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Biomedical subjects

M Joyce

Publications and source records attributed to M Joyce.

At least 19 recordsLinked to original sources
PubMed2001

Pharmacodynamic and pharmacokinetic properties of a premixed 85/15 human insulin preparation.

BACKGROUND: Many patients with diabetes use mixtures of fast-acting (regular human) insulin and intermediate-acting (neutral protamine Hagedorn [NPH]) insulin to control their blood glucose levels. Premixed insulin is available in a 70%/30% mixture and a 50%/50% mixture of NPH/regular human insulin. For some patients, however, a premixed formulation containing > or =30% regular human insulin can provide too much fast-acting insulin, potentially causing an increased risk for hypoglycemia in the early hours after injection. OBJECTIVE: The pharmacokinetic and pharmacodynamic properties of a premixed formulation of 85% NPH insulin and 15% regular human insulin (85/15) were compared with those of a premixed 70%/30% NPH/regular human insulin preparation and 100% NPH insulin. METHODS: A 12-hour euglycemic clamp approach was used to assess glucose-lowering effects and serum insulin levels in 36 healthy male volunteers in a single-dose (0.5 U/kg), randomized, double-blind, 3-period, crossover study. RESULTS: From 0 to 8 hours after injection, the glucose-lowering effects and serum insulin levels for the 85/15 premixed insulin preparation were significantly greater than those for NPH insulin (P < or = 0.05) but significantly less than those for the 70/30 premixed insulin preparation. The mean (+/- SEM) maximum glucose infusion rate (GIRmax) was 8+/-0.6 mg/(min x kg) for the 85/15 preparation, 7+/-0.6 mg/(min x kg) for NPH, and 9+/-0.6 mg/(min x kg) for the 70/30 preparation, with time to peak GIR (tmax(GIR)) occurring at 313, 360, and 272 minutes, respectively. Time to peak insulin levels did not differ significantly for the 3 preparations, but maximum serum insulin concentration (Cmax(ins)) was significantly different between the groups (70/30 premix: 54+/-2.2 microU/mL; 85/15 premix: 44+/-2.4 microU/mL; NPH: 35+/-1.7 microU/mL). Glucodynamic effect and serum insulin levels did not differ significantly among preparations during the interval from 8 to 12 hours after injection. Mean serum C-peptide levels ranged from -0.6 to 1.0 ng/mL for each preparation during the 12-hour period after injection. CONCLUSIONS: The 85/15 premixed insulin preparation demonstrated clinical pharmacokinetic and pharmacodynamic properties that were intermediate between, and significantly different from, those of NPH insulin and the 70/30 premixed insulin preparation.

Adolescent↗
PubMed2001

Pravastatin attenuates lower torso ischaemia-reperfusion-induced lung injury by upregulating constitutive endothelial nitric oxide synthase.

OBJECTIVES: to elicit whether pre-treatment with pravastatin will prevent or ameliorate the acute lung injury that occurs following lower torso ischaemia-reperfusion (IR) in an experimental animal model. MATERIALS AND METHODS: male Sprague-Dawley rats were randomised into three groups (n=7/group). The control group underwent a sham laparotomy and aortic dissection. The second group underwent infrarenal aortic cross clamping for 30 min followed by reperfusion for 120 min. The third group pre-treated with pravastatin sodium (0.4 mg/kg/day over 5 days) were again subjected to an ischaemia-reperfusion (IR) injury. The parameters used to assess lung injury included: Wet to dry lung weight ratio (W:D), myeloperoxidase activity (MPO), protein concentration (BALprot) and neutrophil count (BAL PMN) of bronchoaveolar lavage fluid. Western blotting was used to determine the expression of constitutive endothelial nitric oxide synthase (ecNOS) within lung tissue. RESULTS: IR causes an acute lung injury as indicated by statistically significant differences in W:D lung weight ratios, MPO activity, neutrophil count and BALprotein concentration in the IR group over that of controls. Pre-treatment with pravastatin attenuated this neutrophil infiltration and microvascular leakage. The pravastatin group showed a marked increased expression of ecNOS over that of the IR group and controls. CONCLUSION: this data indicates that pre-treatment with pravastatin protects against ischaemia-reperfusion induced lung injury in an experimental animal model. We believe that its mechanism of action involves an upregulation of ecNOS, which increases basal expression of nitric oxide providing protective effects on the pulmonary circulation against microvascular injury.

Analysis of Variance↗
PubMed2000

Profilin enhances Cdc42-induced nucleation of actin polymerization.

We find that profilin contributes in several ways to Cdc42-induced nucleation of actin filaments in high speed supernatant of lysed neutrophils. Depletion of profilin inhibited Cdc42-induced nucleation; re-addition of profilin restored much of the activity. Mutant profilins with a decreased affinity for either actin or poly-l-proline were less effective at restoring activity. Whereas Cdc42 must activate Wiskott-Aldrich Syndrome protein (WASP) to stimulate nucleation by the Arp2/3 complex, VCA (verpolin homology, cofilin, and acidic domain contained in the COOH-terminal fragment of N-WASP) constitutively activates the Arp2/3 complex. Nucleation by VCA was not inhibited by profilin depletion. With purified N-WASP and Arp2/3 complex, Cdc42-induced nucleation did not require profilin but was enhanced by profilin, wild-type profilin being more effective than mutant profilin with reduced affinity for poly-l-proline. Nucleation by the Arp2/3 complex is a function of the free G-actin concentration. Thus, when profilin addition decreased the free G-actin concentration, it inhibited Cdc42- and VCA-induced nucleation. However, when profilin was added with G-actin in a ratio that maintained the initial free G-actin concentration, it increased the rate of both Cdc42- and VCA-induced nucleation. This enhancement, also seen with purified proteins, was greatest when the free G-actin concentration was low. These data suggest that under conditions present in intact cells, profilin enhances nucleation by activated Arp2/3 complex.

Actins↗
PubMed2000

Phase II trial of liposomal doxorubicin (Doxil) in advanced soft tissue sarcomas.

PURPOSE: To assess the objective response rate, toxicity experienced, progression-free survival, and overall survival of patients with previously untreated advanced soft tissue sarcomas treated with a liposomal doxorubicin formulation (Doxil). METHODS: Patients with metastatic or recurrent soft tissue sarcoma who had received no prior chemotherapy for advanced disease were treated with liposomal doxorubicin (Doxil) according to a two stage accrual design. Doxil was administered at 50 mg/m2 every 4 weeks. A total of 15 patients were treated and are evaluable for response and toxicity. RESULTS: The male/female ratio was 7/8, the median age was 60 years (34-75) and the ECOG performance status was 0-1 in >90% of patients. Leiomyosarcoma (7/15) and malignant fibrous histiocytoma (2/15) were the most common histologic diagnoses. No objective responses were observed in the 15 evaluable patients. No lethal toxicity occurred. Grade 3-4 leukopenia or neutropenia were reported in 3/15 (20%) patients. Grade 3 mucositis or hand-foot syndrome occurred in 2/15 (13%) and 1/15 (7%) patients respectively and seemed more severe in older patients. The median time to progression was 1.9 months (range 0.9-6.2). Twelve patients have now died. The Kaplan-Meier estimate of median overall survival is 12.3 months. As called for in the study design, accrual was terminated because no responses were obtained in the first 15 patients. CONCLUSION: Though well-tolerated, Doxil given according to this dose and schedule to patients with advanced soft tissue sarcoma had no significant therapeutic activity. A correlation between older age and skin/mucosal toxicity of Doxil is suggested in this study but needs confirmation. Future investigations of Doxil in soft tissue sarcomas should use a different schedule and dose.

Adult↗
PubMed1999

Bone mineral density in patients with treated Addison's disease.

Some studies have reported low bone mineral density (BMD) in patients with Addison's disease, whereas others have found BMD to be normal. It is possible that over-replacement of corticosteroids and adrenal androgen deficiency may contribute to a reduction in BMD in these patients. The aims of this study were to examine BMD using dual-energy X-ray absorptiometry in patients with treated Addison's disease at multiple skeletal sites and to investigate the relationships between these measurements and corticosteroid dose. Nineteen men, 3 premenopausal and 7 postmenopausal women with Addison's disease were studied and data from these patients were analyzed separately and as a group. The mean SEM age and duration of Addison's disease of the men were 44 +/- 3.8 years and 15 +/- 2.2 years, in the premenopausal women 40 +/- 2 years and 5 +/- 2.4 years, and in the postmenopausal women 68 +/- 4 years and 20 +/- 5 years, respectively. Eight men were unexpectedly hypogonadal (serum testosterone <13 nmol/l). BMD was expressed as a percent of values in normal controls (n = 418) adjusted for age, sex, ethnic origin, menopausal status and body weight. In the whole group (n = 29), mean BMD of the patients with Addison's disease was not different from normal at any site [mean (+/- SEM) lumbar spine 99.5% +/- 2.9%; femoral neck 99.3% +/- 2.5%; Ward's triangle 96.2% +/- 3.5%; trochanter 99.2% +/- 2.9%; radius 99.8% +/- 2.1%; total body 98.5% +/- 1.4%]. However, there was a wide range of bone densities, with some patients having a low BMD at multiple sites. Bone density was negatively correlated with current and cumulative corticosteroid dose per kilogram body weight and duration of Addison's disease. In conclusion, BMD in patients with Addison's disease is little different from normal, but may be lower in patients with disease of long duration and a high cumulative corticosteroid dose. Unexpected hypogonadism in men with Addison's disease is common.

Absorptiometry, Photon↗
PubMed1999

Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects.

OBJECTIVE: To study the pharmacokinetic and pharmacodynamic profile of insulin aspart (a new fast-acting human insulin analog) after subcutaneous administration in the deltoid, abdominal, and thigh sites and to compare this profile with regular human insulin (Novolin; Novo Nordisk A/S, Copenhagen). RESEARCH DESIGN AND METHODS: A total of 20 healthy subjects were studied in a single-center six-period double-blind randomized crossover trial with 6 study days and a washout period of 1 week between each single daily dose of the trial drug. Subjects were randomized to receive a single dose of 0.2 U/kg of insulin aspart or regular insulin on each of the 6 study days in three different sites (the deltoid, the abdomen, and the thigh) during a 10-h euglycemic clamp (two drugs and three injection sites). Pharmacokinetic and pharmacodynamic measurements were derived from blood sample measurements of glucose, insulin, and C-peptide during these clamps. RESULTS: The pharmacodynamic data from the euglycemic clamp study showed that, regardless of injection site, the maximal glucose infusion rate (GIR Cmax) was greater and occurred at an earlier time (GIR Tmax) after administration of insulin aspart than regular insulin (GIR Cmax: abdomen 813 vs. 708, deltoid 861 vs. 736, and thigh 857 vs. 720 g/min, P < 0.05 for all; GIR Tmax: abdomen 94 vs. 173, deltoid 111 vs. 192, and thigh 145 vs. 193 g/min, P < 0.05 for all). Pharmacokinetic parameters were also consistent with faster absorption and higher peak insulin concentrations after insulin aspart administration. From all sites, the peak insulin concentration (Cmax) was higher and occurred earlier (Tmax) after administration of insulin aspart than of regular insulin (Cmax: abdomen 501 vs. 260, deltoid 506 vs. 252, thigh 422 vs. 220 pmol/l, P < 0.001 for all sites; Tmax: abdomen 52 vs. 109, deltoid 54 vs. 98, and thigh 60 vs. 107 min, P < 0.01 for all sites). The absorption and glucose-lowering action of insulin aspart did not differ between sites (similar GIR Cmax, Tmax, and area under the curve parameters). However, the duration of the glucose-lowering effect was up to 34 min shorter (P < 0.01) for the abdomen injections than for the deltoid or thigh injections (lower time of 50% glucose disposal). In addition, the amount of glucose infused was significantly lower by 10-14% in the abdomen than in other sites. CONCLUSIONS: Subcutaneous administration of insulin aspart causes a more rapid and intense maximal effect compared with regular insulin during euglycemic clamp studies in nondiabetic subjects. Abdominal administration of insulin aspart has a shorter duration of glucose-lowering effect compared with administration in the deltoid or thigh.

Absorption↗
PubMed1999

Have family income mobility patterns changed?

We examine the mobility of individuals in the United States based on equivalent family income--that is, total income of all family members adjusted for family size according to the equivalence scale implicit in the U.S. poverty line. Our analysis, which tracks movements across quintiles, centers on four questions: How much movement is there across the family income distribution? How has this mobility changed over time? To what extent are the movements attributable to factors related to changes in family composition versus events in the labor markets? In light of major socioeconomic changes occurring in the quarter-century under study, have the determinants of mobility changed over time? Our findings indicate that mobility rates in the 1980s differed little from those in the 1970s. However, individuals in families headed by a young person or a person without a college education were less likely to experience upward mobility in the 1980s than in the 1970s.

Adolescent↗
PubMed1998

Mechanism of Cdc42-induced actin polymerization in neutrophil extracts.

Cdc42, activated with GTPgammaS, induces actin polymerization in supernatants of lysed neutrophils. This polymerization, like that induced by agonists, requires elongation at filament barbed ends. To determine if creation of free barbed ends was sufficient to induce actin polymerization, free barbed ends in the form of spectrin-actin seeds or sheared F-actin filaments were added to cell supernatants. Neither induced polymerization. Furthermore, the presence of spectrin-actin seeds did not increase the rate of Cdc42-induced polymerization, suggesting that the presence of Cdc42 did not facilitate polymerization from spectrin-actin seeds such as might have been the case if Cdc42 inhibited capping or released G-actin from a sequestered pool. Electron microscopy revealed that Cdc42-induced filaments elongated rapidly, achieving a mean length greater than 1 micron in 15 s. The mean length of filaments formed from spectrin-actin seeds was <0.4 micron. Had spectrin-actin seeds elongated at comparable rates before they were capped, they would have induced longer filaments. There was little change in mean length of Cdc42-induced filaments between 15 s and 5 min, suggesting that the increase in F-actin over this time was due to an increase in filament number. These data suggest that Cdc42 induction of actin polymerization requires both creation of free barbed ends and facilitated elongation at these ends.

Actin Cytoskeleton↗
PubMed1998

Metastases that interfere with circulation.

OBJECTIVES: To review the nursing implications of select circulatory problems caused by metastatic cancer. DATA SOURCES: Journal articles, research studies, and book chapters relating to circulatory problems associated with metastatic disease. CONCLUSIONS: During the metastatic process, tumor cells can interfere with circulation. As a result, circulatory impairments can range from life threatening to manifestations that may alter a person's quality of life. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses have a responsibility to seek current knowledge about therapeutic and supportive care for persons experiencing circulatory alterations. Collaboration with colleagues can facilitate patient care in these clinical situations. Patient education can be supportive and may enhance optimal outcomes.

Ascites↗
PubMed1997

Evidence for decreased splanchnic glucose uptake after oral glucose administration in non-insulin-dependent diabetes mellitus.

The role of splanchnic glucose uptake (SGU) after oral glucose administration as a potential factor contributing to postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) has not been established conclusively. Therefore, we investigated SGU in six patients with NIDDM and six weight-matched control subjects by means of the hepatic vein catheterization (HVC) technique. In a second part, we examined the applicability of the recently developed OG-CLAMP technique in NIDDM by comparing SGU and first-pass SGU during HVC with SGU during the OG-CLAMP experiment. The OG-CLAMP method combines a euglycemic, hyperinsulinemic clamp and an oral glucose tolerance test (75 g) during steady state glucose infusion (GINF). During HVC, SGU equals the splanchnic fractional extraction times the total (oral and arterial) glucose load presented to the liver. For OG-CLAMP, SGU was calculated as first-pass SGU by subtracting the integrated decrease in GINF over 180 min from 75 g. Cumulative splanchnic glucose output after oral glucose correlated significantly between both methods and was increased significantly in NIDDM patients (73.1+/-5.1 g for HVC, 76.5+/-5.5 for OG-CLAMP) compared with nondiabetic patients (46.7+/-4.4 g for HVC, 57.5+/-1.9 for OG-CLAMP). Thus, in NIDDM patients, SGU (7.4+/-2.1 vs. 37.8+/-5.9% in nondiabetic patients, P < 0.001) and first-pass SGU (4.7+/-1.7 vs. 26.5+/-5.1% in nondiabetic patients, P < 0.01) were decreased significantly during HVC, as was SGU during OG-CLAMP (3.9+/-1.7 vs. 23.4+/-2.5% in nondiabetic patients, P < 0.0001). SGU measured during OG-CLAMP correlated significantly with SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.94, P < 0.01 for nondiabetic patients) and first-pass SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.84, P < 0.05 for nondiabetic patients) during HVC. In conclusion, (a) SGU after oral glucose administration is decreased in NIDDM as measured by both methods, and (b) SGU during the OG-CLAMP is well-correlated to SGU and first-pass SGU during HVC in NIDDM. The decrease in SGU in NIDDM might contribute to postprandial hyperglycemia in diabetic subjects.

Administration, Oral↗
PubMed1997

Regulation of actin polymerization in cell-free systems by GTPgammaS and Cdc42.

We have established a cell-free system to investigate pathways that regulate actin polymerization. Addition of GTPgammaS to lysates of polymorphonuclear leukocytes (PMNs) or Dictyostelium discoideum amoeba induced formation of filamentous actin. The GTPgammaS appeared to act via a small G-protein, since it was active in lysates ofD. discoideum mutants missing either the alpha2- or beta-subunit of the heterotrimeric G-protein required for chemoattractant-induced actin polymerization in living cells. Furthermore, recombinant Cdc42, but not Rho or Rac, induced polymerization in the cell-free system. The Cdc42-induced increase in filamentous actin required GTPgammaS binding and was inhibited by a fragment of the enzyme PAK1 that binds Cdc42. In a high speed supernatant, GTPgammaS alone was ineffective, but GTPgammaS-loaded Cdc42 induced actin polymerization, suggesting that the response was limited by guanine nucleotide exchange. Stimulating exchange by chelating magnesium, by adding acidic phospholipids, or by adding the exchange factors Cdc24 or Dbl restored the ability of GTPgammaS to induce polymerization. The stimulation of actin polymerization did not correlate with PIP2 synthesis.

Actins↗
PubMed1997

Flow cytometric cell sorting combined with molecular chimerism analysis to detect minimal recurrent leukemia: good news and bad news.

Allogeneic BMT offers the possibility of cure for a variety of hematopoietic malignancies, but disease relapse remains a major cause of treatment failure. This report describes two cases in which flow cytometric cell sorting (FACS) and molecular chimerism analysis were combined to increase the sensitivity of minimal residual disease (MRD) detection. In the first case this approach was used to demonstrate that a suspicious phenotype was not recurrent leukemia, thus preventing the use of potentially toxic therapy. In the second case the recurrence of a leukemia which was undetectable by conventional analysis was confirmed. The potential benefits of combining these MRD detection methods are discussed.

Adolescent↗
PubMed1996

Comparison of changes in endothelial adhesion molecule expression following UVB irradiation of skin and a human dermal microvascular cell line (HMEC-1).

We have assessed the pattern of dermal endothelial adhesion molecule expression following broadband UVB irradiation in vivo and in vitro. Skin biopsies were taken from 4 human volunteers at baseline and at 4, 8 and 24 h post-irradiation with 2.5 minimal erythema doses of UVB. Sections were stained immunohistochemically for E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1). CD31 and neutrophil elastase. The effect of direct UVB irradiation on E-selectin, ICAM-1 and VCAM-1 was examined in a human dermal microvascular endothelial cell line, HMEC-1. Cultured HMEC-1 were irradiated with 2.5-40 mJ/cm2 of UVB, and assessed for adhesion molecule expression by immunofluorescence microscopy and fluorescence-activated cell sorter analysis. In vivo, E-selectin was minimally expressed on EC at baseline and was induced by 4 h following irradiation, P < 0.01. ICAM-1 was moderately expressed at baseline and appeared mildly induced at 24 h, although this did not reach statistical significance. VCAM-1 was weakly expressed in unirradiated skin while CD31 was moderately expressed, but neither was induced by UVB irradiation. A significant neutrophilic infiltrate appeared by 8 h and was maximal at 24 h, P < 0.05. Neutrophil infiltration correlated with E-selectin expression, r = 0.96. In HMEC-1, ICAM-1 was upregulated at 24 h post-irradiation, with an increase in mean channel fluorescence from 100% at baseline to 145 (SD12)% at 24 h, P < 0.05. No change was seen in expression of E-selectin, VCAM-1 or CD31. These studies support the involvement of endothelial adhesion molecules E-selectin and ICAM-1 in UVB-induced inflammation. Whereas ICAM-1 is upregulated by direct irradiation of endothelial cells, E-selectin stimulation appears to be an indirect effect.

Adult↗
PubMed1995

Effects of treatment setup variation on beam's eye view dosimetry for radiation therapy using the multileaf collimator vs. the cerrobend block.

PURPOSE: The purpose of this study is to quantify and compare retrospectively the effects of treatment setup variation on beam's eye view (BEV) dosimetry for radiation therapy using a multileaf collimator (MLC) vs. cerrobend block. METHODS AND MATERIALS: A study was performed on a group of 18 patients with cancer of the head and neck, lung, and pelvis who were treated with irregularly shaped fields. The BEV dosimetry of the fields shaped with cerrobend blocks and the MLC was measured with films at the depth of dose prescription in a solid water phantom. A "one-half-leaf" insertion convention was used to shape the MLC. In addition, an average of 15 sequential daily port films was taken per patient during the course of radiotherapy. The port films were aligned with the prescription film for each patient. Systematic error and random error of treatment setup for each patient were calculated. The effects of setup variation were incorporated by convolving the patient portal imaging data with the corresponding BEV film dosimetry. Two parameters were used to quantify the BEV dosimetry. First, the field penumbra width was calculated, which represented the average of the normal separations between 20 and 80% isodose lines along the prescription outline. Second, the ratio of areas covered by the 90 and 20% isodose lines, A90/20, was determined. The BEV dosimetry was then characterized with and without the effects of treatment setup variation. In addition, the difference in BEV dosimetry between the cerrobend block and the MLC was used to estimate the corresponding changes in tumor control probability (TCP). These changes were also compared to the changes in TCP for the treatment with or without the effects of random setup variation. RESULTS: With or without daily setup variation, the use of cerrobend block was more favorable than the MLC in terms of the field penumbra width and A90/20 for all treatment sites. In the absence of daily variation, the MLC field penumbra width was on average 1.3 mm larger than that of the cerrobend block, and 0.9 mm larger in the presence of daily setup variation. Similarly, the ratio A90/20 of the cerrobend block was on average 0.03 larger than that of MLC without daily setup variation, and 0.02 with daily setup variation. The difference in field penumbra width and A90/20 between the MLC and the cerrobend block was slightly reduced due to the effects of daily setup variation. For both the cerrobend block and the MLC, daily setup variation produced a significant increase in the field penumbra width, 2.3 mm for the cerrobend block and 1.9 mm for the MLC, and a decrease in the A90/20, 0.06 for the former and 0.05 for the latter. The change due to the daily setup variation was about a factor of 2 larger than the changes due to replacing the cerrobend block with the MLC. Using the TCP model, the change in TCP due to the daily setup variation was more than a factor of 3 larger than the change in TCP due to replacing the cerrobend block with the MLC. It was noted that the average changes in the penumbra, the A90/20 and the TCP calculated for the patient population did not adequately describe the changes for the individual patient. CONCLUSION: Our results do not show significant dosimetric differences between the MLC and the cerrobend block in conventional radiation treatment, whether or not daily setup variation was taken into consideration. The effects of daily setup variation alone produced a larger dosimetric change. The same results were obtained when the data were applied to calculate changes in TCP. For optimal radiation therapy, efforts should be concentrated on reducing daily setup variation. Our results also demonstrate the importance of frequent evaluation of MLC treatment using electronic portal imaging devices.

Equipment Design↗