn2+ induction of the expression vector. Nonmetastatic LLC were not migratory nor invasive. However, nonmetastatic LLC that were stably transfected with a C alpha gene were both migratory and invasive, particularly when C alpha expression was further induced with Zn2+. The results of these in vitro studies show that PKA can enhance the metastatic characteristics of LLC.
Animals↗
Relationship of life satisfaction to impairment, disability, and handicap among persons with spinal cord injury living in the community.
The level and correlates of the life satisfaction of persons with spinal cord injury who are residing in the community were investigated. One hundred men and 40 women were chosen randomly from a cohort of 640 persons with spinal cord injury residing in a 13-county area in southeast Texas. The mean Life Satisfaction Index-A (LSIA-A) was lower than reported previously for persons in the general population. The LSIA-A was not correlated significantly with chronologic variables, the ASIA Total Motor Index Score, or a self-report version of the Functional Independence Measure. The LSIA-A was associated positively with self-assessed health, perceived control, and social support, as well as with the Social Integration, Occupation, and Mobility dimensions of the Craig Handicap Assessment and Reporting Technique. From the standpoint of an augmented version of the World Health Organization model of disablement, the life satisfaction of persons with spinal cord injury appears to be influenced, albeit indirectly, by selective aspects of their social role performance (handicap), but not by their degree of impairment or disability.
Activities of Daily Living↗