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Print version ISSN 0034-7094On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.54 no.5 Campinas Sept./Oct. 2004
Ketamine and preemptive analgesia*
Cetamina y analgesia preemptiva
Caio Márcio Barros de Oliveira, M.D.I; Rioko Kimiko Sakata, TSA, M.D.II; Adriana Machado Issy, M.D.II; João Batista Santos Garcia, TSA, M.D.III
Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da UNIFESP
IIProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva da UNIFESP EPM
IIIProfessor Adjunto da Disciplina de Anestesiologia da UFMA
BACKAGROUND AND OBJECTIVES:
Since the finding that ketamine blocks NMDA receptors in the neurons of spinal
dorsal horn, it has been used to inhibit or decrease central sensitization triggered
by nociceptive stimulations. This study aimed at presenting pharmacological
aspects of racemic ketamine and its levogyrous compound, as well as its usefulness
for preemptive analgesia.
CONTENTS: Current preemptive analgesia concepts, pharmacological aspects of ketamine and its levogyrous compound, as well as experimental and clinical trials on ketamine and its use in preemptive analgesia are presented.
CONCLUSIONS: The efficacy of ketamine in inhibiting or decreasing central sensitization triggered by nociceptive stimulations is not totally confirmed, probably due to different study and statistical analysis methods.
Key Words: ANALGESIA, Preemptive, ANESTHETICS, Venous: ketamine
JUSTIFICATIVA Y OBJETIVOS:
Desde la descubierta de que la cetamina bloquea los receptores NMDA en los
neuronios del cuerno dorsal de la médula, ella ha sido usada para inhibir
o reducir la sensibilización central provocada por estímulos nociceptivos.
Así, este trabajo tiene por finalidad mostrar aspectos farmacológicos
de la cetamina racemica y de su compuesto levogiro y su empleo en la analgesia
CONTENIDO: Se presentan conceptos actuales sobre analgesia preemptiva, aspectos farmacológicos de la cetamina y su derivado levogiro, bien como estudios experimentales y clínicos sobre la cetamina y su uso en analgesia preemptiva.
CONCLUSIONES: Aun no está totalmente comprobada la eficacia de la cetamina en inhibir o reducir la sensibilización central provocada por estímulos nociceptivos. Probablemente eso se deba al uso de diferentes métodos de estudio y de análisis estadística.
Central sensitization has been studied in several experimental animal models by Woolf 1. Wall 2, pioneer in using the term "preemptive analgesia", has observed decreased central changes when opioids and local anesthetics were administered alone or in association before surgical incision, with decreased postoperative pain.
Studies have shown that general anesthesia promotes decreased peripheral painful impulses transmission to central nervous system, however is unable to totally inhibit them 3. So, nociceptive stimulations promote central sensitization, responsible for increased postoperative pain and analgesic consumption. Postoperative pain depends not only on surgical incision, but also on factors such as: surgery type and length, tissue injury extension and nature, drugs pharmacological activity, and additional intra and postoperative analgesia 4,5.
Preemptive analgesia aims at blocking or decreasing central sensitization and pathological pain, which is different from physiological pain for being excessively severe and induced by non-painful stimulations 6,7.
Kissin 8 has recently reported that, for adequate preemptive analgesia approach, it is critical to evaluate analgesic efficacy of a treatment and its immediate postoperative duration. For this reason, it is possible that several studies have failed in showing a preemptive effect.
Some preemptive analgesia definitions are used by different authors, making difficult the evaluation and comparison of results. Preemptive analgesia is defined in different ways: 1 - that induced before surgical stimulation; 2 - that preventing surgical incision-induced central sensitization; 3 - that preventing the establishment of central sensitization by surgical incision and postoperative inflammatory processes.
The first definition may lead to a false conclusion, because analgesia should be enough to block afferent impulses, and not be simply administered before incision.
The second concept expresses preemptive analgesia in a strict sense, considering only intraoperative nociceptive phenomena. The difference among study groups would be only with regard to agents administration timing (before or after incision). Authors who do not believe in preemptive analgesia effectiveness in general adopt this concept in their studies, which is inadequate because it excludes central neuroplasticity induced by immediate postoperative period inflammatory reaction.
The third definition is more complete and encompasses central sensitization promoted both by surgical injury and inflammatory process, involving intra and immediate postoperative periods. According to surgical nature, there is predominance of surgical stimulation or of inflammatory stimulation on neuroplasticity.
A review of the literature about postoperative analgesia has shown that preventive approach, that is, applied to any surgical procedure moment, is more adequate than preemptive approach for decreasing postoperative pain and analgesic consumption 4. For such, NMDA receptor antagonists have been considered the most effective drugs.
This study aimed at presenting pharmacological aspects of racemic ketamine and its levogyrous compound, in addition to its usefulness for preemptive analgesia.
KETAMINE - PHARMACOLOGICAL ASPECTS
Ketamine, 2-(o-chlorophenyl)-2-(methylamine)-cycloexa- none, was synthesized in 1963 by Stevens, and was used for the first time in humans in 1965, by Corssen and Domino. This liposoluble phencyclidine with molecular weight of 238 daltons and pKa of 7.5 9-13 may be clinically used in the racemic form or as levogyrous isomer S (+) ketamine).
S (+) ketamine is considered 3 to 4 times more potent than the dextrogyrous isomer (R- ketamine) for pain relief and, in equianalgesic doses produces less psychic changes and agitation than racemic and dextrogyrous forms 14-21. S(+) ketamine is twice as potent as the racemic form to prevent spinal cord central sensitization 22.
This agent has 93% bioavailability 23 and 186 minutes plasma half-life 24. For being highly liposoluble, it has a large distribution volume of approximately 3 L.kg-1. Ketamine is metabolized by liver microsomal enzymes through N-demethylation, forming norketamine. This, in turn, is hydroxilated into hydroxynorketamine. These products are conjugated to hydrosoluble glycuronide products excreted by the urine 25,26. Its plasma clearance is also relatively high, varying 890 to 1227 mL.min-1, corresponding to a short excretion half-life of 2 to 3 hours 24,27.
Although being administered through different routes (intravenous, muscular, oral, rectal and nasal), intravenous and muscular routes are most commonly used in the clinical practice because therapeutic plasma concentration is more rapidly reached 28.
After intravenous administration, maximum ketamine effects are observed in 30 to 60 seconds, and distribution half-life is relatively short (11 to 16 minutes).
Ketamine is rapidly absorbed after muscular administration, with absorption half-life of 2 to 17 minutes 24.
Ketamine acts on several receptors, including nicotinic 29, muscarinic 30, µ, d and k opioids 30-32 and changes central and peripheral nervous system sodium channels 29, monoaminergic channels and frequency-dependent calcium channels 33. Ketamine also blocks, in a non-competitive manner, NMDA receptors and the highest its dose, the highest its affinity for such receptors 34-39. S(+) ketamine has higher affinity for NMDA receptors as compared to the racemic form, in addition to being twice as potent in preventing spinal central sensitization 22.
As to cardiovascular system, ketamine increases blood pressure, heart rate and cardiac output. Equipotent S(+) ketamine dose, although lower than the racemic mixture, leads to similar hemodynamic changes 40.
There is minor respiratory system effect, and apnea after anesthetic ketamine doses (intravenous 2 mg.kg-1) is very uncommon 41.
This drug has dissociative effect and patients seem cataleptic, remaining with eyes open and maintaining several reflexes although not safely protective 41.
Ketamine-induced amnesia is less pronounced as compared to benzodiazepines. After its administration, pupils are moderately dilated and there is nystagmus. Tearing and salivation are common.
Ketamine increases brain metabolism and blood flow, as well as intracranial pressure. It produces undesirable psychological effects, especially in the postoperative period, called emergency reactions. Most common are: nightmares, extracorporeal experiences (sensation of leaving the body) and illusions. The incidence of these effects varies 5% to more than 30% after anesthetic induction doses. Age and gender are some of the factors associated to these changes. Individuals with history of psychiatric disease have more frequent episodes. High intravenous ketamine doses (> 2 mg.kg-1), at high infusion rates (> 40 mg.min-1), cause more psychomimetic effects 25.
Ketamine plays an important rote in Anesthesiology for its bronchodilator and sympathomimetic properties. Currently, ketamine-induced psychic effects are still major obstacles for its comprehensive clinical use 42.
This drug may be used in patients with respiratory or cardiovascular system disorders, except for ischemic cardiomyopathy. It may be used in patients with chronic obstructive pulmonary disease and bronchial hyper-reactivity 43. It depresses myocardium when there is catecholamine reserves depletion in hypovolemic patients 44.
Since ketamine preserves heart rate and right atrial pressure through its effects on sympathetic nervous system, it has been used for anesthetic induction in patients with cardiac tamponade, restrictive pericarditis and congenital heart disease with proneness for right to left blood flow bypass 45.
The association of ketamine and diazepam or midazolam is used in continuous infusion to induce anesthesia in patients with valve or ischemic myocardial disease 46.
Psychomimetic reactions in children are less intense and frequent as compared to adults 47 and ketamine has been used for radiotherapy, radiological evaluations, dental treatments 48 and heart catheterization. When there is high pulmonary vascular resistance, ketamine may worsen the situation 49.
Recommended anesthetic induction doses are bolus 0.5 to 2 mg.kg-1, and 30 to 90 µg.kg-1.min-1 for maintenance. Muscular dose is 4 to 6 mg.kg-1.
Oral 3 to 10 mg.kg-1 ketamine induces sedation in 20 to 45 minutes. In comparing three different racemic ketamine doses as single oral agent, 8 mg.kg-1 has been considered the most effective for children, however recovery has been delayed 50. The association of barbiturates or benzodiazepines and antisyalogogues decreases ketamine dose 25. It seems to be no difference between racemic ketamine alone or associated with midazolam in post-anesthetic recovery time of children submitted to general anesthesia with sevoflurane 51.
Rectal S(+) ketamine as preanesthetic medication in children has been less effective and has promoted higher incidence of side effects as compared to midazolam 52.
Ketamine has been associated to regional anesthesia both in adults and children and intravenous 0.5 mg.kg-1 ketamine with 0.15 mg.kg-1 diazepam has not produced so many side effects 53.
KETAMINE AND CENTRAL SENSITIZATION
Although in clinical use for more than 30 years, ketamines property of blocking nociceptive stimulation-induced central sensitization was only discovered in the 90s 54,55.
Initially, it was thought that ketamine analgesic effects were mediated by its interaction with opioid receptors, however, subanesthetic doses 38 and non-reversion of analgesia by naloxone, an opioid antagonist 56, made this hypothesis improbable.
In low doses, ketamine inhibits, in competitive and non-competitive manner, NMDA (N-methyl-D-aspartate) receptors ion channels of the postsynaptic membrane of neurons of spinal dorsal horn. At this site, there are two binding points for ketamine: one within the receptor channel (which will decrease channel opening time) and the other in the receptors hydrophobic portion (which will decrease channel opening frequency) 28,42,57,58.
Ketamine dose is considered low when below 2 mg.kg-1 in muscular bolus, below 1 mg.kg-1 in intravenous or epidural bolus, and < 20 µg.kg-1.min-1 in continuous infusion 22,28,39,59-62.
Repetitive amyelic C fibers activity triggers central sensitization, characterized by increased spontaneous neuronal activation, decreased threshold or increased responsiveness to afferent impulses, prolonged discharges after repeated stimulations and peripheral receptive fields expansion of dorsal horn neurons 63,64.
With afferent impulses in enough frequencies or intensities, there is neuropeptides release (P substance, neurokinin A, somatostatin and peptide genetically related to calcitonin) and of excitatory aminoacids (glutamate and aspartate). These substances generate slow (produced by amyelic C fibers) and fast (produced by A d fibers of low excitability threshold) excitatory pre-synaptic potentials 57.
Rapid excitatory postsynaptic potentials generate short lasting ion currents to inside the cell and are mediated by glutamate action via AMPA receptors (alpha-amino-3-hydroxy-5- methyl-4-isoxasolpropionic), bound to sodium ion channel and metabothropic receptors, bound to membrane G protein and C phospholipase, which are known as non-NMDA receptors (N-methyl-D-aspartate).
Slow excitatory postsynaptic potentials are mostly generated by the action of glutamate on NMDA receptors and substance P and neurokinin A (tachykinins) action on neurokinin-1 (NK1) and neurokinin-2 (NK2) receptors, respectively, which are coupled to G protein and located in spinal dorsal horn 57,65-68.
Since slow potentials duration is long, there is build up during repetitive afferent fibers stimulation, producing prolonged postsynaptic depolarization and leading to progressive increase in discharging frequency. This phenomenon is known as wind up and is associated to NMDA receptors activation. For this activation to occur, there must be glutamate binding to these receptors and tachykinins modulating action, leading to channel unblocking by magnesium shift inside it (frequency-dependent effect) with consequent entrance of calcium in the neuron. With this, NMDA receptor is activated and the result is amplification and prolongation of responses implied in hyperalgesia 57,69,70.
Tachykinins play a major role in potentiating NMDA receptors-mediated changes. Tachykinins binding to receptors promotes diacylglycerol (DAG) increase and inositol 1,4,5-triphosphate (IP3) formation. In the presence of phosphatidylserine and calcium, DAG activates proteinokinase C (PKC) with proteins phosphorilation.
NMDA receptors phosphorilation promotes changes in magnesium ion binding, helping calcium entrance in the cell. There is higher proteinokinase C activation with increased intracellular calcium. IP3 may promote intracellular vesicles calcium release with further PKC activation. This calcium increase inside the cell through a frequency-dependent mechanism is also related to neurokinin receptors 70,71, promotes nitric oxide synthetase (NOS) and protoncogenes transcription (genes regulating DNA transcriptional process). NOS generates nitric oxide (NO) which, acting as a second messenger via cGMP, activates proteinokinases responsible for ion channels phosphorilation and activation. NO spreads in retrograde manner to the presynaptic terminal where it stimulates further glutamate release 71,72.
C-fos and c-jun protoncogenes are expressed in spinal dorsal horn after painful stimulations conducted by A d and C fibers, producing transcription protein (Fos). This acts on pre-prodinorphin and pre-proencephalin genes generating dinorphin and encephalin. Encephalin has antinociceptive effects decreasing neurplasticity and hyperalgesia, while dinorphin promotes direct neuronal excitation (causing hyperalgesia) and antinociception (by a negative feedback mechanism).
Protoncogenes also activate transcription of Messenger RNA controller of protein synthesis, such as glutamate receptors (increasing their density in the membrane and making neuron more sensitive to this neurotransmitter), ion channels (increasing their excitability) and enzymes such as phosphorilases and proteinokinases. These changes are long-lasting and possibly permanent, making such neurons hypersensitive for long periods 70,73.
This way, ketamine may be important in central sensitization modulation. Its administration before painful stimulation would then have a preemptive effect 63,69,73-76.
KETAMINE AND POSTOPERATIVE PAIN
Since the finding that ketamine could decrease central sensitivity through its NMDA receptor antagonist effect, several experimental and clinical studies have been performed with this drug for postoperative pain relief. Most studies are difficult to interpret due to problems with the method or the statistical analysis of data 28. Studies have used different administration routes and low dose ketamine as single agent or associated to other analgesics.
Ketamine has been tested in animals and human volunteers through different methods. Intravenous racemic ketamine decreases formalin-induced central stimulation in cats with spinal cord sectioned at the encephalic trunk, with best results when administered before formalin injection 81. Using visceral stimulation in rats, a study has shown antinociceptive effects of 4 mg.kg-1 epidural or 10 mg.kg-1 intravenous racemic ketamine doses 77. Some authors 78,79 have observed marked decrease in neuropathic pain induced in rats with epidural racemic ketamine. Also in rats, racemic ketamine has decreased peripheral hyperalgesia triggered by thermal stimulation 80.
In volunteers submitted to burns, racemic ketamine decreases central sensitization both by intravenous 82,83 and subcutaneous 84 routes. This effect has not been observed with oral administration 85.
Intravenous ketamine decreases acute pain intensity caused by experimental electric stimulation 86,87. There has been increased pain threshold in volunteers submitted to dental pulp A d nervous fibers stimulation after intravenous ketamine, without analgesic difference between S(+) and R(-) enantiomers 88.
Attenuation of hyperalgesia triggered by carrageenam injection in rear paws of rats has been observed after epidural S(+) ketamine 89. Through the same administration route, S(+) ketamine has promoted analgesic effects in rats submitted to thermal stimulations 90. S(+) ketamine has also potentiated morphine and dexmedetomidine analgesic effects 91, as well as of epidural endomorphine-1 92 in rats submitted to thermal stimulations.
Intravenously, S(+) ketamine has promoted more prolonged secondary hyperalgesia inhibition in volunteers submitted to electric stimulation 93. It has also reversed hyperalgesia after remifentanil infusion withdrawal 94.
Different administration routes have been used for clinical trials with racemic ketamine or its levogyrous component, in low doses, alone or associated to other analgesic drugs.
Oral racemic ketamine analgesic efficacy has been evaluated in children submitted to lip laceration repair 95,96, but there has been inadequate postoperative analgesic effect.
Muscular ketamine doses varying 0.1 mg.kg-1 to 1 mg.kg-1 have been evaluated 98. Ketamine has been used in bolus injection 20,99-101 or according to request of patients submitted to different surgical procedures 98, Studies with ketamine, both as single agent 28,101 or in association with opioids 102, have shown analgesic effects.
Results have indicated that 0.5 to 1 mg.kg-1 bolus racemic ketamine, have been effective and with twice the analgesic potency as compared to meperidine, however less potent than morphine 102. Administered before tonsillectomy in children, ketamine has promoted increased analgesic effect of the association of morphine and paracetamol, with decreased additional analgesic consumption and satisfactory swallowing in the postoperative period 97.
Ketamine associated to opioids provides more prolonged analgesia as compared to the single use of one of the drugs 100. In low doses, ketamine does not promote hemodynamic or respiratory depressing effects, being psychomimetic effects or sedation also uncommon. Low dose subcutaneous ketamine (1.7 µg.kg-1) after abdominal surgery has not triggered side effects and has promoted postoperative analgesia equivalent to 2 mg.h-1 morphine infusion 103. Subcutaneous ketamine, however, may cause significant inflammatory reaction at injection site 104.
Intravenous ketamine has been used in bolus37,105, bolus followed by continuous infusion 39,62,106-108, continuous infusion alone or associated to opioid or benzodiazepine 62,109-112 and in patient-controlled analgesia PCA) 113-117.
Intravenous racemic ketamine analgesic efficacy depends on infusion dose, on initial dose and on the association of opioids. Bolus ketamine doses above 300 µg.kg-1 promote effective and short duration pain relief 37. In doses below 4 µg.kg-1.min-1, there has been no effect on postoperative pain or morphine consumption 37, with anti-hyperalgesic effects with 1 to 6 µg.kg-1.min-1 107,110.
Several studies have shown that low dose ketamine was safe, being potent opioid adjuvant both in pain relief quality and decreased postoperative opioid consumption 39,62,100,113,118-120. After testing different combinations of morphine and racemic ketamine in patient-controlled intravenous analgesia (PCA), a study has observed that 1:1 ratio of this solution promotes the best analgesic effect with less side effects in patients submitted to hip or spinal surgeries 117. However, other studies were unable to show this benefit in other surgical procedures 121-123 with R(-) ketamine 124 or other racemic ketamine doses 112,114.
Potentiation of opioid effects with intravenous racemic ketamine has not been observed in children during appendicectomy 115, similar to other study after tonsillectomy 125, in disagreement with the positive result mentioned 97.
Due to low intravenous ketamine therapeutic index, it is interesting to associate it to other agents for postoperative pain relief, according to some authors 42,126.
Spinally, racemic ketamine may be used alone or associated to local anesthetic or opioids. After injection, ketamine is rapidly absorbed from the epidural space to systemic circulation with 77% ± 22% bioavailability.
Sacral epidural racemic ketamine has promoted adequate postoperative analgesia in children submitted to orchipexy 60 or inguinal herniorrhaphy 127. When administered alone by lumbar epidural route in adults, ketamine has not promoted effective postoperative analgesia 28,128, unless if used in high doses 129. On the other hand, it has promoted better pain relief when epidurally injected in low dose associated to morphine or local anesthetics 130-135. Sandler et al. 136, in editorial, have called the attention for the promising use of epidural racemic ketamine associated to other analgesic agents.
Sub-anesthetic epidural ketamine doses have promoted satisfactory analgesic effects in patients submitted to hip or knee arthroplasty 130,131. This effect has not been observed in a different study 137. Tan et al. 138 have obtained effective postoperative analgesia in patients submitted to lower abdominal surgeries with ketamine associated to morphine in epidural PCA. Results were also favorable in upper abdominal surgeries with the association of epidural ketamine and morphine, with decreased intraoperative opioid consumption 134,139,140. Epidural ketamine administered before incision has promoted satisfactory post-hysterectomy pain control 133.
Racemic ketamine and its levogyrous compound, even without preservatives, may be associated to spinal neurotoxicity and should not be spinally injected, especially in high doses 130,136,141-143, although chlorobutanol (preservative) is considered the major culprit 144,145. There are evidences that spinal ketamine continuous infusion is related to histopathologic findings of spinal cord vacuolization 146,147.
On the other hand, there are studies with sacral epidural racemic ketamine 60 or S(+) ketamine 21,61,148,149 in children, or lumbar epidural in adults 120,130 which have not reported neurotoxicity, being especially recommended preservative-free ketamine 150.
Clinical trials with S(+) ketamine have been recently published. Marhofer et al. 61 have reported that 1 mg.kg-1 sacral epidural levoketamine has promoted intra and postoperative analgesia equivalent to 0.25% bupivacaine with epinephrine in the same volume in children submitted to inguinal herniorrhaphy. Also studying this surgery in children, Koinig et al. 21 have observed that sacral epidural S(+) ketamine has induced more effective intra and postoperative analgesia as compared to muscular ketamine, in spite of lower serum ketamine levels after sacral administration, suggesting local analgesic effect.
Sacral epidural S(+) ketamine prolongs 0.125% bupivacaine analgesia in children submitted to brief surgeries 151. For similar pediatric procedures, S(+) ketamine has induced more prolonged analgesia as compared to the association of clonidine and bupivacaine in sacral epidural anesthesia 152, observing better results with the association of both drugs to local anesthetics 148.
Sub-anesthetic S(+) ketamine doses with epidural ropivacaine before incision have promoted better analgesic effect as compared to local anesthetics alone, in patients submitted to total knee replacement 153.
On the other hand, no long lasting analgesia or opioid effects potentiation has been shown with intravenous levoketamine before induction in patients submitted to anterior cruciate ligament injury repair 22, but these authors have used continuous intraoperative remifentanil, which could have inhibited central neuroplasticity in both studied groups. In addition, remifentanil may promote hyperalgesia and acute tolerance in the immediate postoperative period, thus interfering with S(+) ketamine preemptive effect 154,155.
Due to differences in preemptive analgesia concepts, ketamine doses, administration timing with regard to surgical incision, surgery types and statistical analysis, it is difficult to evaluate and confirm the clinical efficacy of ketamine in decreasing post-surgical stimulation central sensitization. Although S(+) ketamine being more potent than racemic ketamine, there are few studies justifying its superiority in central sensitization blockade. So, further studies are necessary to evaluate the importance of ketamine in preemptive analgesia.
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49. Wolfe RR, Loehr JP, Schaffer MS - Hemodynamic effects of ketamine, hypoxia and hyperoxia in children with surgically treated congenital heart disease residing greater than or equal to 1,200 meters above sea level. Am J Cardiol, 1991;67:84-87. [ Links ]
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53. Korttila K, Levanen J - Untoward effects of ketamine combined with diazepam for supplementing conduction anaesthesia in young and middle-aged adults. Acta Anaesthesiol Scand, 1978;22:640-648. [ Links ]
54. Mao J, Price DD, Hayes RL - Differential role of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy. Brain Res, 1992;598:271-278. [ Links ]
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85. Mikkelsen S, Jorgensen H, Larsen PS et al - Effect of oral ketamine on secondary hyperalgesia, thermal and mechanical pain thresholds, and sedation in humans. Reg Anesth Pain Med, 2000;25:452-458. [ Links ]
86. Smith DC, Mader TJ, Smithline HA - Low dose intravenous ketamine as an analgesic: a pilot study using an experimental model of acute pain. Am J Emerg Med, 2001;19:531-532. [ Links ]
87. Bossard AE, Guirimand F, Fletcher D et al - Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers. Pain, 2002;98:47-57. [ Links ]
88. Rabben T - Effects of the NMDA receptor antagonist ketamine in electrically induced Ad-fiber pain. Methods Find Exp Clin Pharmacol, 2000;22:185-189. [ Links ]
89. Klimscha W, Horvath G, Szikszay M et al - Antinociceptive effect of the S(+)-enantiomer of ketamine on carrageenam hyperalgesia after intrathecal administration in rats. Anesth Analg, 1998;86:561-565. [ Links ]
90. Horvath G, Joo G, Klimscha W et al - The interaction of S(+)-ketamine with dexmedetomidine after intrathecal administration in rats. Eur J Anaesthesiol, 2000;17:176-177. [ Links ]
91. Joo G, Horvath G, Klimscha W et al - The effects of ketamine and its enantiomers on the morphine- or dexmedetomidine-induced antinociception after intrathecal administration in rats. Anesthesiology, 2000;93:231-241. [ Links ]
92. Horvath G, Joo G, Dobos I et al - The synergistic antinociceptive interactions of endomorphin-1 with dexmedetomidine and/or S(+)-ketamine in rats. Anesth Analg, 2001;93:1018-1024. [ Links ]
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94. Koppert W, Sittl R, Scheuber K et al - Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology, 2003;99:152-159. [ Links ]
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96. Hollman GA, Perloff WH - Efficacy of oral ketamine for providing sedation and analgesia to children requiring laceration repair. Pediatr Emerg Care, 1995;11:399. [ Links ]
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98. Dich-Nielsen JO, Svendsen LB, Berthelsen P - Intramuscular low-dose ketamine versus pethidine for postoperative pain treatment after thoracic surgery. Acta Anaesthesiol Scand, 1992;36:583-587. [ Links ]
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100. Parkhouse J, Marriott G - Postoperative analgesia with ketamine and pethidine. Anaesthesia, 1977;32:285-289. [ Links ]
101. Marcus RJ, Victoria BA, Rushman SC et al - Comparison of ketamine and morphine for analgesia after tonsillectomy in children. Br J Anaesth, 2000;84:739-742. [ Links ]
102. Hagelin A, Lundberg D - Ketamine for postoperative analgesia after upper abdominal surgery. Clin Ther, 1981;4:229-233. [ Links ]
103. Bhattacharya A, Gurnani A, Sharma PK et al - Subcutaneous infusion of ketamine and morphine for relief of postoperative pain: a double-blind comparative study. Ann Acad Med Singapore, 1994;23:456-459. [ Links ]
104. Eide K, Stubhaug A, Oye I et al - Continuous subcutaneous administration of the N-methyl-D-aspartatic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain, 1995;61:221-228. [ Links ]
105. Kee WD, Khaw KS, Ma ML et al - Postoperative analgesic requirement after cesarean section: a comparison of anesthetic induction with ketamine or thiopental. Anesth Analg, 1997;85:1294-1298. [ Links ]
106. Owen H, Reekie RM, Clements JA et al - Analgesia from morphine and ketamine. A comparison of infusions of morphine and ketamine for postoperative analgesia. Anaesthesia, 1987;42:1051-1056. [ Links ]
107. Jahangir SM, Islam F, Aziz L - Ketamine infusion for postoperative analgesia in asthmatics: a comparison with intermittent meperidine. Anesth Analg, 1993;76:45-49. [ Links ]
108. Fu ES, Miguel R, Scharf JE - Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg, 1997;84:1086-1090. [ Links ]
109. Edwards ND, Fletcher A, Cole JR et al - Combined infusions of morphine and ketamine for postoperative pain in elderly patients. Anaesthesia, 1993;48:124-127. [ Links ]
110. Stubhaug A, Breivik H, Eide PK et al - Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand, 1997;41:1124-1132. [ Links ]
111. Wilder-Smith OH, Arendt-Nielsen L, Gaumann D et al - Sensory changes and pain after abdominal hysterectomy: a comparison of anesthetic supplementation with fentanyl versus magnesium or ketamine. Anesth Analg, 1998;86:95-101. [ Links ]
112. Holthusen H, Backhaus P, Boeminghaus F et al - Preemptive analgesia: no relevant advantage of preoperative compared with postoperative intravenous administration of morphine, ketamine and clonidine in patients undergoing transperitoneal tumor nephrectomy. Reg Anesth Pain Med, 2002;27:249-253. [ Links ]
113. Javery KB, Ussery TW, Steger H et al - Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth, 1996;43:212-215. [ Links ]
114. Reeves M, Lindholm DE, Myles PS et al - Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: a double-blinded, randomized controlled trial. Anesth Analg, 2001;93:116-120. [ Links ]
115. Dix P, Martindale S, Stoddart PA - Double-blind randomized placebo-controlled trial of the effect of ketamine on postoperative morphine consumption in children following appendicectomy. Paediatr Anaesth, 2003;13:422-426. [ Links ]
116. Unlugenç H, Ozalevli M, Guler T et al - Postoperative pain management with intravenous patient-controlled morphine: comparison of the effect of adding magnesium or ketamine. Eur J Anaesthesiol, 2003;20:416-421. [ Links ]
117. Sveticic G, Gentilini A, Eichenberger U et al - Combinations of morphine with ketamine for patient-controlled analgesia: a new optimization method. Anesthesiology, 2003;98:1195-1205. [ Links ]
118. Menigaux C, Fletcher D, Dupont X et al - The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg, 2000;90:129-135. [ Links ]
119. Menigaux C, Guignard B, Fletcher D et al - Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg, 2001;93:606-612. [ Links ]
120. De Kock M, Lavandhomme P, Waterloos H - "Balanced analgesia" in the perioperative period: is there a place for ketamine? Pain, 2001;92:373-380. [ Links ]
121. Adam F, Libier M, Oszustowicz T et al - Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy. Anesth Analg, 1999;89:444-447. [ Links ]
122. Heinke W, Grimm D - Preemptive effects caused by co-analgesia with ketamine in gynecological laparotomies? Anaesthesiol Reanim, 1999;24:60-64. [ Links ]
123. Dahl V, Ernoe PE, Steen T et al - Does ketamine have preemptive effects in women undergoing abdominal hysterectomy procedures? Anesth Analg, 2000;90:1419-1422. [ Links ]
124. Mathisen LC, Aasbo V, Raeder J - Lack of pre-emptive analgesic effect of (R)-ketamine in laparoscopic cholecystectomy. Acta Anaesthesiol Scand, 1999;43:220-224. [ Links ]
125. OFlaherty J, Lin C - Does ketamine or magnesium affect posttonsillectomy pain in children? Paediatr Anaesth, 2003;13:413-421. [ Links ]
126. Sang CN - NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage, 2000;19:(Suppl1):S21-S25. [ Links ]
127. Moiniche S, Kehlet H, Dahl JB - A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology, 2002;96:725-741. [ Links ]
128. Peat SJ, Bras P, Hanna MH - A double-blind comparison of epidural ketamine and diamorphine for postoperative analgesia. Anaesthesia, 1989;44:555-558. [ Links ]
129. Gebhardt B - Epidural and intrathecal administration of ketamine - pharmacology and clinical results. Anaesthesist, 1994;43:S34-S40. [ Links ]
130. Wong CS, Liaw WJ, Tung CS et al - Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth, 1996;21:534-541. [ Links ]
131. Wong CS, Lu CC, Cherng CH et al - Pre-emptive analgesia with ketamine, morphine and epidural lidocaine prior to total knee replacement. Can J Anaesth, 1997;44:31-37. [ Links ]
132. Chia YY, Liu K, Liu YC et al - Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Anesth Analg, 1998;86: 1245-1249. [ Links ]
133. Abdel-Ghaffar ME, Abdulatif M, Al-Ghamdi A et al - Epidural ketamine reduces post-operative epidural PCA consumption of fentanyl/bupivacaine. Can J Anaesth, 1998;45:103-109. [ Links ]
134. Wu CT, Yeh CC, Yu JC et al - Pre-incisional epidural ketamine, morphine and bupivacaine combined with epidural and general anaesthesia provides pre-emptive analgesia for upper abdominal surgery. Acta Anaesthesiol Scand, 2000;44:63-68. [ Links ]
135. Taura P, Fuster J, Blasi A et al - Postoperative pain relief after hepatic resection in cirrhotic patients: the efficacy of a single small dose of ketamine plus morphine epidurally. Anesth Analg, 2003;96:475-480. [ Links ]
136. Sandler AN, Schmid R, Katz J - Epidural ketamine for postoperative analgesia. Can J Anaesth, 1998;45:99-102. [ Links ]
137. Weir PS, Fee JPH - Double-blind comparison of extradural block with three bupivacaine-ketamine mixtures in knee arthroplasty. Br J Anaesth, 1998;80:299-301. [ Links ]
138. Tan PH, Kuo MC, Kao PF et al - Patient-controlled epidural analgesia with morphine plus ketamine for post-operative pain relief. Eur J Anaesthesiol, 1999;16:820-825. [ Links ]
139. Subramaniam B, Subramaniam K, Pawar DK et al - Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra and postoperative opioid-sparing effect. Anesth Analg, 2001;93:1321-1326. [ Links ]
140. Subramaniam K, Subramaniam B, Pawar DK et al - Evaluation of the safety and efficacy of epidural ketamine combined with morphine for postoperative analgesia after major upper abdominal surgery. J Clin Anesth, 2001;13:339-344. [ Links ]
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142. Yaksh TL - Epidural ketamine: a useful, mechanistically novel adjuvant for epidural morphine? Reg Anesth, 1996;21:508-513. [ Links ]
143. Eisenach JC, Yaksh TL - Epidural ketamine in healthy children - whats the point? Anesth Analg, 2003;96:626-627. [ Links ]
144. Malinovsky JM, Lepage JY, Cozian A et al - Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology, 1993;78:109-115. [ Links ]
145. Borgbjerg FM, Svensson BA, Frigast C et al - Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and electron microscopic examination. Anesth Analg, 1994;79:105-111. [ Links ]
146. Karpinski N, Dunn J, Hansen L et al - Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain, 1997;73:103-105. [ Links ]
147. Stotz M, Oehen HP, Gerber H - Histological findings after long-term infusion of intrathecal ketamine for chronic pain: a case report. J Pain Symptom Manage, 1999;18:223-228. [ Links ]
148. Hager H, Marhofer P, Sitzwohl C et al - Caudal clonidine prolongs analgesia from caudal S(+)-ketamine in children. Anesth Analg, 2002;94:1169-1172. [ Links ]
149. Marhofer P, Semsroth M - Epidural ketamine in healthy children - whats the point? Anesth Analg, 2003;96:626-627. [ Links ]
150. Lima J, Beggs S, Howard R - Neural toxicity of ketamine and other NMDA antagonists. Pain, 2000;88:311-312. [ Links ]
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152. De Negri P, Ivani G, Visconti C et al - How to prolong postoperative analgesia after caudal anaesthesia with ropivacaine in children: S-ketamine versus clonidine. Paediatr Anaesth, 2001;11:679-683. [ Links ]
153. Himmelseher S, Ziegler-Pithamitsis D, Argiriadou H et al - Small-dose S(+)-ketamine reduces postoperative pain when applied with ropivacaine in epidural anesthesia for total knee arthroplasty. Anesth Analg, 2001;92:1290-1295. [ Links ]
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155. Luginbuhl M, Gerber A, Schnider T et al - Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg, 2003;96: 726-732. [ Links ]
Dra. Rioko Kimiko Sakata
Rua Três de Maio, 61/51 Vila Clementino
04044-020 São Paulo, Brazil
Submitted for publication October 13, 2003
Accepted for publication February 11, 2004
* Received from Disciplina de Anestesiologia, Dor e Terapia Intensiva de Universidade Federal do Estado de São Paulo, Escola Paulista de Medicina (UNIFESP EPM), São Paulo, SP


text:
Search 1000s of commercial spaces by size, location, and price.
|Maria Jocelyn G. Gayagoy, BS Pharmacy Store Health Point Of Interest|
|Debra Short, PharmD Pharmacy Store Health Point Of Interest|
|Helen E. Spencer, Pharm Pharmacy Store Health Point Of Interest|
The typical asking rate per listing is in the $10's per square foot per year. The Lakeview submarket is going through a an increase in rates. In the last 3 months, the median rate rose $2 per sqft per year. That's a 10% increase in rent.
|Median Rate||Median Size|

domain: economics


Shad is one of North America’s most thoughtful and skilled hip-hop artists and we here in Canada are proud to call him one of our own. The gifted MC has won a Juno and been nominated for the Polaris Music Prize twice, most recently for his record TSOL. Its stunning follow-up is Flying Colours, which is out now via Black Box and brings Shad to a city near you on his extensive North American tour. Here he discusses his recent stint co-hosting the Polaris Music Prize, his new album and why we’re all doing ok, stepping up his skills, Jay Z’s recent output, hip-hop’s fascination with guest stars, Canadian politics and multiculturalism, the song “Yall Know Me” and more.
Related links: shadk.com weareblackbox.com vishkhanna.com
Listen, subscribe, rate/review on iTunes.


text:
Factories fail to compete with cheap imports
Kathmandu, January 23
Sugar factories in the country have been hit hard as they have failed to compete with cheaper imported sugar in the domestic market.
Though the government managed to forge consensus between sugarcane farmers and sugar mills to fix support price before plantation season to safeguard the cane growers, it has not been doing much to protect domestic industry that has been adversely affected along with global fall in price of sugar and low customs tariff.
The support price for sugarcane last year was fixed at Rs 531.20 per quintal. However, sugar mills have huge outstanding dues to farmers as their production has remained stuck at warehouses since a few months along with rampant fall in sugar price in the global market.
Ministry of Agricultural Development (MoAD) had proposed Ministry of Finance (MoF) to hike customs tariff on sugar to protect domestic factories a month back citing that the negative impact on sugar mills would ultimately hit cane growers. However, the MoF has not taken the proposal of the MoAD into due consideration yet.
The MoAD plans to make the country self-reliant in sugar production with introduction of safeguard policies for farmers, like support price of sugarcane. Since the last few years, the support price is being fixed through tripartite meeting among the government (MoAD and Ministry of Industry), cane growers and sugar mills.
Normally in a free market economy, import cannot be curbed by raising customs tariff. However, high-ranking officials of MoAD said that the ministry is mulling over this option as it aims to make the country self-sufficient in sugar production. Apart from fixing support price to safeguard farmers, MoAD is planning to extend subsidy on seeds, fertilisers, ensure low interest credit and insurance to encourage farmers.
“Even though it is a free market economy, India has adopted measures to raise tariff to 50 per cent through federal budget to protect their factories and cane growers,” a high-ranking official at the MoAD told The Himalayan Times, adding, “The price reduction in sugar could be just a short-term phenomenon, but our economy will suffer once the price of sugar starts to rise if we are unable to make timely intervention to sustain our production base.”
Sugar mills and farmers have long been at odds over the rate for sugarcane. “Cane growers are quite happy since the government started mediating between them and the sugar mills to fix support price, and subsequently production of sugarcane increased immensely,” as per MoAD officials. “It is leading us towards being self-sufficient in sugar production.”
While MoAD’s proposal to hike tariff has also invited criticism that the move would pamper sugar mills instead of encouraging them to be competent, Secretary at MoAD Suroj Pokharel pointed out that a number of countries have been providing subsidies on farming to minimise their production cost and export cheaper products worldwide. He further said there will be adverse impact on jobs and production of sugarcane in this duty regime.
Customs tariff of sugarcane is 15 per cent at present. The government had reduced the tariff of sugar to 15 per cent from 30 per cent some three years back when domestic production was very low. Back then, farmers were not too enthused about sugarcane farming as the mills did not offer them satisfactory price.
MoF officials refused to comment on the issue saying that they are studying the current situation.
Sugar mill owners have said that it is only a question of protecting domestic factories and farmers or not. “We have proposed the government to either hike the customs tariff or to incentivise the sugar mills,” said Rajesh Kediya, chairman of Indushankar Sugar mill. “Just like Dairy Development Corporation raises price of milk to support livestock farmers, beneficiary of the sugar mills are ultimately the cane growers.”
Kediya further said that while fixing the support price of sugarcane at Rs 531.20 per quintal at farm rate, the MoAD has proposed the price based on Rs 72 per kg market price of sugar. One quintal of sugarcane produces around nine kilos of sugar. In this regard, the production and transportation cost per kg of sugar would come to Rs 64, while import price of sugar including value added tax (VAT) is Rs 60 per kg. Sugar mills have said that they cannot sell sugar at around Rs 66.50 per kg, which is the prevailing market rate.
As per the data of the Department of Customs, around 60,000 tonnes of sugar has already been imported in five months of this fiscal. As per sugar manufacturers, total production of domestic factories is 175,000 tonnes, whereas the demand hovers between 210,000 and 220,000 tonnes per annum.
Sugar mill owners have urged the government to reduce the customs if the sugar mills start to cartel in price and increase the rate above Rs 72 per kg as agreed with the government during fixation of support price.
Number of sugar mills in operation: 13
Capacity utilisation: 35% to 40%
Production: 175,000 tonnes per year
Demand: 220,000 tonnes per year
Sugarcane cultivation: 67,000 hectares
Cane production: 2.96 million tonnes per annum
Source: MoAD/Nepal Sugar Mills Association

domain: politics


text:
New Australian online grocery retailer teams up with Aussie Farmers’ Direct
A new Australian online grocery retailer called The General Store, has begun servicing homes across Melbourne, Geelong, Bendigo and Ballarat.
The General Store, which delivers groceries to consumers’ doorsteps, has partnered with online home delivery business Aussie Farmers’ Direct “so that customers can have their whole weekly shop, including fresh food staples, delivered to their doorstep”. The General Store said it is working to bring back the ‘local corner store’ concept through a modern online platform where everyday household essentials are delivered by a local small business franchisee to a household.
Australian Food News reported in April 2013 that a report from Australian industry research group BIS Shrapnel had found that corner stores were continuing to disappear as service stations moved towards having convenience stores within the station. The BIS Shrapnel Route Trade Market report found that the number of independent convenience stores in Australia had declined 34 per cent from 4,131 in 2010 to just 2,725 stores in 2012, a decline of 1,406 stores.
The new retailer has been welcomed by the Australian Retailers’ Association.
“The launch of The General Store means more choice for consumers and offers local manufacturers a new channel to market,” said Russell Zimmerman, Australian Retailers’ Association Executive Director. “The more players in the grocery space, the more fair the playing field will become,” he said.
Aussie Farmers’ Direct partnership
The General Store said it has “similar values” to Aussie Farmers’ Direct; where Aussie Farmers’ Direct works with local farmers, The General Store works to offer local manufacturers a new platform to reach Australian consumers.
The General Store’s ‘Australian-made’ policy
The General Store said it has been able to ensure there is an Australian product available in every grocery category except band-aids and razors, which are not manufactured in Australia. The Company said it was on the look out for an Australian manufacturer of either of these products and would welcome information about local manufacturers.
The order site for The General Store includes a transparent symbol guide system to help consumers navigate how much of each product is made or grown in Australia “so they can make an informed decision about each product”. The order site also has a function where consumers can select to only see Australian made products.
“The General Store is great news for the country, as well as for Australian consumers who will enjoy more competition and choice in the Australian grocery space,” said Brendan Shaw, The General Store CEO. “It feels like every week there’s another local manufacturer closing down due to the numerous pressures they face, and we want to do something about that,” he said.
The General Store said it also donates 5 per cent of the sales margin on non-Australian products to rural Australian communities.
The new Australian online grocer is part of a tentative trend towards online retailing in the food sector. In the US market, online giants Amazon and Google have both tested the concept of online groceries. Australian Food News reported in July 2013 that online shopping was on the rise in Australia, with Food and Beverages among the top five categories by expenditure online in Australia.

domain: news


text:
By GENE ESPY
A pinwheel ceremony was held last week at the Department of Family and Children services offices in Summerville. The ceremony is to mark the number of substantiated child abuse or neglect cases in the county that were reported to DFCS in 2018. Each pinwheel placed in the front yard of the DFCS office stands for a case of substantiated child abuse or neglect in the county in 2018.
Also at the ceremony, three balloons were released to commemorate a death due to child abuse or neglect.
A large group of City of Summerville officials, firemen and police officials, and representatives of the Chattooga County Sheriff’s Department were on hand to mark the occasion.
Kim Humphrey, of DFCS, thanked everyone for attending the event to remember children who have suffered from abuse and neglect, particularly those within Chattooga County.
“We especially want to recognize those members of law enforcement, EMS, 9-1-1, firemen, first responders, coroner, DFCS staff and members of the judicial system for their acts of kindness to children they encounter during their work,” Mrs. Humphrey said. “Your compassion is noted and appreciated.”
Heather Abee from DFCS said that in Chattooga County, during the calendar year 2018, DFCS received 402 reports of child abuse or neglect. Some of these, approximately 200, involved situations where DFCS could offer the family services that met their needs, whether these were needs of food, housing or counseling services.
“We also investigated approximately 200 incidents of maltreatment, either child abuse or neglect,” Abee said. “There were 140 children who were substantiated victims of child abuse or neglect.”
DFCS also served many families through family preservation and foster care services to strengthen and reunify families, she continued.
“Sadly, we also must report on some child deaths for the past year,” Abee added.
Vicky Van Pelt said, “A pinwheel will be “planted” today to represent these children. But we feel that one incident is one too many.”
Delight Duke said that supporting local programs that make a difference for our families is important. There is currently a statewide initiative to help parents understand issues around co-sleeping and other baby sleep patterns.
“You can volunteer in local activities for children through the schools, recreation departments, 4-H, church, or the public library,” Mrs. Duke said. “Contact DFCS, the schools, or Family Connection to learn about these and other opportunities to work with children and their families in the county.”
“The average citizen isn’t aware of how serious the problem of child abuse and neglect is in our community,” Michelle Floyd said.
She said the purpose of the pinwheels event is to show the public how truly frightening the problem is, and to focus on ways to prevent these incidents from occurring.
“Share the information at church, at work, with friends and family members,” Mrs. Floyd added.
She said to encourage stressed out parents or guardians to seek help through counseling, talking with a pastor, or calling DFCS to ask for help.
“Unfortunately, this year we will launch three balloons, signifying our remembrance of a child’s death due to abuse or neglect,” Ms. Abee said. “We mourn their loss with their families and pray that the families who mourn are comforted.”

domain: sociology


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To understand more about the Fiorino surname is always to learn more about the folks who probably share common origins and ancestors. That is one of the reasoned explanations why its normal that the Fiorino surname is more represented in a single or higher countries of this globe compared to others. Right Here you can find out by which countries of the world there are more people who have the surname Fiorino.
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The possibility of examining on a globe map about which nations hold a greater number of Fiorino on earth, assists us a lot. By placing ourselves regarding the map, for a concrete nation, we can understand tangible number of individuals with the surname Fiorino, to have this way the complete information of all the Fiorino that one may currently find in that nation. All this also assists us to understand not just where the surname Fiorino arises from, but also in what way individuals who're initially an element of the family that bears the surname Fiorino have moved and relocated. Just as, you can see by which places they've settled and grown up, and that's why if Fiorino is our surname, this indicates interesting to which other nations associated with the globe it is possible that certain of our ancestors once relocated to.
In the event that you view it carefully, at apellidos.de we provide everything required to enable you to have the real data of which nations have actually the greatest number of people aided by the surname Fiorino in the whole world. Moreover, you can see them in a very visual way on our map, in which the countries aided by the highest number of people aided by the surname Fiorino is visible painted in a more powerful tone. In this manner, along with a single look, you can easily locate in which nations Fiorino is a common surname, as well as in which countries Fiorino is an uncommon or non-existent surname.

domain: geography


YAO is an open-source application engine, written in Golang, that provides a powerful command-line tool for immediate download and use. It is highly suitable for developing a wide range of applications such as business systems, website/APP APIs, admin panels, and self-built low-code platforms.
It enables the creation of web services and applications in just minutes. It is well-suited for a wide range of use-cases including AI, IoT, Industrial Internet, Connected Vehicles, DevOps, Energy, Finance, and many more. With YAO, you can confidently build robust solutions to meet your needs.
Yao simplifies web service development by using processes. Yao is an app engine that allows developers to create a database model, write API services, and design a dashboard interface using JSON for web and hardware applications.
It is based on the flow-based programming concept and developed in the Go language. Yao supports various methods to expand the data stream processor, making it highly versatile. It can replace programming languages in most scenarios and offers 10 times better reusability and coding efficiency compared to traditional programming languages like PHP and Java.
Yao includes a built-in data management system. By using JSON to describe the interface layout, it enables the realization of 90% of common interface interaction functions. It is particularly suitable for quickly creating various management backgrounds, CRM, ERP, and other internal enterprise systems.
Additional interactive functions can be implemented by writing extension components or HTML pages. The built-in management system is not tied to Yao and can be used with any front-end technologies such as Vue and React to create the management interface.
The YAO DSL can be written in multiple ways:
- Manual creation
- Contextual logic generation using automated scripts
- Visual creation through the "drag and drop" editor
- Flow-based programming concept
- Go language development
- Database model creation
- API service writing
- Dashboard interface design using JSON
- Versatile data stream processor expansion methods
- Replaces traditional programming languages like PHP and Java
- 10 times better reusability and coding efficiency
- Built-in data management system
- JSON-based interface layout description
- Supports 90% of common interface interaction functions
- Suitable for creating management backgrounds, CRM, ERP, and other enterprise systems
- Additional interactive functions can be implemented through extension components or HTML pages
- Compatible with front-end technologies like Vue and React for creating the management interface
- Query engine
- File-system routing


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The podium with an extendable STOP sign is one of two used by Governor Nathan Deal during his 2012 "Stop Means Stop" campaign to increase safety awareness of Georgia's school buses. The podium is even signed by Governor Deal and his wife.
At yesterday's brief ceremony Harris Blackwood, director of the Governor's Office of Highway Safety, said Langston Chapel Middle School was selected to receive the podium because of the school's "remarkable" emphasis on school bus safety.
Principal Karen Doty said the podium "...will remind us and our school system just how important it is to remind children about school bus safety."
From there Blackwood and other state officials went to Sweetheart Circle on the Georgia Southern University campus and hosted a news conference about efforts to cut down on the number of crashes involving teen drivers which result in injuries and fatalities.
University President Brooks Keel told the gathering there are 20,500 students and the school is conducting a campaign to prevent young people from being killed senselessly.
According to a Georgia Southern release, the number one cause of teenage deaths in Georgia and the nation is traffic crashes.


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Jump you way through the course as the obstacles increase in difficulty. ALWAYS RIGHT, related to it's direction!Avoid walls, don't go beyond the screen and watch out for the traps! Just an endless journey through different rooms. Race through the maze of blocks in order to stay alive.
- Tons of different options that will keep you entertained for ages.
Yet some places, crowded with history, keeps silent weeps and whispers hidden between the nostalgia of old statues and dusty books. You will find yourself trapped by needing to match two blues, or missing a square earlier on the board. Feel the extreme speed through the most spectacular environments like snow, deserts or forests at different levels.
Toast Shooter is a fast action packed arcade style tap-the-right-item game!Get your Jelly Cannon ready for all those tasty butter toasts jumping out of the toasters. Dark Toast=========Taping a Dark Toast decreases your Jelly Power. Swipe up to jump low approaching objects or swipe down to slide under higher approaching objects.
1) Awesome street race game!! 2) Check out the screen shots and see for yourself 3) Compete against your friends
With 1200 levels of gameplay, there is no end to the amount of not matching you can do.
Owl caught a mouse and carries it home. Focus and collect coins, crash into your opponents and generate insane scores.Avoid obtacles to level up, you will aim at the American dream. Can you accept the challenge and fight for the survival of the human race? We need you. Pet Animal Sounds for Kids!!!Perfect app for your little baby to learn about animal sounds and names.
Game Center Leaderboards.

domain: game


Dr. Iain Walker is a scientist at Lawrence Berkeley National Laboratory (LBNL). He has more than 30 years of experience as a building scientist, conducting research on energy retrofits, zero energy homes and IAQ issues in residential buildings. He is the current chair of the US national residential ventilation standard (ASHRAE 62.2) and serves on standards and technical committees for ASHRAE, ASTM and other national and international standards and professional organizations. He is an ASHRAE Fellow, leads the US DOE national efforts on IAQ in homes and international efforts with the IEA's Air Infiltration and Ventilation Center.
Mechanical Staff Scientist/Engineer
Development of Smart Ventilation Control Algorithms for Humidity Control in High-Performance Homes in Humid U.S. Climates
Measured performance of filtration and ventilation systems for fine and ultrafine particles and ozone in an unoccupied modern California house
A simplified model for estimating population-scale energy impacts of building envelope air-tightening and mechanical ventilation retrofits


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Intellect Devourer - Demons of the Skull [Things You Might Have Missed 2020]
Angry Metal Guy
Here’s a heartwarming tale of perseverance in the Aussie death metal underground. Intellect Devourer formed way back in 1991, and after releasing a couple of demos, enduring splits, hiatuses and reformations, finally recorded their full-length debut, entitled Demons of the Skull, in 2020. Featuring members from various other bands, including Mournful Congregation and StarGazer, Intellect Devourer bring a wealth of battle hardened experience into an inspired batch of old school technical death songs, where the writing roots stretch back to their forays in the early ’90s.
What you get is raw, gritty, pretension-free death, an album that claws for the jugular, with an inspired mix of hook-laden butchery and slick technicality. Clocking in at a lean and mean shade under half an hour, Demons of the Skull is the perfect length for such a dense, stabbing display of old school brutality, flashy technical chops, and a truckload of killer riffs. There is an immediacy to the album that speaks of Intellect Devourer‘s song crafting skills. Shreddy guitar work, nimble, attention grabbing basslines, and ever shifting rhythmic complexities are grounded by thick, headbangable grooves and genuinely catchy riffs. The songs are dynamic, compelling components of a unified whole, resulting in a collection that feels fresh and never monotonous, with tempo shifts aplenty within fluid structures. Vocally, the rancid, occasionally decipherable growls are downright vicious and perfectly suited to the material. The bludgeoning blasts and ferocity of opener “Damien Rose from the Tomb of Jesus” wields unhinged aggression with murderous abandon, featuring meaty grooves, melodic soloing, and colossal mid-section. It’s a short, power packed blast that sets the tone for what is to follow.
This shit hammers with bruising, tight and relentless riffage. Intellect Devourer‘s satisfyingly rugged, underground exterior, comes steeped in dank, evil atmosphere that early Morbid Angel would be proud of. The darker strains of the classic Floridian scene from yesteryear embellish songs that mix technical expertise with tasty melodic strains, courtesy of the dashing solos, and punchy melodic counterpoint of the ever present bass. Intellect Devourer pull no punches, and while the music is labelled as tech-death, this is a different beast to your average modern tech-death album. From a technical perspective Intellect Devourer impress with their collective prowess and masterful use of dynamics. However, it is the genuinely memorable songcraft that bumps the album up a level. Written back in the early ’90s, “Prayer to Thessaly” is a demented throwback, a blackened assault of blasphemous death that grips the throat and does not let up. Chest caving blasts, thrashy bursts and fast fingered fretwork keep the speed jacked, but Intellect Devourer prove just as adept at slower paces, such as the sick grooves and doomy lurches on “Sorrow Incarnate” and mighty closer, “Waves of Blood.”
Demons of the Skull plays like a refurbished relic from another time, and I mean that in the best possible way. Although Intellect Devourer‘s dated marketing schemes leave a bit to be desired, this mysterious outfit delivered an accomplished and intelligent meshing of death metal’s past and present, delivered with finesse and no-nonsense attitude. Death metal has reigned supreme in 2020, but amidst the bevy of excellent releases, be sure to check out this sleeper gem.
Tracks to Check Out: “Demons of the Skull,” “Sorrow Incarnate,” “Prayer to Thessaly,” “Waves of Blood.”
The post Intellect Devourer – Demons of the Skull [Things You Might Have Missed 2020] appeared first on Angry Metal Guy.Sat Jan 23 15:45:39 GMT 2021

domain: artistic


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The capital city of Baritaria with the Gurudev river running through it, is a mass of spires and gothic cubbyholes surrounding Coronation Bridge and the Royal Residence. The one true
metropolis in the tiny island makes its main source of income from tourism and flocks of
artists who come to study in its nurturing atmosphere.
occupation: fine art student, bakery shop boy.
likes: Baritaria, cabbage pies, cats, painting, old places.
dislikes: English tourists,
modern art, revisionist
occupation: tour guide
likes: practicing English, sex, playing accordion, the royal family, discount bread.
dislikes: the police, people who don't tip, not having sex.

domain: travel


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Interested in Zentangle Artist? On this page, we have collected links for you, where you will receive the most necessary information about Zentangle Artist.
Zentangle Apprentice Designed to share the Zentangle method with a younger audience. This is the perfect way to be sure your school or organization gets the most out of the original Zentangle method developed by Rick and Maria.
Stephanie Jennifer is a Certified Zentangle Teacher based in Singapore and teaches the Zentangle® method to both adults and children (aged 7-years and above). Find out more here. art class for children Singapore. art class for adults singapore. art classes Singapor
We believe that life is an art form and that each person is an artist. The Zentangle Method is an elegant metaphor and model for inspiring a deliberate artistry in life. For this reason, we deliberately do not include an eraser in our Zentangle Kit or use it as part of a Zentangle practice. We have no eraser in life, so why in a Zentangle Kit?
Maria was using them in her art and design work and Rick was using them in analyzing the price movements of companies and commodities. This was a forecast of the aspect of Zentangle art which mirrors the geometric and fractal nature of the patterns found throughout creation.
Savor this time as you discover and enjoy all that the Zentangle Method (and you!) have to offer. Explore this website, beginning with the links on the left. Take a Zentangle class with a Certified Zentangle Teacher. Create some Zentangle art and you will understand why we say, "Life is an art form and that each of us is an artist."
Aug 18, 2018 - Explore Karen Coombs's board "Zentangle Art", followed by 9734 people on Pinterest. See more ideas about zentangle art, zentangle, art.5.3K pins
Jan 28, 2021 · But if you have a group that's interested in learning Zentangle, please contact me. I have a variety of classes and workshops for groups, and I'm willing to travel. I currently live in Surrey BC (Canada), and can be contacted at margaret.bremner.artist(at)gmail(dot)com or 306.371.3735.
We hope you have found all the information you need about Zentangle Artist through the links above.


Well, it's Pride Month, which is a time of celebration for all orientations, biological sexes, and genders. Thirty full days of celebrating all the letters in the LGBTQ+ alphabet -- what fun! We at The Babylon Bee don't want to get left behind, of course, so let's kick off Pride Month with a list of our top two genders!
We had all our writers vote on their favorite genders and narrowed it down to just the best two. Here they are:
1. Women - Women took the top slot this year. Congratulations, women! Women are great. One of the best genders of all time-- everyone says so. They are really beautiful to look at, especially when they are married to you and they smile at you with those beautiful faces of theirs. According to experts, women make life worth living and fill the world with sweetness, warmth, and love! They have the amazing ability to think about 32 things at the same time and predict infinite possible outcomes to every scenario, kind of like Dr. Strange. Amazing!
Women are so amazing, in fact, that men spent thousands of years fighting wars and building civilization just so women could have air conditioning. Many of us Babylon Bee writers have even selected one wonderful person of this gender to spend the rest of our lives with, since they are so amazing.
Great job, women!
2. Men - Coming in a close second was men. Many of us were surprised that men didn't take the top slot. They have the distinct advantage, after all, of being able to pick what restaurant they want to go to. They are handy around the house. They also drive better and are way better at telling Dad jokes. They also risk their lives climbing high telephone poles and working on dangerous oil rigs, all so women can have air conditioning. But those factors just weren't enough to push them to the top. They tend to be way less good-looking than women, and way smellier. Better luck next time, men!
Congrats to the winners, and check back next year to see whether the same two genders top our list!


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A fisherman spotted an overturned car in a Utah river yesterday—and when first responders showed up, they looked inside and found a dead mom and her 18-month-old girl still alive some 14 hours after the accident may have happened, NBC News reports. Police officers "tipped the car on its side and were able to get the infant out," police lieutenant Matt Johnson tells the Daily Herald. The mother—identified by the AP as Lynn Groesbeck, 25, of Springville—was in the driver's seat, and the infant in the back. Authorities say a helicopter flew the baby from Spanish Fork River, south of Provo, to a Salt Lake City hospital in critical condition, where she was upgraded to stable but critical.
"This is just a tragedy all the way around," Johnson tells CNN. "There's not anything at the scene, as far as evidence goes, as why the vehicle left roadway. There were no skid marks to show evasive maneuvers." That said, KTLA reports that police say the mother may have hit an embankment at one end of the bridge and fallen into the river. A resident says she heard a big crash at about 10:30 Friday night, but went outside and saw nothing. If that timing is true, then the baby—who was not underwater during the ordeal—survived more than half a day before being hauled out yesterday afternoon. (Read more car crash stories.)


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Some House Republicansprivately expect a spending fight to trigger a government shutdown in October, with one member telling Axios they "wouldn't be making any plans" for that month.
Why it matters: Speaker Kevin McCarthy's ranks include members who are skeptical he can pull off another legislative survival by the end of September — with worker furloughs and shuttered federal services at stake.
A senior GOP source darkly recommended that congressional trips overseas “should be bought with refundable tickets” if they’re in early October.
Zoom in: House conservatives oppose the use of an "omnibus" to package all 12 must-pass appropriations bills together — but lawmakers are pessimistic about the odds of passing the bills individually by Sept. 30.
Six GOP lawmakers told Axios they expect to be tied up during all of September as they race to pass the spending bills and get them negotiated with the Senate.
Many of the House GOP's appropriations bills are being loaded with measures on hot-button topics like abortion that could threaten passage — and make it harder to negotiate with the Democratic-controlled Senate.
"It is kind of hard to imagine that there's like a smooth sailing deal without some like serious negotiation style, pushing and pulling,” one senior GOP lawmaker said.
With most functions of government lacking funding, federal benefits like food stamps would halt, and services like national parks would be closed.
Only workers deemed essential — such as military and federal law enforcement — would be allowed to work. Those not on the list would be furloughed until the government reopens.
Between the lines: Congress can extend the existing budget with a continuing resolution and provide members with more time to hash out a deal.
But many members are alarmed by the debt ceiling deal's across-the-board 1% cut to discretionary spending that kicks in on Jan. 1 unless Congress can pass a new budget.
What's next: Talks of minibuses — which could link some of the 12 appropriations bills together without being a single big package — are emerging despite conservatives balking at the idea of bundling the bills.
McCarthy told reporters this month that he won't put an omnibus on the floor, but isn't opposed to linking bills.
“I think anything but voting on 12 appropriations bills is going to be a no go,” one senior lawmaker said.


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Combat Voice – Chaotic Universe (CD Album – EK Product)Posted on 30/01/13
Content: Combat Voice is one more Belgian project signed to EK Project. Richard Guillaume and Bernard Feron (previously involved in Mono Electronic Density and who was the original singer of FuzeBoxMachine) set up this new project in 2010. After a lesser promoted and rather unknown self-released debut CD they now have the opportunity on EK Product to reach a wider audience.
From start on Combat Voice reveals their retro-EBM influences. The compositions are rather minimal, rather simplistic but based upon strong bass lines and sequences plus good-old synth layers. Combat Voice sounds dark and minimalistic. I have a little problem with the vocals which are rather compressed and suffering from some lack of production. The way of singing is monotone. The backing vocals by Richard Guillaume are sometimes reminding to another –and more famous Richard while it reveals the retro EBM inspiration of the band.
Most of the songs reveal some good ideas, but I’m missing more elaboration. It all sounds a bit rudimentary. A few harder songs like “Absolute Mind Control” and “Adrenaline Fix” are much more convincing and definitely show the right path to walk on. In a different and really quiet style the song “Chaotic Universe” is quite interesting. There’s a great bass sequence running through the song reminding me of the music/tune of Brian De Palma’s movie “Body Double”. I also like the string sections that reinforce the song. From a pure artistic point of view this song for sure is the most achieved song of the album.
Conclusion: Combat Voice has to improve the global production of their work while holding on some interesting ideas they showed in the bass lines and synth parts. Nevertheless, I’m sure “Chaotic Universe” will catch the attention of retro-EBM lovers.
Best songs: “Absolute Mind Control”, “Chaotic Universe”, “Adrenaline Fix”.
Rate: (Tor Cleenics:6/7)Tor Cleenics.
Band: www.combatvoice.com / www.facebook.com/pages/Combat-Voice/167498606627622
Label: www.ekproduct.com / www.myspace.com/ekproduct / www.facebook.com/EKProduct
Get your industrial music CDs at the following eBay sites:
|eBay USA||eBay België/Belgique|
|eBay UK||eBay France|
|eBay DE||eBay Nederland|
Boxing Day is a holiday traditionally celebrated the day following Christmas Day, when servants and tradespeople would receive gifts, known as a 'Christmas box'. (...)
After releasing their debut album 'Tot of the mun' earlier in 2014, the Russian electropop band Radiomun releases a double single before Xmas. (...)
This is the first trace of their up-coming album which will be out later next year via United Machine Records. You can watch the videos for both singles above. (...)
Out by the end of January is Marilyn Manson's newest album 'The Pale Emperor'. (...)
Out now is the newest video, 'Eternity', by the German electron act Ex Machina. The music project is the work of the duo Claudio Chiriatti and Tobias Schwerdt. (...)
Exactly one year after their first steps on the Alfa Matrix label with the club hit EP 'Life Is Short', the Spanish duo Mondträume returns with the new single 'Still Beating'. (...)


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For military personnel, owning a home is not just a financial milestone but a symbol of stability in a life filled with deployments and relocations.
The Department of Veterans Affairs (VA) loan program plays a vital role in making homeownership accessible to those who have served our nation.
However, navigating the VA loan process can be a challenging task. Understanding the steps involved can help American veterans make an informed decision in the process of buying a home.
Guide to VA Loans
Step 1: Eligibility Assessment
The VA loan program is exclusively available to current and former members of the military, including:
- Active-duty service members
- National Guard members
The first step in the VA loan process is determining your eligibility. You can do this by obtaining a Certificate of Eligibility (COE) through the VA or by working with an approved lender who can assist in obtaining this important document.
Step 2: Find a VA-Approved Lender
Once eligibility is confirmed, the next step is to find a VA-approved lender with experience in handling VA home loans.
Keep in mind that not all lenders are authorized to issue VA loans, so it’s important to choose one with experience in handling these unique mortgages.
VA-approved lenders understand the specific requirements of the VA loan process, making the entire process of taking out a loan and buying a home smoother.
Step 3: Pre-Approval and Financial Assessment
Before looking into the housing market, it’s advisable to get pre-approved for a VA loan. This involves a comprehensive financial assessment, including an analysis of your credit score, income, and debt-to-income ratio.
A pre-approval not only helps you understand the loan amount you qualify for but also improves your credibility as a buyer when you start negotiating with sellers.
Step 4: House Hunting and Offer Submission
With the pre-approval in hand, you can start with the exciting phase of house hunting.
Now, when selecting a property, keep in mind the VA’s minimum property requirements (MPRs). These requirements ensure that the property meets certain standards to guarantee a safe and habitable living environment for veterans and their families.
Once you find the right home, submit your offer and enter into negotiations with the seller.
Step 5: VA Appraisal
After reaching an agreement with the seller, the next step is the VA appraisal. Unlike a conventional appraisal, the VA appraisal serves a dual purpose – determining the property’s value and ensuring it meets the MPRs.
The appraisal is conducted by a VA-assigned appraiser who assesses the home’s condition and compares it to similar properties in the area. The results of the appraisal can influence the loan amount as well as the negotiations with the seller.
Step 6: Loan Underwriting
With a favorable appraisal, the VA loan enters the underwriting phase. During this step, the lender reviews all aspects of the loan application, including the property appraisal, credit history, and income documentation.
Underwriters verify that the loan meets VA guidelines and that the borrower’s financial profile aligns with the requirements. This thorough examination ensures that both the borrower and the property are eligible for VA financing.
Step 7: Loan Approval and Closing
Once the underwriting process is complete, the lender issues a final loan approval. At this point, you should receive a clear-to-close, indicating that the loan is ready for closing.
The closing will require signing the necessary paperwork to finalize the home purchase. At this point, you should pay close attention to the details and make sure you fully understand the terms of the loan, including interest rates, closing costs, and any other relevant fees.
Step 8: Move In and Enjoy Having Your Own Place to Call Home
VA loans offer a number of advantages, such as competitive interest rates, lenient credit score criteria, and no down payment requirements.
Additionally, the VA provides assistance to borrowers facing financial difficulties, offering a safety net that reflects the government’s commitment to supporting those who have served.
With this help from the VA comes a successful closing, and you can move into your new home and enjoy the benefits of homeownership.
To successfully obtain a VA loan, you’ll need to carefully plan every step of the way and pay very close attention to detail. The process might seem complicated at times, but the benefits the VA offers for military homebuyers are well worth the effort.
From determining eligibility to closing the deal, each step in the process plays a vital role in ensuring a smooth and successful home purchase.
By understanding the ins and outs of the VA loan process, you can confidently pursue your dream of owning a house and securing a stable and comfortable place for yourself and your entire family.


Nginx Proxy Manager is an intuitive solution designed to simplify the process of hosting your own websites and services. With its easy-to-use interface and powerful functionality, it enables secure and efficient service exposure, even without in-depth knowledge of Nginx or Letsencrypt. Ideal for home networks or any private network requiring secure web service exposure.
- Intuitive Admin Interface: A beautiful admin panel based on Tabler ensures a pleasant user experience while managing proxy hosts and SSL certificates.
- Domain Forwarding: Easily set up forwarding domains, redirections, and custom 404 pages with no need for extensive Nginx knowledge.
- Automated SSL: Leverage Let's Encrypt for free SSL certificates or use your own custom SSL to secure your services.
- Access Control: Implement Access Lists and HTTP Authentication to protect your hosted services.
- Advanced Configurations: For power users, advanced Nginx configurations are accessible for fine-tuned control.
- User Management: Manage user permissions with an audit log feature to keep track of changes and access.
Nginx Proxy Manager Screenshots
Suggested Developer Use Cases
- Create a secure entry point for home automation systems, allowing remote management without compromising security.
- Use as part of a CI/CD pipeline to dynamically manage staging environments with unique subdomains and SSL certificates.
- Integrate into IoT projects to securely expose device management interfaces over the internet with minimal configuration effort.
|Monday, November 27, 2023