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This study investigated the nausea-like behavior induced by road transportation in goats, and the effects of an anti-motion sickness (MS) medication on this behavior. In the first experiment, 11 adult Shiba goats were road transported twice with either a saline (control) or a commercial anti-MS medication (Travelmin) injection at the first or second transportation. Almost all goats showed nausea-like behavior, which was defined as pointing their heads downward, closing their eyes, and staying relatively still. These goats did not respond when they were touched during blood collection. The anti-MS medication significantly reduced the total time spent in nausea-like behavior (P < 0.05) and tended to increase the frequency of escape attempts during blood collection (P < 0.1). In a second experiment, the effects of the anti-MS medication were examined in goats held under normal housing. The anti-MS medication increased the time spent feeding (P < 0.01) and reduced the time spent in rumination (P < 0.05) but did not change the frequency of lying down nor plasma cortisol concentrations. Our results indicate that the nausea-like behavior in transported goats might be induced, at least in part, by regulatory mechanisms similar to the MS., (© 2024 Japanese Society of Animal Science.)

The purpose of this study was to evaluate the pharmacokinetics of intravenous (IV) ondansetron in a population of hospitalized dogs exhibiting clinical signs of nausea. The causes of nausea included pancreatitis, gastroenteritis, endocarditis, chemotherapy-induced nausea, diabetes mellitus and ketoacidosis, acute kidney injury with aspiration pneumonia, pyometra, uroabdomen, neoplasia, and hepatopathy. Twenty-four dogs were randomly assigned to one of the following IV ondansetron protocols: 1 mg/kg q12h, 0.5 mg/kg q12h, 1 mg/kg q8h, 0.5 mg/kg q8h. Serum was collected at 0, 0.25, 0.5, 1, 2, 4, 8, 16, and 24 h after the first dose, and nausea scores were recorded at multiple time points. Ondansetron and arginine vasopressin (AVP) concentrations were measured via high-performance liquid chromatography coupled to tandem mass spectrometry and ELISA, respectively. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Ondansetron displayed linear pharmacokinetics. In the 0.5 mg/kg group, mean C max  = 214 ng/ml, AUC 0-8h  = 463 ng/ml*h, and calculated half-life was 1.9 h. In the 1 mg/kg group, mean C max  = 541 ng/ml, AUC 0-8h  = 1057 ng/ml*h and calculated half-life was 1.6 h. Serum ondansetron concentrations were not significantly different between dogs that required rescue anti-nausea medication (non-responders) and dogs that did not require rescue therapy (responders). In total, 83.3% of patients in the 0.5 mg/kg q8h, 0.5 mg/kg q12h, and 1 mg/kg q8h groups had improvement in nausea scores. In total, 66.7% of patients in the 1 mg/kg q12h group had improvement in nausea scores. In total, 33% of patients had resolution of nausea in the 0.5 mg/kg q8h, 1 mg/kg q8h, and 1 mg/kg q12h groups, and 16% of patients had resolution of nausea in the 0.5 mg/kg q12h group. AVP concentrations were highly variable and did not correlate with nausea scores. Nausea scores significantly decreased regardless of dosage protocol. AVP was not a reliable biomarker of nausea in this group of dogs., (© 2022 The Authors. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.)

Background: Nausea and emesis can be, among other signs, common manifestations of acute vestibular system dysfunction in dogs. Currently, antiemetic drugs, such as maropitant and metoclopramide, are used commonly, but do not appear to control nausea. A non-placebo-controlled preliminary study suggested good efficacy of 5-HT3-receptor antagonists, such as ondansetron, against nausea in dogs with vestibular syndrome., Objectives: To assess and confirm the effect of ondansetron on behavior suggestive of nausea in dogs with vestibular syndrome., Animals: Fourteen dogs with vestibular syndrome and clinical signs of nausea presented to a neurology service., Methods: Placebo-controlled, double-blinded, crossover study. Behavioral assessment was performed hourly for 4 hours using an established numerical rating scale. The criteria salivation, lip licking, vocalization, restlessness, lethargy, and general nausea were scored. The occurrence of emesis was recorded. After scoring at T0 (pre-dose) and T2 (2 hours post-dose) either ondansetron (0.5 mg/kg) or placebo was injected IV. Two hours post-dose, treatments were switched. Blood samples were collected to measure serum arginine vasopressin (AVP) concentration, which previously has been shown to correlate with clinical signs of nausea., Results: Clinical resolution of nausea was observed 1 hour after administration of ondansetron, whereas serum AVP concentration decreased 4 hours after ondansetron administration., Conclusion and Clinical Importance: Administration of ondansetron IV is beneficial for dogs with nausea secondary to acute vestibular syndrome. Ondansetron substantially and rapidly decreased clinical signs of nausea behavior and stopped emesis., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Chronic large bowel diarrhea is common in dogs and can have a significant impact on their overall health and well being. We evaluated the safety and efficacy of a therapeutic food with select dietary plant fibers known to contain antioxidant and polyphenol compounds on clinical signs in dogs with chronic diarrhea., Methods: A prospective clinical study was conducted in 31 adult dogs currently experiencing chronic diarrhea from private veterinary practices in the United States. Enrolled dogs were switched to a complete and balanced dry therapeutic food containing whole grains and polyphenol-containing fiber sources for 56 days. Veterinarians evaluated changes from baseline in overall clinical signs, recurrence of clinical signs, and stool parameters at Days 2, 3, 4, 28, and 56. Dog owners evaluated stool consistency daily and nausea/vomiting, quality of life (QoL), and stooling behaviors at Days 1, 14, 28, and 56. Statistical analysis was performed using a mixed-effects model with Day as a fixed-effect., Results: Assessments of overall clinical response and stool parameters indicated that diarrhea improved significantly within 1 day of initiating the therapeutic food. Veterinarians reported that 68% of dogs had complete resolution of their clinical signs by Day 56 and the remaining 32% experienced improvement (P < 0.05), with no cases of recurrence. Veterinarians also reported improvement in stool consistency (P < 0.001) and reductions of blood and mucus in stool (P < 0.001). Significant improvements in nausea/vomiting, stooling behaviors, and quality of life (QoL) were reported by dog owners after 28 days and were sustained through day 56 (P < 0.05). The therapeutic food was safe and well tolerated., Conclusions: In dogs with chronic large bowel diarrhea, the therapeutic food rapidly improved stool consistency, resolved clinical signs, and improved stooling behaviors and QoL. Therapeutic foods supplemented with fiber sources rich in antioxidant and anti-inflammatory compounds contribute to rapid resolution of chronic diarrhea without recurrence and may contribute to long term health., (© 2022. The Author(s).)

Objective: To compare effectiveness of maropitant and ondansetron in preventing preoperative vomiting and nausea in healthy dogs premedicated with a combination of hydromorphone, acepromazine, and glycopyrrolate., Animals: 88 dogs owned by rescue organizations., Procedures: Dogs received maropitant (n = 29) or ondansetron (28) PO 2 hours prior to premedication or did not receive an antiemetic (31; control). Dogs were evaluated for vomiting, nausea, and severity of nausea (scored for 6 signs) for 15 minutes following premedication with hydromorphone, acepromazine, and glycopyrrolate., Results: A significantly lower percentage of dogs vomited after receiving maropitant (3/29 [10%]), compared with control dogs (19/31 [62%]) and dogs that received ondansetron (15/28 [54%]). A significantly lower percentage of dogs appeared nauseated after receiving maropitant (3/29 [10%]), compared with control dogs (27/31 [87%]) and dogs that received ondansetron (14/28 [50%]), and a significantly lower percentage of dogs appeared nauseated after receiving ondansetron, compared with control dogs. Nausea severity scores for hypersalivation, lip licking, hard swallowing, and hunched posture were significantly lower for dogs that received maropitant than for control dogs, and scores for hypersalivation, lip licking, and hard swallowing were significantly lower for dogs that received ondansetron than for control dogs., Conclusions and Clinical Relevance: Oral administration of maropitant 2 hours prior to premedication with hydromorphone reduced the incidence of vomiting and the incidence and severity of nausea in healthy dogs. Oral administration of ondansetron reduced the incidence and severity of nausea but not the incidence of vomiting.

Background: Vestibular syndrome is often accompanied by nausea. Drugs currently approved for its treatment have been developed to stop vomiting but not nausea. The efficacy of 5-HT 3 receptor antagonists to reduce nausea has been described for chemotherapy, but not for nausea secondary to vestibular disorders., Methods: Sixteen dogs with vestibular syndrome-associated nausea were included in the open-label, multicentre study. The intensity of nausea-like behaviour was analysed before ondansetron administration (0.5 mg/kg i.v.) and 2 h afterwards, using a validated 5-point-scale. The occurrence and frequency of salivation, lip licking, restlessness, vocalisation, lethargy, and vomiting were assessed., Results: All dogs initially showed signs of nausea, whereas only 31% showed vomitus. The intensity of nausea was significantly reduced in all dogs (p ≤ 0.0001) 2 h after ondansetron administration, including the clinical signs of nausea analysed in 11 dogs (salivation [p = 0.0078], lip licking [p = 0.0078], restlessness [p = 0.0039], and lethargy [p = 0.0078]) except for vocalisation (p > 0.9999)., Conclusions: The results provide preliminary evidence of the potential benefit of ondansetron in the treatment of nausea, which was present in all examined dogs. Vomiting was only observed in 5 dogs indicating that nausea can occur separately and should not be perceived only as a preceding stimulation of the vomiting centre.

Objective: To determine the effect of aquapuncture at acupuncture point Pericardium 6 (PC-6) on the incidence of dexmedetomidine-induced vomiting and nausea in cats., Study Design: Randomized, prospective, crossover study., Animals: A group of 22 cats, 14 females and eight males, aged 1-12 years and weighing 3.8-5.9 kg., Methods: Each cat was administered treatments in random order at ≥1 week intervals. For treatment (DEX-A), cats were administered PC-6 stimulation by aquapuncture (0.25 mL/250 μg vitamin B12 injection subcutaneously at PC-6). After 30 minutes, dexmedetomidine (10 μg kg -1 ) was administered intramuscularly (IM). For control treatment (DEX), cats were administered only dexmedetomidine (10 μg kg -1 ) IM. Incidence of vomiting, number of vomiting episodes and time to first vomiting were recorded by an observer unaware of treatment allocation. At 30 minutes after dexmedetomidine administration, atipamezole (0.1 mg kg -1 ) was injected IM. Behavior was video recorded and later scored by two observers for clinical signs of nausea. A regression model (analysis of covariance) was used to detect the influence of aquapuncture on vomiting and nausea. Significance was set at p < 0.05., Results: Of 21 cats, 18 (85%) and 16 cats (76%) vomited in DEX-A and DEX, respectively. There was no significant difference in the incidence of vomiting (p = 0.55), number of vomiting episodes (p = 0.55), mean time to vomit (p = 0.88) or nausea score (p = 0.51) between DEX-A and DEX., Conclusions and Clinical Relevance: PC-6 aquapuncture did not reduce the incidence of dexmedetomidine-induced vomiting or severity of nausea in cats., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Combretastatin A4-Phosphate (CA4P) is a vascular disrupting agent revealing promising results in cancer treatments for humans. The aim of this study was to investigate the safety and adverse events of CA4P in healthy dogs as a prerequisite to application of CA4P in dogs with cancer. Ten healthy dogs were included. The effects of escalating doses of CA4P on physical, haematological and biochemical parameters, systolic arterial blood pressure, electrocardiogram, echocardiographic variables and general wellbeing were characterised. Three different doses were tested: 50, 75 and 100 mg m -2 . At all 3 CA4P doses, nausea, abdominal discomfort as well as diarrhoea were observed for several hours following administration. Likewise, a low-grade neutropenia was observed in all dogs. Doses of 75 and 100 mg m -2 additionally induced vomiting and elevation of serum cardiac troponine I levels. At 100 mg m -2 , low-grade hypertension and high-grade neurotoxicity were also observed. In healthy dogs, doses up to 75 mg m -2 seem to be well tolerated. The severity of the neurotoxicity observed at 100 mg m -2 , although transient, does not invite to use this dose in canine oncology patients., (© 2017 John Wiley & Sons Ltd.)

Objective: To evaluate whether subcutaneous (SC) metoclopramide (0.2 mg kg -1 ) administered 30 minutes prior to (T30) or simultaneously with (T0) intramuscular (IM) morphine (0.2 mg kg -1 ) and dexmedetomidine (0.003 mg kg -1 ) reduces the incidence of nausea and emesis in healthy dogs., Study Design: Prospective, randomized and blinded study., Animals: A total of 45 dogs scheduled for elective procedures., Methods: Dogs were assigned randomly to three groups to be administered SC metoclopramide (0.2 mg kg -1 ) 30 minutes before (group M30) or simultaneously (group M0) to IM morphine (0.2 mg kg -1 ) and dexmedetomidine (0.003 mg kg -1 ). Dogs in the control group (group C) were administered SC saline at T30 and T0. Dogs were observed for 30 minutes after premedication to evaluate signs of nausea (continuous lip-licking and sialorrhoea) and emesis. Signs of pain or discomfort caused by SC injections were also recorded., Results: There were no statistical differences amongst groups for age, body weight and sex. More dogs developed continuous lip-licking in group C (12/15, 80.0%) compared to dogs in group M30 (1/15, 6.7%) and dogs in group M0 (5/15, 33.3%; p = 0.0001 and p = 0.01, respectively). More dogs developed sialorrhoea in group M0 (8/15, 53.3%) and in group C (10/15, 66.7%) compared to dogs in group M30 (2/15, 13.3%; p = 0.03 and p = 0.004, respectively). More dogs vomited in group M0 (4/15, 26.7%) and in group C (9/15, 60.0%) compared to dogs in group M30 (0/15, 0.0%; p = 0.05 and p = 0.0003, respectively). None of the dogs demonstrated signs of pain or discomfort during SC metoclopramide injection., Conclusions and Clinical Relevance: Subcutaneous metoclopramide at 0.2 mg kg -1 may reduce IM morphine and dexmedetomidine-induced nausea and emesis if administered 30 minutes in advance. It is effective in reducing lip-licking even when administered concurrently with IM morphine-dexmedetomidine., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m 2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT 3 antagonist), maropitant (1 mg/kg; NK 1 antagonist) or metoclopramide (0.5 mg/kg; D 2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations., Results: The placebo treated group vomited an average number of 7 times (range 2-13). None of the dogs in either the ondansetron or maropitant treated groups vomited during the observation period. The onset of nausea-like behaviour in the placebo-treated group occurred at t 3.5h and peaked at t 4.75h with nausea behaviour score of 58.5 ± 4.6 mm. Ondansetron and maropitant reduced overall the area under the curve of nausea behaviour score by 90% and 25%, respectively. Metoclopramide had no effect on either vomiting or nausea. Cisplatin-induced nausea and vomiting caused concomitant increases in AVP and cortisol. In the placebo-treated group, AVP and cortisol increased from t 2.5h , peaked at t 5h (11.3 ± 2.9 pmol L -1 and 334.0 ± 46.7 nmol/L, respectively) and returned to baseline by t 8h . AVP and cortisol increases were completely prevented by ondansetron and only partially by maropitant, while metoclopramide had no effect. The terminal half-lives (harmonic mean ± pseudo SD) for ondansetron, maropitant and metoclopramide were 1.21 ± 0.51, 5.62 ± 0.77 and 0.87 ± 0.17 h respectively., Conclusions: 5-HT 3 receptor antagonist ondansetron demonstrates the greatest anti-emetic and anti-nausea efficacy of the three drugs. AVP and cortisol appear to be selective biomarkers of nausea rather than emesis, providing a means of objectively measuring of nausea in the dog.

Morphine is widely used as a preanesthetic agent in dogs, but it often produces signs of nausea and vomiting. Maropitant (MRP) and metoclopramide (MCP) prevent emesis attributable to the opioid agent apomorphine in dogs. We evaluated the antiemetic efficacy and the discomfort in response to SQ injection of MRP [1 mg/kg body weight (BW)], MCP (0.5 mg/kg BW), and normal saline (SAL; 0.1 mL/kg BW) administered to 63 dogs, 45 minutes prior to morphine (0.5 mg/kg BW) and acepromazine (0.05 mg/kg BW). Dogs were observed for signs of nausea (ptyalism, lip licking, and increased swallowing) and vomiting for 30 minutes after morphine/acepromazine. The incidence of emesis was 0% for MRP, 38% for MCP, and 71% for SAL ( P < 0.001). The incidence of signs of nausea was not different between groups. Discomfort due to injection was higher after MRP (48%), than after MCP (9.8%) and SAL (4.8%) ( P < 0.001).

Objective: To evaluate the effect of needling at acupuncture point Pericardium 6 on hydromorphone-induced nausea and vomiting., Study Design: Randomized controlled clinical study., Animals: Eighty-one mixed-breed, healthy dogs aged 1.8 ± 1.6 years and weighing 14.5 ± 5.6 kg, admitted for elective ovariohysterectomy (n = 75) or castration (n = 6)., Methods: Dogs were randomly assigned to one of three groups: acupuncture at Pericardium 6 (AT, n = 27); alternative acupuncture at Lung 5 (ST, n = 27), and no acupuncture (CT, n = 27). During time 0-30 minutes (baseline), occurrences of hypersalivation, vomiting and licking were recorded. At 30 minutes, subjects were administered hydromorphone (0.1 mg kg(-1) ) in combination with acepromazine (0.03 mg kg(-1) ) intramuscularly. During time 30-45 minutes (post-injection), occurrences of hypersalivation, vomiting and licking were recorded by an observer unaware of group assignment. Groups were compared using a Kruskal-Wallis test followed by a Dunn's post-test, or Fisher's exact tests when appropriate., Results: There were no significant differences in age, weight or baseline observations among groups. Vomiting incidence post-injection was higher in the CT (20/27, 74.1%) and ST (22/27, 81.5%) groups than in the AT (10/27, 37.0%) group (p = 0.0129 and p = 0.002, respectively). The number of vomiting episodes [median (range)] after opioid administration was higher in the ST [1 (1-6)] than the AT [0 (0-2)] group (p = 0.0040). There were no differences in the median number of vomiting episodes between the ST and CT [1 (0-3)] or AT and CT groups. There were no differences in hypersalivation or licking among groups after hydromorphone-acepromazine administration., Conclusions and Clinical Relevance: Pericardium 6 acupuncture reduced the incidence of hydromorphone-induced vomiting in healthy dogs. This cost-effective technique can improve patient well-being and comfort during the perioperative period., (© 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

We have recently demonstrated that voluntary or forced running in activity wheels yields pica behavior (kaolin clay intake) in rats (Nakajima, 2016; Nakajima and Katayama, 2014). The present study provides experimental evidence that a single 40-min session of swimming in water also generates pica in rats, while showering rats with water does not produce such behavior. Because kaolin intake has been regarded as a measure of nausea in rats, this finding suggests that swimming activity, as well as voluntary or forced running, induces nausea in rats., (Copyright © 2016. Published by Elsevier B.V.)

OBJECTIVE To evaluate the effects of maropitant in cats receiving dexmedetomidine and morphine. DESIGN Randomized controlled trial. ANIMALS 66 healthy female domestic shorthair cats. PROCEDURES Cats were randomly assigned to receive maropitant (1 mg/kg [0.45 mg/lb], SC; maropitant group; n = 32) or saline (0.9% NaCl) solution (0.1 mL/kg [0.045 mL/lb], SC; control group; 34) 20 hours before IM administration of dexmedetomidine (20 μg/kg [9.1 μg/lb]) and morphine (0.1 mg/kg). Following administration of dexmedetomidine and morphine, the incidences of emesis, retching, and signs of nausea (sialorrhea and lip licking) were compared between the 2 groups. The aversive behavioral response of each cat to injection of maropitant or saline solution was scored on a visual analogue scale by each of 4 observers who were unaware of the treatment administered. RESULTS Only 1 of 32 cats in the maropitant group vomited, whereas 20 of 34 control cats vomited. The incidences of emesis and retching for the maropitant group were significantly lower than those for the control group. The incidence of signs of nausea did not differ between the 2 groups. Visual analogue scale scores for the maropitant group were significantly higher than those for the control group. CONCLUSIONS AND CLINICAL RELEVANCE Results of the present study indicated that administration of maropitant to healthy cats approximately 20 hours prior to administration of dexmedetomidine and morphine significantly decreased the incidence of emesis but did not decrease the incidence of signs of nausea. However, maropitant appeared to cause substantial discomfort when injected SC.

Nausea is a subjective sensation, which often acts as a signal that emesis is imminent. It is a widespread problem that occurs as a clinical sign of disease or as an adverse effect of a drug therapy or surgical procedure. The mechanisms of nausea are complex and the neural pathways are currently poorly understood. This review summarises the current knowledge of nausea mechanisms, the available animal models for nausea research and the anti-nausea properties of commercially available anti-emetic drugs. The review also presents subjective assessment and scoring of nausea. A better understanding of the underlying mechanisms of nausea might reveal potential clinically useful biomarkers for objective measurement of nausea in species of veterinary interest., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate the effect of dosing interval on the efficacy of maropitant for prevention of opioid-induced vomiting and signs of nausea in dogs., Design: Randomized prospective clinical study., Animals: 50 client-owned dogs that underwent an elective surgical procedure. Procedures: Dogs were randomly assigned to receive maropitant (1 mg/kg [0.45 mg/lb], SC), then hydromorphone (0.1 mg/kg [0.045 mg/lb], IM) at 0 (simultaneously; group 0; n = 10), 15 (group 15; 10), 30 (group 30; 10), 45 (group 45; 10), or 60 (group 60; 10) minutes later. Dogs were monitored for vomiting and signs of nausea for 30 minutes after hydromorphone administration. A historical control group of similar dogs (n = 9) that were administered hydromorphone (0.1 mg/kg, IM) but not maropitant served as the referent for comparison purposes., Results: Vomiting was recorded for 6 dogs in group 0 and 2 dogs in group 15. Signs of nausea were recorded for 10 dogs in group 0, 9 dogs in group 15, 8 dogs in group 30, 6 dogs in group 45, and 1 dog in group 60. Compared with dogs in the historical control group, vomiting was significantly decreased and prevented when maropitant was administered 15 and 30 minutes, respectively, before hydromorphone; signs of nausea were significantly decreased only when maropitant was administered 60 minutes before hydromorphone., Conclusions and Clinical Relevance: Results indicated that vomiting was significantly decreased and then prevented when maropitant was administered to dogs 15 and 30 minutes before hydromorphone. However, signs of nausea were significantly decreased only when the dosing interval was 60 minutes.

Practical Relevance: The control of nausea and vomiting in cats is important in order to prevent the development of food aversion, anorexia (with its associated complications of weight loss and dehydration), and hepatic lipidosis., Clinical Challenges: There are several antiemetic drugs that are clinically effective in cats. Making a rational choice from the available options requires knowledge of the likely cause of the vomiting, and the mechanisms of action and side effects of each drug. For example, a drug such as prochlorperazine, which can cause sedation, may be a useful first-line choice in a hospitalized cat that requires mild sedation to be handled, but would be undesirable in a critically ill cat., Audience: For companion animal and feline practitioners, the vomiting cat is a common presentation., Evidence Base: The guidance provided in this review draws on the findings of clinical trials in humans, experimental studies in cats, some clinical trials in cats, and clinical experience., (Copyright 2010 Elsevier Ltd. All rights reserved.)