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M Mone

Publications and source records attributed to M Mone.

12 recordsLinked to original sources
PubMed2005

Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats.

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.

Adamantane↗
PubMed2004

Binding of receptor for advanced glycation end products (RAGE) ligands is not sufficient to induce inflammatory signals: lack of activity of endotoxin-free albumin-derived advanced glycation end products.

AIMS/HYPOTHESIS: Activation of the receptor for advanced glycation end products (RAGE) reportedly triggers cellular responses implicated in the pathogenesis of diabetes, such as increasing vascular cell adhesion molecule-1 (VCAM-1) expression on vascular endothelial cells and inducing TNF-alpha secretion by mononuclear cells. The objective of this study was to evaluate whether RAGE binding affinity of AGE-BSAs and cellular activation correlate. METHODS: To produce AGEs with varying glycation, bovine albumin AGEs were prepared with 500 mmol/l of glucose, fructose or ribose at times of incubation from 1 to 12 weeks. In addition, AGE-BSA was generated using either glyoxylic acid or glycolaldehyde. Cellular binding of the AGE-BSAs and the effect on endothelial cell VCAM-1 expression were studied in RAGE-expressing human microvascular endothelial cell line-4 cells. Induction of TNF-alpha secretion was assessed using RAGE-expressing human peripheral blood mononuclear cells (PBMCs). RESULTS: Cellular binding of the different AGE preparations correlated well with RAGE affinity. Interestingly, we found that the AGE preparations, which were essentially endotoxin free (< or =0.2 ng/mg protein), were incapable of inducing VCAM-1 or TNF-alpha secretion regardless of RAGE binding affinity, AGE concentration or incubation time. In contrast, the reported RAGE ligand S100b was confirmed to induce VCAM-1 expression on endothelial cells and TNF-alpha secretion by PBMCs after 24 h of treatment. CONCLUSIONS/INTERPRETATION: The results of this study suggest that AGE modification and high RAGE binding affinity are not sufficient to generate pro-inflammatory signalling molecules. Thus, RAGE binding affinity of AGE-BSAs does not seem to correlate with cellular activation. Our findings using AGEs with strong RAGE-binding properties indicate that AGEs may not uniformly play a role in cellular activation.

Animals↗
PubMed1998

Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.

A randomized, controlled clinical trial was performed with patients with acute respiratory distress syndrome (ARDS) to compare the effect of conventional therapy or inhaled nitric oxide (iNO) on oxygenation. Patients were randomized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses: (1) that iNO would improve oxygenation during the 72 h after randomization, as compared with conventional therapy; and (2) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2) could be decreased by > or = 0.15 within 72 h after randomization. There were two major findings. First, That iNO as compared with conventional therapy increased Pa(O2)/FI(O2) at 1 h, 12 h, and possibly 24 h. Beyond 24 h, the two groups had an equivalent improvement in Pa(O2)/FI(O2). Second, that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2) > or = 0.15 during the 72 h following randomization (11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy, p = 0.55). In patients with severe ARDS, our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy.

Administration, Inhalation↗
PubMed1990

Anaemia and marrow blood flow in the rat.

An increase in bone marrow blood flow has been previously described in anaemic rabbits and dogs. We examined the effect of haemorrhage and haemolysis in female Sprague-Dawley rats, with the hypothesis that high blood flow was related to hyperplasia of bone marrow tissue and that the increase would affect bone as well. Blood flow was measured in tibia and femur by the microspheres trapping method. Chronic anaemia was accompanied at day 32 by a marked increase (factor of 1.7-1.9) in blood flow to bone marrow and to bone. On the other hand, no increase in blood flow was observed in chronic compensated anaemia, showing that anaemia per se and not stimulation of erythropoiesis was responsible for the increase. We then explored the effect on blood flow of two factors associated with anaemia. Erythropoietin 4 U/d for 4 d failed to induce any increase in bone and marrow blood flow. Systemic hypoxia (76 mmHg for 3 d) reduced the fraction of cardiac output conveyed to bone and marrow by 40-50%, but this decrease was more than compensated by an increase in cardiac output. We conclude that neither erythropoietin nor low tissue pO2 is the direct cause for the increase in bone and marrow blood flow observed in anaemia.

Anemia↗
PubMed1988

Bone loss and bone blood flow in paraplegic rats treated with calcitonin, diphosphonate, and indomethacin.

Sham-operated (SO) and paraplegic rats were treated from the day of operation during a period of 4 or 6 weeks with salmon calcitonin 4 IU/kg/day or a diphosphonate (APD) 1mM/kg/day or indomethacin 2.5 mg/kg/day. The consequence of spinal cord section on the femur and tibia is a loss of mineral which affects predominantly trabecular bone (-24 and -13% in calcium content for the tibial metaphysis and the whole bone, respectively, when compared with the SO controls), a twofold increase in bone blood flow as measured by the technique of the microspheres trapping, a moderate decrease of the 72 hour 45Ca accretion rate in the bone shaft, and an increase in the number of metaphyseal osteoclasts in the tibia. In paraplegics, all three drugs inhibit bone loss to some degree, calcitonin and indomethacin being mostly effective on the cortical bone of the shaft, and APD tremendously increasing the trabecular network of the metaphysis. APD is the only drug to exhibit a significant effect on the calcium content of the bones of the SO controls, but some effect is apparent for calcitonin on X-rays and histological preparations. The increase in bone blood flow in paraplegics is unaffected, this point being discussed in view of the hypothesis of the resorptive action of prostaglandins produced by newly formed vessels. 45Ca accretion rate increases in the shaft of calcitonin-treated paraplegics, whereas it decreases in APD-treated controls and paraplegics. The number of osteoclasts decreases in paraplegics treated with calcitonin and indomethacin, and increases in both controls and paraplegics treated with APD.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of ethinyl estradiol on intestinal membrane structure and function in the rabbit.

Structural and functional properties of the small intestinal microvillus membrane were evaluated in the rabbit after administration of ethinyl estradiol, a synthetic estrogen with a demonstrated propensity to alter hepatic membrane lipid fluidity, and promote cholestasis. In the jejunum, no estrogen-induced changes in microvillus membrane total lipid, cholesterol or phospholipid content were observed. However, the ileal microvillus membrane in estradiol-treated animals demonstrates significant reductions vs. controls (per mg protein) in total lipid (0.55 milligrams vs. 0.89 milligrams) [corrected] and phospholipid (206.7 micrograms vs. 304.91 micrograms) (p less than 0.001) content, as well as modifications in specific phospholipid species. The increase in the ileal microvillus membrane cholesterol: phospholipid molar ratio (0.65 vs. 0.51, p less than 0.05) was associated with a significant decrease in membrane lipid fluidity reflected by an increase in fluorescence anisotropy measurements utilizing diphenyl hexatriene as the fluorophore (r at 25 degrees C = 0.306 vs. 0.282, p less than 0.05). Thermotropic lipid phase transitions, assessed by Arrhenius plots of both fluorescence data and ileal microvillus membrane p-nitrophenylphosphatase activity demonstrate that phase changes occur between and 24 and 28 degrees C in both treated and untreated groups. Within the temperature range studied (40-10 degrees C) no differences from control were observed in microvillus membrane alkaline phosphatase activity following estrogen treatment. These data therefore indicate that ethinyl estradiol-induced effects on microvillus membrane lipid composition and physical properties occur predominantly in the ileum and appear to be related, in part, to specific alterations in the availability of phospholipid following estrogen treatment.

4-Nitrophenylphosphatase↗
PubMed1986

The effect of orchidectomy on bone metabolism in aging rats.

We have shown that orchidectomy in postpubertal 55-day-old rats led beyond 2 months to a decrease in bone growth and loss of weight. At 1 month postorchidectomy, we observed a three-fold increase in bone blood flow, an increase in calcium accretion rate, and an increase in the number of osteoclasts in the metaphysis. In the present experimental study, orchidectomy was performed in 1-year-old rats when bone growth in length was no longer measurable. In the tibia and femur we observed a decrease in bone volume, a still more rapid decrease of bone calcium during the first postoperative month, a thinning of the cortical width, an initial increase in calcium accretion rate (+20% when compared to 31 days controls) followed by a decrease at 120 days (-22% and -11% when compared to controls for tibia and femur respectively), a 29% increase in bone blood flow, and an increase in the number of osteoclasts. We conclude that androgen deprivation in young and old animals leads to a modified bone architecture, independent of the androgen impact on bone growth.

Animals↗
PubMed1985

Intestinal membrane lipid composition and fluidity during development in the rat.

We have characterized microvillus membrane (MVM) lipid composition and derived estimates of membrane fluidity using fluorescence polarization [with 1,6-diphenyl-1,3,5-hexatriene (DPH) as the probe] in MVM from the jejunum and ileum of suckling (day 14-20) and mature postweaning (day 28-49) rats. The anisotropic values are lower (i.e., increased fluidity) in MVM from jejunum and ileum of suckling rats compared with values from MVM of mature rats, suggesting a more disordered molecular environment in MVMs of suckling animals, although the ileal MVM was relatively less fluid than jejunal membranes in both groups. Anisotropic determinations in protein-free MVM liposomes demonstrate that protein-lipid interactions are major determinants of fluidity estimates. Arrhenius plots of DPH anisotropies in MVM and MVM liposomes indicate a thermotropic lipid-phase transition at 23 degrees C in mature rat jejunum and ileum; however, no clear transition point was observed in 14- to 20-day animals. In addition, both the jejunal and ileal MVM in suckling animals contained greater amounts of total lipid, cholesterol, and phospholipid per milligram protein than did mature MVM preparations. Membrane phospholipid composition changed with age, with a decrease in sphingomyelin and an increase in phosphatidylcholine in the jejunum of the postweaning animal and with similar weight ratios of saturated to unsaturated fatty acids in both age groups. The data demonstrate that the small intestinal MVM manifests both age-dependent and regional proximal-distal differences in lipid composition and biophysical properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Growth and bone haemodynamic responses to castration in male rats. Reversibility by testosterone.

Orchidectomy in postpubertal 55 day old rats, compared to sham-operated controls, led beyond 2 months to a decrease in body weight (87% of controls by 120 d), tibial length (97% of controls) and in tibial calcium content (85% of controls). Bone plasma flow increased three times to reach a peak at 31 days; it was decreased but no significantly at 86 and 120 days. The number of osteoclasts was maximal at 51 days (X 2.3) and was still elevated at 120 days. The calcium accretion rate increased briefly at 31 days (110% of controls) and was diminished at 86 and 120 days (78% of controls). The initial 'physiological' changes in the tibia occurred before any weight change and might be directly due to the lack of androgens. They can be interpreted as inducing the conditions for enhanced bone resorption. Testosterone replacement therapy, initiated after the initial haemodynamic response, inhibited the negative effect of castration on bone growth.

Age Factors↗
PubMedDate not supplied

Return to work as a measure of outcome in adults hospitalized for acute burn treatment.

Rehabilitation of patients with burn injuries is receiving renewed interest because survival has improved, and health reform has mandated outcomes assessment. To determine factors affecting return to work, a survey was conducted among 234 employed patients treated from 1986 through 1993. The mean burn size was 13.3% total body surface area. Patients returned to work in a mean of 14.3 weeks; a number initially returned to light-duty or part-time jobs as a "bridge" to full-time employment. Length of hospitalization, number of surgeries, total and full-thickness burn size, and subjective assessments by patients of their functional ability correlated with time off work. Patients with health insurance were more likely to resume work than was expected, whereas those covered by Medicaid and those involved in injury-related lawsuits were less likely to return to work. It is hoped that this information can be used to design interventions aimed at improving this outcome of burn treatment.

Acute Disease↗
PubMedDate not supplied

Resuscitation of thermally injured patients with oxygen transport criteria as goals of therapy.

Resuscitation from shock based on oxygen transport criteria has been widely used in trauma and surgical patients, but has not been examined in thermally injured patients. To study the possible efficacy of this type of resuscitation, the oxygen transport characteristics of burn resuscitation were studied in nine adults, of whom six had inhalation injuries, with a mean burn size of 45% total body surface area and a mean age of 33.4 years, who were resuscitated based on oxygen transport criteria. Pulmonary artery balloon flotation catheters were placed and hemodynamic and oxygen transport parameters (Fick method) were measured hourly for 6 hours. Patients received fluid boluses in addition to resuscitation calculated by the Parkland formula, until the pulmonary artery wedge pressure reached 15 mm Hg, after which dobutamine infusions (5 micrograms/kg/min) were initiated. Cardiac index increased from 2.51 to 6.57 L/min/m2 (p < 0.05), whereas systemic vascular resistance fell from 1534 to 584 dyne sec/cm5 (p < 0.05). Oxygen delivery (DO2I) and oxygen consumption (VO2I) indexes increased significantly during the study period (573 +/- 47 to 1028 +/- 57, and 132 +/- 8 to 172 +/- 16 ml/min/m2, respectively; p < 0.05). VO2I appeared dependent on DO2I at levels of DO2I less than 800 ml/min/m2. In this study, depressed cardiovascular function in patients with burn injuries responded to volume loading and inotropic support much as it does in patients with shock of other etiologies. Whether oxygen transport-based resuscitation is effective in improving survival or the incidence of multiple organ failure is unknown and will need to be evaluated in randomized trials.

Adult↗