Adrenal function under long-term raloxifene administration.

The aim of the present study was to evaluate the effect of long-term (12 months) administration of raloxifene hydrochloride (60 mg/day) on the steroid production of the adrenal cortex and on the hypothalamic-pituitary-adrenal axis in postmenopausal women. We performed a basal evaluation, a corticotropin releasing factor (CRF) (100 microg i.v. bolus) test and a dexamethasone (DXM) (0.25 mg) suppression-adrenocorticotropic hormone (ACTH) (10 microg i.v. bolus) stimulation test in 11 postmenopausal women, before and after 3, 6 and 12 months of raloxifene treatment. Raloxifene administration significantly modified circulating levels of adrenal steroids, decreasing cortisol (-24%), dehydroepiandrosterone (DHEA) (-36%), and its sulfate (DHEAS) (-41%), and androstenedione (-29%), and increasing circulating allopregnanolone (+39%) levels. Progesterone and 17OH-progesterone levels remained unmodified, while estradiol and estrone levels showed a significant decrease (-51% for estradiol and -61% for estrone). We also observed an increase in circulating ACTH (+58%) and beta-endorphin (+120%). No modifications in the hormonal responses to CRF were observed during the treatment. DXM significantly suppressed circulating steroids at any time with a lower suppression of cortisol from the third month and a higher suppression of DHEA at 12 months. ACTH administration was associated with a significantly blunted cortisol response from the sixth month and a significantly increased response of allopregnanolone from the third month. The present data exclude a raloxifene effect on pituitary sensitivity to CRF and demonstrate a reduced adrenal sensitivity to ACTH, sustained by the opposite changes in basal cortisol and Delta5 androgens, which were reduced, and in ACTH and beta-endorphin, which were increased, as well by the reduced response of cortisol to the direct ACTH stimulus. The reduction of circulating cortisol levels and cortisol response to the ACTH challenge suggests that raloxifene protects against the neurotoxic effects of endogenous glucocorticoids. Furthermore, the progressive increase in basal allopregnanolone and its increased response to ACTH indicate that chronic raloxifene administration exerts direct effects on the pattern of adrenal enzymes, leading to specific changes in the circulating levels of this anxiolytic progesterone metabolite. The important reduction in the circulating levels of estradiol and estrone under long-term raloxifene administration may represent a further mechanism by which this molecule may exert a protective effect against breast and endometrial malignancies.     

Minimum effective anesthetic concentration (MEAC) for sciatic nerve block: subgluteus and popliteal approaches

BACKGROUND: We tested the hypothesis that using a subgluteus approach to the sciatic nerve requires a lower concentration of mepivacaine to obtain complete anesthesia as compared with the popliteal approach. METHODS: With midazolam premedication (0.05 mg kg(-1) iv), 48 patients undergoing hallux valgus repair were randomly allocated to receive a sciatic nerve block using either a posterior popliteal (group Popliteal, n = 24) or subgluteus (group Subgluteus, n = 24) approach with 30 mL of local anesthetic injected after elicitation of plantar flexion of the foot with a current 相似文献   

Role of amiodarone on the systemic inflammatory response induced by cardiac surgery: proinflammatory actions

PURPOSE: Amiodarone (AMIO), a widely used anti-arrhythmic drug, has been shown to reduce the incidence of atrial fibrillation after cardiac surgery and also to exert immunomodulatory actions in vitro and proinflammatory effects in vivo. The present study investigated the immunomodulatory properties of AMIO in the inflammatory response induced by cardiac surgery with cardiopulmonary bypass (CPB). METHODS: In this double-blind, placebo-controlled trial, 20 patients undergoing elective coronary artery bypass graft were randomized to receive placebo or AMIO 600 mg day(-1) orally for seven days before surgery and 45 mg hr(-1) intravenously for 48 hr postoperatively. Plasma levels of the proinflammatory markers C-reactive protein (CRP), fibrinogen (FBG), tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and the antiinflammatory marker IL-10, were compared before and after surgery. RESULTS: Ninety-six hours after start of surgery, plasma levels of FBG had more than doubled (2.2 +/- 0.5-fold increase, P < 0.0001). Overall, FBG formation was significantly increased in the AMIO group (P = 0.048). Monocyte chemoattractant protein 1 secretion transiently increased four hours after start of surgery (6.6 +/- 4.5-fold increase) but rapidly declined thereafter, (P < 0.0001). There was a trend toward higher MCP-1 plasma concentrations in the AMIO group (P = 0.13). The plasma levels of CRP, TNF-alpha, IL-6 and Il-10 changed significantly over time, but were not altered by AMIO treatment. CONCLUSION: In the inflammatory response induced by cardiac surgery with CPB, our data suggest that AMIO treatment is associated with a selective trend toward proinflammatory actions.     

Lipid-drug conjugate nanoparticles of the hydrophilic drug diminazene-cytotoxicity testing and mouse serum adsorption.

Sleeping sickness is a widely distributed disease in great parts of Africa. It is caused by Trypanosoma brucei gambiense and rhodiense, transmitted by the Tse-Tse fly. After a hemolymphatic stage, the parasites enter the central nervous system where they cannot be reached by hydrophilic drugs. To potentially deliver the hydrophilic antitrypanosomal drug diminazene diaceturate to the brain of infected mice, the drug was formulated as lipid-drug conjugate (LDC) nanoparticles (NP) by combination with stearic- (SA) and oleic acid (OA). To estimate the in vivo compatibility, the particles were incubated with human granulocytes. Because as potential delivery mechanism the absorption of specific serum proteins (ApoE, Apo AI and Apo AIV) was found to be responsible for the delivery of nanoparticles to the brain, demonstrated using PBCA nanoparticles coated with polysorbate 80 (LDL uptake mechanism) the nanoparticles were incubated with mouse serum and the adsorption pattern was determined using the 2-D PAGE technique. As a result of this study, the cytotoxic potential was shown to decrease when diminazene is part of the particle matrix compared to pure fatty acid nanoparticles and the mouse serum protein adsorption pattern differs from the samples studied earlier in human serum. Especially, the fact concerning Apo-E that could be detected when the particles were incubated in human serum is absent after the mouse serum incubation, potentially, is a critical point for the delivery via the LDL-uptake mechanism but the data demonstrate that LDC nanoparticles, with 33% (wt/wt) drug loading capacity possess the potential to act as a delivery system for hydrophilic drugs like diminazene diaceturate and that further studies have to demonstrate the usability as a brain delivery system.     

Highly oxygen-permeable copoly(methacrylate/siloxane)s with perfluoroalkyl ester groups

Basic materials for contact lenses were obtained by radical copolymerization of linear α,ω-bis(methacryloyloxy)-terminated oligo- and poly(dimethylsiloxane)s, methyl methacrylate and 2,2,3,3,4,4,4-heptafuorobutyl methacrylate. Oxygen permeabilities, contact angles and ball indentation hardness were determined.     

Effects of heart rate on phasic Y-graft blood flow and flow reserve in patients with complete arterial myocardial revascularizaton: an intravascular Doppler catheter study.

OBJECTIVE: It is not well established whether the blood flow of arterial composite Y-grafts can efficiently respond to the flow demand of the coronary system early postoperatively. The aim of this study was to evaluate if soon after the operation, arterial composite Y-grafts can increase blood flow in response to an increase in myocardial oxygen consumption (MVO2). METHODS: Twenty-seven patients who received complete arterial myocardial revascularization using the left internal thoracic artery (LITA) and the radial artery (RA) as composite Y-graft gave their consent to a pre-discharge coronary angiography and intravascular flow velocity measurements using a Doppler guide wire. Flow measurements were performed in the LITA main stem, the distal LITA and the RA, both at rest and during atrial pacing at the 85% of the patient age-predicted maximum. The heart rate-systolic blood pressure product was considered as an indirect index of MVO2. Hyperemic flow was determined after injection of adenosine. The flow reserve (FR) was defined as the ratio of blood flow during maximal hyperemia (Qmax) to baseline flow (Qbasal). RESULTS: Atrial pacing increased MVO2 significantly (P<0.000). None of the patients developed ischemic S-T segment modifications or complained of chest pain. Q(basal) increased significantly in the LITA main stem (P=0.001), distal LITA (P=0.041) and RA (P=0.004) while Qmax did not change significantly. As a consequence, the FR decreased in the LITA main stem (P=0.002), distal LITA (P<0.000) and RA (P<0.000) but was not completely exhausted. CONCLUSIONS: Soon after the operation, arterial composite Y-grafts can significantly increase blood flow in response to conditions of increased MVO2, keeping normal the myocardial O2 supply-to-demand ratio.     

APOE epsilon3 gene transfer attenuates brain damage after experimental stroke.

Apolipoprotein E (apoE, protein; APOE, gene) is the major lipid-transport protein in the brain and plays an important role in modulating the outcome and regenerative processes after acute brain injury. The aim of the present study was to determine if gene transfer of the epsilon3 form of APOE improves outcome in a murine model of transient focal cerebral ischaemia. Mice received an intrastriatal injection of vehicle, a second-generation adenoviral vector containing the green fluorescent protein gene (Ad-GFP) or a vector containing the APOE epsilon3 gene (Ad-APOE) 3 days before 60 mins focal ischaemia. Green fluorescent protein expression was observed in cells throughout the striatum and subcortical white matter indicating successful gene transfer and expression. ApoE levels in the brain were significantly increased after Ad-APOE compared with Ad-GFP or vehicle treatment. Ad-APOE treatment reduced the volume of ischaemic damage by 50% compared with Ad-GFP or vehicle treatment (13+/-3 versus 29+/-4 versus 27+/-5 mm(3)). The extent of postischaemic apoE immunoreactivity was enhanced in Ad-APOE compared with Ad-GFP or vehicle treated mice. These results show the ability of APOE gene transfer to markedly improve outcome after cerebral ischaemia and suggest that modulating apoE levels may be a potential strategy in human stroke therapy.     

A new shape for an old function: lasting effect of a physiologic surgical restoration of the left ventricle

Background  

Long-term morphofunctional outcome may vary widely in surgical anterior left ventricular wall restoration, suggesting variability in post-surgical remodeling similar to that observed following acute myocardial infarction. The aim of this pilot study was to demonstrate that surgical restoration obtained with a particular shape of endoventricular patch leads to steady morphofunctional ventricular improvement when geometry, volume and residual akinesia can be restored as normal as possible.