Experimental study of the role of blocking 5-HT3-receptors of serotonin and D2-receptors of dopamine in the mechanism of early radiation vomiting in dogs

The experiments on dogs exposed to 137Cs gamma quanta at doses of 8 and 20 Gy showed that Latranum, a selective blocker of serotonin 5-HT3-receptors, is a more efficient antiemetic than Dimetpramidum, a D2-dophamin lytic. This is suggested by fewer animals with emetic reaction or by less severe vomiting in case they have any. The results, taking account of earlier data obtained in the experiments on M. fascicularis monkeys, show that the antiemetic effect of the blocker of serotonin 5-HT3-receptors Latranum is not species-specific and equally well manifests itself in animals with different constitutions of the chemoreceptor trigger zone.     

An experimental study of the role of a blockade of serotonin 5-HT3 receptors and dopamine D2 receptors in the mechanism of the occurrence of early radiation vomiting in monkeys

The experiments with M. fasciculata monkeys exposed to 137Cs gamma-radiation with a dose of 6.9 Gy showed that Latranum, a blocker of serotonin 5-HT3 receptors, is a more efficient antiemetic than Dimetphramidum, a D2 dophamin lytic. This is suggested by fewer animals with emetic reaction of by less severe vomiting in case they have any. The results agree well with a hypothesis that serotonin receptors are dominant in the chemoreceptor trigger zone of monkeys.     

Animal models in the study of vomiting

The emetic responses to various pharmacological agents, cytotoxins, and radiation are compared among animal species. The species included for comparison are the human, nonhuman primate, dog, cat, and ferret. The categories of pharmacologic compounds include both those compounds that act on identified membrane receptors (e.g., cholinergic agonists, catecholamines, and neuroactive peptides) and those that act on unidentified receptors (e.g., cardiac glycosides and Veratrum alkaloids, among others). Emphasis is placed on emetic dose-response relations and threshold ED50 and ED100 values calculated from these relations, as indices of species sensitivity to emetic stimuli. For the more noxious emetics, the cytotoxins and radiation, the latency to the first emetic episode and duration of emesis are also compared across species. The effect that peripheral and central nerve lesions have on species differences in emetic responses to stimuli is also discussed.     

Acute radiation-induced vomiting in area postrema-ablated cats

A dose-response relationship was established in normal unanesthetized cats for emetic incidence, latency to onset of vomiting, and duration of emetic activity over a period of 24 h after whole-body exposure to 60Co radiation at selected doses between 7.5 and 90 Gy. Each episode of vomiting, i.e., retching and expulsion, was recorded oscillographically as its characteristic intrathoracic pressure waveform by means of a catheter inserted some days before into the superior vena cava. The gamma-radiation dose of 45 Gy evoked vomiting optimally with an incidence of 92% and an average onset time of 98 min. When administered to animals prepared chronically with surgical ablation of the area postrema, the same dose of radiation evoked vomiting in four of five test cases and with an average time to onset that was not by either measure significantly different from normal. Vomiting was also elicited in all of six normal cats exposed to an intestinal dose of 45 Gy X radiation with the head shielded. The same form of irradiation evoked vomiting in two of three chronically postremectomized cats. Successful ablation of the area postrema was determined functionally by emetic refractoriness to an injection of digitalis and confirmed for completeness by histological examination. It is concluded that the area postrema is not an essential element in the reflex mechanism of radiation-induced vomiting and, therefore, no physiological basis exists for dependence on a centrally acting chemogenic factor in radioemesis.     

Mechanics of vomiting: a minireview

In a cineradiographic analysis of the vomiting reflex in response to i.v. administration of an emetic drug (lanatoside C, 12 mg/kg) in cats, it was shown that the vomiting act is preceded by cyclic periods of abnormal peristaltic activity of the small bowel and inhibition of gastric peristalsis. It was further observed that massive antiperistalsis of the upper small bowel with reflux into the stomach is a common occurrence in the period immediately preceding vomiting. The emetic act itself is composed of phases of esophageal dilation, gastric emptying, gastric reflux, and esophageal collapse in cyclic repetition. The response of the esophagus and the stomach during emesis is passive, with external pressures and forces apparently providing the expulsive forces, the gastric bolus being contained by contraction of the pylorus and probably an upper esophageal or pharyngeal barrier. Earlier studies were conducted in cats in which observations were made on changes in thoracic venous pressure, abdominal venous pressure, and arterial blood pressure associated with vomiting induced by Veratrum alkaloids. Retching was characterized by a growing series of brief negative intrathoracic pressure pulses mirrored by positive pressure pulses in the abdomen. Expulsion then occurred and was followed with a sudden reversal of intrathoracic pressure from negative to positive. Expulsion involved a more sustained abdominal contraction, but both retching and expulsion were brought about by the same set of muscles, according to their EMG profiles. From results observed following phrenicotomy and spinal cord section at T5, it was concluded that the diaphragm, acting together with the inspiratory muscles against a closed glotis is responsible for the negative intrathoracic pressure that occurs in retching.(ABSTRACT TRUNCATED AT 250 WORDS)     

The origin of the vomiting response: a neuroanatomical hypothesis

The connections of area postrema include a set of nuclei with a common topographical location immediately deep to the ependyma or pia mater. These nuclei are all within two principal synapses of the area postrema and can be reached by more than one route from it. There is direct evidence that, like the area postrema, a number of these nuclei participate in vomiting. It is suggested that the paraventricular system may act as a distributed pattern generator for the several processes known to be integrated in the emetic response. It is also suggested that the other functions of the paraventricular nuclei, mainly homeostatic in mammals, have all evolved from a prototypical behaviour pattern of escape from, and subsequent avoidance of, noxious stimuli. Thus, through this system of nuclei, blood pressure, respiration, gastrointestinal motility and secretion, fluid and electrolyte balance, and the ingestion of food may all be influenced by noxious situations.     

Factors affecting nausea and vomiting in the plastic surgery patient

In plastic and reconstructive surgery, nausea and vomiting are annoying and often dangerous phenomena, yet attempts to suppress them therapeutically may cause physiological actions of an undesirable nature. Nevertheless, it is possible, through clinical observation and the taking of a careful history, to identify many patients who are at highest risk of suffering undue damage from emetic episodes. Skillful selection of surgical and anesthetic measures that safely limit provocation of the vomiting reflex and the careful use of effective antiemetic drugs in patients particularly at risk can effectively reduce the incidence of what may be our patient's most unpleasant and dangerous perioperative experience.     

Digestive tract motor correlates of vomiting and nausea

The digestive tract from the upper esophageal sphincter to the ileum participates in the vomiting process, but the role of the digestive tract in nausea is unclear. In preparation for vomiting, the proximal stomach relaxes and the small intestine is evacuated orad in a single mass movement by a retrograde giant contraction and caudad in a stripping fashion by a series of phasic contractions. Orad evacuation of the small intestine may not only remove offending substances but may also dilute. or buffer gastric contents with intestinal and pancreaticobiliary secretions. In association with retching and vomiting, the striated muscle of the esophagus contracts longitudinally, pulling the relaxed proximal stomach into the thoracic cavity forming a funnel from stomach to esophagus. However, gastric evacuation does not occur until the hiatal fibers of the diaphragm relax during vomitus expulsion. Nausea is a subjective feeling in humans that is difficult to identify in animals. Various changes in digestive tract activity have been associated with nausea, but no evidence suggests that these events cause nausea. The prodromal signs of vomiting (e.g., increased heart rate and respiration) that occur concomitantly with the gastrointestinal motor correlates of vomiting have been considered autonomic indices of nausea in animals, but this has not been proven. Regardless, the gastrointestinal motor correlates of vomiting do not cause the prodromata. The emetic central pattern generator may be organized in parallel with respect to its individual autonomic correlates, but as groups of responses, the autonomic and somatomotor correlates may be organized in series.     

Identification and Characterization of a Novel Staphylococcal Emetic Toxin

Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus have superantigenic and emetic activities, which cause toxic shock syndrome and staphylococcal food poisoning, respectively. Our previous study demonstrated that the sequence of SET has a low level of similarity to the sequences of other SEs and exhibits atypical bioactivities. Hence, we further explored whether there is an additional SET-related gene in S. aureus strains. One SET-like gene was found in the genome of S. aureus isolates that originated from a case of food poisoning, a human nasal swab, and a case of bovine mastitis. The deduced amino acid sequence of the SET-like gene showed 32% identity with the amino acid sequence of SET. The SET-like gene product was designated SElY. In the food poisoning and nasal swab isolates, mRNA encoding SElY was highly expressed in the early log phase of cultivation, whereas a high level of expression of this mRNA was found in the bovine mastitis isolate at the early stationary phase. To estimate whether SElY has both superantigenic and emetic activities, recombinant SElY was prepared. Cell proliferation and cytokine production were examined to assess the superantigenic activity of SElY. SElY exhibited superantigenic activity in human peripheral blood mononuclear cells but not in mouse splenocytes. In addition, SElY exhibited emetic activity in house musk shrews after intraperitoneal and oral administration. However, the stability of SElY against heating and pepsin and trypsin digestion was different from that of SET and SEA. From these results, we identified SElY to be a novel staphylococcal emetic toxin.     

The emetic activity of staphylococcal enterotoxins,SEK, SEL,SEM, SEN and SEO in a small emetic animal model,the house musk shrew

Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus are the most recognizable causative agents of emetic food poisoning in humans. New types of SEs and SE‐like (SEl) toxins have been reported. Several epidemiological investigations have shown that the SEs and SEl genes, particularly, SEK, SEL, SEM, SEN and SEO genes, are frequently detected in strains isolated from patients with food poisoning. The purpose of the present study was to evaluate the emetic activity of recently identified SEs using a small emetic animal model, the house musk shrew. The emetic activity of these SEs in house musk shrews was evaluated by intraperitoneal administration and emetic responses, including the number of shrews that vomited, emetic frequency and latency of vomiting were documented. It was found that SEs induce emetic responses in these animals. This is the first time to demonstrate that SEK, SEL, SEM, SEN and SEO possess emetic activity in the house musk shrew.     

Evidence for non-ribosomal peptide synthetase production of cereulide (the emetic toxin) in Bacillus cereus

Little is known about the process whereby the emetic toxin (or cereulide) of Bacillus cereus is produced. Two cereulide-producing strains of B. cereus were cloned and sequenced following polymerase chain reaction (PCR) amplification with primers that were specific for conserved regions of non-ribosomal peptide synthetase (NRPS) genes. The cloned regions of the B. cereus strains were highly homologous to conserved regions of other peptide synthetase nucleotide sequences. Primers were designed for two variable regions of the NRPS gene sequence to ensure specificity for the emetic strains. A total of 86 B. cereus strains of known emetic or non-emetic activity were screened using these primers. All of the emetic strains (n=30) displayed a 188 bp band following amplification and gel electrophoresis. We have developed an improved method of identifying emetic strains of B. cereus and provided evidence that cereulide is produced by peptide synthetases.     

The inhibitory effect of halothane on the emetic response in the ferret

Emesis and nausea are often associated with anaesthesia and continue to be a common clinical problem. Past clinical studies have demonstrated that halothane produces a higher incidence of vomiting compared with other anaesthetics, but some investigators have described an antiemetic effect. The purpose of this study was to investigate the effects of various doses of halothane on the emetic response in the decerebrate ferret. Following a control emetic response, a maximum of six increasing cumulative concentrations of halothane were delivered. At the end of each delivery period, the supradiaphragmatic vagal communicating branch, which has been shown to reproducibly elicit vomiting, was electrically stimulated and the emetic response was monitored. An increase in halothane concentration produced a marked depression of tongue, abdominal muscle, and diaphragm EMG activity as well as a decrease in central venous pressure. Licking, a prodromal response comparable to nausea in the human, appeared to be most sensitive. An increase in latency of the emetic response occurred as the concentration of halothane was increased. All phases of the response were observed at concentrations below 0.6 vol% halothane. At 0.6 vol% halothane, 75% of the animals vomited. At higher concentrations, the emetic response was completely abolished. One hour post-halothane, all latencies had returned to near control values. The methods utilized in this study provided a model that was not complicated by a large number of variables usually present in clinical studies. These data demonstrate that halothane exerts an inhibitory, concentration-dependent, and reversible effect on the emetic response in the ferret and provide further support that halothane alone does not possess emetic properties at clinical properties at clinical concentrations.     

Bacillus cereus is common in the environment but emetic toxin producing isolates are rare

AIMS: To determine the incidence of emetic toxin producing Bacillus cereus in soil, animal faeces and selected vegetable produce to compare the results with the previously reported high incidence in rice paddy fields. To examine whether the emetic toxin has antibiotic activity. METHODS AND RESULTS: The incidence of emetic toxin producing B. cereus was evaluated by plating on selective agar 271 samples of soils, animal faeces, raw and processed vegetables. Overall, 45.8% of samples were positive for B. cereus. One hundred and seventy-seven B. cereus isolates were recovered at 30 degrees C with the grand mean spore count being 2.6 +/- 1.7 log(10) CFU g(-1) and 148 B. cereus isolates were recovered at 7 degrees C with the grand mean spore count being 2.2 +/- 1.2 log(10) CFU g(-1) of the 177 B. cereus isolated at 30 degrees C, only 3 were positive for emetic toxin production at a titre of 1/64, 1/32, 1/16, respectively. Also, 1 of 148 B. cereus isolated at 7 degrees C was positive for emetic toxin production to a titre of 1/128. All positive isolates came from washed or unwashed potato skins, one was psychrotrophic as determined by PCR and growth at 7 degrees C on subculture. The emetic toxin was not shown to have any antibiotic effects in growth inhibition studies. CONCLUSIONS: While B. cereus was a common isolate, the incidence of the emetic strain was rare. This is in contrast to previous findings of the high incidence in rice paddy fields and the processing environment, which may suggest rice is a selective area for growth of the emetic strain of B. cereus. SIGNIFICANCE AND IMPACT OF STUDY: The finding that a psychrotrophic isolate of B. cereus can produce emetic toxin is the first ever such observation and suggests the possibility that psychrotrophic isolates could grow in refrigerated fresh foods and cause emesis. The incidence of emetic B. cereus strains in rice paddy fields now requires further study for comparison with the low incidence found in other soils. The emetic toxin failed to inhibit the growth of other bacterial, fungal and yeast species. Whether the toxin (which is similar in structure to the antibiotic valinomycin) plays a competitive role in the environment therefore remains unclear.     

Area postrema: cholinergic and noradrenergic regulation of emesis. A new concept

In unanaesthetized cats the biochemical mechanisms and the functional characteristics of the emetic action of injection of noradrenaline and McN-A-343, a ganglionic muscarinic stimulant into the cerebral ventricle (i.c.v.) through chronically implanted cannulae were investigated. Both produced dose-dependent and shortlasting emetic response. The emesis evoked by noradrenaline was abolished, whereas the emesis induced by McN-A-343 was not completely blocked after ablation of the area postrema. Further, the emetic response to noradrenaline as well as to McN-A-343 was attenuated or blocked in cats pretreated with 6-hydroxydopamine (i.c.v.) and hemicholinium (i.c.v.); it was abolished in cats pretreated with reserpine (i.c.v.). On the other hand, the emetic response to i.c.v. noradrenaline and to i.c.v. McN-A-343 was not virtually altered in cats pretreated with bretylium (i.c.v.), alpha-methyl-p-tyrosine (i.c.v.) and 5,6-dihydroxytryptamine (i.c.v.). It is postulated that noradrenergic neurones as well as cholinergic axon terminals within the area postrema are necessary for the emetic action of noradrenaline, whereas cholinergic axon terminals within the area postrema subserve the emetic response to McN-A-343. A functional link between cholinergic terminals and noradrenergic neurones as well as a modulatory role of noradrenergic afferents on cholinergic afferents mediating emesis within the area postrema is further proposed. Thus, noradrenergic neurones might represent a common site of confluence of different inputs subserving the emesis in the area postrema. Finally, cholinergic terminals sometimes bypass this area and synapse in the emetic regions of the brainstem regulating emesis.     

Diagnostic real-time PCR assays for the detection of emetic Bacillus cereus strains in foods and recent food-borne outbreaks

Cereulide-producing Bacillus cereus can cause an emetic type of food-borne disease that mimics the symptoms provoked by Staphylococcus aureus. Based on the recently discovered genetic background for cereulide formation, a novel 5' nuclease (TaqMan) real-time PCR assay was developed to provide a rapid and sensitive method for the specific detection of emetic B. cereus in food. The TaqMan assay includes an internal amplification control and primers and a probe designed to target a highly specific part of the cereulide synthetase genes. Additionally, a specific SYBR green I assay was developed and extended to create a duplex SYBR green I assay for the one-step identification and discrimination of the two emesis-causing food pathogens B. cereus and S. aureus. The inclusivity and exclusivity of the assay were assessed using a panel of 100 strains, including 23 emetic B. cereus and 14 S. aureus strains. Different methods for DNA isolation from artificially contaminated foods were evaluated, and established real-time assays were used to analyze two recent emetic food poisonings in southern Germany. One of the food-borne outbreaks included 17 children visiting a day care center who vomited after consuming a reheated rice dish, collapsed, and were hospitalized; the other case concerned a single food-poisoning incident occurring after consumption of cauliflower. Within 2 h, the etiological agent of these food poisonings was identified as emetic B. cereus by using the real-time PCR assay.     

Prevalence, phenotypic traits and molecular characterization of emetic toxin-producing Bacillus cereus strains isolated from human stools in Korea

Aims: To investigate the prevalence and genotypic/phenotypic characters of emetic toxin‐producing Bacillus cereus strains isolated from sporadic food poisoning cases in Korea. Methods and Results: The prevalence of emetic B. cereus was determined in 56 899 stool samples from sporadic food poisoning cases in Korea between 2004 and 2006. We assessed toxin profiles, phenotypic traits and antibiotic resistance. The molecular subtyping was ascertained using an automated repetitive sequence‐based PCR (rep‐PCR) system, DiversiLab?, with these emetic strains isolated from sporadic food poisoning cases and other emetic strains isolated from an outbreak and food samples. Emetic B. cereus was present in 0·012% of sporadic food poisoning cases. The prevalence of nheABC, hblCDA, cytK and entFM enterotoxin genes among emetic strains was 100, 14·3, 14·3 and 100%, respectively. Most emetic strains were negative for salicin hydrolysis (100%), starch fermentation (85·7%) and haemolysis (85·7%). One emetic isolate, VK7, exhibited several unique traits, such as harbouring the hbl gene and ability to hydrolyse starch. All isolated strains were highly resistant to β‐lactam antibiotics. All emetic strains except VK7 exhibited an identical rep‐PCR banding pattern, while nonemetic strains were classified into various pulsotypes. Conclusions: Most emetic strains except one isolate exhibited similar genotypic/phenotypic traits and subtyping pattern. Automatic rep‐PCR (DiversiLab?) may be used to discriminate emetic strains from nonemetic strains, although we could not distinguish between most emetic strains using that. Significance and Impact of the Study: Result of this study may contribute an extended database on the prevalence and toxigenic traits of emetic B. cereus strains isolated from Korea.     

Toxin-producing ability among Bacillus spp. outside the Bacillus cereus group

A total of 333 Bacillus spp. isolated from foods, water, and food plants were examined for the production of possible enterotoxins and emetic toxins using a cytotoxicity assay on Vero cells, the boar spermatozoa motility assay, and a liquid chromatography-mass spectrometry method. Eight strains produced detectable toxins; six strains were cytotoxic, three strains produced putative emetic toxins (different in size from cereulide), and one strain produced both cytotoxin(s) and putative emetic toxin(s). The toxin-producing strains could be assigned to four different species, B. subtilis, B. mojavensis, B. pumilus, or B. fusiformis, by using a polyphasic approach including biochemical, chemotaxonomic, and DNA-based analyses. Four of the strains produced cytotoxins that were concentrated by ammonium sulfate followed by dialysis, and two strains produced cytotoxins that were not concentrated by such a treatment. Two cultures maintained full cytotoxic activity, two cultures reduced their activity, and two cultures lost their activity after boiling. The two most cytotoxic strains (both B. mojavensis) were tested for toxin production at different temperatures. One of these strains produced cytotoxin at growth temperatures ranging from 25 to 42 degrees C, and no reduction in activity was observed even after 24 h of growth at 42 degrees C. The strains that produced putative emetic toxins were tested for the influence of time and temperature on the toxin production. It was shown that they produced putative emetic toxin faster or just as fast at 30 as at 22 degrees C. None of the cytotoxic strains produced B. cereus-like enterotoxins as tested by PCR or by immunological methods.     

Emetic responses and neural activity in young musk shrews during the breast-feeding/weaning period: comparison between the high and low emetic response strains using a shaking stimulus.

The high emetic response (HER) strain and low emetic response (LER) strain of musk shrews (Suncus murinus) markedly differ in the emetic reflex in adults. However, there have been no studies on young musk shrews. We gave a shaking stimulus to young musk shrews aged 10 days or more that were obtained by mating within each strain and observed emetic responses. In the HER strain, no animal aged 10 days vomited, but vomiting was observed in 1 of 5 animals each aged 12 and 14 days, 2 of 5 animals aged 16 days, and all animals aged 18 days or more. In the LER strain, no vomiting was observed until the age of 14 days, but at the age of 16 days or more, 1 or 2 of 5 animals at each age vomited. After stimulation, activated neurons of the dorsal vagal complex and the dorsal reticular formation of the nucleus ambiguus (Amb) were examined by Fos immunohistochemistry. This morphometric study demonstrated that the numbers of Fos-positive neurons in the nucleus of the solitary tract and the dorsal reticular formation of the Amb were significantly larger in the animals that vomited in the HER strain than animals that did not vomit in the LER strain. We suggest that neurons in these regions are involved in emetic responses, as is the case in adult animals.     

Forced regurgitation with tartar emetic as an effective and safe method to study diet composition in hooded crow nestlings

The effectiveness of tartar emetic in causing forced regurgitation was tested in hooded crow (Corvus corone cornix) nestlings from a protected area in western Poland. Tartar emetic was highly effective in causing regurgitation. In 84 of 98 cases (85.7%), nestlings responded by vomiting reflexes, producing 81 food samples (82.6% of all cases). After the procedure no bird was observed to develop negative symptoms. Survival of the birds subjected to forced regurgitation was higher than in the control group (no emetic), which is probably related to the administration of glucose to the birds after enforced regurgitation. Even repeated administration of tartar emetic was without negative effects on the nestlings. The use of tartar emetic does not require frequent visits at the nests, limiting the probability of cannibalistic behaviour and nest predation.     

Emesis of rhesus monkeys induced by intragastric administration with the HEp-2 vacuolation factor (cereulide) produced by Bacillus cereus

Abstract To study the correlation between emetic toxin and HEp-2 vacuole activity produced by Bacillus cereus isolated from an outbreak of vomiting-type food poisoning, some properties and emetic activities of both purified HEp-2 factor (cereulide) and partially purified factor to rhesus monkeys were determined. The results indicate that both cereulide and partially purified factor were very stable to digestion with proteolytic enzymes, different pH, and heating. Vomiting was induced in the rhesus monkeys orally administered with both substances. From these findings, cereulide (or HEp-2 vacuole factor) is strongly suggested to be an emetic toxin itself.