Association between the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene and postoperative analgesic requirements.

An association between postoperative analgesic requirements in subjects who underwent orthognathic surgery and the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene was suggested by our previous genome-wide association study. To verify this association, we analyzed the association between the rs1465040 SNP and analgesic requirements, including opioid requirements, after open abdominal surgery. The association between the rs1465040 SNP and postoperative analgesic requirements was confirmed in the open abdominal surgery group (P = 0.036), suggesting that the TRPC3 SNP may contribute to predicting postoperative analgesic requirements.

[A case of acute renal failure following compartment syndrome after the surgery for femoral neck fracture].

Compartment syndrome is known to develop after a prolonged surgery in the lithotomy position. We experienced acute renal failure following compartment syndrome after the surgery in hemilithotomy position. A 62-year-old man underwent a left hip fixation for femoral neck fracture. The surgical leg was placed into traction in a foot piece and the intact leg was placed in the hemilithotomy position. Because of the difficulty in repositioning and the trouble with fluoroscope, the surgery took over 5 hours. He suffered acute pain, swelling and spasm in his intact leg placed into hemilithotomy after the surgery. Creatine kinase, blood urea nitrogen and creatinine markedly increased and myoglobinuria was recognized. We diagnosed an acute renal failure following compartment syndrome and treated him in the ICU on close monitoring. In spite of the treatment with massive transfusion and diuretics, he needed hemodialysis twice and then his renal function improved. Prevention is most essential for compartment syndrome after a prolonged surgery in the lithotomy position. Risk factors should be recognized before surgery and appropriate action should be taken such as using Allen stirrups and avoiding hypotension, hypovolemia and the prolonged lithotomy position with exaggerated elevation of legs.

Effects of acetaldehyde on action potentials and Ca2+ currents in single atrial myocytes from the bullfrog.

AIM: The purpose of the present study was to examine the effects of acetaldehyde on the contractile force and membrane potentials and currents in the bullfrog heart. METHODS: Contractile force was recorded using right atrial tissues, and membrane potentials and currents were measured by using whole cell patch clamp methods in right atrial myocytes. RESULTS: Acetaldehyde at 500 µmol/l and 1 mmol/l increased the contractile force significantly. Acetaldehyde at 300 and 500 µmol/l increased the overshoot and the plateau of electrically induced action potentials in a concentration-dependent and reversible manner, while the resting membrane potential did not change. The duration of the action potential (APD(90)) measured at the 90% repolarization level was shortened. The L-type Ca(2+) current (I(Ca)) increased significantly when 300 and 500 µmol/l were applied. The fast transient inward current, the inward rectifying potassium current and the outward delayed-rectifier potassium current were not changed following acetaldehyde application (500 µmol/l or 1 mmol/l). CONCLUSION: These results suggest that acetaldehyde increased the I(Ca), thereby increased the contractile force, the overshoot and the plateau of action potentials. The shortening of APD(90) may be due to the acceleration of the current decay during the I(Ca) inactivation phase.

[Genetic polymorphisms and human sensitivity to pain and opioids].

It has been known widely that sensitivity to pain and opioid analgesics varies widely among individual subjects. Because of this variability, a dose of an opioid analgesic that can produce satisfactory pain relief without adverse effects in some patients might cause underdosing or overdosing in other patients, which is often problematic in the clinic. Individual differences can be attributed to both genetic and environmental factors, although the relative influence of each of these factors can be diverse. Numerous molecules have been identifled to be involved in the transduction, conduction, transmission and modulation of pain, as well as pharmacological effects of opioids. Further, many technologies of genotyping polymorphisms, most often single nucleotide polymorphisms (SNPs), have been developed and advanced, leading to accelerated understanding of many associations between various genetic polymorphisms and sensitivity to pain and opioids. In this article, we review the evidence of these associations accumulated thus far.

Hypotensive and hypertensive effects of acetaldehyde on blood pressure in rats.

Intravenous injection of acetaldehyde produced hypotensive actions in pentobarbital-anaesthetised whole rats, but hypertensive actions in pithed rats. The hypotensive effects of acetaldehyde in whole rats were abolished by pre-treatment with yohimbine. In pithed rats, the hypertensive effects of acetaldehyde were significantly attenuated by prazosin and phentolamine, and in rats that had been pre-treated with reserpine. Our results suggest that the hypertensive actions of acetaldehyde in pithed rats are due to the release of catecholamines, which subsequently leads to vasoconstriction. In whole rats the hypotensive actions of acetaldehyde may be due to alpha2-adrenoceptor stimulation in the central nervous or peripheral system.

[Preoperative evaluation and anesthetic management of a patient with Brugada syndrome-like ECG].

Brugada syndrome has been known as one of the causes of sudden death due to ventricular fibrillation. We experienced anesthetic management of seven patients with ECG showing Brugada syndrome before surgery, even though they had no symptoms nor family history. All of them showed no problems through-out the operation. Such patients are often untreated, but they have the risks of cardiac accidents such as ventricular fibrillation or sudden death. For preoperative evaluation of patients with Brugada syndrome-like ECG, it is important to ask them their experience of syncope and family history. Ultrasonic cardiography and Holter ECG recording should be done. External defibrillator should be prepared and parasympathetic dominant condition must be avoided during the anesthetic management.

Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies.

BACKGROUND: Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although several candidate gene variations have been reported by candidate gene studies or genome-wide association studies (GWASs) to be associated with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese subjects. RESULTS: The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and CPD, the nonsynonymous rs2653349 SNP (located on the gene that encodes orexin [hypocretin] receptor 2) was selected as the most notable SNP associated with FTND, with a p value of 0.0005921 in the two-stage GWAS. This possible association was replicated for the remaining 374 samples. This SNP was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and susceptibility to goiter. CONCLUSIONS: Although the p value did not reach a conventional genome-wide level of significance in our two-stage GWAS, we obtained significant results in the subsequent analyses that suggest that the rs2653349 SNP (Val308Ile) could be a genetic factor that is related to nicotine dependence and possibly pain, schizotypal personality traits, and goiter in the Japanese population.

Association between KCNJ6 (GIRK2) gene polymorphisms and postoperative analgesic requirements after major abdominal surgery.

Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5'-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean+/-SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45+/-9.27 mg, 10.84+/-2.24 mg, and 13.07+/-2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.

Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype.

AIMS: The association between SNPs of the human OPRM1 gene encoding the micro-opioid receptor and postoperative analgesic requirements in surgical patients remains controversial. Here, we evaluate whether any of the five tag SNPs (A118G, IVS2+G691C, IVS3+G5953A, IVS3+A8449G and TAA+A2109G) representing the four linkage disequilibrium blocks of the OPRM1 gene influences postoperative analgesic requirements. MATERIALS & METHODS: We studied 138 adult Japanese patients who underwent major open abdominal surgery under combined general and epidural anesthesia and received continuous postoperative epidural analgesia with opioids. RESULTS: The 118G homozygous (GG) patients required 24-h postoperative analgesics more than 118A homozygous (AA) and heterozygous (AG) patients. Tag SNP haplotypes also were associated with 24-h postoperative analgesic requirements. CONCLUSIONS: These results suggest that OPRM1 gene tag SNP genotypes and haplotypes can primarily contribute to prediction of postoperative analgesic requirements in individual patients undergoing major open abdominal surgery.

Prospective study of estramustine phosphate for hormone refractory prostate cancer patients following androgen deprivation therapy.

INTRODUCTION: Estramustine phosphate (EMP) in combination with other cytotoxic agents has been widely used in clinical trials as an anti-tumor agent for the treatment of hormone-refractory prostate cancer (HRPC). However, few prospective studies have considered the efficacy of EMP monotherapy for HRPC patients following androgen-deprivation therapy (ADT), given the availability of methods to measure prostate-specific antigen (PSA) levels in the serum. We therefore initiated a prospective study to determine whether EMP is efficient for HRPC following ADT using changes in PSA levels as the major endpoint. METHODS: After a diagnosis of anti-androgen withdrawal syndrome had been excluded, 34 patients with HRPC who showed an elevated serum PSA level in 3 or more sequential tests following ADT were treated orally with 560 mg/day of EMP. The clinical stage and the median PSA value for inclusion in the study were D2 and 25.9 (range 6.5-540.8) ng/ml, respectively. Treatment was continued until evidence of disease progression reappeared or until severe adverse effects appeared. RESULTS: Of the 34 patients enrolled, 29 were evaluated, while the other 5 (15%) patients were discontinued due to severe gastrointestinal side effects. Seven of the 29 patients (24%) showed a decrease of 50% or greater in serum PSA levels from the initially elevated values, with the median duration of PSA response being 8.0 (range 2.2-18.8) months. Baseline PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase, performance status, and length of time of initial hormonal treatment did not correlate with the PSA response. With a median follow-up time of 20.0 (range 3.2-45.6) months, the cancer-specific survival rate at 2 years was 83% in the PSA responders and 44% in the non-responders. The PSA response was correlated with cancer-specific survival (p = 0.029). CONCLUSIONS: Following ADT one quarter of HRPC patients responded to EMP, with more than 50% of patients showing a decrease in PSA levels and an enhanced survival rate.

Thyroid hormone induces the expression of 4-1BB and activation of caspases in a thyroid hormone receptor-dependent manner.

Thyroid hormone has various effects on cell proliferation, growth and apoptosis. To gain more insight into the molecular dynamics caused by thyroid hormone, gene expression in HeLaTR cells that constitutively overexpressed the thyroid hormone receptor (TR) was analyzed. Gene expression profiling of the HeLaTR cells with an oligonucleotide microarray yielded 229 genes whose expression was significantly altered by T3. Among these genes, the expression of 4-1BB, which is known to initiate a signal cascade activating NF-kappaB, was significantly up-regulated by T3. Although treatment of the HeLaTR cells with T3 did not induce expression of NF-kappaB reporter luciferase, even in the presence of the 4-1BB-Ligand, it increased the caspase activities. An increase in the caspase activities was also observed in the HeLaTR cells transfected with 4-1BB cDNA, and the 4-1BB-Ligand further increased the caspase activities of the HeLaTR cells overexpressing the 4-1BB. Furthermore, up-regulation of 4-1BB and an increase in caspase activities also occurred in the rat FRTL cells that expressed only authentic TR. These results demonstrate that the expression of 4-1BB serves as the mediator of signals from T3 to activate caspases.