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Although northern highbush blueberry (Vaccinium corymbosum L.) fields are often fertigated using soluble or liquid fertilizers, recommendations for applying most nutrients to the crop, including K, are based on the use of granular fertilizers. The objective of the present study was to compare fertigation to granular application of K in a mature planting of Duke, a popular early season blueberry cultivar that ripens from June through July in Oregon and Washington. The plants were grown on raised beds and irrigated using two lines of drip tubing per row. Treatments were initiated in 2016 and included no K fertilizer, a single application of granular potassium sulfate (K2SO4) in April, and fertigation once a week from April to August with soluble K2SO4 or liquid potassium thiosulfate (K2S2O3). Each treatment was applied for 2 years at a total rate of 70 kg·ha−1 K per year. The plants were also fertigated with 168 and 224 kg·ha−1 N in 2016 and 2017, respectively, and 30 kg·ha−1 P per year. Although extractable soil K was initially low at the site (144 mg·kg−1), the treatments had no effect on plant dry weight, yield, fruit quality, or the concentration of K in recently expanded leaves. However, during the first year of the study, K fertigation with K2SO4 or K2S2O3 reduced soil pH and increased the concentrations of K+, Ca2+, Mn2+, and SO42− in the soil solution under the drip emitters compared with no K or granular K2SO4, whereas granular application of K2SO4 resulted in higher concentrations of K+ between the emitters than any other treatment. Fertigation also affected the concentration of K in the fruit during the first year, although in this case, the concentration was lower with K fertigation than with no K or granular applications of K2SO4. During the second year, fertigation and granular K continued to result in higher concentrations of K+ in soil solution under and between the drip emitters, respectively, but at this point, extractable soil K was higher with each of the K fertilizers than with no K. Consequently, the concentration of K in leaves sampled from entire plants in late September that year was higher with any of the K fertilizers than with no K. Potassium fertilization also altered concentrations of other nutrients in the plants, including Mg, S, B, Cu, and Mn in the leaves; Ca, Mg, and B in the fruit; Mn and Zn in the woody canes; and P, Mg, S, and Mn in the crown. In many cases, concentrations of these nutrients were higher with one or more of the K fertilizers than with no K. Thus, regardless of the application method, K2SO4 and K2S2O3 appear to be good sources for increasing availability of K and other nutrients in the plants and soil. However, the amount of K in the plants was sufficient at the site, and therefore, none of the fertilizers provided a short-term benefit to growth or fruit production in the present study.

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (

[Image: see text] Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.

Mutations in the skeletal muscle ryanodine receptor gene (RYR1) can cause susceptibility to malignant hyperthermia (MH), a potentially lethal genetic condition triggered by volatile anesthetics. MH is associated with hypermetabolism which has directed research interest into oxidative phosphorylation (OXPHOS) and muscle bioenergetics. The most common cause of MH in the United Kingdom is the c.7300G>A RYR1 variant, which is present in ~16% of MH families. Our study focuses on the MH susceptible G2435R-RYR1 knock-in mouse model, which is the murine equivalent of the human c.7300G>A genotype. Using a combination of transcriptomics, protein expression and functional analysis, we investigated adult muscle fiber bioenergetics in this mouse model. RNA sequencing data showed reduced expression of genes associated with mitochondria and fatty acid oxidation in RYR1 mutants when compared to wild-type (WT) controls. Mitochondrial function was assessed by measuring oxygen consumption rates in permeabilized muscle fibers. Comparisons between WT and homozygous G2435R-RYR1 mitochondria showed a significant increase in complex I-facilitated OXPHOS in mutant muscle. Furthermore, we observed a gene-dose specific increase in reactive oxygen species production in G2435R-RYR1 muscle fibers. Collectively these findings provide evidence of metabolic defects in G2435R-RYR1 knock-in mouse muscle under basal conditions. Differences in metabolic profile could be the result of differential gene expression in metabolic pathways, in conjunction with mitochondrial damage accumulated from chronic exposure to increased oxidative stress.

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.

We present a case of difficult anesthesia for obstetrical surgery. The case involved a morbidly obese patient requiring anesthesia for a cesarean section and was punctuated by difficult and ultimately failed neuraxial anesthesia, semi-urgent induction of general anesthesia, and management of the difficult airway.

In this paper, we propose an analytic approach based on gene set variation analysis (GSVA) and network analysis to compare different mouse inflammatory bowel disease (IBD) models and assess their pertinence to Crohn’s disease and ulcerative colitis.

A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.

A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.

OBJECTIVE Therapeutic options for brain metastases (BMs) that recur after stereotactic radiosurgery (SRS) remain limited. METHODS The authors provide the collective experience of 4 institutions where treatment of BMs that recurred after SRS was performed with stereotactic laser ablation (SLA). RESULTS Twenty-six BMs (in 23 patients) that recurred after SRS were treated with SLA (2 patients each underwent 2 SLAs for separate lesions, and a third underwent 2 serial SLAs for discrete BMs). Histological findings in the BMs treated included the following: breast (n = 6); lung (n = 6); melanoma (n = 5); colon (n = 2); ovarian (n = 1); bladder (n = 1); esophageal (n = 1); and sarcoma (n = 1). With a median follow-up duration of 141 days (range 64–794 days), 9 of the SLA-treated BMs progressed despite treatment (35%). All cases of progression occurred in BMs in which < 80% ablation was achieved, whereas no disease progression was observed in BMs in which ≥ 80% ablation was achieved. Five BMs were treated with SLA, followed 1 month later by adjuvant SRS (5 Gy daily × 5 days). No disease progression was observed in these patients despite ablation efficiency of < 80%, suggesting that adjuvant hypofractionated SRS enhances the efficacy of SLA. Of the 23 SLA-treated patients, 3 suffered transient hemiparesis (13%), 1 developed hydrocephalus requiring temporary ventricular drainage (4%), and 1 patient who underwent SLA of a 28.9-cm3 lesion suffered a neurological deficit requiring an emergency hemicraniectomy (4%). Although there is significant heterogeneity in corticosteroid treatment post-SLA, most patients underwent a 2-week taper. CONCLUSIONS Stereotactic laser ablation is an effective treatment option for BMs in which SRS fails. Ablation of ≥ 80% of BMs is associated with decreased risk of disease progression. The efficacy of SLA in this setting may be augmented by adjuvant hypofractionated SRS.

OBJECTIVE Stereotactic laser ablation (SLA) is typically performed in the setting of intraoperative MRI or in a staged manner in which probe insertion is performed in the operating room and thermal ablation takes place in an MRI suite. METHODS The authors describe their experience, in which SLA for glioblastoma (GBM) treatment was performed entirely within a conventional MRI suite using the SmartFrame stereotactic device. RESULTS All 10 patients with GBM (2 with isocitrate dehydrogenase 1 mutation [mIDH1] and 8 with wild-type IDH1 [wtIDH1]) were followed for > 6 months. One of these patients underwent 2 independent SLAs approximately 12 months apart. Biopsies were performed prior to SLA for all patients. There were no perioperative morbidities, wound infections, or unplanned 30-day readmissions. The average time for a 3-trajectory SLA (n = 3) was 436 ± 102 minutes; for a 2-trajectory SLA (n = 4) was 321 ± 85 minutes; and for a single-trajectory SLA (n = 4) was 254 ± 28 minutes. No tumor recurrence occurred within the blue isotherm line ablation zone, although 2 patients experienced recurrence immediately adjacent to the blue isotherm ablation line. Overall survival for the patient cohort averaged 356 days, with the 2 patients who had mIDH1 GBMs exhibiting the longest survival (811 and 654 days). CONCLUSIONS Multitrajectory SLA for treatment of GBM can be safely performed using the SmartFrame stereotactic device in a conventional MRI suite.

BACKGROUND Real-time magnetic resonance imaging (MRI) visualization during stereotactic needle biopsies affords several valuable benefits to the neurosurgeon, including the opportunity to visually confirm the biopsy site at the time of surgery. Until now, reported experiences with this technique have been limited to the setting of intraoperative MRI or dedicated procedural MRI suites with modified ventilation systems. OBJECTIVE To describe our experience with 11 consecutive patients who underwent real-time MRI-guided biopsy performed using SmartFrame® stereotaxis (MRI Interventions, Irvine, California) in the setting of a conventional diagnostic MRI suite. METHODS This is a case series of patients that underwent real-time MRI-guided biopsy at a single institution. RESULTS Four of the 11 lesions were previously biopsied by experienced neurosurgeons, yielding tissues that were nondiagnostic. Six of these lesions were sub-cubic centimeter in volume. One lesion was associated with aberrant venous anatomy. Two patients underwent laser thermal ablation in the same setting. There were no perioperative complications or unplanned 30-day readmission. All patients were discharged on postoperative day 1 to home. The operative time for the biopsy averaged 165 ± 24 min. Illustrative examples are reviewed. CONCLUSION Real-time MRI-guided needle biopsy can be safely performed in the setting of a conventional diagnostic MRI suite. This technique provides neurosurgeons with the opportunity to visualize and confirm the biopsy site and allows for real-time adjustments in surgical maneuvers.

A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatty acid amides: anandamide, oleoyl ethanolamide, and palmitoyl ethanolamide, in the rat, dog, and cynomolgous monkey. The elevation of the levels of these lipids in the plasma of monkeys suggests that FAAH-2 may not play a significant role in regulating plasma levels of fatty acid ethanolamides in primates.

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family. It catalyzes the hydrolysis of several endogenous biologically active lipids, including anandamide (arachidonoyl ethanolamide), oleoyl ethanolamide, and palmitoyl ethanolamide. These endogenous FAAH substrates have been shown to be involved in a variety of physiological and pathological processes, including synaptic regulation, regulation of sleep and feeding, locomotor activity, pain and inflammation. Here we describe the biochemical and biological properties of a potent and selective FAAH inhibitor, 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide (JNJ-1661010). The time-dependence of apparent IC(50) values at rat and human recombinant FAAH, dialysis and mass spectrometry data indicate that the acyl piperazinyl fragment of JNJ-1661010 forms a covalent bond with the enzyme. This bond is slowly hydrolyzed, with release of the piperazinyl fragment and recovery of enzyme activity. The lack of inhibition observed in a rat liver esterase assay suggests that JNJ-1661010 is not a general esterase inhibitor. JNJ-1661010 is >100-fold preferentially selective for FAAH-1 when compared to FAAH-2. JNJ-1661010 dose-dependently increases arachidonoyl ethanolamide, oleoyl ethanolamide, and palmitoyl ethanolamide in the rat brain. The compound attenuates tactile allodynia in the rat mild thermal injury model of acute tissue damage and in the rat spinal nerve ligation (Chung) model of neuropathic pain. JNJ-1661010 also diminishes thermal hyperalgesia in the inflammatory rat carrageenan paw model. These data suggest that FAAH inhibitors with modes of action similar to JNJ-1661010 may be useful clinically as broad-spectrum analgesics.

Efforts to improve the properties of the well studied ketooxazole FAAH inhibitor OL-135 resulted in the discovery of a novel propylpiperidine series of FAAH inhibitors that has a modular design and superior properties to OL-135. The efficacy of one of these compounds was demonstrated in a rat spinal nerve ligation model of neuropathic pain in rats.

The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.

It is widely accepted that small-molecule drugs, despite their selectivity at primary targets, exert pharmacological effects (and safety liabilities) through a multiplicity of pathways. As such, it has proved extremely difficult to experimentally assess polypharmacology in an agnostic fashion. Profiling of metabolites produced as part of physiological responses to pharmacological stimuli provides a unique opportunity to explore drug pharmacology. A total of 122 eicosanoid lipids in human whole blood were monitored from 10 different donors upon stimulation with several inducers of immunological responses and treatment with modulators of prostaglandin (PG) and leukotriene biosynthesis, including clinical and investigational molecules. Such analysis revealed differentiation between drugs nominally targeting different eicosanoid biosynthetic enzymes, or even those designed to target the same enzyme. Profiled agents, some of them marketed products, affect eicosanoid biosynthesis in ways that cannot be predicted from information on their intended targets. As an example, we used this platform to discriminate drugs based on their ability to silence PG biosynthesis in response to bacterial lipopolysaccharide, resulting in differential pharmacological activity in an in vivo model of endotoxemia. Some of the observed effects are subject to variability among individuals, indicating a potential application of this methodology to the patient stratification, based on their responses to benchmark drugs and experimental compounds read on the eicosanome via a simple blood test.

This chapter will help the reader better understand scenarios common to operating room and perioperative resource management. These include optimization of room assignments and distribution of providers, financial considerations, resident work-hour rules and restrictions, and operating room efficiency.

The ex-utero intrapartum treatment (EXIT) procedure is an uncommon operation indicated for fetal lesions with the potential to cause life-threatening airway obstruction immediately after delivery. By maintaining utero-placental circulation, the fetal airway can be evaluated and secured prior to delivery. The anesthetic goals for the EXIT procedure differ significantly from a cesarean delivery and include profound uterine relaxation, fetal anesthesia and maintenance of the maternal-fetal circulation. We present a case of an uneventful EXIT procedure and include a discussion of the anesthetic goals for this operation.

Introduction The average time spent playing video games is increasing. Prolonged immobility associated with gaming may therefore be an important risk factor for venous thromboembolism. We report a case of deep vein thrombosis associated with prolonged playing of PlayStation® games. Case presentation A 31-year-old Caucasian man, an exterior painter, presented with a three-day history of left leg pain and swelling after playing PlayStation® games for almost eight hours a day for four consecutive days. Doppler ultrasound of the left leg confirmed extensive left leg deep venous thrombosis requiring thrombolysis and anticoagulation. Conclusions Video gaming should be considered a risk factor for venous thromboembolism. Further studies are needed to estimate the degree of risk associated with prolonged periods of playing video games, and education for preventing venous thrombosis should be provided to gamers.

Background The Surgical Care Improvement Project (SCIP) was designed to reduce perioperative complications. We describe our institutional experience in 6 major areas: surgical site infection, venous thromboembolism prevention, use of perioperative β-blockade, serum glucose level greater than 200 mg/dL, normothermia, and the use of electric razors for hair removal. Methods This was a retrospective review of surgical cases. Evidence-based training and standardization of system and process were undertaken. Compliance with SCIP guidelines was determined. Results Overall SCIP compliance improved from 80% to 94% over a 2-year period. Standardized antibiotic dosing times improved compliance to more than 90%. Appropriate preoperative antibiotic choice improved to 100%. Cessation of antibiotics postoperatively within 24 hours remains a difficult task. Venous thromboembolism prophylaxis has been difficult to achieve because of postoperative bleeding concerns. Administration of β-blockers has remained one of the most difficult problems to correct because of the multiplicity of avenues by which a patient may arrive to the operating suite. Conclusions Achievement of the SCIP goals is a formidable, but achievable, process requiring individual, cultural, systems, and institutional changes to achieve success.

Cannabinoid ligands have been shown to be anti-nociceptive in animal models of acute and chronic pain by acting at the two known cannabinoid receptors, cannabinoid-1 receptor (CB-1) and cannabinoid-2 receptor (CB-2). A major concern with the use of cannabinoids for pain relief is that they activate receptors at sites other than those involved in the transmission of nociceptive stimuli. An alternative approach is to target the naturally occurring endocannabinoids, such as anandamide (AEA), 2-arachidonylglycerol (2-AG) and N -arachidonylglycine ( N -AG). However in vivo results obtained with these compounds appear to be weak, most probably due to their rapid degradation and subsequent short half-life. The predominant enzyme responsible for the hydrolysis of anandamide (and some other endocannabinoids) in the brain is fatty acid amide hydrolase (FAAH). Recently, the α-ketoheterocycle OL135 has been synthesized and shown to be a highly potent and selective inhibitor of FAAH with efficacy in pain models in vivo . In the present study, we have adapted the mild thermal injury (MTI) model of acute pain for the mouse and pharmacologically characterized this model by showing significant reversal of the tactile allodynia by morphine (3, 5 and 10 mg kg −1 s.c.), gabapentin (100 and 300 mg kg −1 i.p.), ibuprofen (100 mg kg −1 i.p.) and OL135 (10, 30 and 100 mg kg −1 i.p.). Furthermore we have demonstrated, using this model, that a subtherapeutic dose of OL135 can enable the endocannabinoids AEA and 2-AG, but not N -AG to be active at doses where they are otherwise nonanalgesic (20 mg kg −1 i.p.). The implications of this model in the study of pain in mice, and the therapeutic potential of FAAH inhibition to provide analgesia without the undesirable side effects of direct agonism of cannabinoid receptors are discussed.

Hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels contribute to rhythmic spontaneous activity in the heart and CNS. Ectopic spontaneous neuronal activity has been implicated in the development and maintenance of acute and chronic hyperalgesia, allodynia and spontaneous pain. Previously, we documented that systemic administration of ZD7288, a specific blocker of pacemaker current (I(h)), decreased ectopic activity in dorsal root ganglion (DRG) and reversed tactile allodynia in spinal nerve ligated (SNL) rats [Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM, Dubin AE (2003) Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J Neurosci 23:1169-1178]. Spontaneous pain is the chief clinical manifestation of peripheral nerve injury; however, a role for I(h) in spontaneous pain has not been described. Here, in further rat studies, we report that systemic administration of ZD7288 reversed spontaneous pain induced by mild thermal injury (MTI) and tactile allodynia induced by SNL and MTI. In contrast, ZD7288 did not reduce thermal hyperalgesia. An important locus of action appears to be in the skin since intraplantar (local) administration of ZD7288 completely suppressed tactile allodynia arising from MTI and SNL and reduced spontaneous pain due to MTI. Immunohistochemical staining of plantar skin sections detected HCN1-HCN4 expression in mechanosensory structures (e.g., Meissner's corpuscles and Merkel cells). Collectively, these data suggest that expression and modulation of I(h) in the peripheral nervous system, including specialized sensory structures, may play a significant role in sensory processing and contribute to spontaneous pain and tactile allodynia.

1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. 2 Elevated brain concentrations of anandamide (350 pmol g(-1) of tissue vs 60 pmol g(-1) in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg(-1)) i.p. 15 min prior to 20 mg kg(-1) i.p. anandamide. 3 Predosing rats with OL135 (2-60 mg kg(-1) i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg(-1) intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains. 4 OL135 (100 mg kg(-1) i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH(+/+)mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH(-/-) mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED(50) between 6 and 9 mg kg(-1). The plasma concentration at the ED(50) in both models was 0.7 microM (240 ng ml(-1)). 6 In the rat SNL model, coadministration of the selective CB(2) receptor antagonist SR144528 (5 mg kg(-1) i.p.), with 20 mg kg(-1) OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB(1) antagonist SR141716A (5 mg kg(-1) i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg(-1) i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg(-1)) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg(-1), i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.

High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.

Abnormal spontaneous firing is well described in axotomized sensory neurons and likely contributes to nerve injury-induced pain. The hyperpolarization-activated current I h initiates spontaneous, rhythmic depolarization in the sinoatrial node and central neurons. This study was undertaken to investigate the possible contribution of I h to primary afferent ectopic discharge and pain behavior in nerve-injured rats. Nerve injury was produced by tight ligation of lumbar spinal nerves (L5/6). Two weeks later, rats showed marked mechanical allodynia. Withdrawal thresholds were measured before and after administration of saline or the specific I h antagonist ZD7288 (1, 3, or 10 mg/kg, intraperitoneally). ZD7288 dose-dependently reversed mechanical allodynia. In a second experiment, we performed both in vivo and in vitro extracellular single unit recordings from teased dorsal root fascicles. Intravenous infusion (2.5 or 5 mg/kg) of ZD7288 during a period of 10 minutes significantly blocked ectopic discharges in vivo. Perfusion (25 to 100 μmol/L) of ZD7288 for 5 minutes in vitro almost completely blocked ectopic discharges from large myelinated fibers (Aβ) while partially suppressing ectopic discharge from thinly myelinated fibers (Aδ). We conclude from these data that in axotomized sensory neurons, a ZD7288-sensitive current contributes to spontaneous discharges in myelinated fibers. Thus, I h might substantially contribute to the pathophysiology of nerve injury-related neuropathic pain. Perspective The current study investigated the mechanism of abnormal spontaneous discharges (ectopic discharges) from axotomized sensory afferents. Ectopic discharges are a main driving source of nerve injury-induced neuropathic pain. Understanding the mechanism of ectopic discharges and identifying how to control them will be useful toward developing new therapies.

Cytokine growth factors of the interleukin (IL)-6 family have recently been shown to play an important role in central nervous system (CNS) development, repair, and inflammation. These cytokines, which interact via specific membrane receptors, share a signal-transducing receptor subunit, glycoprotein 130 (gp130). Gp130 is expressed by motoneurons in the gray matter of the rat spinal cord and by several brainstem nuclei that project to the spinal cord including the red, reticular, and vestibular nuclei. In this study, we examined whether stimulation of gp130 signaling, with the use of grafts of fibroblasts genetically modified to deliver the fusion protein, hyper-IL-6 (H-IL-6), which consists of the cytokine growth factor, IL-6, and its alpha receptor, would elicit growth of injured spinal cord axons. Particular emphasis was placed on examining the potentially competing effects of growth factor versus proinflammatory influences of H-IL-6 in the context of spinal cord injury. Our results demonstrated that grafts delivering H-IL-6 induce a sixfold increase in the number of neutrophils (P < 0.05) and a twofold increase in the areas of spinal tissue occupied by macrophages and activated microglia (P < 0.01) at the site of the spinal cord injury when compared with control grafts. Of note, this augmentation in inflammatory cell infiltration correlated with a significant twofold increase in lesion size (P < 0.05) and a fourfold reduction in axonal growth (P < 0.01) at the lesion site. Thus, potential neurotrophic properties of this cytokine family of growth factors must be balanced against their inflammatory properties when considering therapeutic application to CNS injury.

A full-length cDNA coding for common carp diazepam-binding inhibitor (DBI)/endozepine (EP)/acyl-CoA-binding protein (ACBP) was isolated and sequenced. The deduced DBI/EP/ACBP is comprised of 87 amino acids (including initiating methionine) without possessing a signal peptide. Common carp DBI/EP/ACBP displays 77%, 78%, 70%, 63%, 61% and 45% identity with human, bovine, rat, frog, duck and yeast DBI/EP/ACBP, respectively.

Flow through pump components, such as an inducer and an impeller, is efficiently simulated by solving the incompressible Navier-Stokes equations. The solution method is based on the pseudocompressibility approach and uses an implicit-upwind differencing scheme together with the Gauss-Seidel line relaxation method. Current computations use one-equation Baldwin-Barth turbulence model which is derived from a simplified form of the standard k-epsilon model equations. The resulting computer code is applied to the flow analysis inside a generic rocket engine pump inducer, a fuel pump impeller, and SSME high-pressure fuel turbopump impeller. Numerical results of inducer flow are compared with experimental measurements. Flow analyses at 80-, 100-, and 120-percent of design conditions are presented.

A numerical method is developed for solving the incompressible Navier-Stokes equations using the concept of pseudocompressibility. A lower-upper symmetric-Gauss-Seidel implicit scheme is developed for three-dimensional incompressible viscous flow computations. The present algorithm offers additional advantages when solving the flow equations with source terms. Complete vectorizability of the algorithm on oblique planes of sweep in three-dimensions is accomplished in a new flow solver, INS3D-LU code. Spatial differencing is a second-order accurate semi-discrete finite-volume method augmented by a third-order accurate numerical dissipation model which is based on spectral-radii. Comparison of numerical solutions for a curved duct with experimental data shows good agreement. The method is applied to calculate the inducer flow of the Space Shuttle Main Engine turbopump.