Sildenafil treatment of serotonin reuptake inhibitor-induced sexual dysfunction.
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Adult↗
Biomedical subjects
R G Bennett
Publications and source records attributed to R G Bennett.
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↗
Surgical pearl: the self-removable suture.
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Dermatologic Surgical Procedures↗
Project REACH: a program to train community-based lay health educators.
The major purpose of this project was to test the feasibility of recruiting and training volunteers as lay health educators who could coordinate and reinforce the educational efforts of health care providers. A committee of health care professionals designed a 16-hour program. Twenty-five volunteers from T1 religious institutions and 4 retirement communities completed the 8-week program. The program was successful in identifying, recruiting, and training volunteers from racially and religiously diverse institutions. Favorable outcomes included participants' satisfaction and success in organizing numerous educational and screening programs in their communities.
Aged↗
Accuracy of patient care staff in estimating and documenting meal intake of nursing home residents.
OBJECTIVES: To determine the accuracy of patient care staff estimates and documentation of food intake of residents in nursing homes. DESIGN: Prospective, observed, unblinded cohort study. SETTING: Three urban nursing home facilities. SUBJECTS: Staff estimation and documentation of 27 nursing home residents' meal intake. MEASUREMENTS: Actual amount consumed by 27 nursing home residents was ascertained by weighing food and caloric fluids on resident trays before and after one lunch time meal. Staff estimates and documentation of percent of meal consumed was compared with actual intake. RESULTS: Patient care staff estimates differed from actual intake by approximately 20%, and in most instances intake was overestimated. Almost one-third of the residents at risk for nutritional problems were not identified correctly by staff. Chart documentation of meal intake frequently did not reflect either actual amount of meal consumed or the staff's estimation of what was eaten. CONCLUSION: Study findings indicate that the present system used to document nursing home residents' intake is inadequate and that a more accurate mechanism or an entirely different process for identifying residents at risk for nutritional problems should be developed and implemented.
Aged↗
Characterization of the insulin inhibition of the peptidolytic activities of the insulin-degrading enzyme-proteasome complex.
Insulin-degrading enzyme (IDE) is a component of a cytosolic complex that includes multicatalytic proteinase (MCP), the major cytoplasmic proteolytic activity. Insulin, the primary substrate for IDE, inhibits the proteolytic activity of the IDE-MCP complex but not of purified MCP. This provides a regulatory role for IDE in cellular proteolysis and a potential mechanism for intracellular insulin action. To examine the specificity and to explore the mechanisms for the IDE-MCP interaction, we studied the functional interaction of a variety of peptides with the complex. Atrial natriuretic peptide (ANP), relaxin, glucagon, proinsulin, and insulin-like growth factor II (IGF-II) bind to and are degraded by IDE. These peptides have significant inhibitory effects on the chymotrypsin-like and trypsin-like MCP catalytic activities but not the peptidyl-glutamyl hydrolyzing activity. A panel of peptides that are not ligands of IDE had no effect. To explore the potential mechanism for the IDE control of MCP activity, dose response curves for insulin-like growth factor I (IGF-I) and IGF-II effects on MCP chymotrypsin-like activity were determined. IGF-II, which (similar to insulin) is a good substrate for IDE, had a substantial inhibitory effect, whereas IGF-I, which is bound but poorly degraded, had little inhibitory activity on MCP. Proinsulin, another ligand of IDE that is tightly bound but poorly degraded, had a partial effect on MCP activity, but inhibited the full insulin effect. These data suggest a requirement for both the binding and degradation of IDE ligands for the full inhibition of MCP. Insulin-sized degradation products, substrates of IDE, also inhibited MCP activity. Further examination of the insulin effect on MCP included kinetic studies. Insulin produced a noncompetitive inhibition of both the chymotrypsin-like and trypsin-like activities of MCP. These data suggest that the insulin-IDE effect on MCP is due to conformational changes in the IDE-MCP complex and provide an intracellular mechanism of action for insulin.
Animals↗
The significance of intracellular insulin to insulin action.
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Cyclic AMP↗
Pressure-relieving strategies for preventing and treating pressure sores.
Pressure-relieving strategies remain the foundation for the prevention and treatment of pressure sores. Although the published literature is inadequate, rational treatment decisions can be made if they are based on an understanding of the mechanisms by which pressure relief results with a particular device or strategy. This article reviews the theoretic and practical approaches to managing tissue loads so that rational choices of the most cost-effective strategies for preventing and treating pressure sores can be made when caring for patients.
Beds↗
Hepatitis B virus vaccination for older adults.
OBJECTIVE: To compare in adults more than 50 years old the tolerability and immunogenicity of vaccination with recombinant hepatitis B surface antigen (HBs) compared with vaccination with recombinant hepatitis B protein PreS2 + S, and to investigate the safety and immunogenicity of a fourth vaccine dose in poor and non-responders. DESIGN: Randomized, double-blind prospective study. SETTING: General clinical research center for outpatient evaluation and vaccination. SUBJECTS: Adults older than age 50 who were in general good health and with no known risk factors for acquiring or serologic evidence of hepatitis B virus infection. INTERVENTION: Subjects were randomized to receive 10 mcg HBs (Recombivax, Merck, Sharp and Dohme), 12 mcg PreS2 + S, or 24 mcg PreS2 + S vaccine at 0, 1, and 6 months. Poor and non-responders (anti-Hbs < 10 mIU/mL at month 9 and/or 12) were encouraged to receive a fourth vaccine injection. MEASUREMENTS: Diary records of temperature and local and systemic reactions following each vaccination were maintained by all subjects. Anti-HBs levels were measured by radioimmunoassay before the first injection, at 1, 2, 3, 6, 7, 9, and 12 months after for all subjects, and 1 month after the fourth injection for the group of poor and non-responders. MAIN RESULTS: Twenty men and nine women (mean age +/- SD, 66 +/- 8.0 years) were enrolled. Ten subjects received HBs vaccine, nine received 12 mcg PreS2 + S vaccine, and 10 received 24 mcg PreS2 + S vaccine. One subject in the HBs group dropped out, and data were analyzed for the remaining 28 subjects. There were no differences in rates of side effects reported by each of the three groups. Overall, minor local adverse reactions occurred in 12 (40%) after at least one of the first three vaccinations. Systemic side effects occurred in five (17%) after the first vaccination, in one after the second, but in none after the third. The 24-mcg PreS2 + S vaccine was not more immunogenic than the HBs vaccine, and the 12-mcg PreS2 + S vaccine was judged inadequate. Nineteen of 22 (86%) poor and non-responders received a fourth vaccination. Minor local adverse reactions were reported by six (32%), and none reported a systemic side effect. For the 12 subjects receiving a fourth injection of HBs or 24 mcg PreS2 + S vaccine, the proportion of responders 1 month following the fourth injection was greater than for 1 month following the third injection (11 of 12 [92%] versus 12 of 19 [63%], respectively, P < .05). CONCLUSION: For adults more than 50 years of age who have low anti-HBs levels after three vaccine injections, a fourth injection is well tolerated and results in improved immunogenic response.
Age Factors↗
Acne keloidalis nuchae: treatment with excision and second-intention healing.
BACKGROUND: Acne keloidalis nuchae (AKN) is a chronic inflammatory disorder of the posterior aspect of the neck and occipital region of the scalp. Despite numerous medical and surgical treatment modalities, few offer cure or a superior cosmetic result for patients with extensive disease. OBJECTIVE: Our purpose was to determine whether excision with second-intention healing is an effective therapeutic modality for AKN. METHODS: Excision of the involved area to the level of the muscle fascia or deep subcutaneous tissue was performed in six patients. Postoperative sites healed by second intention. RESULTS: Four of six patients had a horizontal elliptic excision of the involved area that included the posterior hairline, with good to excellent results. The other two, who received nonelliptic excision of affected scalp that spared the hairline, had slower wound healing and poor contraction. CONCLUSION: Best results were achieved in excision of AKN with second-intention healing when the excision was a horizontal ellipse of the posterior aspect of the scalp including the posterior hairline.
Acne Keloid↗
Success of delayed full-thickness skin grafts after Mohs micrographic surgery.
BACKGROUND: Specific factors affect the outcome of full-thickness skin grafts after Mohs micrographic surgery. No recent clinical studies have systematically investigated the clinical factors that may affect the success of full-thickness skin grafts. OBJECTIVE: Our objective was to analyze patient data to define factors that may influence the success of full-thickness skin grafts. METHODS: We reviewed the clinical course of 117 patients who had full-thickness skin grafts after Mohs micrographic surgery. We analyzed these cases using patient variables, tumor variables, and skin graft variables and then correlated these variables to skin graft success. RESULTS: Delay of skin graft placement (> 1 day) was significantly correlated with subsequent skin graft success (p = 0.015). Skin graft necrosis was more likely to develop in men than in women (p = 0.021). CONCLUSION: A delay of 2 to 8 days between Mohs micrographic surgery and full-thickness skin graft placement resulted in a lower incidence of skin graft necrosis than no delay or a delay of 1 day.
Adult↗
Prevention and treatment of pressure sores.
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Bandages↗
Plasma specific gravity for identifying hypovolaemia.
To define ranges of plasma specific gravity useful for identifying volume depletion in older adults, plasma specific gravity was measured in 170 young adults (mean age 28 years) and 100 retirees (mean age 81 years), and ranges of values likely to be associated with volume depletion were defined. Subsequently, measurements of plasma specific gravity were made in 68 older emergency room (ER) patients (mean age 74 years), a few of whom had obvious reasons for being hypovolaemic, e.g. dehydrating diarrhoea, and these results were compared to those for the control groups. Ranges for plasma specific gravity useful for identifying volume depletion were designated as possible hypovolaemia (1.0265-1.0279), probable hypovolaemia (1.0280-1.0294), and hypovolaemia (> or = 1.0295). Using these definitions, there were more older ER patients compared to both young and old control group subjects, respectively, with probable hypovolaemia (21% vs. 5% and 8%; p < 0.03) and hypovolaemia (16% vs. 0% and 0%; p < 0.03). This study establishes ranges for plasma specific gravity for young and old adults likely to be associated with hypovolaemia, and shows that based upon measurement of plasma specific gravity, older ER patients may often be hypovolemic even in the absence of obvious fluid-wasting illnesses. Future studies are needed to identify the risk factors for hypovolaemia in ER patients, and more vigorously substantiate the findings of this study.
Adult↗