In re Megestrol acetate treatment.
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Aged↗
Biomedical subjects
R G Bennett
Publications and source records attributed to R G Bennett.
The effect of stitch type on flap tip blood flow.
BACKGROUND: The 3-point corner stitch is generally used for apposition of skin flap tips to recipient wound corners. This stitch theoretically provides better blood flow, leading to improved flap tip survival, than alternative suture techniques. However, this assumption is not based on human experimental data. OBJECTIVE: We tested in patients whether certain stitch types influence flap tip blood flow and necrosis. METHODS: Flap tips were closed with either a 3-point corner stitch, a vertical loop stitch at the tip, or two vertical loop stitches adjacent to the tip. Blood flow was indirectly measured by means of the laser Doppler imager, and flap tips were observed for subsequent necrosis. RESULTS: The 3-point corner stitch resulted in a higher overall mean percent flux ratio implying greater blood flow than the other stitch types used. However, none of the stitch types resulted in a large number of necrotic flap tips. CONCLUSION: The 3-point corner stitch provides increased blood flow to flap tips that may be critical when flap tip survival is problematic.
Dermatologic Surgical Procedures↗
Insulin inhibits peroxisomal fatty acid oxidation in isolated rat hepatocytes.
Inhibition by insulin of long chain fatty acid oxidation in mitochondria is mediated in part by elevating malonyl-CoA levels, which inhibit carnitine palmitoyl-transferase I. Whether insulin alters peroxisomal oxidation has not been studied. We present data which show that insulin inhibits the oxidation of palmitic acid by peroxisomes (IC(50) = 8.5 x 10(-11) M) at hormone concentrations 100-fold less than those needed for mitochondrial inhibition (IC(50) = 1.3 x 10(-8) M). We used a purified peroxisome preparation to study the mechanism of insulin action. Insulin had a direct effect in the peroxisome preparations to decrease oxygen consumption, fatty acyl-CoA oxidizing system activity and acyl-CoA oxidase by approximately 40%, 30% and 15%, respectively. Since insulin degrading enzyme (IDE) is an insulin-binding protein known to be in peroxisomes, we studied the effect of an inhibitory anti-IDE antibody on the ability of insulin to inhibit the fatty acyl-CoA oxidizing system. The antibody eliminated the inhibitory effect of insulin. We conclude that insulin inhibits peroxisomal fatty acid oxidation by a mechanism requiring IDE.
Acyl Coenzyme A↗
Insulin and analogue effects on protein degradation in different cell types. Dissociation between binding and activity.
In adult animals, the major effect of insulin on protein turnover is inhibition of protein degradation. Cellular protein degradation is under the control of multiple systems, including lysosomes, proteasomes, calpains, and giant protease. Insulin has been shown to alter proteasome activity in vitro and in vivo. We examined the inhibition of protein degradation by insulin and insulin analogues (Lys(B28),Pro(B29)-insulin (LysPro), Asp(B10)-insulin (B10), and Glu(B4),Gln(B16),Phe(B17)-insulin (EQF)) in H4, HepG2, and L6 cells. These effects were compared with receptor binding. Protein degradation was examined by release of trichloroacetic acid-soluble radioactivity from cells previously labeled with [(3)H]leucine. Short- and intermediate-lived proteins were examined. H4 cells bound insulin with an EC(50) of 4.6 x 10(-9) m. LysPro was similar. The affinity of B10 was increased 2-fold; that of EQF decreased 15-fold. Protein degradation inhibition in H4 cells was highly sensitive to insulin (EC(50) = 4.2 x 10(-11) and 1.6 x 10(-10) m, short- and intermediate-lived protein degradation, respectively) and analogues. Despite similar binding, LysPro was 11- to 18-fold more potent than insulin at inhibiting protein degradation. Conversely, although EQF showed lower binding to H4 cells than insulin, its action was similar. The relative binding potencies of analogues in HepG2 cells were similar to those in H4 cells. Examination of protein degradation showed insulin, LysPro, and B10 were equivalent while EQF was less potent. L6 cells showed no difference in the binding of the analogues compared with insulin, but their effect on protein degradation was similar to that seen in HepG2 cells except B10 inhibited intermediate-lived protein degradation better than insulin. These studies illustrate the complexities of cellular protein degradation and the effects of insulin. The effect of insulin and analogues on protein degradation vary significantly in different cell types and with different experimental conditions. The differences seen in the action of the analogues cannot be attributed to binding differences. Post-receptor mechanisms, including intracellular processing and degradation, must be considered.
Animals↗
Degradation of amylin by insulin-degrading enzyme.
A pathological feature of Type 2 diabetes is deposits in the pancreatic islets primarily composed of amylin (islet amyloid polypeptide). Although much attention has been paid to the expression and secretion of amylin, little is known about the enzymes involved in amylin turnover. Recent reports suggest that insulin-degrading enzyme (IDE) may have specificity for amyloidogenic proteins, and therefore we sought to determine whether amylin is an IDE substrate. Amylin-degrading activity co-purified with IDE from rat muscle through several chromatographic steps. Metalloproteinase inhibitors inactivated amylin-degrading activity with a pattern consistent with the enzymatic properties of IDE, whereas inhibitors of acid and serine proteases, calpains, and the proteasome were ineffective. Amylin degradation was inhibited by insulin in a dose-dependent manner, whereas insulin degradation was inhibited by amylin. Other substrates of IDE such as atrial natriuretic peptide and glucagon also competitively inhibited amylin degradation. Radiolabeled amylin and insulin were both covalently cross-linked to a protein of 110 kDa, and the binding was competitively inhibited by either unlabeled insulin or amylin. Finally, a monoclonal anti-IDE antibody immunoprecipitated both insulin- and amylin-degrading activities. The data strongly suggest that IDE is an amylin-degrading enzyme and plays an important role in the clearance of amylin and the prevention of islet amyloid formation.
Amyloid↗
Postoperative stroke after stopping warfarin for cutaneous surgery.
BACKGROUND: Two patients undergoing cutaneous surgery had thromboembolic strokes within 1 week after surgery. Both patients had been taking warfarin for prevention of thromboembolism and warfarin was stopped 3-7 days prior to surgery. OBJECTIVE: To examine the rationale and problems associated with preoperative warfarin discontinuation. METHODS: Review of the medical literature. RESULTS: When warfarin is stopped prior to surgery and restarted soon after surgery, the patient is at increased risk for thromboembolism. Although it is commonly believed that continuing warfarin during surgery is associated with an increased bleeding risk, for cutaneous surgery, this risk is extremely low and can be easily managed. CONCLUSION: Warfarin should not be discontinued prior to cutaneous surgery because of the risk of thromboembolic stroke.
Aged↗
Dermatofibrosarcoma protuberans growing around plantar aponeurosis: excision by Mohs micrographic surgery.
BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a spindle cell malignancy that has a high local recurrence rate after excision with minimal or no immediate tissue margin assessment. DFSP is exceedingly rare on the palms and soles. OBJECTIVE: To report a case of a locally aggressive DFSP on the sole excised using Mohs micrographic surgery. METHODS: Case report and review of the literature. RESULTS: Mohs micrographic surgery unmasked tumor infiltration that extended around plantar aponeurosis and into underlying plantar muscle fascia. CONCLUSION: Mohs micrographic surgery should be considered the treatment of choice for DFSP, especially in acral locations. This technique allows the surgeon to trace out deep tumor extensions that may wrap around underlying tendon, a finding that may not be appreciated clinically.
Adult↗
The increasing medical malpractice risk related to pressure ulcers in the United States.
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Age Distribution↗
Insulin inhibits the ubiquitin-dependent degrading activity of the 26S proteasome.
A major metabolic effect of insulin is inhibition of cellular proteolysis, but the proteolytic systems involved are unclear. Tissues have multiple proteolytic systems, including the ATP- and ubiquitin-dependent proteasome pathway. The effect of insulin on this pathway was examined in vitro and in cultured cells. Insulin inhibited ATP- and ubiquitin-dependent lysozyme degradation more than 90% by reticulocyte extract, in a dose-dependent manner (IC50 approximately 50 nM). Insulin did not reduce the conjugation of ubiquitin to lysozyme and was not itself ubiquitin-conjugated. In HepG2 cells, insulin increased ubiquitin-conjugate accumulation 80%. The association between the 26S proteasome and an intracellular protease, the insulin-degrading enzyme (IDE), was examined by a purification scheme designed to enrich for the 26S proteasome. Copurification of IDE activity and immunoreactivity with the proteasome were detected through several chromatographic steps. Glycerol gradient analysis revealed cosedimentation of IDE with the 20S proteasome and possibly with the 26S proteasome. The proteasome-associated IDE was displaced when the samples were treated with insulin. These results suggest that insulin regulates protein catabolism, at least in part, by decreasing ubiquitin-mediated proteasomal activity, and provides a new target for insulin action. The displacement of IDE from the proteasome provides a mechanism for this insulin action.
Adenosine Triphosphate↗
Impact of Leptoglossus occidentalis (Hemiptera: Coreidae) on Douglas-fir seed production.
We investigated the effect of feeding by the western conifer-seed bug, Leptoglossus occidentalis Heidemann, on seed production in developing cones of coastal Douglas-fir, Pseudostuga menziesii (Mirb.) Franco, with respect to seed bug life stage and sex (nymphs, adult females, and adult males) and timing of feeding (early, mid-, and late season cone development). Feeding by females on caged cones for a 2-wk period during late season cone development reduced the proportion of full seeds in cones by approximately 70% compared with caged control cones. There was no significant difference among nymphs, adult females, and adult males with respect to the proportion of empty or partially fed-upon seeds produced during the same feeding period. Feeding by nymphs for 2 wk early in the season resulted in a threefold increase in the number of unextractable seeds fused to cones compared with the control. Weight measurements of harvested seeds indicated that radiography is an accurate tool to distinguish among Douglas-fir seeds that have sustained light, moderate, or severe damage. Determining the full impact of L. occidentalis on conifer seed production will require the development of a reliable method to distinguish between naturally aborted seeds and seeds emptied through feeding by seed bugs.
Animals↗
Managing nursing assistant absenteeism.
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Absenteeism↗
Sildenafil treatment of serotonin reuptake inhibitor-induced sexual dysfunction.
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Adult↗
Insulin acts intracellularly on proteasomes through insulin-degrading enzyme.
Insulin decreases cellular protein degradation, but the mechanism of this action is poorly understood. We have shown that insulin can have an inhibitory effect on the action of the proteasome in vitro, which requires the presence of insulin degrading enzyme (IDE). In this study we have used an antibody which inhibits the activity of IDE to show that IDE is required for insulin inhibition of protein degradation in intact cells. The anti-IDE antibody blocked the insulin effect on cellular degradation of proteins prelabeled with radioactive amino acids. The anti-IDE antibody also decreased insulin inhibition of proteasome degradation of a specific substrate in intact cells. These data suggest that insulin works intracellularly via IDE to inhibit protein degradation by the proteasome. Thus, IDE may function as an intracellular mediator for insulin effects on protein degradation. This is a novel signal transduction mechanism for peptide hormones.
Animals↗
Low airloss hydrotherapy versus standard care for incontinent hospitalized patients.
OBJECTIVE: To determine whether low airloss hydrotherapy reduces the incidence of new skin lesions associated with incontinence in hospitalized patients and results in more rapid healing of existing pressure sores compared with standard care. To assess subjectively patient and nursing satisfaction related to using low airloss hydrotherapy beds. DESIGN: Randomized, prospective, unblinded study. SETTING: Acute and chronic hospital wards. PARTICIPANTS: A total of 116 newly admitted, incontinent, hospitalized patients with and without existing pressure sores. INTERVENTION: Low airloss hydrotherapy compared with treatment on hospital beds and mattresses ordered by the patient's attending physician. MEASUREMENTS: Incidence rates of new skin lesion development, e.g., pressure sores, candidiasis, and chemical irritation; improvement in existing pressure sore size, volume, and status; subjective assessment of patient and nursing satisfaction. RESULTS: Possible hypothermia was identified in two patients during the first week of the study, and patient and nursing dissatisfaction with low airloss hydrotherapy remained high throughout the first months of the study. Therefore, two major modifications in the initial protocol were made: (1) increased patient temperature monitoring for hypothermia was initiated in Week 2 of the study and (2) increased staff resources for in-service training on bed use began in Week 18 of the study. After the latter change, 58 subjects were randomized to low airloss hydrotherapy and 58 to standard care. Subjects were old (median age > or = 80 years), and almost all were bedbound or nonambulatory. The median (range) length of follow-up for subjects in the treatment group was significantly shorter than for those in the control group (4 (1-60) days versus 6 (1-62) days, respectively, P = .017) because there were more dropouts from the treatment group (24 (36%) of 58 versus 2 (3%) of 58, P = .0001). The major reasons dropout occurred were patient or family dissatisfaction (12 (21%)), new or worsened skin lesions thought to be related to bed use (4 (7%)), and hypothermia < 97 degrees F (4 (7%)). The total cumulative incidence of new truncal skin lesions within 9 days of enrollment was greater in the treatment than in the control group (48% versus 14%, respectively, P < 0.01). Too few patients with existing pressure sores were treated for too short a period of time to assess the effect of low airloss hydrotherapy on pressure sore healing. Because only 10 patients treated on low airloss hydrotherapy beds were able to complete satisfaction surveys meaningfully, interpretation of these data is difficult. Only nine (21%) of 44 nurses subjectively reported overall satisfaction using the low airloss hydrotherapy bed. CONCLUSIONS: This study shows the value of a rigorously designed clinically based evaluation of a new product developed for older patients. The results of the study led to re-engineering of the prototype low airloss hydrotherapy bed as well as a change in marketing strategy. Studies of products targeted to the prevention and treatment of pressure sores in older patients should be undertaken before generalized marketing begins.
Aged↗
Insulin degradation: progress and potential.
Insulin degradation is a regulated process that plays a role in controlling insulin action by removing and inactivating the hormone. Abnormalities in insulin clearance and degradation are present in various pathological conditions including type 2 diabetes and obesity and may be important in producing clinical problems. The uptake, processing, and degradation of insulin by cells is a complex process with multiple intracellular pathways. Most evidence supports IDE as the primary degradative mechanism, but other systems (PDI, lysosomes, and other enzymes) undoubtedly contribute to insulin metabolism. Recent studies support a multifunctional role for IDE, as an intracellular binding, regulatory, and degradative protein. IDE increases proteasome and steroid hormone receptor activity, and this activation is reversed by insulin. This raises the possibility of a direct intracellular interaction of insulin with IDE that could modulate protein and fat metabolism. The recent findings would place intracellular insulin-IDE interaction into the insulin signal transduction pathway for mediating the intermediate effects of insulin on fat and protein turnover.
Amino Acid Sequence↗
Regulation of multicatalytic enzyme activity by insulin and the insulin-degrading enzyme.
The insulin-degrading enzyme (IDE) plays an important role in the cellular metabolism of insulin. Recent studies have also suggested a regulatory role for this protein in controlling the activity of cytoplasmic protein complexes, including the proteasome [multicatalytic proteinase (MCP)] and the glucocorticoid and androgen receptors. Binding of IDE to these complexes increases their activity, whereas the addition of substrates for IDE inhibits activity. This provides a potential mechanism of action for internalized insulin and other IDE substrates in the control of protein turnover. To examine further the interactions, partially purified IDE-MCP complex was treated with EDTA or EGTA, and activity was measured in the absence and presence of various divalent cations (Ca2+, Mn2+, Co2+, and Zn2+) and insulin. EDTA treatment reduced MCP activity and eliminated the effect of insulin on the complex. Divalent cations partially or completely restored MCP activity, but did not restore the effect of insulin. EGTA treatment had a lesser effect on MCP activity, but abolished insulin inhibition of activity. Divalent cations restored the insulin effect. Inhibitors of IDE also blocked the insulin effect on MCP activity, as did treatment with SDS. These findings suggest that conformational changes in the complex may play a role in the insulin control of MCP activity.
Calcium↗
Insulin inhibition of proteasome activity in intact cells.
Cellular homeostasis requires regulation of protein turnover. Protein degradation is an essential component of this process and is inhibited by insulin. The importance of cytosolic proteolysis in overall cellular protein degradation is increasingly apparent and an insulin effect on this system has been suggested but not proven. The present study shows that a membrane permeable substrate of the proteasome is degraded in HepG2 cells and that insulin inhibits its degradation both by isolated proteasomes and by intact cells. Inhibitors of the proteasome suppress degradation, and in the presence of these inhibitors insulin has no further effect. This is the first demonstration that insulin inhibition of cellular protein degradation is due to an effect on proteasomes.
Cysteine Endopeptidases↗