Sialorphin Potentiates Effects of [Met5]Enkephalin without Toxicity by Action other than Peptidase Inhibition.

This dose-response study investigated the effects of sialorphin on [Met5]enkephalin (ME)-induced inhibition of contractions in mouse vas deferens and antinociception in male rats. Differences were compared among combinations of three chemical peptidase inhibitors: amastatin, captopril, and phosphoramidon. The ratio of potencies of ME in mouse vas deferens pretreated with both sialorphin (100 µM) and a mixture of the three peptidase inhibitors (1 µM each) was higher than that with the mixture of peptidase inhibitors alone at any dose. Intrathecal administration of sialorphin (100-400 nmol) significantly and dose dependently increased ME (3 nmol)-induced antinociception with the mixture of three peptidase inhibitors (10 nmol each). The degree of antinociception with a combination of any two of the peptidase inhibitors (10 nmol each) in the absence of sialorphin was less than that in the presence of sialorphin (200 nmol). Pretreatment with both sialorphin (200 nmol) and the mixture of three peptidase inhibitors (10 nmol each) produced an approximately 100-fold augmentation in ME (10 nmol)-induced antinociception, but without signs of toxicity such as motor dysfunction in rats. Radioligand receptor binding assay revealed that sialorphin did not affect either binding affinity or maximal binding capacity of [d-Ala2,N-MePhe4,Gly-ol5]enkephalin. These results indicate that sialorphin potentiates the effects of ME without toxicity by a mechanism other than peptidase inhibition and with no effect on its affinity to µ-opioid receptors. SIGNIFICANCE STATEMENT: Sialorphin is regarded as an endogenous peptidase inhibitor that interacts with enkephalin-degrading enzymes. The results of these in vitro and in vivo studies confirm that sialorphin potentiates the effects of [Met5]enkephalin without toxicity by an action other than peptidase inhibition. This suggests that sialorphin offers the advantage of reducing or negating the side effects of opioid drugs and endogenous opioid peptides.

Evaluation of lead aprons and their maintenance and management at our hospital.

Lead aprons are worn by medical workers to reduce the effects of the radiation doses to which they are exposed during radiography and surgery performed with radioscopic apparatus. Regarding the management of such aprons, the Radiation Protection Section of the Japanese Society of Radiological Technology issued the "Guidelines for the Management of Lead Aprons" in 2000, and common management criteria have been set for all institutions. However, we found that the lead aprons used in operating rooms had not been closely inspected before 2014 in our hospital. Thus, we examined the extent of damage of such aprons in our operation room via computed tomography (CT) scout imaging, as well as visual and tactile inspections. Although no abnormality was detected upon visual and tactile inspections, CT images revealed that protective aprons used for 6 years or more had damaged internal radiation shields, thus risking radiation exposure. In response to these results, we fully realized the need to examine the date of the initial use of currently used lead aprons, to routinely perform visual and tactile inspections, and to regularly evaluate the extent of damage to the internal radiation shields via fluoroscopy in cooperation with the radiation management section.

Antinociceptive effect of intracerebroventricular administration of D-serine on formalin-induced pain.

PURPOSE: In a previous study using the tail-flick test, we found that intracerebroventricular administration of D-serine, an endogenous co-agonist at the glycine sites of N-methyl-D-aspartate (NMDA) receptors, elicited an antinociceptive effect on thermal nociception. The purpose of the present study was to evaluate the effect of intracerebroventricular administration of D-serine on nociception induced by tissue damage or inflammation using the formalin test. METHODS: Infusion of drugs into the third ventricle in rat was performed via indwelling cannulae. Drugs were infused at a volume of 10 µl over 2 min, and the infusion cannula was left in place for 2 min before removal. The formalin test was performed 10 min after drug administration. RESULTS: Intracerebroventricular administration of D-serine significantly and dose-dependently decreased the number of flinches in both the early and late phases in the formalin test. This antinociceptive effect was antagonized by intracerebroventricular administration of L-701,324, a selective antagonist at the glycine sites of NMDA receptors. CONCLUSION: The present data suggest that activation of NMDA receptors via glycine sites at the supraspinal level induces an antinociceptive effect on both acute and tonic pain.

Effect of Back-Cut Point Needle Bevel Angle on Deterioration After Multiple Punctures in Central Vein Simulation.

Background: Multiple needle punctures during central venous line insertion can lead to serious complications. Needle deterioration owing to repeated punctures may be a major cause. We hypothesized that there is an optimal bevel angle for a back-cut point needle that is resistant to deterioration. In this study, we examined the effect of bevel angle differences in a back-cut point needle on needle tip deterioration caused by multiple punctures. Methods: The resin target was punctured perpendicularly using back-cut point needles with three bevel angles (15°, 17°, and 19°; n=8 for each angle) at a speed of 200 mm/min. The same needle was used for ten consecutive punctures at different locations on the target. The force applied to the needle was recorded as puncture force. The puncture force waveform is bimodal. The second peak values, which formed the maximum values of puncture force, were the focus of the main analysis. We considered a 5% elevation from the first to the 10th puncture force as needle deterioration, and the average slope value of the regression line between the puncture number and puncture force was used. When the upper limit of the 95% confidence interval (CI) of the slope value was less than 0.008889, the needle was considered to be resistant to deterioration. Results: The slopes of the second peak values during 10 consecutive punctures for each bevel angle (15°, 17°, 19°) were 0.003011 ± 0.01085 [-0.006056, 0.012077], 0.006116±0.007431 [-0.000096, 0.012328], and 0.001515 ± 0.005783 [-0.003320, 0.006349], respectively (mean ± standard deviation [95% CI]). Only the 19° angle needle had a smaller upper limit of the 95% CI for a slope value of 0.008889. Conclusion: The 19° bevel angle back-cut point needle was more resistant to deterioration than the 15° and 17° angle needles were.

The effects of the early administration of sivelestat sodium, a selective neutrophil elastase inhibitor, on the postoperative course after radical surgery for esophageal cancer.

PURPOSE: The goal of this retrospective study was to evaluate the effects of perioperative administration of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, on the clinical course after radical surgery for esophageal cancer. METHODS: The effects of sivelestat on postoperative systemic inflammatory reactions and respiratory function were examined in 53 patients who underwent radical surgery for esophageal cancer between April 2004 and March 2005 with (n = 26, sivelestat group) and without (n = 27, control group) the administration of sivelestat. RESULTS: The average age in the sivelestat group was higher than that in the control group, but there were no other differences in the background factors between the two groups. The postoperative oxygenation (PaO(2)/FiO(2) ratio) did not differ between the groups, but the decrease in oxygen saturation (SpO(2)) was significantly inhibited in the sivelestat group compared with the control group (p < 0.01). A significant inhibition of the increase in the CRP level also occurred in the sivelestat group (p < 0.01). The patients in the sivelestat group were also hospitalized for shorter periods compared to those in the control group. CONCLUSION: The early administration of sivelestat to patients receiving radical surgery for esophageal cancer can inhibit postoperative systemic inflammatory reactions and it might also have a beneficial effect on the prognosis.

Free d-Amino Acids in Salivary Gland in Rat.

Free d-amino acids, which are enantiomers of l-amino acids, are found in mammals, including humans, and play an important role in a range of physiological functions in the central nervous system and peripheral tissues. Several d-amino acids have been observed in saliva, but their origin and the enzymes involved in their metabolism and catabolism remain to be clarified. In the present study, large amounts of d-aspartic acid and small amounts of d-serine and d-alanine were detected in all three major salivary glands in rat. No other d-enantiomers were detected. Protein expression of d-amino acid oxidase and d-aspartate oxidase, the enzymes responsible for the oxidative deamination of neutral and dicarboxylic d-amino acids, respectively, were detected in all three types of salivary gland. Furthermore, protein expression of the d-serine metabolic enzyme, serine racemase, in parotid glands amounted to approximately 40% of that observed in the cerebral cortex. The N-methyl-d-aspartic acid subunit proteins NR1 and NR2D were detected in all three major salivary glands. The results of the present study suggest that d-amino acids play a physiological role in a range of endocrine and exocrine function in salivary glands.

Midazolam attenuates the antinociception induced by d-serine or morphine at the supraspinal level in rats.

Our recent study has shown that the intracerebroventricular administration of d-serine, an endogenous and selective agonist for the glycine site of the N-methyl-d-aspartate receptor, alone or in combination with morphine, leads to the potentiation of antinociception on the tail-flick response. Although there is a variety of information concerning the effects of benzodiazepines on opioid-induced antinociception, little is known about the effect of benzodiazepines on the N-methyl-d-aspartate receptor agonist-induced antinociception. To clarify the analgesic interactions among the benzodiazepine/GABA(A), N-methyl-d-aspartate and opioid receptors at the supraspinal level, we investigated the effects of intracerebroventricular administration of midazolam, a benzodiazepine receptor agonist, on the antinociception evoked by the intracerebroventricular application of d-serine or morphine. The intracerebroventricular administration of midazolam alone produced hyperalgesia on the tail-flick response in a benzodiazepine receptor antagonist, flumazenil-reversible manner. The antinociception induced by the intracerebroventricular application of d-serine or morphine was attenuated by the intracerebroventricular administration of midazolam. In addition, this inhibitory effect of midazolam on the antinociception of d-serine or morphine was antagonized by the intracerebroventricular administration of flumazenil. Together with the facts that d-serine and midazolam act as selective agonists for the glycine site of the N-methyl-d-aspartate receptor and benzodiazepine/GABA(A) receptor, respectively, these observations suggest a functional interaction between the NMDA and benzodiazepine/GABA(A) receptors in the regulation of antinociception at the supraspinal level.

Activation of supraspinal NMDA receptors by both D-serine alone or in combination with morphine leads to the potentiation of antinociception in tail-flick test of rats.

Although there is a variety of information concerning the effects of the N-methyl-D-aspartate (NMDA) receptor on opioid-induced antinociception at the spinal level, little is known about the effects at the supraspinal level. To clarify the role of the NMDA receptor on the morphine-induced antinociception at the supraspinal level, we investigated the effects of the intracerebroventricular (i.c.v.) administration of D-serine, a selective agonist for the glycine site of the NMDA receptors, alone or in combination with morphine using the tail-flick test. The i.c.v. administration of D-serine, but not L-serine, alone produced a dose-dependent antinociception in the tail-flick response. D-Serine also dose-dependently potentiated the antinociceptive effect induced by the i.c.v. administration of morphine and the simultaneous administration produced an additive effect. The potentiation of the antinociception produced by both D-serine alone or in combination with morphine was dose-dependently attenuated by the i.c.v. administration of L-701,324, a selective antagonist for the glycine site of the NMDA receptors. In addition, the potentiation of the D-serine-induced antinociception was antagonized by the i.c.v. administration of naloxone, a nonselective opioid receptor antagonist. These observations, together with the fact that D-serine is an endogenous and selective co-agonist for the glycine site of the NMDA receptors, strongly suggested that the activation of the supraspinal NMDA receptors by D-serine leads to the potentiation of the antinociception in the tail-flick test and that endogenous D-serine could modulate the mu-opioid receptor mediated antinociception via the glycine site of the NMDA receptors at the supraspinal level.

Conduction analysis of cement interface temperature in total knee arthroplasty.

We applied an axisymmetric model of the tibia to a finite element method and analyzed the heat conduction from bone cement in total knee arthroplasty using numerical simulation with the finite element analysis software, ABACUS. We hypothesized the thermal necrotic map of bone. Moreover, we suggested a method for preventing thermal necrosis of bone using this simulation. We adopted an initial temperature of 32?C and a cement layer of 3mm to our simulation and analyzed heat conduction. The maximum temperature into the cement layer was 65?C and 56?C at the bone-cement interface 200 sec after the start of heat generation. Bone necrosis was observed approximately 2mm from the bone-cement interface. To thin the cement layer, the maximum temperature and bone necrotic area reduced. At a cement layer of less than 1mm no bone necrotic area was observed. To lower the initial temperature of the bone surface, the maximum temperature and bone necrotic area was also reduced. At an initial temperature of less than 28?C we did not find any bone necrosis. Even if we hypothesized pouring cold water around the prosthesis, the maximum temperature did not reduce at any time, neither did the necrotic area reduce. We should make the cement layer as thin as possible and cool the bone before cementing to prevent thermal bone necrosis.

Applicability of a compact PT-INR measuring device CoaguChek XS to perioperative management.

OBJECTIVE: In perioperative management, prothrombin time (PT) expressed as the international normalized ratio (INR) is an important preoperative test to assess bleeding risk. It is also used to assess the effect of discontinuing anticoagulant therapy, to determine whether to treat patients with vitamin K or fresh frozen plasma, and to decide whether a deep nerve block (e.g., epidural anesthesia) is needed. Compared with other devices used to measure prothrombin time, the CoaguChek XS is a smaller, lighter and more convenient-to-use PT-INR monitoring system that requires a smaller venous, skin puncture or arterial blood sample than other systems. In a surgical setting, it is often more convenient to collect arterial blood. However, the applicability of arterial blood PT-INR values has not been verified. METHODS: We evaluated the usefulness of the CoaguChek XS in anesthetic management by comparing PT-INR values for arterial blood with those of venous blood in 50 patients who were scheduled for elective surgery under general anesthesia. RESULTS: Arterial PT-INR values were well correlated with venous PT-INR values (r2 = 0.9239; regression line y = 0.9537x + 0.0505). CONCLUSION: These results indicate that the CoaguChek XS system can provide arterial PT-INR values and should be available in operating and emergency rooms.