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Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated auranofin resistant T. gondii lines through chemical mutagenesis to identify the molecular target of this drug. Resistant clones were confirmed with a competition assay using wild-type T. gondii expressing yellow fluorescence protein (YFP) as a reference strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of our resistant lines. Subsequent whole genomic sequencing analysis (WGS) did not reveal a consensus resistance locus, although many have point mutations in genes encoding redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient to confer resistance when introduced into wild-type parasites. Resistant clones accumulated less ROS than their wild type counterparts. Our results demonstrate that resistance to auranofin in T. gondii enhances its ability to abate oxidative stress through diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin anti-parasitic activity as disruption of redox homeostasis.

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Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). 13 C magnetic resonance spectroscopy (MRS) during [1-13 C]glucose i.v. infusion was employed to detect 13 C incorporation into whole-brain glycogen in male Goto-Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1-13 C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1-13 C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (Tmax ) and a tendency for reduced cerebral metabolic rate of glucose (CMRglc ; -29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography-mass spectrometry was employed to measure regional 13 C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes-induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism.

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Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

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The aim of this study was to compare the feasibility and efficacy between two techniques of ultrasound-guided lateral femoral cutaneous nerve with or without locating the nerve. The study enrolled 106 patients undergoing knee surgery who received 5 ml of 1% mepivacaine immediately under the inguinal ligament 1 to 2 cm medial to the anterior superior iliac spine (subinguinal technique) or around the lateral femoral cutaneous nerve located (nerve-targeting technique). The time required to perform the block and the onset time of the block were similar for both techniques. However, a significantly higher percentage of patients obtained loss of pinprick sensation on the lateral thigh within 10 minutes with the subinguinal technique than with the nerve-targeting technique. The findings suggest that ultrasound-guided lateral femoral cutaneous nerve blocks can be easily performed and that injecting local anaesthetic immediately under the inguinal ligament rather than around the nerve itself blocks the nerve more reliably.

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We compared haemodynamic changes following induction of anaesthesia with propofol during tracheal intubation with and without epidural anaesthesia. Nineteen patients were divided into two groups to receive epidurally administered saline (Group C) or lidocaine 1.5% (Group E). The propofol infusion was started to produce blood concentrations of 3 microg.ml(-1), and following fentanyl and vecuronium administration, tracheal intubation was performed. Mean arterial blood pressure (MBP), heart rate (HR), Bispectral index and effect-site propofol concentration were recorded. Time to loss of consciousness was significantly shorter in Group E than in Group C. The effect-site propofol concentration at loss of consciousness was significantly lower in Group E than in Group C. MBP and HR were significantly lower following propofol induction in both groups, and were significantly increased following intubation in Group C but not in Group E. In conclusion, epidural anaesthesia did not produce profound hypotension following induction of anaesthesia and produced a reduction in the haemodynamic response to tracheal intubation during a target controlled infusion of propofol.

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A 71-yr-old female with a malignant thyroid tumour was to undergo thyroidectomy under general anaesthesia. Preoperative chest x-ray and plain computed tomography (CT) showed severe tracheal stenosis. Three-dimensional figures of the trachea and a virtual bronchoscopic movie were obtained from multi-slice CT to evaluate the stenotic region and to simulate fibroscopic tracheal intubation, respectively. After induction of general anaesthesia with propofol, a tracheal tube was successfully passed through the stenotic region under the guide of a fibroscope as simulated in the virtual movie. We conclude that multi-slice CT is useful for preoperative airway evaluation for patients with stenosis and distortion of the trachea.

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(Midazolam is often used for premedication; it is known to promote vasodilation and may therefore affect redistribution of heat during surgery. We examined the effect of pre-operative administration of midazolam on the development of intra-operative hypothermia. Forty-five patients were randomly allocated to one of three groups to receive no premedication (Group C), IM midazolam 0.04 mg.kg(-1) (Group M1) or 0.08 mg.kg(-1) (Group M2) 30 min prior to anaesthesia. Sedation levels were assessed, and then general anaesthesia was induced and maintained using propofol and fentanyl. During surgery, core temperature, which was similar for the three groups prior to induction of anaesthesia, decreased significantly less in the midazolam groups M1 and M2 compared to the control group C. Patients who were more heavily sedated prior to induction of anaesthesia, had significantly lower core temperatures peri-operatively than those who were less sedated, and core temperatures in unpremedicated patients fell to significantly lower levels during surgery than those who were drowsy. We conclude that pre-operative administration of midazolam produces an effect on the development of peri-operative hypothermia. We found that moderate pre-operative sedation reduces the peri-operative heat loss, possibly by affecting core-to-peripheral heat distribution.

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BACKGROUND: The authors compared the effects of epidural anaesthesia with lidocaine 1% and lidocaine 2% on haemodynamic variables, sevoflurane requirements, and stress hormone responses during surgery under combined epidural/general anaesthesia with bispectral index score (BIS) kept within the range 40-50. METHODS: Thirty-three patients undergoing lower abdominal surgery were randomly divided into two groups to receive lidocaine 1% or 2% by epidural with sevoflurane general anaesthesia. Sevoflurane was adjusted to achieve a target BIS of 40-50 during maintenance of anaesthesia with nitrous oxide 60% in oxygen. Measurements included the inspired (FI(SEVO)) and the end-tidal sevoflurane concentrations (E'(SEVO)), blood pressure (BP), and heart rate (HR) before surgery and every 5 min during surgery for 2 h. Plasma samples were taken immediately before and during surgery for measurements of catecholamines, cortisol, and lidocaine. RESULTS: During surgery, both groups were similar for HR, BP and BIS, but FI(SEVO) and E'(SEVO) were significantly higher and more variable with lidocaine 1% than with 2%. Intraoperative plasma concentrations of epinephrine and cortisol were found to be higher with lidocaine 1% as compared with 2%. CONCLUSIONS: To maintain BIS of 40-50 during combined epidural/general anaesthesia for lower abdominal surgery, sevoflurane concentrations were lower and less variable with lidocaine 2% than with 1%. In addition, the larger concentration of lidocaine suppressed the stress hormone responses better.

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A healthy woman developed neurological symptoms after two consecutive Caesarean sections under combined spinal and epidural anaesthesia. Amethocaine was used for spinal anaesthesia and mepivacaine for epidural anaesthesia on both occasions, and a combination of fentanyl and bupivacaine was continuously infused for pain relief after the second. Her symptoms on both occasions were similar, including pain in the buttocks of 7-11 days duration and numbness in the sacral area of 5-6 months.

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PURPOSE: Perioperative hypothermia results largely from core-to-peripheral heat redistribution. Droperidol, which is often used for premedication, promotes vasodilation, and thus may affect redistribution of heat. Accordingly, we tested the hypothesis that preanesthetic droperidol would affect perioperative hypothermia. METHODS: Twenty-three ASA physical status I patients scheduled for arthroscopic ligament reconstruction were randomly assigned to two groups to receive no premedication or im droperidol 0.1 mg x kg(-1) 30 min before anesthesia. Anesthesia was induced and maintained with propofol and fentanyl. We monitored core (tympanic) and peripheral (palm) temperatures, and skin (fingertip) blood flow for two hours after the induction of anesthesia during surgery. RESULTS: Before the induction of anesthesia, patients given droperidol were more deeply sedated than those given no premedication. Core temperature, which was similar in both groups before induction, decreased significantly more in the control than in the droperidol patients (0.75 +/- 0.34 degrees C and 0.37 +/- 0.20 degrees C, respectively, at 75 min after induction; P <0.01). Preinduction peripheral temperature and skin blood flow were lower in the control group than in the droperidol group, but the two variables became similar in both groups after induction. CONCLUSION: The results of the present study confirm our hypothesis that premedication with droperidol affects perioperative hypothermia. Droperidol may prevent core-to-peripheral heat redistribution after the induction of anesthesia.

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UNLABELLED: To examine whether adolescents and adults might develop different anesthetic distribution and hemodynamic consequences after spinal injection of 0.5% tetracaine in 7.5% or 0.75% glucose, we studied 100 ASA I or II patients who were scheduled for elective surgery to the lower limb and fulfilled the following criteria: age between 13 and 16 yr (Adolescent group, n = 40) or between 25 and 74 yr (Adult group, n = 60); height between 155 and 180 cm; and body mass index between 18 and 32 kg/m(2). Patients in each group were then randomly divided into two equal subgroups to receive spinal anesthesia with 0.5% tetracaine in either 7.5% or 0.75% glucose with 0.125% phenylephrine at the L3-4 interspace. With patients in the supine horizontal position, neural block was assessed by cold, pinprick, and touch sensation and a modified Bromage scale after the injection of the study drug. The 7.5% glucose solution produced a significantly higher and faster spread of blockade in adolescents than in adults. In contrast, there were no differences in the levels of three sensory modalities between the two age groups after the 0.75% glucose solution, which produced a lower spread of blockade than the 7.5% glucose solution in either age group. Adolescents given the 0.75% glucose solution developed a smaller maximum decrease in systolic pressure than those given the heavier solution. We conclude that adolescents may develop an extensive level of blockade more easily and quickly than adults after intrathecal hyperbaric tetracaine, but that the difference may be reduced by using a less heavy solution. IMPLICATIONS: The influence of age on the characteristics of spinal anesthesia is still controversial. Our results show that adolescents develop blockade more extensively and quickly than adults after spinal anesthesia with 0.5%tetracaine in 7.5% glucose but not after the 0.75% glucose solution.

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BACKGROUND AND OBJECTIVES: Interstitial cystitis (IC) is characterized clinically by lower abdominal pain, pain during urination, and increased frequency of urination. Treatment of the symptoms in IC remains challenging. We report effective treatment using lumbar sympathetic block for 2 patients with IC. CASE REPORT: A 63-year-old and 78-year-old woman were diagnosed with IC. Medical therapy with nonsteroidal anti-inflammatory drugs (NSAID), anticholinergics, and hydrodistention of the bladder failed to improve their symptoms. Subsequently, a continuous lumbar epidural block using 1% mepivacaine was used in these patients. A transient reduction of the symptoms in both patients was achieved. A lumbar sympathetic block with a neurolytic agent produced almost complete, and long-lasting relief of their symptoms. CONCLUSION: Lumbar sympathetic block using a neurolytic agent produced long-lasting pain relief in 2 patients with IC. Reg Anesth Pain Med 2001;26:271-273.

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The alpha-adrenergic agonists have been demonstrated to have synergistic effects with opioids and local anesthetics in animal research. The present study was performed to determine whether the addition of adrenaline improves the analgesic effects of an epidural infusion of a combination of fentanyl and bupivacaine after abdominal surgery. We studied 90 ASA 1 or 2 patients scheduled for abdominal surgery under epidural anaesthesia, with or without general anaesthesia. Patients were randomly divided into two groups to receive a postoperative epidural infusion of fentanyl 5 micrograms/ml in bupivacaine 0.2%, with or without adrenaline 5 micrograms/ml, at a rate of 2 ml/h for more than 48 hours. Postoperative pain relief was assessed using visual analog scales (VAS), both at rest and during coughing, at 2, 24, and 48 hours after surgery. The number of rescue analgesics and side-effects such as nausea, vomiting, pruritus, respiratory depression, headache, muscle weakness, and hypotension were recorded. Patients who received adrenaline (n = 40) reported significantly lower mean VAS scores than those who received no adrenaline (n = 37), both at rest at 24 hours postoperatively and during coughing at 24 and 48 hours. The number of additional analgesics and incidence of side-effects did not differ between groups. In conclusion, the results of the present study demonstrate that the addition of adrenaline to a combination of fentanyl and bupivacaine improves the quality of epidural analgesia after abdominal surgery. Under the conditions of the study, we did not detect any disadvantage from the addition of adrenaline.

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There is scant information in the literature regarding central neuraxial blockade in patients with previous back surgery or severe kyphoscoliosis. This report describes a 58-year-old female and an 84-year-old female with spinal instrumentation who presented for orthopedic surgery under neuraxial blockade. In both cases, multiple attempts of needle insertion using standard technique were unsuccessful, whereas spinal combined with epidural anesthesia was performed successfully using image intensifier. The anatomical considerations and difficulties in achieving reliable neuraxial blockade after spinal instrumentation are reviewed. Neuraxial blockade using image intensifier may provide less technical difficulty and a more reliable result in such patients.

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UNLABELLED: Transcutaneous electrical stimulation (TES), a 60-mA, 50-Hz continuous square wave, has been considered equivalent to surgical incision. We examined whether TES at a smaller current (10 mA) can be used to predict surgical anesthesia and compare the results with sensory block to cold, pinprick, and touch after the administration of spinal tetracaine. Two groups of 40 consecutive patients, 17-69 yr old and 70 yr old or older received a subarachnoid injection of 0. 5% tetracaine in 10% glucose or saline according to the type of surgery. Patients undergoing abdominal surgery received glucose solution, and those scheduled for lower extremities surgery received saline solution, and thus, the resultant four groups of patients were studied. Neural block was assessed by the loss of sensation to cold, pinprick, touch, and TES at 10 mA (T10s), and tolerance (i.e., the loss of pain or discomfort) to TES at 10 (T10p) and 60 (T60) mA. Dermatomal levels of sensory block to cold, pinprick, and touch that were cephalad to T60 varied widely. In contrast, dermatomal levels of T10s and T10p cephalad to T60 were less variable, and the difference between T10s and T60 was the smallest among all the differences in any groups. Our results demonstrate that, regardless of patient age and baricity of a local anesthetic solution, T10s is a good predictor of T60 equivalent to the dermatomal level of surgical anesthesia. IMPLICATIONS: Our results show that the loss of sensation to transcutaneous electrical stimulation at 10 mA, but not cold, pinprick, or touch, is a good predictor of the dermatomal level of block to transcutaneous electrical stimulation at 60 mA, which is considered equivalent to the dermatomal level of surgical anesthesia after the administration of spinal anesthesia.

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The extent of sensory block is determined by the cephalad distribution of the local anesthetic in the cerebrospinal fluid and uptake by neuronal tissue in sufficient amounts to produce the block. Out of many factors that have been considered to affect the distribution, this paper discusses factors involved in patient characteristics and technique of injection; the age of the patient, the volume of cerebrospinal fluid, the rate of injection, the site of injection, and the position of the patient. Each of the factors does not seem to have a major impact on the level of sensory block as compared with characteristics of anesthetic solutions discussed in the previous review, but this has not been fully understood. Recent studies have shown that the management of posture to control the level of spinal anesthesia is not so easy as previously thought. It is my conclusion that knowledge of these factors is essential in the performance of reliable and safe spinal anesthesia.

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The practitioner of spinal anesthesia needs to know the minimum block he or she can expect in order to guarantee the adequate anesthesia to perform a given operation. At the same time, the anesthesiologist needs to know the maximum extent of block, for which he or she must be prepared to avoid being caught unaware. The height of sensory block is determined by the cephalad distribution of the local anesthetic in the cerebrospinal fluid and uptake by neuronal tissue in sufficient amounts to produce the block. Out of many factors that have been considered to affect the distribution, this paper discusses characteristics of anesthetic solutions. It has been suggested that solutions that are marginally hyperbaric can safely produce relatively consistent blocks with an extent that is suitable for many operations performed under spinal anesthesia.

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UNLABELLED: This study was designed to investigate the effects of ketamine, an N-methyl-D-aspartate receptor antagonist, on the development of tolerance to morphine and morphine antinociception during intrathecal infusion. Two intrathecal catheters were implanted in the subarachnoid space in male rats under pentobarbital anesthesia. One catheter was used for the intrathecal infusion with the following solutions: morphine 1 microg x kg(-1) x hr(-1)(M1) and 5 microg x kg(-1) x hr(-1) (M5);ketamine 250 microg x kg(-1) x hr(-1) (K250); morphine plus ketamine, 1 microg x kg(-1) x hr(-1) plus 250 microg x kg(-1) x hr(-1) (M1 + K250) and 5 microg x kg(-1) x hr(-1) + 250 microg x kg(-1) x hr(-1) (M5 + K250); or saline. The other catheter was used for morphine challenge tests. The responses to noxious somatic and visceral stimuli were measured by tail flick (TF) and colorectal distension (CD) tests, respectively. Measurements were performed once a day for 7 days. Challenge tests with intrathecal morphine were performed to assess the magnitude of tolerance on Day 5 and Day 7. The antinociceptive effect was evaluated by using the percent of maximal possible effect (%MPE). Morphine infusion produced significant increases in %MPEs in TF and CD tests, while the saline and K250 infusions did not show any changes. The M1 + K250 infusion significantly increased the %MPEs in TF and CD tests, although the M1 and K250 infusions alone showed no changes. M5 + K250 enhanced the increases of %MPEs in TF and CD tests compared with the M5 infusion alone. In the challenge tests, the M1 + K250 infusion showed no significant decrease in %MPEs and TF and CD tests. The M5 + K250 infusion significantly inhibited those decreases in %MPEs, although the M5 infusion showed significant decreases in TF and CD tests. We concluded that ketamine attenuated the development of morphine tolerance to antinociceptive effects and increased the somatic and visceral antinociception of morphine. IMPLICATIONS: Intrathecally coinfused ketamine attenuated morphine tolerance to somatic and visceral antinociception and increased morphine antinociception at the spinal level. These results suggest that a combination of morphine with ketamine may have an advantage in long-term use of opioids for controlling visceral as well as somatic pain.

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