A case series of continuous paravertebral block in minimally invasive cardiac surgery.

BACKGROUND: Minimally invasive cardiac surgery (MICS), via minithoracotomy, is thought to be a fast track to extubation and recovery after surgery. For this, good coverage analgesia is essential. Epidural anesthesia, a standard technique for thoracic surgery, has high risk of complications, such as epidural abscess and spinal hematoma in open-heart surgery. Based on the hypothesis that continuous paravertebral block (CPVB), a less invasive regional anesthetic technique, is safe and effective in open-heart surgery, we applied CPVB to MICS with thoracotomy. FINDINGS: To assess whether CPVB could be used in open-heart surgery with fewer potential complications, we investigated our medical records of the 87 adult patients who underwent MICS at Akashi Medical Center, Hyogo, Japan, between March 2009 and May 2016. We collected data of CPVB-related complications, postextubation respiratory failure, duration of intubation, and other analgesic use from hospital clinical records. We observed no severe CPVB-related complications, such as hematoma, neuropathy, or abscess. PT-INR longer than 1.1 was associated with CPVB-related minor bleeding. Forty-three patients (47.4%) were extubated within 1 h after surgery, and there were no postextubation respiratory failures in any patients. CONCLUSIONS: We observed no cases of severe CPVB-related complications or postextubation respiratory failure in any of our patients who underwent MICS. Preoperative prolongation of PT-INR was associated with CPVB-related minor bleeding.

A novel Nrf2 activator from microbial transformation inhibits radiation-induced dermatitis in mice.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that regulates many antioxidants, and we have recently succeeded in obtaining a novel Nrf2 activator, RS9, from microbial transformation. RS9 is categorized as a triterpenoid, and well-known triterpenoids such as RTA 402 (bardoxolone methyl) and RTA 408 have been tested in clinical trials. RTA 408 lotion is currently being tested in patients at risk for radiation dermatitis. This prompted us to study the profiles of RS9 in the skin. All the above triterpenoids increased the level of an Nrf2-targeted gene, NADPH:quinone oxidoreductase-1, in normal human epidermal keratinocytes. Among them, the activity of RS9 was prominent; furthermore, the cellular toxicity was less compared with RTA compounds. BALB/c mice were irradiated with 30 Gy/day on Day 0, and compounds were topically applied on the back once daily from Day 1 to Day 30. Dermatitis scores peaked on Day 18, with a score of 2.6 in vehicle-treated mice, and topical applications of 0.1% RTA 402, RTA 408 and RS9 reduced the scores to 1.8, 2.0 and 1.4, respectively. Moreover, the percentage of animals with scores ≥2 was analyzed, and 0.1% RS9 suppressed the percentage from 100% to 47%. These results imply that RS9 has potential efficacy for treating radiation dermatitis.

Novel Nrf2 activators from microbial transformation products inhibit blood-retinal barrier permeability in rabbits.

BACKGROUND AND PURPOSE: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of the Nrf2 pathway seems protective for many organs, and although a well-known Nrf2 activator, bardoxolone methyl, was evaluated clinically for treating chronic kidney disease, it was found to induce adverse events. Many bardoxolone methyl derivatives, mostly derived by chemical modifications, have already been studied. However, we adopted a biotransformation technique to obtain a novel Nrf2 activator. EXPERIMENTAL APPROACH: The potent novel Nrf2 activator, RS9, was obtained from microbial transformation products. Its Nrf2 activity was evaluated by determining NADPH:quinone oxidoreductase-1 induction activity in Hepa1c1c7 cells. We also investigated the effects of RS9 on oxygen-induced retinopathy in rats and glycated albumin-induced blood-retinal barrier permeability in rabbits because many ocular diseases are associated with oxidative stress and inflammation. KEY RESULTS: Bardoxolone methyl doubled the specific activity of Nrf2 in Hepa1c1c7 cells at a much higher concentration than RS9. Moreover, the induction of Nrf2-targeted genes was observed at a one-tenth lower concentration of RS9. Interestingly, the cytotoxicity of RS9 was substantially reduced compared with bardoxolone methyl. Oral and intravitreal administration of RS9 ameliorated the pathological scores and leakage in the models of retinopathy in rats and ocular inflammation in rabbits respectively. CONCLUSION AND IMPLICATIONS: Nrf2 activators are applicable for treating ocular diseases and novel Nrf2 activators have potential as a unique method for prevention and treatment of retinovascular disease.

[Optimal catheter position for PreSep central venous oximetry catheter].

BACKGROUND & METHODS: To evaluate optimal catheter position for PreSep central venous oximetry catheter, we inserted the catheter through a sheath introducer with contamination shield and conducted its in vivo calibration in twenty-eight patients. In the event of calibration failure due to unstable signals, the catheter was advanced until calibration became possible. If SQI rose to 3 or 4 during surgery, we readjusted the catheter position to resume reliable monitoring. At the conclusion of surgery, the catheter position was checked radiologically and the distance between the catheter tip and the upper border of the clavicle was measured. RESULTS: In 70% of the patients, calibration was performed successfully when the catheter was inserted for 12-14 cm from the top of the groove between the sternal and clavicular heads of the sternocleidomastoid muscle, which led to positioning of the catheter tip 5-7 cm from the upper border of the clavicle. However, there was a considerable variation within the total patient sample and no definite correlation was found between catheter positions and patient's height. In 30% of the patient, readjustment of the catheter was required during surgery. CONCLUSIONS: Use of a sheath introducer with contamination shield seems to be useful for positioning the PreSep catheter.

Predictability of idiosyncratic drug toxicity risk for carboxylic acid-containing drugs based on the chemical stability of acyl glucuronide.

Acyl glucuronides (AGs) formed from carboxylic acid-containing drugs have been considered to be a cause of idiosyncratic drug toxicity (IDT). Chemical stability of AGs is supposed to relate to their reactivity. In this study, the half-lives of 21 AGs of carboxylic drugs in potassium phosphate buffer (KPB), human serum albumin (HSA) solution, and human fresh plasma were analyzed in relation to the IDT risk derived from these drugs. The carboxylic drugs were classified into three safety categories of "safe," "warning," and "withdrawn" in terms of their IDT risk. As for the results, the half-lives of AGs in KPB correlated with the IDT risk better than those in HSA solution or in human fresh plasma with regard to the separation of the safe drugs from the warning drugs or the withdrawn drugs. In KPB, whereas the half-lives in the safe category were 7.2 h or longer, those in the withdrawn category were 1.7 h or shorter. The classification value of the half-life in KPB, which separated the safe drugs from the withdrawn drugs was calculated to be 3.6 h by regression analysis. In conclusion, this is the first report that clearly shows the relationship between the IDT risk and chemical stability of AGs in several in vitro systems. The KPB system was considered to be the best for evaluating the stability of AGs, and the classification value of the half-life in KPB serves as a useful key predictor for the IDT risk.

A novel assay of bacterial peptidoglycan synthesis for natural product screening.

Although a large number of microbial metabolites have been discovered as inhibitors of bacterial peptidoglycan biosynthesis, only a few inhibitors were reported for the pathway of UDP-MurNAc-pentapeptide formation, partly because of the lack of assays appropriate for natural product screening. Among the pathway enzymes, D-Ala racemase (Alr), D-Ala:D-Ala ligase (Ddl) and UDP-MurNAc-tripeptide:D-Ala-D-Ala transferase (MurF) are particularly attractive as antibacterial targets, because these enzymes are essential for growth and utilize low-molecular-weight substrates. Using dansylated UDP-MurNAc-tripeptide and L-Ala as the substrates, we established a cell-free assay to measure the sequential reactions of Alr, Ddl and MurF coupled with translocase I. This assay is sensitive and robust enough to screen mixtures of microbial metabolites, and enables us to distinguish the inhibitors for D-Ala-D-Ala formation, MurF and translocase I. D-cycloserine, the D-Ala-D-Ala pathway inhibitor, was successfully detected by this assay (IC(50)=1.7 microg ml(-1)). In a large-scale screening of natural products, we have identified inhibitors for D-Ala-D-Ala synthesis pathway, MurF and translocase I.

Carbocisteine can scavenge reactive oxygen species in vitro.

BACKGROUND AND OBJECTIVE: Reactive oxygen species (ROS) play an important role in the pathogenesis of various respiratory diseases. Carbocisteine, a mucoregulatory drug, is used in the treatment of several disease states but little information is available about its scavenger effects on ROS. The present study was designed to examine the scavenger effects of carbocisteine on ROS. METHODS: The oxidation-reduction potential of carbocisteine was measured, and its scavenger effects on hypochlorous acid (HOCl), hydrogen peroxide (H(2)O(2)), hydroxyl radical (OH(*)) and peroxynitrite (ONOO(-)) were examined in cell-free conditions. The effects of carbocisteine on ROS generated from rat neutrophils, intracellular oxidative stress and release of inflammatory cytokines (IL-8 and IL-6) from IL-1 beta-induced airway epithelial cells, NCI-H292 cells, were investigated. RESULTS: Carbocisteine provided a reducing stage and showed scavenger effects on H(2)O(2), HOCl, OH(*) and ONOO(-) in cell-free conditions. Carbocisteine inhibited ROS generation from rat neutrophils, intracellular oxidative stress and release of IL-8 and IL-6 from NCI-H292 cells. N-acetyl-L-cysteine, a radical scavenger, also inhibited these events related to ROS as well as carbocisteine. CONCLUSIONS: These results suggest that carbocisteine could exert anti-inflammatory and anti-oxidant effects through directly scavenging ROS in addition to its previously known mucoregulatory effect.

Prognostic predictor with multiple fuzzy neural models using expression profiles from DNA microarray for metastases of breast cancer.

Gene expression profiling data from DNA microarray were analyzed using the fuzzy neural network (FNN) modeling method for predicting the distant metastases of breast cancer. The best model consisting of five genes was able to predict metastases of breast cancer with 94% accuracy. Furthermore, 100% accuracy was achieved by majoritarian decision using only 25 genes from five noninferior models which were constructed independently. From the constructed model, gene expression rules, which may cause distant metastases, were explicitly extracted and 60% of the metastases cases could be explained by this rule. The FNN modeling method described in this paper enables precise extraction of significant biological markers affecting prognosis without prior knowledge.