We have studied the interaction between some heavy metal ions, as compared with earth alkali ions, and calmodulin, a tissue protein which binds Ca2+ and mediates some of its effects. 1. Calmodulin dependent phosphodiesterase was activated with Pb2+, Ca2+, Sr2+, Ba2+, and Cd2+ (EC50 about 0.8 microM). The maximal activation achieved decreases in the order given. Hg2+, Sn2+, Fe2+, Cu2+, Ni2+, Bi3+, and Sb3+ up to 20 microM did not activate. 2. Pb2+ can replace Ca2+ with respect to the calmodulin-dependent phosphorylation of brain membranes. With high Pb2+ concentrations, phosphorylation was inhibited. 3. Calmodulin binding to brain membranes was enhanced with concentrations below 10(-4)M in the following order: Pb2+ greater than or equal to Ca2+ approximately Sr2+ greater than Cd2+ greater than Mn2+ greater than Ba2+. In contrast Mg2+, Hg2+, Sn2+, Fe2+, Ni2+, Co2+, and Cu2+ triggered, if at all, a non-saturable binding of calmodulin. 4. In the flow-dialysis, other ions competed with 45Ca2+ binding to calmodulin in the following order: Pb2+ approximately Ca2+ greater than Mn2+, Ba2+, Cd2+, Sr2+. Thus among the ions investigated Pb2+ is a fully potent substitute for Ca2+ in every calmodulin-dependent reaction investigated. Cd2+ is always much less potent. The earth alkali ions Sr2+ and Ba2+ take an intermediate position. It remains to be shown whether calmodulin is merely a storage site for Pb2+, or whether the resulting functional changes play a role in Pb2+ poisoning.

In this prospective, observational study we explored whether A118G single nucleotide polymorphism in the human mu-opioid receptor (MOR) gene could explain the inter-individual differences in opioid analgesic requirements in patients with acute postoperative pain and chronic pain. The frequency of the wild-type A118 MOR (major) and variant G118 MOR (minor) alleles in the subjects with chronic, noncancer pain (n = 121) and opioid-naïve subjects with acute postoperative pain (n = 101), serving as the control group, were examined. The relationships among the A118G MOR genotype, opioid requirements, and the numerical pain score were analyzed in both groups. The frequency of the minor allele was significantly lower in the subjects with chronic pain when compared with the group with acute postoperative pain (0.079 versus 0.158; P = 0.009 by chi2 test). No statistically significant association was observed between the presence of A118G MOR polymorphism and the average postoperative pain score or the doses of morphine used in the immediate postoperative period. In the high-quartile, opioid utilization, chronic pain patients, the homozygotic carriers of the major allele required significantly higher opioid dose than did the carriers of the minor allele. The results indicate that although the presence of the minor allele does not appear to affect opioid analgesic use in acute postoperative pain, the minor allele is less common in chronic pain patients, especially in those requiring higher doses of opioid analgesics.

Background: A family history has been established as a risk factor for postoperative nausea and vomiting (PONV), but the identities of susceptibility genes remain unknown. The goal of this study was to identify the genetic loci that may contribute to PONV susceptibility in an adult population. Methods:The authors performed a genome-wide association study involving pooling of DNA obtained from 122 patients with severe PONV and 129 matched controls. Each pool was hybridized to a single nucleotide polymorphism (SNP) microarray, and probe intensity was used to predict allele frequency. Differences in allele frequency between SNP in the PONV and control groups were ranked after accounting for the pooling error. The highest ranking SNPs were selected for individual genotyping in the subjects from whom the DNA pool was comprised and in the new verification cohort consisting of 208 subjects (104 PONV patients and 104 controls). Results: The authors identified 41 SNP targets showing substantial difference in allelic frequency between pools. These markers were first genotyped in the individual DNA samples from which the pools were comprised. The authors observed evidence for an association between PONV and 19 different loci in the genome. In the separate verification cohort, the association with PONV was observed for four SNPs. This association remained significant after correcting

Summary.  Aims: Decreased platelet responsiveness to acetylsalicylic acid (ASA) reported previously in diabetic patients could be attributed to patient‐based, clinical, genetic and cellular factors. The objective of the present study was to investigate the effect of the genomic polymorphism on the platelet reactivity in diabetic patients treated with ASA. Methods and results: The study cohort consisted of 295 Caucasians with diabetes type 2 who had been taking ASA tablets at the dose of 75 mg per day for at least 3 months for primary or secondary prevention of myocardial infarction (MI). Platelet reactivity analyzes were performed using VerifyNow ASA and PFA‐100 assays. Genotyping for the selected 27 single nucleotide polymorphisms (SNPs) within 19 genes was performed using a Sequenom iPLEX platform. The results indicate that the statistically significant differences in platelet reactivity were observed in the PFA‐100 assay for SNPs in following genes: TXBA2R (rs1131882), ADRA2A (rs4311994), PLA2G7 (rs7756935) and 9p21.3 (rs10120688) (P = 0.02, P = 0.03, P = 0.02, P = 0.03, respectively, all significance levels corrected for multiple comparisons). When using the VerifyNow ASA test, a weak nominal statistical significance (i.e. before multiple comparison testing) was observed for two SNPs in the GPVI gene: rs1671152 and rs1613662 [P = 0.025 (0.5) for both SNPs, corrected for multiple comparisons test]. Conclusions: The results from the present study suggest that the four analyzed genes may contribute to platelet reactivity measured with the PFA‐100 assay in the diabetic population treated with ASA.

Tracheal intubation, performed routinely during general anaesthesia in patients undergoing intraocular surgery, may have adverse effects on cardiovascular function and intraocular pressure. This study assessed the suitability of the laryngeal mask airway (LMA) as a substitute for tracheal intubation. Intraocular and systemic pressor effects, heart rate changes and catecholamine concentrations were measured in two groups of 10 patients receiving standardized anaesthesia with either a tracheal tube (TT) or a LMA. There were significantly smaller changes in the pressor responses to insertion and in concentrations of catecholamines at critical times in the anaesthetic sequence in the LMA group. Mean (SEM) rate-pressure product was significantly smaller in the LMA group compared with the TT group after both insertion (8276 (730) vs 13307 (1348), P < 0.01) and removal (10152 (595) vs 14137 (1044), P < 0.01) of the airway device. The change in intraocular pressure was significantly less in the LMA group at all time points after airway instrumentation than that in the TT group, with the greatest difference after extubation (-2.3 (2.4) mm Hg vs 14.5 (3.4) mm Hg, P < 0.01).

The investigated water warming system, by virtue of its ability to deliver heat to a greater percentage of the body, results in better maintenance of intraoperative normothermia that does forced-air warming applied only to the upper extremities, as is common practice.

Modulation of Ca 2ϩ channels by heterologously expressed wild-type and mutant human -opioid receptors (hMORs) containing the A118G single-nucleotide polymorphism. J Neurophysiol 97: 1058 -1067, 2007. First published December 6, 2006; doi:10.1152/jn.01007.2006. The most common single-nucleotide polymorphism (SNP) of the human -opioid receptor (hMOR) gene occurs at position 118 (A118G) and results in substitution of asparagine to aspartate at the N-terminus. The purpose of the present study was to compare the pharmacological profile of several opioid agonists to heterologously expressed hMOR and N-type Ca 2ϩ channels in sympathetic neurons. cDNA constructs coding for wild-type and mutant hMOR were microinjected in rat superior cervical ganglion neurons and N-type Ca 2ϩ channel modulation was investigated using the whole cell variant of the patch-clamp technique. Concentration-response relationships were generated with the following selective MOR agonists: DAMGO, morphine, morphine-6-glucuronide (M-6-G), and endomorphin I. The estimated maximal inhibition for the agonists ranged from 52 to 64% for neurons expressing either hMOR subtype. The rank order of potencies for estimated EC 50 values (nM) in cells expressing wild-type hMOR was: DAMGO (31) Ͼ Ͼ morphine (76) Х M-6-G (77) Х endomorphin I (86). On the other hand, the rank order in mutant-expressing neurons was: DAMGO (14) Ͼ Ͼ morphine (39) Ͼ Ͼ endomorphin I (74) Х M-6-G (82), with a twofold leftward shift for both DAMGO and morphine. The DAMGO-mediated Ca 2ϩ current inhibition was abolished by the selective MOR blocker, CTAP, and by pertussis toxin pretreatment of neurons expressing either hMOR subtype. These results suggest that the A118G variant MOR exhibits an altered signal transduction pathway and may help explain the variability of responses to opiates observed with carriers of the mutant allele.

The pressor response to tracheal intubation is known to be exaggerated in patients with gestational proteinuric hypertension (GPH). We have studied the effect of pretreatment with magnesium sulphate 40 mg kg-1 or 30 mg kg-1 with alfentanil 7.5 micrograms kg-1 on this pressor response in 38 patients with moderate to severe GPH. The magnesium-alfentanil combination produced better control of arterial pressure and heart rate than magnesium alone, although both techniques provided good cardiovascular control. There was no significant difference in fetal outcome between groups. Both pretreatment methods produced satisfactory control of catecholamine release.