The effect of increasing the sulfation level of chondroitin sulfate on anticoagulant specific activity and activation of the kinin system.

Oversulfated chondroitin sulfate (OSCS) was identified as a contaminant in certain heparin preparations as the cause of adverse reactions in patients. OSCS was found to possess both plasma anticoagulant activity and the ability to activate prekallikrein to kallikrein. Differentially sulfated chondroitin sulfates were prepared by synthetic modification of chondroitin sulfate and were compared to the activity of OSCS purified from contaminated heparin. Whilst chondroitin sulfate was found to have minimal anticoagulant activity, increasing sulfation levels produced an anticoagulant response which we directly show for the first time is mediated through heparin cofactor II. However, the tetra-sulfated preparations did not possess any higher anticoagulant activity than several tri-sulfated variants, and also had lower heparin cofactor II mediated activity. Activation of prekallikrein was concentration dependent for all samples, and broadly increased with the degree of sulfation, though the di-sulfated preparation was able to form more kallikrein than some of the tri-sulfated preparations. The ability of the samples to activate the kinin system, as measured by bradykinin, was observed to be through kallikrein generation. These results show that whilst an increase in sulfation of chondroitin sulfate did cause an increase in anticoagulant activity and activation of the kinin system, there may be subtler structural interactions other than sulfation at play given the different responses observed.

Cyr61 is a target for heparin in reducing MV3 melanoma cell adhesion and migration via the integrin VLA-4.

The integrin VLA-4 is important for the metastatic dissemination of melanoma cells. We could recently show that heparin can block VLA-4 binding, which contributes, next to blocking P- and L-selectin, to the understanding of antimetastatic activities of heparin. The matricellular ligand Cyr61, secreted by numerous tumours, is responsible for increased tumourigenicity and metastasis. This has been attributed to Cyr61 binding to, and thus activating integrins. However, a VLA-4/Cyr61 axis has not yet been reported. Since Cyr61 possesses heparin binding capabilities, Cyr61 can be supposed as potential target for heparin to indirectly interfere with integrin functions. The present in vitro studies address (i) the existence of a Cyr61/VLA-4 axis and (ii) the functional relevance of heparin interference via Cyr61. The C-terminal module III of Cyr61 could be exposed as nanomolar affine binding site for VLA-4. A shRNA-based knockdown of Cyr61 in MV3 human melanoma cells reduced VLA-4-mediated cell binding to VCAM-1, migration on fibronectin, and integrin signalling functions significantly. Using a biosensor approach we provide insight into heparin interference with this process. The low-molecular-weight heparin tinzaparin, but not the pentasaccharide fondaparinux, binds module IV of Cyr61 with micromolar affinity. But tinzaparin cannot interfere with Cyr61 accumulation onto syndecan-4, indicating different Cyr61 binding sites for heparin and other GAGs. Nonetheless, tinzaparin affects the VLA-4 binding and signalling functions selectively via Cyr61 already at very low concentration most likely by blocking the cellular secreted free Cyr61. This study emphasises Cyr61 as promising, and hitherto not considered target for heparin to selectively influence integrin functions.

Inhalation anesthetics: a review.

Inhalation agents represent a basic drug used in modern balanced anesthesia. In the present review, the pharmacokinetics, effectiveness and clinical effects of inhalation agents on different systems are discussed. Data concerning the metabolism and related toxicity of halogenated agents is reviewed, with particular regard to the problem of chronic exposure to traces of anesthetic gases in the operating room. The cardioprotective effect of halogenated agents and the actual role of nitrous oxide and xenon are discussed. The different mechanisms of action of the inhalation agents and the evolution from a unitary theory of inhaled anesthetics to a multiple mechanism concept are presented.

Probability mapping of indoor radon-prone areas using disjunctive kriging.

After a reference to the use of maps of radon-prone areas for indoor radon risk management, and to the methods used to produce them, there is a brief illustration of the geostatistical method of disjunctive kriging (DK) introduced by G. Matheron as a substitute for conditional expectation. There are some good reasons of using this method for the mapping of radon-prone areas as follows: (1) spatial correlation is exploited; (2) unbiasedness is conserved even in the conditions of quasi-stationarity; (3) lognormality of the data is not required; (4) choosing the point estimation allows drawing up smooth probability maps. An application of DK is also presented for the production of probability maps in a campaign of indoor radon measurements conducted by Institute for Environmental Protection and Research, in the provinces of Rome and Viterbo (Central Italy). In the application, it is assessed in particular how much the spatial correlation, even though low, influences the results.

A 3-O-methylated mannogalactan from Pleurotus pulmonarius: structure and antinociceptive effect.

A polysaccharide (Mw 2.39x10(4)g/mol) was extracted with cold water from the basidiomycete Pleurotus pulmonarius, and its antinociceptive and anti-inflammatory properties were evaluated. It was a mannogalactan (MG), whose structure was characterized using mono- and two-dimensional NMR spectroscopy, methylation analysis, and a controlled Smith degradation. It had a main chain of (1-->6)-linked alpha-D-galactopyranosyl and 3-O-methyl-alpha-D-galactopyranosyl units, both of which are partially substituted at O-2 by beta-D-mannopyranosyl non-reducing ends. The MG was tested for its effects on the acetic acid-induced writhing reaction in mice, a typical model for inflammatory pain, causing a marked and dose-dependent inhibition of the nociceptive response, with ID50 of 16.2 (14.7-17.7)mg/kg and inhibition of 93+/-3% at a dose of 30mg/kg. An inflammatory response was not inhibited.

Dilatative percutaneous tracheostomy during double antiplatelet therapy: two consecutive cases.

This article reports two cases of dilatative percutaneous tracheostomy performed on patients treated with double antiplatelet therapy. Both patients had cardiac arrest following myocardial infarction. After primary angioplasty with stent placement, a double antiplatelet therapy was started. Due to poor neurological outcome, dilatative percutaneous tracheostomy was performed on both patients. Antiplatelet therapy was not discontinued because of the unacceptable risk of stent thrombosis. No immediate or late hemorrhagic complications occurred. In our experience, dilatative percutaneous tracheostomy during double antiplatelet therapy can be safely performed in selected patients without other risk factors.

Determination of thorium isotopes in mineral and environmental water and soil samples by alpha-spectrometry and the fate of thorium in water.

A method has been developed for determination of thorium isotopes in water and soil samples by alpha-spectrometry. After fusion with Na(2)CO(3) and Na(2)O(2) at 600 degrees C, soil samples were leached with HNO(3) and HCl. Thorium in water sample or in soil leaching solution was coprecipitated together with iron (III) as hydroxides and/or carbonates at pH 9 with ammonia solution, separated from uranium and other alpha-emitters by a Microthene-TOPO (tri-octyl-phosphine oxide) chromatographic column, electrodeposited on a stainless steel disk, and measured by alpha-spectrometry. The method was checked with two certified reference materials supplied by the IAEA, and reliable results were obtained. The detection limits of the method for water (soil) samples are 0.44 microBq l(-1) (0.070 Bq kg(-1)) for (232)Th, 0.80 microBq l(-1) (0.13 Bq kg(-1)) for (230)Th and 1.0 microBq l(-1) (0.16 Bq kg(-1)) for (228)Th, respectively, if 100 l of water (0.50 g) for each sample are analysed. A variety of water or soil samples were analysed using this procedure and giving average thorium yields of 75.5+/-14.2% for water and 93.4+/-4.5% for soil. The obtained concentrations of thorium isotopes in water samples are in the range of 0.0007-0.0326 mBq l(-1) for (232)Th,

Effect of nitrous oxide on desflurane MACBAR at two target-controlled concentrations of remifentanil.

BACKGROUND: The aim of this prospective, randomized, double-blind study was to determine the effect of nitrous oxide on the desflurane requirement for blunting sympathetic response following surgical incision (MACBAR) when desflurane was combined with two different target-controlled concentrations of remifentanil (1 and 3 ng/mL). METHODS: A total of 103 patients, aged 20-50 years, ASA physical status I, scheduled to undergo general anesthesia for elective abdominal surgery, were randomly allocated to receive anesthesia with desflurane alone (Group A, n = 53), or with the addition of 60% nitrous oxide (Group N, n = 50). Patients of both groups were further assigned to receive a target-controlled plasma concentration of 1 ng/mL (Group A1, n = 27; Group N1, n = 26) or 3 ng/mL remifentanil (Group A3, n = 26, Group N3, n = 24). Sympathetic responses to surgical incision were determined after a 20 min period of constant end-tidal desflurane and target-controlled remifentanil concentrations. Predetermined end-tidal desflurane concentrations and the MACBAR for each group were determined using an up-and-down sequential allocation technique. RESULTS: A total of 98 patients completed the study. The MACBAR of desflurane was 5.2% (95% confidence interval [CI95: 4.9-5.5%]) in Group A1 and 2.7% (CI95: 2.6-2.8%) in Group N1 (P<0.001), while in Groups A3 and N3 the MACBAR of desflurane was 2.2% (CI95:2-2.4%) and 2% (CI95:1.9-2.2%), respectively (P<0.01). When considering a minimum anesthetic concentration (MAC) value with a contribution of 60% nitrous oxide (0.55 MAC) in this population, the combined MACBAR values (expressed as multiples of the MAC) were 1.9 MAC for group A1, 1 MAC for group N1, 0.8 MAC for group A3, and 0.7 MAC for group N3. CONCLUSION: The addition of 60% nitrous oxide reduces the MACBAR of desflurane by 52% when using a remifentanil concentration of 1 ng/mL, and reduces the MACBAR by 10% when using a remifentanil concentration of 3 ng/mL.

Site-specific interactions of copper(II) ions with heparin revealed with complementary (SRCD, NMR, FTIR and EPR) spectroscopic techniques.

The interactions between Cu(II) ions and heparin were investigated using several complementary spectroscopic techniques. NMR indicated an initial binding phase involving specific coordination to four points in the structure that recur in slightly different environments throughout the heparin chain; the carboxylic acid group and the ring oxygen of iduronate-2-O-sulfate, the glycosidic oxygen between this residue and the adjacent (towards the reducing end) glucosamine and the 6-O-sulfate group. In contrast, the later binding phase showed little structural specificity. One- and two-dimensional correlated FTIR revealed that complex out of phase (asynchronous) conformational changes also occurred during the titration of Cu(II) ions into heparin, involving the CO and N-H stretches. EPR demonstrated that the environments of the Cu(II) ions in the initial binding phase were tetragonal (with slightly varied geometry), while the later non-specific phases exhibited conventional coordination. Visible spectroscopy confirmed a shift of the absorbance maximum. Titration of Cu(II) ions into a solution of heparin indicated (both by analysis of FTIR and EPR spectra) that the initial binding phase was complete by 15-20 Cu(II) ions per chain; thereafter the ions bound in the non-specific mode. Hetero-correlation spectroscopy (FTIR-CD) improved resolution and assisted assignment of the broad CD features from the FTIR spectra and indicated both in-phase and more complex out of phase (synchronous and asynchronous, respectively) changes in interactions within the heparin molecule during the titration of Cu(II) ions.

Midazolam and pethidine versus propofol and fentanyl patient controlled sedation/analgesia for upper gastrointestinal tract ultrasound endoscopy: a prospective randomized controlled trial.

BACKGROUND AND OBJECTIVES: The aim of this prospective, randomized study was to compare the standard regimen of midazolam and pethidine administered by the gastroenterologist versus patient controlled sedation with a propofol-fentanyl mixture during upper gastrointestinal tract endoscopic ultrasonography. Our primary end-points were patient satisfaction and patient cooperation assessed by endoscopist. METHODS: Fifty-four consecutive patients, undergoing endoscopic ultrasonography, received sedation with midazolam and pethidine (Group M: n=27) or propofol and fentanyl (Group P: n=27). Group M: pethidine 0.7mg/kg midazolam 0.04mg/kg before examination; boluses of same drugs if the sedation was insufficient plus a sham patient controlled sedation analgesia; Group P: propofol 17mg plus fentanyl 15microg before examination and a patient controlled sedation analgesia pump containing 170mg propofol plus 150microg fentanyl injecting 0.5ml every time the patient pressed the button (no "lock out"). Boluses of 1ml of the same mixture if the sedation was insufficient. RESULTS: Group M: mean dosage of pethidine and midazolam 88.6 and 5mg, respectively. Group P: mean dosage of propofol and fentanyl 119.7mg and 106microg, respectively. Both groups were similar for duration and difficulty of the procedure, the grade of sedation (Observer's Assessment of Alertness/Sedation Score) and judgement by endoscopist and patient about cooperation and satisfaction. The only difference between groups was about the extra boluses administered during the procedure. CONCLUSION: This study demonstrated that a patient controlled sedation analgesia with propofol and fentanyl is an effective and safe technique for upper gastrointestinal tract endoscopic ultrasonography procedures and results in a high level of satisfaction both for patients and operator.

Target-controlled infusion during monitored anesthesia care in patients undergoing EUS: propofol alone versus midazolam plus propofol. A prospective double-blind randomised controlled trial.

BACKGROUND: It has been speculated that midazolam may be effective in reducing the required dose of propofol during sedation. AIM: To evaluate the sparing effect of midazolam during target-controlled propofol infusion. METHODS: Two hundred-seventy patients undergoing upper endoscopic ultrasound were randomised to receive sedation with propofol plus placebo (group A) or plus midazolam (group B). Outcome parameters were the procedure duration, the discharge time and the satisfaction of patients, operator and nurse about the quality of sedation. RESULTS: The mean propofol dose administered was 364+/-207 mg in group A and 394+/-204 mg in group B. Mean procedure duration (group A: 32+/-17 min, group B: 35+/-22 min) and discharge time (group A: 39+/-30 min, group B: 38+/-24 min) were similar in both groups. No severe complications were observed. The quality of sedation was judged satisfactory for all patients by both the endoscopist and the nurse assistant without any difference between the two groups. No patient remembered the procedure or reported it as unpleasant. CONCLUSIONS: Target-controlled propofol infusion provides safe and effective sedation; premedication with low dose of midazolam does not reduce the total amount of propofol administered. Further studies are needed to compare propofol alone with propofol co-administered with opioid.

The effect of adding two target-controlled concentrations (1-3 ng mL -1 ) of remifentanil on MAC BAR of desflurane.

BACKGROUND AND OBJECTIVES: The aim of this prospective, randomized, double-blind study was to determine the effects of adding two different target-controlled concentrations of remifentanil (1 and 3 ng mL(-1)) on the desflurane requirement for blunting sympathetic responses after surgical incision (minimum anaesthetic concentration (MAC(BAR)). METHODS: 67 patients, aged 20-50 yr, ASA I, undergoing general anaesthesia for elective abdominal surgery were enrolled and randomly allocated to receive no remifentanil infusion (n = 21) or a target-controlled effect-site concentration of 1 ng mL(-1) (n = 24) or 3 ng mL(-1) remifentanil (n = 22). All patients were anaesthetized with propofol, cisatracurium and desflurane with a mixture of 60% nitrous oxide in oxygen. Sympathetic responses to surgical incision were determined after a 20-min period of stable end-tidal desflurane and target-controlled remifentanil concentrations. Predetermined end-tidal desflurane concentrations and the MAC(BAR) for each group were determined using an up-and-down sequential-allocation technique. RESULTS: The MAC(BAR) of desflurane was higher in the group receiving no remifentanil (6.25% [95% confidence interval: 5.9-6.5%]) as compared with patients of the groups receiving 1 ng mL(-1) (2.7% [2.6-2.8%]; P < 0.001) and 3 ng mL(-1) remifentanil (2% [1.9-2.2%]; P < 0.01). When considering a MAC value in this age population and the contribution of 60% nitrous oxide (0.55 MAC), the combined MAC(BAR) values, expressed as multiples of the MAC, were 1.9, 0.8 and 0.6 MAC, in the three groups, respectively. CONCLUSION: A target-controlled concentration of 1 ng mL(-1) remifentanil results in a 57% decrease in the MAC(BAR) of desflurane combined with 60% nitrous oxide. Increasing the target concentration of remifentanil to 3 ng mL(-1) produces a further 26% decrease in the MAC(BAR) values of desflurane.

The effect of adding nitrous oxide on MAC of sevoflurane combined with two target-controlled concentrations of remifentanil in women.

BACKGROUND AND OBJECTIVE: The aim of this prospective, randomized, double-blind study was to determine the effects of adding nitrous oxide on sevoflurane requirement for blunting sympathetic responses after surgical incision combined with two different target-controlled concentrations of remifentanil (1 and 3 ng mL(-1)) in female. METHODS: 102 female patients, aged 20-50 yr, ASA I, undergoing general anaesthesia for elective abdominal surgery were enrolled and randomly allocated to receive sevoflurane anaesthesia alone (Group A, n=53), or with the addition of 60% nitrous oxide (Group N, n=49). Patients of both groups were further assigned to receive a target-controlled remifentanil infusion with an effect-site concentration of either 1 ng mL(-1) (Group N1, n=27; Group A1, n=30), or 3 ng mL(-1) (Group N3, n=22; Group A3, n=23). Sympathetic responses to surgical incision were determined after a 20-min period of stable end-tidal sevoflurane and target-controlled remifentanil concentrations. Predetermined end-tidal sevoflurane concentrations and minimum alveolar concentration (MAC) for each group were determined using an up-and-down sequential allocation technique. RESULTS: The MAC of sevoflurane was 3.96% (95% confidence interval, CI95: 3.69-4.23%) in Group A1 and 1.2% (CI95: 0.9-1.3%) in Group N1 (P < 0.01), while in Groups A3 and N3 the MAC of sevoflurane was 0.36% (CI95: 0.24-0.47%) and 0.18% (CI95: 0.1-0.3%), respectively (P < 0.05). CONCLUSION: Adding 60% nitrous oxide reduces the MAC of sevoflurane by 70% when using a remifentanil concentration of 1 ng mL(-1) and 50% when using a remifentanil concentration of 3 ng mL(-1).

Different anesthesiological management in two high risk pregnant women with heart failure undergoing emergency cesarean section.

Pregnancy exacerbates heart diseases. The aim of this clinical report is to review the different anesthesiological management of emergent cesarean section in 2 patients with heart failure. The pathophysiology of heart failure is described according to the primary cause of disease, as well as the impact of 2 different anesthetic techniques. Two case reports of a university referral hospital are presented. Both patients left the hospital in good general conditions. Case 1: a pregnant patient with severe aortic regurgitation who received epidural anesthesia. Case 2: a pregnant patient with peripartum cardiomyopathy who was given general anesthesia. Medical and surgical therapies for aortic regurgitation and peripartum dilated cardiomyopathy are evolving. Adequate knowledge of anesthesiology is required to appropriately manage these cases. We tailored the anesthetic technique to the specific characteristics of our 2 patients. The beneficial effects of sympathectomy were observed in the postoperative period of case 1; the use of high doses opiates minimised dangerous cardiovascular changes in case 2, but rapid resuscitation of the baby should be available. Selection of the anesthetic technique in obstetrics is the most challenging issue for the anesthesiologist: extensive knowledge of the pathophysiology of heart disease is required for an optimal choice.