Predicting Neuroinflammation in Morphine Tolerance for Tolerance Therapy from Immunostaining Images of Rat Spinal Cord.

Long-term morphine treatment leads to tolerance which attenuates analgesic effect and hampers clinical utilization. Recent studies have sought to reveal the mechanism of opioid receptors and neuroinflammation by observing morphological changes of cells in the rat spinal cord. This work proposes a high-content screening (HCS) based computational method, HCS-Morph, for predicting neuroinflammation in morphine tolerance to facilitate the development of tolerance therapy using immunostaining images for astrocytes, microglia, and neurons in the spinal cord. HCS-Morph first extracts numerous HCS-based features of cellular phenotypes. Next, an inheritable bi-objective genetic algorithm is used to identify a minimal set of features by maximizing the prediction accuracy of neuroinflammation. Finally, a mathematic model using a support vector machine with the identified features is established to predict drug-treated images to assess the effects of tolerance therapy. The dataset consists of 15 saline controls (1 µl/h), 15 morphine-tolerant rats (15 µg/h), and 10 rats receiving a co-infusion of morphine (15 µg/h) and gabapentin (15 µg/h, Sigma). The three individual models of astrocytes, microglia, and neurons for predicting neuroinflammation yielded respective Jackknife test accuracies of 96.67%, 90.00%, and 86.67% on the 30 rats, and respective independent test accuracies of 100%, 90%, and 60% on the 10 co-infused rats. The experimental results suggest that neuroinflammation activity expresses more predominantly in astrocytes and microglia than in neuron cells. The set of features for predicting neuroinflammation from images of astrocytes comprises mean cell intensity, total cell area, and second-order geometric moment (relating to cell distribution), relevant to cell communication, cell extension, and cell migration, respectively. The present investigation provides the first evidence for the role of gabapentin in the attenuation of morphine tolerance from phenotypic changes of astrocytes and microglia. Based on neuroinflammation prediction, the proposed computer-aided image diagnosis system can greatly facilitate the development of tolerance therapy with anti-inflammatory drugs.

Anesthetic premedication: new horizons of an old practice.

The practice of anesthetic premedication embarked upon soon after ether and chloroform were introduced as general anesthetics in the middle of the 19(th) century. By applying opioids and anticholinergics before surgery, the surgical patients could achieve a less anxious state, and more importantly, they would acquire a smoother course during the tedious and dangerous induction stage. Premedication with opioids and anticholinergics was not a routine practice in the 20(th) century when intravenous anesthetics were primarily used as induction agents that significantly shorten the induction time. The current practice of anesthetic premedication has evolved into a generalized scheme that incorporates several aspects of patient care: decreasing preoperative anxiety, dampening intraoperative noxious stimulus and its associated neuroendocrinological changes, and minimizing postoperative adverse effects of anesthesia and surgery. Rational use of premedication in modern anesthesia practice should be justified by individual needs, the types of surgery, and the anesthetic agents and techniques used. In this article, we will provide our readers with updated information about premedication of surgical patients with a focus on the recent application of second generation serotonin type 3 antagonist, antidepressants, and anticonvulsants.

FRKAS: knowledge acquisition using a fuzzy rule base approach to insight of DNA-binding domains/proteins.

Numerous prediction methods of DNA-binding domains/proteins were proposed by identifying informative features and designing effective classifiers. These researches reveal that the DNA-protein binding mechanism is complicated and existing accurate predictors such as support vector machine (SVM) with position specific scoring matrices (PSSMs) are regarded as black-box methods which are not easily interpretable for biologists. In this study, we propose an ensemble fuzzy rule base classifier consisting of a set of interpretable fuzzy rule classifiers (iFRCs) using informative physicochemical properties as features. In designing iFRCs, feature selection, membership function design, and fuzzy rule base generation are all simultaneously optimized using an intelligent genetic algorithm (IGA). IGA maximizes prediction accuracy, minimizes the number of features selected, and minimizes the number of fuzzy rules to generate an accurate and concise fuzzy rule base. Benchmark datasets of DNA-binding domains are used to evaluate the proposed ensemble classifier of 30 iFRCs. Each iFRC has a mean test accuracy of 77.46%, and the ensemble classifier has a test accuracy of 83.33%, where the method of SVM with PSSMs has the accuracy of 82.81%. The physicochemical properties of the first two ranks according to their contribution are positive charge and Van Der Waals volume. Charge complementarity between protein and DNA is thought to be important in the first step of recognition between protein and DNA. The amino acid residues of binding peptides have larger Van Der Waals volumes and positive charges than those of non-binding ones. The proposed knowledge acquisition method by establishing a fuzzy rule-based classifier can also be applicable to predict and analyze other protein functions from sequences.

Prediction and analysis of protein solubility using a novel scoring card method with dipeptide composition.

BACKGROUND: Existing methods for predicting protein solubility on overexpression in Escherichia coli advance performance by using ensemble classifiers such as two-stage support vector machine (SVM) based classifiers and a number of feature types such as physicochemical properties, amino acid and dipeptide composition, accompanied with feature selection. It is desirable to develop a simple and easily interpretable method for predicting protein solubility, compared to existing complex SVM-based methods. RESULTS: This study proposes a novel scoring card method (SCM) by using dipeptide composition only to estimate solubility scores of sequences for predicting protein solubility. SCM calculates the propensities of 400 individual dipeptides to be soluble using statistic discrimination between soluble and insoluble proteins of a training data set. Consequently, the propensity scores of all dipeptides are further optimized using an intelligent genetic algorithm. The solubility score of a sequence is determined by the weighted sum of all propensity scores and dipeptide composition. To evaluate SCM by performance comparisons, four data sets with different sizes and variation degrees of experimental conditions were used. The results show that the simple method SCM with interpretable propensities of dipeptides has promising performance, compared with existing SVM-based ensemble methods with a number of feature types. Furthermore, the propensities of dipeptides and solubility scores of sequences can provide insights to protein solubility. For example, the analysis of dipeptide scores shows high propensity of α-helix structure and thermophilic proteins to be soluble. CONCLUSIONS: The propensities of individual dipeptides to be soluble are varied for proteins under altered experimental conditions. For accurately predicting protein solubility using SCM, it is better to customize the score card of dipeptide propensities by using a training data set under the same specified experimental conditions. The proposed method SCM with solubility scores and dipeptide propensities can be easily applied to the protein function prediction problems that dipeptide composition features play an important role. AVAILABILITY: The used datasets, source codes of SCM, and supplementary files are available at http://iclab.life.nctu.edu.tw/SCM/.

Preoperative gabapentin prevents intrathecal morphine-induced pruritus after orthopedic surgery.

BACKGROUND: Pruritus is the most common side effect of intrathecal morphine. Gabapentin is an anticonvulsant and had been reported to be effective in some chronic pruritus conditions. Its effect in intrathecal morphine-induced pruritus has not yet undergone an evaluation. METHODS: We randomly allocated 86 patients scheduled for lower limb surgery under spinal anesthesia into two equal groups that received either gabapentin 1200 mg or placebo 2 h before operation in a prospective, double-blind manner. All patients received an intrathecal injection of 15 mg of 0.5% isobaric bupivacaine and 0.2 mg preservative-free morphine. Pruritus was evaluated at 3, 6, 9, 12, and 24 h after intrathecal morphine administration. RESULTS: The incidence of pruritus was significantly more frequent in the placebo group compared with the gabapentin group (77.5% vs 47.5%; P = 0.01). The onset time of pruritus in the gabapentin group (6.2 +/- 1.8 h) was significantly delayed compared with that in the placebo group (3.1 +/- 0.8 h) (P < 0.0001). The severity of pruritus was significantly more in the placebo group compared with the gabapentin group at 3 and 6 h after intrathecal morphine injection. CONCLUSION: Preoperative gabapentin prevents pruritus induced by intrathecal morphine in patients undergoing lower limb surgery with spinal anesthesia.

Closed-circuit isoflurane-based anesthesia provides better fast-tracking anesthesia than fentanyl/propofol-based anesthesia for off-pump coronary artery bypass graft surgery.

BACKGROUND: In recent years, low-dose fentanyl combined with short-acting hypnotic drug has been thought to be better than traditional high-dose fentanyl in cardiac anesthesia. On the other hand, the practice of closed-circuit inhaled anesthesia offers many advantages, including hemodynamic stability, maintenance of adequate anesthesia depth and early recovery. This study sought to evaluate the effect of closed-circuit isoflurane-based anesthesia (CIA) and fentanyl/propofol-based anesthesia (FPA) on off-pump coronary artery bypass graft (OPCABG) surgery. METHODS: Fifty patients scheduled for elective OPCABG surgery were enrolled and randomly assigned to receive either CIA (n = 25) or FPA (n = 25). In the CIA group, anesthesia was induced with fentanyl 2 microg/kg and midazolam 0.05 mg/kg, followed by 2% isoflurane in oxygen (oxygen flow rate = 3 L/min) via mask ventilation for 30 min. Pancuronium 0.1-0.15 mg/kg was given thereafter to facilitate endotracheal intubation. Anesthesia was maintained by isoflurane in a minimal oxygen flow of 300 mL/min, with the vaporizer adjusted to deliver 3%-5% concentration. In the FPA group, anesthesia was induced with fentanyl 10-15 microg/kg and midazolam 0.05 mg/kg; and pancuronium 0.1-0.15mg/kg was used for endotracheal intubation. Anesthesia was maintained by propofol 2-6 mg/kg/hr and fentanyl 1-2 microg/kg/hr, and an incremental bolus of i.v. propofol 20 mg was given if the patient's mean blood pressure (MBP) exceeded 85 mmHg. An inotropic agent was given if the patient's MBP dropped below 65 mmHg or if the patient experienced a decrease in MBP greater than 20% of the preinduction value. The time of extubation, length of stay in the intensive care unit, and inotropic requirements were recorded. RESULTS: The patients in the CIA group were extubated earlier than those in the FPA group (281.3 +/- 32.5 min versus 311.3 +/- 38.5 min, respectively; P < 0.05), although there was no statistical difference in the length of stay in the intensive care unit (29.6 +/- 4.8 hr versus 30.1 +/- 7.6 hr, respectively; P = 0.4). The use of inotropic agent in the CIA group was less than in the FPA group (16% vs. 56%, P < 0.01). Dopamine requirement was less in the CIA group than in the FPA group (0.8 +/- 0.3 vs. 3.7 +/- 0.4 microg/kg/min, respectively; P < 0.01). CONCLUSIONS: These results suggest that CIA, as compared with FPA, provides a significant reduction in the time to extubation after OPCABG surgery with less use of inotropic agents.

ESVM: evolutionary support vector machine for automatic feature selection and classification of microarray data.

An optimal design of support vector machine (SVM)-based classifiers for prediction aims to optimize the combination of feature selection, parameter setting of SVM, and cross-validation methods. However, SVMs do not offer the mechanism of automatic internal relevant feature detection. The appropriate setting of their control parameters is often treated as another independent problem. This paper proposes an evolutionary approach to designing an SVM-based classifier (named ESVM) by simultaneous optimization of automatic feature selection and parameter tuning using an intelligent genetic algorithm, combined with k-fold cross-validation regarded as an estimator of generalization ability. To illustrate and evaluate the efficiency of ESVM, a typical application to microarray classification using 11 multi-class datasets is adopted. By considering model uncertainty, a frequency-based technique by voting on multiple sets of potentially informative features is used to identify the most effective subset of genes. It is shown that ESVM can obtain a high accuracy of 96.88% with a small number 10.0 of selected genes using 10-fold cross-validation for the 11 datasets averagely. The merits of ESVM are three-fold: (1) automatic feature selection and parameter setting embedded into ESVM can advance prediction abilities, compared to traditional SVMs; (2) ESVM can serve not only as an accurate classifier but also as an adaptive feature extractor; (3) ESVM is developed as an efficient tool so that various SVMs can be used conveniently as the core of ESVM for bioinformatics problems.

Closed-circuit anesthesia prolongs the neuromuscular blockade of rocuronium.

BACKGROUND: Volatile anesthetics are known to potentiate the neuromuscular blocking effect of nondepolarizing muscle relaxants. The influences of anesthetic techniques, closed-circuit anesthesia (CCA) and high flow semi-closed anesthesia (SCA), on the neuromuscular blockade of rocuronium has not yet been studied in detail. This study was purposed to compare the effects of isoflurane conveyed in minimal flow (CCA) and in high flow (SCA) on the neuromuscular blockade of rocuronium. METHODS: Fifty females scheduled for elective laparoscopic gynecological surgery were enrolled for study and randomly assigned to receive either CCA (n = 25) or SCA (n = 25). Anesthesia was induced with fentanyl 2 micrograms/kg, thiopental 5 mg/kg and rocuronium 0.6 mg/kg. Two percent isoflurane in high O2 flow (3 l/min) was given for 10 min to all patients initially to wash isoflurane in the functional residual capacity of both lungs and the breathing circuit. After the wash in, for CCA group, the O2 flow was reduced to 300 ml/min with isoflurane vaporizer setting adjusted to 3-5% for anesthesia maintenance, while for SCA group, anesthesia was maintained with 1.5-2% isoflurane in 3 l/min O2 flow throughout the surgery. Electromyogram was used to determine neuromuscular blockade. Rocuronium (0.15 mg/kg) was given to maintain muscle relaxation when T1 reached 25% of control. We maintained the anesthetic depth until the recordings of T1 twitch response which reached 75% was completed. Onset time, duration, recovery index and intubating conditions were recorded. The hemodynamic parameters and the inhaled/exhaled concentrations were also measured every 15 min after skin incision in both groups. RESULTS: The onset time and intubating conditions were similar in both groups. In comparison with SCA group, longer clinical durations (54.1 +/- 14.4 vs. 45.4 +/- 9.2 min, P < 0.05), longer durations of maintained dose (41.1 +/- 11.1 vs. 30.2 +/- 8.6 min, P < 0.01) and longer recovery index (34.2 +/- 10.7 vs. 20.9 +/- 5.4 min, P < 0.0001) were observed in CCA group. CONCLUSIONS: We conclude that CCA may further prolong the neuromuscular blocking effect of rocuronium than SCA.

A lethal pulmonary embolism during percutaneous vertebroplasty.

IMPLICATIONS: This case report describes a fatal cardiac arrest during percutaneous vertebroplasty. This serves to remind us that life threatening intraoperative pulmonary embolism may occur in this minimal invasive procedure. Surgical precautions and invasive cardiovascular monitoring may be required in high-risk patients.

Epidural morphine delays the onset of tourniquet pain during epidural lidocaine anesthesia.

UNLABELLED: We conducted a randomized, double-blinded study to examine the onset time of tourniquet pain during epidural lidocaine anesthesia either with or without morphine in the epidural solution. Forty-five patients undergoing knee surgery with a thigh tourniquet were randomly allocated into 3 groups of 15 patients each: epidural morphine (EM; epidural administration of 17 mL of 2% lidocaine plus 2 mg of morphine, followed by IV injection of 0.2 mL of normal saline), IV morphine (IVM; 17 mL of 2% lidocaine plus 0.2 mL of normal saline, followed by IVM 2 mg IV), and control (17 mL of 2% lidocaine plus 0.2 mL of normal saline, followed by 0.2 mL of normal saline IV). The onset time of tourniquet pain was recorded. The level of sensory block was determined by the pinprick method at the occurrence of tourniquet pain. Hemodynamic changes and side effects of EM were also recorded. The onset time of tourniquet pain from both the epidural injection and the tourniquet inflation were significantly longer in the EM group (103 +/- 15 min and 80 +/- 15 min, respectively) compared with the IVM group (74 +/- 12 min and 50 +/- 12 min, respectively; P < 0.05) and the Control group (67 +/- 9 min and 45 +/- 9 min, respectively; P < 0.05). The level of sensory block at the onset of tourniquet pain and hemodynamic changes were not different among the three groups. Only two and three patients in the EM group complained of nausea/vomiting and pruritus, respectively. Respiratory depression was not observed in any patient. We conclude that epidural injection of the mixture of 2 mg of morphine and 2% lidocaine solution delayed the onset of tourniquet pain during epidural lidocaine anesthesia without significant morphine-related side effects. IMPLICATIONS: We examined the effect of epidural morphine on the onset of tourniquet pain during epidural lidocaine anesthesia. We found that the addition of 2 mg of morphine to epidural 2% lidocaine significantly delayed the onset of tourniquet pain without increasing morphine-related side effects.